JPH0559043A - Pyridine derivative and its production - Google Patents

Abstract

PURPOSE:To obtain a new pyridine derivative useful for preventing and treating gastric ulcer, duodenal ulcer, gastritis, etc., having strongly inhibitory action on secretion of acid in the stomach and protecting actin on gastric mucosa. CONSTITUTION:A compound shown by formula I (R<1> is substituent group on benzene ring; R<2> and R<3> are H or methyl; n is 0 or 1) or a salt thereof such as 2-[(4-difluoromethoxy-3-methyl-2pyridyl)methylthio]benzimidazole. The compound is obtained by reacting a compound shown by formula II (R<4> is substituent group on benzene ring) with chlorodifluoromethane and optionally subjecting to oxidation reaction. The compound has both inhibitory action on secretion of acid in the stomach, an attack factor and enhancing action on protecting ability of gastric mucosa.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a pyridine derivative useful as an antiulcer agent and a method for producing the same.

[0002]

2. Description of the Related Art Pyridine derivatives having an antiulcer action include, for example, JP-A-54-141783, JP-A-58-135881, and JP-A-61-50978.
JP-A-64-6270, JP-A-63-1
Compounds described in Japanese Patent No. 45265 and the like (none of these compounds have a difluoromethoxy group at the 4-position of the pyridine ring) are known. However, a compound having a stronger gastric mucosa protective action than these known compounds has been desired.

[0003]

Gastrointestinal ulcers are considered to be caused by an imbalance in the balance between attacking factors such as hydrochloric acid and pepsin and protective factors on the mucosal side such as mucous membrane secretion and mucosal blood flow. Therefore, there has been a demand for a drug that has an action of suppressing gastric acid secretion, which is an attacking factor, as well as an action of enhancing the defense ability of gastric mucosa.

[0004]

[Means for Solving the Problems] The inventors of the present invention have conducted extensive studies for the purpose of obtaining an anti-ulcer agent having both excellent gastric acid secretion inhibitory action and gastric mucosa protective action. The present invention was completed as a result of discovering that it conforms to the above and conducting further research. The present invention provides (1) general formula

[Chemical 4] [Wherein R ¹ represents a substituent on the benzene ring, R ² and R ³
Are the same or different and each is hydrogen or methyl, and n is 0 or 1. ] The pyridine derivative represented by these or its salt, and (2) general formula

[Chemical 5] [Wherein R ⁴ represents a substituent on the benzene ring, R ² and R ³
Are the same or different and each represents hydrogen or methyl. ] The compound of the formula (I) or a salt thereof is characterized by reacting the compound represented by the formula with chlorodifluoromethane, and optionally subjecting it to an oxidation reaction. In the above general formulas (I) and (II), R ¹ or R ⁴ is preferably, for example, hydrogen, a hydroxyl group, a halogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, or a substituted alkyl group. And an optionally substituted alkoxy group and the like. Next, each of the above substituents will be described. Halogen atoms include fluorine, chlorine, bromine and iodine. In this, fluorine,
Chlorine is preferred. Further, fluorine is particularly preferable. Examples of the alkyl group in the optionally substituted alkyl group include a linear or branched alkyl group having 1 to 10 carbon atoms. Specific examples of the alkyl group include, for example, methyl, ethyl, n-propyl, isopropyl, n
-Butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl and the like can be mentioned. Of these, a linear or branched alkyl group having 1 to 6 carbon atoms is preferable. Further, a linear or branched alkyl group having 1 to 3 carbon atoms is particularly preferable. Examples of the substituent in the alkyl group include halogen, nitro, amino group (which may have 1 or 2 acyl groups, alkyl groups and the like), cyano group, hydroxy group, carboxy group, amidino. Group, guanidino group, carbamoyl group and the like. Examples of the cycloalkyl group in the optionally substituted cycloalkyl group include a cycloalkyl group having 3 to 7 carbon atoms. Specific examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
Examples of the substituent in the cycloalkyl group include halogen, nitro, amino group (alkyl group, acyl group, etc.
It may have two substituents. ), Cyano group, hydroxy group, carboxy group, amidino group, guanidino group, carbamoyl group and the like. The alkenyl group in the optionally substituted alkenyl group is, for example, a linear or branched alkenyl group having 2 to 16 carbon atoms. Specific examples of the alkenyl group include allyl
(allyl), vinyl, crotyl, 2-penten-1-yl, 3
-Penten-1-yl, 2-hexen-1-yl, 3-hexen-1-yl, 2-methyl-2-propen-1-yl, 3-methyl-2-buten-1-yl and the like. .. Of these, a linear or branched alkenyl group having 2 to 6 carbon atoms is preferable. Further, a linear or branched alkenyl group having 2 to 4 carbon atoms is preferable. Examples of the substituent in the alkenyl group include halogen, nitro, amino group (which may have 1 or 2 alkyl groups, acyl groups and the like as substituents), cyano group, amidino group, guanidino group and the like. Groups. The alkenyl group includes isomers (E, Z isomers) related to the double bond. Examples of the alkoxy group in the optionally substituted alkoxy group include an alkoxy group having 1 to 10 carbon atoms. Specific examples of the alkoxy group include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, hexyloxy, heptyloxy, nonyloxy. , Cyclobutoxy, cyclopentoxy, cyclohexyloxy and the like. Of these, an alkoxy group having 1 to 6 carbon atoms is preferable. Further, an alkoxy group having 1 to 3 carbon atoms is particularly preferable. Examples of the substituent in the alkoxy group include groups such as halogen, nitro, amino group (which may have 1 or 2 alkyl groups, acyl groups and the like as substituents), amidino group, guanidino group and the like. Be done. Examples of the halogen of the substituents on the alkyl group, cycloalkyl group, alkenyl group and alkoxy group include chlorine, bromine, fluorine and iodine. The alkyl group in the alkylamino group, which is a substituent on the alkyl group, cycloalkyl group, alkenyl group and alkoxy group, is preferably, for example, a linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, n-hexyl and isohexyl. Among them, a linear or branched alkyl group having 1 to 4 carbon atoms is particularly preferable. Examples of the acyl group in the acylamino group which is a substituent on the alkyl group, cycloalkyl group, alkenyl group and alkoxy group include an acyl group derived from an organic carboxylic acid. Of these, an alkanoyl group having 1 to 6 carbon atoms is preferable. Specific examples include formyl,
Acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl and the like can be mentioned. Among them, an alkanoyl group having 1 to 4 carbon atoms is particularly preferable. The number of substituents on the alkyl group, cycloalkyl group, alkenyl group and alkoxy group is 1 to 6, preferably 1 to 3. Specific examples of the substituted alkyl group represented by R ¹ or R ⁴ include, for example, trifluoromethyl, trifluoroethyl, difluoromethyl, trichloromethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyethyl, Ethoxyethyl, 1-methoxyethyl, 2-methoxyethyl, 2,2-
Examples thereof include dimethoxyethyl, 2,2-diethoxyethyl, 2-diethylphosphorylethyl and the like. Of these, difluoromethyl, trifluoromethyl and hydroxymethyl are preferable. Furthermore, trifluoromethyl is particularly preferable. Specific examples of the substituted cycloalkyl group represented by R ¹ or R ⁴ include 2-aminocyclopropan-1-yl, 4-hydroxycyclopentane-
1-yl, 2,2-difluorocyclopentan-1-yl and the like can be mentioned. Specific examples of the substituted alkenyl group include 2,2-dichlorovinyl, 3-hydroxy-2-propen-1-yl, 2-methoxyvinyl and the like. Specific examples of the substituted alkoxy group represented by R ¹ or R ⁴ include, for example, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, 2-methoxyethoxy, 4-chlorobenzyloxy,
2- (3,4-dimethoxyphenyl) ethoxy and the like can be mentioned. Of these, difluoromethoxy is particularly preferred. The positions of R ¹ and R ^{4 on} the benzene ring include 4-position and 5-position, of which 5-position is preferable. (The number of the position on the benzene ring is described in Table 1 of Examples 3 to 6)

The sulfide derivative (I) (n = 0) or its salt, which is the object compound of the present invention, is the starting compound (II).
It can be produced by reacting with chlorodifluoromethane. It is convenient to carry out this reaction in the presence of a base. Examples of the base include alkali metal hydride such as sodium hydride and potassium hydride, alkali metal such as sodium and potassium, sodium alcoholate such as sodium methoxide and sodium ethoxide, potassium carbonate and sodium carbonate. Alkaline metal carbonates, triethylamine, 1,8-diazabicyclo [5,4,0] unde-7-sen (DB
U), 1,5-diazabicyclo [4,3,0] non-5
Examples include organic amines such as -ene (DBN). This reaction is usually performed in a solvent that does not adversely affect the reaction. Examples of such a solvent include methanol,
Examples thereof include alcohols such as ethanol, ethers such as ether and tetrahydrofuran, dimethylformamide, and dimethylsulfoxide. The amount of chlorodifluoromethane used in the above reaction is usually in large excess. That is, it is about 10 to 100 equivalents, more preferably about 15 to 8 equivalents to the starting compound (II).
Use 0 equivalents. The amount of the base used in the above reaction is usually slightly in excess of the equivalent amount, but a large excess of base may be used. That is, it is used in an amount of about 1 to 10 equivalents, more preferably about 1.1 to 4 equivalents, relative to the starting compound (II). The reaction temperature is usually about 0 ° C to about the boiling point of the solvent used, more preferably about 20 ° C to 8 ° C.
It is 0 ° C. The reaction time is about 0.2 to 24 hours, more preferably about 0.5 to 2 hours. When R ⁴ is a hydroxyl group, it can be converted to difluoromethoxy by reacting with chlorodifluoromethane.
At this time, the 4-position hydroxyl group of the pyridine ring is more reactive than the hydroxyl group on the benzene ring and can be selectively converted to difluoromethoxy.

The sulfinyl derivative (I) (n = 1) or a salt thereof which is the object compound of the present invention is a compound (I)
It can be produced by subjecting (n = 0) or a salt thereof to an oxidation reaction. Examples of the oxidizing agent used here include perchloric acid such as metachloroperbenzoic acid, hydrogen peroxide, peracetic acid, trifluoroperacetic acid and permaleic acid, sodium bromate, sodium hypochlorite and the like. .. Examples of the solvent used in the reaction include halogenated hydrocarbons such as chloroform and dichloromethane, ethers such as tetrahydrofuran and dioxane, amides such as dimethylformamide, and water, which can be used alone or in combination. .. The amount of the oxidizing agent to be used is preferably approximately equivalent to or slightly excessive with respect to the compound (I) (n = 0) or its salt. Ie about 1
To 3 equivalents, more preferably about 1 to 1.5 equivalents. The reaction temperature ranges from under ice cooling to around the boiling point of the solvent used, usually under ice cooling to room temperature, and more preferably about 0.
It is carried out at -10 ° C. The reaction time is usually about 0.
1 to 24 hours, more preferably about 0.1 to 4
It's time. Furthermore, the method of oxidizing with hydrogen peroxide in the presence of a vanadium compound disclosed in EP-A-302720 can also be effectively used. The target compound (I) produced by the above reaction can be isolated and purified by a conventional means such as recrystallization and chromatography.

The compound (I) of the present invention may be converted into a pharmaceutically acceptable salt by a commonly used means. Examples of the salt include hydrochloric acid, bromic acid, iodic acid, phosphoric acid,
Examples thereof include salts with inorganic acids such as nitric acid and sulfuric acid and salts with organic acids such as acetic acid and citric acid. In the compound (I), the salt of the compound in which n = 0 is stable, and the salt of the compound in which n = 1 is unstable as an aqueous solution but may exist. In the compound (I), the compound of n = 1 or a salt thereof can be stabilized by blending a basic inorganic salt such as magnesium carbonate, precipitated calcium carbonate, disodium hydrogen phosphate and the like.

Next, the starting compound (II) can be produced, for example, by the method represented by the following reaction formula.

[Chemical 6] [In the formula, R ⁵ is a substituent on the benzene ring, R ⁶ is lower alkyl or aralkyl, and R ² and R ³ are as defined above. In the above formula, the substituent represented by R ⁵ is the above R ¹
And those similar to the substituent represented by R ⁴ . In the above formula, the lower alkyl represented by R ⁶ is
Examples thereof include linear or branched alkyl having 1 to 5 carbon atoms such as methyl, ethyl, isopropyl, propyl, butyl, isobutyl, pentyl and neopentyl. Examples of the aralkyl represented by R ⁶ include benzyl and 4-chlorobenzyl.

In this production method, the compound represented by the general formula (III) is subjected to an ether bond cleavage reaction with an acid to produce a hydroxy derivative of the general formula (II). Examples of the acid used in this reaction include hydrohalic acid such as hydrogen bromide and hydrogen chloride. The above reaction is carried out in a solvent that does not adversely influence the reaction.
Examples of such a solvent include water and acetic acid. The reaction temperature is appropriately selected from 20 ° C. to around the boiling point of the solvent. The reaction time is about 1 to 100 hours, preferably 3 to 50 hours. The compound represented by the general formula (III) can be prepared by a known method, for example, European Patent No. 174.
It can be produced by the method disclosed in Japanese Patent No. 726 and European Patent No. 175464 or a method analogous thereto.

Next, the pharmacological action of the compound of the present invention will be described. The role of acids in the development of gastric and duodenal ulcers is well known, but in addition, the importance of gastric mucosal protection has recently been recognized [American Journal of Physiology (Am.J.Physiol .), 24
5 , G601 (1983)] . As a method for measuring the gastric mucosa protective ability, a method developed by Robert et al. Using gastric mucosal damage by ethanol as an index [Gastroenterology 77 , 761]
(1979]), which was used to examine the action of the compound of the present invention.

Experimental Method 7-week-old Sprague Dawle
y) Male rats were subjected to the experiment after fasting for 24 hours. The test compound was intragastrically administered using an oral probe, and 30 minutes later, 1 ml of 100% ethanol was orally administered. 60 minutes after the administration of ethanol, the animals were killed with carbon dioxide. The stomach was removed together with the lower esophagus and the duodenum, the esophagus was occluded with a clip, and the 1% formalin solution 1
After injecting 0 ml, the duodenum was closed with a clip, and the whole stomach was immersed in a 1% formalin solution. After about 15 minutes, the stomach was incised along the large radius, and the length of the mucosal damage occurring in the body of the stomach was measured using a stereoscopic microscope with a grid (× 10). The total length of damage was measured for each rat, the average length was calculated for each group, and the inhibition rate was calculated from the difference from the control group. All test compounds were suspended in 5% arabic gum solution and 2 ml /
A dose of kg was administered.

Experimental Results 2-[(4-difluoromethoxy-3-methyl-2-) produced in Example 2 described later using 6 rats per group
When 1,3 and 10 mg / kg of pyridyl) methylsulfinyl] benzimidazole were administered and the ID ₅₀ value was determined, it was 4.5 mg / kg.

As described above, the compound of the present invention exhibits an excellent gastric mucosal protective action. The toxicity of the compound (I) or a salt thereof of the present invention is generally low. For example, no compound died even when the compound used in the above-described experiment for gastric mucosal protective action was orally administered to mice at 300 mg / kg. Thus, the compound (I) of the present invention or a salt thereof has antiulcer action, gastric acid secretion inhibitory action, gastric mucous membrane defense action, etc., low toxicity, and is relatively stable as a chemical substance. .. Therefore, the compound (I) of the present invention or a salt thereof can be used for treating gastrointestinal ulcer in mammals (eg, mouse, rat, rabbit, dog, cat, human etc.). In order to use the compound (I) of the present invention or a salt thereof as an anti-ulcer agent for the treatment of gastrointestinal ulcer in mammals, for example, the compound (I) or a salt thereof is a pharmaceutically acceptable carrier, excipient, It can be orally administered in the form of capsules, tablets, granules, etc. by mixing with a diluent. The dose for adults is about 0.01 to 30 mg / kg / day, more preferably about 0.1 to 3 mg / kg / day. Further, in the compound (I) of the present invention or a salt thereof, the compound with n = 0 is useful as a starting compound for producing the compound with n = 1.

[0014]

EXAMPLES Next, the starting compound used in the method of the present invention and the method for producing the compound (I) of the present invention or a salt thereof are described
Each will be specifically described with reference examples and examples. Reference Example 1 47% of 2-[(4-methoxy-3-methyl-2-pyridyl) methylthio] benzimidazole (16.6 g)
A solution of HBr in water (250 ml) was heated at reflux for 24 hours. The reaction mixture was concentrated under reduced pressure, the residue was neutralized with saturated aqueous sodium hydrogen carbonate solution, and the separated oily substance was subjected to silica gel column chromatography. Elute with chloroform-methanol (25: 2, v / v) to give 2-[(4
-Hydroxy-3-methyl-2-pyridyl) methylthio] benzimidazole (10.8 g) was obtained as a colorless powder. ¹ H-NMR (δppm in CDCl ₃ ): 2.12 (3H, s), 4.38 (2
H, s), 6.43 (1H, d, J = 7Hz), 7.1-7.3 (2H, m), 7.4-7.6 (3H, m) By treating the above powder with hydrogen chloride ethanol solution (8N), 2 The hydrochloride salt was obtained as crystals. Recrystallized from ethanol, colorless prism crystals. Melting point 233-235 [deg.] C. Elemental analysis Calculated as C ₁₄ H ₁₃ N ₃ OS / 2HC1: C, 48.84; H, 4.39; N, 12.21 Analytical value: C, 48.59; H, 4.29; N, 12.16

Reference Example 2 5-Fluoro-2-[(4-methoxy-3-methyl-2)
-Pyridyl) methylthio] benzimidazole (5.5
A solution of g) in 47% HBr in water (50 ml) was heated under reflux for 24 hours. The reaction mixture was concentrated under reduced pressure, the residual oil was neutralized with saturated aqueous sodium hydrogen carbonate solution, ethyl acetate (50 ml) was added, and 5-fluoro-2-[(4-hydroxy-3-methyl-2-pyridyl) was added. Methylthio] benzimidazole (3.2 g, 62%) was obtained. Recrystallized from ethanol, colorless needles. Melting point 232-233 [deg.] C. Elemental analysis Calculated as C ₁₄ H ₁₂ N ₃ OSF: C, 58.12; H, 4.18; N, 14.52 Analytical value: C, 58.00; H, 3.94; N, 14.52

Reference Example 3 In the same manner as in Reference Example 1, 2-[(4-hydroxy-3-me
Cyl-2-pyridyl) methylthio] -5-trifluoro
A colorless powder of methylbenzimidazole was obtained. ¹ H-NMR (δppm in CDCl₃): 2.35 (3H, s), 4.41 (2
H, s), 6.35 (1H, d,J= 7Hz), 7.05 (1H, d,J= 7Hz), 7.5-7.9 (3H,
m)

Reference Example 4 2-[(4-methoxy-3-methyl-2-pyridyl) methylthio] -5-propoxybenzimidazole (5.
A solution of 5 g) of 47% HBr in water (50 ml) was heated under reflux for 24 hours. The reaction mixture was concentrated under reduced pressure, and the residual oily substance was neutralized with a saturated aqueous sodium hydrogen carbonate solution. The separated oily substance was subjected to silica gel chromatography and eluted with chloroform-methanol (10: 1, v / v) to give 5-hydroxy-2-[(4-hydroxy-3).
A colorless powder of -methyl-2-pyridyl) methylthio] benzimidazole (3.2 g, 72%) was obtained. ¹ H-NMR (δ ppm in CD ₃ OD): 1.96 (3 H, s), 4.20 (2
H, s), 6.37 (1H, d, J = 7Hz), 6.75 (1H, double d, J = 8 and 2H
z), 6.86 (1H, d, J = 2Hz), 7.33 (1H, d, J = 8Hz), 7.68 (1H, d, J = 7
Hz)

Reference Example 5 In the same manner as in Reference Example 1, 2-[(3,5-dimethyl-4-
Hydroxy-2-pyridyl) methylthio] benzimidazole dihydrochloride was obtained. Recrystallized from methanol, colorless prism crystals. Melting point 245-247 [deg.] C. Elemental analysis Calculated as C ₁₅ H ₁₅ N ₃ OS / 2HCl: C, 50.28; H, 4.78; N, 11.73 Analytical value: C, 49.90; H, 4.75; N, 11.48

Reference Example 6 In the same manner as in Reference Example 1, 2-[(3,5-dimethyl-4-
Hydroxy-2-pyridyl) methylthio] -5-fluorobenzimidazole dihydrochloride was obtained. Recrystallized from methanol, colorless prism crystals. Melting point 228-230 [deg.] C. Elemental analysis Calculated as C ₁₅ H ₁₄ N ₃ OSF · 2HCl: C, 47.88; H, 4.29; N, 11.17 Analytical value: C, 47.61; H, 4.44; N, 10.91

Example 1 2-[(4-hydroxy-3-methyl-2-pyridyl)
Methylthio] benzimidazole (10.5 g) was added to N,
It was dissolved in N-dimethylformamide (DMF) (100 ml), and 1,8-diazabicyclo [5,4,0] unde-7
-Cen (DBU) (7.1 g) was added and chlorodifluoromethane was introduced at room temperature for 3 hours. The reaction mixture was washed with water (5
(00 ml) and extracted with ethyl acetate. After ethyl acetate layer was washed with water, dried (MgSO _4), and the solvent was distilled off, the residue was subjected to silica gel column chromatography. 2-[(4-Difluoromethoxy-3-methyl-2-pyridyl) methylthio] benzimidazole (2.5 g, 20%) was obtained from the portion eluted with chloroform-methanol (100: 1, v / v). It was Recrystallized from ethyl acetate-hexane, colorless needle crystals. Melting point 99-100 [deg.] C. Elemental analysis Calculated as C ₁₅ H ₁₃ N ₃ OSF ₂ : C, 56.06; H, 4.08; N, 13.08 Analytical value: C, 56.24; H, 4.04; N, 13.07

Example 2 2-[(4-Difluoromethoxy-3-methyl-2-pyridyl) methylthio] benzimidazole (2.0 g)
Was dissolved in chloroform (20 ml) -methanol (10 ml), and under ice cooling, metachloroperbenzoic acid (MCPBA)
A solution of (80%, 1.5 g) in chloroform (20 ml) was added dropwise. The reaction mixture was washed saturated aqueous sodium hydrogen carbonate solution, and then the water dried (MgSO _4). The solvent was distilled off, and the remaining solid was subjected to silica gel column chromatography. Ethyl acetate-methanol (100: 3, v /
2-[(4-Difluoromethoxy-3-methyl-2-pyridyl) methylsulfinyl] benzimidazole (1.5 g, 71%) was obtained from the portion eluted in v).
Recrystallized from ethyl acetate-ether, colorless needle crystals. Melting point
157-158 ° C (decomposition). Elemental analysis _{C 15 H 13 N 3 O 2} SF 2 Calculated: C, 53.41; H, 3.88 ; N, 12.46 analysis: C, 53.47; H, 4.05 ; N, 12.45

Examples 3 to 6 In the same manner as in Example 1, compounds shown in Table 1 were obtained.

[Table 1]

Example 7 5-Hydroxy-2-[(4-hydroxy-3-methyl-2-pyridyl) methylthio] benzimidazole (3.1 g) was added to N, N-dimethylformamide (60 m).
1,8-diazabicyclo [5,4,0] unde-7-cene (3.9 g) was added, and chlorodifluoromethane was introduced at room temperature for 1 hour. Pour the reaction mixture into water,
It was extracted with ethyl acetate. The ethyl acetate layer is washed with water and dried (M
After gSO ₄ ) the solvent was evaporated and the residual oil was subjected to silica gel column chromatography. Chloroform-methanol (20: 1, v / v)
Obtained 5-difluoromethoxy-2-[(4-difluoromethoxy-3-methyl-2-pyridyl) methylthio] benzimidazole. Recrystallized from ethyl acetate-hexane, colorless prism crystals. Melting point 181-182 [deg.] C. Calculated elemental analysis _{C 16 H 13 N 3 O 2} SF 4: C, 49.61; H, 3.38; N, 10.85 analysis: C, 49.46; H, 3.34 ; N, 10.77

Example 8 According to the silica gel column chromatography of Example 7, 5-
From the part that elutes after difluoromethoxy-2-[(4-difluoromethoxy-3-methyl-2-pyridyl) methylthio] benzimidazole, 2-[(4-difluoromethoxy-3-methyl-2-pyridyl) methylthio] -5-Hydroxybenzimidazole was obtained. Recrystallized from ethyl acetate, colorless needle crystals. Melting point 214-215
° C. Elemental analysis _{C 15 H 13 N 3 O 2} SF 2 Calculated: C, 53.40; H, 3.88 ; N, 12.46 analysis: C, 53.28; H, 3.89 ; N, 12.31

Examples 9 to 12 The compounds of [Table 2] were obtained in the same manner as in Example 2.

[Table 2]

[0026]

The compound (I) of the present invention has both a strong gastric acid secretion inhibitory action and a gastric mucosa protective action, and as a result, shows a remarkable antiulcer action, and has relatively high stability. It is also highly safe in terms of acute toxicity test results in mice. Therefore, the compound (I) of the present invention is useful for the prevention and treatment of gastric ulcer, duodenal ulcer, gastritis and the like.

Claims (2)

[Claims] 1. A general formula: [In the formula, R ¹ represents a substituent on the benzene ring, R ² and R ³ are the same or different and each represents hydrogen or methyl, and n represents 0 or 1. ] The pyridine derivative represented by these, or its salt. 2. A general formula: [Wherein R ⁴ represents a substituent on the benzene ring, R ² and R ³
Are the same or different and each represents hydrogen or methyl. ] The compound represented by the formula] and chlorodifluoromethane are reacted, and if necessary, subjected to an oxidation reaction. [In the formula, R ¹ , R ² , R ³ and n have the same meanings as described above. ] The manufacturing method of the pyridine derivative represented by these, or its salt.