JP2576843B2 - Pyridine derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a pyridine derivative having an excellent antiulcer activity.

[0002]

2. Prior Art and Problems to be Solved by the Invention
The cause of peptic ulcers such as duodenal ulcers is that autolysis is caused by an aggressive factor such as acid and pepsin and a protective factor such as mucosal resistance, mucus, blood flow, and duodenal imbalance, causing ulcers. It is explained. Treatment of peptic ulcer is medical treatment in principle, and various drug treatments have been attempted. Currently, the anti-ulcer agents which are most used, cimetidine based on histamine H ₂ receptor antagonism (cimetidine), ranitidine (ranitidine)
And the like. However, these drugs have been reported as side effects such as anti-androgenic action, hepatic metabolic enzyme activity inhibitory action and the like.

[0003] Under such circumstances, it has recently been suggested that an inhibitor of an enzyme called ATPase, which is specifically present in gastric wall cells, can be an excellent acid secretion inhibitor. Among these compounds, omeprazole, which is a benzimidazole derivative represented by the following structural formula, is known as a compound that has received the most attention at present (JP-A-54-1).
No. 41783).

[0004]

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Subsequently, various benzimidazole compounds having an anti-ulcer effect have been proposed, for example, Japanese Patent Application Laid-Open No.
-181277, JP-A-61-245
Compounds described in Japanese Patent Publication No. 89 can be exemplified.

[0006] In view of such circumstances, the present inventors have been found to be more excellent in antiulcer activity and more safe than the conventionally known benzimidazole derivatives represented by omeprazole. We have been conducting intensive research to find compounds.

[0007]

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

[0008]

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The present inventors have continued the search for the above-mentioned purpose, and as a result, as a result, the pyridine derivative represented by the above formula (I) or a pharmaceutically acceptable salt thereof, The following chemical structural formula (II) obtained by

[0010]

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The present inventors have found that the sulfinyl derivative represented by the formula (1) is a compound having higher safety and a better antiulcer activity, and completed the present invention. Accordingly, an object of the present invention is to provide a novel pyridine derivative effective as a peptic ulcer and a pharmacologically acceptable salt thereof,
Another object of the present invention is to provide a method for producing the compound or a pharmacologically acceptable salt thereof.

According to the present invention, as shown in the above formula (I),
Particularly focusing on the 4-position of the pyridine ring, it has been completed, 4-position is a methoxypropoxy group of the formula _{-O- (CH 2) 3 -OCH 3} . This compound of the present invention is a compound that has not been disclosed before and is a novel compound.

More specifically, for example, Japanese Patent Application Laid-Open No.
JP-A-181277 and JP-A-54-141783 disclose a compound in which the 4-position of the pyridine ring is a methoxyethoxy group. Is a methoxypropoxy group,
The compound of the present invention and the compound disclosed in the above publication are clearly different compounds. Furthermore, in these publications, in these publications, a hydrogen atom is present in both the 3- and 5-positions of the pyridine ring, a cycloalkyl group is substituted on the phenyl ring of the benzimidazole ring, and
It specifically discloses only the case where the 3,5-positions are all hydrogen atoms and the 4,5-, 6-positions of the benzimidazole ring are all substituted with methyl groups. Furthermore, the above-mentioned JP-A-61
Japanese Patent No. -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, which is different from the compound of the present invention.

In the present invention, the pharmacologically acceptable salt means an inorganic acid salt such as hydrochloride, hydrobromide, sulfate, phosphate, etc., for example, acetate, maleate, tartrate, methanesulfonic acid. Examples thereof include salts, organic acid salts such as benzenesulfonate and toluenesulfonate, and salts with amino acids such as arginine, aspartic acid, and glutamic acid. Furthermore, metal salts such as Na, K, Ca, and Mg may be taken, and are included in the pharmacologically acceptable salts of the present invention. A particularly preferred pharmacologically acceptable salt is the sodium salt. In addition, the compounds of the present invention may be hydrates or stereoisomers, but needless to say, these are included in the present invention.

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

[0016]

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That is, by reacting a compound represented by the formula (III) with a halogen compound or a sulfonate compound represented by the formula (IV), the desired compound of the present invention represented by the formula (I) is obtained. Obtainable.

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

It is preferable to carry out the reaction in the presence of a deoxidizing agent. As the deoxidizing agent, for example, potassium carbonate, sodium carbonate, alkali metal carbonate or hydrogencarbonate such as sodium hydrogencarbonate, sodium hydroxide, alkali hydroxide such as potassium hydroxide, pyridine,
Organic amines such as triethylamine are exemplified. Examples of the solvent used for the reaction include alcohols such as methyl alcohol and ethyl alcohol, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, and a mixture of these with water. The reaction temperature is from -40 ° C to the boiling point of the solvent, preferably from about 0 to 60 ° C.

[0020]

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That is, the halogenated compound represented by the formula (V) is reacted with methanol represented by the formula (VI) to obtain the target compound of the present invention represented by the formula (I). This reaction is also preferably performed in the presence of a deoxidizing agent.
As a deoxidizing agent, potassium carbonate or bicarbonate of an alkali metal such as potassium carbonate and sodium carbonate, sodium hydroxide, alkali hydroxide such as potassium hydroxide,
Or triethylamine. Examples of the reaction solvent include ethers such as tetrahydrofuran and dioxane; ketones such as acetone and methyl ethyl ketone; benzene solvents such as benzene, toluene and xylene; and acetonitrile, dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric acid triamide. . The reaction is carried out at a temperature from ice-cooling to the boiling point of the solvent.

The thus-obtained compound of the formula (I), which is the target compound of the present invention, is prepared by the following production method C
As shown by, by oxidizing using a suitable oxidizing agent, a sulfinyl derivative represented by the formula (II) having more excellent antiulcer activity can be obtained. Although the compound of the present invention itself has a gastric acid secretion inhibitory action, the sulfinyl derivative represented by the formula (II) obtained by oxidizing the compound of the present invention is a remarkably excellent antiulcer agent based on the gastric acid secretion inhibitory action. Is highly useful as an intermediate of the sulfinyl derivative represented by the formula (II). When the compound of the present invention is administered, the compound is oxidized in the body to give the compound of the formula (I
The sulfinyl derivative represented by I) can be expected to be an excellent anti-ulcer agent.

[0023]

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The oxidation reaction includes, for example, hydrogen peroxide, peracetic acid,
It can be carried out by an ordinary method using an oxidizing agent such as m-chloroperbenzoic acid, sodium hypochlorite, sodium bromite and the like. As a solvent used in the reaction, a solvent selected from dichloromethane, chloroform, benzene, toluene, methanol, ethanol and the like is usually used. Reaction temperatures range from about -70 ° C to the boiling point of the solvent, preferably from -60 to 25 ° C.

The target substance (I) obtained by the above method is
A salt formation reaction can be carried out by a conventional method to form the desired pharmacologically acceptable salt described above.

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

[0027]

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(Wherein Hal and Y have the above-mentioned meanings) (First step) 4-chloro-2,3-dimethylpyridine-1
Reacting a 4-halogenopyridine-oxide derivative (VII) such as an oxide 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). Can be.

As the base, for example, sodium hydride,
Alkali metal hydrides such as potassium hydride, alkali metals such as sodium metal, sodium alcoholate such as sodium methoxide, sodium hydroxide,
An alkali hydroxide such as potassium hydroxide may be used. This reaction is carried out without solvent, or for example, tetrahydrofuran,
The reaction is carried out in a solvent selected from ethers such as dioxane, ketones such as acetone and methyl ethyl ketone, benzene solvents such as benzene, toluene and xylene, acetonitrile, dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide. The reaction temperature is appropriately selected from under ice-cooling to the boiling point of the solvent.

(Second step) Formula (IX) obtained in the first step
About 60 to 100 in acetic anhydride
By heating to ℃, an acetoxymethylpyridine derivative represented by the formula (X) is obtained.

(Third Step) The acetoxymethylpyridine derivative (X) obtained in the second step is hydrolyzed to obtain a compound of the formula (XI)
Is a step of obtaining a 2-hydroxymethylpyridine derivative represented by the following formula: The hydrolysis is usually carried out with an 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 compound of the formula
A 2-halogenomethylpyridine derivative represented by (IV) can be obtained. At this time, as a solvent, for example, chloroform, dichloromethane and the like are used. Also, 2-
The sulfonyloxy derivative represented by the formula (IV) can be obtained by sulfonylating the hydroxymethylpyridine derivative (XI) with an active sulfonyl chloride such as methanesulfonyl chloride. At this time, as a solvent, for example, chloroform, dichloromethane, ether, tetrahydrofuran, pyridine, benzene and the like are used.

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

[0034]

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[0035]

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(First step) A compound represented by the formula (VII) (Hal represents a halogen atom, for example, a chlorine atom) is condensed with a compound represented by the formula (XII) by a conventional method. The compound is reacted to obtain a compound represented by the formula (XIII).

The reaction is preferably carried out with sodium hydride,
The reaction is performed in the presence of a base such as an alkali metal hydride such as potassium hydride, an alkali metal such as metal sodium, or an alkali hydroxide such as sodium hydroxide or potassium hydroxide. This reaction is carried out without solvent or for example, ethers such as tetrahydrofuran and dioxane, acetone, ketones such as methyl ethyl ketone, benzene, toluene,
The reaction is performed in a benzene-based solvent such as xylene, or a solvent such as acetonitrile, dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide. The reaction temperature is appropriately selected from the temperature under ice cooling to the boiling point of the solvent.

(Second step) The obtained alkoxy derivative (X
III) to obtain compound (XIV). As a specific method, for example, a reduced form (XIV) can be obtained by a method of hydrogenating 10% palladium on carbon in a mixed solution of acetic anhydride and acetic acid.

(Third step) The obtained compound (XIV) is halogenated with a chlorinating agent such as thionyl chloride to give a 3-halogenopropyl derivative represented by the formula (XV). it can. At this time, as a reaction solvent,
For example, chloroform, dichloromethane and the like are used.

(Fourth Step) The compound (XV) is reacted with methanol represented by the formula (VI) to obtain a compound represented by the formula (XVI). This reaction is also performed in Production method B.
As in the case of the above, it is preferable to carry out the reaction in the presence of a deoxidizing agent.

(Fifth Step) The obtained compound (XVI) is oxidized using an oxidizing agent such as hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, etc. to obtain an N-oxide compound (IX). be able to.

In the production method A, among the compounds represented by the formula (IV) used as starting materials, the compound wherein Y is a halogen atom can also be produced by the following method.

[0043]

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(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 V ′) can be obtained. At this time, as a reaction solvent, for example, chloroform, dichloromethane and the like can be used.

Compound (V) as a starting material in Production Method B can be produced, for example, by the following method.

[0046]

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(In the formula, Hal represents a halogen atom.) (First step) In this step, the compound represented by the formula (XIII) is converted into an acetyl form (XVII) by a conventional method. For example, acetic anhydride, acetyl chloride and the like are used.

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

(Third step) The diol (XVIII) is halogenated with a chlorinating agent such as thionyl chloride to give a compound of the formula (X
IX) is obtained. In this case, for example, chloroform, dichloromethane or the like is used as the reaction solvent.

(Fourth Step) The obtained dihalogen (XIX)
Is reacted with a compound represented by the formula (III) to give a compound represented by the formula (V)
Is a step of obtaining a sulfide derivative represented by the following formula: This reaction is preferably a deoxidizing agent selected from alkali metal carbonates or bicarbonates such as potassium carbonate, sodium carbonate, sodium bicarbonate and the like, and alkali hydroxides such as sodium hydroxide and potassium hydroxide. Perform in the presence of 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 from about 40 to 60 ° C.

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

[0052]

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(In the formula, Hal represents a halogen atom.) That is, the compound (XX) is halogenated by a conventional method to obtain a halogenated compound (V). Specifically, it is halogenated with a chlorinating agent such as thionyl chloride. In this case, as a solvent for the reaction, chloroform, dichloromethane, or the like is used as a preferable solvent, and a reaction temperature of about room temperature to about 80 ° C. gives a preferable result.

Next, pharmacological experimental examples will be shown to explain the effects of the compounds of the present invention in detail. In addition, the pharmacological experimental example was performed on the sulfinyl derivative obtained by oxidizing the compound of the present invention.

Pharmacological Experimental Example 1 H ⁺ -K ⁺ -ATPase Activity Inhibitory Activity (1) Adjustment of H ⁺ -K ⁺ ATPase Saccoman (Saccoman) was obtained from the fundic gland of fresh pig gastric mucosa.
i) et al. [Biochem. and Biophys. Acta, 464 , 313].
(1977)].

(2) Measurement of H ⁺ -K ⁺ ATPase Activity Various concentrations of sulfinyl derivatives and omeprazole as a control and O ⁺ -K ⁺ ATPase, 10 μg
Incubation was carried out at 37 ° C. for 30 minutes in a 40 mM Tris.HCl buffer at pH 7.40 with protein / ml. 10 minutes after adding 1 μg / ml gramicidin D and 15 mM KCl, 3 mM MgCl ₂ and ATP
To initiate the ATPase reaction and release the inorganic phosphate released after 10 minutes.
Yoda and Hokin method (Biochem. Biophys. Res., Co.
m., 40 , 880, 1970). The test compound was dissolved in methanol and used. For the inhibitory effect, the difference between the measured values in the test compound was determined from the measured values in the control group to which only the solvent was added, and this was calculated as a percentage of the measured value in the control group. Table 1
It is shown by the IC _50. (3) Result

[0057]

[Table 1]

Pharmacological Experimental Example 2 Gastric Acid Secretion Inhibiting Effect (Method) Chronic gastric fistula dog
dogs), continuous histamine infusion (100 μg / kg
/ hr) induced acid secretion. One hour after the start of histamine infusion, the test drug was administered into the duodenum, and the amount of acid secreted one hour after that was compared with that of a non-administered control group.

As test compounds, the following sulfinyl derivatives and omeprazole were selected as control compounds. Sulfinyl derivative; 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole sodium salt (Results) Table 2 shows the inhibitory effect (% inhibition) of the test drug on histamine-stimulated acid secretion in chronic Fistra dogs.

[0060]

[Table 2]

The ID ₅₀ determined from the dose response curve was 59.9 μg / kg for the sulfinyl derivative and 112.2 μg for omeprazole.
g / kg, indicating that the sulfinyl derivative derived from the target compound of the present invention was twice as potent as omeprazole.

Pharmacological Experimental Example 3 Recovery of acid secretion ability (method) Chronic Fistra dogs were used. The test drug was administered into the duodenum, and pentagastrin was intramuscularly injected 1, 24, 48 and 72 hours later, and the acid secretion ability was compared with that of the control group.

As the test drugs, the following sulfinyl derivatives and omeprazole were selected in the same manner as in Pharmacological Experimental Example 2. Sulfinyl derivative; 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole sodium salt (Results) The results are shown in Table 3. 4 mg / kg of both the sulfinyl derivative and omeprazole were administered into the duodenum,
After a time, when pentagastrin was intramuscularly injected, acid secretion was completely suppressed. The sulfinyl derivative showed 61.9% and 121.5% of acid secretion in the control group 24 and 48 hours later, while omeprazole 108.4% in 72 hours.
Acid secretion was observed. For complete recovery of acid secretion, the sulfinyl derivative requires 48 hours and omeprazole requires 72 hours.
It took time.

[0064]

[Table 3]

As is clear from the above pharmacological experimental examples, the sulfinyl derivative derived from the target compound of the present invention is:
All have strong H ⁺ -K ⁺ ATPase activity inhibitory activity, and furthermore, have lower gastric acid secretion inhibitory activity than omeprazole, which is the most noticeable compound having a benzimidazole skeleton. Was found to be excellent. Even more surprisingly, it has been found that the sulfinyl derivative derived from the target compound of the present invention has a remarkably superior ability to restore gastric acid secretion as compared to omeprazole.

The H ⁺ -K ⁺ ATPase inhibitor inhibits the final process of gastric acid secretion, and therefore has the characteristics of strongly suppressing acid secretion even with any stimulus and having high organ specificity. , H ₂ - is a possibility that the anti-ulcer agent to replace blocker. In fact ulcer healing period of omeprazole H ₂ -
It has also been reported that blockers have significantly reduced that. However, if the duration of the acid secretion inhibitory action is too long, hypergastrinemia causes proliferation of enterochromaffin-like cells (Enterochromaffin Like cells), formation of carcinoids, proliferation of gastric bacteria, N-
Complicated problems such as the production, increase of nitroso compounds, and difficulty in selecting a dose can occur.

Accordingly, H ⁺ -K ⁺ ATPase inhibitors include:
There is a need for a drug that not only has a strong effect but also has a faster recovery of gastric acid secretion. As a result of repeated search and research from such points, the present invention has found that a sulfinyl derivative obtained by oxidizing the target compound of the present invention satisfies this point, and has completed the present invention.

The toxicity of the compound of the present invention is as follows. The compound of the present invention and the sulfinyl derivative obtained by oxidizing the compound were beagle (10 mg / kg) and rat (50 mg / kg).
kg) for 1 week after oral administration, no toxicological effects were observed.

The compound of the present invention itself has a gastric acid secretion inhibitory action, and the sulfinyl derivative obtained by oxidizing it has the following properties:
As described above, it has an excellent gastric acid secretion inhibitory action based on a strong H ⁺ -K ⁺ ATPase activity inhibitory action, and its recovery ability is high and safety is high, so treatment of peptic ulcer of human or animal -Useful as a prophylactic agent. In particular, since the sulfinyl derivative obtained by oxidizing the compound of the present invention has a strong gastric acid secretion inhibitory action as described above, the compound of the present invention is useful as an intermediate thereof.

When the compound of the present invention is administered as a therapeutic or prophylactic agent for peptic ulcer, it may be orally administered as powders, granules, capsules, syrups and the like, or may be administered as a suppository, injection, or external use. It may be administered parenterally as an agent or infusion. The dose varies significantly depending on the severity of the symptoms, age, type of ulcer, etc., but usually about 0.01 to 200 mg / k per day.
g, preferably 0.05 to 50 mg / kg, more preferably 0.1 to 1
0 mg / kg is administered once or several times a day.

In the preparation of a pharmaceutical preparation, it is produced by a conventional method using a conventional pharmaceutical carrier. That is, when preparing a solid preparation for oral use, excipients, a binder, and a disintegrant, if necessary,
After adding a lubricant, a coloring agent, a flavoring agent, and the like, tablets, coated tablets, granules, powders, capsules, and the like are prepared in a conventional manner. As excipients, for example, lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose, silicon dioxide, etc., as binders, for example, polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, Hydroxypropyl cellulose, hydroxypropyl starch, polyvinylpyrrolidone, etc., as disintegrants, for example, starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium hydrogen carbonate, calcium citrate, dextrin, pectin, etc., as lubricants For example, magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oils and the like are those that are permitted to be added to pharmaceuticals as coloring agents, but as flavoring agents Include cocoa powder, menthol, aromatic acid, peppermint oil, borneol, cinnamon powder and the like are used. Of course, these tablets and granules may be sugar-coated, gelatin-coated and optionally coated as needed. When preparing an injection, a pH adjuster, a buffer, a stabilizer, a solubilizing agent, and the like are added to the main drug, if necessary, to give a subcutaneous, intramuscular, or intravenous injection according to a conventional method.

[0072]

The following are examples of the present invention, but it goes without saying that the present invention is not limited to these examples. In addition, the production example indicates a production example of a raw material when producing the target substance of the present invention, and the application example indicates an application example in which the target substance of the present invention is used for production of a sulfinyl derivative.

Production Example 1 4- (3-methoxypropoxy) -2,3-dimethylpyri
Gin-N-oxide

[0074]

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2.0 g (22 mmol) of 3-methoxypropanol was dissolved in 50 ml of dimethyl sulfoxide, and 2.7 g (66 mmol) of sodium hydride was added thereto at room temperature.
Stirred for hours. After allowing to cool to room temperature, 3.0 g (19 mmol) of 4-chloro-2,3-dimethylpyridine-N-oxide was added. Thereafter, the mixture was stirred at 40 ° C. for 1 hour. After completion of the reaction, dimethyl sulfoxide was distilled off, and the residue was generated by silica gel column chromatography to obtain 760 mg of 4- (3-methoxypropoxy) -2,3-dimethylpyridine-N-oxide.

¹ H-NMR (CDCl ₃ ) δ; 2.1 (m, 2H), 2.2 (s, 3
H), 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, 1
H) Production Example 2 2-Chloromethyl-4- (3-methoxypropoxy)-
3-methylpyridine

[0077]

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4- (3-methoxypropoxy) -2,3-
20 ml of acetic anhydride was added to 760 mg (3.6 mmol) of dimethylpyridine-N-oxide and reacted at 90 ° C. for 1 hour. The acetic anhydride was distilled off, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The chloroform was concentrated to give 700 mg of 2-acetoxymethyl-4- (3-methoxypropoxy) -3-methylpyridine (brown oil). This 2-acetoxymethyl-4- (3-methoxypropoxy) -3
500 mg of sodium hydroxide and 15 cc of ethanol were added to -methylpyridine, and the mixture was stirred at 50 ° C for 1 hour. After completion of the reaction, ethanol was distilled off, water was added, and the mixture was extracted with chloroform. By concentrating the chloroform layer, 2-hydroxymethyl-
450 mg of 4- (3-methoxypropoxy) -3-methylpyridine were obtained (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 = 7 Hz, 1H), 8.24 (d, J = 7 Hz, 1H) 2-hydroxymethyl-4- (3-methoxypropoxy) -3-methylpyridine 450 mg obtained above Was dissolved in 20 ml of dichloromethane, and 760 mg of thionyl chloride was added dropwise at 0 ° C., followed by stirring at room temperature for 2 hours. After the completion of the reaction, dichloromethane and thionyl chloride were distilled off, and a saturated aqueous solution of sodium hydrogen carbonate and chloroform were added thereto for extraction. By concentrating the chloroform layer, 2-chloromethyl-4-
(3-methoxypropoxy) -3-methylpyridine
70 mg were 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 = 5.7H
z, 2H), 4.69 (s, 2H), 6.71 (d, J = 7Hz, 1H), 8.26 (d, J = 7Hz,
1H) Example 1 2-[{4- (3-methoxypropoxy) -3-methyl
Pyridin-2-yl {methylthio] -1H-benzimida
Zol

[0080]

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2-mercapto-1H-benzimidazole
20 cc of ethanol was added to 280 mg (1.8 mmol), 470 mg (2 mmol) of 2-chloromethyl-4- (3-methoxypropoxy) -3-methylpyridine, and 100 mg (2.4 mmol) of sodium hydroxide, followed by stirring at 50 ° C for 3 hours. After completion of the reaction, ethanol was distilled off, and the residue was purified by silica gel column chromatography to give 2-[{4- (3-methoxypropoxy)-.
590 mg (pale yellow crystal) of 3-methylpyridin-2-yl {methylthio] -1H-benzimidazole was obtained.

¹ H-NMR (CDCl ₃ ) δ; 2.09 (t, J = 6.1 Hz, 2
H), 2.26 (s, 3H), 3.35 (s, 3H), 3.56 (t, J = 6.1Hz, 2H), 4.1
3 (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 = 6.1 Hz, 1H) Application Example 1 2- {4- (3-methoxypropoxy) -3-methylpi
Lysin-2-yl @ methylsulfinyl-1H-benzi
Midazole

[0083]

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2-[｛4- (3-methoxypropoxy)
-3-methylpyridin-2-yl {methylthio] -1H-
5 g of benzimidazole was dissolved in 100 ml of dichloromethane / 25 ml of diethyl ether, and 2.83 g of m-chloroperbenzoic acid (85%) was added little by little at -45 ° C. After 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. After washing the aqueous layer twice with 20 ml of dichloromethane, the aqueous layer was adjusted to pH 11 by adding a 2M aqueous solution of ammonium acetate. Then, the aqueous layer was extracted three times with 50 ml of dichloromethane, and the dichloromethane layer was washed twice with 50 ml of a saturated aqueous sodium hydrogen carbonate solution and dried over magnesium sulfate. The dichloromethane was distilled off and the resulting oil was crystallized from 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, 2H), 6.70 (d, J = 5.7Hz, 1H), 7.07 ~ 7.30 (m, 2H),
7.30-7.60 (br, s, 2H), 8.27 (d, J = 5.7Hz, 1H) Application Example 2 2-[{4- (3-methoxypropoxy) -3-methyl
Pyridin-2-yl {methylsulfinyl) -1H-ben
Zimidazole sodium salt

[0086]

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2-[｛4- (3-methoxypropoxy)
-3-methylpyridin-2-yl {methylthio] -1H-
500 mg (1.46 mmol) of benzimidazole in dichloromethane
It was dissolved in 20 cc, and 320 mg of m-chloroperbenzoic acid (85%) was added little by little at -45 ° C. After completion of the reaction, 370 mg of triethylamine was added, and the temperature was raised to -10 ° C. 30 ml of a saturated aqueous solution of sodium carbonate 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 14.6 cc of a 0.1N aqueous sodium hydroxide solution. Water was azeotroped three times with 30 cc of ethanol and dried under vacuum. The white crystals obtained by adding ether are washed with ether three times by decantation, and then dried in vacuo to give 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl}.
Methylsulfinyl] -1H-benzimidazole sodium salt (530 mg) was obtained.

Melting point: 140 to 141 ° C. (decomposition) M ^{+ 1} : 382 ¹ H-NMR (DMSO-d ₆ ) δ; 1.99 (t, J = 6.1 Hz, 2H), 2.17 (s, 3)
H), 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)

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Seiichiro Nomoto 1-14-2-2 Kariya-cho, Ushiku City, Ibaraki Prefecture (72) Inventor Makoto Okita 110-8, Arakawaokihashi Honishi, Arakawa Tsuchiura City, Ibaraki Prefecture 303 Yubara Mansion 303 (72) Invention Person Naoyuki Shimomura 2-23-5, Akumabo, Sakuramura, Niigata-gun, Ibaraki Prefecture Maison Gakuen 207 (72) Inventor Toshihiko Kaneko 4-18-4 Kasuga, Yatabe-cho, Niigata-gun, Ibaraki Market Apartment 203 (72) Inventor Masatoshi Fujimoto Ibaraki Prefecture 2-5-4 Tokodai, Toyosato-cho, Tsukuba-gun (72) Inventor Manabu Murakami 1-6-8, Tokodai, Toyosato-cho, Tsukuba-gun, Ibaraki Prefecture (72) Kiyoshi Okeya 1-9- Toyodai, Toyosato-cho, Tsukuba-gun, Ibaraki 16 (72) Inventor Hideaki Fujisaki 2-24-2, Umezono, Sakuramura, Shinji-gun, Ibaraki Prefecture (72) Inventor Hisashi Shibata 110-8 Off Arakawa, Tsuchiura-shi, Ibaraki Prefecture Yubara Mansion 205 (72) Inventor Yasuo Wakabayashi Mito, Ibaraki Prefecture 368 Yoshida-cho, Ichimoto

Claims (3)

(57) [Claims] 1. A pyridine derivative represented by the following chemical structural formula or a pharmacologically acceptable salt thereof. Embedded image 2. The following chemical structural formula: And a compound represented by the following chemical structural formula: (Wherein, Y represents a halogen atom or various sulfonyloxy groups), and reacted with the compound represented by the following chemical structural formula. A method for producing the pyridine derivative or a pharmacologically acceptable salt thereof, characterized by obtaining a pyridine derivative represented by the formula: 3. The following chemical structural formula: (Wherein, Hal represents a halogen atom), and methanol is reacted with the halogen compound represented by the following chemical structural formula. A method for producing the pyridine derivative or a pharmacologically acceptable salt thereof, characterized by obtaining a pyridine derivative represented by the formula: