KR910010078B1 - Process for preparing tetrahydro quinolines and their salts imidazo pyridines and their salts - Google Patents

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Description

Tetrahydroquinoline derivatives and salts thereof, imidazopyridine derivatives and methods for preparing the salts thereof

The present invention relates to tetrahydroquinoline derivatives and salts thereof, and to imidazopyridine derivatives and methods for preparing the salts thereof. More particularly, the present invention relates to tetrahydroquinoline derivatives having excellent anti-peptic ulcer activity, salts thereof, and imidazopyridine derivatives and methods of preparing the salts thereof.

The novel tetrahydroquinoline derivatives and salts thereof according to the present invention are represented by the following general formula (1), and the novel imidazopyridine derivatives and salts thereof are represented by the following general formula (20).

는 테트라히드로퀴놀린 부분의 2- 내지 8-위치에 치환되어 있다.Wherein R ^1a and R ^2a are the same or different, and each is a hydrogen atom, a halogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, a lower alkenyloxy group, a lower alkynyloxy group or a lower alkoxy-lower alkoxy group; R ^3a and R ^4a are the same or different, and each is a hydrogen atom, a halogen atom, a nitro group, a lower alkyl group, a lower alkoxy group or a lower alkanoyl group having a halogen atom as a substituent; C1 is 0 or 1;

Is substituted in the 2- to 8-positions of the tetrahydroquinoline moiety.

In which one of Z or Y is -CH =, the other is nitrogen atom = N-; R ^1b and R ^2b are the same or different and each is a hydrogen atom, a lower alkoxycarbonyl group, a halogen atom, a lower alkyl group, an amino group or a hydroxy group; R ^3b , R ^4b and R ^5b are the same or different and each is a hydrogen atom, a lower alkoxy group or a lower alkyl group; A is a lower alkylene group; C1 is 0 or 1; If Y is = CH-, Z is nitrogen = N- and Cl is 0, then R ^3b , R ^4b and R ^5b are not hydrogen atoms at the same time.

The novel tetrahydroquinoline derivatives of formula (1) and salts thereof and imidazopyridine derivatives of formula (20) and salts thereof have excellent anti-digestive ulcer activity useful for treating peptic ulcers such as gastric ulcer and duodenal ulcer. .

The production rate of hydrochloric acid in the gastric juice secreted by the gastric mucosa is controlled by physiological factors, among which the biochemical mechanism regarding the production rate of hydrogen ions (H ⁺ ) has a critical effect as a rate limiting factor.

Recently, it has been found that adenosine triphosphatase (ATPase) regulates the production of hydrochloric acid by hydrogen ions (H ⁺ ) and potassium ions (K ⁺ ) in gastric wall cells.

The ATPase is an enzyme uniquely present in gastric wall cells and acts as an important enzyme in a so-called `` proton pump ''. Thus, inhibitors affecting the activity of ATPase may be useful samples for inhibiting the secretion of hydrochloric acid produced in the stomach.

Tetrahydroquinoline derivatives of the general formula (1) and salts thereof and imidazopyridine derivatives of the general formula (20) and salts thereof have a function of inhibiting gastric acid secretion and protecting gastric wall cells, And salts thereof and imidazopyridine derivatives and salts thereof inhibit peptic ulcer factors by inhibiting attack factors and also having protective factors. Moreover, tetrahydroquinoline derivatives and salts thereof and imidazopyridine derivatives and salts thereof according to the present invention also have other characteristics, such as low toxicity and a feature of inhibiting gastric acid secretion.

Compounds having a structure similar to the chemical structure of the tetrahydroquinoline derivative of formula (1) are disclosed in British Patent No. 1,234,058; 1,500,043; US Patent No. 4,045,563; 4,359,465, 3,808,005; And in German Patent Application Publication No. 2,164,661.

Furthermore, compounds having a structure similar to the chemical structure of the imidazopyridine derivative of the general formula (20) are described in European Patent Application No. 0130729 (corresponding to Japanese Patent Application Publication No. 60-36,483 (1985)). have.

Among these documents, for example, British Patent No. 1,234,058 discloses pyridylalkyloxy and pyridylalkylthiazole derivatives of the following formulas having anti-tuberculosis, insecticidal action, antibacterial action, antiviral action, antiparasitic action and anti-inflammatory action. It is described.

The pyridylalkyloxy and pyridylalkylthiazole derivatives of the aforementioned documents are similar to the imidazopyridine derivatives described herein, except for the pyridylalkylthiazole derivatives, the pyridylalkyloxy derivatives are pharmacologically described below herein. As can be seen from the test results, the anti-inflammatory ulcer activity is very weak.

An object of the present invention is to provide a novel tetrahydroquinoline derivative represented by the general formula (1) and salts thereof, and a novel imidazopyridine derivative represented by the general formula (20) and a method for preparing the salts thereof.

In the present specification, the lower alkyl group is a straight or branched chain alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and hexyl groups.

Lower alkoxy groups are straight or branched chain alkoxy groups having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy and hexyloxy groups.

Examples of halogen atoms are fluorine, chlorine, bromine and iodine atoms.

Lower alkyl groups which may have a halogen atom as a substituent are, in addition to the above alkyl groups, trifluoromethyl, 2,2-difluoroethyl, 1,1-dichloroethyl, dichloromethyl, trichloromethyl, tribromomethyl, 2, 2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-chloroethyl, 1,2-dichloroethyl, 3,3,3-trichloropropyl, 3-fluoropropyl, 4-chloro It is a C1-C6 alkyl group which can contain 1-3 halogen atoms as a substituent like butyl and 3-chloro- 2-methylpropyl group.

Lower alkanoyl groups are straight or branched chain alkanoyl groups having 1 to 6 carbon atoms such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl and hexanoyl groups.

Lower alkenyloxy groups include straight chains having 2 to 6 carbon atoms such as vinyloxy, allyloxy, 2-butenyloxy, 3-butenyloxy, 1-methylallyloxy, 2-pentenyloxy and 2-hexenyloxy groups; It is a branched chain alkenyloxy group.

Alkynyloxy groups include, for example, ethynyloxy, 2-propynyloxy, 2-butynyloxy, 3-butynyloxy, 1-methyl-2-propynyloxy, 2-pentynyloxy and 2-hexynyloxy groups. It is a C2-C6 linear or branched alkenyloxy group.

Lower alkoxy-lower alkoxy groups include methoxymethoxy, ethoxymethoxy, propoxymethoxy, butoxymethoxy, pentyloxymethoxy, hexoxymethoxy, 2-methoxymethoxy, 1-methoxyethoxy , 2-propoxyoxy, 2-hexoxyethoxy, 3-methoxypropoxy, 1-methoxypropoxy, 3-butoxypropoxy, 3-pentyloxypropoxy, 4-methoxybutoxy, 3-propoxybutoxy, 4-hexyloxybutoxy, 5-ethoxypentyloxy, 3-propoxypentyloxy, 6-methoxyhexyloxy, 2-ethoxyhexyloxy and 3-pentyloxyhexyloxy It is a C1-C6 linear or branched alkyl group which has a C1-C6 linear or branched alkyl group as a substituent as a substituent.

Lower alkylene groups include carbon atoms such as methylene, ethylene, trimethylene, methylmethylene, ethylmethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, tetramethylene, pentamethylene and hexamethylene To 6 or a straight or branched chain alkylene group.

Lower alkoxy carbonyl groups include alkoxy such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl groups The part is an alkoxycarbonyl group having 1 to 6 carbon atoms.

The tetrahydroquinoline derivative represented by General formula (1) and its salt can be manufactured by various methods, for example as follows.

[Scheme -1]

Wherein R ^1a , R ^2a , R ^3a and R ^4a have been defined above; X ¹ and X ² are a mercapto group, a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group, respectively; When X ¹ is a mercapto group, X ² is a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group; When X ² is a mercapto group, X ¹ is a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group.

In formulas (2) and (3), X ¹ and / or X ² are halogen atoms as defined above; Examples of lower alkalsulfonyloxy groups include methanesulfonyloxy, ethanesulfonyloxy, isopropanesulfonyloxy, propanesulfonyloxy, butanesulfonyloxy, t-butanesulfonyloxy, pentansulfonyloxy and hexanesulfo A silyloxy group; Examples of the arylsulfonyloxy group include phenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy, 3-chlorophenylsul Phonyloxy and α-naphthylsulfonyloxy group; Examples of the aralkylsulfonyloxy group include benzylsulfonyloxy, 2-phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4-nitro Substituted or unsubstituted aralkylsulfonyloxy groups such as benzylsulfonyloxy, 4-methoxybenzylsulfonyloxy, 3-chlorobenzylsulfonyloxy and α-naphthylmethylsulfonyloxy groups.

The reaction of the compound of formula (2) with the compound of formula (3) is carried out in a suitable solvent in the presence of a basic compound.

Solvents used in the reaction include water; Alcohols such as methanol, ethanol, or isopropanol; Aromatic hydrocarbons such as benzene, toluene or xylene; Ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme; Ketones such as acetone; Esters such as methyl acetate or ethyl acetate; Polar solvents such as N, N-dimethylformamide, dimethylsulfoxide or hexamethylphosphortriamide; Or a solvent having no adverse effect, such as a solvent mixed with these.

Basic compounds used for the reaction include inorganic bases such as sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or silver carbonate; Alkali metals such as metal sodium or metal potassium; Alcoholates such as sodium methylate or sodium ethylate; Triethylamine, pyridine, N, N-dimethylaminopyridine, N-methylmorpholine, 1,5-diazabicyclo [4,3,0] nonene-5 (DBN), 1,8-diazabicyclo [5 Organic bases such as, 4,0] -undecene-7 (DBU) or 1,4-diazabicyclo [2,2,2] octane (DABCO).

The reaction is generally carried out at 0 to 150 캜, preferably at about 0 to 100 캜 for 1 to 10 hours. The content of the compound of the general formula (2) reacting with the compound of the general formula (3) is equal to or greater than the number of moles, and is preferably twice the number of moles.

[Scheme -2]

In formula, R <^1a> , R <^2a> , R <^3a> and R <^4a> are the same as the above.

Oxidation of the compound of formula (1a) is carried out in a suitable solvent in the presence of an oxidizing agent.

Solvents used for oxidation include water; Organic acids such as formic acid, acetic acid or trifluoroacetic acid; Alcohols such as methanol, ethanol or isopropanol; It is a solvent with no adverse effects, such as halogenated hydrocarbons such as chloroform, dichloromethane or dichloroethane. The oxidizing agents used for the oxidation include peracids such as performic acid, peracetic acid, trifluoroperacetic acid, perbenzoic acid, m-chloroperbenzoic acid or O-carboxyperacetic acid; Hydrogen peroxide; Chromic acid; Chromates such as sodium chromate or potassium chromate; Permanganitis, such as permanganic acid, sodium permanganitis or potassium permanganitis; Iodate, such as sodium metaiodate; It is an oxidizing agent capable of oxidizing sulfide groups to sulfoxide groups, such as selenium compounds such as selenium dioxide.

The content ratio of the oxidizing agent to the content of the compound of the general formula (1a) is equal to or greater than equimolar, preferably 1.5 times the molar number. The oxidation reaction is generally -70 to 40 ° C, preferably -70 ° C to room temperature, and the reaction time is about 5 minutes to 3 hours.

Scheme -3

In the formula, R ^1a , R ^2a , R ^3a and R ^4a are the same as above, and X ³ and X ⁴ are each a halogen atom.

In the above formula, reaction (i) of the general formula (2a) and the thiourea (4) compound is carried out in the presence or absence of a solvent. Solvents used in the reaction include alcohols such as methanol, ethanol or propanol; Ethers such as diethyl ether, tetrahydrofuran, dioxane or ethylene glycol monomethyl ether; Aromatic hydrocarbons such as benzene, toluene or xylene; Ketones such as acetone or methyl ethyl ketone; Or polar solvents such as N, N-dimethylformamide, dimethylsulfoxide or hexamethylphosphortriamide (HMPA).

The content of thiourea (4) used in the reaction is generally equal to or greater than the molar number of moles of the compound of the general formula (2a), and preferably 2 times.

The reaction is generally from room temperature to 200 ° C., preferably from room temperature to about 150 ° C. and completes for about 1 to 5 hours.

The reaction (ii) of the intermediate obtained in reaction (i) with the compound of general formula (3a) is generally carried out in the presence of a condensing agent. Generally as a condensing agent used for reaction (ii), a basic compound is used. Examples of the basic compound include inorganic basic compounds such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate or silver carbonate; Alkali metals such as metal sodium or metal potassium; Alcoholates such as sodium methylate or sodium ethylate; Organic base compounds such as triethylamine, pyridine, N, N-dimethylaniline, N-methylmorpholine, 4-methylaminopyridine, DBN, DBU or DABCO.

The reaction is carried out in the absence or presence of a solvent. Solvents include water; Alcohols such as methanol, ethanol, propanol, butanol or ethylene glycol; Ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme or diglyme; Ketones such as acetone or methyl ethyl ketone; Aromatic hydrocarbons such as benzene, toluene or xylene; Aprotic polar solvents such as esters N, N-dimethylformamide, dimethylsulfoxide or hexamethylphosphor triamide such as methyl acetate or ethyl acetate; Or a mixed solvent thereof.

Moreover, the reaction is advantageously carried out in the presence of a metal iodide such as sodium iodide or potassium iodide.

The content ratio of the compound (2a) to the compound (3a) is not particularly limited and can be selected in a wide range, and generally 0.5 to 5 times, preferably 0.5 to 2 times the number of moles of the compound (3a) Reaction with 2a). The reaction temperature is also not particularly limited, and is generally -30 to 200 ° C, preferably 0 to 160 ° C, and is usually completed within 1 to 30 hours.

[Scheme -4]

Wherein R ^1a and R ^2a are the same as defined above; R5 ^a is a lower alkanoyl group; X ⁵ and X ⁶ are each a halogen atom.

The reaction of the compound of formula (5) with the compound of formula (6) or (7) is carried out in the presence or absence of a suitable solvent. Solvents used in the reaction include halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; Aromatic hydrocarbons such as benzene, toluene or xylene; Ethers such as diethyl ether, tetrahydrofuran, or dioxane; Or a solvent having no adverse effect, such as pyridine.

The content ratio of the compound of the formula (6) or (7) to the content of the compound of the formula (5) is more than equimolar, preferably an excess of the compound of the formula (6) or (7) is used. The reaction is generally 0 to 150 ° C., preferably 0 to 100 ° C. and completes in 1 to 5 hours.

The hydrolysis reaction of the compound of formula (8) includes hydrochloric acid, halogen acid such as bromic acid, inorganic acid such as sulfuric acid or phosphoric acid; In the presence of a hydrolysis catalyst such as alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, sodium carbonate, potassium carbonate, or alkali metal carbonates such as sodium bicarbonate or alkali metal compounds such as hydrogen carbonate, a suitable solvent (e.g. water In the presence of an alcohol such as methanol, ethanol or a mixed solvent thereof) or in the absence of a solvent, the reaction is carried out at room temperature to 150 ° C, preferably 50 to 100 ° C, for 30 minutes to 24 hours.

Halogenation of the compound of formula (9) is carried out in the presence or absence of a solvent with conventional halogenating agents. Halogenating agents include halogen molecules such as bromine or chlorine; Halogen acids such as bromic acid and hydrochloric acid; Phosphorus halides such as thionylchloride, phosphorus pentachloride, phosphorus tribromide or phosphorus octacyclochloride.

The content ratio of the halogenating agent used is more than equimolar, preferably excess, with respect to the compound of general formula (9). Solvents used in the halogenation reaction include halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; Acetic acid; Propionic acid, sulfuric acid or water. Halogenation reaction is generally 0-150 degreeC, Preferably it is 0-100 degreeC, and completes in 1 to 24 hours.

On the other hand, the compound of formula (3b) can be prepared by directly reacting the compound of formula (5) with a halogenating agent in the presence or absence of a solvent. The solvent used for halogenation is a solvent used for halogenating the compound of formula (9).

Halogenating agents are alkanes or arylsulfonyl halides such as methanesulfonyl chloride, p-toluenesulfonylchloride or benzenesulfonyl chloride.

The content of the halogenating agent is at least equimolar to the compound of formula (5), preferably twice. Halogenation reaction is generally 0-150 degreeC, Preferably it is 0-100 degreeC, and completes in 1 to 10 hours.

Scheme -5

In formula, R <^1a> , R <^2a> and X <^6> are the same as the above.

Reduction of the compound of formula (10) is carried out using conventional hydrogenating agents. Hydrogenating agents are dialkylaluminum hydrides or diboranes such as sodium borohydride, lithium aluminum hydride or diisobutylaluminum hydride (DIBAL). The content of the halogenating agent is generally 0.1 to 3 times the molar number, and preferably 0.5 to 2 times the molar number of the compound of the general formula (10). This reduction reaction is water; Lower alcohols such as methanol, ethanol or isopropanol; Ethers such as tetrahydrofuran, diethyl ether or diglyme; Aromatic hydrocarbons such as benzene, toluene or xylene and appropriate solvents are usually completed in 10 minutes to 5 hours at -60 to 50 ° C, preferably -40 to room temperature.

When lithium aluminum hydride, dialkylaluminum hydride or diborane is used as the reducing agent, anhydrous solvents such as diethyl ether, tetrahydrofuran, diglyme, benzene, toluene or xylene are used.

Halogenation of the compound of formula (11) is carried out under the conditions when the compound of formula (9) is halogenated.

In Scheme-4, the compound of general formula (5) which is a starting material may be prepared by the method of the novel compound of Scheme-6.

Scheme -6

Wherein R ^1a is as defined above; R ^5a is a lower alkyl group, lower alkenyl group, lower alkynyl group or lower alkoxy-lower alkyl group; R ^1a is substituted at the 2- or 3- position of the tetrahydroquinoline site.

Oxidation of the compound of formula (12) is reacted with an oxidizing agent in a suitable solvent. Examples of the solvent and oxidizing agent used for the oxidation are those used for oxidizing the compound of the general formula (1a) in Scheme-2 described above. The content of the oxidizing agent is at least equimolar, preferably 1.5 times, relative to the compound of formula (12). The oxidation is generally completed within 5 minutes to 5 hours at −20 to 120 ° C., preferably at −20 to about 100 ° C.

The nitration of the compound of formula (13) is carried out under the same conditions as those for nitrating a conventional aromatic compound, for example using a nitrating agent in the presence or absence of a suitable inert solvent.

Acetic acid, acetic anhydride, concentrated sulfuric acid, etc. are mentioned as an inert solvent. Nitrogenating agents are fuming nitric acid, concentrated nitric acid, mixed acids (mixture of nitric acid with sulfuric acid, fuming sulfuric acid, phosphoric acid or acetic anhydride) or mixtures of sulfuric acid with alkali metal nitrates such as potassium nitrate, sodium nitrate. The content of the nitrating agent described above is equimolar to the starting material and is usually in excess. The nitration is advantageously carried out at 0 ° C. to 100 ° C. for 1 to 6 hours.

The reaction of the compound of formula (14) with the compound of formula (15) is carried out in the presence or absence of a suitable solvent in the presence of a basic compound.

As a reaction solvent, Aromatic hydrocarbons, such as benzene, toluene, and xylene; Ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme or diglyme; Ketones such as acetone; Esters such as methyl acetate, or ethyl acetate; Aprotic polar solvents such as N, N-dimethylformamide, dimethylsulfoxide or hexamethylphosphortriamide; Or mixtures thereof.

The basic compound used for this reaction is the same as that used by Scheme-1.

The content of the compound of formula (15) is equimolar to the compound of formula (14) and is generally excess. The reaction is generally completed within 1 to 5 hours at 0 to 150 ° C, preferably at room temperature to 100 ° C.

The imidazopyridine derivative and its salt represented by General formula (20) can be manufactured by various methods, for example, it is manufactured by the following method.

Scheme -7

Wherein R ^1b , R ^2b , R ^3b , R ^4b , R ^5b , Z, Y and A are as defined above; R ^6b and R ^7b are a mercapto group, a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group, respectively; When R ^6b is a merkato group, R ^7b is a halogen atom, a lower sulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group; When R ^7b is a mercapto group, R ^6b is a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group.

In the definitions of R ^6b and / or R ^7b of the general formulas (21) and (22), halogen atoms are as defined above; Lower alkanesulfonyloxy groups are methanesulfonyloxy groups, ethanesulfonyloxy groups, isopropanesulfonyloxy, propanesulfonyloxy, butanesulfonyloxy, t-butanesulfonyloxy, pentanesulfonyloxy and hexasulfonyloxy groups; The arylsulfonyloxy group is phenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy, 3-chlorophenylsulfonyloxy, 2 -A substituted or unsubstituted arylsulfonyloxy group such as methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy, 3-chlorophenylsulfonyloxy and α-naphthylsulfonyloxy group; Aralkylsulfonyloxy groups are benzylsulfonyloxy groups, 2-phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy , Substituted or unsubstituted aralkylsulfonyloxy groups such as 4-methoxybenzylsulfonyloxy, 3-chlorobenzylsulfonyloxy and α-naphthylmethylsulfonyloxy group.

The reaction of the general formula (21) and the compound of the general formula (22) can be carried out in the presence of a basic compound with a suitable solvent. Solvents used in the reaction include water; Alcohols such as methanol, ethanol, isopropanol and the like; Aromatic hydrocarbons such as benzene, toluene, xylene and the like; Ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme and the like; Ketones such as acetone and the like; Esters such as methyl acetate, ethyl acetate and the like; It is an inert solvent that does not adversely affect reactions such as polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide or hexamethylphosphortriamide. Basic compounds used for the reaction include inorganic bases such as sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and silver carbonate; Alkali metals such as metal sodium and potassium metal; Alcoholates such as metal methylate, metal ethylate and the like; And triethylamine, pyridine, N, N-dimethylaminopyridine, 1,5-diazabicyclo [4,3,0] nonene-5 (DBN), 1,8-diazabicyclo [5,4,0] Organic bases such as undecene-7 (DBU), 1,4-diazabicyclo [2,2,2] octa (DABCO), and the like.

The reaction is generally completed at 0-150 ° C., preferably at 0-100 ° C., within about 1 hour to 10 hours.

The content of the compound of formula (22) relative to the compound content of formula (21) is generally at least equimolar, preferably 1.5 times.

Scheme -8

Wherein R ^1b , R ^2b , R ^3b , R ^4b , R ^5b , A, Z and Y are as defined above.

Oxidation of the compound of formula 20a is carried out in a suitable solvent in the presence of an oxidizing agent.

Solvents used for oxidation include water; Organic acids such as formic acid, acetic acid, trifluoroacetic acid and the like; Alcohols such as martenol, ethanol and the like; It is an inert solvent that does not adversely affect halogenated hydrocarbons such as chloroform and dichloromethane. Examples of the oxidizing agent include peracids such as peroric acid, peracetic acid, trifluoroperacetic acid, perbenzoic acid, m-chloroperbenzoic acid and O-carboxyperbenzoic acid; Hydrogen peroxide; Chromic acid; Chromates such as sodium chromate and potassium chromate; Permanganic acid; It is an oxidizing agent capable of oxidizing sulfide groups such as permanganate such as sodium permanganate and potassium permanganate.

The content of the oxidizing agent used in the compound of formula (20a) is equal to or greater than molar, and preferably 1.5 times. Oxidation is generally carried out at -20 to 40 ° C, preferably -20 ° C to about room temperature, and completes in 5 minutes to 3 hours.

Scheme -9

Wherein R ^1b , R ^2b , R ^3b , R ^4b , R ^5b , A, Z and Y are as defined above and R ^8b and R ^9b are each halogen atoms.

Reaction (i) of general formula (21a) and thiourea (4) is carried out in the presence or absence of a solvent.

Solvents used in the reaction include alcohols such as methanol, ethanol and propanol; Ethers such as diethyl ether, tetrahydrofuran, dioxane, ethylene glycol monomethyl ether and the like; Aromatic hydrocarbons such as benzene, toluene, xylene; Ketones such as acetone and methyl ethyl ketone; Polar solvents such as dimethylformamide, dimethylsulfoxide, hexamethylphosphortriamide (HMPA) and the like. The content of thiourea (4) used in the compound of the general formula (21a) is equal to or higher than the molar amount of the compound of the general formula (21a), preferably 2 times. The reaction is generally room temperature to 200 ° C., preferably room temperature to about 150 ° C. and completes in 1 to 5 hours.

Reaction (ii) of the intermediate with the compound of formula (22a) is generally carried out in the presence of a condensing agent. Generally as a condensing agent, a basic compound is used. As a basic compound, Inorganic bases, such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, silver carbonate; Alkali metals such as metal sodium and potassium metal; metal; Alcoholates such as sodium methylate and sodium ethylate; Organic basic compounds such as triethylamine, pyridine, N, N-dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, DBN, DBU, DABCO and the like.

The invention is carried out in the presence or absence of a solvent. Solvents include water; Alcohols such as methanol, ethanol, propanol, butanol, ethylene glycol; Ethers such as diethyl ether, THF, dioxane, monoglyme, diglyme and the like; Ketones such as acetone and methyl ethyl ketone; Aromatic hydrocarbons such as benzene, toluene, xylene; Esters such as methyl acetate, ethyl acetate; It is an inert solvent that does not adversely affect an aprotic polar solvent such as DMF, DMSO, HMPA and the like.

This reaction is advantageously carried out in the presence of metal iodine such as sodium iodide, potassium iodide. The content ratio of the compound of the general formula (21a) to the content of the compound of the general formula (22a) is not particularly limited and may be selected in a wide range. Preferably it is a molar content of 0.5 to 2 times. The reaction temperature is not particularly limited and is generally -30 to 200 ° C, preferably 0 to 160 ° C, and is usually completed in about 1 to 30 hours.

Compounds of formula (21) partially contain novel compounds and can be prepared according to the following Scheme -10.

Scheme -10

Wherein R ^1b , R ^2b , Z and Y are as defined above and R ^10b is a halogen atom.

Amination of the compound of formula (23) can be carried out by reaction with an aminoating agent in a suitable solvent. Solvents used for amination include ethers such as dimethyl ether, tetrahydrofuran, dioxane and the like; Aromatic hydrocarbons such as benzene, toluene, xylene; Alcohols such as methanol, ethanol, isopropanol and the like; Polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide, HMPA and the like.

The amination agent used for the reaction includes ammonia gas, ammonia water, sodium amide and the like.

The content of the aminoating agent is more than equimolar to the compound of formula (23), and is generally excess. Amination is generally from 0 to 200 ° C., preferably from room temperature to about 150 ° C., for about 5 minutes to 10 hours.

Reduction of the compound of formula (24) can be carried out, for example, by (i) catalytic reduction in a suitable solvent or (ii) a mixture of a metal or metal salt with an acid in an inert solvent; It is carried out with a reducing agent such as a mixture of metal or metal salts with alkali metal hydroxides, sulfides and ammonium salts.

In carrying out the catalytic reduction, the solvent used for the reduction is water; Alcohols such as acetic acid, methanol, ethanol, isopropanol and the like; Hydrocarbons such as hexane, cyclohexane and the like; Ethers such as diethylene glycol dimethyl ether, dioxane, THF, diethyl ether and the like; Esters such as ethyl acetate, methyl acetate and the like; Aprotic polar solvents such as N, N-dimethylformamide and the like; And these are mixtures.

Catalysts used for the catalytic reduction are palladium, palladium black, palladium-carbon, platinum, platinum oxide, copper chromite rani nickel and the like.

The content of the catalyst used for the catalytic reduction is 0.02 to 1.00 times the content of the compound of formula (24). The reduction is generally completed at -20 to 100 ° C., preferably at 0 to 70 ° C., and generally at 0.5 to 10 hours under hydrogen pressure of 1 to 10 atmospheres.

In carrying out the reduction (ii), a mixture of iron, zinc, tin or tin (II) chloride with an inorganic acid such as hydrochloric acid or sulfuric acid; Iron, iron (II) chloride, zinc or tin; Mixtures of alkali metal hydroxides such as sodium hydroxide, sulfides such as ammonium sulfide, aqueous ammonia and ammonium salts such as ammonium chloride can be used as reducing agents. Inert solvents used for reduction include solvents such as water, acetic acid, methanol, ethanol and dioxane. The above-mentioned reduction reaction conditions may be appropriately selected depending on the reducing agent, and the reaction is generally completed at about -50 to 100 ° C to complete in about 0.5 to 10 hours. For example, in the case of using hydrochloric acid and tin (II) chloride as reducing agents, the reaction is advantageously carried out at -20 ° C to 70 ° C. The content of the reducing agent is greater than or equal to molar relative to the starting material to be reduced, preferably equal to or equal to three times.

The reaction of the compounds of formula (25) and (26) is carried out in a suitable solvent. As a solvent, Alcohol, such as methanol, ethanol, isopropanol; Aromatic hydrocarbons such as benzene, toluene, xylene and the like; Halogenated hydrocarbons such as chloroform, dichloromethane, carbon tetrachloride and the like; Ethers such as diethyl ether, tetrahydrofuran, dioxane and the like; Polar solvents such as N, N-dimethylformamide, dimethylsulfoxide, hexamethylphosphor triamide and the like.

The reaction is generally completed in 1 to about 24 hours at 0 to 100 ° C, preferably 0 to about 50 ° C.

Among the compounds of the general formula (20), at least one compound in which R ^1b and R ^2b is an amino group can be diazotized to be converted into a compound in which R ^1b and R ^2b of the general formula (20) are hydroxy groups. The diazotization is carried out by reaction with a diazotizing agent in the presence of a suitable solvent and acid. Solvents used for diazotization include water; Ethers such as dioxane, tetrahydrofuran and the like; And mixtures thereof. Acids used for diazotization include metal acids such as hydrochloric acid, bromic acid, sulfuric acid, and the like; Organic acids such as acetic acid and propionic acid.

Diazoating agents are alkyl nitrites such as sodium nitrite, ethyl nitrite, isoamyl. The content of the diazotizing agent is at least equimolar to the starting material, preferably 1 to 1.5 times. Diazolation is completed within 5 minutes to 3 hours at 0-5 ° C.

Among the compounds represented by the general formula (1), at least one compound of which R ^1a or R ^4a is a halogen atom is selected from the general formula (1) according to the conditions used to hydrolyze the compound of general formula (8) in Scheme-4. The compound may be hydrolyzed to convert it into a compound wherein at least one R ^1a or R ^4a is a hydroxy group.

Among the tetrahydroquinoline derivatives of the general formula (1) and the imidazopyridine derivatives of the general formula (20), the compound having an acid group can be easily converted into a salt by reacting with a conventional pharmaceutically acceptable salt.

Pharmaceutically acceptable basic compounds include metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide and the like; Metal carbonates and hydrogen carbonates such as sodium carbonate, sodium hydrogen carbonate and the like; Alkali metal alcoholates such as sodium methylate, potassium ethylate and the like. Furthermore, among the tetrahydroquinoline derivatives of the general formula (1) and the imidazopyridine derivatives of the general formula (20), the compound having a basic group can be easily converted into its acid addition salt by reaction with a conventional pharmaceutically acceptable acid. . Pharmaceutically acceptable acids include inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, bromic acid, and the like; Organic acids such as acetic acid, p-toluenesulfonic acid, ethanesulfonic acid, oxalic acid, maleic acid, succinic acid, benzoic acid and the like.

Compounds prepared according to the invention inevitably include optical isomers and stereoisomers.

Compounds prepared by the above-described various reaction schemes according to the present invention can be easily separated and purified in the reaction system by conventional separation methods such as distillation, recrystallization, column chromatography, prepared thin layer chromatography, solvent extraction and the like.

The compounds of the present invention are usually useful as anti-digestive ulcers and can be used in the form of pharmaceutical compositions with conventional pharmaceutically acceptable carriers. Examples of pharmaceutically acceptable carriers are excipients and diluents such as fillers, diluents, binders, lubricants and the like depending on the pharmaceutical composition of the desired type. Pharmaceutical compositions can be prepared in the desired unit form, such as tablets, pills, powders, solutions, suspensions, emulsifiers, granules, capsules, suppositories, injections (solutions, suspensions, etc.).

Examples of carriers widely used in the art for molding into tablets include excipients such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and the like; Binders such as water, ethanol, propanol, simple serum, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, calcium phosphate polyvinyl pyrrolidone and the like; Such as dried starch, sodium alginate, agar-agar powder, laminalia powder, sodium bicarbonate calcium carbonate, fatty acid ester of polyoxyethylene sorbitan, sodium laurylsulfonate, monoglyceride of stearate, starch, lactose, etc. Disintegrants; Degradation inhibitors such as sucrose, stearin, coconut butter, hydrogenated oils, and the like; Absorption promoters such as quaternary ammonium base, sodium laurylsulfonate, and the like; Hydrating agents such as glycerin, starch and the like; Adsorbents such as starch, lactose, kaolin, bentonite, colloidal silicic acid and the like; And lubricants such as purified talc, stearate, boric acid powder, polyethylene glycol and the like.

If desired, tablets may be recoated with conventional coating materials, e.g., tablets coated with sugar, tablets coated with gelatin film, tablets coated with enteric coating layers, films or bilayers. As well as multilayer membrane tablets. To prepare the pill, any known carrier can be used, for example, excipients such as glucooso, lactose, starch, coconut butter, hydrogenated cooking oil, kaolin, activity and the like; Binders such as powdered gum arabic, powdered tragant gum, gelatin, ethanol and the like; Degrading agents such as laminaria, agar-agar and the like.

Known carriers are widely used for the preparation of suppositories, for example polyethylene glycols, coconut butter, higher alcohols, gelatin, semi-synthetic glycerides and the like.

For the preparation of injectables, it is desirable to further culture the prepared solutions and suspensions so that they form blood and copper fluid.

Any known carrier can be used to prepare the injections in solution, emulsifiers and suspensions, for example water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxy Ethylene sorbitan fatty acid esters and the like; Glucose or glycerin is added to the injection of the antipyretic ulcer composition to make an isotonic solution.

Moreover, if desired, conventional solubilizers, buffers, analgesics can be added. Coloring agents, preservatives, fragrances, flavors, sweeteners, and other agents can also be added to the desired agents.

The content of the tetrahydroquinoline derivative of the general formula (1) and the imidazopyridine derivative of the general formula (20) contained in the anti-digestive ulcer composition of the present invention is not particularly limited, but may be appropriately selected in a wide range. As such, the content of the derivative in the pharmaceutical composition is generally 1 to 70% by weight, preferably 5 to 50% by weight.

The method of administering the anti-digestive ulcer composition is not particularly limited and may be administered in various forms in consideration of the age, sex, symptoms, and conditions of the patient. For example, orally by tablets, emperors, solutions, suspensions, emulsifiers, granules and capsules; Injections are injected intravenously alone or administered in conjunction with glucose solutions, amino acid solutions, etc., which are conventional fusion agents; If necessary, injections are injected intramuscularly, intracutaneously, subcutaneously, intraperitoneally; Suppositories are administered rectally.

The dosage of the anti-digestive ulcer composition containing the tetrahydroquinoline derivative and / or imidazopyridine derivative according to the present invention is generally derived from the derivative per kilogram of body weight per day, depending on the method of administration, the age, sex, condition and other conditions of the patient. It is 0.6-50 mg and may contain 10-1000 mg of active ingredient in a dosage unit.

Next, examples, reference examples, examples and pharmacological tests of pharmaceutical preparations according to the present invention are described, but the present invention is not limited thereto.

[Production Example-1 of Film-coated Tablets]

4-aryloxy-8- (2-benzimidazolyl) sulfinyl-3-methyl-5,6,7,8 150 g

Tetrahydroquinoline

Avicel 40 g

(Trade name of microcrystalline cellulose, manufactured by Asahi Chemical Co., Ltd.)

30 g of corn starch

2g magnesium stearate

10 g of hydroxypropal methylcellulose

Polyethylene glycol-6000 3 g

Castor Oil 40g

40 g of ethanol

4-aryloxy-8- (2-benzimidazolyl) sulfinyl-3-methyl-5,6,7,8-tetrahydroquinoline, Avicel, corn starch and magnesium stearate are mixed together and ground, The resulting mixture is molded into tablets using a purifier (R10 mm). Subsequently, the film-coated tablet having the above-mentioned composition was prepared by coating with a film coating agent containing hydroxy propyl methyl cellulose, polyethylene glycol-6000, castor oil and ethanol.

[Production Example-2 of Film-coated Tablets]

5- (5-methoxy-2-benzimidazolyl) sulfinyl-5,6,7,8 150 g

Tetrahydroquinoline

Avicel 40 g

(Trade name of microcrystalline cellulose, manufactured by Asahi Chemical Co., Ltd.)

30 g of corn starch

2g magnesium stearate

10 g of hydroxypropal methylcellulose

Polyethylene glycol-6000 3 g

Castor Oil 40g

40 g of ethanol

In the same manner as described in the Production Example-1 of the above-described film-coated tablet, a film-coated tablet having the above composition is obtained.

[Production Example-3 of Film-coated Tablets]

150 g of 2-[(3,5-dimethyl-4-methoxy-2-pyridyl) -methylthio]

Imidazo [4,5-b] pyridine

Avicel 40 g

(Trade name of microcrystalline cellulose, manufactured by Asahi Chemical Co., Ltd.)

30 g of corn starch

2g magnesium stearate

10 g of hydroxypropal methylcellulose

Polyethylene glycol-6000 3 g

Castor Oil 40g

40 g of ethanol

In a similar manner to that described in Preparation Example-1 of the above-described film-coated tablet, a film-coated tablet having the above composition was prepared.

[Production Example-1 of Multilayer Tablet]

4-allyloxy-8- (5,6-dimethyl-2-benzimidazolyl) sulfinyl-3- 150.0 g

Methyl-5,6,7,8-tetrahydroquinoline

1.0 g citric acid

Lactose 33.5g

Calcium phosphate 70.0g

Pluronic F-68 30.0 g

(Trade name of polyoxyalkylene derivative of nonionic propylene glycol

BASF-Wyandotte company)

Sodium Lauryl Sulfate 15.0 g

15.0 g of polyvinyl pyrrolidone

Polyethylene glycol 4.5 g

(Carbowax 1500, Union Carbide company make)

Polyethylene glycol 45.0 g

(Carbowax 6000, Union Carbide company make)

30.0 g of corn starch

3.0 g of dry sodium lauryl sulfate

3.0 g of dry magnesium stearate

Enough ethanol

4-allyloxy-8- (5,6-dimethyl-2-benzimidazolyl) -sulfinyl-3-methyl-5,6,7,8-tetrahydroquinoline, citric acid, lactose, calcium phosphate, flu Ronic F-68 and sodium laurylsulfate are mixed together. The resulting mixture is filtered through a 60th screen, and the filtered mixture is then wet granulated with an alcoholic solution containing polyvinyl pyrrolidone, carbowax 1500 and carbowax 6000. Ethanol is added to the granules if necessary to make a semi-conductor like paste. Corn starch is then added and kneading is continued until the mixture is formed into particles having a uniform particle size. The obtained granules are filtered through a No. 10 screen, and the filtered granules are placed in a tray and dried in an oven at 100 ° C. for 12-14 hours. The dried granules are filtered through a screen No. 16, and the filtered granules are mixed with dry sodium laurylsulfate and dry magnesium stearate, and the obtained mixture is then cast into a desired form using a tablet machine. The surface of the obtained tablet (nuclear portion of the intended multi-layered tablet) is varnished and the surface of the varnished tablet (nucleated portion) is recoated with talc powder so that the surface of the tablet is moisture resistant. The surface of the nucleus is coated with an inner-coat layer and coated with a sufficient number of varnish layers to prepare tablets for oral administration. The inner- and soft-film layers are recoated on the surface of the nucleus to form a complete spherical and soft surface. The surface of the obtained multilayered tablet is then pigment-coated until the desired color is obtained. The multilayer tablet is dried and the surface is polished to produce a tablet with uniform gloss.

[Production Example-2 of Multilayer Tablet]

5- (5-methoxy-2-benzimidazolyl) sulfinyl 150.0 g

-3-methyl-5,6,7,8-tetrahydroquinoline

Citric acid

1.0 g citric acid

Lactose 33.5g

Calcium phosphate 70.0g

Pluronic F-68 30.0 g

(Polyoxyalkylene of nonionic propylene glycol

Product Name of Derivative

BASF-Wyandotte company)

Sodium Lauryl Sulfate 15.0 g

15.0 g of polyvinyl pyrrolidone

Polyethylene glycol 4.5 g

(Carbowax 1500, Union Carbide company make)

Polyethylene glycol 45.0 g

(Carbowax 6000, Union Carbide company make)

30.0 g of corn starch

3.0 g of dry sodium lauryl sulfate

3.0 g of dry magnesium stearate

Enough ethanol

The multilayer tablet which has the said composition is manufactured by the method similar to what was described in manufacture example-1 of the multilayer tablet mentioned above.

[Production Example-3 of Multilayer Tablet]

5-methyl-2-[(3,5-dimethyl-4-methoxy 150.0 g

-2-pyridyl) metallthio] imidazo [4,5-b]

Pyridine

1.0 g citric acid

Lactose 33.5g

Calcium phosphate 70.0g

Pluronic F-68 30.0 g

(Polyoxyalkylene of nonionic propylene glycol

Product Name of Derivative

BASF-Wyandotte company)

Sodium Lauryl Sulfate 15.0 g

15.0 g of polyvinyl pyrrolidone

Polyethylene glycol 4.5 g

(Carbowax 1500, Union Carbide company make)

Polyethylene glycol 45.0 g

(Carbowax 6000, Union Carbide company make)

30.0 g of corn starch

3.0 g of dry sodium lauryl sulfate

3.0 g of dry magnesium stearate

Enough ethanol

A multilayer tablet having the composition was prepared in a similar manner to that described in Preparation Example-1 of the multilayer tablet described above.

[Production Example-1 of Injection Solution]

5.0 g of 4-allyloxy-8- (2-benzimidazolyl) sulfinyl

-3-methyl-5,6,7,8-tetrahydroquinoline

0.3 g of polyethylene glycol (molecular weight: 4000)

0.9 g of sodium chloride

0.4 g of polyoxyethylene sorbitan monooleate

0.1 g sodium metabisulfite

0.18 g of methyl para-hydroxybenzoate

Propyl para-hydroxybenzoate 0.02 g

10.0ml distilled water for injection

Methyl para-hydroxy benzoate, propyl para-hydroxy benzoate, sodium meta bisulfite and sodium chloride are dissolved at 80 ° C. under stirring in ½ volume of the above-mentioned distilled water for injection. The resulting solution was cooled to 40 ° C. and then 4-allyloxy-8- (2-benzimidazolyl) sulfinyl-3-methyl-5,6,7,8-tetrahydroquinoline, followed by polyethylene glycol and poly Oxyethylene sorbitan monooleate is dissolved. A residual volume of distilled water for injection is then added to the solution to adjust the final volume of the preparation, and the resulting injection solution is sterilized using a suitable filter paper to prepare the desired injection.

[Production Example-2 of Injection Solution]

5.0 g of 8- (5-methoxy-2-benzimidazolyl) sulfinyl

-5,6,7,8-tetrahydroquinoline

0.3 g of polyethylene glycol (molecular weight: 4000)

0.9 g of sodium chloride

0.4 g of polyoxyethylene sorbitan monooleate

0.1 g sodium metabisulfite

0.18 g of methyl para-hydroxybenzoate

Propyl para-hydroxybenzoate 0.02 g

10.0ml distilled water for injection

An injection solution having the composition described above is prepared in a similar manner to that described in Preparation Example-1 of the aforementioned injection solution.

[Production Example-3 of Injection Solution]

5-chloro-2- [3,5-dimethyl-4-methoxy-5.0 g

2-pyridyl) methylthio] imidazo [4,5-b)

Pyridine

0.3 g of polyethylene glycol (molecular weight: 4000)

0.9 g of sodium chloride

0.4 g of polyoxyethylene sorbitan monooleate

0.1 g sodium metabisulfite

0.18 g of methyl para-hydroxybenzoate

Propyl para-hydroxybenzoate 0.02 g

10.0ml distilled water for injection

An injection solution having the composition described above is prepared in a similar manner to that described in Preparation Example-1 of the aforementioned injection solution.

Reference Example 1

6.5 g of 3-methyl-5,6,7,8-tetrahydroquinoline-N-oxide was added dropwise by stirring under ice-cooling to a mixture of 7 ml fuming nitric acid and 7 ml concentrated sulfuric acid. The reaction mixture is stirred at 40 ° C. for 2 hours and then further at 60 ° C. for 2 hours. The reaction mixture is poured into a cold aqueous sodium hydroxide solution and extracted with chloroform. The chloroform layer is washed with saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. Evaporate chloroform and recrystallize the residue with ethyl acetate-ethanol-n-hexane to give 5.3 g of 3-methyl-4-nitro-5,6,7,8-tetrahydroquinoline-N-oxide. .

Melting Point 140 ~ 142 ℃

Reference Example 2

2.0 g of 3-methyl-4-nitro-5,6,7,8-tetrahydroquinoline-N-oxide are dissolved in allyl alcohol. 0.6 g sodium hydroxide is added and the mixture is stirred at 70-80 ° C. for 3 hours. After completion of the reaction, the reaction mixture is concentrated under reduced pressure, water is added to the residue and extracted with chloroform. The chloroform layer is washed with saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. Chloroform was evaporated under reduced pressure to yield 1.4 g of a brown oily substance, 4-allyloxy-3-methyl-5,6,7,8-tetrahydroquinoline-N-oxide.

NMR (CDCl ₃ ) δ: 1.50 to 2.10 (m, 4H), 2.21 (s, 3H), 2.80 (t, 2H), 2.89 (t, 2H), 4.00 to 4.50 (m, 2H), 4.90 to 5.50 ( m, 2H), 5.80-6.30 (m, 1H), 8.00 (s, 1H).

Reference Example 3

To 4.8 g of 4-allyloxy-3-methyl-5,6,7,8-tetrahydroquinoline-N-oxide, 5 ml of acetic anhydride is added and the mixture is stirred at 90 ° C. for 5 hours. After completion of the reaction, acetic anhydride is evaporated under reduced pressure and water is added to the obtained residue and extracted with chloroform. The chloroform layer is washed with aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Chloroform was evaporated under reduced pressure to afford 8-acetoxy-4-allyloxy-3-methyl-5,6,7,8-tetrahydroquinoline (5.0 g) as a brown oily substance.

NMR (CDCl ₃ ) δ: 1.70 to 2.20 (m, 4H), 2.25 (s, 3H), 2.50 to 3.00 (m, 2H), 4.30 to 4.50 (m, 2H), 5.20 to 5.50 (m, 2H), 5.91 (t, 1H), 5.80 to 6.40 (m, 1H), 8.30 (s, 1H).

Reference Example 4

5.0 g of 8-acetoxy-4-allyloxy-3-methyl-5,6,7,8-tetrahydroquinoline is dissolved in 20 ml of methanol. A solution of 2.3 g sodium hydroxide dissolved in 20 ml of water is added to the solution and the mixture is refluxed for 1 hour. After completion of the reaction, methanol is evaporated and water is added to the residue obtained and extracted with chloroform. The chloroform layer is washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Chloroform is evaporated to afford 4-allyloxy-8-hydroxy-3-methyl-5,6,7,8-tetrahydroquinoline (3.5 g) as a brown oil.

NMR (CDCl ₃ ) δ: 1.50 to 2.50 (m, 4H), 2.21 (s, 3H), 2.72 (t, 2H), 4.30 to 4.50 (m, 2H), 4.67 (t, 1H), 5.10 to 5.50 ( m, 2H), 5.80 to 6.30 (m, 1H), 8.21 (s, 1H).

Reference Example 5

3.5 g of 4-allyloxy-8-hydroxy-3-methyl-5,6,7,8-tetrahydroquinoline was dissolved in 40 ml of chloroform, a solution consisting of 2.8 g of phosphorus tribromide and 5 ml of chloroform Was added dropwise by ice-cooling to the solution. The reaction mixture is stirred for 2 hours under ice cooling and further stirred for 2 hours at room temperature. The reaction mixture is poured into cold aqueous sodium chloride solution and extracted with chloroform. The chloroform layer is washed with saturated aqueous sodium chloride solution and then with anhydrous magnesium sulfate. Chloroform was evaporated and the resulting residue was purified by silica gel column chromatography (eluent: methylene chloride / methanol = 100/1) to give 1.3 g of 4-allyloxy-8-bromo-3-methyl-5,6, 7,8-tetrahydroquinoline is obtained.

NMR (CDCl ₃ ) δ: 1.60 to 3.20 (m, 6H), 2.23 (s, 3H), 4.30 to 4.50 (m, 2H), 5.20 to 5.60 (m, 3H), 5.80 to 6.30 (m, 1H), 8.29 (s, 1 H).

Reference Example 6

7.02 g of 3-methyl-5,6,7,8-tetrahydroquinoline-N-oxide is dissolved in acetic anhydride and the solution is stirred at 90 ° C. and heated for 3.5 hours. Acetic anhydride is evaporated under reduced pressure, and the residue is added with an aqueous sodium carbonate solution to alkalinize and extracted with chloroform. The chloroform layer is washed with saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the residue is purified by silica gel column chromatography (eluent: dichloromethane) to afford 7.18 g of 3-methyl-8-acetoxy-5,6,7,8-tetrahydroquinoline.

NMR (CDCl ₃ ) δ: 1.60 to 2.30 (m, 4H), 2.10 (s, 3H), 2.30 (s, 3H), 2.60 to 2.90 (m, 2H), 5.92 (t, 1H), 7.26 (d, 1H), 8.33 (d, 1H).

Reference Example 7

1.50 g of 3-methyl-8-hydroxy-5,6,7,8-tetrahydroquinoline is dissolved in 20 ml of chloroform, and a solution consisting of 1.35 g of phosphorus tribromide and 5 ml of chloroform is ice-cooled. Add drop wise, and stir the mixture for 2 hours under ice-cooling and at room temperature overnight. To the reaction mixture is added 5% aqueous sodium chloride solution and extracted with chloroform. The chloroform layer is washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Evaporate the solvent to afford 1.80 g of 3-methyl-8-bromo-5,6,7,8-tetrahydroquinoline.

NMR (CDCl ₃ ) δ: 1.80 to 2.60 (m, 4H), 2.28 (s, 3H), 2.60 to 3.00 (m, 2H), 5.50 to 5.60 (m, 1H), 7.23 (d, 1H), 8.30 ( d, 1H).

Reference Example 8

4.11 g of 3-methyl-8-acetoxy-5,6,7,8-tetrahydroquinoline was dissolved in 15 ml of 30% aqueous sodium hydroxide solution and 15 ml of methanol, and the resulting mixture was stirred at 65 DEG C for 3 hours. Heat and stir. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5/1) to yield 1.50 g of 3-methyl-8-hydroxy-5,6,7,8 Tetrahydroquinoline is obtained.

NMR (CDCl ₃ ) δ: 1.50 to 2.50 (m, 4H), 2.27 (s, 3H), 2.73 (t, 2H), 4.65 (t, 1H), 7.23 (d, 1H), 8.25 (d, 1H) .

Reference Example 9

To 7.02 g of 3-methyl-5,6,7,8-tetrahydroquinoline are added 9.62 g of methanesulfonyl chloride under ice cooling. The reaction mixture is stirred under ice cooling for 2 hours and at 80 ° C. for 3 hours. Water is added to the reaction mixture, sodium carbonate is added to the solution for alkalinization and extraction with diethyl ether. The diethyl ether layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The residue obtained after evaporation of the solvent was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 100/1) to give 2.74 g of 3-methyl-8-chloro-5,6,7,8-tetrahydro Obtain quinoline.

NMR (CDCl ₃ ) δ: 1.70 to 2.50 (m, 4H), 2.30 (s, 3H), 2.50 to 3.00 (m, 2H), 5.28 (t, 1H), 7.23 (d, 1H), 8.32 (d, 1H).

Reference Example 10

0.97 g of 7,8-dihydro-3-methylquinolin-5 (6H) -one is dissolved in 20 ml of methanol, the solution is ice-cooled, and 0.23 g of sodium borohydride is added, and the mixture is then stirred at room temperature for 3 hours. Stir. Water was added to the reaction mixture, methanol was evaporated and extracted with chloroform, and then the chloroform extract was dried over anhydrous magnesium sulfate. The solvent is evaporated to yield 0.98 g of 3-methyl-5-hydroxy-5,6,7,8-tetrahydroquinoline, a colorless oily substance.

NMR (CDCl ₃ ) δ: 1.60 to 2.20 (m, 4H), 2.27 (s, 3H), 2.83 (t, 2H), 3.28 (bs, 1H), 4.7 to 4.8 (m, 1H), 7.57 (d, 1H), 8.15 (d, 1H).

Reference Example 11

The reaction is carried out according to the method similar to Reference Example 11, except that 3-methyl-5-bromo-5,6,7,8-tetrahydroquinoline is obtained using an appropriate starting material.

NMR (CDCl ₃ ) δ: 1.80 to 2.50 (m, 4H), 2.28 (s, 3H), 2.80 to 3.20 (m, 2H), 5.43 (t, 1H), 7.43 (bs, 1H), 8.25 (bs, 1H).

Reference Example 12

23 g of methyl 6-chloro-5-nitronicotinate is dissolved in 200 ml of dioxane. Stir at room temperature and introduce ammonia gas into the solution. Ten minutes after the introduction of ammonia gas, the crystals formed in the reaction mixture are collected by filtration. Recrystallization from dimethylformamide (DMF) yields 18 g of methyl 6-amino-5-nitroniconate, a yellow needle-like crystal.

Melting Point: 195∼196 ℃

Reference Example 13

1 g of methyl 6-amino-5-nitronicotinate is dissolved in 10 ml of methanol. 0.1 g of this solution is added 0.1 g of 5% palladium-carbon and the hydrogen gas is absorbed under atmospheric pressure at room temperature. The reaction stops when the stoichiometric amount of hydrogen is absorbed. The reaction mixture is filtered to collect crystals and the solvent is evaporated. The residue is recrystallized from ethanol to give methyl 5,6-diaminoniconate (0.8 g) as yellow needle-like crystals.

Melting Point: 154 ~ 155 ℃

Reference Example 14

0.2 g of methyl 5,6-diaminoniconate is dissolved in 5 ml of dimethylformamide and 1.2 ml of carbon disulfate is added to the solution and the mixture is stirred at room temperature for 18 hours. The solvent is evaporated and the residue obtained is recrystallized from dimethylformamide to give 2-mercapto-5-methoxycarbonylimidazo [4,5-b] pyridine (0.2 g) as a yellow powdery substance.

Melting Point: 233 ~ 234 ℃

Reference Examples 15 to 20

The reaction was carried out according to the method similar to Reference Example 14, but using the appropriate starting material to obtain the compound shown in Table 1.

TABLE 1

Example 1

0.5 g of 2-mercamptobenzimidazole was dissolved in 30 ml of methanol, and 0.2 g of aqueous sodium hydroxide solution dissolved in 10 ml of water was added to the solution, and 0.6 g of 4-allyloxy-8-bromo-3 -Methyl-5,6,7,8-tetrahydroquinoline is further added and the entire mixture is refluxed for 2 hours. Methanol is evaporated from the reaction mixture, water is added to the residue and extracted with chloroform. The chloroform extract was dried over anhydrous magnesium sulfate, the chloroform was evaporated, and the obtained residue was purified by silica gel column chromatography (eluent: methylene chloride / methanol = 100/1) to give a pale brown oily substance, 4-allyloxy-8. Obtain-(2-benzimidazolyl) thio-3-methyl-5,6,7,8-tetrahydroquinoline (0.7 g).

NMR (CDCl ₃ ) δ: 1.70 to 2.10 (m, 2H), 2.10 to 2.50 (m, 2H), 2.29 (s, 3H), 2.60 to 3.10 (m, 2H), 4.30 to 4.50 (m, 2H), 4.77 (t, 1H), 5.20 to 5.50 (m, 2H), 5.80 to 6.50 (m, 1H), 7.10 to 7.30 (m, 2H), 7.40 to 7.70 (m, 2H), 8.33 (s, 1H).

EXAMPLES 2-4

The reaction is carried out according to a similar method as in Example 1, except that the compounds of Examples 2 to 14 shown in the following table are prepared using appropriate starting materials.

TABLE 2

Example 15

0.7 g of 4-allyloxy-8- (2-benzimidazolyl) thio-3-methyl-5,6,7,8-tetrahydroquinoline are dissolved in 30 ml of methylene chloride and the solution is -50 to After cooling to −60 ° C., a solution of 0.43 g of 80% -m-chloroperbenzoic acid dissolved in 10 ml of methylene chloride is added to the solution and the reaction mixture is stirred at this temperature for 20 minutes. After completion of the reaction, the reaction mixture is washed with aqueous sodium carbonate solution and dried over anhydrous magnesium sulfate. Methylene chloride was evaporated under reduced pressure, and the residue was recrystallized from diethyl ether to give the white powdery crystals 4-allyloxy-8- (2-benzimidazolyl) sulfinyl-3-methyl-5,6,7, 8-tetrahydroquinoline (0.4 g) is obtained.

Melting Point: 100-102 ° C (Decomposition)

[Examples 16-28]

The reaction is carried out according to a method similar to that of Example 15, except that the compounds of Examples 16 to 28 shown in Table 3 are obtained using an appropriate starting material.

TABLE 3

Example 29

0.46 g of 2-chlorobenzimidazole, 0.2 g of thiourea and 10 ml of ethanol are mixed and the mixture is refluxed for 2 hours. 0.62 g of 4-allyloxy-8-bromo-3-methyl-5,6,7,8-tetrahydroquinoline and 0.3 g of sodium hydroxide are added to the reaction mixture and the entire mixture is refluxed for 5 hours. After completion of the reaction, ethanol is evaporated, water is added to the residue, followed by extraction with chloroform, the chloroform extract is dried over anhydrous magnesium sulfate and chloroform is evaporated. The resulting residue was purified by silica gel column chromatography (eluent: methylene chloride / methanol = 100/1) to give a pale brown oily substance, 4-allyloxy-8- (2-benzimidazolyl) thio-3-methyl-. 5,6,7,8-tetrahydroquinoline (0.5 g) is obtained.

NMR (CDCl ₃ ) δ: 1.70 to 2.10 (m, 2H), 2.10 to 2.50 (m, 2H), 2.29 (s, 3H), 2.60 to 3.10 (m, 2H), 4.30 to 4.50 (m, 2H), 4.77 (t, 1H), 5.20 to 5.50 (m, 2H), 5.80 to 6.50 (m, 1H), 7.10 to 7.30 (m, 2H), 7.40 to 7.70 (m, 2H), 8.33 (s, 1H).

The reaction is carried out according to a method similar to that of Example 29, except that the compound of Examples 2 to 14 described above is obtained using an appropriate starting material.

Example 30

4.00 g of 3-methyl-8- (5-methoxy-2-benzimidazolyl) thio-5,6,7,8-tetrahydroquinoline are dissolved in 80 ml of dichloromethane and dissolved in 30 ml of dichloromethane. A solution of 2.37 g of m-chloroperbenzoic acid (85%) was slowly added dropwise to the solution at -10 ° C. After all were added dropwise, the reaction mixture was stirred at -10 ° C to 4 ° C for 15 minutes. Water was added to the reaction mixture, followed by alkali addition with sodium carbonate followed by extraction with diethyl ether. The diethyl ether layer was washed with saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The extract was evaporated to remove the solvent and recrystallized from dichloromethane-diethyl ether to give the white powdery crystals 3-methyl-8- (5-methoxy-2-benzimidazolyl) sulfinyl-5,6,7, 8-tetrahydroquinoline (2.30 g) is obtained.

Melting Point: 114 ~ 114.5 ℃ (Decomposition)

[Examples 31 to 64]

The reaction was carried out according to the method similar to Example 30, to prepare the compounds of Examples 31 to 64 shown in Table 4 below.

TABLE 4

Example 65

2.80 g of sodium hydride is dissolved in 15 ml of water and 200 ml of methanol, to which 10.63 g of 2-mercapto-5-methoxybenzimidazole is added and the reaction mixture is stirred at 55 ° C. and heated for 30 minutes. 3-methyl-8-bromo-5,6,7,8-tetrahydroquinoline is added to 13.33 g of the reaction mixture, and the whole mixture is heated and stirred for 2.5 hours.

After completion of the reaction, the solvent was evaporated under reduced pressure, and a small amount of 30% aqueous sodium hydroxide solution was added to the residue, followed by extraction with chloroform. The chloroform layer is washed with saturated aqueous sodium chloride solution, the extract is dried over anhydrous magnesium sulfate and the solvent is evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 100/1) to give 3-methyl-8- (5-methoxy-2-benzimidazolyl) thio-5, a colorless substance similar to caramel. 6,7,8-tetrahydroquinoline (18.80 g) is obtained.

NMR (CDCl ₃ ) δ: 1.60 to 2.00 (m, 2H), 2.00 to 2.40 (m, 2H), 2.27 (s, 3H), 2.72 (t, 2H), 3.78 (s, 3H), 4.78 (t, 1H), 6.77 (dd, 1H), 7.00 (d, 1H), 7.22 (d, 1H), 7.40 (d, 1H), 8.23 (d, 1H).

[Examples 66-99]

The reaction is carried out according to a method similar to Example 65, except that the compounds of Examples 66 to 99 shown in Table 5 are obtained using the appropriate starting materials.

TABLE 5

Example 100

0.55 g of 2-chloro-5-methoxybenzimidazole, 0.2 g of thiourea and 10 ml of ethanol are mixed and refluxed for 2 hours. 0.5 ml of 3-methyl-8-bromo-5,6,7,8-tetrahydroquinoline and 5 ml of aqueous solution containing 0.3 g of sodium hydroxide are added and the resulting mixture is refluxed for 5 hours.

After completion of the reaction, ethanol was evaporated and water was added to the residue, followed by extraction with chloroform. The chloroform extract is dried over anhydrous magnesium sulfate and the chloroform is evaporated. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 100/1) to give a colorless substance similar to caramel 8- (5-methoxy-2-benzimidazolyl) thio-3-methyl -5,6,7,8-tetrahydroquinoline (0.5 g) is obtained.

NMR (CDCl ₃ ) δ: 1.60 to 2.00 (m, 2H), 2.00 to 2.40 (m, 2H), 2.27 (s, 3H), 2.72 (t, 2H), 3.78 (s, 3H), 4.78 (t, 1H), 6.77 (dd, 1H), 7.00 (d, 1H), 7.22 (d, 1H), 7.40 (d, 1H), 8.23 (d, 1H).

The reaction is carried out according to the same method as in Example 100, except that the compounds of Examples 66 to 99 are prepared using an appropriate starting material.

Example 101

20 ml of 20% hydrochloric acid is added to 0.8 g of 2-chloro-8-[(5-methoxy-2-benzimidazolyl) thio-5,6,7,8-tetrahydroquinoline and the mixture is 70-80 Stir at 1 ° C. for 1 h. After cooling the reaction mixture, the precipitated crystals were collected by filtration and recrystallized from ethanol to give 2-hydroxy-8-[(5-methoxy-2-benzimidazolyl) thio]-as white powdery crystals. 5,6,7,8-tetrahydroquinoline (0.4 g) is obtained.

Melting Point: 217-218 ° C (Decomposition)

Example 102

1.5 g of 2-mercaptoimidazo [4,5-b] pyridine is dissolved in 50 ml of dimethylformamide, ice-cooled to this solution and 0.88 g of 60% sodium hydroxide (stored in oil) is added to the mixture. Stir at temperature for 30 minutes. 2.2 g of 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride is added to the reaction mixture, and the whole mixture is stirred and heated for 3 hours. After completion of the reaction, dimethylformamide is evaporated, then water is added to the residue and extracted with chloroform.

The chloroform extract is washed with water and dried over anhydrous magnesium sulfate. By evaporating chloroform and recrystallization of the residue from ethanol, white powdery crystals 2-[(3,5-dimethyl-4-methoxy-2-pyridyl) methylthio] imidazo [4,5-b] pyridine ( 1.3 g) is obtained.

Melting Point: 186 ~ 188 ° C

[Examples 103 to 116]

79=0이다)으로 표시된 실시예 103∼116의 화합물을 제조한다.The reaction was carried out according to a method similar to that of Example 102, using the appropriate starting materials shown in Table 6, formula (20)

79 = 0) to prepare the compounds of Examples 103-116.

TABLE 6

Example 117

0.4 g of 2-[(3,5-dimethyl-4-methoxy-2-pyridyl) methylthio] amida [4,5-b] pyridine is dissolved in 40 ml of chloroform and stirred under ice-cooling solution. 0.27 g of m-chloroperbenzoic acid (85%) is added. The whole reaction mixture is stirred at the same temperature for 20 minutes. After completion of the reaction the reaction mixture is concentrated under reduced pressure and the residue is washed with diethyl ether. Recrystallization from ethanol yields 2-[(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] amida [4,5-b] pyridine (1.15 g) as light brown powdery crystals. do. Melting Point 169 ~ 170 ℃

[Examples 118 to 128]

The reaction is carried out according to a similar method as in Example 117, using the appropriate starting material, to prepare the compounds of Examples 118-128 represented by the general formula (20) (wherein L = 0) shown in Table 7.

TABLE 7

Example 129

737 mg of 2-chloro-imidazo [4,5-b] pyridine, 0.4 g of thiourea and 20 ml of ethanol are mixed and the mixture is refluxed for 2 hours. 666 mg of 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride is added to the reaction mixture and refluxed for 5 hours. After completion of the reaction, ethanol is evaporated, water is added to the residue and the solution is extracted with chloroform. The chloroform extract is dried over anhydrous magnesium sulfate and the chloroform is evaporated. The residue was recrystallized from ethanol to give 2-[(3,5-dimethyl-4-methoxy-2-pyridyl) methylthio] imidazo [4,5-b] pyridine (450 mg) as white powdery crystals. do. Melting Point: 186 ~ 188 ° C

The reaction is carried out according to the same method as in Example 129, except that the compounds of Examples 103 to 115 are prepared using an appropriate starting material.

Example 130

0.2 g of 6-amino-2-[(3,5-dimethyl-4-methoxy-2-pyridyl) methylthio] imidazo [4,5-b] pyridine in 3 ml of water and 0.1 ml of concentrated sulfuric acid It is dissolved in a mixture consisting of. The mixture is stirred at 0 ° C., 59 mg of sodium nitrite is added and the mixture is further stirred at the same temperature for 1 hour. The reaction solution was added to an aqueous 4N-sodium hydroxide solution, neutralized, and the formed crystals were collected by filtration. Recrystallized from ethanol, yellow powdery crystals 6-hydroxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl) methylthio] imidazo [4,5-b] pyridine (0.2 g) To obtain. Melting Point: 178 ~ 179.5 ℃

The pharmaceutical action of the compounds of the present invention can be seen from the following test results.

Pharmacy Test-1

Inhibitory effect on the action of H ⁺ -K ⁺ -ATPase

1) Test method

H ⁺ -K ⁺ -ATPase (hydrogen-potassium-activated adenosine triphosphatase) (protein content: 10 mcg) prepared in pig stomach containing 2 mM piperazine-N, N'-bis (2-ethanesulfonic acid) PIPES Tris buffer solution PIPES-tris (hydroxymethyl) -2-amino-1,3-propanediol buffer solution (pH = 6.1) and then the resulting mixture is left at room temperature.

Each test compound is dissolved in dimethylformamide and a dimethylformamide solution is added to the H ⁺ -K ⁺ -ATPase buffer described above to bring the final concentration of the test compound to 1.0%. Each mixture thus prepared is reacted at room temperature for 30 minutes.

The reaction mixture was then divided into two, one of which was added 1 ml of 75 mM PIPES-tris buffer (pH = 7.4, containing 4 mM MgCl ₂ , 4 mM Na ₂ ATP and 20 mM KCl), and another portion To the reaction mixture was added 1 ml of 75 mM PIPES-Tris buffer (pH = 7.4, containing 4 mM MgCl ₂ and 4 mM Na ₂ ATP).

Each of these two sample solutions is allowed to react for 30 minutes at 37 ° C. 0.3 ml of 40% trichloroacetic acid was added to each reaction mixture to stop the reaction, followed by centrifugation at 3,000 rpm for 10 minutes to obtain a supernatant. The inorganic phosphoric acid formed in the reaction mixture is determined according to the method described in C.H. Fiske Y. Subbarow: J. Biol. Chem., Vol. 66, 375-400 (1925). The amount of inorganic phosphoric acid determined using PIPES-Tris buffer containing 20 mM KCl minus the amount of inorganic phosphoric acid determined using PIPES-Tris buffer containing no 20 mM KCl was added to unit time and unit protein. Conversion to enzymatic activity.

The percent inhibition of each test compound is obtained from the enzymatic activity for each dose in the test and control groups, and the IC ₅₀ (50% inhibition dose of each test compound) is calculated from the percent inhibition. The results are shown in Table 8 below.

2) test compound

(1) 4-allyloxy-8- (2-benzimidazolyl) sulfinyl-3-methyl-5,6,7,8-tetrahydroquinoline

(2) 4-allyloxy-8- (5,6-difluoro-2-benzimidazolyl) -sulfinyl-3-methyl-5,6,7,8-tetrahydroquinoline

(3) 8- (5-fluoro-2-benzimidazolyl) sulfinyl-3-methyl-4-propargyloxy-5,6,7,8-tetrahydroquinoline

(4) 4-allyloxy-8- (5,6-dimethyl-2-benzimidazolyl) -sulfinyl-3-methyl-5,6,7,8-tetrahydroquinoline

(5) 4-allyloxy-8- (5,6-dichloro-2-benzimidazolyl) -sulfinyl-3-methyl-5,6,7,8-tetrahydroquinoline

(6) 8- (5,6-dimethyl) -2-benzimidazolyl) sulfinyl-3-methyl-4-propargyloxy-5,6,7,8-tetrahydroquinoline

(7) 8- (2-benzimidazolyl) sulfinyl-3-methyl-4-propargyloxy-5,6,7,8-tetrahydroquinoline

(8) 8- (5,6-dichloro-2-benzimidazolyl) sulfinyl-3-methyl-4-propargyloxy-5,6,7,8-tetrahydroquinoline

(9) 8- (2-benzimidazolyl) sulfinyl-4- (2-methoxy-ethoxy) -3-methyl-5,6,7,8-tetrahydroquinoline

(10) 8- (5-fluoro-2-benzimidazolyl) sulfinyl-4- (2-methoxyethoxy) -3-methyl-5,6,7,8-tetrahydroquinoline

(11) 4-allyloxy-8- (5-fluoro-2-benzimidazolyl) -sulfinyl-3-methyl-5,6,7,8-tetrahydroquinoline

(12) 8- (2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline

(13) 4-methyl-8- (5-methoxy-2-benzimidazolyl) -sulfinyl-5,6,7,8-tetrahydroquinoline

(14) 3-methyl-8- (5-methoxy-2-benzimidazolyl) -sulfinyl-5,6,7,8-tetrahydroquinoline

(15) 3-methyl-8- (2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline

(16) 3-methyl-8- (5-methyl-2-benzimidazolyl) -sulfinyl-5,6,7,8-tetrahydroquinoline

(17) 8- (5-methyl-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline

(18) 3-methyl-8- (5-acetyl-2-benzimidazolyl) -sulfinyl-5,6,7,8-tetrahydroquinoline

(19) 3-methyl-8- (5,6-dimethoxy-2-benzimidazolyl) -sulfinyl-5,6,7,8-tetrahydroquinoline

(20) 8- (5-chloro-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline

(21) 2-chloro-8- (5-methoxy-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline

(22) 2-chloro-3-methyl-8- (5-methoxy-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline

(23) 8- (5-methoxy-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline

(24) 4-methoxy-8- (5-methoxy-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline

(25) 4-methoxy-8- (5-trifluoromethyl-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline

(26) 3-methyl-8- (5-methoxy-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline

(27) 3-methyl-8- (5-trifluoromethyl-2-benzimidazolyl) -sulfinyl-5,6,7,8-tetrahydroquinoline

(28) 8- (5-trifluoromethyl-2-benzimidazolyl) -sulfinyl-5,6,7,8-tetrahydroquinoline

(29) 2-hydroxy-8- (5-methoxy-2-benzimidazolyl) -sulfinyl-5,6,7,8-tetrahydroquinoline

(30) 8- (5,6-dimethoxy-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline

(31) 8- (5-nitro-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline

(32) 8- (5-fluoro-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline

(33) 8- (4-methyl-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline

(34) 3-methyl-4-methoxy-8- (5-fluoro-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline

(35) 3-Methyl-4-methoxy-8- (2-benzimidazolyl) -sulfinyl-5,6,7,8-tetrahydroquinoline

(36) 8- (5,6-dichloro-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline

(37) 8- (5-ethoxy-6-fluoro-2-benzimidazolyl) -sulfinyl-5,6,7,8-tetrahydroquinoline

(38) 3-methyl-4-methoxy-8- (5,6-dimethyl-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline

(39) 3-methyl-5- (5-trifluoromethyl-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline

(40) 3-methyl-8- (5-fluoro-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline

(41) 3-methyl-4-methoxy-8- (5,6-dichloro-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline

(42) 3-methyl-4-methoxy-8- (5-ethoxy-6-fluoro-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline

(43) 3-methyl-4-methoxy-8- (5,6-difluoro-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline

(44) 3-methyl-5- (5-trifluoromethyl-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline

(45) 5-bromo-2-[(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] imidazo [4,5-b] pyridine

(46) 2-[(3,5-dimethyl-4-methoxy-2-pyridyl) -methylsulfinyl] imidazo [4,5-b] pyridine

(47) 2- (2-pyridylmethylthio) imidazo [4,5-b] pyridine (compound described in British Patent No. 1,234,058)

(48) 3-methyl-4-methoxy-8- (5-fluoro-6-methoxy-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline

(49) 3-methyl-4-methoxy-8- (5-methoxy-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline

(50) 3-methyl-4-methoxy-8- (5-chloro-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline

(51) 4-methoxy-8- (5-fluoro-2-benzimidazolyl) -sulfinyl-5,6,7,8-tetrahydroquinoline

(52) 3-methyl-8- (5,6-dichloro-2-benzimidazolyl) -sulfinyl-5,6,7,8-tetrahydroquinoline

(53) 3-methyl-8- (5,6-dimethyl-2-benzimidazolyl) -sulfinyl-5,6,7,8-tetrahydroquinoline

3) Test result

The test results are shown in Table 8 below.

TABLE 8

Pharmacy Test-2

Inhibitory Effect on Hydrochloric Acid in the Stomach

1) Test method

Male Wister rats should be used as test animals. After the test animal is fasted for 24 hours, the pyloric sphincter of the test animal is tied with an anesthetic with ultan (1.5 g / kg) and a gastric perfusion cannula is inserted above.

Gastric perfusion is carried out with saline via an oral catheter, and the amount of gastric fluid secreted is determined by determining the pH and titrating the total acidity of the perfusate.

The secretion of gastric juice is promoted by continuous injection through the femoral vein at a rate of 1 mg / kg / hour histamine dihydrochloride as secretion promoter and the effect of each test compound is tested. Each test compound is dissolved in dimethylformamide and a predetermined dose (up to: 30 mg / kg) of each test compound is administered to the duodenum in the form of a solution.

Before administering the test compound, the percentage of hydrochloric acid secretion is calculated using the value of secreted hydrochloric acid as a control. ED ₅₀ values are calculated from the percent inhibition of each test compound and mathematically processed according to the ProBit (probability unit) method.

2) Test result

The test results are shown in Table 9 below.

TABLE 9

Claims (6)

A tetrahydroquinoline derivative of the following general formula (1a) is obtained by reacting a benzimidazole derivative of the following general formula (2) with a tetrahydroquinoline derivative of the following general formula (3) to the following general formula (1) Method for producing a tetrahydroquinoline derivative represented.

(Wherein R ^1a and R ^2a are the same or different and each is a hydrogen atom, a halogen atom, hydroxy, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a C ₂ -C ₆ alkenyloxy group, A C ₂ -C ₆ alkynyloxy group or a C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkoxy group; R ^3a and R ^4a are the same or different and are each a hydrogen atom, a halogen atom, or a substituent of 1 to 3 as a substituent A C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkyl group, a nitro group or a C ₁ -C ₆ alkanoyl group having an atom;

Any one of positions 2 to 8 of the tetrahydroquinoline moiety at the substituted position of the group is possible; X ¹ is a mercapto group, a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group; X ² is a mercapto group, a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group; When X ¹ is a mercapto group, X ² is a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group; When X ² is a mercapto group, X ¹ is a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group; ℓ is 0 or 1) The imidazopyridine derivative represented by the following general formula (20a) is obtained by reacting an imidazopyridine derivative represented by the following general formula (21) with the pyridine derivative represented by the following general formula (22). Method for preparing imidazopyridine derivatives.

Wherein R ^1b and R ^2b are the same or different and are each a hydrogen atom, a C ₁ -C ₆ alkoxy-carbonyl group, a halogen atom, a C ₁ -C ₆ alkyl group, an amino group or a hydroxy group; R ^3b , R ^4b and R ^5b is the same or different and is a hydrogen atom, a C ₁ -C ₆ alkoxy group or a C ₁ -C ₆ alkyl group, respectively; R ^6b is a mercapto group, a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group or An aralkylsulfonyloxy group; R ^7b is a mercapto group, a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group; when R ^6b is a mercapto group, R ^7b is a halogen atom, lower An alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group, if R ^7b is a mercapto group, R ^6b is a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group; A is C ₁ ~C ₆ alkyl group; and Z If one of Y is a group of the formula -CH =, the other is a nitrogen atom -N =, l is 0 or 1, Y is a group of the formula -CH =, Z is a nitrogen atom -N =, If 0, R ^3b , R ^4b and R ^5b must not be hydrogen at the same time.) A method for producing a tetrahydroquinoline derivative represented by the following general formula (1), wherein the tetrahydroquinoline derivative of the general formula (1a) is oxidized to obtain a tetrahydroquinoline derivative of the following general formula (1b).

^Wherein R ^1a , R ^2a , R ^3a , R ^4a , L and

Substitution position of the group is as defined in claim 1) (Iii) a benzimidazol derivative of the following general formula (2a) and a thiourea of the following general formula (4) are reacted to obtain an intermediate product, and (ii) the tetrahydroquinoline derivative of the following general formula (3a). The reaction method of the tetrahydroquinoline derivative represented by following General formula (1) characterized by obtaining the tetrahydroquinoline derivative of following General formula (1a).

^Wherein R ^1a , R ^2a , R ^3a , R ^4a , L and

The position of substitution of the group is as defined in claim 1; X ³ and X ⁴ are halogen atoms; expression

The substituted position of the group may be any one of positions 2 to 8 of the tetrahydroquinoline moiety.) A method for producing an imidazopyridine derivative represented by the following general formula (20), characterized by obtaining an imidazopyridine derivative of the following general formula (20a) and an imidazopyridine derivative of the following general formula (20b).

(Wherein R ^1b , R ^2b , R ^3b , R ^4b , R ^5b , A, Y, Z and L are as defined in claim 2). (Iii) reacting an imidazopyridine derivative of the following general formula (21a) with a thiourea of the following general formula (4) to obtain an intermediate product, and (ii) reacting this intermediate product with a pyridine derivative of the following general formula (22a) A method for producing an imidazopyridine derivative represented by the following general formula (20), wherein the imidazopyridine derivative of the following general formula (20a) is obtained.

(Wherein R ^1b , R ^2b , R ^3b , R ^4b , R ^5b , A, Y, Z and L are as defined in claim 2; R ^8b and R ^9b are halogen atoms.)