WO1989000566A1

WO1989000566A1 - Pyridine compounds and medicinal use thereof

Info

Publication number: WO1989000566A1
Application number: PCT/JP1988/000716
Authority: WO
Inventors: Takeshi Kawakita; Mitsuharu Sano; Yuji Ono; Keiichiro Haga
Original assignee: Yoshitomi Pharmaceutical Industries, Ltd.
Priority date: 1987-07-21
Filing date: 1988-07-18
Publication date: 1989-01-26

Abstract

The invention is related to pyridine compounds represented by general formula (I) (wherein R1 represents hydrogen, halogen, alkyl, alkoxy, alkoxycarbonyl or haloalkyl, R2 and R3, which may be the same or different, each represents hydrogen, halogen or alkyl, L represents a group represented by formula (II) (provided that, when one of R4 and R5 represents hydrogen, the other represents hydrogen, alkyl, phenyl, substituted phenyl, aralkyl, substituted aralkyl or acyl and, when one of R4 and R5 represents alkyl, phenyl, substituted phenyl, aralkyl, substituted aralkyl or acyl, the other represents phenyl, substituted phenyl, aralkyl, substituted aralkyl or acyl, or R4 and R5 taken together with the adjacent nitrogen atom represent a group forming an optionally fused heterocyclic ring) or a group represented by formula (III) (wherein R6 represents hydrogen, alkyl or acyl, Z represents methylene, oxygen or sulfur, and l and m, which may be the same or different, each represents 0 or an integer of 1 to 3), and n represents 0 or an integer of 1 to 8) or pharmaceutically acceptable salts thereof, and their medicinal use. These compounds have anti-ulcerous, gastric acid secretion depressing, gastrointestinal cell protecting and antidiarrhea effects, thus being useful as drugs for prevention and treatment of diseases of digestive organs.

Description

Specification

Viridin compounds and their pharmaceutical uses

"Technical field"

The present invention relates to a novel pyridine compound having an anti-ulcer action, a gastric acid secretion inhibitory action, a gastrointestinal cell protective action, an anti-diarrheal action, etc., a pharmaceutically acceptable salt thereof, and a pharmaceutical use thereof.

"Background technology"

In recent years, among those being developed as anti-ulcer agents, 5-methoxy 21 (4-methoxy 3,5-dimethyl-2) disclosed in Japanese Patent Publication No. 60-34956 is disclosed. —Pyridyl) methyl sulfinyl-1H —Benzimidazole (generic name: omebrazole) has been confirmed to be clinically useful.

Since then, a large number of compounds have been reported. For example, Japanese Patent Publication No. 59-181277 discloses that the 4-position of viridyl is substituted with an alkyl substituent on the amino nitrogen; Compounds having two carbon atoms and substituted by dialkylaminoalkoxy containing 1 to 4 carbon atoms in the alkoxy group are included. However, the disclosure of this publication is very extensive, and only 2— (N, N—dimethylamino) ethoxy is described as an example of the substituent. It does not contain any data to specifically grasp the effects and effects. -

"Disclosure of Invention J

The present inventors have conducted intensive studies with the aim of developing a prophylactic / therapeutic agent for gastrointestinal diseases, and as a result, have found that To

In the above formula, each symbol is defined as follows.

Wherein R ¹ is hydrogen, halogen, alkyl, alkoxy, alkoxycarbonyl or haloalkyl,

, R ³ are the same or different and represent hydrogen, halogen or alkyl,

L is the formula

(Where one of R ⁴ and R ⁵ represents hydrogen.The other represents hydrogen, alkyl, phenyl, substituted phenyl, aralkyl, substituted aralkyl, or acyl, and one of R ⁴ and R ⁵ represents When referring to alkyl. Phenyl, substituted phenyl, aralkyl, substituted aralkyl, acyl, etc .: ¾ "indicates phenyl, substituted phenyl, aralkyl, substituted aralkyl, acyl, or R ^{And 4} and R ⁵ are bonded together with an adjacent nitrogen atom to form a heterocyclic ring which may be condensed.) Or a formula:

(CH ₂₎ Z Wherein R ⁶ is hydrogen, alkyl or acyl, Z is methylene, oxygen or sulfur, 1 and m are the same or different and each represents 0 or an integer of 1-3. and

n represents 0 or an integer of 1 to 8. ]

And a pharmaceutically acceptable salt thereof and a pharmaceutical use thereof.

术 In the description, halogen refers to chlorine, bromine, fluorine, and iodine, and alkyl refers to methyl, ethyl, propyl, isopropyl, butino, isobutyl, tertiary butyl, pentyl, hexyl, Alkyl having 1 to 20 carbon atoms such as octyl, decyl, dodecyl, octadecyl, eicosyl, etc., and alkoxy is methoxy, ethoxy, propoxy, isopropoxy, butoxy, butoxy, isobutoxy, tertiary. Alkoxy having 1 to 20 carbon atoms such as butoxy, pentyloxy, hexyloxy, octyloxy, decyloxy, dodecyloxy, octadecyloxy, eicosiloxy, etc., and alkoxycarbonyl are methoxycarbonyl, ethoxycarbonyl, propoxy. Norebonil, Isopropoxy canolevonil, Butoki Cicarbonyl, isobutoxycarbonyl, tertiary butoxycarboninole, pentinoleoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, desinoleoxycarbonyl, dodecyloxycanolebonyl, octadecylo Alkoxy mono-alkanols with 1 to 20 carbon atoms, such as xixanolone and eicosiloxycarbonyl, are referred to as tri-norolequinole, and tri-norolequinol, 2, 2, and 2 — tri. Fluoroethyl, 2,3,3 Trifluoropropyl, 1,1,2,2—Tetrafluroethyl, 2,2, 3, 3 — Tetrafluropropyl, etc., having 1 to 4 carbon atoms, such as aralkyl, and aralkyl are benzyl, 1-phenyl-2-ethyl, 2 — phenyl-etinolle, 3-phenylphenyl, 4-phenyl-2. A phenyl-substituted alkyl group having 1 to 8 carbon atoms, such as rubutyl, & phenylhexyl, and 8-phenyloctyl, and acetyl is acetyl, buocyl pionyl, isopropionyl, butylyl, pinodylol, and nodelli. Alkenyl or benzoyl having 1 to 5 carbon atoms, such as phenyl, is substituted with 1 to 3 halogens, alkyl, alkoxy, A-alkyl, hydroxyl, hydroxy, or substituted phenyl or substituted aralkyl. An optionally condensed heterocyclic ring formed from a group selected from toro and amino with an adjacent nitrogen atom includes 1-pyrrolidine, biperidine, and 1-bipe Radinzole, 4-Alkyl-1-biperazinyl, 4-Aralkyl-1-piperazinyl, 4-Substituted alanolexicle-1-Biperazul, 4-Alzolequinole 1 One homobiradizinyl, 4-Acilyl-1 homopiperazinyl, morpholino, Chi Omorpholino, 2—oxo-1 1-pipiridinyl, isoindrin-1 2—yl, 1, 2, 3, 4—tetrahydroquinoline-1 1-yl, 1, 2, 3 , 4—Tetrahydroysoquinolin-12-yl (these isoindolin ring and 1,2,3,4 —tetrahydroquinoline ring are halogen, alkyl, alkoxy , Non-alkyl, hydroxyl, nitro, amino, and oxo may be substituted by any combination of 1 to 3 substituents.).

In a preferred group of compounds of the invention, L is of the formula: R ⁴

N

R ³

Wherein R is alkyl, R ⁵ is aralkyl or substituted aralkyl, or R ⁴ and R ⁵ are bonded together with the adjacent nitrogen atom to form a condensed group. It is a compound of the general formula (I) showing a group forming a good heterocyclic ring. In a more preferred group of compounds, L is N-benzyl N-methylamino and has from 1 to 3 halogen atoms, alkyl groups having 1 to 4 carbon atoms or alkoxy groups having 1 to 4 carbon atoms as substituents. It is a compound of the general formula (I) which may be 1,2,3,4-tetrahydroquinoline-1-yl.

The compound of the general formula (I) of the present invention may have various isomers. The invention contemplates one of these isomers or a mixture of these isomers.

Pharmaceutically acceptable salts of the pyridine compounds of the general formula (I) include hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, acetate, and citrate. Acid addition salts such as salts, maleates, fumarates, malonates, lingates, tartrates, succinates, methansulfonates and the general formula

[Formula Φ, m is 1, 2 or 4, and A ^{m +} is L i N a K +, Mg ^{2 +} , Ca ^{2 +} , Ti ^{4 +} , N ⁺ (R) ₄ (where R is alkyl having 1 to 4 carbon atoms) or C ⁺ (NH ₂ ) ₃ Is shown. ] The salt represented by these is mentioned.

Of the compounds of the general formula (1), sodium salts, calcium salts: and magnesium salts are particularly preferred.

The compounds of the present invention also exist as hydrates (hemihydrate, monohydrate, sesquihydrate, etc.) and solvates, and these are also included in the present invention.

Specific examples of the compound of the general formula (I) of the present invention are as follows, but the present invention is not limited thereto.

◎ 2-[3-methyl 1 4-(: 2-1-pyridine) 1-2-viridyl] 1-^

◎ 2-[3-methyl 4-1 [2-(4-methyl 1 1-piperazinyl) ethoxy] 1-2 1 -bisyl] methyl 2-1 H-benzimidazole

◎ 2-[3-methyl 4-(2-morpholino ethoxy) 1-2-1 -bisyl] methylsulfinyl 1 1 H ^ zimidimidazole

◎ 2— [3—Methyl 1 4 1 [2— (1—Methyl 1 2—pyrrolidinyl) ethoxy] 1 2—Pyridyl] Methyl sulfi 2 1 1

◎ 2--[3-methyl 4-(1-methyl 4-pyridyloxy)] 1-1-pyridyl] methyl sulfinyl-1 Η-benzy Midazoll

◎ 2 — [3 — methyl 1 4 — (2 — (1, 2, 3, 4 — tetrahydroi sokinolin 1 2 — yl) ethoxy) 1 2 — viridyl] Chilsulfel 1H-Benzi midazole

◎ 2-[3-methyl 4-1 (2-(N 1 ^ ^ N-1 N-proviramino) ethoxy) 1 2-pyridyl] methylsulfinyl-1-Benzimidazole

◎ 5-black mouth 1 2-[3-methyl 4-1 (2-(Ν-benzyl-1-ethylamino) ethoxy) 1 2-pyridyl] methyl luffy 2 1 Penzi midazole

◎ 2-[3-Methyl 1-4 (2-(6-Chlorine; 1, 2, 3, 4-Tetrahydrodisoquinoline 1-2-yl) Etoxy) 1-pyridyl) methyl sulfone 2 1— ^ =

◎ 2-[3-methyl 4-1 (2-(6-methyl 1, 2, 3, 4-tetrahydro 1-sokinoline 1 2-ikule) ethoxy) 1 2 — Pyridyl] methylsylrefinyl 1 Η—benzymidazole

◎ 2-[3-methyl 4-1 (1-methyl 2-piperi zirmetoxy) 1 2-bilithil] methyl 2-1

◎ 2-[3-methyl 1 4-[2-[Ν-methyl 1-(2-phenylethyl) amino] ethoxy] 1 2-pyridinole] methyl 1-^-n-imidazole

◎ 2-[3-methyl 4- 1 [2-[N-methyl 1 N-(3-fenirupu building) amino] ethoxy] 1 2-Viridyl] One 1 H—Benzy Midazo

◎ 2 — [3-Methyl-41 C 2 -C-(3-Methoxybenzil)-1-N-methylamine]] 1-2-Viridyl] Methylsulfuric acid 1 H- Benzi midazole

◎ 2 1 [3-methyl--2-(N-(4 -fluorobenzyl)-1-N-methylamino] ethoxy]-1-2-pyridyl] methylsulfinyl-1 H-Benzi Midazol

◎ 2-[3-1-4 1 [2-! : N— (3,4,5-trimethoxybenzyl) -1-N-methylamino] ethoxy] 1-2—pyridyl] methylsulfuryl 2-H 1-benzimidazole

◎ 2-[3-methyl 1 4 1 [2-[N-(4-bromobenzyl) 1 N-methylamino] ethoxy] 1 2-pyridyl] methyl sulfyl 1 H- Benzi midazole

◎ 2— [3—Methyl-1-41 [2— (N-Methylanilino) ethoxy] 1-2-Pyridyl] methylsulfuryl 2-H1H-benzimidazole

◎ 2-[3-methyl 4-[2-(N-methyl p-black mouth a2 lino) ethoxy] 1 2-pyridyl] methylsnorefinil 1 H-Benzi dazonole

◎ 2 — [3——Methyl 1 4 1 2— [N— (0—Black benzene) 1—N—Methylamino] ethoxy} —2—Pyridyl] methyl sulfy Niruichi 1 H—Benzi midazole ◎ 2-[3-methyl-4-1 [2-(N-(p-black benzene) 1-N-methylamino] ethanol] 1-2-Pyridyl] methyl sulfinyl 1 H—Benzimidazole

◎ 2-[3-methyl-4-1 [2-[N-methyl-N-(p-methylbenzyl) amino] ethoxy] 1 2-pyridyl] methyl-sulfinyl-1 H- Nzi Midazoru

◎ 2 — [3 -methyl 4-[2 — (N-benzyl-1-N-ethyl) amino ethoxy] 1 2 — pyridyl] methyl sulfi 2 h 1 H-benzimidazole

◎ 2-[3-methyl 4- 1 [2-(2-oxo 1-1-1-bilolidinyl) ethoxy] 1 2-pyridyl] methylsulfur 2-1 H-Benziimidazole

◎ 2-[3-methyl 1 4 1 [3-(N-benzyl-N-methyl) amino probox] 2-Bili-syl] methyl sulf 2-1 H-benzene Le

◎ 2 — [3 — Methyl 1 4 1 (3 — Biperi dino Proboxy) 1

2 — pyridyl) methyl sulf 2 h 1 H

◎ 2-[3-methyl 4-1 (3-morpholino-pro-boxy) 1 2-pyridyl] methyl 2-1 H-Benzimi dazo 1

◎ 2-[3-Metinole 4-(4-1 Mole-Horinov Tokishi) 1-2-1-Pyryl] Methyl Sulfur 2 H 1 H ^ Nzimi Dazol

◎ 5—Methoxy 1—2— [3—Methyl 1—4—1—2— (N-benzyl-N—methyl) aminotoxin] —12 pyridyl] methyl Sulfinyl-1H

◎ 2— [3—Nutyl-4 —— [2— (N ^ N-dilu N-methylamino) ethoxy] 1 2—Viridyl] Methylsulfi 2ru 1H—Benzimidazole Natri Plum salt

◎ 2— [3—Methylenol 4 1 [2— (N-benzyl-N-methylamino) ethoxy] 1-2—pyridyl] methylsulfinyl-1H-benzimidazole

◎ 2— [3—Methyl-yl 4- (2— (N-methylanilino) ethoxy) 1-2—Viridyl] methylsulfuryl 2H 1H—Venes imidazole.Sodium salt

0 2— [3-methyl-1 4-—2- [N- (3'4,5-trimethoxybenzyl) -1-N-methylamino] ethoxy] -2-pyridyl] methylsolefi; Lou 1 H—Benzi midazotium salt

The compound of the general formula (I) of the present invention has the general formula

(Equations Φ and R ¹ are as defined above.

And a compound represented by the general formula

Y-

[Wherein, Υ represents a reactive atom or group (halogen or methane) Sulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, and other sulfonyloxy groups), and other symbols are as defined above. ]

Or a compound of the general formula obtained by reacting an acid addition salt thereof, preferably

(In the formula, each symbol is as defined above.)

By subjecting the compound of the formula (1) to an oxidation reaction.

The reaction between compound (III) and compound (H) is usually carried out in a solvent inert to the reaction (eg, water or methanol, ethanol, dimethylformamino, or a mixed solvent thereof, preferably aqueous ethanol). Medium bases (sodium hydroxide, sodium hydroxide, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, carbonate) Temperature from about 0'C to the boiling point of the solvent used, preferably 20% in the presence of sodium, carbonated carbonate, metallic sodium, triethylamine, pyridine, etc. It takes about 10 minutes to 24 hours, preferably 30 minutes to 3 hours.

Next, the oxidizing agents used in the oxidation reaction include perbenzoic acid, peracetic acid, peracetic acid, perfluoroacetic acid, permaleic acid, sodium hypobromite, and sodium hypochlorite. Emissions include tritium and hydrogen peroxide. The reaction is usually carried out in an inert solvent (water or Organic acids (formic acid, acetic acid, propionic acid, butyric acid, maleic acid, fumaric acid, malonic acid, etc.) in rometan, chloroform, tedrohydrofuran, dioxane, dimethylformamide or mixtures thereof. In the presence of succinic acid, benzoic acid, medicro-benzoic acid, paranthrobenzoic acid, phthalic acid, etc., in the temperature range from 170 ° C to the boiling point of the solvent used, usually from 150 to room temperature, preferably from room temperature. — 20 to 0 hours, progressing in about 5 minutes to 24 hours, preferably about 5 minutes to 20 hours.

The compound (Γ) thus produced can be isolated and purified by conventional means such as recrystallization, column chromatography and the like.

The optical isomer of the compound (I) of the present invention can be produced by subjecting the reaction product to fractional crystallization or the like, or by performing the above-mentioned reaction using a raw material compound that has been optically resolved in advance.

The compound represented by the general formula (II) of the present invention includes hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, citric acid, maleic acid, fumaric acid, malonic acid, and lingo. The above-mentioned acid addition salt can be obtained by treating with an acid, tartaric acid, succinic acid, methanesulfonic acid or the like in a conventional manner. Further, the salt compound of the general formula (I ′) can be obtained by reacting a compound of the general formula (I) with a corresponding base.

The compound of the present invention has an anti-ulcer effect, an inhibitory effect on gastric acid secretion, a protective effect on gastrointestinal cells, an anti-diarrheal effect, and prevents digestive system diseases (gastric ulcer, duodenal ulcer, gastritis, diarrhea, colitis, etc.). · Useful as a therapeutic It is. In addition, it has low toxicity, is stable against acids and the like, and has characteristics such as a small increase in blood gastrin level.

The pharmacological action of these compounds of the invention is described by Ghosh et al. [Pretty's 'Journal of Ob' Pharmacology (Br. J. Pharmacol.) Vol. );)) Etc.

When the compound of the present invention is used as a medicament, a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof may be added to a pharmaceutically acceptable excipient, carrier, diluent, solubilizing agent, or the like. It can be administered in the form of capsules, tablets (including sugar-coated tablets and film-coated tablets), granules, injections, and infusions by mixing with additives. In the case of oral administration, the dose is about 0.01 to 30 nig / kgs per adult per day, preferably 0.1 to 3 mZkg, but may vary depending on the patient's condition, age, drug resistance, etc. Needless to say.

Hereinafter, the present invention will be specifically described with reference to Reference Examples and Examples, but it goes without saying that the present invention is not limited thereto. Reference example 1

2—Chloromethyl-3—Methynole-4 1 [2— (N-Benzyl-1-N-methylamino) ethoxy] pyridine dihydrochloride 4.8 g 2—Melcaptobenzymidazole Add 1.7 g and 12.5% sodium hydroxide 20 to 50 Φ of ethanol and heat to reflux for 2 hours. After completion of the reaction, ethanol was distilled off, water was added to the residue, and the precipitated crystals were collected by filtration and recrystallized from acetonitrile to give a melting point of 122 to 126'C (decomposition). Of 2 — [3 — methyl one 4- [2-((1-benzyl-N-methylamino) ethoxy] -12-pyridyl] methylthio-1H-benzimidazole is obtained.

Reference example 2

2—Cl-methyl-3—Methyl-1- (2-bi,} diethoxy) bilidine 'dihydrochloride 8.2 g 2—Mercaptobenzimidazole 3. Add 3 g and 29% sodium hydroxide 20 ^ to the ethanol 10 Ο η ζ β φ and heat to reflux for 1 hour. After the reaction is completed, ethanol is distilled off, water is added to the residue, and the mixture is saturated with potassium carbonate and extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulfate, and the solvent is distilled off. When the residue was recrystallized from acetonitrile, the melting point was 105 to 110, and the 2- [3-methyl 4-

(2 — (Bilidinoethoxy) 1 2 — pyridyl) methylthio

1 Η—Benzi midazole is obtained.

Reference example 3

2—Cross mouth methyl 3—Methyl 4— [2— (4-Methyl-1-piperazinyl) ethoxy] pyridin '3 hydrochloride 4.3 g 2—Melcaptobenzimidazole 1.5 And 15% sodium hydroxide 15 in ethanol 50, and heat to reflux for 1 hour. After completion of the reaction, ethanol is distilled off, water is added to the residue, and the mixture is extracted with ethyl acetate. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting residue was recrystallized from acetonitrile. Melting point 103: 2- (3) of L05'C (decomposed) —Methyl 1 4 1 (2— (4—Methyl 1 1—Birajur) ethoxy) 1 2—Pyridyl] Methylthio—1 Η—Benzymidazole Can be

Reference example 4

2—Chloromethyl-3—Methyl-4- (2—morpholinoethoxy) bilidine 'dihydrochloride 5.0 g 2—Melcaptobenzimidazole 2.2 g and 8% sodium hydroxide Is added to 100 mi of ethanol containing 20 mM and heated to reflux for 1 hour. After completion of the reaction, ethanol is distilled off, water is added to the residue, and the mixture is saturated with potassium carbonate and extracted with ethyl acetate. After the extract was dried over anhydrous magnesium carbonate, the solvent was distilled off, the residue was applied to silica gel chromatography, and eluted with 2% methanol chloroform. (2-morpholinoethoxy) -1-pyridyl] methylthio-1H-benzimidazole is obtained as an oil.

¹ H-NMR (CDC £ ₃ ): 6 (ppm) =

2.28 (s, 3H), 2.50 to 2.70 and 3.68 to 3.84 (m, 8H respectively), 2.88 (t, 2Η), 4.20 (t, 2H), 4.40 (s, 2H), 6.76 and

8.34 (d, 2H respectively), 7 · 08 to 7.26 and 7 · 44 to 7 · 60 (m, 4H respectively)

Reference example 5

2 —Chlorome Chinole 3 —Methyl 1 4 1 [2— (1—Methyl-2—pyrrolidinyl) ethoxy] pyridine dihydrochloride 12.1 g 2 —Melcaptovenzi midazo The solution is added to a solution of ethanol 100 containing 4.8 g / l and 23% sodium hydroxide 20 and heated under reflux for 1 hour. After completion of the reaction, ethanol is distilled off, water is added to the residue, and the mixture is saturated with potassium carbonate and extracted with ethyl acetate. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting residue was subjected to silica gel column chromatography, eluted with chloroform, and crystallized from acetone. 8 5 to 87 • C 2 — [3-Methyl-1 4 — [2 — (1-Methyl-2-virolidinyl) ethoxy] -12-Bisyl] methylthio-1H-Benzimidazole Can be

Reference example 6

2—Chloromethyl-1 3—Methyl-[(1-methyl-2-piridinyl) methoxy] viridine 'dihydrochloride 16 5 g is added to a solution of 5.1 g of 2-mercaptobenzimidazole and 150% of ethanol containing 28% of sodium hydroxide / 30, and the mixture is briefly heated to reflux for 1 hour. After completion of the reaction, ethanol is distilled off, water is added to the residue, and the mixture is saturated with carbon dioxide lime, and extracted with lip-mouth form. After the extract was dried over anhydrous calcium carbonate, the solvent was distilled off, and the obtained residue was subjected to silica gel column chromatography, and eluted with 4% methanol / lluc mouth form. When crystallized from tonic ether, the melting point is 125-127, 2- [3-methyl-4 — [(1-methyl-2-pyridinyl) methoxy] 12-pyridyl] 1-Methylthio-1-benzimidazole is obtained.

Hereinafter, the following compounds are produced in the same manner.

◎ 2 — [3 — methyl 4- (2 — (benzyl-Ν-methylnoramino) ethoxy] 1 2 — thiol] methylthio 1 5 — methoxy Γ Η — benzimidazole, light brown Crystal, melting point 1 2 1 to 1 22 ° C

◎ 2 1 [3 — methyl 1 4 — [2-[N— (p — 1) N-methylamino] ethoxy] 1-2-pyridyl] methylthio 1H-benzimidazole, colorless crystal, melting point 1 10 to 11 3 * C

◎ 2-[3-methyl 4-[2-[N -methyl N-(4-methylbenzyl) amino] ethoxy] 1-2-pyridyl] methyl-1 H-Benziimidazole, Colorless crystal, melting point 99-102C

◎ 2 — [3-methyl 1 4 1 [2-(1, 2, 3, 4-tetrahidroi sokinolin 1 2-yl) ethoxy] 1 2-pyridyl] methylthio-1 H-Benzymidazole, light brown crystal, melting point

9 2 to 9 5 'C

◎ 2-[3-methyl 4-[2-(N ^ N-dilu N-ethylamino) ethoxy] 1 2-pyridyl] methylthio 1 1-Benzimidazole, oil

! Η-NMR (CDC £ ₃ ): δ ( _PP m) = 1.10 (t, 3H), 2.14 (s, 3Η), 2.68 (q, 2Η), 2.92 (t, 2Η), 3.70 (s, 2Η), 4.04 (t, 2Η), 4.36 (s, 2Η), 6, 62 and 8.30 (d, 2H, respectively), 7.00 to 7.64 (m, 9H, respectively)

◎ 2-[3-methyl 4-1 [2-(N-benzyl-N-propylamino) ethoxy] 1-2-pyridyl] methylthio 1 H-benzimidazole, oil,

¹ H-NMR (C and C £ ₃ ): δ (ppm) = 0.90 (t, 3H), 1.54 (m, 2Η), 2.24 (s, 3Η), 2.56 (t, 2Η), 2.91 (t, 2Η) ), 3.69 (s, 2Ή), 4.04 (t, 2H), 4.36 (s, 2H), 6.62 and 8.28 (each d, 2H), 6.96 to 7.64 (m, 9H each) ◎ 5—Chlorolo 2— [3—Methyl-1——2— (N-benzyl-1-N-ethylamino) ethoxy] 1-2-Bilisyl] Metilchio 1 H—Benzimidazo-1 , Light brown crystals, melting point 1 2 4 ~

1 2 5

◎ 21- [3-Methyl-1-41- [2- (N-methylarino) ethoxy] 1-2-Bisyl] methylthio-1H-Benzymidazol, oil,

¹ H-NMR (CDCH z): δ ( _PP m) = 2.22 (s _s 3H), 3.02 (s, 3H), 3.90 (m, 2H), 4.15 (m, 2H), 4.38 (s, 2H), 6.70 (in, 4H), 7.15 (m, 4H) _s 7.45 (m, 2H), 8.20 (d, 1H)

◎ 2-[3-methyl 4- 1 (3-morpholinopoxy) 1 2-pyridyl] methythio 1 1 ox 1 benzimidazole, melting point 1 48-150 (decomposition)

◎ 2 — [3 — methyl 4 — (3 — biphenyl dibenzoboxyl) 1-2-pyridyl] methylthio _ 1 H — benzodimidazole, melting point 11 4 to 11 5 X (decomposition)

◎ 2 1 [3-methyl 1 4-C 2-(-methyl-N-(2-phenylethyl) amino] ethoxy] 1 2-pyridyl] methylthio 1 H-benzoimidazole

¹ H-NMR (CDC £ ₃ ): δ (ppm) = 2.24 (s, 3H), 2.44 (s, 3Η), 2.60 to 2.84 (m, 4Η), 2.92 (t, 2Η), 4.12 (t, 2H ), 4.39 (s, 2Η), 6.72 and 8.32 (d, 2H respectively), 7.10 to 7.35 And 7.40 to 7.60 (m, 9H respectively)

® 2-[3-methyl 4-(4-mono-renovated) 1 2-viridyl] 1-H-benzimidazole

¹ H-NMR (CDC £ ₃ ): 6 (ppm) = 1.50 to 2000 and 2.30 to 2.55 (m, 10H respectively), 3.55 to 3.80 (m, 4H), 4.00 (t, 2H), 4.30 (3 , 21!), 6.70 and 8.25 (d, 2H respectively), 7.00-7,35 and 7.40-7.60 (m, 4H each)

¹ H-NMR (CDC £ ₃ ) * '(ppm) = 1-64-2,10 (m, 2H), 2.22 (s, 3H), 2.39 (s, 3H), 2.52 and 2,68 (each t , 4H), 2.86 (t, 2H), 4.11 (t, 2H) _s 4.40 (s, 2H), 6.72 and

8.32 (each d, 2H), 04-7.40 and 740-7.70 (each m, 9H)

◎ 2-[3-methyl 1-4 1 [3-(N-benzyl-N-methylamino) proboxy] 1 2-pyridyl] methylthio 1 H-benzimidazole

^{_{1 H - NMR (CDC £ 3}} ): (ppm) = 1.80~2.12 (m, 2H), 2.04 (s, 3H), 2.24 (s, 3H), 2.52 (t, 2H), 3.50 (s, 2H) , 4.03 (t, 2H), 4.40 (s, 2H), 6.70 and 8.30 (d, 2H respectively), 7.00-7.40 and 7.45-7.7 (m, 9H each)

© 2-[3-Methyl-4-1-[2-[N-(3-methoxybenzil)-1-N-methylamino] ethoxy]-1-2-Pyridyl] methylthio-1H ^ Nsui midazole, melting point 89-91 'C (decomposition) ◎ 2-[3-Methyl-4-1-2-CN-(2-mouth π-benzyl) 1-N-methylamino] ethoxy] 1-2-Pyridyl] methyl-1 H-Benzimidazole , Melting point 1 2 7-: I 30 0 (decomposition)

◎ 2-[3-methyl 1 4 1 [2-C Ν-(4 -fluorobenzyl) 1 -methylamino] ethoxy] 1 2-viridyl] methylthio 1 H-benzimidazole

^-MRCCDC £ ₃ ): δ (ppm) = 2.25 is, 3H), 2.40 (s, 3H), 2,80 (t, 2H), 3.50 (s, 2H), 4.18 (t, 2H), 4.50 ( s ₅ 2H), 6.65 and 8.25 (each d, 2H), 7.00~7.55 (each m, 8H)

Ή-NM R (CDC £ ₃ )? 6 ( _PP m) = 2.25 (s, 3H), 2.39 is, 3H), 2.80 (t, 2H), 3.60 (s, 2H), 3.70 (s, 9H), 4.10 (t, 2H), 4.42 (s, 2H), 6,75 and 8.35 (d, 2H respectively), T.00 ~ "? 45 and 7.50 ~ 7.80 (m, 6H each)

Example 1

2 1 [3 1 methyl 1 4-[2-(N-benzyl-N-methyl amino) ethoxy 1 2-pyridyl] methylthio 1 H-benzimidazo 1 L 6 g To the 100 solution, add metachlorobenzoic acid and stir at room temperature for 20 minutes. After cooling to 30'C, add 1.0 g of 80% metachloroperbenzoic acid, stir for 15 minutes, and then pass through an ammonia gas, and filter off the formed precipitate. You. The filtrate was concentrated under reduced pressure, the residue was applied to silica gel, and the mixture was eluted with ethanol-containing ammonia at 4%. [2— (N-benzyl-N-methylamino) ethoxy] -12-viridyl] methylsulfinyl 1H-benzimidazole is obtained as an amorphous powder.

¹ H-NMR (CDC £ ₃ ): δ (ppm) = 2.12 (s, 3H), 2.32 (s, 3Η), 2.80 (t, 2Η), 3.60 (s, 2Η), 4.05 (t, 2Η), 4.70 (s, 2H), 6.62 and 8.24 (d, 2H respectively), 7000 to 7.36 and 7.40 to 7.66 (m, 9H each)

Example 2

2— [3-Methyl-41- (2—Biberidino ethoxy) -1-2-Viridyl] Metylthio-1H-Benzimidazole 2.5 g of chloroform 12.5 B. Add 1.1 g of oral benzoic acid and stir at room temperature for 20 minutes. After cooling to a temperature of 1.8%, add 1.7% of 80% methanol orbital perbenzoic acid, stir for 20 minutes, then pass through ammonia gas, and filter off the resulting precipitate. The filtrate was concentrated under reduced pressure, the residue was applied to silica gel chromatography, and eluted with a cross-sectional form having a 12% ethanolic ammonia to give 2— [3-methyl-14. 1- (2-piperidinoethoxy) 1-2-bilyzyl] methylsulfinyl-1H ^ nzimidazole is obtained as an amorphous powder.

¹ H-NMR (CDC £ ₃ ): 6 (ppm) = 1.20-1.80 and 2.40-2.60 (m each), 2.14 (s, 3H), 2.80 (t, 2H), 4.12 (t, 2H), 4.76 ( s, 2fi), 6.70 and 8.26 (d, 2H respectively), 7.20 Up to 7.40 and 7.52 to 7.76 (m, 4H respectively)

Example 3

2-3 3-Methyl-1-41 [2— (4-Methyl-1-1-biperazinyl) ethoxy] 1-2—Pyridyl] methylthio-1H-Benzimidazole 1.6 g Cloth form 10 0 0 To the solution, add 1.4 g of metaclo-benzoic acid and stir at room temperature for 20 minutes. — After cooling to 35 • C, add 1.7 g of 80% metabenzoic perbenzoic acid, stir for 10 minutes, and then pass ammonia gas through to remove the formed sediment. After concentration, the residue was subjected to silica gel column chromatography and eluted with a 16% ethanolaceous ammonia-containing mouth-mouthed form, which gave 2- [3—methyl 4 -— [2—

(-Methyl-1-biradizyl) ethoxy] 1-2-Viridyl] methylsulfinyl 1H-Benzimidazole is obtained as an amorphous powder.

^{_{1 H - NMR (CDC & 3}} ): 6 (ppm) = 2.14 (s, 3H), 2.36

(s, 31), 2.4 ~ 2,70 (m, 8H) 2.82 (t, 2H), 4.10 (t, 2Η), 4.76 (s, 2H), 6.66 and 8.24 (d, 2H), 7.20 ~ 740 and 7.48 to 7.66 (m, H respectively)

Example 4

2— [3—Methyl-1-41 (2—Morpholinoethoxy) 1-2—Viridyl] Metylthio-1H—Benzimidazonole 3.0 g of na-form 200 solution Add benzoic acid (1.2 g) and stir at room temperature for 20 minutes. After cooling to 15'C, add 2.0 g of 80% methanol orbital perbenzoic acid, stir for 20 minutes, and then pass ammonia gas through to remove the formed precipitate. The filtrate was concentrated under reduced pressure, The residue was applied to silica gel chromatography and eluted with a chloroform form containing 5% of ethanolic ammonia. As a result, 2- [3-methyl-4-1 (2-morpholinoethoxy) -1 2-Pyridyl) methyl sulfite 1H-Benzymidazole is obtained as an amorphous powder.

^{_{1 H - NMR (CDC £ 3}} ): δ (ppm) = 2.16 (s, 3H), 2.52 ~2.68 Oyobi 3,68～3.80 (each m, 8H), 2.82 (t s 2H), 4.12 (t , 2H), 4.79 (s, 2H), 6.68 and 8,28 (d, 2H, respectively), 7.20 to 7.40 and 750 to 7.70 (m, 4H, respectively)

Example 5

2-[3-methyl 1 4 1 [2-(1 -methyl 2-pyrrolidinyl) ethoxy] 1 2-viridyl] methylthio 1 H-benzimidazole 3.0 g To a solution of 20 ml of formaldehyde in mouth, add 1.2 g of methanolic benzoate and stir at room temperature for 20 minutes. After cooling, the mixture was added with 2.0 g of 80% methanolic perbenzoic acid, stirred for 20 minutes, then passed through ammonia gas, and the resulting precipitate was filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel gel chromatography. The residue was eluted with chloroform containing 8% ethanolic ammonia, and the result was 2— [3—methyl 4-1-1 [2— (1-Methyl-1-2-pyrrolidinyl) ethoxy] 1-2-Pyridyl] methylsulfuryl 1H-Benzimidazole is obtained as an amorphous powder.

¹ H-NR (CDC £ ₃ ): δ (ppm) = 1.20 to 1.90 and '90 to 3.19 (m, 7H respectively), 2.12 (s, 3H), 2.32 (s, 3H), .20 (t, 2H ), 4.00 (t, 2H), 4.76 (s, 2H), 6.67 and 8.25 (each d, 2H), 7.20-7.36 and 7.50-7.65 (each m, 4H)

Example 6

2— [3—Methyl-4-1 (1-methyl-1-4-biperyl ziroxy) 1-2-Viridyl] Methylthio-1H—Benzi Midazol Oral benzoic acid

Add 1.5 g and stir at room temperature for 20 minutes. — After cooling to 2 O'C, add 2.3 g of 80% perbenzoic acid perbenzoic acid, stir for 20 minutes, then pass ammonia gas, and filter off the resulting precipitate. The filtrate was concentrated under reduced pressure, and the residue was applied to a silica gel gel column and eluted with a gel form containing 10% ethanolic ammonia to give 2 — [3 — methyl 1 4 — (1 —Methyl 4-bipericyloxy) 1 2 —Viridyl] Methinolesulfinyl 1 H 1 Benzimidazole is obtained as an amorphous powder.

¹ H-NMR (CDC £ ₃ ): δ (ppm) = 1.60 to 2.04, 2.20 to 2.70 and 4 „24 to 4,52 (m, 9H respectively), 2.12 (s, 3H), 2.30 is, 3H) 4.80 (s, 2H), 6.64 and 8.23 (d, 2H respectively), 7.20 to 7.36 and 7.50 to 7.66 (m, 4Η each)

Example 7

2— [3—Methyl-4— [2— (N-benzyl N-methylamino) ethoxy]] 1 2—pyridyl] methylsulfuryl 2H 1H—benzimidazole 2.6 g ethanol & Dissolve in 0, and add 0.247 g of sodium hydroxide solution 20 ^ to this, and stir at room temperature for 30 minutes. After completion of the reaction, the mixture is concentrated under reduced pressure, and the residue is dissolved using acetone 20 ^. Getyl ether 100 in solution Add ^, vigorously stir, and then filter to give 2- [3-Methyl-41- [2- (N-benzyl-N-methylamino) ethoxy] 1-2-pyridyl] methylsulf 2 1H-Venzi midazole sodium salt is obtained as an amorphous powder.

¹ H-NMR (CDC £ ₃ ): δ (ppm) = 1.70 (s, 3H), 2.24 (s, 3fl), 2.65 (m, 2H), 3.20 to 4.70 (m, 6Η), 6.10 (m , 1Η), 6.90 (m, 2H), 7000 to 750 (m, 7H), 7.65 (m, 1H)

Example 8

2-[3-methyl 1 4 1 [2-(N-benzyl-N-methyl amino) ethoxy] 1 2-pyridyl] methyl selenium 1 H-venzi midazol Dissolve 7.33 g of sodium salt in 150 id of water, add 0.938 g of calcium chloride 50 in aqueous solution, and stir at room temperature for 30 minutes. The precipitated crystals are filtered and washed thoroughly with water to give 2-[3-methyl-41-[2-(N-benzyl-N-methylamino) ethoxy] 1-2-pyridyl The methylsulfinyl 1H-benzimidazole-calcium salt is obtained as colorless crystals.

¹ H-NMR (CDC £ ₃ ): δ (ppm) = 2.15 (s, 3H), 2.35 (s, 3Η), 2.85 (t, 2Η), 3.62 (s, 2H), 4.09 (t, 2H), 4.55 (q, 2H), 6.65 (d, 1H), 7.02 (t, 2H), 721 to 7.36 (m, 5H, respectively), 7.6 (t, 2H), 8.18 (d, 1H)

The following compounds are obtained in the same manner as in the above examples.

◎ 2-[3-methyl 4-1 [2-(N-benzyl-N-methyl olefin) ethoxy] 1 2-pyridyl] methylsulfur 2-5-medox 1 H-Benzi midazole, amorphous powder ¹ H-NMR (CDCJ £ ₃ ): δ (ppm) = 2,10 (s, 3H), 2.32 (s, 3H), 2.80 (t, 2H), 3. & 0 (s, 2H), 3.80 (s , 3H), 4.05 (t, 2H), 4.75 (s, 2H), 6,61 and 8,25 (d, 2H respectively), 6.85 to 760 (m, 81 each)

® 2-[3-methyl-41-[2-C-(p-black benzene) 1-methylamino] ethoxy] 1 2-pyridyl] methylsulfinyl-1H —Benzui midazole, amorphous powder,

¹ H-NMR (COC & _s ) t δ (pprn) = 2.12 (s, 3H), 2.30 (s, 3H), 2.80 (t, 2H), 3.54 (s, 2H), 4. 03 (t, 2H), 4.76 (d, 2H), 6.62 and 8.24 (each d, 2H) _s 7.00 to 7.T0 (each m, 8H)

◎ 2-[3-methyl 1 4-[2-[N -methyl N-(4 -methylbenzyl) amino] 1 2-Viridyl] methyl sulfinyl 1 H- Nsui midazole, amorphous powder,

l H—NMR (CDC £ ₃ ): δ (ppm) = 2.12 (s, 3H), 2.32 (s, 6Η), 2.80 (t, 2H), 3.54 (s, 2H), 4.04 (t, 2H), 4.76 (d, 2H), 6.60 and 8.23 (d, 2H respectively), 6.80-7.70 (m, 8H each)

◎ 2 — [3 — methyl 1 4 1 [2 — (1, 2, 3, 4 — tetra dani doro sokinoline 1 2 — yl) ethoxy] 1 2 — viridyl] methylsulfy 1-H-benzimidazole, amorphous powder, 1 H-NMR (CDCH z) δ (ppm) = 2.18 (s, 3H), 2.90 (s, 4H), 3.00 Ct, 2H), 3.76 (s , 2H), 20 (t, 2H), 4.74 (d, 2H), 6.70 and 8.26 (d, 2H each), 6.84 to 7.76 (m, 8H each) ◎ 2 — [3 -methyl 4- 1 [2-(panjiru N-ethylamino) ethoxy] 1 2-viridyl] methylsulfur 2-1 1-venzimidazole, amorphous powder ,

¹ H-NMR (CDC £ ₃ ): ff (ppm) = 1.10 (t, 3H), 2.12 (s, 3H), 2.65 (q, 2H), 2.88 (t, 2H), 3.68 (s, 2H), 3.98 (t, 2H), 4.76 (d, 2H), 6.56 and 8.22 (each d, 2H), 7,00 to 7.70 (m, 9H each)

◎ 2-[3-methyl 4- 1 [2-(N-benzyl N-proviramino) ethoxy] 1 2-pyridyl] methylsulfiel 1 1-H-benzimidazole, amorphous Powder,

¹ H-NMR (CDC £ ₃ ): δ (ppm) = 0.89 (t, 3H), 1.54 (m, 2Η), 2.13 (s, 3H), 2.52 (t, 2H), 2.86 (t, 2H), 3.67 (s, 2H), 3.98 (t, 2H), 4.74 (d, 2H), 6.56 and 8.22 (d, 2H each), 7.00 to 7.74 (m, 9H each)

◎ 5-chloro 2-[3-methyl-4-[2-(N-benzyl-N-ethylamine) ethoxy] 1 2-pyridyl] methyls-2-1 H-Benzi midazole, amorphous powder,

¹ H-NMR (CDC £ ₃ ): δ (ppm) = 1.07 (t, 3H), 2.09 (s, 3Η), 2.64, 2Η), 2.86 (t, 2H), 3.66 (s, 2H), 3.98 ( t, 2H), 4.74 (d, 2H), 6.58 and 8.20 (each d, 2H), 7.10 to 7.64 (m, 8H each)

◎ 2-[3-methyl 4-[2-(N-methylanilino) ethoxy] 1 2-pyridyl] methylsulfuryl 2 1H-^ ^ Nzimidazole, amorphous powder ,.

¹ H-NMR (CDC £ ₃ ): 6 (ppm) = 2.02 (s, 3H), 2.98 (s, 3H), 3.90 (m, 2H), 4.10 (m, 2H), 4.75 (s, 2H), 6,70 (m, 4H), 7.15 Cm, 4H), 7.45 (m, 2H), 8.18 (d, 1H)

◎ 2-[3-Methyl-4-1 [2-(N-methylarino) ethoxy] 1-2-pyridyl] methylsulfi-2-ru 1 fi-benzimidazole sodium salt, amorphous powder ,

¹ H-NMR (CDC iz) I δ (ppm) = 1.75 (s, 3H), 2.90 (s, 3H), 3.20 to 70 (m, 6H), 6.05 (m, 1H), 6.30 to .50 Cm , 9H), 7.60 (m, 1H)

◎ 2 ― [3-Methyl-4-1 (31-morpholinop-box) 1 2-Viridyl] methylsulfinyl 1H-benzimidazol

¹ H-NMR (CDC £ ₃ ) r <y (ppm) = 1, 90-2.15 and 2 * 35-2.60 (m, 8H respectively), 2.18 (s, 3H), 3.73 and 3.75 (t, 4H), 4.04 (t, 2H), 4.78 (s, 2H), 6.70 and 8.28 (d, 2Η respectively), 7.20 to 7.40 and 7.50 to 7.70 (m, 4H each)-© 2 — [3-methyl-1 4 — (3 — biperidinopropoxy) 1- 2-pyridyl] methyl sulfite 2 1 H-benzimidazole

¹ H-NMR (CDC £ ₃ ): δ (ppm) =

1.30-1.80 and 1.90-2.10 (m, 10H respectively), 2.15 (s, 3H), 2.30-2.60 (m, 4H), 4.04 (t, 2Η), 4.75 (s, 2Η), 6.70 and 8.30 ( D, 2H), 7. 20 ~ 7.40 and 7,50 ~ 7V70 (m, 4H respectively)

◎ 2 — [3—Methyl 1 4 — [2 — (2 —Oxo 1 1 Dinyl) ethoxy] 1 2-pyridyl] methylsulfur 2 1 H-Benzymidazole

¹ H-NMR (CDC £ ₃ ): δ (ppra) =

1.80-2.10, 2.20-2.50 (m, 4H), 2.12 (s, 3H), 3.50 (t, 2H), 3.70 (t, 2H), 4.10 (t, 2H), 4.74 (s, 2H) , 6.65 and 8.24 (d, 2H, respectively), 7-20 to 7.40 and 7.40 to 7.80 (nt, 4H, respectively)

◎ 2-[3-methyl 4-1 (1-methyl 2-biperiyl methoxy) 1 2-viridyl] methyl sulfi 2 2 1 H-^ Nozimidazoru

¹ H-NMR (CDC £ ₃ ): δ (ppm) = 1.20 ~; L90 and 2.70 ~ 300 (m, 9H respectively), 2.16 (s, 3H), 2.35 (s, 3H), 3.80 ~ 4.20 (m, 2Η), 4.78 (s, 2H), 6.66 and 8.28 (d, 2H respectively), 7.20 to 7.40 and 7.50 to 7.70 (m, 4H each)

◎ 2 — [3 -methyl 4-[2-[N-methyl-N- (2 -phenylethyl) amino] ethoxy] 1 2 -pyridyl] methyl sulfinyl 1 H-benzi Midazole

¹ H-NMR (CDC £ ₃ ): δ (ppm) = 2.13 (s, 3H), 2.42 (s, 3Η), 2.60-2.80 (m, 4Η), 2.88 (t, 2Η), 4.40 (t , 2Η), 4.74 (s, 2Η), 6.63 and 8.24 (d, 2H respectively), 7.00 to 7.40 'and 7.44 to 7.70 (m, 9H each)

◎ 2-[3-methyl 4-(4-morpholinobutoxy) 1 2-pyridyl] methylsolefinil-1 H ^

^{1 Η - NMR (C Ό C} £ 3): 6 (ppm) =

.40-2.00 and 2.30-2.60 (m, 10H respectively), 3.50-3.80 (m, 4H), 4.00 (t 2H), 4.78 (s, 2H) 6.68 and 8.28

(Respectively d, 2H), 7.20 7.40 and 7 · 50 7.70 (respectively, m, 4H) ® 2-[3-methyl-4- [2-[N-methyl-1 N-(3-phenylpropyl)] [Mino] ethoxy] 1-2-pyridyl] methylsulfinyl-1H-benzimidazole

¹ H-NMR (CDG £ ₃ ) δ (ppm) 60 1.96 (m, 2H), 2.14 (s, 3H), 2.33 (s 3H), 2,44 and 2 64 (t, 4H, respectively) 2.80 (t, 2H), 4.04 (t, 2H), 4.75 (s, 2H) _s 6, 65 and 8.26 (d, 2H 7.00-40 and 7.40-ma, 70 (m, 9H each)

◎ 2- 3 -methyl 1-4 [3-(N-benzyl N-methyl azo miso) propoxy] 1-2-viridyl] methyls ^ finyl: L H-benzimidazole

¹ H-NMR (CDC £ ₃ ) ι δ (ppm) = 1 ・ 80 2.10 (m, 2H), 2.05 Cs, 3Η), 2.25 (s, 3H) 2.55 (t, 2H), 3.50 (s, 2H) , 4.01 (t, 2H), 4.74 (s, 2H), 6.66 and 8.26 (d, 2H respectively), 7.10 7.40 and 7 45 7,70 (ra, 9H each)

◎ 2-[3-Methyl 1 4 1 [2-[N ^ (3-methoxybenzil) 1 N-methylamino] ethoxy] 1 2-Pyridyl] methylsulfinyl 1 1 H—benzimidazole

¹ H-NMR (CDC £ ₃ ) δ (ppm) = 2.15 (s, 3H),

2.40 (s, 3Η), 2.80 (t, 2Η), 3.55 (s, 2Η), 3.80 (s, 3Η), 4.05 (t, 2Η), 4.80 (s, 2H), 666 and 8.25 (d, 2H), 6 80 7 „00 7.05 7.45 and 7 50 7.Τ0 (m, 8H respectively)

◎ 2-[3-methyl 1 4 1 [2-! : N — (2-benzene) 1-N-methylamino] ethoxy] 1-2-viridyl] methyl Sulfinyl 1H—Benzi midazole

¹ H-NMR (CDC £ ₃ ): δ (ppm) = 2.14 (s, 3H), 2.37 (s, 3Η), 2.90 (t, 2H), 3.70 (s, 2H), 4.10 (t, 2H), 4.78 (s, 2H), 6.65 and 8.27 (d, 2H respectively), 7.07 to 7.70 (m, 8H each)

◎ 2-[3-methyl 4- 1 [2-C N-(4-fluorobenzyl)-1 N-methylamino] ethoxy] 1 2-viridyl] methyl sulfyl 2 H 1 H-venzi midazole

¹ H-MR (CDC £ ₃ ): δ (ppm) = 2.12 (s, 3H), 2.30 (s, 3H), 2.77 (t, 2H), 3.52 (s, 2H), 4.00 (t, 2H), 4.77 (s, 2H), 6.62 and 8.23 (d, 2H respectively), 7.00 ~ 750 and 752 ~ 70 (m, 8Η each)

◎ 2 — [3-methyl 1-4 1 [2-[Ν-(3, 4, 5-trimethoxybenzyl) 1-methylamino] ethoxy] 1-2-biphenyl] methylsulfur Two roux 1 Η—Benzi midazole

^{_{1 Η - NMR (CDC £ 3}} ): δ (ppm) = 2.24 (s, 3H), 2.40 (s, 3Η), 2.80 (t, 2H), 3.62 (s, 2H), 3.69 (s, 9H), 4.12 (t, 2H), 4.82 (s, 2H), 6.7 and 8.36 (d, 2H respectively), 7.00-7.45 and 7.50-7.80 (m, 6H each)

◎ 2 — [3-methyl 1 4-[2-[N-(3,, 5-trimethoxybenzyl) 1-methyl-amino] ethoxy] 1 2-pyridinole] Metyls Noref Ininolay 1 Η ^ Nzimidazole 'sodium salt

^{_{1 Η - NMR (CDC £ 3}} ): δ (ppm) =

.95 (br.s, 3H), 2.15 (s, 3Η), 2.75 (br.s, 2Η), 3.48 (s, 2ff), 3.70 (br.s, 2ff), 3.80 (s, 9H), 4.50 (br.s, 2H), 6.20 and 7.80 (br.s, 2H), 6.80 ~ "? 30. 7.35 to 7.65 (m, 6H respectively)

◎ 2-[3-methyl 4- 1 [2-(N-(4 -bromobenzyl) 1-N-methylamino] ethoxy] 1 2-viridyl] Methyl sulfi 2-1 H-Benzi midazole

l H-NMR (CDC £ ₃ ): δ (ppni) = 2.16 (s, 3H), 2.37 (s, 3Η), 2.92 (t, 2Η), 3.53 (s, 2H), 4.05 (t, 2H) , 4.80 (s, 2H), 6.65 (d, 1H), 7: 00-Τ. 80 (each m, 8H) _s 8.25 (each d, 1H)

Formulation example

Tablets Active ingredient 5 m The tablets have the following composition.

5 mg of the compound of Example 1

Corn starch 1 5 mg

5 7 ig

Microcrystalline cellulose 40 mg

Magnesium stearate 3 mg_

120 mg

Capsule A capsule containing 3 mg of the active ingredient is prepared according to the following composition.

3 mg of the compound of Example 1

Cornstarch 30 mg

Lactose 6 mg

Hydroxypropyl cellulose 6 mg _

100 mg Although the present invention has been fully described in the foregoing specification and the examples contained therein, various changes and modifications can be made without departing from the spirit and scope of the present invention.

Claims

The scope of the claims

1. General formula

Η

Wherein R ¹ is hydrogen, halogen, alkyl, alkoxy, alkoxycarbonyl or haloalkyl;

R ² and R ³ are the same or different and represent hydrogen, halogen or alkyl,

L is the formula:.

/ R

-N <

, R ⁵

(Where one of R and R ^s represents hydrogen, and the other represents hydrogen, aralkyl, phenyl, substituted phenyl, aralkyl-substituted aralkyl, acyl, and R ⁴ , R ^{5 represents} When one represents alkyl-phenyl, substituted phenyl, aralkyl, substituted aralkyl, acyl, the other represents phenyl, substituted phenyl, aralkyl, substituted aralkyl, acyl, or R ⁴ and R ⁵ Represents a group which, together with an adjacent nitrogen atom, forms a heterocyclic ring which may be condensed.)

Wherein R ⁶ is hydrogen, alkyl or acyl, Z is methylene, oxygen or sulfur, and i and m are the same or different.

3.5

Represents 0 and an integer of 1 to 3. ), And

n represents 0 or an integer of 1 to 8. ]

Or a pharmaceutically acceptable compound represented by

2. L is the formula:

Z R

-

\ R ⁵

Wherein R ⁴ represents alkyl, R ⁵ represents aralkyl or substituted aralkyl, or R ⁴ and R ⁵ are bonded together with the adjacent nitrogen atom to form a condensed group. 2. The pyridine compound or a pharmaceutically acceptable salt thereof according to claim 1, which represents a group forming a good heterocyclic ring.

3. L is the formula:

/ R ⁴

-<

ヽ R ⁵

Wherein R ⁴ represents an alkyl having 1 to 4 carbons, R ^s represents a benzyl which may have a halogen or an alkyl having 1 to 4 carbons as a substituent, 2. The pyridine compound according to claim 1, which is 2-phenylethyl or a pharmaceutically acceptable fe thereof.

4. L may have 1 to 3 halogen, alkyl having 1 to 4 carbons or alkoxy having 1 to 4 carbons as a substituent

2. The pyridine compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the pyridine compound is 1,2,3,4—tetrahydroysoquinolin-12-yl.

5.2— [3—Methyl-4-1 (2— (N-benzyl N-methyl) aminoethoxy] 1-2—Viridyl] methylsulfuryl 2-H 1-Benzimidazole, 2-—3 Methyl 1 4 1 [2 —

[N-methyl-1-N- (2-phenylethyl) amino] ethoxy] —2-pyridyl] methylsulfinyl-1H-benzimidazol, 2 1 3–methyl-1 4 1 [2— (N— (4-chlorobenzyl) -1-N-methyl) amino ethoxy] 1-2-pyridyl] methylsulfinyl 1H-benzimidazole, 2— [3—methyl 1- (2—CN- (4-fluorobenzyl) -1-N-methylamino) ethoxy] -1-pyridyl] methylsulfinyl-1

H Nsui midazole, 2— [3—Methyl-1-41 [2— [N-Methyl-N— (4-Methylbenzyl) amino] ethoxy] 1-2—Viridyl] Methylsulfinyl Nil-1 H—Benzimidazole , 2-[3-methyl 1-4 (2-morpholinoethoxy) 1-2-viridyl] methylsulfi-1-1 H-benzimidazole and 2 _ [3-methyl 1-4 1 [2-(1 , 2,3,4 —tetrahydropisisoquinolin-2 —yl) ethoxy] 1 2 —pyridyl] methyls J-refinyl-1H-benzimidazole is selected from claim 1. Or a pharmaceutically acceptable salt thereof. —-—

6. A pharmaceutical composition comprising the viridin compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.