JPH0674272B2 - Pyridine derivative and ulcer therapeutic agent containing the same - Google Patents

Description

TECHNICAL FIELD The present invention relates to a pyridine derivative having an excellent antiulcer activity.

[Problems to be Solved by Prior Art and Invention]

The causes of peptic ulcer such as gastric / duodenal ulcer are attack factors such as acid and pepsin, mucosal resistance, mucus, blood flow,
It is explained that the imbalance of defense factors such as duodenal control causes autolysis and ulcers.

In principle, medical treatment for peptic ulcer is medical treatment, and various drug therapies have been tried. Currently, the most used antiulcer agents are cimetidine and ranitidine, which are based on histamine H ₂ receptor antagonism.
And so on. However, these drugs have been reported to have side effects such as anti-androgen action and liver synergistic enzyme inhibitory action.

Under such circumstances, it has been recently suggested that an inhibitor of an enzyme called ATPase specifically present in gastric parietal cells can be an excellent acid secretion inhibitor. Among these, omeprazole, which is a benzimidazole-based derivative having the following structural formula, is known as a compound that is currently receiving the most attention (Japanese Patent Application Laid-Open No. 54-141783).

Thereafter, various benzimidazole compounds having an anti-ulcer effect have been proposed, for example, the compounds described in JP-A-59-181277 and the compounds described in JP-A-61-24589. Can be mentioned.

In view of such a situation, the present inventors have to find a compound that is more excellent in anti-ulcer action than a conventionally known compound of a benzimidazole derivative represented by omeprazole and has higher stability. , And has continued to research earnestly.

[Structure and Effect of Invention]

The object compound of the present invention is a pyridine derivative represented by the following chemical structural formula (I) or a pharmaceutically acceptable salt thereof.

The present inventors have continued exploratory research for the above-mentioned purpose, and as a result, as described above, the pyridine derivative represented by the formula (I) or a pharmacologically acceptable salt thereof has higher safety, The inventors have found that the compound has a more excellent anti-ulcer action, and completed the present invention.

Therefore, an object of the present invention is to provide a novel pyridine derivative effective as a peptic ulcer agent and a pharmacologically acceptable salt thereof, and a method for producing the compound or a pharmacologically acceptable salt thereof. It is another object of the present invention to provide a drug containing the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention was completed by paying particular attention to the 4-position of the pyridine ring as shown in the above formula (I), and the 4-position is represented by the formula —O—.
(CH ₂₎ a methoxypropoxy group represented by ₃ -OCH _3.

This compound of the present invention is a compound that has not been disclosed so far and is a novel compound.

More specifically, for example, the above-mentioned JP-A-59-181277 and JP-A-54-141783 disclose compounds in which the 4-position of the pyridine ring is a methoxyethoxy group, but in the present invention, In the above definition of formula (I), the 4-position of the pyridine ring is a methoxypropoxy group, and the compound of the present invention and the compound of the above-mentioned publication are clearly different compounds.

Further addition, in these publications, when the 3,5 position of the pyridine ring is a hydrogen atom, when the phenyl ring of the benzimidazole ring is substituted with a cycloalkyl group, It is specifically disclosed only when the 5- and 5-positions are both hydrogen atoms, and the 4- and 5-positions of the benzimidazole ring are both substituted with a methyl group.

Furthermore, the above-mentioned JP-A No. 61-24589 specifically discloses a compound in which the 4-position of the pyridine ring is substituted only with a phenylalkoxy group such as a benzyloxy group. Different from the compound.

In the present invention, the pharmacologically acceptable salt means an inorganic acid salt such as hydrochloride, hydrobromide, sulfate and phosphate, for example, acetate, maleate, tartrate, methanesulfonate and benzene. Sulfonates, organic acid salts such as toluene sulfonates, or for example arginine, aspartic acid,
Examples thereof include salts with amino acids such as glutamic acid.

Further, it may take a metal salt such as Na, K, Ca, and Mg, and is included in the pharmacologically acceptable salt of the present invention. A particularly preferred pharmacologically acceptable salt is the sodium salt.

Further, the compounds of the present invention are hydrates and stereoisomers exist, but it goes without saying that these are included in the present invention.

Production Method The compound of the present invention can be produced, for example, by the method as described in Examples below, but generally it is as follows.

Manufacturing method A That is, by reacting the compound represented by the formula (II) with the halogen compound or the sulfonate compound represented by the formula (III), the thioether (IV) can be obtained.

In the definition of Y, halogen is, for example, chlorine, bromine,
Meaning iodine and the like, various sulfonyloxy groups include, for example, alkylsulfonyloxy groups such as methylsulfonyloxy group and ethylsulfonyloxy group, aromatic sulfonyloxy groups such as benzenesulfonyloxy group and tosyloxy group. .

It is preferable to carry out this reaction in the presence of a deoxidizing agent. Examples of the deoxidizing agent include alkali metal carbonates or hydrogen carbonates such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate, alkali hydroxides such as sodium hydroxide and potassium hydroxide, organic substances such as pyridine and triethylamine. Examples include amines. Examples of the solvent used in the reaction include alcohols such as methyl alcohol and ethyl alcohol, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, and mixtures of these with water.

The reaction temperature is -40 ° C to the boiling point of the solvent, preferably about 0-60 ° C.

Further, by subjecting the obtained compound (IV) to an oxidation reaction, the target substance, the sulfinyl derivative (I), can be easily obtained.

The oxidation reaction can be carried out by an ordinary method using an oxidizing agent such as hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, sodium hypochlorite or sodium bromate.
The solvent used in the reaction is usually dichloromethane, chloroform, benzene, toluene, methanol,
A solvent selected from ethanol and the like is used. The reaction temperature ranges from about -70 ° C to the boiling point of the solvent, preferably -60 to 25 ° C.

Manufacturing method B That is, the halogen compound represented by the formula (V) is replaced by the formula (VI)
A thioether body represented by the formula (IV) can be obtained by reacting with methanol represented by This reaction is also preferably carried out in the presence of a deoxidizing agent. Examples of the deoxidizing agent include alkali metal carbonates or hydrogen carbonates such as potassium carbonate and sodium carbonate, alkali hydroxides such as sodium hydroxide and potassium hydroxide, and triethylamine. Examples of the reaction solvent include ethers such as tetrahydrofuran and dioxane, ketones such as acetone and methyl ethyl ketone, benzene-based solvents such as benzene, toluene, and xylene, and acetonitrile, dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide. . The reaction temperature is from ice cooling to the boiling point of the solvent.

The thioether derivative (IV) thus obtained can be oxidized with a suitable oxidizing agent as shown in the production method A to obtain the target substance, the sulfinyl derivative represented by the formula (I). it can.

The target substance (I) obtained by the above method can be subjected to a thermogenic reaction by a conventional method to form the desired pharmacologically acceptable salt described above.

Method for Producing Starting Material The compound represented by the formula (III) used as a starting material in Production Method A can be produced, for example, by the following method.

(In the formula, Hal and Y have the above-mentioned meanings.) (First step) 4-halogenopyridine-oxide derivative (VII) such as 4-chloro-2,3-dimethylpyridine-1-oxide
Is reacted with an alcohol derivative represented by the formula (VIII) in the presence of a base to obtain an alkoxy derivative represented by the formula (IX).

Examples of the base include alkali metal hydrides such as sodium hydride and potassium hydride, alkali metal such as sodium metal, sodium alcoholate such as sodium methoxide, and hydroxide such as sodium hydroxide and potassium hydroxide. Examples include alkali. This reaction is solvent-free, or ethers such as tetrahydrofuran and dioxane, acetone, ketones such as methyl ethyl ketone, benzene-based solvents such as benzene, toluene and xylene, acetonitrile, dimethylformamide,
It is carried out in a solvent selected from dimethyl sulfoxide, hexamethylphosphoric triamide and the like. The reaction temperature is appropriately selected from under ice cooling to the boiling point of the solvent.

(Second step) By heating the alkoxy derivative represented by the formula (IX) obtained in the first step in acetic anhydride to about 60 to 100 ° C,
An acetoxymethylpyridine derivative represented by the formula (X) is obtained.

(Third step) In the third step, the acetoxymethylpyridine derivative (X) obtained in the second step is hydrolyzed to obtain a 2-hydroxymethylpyridine derivative represented by the formula (XI).

The hydrolysis is usually performed with alkali.

(Fourth Step) The 2-hydroxymethylpyridine derivative (XI) obtained in the third step is halogenated with a chlorinating agent such as thionyl chloride to give a 2-halogeno compound represented by the formula (III). A methylpyridine derivative can be obtained. At this time, for example, chloroform or dichloromethane is used as the solvent. Further, the sulfonyloxy derivative represented by the formula (III) can be obtained by sulfonylating the 2-hydroxymethylpyridine derivative (XI) with an active sulfonyl chloride such as methanesulfonyl chloride. At this time, as the solvent, for example, chloroform, dichloromethane, ether, tetrahydrofuran, pyridine, benzene and the like are used.

The compound represented by the formula (IX) can also be obtained by the following method by the above method.

(First Step) A compound represented by the formula (VII) (wherein Hal has a halogen atom, for example, a chlorine atom) is subjected to a condensation reaction with a compound represented by the formula (XII) by a conventional method. Formula (XIII)
A compound represented by

This reaction is preferably carried out in the presence of a base such as an alkali metal hydride such as sodium hydride or potassium hydride, an alkali metal such as metal sodium, an alkali hydroxide such as sodium hydroxide or potassium hydroxide.

In addition, this reaction is solvent-free or, for example, tetrahydrofuran,
It is carried out in ethers such as dioxane, ketones such as acetone and methyl ethyl ketone, benzene-based solvents such as benzene, toluene and xylene, and solvents such as acetonitrile, dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide. The reaction temperature is appropriately selected under ice-cooling to the boiling point of the solvent.

(Second step) In this step, the obtained alkoxy derivative (XIII) is reduced to obtain the compound (XIV). As a specific method, for example, a reductant (XIV) can be prepared by hydrogenation in a mixed solution of acetic anhydride-acetic acid using 10% palladium-carbon as a catalyst.
Can be obtained.

(Third Step) By halogenating the obtained compound (XIV) with a chlorinating agent such as thionyl chloride, a 3-halogenopropyl derivative represented by the formula (XV) can be obtained. At this time, as the reaction solvent, for example, chloroform,
Dichloromethane or the like is used.

(Fourth Step) The compound (XV) thus obtained is reacted with methanol represented by the formula (VI) to obtain a compound represented by the formula (XIV). Similar to the production method B, the powder reaction also gives good results in the presence of a deoxidizing agent.

(Fifth Step) The obtained compound (XVI) can be oxidized with an oxidizing agent such as hydrogen peroxide, peracetic acid, or m-chloroperbenzoic acid to obtain an N-oxide compound.

In the production method A, the compound represented by the formula (III) and used as a starting material in which Y is a halogen atom can also be produced by the following method.

(In the formula, Hal represents a halogen atom.) The compound represented by the formula (XI) is halogenated with a chlorinating agent such as thionyl chloride at room temperature to 0 ° C.
A halogenomethylpyridine derivative represented by I ′) can be obtained. At this time, for example, chloroform or dichloromethane can be used as the reaction solvent.

Compound (V) which is the starting material in production method B can be produced, for example, by the following method.

(In the formula, Hal means a halogen atom.) (First step) This is a step of converting the compound represented by the formula (XIII) into an acetyl form (XVII) by a conventional method. As a specific example, acetic anhydride, acetyl chloride or the like is used.

(Second step) The obtained acetyl body (XVII) is hydrolyzed in the presence of an acid or a base to obtain a diol body (XVIII).

(Third Step) The diol (XVIII) is halogenated with a chlorinating agent such as thionyl chloride to obtain a dihalogen represented by the formula (XIX). In this case, for example, chloroform or dichloromethane is used as the reaction solvent.

(Fourth Step) In the fourth step, the obtained dihalogen compound (XIX) is reacted with a compound represented by the formula (II) to obtain a sulfide derivative represented by the formula (V).

This reaction is preferably potassium carbonate, sodium carbonate,
It is carried out in the presence of a deoxidizing agent selected from alkali metal carbonates or hydrogen carbonates such as sodium hydrogen carbonate and the like, and alkali hydroxides such as sodium hydroxide and potassium hydroxide. Examples of the solvent used in the reaction include alcohols such as ethanol and methanol, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide, and mixtures of these with water. The reaction temperature is from 0 ° C to the boiling point of the solvent, preferably about 40-60 ° C.

The compound (V) used as a starting material in the production method B can also be produced by the following method.

(In the formula, Hal means a halogen atom.) That is, the compound (XX) can be halogenated by a conventional method to obtain a compound (V) which is a halogen compound. Specifically, it is halogenated with a chlorinating agent such as thionyl chloride. At this time, chloroform, dichloromethane or the like is preferably used as a solvent for the reaction, and the reaction temperature is preferably from room temperature to about 80 ° C.

Next, examples of pharmacological experiments are shown to explain the effects of the compounds of the present invention in detail.

Pharmacological Experimental Example 1 Inhibition of H ⁺ -K ⁺ ATPase activity (1) Preparation of H ⁺ -K ⁺ -ATPase Saccoman (Saccoman) from the fundic gland of fresh pig gastric mucosa
i) et al. [Biochem. and Biophys. Acta, 464 , 313 (197
7)] was modified.

(2) Measurement of H ⁺ -K ⁺ ATPase activity Various concentrations of the compound of the present invention and omeprazole as a control drug, H ⁺ -K ⁺ ATPase, 10 µg protein /
30 ml at 37 ° C in 40 mM Tris-HCl buffer at pH 7.40 with 30 ml
Incubated for minutes. 1 μg / ml gramicidin D and
10 minutes after the addition of 15 mM KCl, the ATPase reaction was initiated with 3 mM MgCl ₂ and ATP, and after 10 minutes, the released inorganic phosphate was treated with the method of Yoda and Hokin (Biochem.Biophys.Res., Com., 40 , 880, 1970).

The test compound was dissolved in methanol before use. The inhibitory effect was determined by calculating the difference between the measured values of the test compound from the measured values of the control group to which only the solvent was added, and calculating the difference as a percentage of the measured value of the control group. Table 1 shows IC ₅₀ .

(3) Result Pharmacological Experiment 2 Gastric acid secretion inhibitory effect (method) Chronic gastric fistuladogs were used to induce acid secretion by continuous intravenous infusion of histamine (100 μg / kg / hr).

The test drug was administered into the duodenum 1 hour after the start of histamine infusion, and the acid secretion amount 1 hour after that was compared with the non-administration control group.

As the test compound, omeprazole was selected as the following compound of the present invention and a control compound.

The compound of the present invention; 2-[{4- (3-methoxypropoxy)
-3-Methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole sodium salt (Result) Table 2 shows.

Table 2 shows the inhibitory effect (% of inhibition) of the test drug on histamine-stimulated acid secretion in chronic Fistra dogs.

The ID ₅₀ determined from the dose-response curve was 59.9μ for the compound of the present invention.
Since g / kg and omeprazole were 112.2 μg / kg, the compound of the present invention was twice as potent as omeprazole.

Pharmacological Experimental Example 3 Recovery of Acid Secretion (Method) Chronic Fistra dogs were used.

Administered the test drug into the duodenum, 1, 24, 48, 72
After a period of time, pentagastrin was intramuscularly injected, and the acid secretion ability was compared with that of the control group.

As the test drug, the following compound of the present invention and omeprazole were selected as in the case of Pharmacological Experiment 2. Compound of the present invention; 2-
[{4- (3-Methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole sodium salt (result) The results are shown in Table 3.

When 4 mg / kg of both the compound of the present invention and omeprazole were administered into the duodenum and pentagastrin was intramuscularly injected 1 hour later, the acid secretion was completely suppressed.

The compound of the present invention was compared with the control group after 24 and 48 hours, respectively.
Acid secretion of 1.9% and 121.5% was observed, while that of omeprazole was 108.4% after 72 hours. It took 48 hours for the compound of the present invention and 72 hours for omeprazole to recover the acid secretion upon completion.

As is clear from the above-mentioned pharmacological experimental examples, the compound of the present invention is
Both have a strong H ⁺ -K ⁺ ATPase activity inhibitory action, further compared with omeprazole, which is the most noticeable compound having a benzimidazole skeleton, compared with the compound of the present invention, It was found that the gastric acid secretion inhibitory effect was excellent.

What is more surprising is that the compounds of the present invention were found to have remarkably superior ability to restore gastric acid secretion as compared with omeprazole.

H ⁺ -K ⁺ ATP ase inhibitors, since it inhibits the final step of gastric acid secretion, strongly inhibit acid secretion for any stimulus, characterized in that a high single organ specificity, H ₂ -May be an anti-ulcer drug that replaces the blocker. In fact ulcer healing period of omeprazole H ₂ - it has also been reported results that it was significantly shortened blocker.

However, if the duration of acid secretion inhibitory action is too long, hypergastrinemia causes proliferation of enterochromaffin-like cells, formation of carcinoids, proliferation of gastric bacteria, and production of N-nitroso compounds. Difficult problems can occur, such as increase, increase, and difficulty in selecting dose.

Therefore, as an H ⁺ -K ⁺ ATPase inhibitor, one having a strong action and a more rapid recovery of gastric acid secretion is desired.

The present invention has completed the present invention by discovering that the compound of the present invention satisfies this point as a result of repeated researches from such points.

The toxicity of the compound of the present invention is as follows.

As a result of continuous administration of the compound of the present invention (Example 2) to beagle (10 mg / kg) and rat (50 kg / kg) by oral administration for 1 week, no toxicological effects were observed.

Therefore, the compound of the present invention has an excellent gastric acid secretion inhibitory action based on a strong H ⁺ -K ⁺ ATPase activity inhibitory action, and also has a high recovery ability and high safety. It is useful as a therapeutic / preventive agent for anti-ulcer.

When the compound of the present invention is administered as a therapeutic / preventive agent for peptic antiulcer, it may be orally administered as a powder, granules, capsules, syrups, etc., or suppositories, injections,
You may administer parenterally as an external preparation and a drip. The dose varies significantly depending on the degree of symptoms, age, type of ulcer, etc., but usually about 0.01 to 200 mg / kg per day, preferably
0.05 to 50 mg / kg, more preferably 0.1 to 10 mg / kg daily
~ Administer in several divided doses.

When formulating, a usual pharmaceutical carrier is used and it is manufactured by a conventional method.

That is, when preparing a solid preparation for oral use, an excipient, and if necessary, a binder, a disintegrating agent, a lubricant, a coloring agent, a flavoring agent, etc. are added to the main drug, and then a tablet is prepared by a conventional method. Coated tablets, granules, powders, capsules, etc.

As the excipient, for example, lactose, corn starch, sucrose,
Glucose, sorbit, crystalline cellulose, silicon dioxide, etc., as the binder, for example, polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl cellulose, hydroxypropyl starch, polyvinyl pyrrolidone, etc. Examples of the disintegrant include starch, agar, gelatin, crystalline cellulose, calcium carbonate, sodium hydrogen carbonate, calcium citrate, dextrin, pectin and the like, and examples of the lubricant include magnesium stearate, talc, polyethylene glycol and silica. , Hardened vegetable oils, etc., which are allowed to be added to pharmaceuticals as coloring agents,
As the flavoring agent, cocoa powder, mentha brain, aromatic acid, mentha oil, Borneolum, cinnamon powder and the like are used. These tablets,
Needless to say, the granules may be coated with sugar, gelatin or the like, if necessary.

When preparing an injection, a pH adjusting agent, a buffering agent, a stabilizer, a solubilizing agent, etc. are added to the main drug as necessary, and a subcutaneous, intramuscular or intravenous injection is prepared by a conventional method.

〔Example〕

Next, examples of the present invention will be listed, but it goes without saying that the present invention is not limited thereto.

The production examples refer to the production of raw materials when producing the target substance of the present invention.

Example 1 4- (3-Methoxypropoxy) -2,3-dimethylpyridine-N-oxide 2.0 g (22 mmol) of 3-methoxypropanol was dissolved in 50 ml of dimethyl sulfoxide, and 2.7 g of sodium hydride was added.
(66 mmol) was added at room temperature and then stirred at 60 ° C. for 1 hour. After allowing to cool to room temperature, 3.0 g (19 mmol) of 4-chloro-2,3-dimethylpyridine-N-oxide was added. Then 40 ° C
It was stirred for 1 hour. After the reaction was completed, dimethyl sulfoxide was distilled off, and the residue was generated by silica gel column chromatography.
760 mg of-(3-methoxypropoxy) -2,3-dimethylpyridine-N-oxide was obtained. ¹ H-NMR (CDCl ₃ ) δ; 2.1 (m, 2H), 2.2 (s, 3H) 2.54 (s, 3H), 3.35 (s, 3H),
3.55 (t, J = 6Hz, 2H), 4.1 (t, J = 6Hz, 2H), 6.65 (d, J =
7.4Hz, 1H), 8.16 (d, J = 7.4Hz, 1H) Production Example 2 2-Chloromethyl-4- (3-methoxypropoxy)-
3-methylpyridine 20 ml of acetic anhydride was added to 760 mg (3.6 mmol) of 4- (3-methoxypropoxy) -2,3-dimethylpyridine-N-oxide, and the mixture was reacted at 90 ° C for 1 hour. Acetic anhydride was distilled off, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. Chloroform was concentrated to obtain 700 mg of 2-acetoxymethyl-4- (3-methoxypropoxy) -3-methylpyridine (brown oil).

500 ml of sodium hydroxide was added to the 2-acetoxymethyl-4- (3-methoxypropoxy) -3-methylpyridine.
g and 15 cc of ethanol were added, and the mixture was stirred at 50 ° C for 1 hour. After the reaction was completed, ethanol was distilled off, water was added, and the mixture was extracted with chloroform. The chloroform layer was concentrated to obtain 450 mg of 2-hydroxymethyl-4- (3-methoxypropoxy) -3-methylpyridine (brown oil). ¹ H-NMR (CDCl ₃ ) δ; 2.04 (s, 3H), 2.1 (m, 2H), 3.35 (s, 3H), 3.56 (t, J =
5.7Hz, 2H), 4.12 (t, J = 5.7Hz, 2H), 4.64 (s, 2H), 6.7
(D, J = 7Hz, 1H), 8.24 (d, J = 7Hz, 1H) 450 mg of 2-hydroxymethyl-4- (3-methoxypropoxy) -3-methylpyridine obtained above was dissolved in 20 ml of dichloromethane. Thionyl chloride (760 mg) was added dropwise to the mixture at 0 ° C., and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, dichloromethane and thionyl chloride were distilled off, and saturated aqueous sodium hydrogen carbonate solution and chloroform were added for extraction. By concentrating the chloroform layer, 2-chloromethyl-4-
(3-Methoxypropoxy) -3-methylpyridine was added to 47
0 mg was obtained (brown crystals). ¹ H-NMR (CDCl ₃ ) δ; 2.1 (m, 2H), 2.27 (s, 3H), 3.36 (s, 3H), 3.56 (t, J =
5.7Hz, 2H), 4.12 (t, J = 5.7Hz, 2H), 4.69 (s, 2H), 6.71
(D, J = 7Hz, 1H), 8.26 (d, J = 7Hz, 1H) Production Example 3 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H benz Imidazole 2-Mercapto-1H-benzimidazole 280mg (1.8mm
ol), 2-chloromethyl-4- (3-methoxypropoxy) -3-methylpyridine (470 mg, 2 mmol), sodium hydroxide (100 mg, 2.4 mmol), and ethanol (20 cc) added to the mixture at 50 ° C.
And stirred for 3 hours. After the reaction is completed, ethanol is distilled off,
The residue was purified by ¹ H-silica gel column chromatography to give 2-[{4- (3-methoxypropoxy) -3-
590 mg (pale yellow crystal) of methylpyridin-2-yl} methylthio] -1H-benzimidazole was obtained. ¹ H-NMR (CDCl ₃ ) δ; 2.09 (t, J = 6.1 Hz, 2H), 2.26 (s, 3H), 3.35 (s, 3H), 3.
56 (t, J = 6.1Hz, 2H), 4.13 (t, J = 6.1Hz, 2H), 4.37 (s,
2H), 6.76 (d, J = 6.1Hz, 1H), 7.1 to 7.25 (m, 2H), 7.5
(Br, s, 2H), 8.33 (d, J = 6.1Hz, 1H) Example 1 2- {4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl-1H-benzimidazole 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole (5 g) in dichloromethane (100 ml) / diethyl ether (25 ml)
And m-chloroperbenzoic acid (85
%) 2.83 g was added in small portions. After completion of the reaction, 2 g of triethylamine was added, the temperature was raised to -10 ° C, 50 ml of 1N-sodium hydroxide was added, and the mixture was stirred at room temperature for 30 minutes. The aqueous layer was washed twice with 20 ml of dichloromethane, and the aqueous layer was adjusted to pH 11 with 2M aqueous ammonium acetate solution. Then, the aqueous layer was extracted with 50 ml of dichloromethane three times, and the dichloromethane layer was extracted with 50 ml.
It was washed twice with ml of saturated aqueous sodium hydrogen carbonate solution and dried over magnesium sulfate. Distill off the dichloromethane,
The resulting oil was crystallized with dichloromethane-ether to give 4.17 g of the title compound as white crystals.

Melting point; 99 to 100 ° C (decomposition) ¹ H-NMR (CDCl ₃ ) δ; 1.83 to 2.09 (m, 2H), 2.13 (s, 3H), 3.34 (s, 3H), 3.52
(T, J = 6.2Hz, 2H), 4.05 (t, J = 6.2Hz, 2H), 4.79 (s, 2
H), 6.70 (d, J = 5.7Hz, 1H), 7.07 to 7.30 (m, 2H), 7.30
~ 7.60 (br, s, 2H), 8.27 (d, J = 5.7Hz, 1H) Example 2 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl]- 1H-benzimidazole sodium salt 2-[{4- (3-Methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole (500 mg, 1.46 mmol) was dissolved in dichloromethane (20 cc), and m-chloroperoxide was added at -45 ° C. Benzoic acid (85%) 320m
g was added in small portions. After completion of the reaction, triethylamine 370
mg was added and the temperature was raised to -10 ° C. 30 ml of saturated sodium carbonate aqueous solution was added, and the mixture was stirred at room temperature for 30 minutes. After extraction with dichloromethane and drying over magnesium sulfate, dichloromethane was distilled off and the crude product obtained was dissolved by adding 0.1N-sodium hydroxide aqueous solution 14.6 cc. Water was azeotroped 3 times with 30 cc of ethanol and vacuum dried. The white crystals obtained by adding ether were washed with ether three times by decantation and then vacuum dried to give 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H. − Benzimidazole sodium salt 53
0 mg was obtained.

Melting point; 140-141 ° C (decomposition) M ⁺¹ : 382 ¹ H-NMR (DMSO-d ₆ ) δ; 1.99 (t, 6.1Hz, 2H), 2.17 (s, 3H), 3.25 (s, 3H) , 3.49
(T, J = 6.1Hz, 2H), 4.09 (t, J = 6.1Hz, 2H), 4.56 (ABq,
J = 14.1Hz, Δν = 21.3Hz, 2H), 6.8〜6.9 (m, 3H), 7.4〜
7.5 (m, 2H), 8.27 (d, J = 5.7Hz, 1H)

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Seiichiro Nomoto 1-1342-2 Kariyacho, Ushiku-shi, Ibaraki (72) Inventor Makoto Okita 110-8 Arakawaokihashimotonishi, Arakawa, Tsuchiura-shi, Ibaraki 303 (72) Inventor Naoyuki Shimomura 2-23-5 Sakuramura Tenkubo, Shinji-gun, Ibaraki Prefecture 207 (72) Inventor Toshihiko Kaneko 4-18-4 Kasuga, Yatabe-cho, Niiji-gun, Ibaraki 203 (72) Inventor Masatoshi Fujimoto Ibaraki Prefecture 2-5-4 Tokodai, Toyosato-cho, Tsukuba-gun 2-5-4 (72) Manabu Murakami 1-6-8 Tokodai, Toyosato-cho, Tsukuba-gun, Ibaraki Prefecture (72) Inventor Kiyoshi Oketani 1-9-9 Tokodai, Toyo-cho, Tsukuba-gun, Ibaraki Prefecture 16 (72) Inventor Hideaki Fujisaki 2-24-2 Umezono Sakuramura, Shinji-gun, Ibaraki Prefecture (72) Inventor Hisashi Shibata 110-8 Arakawaoki, Tsuchiura City, Ibaraki Prefecture 205-8 Yubara Mansion 205 (72) Inventor Yoshio Wakabayashi Imizu, Ibaraki Prefecture City Motoyoshida Town, 368

Claims (7)

[Claims] 1. A pyridine derivative represented by the following chemical structural formula or a pharmaceutically acceptable salt thereof. 2. The pyridine derivative according to claim 1, which is represented by the following chemical structural formula in which the pharmacologically acceptable salt is a sodium salt. 3. The following chemical structural formula By oxidizing the compound represented by A method for producing the above-mentioned pyridine derivative or a pharmaceutically acceptable salt thereof, which comprises obtaining a pyridine derivative represented by the formula (1) and further performing a salt-forming reaction if necessary. 4. The following chemical structural formula An anti-ulcer therapeutic agent comprising a pyridine derivative represented by: or a pharmacologically acceptable salt thereof as an active ingredient. 5. The anti-ulcer therapeutic agent according to claim 4, which is represented by the following chemical structural formula in which the pharmacologically acceptable salt is a sodium salt. 6. The following chemical constitutive formula A gastric acid secretion inhibitor comprising a pyridine derivative represented by: or a pharmacologically acceptable salt thereof as an active ingredient. 7. The gastric acid secretion inhibitor according to claim 6, which is represented by the following chemical structural formula in which the pharmacologically acceptable salt is a sodium salt.