DD290192A5 - PYRIDINE DERIVATIVE WITH ANTIULACEROESER EFFECT - Google Patents

Abstract

The invention relates to a process for the preparation of a pyridine derivative of the general formula in which the substituents have the meaning given in the description. The novel compounds have a pharmacological action, and in particular an anti-inflammatory activity, which makes them suitable as active ingredients in medicaments for the treatment and prevention of peptic ulcers. Formula (I) {pyridine derivative; Production method; Drug; anti-oxidative activity; medical treatment}

Description

wherein R ^{8 is} an acetoxy group or lower alkyl group, or 9. a group of the formula -OR ⁹ ,

wherein R ^{9 is} a hydrogen atom or a lower alkyl group or aryl group, η is 0 to 2; m is 2 to 10 and

J and K, which may be the same or different, each represents a hydrogen atom or a lower alkyl group, provided that when Z is a group of the above category 9, R ^{9 is} a lower alkyl group and η is 3 to 10, and pharmaceutically acceptable salts thereof, characterized by

a) reacting the compound of formula II with the compound of formula III, wherein Y is hydrogen or a sulphonyloxy group, to a compound of formula I ', wherein η is zero, and, if appropriate, the resulting compound Γ to the compound 1 "is oxidized, wherein η is 1; and optionally the resulting compound I ", wherein 1 is, is oxidized to the compound of formula I, wherein η is 2; or optionally the resulting compound of formula Γ, wherein w is zero, is oxidized to the compound of formula Γ" where η is 2; or

b) reacting the compound of formula IV, wherein Hal is a halogen atom, with Z-H, wherein Z is as defined above, only compound of formula Γ, wherein η is zero, and if necessary, carrying out any of the above optional steps according to a); or

c) reacting a compound of the formula VI with a compound of the formula VII: R ³ -Hal, wherein R ^{3 is} a halogen atom and R ^{3 is} lower alkyl-phenyl, benzyl or lower alkoxycarbonyl, to give a compound 1 "", wherein X-NR ³ , and if necessary, performing one of the optional steps above according to a).

Field of application of the invention

The invention relates to a process for the preparation of novel pyridine derivatives having efficacy in the treatment or prevention of peptic ulcers.

Characteristic of the known state of the art

The duodenal ulcers and gastric ulcer, collectively known as peptic ulcers, are localized erosions of the mucosal membrane of the duodenum or stomach which expose the underlying layers of the intestinal wall to the acid secretions of the stomach and the proteolytic enzyme pepsin. They are believed to be caused by autolysis, which in turn is caused by imbalance between attacking factors such as acid or pepsin, and defensive factors such as mucosal membrane resistance, mucus secretion, blood flow, or duodenum control. Peptic ulcer formation is the most common disease of the gastrointestinal tract and it is estimated that approximately 10 to 20% of the adult male population will suffer from peptic ulcer at some point in life. Peptic ulcers are, in principle, cured or prevented by medical treatment, with numerous pharmacotherapies have been proposed, some with a high degree of success.

Clinically useful methods include Hj blockers such as cimotidine and ranitidine as anti-ulcer agents. Recently, it has been suggested that inhibitors of H ⁺ -K -ATPase, an enzyme found specifically in the parietal cells of the Mage, can effectively inhibit gastric acid secretion in mammals, including humans, because it has been suggested that it may be found to be less effective this point of view could be about a new class of antiulcer drug. In particular, a wide variety of compounds having a benzimidazole structure have been proposed. Among these compounds, omeprazole, currently under active development, is considered to be the most promising compound; See U.S. Patents 4,337,257, 4,224,331, and 4,808,903. These patents describe compounds having a methoxy group at the 4-position of the pyridine ring, wherein omeprazole has the formula

OCH

having,

and furthermore 2- (4-methoxyethoxypyridin-2-yl) methylsulfinyl-5-methyl-1H-benzimidazole in whose working

Embodiment. Related benzimidazole-type compounds having anti-ulcer properties are described in GB-PS2134523A. Specifically described are compounds in which the 4-position of the pyridine ring with e'r.er alkoxyalkoxy group

is substituted, wherein each alkoxy group contains 1 to 2 carbon atoms. Embodiment 157 of this patent discloses 2- (3,5-dimethyl-4-methoxyethoxypyridin-2-yl) methylsulfinyl-5-phenylm H-benzimidazole. Likewise others will

Substitutions on different positions of the benzimidazole and pyridine rings described. Biological tests reported in Tables 4 and 5 of this published patent specification refer to

Significant biological effects on gastric acid secretion in both isolated cells and laboratory animals when the 4-Pusition on the pyridine ring is substituted with a methoxy group.

Additional compounds of the benzimidazole type in which there are dom substituents at the 4-position on the pyridine ring

is a benzyloxy group, are described in EP-PS0167943.

Object of the invention

The aim of the invention is the development of new drugs with improved properties, in particular with anti-oxidative activity.

Explanation of the essence of the invention

A class of novel compounds with better antiulcer activity than omeprazole has been found, which is currently considered the most significant of the anti-ulcer compounds of the benzimidazole type. As a result of intensive studies it has been found that compounds of the formula (I) have a stronger effect in comparison with omeprazole in the sense of an inhibition of gastric acid secretion

 The present invention therefore relates to a class of pyridine derivatives represented by the general formula I

VJ- ( ⁰

wherein R ¹ and R ² , equal to or different from each other, each represent a hydrogen atom, a lower alkyl, lower

Alkoxy, halogenated lower alkyl, lower alxoxycarbonyl or carboxyl group or a hylogene atom; X is a group represented by the formula -O-, -S- or -N- (wherein R ^{3 represents} a hydrogen atom or a lower one

R ³

Alkyl, phenyl, benzyl or lower alkoxycarbonyl group); and A represents: 1. a group of the formula:

-O (CHj) pOR ⁴ ₍

where ρ is an integer from 1 to 3 and R ^{4 is} a hydrogen atom or a lower alkyl, aryl or aralkyl group,

2. a group of the general formula:

-O- (CH ₂ ) qR ^s

where q is an integer from 1 to 3 and R ^{6 is} a halogen atom or an alkoxycarbonyl, aryl or heteroaryl group,

3. a group of the general formula:

-O- (CHj) -O- (CHj), - O-R ^e ί

wherein r and s are each independently an integer from 1 to 5, and wherein R ^s corresponds to a hydrogen atom or a lower alkyl group,

4. a group of the formula:

5. a group of formula:

 Ö

6. a group of the formula:

7. a group of the general formula: (O)

-S-A, where t is an integer from O to 2 and A is a group of the general formula

where B is -NH-, -O- or -S-), or a lower alkyl, alkoxycarbonylmethyl, pyridyl or a furyl-Gruppo or a group of the general formula:

• (0H ₂ ) _w

stands

8. a group of the general formula:

R ⁸

in which R ⁸ corresponds to an acetoxy group or a lower alkyl group,

9. a group of the general formula:

-OR ⁹

wherein R ^{9 is} a hydrogen atom or a lower alkyl or aryl group; η is an integer of 0 to 2; m is an integer from 2 to 10,

J and K, equal to or different from each other, each represents a hydrogen atom or a lower alkyl group among A specification that R ⁹ corresponds to a lower alkyl group, if Z is one of the groups falling under the above category (9)

corresponds, m stands for an integer digit from 3 to 10,

and their pharmaceutically acceptable salts.

The same definitions for R ¹ , R ² , X, n, J, K, Z, and m are used throughout the following specification and in U.S. Patent Nos. 5,496,074;

uses the appended claims.

Likewise disclosed are pharmaceutical compositions containing these compounds as active ingredient (s)

as well as methods of preventing or treating peptic ulcers in mammals, including humans, using these pharmaceutical compositions.

In the definition given above of the compounds of the general formula (I), it may be stated in the above with reference to R ¹ , R ² , R ³ , R ⁴ , R ⁸ , A, R ⁷ , R ⁸ , J and K in the compound (I) of the present invention are defined by a lower alkyl group

straight chain or branched Alkvl group having 1 to 6 carbon atoms. Examples include methyl, ethyl, n -propyl, n-butyl, isopropyl, isobutyl, 1-methylpropyl, tert-butyl, n -pentyl, 1-ethylpropyl, isoamyl and n-hexyl groups, among which

Methyl and ethyl groups are most preferred. In the lower alkoxy group and the lower alkoxy component defined above with respect to R 'and R ²

The lower alkoxycarbonyl group may be an alkoxy group derived from the above lower alkyl group. Methoxy and ethoxy groups are most preferred.

The halogen atom defined above includes chlorine, bromine, iodine and fluorine. The aryl group defined above with respect to R ⁴ and R ^s can be phenyl, ToIyI, XyIyI, naphthyl or

may be those which may be substituted with a lower alkoxy or hydroxyl group, a halogen atom or the like.

Examples of the arylalkyl defined above with respect to R ⁴ include benzyl and phenethyl groups. Examples of the heteroaryl group defined above with respect to R ⁶ include pyridyl and furyl groups. In the definition of Z in the general formula (I), the groups 1, 2, 3, 4, 5 and 9 are preferable. Group 9 will be at the

most preferred. With respect to R ¹ and R ² , for both radicals, hydrogen atoms and, moreover, a combination of a lower alkyl, such as methyl, for R ¹ and hydrogen for R ^{2 are} preferred. X is preferably -NH ³ , where R ^{3 is} for

Hydrogen stands. A preferred value for η is 1. The preferred substitutions for J and K are each hydrogen or J.

lower alkyl such as methyl, and K is hydrogen, or K is lower alkyl, such as methyl, among others, when J

Is hydrogen. Thus, independently of one another, J or K are preferably hydrogen or methyl, in the preferred one Variant is J methyl and K is hydrogen. A first preferred class of compounds which fall under the compounds of general formula (I) are Compounds represented by the following formula:

0 (CH ₂ ) _m -0R ⁹

(A)

(wherein R ¹ , R ² , J, m and R ^{8 have} the same meanings as in the above definition). In formula A, the preferred R ¹ and R ² substituents are each hydrogen, or R ¹ is 3-lower alkoxy, 5-lower alkyl or 5-halogenated lower alkyl, and R ² is hydrogen. The preferred substituent for J is hydrogen or methyl; the preferred value for m is in the range of 3 to 10, with 3 being most preferred; and the preferred R ⁹ substituent is lower alkyl, including methyl or aryl. Un'er these possibilities for the compounds of formula A, the preferred combination is that R ¹ and R ^{2 are} both hydrogen, J is methyl, m is 3 and R ^{9 is} methyl.

A second group of preferred compounds are combinations of the above substituents wherein both R ¹ and R ^{2 are} hydrogen, J is hydrogen, m is 3, and R ^{8 is} methyl.

A third group of preferred compounds covered by Formula A is formed when both R ¹ and R ^{2 are} hydrogen, J is methyl, m is 2 and R ^{9 is} benzyl.

A second class of compounds covered by the general formula (I) is represented by the following formula:

^r1 -T 0

(wherein R ', R ² , J, p, m and R ^{4 have} the same meanings as given above). In formula (B), the preferred substituents for R 'and R * are each hydrogen; or R ² is hydrogen when R 'is 5-lower alkoxy, 5-lower alkyl or 5-halo-lower alkoxy. The preferred value of m is 2 or 3; the preferred value for ρ is 2 or 3; and the preferred substituent for R ⁴ is methyl or benzyl. Of the above possibilities for formula (B), the most preferred combination is that in which R ^{1 is} 5-methyl, R ^{2 is} hydrogen, J is methyl, m is 2, ρ is 2, and id is R ^{4 is} methyl.

Examples of a pharmaceutically acceptable salt include salts with inorganic acids such as hydrochloric acid, hydrobromide. Sulfate and phosphate; those with organic acids such as acetate, maleate, tartrate, methanesulfonate, benzene sulfonate and toluenesulfonate; and those with amino acids such as arginine, aspartic jure and glutamic acid. Some of the compounds of this invention may form a salt with a metal such as Na, K, Ca or Mg. The metal salts are also included among the pharmaceutically acceptable salts of the present invention. As a metal salt may be present, for example, compounds of general formula (I) in which X corresponds to a group of -N-, wherein R ³

R ³

represents a Wassei atom of the substance, or also compounds of the general formula (I) in which Z corresponds to a group which falls ur ter the category © and where B corresponds to a group of -NH-.

Although the compound of the present invention may also exist as a hydrate or as a stereoisomer, it will be understood that these hydrates and stereoisomers are also i.i. : len scope of the present invention are included. In the following, the effect of the invention Verbi ^r dung will be described with reference to the following pharmacological experiments.

Pharmacological experiment

Inhibition against H ⁺ -K ⁺ ATPase activity

(1) Preparation of H ⁺ -K ⁺ -ATPaSe

Produced from the fundic glands of a fresh porcine mucous membrane by a modified method of Saccomani et al. (See Biochem., Biophys. Acta, 464,313 [1977]).

(2) Measurement of H ⁺ -K ⁺ ATPase activity

The compound of the invention was incubated for 30 min at 37 ⁰ C at various concentrations in a 4OmM Tris-HCI buffer solution having a pH of 7.40 together with H ⁺ -K ⁺ -ATPase and 1Opg / ml of a protein, after which 15 mM KCI were added. After 10 minutes, the ATPase reaction was initiated by the addition of 3 mM MgCl ₂ and ATP. After 10 minutes, the amount of inorganic phosphoric acid liberated by the method of Voda and Hokin (see Biochem.

Biophys. Res. Com., 40, 8080 [1970]).

The test compound was used as a solution in methanol.

The inhibitory effect was determined by subtracting the detected amount of inorganic acid released after adding a test solution from that amount of inorganic acid released after adding only one solvent to thereby obtain a difference, to which this difference divided by the latter amount and reported as a percentage. The inhibitory effect is in Tabel ^! , 1 shown as IC ₅₀ .

(3) The results are shown in Table 1.

Table I

connection

OCH ₂ CH ₂ OCH ₂

CH

N ^) - S-CH,

M / L

9.2x10

CH.

CH ₃ O

N H

VV S-CH,

Λ -

OCH ₂ CH ₂ OCH ₂

1ο4χ1Ο

-6

OCH ₂ CH ₂ OCH ₂

1.0x10

-6

CH.

S-CH ₂ * ^ N

1.1x10

-5

Connection IC ₅₀ (M)

2.4x10

, -5

^CH

5,5x10

CH-O

3-CH,

1,7x10 "

CH.

0- (CH ₂ ) ₂ -OCH ₂

1.2x10

CH.

CH ₃ O

1,3x10

, -5

No.

connection

IC ₅₀ (M)

OCH ₂ CH ₂ OH

10

CH.

nVs-ch,

H

l ₀ 9xl0

-6

^CH 3 °

CH,

OCH ₂ CH ₂ OCh ₂ CH ₂ OCH ₂

N Na

11

4,2x10

, -5

12

CH.

S-CH,

OCH ₂ CH ₂ OCH ₂ CH ₂ OCh ₂

2.6x10

-6

N / A

OCH ₂ CH ₂ OCH ₂ CH ₂ OCH,

__ / 6 * 3x10

. 7

No.

connection

IC ₅₀ (M)

CH.

0- (i

14 CH ₃ O

1.0x10

-5

0- (CH ₂ ) ₂ -N.

7.2x10

-6

16 ^CF 3

CH ..

0- (CH ₂ ) ₂ -N

xx:

1.7x10

^CH 3, OCH ₂ CH ₉ OH 3.5X10 " ⁶ T NVs-CHp ^ H ^U T Ά 17 3o3xlO " ^{6 CH} 3 s OCH ₂ CH ₂ OOH ₂ CH ₂ OCh \ -S-CH ₉ ^ 18 N / A O ^ N · ^ •

connection

OCH ₂ CH ₂ CH ₂ OCH ₃

1 _β 7χ10

OCH ₂ CH ₂ SCH ₃

2 "3xl0

-6

N / A

CH.

OCH ₂ CH ₂ O

1.3x10

-6

CH. OCH ₂ CH ₂ CH ₂ OH

\) r S-CH ₂

N I H

ΙβθχΙΟ

-6

CH.

1.4x10

-6

2 "* N

24 omeprazole

1,1x10

, -5

From the experimental results, it is apparent that the compound of the present invention exerts a strong inhibitory action on the activity of H ⁺ -K ⁺ ATPase and is highly safe so that it can effectively inhibit the secretion of an acid and, therefore, for the therapy or prevention of human and animal peptic ulcers.

Moreover, the compound according to the invention exhibits an excellent counteraction to the secretion of an acid and is therefore superior to the already known compound in this respect.

Dogs with chronic gastric fistula were used. The test compound was intraduodenally administered to each dog in an amount of 4 mg per kg. At 1.24.48 and 72 hours after the time of administration, the dog was injected intramuscularly with pentagastrin (6 micrograms per kg). Gastric acid secretion and gastric acid reabsorption were determined as a percentage of the control reaction. The results of this experiment are shown in Table 3. The results show that in both tests of Compound 19 and omeprazole, pentagastrin-stimulated gastric acid secretion was completely inhibited within one hour after intraduodenal administration. The acid output in compound 19 was 61.9% and 121.5% after 24 h and 48 h, respectively, compared to the control group. On the other hand, in the same test using omeprazole, gastric acid secretion was 108.4% after 72 hours. Compounds 19 and omeprazole required 48 hours and 72 hours, respectively, to cause gastric acid reuptake.

Pharmacological Review 2 Inhibitory Effect on Niagenic Acid Secretion

Dogs with chronic gastric fistula were used. The gastric acid secretion of each dog was stimulated by infusing 100 micrograi-histamine per kg per hour. After one hour of histamine infusion, the respective test compound was intraduodenally administered to the respective dog, whereupon one hour after the administration the amount of gastric acid secretion was determined for each test dog. The results were compared with the control group, which had not been administered a test compound, whereupon the percent inhibitory effect was calculated.

The inhibitory effect exerted by the test compound on the histamine-stimulated gastric acid secretion of chronic gastric fistula bearing dogs is shown in Table 2. The ID & j values calculated from the dose-inhibition curve of the test compounds are 59.9 micrograms per kilogram for Compound 19 and 112.2 micrograms per kilogram for omeprazole, indicating that Compound 19 was two times more potent than omeprazole. The compound 19 is shown in Table 1 of Experiment 1 and in Example 33 below.

Table 2

Percent inhibition of acid release

pg / kg pre-bound 19 ohmprnol

31.25 62.5 125 250 500 1000 34.4 50.1 67.7 87.4 100.0 24 hours 41.1 48.6 62.1 91.2 100.0 72 h Table 3 61.9 32.3 103.4 connection 1h 48 h Compound 19 omeprazole 0 0.3 69.1

The results of the three pharmacological experiments presented above show that the compound according to the invention has a considerable inhibitory effect on H ⁺ -K ⁺ -ATPase. Among these compounds, compound 19 of the invention unexpectedly has a stronger gastric acid secretion inhibitory effect than is comparatively in omeprazole, which per se causes a strong inhibition of gastric acid secretion among the benzimidazole-type compounds.

In addition, it should be noted that the compound of the present invention unexpectedly causes a more rapid re-establishment of gastric acid secretion than omeprazole.

At present, it is believed that the H ⁺ -K ⁺ -ATPase inhibitory agent has a stronger gastric acid secretion inhibitory effect than an H2-BU eker compound, and thus has the potential to become the first anti-ulcer agent of choice in the future to become.

If, however, a stronger inhibitory effect on gastric acid secretion is desirable. co, on the other hand, too long a lasting inhibition of gastric acid secretion in an anti-ulcer agent nirtit advantageous. The latter, for example, leads to a proliferation of enterochromaffin-like cells (ECL cells) as well as to a carcinoid formation induced by hypergastrinemia as described in "Digestion", Volume 35, I.Delivery, pages 42 to 55 (1986); Increase of the bacterial gastric flora as well as an endogenous production of vcv. N-nitro compounds as described in "Brit.Med.J.", volume 289, page 717 (1984); as well as difficulties in determining the appropriate dosage regimen.

Most preferable, therefore, is an H ⁺ -K ⁺ ATPase-inhibiting agent, which has an excellent effect on the resumption of gastric acid secretion.

With respect to Compound 19 (Embodiment 33), no toxicological influence is observed where it is a representative compound of the present invention orally administered to Beagle dogs in an amount of 10 mg / kg per day for one week and, if necessary, for one week was administered orally to rats at 50mg / kg per day.

Thus, compound 19, as a representative example of the present invention, exhibits a significant inhibitory effect on the activity of H ⁺ -K ⁺ ATPase, coupled with the desirable property of excellent recovery of gastric acid secretion.

Compound 19, as a proxy of the compounds of the invention, is considered to be effective for the treatment or

Contraception of peptic ulcers (gastric ulcers and duodenal ulcers) viewed at throne including dom humans,

The orvorungsgemäßo Vorbindung is administered for Thorapio or contraception of popunton Gnschwüron Entwodor orally as Pulvor, granules, capsule or syrup or parenteral ils eino injection odor also as an externally applied preparation or in drop form or as a suppository. Although the dose varies considerably depending on the symptoms, the age and type of the ulcer (s), it may be about 0.01 to 200 mg / kg, preferably 0.05 to 50 mg / kg or better still 0.1 up to 10mg / kg per day botragon and may be administered as a single or divided dose, for example, 2 to 4 times a day.

The drug can be processed to pharmaceutical dosage form using conventional formulating ancestor. Specifically, a solid medicament for oral administration can be prepared by mixing an active ingredient with filler and, if necessary, binder, excipient, lubricant, colorants, corrigents or the like, and then processing the resulting mixture into tablets, coated tablets, granules, powders or capsules can.

Beispiolo for fillers are lactose, corn starch, sucrose, glucose sorbitol, crystalline cellulosic and silica, while suitable as binders polyvinyl alcohol, polyvinyl ether, ethyl cellulose, Mothylcollulose, Akaziongummi, tragacanth, gelatin, shellac, hydroxypropyl cellulose, hydroxypropyl starch and polyvinylpyrrolidone. Examples of oinone disintegrating agent are starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin and pectin, while magnesium stoarate, talc, polyethylene glycol, kieselordo and hydrogenated vegetable oils are suitable as lubricants. The colorant may be any agent approved for use in conjunction with medicaments. Examples of flavor improving agents are cocoa powder, mint herb, aroma powder, mint oil, borneol and powdered cinnamon bark. Of course, these tablets and granules may, if necessary, be coated with sugar, gelatin or the like.

The inoculum preparation can be prepared by mixing an active ingredient with a pH adjusting agent, buffer, stabilizer, dissolution assistant or the like, and treating the thus obtained mixture by a conventional subcutaneous, intramuscular or intravenous injection-type injection liquid.

Manufacturing process

The compound of the invention can be prepared by various processes, of which representative examples are described below.

Manufacturing process A

R ¹

wherein R ¹ , R ¹ and X are as defined above

Z 0- (CH₂)_m-Z

Y-OE.

wherein m, Z, J and K are as defined above and Y is a halogen atom or a sulphonyloxy group

-OE-

0- (0H ₂ ) _m -Z

⁰¹¹ ^ ₁ J- ⁸ (P)

oxidation

J 0- (0H ₂ ) _m -Z

That is, a compound represented by the general formula (II) is reacted with a halide represented by the general formula (III) to obtain a compound represented by the general formula (I '), which is is a compound of the invention.

Examples of the halogen atom defined with respect to Y include chlorine, bromine and iodine, while examples of the sulfonyloxy group include alkylsulfonyloxy groups such as methylsulfonyloxy and ethylsulfonyloxy groups, and aromatic sulfonyloxy groups such as benzenesulfonyloxy and tosyloxy groups.

The above reaction is preferably carried out in the presence of an acidic detergent. Examples of the acidic detergent are carbonates and hydrocarbonates of alkali metals such as potassium carbonate, sodium carbonate and sodium hydrogencarbonate; Alkali hydroxides such as sodium hydroxide and potassium hydroxide, and organic amines such as pyridine and triethylamine. Examples of the solvent to be used in the reaction are alcohols such as methyl and ethyl alcohols, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide, and mixtures of these with water.

The reaction temperature may range from -40 ° C to the boiling point of the solvent used, preferably it is

at about 0 to 6O ⁰ C.

The obtained compound (I ') can be easily oxidized to its sulfinyl derivative (I "), which is an objective compound of the present invention corresponding to a compound of the general formula (I) in which η is 1.

This oxidation can be carried out by a usual process by using an oxidizing agent such as hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, sodium hypochlorite or sodium hypobromite. The solvent to be used in the oxidation is generally selected from dichloromethane, chloroform, benzene, toluene, methanol, ethanol and the like. The oxidation temperature may range from -7O ⁰ C to the boiling point of the solvent used is preferably from ⁰ C to -6O 25'C.

Further, a sulfone derivative which is an object compound of the present invention and which corresponds to a compound of the formula (I) wherein η is 2, for example, can be prepared by the following process:

OH,

oxidation

o- (CH ₂ ) _m -z

- K

Wherein R ¹ , R ² , X, J, m and Z are as defined above. Here, the thioether derivative represented by the general formula (I '), which is an objective compound of the present invention, is oxidized to its sulfone derivative represented by the general formol (C "), which is a another target compound of the present invention.

More specifically, the sulfone derivative (Γ ") which is a ziol compound of the present invention can be prepared by dissolving the compound (P) in a solvent which is selected from aromatic hydrocarbons such as bonzes, toluene and the like Xylenes; halogenating hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride; water; alcohols such as methanol and ethanol; ethylacotate; acetone; acetic acid and the like to obtain a solution; adding at least twice equivalent amount of oxidizing agents such as hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid 'acid, sodium hypochlorite, sodium m-periodate and the like to the solution under cooling with ice or at room temperature and by reacting the compound (I') with the oxidizing agent.

Alternatively, the sulfone dorivate (I "') can be prepared by dissolving the sulfoxide dorivative (I") obtained by the above method in a solvent such as chloroform, adding an oxidizing agent such as m-chloroperbenzoic acid to the gononnenone solution, and reacting the sulfoxide -Derivats (I ") with the oxidizing agent.

Manufacturing process B

»1 year

K (I ·)

OH,

0- (0H ₂ ) _m -Z

K (I »)

wherein R ¹ , R ² , X, m, J, K and Z are as defined above, and Hal is a halogen atom.

That is, an object compound represented by the general formula (I) can be prepared by reacting a halide represented by the general formula (IV) with an alcohol, thiol or amine represented by the general formula Z-H (V). This reaction is preferably carried out in the presence of an acidic cleaning agent. Examples of the acidic detergent include carbonates and bicarbonates of alkali metals such as potassium carbonate and sodium carbonate; Alkali hydroxides such as sodium hydroxide and potassium hydroxide, and triethylamine. Examples of the solvent to be used in the reaction include ethers such as tetrahydrofuran and dioxane; Ketones such as acetone and methyl ethyl ketone; Benzene homologs such as benzene, toluene and xylene; acetonitrile; dimethylformamide; Dimethylsulfoxide and hexamethylphosphoric triamide. The reaction can be carried out either under cooling by ice or at a temperature not exceeding the boiling point of the solvent used.

The obtained compound (I '), which is an object compound of the present invention, can be oxidized in a similar manner in its sulfinyl derivative represented by the general formula (I ") as described above in the preparation process A. has been.

Manufacturing process C

A compound represented by the general formula (I) in which X represents a group represented by the formula -N-

R ³

where R ^{3 has been selected} from the corresponding groups defined above except for one hydrogen atom) can be prepared by the following process:

(VI)

R ³ shark

(VII)

wherein R ¹ , R ² , η, J, K, m and Z are as defined above; Hal represents a halogen atom, and R ³ is selected from those other than the hydrogen atom as defined for R ³ with respect to formula (I), that is, lower alkyl, phenyl, benzyl, or the like lower alkoxycarbonyl group.

That is, a compound represented by the general formula (I "") which is an objective compound of the present invention can be obtained by condensing a compound represented by the general formula (VI) with a compound represented by the general formula (VII) represented halide can be prepared using a conventional method.

This condensation is carried out in the absence of any solvent or in a condensation-inert organic solvent selected from benzene, ethanol, xylene, tetrahydrofuran, chloroform, carbon tetrachloride, dimethylformamide and the like either at room temperature or under cooling with ice or heating for several hours usual procedure carried out. The condensation can be promoted by use of a dehydrohalogenating agent selected from inorganic salts such as sodium hydrogencarbonate, potassium carbonate, sodium carbonate and caustic soda or organic bases such as triethylamine, pyridine, pyrimidine and diethylaniline.

Further, the thioether derivative represented by the general formula (I "") in which η is zero and which is formed by condensing a compound represented by the general formula (VI) in which η is zero with a halide ( VII) has been prepared after dam same process as that described above readily oxidized into the corresponding sulfoxide (n = 1) or sulfone (n = 2) derivative.

Process for the production of starting materials

The compound represented by the general formula (III) and to be used as the starting material in the preparation process A can be produced, for example, by the following method:

Hal

'ti' (VIII)

(Step 1)

HO- (CH ₂ J _n -Z (IX)

(Level 2)

CH ₃ -CO-CH ₂ "N

(Level 3)

O- (CH ₂ ) _m -Z

HIGH,

(X)

(XI) (XII)

(Step 4)

0- (0H ₂ ) _m -Z

Y-GH ₂

(III)

where m, Z, J, K and Y correspond to the above definitions. (Step!)

A 4-halopyridine oxide derivative (VIII) (for example, 4-chloro-2,3-dimethylpyridine-1-oxide) is reacted with an alcohol derivative represented by the general formula (IX) in the presence of a base to give a to obtain alkoxy derivative represented by the general formula (X).

Examples of the base include alkali metal hydrides such as sodium hydride and potassium hydride; Alkali metals such as metallic sodium; Sodium alcoholates such as sodium methoxide and alkali metal hydroxides such as sodium hydroxide and

Potassium hydroxide.

This reaction is carried out either in the absence of any solvent or in any of ethers such as tetrahydrofuran and dioxane; Ketones such as acetone and methyl ethyl ketone; Benzene homologs such as benzene, toluene and xylene; acetonitrile; dimethylformamide; dimethyl sulfoxide; Hexameihylphosphortriamid and the like selected solvents at a lying between the ice-cooling temperature and the boiling point of the solvent used

Temperature performed. (Step 2)

The alkoxy derivative of the general formula (X) prepared in Step 1 is heated in acetic anhydride to a temperature of about 60 to 100 ° C to obtain an acetoxymethylpyridine derivative represented by the general formula (XI)

win. (Step 3)

The acetoxymethylpyridine derivative (XI) prepared in Step 2 is represented by that represented by the general formula (XII)

hydrolyzed corresponding 2-hydroxymethylpyridine derivative.

This hydrolysis is generally carried out under alkaline conditions.

(Step 4)

The 2-hydroxymethylpyridine derivative (XII) prepared in Step 3 is halogenated with, for example, a chlorinating agent such as thionyl chloride to give a 2-halometylpyridine derivative represented by the general formula (III). In this halogenation, for example, chloroform or dichloromethane is used as the solvent. Further, the 2-hydroxymethylpyridine derivative (XII) is reacted with an active sulfonyl chloride such as methanesulfonyl chloride to obtain a sulfonyloxy derivative represented by the general formula (III). In this reaction, for example, chloroform, dichloromethane, ether, tetrahydrofuran, pyridine or benzene is used as the solvent.

Alternatively, the compound to be used in the above process and represented by the general formula (X) may be used

be prepared by the following process:

shark

(VIII)

(Step 1)

(XIII)

0- (0H ₂ ) _m -0H K

(XIV)

(Step 2)

0- (CH ₂ ) _m -0H

'Level 3)

(Level 4)

(Level 5)

(XV)

(XVI)

H - Z (V)

O- (CH ₂ ) _m -Z

(X \ -χ

0- (CH ₂ ) _m -Z

(X)

(Step 1)

One represented by the general formula (VIII)! A compound in which Hal represents a halogen atom such as a chlorine atom is condensed in a conventional manner with a compound represented by the general formula (XIII) to obtain a compound represented by the general formula (XIV).

This condensation is preferably carried out in the presence of a base selected from alkali metal hydrides such as sodium hydride and potassium hydride; Alkali metals such as metallic sodium; Alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and the like.

The condensation is carried out either in the absence of any solvent or in any of ethers such as tetrahydrofuran and dioxane; Ketones such as acetone and methyl ethyl ketone; Benzene homologues such as benzene, toluene and xylene; acetonitrile; dimethylformamide; dimethyl sulfoxide; Hexamethylphosphortriamid and the like selected solvent is carried out at a temperature which is suitably selected from a range ranging from cooling temperatures using ice to Siedepun ^{u of} the solvent used.

.(Step 2)

The recovered alkoxy derivative it (XIV) is reduced to compound (XV). More specifically, the alkoxy derivative (XIV) is hydrogenated in the presence of a 10% palladium / carbon catalyst in an acetic anhydride / acetic acid mixture to afford the reduction product (XV).

(Step 3)

The obtained compound (XV) is halogenated with a chlorinating agent such as thionyl chloride to obtain a 2-haloethyl derivative represented by the general formula (XVI). In this halogenation

For example, chloroform or dichloromethane are used as the solvent.

(Scnritt 4)

The obtained compound XV, ') is reacted with an alcohol, thiol or amine represented by the general formula (V) to give a compound represented by the general formula (XVII). This reaction is preferably carried out in the presence of an acidic cleaning agent as in the reaction of the manufacturing process B.

(Step 5)

The obtained compound (XVII) is oxidized with an oxidizing agent such as hydrogen peroxide, poroacetic acid or m-chloroperbenzoic acid to recover the corresponding N-oxide derivative.

Alternatively, the compound of the general formula (III) to be used as a starting material in the preparation process A may be prepared by the following process:

O- (CH ₂ ) _m -ZK

HO-OH ₂

HaI-OH ₂ '

(XII)

(IXI) ₁

wherein Hal corresponds to a halogen atom and wherein Z and m correspond to the definitions given above.

A compound represented by the general formula (XII) is exemplified by a chlorinating agent such as

Thionyl chloride halogenated at a temperature between ^{0 0} C and room temperature to obtain a represented by the general formula (III) halomethylpyridine derivative.

In this halogenation, for example, chloroform or dichloromethane are used as the solvent.

The compound (IV) to be grown as a starting material in the production process B can be produced, for example, by the following process:

(XIV)

(Step 1)

Il

CH ₃ -CO-CH ₂

(Level 2)

₂ J _n -O-CCH ₃

(XVIII)

(Level 3)

HO-Crl

0- (CH ₂ ) _m -0H K

(XIX)

Hal-CH

(Level 4)

0- (CH ₂ ) _m -Hal

(XX)

(II)

D 0- (CH ₂ ) _m -Hal

\ 3 ~ ^κ

where Hal corresponds to a halogen atom and the other values correspond to the above definitions.

(Step 1)

A compound represented by the general formula (XIV) is converted to the corresponding acetylate (XVIII) in a conventional manner, in this reaction, for example, acetic anhydride or acetyl chloride

used. (Step 2)

The recovered acetylate is hydrolysed in the presence of an acid or base to give the corresponding diol derivative (XIX).

to win.

(Step 3)

The diol-dianivate (XIX) is halogenated, for example, with a chlorination agent such as iodine thionyl chloride, to give a solution which has been converted by dio

to obtain generalized formol (XX) dihalogonide. For example, in the case of diosorous hulogony reduction, chloroform or Mothylonchloritl is used as a solvent.

(Step A)

The gowonneno DihnlojOnid (XX) is with oinor by dio allgomoino formula (II) represented Vorzug to Roaction

brought to win a by dio allgomoino Formol (IV) ropra'sonticrtos sulfide dorivat.

This reaction is carried out in the presence of oinos sauron cleaning agent, wolchos under carbonates and Hydrocarbon carbonates of alkali metals such as potassium carbonate and sodium carbonate sowio alkali hydroxides such as Sodium hydroxide and potassium hydroxide is selected. Examples of the solvent to be used in the reaction

wio include alcohols such as ethanol and methanol, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide sowio (loron Gomischo with water. Dio Rouktionstomporatur may used from ⁰ ° C up to the Siodopunkttomporatur "

Solvent ranges and cheats preferably 40 to 60 ° C. Alternatively, the precursor (IV) to be used as a starting material in Preparation B can be replaced by

following process are produced:

OH ₂

halogenation

J O- (CH ₂ ) _m -hal

OH ₂ ~

wherein Hal corresponds to a halogen atom and the other values correspond to the above definitions. That is, the compound (IV) can be obtained by halogenating the compound (I "") which is an object compound of the present invention and which is produced according to a usual procedure by the preparation process A. " More specifically, a compound represented by the general formula (I ""') is halogenated with, for example, a chlorinating agent such as thionyl chloride to obtain a halide represented by the general formula (IV). In this halogenation, chloroform or dichloromethane is preferably used as the solvent, and preferably the Reaktionstomperatur ranges from room temperature to 8O ⁰ C.

AusfOhrungsbelspiele

In the following, embodiments of the present invention will be described, not to mention that the present invention is not limited by these embodiments. The following preparative embodiments are directed to the preparation of raw materials to be used in the preparation of the subject compounds of the present invention.

Preparative Embodiment 1 Synthesis of 4- (2-benzyloxyethoxy) -2,3-dimethylpyridine Dinoxide

OH,

00H ₂ CH ₂ OOH,

OH,

1.82 g (79.13 mmol) of Na was added to 50 ml of benzyloxyethanol to obtain a mixture. This mixture was for 2 hours at 5O ⁰ C vorrührt. To the resulting mixture was added 5.0 g (31.76 mmol) of 4-chloro-2,3-dimethylpyridine N-oxide at room temperature. The mixture thus obtained was stirred for 1.5 hours at 11O ⁰ C, cooled to room temperature and t ,, ι. to remove the insoluble substance. The filtrate was adsorbed on silica gel with dichloromethane. The silica gel was treated with 5 to 30% ethyl acetate in hexanes to elute bonacyloxyethanol. Then, the resulting silica gel was treated with 5 to 30% methanol in ethyl acetate to obtain 7.15 g of the 4- (2-benzyloxyothoxy) -2,3-dimethylpyridine N-oxide in the form of oily oil.

¹ H-NMR (CDCl ₁ ) δ; 2.20 (s, 3H), 2.47 (s, 3H), 3.8 ~ 4.0 (m, 2H), 4.1 ~ 4.25 (m, 2H), 4.6 (s, 2H), 6.65 (d, J = 7.03Hz, 1H), 7.33 (s, 5H), 8.12 (d, J = 7.03Hz, 1H)

PrAperative Version 2 Synthesis of 4- (2-benzyloxyethoxy) -2-hydroxymethyl-3-methylpyridine

0OH ₂ OH ₂ OOH ₂ -

A mixture of 6.5 g 4- (2-benzyloxyethoxy-2,3-dimethylpyridine-N-oxide and 56ml of acetic anhydride was stirred for one hour at 80 to 9O ⁰ C and distilled to remove the acetic anhydride. The obtained residue was purified with The extract was dried over magnesium sulfate and distilled to remove the methyl ethyl ketone to give 7.0 g of 2-acetoxymethyl-4- (2-benzyloxyethoxy) -3-. This intermediate was dissolved in 90 ml of ethanol, to which was added 1.43 g of sodium hydroxide, and the resulting mixture was stirred for one hour at 40 ° C., followed by addition of water.

The obtained extract was dried over magnesium sulfate to afford 5.4 g of 4- (2-benzyloxyethoxy) -2-hydroxymethyl-methylpyridine.

'H-NMR (CDCI ₃₎ δ; 2.06 (s, 3H), 3.7 ~ 3.95 (m, 2H), 4.0 ~ 4.3 (m, 2H), 4.6 (s, 4H), 6.70 (d, J = 6.7Hz, 1H), 7.33 (s, 5H), 8.27 (d, J = 6.7Hz, 1H)

Preparative Embodiment 3 Synther β of 4- (2-benzyloxyethoxy) -2-chloromethyl-3-methyl | / ridin

00H ₂ OH ₂ OOH ₂ '

010H ₂

5.3 g of 4- (2-benzyloxyethoxy) -2-hydroxymethyl-3-methylpyridine was dissolved in 60 ml of chloroform to obtain a solution. To the above solution, under cooling with ice, was added dropwise a solution of 5.8 g of thionyl chloride in 40 ml of chloroform. The resulting mixture was stirred at room temperature for 7 hours and distilled under reduced pressure to give a residue. To the residue was added 200 ml of an aqueous 2N sodium carbonate solution. The mixture thus obtained was extracted with chloroform, and the extract was dried over magnesium sulfate and distilled to remove the chloroform. Were recovered 6.3 g of the title compound.

'H-NMR (CDCI ₃₎ δ; 2.27 (s, 3H), 3.5~4.25 (m, 4H), 4.56 (s, 2H), 4.66 (s, 2H), 6.7 (d, J = 5, 71 Hz, 1 H), 7.30 (s, 5H), 8.27 (d, J = 5.71 Hz, 1H)

EMBODIMENT 1 2 - [{4- (2-Benzyloxyol-hoxy) -3-methyl-pyrl-2-yl} -methyltholo] -benzimidazole

00H ₂ OH ₂ OOH ₂ '

A mixture of 1.0 g of 2-mercaptobenzimidazole, 2.0 g of 4- (2-Bonzyloxyethoxy) -2-chloromethyl-3-methylpyridine, 302mg of sodium hydroxide and 40 ml of ethanol was stirred 1.5 hours long untar heating to 6O ⁰ C and under reduced pressure distilled to remove the ethanol. The residue thus obtained was subjected to silica gel column chromatography. The column was treated with 30 to 60% ethyl acetate in η-hexane to obtain 2.0 g of the title compound as white crystals.

'H-NMR (CDCI ₃₎ δ; 2.28 (s, 3H), 3.8 ~ 3.9 (m, 2H), 4.15~4.25 (m, 2H), 4.37 (s, 2H), 4.62 (s, 2H), 6.74 (d, J = 5.71 Hz, 1H),

7.11 ~ 7.65 (m, 9H), 8.32 (d, J = 5.71 Hz, 1H)

Example 2 2 - [{4- (2-Benzyloxy-ethoxy) -3-methylpyridin-2-yl} methylsulfinyl] benzimidazole

00HgOH ₂ OOH ₂ '

RTN

0.98 g of the above-prepared thioether was dissolved in 40 ml of dichloromethane to give a solution. To the solution were added portionwise 521 mg of m-Chloroperbenzoesäiire at a temperature of -30 to ⁰ -4o C and then added 461 mg of triethylamine. The mixture thus obtained was warmed to ⁰ ° C, whereupon 20 ml of a 1N aqueous sodium carbonate solution was added. The recovered mixture was stirred for 30 minutes and extracted with dichloromethane. The extract was washed with a saturated aqueous saline solution, dried over magnesium sulfate and distilled to remove the dichloromethane. The obtained residue was crystallized from a dichloromethane / ether mixture to give 0.78 g of the title compound in the form of a crystal

M ⁺ '(determined by FAB mass spectrometry: the same applies hereinafter): 422 ¹ H-NMR (CDCl ₃ ) δ; 2.2 (s, 3H), 3.65~3.98 (m, 2H), 4.04~4.28 (m, 2H), 4.59 (s, 2H), 4.78 (s, 2H), 6.98 (d, J = 4.6Hz, 1H),

7.05 ~ 7.8 (m, 9H), 8.22 (d, J = 4.6Hz, 1H), 13.6 (bs, 1H)

Exemplary embodiments 3 to 5 The following compounds were prepared in a similar manner to those described in Embodiment 1 or 2 Made connections.

(Embodiment 3) 2 - [{4- (2-Benzyloxyothoxy) -3-methylpyrldin-2-yl} -methylsulfinyl] -5-methoxy-1H-benzimidazole

'OH ₂ CJH ₂ OOH,

¹ H-NMR (CDCl,) δ; 2.13 (s, 3H), 3.78 (s, 3H), 3.62-3.90 (m, 2H), 4.1 ~ 4.3 (m, 2H), 4.5 (s, 2H) , 4.7 (s, 2H), 6.75-7.12 (m, 3H), 7.23 (s, 5H), 7.48 (d, J = 9H :, 1H), 8.14 (d, J = 7.9Hz, 1H)

(Outline 4) 2 - [{4- (2-Benzyloxyethoxy) -3-methylpyridyl-2-yl) methylsulfinyl} -5-trifluoroniethyl-1H-benzimidazole

0OH ₂ OH ₂ OOH ₂ -

¹ H-NMR (CDCl ₃ ) δ; 2.18 (s, 3H), 3.7- 3.92 (m, 2H), 4.1-4.34 (m, 2H), 4.58 (s, 2H), 4.78 (s, 2H), 6.94 (d, J = 5.71 Hz, 1H), 7.32 (s, 5H), 7.59 (d, J = 8.97Hz, 1H), 7.83 (i.e. , J = 8.79Hz, 1H), 7.99 (s, 1H), 8.17 (d, J = 5.71Hz, 1H)

(Embodiment 5) 2 - [(4- (2- (2-Methoxyethoxy)) ethoxy-3-methylpyrldin-2-yl) methylsulphinyl] -5-trllluoromethyl-1H-benzimidazole

0OH ₂ OH ₂ OOH ₂ OH ₂ OCh ₃

3 - CH.

¹ H-NMR (CDCl ₃ ) δ; 2.19 (s, 3H), 3.38 (s, 3H), 3.4-4.3 (m, 8H), 4.78 (ABq, J = 13.6Hz, Δν = 12.5Hz, 2H ), 6.72 (d, J 5.62Hz, 1H), 7.49 (d, J = 9Hz, 1H), 7.64 (d, J = 9Hz, 1H), 8.02 (bs, 1H), 8.26 (d, J = 5.62Hz, 1H)

EXAMPLES bplspl Sodium salt of 2 - [{4- (2- (2-Mothoxyothoxy)) othoxy-3-methylpyrldyl-2-yl] -othylsulfli.yl) -1H -benzimidazole

0.45 g of 2 - [(4- (2- (2-methoxyethoxy)) ethoxy-3-methylpyridin-2-yl} methylthio] benzimidazole was dissolved in 40 ml of dichloromethane to yield a solution m-chloroporbenzoic acid was added at -40 ° C, to which was added 0.16 g of triethylamine, and the resulting mixture was warmed to ⁰ ° C, to which was added 20 ml of a 1N sodium hydrogencarbonate aqueous solution, and the resulting mixture was stirred for 30 minutes and The extract was dried over magnesium sulphate and distilled to remove the dichloromethane, to which was added 12.1 ml of an aqueous 0.1 N sodium hydroxide solution, and the resulting mixture was stirred at room temperature for one hour. The resulting mixture was evaporated to dryness under reduced pressure and the resulting residue was crystallized from an ethanol / ether mixture to give 0.42g of the title sodium salt.

¹ H-NMR (DMGO-de) δ; 2.16 (s, 3H), 3.25 (s, 3H), 3.3 ~ 3.9 (m, 6H), 4.0~4.14 (m, 2H), 4.55 (ABq, J = 13.18Hz, Δ ^ = 13.55Hz, 2H), 6.8 ~ 6.9 (m, 3H), 7.4 ~ 7.5 (dd, J = 6.15Hz, 3.08Hz , 2H), 8.28 (d, J - 5.27 Hz, 1H)

Execution games 7 to 10 The following compounds were prepared in a manner similar to that described in Example 6.

(Embodiment 7)

Sodium salt of 5-methoxy-2 - [(4- (2- (2-methoxyethoxy)) - ethoxy-3-methylpyrldin-2-yl} methylsulfinyl] -1H-benzimidazole

CH,

CH-O

S - CH,

OCH ₂ OH ₂ OCH ₂ Oh ₂ OOH ₃

¹ H-NMR (CD ₃ OD) δ; 2.14 (s, 3H), 3.34 (s, 3H), 3.6 (m, 4H), 3.84 (s, 5H), 4.18 (m, 2H), 6.76 (d , J = 9.36Hz, 2.52Hz, 1H), 6.9 (d, J --- 5.76Hz, 1H), 7.14 (d, J = 2.52Hz, 1H), 7 , 5 (d, J = 9.36Hz, 1H), 8.26 (d, J = 5.76Hz, 1H)

(Embodiment 8)

Sodium salt of 2 - [(4- (2- (2-benzyloxyethoxy) ethoxy-3-, 2-methylpyridin-2-yl) methylsulfinyl] -1H-benzimidazole

OCH ₂ OH ₂ OCH ₂ OH ₂ OOh ₂ -

¹ H-NMR (DMSO-d _e ) δ; 2.16 (s, 3H), 3.4 ~ 3.9 (m, 6H), 3.96~4.28 (m, 2H), 4.49 (s, 2H), 4.6 (ABq, J = 12.6Hz, 12.85Hz, 2H), 6.8 ~ 7.2 (m, 3H), 7.29 (s 5H), 7.5 (dd, J = 6.16Hz, 3.08Hz, 2H), 8.25 (d, J = 5.71 Hz, 1H)

(Embodiment 9)

Sodium salt of 2 - [(4- (2- (2-Bonzyloxyothoxy)) ethoxy-3-methylpyridin-2-yl) methylsulfinyl] -5-methoxybenzimidazole

¹ H-NMR (DMSO-d ₆ ) δ; 2.16 (s, 3H), 3.63 (m, 4H), 3.74 (s, 3H) 3.85 (m, 2H), 4.18 (m, 2H), 4.49 (s, 2H), 4.55 (ABq ₁ J = 13.18Hz, Atf = 13.55Hz, 2H), 6.6 (dd, J = 9.35Hz, 3.20Hz, 1H), 7.03 (d, J = 2.63Hz, 1H), 6.89 (d, J = 5.72Hz, 1H), 8.26 (d, J = 5.72Hz, 1H)

(Embodiment 10)

Sodium salt of 2 - [{4- (2- (2-benzyloxyethoxy)} ethoxy-3-methylpyrldin-2-yl} methylsulfinyl] -5-trifluoromethylbenzimidazole

CH.

0OH ₂ OH ₂ OOH ₂ Ch ₂ OOH ₂ - ^ γ

'H-NMR (DMSO-de) δ; 2.16 (s, 3H), 3.62 (m, 4H), 3.79 (m, 2H), 4.19 (m, 2H), 4.48 (s, 2H), 4.57 (ABq, J = 13,18Hz, Δ ^ = 12,29Hz, 2H), 6,93 (d, J = 5,71Hz, 1H), 7,16 (dd, J = 8,35Hz, 1, 75Hz, 1H), 7.29 (s, 5H), 7.62 (d, J = 8.35Hz, 1H), 7.83 (s, 1H), 8.28 (d, J = 5 , 71 Hz, 1H)

Preparative Embodiment 4 4- (2-Hydroxyethoxy) -2,3-dimothylpyridine N-oxld

00H ₂ OH ₂ OH

4.60 g (0.2 mol) of metallic sodium was dissolved in 80 ml of ethylene glycol while cooling with ice to obtain a solution. This solution was stirred in a nitrogen atmosphere for one hour at 100 ° C, whereupon 15.76 g (0.1 mol) of 4-chloro-2,3-dimethylpyridine-N-oxide were added at room temperature. The mixture thus obtained was stirred at 120 ° C for 2 hours.

After completion of the reaction, the reaction mixture was distilled to dryness to handle the ethylene glycol. The

The residue obtained was purified by silica gel column chromatography (solvent: chloroform / methanol = 19: 1) to obtain 13.28 g of 4- (2-hydroxyethoxy) -2,3-dimethylpyridine N-oxide in the form of a white crystal.

'H-NMR (CD ₃ OD) O;

2.29 (s, 3H), 2.55 (s, 3H), 3.93 (t, 2H), 4.20 (t, 2H), 7.04 (d, H), 8, 18 (d, H)

Preparative Example 5 4- (2-chloroethoxy) -2,3-dimethylpyridine-N-oxide

00H ₂ OH ₂ oil

OH

1.0ml of thionyl chloride was gradually added to a solution of 0.92g (5mmol) of 4- (2-hydroxyethoxy) -2,3-dimethylpyridine-Noxide in 10ml of chloroform with cooling with ice. The recovered mixture was refluxed for 2 hours, cooled by standing, neutralized with a saturated aqueous sodium bicarbonate solution and extracted twice with 100 ml of methyl ethyl ketone. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated and goronigt by silica gel column chromatography (solvent: chloroform / methanol = 19: 1) to obtain 0.56g of 4- (2-chloroethoxy) -2,3-dimethylpyridine N-oxide in the form of a colorless crystal ,

'H-NMR (CDCI ₃₎ O;

2.24 (s, 3H), 2.54 (s, 3H), 3.86 (t, 2H). 4.28 (t, 2H), 6.62 (d, H), 8.17 (d, H)

Preparative Embodiment 6 2,3-Dimethyl-4- (2-succinylmldoethoxy) pyridine-N-oxide

A mixture of 0.40 g (2 mmol) of 4- (2-chloroethoxy) -2,3-dimethylpyridine N-oxide, 0.30 g (3 mmol) of succinimide, 0.48 g (3.5 mmol) of potassium carbonate and 30 mL of methyl ethyl ketone was added under reflux Heated for 2h, cooled by standing and filtered. The filtrate was evaporated to dryness to remove the methyl ethyl ketone. The obtained residue was purified by silica gel column chromatography (solvent: CHCl ₃ / MeOH = 19: 1) to obtain 0.12 g of 2,3-dimeth / 4- (2-succinimidoethoxy) pyridine N-oxide in the form of white To win crystal.

¹ H-NMR (CDCl ₃ ) S;

2.12 (s, 3H), 2.49 (s, 3H), 2.73 (s, 4H), 3.80~4.25 (m, 4H), 6.51 (d, H), 8 , 03 (d, H)

Preparative Embodiment 7 2-Chloromethyl-3-methyl-4- (2-succinylmidoethoxy) pyridine

Oi

0.12 g of 2,3-dimethyl-4- (2-succinimidoethoxy) -pyridine-N-oxide was dissolved in 5 ml of acetic anhydride to provide a solution. This solution was bsi 1oC ⁰ CO ₁ Sm iang veirüiul and cooled, followed by 30 rn! Ethanol were added. The resulting mixture was stirred at room temperature for 0.5h and distilled to remove the solvent. On

thus, 0.14 g of crude 2-acetoxymethyl-3-methyl-4- (2-succinimidoethoxy) pyridine was recovered in the form of an oil.

¹ H-NMa (CDCl ₃ ) S;

2.10 (s, 3H), 2.14 (s, 3H), 2.72 (s, 4H), 3.72~4.24 (m, 4H), 5.15 (s, 2H), 6 , 61 (d, H), 8,24 (d, H)

This acetoxymethyl derivative was dissolved as such in 5 ml of 1N HCl to provide a solution. This solution was stirred for 0.5 h at 100 ⁰ C ve, cooled, neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted twice with 100 ml of chloroform. The recovered extract was dried over magnesium sulfate and filtered. The filtrate was concentrated to afford 0.12 g of 2-hydroxymethyl-3-methyl-4- (2-succinimidoethoxy) pyridine as a colorless crystal.

¹ H-NMR (CDCl ₃ ) O;

  1.93 (s, 3H), 2.68 (s, 4H), 3.80~4.22 (m, 4H), 4.56 (s, 2H), 6.59 (d, H), 8 , 21 (d, H)

This crude hydroxymethyl derivative was dissolved in the present form in 5 ml of chloroform to provide a solution. While cooling with ice, 0.11 g of thionyl chloride was added dropwise to this solution. The recovered mixture was refluxed for 0.5 hours, cooled, neutralized with a saturated aqueous sodium hydrogencarbonate solution and extracted twice with 100 ml of chloroform. The recovered extract was dried over magnesium sulfate and filtered. The filtrate was concentrated and dried in vacuo to afford 0.07 g of 2-chloromethyl-3-methyl-4- (2-succinimidoethoxy) pyridine in the form of a white semi-crystal.

¹ H-NMR (CDCl ₃ ) O;

2.15 (s, 3H), 2.68 (s, 4H), 3.80~4.20 (m, 4H), 4.60 (s, 2H), 6.61 (d, H), 8.22 (d, H)

Embodiment 11 2 - [{3-Methyl-4- (2-succinimethoxy) pyridin-2-yl} methylthio] -1H-benzimidazole

OH

0- (0H ₂ ) ₂ - N

S-OH,

A mixture of 0.03 g (0.18 mmol) 2-mercapto-1H-benzimidazole, 0.06 g (0.21 mmol) 2-chloromethyl-3-methyl-4- (2-succinimidoethoxylpyridine, 0.03 g (0, 21 mmol) of potassium carbonate and 10 ml of methyl ethyl ketone were heated under reflux in a nitrogen atmosphere for 3 hours, cooled and filtered The filtrate was concentrated and dried in vacuo then water was added The resulting mixture was extracted three times with 50 ml of chloroform dried over magnesium sulfate and filtered, The filtrate was concentrated and purified by silica gel column chromatography to obtain 0.08 g of 2 - [{3-methyl-4- (2-suc-quinimidoethoxy) pyridin-2-yl} methylthio] -1H-benzimidazole To gain the shape of a white crystal.

¹ H-NMR (CDCl ₃ ) O;

2.09 (s, 3H), 2.63 (s, 4H), 3.72~4.16 (m, 4H), 4.27 (s, 2H), 6.53 (d, H), 6 , 90 ~ 7.50 (m, 4H), 8.18 (d, H)

Illustrative Embodiment 12 2 - [{3-Methyl-4- (2-succinimoldethoxy) pyrldln-2-yl} methylsulfinyl] -1H-benzimidazole

0- (0H ₂ ) ₂ - N

0.18 g of 95% m-chloroperbenzoic acid was gradually added to a solution of 0.40 g (1 mmol) of 2 - [{- 3-methyl-4- (2-succinimidoethoxy) -pyridin-2-yl-methylthio] -1 H-. benzimidazole in 20ml dichloromethane at -60 ° C to obtain a mixture. This mixture was stirred for 0.5 h and then treated with 0.15 g of triethylamine. The mixture thus obtained was heated to -1O ⁰ C and then treated with 30ml of a gesät.igten aqueous sodium bicarbonate solution. The recovered mixture was stirred for 0.5 h and then extracted twice with 50 ml of dichloromethane. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated and dried in vacuo to obtain a crude product. This colloidal product was crystallized from dichloromethane / diethyl ether to obtain 0.36 g of 2 - [{3-methyl-4- (2-succimmidoethoxy) pyridin-2-yl} methylsulfinyl] -1H-benzimidazot as a white crystal.

'H-NMR (CDCI ₃₎ S; 2.12 (s, 3H), 2.73 (s, 4H), 3.83~4.29 (m, 4H), 4.56~4.92 (m, 2H), 6.65 ( d, H), 7.17-7.72 (m, 4H), 8.25 (d, H)

Embodiment 13 5-Mothoxy-2 - / (3-methyl-4- (2-succinimitloethoxy) pyrldin-2-yl} -mothylthio / -1H-benzimidazole

CH ₃ O

S-CH

0- (CH ₂ J ₂ -N

The title compound was prepared in a manner similar to that described in Example 11. ¹ H-NMR (CDCl ₃ ) O; 2.20 (s, 3H), 2.74 (s, 4H), 3.84 (s, 3H), 3.88~4.38 (m, 4H), 4.35 (s, 2H) , 6.71 (d, H), 6.80 ~ 7.48 (m, 3H), 8.35 (d, H)

Embodiment 14

2 - / {3-Methyl-4- {2-succinimidoethoxy) pyridin-2-yl} -methylthio / -5-trifluoromethyl-1H-benzimidazole

VV-S-CH

The title compound was prepared in a manner similar to that described in Example 11. ¹ H-NMR (CDCl ₃ ) O; 2.22 (s, 3H), 2.75 (s, 4H), 3.88~4.08 (m, 2H), 4.08~4.28 (m, 2H), 4.45 (s, 2H), 6.73 (d, H), 7.32 ~ 7.86 (m, 3H), 8.32 (d, H)

Embodiment 15 5-Methoxy-2 - [{3-methyl-4- (2-succinolidoethoxy) pyrldln-2-yl} methylsulfinyl] -1H-benzimidazole

0- (0H ₂ ) ₂ - H

CH ₃ O

The title compound was prepared in a manner similar to that described in Example 12. 'H-NMR (CDCI ₃₎ S; 2.13 (s, 3H), 2.74 (s, 4H), 3.86 (s, 3H), 3.60~4.30 (m, 4H), 4.50~4.90 (m , 2H), 6.65 (d, H), 6.80 ~ 7.68 (m, 3H), 8.25 (d, H)

Embodiment 16 2 - [{3-Methyl-4- (2-succinylmidoethoxy) pyridin-2-yl} methylsulfinyl] -1H-trifluoro-ethylbenzimidazole

The title compound was prepared in a manner similar to that described in Example 12. ¹ H-NIvIR (CDCl ₃ ) O; 2.23 (s, 3H), 2.75 (s, 4H), 3.80~4.45 (m, 4H), 4.67 (m, 2H), 6.74 (d, H), 7 , 30 ~ 8.00 (m, 3H), 8.37 (d, H)

Preparative Example 8 2,3-Dimethyl-4- (2-pyridylmethoxyethoxy) pyridine-N-oxld

OH.CH,

0.39 g of 60% sodium hydride was added to a suspension of 1.2 g (6.5 mmol) of 4- (2-hydroxyethoxy) -2,3-dimethylpyridine N-oxide in 40 mM tetrahydrofuran while cooling with ice in a nitrogen atmosphere to produce a mixture. This mixture was stirred for 0.5 h and then admixed with 0.83 g (6.5 mmol) of 2-chloromethylpyridine. The resulting mixture was heated at reflux for 8 hours, cooled and filtered. The filtrate was concentrated and purified by column chromatography (solvent: ethyl acetate / n-hexane = 4: 1 ~CHCl ₃ / MeOH = 19: 1) to give 0.61 g of 2,3-dimethyl-4- (2-pyridylmethoxyethoxy) pyridine. To obtain N-oxide.

¹ H-NIvIR (CDCl ₃ ) O;

2.20 (s, 3H), 2.50 (s, 3H), 3.80~4.04 (m, 2H), 4.04~4.28 (m, 2H), 4.70 (s, 2H), 6.60 (d, H), 7.00 - 7.74 (m, 3H), 8.04 (d,

H), 8.45 (d, H)

Preparative Embodiment 9 2-Hydroxymethyl-3-methyl-4- (2-pyrldylmethoxyethoxy) pyridine

CH

-Ό

A mixture of 0.60 g of 2- _{l of} 3-dimethyl-4- (2-pyridinylthiethoxyethoxy) -pyridine N-oxide and acetic anhydride was stirred at 100 ° C. for 0.5 h and cooled and then admixed with 40 ml of ethanol. The resulting mixture was stirred at room temperature for 0.5h and distilled to remove the solvent. The residue was dried in vacuo to give 0.47 g of crude 2-acetoxymethyl-3-methyl-4- (2-pyridylmethoxyethoxy) -pyridine in the form of an oil. This crude intermediate was dissolved as such in 1N HCl to recover a solution. This solution was stirred for one hour at 100 ⁰ C, cooled, neutralized with a saturated aqueous sodium bicarbonate solution and extracted twice with 50 ml of dichloromethane. The extract was dried over magnesium sulfate and filtered. The kiltrate was concentrated and goronated by silica gel column chromatography (solvent: ethyl acetate) to obtain 0.40 g of 2-hydroxymethyl-3-methyl-4- (2-pyridylmethoxyethoxy) pyridine in the form of a colorless Somikristalls.

Embodiment 17 2 - [{3-Methyl-4- (2-pyridylmethoxyethoxy) pyrldin-2-yl} methylthio] -1H-benzimidazole

0.71 g (6 mmol) of thionyl chloride was added to a solution of 0.40 g (1.5 mmol) of 2-hydroxymethyl-3-methyl-4- (2-pyridylmethoxyethoxy) -pyridine in 10 ml of chloroform with cooling by ice to obtain a mixture produce. This mixture was stirred at 0 ° C for two hours. After completion of the reaction, the mixture was neutralized with a saturated aqueous sodium hydrogencarbonate solution and extracted four times with 50 ml of chloroform. The extract was dried over magnesium sulfate and filtered. The obtained fitrate was concentrated and dried in vacuo to obtain 0.42 g of crude 2-chloro-methyl-3-methyl-4- (2-pyridylmethoxyethoxy) pyridine as a semicrystal.

A mixture of 0.40 g of this crude intermediate, 0.18 g 2-mercapto-1H-benzimidazole, 0.19 g of potassium carbonate and 30 ml of methyl ethyl ketone was heated under reflux for 2 hours in a nitrogen atmosphere, cooled and filtered. The filtrate was concentrated and purified by silica gel column chromatography (solvent: ethyl acetate / n-hexane) to give 0.38 g of 2 - [{3-methyl-4- (2-pyridylmethoxyethoxy) pyridin-2-yl} methylthio) - To win 1 H-benzimidazole in the form of a colorless oil.

¹ H-NMR (CDCl ₃ ) O;

2.26 (s, 3H), 3.80~4.04 (m, 2H), 4.10~4.28 (m, 2H), 4.35 (s, 2H), 4.70 (s, 2H), 6.70 (d, H), 6.94 ~ 7.20 (m, 7H), 8.25

(d, H), 8.45 (d, H)

Embodiment 18 2 - [{3-Methyl-4- (2-pyridylmethoxyethoxy) pyridin-2-yl} -methylsulfinyl] -1H-benzimidazole

OCH _K

H 0

0.16 g m-chloroperbenzoic acid were added to a solution of 0.38 g of 2- | {3-methyl-4- (2-pyridylmethoxyethoxy) pyridine-2-yl} methylthio) -1 H-benzimidazole in 20 ml of dichloromethane at -60 ⁰ C. in a nitrogen atmosphere to obtain a mixture. This mixture was stirred for 0.5h. After completion of the reaction, 0.16 g of triethylamine was added to the reaction mixture. The mixture obtained was warmed to -1O ⁰ C, then 30 ml of a saturated aqueous sodium hydrogen carbonate solution were added. The recovered mixture was stirred at room temperature for 0.5h and extracted three times with 50ml of dichloromethane. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated and dried in vacuo to recover a crude product. This crude product was made

Dichloromethane / diethyl ether crystallizes to give 0.31 g of 2 × | 3-β-methyl-4- (2-pyrrole).

¹ H-NMR (CDCl ₃ ) O;

2.17 (s, 3H), 3.83~4.06 (m, 2H), 4.06~4.34 (m, 2H), 4.72 (s, 2H), 4.64~ 4.84 (m,? H), 6.70 (d, H), 7.04? 7.80 (m, 7H), 8.27 (d, H), 8.55 (d, H).

Preparative Embodiment 10 2,3-Dimethyl-4- [2- (2-pyrrolidone) ethoxy] pyridine-N-oxide

0- (0H ₂ ) ₂ -

0.42 g of sodium hydride was added to 30 ml of Ν, Ν-dimetylafiamide at room temperature to obtain a mixture. This mixture was cooled to 0 ° C and then treated with 0.74 g of 2-pyrrolidone. The mixture thus obtained was stirred at 8O ⁰ C for 1.5 hours, then cooled to room temperature and then treated with 1.17 g of 4- (2-chloroethoxy) -2,3-dimethylpyridine N-oxide. The recovered mixture was stirred for 5 hours at 60 to 80 ° C and cooled, after which 20 cm ^{3 of} saturated aqueous sodium bicarbonate solution was added. The mixture thus obtained was extracted with chloroform. The extract was dried over magnesium sulfate and filtered. The filirat was concentrated to obtain a crude product. This crude product was purified by silica gel column chromatography to recover 430 mg of 2,3-dimethyl-4- | 2- (2-pyrrolidone) ethoxy) pyridine N-oxide in the form of a yellow crystal.

¹ H-NMR (CDCl ₃ ) O;

2.2 (s, 3H), 2.54 (s, 3H), 1.9 ~ 2.5 (m, 4H), 3.57 (t, J = 7Hz, 2H), 3.73 (t, J = 6Hz, 2H), 4.16 (t, J = 6Hz, 2H), 6.65 (d, J = 7Hz, 1H), 8.15 (d, J = 7.1H)

Preparative Example 11 2-Chloromethyl-3-methyl-4- [2- (2-pyrrolidone) ethoxy] pyridine

0- (CH ₂ ) ₂ - N

010H ₂

10 cm ^{3 of} acetic anhydride was added to 0.65 g of 2,3-dimethyl-4- [2- (2-pyrrolidone) ethoxy] pyridine N-oxide at room temperature to obtain a mixture. This mixture was stirred at 90 ° C for 2 h and then treated with ethanol. The mixture thus obtained was distilled under reduced pressure to obtain 0.79 g of crude 2-acetoxymethyl-3-methyl-4- [2- (2-pyrrolidone) ethoxy) pyridine.

To this crude intermediate product was added 20 cm ^{3 of} 1N HCl to obtain a mixture. This mixture was stirred at 100 ⁰ C for 2 h, cooled, neutralized with a saturated aqueous sodium bicarbonate solution and extracted with chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was distilled under a reduced pressure to give 510 mg of crude 2-hydroxymethyl-3-methyl-4- | 2- (2-pyrrolidone) ethoxy] pyridine in the form of an ocher-colored crystal.

¹ H-NMR (CDCl ₃ ) O;

2.04 (s, 3H), 1.9 ~ 2.6 6m, 4H), 3.58 (t, J = 7Hz, 2H), 3.73 (t, J = 6Hz, 2H), 4.2 (t, J = 6Hz, 2H), 4.65 (s, 2H), 6.7 (d, J = 7Hz, 1H), 8.3 (d, J = 7Hz, 1H)

500mg of this crude intermediate was dissolved in 10ml of dichloromethane to obtain a solution. To this solution was C 1.19 g of thionyl chloride was added dropwise at -2O ^0th The recovered mixture was stirred at room temperature for 30 minutes, neutralized with a saturated aqueous sodium hydrogencarbonate solution and extracted with chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was distilled under reduced pressure to obtain 0.57 mg of crude 2-chloromethyl-3-methyl-4- [2- (2-pyrrolidone) ethoxy] pyridine in the form of an oil.

¹ H-NMR (CDCl ₃ ) O;

2.25 (s, 3H), 1.8 ~ 2.5 (m, 4H), 3.54 (t, J = 7Hz, 2H), 3.68 (t, J = 6Hz, 2H ), 4.1 (t, J = 6Hz, 2H), 6.62 (d, J = 6Hz, 1H), 8.22 (d, J = 6Hz, 1H)

Exemplary Embodiment 19 2- [3-Methyl-4- (2- (2-pyrrolidone) ethoxy) pyridin-2-yl-methylthio-1H-benzimidazole

20 cm ^{3 of} methyl ethyl ketone were added to a mixture of 0.55 g of 2-chloromethyl-3-methyl-4- | 2- (2-pyrrolidone) othoxy] pyridine, 0.3 g of 2-mercapto-1H-benzimidazole and 0, m33g of potassium carbonate. to create a mixture. This mixture was heated under reflux for 2 hours and filtered. The filtrate was concentrated to recover a crude product. This crude product was goronigt mi'.tols silica gel column chromatography to win 0.27 g of the title compound as a pale yellow crystal.

'H-NMR (CDCI ₃₎ O;

2.26 (s, 3H), 1.8 ~ 2.5 (m, 4H), 3.57 (t, J = 7Hz, 2H), 3.7 (t, J = 6Hz, 2 ^), 4 , 13 (t, J = 6Hz, 2H), 4.34 (s, 2H), 6.66

(d, J = 6Hz, 1H), 7,0- /, 55 (m.4H), 0,25 (d, J = 6Hz, 1H)

Embodiment 20 5-Mothoxy-2- [3-methyl-4- {2- (2-pyrrolidone) ethoxy} -pyridin-2-yl] methylthio-1H-benzimidazole

0- (CH ₂ ) ₂ -

The title compound was prepared in a manner similar to that described in Example 19.

'H-NMR (CDCI ₃₎ O;

2.24 (s, 3H), 1.9 ~ 2.5 (m, 4H), 3.56 (t, J = 7Hz, 2H), 3.72 (t, J = 6Hz, 2H), 3, 83 (s, 3H), 4.17 (t, J = 6Hz, 2H), 4.4 (s, 2H),

6.6 ~ 7.5 (m, 4H), 8.35 (d, J = 6Hz, 1H)

Embodiment 21 2- [3-Methyl-4- {2- (2-pyrrolidone) ethoxy) pyridin-2-yl] methylthio-5-trifluoromethyl-1H-benzimidazole

S OH,

The title compound was prepared in a manner similar to that described in Example 19. 'H-NMR (CDCI,) 6;

2.28 (s, 3H), 1.9-2.55 (m, 4H), 3.57 (t, J = 7Hz, 2H), 3.74 (t, J = 6Hz, 2H), 4, 2 (t, J = 6Hz, 2H), 4.4 (s, 2H), 6.77 (d, J = 6Hz, 1H), 7.27 ~ 7.85 (m, 3H), 8.38 (d, J = 6Hz, 1H)

Implementation Guide 22

0.27 g of 2-l3-methyl-4- (2- (2-pyrrolidone) -fithoxy} -pyridin-2-yl] -methylthio-1H-benzimidazole was dissolved in 20 ml of dichloromethane to give a solution ⁰ C was added 0.12 g of 95% m-chloroperbenzoic acid at -6O. The mixture thus obtained was stirred at -50 to ⁰ C for 4 hours -4o ührt veri and then added with 0.09 g of triethylamine and a saturated aqueous sodium hydrogen carbonate solution The resulting mixture was extracted with dichloromethane The extract was dried over magnesium sulfate and filtered The filtrate was concentrated to give a crude product This crude product was crystallized from dichloromethane / ether to give 0.18 g of the title compound.

¹ H-NMR (CDCl ₃ ) O;

2.18 (s, 3H), 1.9 ~ 2.5 (m, 4H), 3.53 (t, J = 7Hz, 2H), 3.73 (t, J = 6Hz, 2H), 4, 16 (t, J = 6Hz, 2H), 4.74 (ASq, J = 14Hz, Δι? = 16Hz, 2H), 6.7 (d, J = 6Hz, 1H), 7.2 ~ 7.7 (m, 4H), 8.25 (d, J = 6Hz, 1H)

Exemplary Embodiment 23 5-Methoxy-2- [3-methyl-4- {2- (2-pyrrolidone) ethoxy} -pyrldin-2-yl] methylsulfinyl-1H-benzimidazole

0- (0H ₂ ) ₂ -

The title compound was prepared in a manner similar to that described in Example 22. ¹ H-NMR (CDCl ₃ ) O;

2.17 (s, 3H), 1.9 ~ 2.5 (m, 4H), 3.38~3.78 (m, 4H), 3.8 (s, 3H), 4.1 (t, J = 6Hz, 2H), 4.66 (ABq, J = 13Hz ₁ A ^ 2.4Hz, 2H), 6.6 (d, J = 6Hz, 1H), 6.77 ~ 7.6 (m, 3H), 8,17 (d, J = 6Hz, 1H)

Embodiment 24 2- [3 * Mθthoxy * 4 * (2 * (2 * pyrrolidone) θthoxv] pyrldln * 2 * γl] * mθthylsul (lnvl * 5-trifluoromethyl) -1H-benzenium diazole

O - (0H _a ) ₂ -

The title compound was prepared in a manner similar to that described in Embodiment Biol. 'H-NMR (CDCI ₃₎ O;

2.17 (s, 3H), 1.8 ~ 2.55 (m, 4H), 3.4 ~ 3.8 (m, 4H), 4.75 (ABq, J = 14.3Hz, Δ »? = 17.5Hz, 2H), 6.69 (d, J = 6Hz, 1H), 7.24 ~ 8.0 (m, 3H), 8.2 (d, J = 6Hz, 1H)

Preparative Embodiment 12 2-Chloromethyl-4- (2-hydroxyethoxy) -3-methylpyridine

OH

0- (CH ₉ ) o-0H I

CICH,

X)

15 ml of acetic anhydride was added to 25 g of 4- (2-hydroxyethoxy) -2,3-dimethylpyridine N-oxide to obtain a solution. This solution was stirred for 2 h at 90 ° C and then treated with ethanol. The mixture thus obtained was distilled under reduced pressure to afford 4- (2-acetoxyethoxy) -2-acetoxymethyl-3-methylpyridine. To this intermediate was added 20 g of sodium hydroxide, 20 ml of water and 50 ml of ethanol to obtain a mixture. This mixture was stirred at room temperature for 10 minutes and distilled to remove the ethanol, whereupon 50 ml of a saturated aqueous saline solution was added. The resulting mixture was extracted with 2-butanone. The extract was dried over magnesium sulfate and filtered. The filtrate was distilled under reduced pressure to obtain 20 g of 4- (2-hydroxyethoxy) -2-hydroxymethyl-3-methylpyridine.

'H NMR (CDCl ₅ ) O;

2.20 (s, 3H), 3.9~4.2 (m, 4H), 4.50 (s, 2H), 6.63 (d, J = 6Hz, 1H), 8.15 (i.e. J = 6Hz, 1H)

11.9 g of the 4- (2-hydroxyethoxy) -2-hydroxymethyl-3-methylpyridine prepared in the above manner were dissolved in 200 ml of dichloromethane to obtain a solution. To this solution was added 24 ml of thionyl chloride dropwise at ⁰ ° C. The resulting mixture was stirred at room temperature for 2 hours and distilled under reduced pressure to remove the dichloromethane and excess thionyl chloride. To the residue was added a saturated aqueous sodium hydrogencarbonate solution to obtain a mixture. This mixture was extracted with chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated to obtain 10.9 g of 2-chloromethyl-4- (2-hydroxyethoxy) -3-methylpyridine.

¹ H-NMR (CDCl ₃ ) O;

2.3 (s, 3H), 3.9~4.2 (m, 4H), 4.69 (s, 2H), 6.73 (d, J = 6Hz, 1H), 8.3 (i.e. , J = 6Hz, 1H)

Embodiment 25 2- [4- (2-Hydroxyethoxy) -3-methylpyridin-2-yl] methylthio-5-methoxy-1H-benzimidazole

0OH ^ÖH 3,

60 ml of ethanol was added to a mixture of 0.7 g of 2-chloromethyl-4- (2-hydroxyethoxy) -3-methylpyridine, 0.63 g of 2-mercapto-5-methoxy-1H-benzimidazole and 0.16 g of sodium hydroxide to give a gum to obtain. This mixture was stirred for one hour at 6O ⁰ C, concentrated and goreinigt by silica gel column to obtain 1.08 g of the title compound.

¹ H-NMR (DMSO-d _e ) δ;

2.2 (s, 3H), 3.72 (s, 3H), 3.6 ~ 4.1 (m, 4H), 4.6 (s, 2H), 6.6 ~ 7.35 (m, 4H), 8.14 (d, J = OHz, 1H)

Exemplary Embodiment 26 2- [4- (2-Hydroxyethoxy) -3-methylpyrldyl-2-yl-methylthio-1H-benzylmidazole

The Title Veroindung was prepared in a manner similar to that described in Example 25. ¹ H-NMR (DMSO-d _e ) 6; 2.24 (s, 3H), 3.6 ~ 4.18 (m, 4H), 4.7 (s, 2H), 6.93 (d, J = 6Hz, 1H), 7.0 ~ 7 , 6 (m, 4H), 8.25 (d, J = 6Hz, 1H)

Embodiment 27 2- [4- (2-Hydroxyethoxy) -3-methylpyridin-2-yl] methylthio-5-trifluoromethyl-1H-benzimidazole

00H ₂ OH ₂ OH

Oi ¹ .

The title compound was prepared in a manner similar to that described in Example 25. ¹ H-NMR (DMSO-de) δ; 2.25 (s, 3H), 3.6 ~ 4.2 (m, 4H), 4.75 (s, 2H), 6.96 (d, J = 6Hz, 1H), 7.3 ~ 7 , 9 (ni, 3H), 8.25 (d, J = 6Hz, 1H)

Embodiment 28 2- [4- (2-Hydroxyethoxy) -3-methylpyrldin-2-yl] -methylsulfinyl-5-methoxy-1H-benzimidazole

CH

00H ₂ OH ₂ OH

0.9 g of 2- [4- (2-hydroxyethoxy) -3-methylpyridin-2-yl] methylthio-5-ethoxy-1H-benzimidazci was dissolved in a mixture of 5 ml of methanol and 80 ml of dichloromethane to obtain a solution. To this solution was added 0.51 g of m-chloroperbenzoic acid at -60 ° C. The mixture thus obtained was stirred at -50 to -4O ⁰ C for 4.5 hours and then treated with 0.38 g of triethylamine. To the obtained mixture was added a saturated aqueous sodium hydrogencarbonate solution, and the resulting mixture was extracted with chloroform. The extract

was dried over magnesium sulfate and filtered. The filtrate was distilled under pre-pressure to obtain a crude product. This crude product was crystallized from dichloromethane / isopropyl ether to yield 0.5% of the title precursor.

¹ H-NMR (DMSO-d ₆ ) δ;

H) ₁ S ₁ O-4,18 (m, 4H), 4,73 (ABq, J = 14HZ, Δ ^ = 8Hz, 2H), 6,8 ~ 7,6 (m, 4H), 8,21 (d, J = 6Hz, 1H)

Exemplary Compound 29 2- [4- (2-Hydroxyethoxy) -3-methylpyrldln-2-yl] -othylsulphinyl-1H-benzimidazole

00H ₂ OH ₂ OH

H 0

The title compound was recovered in a Wciso similar to that described in Example 28

M * ': 332

¹ H-NMR (DMSO-d,) δ; 2.17 (s, 3H), 3.6 ~ 4.2 (m, 4H), 4.74 (s, 2H), 6.95 (d, J = 6Hz, 1H), 7.18 ~ 7 , 77 (m, 4H), 8.22 (d, J = 6Hz, 2H)

Embodiment 30 2- [4- (2-Hydroxyethoxy) -3-methylpyrldin-2-yl] methylsulfinyl-5-trifluoromethyl-1H-banzlmldazole

OCH ₂ OH ₂ OH

S - OH,

The title compound was prepared in a manner similar to that described in Example 28.

Preparative Embodiment 13 4- (3-Methoxypropoxy) -2,3-dimethylpyridine N-N-oxide

00H ₂ OH ₂ OH ₂ OOH ₃

OH

2.0 g (22 mmol) of 3-methoxypropanol was dissolved in 50 ml of dimothylsulfoxide to give a solution. To this solution was added at room temperature 2.7 g (66 mmol) of sodium hydride. The mixture thus obtained was stirred at 60 ° C. for one hour, cooled to room temperature by standing and admixed with 3.0 g (19 mmol) of 4-chloro-2,3-dimethylpyridine N-oxide. The recovered mixture was stirred at 40 ° C for one hour. After completion of the reaction, the reaction mixture was distilled to remove the dimethyl sulfoxide. The obtained residue was purified by silica gel column chromatography to obtain 760 mg of 4- (3-methoxypropoxy) -2,3-dimethylpyridine N-oxide.

¹ H-NMR (CDCl ₃ ) O;

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)

Preparatory Section 14 2-chloromethyl-4- (3-methoxypropoxy) -3-methylpyridine

00H ₂ CH ₂ OH ₂ OOH ₃

20ml of acetic anhydride was added 4- (3-methoxypropoxy) -2,3-dimothylpyridin-N-oxide was added to 760mg (3,6mmol) to perform C for one hour the reaction at 9O ^0th The reaction mixture was distilled to remove the acetic anhydride and then treated with a saturated aqueous Natriumh, bicarbonate solution. The mixture thus obtained was extracted with chloroform. The extract was concentrated to obtain 700 mg of 2-acetoxymethyl-4- (3-methoxypropoxy) -3-methylpyridine in the form of a brown oil.

The 2-acetoxymethyl-4 prepared in the above manner (3-methoxypropoxy) -3-methylpyridine 500mg of sodium hydroxide and 15 cm ³ of ethanol were added. The mixture obtained was stirred for one hour at 5O ⁰ C. After completion of the reaction, the reaction mixture was distilled to remove the ethanol, and then water was added. The recovered mixture was extracted with chloroform. The obtained chloroform layer was concentrated to obtain 450 mg of 2-hydroxymethyl-4- (3-methoxypropoxy) -3-methylpyridine as a brown oil.

¹ H-NMR (CDCl ₃ ) O;

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 the above-prepared 2-hydroxymethyl-4- (3-tiethoxypropoxy) -3-methylpyridine was dissolved in 20 ml of dichloromethane to obtain a solution. To this solution was added dropwise 760 mg of thionyl chloride at ⁰ ° C. The recovered mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was distilled to remove the dichloromethane and thionyl chloride. To the residue thus obtained was added a saturated aqueous sodium hydrogencarbonate solution. The recovered mixture was extracted with chloroform. The recovered chloroform layer was concentrated to obtain 470 mg of 2-chloromethyl-4- (3-methoxypropoxy) -3-methylpyridine as a brown crystal.

¹ H-NMR (CDCl ₃ ) O;

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)

Embodiment 31 2 - [{4- (3-Methoxypropoxy) -3-methylpyridin-2-yl) -methylthio] -1H-benzimidazole

00H ₂ OH ₂ OH ₂ OCH ₃

20cm ^{3 of} ethanol was added to a mixture of 280mg (1.8mmol) 2-mercapto-1H-benzimidazole, 470mg (2mmol) 2-chloromethyl-4- (3-methoxypropoxy) -3-methylpyridine and 100mg (2.4mmol). Added sodium hydroxide. The mixture obtained was stirred long C for 3 h at 5O ^0th After completion of the reaction, the reaction mixture was distilled to remove the ethanol. The obtained residue was purified by silica gel column chromatography to obtain 590 mg of 2 - [{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthiol] -1H-benzimidazole as a pale yellow crystal.

'H-NMR (CDCI ₃₎ O;

2.09 (t, J = 6.1 Hz, 2H), 2.26 (s, 3H), 3.35 (s, 3H), 3.56 (t, J = 6.1 Hz, 2H), 4.13 (t, J = 6.1 Hz, 2H), 4.37 (s, 2H), 6.76 (d, J = 6.1 Hz, 1H), 7.1 ~ 7.25 (m, 2H), 7.5 for, s, 2H), 8.33 (d, J = 6.1 Hz, 1H)

Embodiment 32

00H ₂ OH ₂ OH ₂ UOH ₃

5g 2 - ({4- (3-Methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-b'-nzimidazole were dissolved in a mixture of 100 ml of dichloromethane and 25 ml of diethyl ether to give a solution of this solution were 2.83 g of 85% m-chloroperbenzoic acid was added portionwise boi -45 ⁰ C. After completion of the reaction, the reaction mixture 2g of triethylamine was added, the mixture thus obtained was warmed to -10 ° C and treated with 50 ml of 1 N sodium hydroxide. the The resulting aqueous layer was stirred at room temperature for 30 minutes and the aqueous layer obtained was washed twice with 20 ml of dichloromethane and adjusted to pH 11 with a 2% solution of ammonium acetate.The aqueous layer was extracted three times with 50 ml of dichloromethane Washed twice with 50 ml of a saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and distilled to remove the dichloromethane Product was crystallized from dichloromethane / ether to obtain 4.17 g of the title compound as a white crystal. Melting point: 99 to 100 ^° C. (with decomposition).

¹ H-NMR (CDCl ₃ ) O;

1.83 ~ 2.09 (m, 2H), 2.13 (s, 3H), 3.34 (s, 3H), 3.52 (t, J = 6.2Hz, 2H), 4.05 (t, J = 6.2 Hz, 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)

Example 33 Nbtrium salt of 2 - [(4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole

00H ₂ OH ₂ OH ₂ OCH ₃

500 mg (1.46 mmol) of 2 - [(4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio) -1H-benzimidazole was dissolved in 20 cm ^{3 of} dichloromethane to obtain a solution. To this solution was added 320 mg of 85% m-chloroperbenzoic acid in portions at -45 ° C. After completion of the reaction, 370 mg of triethylamine was added to the reaction mixture. The mixture thus obtained was heated to -10 ⁰ C and then treated with 30ml of a saturated aqueous sodium carbonate solution.

The recovered mixture was stirred at room temperature for 30 minutes and extracted with dichloromethane. The extract was dried over magnesium sulfate and distilled to remove the dichloromethane. In this way, a crude product was obtained. This crude product was dissolved ³ of a 0.1 N aqueous sodium hydroxide solution in 14,6cm to obtain a solution. This solution, together with 30 cm ^{3 of} ethanol, was distilled three times with ethanol to remove the water as an azeotropic mixture and dried in vacuo. Ether was added to the residue thus obtained to precipitate a white crystal. This crystal was washed with ether three times by decantation and dried in vacuo to obtain 530 mg of sodium salt of 2-I {4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole. Melting point: 140 to 141 ^° C. (with decomposition)

M ⁺¹ : 382'-H-NMR (DMSO-d ₆ ) δ;

1.99 (t, J = 6.1 Hz, 2H), 2.17 (s, 3H), 3.25 (s, 3H), 3.49 (t, J = 6.1 Hz, 2H), 4.09 (t, J = 6.1 Hz, 2H), 4.56 (ABq, J = 14.1 Hz,

Δ ^ = 21.3Hz, 2H), 6.8 ~ 6.9 (m, 3H), 7.4 ~ 7.5 (m, 2H), 8.27 (d, J = 5.7Hz, 1H )

Embodiment block 134

2 - [{4- (3-hydroxypropoxy) -3-methylpyridyl-2-yl} methylthio] -1H-benzimidazole

OOH ₂

80 ml of ethanol was added to a mixture of 1.39 g (9.27 mmol) 2-mercaptobenzimidazole, 2.0 g (9.27 mmol) 2-chloromethyl-4- (3-hydroxypropoxy) -3-methylpyridine and 0.44 g (11.1 mmol) sodium hydroxide. The mixture thus obtained was stirred at 5O ⁰ C for one hour. After completion of the reaction, the reaction mixture was concentrated. The obtained residue was purified by silica gel column chromatography to obtain 1.7 g of the title compound (56%)

M ⁺ ': 368

'H-NMR (DMSO-d ₆₎ δ;

1.8 ~ 2.1 (m, 2H), 2.24 (s, 3H), 3.6 (t, J = 6Hz, 2H), 4.2 (t, J = 6Hz, 2H), 4, 7 (s, 2H), 7.0 ~ 7.38 (m, 3H), 7.38 ~ 7.6 (m, 2H), 8.35 (d, J = 6Hz, 1H)

Embodiment 35

Sodium salt of 2 - [{4- (3-hydroxypropoxy) -3-methylpyrldin-2-yl} methylsulfinyl] -1H-benzimidazole

00H ₂ CH ₂ OH ₂ OH

1.0 g (3.04 mmol) of 2-l {4- (3-hydroxypropoxy) -3-methylpyridin-2-yl} methylthiol-1H-benzimidazole was dissolved in 100 ml of dichloromethane to give a solution. To this solution was added at -45 ° C 580 mg of 90% m-chloroperbenzoic acid. The resulting mixture was stirred for 2 hours. After completion of the reaction, 470 mg of triethylamine was added to the reaction mixture. The recovered mixture was warmed to -20 ° C and then treated with 30ml of a saturated aqueous sodium bicarbonate solution. The recovered mixture was stirred at room temperature for 30 minutes and extracted with chloroform. The recovered chloroform layer was concentrated to obtain a crude product. This crude product was crystallized from dichloromethane / ether to give 830 mg of 2 - [{4- (3-hydroxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl} -1H-benzimidazole. This product was dissolved in 24 ml of 0.1 N aqueous sodium hydroxide. The recovered solution was co-distilled with ethanol to remove the water as an azeotropic mixture with ethanol and then capped with a vacuum pump while deprived of air. Ether was added to the obtained residue to precipitate a colorless crystal. This crystal was separated by filtration. In this way, 860 mg (77%) of the title compound were recovered.

¹ H-NMR (DMSO-d _e ) δ;

1.7~2.1 (m, 2H), 2.16 (s, 3H), 3.58 (t, J = 6Hz, 2H), 4.12 (t, J = 6Hz, 2H), 4, 55 (ABq, J = 13Hz, A> = 20Hz, 2H), 6.7 ~ 7.0 (m, 3H), 7.3 ~ 7.6 (m, 2H), 8.27 (d, J = 6Hz, 1H)

EMBODIMENT 36 2 - [{4- (2-Chloroethoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole

00H ₂ OH ₂ OI

N. ' H

12.3 g of crude 2-mercaptobenzimidazole, 20 g of 4- (2-chloroethoxy) -2-chloromethyl-3-methylpyridine hydrochloride and 11 g of sodium hydroxide were dissolved in 300 ml of ethanol to give a solution. This solution was stirred at 6O ⁰ C for 2 h stirred and distilled under reduced pressure to remove the ethanol. The obtained residue was chromatographed on a silica gel column and eluted with 40% ethyl acetate in hexane and then with ethyl acetate to obtain 15.5 g of the title compound as a white solid.

'H-NIvIR (CDCl ₃ ) O;

2.24 (3 H, s, CH _3), 3.80 (2 H, t, J = 4 Hz, CH _2), 4.20 (2 H, t, J = 4 Hz, CH _2), 4 , 40 (2H, s, CH ₂ ), 6.62 (1H, d, J = 6Hz, Py-H), 7.00~7.40 (4H, m, Ar-H), 8.28 (1H, d, J = 6Hz, Py-H)

Exemplary embodiment 37

Sodium salt of 2 - [{- 4- (2-methylthloethoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole

OCH ₂ OH ₂ SOH ₃

0.50 g of the thioether prepared in Working Example 35 was dissolved in 20 ml of dichloromethane to obtain a solution. To this solution were 0.36 g of m-chloroperbenzoic acid was added in portions at -50 to ⁰ -4o C. After completion of the reaction, 0.21 g of triethylamine was added to the reaction mixture at the same temperature. The resulting mixture was heated to -2O ⁰ C and then treated with 28 ml of a 1 N aqueous Namumhydrogencarbonat solution. The resulting mixture was stirred for 30 minutes and extracted with dichloromethane. The extract was washed with a saturated aqueous solution of common salt, dried over magnesium sulfate and distilled to remove the dichloromethane.

The crude sulfur oxide obtained was dissolved in 10 ml of ethanol and then treated with 1 g of a 15% aqueous Natriummethylmercaptid solution. The recovered mixture was stirred at 80 ° C for 4 hours and distilled to remove the solvent. The residue was chromatographed on a silica gel column and eluted with 1% triethylamine containing 2% methanol in chloroform and then with 10% methanol in chloroform to obtain a purification product. To this product was added 7.2 ml of 1 N aqueous sodium hydroxide and 20 ml of ethanol. The recovered mixture was evaporated to dryness under reduced pressure to obtain 460 mg of the title compound.

M ": 384

¹ H-NMR (DMSO-d _e ) δ;

2.18 (3H, s, CH _3), 2.90 (2 H, t, J = 7 Hz, CH _2), 4.24 (2 H, t, J ·· = 7 Hz, CH _2), 4.78 (2H, s, CH ₂ ), 6.80~7.60 (4H, m, Ar-H), 6.98 (1H, d, J = 6Hz, Py-H), 8, 30 (1H, d, J = 6Hz, Py-H)

Embodiment 38 2 - [{4- (2-Phenoxyethoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole

OGH ₂ OH ₂ O

N H

A mixture of 1, Og [4- (2-phenoxyethoxy) -3-methylpyridin-2-yl] methanol, 0.60 ml of thionyl chloride and 12 ml of dichloromethane was kept at 40 ° C for 60 minutes to effect roaction. The reaction mixture was distilled to remove the solvent. A brown syrupy residue was thus obtained. To the residue was added 50 ml of ethanol, 0.70 g of sodium hydroxide and 1.2 g of 2-mercaptobenzimidazole. The recovered mixture was heated at 70 ° C. for 2 hours and distilled to remove the ethanol, and the residue was chromatographed on a silica gel column and eluted with 30% ethyl acetate in hexane and then ethyl acetate to give 1.2 g of the title compound as a white To gain solid.

'H-NMR (DMSO-d ₆₎ δ;

2.22 (3H, s), 4.40 (2H, s), 4.70 (2H, s), 6.86 ~ 7.52 (10H, m), 8.28 (1H, d, J = 6Hz)

Implementation example 39

Sodium salt of 2 - [{α-methyl-4- (2-phenoxyethoxy) pyrldin-2-yl} methylsulfinyl] -1H-benzimidazole

00H ₂ CH ₂ O

0.70 g of the thioether prepared in Example 37 was dissolved in 200 ml of dichloromethane to obtain a solution. To this solution was 0.39 g m-chloroperbenzoic acid was added in portions at -30 to -40 ⁰ C. After completion of the reaction, 0.12 g of triethylamine was added to the reaction mixture at the same temperature. The recovered mixture was warmed to -10 ⁰ C and then treated with 10ml of a saturated aqueous sodium bicarbonate solution. The mixture obtained was stirred 30min at -10 to 1O ⁰ C. The resulting dichloromethane layer was washed with a saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and distilled to remove the dichloromethane. The residue thus obtained was dissolved in a mixture of 20 ml of ethanol and 1.8 ml of 1 N aqueous sodium hydroxide to obtain a solution. This solution was evaporated to dryness under reduced pressure. The residue was crystallized from ethanol / ether to give 0.61 g of the title compound as a tan solid.

¹ H-NMR (DMSO-d _e ) δ;

2.17 (3H, s) 4.32 (4H, s), 4.36 (1H, d, J = 13Hz), 4.68 (1H, d, J = 13Hz), 6.74 ~ 7 , 44 (10H, m) 8.22 (1H, d, J = 6H)

Auslührungsbolsplel 40

2 - [{4- (2- (2-chloroethoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazolund2 - [(4- (2- (2-hydroxyethoxy) ethoxy) -3-mothylpyrldln- 2-yl) methylthio] -1H-benzimidazole

0OH ₂ OH ₂ OOH ₂ OH ₂ Cl

0OH ₂ OH ₂ OOH ₂ OH ₂ OH

0.54g of sodium hydroxide was added to an ethanolic solution of 3.1g of a crude mixture of 4- [2- (2-chloroethoxy) ethoxy] -2-chloromethyl-3-methylpyridine and 2-chloromethyl-4- [2- (2-hydroxyethoxy ) ethoxy] -3-methylpyridine, prepared by the chlorination of 2-hydroxymethyl-4- [2- (2-hydroxyethoxy) ethoxy] -3-methylpyridine, and 2.0 g of 2-mercapto-1H benzimidazole added to obtain a mixture. This mixture was stirred for 1.5 hours at 6O ⁰ C, cooled and distilled under reduced pressure to remove the ethanol. The recovered residue was chromatographed over a silica gel column and eluted with ethyl acetate / n-hexane and then with methanol / ethyl acetate to give 1, Og 2-l {4- (2- (2-chloroethoxy) ethoxy) -3-methylpyridine-2. yl} methylthiol-1 H-benzimidazole to win.

¹ H-NMR (CDCl ₃ ) O;

2.28 (s, 3H), 3.56-4.04 (m, 6H), 4.04~4.32 (m, 2H), 4.4 (s, 2H), 6.76 (d, J = 6Hz, 1H), 7.08~7.32 (m, 3H), 7.4~7.68

(m, 2H), 8.36 (d, "= 6Hz, IH), and 1.9 g of 2 - [{4- (2- (2-hydroxyethoxy) ethoxy) -3-metronylpyridin-2-yl} to win methylthiol-1H-benzimidazole.

¹ H-NMR (CDCl ₃ ) O;

2.24 (s, 3H), 3.56~4.28 (m, 8H), 4.4 (s, 2H), 6.12 (d, J = 7Hz, 1H), 7.04~7 , 32 (m, 2H), 7.4 ~ 7.68 (m, 2H), 8.32 (d, J = 7Hz, 1H)

Embodiment 41

Sodium salt of 2 - [{4- (2- (2-chloroethoxy) ethoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole

0OH ₂ 0H ₂ O0H ₂ 0H ₂ 01

Ha 0

0.57 g of m-chloroperbenzoic acid were added in portions to a solution of 1.0 g of 2 - [{4- (2- (2-chloroethoxy) ethoxy) -3-methylpyridin-2-yl} methylthiol-1H-benzimidazole in 80 ml of dichloromethane Stir and dehumidify at -5O ⁰ C added. The resulting mixture was stirred for 2 h and warmed to -30 ° C and then treated at the same temperature with 0.51 g of triethylamine. The mixture thus obtained was made with a 2 N aqueous solution basified NatrR'mcarbonat at -10 ⁰ C and extracted with dichloromethane. The extract was dried over magnesium sulfate and distilled to remove the dichloromethane. In this way, 1.0 g of a residue was recovered. This residue was dissolved in 26 ml of aqueous 0.1 N sodium hydroxide and then added with ethanol. The mixture thus obtained was distilled under reduced pressure. Ethanol was added to the residue obtained, and the mixture thus obtained was distilled again under reduced pressure to recover a residue. Ether was added to this residue to obtain 1.07 g of a crystal.

¹ H-NMR (DMSO-d _e ) δ;

2.17 (s, 3H), 3.56 ~ 3.96 (m, 6H), 4.0-4.28 {m, 2H), 4.04 (d, J = 12.6Hz, 1H), 4.68 (d, J = 12.6Hz, 1H), 6.76-8.04 (m

3H) 7.36-7.6 (m, 2H), 8.26 (d, J = 6Hz, 1H)

Embodiment 42 2 - [{4- (3-Ethoxy) propoxy-3-methylpyrldyl-2-yl} methylthio] -1H-benzimidazole

OCh ₂ CH ₂ OH ₂ OOH ₂ CH ₃

A mixture of 4.2 g of {4- (3-ethoxypropoxy) -3-methylpyridin-2-yl} methyl methanesulfonate, 1.87 g of 2-mercaptobenzimidazole and 30 mL of ethanol was stirred at room temperature for 1 h and distilled to remove the ethanol. The obtained residue was purified by silica gel column chromatography to obtain 0.88 g of the title compound and 5.1 g of methanesulfonate of the title compound.

'H-NMR (CDCI ₃₎ O;

1.19 (t, J = 7.0Hz, 3H), 1.9-2.1 (m, 2H), 2.24 (s, 3H), 3.48 (q, J = 7.0Hz, 2H ), 3.58 (t, J = 6.2Hz, 2H), 4.1Kt ₁ J = 6.2Hz,

2H), 4.38 (s, 2H), 6.73 (d, J = 5.7Hz, 1H), 6.97-7.20 (m, 2H), 7.32-7 , 55 (m, 2H), 8.31 (d, J = 5.7 Hz, 1H)

Embodiment 43

Sodium salt of 2 - [{4- (3-ethoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole

vs

0OH ₂ OH ₂ CH ₂ OOH ₂ CH ₃

Na 0

0.6 g of 2-I {4- (3-ethoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole was dissolved in 30 ml of dichloromethane to give a solution. To this solution were 0.37 g of 85% m-chloroperbenzoic acid at -45 ⁰ C was added. After two hours, 0.43 g of triethylamine and then 30 ml of a saturated aqueous sodium bicarbonate solution were added to the mixture thus obtained. The recovered mixture was vigorously stirred for one hour at room temperature and extracted with dichloromethane. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated to give a residue. This residue was dissolved in 16 ml of aqueous 0.1 N sodium hydroxide and the resulting solution was distilled to remove the water. The residue was dried under reduced pressure and crystallized from ether to give 0.54g of the title compound. ¹ H-NMR (DMSO-d _e ) δ;

1.11 (t, J = 7.0Hz, 3H), 1.7-2.1 (m, 2H), 2.15 (s, 3H), 3.2-3.6 (m, 4H), 3.65 (s, 3H), 4.09 (t, J = 6.2Hz, 2H), 4.49 'ABq, J = 11.8Hz, Δ0 = 17.0Hz, 2H), 6.65-7 , 0 (m, 3H), 7.2 - 7.6 (m, 2H), 8.2 (d, J = 5.6Hz, 1H)

EMBODIMENT 44 2 - [{4- (3-Methoxymethoxy) propoxy-3-methylpyrldyl-2-yl} methylthio] -1H-benzimidazole

0OH Oh ₂ CH _{2 2 2} OOH OOH ₃

Sw-Ohi

A mixture of 1.8 g of {4- (3-methoxymethoxy) propoxy-3-methylpyridin-2-yl} methyl methanesulfonate, 0.76 g of 2-mercaptobenzimidazole, 0.29 g of sodium hydroxide and 50 ml of ethanol was stirred at room temperature for one hour and distilled to remove the ethanol. The obtained residue was purified by silica gel column chromatography to obtain 1.4 g of the title compound.

'H-NMR (CDCI ₃₎ O;

1.9 ~ 2.2 (m, 2H), 2.26 (s, 3H), 3.33 (s, 3H), 3.73 (t, J = 6.1Hz, 2H), 4.16 (t, J = 6.1 Hz, 2H), 4.38 (s, 2H), 4.62 (s, 3H), 6.76 (d, J = 5.7 Hz, 1H), 7, 0 ~ 7.2 (m, 2H), 7.3 ~ 7.6 (m, 2H), 8.34 (d, J = 5.7 Hz, 1H)

Embodiment 45

Sodium salt of 2 - [{4- (3-methoxymethoxy) propoxy-3-methylpyrldyl-2-yl} -methylsulphinyl] -1H-benzimidazole

0OH ₂ Ch ₂ OH ₂ OOH ₂ OCH ₃

0.6 g of 2 - [{4- (3-methoxymethoxy) -propoxy-3-methyl-pyridin-2-yl} -methylthio) -1H-benzimidazole was dissolved in 40 ml of dichloromethane to give a solution. To this solution were 0.35 g of 85% m-chloroperbenzoic acid at -45 ⁰ C was added. After two hours the mixture at -3O ⁰ C 0.64 g of triethylamine and then 40 ml of a saturated aqueous sodium hydrogen carbonate solution were added. The recovered mixture was stirred at room temperature for 30 minutes, and extracted with dichloromethane. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated to give a residue. This residue was dissolved in 14.4 ml of aqueous 0.1 N sodium hydroxide to recover a solution. This solution was distilled to remove the water, and the residue was dried under reduced pressure and crystallized from ether to obtain 0.57 g of the title compound.

'H NMR (DMSCk) ₆ ) δ;

1.9 ~ 2.2 (m, 2H), 2.17 (s, 3H), 3.22 (s, 3H), 3.63 (t, J = 5.7Hz, 2H), 4.12 ( t, J = 5.7Hz, 2H), 4.56 (s, 2H), 4.41-4.85 (2H), 6.84 ~ 7.1 (m, 3H), 7.4 ~ 7 , 62 (m, 2H), 8.26 (d, J = 6.1 Hz, 1H)

Working Example 46 2 - [{4- (2-metlioxyethoxy) ethoxy-3,5-d] methylpyridin-2-yl} methylthio] -1H-benzimidazole

0OH ₂ Gh ₂ OOH ₂ CH ₂ OCH ₃

A mixture of 3.0 g of {4- (2-methoxyethoxy) ethoxy-3,5-dimethylpyridin-2-yl} methyl methanesulfonate, 1.17 g of 2-mercaptobenzimidazole and 30 ml of ethanol was stirred at room temperature for one hour and eluted to remove the Ethanol distilled

 The residue was purified by silica gel column chromatography to obtain 0.8 g of the titanium compound.

'H-NMR (CDCI ₃₎ O;

2.28 (s, 3H), 2.33 (s, 3K), 3.37 (s, 3H), 3.5 ~ 3.9 (m, 6H), 3.9 ~ 4.2 (m, 2H), 4.37 («, 2H), 7.1 ~ 7.3 (m, 2H), 7.3 ~ 7.65 (m,

2H), 8.24 (s, 1H)

Embodiment 47

Sodium salt of 2 - [{4- (2-methoxyethoxy) ethoxy-3,5-dimethylpyrldyl-2-yl) methylsultrinyl] -1H-benzimidazole

0OH ₂ OH ₂ OOH ₂ Oh ₂ OOH ₃

0.5 g of 2 - [{4- (2-methoxyethoxy) ethoxy-3,5-dimethylpyridin-1-yl} methylthioJ-1H-benzimidazole was dissolved in 30 ml of dichloromethane to give a solution. This solution was added at -45 ⁰ C 0.29 g of 85% m-chloroperbenzoic acid. 0.34 g of triethylamine and then 30 ml of a saturated sodium carbonate solution were added after two hours to the mixture thus obtained. The recovered mixture was stirred vigorously at room temperature for one hour and extracted with dichloromethane. The extract was dried over magnesium sulfate and filtered. For recovery of a residue, the filtrate was concentrated. This residue was dissolved in 12 ml of aqueous 0.1 N sodium hydroxide to obtain a solution. This solution was distilled to remove water. The obtained residue was dried under reduced pressure and crystallized from ether to obtain 0.57 g of the title compound.

¹ H-NMR (DMSO-d ₆ ) δ;

2.21 (s, 6H), 3.25 (s, 3H), 3.3 ~ 3.7 (m, 6H), 3.7 ~ 4.0 (m, 2H), 4.39 (ABq, J = 13.2Hz, Δν = 20.7Hz, 2H), 6.65 ~ 6.9 (m, 2H), 7.2 ~ 7.5 (m, 2H), 8.21 (s, 1H)

Embodiment 48 5-Carboxy-2 - [{4- (2-benzyloxy) ethoxy-3-methylpyridin-2-yl) methylthio] -1H-benzimidazole

HOOO

A mixture of 1.26 g S-carboxy ^ -mercaptobenzimidazol, 1.8 g of 4- (2-benzyloxyethoxy) -2-chloromethyl-3-METHYLPYRIDINE, 0.57 g of sodium hydroxide and 150ml of methanol was stirred at 5O ⁰ C for 1.5 hours and concentrated under reduced Distilled pressure to remove the methanol. The obtained residue was purified by silica gel column chromatography and recrystallized from a methanol / ethyl acetate mixture to obtain 1.52 g of the title compound.

'H-NMR (DMSO-d ₆ ) 6;

2.25 (s, 3H) 3.65 ~ 3.3 (m, 2H), 4.1 ~ 4.3 (m, 2H), 4.58 (s, 2H), 4.74 (s, 2H ), 6.95 (d, J = 5.7 Hz, 1H), 7.32 is, 5H), 7.50 (d, J = 8.3Hz, 1H), 7.79 (dd, J = 1.3Hz, 8.3Hz, 1H), 8.04 (s, 1H), 8.24 (d, J = 5.7Hz, 1H)

Embodiment 49 5-Ethoxycarbonyl-2 - [(4- (2-benzyloxy) ethoxy-3-methylpyridin-2-yl} methylthio] -1H-benzimidazole

00H ₂ OH ₂ OOH ₂

S. OH,

A mixture of 1.0 g of 5-carboxy-2 - [{4- (2-benzyloxy) ethoxy-3-methylpyridin-2-yl} methylthio) -1H-benzimidazole, 200 mL of ethanol and 1 mL of concentrated sulfuric acid was added under reflux conditions for 4 h while the system was dehydrated with a molecular sieve. The resulting mixture was neutralized with a saturated aqueous sodium carbonate solution, distilled to remove the ethanol, and then added with a saturated sodium hydrogencarbonate aqueous solution. The thus-obtained mixture was extracted with chloroform. The extract was dried over magnesium sulfate and filtered. The Fittrat was concentrated for the purpose of obtaining a crude product. This crude product was purified by silica gel column chromatography to recover 0.76 g of the title compound.

¹ H-NMR (DMSOd ₆ ) δ;

1.35 (t, J = 7.0 Hz, 3H), 2.25 (s, 3H), 3.7 ~ 3.9 (m, 2H), 4.15 - 4.3 (m , 2 H), 4.24 (q, J = 7.0 Hz, 2 H), 4.57 (s, 2 H), 4.75 (s, 2 H), • 6.96 (d, J = 5.7Hz), 7.32 (s, 5H), 7.52 (d, J = 8.5Hz, 1H), 7.79 (dd, J = 1.3Hz, 8.5Hz, 1H), 8.05 (d, J = 1.3Hz, 1H), 8.24 (d, J = 5.7Hz, 1H)

Embodiment 50 Sodium salt of S-ethoxycarbonyl-2 - [(4- (2-benzyloxy) ethoxy-3-methylpyrldin-2-yl) methylsulf:.) Yl] -1H-benzimidazole

CH ₃ OH ₂ O ₂ O

00H ₂ OH ₂ OCH ₂ -

0.7 g of 5-ethoxycarbonyl-2 - [{4- (2-benzyloxy) ethoxy-3-methylpyridin-2-yl} methylthio] -1H-benzimidazole was dissolved in 50 ml of dichloromethane to obtain a solution. 0.3 g of 85% m-chloroperbenzoic acid was added to this solution at -45 ° C. After two hours, the mixture obtained was heated to -30 ° C. and then admixed with 0.43 g of triethylamine After 30 minutes, the mixture thus obtained was heated to -10 ° C. and admixed with 50 ml of a saturated aqueous sodium bicarbonate solution The mixture was stirred vigorously at room temperature for 30 min and extracted with dichloromethane The extract was dried over magnesium sulfate and filtered The filtrate was concentrated and the residue obtained was dissolved in 10 mL of dichloromethane and then 0.056 g of 60% sodium hydride was added Mixture was stirred at room temperature for 30 minutes and distilled to remove the dichloromethane, and the resulting residue was recrystallized from ether to obtain 0.59 g of the title compound.

¹ H-NMR (DMSO-d _e ) δ;

1.34 (t, J = 7.0Hz, 3H), 2.18 (s, 3H), 3.7 ~ 3.9 (m, 2H), 4.1 ~ 4.3 (m, 2 H), 4.24 (q, J = 7.0 Hz, 2H), 4.57 (s, 3H), 4.65 (s, 2H), 6.94 (d, J = 5, 7Hz, 1H), 7.30 (s, 5H), 7.50 ~ 7.86 (m, 3H), 8.26 (d, J = 5.7Hz, 1H)

Embodiment 51 2- [4- (4-Methoxybutoxy) pyrldln-2-yl] methyltnlo-1H-benzimidazole

0OH ₂ OH ₂ CH ₂ OH ₂ OCH ₃

CHr

A mixture of 2.55 g (0.017 mol) of 2-mercaptobenzimidazole, 5.09 g (0.022 mol) of 2-chloromethyl-4- (4-methoxybutoxy) pyridine, 0.84 g (0.020 mol) of 95% sodium hydroxide and 60 ml of ethanol C 1.5h stirred at 4O ^0th After completion of the reaction, the reaction mixture was distilled to remove the solvent. The obtained residue was purified by silica gel column chromatography (ethyl acetate / n-hexane) to obtain 4.13 g of the title compound.

¹ H-NMR (DMSO-d _e ) δ;

1.43 ~ 1.84 (m 4H), 3.21 (s, 3H), 3.31 (t, J = 6.2Hz, 2H), 3.99 (t, J = 6.2Hz, 2H ), 4.59 (s, 2H), 6.75~6.89 (m, 1H), 7.04~7.21 (m, 2H), 7.25-7.56 (m, 2H) , 8.31 \ d, J = 6.2Hz, 1H)

Embodiment 52

Sodium salt of 2- [4- (4-methoxybutoxy) pyridin-2-yl] -methylsulphinyl-1H-benzimidazole

OCH ₀ OH ₉ OHpOH ₂ OOH ₃

C, C C C J

2.06 g (0.006 mol) of 2- [4- (4-methoxybutoxy) pyridin-2-yl] methylthio-1H-benzimidazole was dissolved in 80 ml of dichloromethane to obtain a solution. This solution at ⁰ -4o C in a nitrogen atmosphere, 1.30 g (0.006 mol) was added 80% chloroperbenzoic acid and 5 ml of methanol. The recovered mixture was stirred for 1.5 hours. After completion of the reaction, 1.0 g of triethylamine was added to the reaction mixture. The mixture thus obtained was heated to -10 ° C and then treated with 50 ml of an aqueous 2 N sodium carbonate solution.

The recovered mixture was stirred at room temperature for 30 minutes and extracted twice with 150 ml of dichloromethane. The extract was dried over magnesium sulfate and filtered. The filtrate was distilled to remove the solvent, and the residue obtained was dried under vacuum conditions to obtain an oil. This oil was dissolved in 54 ml of 0.1 N aqueous sodium hydroxide and then ethanol was added. The mixture thus obtained was distilled to remove the solvent. The obtained residue was washed with ether three times and dried in vacuo to obtain 2.02 g of the title compound as a white powder.

¹ H-NMR (DMSO-d ₆ ) δ;

1.40-1.74 (m, 4H), 3.17~3.40 (m, 2H), 3.23 (s, 3H), 3.66-3.88 (m, 2H), 4.48 (ABq, J = 12.5Hz, Δ ^ = 12.7Hz, 2H), 6.60 ~ 7.00 (m, 3H), 7.35 ~ 7.58 (m, 2H ), 8.32 (d, J = 6.2 Hz, 1H)

Embodiment 53 2- [4- (3-Methoxypropoxy) pyridin-2-yl] methylthio-1H-benzimidazole

A mixture of 1.50 g (0.01 mol) of 2-mercapto-1H-benzimidazole, 3.20 g (0.015 mol) of 2-chloromethyl-4- (3-methoxypropoxy) pyridine, 0.51 g (0.012 mol) of 95 % sodium hydroxide and 60 ml of ethanol was stirred at 4O ⁰ C for 0.5 h long and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate / n-hexane) to obtain 3.27 g of the Tiiel compound as a colorless crystal.

¹ H-NMR (DMSO-do) δ;

1.62 ~ 2 "Z (m, 2H), 3.16 (s, 3H), 3.34 (t, J = 6.2Hz, 2H), 3.97 (t, J = 6.2Hz, 2H ), 4.51 (s, 2H), 6.62~6.84 (m, 1H), 6.88~7.16 (m, 2H), 7.20~7.48 (m, 2H) , 8.20 (d, J = 6.2Hz, 1H)

Ausführungsbelspie! 54

Sodium salt of 2- [4- (3-methoxypropoxy) pyridin-2-yl]> methylsulfinyl-1H-benzimidazole

00H ₉ OH ₉ OH ₀ OOH, ι dd ά i

OH,

1.65 g (0.005 mol) of 2-I4- (3-methoxypropoxy) pyridin-2-yl-methylthio-1H-benzimidazole was dissolved in 50 ml of dichloromethane to provide a solution. To this solution was added at -40 ° C 1.08 g (0.005 mol) of 80% oligom-chloroperbenzoic acid in a nitrogen atmosphere. The resulting mixture was stirred for 15 minutes. After completion of the reaction, 0.8 g of triethylamine was added to the reaction mixture. Oasgewonnene mixture was heated to - 1O ⁰ C and then treated with 30ml of an aqueous 2 N sodium carbonate solution. The recovered mixture was stirred at room temperature for 30 minutes and extracted three times with 100 ml of dichloromethane. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and dried in vacuo. The residue thus obtained was dissolved in 50 ml of aqueous 0.1 N sodium hydroxide and added with ethanol. The recovered mixture was distilled to remove the solvent, and the residue was washed with ether and dried in vacuum to obtain 1.70 g of the title compound as a white crystal.

'H NMR (CMSOA) δ;

1.70-1.98 (m, 2H), 3.22 (s, 3H), 3.37 (t, J = 6.2Hz, 2H), 3.44 ~ 3.89 (m, 2H), 4, 47 (ABq, J = 12.3Hz, Δ / = 10.6Hz, 2H), 6.70 ~ 6.94 (m, 4H), 7.42 ~ 7.53 (m, 2H), 8.32 (d, J = 5.8Hz, 1H)

Embodiment 55 2- [4- {3- (2-Methoxyethoxy) propoxy} -3-methylpyridin-2-yl] methylthio-1H-benzimidazole

OCH ₀ OH ₀ Oh ₀ OCH ₅ CH ₉ OGH.

2.24 g of triethylamine and 1.27 g of methanesulfonyl chloride were added to a solution of 1.4 g of crude 2-hydroxymethyl-4 - {- (2-methoxy)} - 3-m) -thylpyridine in dichloromethane at -30 ° C. The recovered mixture was gradually brought to room temperature and treated with a saturated aqueous sodium hydrogencarbonate solution. Dp., Mixture was stirred for 30min and extracted with chloroform. The extract was dried over magnesium sulfate and distilled under reduced pressure to remove the chloroform. There was thus obtained 1.9 g of crude [4- {3- (3-methoxyethoxy) propoxy} -3-methylpyridin-2-yl) methyl methanesulfonate as a red oil. To this oil was added 0.83 g of 2-mercapto-1H-benzimidazole. The resulting mixture was stirred together with 20 ml of ethanol at room temperature for 30 min and then treated with a saturated aqueous sodium bicarbonate solution. The recovered mixture was stirred at room temperature for 30 minutes and extracted with chloroform. The extract was dried over magnesium sulfate and distilled under reduced pressure to recover a residue. This residue was chromatographed on a silica gel column and eluted with ethyl acetate / n-hexane to obtain 1 55 g of an oil. ¹ H-NMR (CDCl ₃ ) O;

2.12 (q, J = 6.1 B Hz, 2 H), 2.25 (s, 2 H), 3.36 (s, 3 H), 3.56 (m, 2 H), 3, 66 (t, J = 6.15 Hz, 2H), 4.14 (t, J = 6.15 Hz, 2H), 4.37 (s, 2H), 6.77 (d, J = 5 , 72 Hz, 1H), 7.1 ~ 7.25 (m, 2H), 7.528 (m, 2H), 8.33 (d, J = 5.72 Hz, 1H)

Embodiment 56

Sodium salt of 2- [4- {3- (2-methoxyethoxy) propoxy} -3-methylpyridin-2-yl] methylsulfinyl-1H-benzimidazole

OCH ₂ OH ₂ CH ₂ OCH ₂ CH ₂ OCh ₃

681 mg of 85% m-chloroperbenzoic acid were added in portions of a solution of 1.3 g of 2- [4- {3- (2-methoxyethoxy) propoxy} -3-methylpyridin-2-ylmethylthio-IH-benzimidazole in 70 ml of dichloromethane with stirring and Dehumidifying added. The resulting mixture was stirred for 30 minutes and then 483 r. g of triethylamine. The resulting mixture was warmed to -20 ° C and then pre-treated with aqueous 2 N sodium carbonate solution. The resulting mixture was stirred at room temperature for 30 minutes and extracted twice with dichloromethane.

The extract was washed with a saturated aqueous sodium hydrogencarbonate solution, dried over magnesium sulfate and distilled under reduced pressure to obtain a crude oil. To this oil was added 30 ml of aqueous 0.1 N sodium hydroxide and ethanol. The recovered mixture was distilled under reduced pressure in WC to remove the medium.

The si? Ethanol was added to the residue and the resulting mixture was reduced in volume

Distilled pressure to remove the medium. The obtained residue was crystallized from anhydrous ether to obtain 1.24 g of a crystal.

¹ H-NMR (DMSO-dg) δ;

1.98 (q, J = 6.15Hz, 2H), 2.15 (s, 3H), 3.22 (s, 3H), 3.47 (m, 4H), 3.56 (t, J = 6.15H, 2H), 4.09 (t, J = 6.15Hz, 2H), 4.542

(ABq, J = 13.18Hz, Δ? = 14.74Hz, 1H), 6.8 ~ 7 * (m, 3H), 7.39 ~ 7.57 (m, 2H), 8.27 (i.e. , J = 5.71 Hz, 1H)

Illustrative Embodiment 57 2 - [(4- (4-Methoxybutoxy) -3-methylpyrldln-2-yl} methylthio] -1H-benzimidazole

OCH ₂ CH ₂ OH ₂ GH ₂ OOh ₃

611 mg of triethylamine and 686 mg of methanesulfonyl chloride were added to a solution of 0.84 g of crude 2-hydroxy-4- (4-methoxybutoxy) -3-methylpyridine in 30 ml of dichloromethane at -20 ° C with stirring and dehumidifying to obtain a mixture win.

This mixture was gradually brought to room temperature and then treated with a saturated aqueous sodium bicarbonate solution. The resulting mixture was stirred for 30 minutes and extracted with chloroform. The extract was dried over magnesium sulfate and distilled under reduced pressure to remove the chloroform. In this way, an oil was obtained. To this oil was added 560 mg of 2-mercapto-1H-benzimidazole and 30 ml of ethanol. The resulting mixture was stirred at room temperature for 30 minutes, basified with a 2N aqueous sodium carbonate solution and extracted with chloroform. The extract was dried over magnesium sulfate and distilled under reduced pressure to remove the chloroform. The obtained residue was chromatographed on a silica gel column and eluted with ethyl acetate / n-hexane to obtain 0.42 g of an oil.

¹ H-> !. ί (CDCI ₃ ) δ;

1.4~2.16 (m, 4H), 2.26 (s, 3H), 3.35 (s, 3H), 3.45 (t, J = 5.72 Hz, 2H), 4.06 (t, J = 5.72Hz, 2H), 4.37 (s, 2H), 6.74 (d, J = 5.71Hz, 1H), 7.1 ~ 7.2D ( m, 2H), 7.48 ~ 7.56 (m, 2H), 8.33 (d, J = 5.72 Hz, 1H)

Preparative Example 15 [4- {3- (2-Methoxyethoxy) propoxy} -3-methylpyrldin-2-yl] methyl methanesulfonate

0OH ₂ OH ₂ OH ₂ OOH ₂ Ch ₂ OCIH ₃

Il

S - 00H ₂

2.24 g of triethylamine and 1.27 g of methanesulfonyl chloride were added to a solution of 1.4 g of crude 2-hydroxy-4- {3- (2-methoxyethoxy)} - 3-methylpyridine in dichloromethane at -30 ° C to obtain a mixture , This mixture was brought to room temperature and then admixed with a saturated aqueous sodium bicarbonate solution. The recovered mixture was stirred for 30 minutes and extracted with chloroform. The extract was dried over magnesium sulfate and distilled under reduced pressure to remove the chloroform. There were 1.9 ge ^! of crude red oil.

Exemplary Embodiment 58 2- [4- {3- (2-Methoxyethoxy) propoxy) -3-methylpyrldyl-2-yl] methylthio-1H-benzylmiclazole

A mixture of 1.9 g of crude 14- {3- (2-methoxyethoxy) propoxy) -3-methylpyridin-2-ylmethyl methanesulfonate, 0.83 g of 2-mercapto-IH-benzimidazole and 20 ml of ethanol was stirred at room temperature for one hour , basified with a saturated aqueous sodium bicarbonate solution and extracted with chloroform. The extract was dried over magnesium sulfate and distilled under reduced pressure. The concentrated residue was chromatographed over a silica gel column and eluted with ethyl acetate / n-hoxan to recover 1.5 g of an oily product.

¹ H-NMR (CDCl ₃ ) O;

2.12 (q, J = 6.2 Hz, 2H), 2.25 (s, 3H), 3.36 (s, 3H), 3.57 (m, 2H), 3.66 (t, J = 6.2 Hz, 2H), 4.14 (t, J = 6.2 Hz, 2H), 4.37 (s, 2H), 6.77 (d, J = 3 , 1 Hz, 1 H), 7.15 (m, 2 H), 7.53 (m, 2 H), 8.39 (d, J = 3.1 Hz, 1 H)

Preparative Execution Plaque 16 2-Chloromethyl-4- (4-methoxybutoxy) pyridine

0OH ₂ OH ₂ OH ₂ OH ₂ UOH ₃

010H ₂

5.6 g of crude 2-hydroxymethyl-4- (4-methoxybutoxy) pyridine was dissolved in 80 ml of chloroform to give a solution. To this solution was added a solution of 3.8 g of thionyl chloride in 10 ml of chloroform dropwise at 0 ° C. The recovered mixture was stirred at ⁰ ° C. for one hour. After completion of the reaction, the reaction mixture was neutralized with a saturated sodium hydrogencarbonate aqueous solution and extracted twice with 200 ml of chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was distilled to remove the solvent . uifornen. The concentrated residue was dried in vacuo to obtain 5.09 g of the title compound as a crude oil.

¹ H-NMR (CDCl ₃ ) S;

1.55 ~ 2.05 (m, 4H), 3.35 (s, 3H), 3.38 ~ 3.53 (m, 2H), 3.91 ~ 4.17 (m, 2H ), 4.61 (s, 2H), 6.55~7.01 (m, 2H), 8.36 (d,

J = 6.2 Hz, 1H)

Exemplary Embodiment 17 2-Hydroxymethyl-4- (4-methoxybutoxy) pyridine

0OH ₂ OH ₂ OH ₂ CH ₂ OOH ₃

HIGH

5.06 g (0.024 mol) of 4- (4-methoxybutoxy) -2-methylpyridine-1-oxide was dissolved in 80 ml of acetic anhydride to give a solution. This solution was stirred at 100 ^° C. for one hour, cooled and distilled to remove the solvent. To the residue was added 150 ml of 1N hydrochloric acid.

The mixture thus obtained was stirred at 100 ^° C. for one hour, neutralized with sodium bicarbonate and extracted twice with 200 ml of chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was distilled to remove the solvent and the residue was dried in vacuo to afford 5.66 g of the title compound as a crude oil.

¹ H-NMR (CDCl ₃ ) O;

1.58 ~ 2.08 (m, 4H), 3.32 - · 3.54 (m, 2H), 3.34 (s, 3H), 3.82 - 4.16 (m, 2 H), 4.69 (s, 2H), 5.02 (s, 1H), 6.54~6.88 (m, 2H),

8.30 (d, J = 6.2 Hz, 1H)

Preparative Embodiment 18 4- (4-Methoxybutoxy) -2-methylpyridine-1-oxld

0OH ₂ OH ₂ OH ₂ OH ₂ OCIh ₃

6.77 g (0.065 mol) of 4-methoxybutanol was dissolved in 60 ml of dimethylsulfoxide to obtain a solution. To this solution was added 2.6 g (0.065 mol) of 60% sodium hydride at room temperature in a nitrogen atmosphere. The recovered Geniisch was heated to 60 ° C, stirred for one hour and cooled to room temperature. To the resulting mixture, a solution of 4.66 g (0.032 mol) of 4-chloro-2-methylpyridine-1-oxide in 20 ml of dimethylsulfoxide was added dropwise. The mixture thus obtained was stirred for one hour at 4O ⁰ C.

After completion of the reaction, 5 ml of water was added to the mixture, and the resulting mixture was evaporated to dryness to remove the solvent. To the residue was added 150 ml of water. The recovered mixture was extracted four times with 200 ml of chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was distilled to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate / methanol) to obtain 5.06 g of the title compound as an oil.

¹ H-NMR (CDCl ₃ ) O;

1.54 ~ 2.07 (m, 4H), 2.52 (s, 3H), 3.36 (s, 3H), 3.44 (t, J = 6.2Hz, 2H), 4.01 ( t, J = 6.2Hz, 2H), 6, j0 ~ 6.84 (m, 2H), 8.14 (d, J = 5.3Hz, 1H)

Preparative Embodiment 19 4-Methoxybutanol

CH ₃ OCHjCH ₂ CH ₂ CHjOH

27.04 g (0.3 mmol) of 1,4-butanediol was dissolved in 150 ml of tetrahydrofuran to obtain a solution. To this solution was added 7.2 g (0.18 mol) of 60% sodium hydride at 0 ° C in a nitrogen atmosphere. The mixture thus obtained was heated under reflux conditions for one hour and then cooled to ⁰ ° C. To the resulting mixture, 21.73 g (0.15 mol) of 98% methyl iodide was added dropwise. The mixture thus obtained was stirred at a temperature of 30 ⁰ C or below for 1.5 hours long. After completion of the reaction, the reaction mixture was filtered. The filtrate was distilled to remove the solvent. To the residue was added 200 ml of water, and the resulting mixture was washed with 200 ml of η-hexane and extracted with 200 ml of chloroform four times. The extract was dried over magnesium sulfate and filtered. The filtrate was distilled to remove the solvent. Were recovered 14.5 g of the title compound.

'H-NMR (CDCI ₃₎ O;

1.54 ~ 1.80 (m, 4H), 1.71 (s, 1H), 3.32 (s, 3H), 3.34 ~ 3.73 (m, 4H)

Preparative Embodiment 20 2-Chloromethyl-4- (3-methoxypropoxy) pyridine

00H ₂ OH ₂ OH ₂ OOH ₃

GlOH ₂

A solution of 2.60 g (0.022 mol) of thionyl chloride in 10 ml of chloroform was added dropwise to a solution of 3.64 g (0.018 mol) of 2-hydroxymethyl-4-methoxypropoxypyridine in 60 ml of chloroform while cooling with ice. The recovered mixture was stirred for one hour, neutralized with a saturated aqueous solution of sodium hydrogencarbonate and extracted with chloroform. The chloroform layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 3.23 g of the title compound as a crude product.

¹ H-NMR (CDCl ₃ ) O;

1.80 ~ 2.20 (m, 2H), 3.31 (s, 3H), 3.49 (t, J = 6.2Hz, 2H), 4.07 (t, J = 6.2Hz, 2 H), 4.55 (s, 2H), 6.52 ~ 6.96 (m, 2H), 8.26 (d, J = 5.3Hz, 1H)

Prfiparetlves Ex bulation 21 21 2-hydroxymethyl-4- (3-methoxypropoxy) pyridine

OCH ₂ OH ₂ OH ₂ OOH ₃

4.05 g (0.02 mol) of 4-methoxypropoxy-2-methylpyridine-1-oxide was dissolved in 50 ml of acetic anhydride to give a solution. This solution was stirred at 9O ⁰ C for 0.5 h and cooled and then treated with ethanol. The recovered mixture was concentrated under reduced pressure and then replaced with 150 ml of 1N hydrochloric acid. The thus-obtained mixture was stirred at 100 ° C for one hour, cooled, neutralized with sodium hydrogencarbonate and extracted with chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was distilled to remove the solvent. In this way, 3.64 g of the title compound was recovered as a crude product.

¹ H-NMR (CDCl ₃ ) S;

1.83 ~ 2.20 (m, 2H), 3.30 (s, 3H), 3.49 (t, J = 5.3Hz, 2H), 4.05 (t, J = 5.3Hz, 2H ), 4.64 (s, 2H), 4.70 (s, 1H), 6.48 ~ 6.86 (m, 2H), 8.21 (d, J = 6.2Hz, 1H)

Preparative Embodiment 22 4- (3-Methoxypropoxy) -2-methylpyridine-1-oxide

OCH ₂ CH ₂ OH ₂ OCH

5.85 g (0.065 mol) of methoxypropanol was dissolved in 60 ml of dimethyl sulfoxide to obtain a solution. To this solution was added 2.6 g (0.065 mol) of sodium hydride at room temperature in a nitrogen atmosphere. The mixture thus obtained was stirred at 60 ° C for 0.5 h. To the mixture, a solution of 4.66 g (0.0325 mol) of 4-chloro-2-methylpyridine-1-oxide in 20 ml of dimethylsulfoxide was added dropwise while cooling with ice. The mixture was stirred at 40 ° C for 1 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a solid. To this solid was added 200 ml of water. The recovered mixture was extracted with chloroform, and the obtained extract was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate / methanol) to obtain 4.09 g of the title compound.

'H-NMR (CDCI ₃₎ S;

1.80-2.24 (m, 2H), 2.48 (s, 3H), 3.31 (s, 3H), 3.48 (t, J = 6.3Hz, 2H), 4.02 ( t, J = 6.3Hz, 2H), 6.50~6.78 (m, 2H), 8.04 (d, J = 7.2Hz, 1H)

Preparative Example 23 4-Chloro-2-methylpyridine-1-oxide

01

15.4 g (0.1 mol) of 2-methyl-4-nitropyridine-1-oxide were added at -10 ° C to 78.5 g (1 mol) of acetyl chloride. The resulting mixture was stirred with ice cooling for 0.5 hours. After completion of the reaction, 300 ml of ice water was added to the reaction mixture. The recovered mixture was neutralized with sodium carbonate and extracted with chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate / n-hexane / methanol) to obtain 4.7 g of the title compound.

¹ H-NMR (CDCl ₃ ) O; , 2.48 (s, 3H), 6.94~7.30 (m, 2H), 8.09 (d, J = 7.2Hz, 1H)

Embodiment 59 Sodium salt of 2 - [{4- (4-methoxybutoxy) -3-methylpyrldin-2-yl) methylsulfinyl] -1H-benzimidazole

0OH ₂ GH ₂ OH ₂ OH ₂ OuH ₃

0.4 g of 2-I {4- (4-methoxybutoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole was dissolved in 40 ml of dichloromethane with dehydration to obtain a solution. To this solution was added portionwise m-chloroperbenzoic acid 227mg at -40 ⁰ C. The mixture thus obtained was stirred for 30 minutes and then treated with 160 mg of triethylamine. The recovered mixture was warmed to -20 ⁰ C and then treated with 30ml of an aqueous 2N sodium carbonate solution. The recovered mixture was stirred for 40 minutes and extracted with dichloromethane. The extract was washed with a saturated aqueous sodium hydrogencarbonate solution, dried over magnesium sulfate and distilled under reduced pressure to remove the dichloromethane. In this way, 0.43 g of an oily product was recovered. This product was dissolved in a mixture of 11.2 ml of aqueous 0.1 N sodium hydroxide and 30 ml of ethanol, and the resulting solution was distilled under reduced pressure to remove the solvent. Ethanol was added to the residue thus obtained, and the recovered mixture was distilled under reduced pressure to remove the solvent. The residue was crystallized from ethanol / ether to obtain 0.37 g of the title compound in the form of a crystal.

¹ H-NMR (DMSO-de) δ;

1.84 (m, 4H), 2.16 (s, 3H), 3.24 (s, 3H), 3.38 (t, J = 6.2 Hz, 2H), 4.06 (t, J = 6.2 Hz, 2H), 4.55 (ABq, J = 13.2Ηζ, Δ

V = 18.1 Hz, 2H), 6.8 ~ 6.98 (m, 3H), 7.4 ~ 7.6 (m, 2H), 8.27 (d, J = 5.3Hz, 1H )

Preparative Example 24 4- (3-Methoxypropoxy) -2,3,5-trimethylpyridine-1-oxld

00H ₂ OH ₂ OH ₂ OOH ₃

4.5 g (0.05 mol) of methoxypropanol was dissolved in 45 ml of dimethylsulfoxide to give a solution. To this solution was added 2.0 g of 60% sodium hydride at room temperature in a nitrogen atmosphere. The resulting mixture was warmed to 6O ⁰ C and stirred for one hour. After the completion of the reaction, a solution of 4.3 g (0.025 mol) of 4-chloro-2,3,5-trimethylpyridine-1-oxide in 15 ml of dimethyl sulfoxide was added dropwise to the reaction mixture at room temperature. The mixture obtained was stirred at 6O ⁰ C for 5 hours, cooled and distilled ösungsmittels for disposal of 1 to dryness. The residue obtained was added to 200 ml of water. The recovered mixture was extracted with 150 ml of chloroform five times. The extract was dried over magnesium sulfate and filtered. The filtrate was distilled to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate / n-hexane) to obtain 4.27 g of the title compound as an oil.

Preparative Example 25 2-Hydroxymethyl-4- (3-methoxypropoxy) -3,4-dimethylpyridine

00H ₂ OH ₂ OH ₂ OCH ₃ b

T ^ TT

HO

4.25 g (0,019mol) (4- (3-methoxypropoxy) -2,3,5-trimethylpyridine were oxide-1 dissolved in 40 ml of acetic anhydride to obtain a solution. This solution was stirred C. for 30 min at 100 ^0, cooled and distilled in order to remove the solvent. thus, an oil was obtained. to this oil were 50 ml of 1 N hydrochloric acid was added. the mixture obtained was stirred at 100 ⁰ C for one hour, cooled, neutralized with sodium hydrogencarbonate and extracted with 150 ml of chloroform three times. The extract was dried over magnesium sulfate, filtered, and the filtrate was distilled to remove the solvent, and the recovered Ri.kstP.-G was vacuum-dried to obtain 4.70 g of the title compound as a crude oil.

¹ H-NIvIR (CDCl ₃ ) O;

1.80 ~ 2.28 (m, 2H), 2.08 (s, 3H), 2.23 (s, 3H), 3.34 (s, 3H), 3.58 (t, J = 6.2 Hz, 2H), 3.87 (t, J = 6.2 Hz, 2H), 4.57 (s, 2H), • 8.10 (s, 1H)

Preparative Embodiment 26 2-Chloromethyl-4- (3-methoxypropoxy) -3,5-dimethylpyridine

01

CH.

Ear

00H ₂ OH ₂ OH ₂ OOH ₃

4.70 g of crude 2-hyjroxymethyl-4- (3-methoxypropoxy) -3,5-dimethylpyridine was dissolved in 50 ml of chloroform to provide a solution. Dbser A solution of 2.7g thionyl chloride in 10 ml chloroform was added dropwise at 0 ° C was added, and the mixture thus obtained was stirred for one hour at C O ^0th After completion of the reaction, the reaction mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted twice with 150 ml of chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was distilled to remove the solvent. The recovered residue was dried in vacuo to obtain 4.52 g of the title compound as a crude oil.

'H-NMR (C) CI ₃₎ O;

1.70-2.2'J (m, 2H), 2.26 (s, 3H), 2.34 (s, 3H) 3.38 (s, 3H), 3.61 (t, J = 6 , 2Hz, 2H), 3.91 (t, J = 6.2Hz, 2H), 4.67 (s, 2H), 8.18 (s, 1H)

Embodiment 60 2- [4- (3-Mothoxypropoxy) -3,4-dimethylpyridin-2-yl] methylthio-1H-benzimidazole

0OH

A mixture of 2.25 g (0.015 mol) of 2-mercaptobenzimidazole, 4,52g (0,0185mol) of 2-chloromethyl-4- (3-methoxyp ^r opoxy) -3,5-dimethylpyridine, 0.63 g (0.015 mol) 95 % sodium hydroxide and 50 ml of ethanol were stirred at 40 ^° C. for 6 hours. After completion of the reaction, the reaction mixture was distilled to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate / η-hexane) to obtain 4.62 g of the title compound as a pale yellow oil. win.

Embodiment 61 Sodium salt of 2- [4- (3-methoxypropoxy) -3,4-dimethylpyridin-2-yl] -methylsulfinyl-1H-benzimidazole

00H ₂ OH ₂ OH ₂ OCH ₃

1.5 g of 2- [4- (3-methoxypropoxy) -3,4-dimethylpyridin-2-yl) methylthio-1H-benzimidazole were dissolved in 80 ml of dichloromethane with dehydration to obtain a solution. To this solution was added portionwise 870 mg of m-chloroperbenzoic acid at ⁰ C -4o. The resulting mixture was stirred for 30min and then treated with 599mg of triethylamine. The resulting mixture was heated to -2O ⁰ C and then treated with 80ml of an aqueous 2N sodium carbonate solution. The resulting mixture was stirred for one hour and extracted with dichloromethane. The extract was washed with a saturated sodium hydrogencarbonate aqueous solution, dried over magnesium sulfate and distilled under reduced pressure to obtain 1.4 g of a crystal. 800 mg of the crystal was dissolved in a mixture of 21.4 ml of aqueous 0.1 N sodium hydroxide and ethanol. The recovered solution was distilled under reduced pressure to remove the solvent. The obtained residue was dissolved in ethanol, and the solution was distilled under reduced pressure to remove the solvent. The obtained residue was crystallized from ethanol / ether to give 800 mg of a crystal.

'H-NMR (DMSO-d ₆₎ δ;

1.94 (qui, J = 6.2Hz, 2H), 2.17 (s, 3H), 2.19 (s, 3H), 3.25 (s, 3H), 3.51 (t, J = 6.6 Hz, 2 H), 3.80 (t, J = 6.6Hz, 2H), 4.51 (ABq,

J = 13.2Hz, AV = 17.0Hz), 6.8 ~ 6.9 (m, 2H), 7.4 ~ 7.7 (m, 2H), 8.21 (s, 1H)

Exemplary Embodiment 62 2- [4- [3 - {(2-Methoxyethoxy) methoxy} propoxy] -3-methylpyridyl-2-yl] methylthio-1H-benzimidazole

S

1.8 g of 2-hydroxymethyl-4- [3 - {(2-methoxyethoxy) methoxy} propoxy) -3-methylpyridine was dissolved in 40 ml of dichloromethane with dehydration to obtain a solution, followed by the addition of 2.47 g of triethylamine. To the thus obtained mixture was added portionwise while cooling with ice, 1.4 g of methanesulfonyl chloride. The recovered mixture was stirred for 30 minutes, basified with saturated aqueous carbonic acid solution and extracted with chloroform. The extract was dried over magnesium sulfate and distilled under reduced pressure. The residue was dissolved in 30 ml of ethanol and then admixed with 917 mg of 2-mercapto-1H-benzimidazole and 367 mg of sodium hydroxide. The mixture thus obtained was at Raui. Stirred for 30min and distilled under reduced pressure to remove the ethanol. The recovered residue was chromatographed on a silica gel column and eluted with ethyl acetate / n-hexane to obtain 2.1 g of the title thioether compound

¹ H-NMR (CDCl ₃ ) O;

2.11 (qui, J = 6.2Hz, 2H), 2.25 (s, 3H), 3.35 (s, 3H), 3.58 (m, 4H), 3.75 (t, t = 6.2 Hz, 2 H), 4.13 (t, J = 6.2 Hz, 2H), 4.38 (s, 2H), 4.71 (s, 2H), 6.75 (d, J = 5.7Hz, 1H), 7.1 ~ 7.3 (m, 2H), 7.4 ~ 7.6 (m, 2H), 8.32 (d, J = 5.7Hz, 1 H)

EMBODIMENT 63 Sodium salt of 2- [4- [3 - {(2-methoxyethoxy) methoxy} propoxy] -3-methylpyrldyl-2-yl] methylsulfinyl-1H-benzimidazole

0OH ₂ OH ₂ OH ₂ OOH ₂ OOH ₂ OH ₂ OCh,

1.1 g 2 - [4- [3 - {(2-Methoxyethoxy) methoxy} propoxy) -3-methylpyridin-2-yl] methylthio-1H-benzimidazole was dissolved in 80 ml of dichloromethane while dehumidifying to obtain a solution. To this solution was 544 mg m-chloroperbenzoic acid was added in portions at -40 ⁰ C. The resulting mixture was stirred for 30min and then treated with 379mg of triethylamine. The resulting mixture was heated to -2O ⁰ C and then treated with 40 ml of an aqueous 2 N sodium carbonate solution. The resulting mixture was stirred for 30 min. Ur.J extracted with chloroform. The extract was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and distilled under reduced pressure to remove the solvent. The recovered residue was dissolved in a mixture of 24 ml of aqueous 0.1 N sodium hydroxide and 40 ml of ethanol. The recovered solution was distilled under reduced pressure to remove the solvent and then added with 40 ml of ethanol. The resulting mixture was again distilled under reduced pressure to remove the ethanol. The residue was crystallized from ethanol / ether to obtain 0.98 g of the title compound.

¹ H-NMR {DMSO-d _e ) δ;

2.02 (qui, J => 6.2Hz ₁ 2H), 2.17 (s, 3H), 3.23 (s, 3H), 3.49 (m, 4H), 3.65 (t, J = 6.2Hz, 21), 4.12 (t, J = 6.2Hz, 2H), 4.56

(ABq, J = 21.1 Hz, aV = 16.8Hz, 2H), 4.62 (s, 2H), 6.84-6.99 (m, 3H), 7.4 ~ 7.5 (m , 2H), 8.28 (d, J = 5.7Hz, 1H)

Example 27 4- (2-Fluoro-methoxy) -ethoxy-2,3-dimethyl-pyridyl-oxime

OCJH ₂ UH ₂ OGH ₂ P

To a solution of 1.0 g of 4- (2-hydroxyethoxy) -2,3-dimethylpyridine N-oxide in 40 ml of dimethylformamide was gradually added 0.49 g of sodium hydride in a nitrogen atmosphere at room temperature. After ceasing foaming, 1 ml of bromofluoromethane was added to the resulting mixture at -50 ° C. The resulting mixture was gradually heated and stirred for 3h at 15 C to 2O ^0th Ethanol was added to the resulting mixture to use up excess sodium hydride. To this mixture was added 5 ml of aqueous 1N hydrochloric acid, and through the resulting mixture, gaseous nitrogen was passed to expel excess bromofluoromethane. Water was added to the resulting mixture. The mixture thus obtained was extracted with chloroform, and the extract was dried over magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was subjected to chromatography on a silica gel column chromatography and chloroform containing 1 to 5% of methanol to obtain 0.6 g of the title compound.

¹ H-NMR (CDCl ₃ ) S;

2.24 (s, 3H), 2.56 (s, 3H), 4.24 (m, 5H), 5.3 (d, J = 55.8Hz, 2H), 6.54 (d, J = 6.2Hz, 1H), 8.12 (d, J = 6.2Hz, 1H)

Preparative Embodiment 28 4- (2-Fluoromethoxy) ethoxy-2-hydroxymethyl-3-methylpyridine

OCH ₂ OH ₂ OOH ₂ P

HIGH ₂

A crude 4- (2-fluoromethoxy) ethoxy-2,3-dimethylpyridine N-oxide-containing mixture prepared from 6.0 g of crude 4- (2-hydroxyethoxy) -2,3-dimethylpyridine N-oxide and 40 ml of acetic anhydride was heated Stirred to 90 to 100 ⁰ C for 40 minutes and distilled under reduced pressure to remove the acetic anhydride. The residue was made weakly basic with a 2N aqueous sodium carbonate solution and extracted with chloroform. The extract was dried over magnesium sulfate and distilled under pressure to eliminate the solvent. The residue obtained was dissolved in 30 ml of ethanol and then mixed with 0.38 g of sodium hydroxide. The recovered mixture was stirred at room temperature for 30 minutes, made weakly basic with a saturated aqueous ammonium chloride solution and extracted with chloroform. The extract was dried over magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was chromatographed on a silica gel column and eluted with ethyl acetate / n-hexane to obtain 1.2 g of the riveted compound as a crystal.

¹ H-NMR (CDCl ₃ ) S;

2.06 (s,? H), 4.17 (m, 4H), 4.64 (s, 2H), 5.35 (d, J = 56.3Hz, 2H), 6.71 (d, J = 5.7Hz, 1H), 8.30 (d, J = 5.7Hz, 1H)

Preparative Embodiment 29 {4- (2-fluoromethoxy) ethoxy-3-methylpyr! Dln-2-yl} methyl methanesulfonate

CHo-S-O-CH 0

OCH ₂ CH ₂ OCH ₂ P

160 mg Mothansulfonylchlorid was dropwise zugosotzt oiner solution of Ü, 2G4 (? .- Fluoromothoxy) nthoxy-2-hydroxynothyl-3 · methylpyridine and 143mg in 10ml chloroform TrOthylamln untnr dehumidifying \ γλ -SO ^1C. The Gowonnono Gomisch was gradually heated to room temperature, basified with a gosättigton wassrigon notriumhydrogencarbonate solution, and extracted with chloroform. The extract was dried over magnesium sulfate and distilled to remove the solvent. There was recovered 0.30 g of the title compound as a crude oil.

'H-NMR (CDCI ₃₎ O;

2.30 (s, 3H), 3.08 (s, 3H) 4.2 (m, 4H), 6.4 (d, J »G5.8 Wt, 2H), 6.38 (s, 2H) , 6.84 (ti, J »OH /, 1H), 3.36 (d, J» C "1H)

Embodiment Bpl 64 2 - [(4- (2-fluoromethoxy) ethoxy-3-methylpyrldin-2-yl) methylthio] -1H-benzimidazole

A mixture of crude {4 · (^ ΡΙυοΓο ™ β ^ οχν) βΟιοχγ-3 ^ βΜνΙρνΜίη-2 · νΙ) ηιβ ηνΙ · ιτιοΐΓΐ8η5ΐιΚοη8ΐ., Which consists of 0.6 g of 4 · (2 · fluoromethoxylethoxy ^ -hydroxymethyl-a-mfithylpyridin 0.42 g of 2-Morcapto-1H-benzimidazole and 30 ml of ethanol were stirred at room temperature for 30 minutes, distilled and distilled under pre-pressure to remove the ethanol, and the residue obtained was chromatographed on a pad of kiosel gel and eluted with mothanul / ethyl acetate to obtain 0.3 g of an oily product.

¹ H-NMR (CDCl ₃ ) O;

2.25 (see 3H), 2.98 (s, 3H), 4.13 (m, 4H), 4.41 (s, 2H), 5.33 (d, J - 56.3Hz, 2H ), 6.72 (d, J = Sr Hz, 1H), 7.1 ~ 7.2 (m, 2H), 7.4 ~ 7.6 (m, 2H), 8.32 (d, J = 5.7Hz, 1H)

Implementation Guide 65

Sodium salt of 2 - [{4- (2-fluoromethoxy) ethoxy-3-methylpyrldin-2-yl} methylsulfinyl} H-benzimidazole

OCH ₂ CH ₂ OOH ₂ P

184 ms of m-chloroperbenzoic acid were added portionwise to a solution of 0.3 g of 2 - [{4- (2-fluoromethoxy) ethoxy-3-r, .dylpyridin-2-yl} methylthiol-1H-benzimidazole in 30 ml of dhlormothan with stirring and dehumidifying -40 ° C added. The resulting mixture was stirred for 30 minutes and then treated with 129mg of triethylamine. The recovered mixture was brought to room temperature, made weakly basic with a saturated aqueous sodium hydrogencarbonate solution and extracted with chloroform. The extract was dried over magnesium sulfate and distilled under reduced pressure to remove the solvent. The obtained residue was dissolved in a nitrogen atmosphere in 30 ml of anhydrous tetrahydrofuran to obtain a solution. To this solution was added at -2O ⁰ C 36.2 mg 60% sodium hydride. After the foaming ceased, the recovered mixture was distilled under reduced pressure to remove the tetrahydrofuran. The residue was crystallized from anhydrous ether to obtain 7'JOmg of the title compound as a crystal.

¹ H-NMR (DMSO-de) δ;

2.18 (s, 3H), 4.14 (m, 4H), 4.56 (ABq, J = 13.2Hz, A ^ - 21.3Hz, 2H), 5.37 (i.e. , J = 56.7 Hz, 2H), 6.8 ~ 7.0 (m, 3H), 7.4 - 7.5 (m, 2H), 8.29 (d, J = 5, 3 Hz, 1H)

Execution roller ββ

2 · ((4 · {2 · (1 H-Benzimidazol-2-yl-thio) ethoxv} -3-methylpyrldln-2-yl] · methylthyl · H-benzimidazole

A mixture of 1.34 g (G ₁ OMmol) 2 - ({4- (2-chloroethoxy) -3-mothylpyridin-2-yl} mothylthio] -1H-bonzlmidazole, 0.53 g (0.0035 mol) 2-mercapto 1 H-benzimldazol, 0.17 g (0,004mol) 95% sodium hydroxide and 30ml e C was stirred 8h at 8O ⁰ HANOL. After completion of the reaction, the Roaktionsgomlsch was filtriort, u, to remove ι inorganic substance. the filtrate was distilled To remove the solvent, the residue was purified by kiosel gel column chromatography (ethyl acetate / n-hoxan) to obtain 1.08 g of the titled compound as a white clay crystal.

'H NMR (DMSO-d _e ) 6;

2.15 (s, 3H), 3.73 (t, J = 7.1 Hz, 2H), 4.23 (t, J x = 7.1 Hz, 2H), 4.68 (s, 2H) , 6.96-7.22 (m, 5H), 7.32~7.54 (m, 4H), 8.25

(d, J = 5.3Hz, 1H)

Implementation Guide 67 Dl-sodium salt of 2 - [[4- {2- (1H-benzenediazole-2-ylsulphinyl) -ethoxy) -3-methylpyrldin-2-yl] -othylsulphinyl-1H-benzimidazole

N / A

0.90 g (0.002 mol) of 2- (4H-bazimiclazole) -ylthiolethoxy-S-mothylpyridine-1-methylmethylthiol-i H-benzimidazole was suspended in 40 ml of dichloromethane to obtain a suspension of the suspension Mothanol was added until the suspension blew. To the resulting mixture was added 0.43 g (0.002 mol) of 80% m-chloroperbenzoic acid in a nitrogen atmosphere at -60 ° C. The gowonnono mixture was stirred for 0.5 h completion dor reaction, the reaction mixture 0, & g of triethylamine. the obtained mixture was heated at -1O ⁰ C and then mixed with 30ml of a saturated aqueous sodium bicarbonate solution. the mixture obtained was stirred for 0.5 h at room temperature and filtered. the filtrate was extracted three times with 100 ml of dichloromethane, the extract was dried over magnesium sulfate, filtered, the filtrate was distilled to remove the solvent, and 0.14 g of the residue obtained was obtained dissolved in aqueous 0.1 N sodium hydroxide and then treated with ethanol. The recovered mixture was distilled to remove the solvent. The obtained residue was washed with ether to obtain 0.15 g of the title compound as a yellow crystal.

'H-NMR (DMSO-d,) δ;

2.18 (s, 3H), 3.20-3.75 (m, 2H), 4.19~4.74 (m, 4H), 6.68~7.08 (m, 5H), 7, 16 ~ 7.53 (m, 4H), 8.20 (d, J = 6.2Hz, 1H)

291

Export Insurance Scheme 68

V-β _

A mixture of 1.34 g (0.004 mol) of 2- {4- (2-chloro-.oxy) -3-methylpyridin-2-yl} methylthio) -1H-benzimidazole, 0.59 g (0.0035 mol) 2 Mercaptobenzothiazole, 0.17 g (0.004 mol ⁾ , 95% sodium hydroxide and 30 ml of ethanol were pre-stirred for 16 hours at 80 ° C. After completion of the reaction, the reaction mixture was filtered to remove the inorganic substance of the solvent, and the residue was purified by silica gel column chromatography (ethyl acetate / n-hoxan) to obtain 1.20 g of the title compound as a white crystal.

¹ H-NMR (DMSO-de) δ;

2.08 (s, 3H), 3.79 (t, J = 6.2Hz, 2H), 4.40 (t, J = 6.2Hz, 2H), 4.60 (s, 2H), 6, 88 ~ 7.21 (m, 3H), 7.22 ~ 7.50 (m, 4H),

7.68~8.02 (m, 2H), 8.16 (d, J = 6.2 Hz, 1H)

Implementation Certificate 69

Sodium salt of 2 - ([4- (2- (benzyl-2-ylsulyl) ethoxy} -3-methylpyridin-2-yl] methylsulfinyl] -1H-benzimidazole

0.93 g (0.002 mol) of 2 - [[4- {2- (benzothiazol-2-ylthio) ethoxy} -3-methylpyridin-2-yl) methylthio] -1H-benzimidazole was suspended in 40 ml of dichloromethane. Methanol was added to the recovered suspension until the suspension became transparent. To the resulting mixture were added in a nitrogen atmosphere at -6O ⁰ C 0,43g of 80% m-Chloroperbsnzoesäure. The recovered mixture was stirred for 0.5h. After completion of the reaction, 0.6 g of triethylamine was added to the reaction mixture, and the resulting mixture was heated to -10 ° C and then treated with 30 ml of a saturated aqueous sodium bicarbonate solution. The recovered mixture was stirred at room temperature for 0.5 h and extracted twice with 100 ml of dichloromethane. The extract was dried over magnesium sulfate and filtered. The filtrate was distilled to remove the solvent. 0.8 g of the recovered residue was dissolved in aqueous 0.1 N sodium hydroxide and then added with ethanol. The recovered mixture was distilled to remove the solvent. The obtained residue was washed with ether to obtain 0.69 g of the title compound.

'H NMR (DMSO-d _e ) 6;

2 ₍ 06 (s, 3H), 3.66~4.00 (m, 2H), 4.19~4.86 (m, 4H), 6.74~7.04 (m, 3H), 7, 15 ~ 7.54 (m, 4H), 7.64 ~ 7.96 (m, 2H), 8.21

(d, J = 6.2 Hz, 1H)

The following compounds of Working Examples 70 to 91 were prepared in a catfish similar to those described above.

Embodiment 70 2 - [{4- (2-Furanylmethylsulfinyl) ethoxy-3-methylpyridin-2-yl) methylsulfinyl] -1H-benzimidazole

¹ H-NMR (DMSOd,) δ;

2.36 (s, 3H), 3.0 ~ 3.5 (m, 2H), 4.0 ~ 4.6 (m 4H), 4.73 (s, 2H), 6.44 (s, 2H), 7.02 (d, J = 5.4Hz, 1H), 7.16 ~ 7.2 (m, 2H),

7.28 - 7.76 (m, 3H), 8.24 (d, J = 5.4Hz, 1H)

Embodiment 71 2 - [{4- (2- (1,1-dioxothiomorpholino)) -ethoxy-3-methylpyrldin-2-yl) methylthio] -1H-benzimidazole

OCH ₂ OH ₂ -N

¹ H-NMR (DMSO-d _e ) δ;

2.21 (s, 3H), 2.99 (t, J = 5.8Hz, 2H), 3.07 (s, 8H), 4.16 (t, J = 5.8Hz, 2H), 4 , 68 (s, 2H), 6.95 (d, J = 6.1 Hz, 1H), 6.95 ~ 7.2

(m, 2H), 7.3 ~ 7.5 (m, 2H), 8.23 (d, J = 6.1 Hz, 1H)

Embodiment 72 2 - [(3-i-Dimethyl-4- (2-methylsulfonyl) ethoxy} pyridin-2-yl] methylthio-1H-benzimidazole

HOl

¹ H-NMR (DMSO-O ₆ ) δ;

2.28 (s, 3H), 3.08 (s, 3H), 3.72 (t, J = 6.2Hz, 2H), 3.66 (t, J = 6.2Hz, 2H), 3, 94 (s, 2H), 6.8 ~ 7.6 (m, 7H), 8.6 (d, J = 5.7Hz,

Exhaustive solvent 73 2 - ({4- (2-ethoxycarbonylmothoxy) othoxy-3-methylpyrldin-2-yl} -mothylsulfinyl] -1H-bonzimidazole

0OH ₂ OH ₂ OOH ₂ COOCH ₂ Oh,

1.2 (t, J = 7.2Hz, 3H), 2.16 (s, 3H), 3.7e ~ 4.32 (m, 8H), 4.73 ($, 2H), 6.94 ( d, J = 5.4Hz, 1H), 7.12 ~ 7.4 (m, 2H), 7.5 ~ 7.7 (m, 2H), 8.22 UU = 5.4Hz, 1H )

Embodiment bracket 4

2 - [{4- (2-Ethoxyca · lr> ul ^'lr) Vl) ethoxy-3-metbylpyrldin-2-yl) methylsulflnylMH-benzlmldazol

Oh CH _{2 2} SCH ₂ COOCH ₂ CH,

'H-NMR (DMSO-d ₆₎ δ;

1.22 {t, J = 7.2Hz, 3H), 2.16 (s, 3H), 3.16~3.56 (m, 2H), 3.64~4.6 (m, 6H), 4.76 (s, 2H), 7.04 (d, J = 7Hz, 1H),

7.16 ~ 7.24 (m, 2H), 7.32 ~ 7.80 (m, 2H), 8.24 (d, J = 7Hz, 1H)

Embodiment 75 2 - [(3-Methyl-4 - {(2-phenylthio) ethoxy} pyrldin-2-vl] methylthio] -1H-benzimidazole

OCH ₂ CH ₂ S

¹ H-NMR _(CDCl3) O;

2.08 (s, 3H), 3.24 (t, J = 6.1 Hz, 2H), 4.06 (t, J = 6.1 Hz, 2H), 4.38 (s, 2M), 6.52 (d, J = 5.8Hz, 1H), 7.04-7.64 (m, 1OH),

8.23 (d, J = 5.8Hz, 1H)

Embodiment 76 2 - ([3-Methyl-4 - ((2-pyridylthio) ethoxy) pyrldln-2-yl] -methylthlo] -1H-bonzinildazole

Olhos

-O

¹ H NMR (DMSOd ₈ ) O;

2.14 (s, 3H), 3.6 (t, J = o, 1 Hz, 2H), 4.32 (t, J = 6.1 Hz, 2H), 4.7 (s, 2H), 7.0 ~ 7.8 (m, 1OH), 8.2 ~ 8.6 (m, 2H)

Auslührungsbeisplel 77

¹ H-NMR (DMSO-d _e ) δ;

2.16 (s, 3H), 2.64 (s, 3H), 3.16 (m, 2H), 4.44 (m, 2H), 4.78 (s, 2H), 7.0 (i.e. , J = 5.8Hz, 1H), 7.4 ~ 7.5 (m, 2H), 7.5 - 7.7 (m,

2H), 8.2 (d, J = 5.8Hz, 1H)

Auslührungsbolsplol 78 2- [4 - ((2-benzylthio) ethoxy} -3-methylpyrldin-2'yl] methylthio] -1H-benzimidazole

00H ₂ OH ₂ SOH ₂ - / ^

s -

¹ H-NMR (DMSO-d,) δ;

2.24 (s, 3H), 2.84 (t, J = 5.8Hz, 2H), 4.18 (t, 5.8Hz, 2H), 4.68 (s, 2H), 6.86 ( d, J = 6.5Hz, 1H), 7.0 ~ 7.54 (m, 9H), 8.23 (d,

J = 6.5Hz, 1H)

EMBODIMENT 79 2 - [{4- (2-Mothoxy) propoxy-3-methylpyryllile-2-yl} -methylsulfonyl] -1H-benzimidazole

00H ₂ OH ₂ CH ₂ OCH.

¹ H-NMR (DMSO-d,) δ;

2.0 (t, 7.5Hz, 2H), 2.2 (s, 3H), 3.28 (s, 3H), 3.5 (t, J = 7.5Hz, 2H), 4.09 ( t, J = 7, DHz, 2H), 5.06 (s, 2H), 6.92 (d, J = 5.4Hz,

1 H), 7.35 ~ 7.52 (m, 2H), 7.64-7.8 (m, 2H), 8.03 (d, J = 5.4 Hz, 1H)

Embodiment 80 5-Methoxy-2- (4- (3-methoxypropoxy) -3-methylpyrldln-2-yl} methylthio-1H-benzimidazole

OH ₂ CH ₂ CH ₂ OCH ₃

S - CH,

¹ H-NMR _(CDCl3) O;

1.92-2.18 (m, 2H, 2.22 (s, 3H), 3.31 (s, 3H), 3.52 (t, J = 6.1Hz, 2H), 3.80 ( s, 3 H), 4.09 (t, J = 6.1 Hz, 2H), 4.30 (s, 2H), 6.64 ~ 6.81 (m, 2H), 6.97 (d, J = 2.2Hz, 1H), 7.33 (d, J = 8.5Hz), 8.25 (d, J = 5.7Hz, 1H)

Embodiment 81 5-Methyl-2- {4- (3-methoxypropoxy) -3-methypyrldln-2-yl} methylthio-1H-benzimidazole

00H ₂ CH ₂ CH ₂ OCH ₃

S - CH

¹ H-NMR _(CDCl3) O;

1.94 ~ 2.19 (m, 2H), 2.22 (s, 3H), 2.42 (s, 3H), 3.31 (s, 3H), 3.52 (t, J = 6, 1 Hz, 2H), 4.08 (t, J = 6.1 HZ, 2 H), 4.31 (s, 2H), 6.67 (d, J = 5.7 Hz, 1 Hi, 6, 80 ~ 7.00 (m, 1H), 7.15 ~ 7.40 (m, 2H), 8.23 (d, J = 5.7 Hz, 1H)

Embodiment 82 5, e-Dimethyl-2- (4- (3-methoxypropoxy) -3-methylpyrldln-2-yl} methylthio-1H-benzimidazole

00H ₂ OH ₂ OH ₂ OOH,

¹ H-NMR _(CDCl3) O;

1.95-2.17 (m, 2H), 2.24 (s, 3H), 2.34 (s, 6H) 3.35 (s, 3H), 3.55 (t, J = 6.2Hz , 2H), 4.12 (t, J = 6.2Hz, 2H), 4.35 (s, 2H), 6.74

(d, J = 5.7 Hz), 7.29 (s, 2H), 8.32 (d, J = 5.7 Hz)

Exemplary Embodiment 83 5-Chloro-2- {4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio-1H-benzimidazole

Vs

OCH ₂ OH ₂ OH ₂ OCH,

¹ H-NMR _(CDCl3) O;

1.93~2.18 (m, 2H), 2.25 (s, 3H), 3.35 (s, 3H), 3.56 (t, J = 6.2Hz, 2H), 4.13 ( t, J = 6.2Hz, 2H), 4.36 (s, 2H), 6.76 (d,

J = 5.7Hz, 1H), 7.10 (dd, J = 8.8Hz, 2.2Hz, 1H), 7.42 (d, J = 8.8Hz, 1H), 7.50 (d, J = 2.2Hz, 1H), 8.31 (d, J = 5.7

Embodiment 84 2- {4- (3-Methoxypropoxy) -3-methylpyrido) -2-yl} methylthio-5-trifluoromethyl-1H-benzimidazole

OH ₂ CH ₂ CH ₂ CH,

- CH,

'H-NMR _(CDCl3) S;

1.92 ~ 2.19 (m, 2H), 2.27 (s, 3H), 3.36 (s, 3H), 3.56 (t, J = 5.9Hz, 2H), 4.15 ( t, J = 6.1 Hz, 2ί >.), 4.38 (s, 2H), 6.79 (d,

J = 5.7Hz, 1H), 7.23 ~ 7.60 (m, 2H), 7.71 (s, 1H), 8.35 (d, J = 5.7Hz, 1) Embodiment 85 Sodium salt of 5-methoxy-2- {4- (3-methoxypropoxy) -3-methylpyrldln-2-yl} methylsulfinyl-1H-benzimidazole

00H ₂ CH ₂ GH ₂ OCH ₃

¹ H-NMR (DMSO-d _e ) δ;

1.84 ~ 2.06 (m, 2H), 2.14 (s, 3H), 3.Γ5 (s, 3H), 3.49 (t, J = 6.2Hz, 2H), 3.72 ( s, 3H), 4.09 (t, J = 6.2Hz, 2H), 4.53 (ABq, J = 12.7Hz, AV = 18.0Hz, 2H), 6.54 (dd, J = 8 , 8Hz, 2.6Hz, 1H), 6.91 (d, J = 5.7Hz, 1H), 7.00 (d, J = 2.6Hz, 1H), 7.34 (d, ' J = 8.8Hz, 1H), 8.27 (d, J = 5.7Hz, 1H)

Embodiment 86 Sodium salt of 5-methyl-2- {4- (3-methoxypropoxy) -3-methylpyridyl-2-yl) methylisulfinyl-1H-benzimidazole

V,

00H ₂ CH ₂ CH ₂ OCH ₃

Na o

¹ H-NMR (DMSO-d ₆ ) δ;

1.84 ~ 2.05 (m, 2H), 2.14 (s, 3H), 2.37 (s, 3H), 3.25 (s, 3H), 3.48 (t, J = 6, 2Hz, 2H), 4.09 (t, J = 6.2Hz, 2H), 4.53 (ABq, J = 12.8Ηζ, Δΐ> = 17.3Hz, 2H), 6.71 (dd, J = 7.9Hz, 1.5Hz, 1H), 6.91 (d, J = 5.7Hz, 1H), 7.26 (s, 1H), 7.35 (d, J = 7.9Hz, 1H), 8.27 (d, J = 5.7z, 1H)

Embodiment 87 Sodium salt of 5,6-dimethyl-2- {4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl-1H-benzimidazole

OCHoCHoCHoOCH-,

V.S-

¹ H-NMR (DMSOd ₆ ) δ;

1.82 ~ 2.08 (m, 2H), 2.13 (s, 3H), 2.27 (s, 6H), 3.24 (s, 3H), 3.47 (t, J = 6, 6Hz, 2H), 4.08 (t, J = 6.7Hz, 2H), 4.54 (ABq,

J = 13.0Hz ₁ AV = 19.8Hz, 2H), 6.90 (d, J = 5.7Hz, 1H), 7.25 (s, 2H), 8.26 (d, J = 5, 7Hz, 1H) Embodiment 88 Sodium salt of 5-chloro-2- (4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl-1H-benzimidazole

00H ₂ CH ₂ OH ₂ OOH,

¹ H-NMR (DMSO-de) δ;

1.80 ~ 2.06 (m, 2H), 2.13 (s, 3H), 3.25 (s, 3H), 3.48 (t, J = 6.2Hz, 2H) , 4.09 (t, J = 6.2 Hz, 2 H), 4.54 (ABq, J = 12.9 Hz, Δι> = 15.3 Hz, 2 H), 6.65~6.92 (m, 2H), 7.25 ~ 7.50 (m, 2H), 8.27 (d, J = 5.3Hz)

Exemplary embodiment 89 Sodium salt of 2- {4- (3-Mothoxypropoxy) -3-methylpyrldyl-2-yl} methyl-8-butyl-5-trifluoromethyl-1H-benzimidazole

OCH ₂ CH ₂ OH ₂ OOH ₃

S -> CH

¹ H-NMR (DMSO-d _e ) δ;

1.84 ~ 2.06 (m, 2H), 2.14 (s, 3H), 3.25 (s, 3H), 3.48 (t, J = 6.2Hz, 2H) , 4.09 (t, J = 6.1 Hz, 2 H), 4.56 (ABq, J = 13.2 Hz,

Ca) = 13.5 Hz, 2 H), 6.92 (d, J = 5.3 Hz, 1 H),

EMBODIMENT 90 2- (4- (3-Methoxypropoxy) -5-methylpyridin-2-yl) -methylthlo-1H-benzimidazole

00H ₂ OH ₂ CH ₂ OCH,

OH,

'H-NMR _(CDCl3) O;

1.90 ~ 2.24 (m, 2H), 2.16 (s, 3H), 3.31 (s, 3H), 3.51 (t, J = 6.2Hz, 2H) , 4.08 (t, J = 6.2 Hz, 2H), 4.22 (s, 2H), 6.74 (s, 1H),

6.99 - 7.22 (m, 2H), 7.32 ~ 7.58 (m, 2H), 8.16 (s, 1H)

Embodiment 91

Sodium salt of α-H-IS-methoxypropoxyl-S-methylpyridinium-n-methylsulphinyl-1H-benzimidazole

OCH ₂ OH ₂ OH ₂ OOH ₃

S - OH

Na 0

¹ H-NMR (OMSO-d _e ) δ;

1.56 - 1.87 (m, 2H), 2.00 (s, 3H), 3.16 (s, 3H), 3.20 - 3.72 (m, 4H), 6.16 - 6, 60 (m, 2H), 6.49 (s, 1H), 6.68-6.92 (m, 2H),

7.28 ~ 7.50 (m, 2H), 8.13 (s, 1H)

Embodiment 92 i- {4- (3-Methoxypropoxy) -3-methylpyrldin-2-vl) methylthio-benzothiazole

00H ₂ OH ₂ OH ₂ OOH,

A mixture of 0.8 g of 2-chloromethyl-4- (3-methoxypropoxy) -3-methylpyridine hydrochloride, 0.5 g of 2-mercaptobenzothiazole, 0.36 g of sodium hydroxide and 30 ml of ethanol was stirred at room temperature for 6 hours and distilled under reduced pressure, to remove the ethanol. The residue was purified by silica gel column chromatography to obtain 0.85 g of the title compound as a pale yellow crystal.

¹ H-NMR (CDCl ₃ ) O;

1.9-2.2 (m, 2H), 2.30 (s, 3H), 3.35 (s, 3H), 3.56 (t, J = 6.1Hz, 2H) , 4,10 (t, J = 6,1 Hz, 2 H), 4,81 (s, 2 H), 6,70 (d, J = 5,7 Hz,

1 H), 7.1-7.5 (m, 2H), 7.5-7.9 (m, 2H), 8.29 (d, J = 5.7Hz, 1H)

Embodiment 93 2- {4- (3-Methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinylbenzothiazole

00H ₂ OH ₂ OH ₂ OOH ₃

0.6 g of 2- {4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthiobenzothiazole was dissolved in 20 ml of dichloromethane to give a solution. To this solution was added 0.36 g of 80% m-chloroperoenzoic acid at -45 ° C. After one hour, 0.34 g of triethylamine and 30 ml of saturated aqueous sodium bicarbonate solution were added to the mixture thus obtained. The resulting mixture was stirred at room temperature for 30 minutes. The dichloromethane layer was separated, washed twice with a saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate and filtered. The filtrate was concentrated to recover a residue. This residue was purified by silica gel column chromatography to obtain 0.17 g of the title compound as a white crystal.

¹ H-NMR (CDCl ₃ ) O;

1.95-2.18 (m, 2H), 2.20 (s, 3H), 3.34 (s, 3H), 3.54 (t, J = 6.1Hz, 2H), 4.10 (t, J = 6.1Hz, 2H), 4.67 (s, 2H), 6.71 (d, J = 5.7Hz, 1H), 7.40~7.0 (m, 2H) , 7.92 ~ 8.20 (m, 2H), 8.25 (d, J = 5.7 Hz, 1H)

Embodiment 94 2- {4 '(3-Methoxypropoxy) -3-methylphenyl-2-yl) -methylthlo-1-methylbenzimidazole

OCJH ₂ Oh ₂ CH ₂ OCJH ₃

0.5 g of 2- {4- (3-hydroxypropoxy) -3-methylpyridin-2-yl} methylthio-1H-benzimidazole was dissolved in 30 ml of dimethylformamide to give a solution. To this solution was added 0.24 g of 60% IgS sodium hydride at ⁰ ° C. The resulting mixture was stirred at 4O ⁰ C for one hour and cooled again to ^{0 0} C and then treated with 0.5 g of methyl iodide. The recovered mixture was stirred at room temperature for 3 hours. To the resulting mixture was then added saturated aqueous ammonium chloride solution to stop the reaction. The crude mixture was distilled under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography to obtain 0.3 g of the title compound as a pale yellow crystal

¹ H-NMR (CDCl ₃ ) O;

1.95-2.21 (m, 2H), 2.30 (s, 3H), 3.35 (s, 3H), 3.54 (t, J = 6.2Hz, 2H), 3 , 67 (s, 3H), 4,10It ₁ J = 6,2 Hz, 2 H), 4,80 (s, 2 H), 6,68 (d, J = 5,7Hz, 1 H), 7 , 16 ~ 7.30 (m, 3H), 7.57 ~ 7.80 (m, 1H), 8.29 (el, J = 5.7Hz, 1H)

Embodiment 95 2- (4- (3-Methoxypropoxy) -3-methylpyrldln-2-yl} methylsulphinyl-1-methylbenzimidazole

00H ₂ OH ₂ OH ₂ OOH ₃

0.25 g of 2- {4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio-1-methylbenzimidazole was dissolved in 20 ml of dichloromethane to give a solution. To this solution was added at -50 ° C 0.18 g of 80% m-chloroperbenzoic acid. The resulting mixture was stirred for one hour and then treated with 0.14 g of triethylamine and 20 ml of a saturated aqueous sodium bicarbonate solution. The resulting mixture was stirred at room temperature for one hour. The dichloromethane layer was separated, washed twice with a saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and filtered. The filtrate was concentrated to give a residue. This residue was purified by silica gel column chromatography to obtain 0.12 g of the title compound as a pale yellow crystal.

'H-NMR (CDCI ₃₎ O;

1.98 ~ 2.12 (m, 2H), 2.22 (s, 3H), 3.33 (s, 3H), 3.53 (t, J = 6.2Hz, 2H), 3.98 ( s, 3H), 4.06 (t, J = 6.2 Hz, 2H), 4.96 (s, 2H, 6.65 (d, J = 5.7Hz, 1H), 7.25 ~ 7 , 40 (m, 3H), 7.75 ~ 7.87 (m, 1H), 8.15 (d, J = 5.7Hz, 1H)

Embodiment 96 1-Ethoxycarbonyi-2 <(4- (3-methproppropoxy) -3-methvlprldln * 2> yl) methylthylbenzyldecene

0OH ₂ CH ₂ OH ₂ OOII ₃

CO ₂ CH ₂ CH ₃

0.8 g of 2- (4- (3-methoxypropoxy) -3-amylpyridin-2-yl) -othylthio-1H-benzimidazole was dissolved in 10 ml of dimethylformamide to give nine solution of gowinnon. To this solution was added 0.23 g of 60% sodium hydride boi O ⁰ C. The gowonncno mixture was stirred for 15min. 0.4 g of ethyl chlorocarbonate was dropwise added to the resulting mixture at 0 ° C. The mixture thus obtained was stirred at room temperature for one hour. A saturated aqueous solution of ammonium chloride was added to the resulting gum mixture to stop the reaction. The crude mixture was extracted with chloroform. The extract was driedrocknot over magnesium sulfate and filtered. The filtrate was concentrated to obtain a residue. This residue was gorozined by Kiosolgol-Sulolone chromatography to obtain 0.82 g of the title compound as a white crystal.

'H-NMR (CDCI ₃₎ O;

1.50 (t, J = 7.0Hz, 3H), 1.95 ~ 2.20 (m, 2H), 2.32 (s, 3H), 3.36 (s, 3H), 3.56 ( t, J = 6.2 Hz, 2H), 4.10 (t, J = 6.2 Hz, 2H), 4.54 (q, J = 7.0 Hz, 2H), 4.77 (s ,. ¹ H ), 6.69 (d, J = 5.7Hz, 1H), 7.1-7.4 (m, 2H), 7.4-7.7 (m, 1H), 7.7 ~ 7, 95 (m, 1H), 8.30 (d, J = 5.7Hz, 1H)

Routing Applicator 97 1-Etioxylcarbony-2- {4- (3-mothoxypropoxy) -3-methylpyrldyl-2-yl) -othylsulphonyl-benzenediazole

OCH ₂ OH ₂ CH ₂ OOH ₃

0.6 g of 1-ethoxycarbonyl-2- {4- (3-methoxy-propoxy) -3-methyl-pyridin-2-yl} -methylthiazobenzimidazole was dissolved in 20 ml of dichloromethane to obtain a solution. To this solution 0.4 g of m-wurdon Chloroperbonzoesäuro added at -45 ⁰ C. 0.3 g of triethylamine and 20 ml of a saturated aqueous sodium bicarbonate solution were added to the resulting mixture after one hour. The recovered mixture was stirred at room temperature for 30 minutes. The dichloromethane layer was separated, washed twice with a saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and filtered. The filtrate was concentrated to give a residue. This residue was purified by silica gel column chromatography to obtain 0.21 g of the title compound as a yellow oil.

'H-NMR (CDCI ₃₎ O;

1.54 (t, J = 7.0Hz, 3H), 1.99 ~ 2.20 (m, 2H), 2.30 (s, 3H), 3.35 (s, 3HI, 3.55 (t , J = 6.2Hz, 2H), 4.06 (t, J = 6.2Hz, 2H), 4.61 (q, J = 7.0Hz, 2H), 4.74 (ABq, J = 12, 8Hz, AV = 8.6Hz, 2H), 6.60 (d, J = 5.7Hz, 1H), 7.3-7.5 (m, 2H), 7.7 ~ 8.0 (m, 2H), 8.03 (d, J = 5.7 Hz, 1H)

Claims (7)

1. a group of the formula -O- (CH ₂ ) pOR ⁴ , wherein ρ is 1 to 3 and R ^{4 is} a hydrogen atom, a lower alkyl group, aryl group or aralkyl group, 1. A method for the preparation of Pyridinderivatenwr general formula f O- (CH ₂ ) _X -Z wherein R ¹ and R ^{2 may be the} same or different, and each is a hydrogen atom, a lower alkyl, lower alkoxy, lower haloalkoxy, lower alkoxycarbonyl or a halogen atom; X is a group of the formula _O -, - S- or -N- (in which R ^{3 is} a hydrogen atom or a lower alkyl group, phenyl group, R ³ " Benzyl group or lower alkoxycarbonyl group); Z means ( ₂ ) P, wherein q is 1 to 3 and R ^{5 is} a halogen atom or an alkoxycarbonyl group, aryl group or hetaryl group, 2. a group of the formula 3. a group of the formula -O- (CH ₂ ) -O- (CH ₂ ) ₈ -OR ⁶ , wherein r and s are independently 1 to 5 and R ^{6 is} a hydrogen atom or a lower alkyl group. 4. a group of the formula 5. a group of formula O. 6. a group of the formula Λ% N- ^N o 7. a group of the formula -S-A » wherein t is O to 2 and A is a group of the formula is ₍ (wherein B is a group of the formula -NH-, -O- or -S-), a lower alkyl group, alkoxycarbonylmethyl group, pyridyl group or furyl group or a group of the formula _J ~ X - (CH ₂ ) ,, is
8. a group of the formula