JPH0772181B2 - Benzimidazole derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to benzimidazole derivatives and salts thereof.

2. Description of the Related Art The benzimidazole derivatives and salts thereof of the present invention are novel compounds that have not been published in the literature.

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention The present invention aims to provide a compound useful as a pharmaceutical as described below.

Means for Solving the Problems According to the present invention, a benzimidazole derivative represented by the following general formula (1) is provided.

[Wherein R ¹ and R ² are the same or different and each represent a hydrogen atom, a lower alkyl group or a halogen atom, and R ³ is a lower alkyl group, a phenyl group which may have a lower alkyl group as a substituent, or a halogen-substituted lower alkyl group. , An amino group, a lower alkylamino group or a lower alkanoylamino group, R ⁴ represents a hydrogen atom, a lower alkyl group, a nitro group or an amino group, R ⁵
Is a hydrogen atom, a hydroxyl group or a benzyloxy group,
R ⁶ represents a hydrogen atom or a lower alkyl group, respectively, and n is 0 or 1. However, the following cases 1) to 3) are excluded.

1) R ³ is a lower alkyl group, a phenyl group which may have a lower alkyl group as a substituent, an amino group or a lower alkylamino group, R ¹ and R ² are hydrogen atoms, and R ⁴ and R ⁶ are lower alkyl groups. , R ⁵ is a hydroxyl group and n is 0.

2) When R ¹ , R ² , R ⁴ and R ⁶ are all hydrogen atoms, R ³ is a lower alkyl group or a phenyl group, R ⁵ is a hydroxyl group and n is 0.

3) When R ³ is an amino group or a hydrogen atom, R ⁴ , R ⁵ and R ⁶ are both hydrogen atoms, R ¹ and R ² are both hydrogen atoms or both lower alkyl groups and n is 1. The compound of the present invention represented by the above general formula (1) and a salt thereof exhibit pharmacological actions such as antibacterial, antiviral, antiinflammatory, antirheumatic and the like, and accordingly, antibacterial agents, antiviral agents, antiinflammatory agents,
It is useful as a drug such as an antirheumatic drug.

In the present specification, examples of the lower alkyl group include linear or branched lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl groups.

Examples of the phenyl group which may have a lower alkyl group as a substituent include phenyl, 2-methylphenyl,
3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 4-ethylphenyl, 4-propylphenyl, 3- (1-methylethyl) phenyl, 4-tert-butylphenyl, 3-butylphenyl, 4-pentyl Examples thereof include phenyl and 4-hexylphenyl groups.

Examples of halogen-substituted lower alkyl groups include trifluoromethyl, pentafluoroethyl, heptafluoropropyl, nonafluorobutyl, undecafluoropentyl, tridecafluorohexyl groups, and the like.

Examples of the lower alkylamino group include N-methylamino, N-ethylamino, N-propylamino, N- (1
-Methylethyl) amino, N-butylamino, N- (te
rt-Butyl) amino, N-pentylamino, N-hexylamino, N, N-dimethylamino, (N-methyl, N-ethyl) amino, N, N-diethylamino, N, N-dipropylamino, N, Examples thereof include N-dibutylamino, N, N-dipentylamino and N, N-dihexylamino groups.

Examples of the lower alkanoylamino group include acetylamino, propionylamino, butyrylamino, valerylamino, caproylamino and heptanoylamino groups.

The halogen atom includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

The benzimidazole derivative of the present invention can be produced by various methods. Specific examples thereof are shown in the following reaction process formulas.

[Wherein R ¹ , R ² , R ⁴ and R ⁶ are the same as defined above. R ^3a represents a lower alkyl group or a halogen-substituted lower alkyl group. However, R
^{When 3a} is a lower alkyl group, R ¹ and R ² are hydrogen atoms and
R ⁴ and R ⁶ must not both be hydrogen atoms or both lower alkyl groups. The condensation reaction represented by the above reaction process formula-1 is a known method, for example, the method described in Tetrahedron [Tetrahedron, 23 , 3723 (1967)] by Riker et al. (A. Reiker et al.), Or Hugueras et al. J. Figueras et al.) Journal of Organic Chemistry [J.Org.Ch
em., 36 , 3497 (1971)]. More specifically, the condensation reaction may be carried out, for example, with acetic acid, boron trifluoride / ethyl ether complex (BF ₃ · Et ₂ O).
Etc. as a catalyst, using about 1 to 5 times the molar amount of compound (3) with respect to compound (2), without solvent or with tetrahydrofuran (THF), diethyl ether,
In a suitable solvent such as ethers such as dioxane, halogenated hydrocarbons such as chloroform and 1,2-dichloroethane, aromatic hydrocarbons such as benzene, toluene and xylene in a temperature range of about 30 to 200 ° C. Can be implemented.

The compound (4) obtained above can be subjected to the subsequent reduction reaction without isolation from the reaction system, but may be isolated, of course.

For the reduction reaction of the compound (4), for example, the reaction product is transferred into water and a sodium hydrosulfite (Na ₂ S ₂ O ₄ ) aqueous solution in an amount of about 2 to 50 times is added according to a conventional method. Can be implemented by Further, the reduction reaction is
It can also be carried out by using zinc dust in acetic acid, or by catalytic hydrogenation using palladium-carbon, platinum (PtO ₂ ) or the like as a catalyst in a suitable solvent such as ethyl acetate, alcohol, THF or water. Thus, the compound (5) can be obtained.

The subsequent cyclization reaction of the compound (5) can be carried out by reacting the compound (5) with the compound R ^3a —COOH.
The ratio of the compound R ^3a —COOH to be used is usually about 10 to 50 times the molar amount of the compound (5), and the reaction is performed at room temperature to about 100 ° C. for about 1 to 10 times. It proceeds by stirring for a time, and thus the target compound (1a) can be obtained.

[In the formula, R ¹ , R ² , R ⁴ and R ⁶ are the same as defined above. R ^3b represents a lower alkyl group, a halogen-substituted lower alkyl group or a phenyl group which may have a lower alkyl group as a substituent. However, when R _3b is a lower alkyl group or a phenyl group which may have a lower alkyl group as a substituent, R ¹ and
R ² may not be a hydrogen atom and R ⁴ and R ⁶ may not both be a hydrogen atom or a lower alkyl group. The acylation reaction of the compound (4) represented by the above reaction scheme-2 can be carried out in an inert solvent using a suitable acylating agent. Examples of the acylating agent include lower alkylcarbonyl halides such as acetyl chloride, acetyl bromide, propionyl chloride, butyryl chloride, isobutyryl chloride, valeryl chloride, isovaleryl chloride, vivaloyl chloride and heptanoyl chloride, Trifluoroacetyl chloride,
Halogen-substituted lower alkylcarbonyl halides such as pentafluoropropionyl chloride, heptafluorobutyryl chloride, nonafluorovaleryl chloride, undecafluorocaproyl chloride, tridecafluoroheptanoyl chloride, benzoyl chloride and the like can be used. Examples of the inert solvent include TH
F, ethers, chloroform, dichloromethane, dimethylformamide (DMF), N, N-dimethylacetamide (DMA) and the like can be used. The above acylation reaction also proceeds well in the presence of a suitable basic compound such as triethylamine, pyridine, collidine and the like. The amount of the acylating agent and the basic compound to be used is usually about 1 to 3 times the molar amount of the starting compound (4), preferably about 1
~ 1.1 times the molar amount is good, the reaction is generally about -2
It takes about 30 minutes to 3 hours to complete in a temperature range of 0 ° C to 30 ° C.

Further, the reduction reaction of the compound (5) can be carried out in the same manner as that shown in the above reaction process formula-1.

Further, the cyclization reaction of the compound (6) is carried out according to a conventional method in a suitable acid solvent at about 0 ° C to the boiling point of the solvent, preferably at room temperature to 100 ° C for about 10 minutes to 1 hour. Will be done. As the acid solvent, acetic acid, polyphosphoric acid, etc. are usually used.

[Wherein R ¹ , R ² , R ⁴ and R ⁶ are the same as defined above. R ⁷ represents a lower alkyl group. However, the case where R ¹ and R ² are hydrogen atoms and R ⁴ and R ⁶ are both lower alkyl groups is excluded. The reaction of the compound (7) shown in the reaction process formula-3 with the compound (8) is carried out by using the compound (7) in an appropriate solvent in an amount of 1 to 2 times the molar amount of the compound (7). Done. As the solvent, alcohols such as methanol and ethanol can be used. The reaction usually proceeds at room temperature to a temperature near the boiling point of the solvent in about 5 to 25 hours, and thus the target compound (1c) can be obtained.

The decarboxylation reaction of the compound (1c) obtained above can be carried out in a suitable acid solvent. As the acid solvent, for example, hydrochloric acid aqueous solution, sulfuric acid aqueous solution or the like can be used. The reaction usually proceeds from room temperature to around the boiling point of the solvent in about 10 to 25 hours, and the target compound (1d) can be obtained by this reaction.

Further, the reduction reaction of the compound (1c) can be carried out by, for example, ethers or TH
It can be carried out using a conventional reducing agent such as lithium aluminum hydride (LiAlH ₄ ) in a suitable inert solvent such as F 2.
The amount of the reducing agent used is usually about 1 with respect to the compound (1c).
It can be selected from a range of about 10 times the molar amount. The reaction proceeds at a temperature in the vicinity of 0 ° C. to the boiling point of the solvent. The target compound (1e) can be obtained by the above reduction reaction.

[In the formula, R ¹ , R ² , R ⁶ and n are the same as defined above. R ^3c represents a lower alkyl group, a halogen-substituted lower alkyl group, a phenyl group which may have a lower alkyl group, an amino group or a lower alkylamino group. Provided that R ^3c is a lower alkyl group or a phenyl group, R ¹ , R ² and R ⁶ are all hydrogen atoms and n is 0.
Except for. The reaction for removing t-Bu from the compound (1f) represented by the reaction formula-4 is carried out by heat treatment in the presence of an acid in a suitable solvent, and the compound (1g) may be obtained by the reaction. it can. Examples of the acid used here include concentrated hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid and the like. Examples of the solvent include water or an inert solvent such as THF, dioxane, and ethanol that is well mixed with water. The heat treatment can be usually performed at a temperature of about 25 ° C to 150 ° C.

[In the formula, R ¹ , R ² , R ⁵ , R ⁶ and n are the same as defined above. R ^3d represents a lower alkanoylamino group, and R ^4a represents a hydrogen atom, a lower alkyl group or a nitro group. However, when R ^4a is a hydrogen atom, R ^4a
5 must not be a hydroxyl group. ] [In the formula, R ¹ , R ² , R ^3d , R ⁶ and n are the same as defined above. The acylation reaction of compound (1h) and compound (1h ′) shown in the above reaction process formulas -5 and -5 ′ is carried out in a basic solvent or in an inert solvent in the presence of a base catalyst, the starting compound It can be carried out by reacting with an acid anhydride.

As the basic compound, for example, pyridine, collidine, lutidine, triethylamine and the like can be used. As the inert solvent, for example, THF, ether, chloroform, dichloromethane, DMF and the like can be used. In this case, the basic solvent is used as a base catalyst in an amount of about 1 to 3 times the molar amount. As the acid anhydride, for example, acetic anhydride, propionic anhydride, butyric anhydride, valeric anhydride, caproic anhydride,
Heptanoic anhydride or the like can be used.

Further, the partial hydrolysis reaction of the compound (1h ′) shown in the above reaction process formula-5 ′ can be carried out according to an alkaline hydrolysis method using, for example, an alkali hydroxide. Here, sodium hydroxide, potassium hydroxide or the like can be used as the alkali hydroxide, and this is usually equimolar to 20 relative to the compound (1h ′).
It can be used in a range of about double molar amount. The reaction can be generally carried out in a mixed solvent of alcohol, water, etc. at a temperature in the range of about 20 ° C. to the boiling point of the solvent.

[In the formula, R ¹ , R ² , R ⁶ and n are the same as defined above. R ^3e represents a lower alkyl group, a halogen-substituted lower alkyl group or a lower alkanoylamino group. The nitration reaction of the compound (1j) shown in the above reaction process formula-6 is carried out according to a conventional method, for example, using nitric acid, nitric acid-sulfuric acid, nitric acid-acetic acid, nitrate-sulfuric acid or the like without a solvent or a suitable solvent. It can be carried out in a solvent. The above nitrating agent is usually used in a large excess amount with respect to the raw material compound. It is preferable to use acetic acid, sulfuric acid or the like as the solvent. As the reaction temperature, it is generally preferable to adopt a range of about 25 to 100 ° C.

The compound (1k) obtained above can be converted to the compound (1) by reducing the nitro group. The reduction reaction can be carried out by a generally well-known method, for example, a reduction method using an acid and a metal or a metal salt, a reduction method with a sulfide, a catalytic hydrogenation method and the like.
Among them, the method using an acid and a metal or a metal salt is particularly preferable. In this method, hydrochloric acid is typically used as the acid, and tin, iron, nickel, stannous chloride and the like are used as the metal or metal salt, respectively. It is preferably used. Further, as the sulfide used in the reduction method with sulfide, for example, sodium hydrosulfite (Na ₂ S ₂ O ₄ ) or the like is suitable.

[Wherein R ¹ , R ² , R ⁴ and R ⁶ are the same as defined above. R ^3f represents a lower alkyl group, a halogen-substituted lower alkyl group, an amino group or a lower alkanoylamino group, R ^5a represents a hydrogen atom or a benzyloxy group, and X represents a halogen atom. However
Except when R ^3f is an amino group, R ¹ and R ² are both hydrogen atoms or both are lower alkyl groups, and R ⁴ , R ^5a and R ⁶ are hydrogen atoms. ] The compound (9) and the compound (10) shown in the above reaction process formula-7
The reaction with (benzylation reaction) is usually carried out in the presence of a base in an inert solvent. Examples of the base here include metal hydrides such as sodium hydride and lithium hydride,
As the inert solvent, for example, DMF, THF and the like can be preferably used. The benzylation reaction is usually carried out in the temperature range of 0 to 80 ° C. for about 30 minutes to 3 hours, and thus the target compound (1m) can be obtained.

In addition, among the compounds (1 m) obtained by the above reaction process formula-7,
The compound in which R ^5a is a benzyloxy group can be converted to the corresponding compound (1p) by the method shown in the following reaction scheme-8.

[Wherein R ¹ , R ² , R ^3f , R ⁴ and R ⁶ are the same as defined above. The debenzylation reaction of the compound (1m) shown in the above reaction process formula-8 can be carried out according to a usual method. Examples of this method include a method of catalytic hydrogenation using a catalyst such as palladium-carbon or platinum dioxide in a suitable solvent such as ethyl acetate, alcohol, or THF.

The target compound obtained by the method shown in each of the above reaction schemes can be easily isolated and purified by a conventional separation means. Examples of the means include solvent extraction, recrystallization, column chromatography and the like.

Further, the compound (1) of the present invention can be easily converted into a pharmaceutically acceptable acid addition salt by subjecting it to an appropriate acidic compound by an addition reaction according to a conventional method, and the acid addition salt is in a free form. It has the same pharmacological activity as the compound of the present invention, and the present invention also includes such an acid addition salt. As the acidic compound capable of forming the acid addition salt, for example, hydrochloric acid, sulfuric acid, phosphoric acid, inorganic acids such as hydrobromic acid and oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, An organic acid such as benzenesulfonic acid can be exemplified.
Further, among the compounds of the present invention, those having a free carboxyl group can be prepared according to a conventional method by using alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, and other copper salts. And the like, which have the same pharmacological activity as the compound of the present invention in the free form, are included in the scope of the present invention.

Examples Hereinafter, in order to explain the present invention in more detail, production examples of the compound of the present invention will be given as Examples.

Example 1 Preparation of 1- (3,5-di-tert-butyl-4-hydroxyphenyl) -2-trifluoromethylbenzimidazole 2,6-di-tert-butyl-1,4-benzoquinone 2.1 g and o
- dissolving phenylenediamine 1.7g in 100 ml of THF, the solution was added a boron trifluoride-ether complex _{[BF 3 · Et 2 O]} 0.3ml, was refluxed for 15 hours. The crude product obtained by concentration was purified by silica gel column chromatography (developing solvent; diethyl ether: n-hexane = 1: 10) to obtain reddish purple crystals.

The obtained crystals (7.5 g) were dissolved in pyridine (50 ml), trifluoroacetic anhydride (5 ml) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The extract layer was washed with saturated brine and dried over magnesium sulfate,
Concentrated. The obtained crude product was purified by silica gel column chromatography (developing solvent; diethyl ether: n-hexane = 1: 10) to obtain 8.36 g of a red compound.

The compound obtained above was dissolved in 70 ml of THF, and 10% Na ₂ S ₂ O ₄ was added.
An aqueous solution (370 ml) was added, and the mixture was stirred at room temperature for 10 minutes. Water was added to the reaction solution, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated. The resulting crude product was dissolved in 160 ml of acetic acid and stirred at 95-100 ° C for 10 minutes. After completion of the reaction, the mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to make the mixture alkaline, and the mixture was extracted with chloroform. The extraction layer is dried over magnesium sulfate, concentrated, and then subjected to silica gel column chromatography (developing solvent;
Purification with chloroform: ethyl acetate = 50: 1) gave 4.3 g of white crystals of the desired compound.

Structure and physical properties of the obtained compound (melting point and ¹ H-NMR value)
Is shown in Table 1 as Compound No. 1.

Examples 2 to 5 In the same manner as in Example 1, each compound shown in Table 1 (compound
No. 2 to compound No. 5) were produced.

Table 1 also shows the structure and physical properties of each of the obtained compounds.

Example 6 Preparation of 1- (3,5-di-tert-butyl-4-hydroxyphenyl) -2-amino-5,6-dichlorobenzimidazole 2,6-di-tert-butyl-4- (2- Amino-4,5-dichlorophenylamino) -phenol 6.8 g and 1,3-dicarboethoxy-S-methylisourea 4.18 g were added to ethanol 1
It was dissolved in 05 ml and refluxed for 5.5 hours. After completion of the reaction, the crude crystals obtained by concentration were washed with ether to give white crystals 6.8 g
Got This was dissolved in 80 ml of DMF and stirred at 110 ° C. for 24 hours. Water was added to the reaction mixture, extraction was performed with ethyl acetate, and the ethyl acetate layer was dried over magnesium sulfate. The crude crystal obtained by concentration was purified by silica gel column chromatography (developing solvent; chloroform: methanol = 30: 1) to obtain 810 mg of the target compound.

The structure and physical properties of the obtained compound are shown in Table 1 as compound No. 6.

Example 7 1- (3-tert-butyl-4-hydroxyphenyl)-
Preparation of 2-trifluoromethylbenzimidazole 4.3 g of the compound obtained in Example 1 was added with 13.8 ml of phosphoric acid and 2.
5 ml was added and the mixture was stirred at 150 ° C. for 3 hours. After allowing to cool, saturated aqueous sodium hydrogen carbonate was added to make the mixture alkaline, and the mixture was extracted with chloroform. The extract layer is dried over magnesium sulfate, concentrated, and then purified by silica gel column chromatography (developing solvent; chloroform: ethyl acetate = 30: 1) to obtain the target compound 1.
3g was obtained.

The structure and physical properties of the obtained compound are shown in Table 1 as compound No. 7.

Examples 8 to 17 Compound Nos. 8 to 17 shown in Table 1 were produced in the same manner as in Example 7.

Table 1 shows the structure and physical properties of each compound.

Example 18 1- (3-tert-butyl-4-hydroxyphenyl)-
Preparation of 2-acetylaminobenzimidazole 500 mg of the compound obtained in Example 15 was dissolved in 0.5 ml of acetic anhydride and 5 ml of pyridine, and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture, extraction was performed with ethyl acetate, and the ethyl acetate layer was dried over magnesium sulfate. Crystals obtained by concentration 35
0 mg was dissolved in methanol 30 ml, 3.5% sodium hydroxide aqueous solution 10 ml was added to this, and it stirred at room temperature for 30 minutes. After adding hydrochloric acid to neutralize, the mixture was extracted with ethyl acetate, the ethyl acetate layer was dried over magnesium sulfate and concentrated, and the obtained crystals were washed with ether to obtain 150 mg of the target compound.

The structure and physical properties of the obtained compound are shown as No. 18 in Table 1.

Example 19 Preparation of 1- (3-tert-butyl-4-hydroxy-5-nitrophenyl) -2-trifluoromethylbenzimidazole 300 mg of the compound obtained in Example 7 was dissolved in 6 ml of acetic acid,
To this, add 280 ml of concentrated nitric acid dissolved in 0.21 ml of acetic acid,
The mixture was stirred at 0 ° C for 15 minutes. After allowing to cool, saturated aqueous sodium hydrogen carbonate was added to make the mixture alkaline, and the mixture was extracted with chloroform. The extract layer was dried over magnesium sulfate, concentrated, and then purified by silica gel column chromatography (developing solvent; chloroform: n-hexane = 2: 1) to obtain 130 mg of the target compound.

The structure and physical properties of the obtained compound are shown in Table 1 as compound No. 19
Show as.

Example 20 Preparation of 1- (3-tert-butyl-4-hydroxy-5-aminophenyl) -2-trifluoromethylbenzimidazole 80 mg of the compound obtained in Example 19 was dissolved in 3 ml of THF, and water was added thereto. Add 360 mg of Na ₂ S ₂ O ₄ dissolved in 5 ml and stir at room temperature for 30
Stir for minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, concentrated,
The obtained crude product was purified by silica gel column chromatography (developing solvent; chloroform: n-hexane = 5: 1) to obtain 63 mg of the target compound.

The structure and physical properties of the obtained compound are shown in Table 1 as compound No. 20.
Show as.

Example 21 Preparation of 1-benzyl-2-trifluoromethylbenzimidazole 105 mg of sodium hydride was suspended in 5 ml of DMF, and DMF was added thereto.
2-trifluorobenzimidazole 500 dissolved in 5 ml
mg was added, and the mixture was stirred at room temperature for 15 minutes. A solution of 460 mg of benzyl bromide in 3 ml of DMF was added to the reaction mixture, followed by stirring at room temperature for 2.1 hours.

After completion of the reaction, water was added to the reaction mixture and the mixture was extracted with ethyl acetate, and the crude product obtained from the ethyl acetate extraction layer was subjected to silica gel column chromatography (developing solvent; diethyl ether: n-hexane = 5: 1). 630 mg of the target compound after purification
Got

The structure and physical properties of the obtained compound are shown in Table 1 as Compound No. 21.
Show as.

Example 22 Compound No. 22 shown in Table 1 was produced in the same manner as in Example 21.

Table 1 shows the structure and physical properties of the obtained compound.

Example 23 1-[(3-tert-butyl-4-hydroxyphenyl)
Production of Methyl] -2-trifluoromethylbenzimidazole 1.3 g of the compound obtained in Example 22 was dissolved in 80 ml of ethyl acetate, and 10 mg of 10% palladium-carbon as a catalyst was added thereto. The inside of the container was replaced with hydrogen gas, and the mixture was stirred at room temperature for 3 days. The crude product obtained by removing the catalyst and concentrating the liquid was subjected to silica gel column chromatography (developing solvent;
Purify with diethyl ether: n-hexane = 1: 5),
880 mg of the target compound was obtained.

The structure and physical properties of the obtained compound are shown in Table 1 as Compound No. 23.
Show as.

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Claims (1)

[Claims] 1. A general formula [Wherein R ¹ and R ² are the same or different and each represent a hydrogen atom, a lower alkyl group or a halogen atom, and R ³ is a lower alkyl group, a phenyl group which may have a lower alkyl group as a substituent, or a halogen-substituted lower alkyl group. , An amino group, a lower alkylamino group or a lower alkanoylamino group, R ⁴ represents a hydrogen atom, a lower alkyl group, a nitro group or an amino group, R ⁵
Is a hydrogen atom, a hydroxyl group or a benzyloxy group,
R ⁶ represents a hydrogen atom or a lower alkyl group, respectively, and n is 0 or 1. However, the following cases 1) to 3) are excluded. 1) R ³ is a lower alkyl group, a phenyl group which may have a lower alkyl group as a substituent, an amino group or a lower alkylamino group, R ¹ and R ² are hydrogen atoms, and R ⁴ and R ⁶ are lower alkyl groups. , R ⁵ is a hydroxyl group and n is 0. 2) When R ¹ , R ² , R ⁴ and R ⁶ are all hydrogen atoms, R ³ is a lower alkyl group or a phenyl group, R ⁵ is a hydroxyl group and n is 0. 3) When R ³ is an amino group or a hydrogen atom, R ⁴ , R ⁵ and R ⁶ are both hydrogen atoms, R ¹ and R ² are both hydrogen atoms or both lower alkyl groups and n is 1. ] The benzimidazole derivative represented by these, and its salt.