JPH0633255B2 - Tetrahydroquinoline derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel tetrahydroquinoline derivatives,
More specifically, the general formula (1) [Wherein R ¹ and R ² are the same or different and each represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a hydroxyl group, a lower alkenyloxy group, a lower alkynyloxy group or a lower alkoxy lower alkoxy group. , R ³ and R ⁴ are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group optionally substituted with a halogen atom, a lower alkoxy group, a nitro group or a lower alkanoyl group, and A and B are Represents a lower alkylene group, and m and n each represent 0 or 1. In addition, the substituent The substitution position of may be any of positions 2 to 8 of the tetrahydroquinoline skeleton.

However, R ¹ and R ² are both hydrogen atoms, and m is 1, n
There If 0, R ³ and R ⁴ is a hydrogen atom, or shall not a lower alkoxy group and a lower alkanoyl group, or R ³ and R ⁴ are each substituted at the 5-position and 6-position, R ³ When one of R ⁴ and R ^{4 is} a lower alkyl group optionally substituted with a halogen atom, and the other is a hydrogen atom, a lower alkoxy group, a lower alkanoyl group or a lower alkyl group optionally substituted with a halogen atom, , R ¹ and R ² are not both hydrogen atoms, m is 1 and n is 0. ] It is related with the tetrahydroquinoline derivative represented by these, and its salt.

The tetrahydroquinoline derivative represented by the above general formula (1) of the present invention has an anti-ulcer action and is useful as a therapeutic agent for digestive ulcers such as gastric ulcer and duodenal ulcer.

Hydrochloric acid production in the gastric mucosa is regulated by many pharmacological factors, but ultimately the biochemical mechanism of [H ⁺ ] ion production becomes the rate-limiting step. In recent years, H in gastric parietal cells
It was found that ATPase, which has the property of being activated by ⁺ and K ⁺ , controls acid production. This oxygen is an oxygen specifically present in gastric parietal cells and plays a role of a key enzyme of a proton pump, and an inhibitor of this enzyme can be a useful acid secretion inhibitor. INDUSTRIAL APPLICABILITY The compound of the present invention has both acid secretion inhibitory action and cytoprotective action, suppresses ulcer factor from both attacking factor and defense factor, is less toxic, and has a long duration of acid secretion inhibiting action. It has features.

In the present specification, the lower alkyl group has a carbon number of 1 to
6 straight or branched chain alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
Examples thereof include pentyl and hexyl groups.

Examples of the lower alkoxy group include linear or branched alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy and hexyloxy groups.

Halogen atoms include fluorine, chlorine, bromine and iodine.

Examples of the lower alkyl group which may be substituted with a halogen atom include trifluoromethyl, 2,2-difluoroethyl, 1,1-, in addition to the above alkyl group having 1 to 6 carbon atoms.
Dichloroethyl, dichloromethyl, trichloromethyl,
Tribromomethyl, 2,2,2-trifluoroethyl, 2,2,2-
1 to 3 halogen atoms such as trichloroethyl, 2-chloroethyl, 1,2-dichloroethyl, 3,3,3-trichloropropyl, 3-fluoropropyl, 4-chlorobutyl and 3-chloro-2-methylpropyl groups Examples thereof include linear or branched alkyl groups having 1 to 6 carbon atoms.

Examples of the lower alkenyloxy group include vinyloxy, allyloxy, 2-butenyloxy, 3-butenyloxy,
1-methylallyloxy, 2-pentenyloxy, 2-
A linear or branched alkenyloxy group having 2 to 6 carbon atoms such as a hexenyloxy group can be exemplified.

Lower alkynyloxy groups include ethynyloxy, 2
-Propinyloxy, 2-butynyloxy, 3-butynyloxy, 1-methyl-2-propynyloxy, 2-pentynyloxy, 2-hexynyloxy group and the like having 2 carbon atoms
Examples of the straight chain or branched chain alkenyloxy group of ~ 6 can be mentioned.

As lower alkoxy lower alkoxy group, methoxymethoxy, ethoxymethoxy, propoxymethoxy, butoxymethoxy, pentyloxymethoxy, hexyloxymethoxy, 2-methoxyethoxy, 1-methoxyethoxy, 2-propoxyethoxy, 2-hexyloxyethoxy, 3 -Methoxypropoxy, 1-methoxypropoxy, 3-butoxypropoxy, 3-pentyloxypropoxy, 4-methoxybutoxy, 3-propoxybutoxy, 4-hexyloxybutoxy, 5-ethoxypentyloxy, 3-propoxypentyloxy, 6- Methoxyhexyloxy, 2-ethoxyhexyloxy, 3
Examples of the linear or branched alkoxy group having 1 to 6 carbon atoms as a substituent include a linear or branched alkoxy group having 1 to 6 carbon atoms such as a pentyloxyhexyloxy group. be able to.

Examples of the lower alkanoyl group include linear or branched alkanoyl groups having 1 to 6 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl and hexanoyl groups.

As the lower alkylene group, a linear or branched alkylene group having 1 to 6 carbon atoms, for example, methylene, ethylene, trimethylene, methylmethylene, ethylmethylene,
Examples thereof include 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, tetramethylene, pentamethylene and hexamethylene groups.

The compound of the present invention can be produced by various methods, for example, the method shown in the following reaction scheme.

[Reaction formula-1] [Wherein R ¹ , R ² , R ³ , R ⁴ , A, B, m and n
Is the same as above, X ¹ and X ² are each a mercapto group, a halogen atom, a lower alkanesulfonyloxy group,
An arylsulfonyloxy group or an aralkylsulfonyloxy group is shown. However, when X ¹ is a mercapto group, X ² represents a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group, or an aralkylsulfonyloxy group, and 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 the general formulas (2) and (3), X ¹ and / or X ²
The halogen atom shown by is the same as the above,
Specific examples of the lower alkanesulfonyloxy group include methanesulfonyloxy, ethanesulfonyloxy, isopropanesulfonyloxy, propanesulfonyloxy, butanesulfonyloxy, tert-butanesulfonyloxy, pentanesulfonyloxy, and hexanesulfonyloxy groups. As the arylsulfonyloxy group, specifically, phenylsulfonyloxy,
4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy, 3-
Examples thereof include substituted or unsubstituted arylsulfonyloxy groups such as chlorophenylsulfonyloxy and α-naphthylsulfonyloxy, and specific examples of the aralkylsulfonyloxy group include benzylsulfonyloxy and 2
-Phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy, 4-methoxybenzylsulfonyloxy, 3-chlorobenzylsulfonyloxy, α- A substituted or unsubstituted aralkylsulfonyloxy group such as a naphthylmethylsulfonyloxy group can be exemplified.

The reaction between the compounds of general formula (2) and general formula (3) can be carried out in the presence of a basic compound in a suitable solvent. Any solvent can be used as the solvent as long as it does not affect the reaction, for example, water, methanol, ethanol, alcohols such as isopropanol, benzene, toluene, aromatic hydrocarbons such as xylene, Ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme, kents such as acetone, esters such as methyl acetate and ethyl acetate, N, N-dimethylformamide, dimethylsulfoxide or hexamethylphosphoric triamide and the like or their A mixed solvent can be illustrated. Examples of the basic compound used include inorganic bases such as sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate and silver carbonate, alkalis such as metal sodium and metal potassium. Metals, alcoholates such as sodium methylate and sodium ethylate, triethylamine, pyridine, N, N-dimethylaminopyridine, N-methylmorpholine, 1,5-diazabicyclo [4.3.0] nonene-5 (DBN),
1,8-Diazabicyclo [5.4.0] undecene-7 (DBU), 1,4-
An organic base such as diazabicyclo [2.2.2] octane (DABCD) can be exemplified.

The reaction is usually completed at 0 to 150 ° C., preferably at 0 to 100 ° C. for about 1 to 10 hours. The amount of the compound of the general formula (2) used is usually at least equimolar, preferably equimolar to 2 times the molar amount of the compound of the general formula (3).

[Reaction formula-2] [Wherein R ¹ , R ² , R ³ , R ⁴ , A, B, m and n
Is the same as above] The oxidation reaction of the compound of the general formula (1a) is carried out in a suitable solvent in the presence of an oxidizing agent. As the solvent used, any solvent that does not affect the reaction can be used, for example, water, formic acid, acetic acid, organic acids such as trifluoroacetic acid, methanol, ethanol, alcohols such as isopropanol, Examples thereof include halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane. As the oxidizing agent, any oxidizing agent that normally oxidizes a sulfide group to a sulfoxide group can be used, for example, formic acid, peracetic acid, trifluoroperacetic acid, perbenzoic acid, m-chloroperbenzoic acid, 0- Peracids such as carboxyperbenzoic acid, hydrogen peroxide, chromic acid, sodium chromate,
Examples include chromate such as potassium chromate, permanganate, sodium permanganate, permanganate such as potassium permanganate, iodate such as sodium metaperiodate, and selenium compound such as selenium dioxide. . The amount of the oxidizing agent used is at least equimolar, preferably equimolar to 1.5 times the molar amount of the compound of the general formula (1a). The reaction is completed usually at -70 to 40 ° C, preferably -70 ° C to around room temperature in about 5 minutes to 3 hours.

[Reaction Formula-3] [Wherein R ¹ , R ² , R ³ , R ⁴ , A, B, m and n
Is the same as above. X ³ and X ⁴ each represent a halogen atom] The reaction of the compound of general formula (2a) with thiourea (4) is carried out in the presence or absence of a solvent. As the solvent used, for example, alcohols such as methanol, ethanol, propanol, diethyl ether, tetrahydrofuran, dioxane, ethers such as ethylene glycol monomethyl ether, benzene, toluene, aromatic hydrocarbons such as xylene, acetone, Ketones such as methyl ethyl ketone, dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide (HMP
A) etc. can be illustrated. The amount of thiourea (4) to be used is usually at least 1 mol, preferably 1 to 2 times the molar amount of the compound of the general formula (2a).
The reaction is completed usually at room temperature to 200 ° C, preferably at room temperature to 150 ° C in about 1 to 5 hours.

The reaction between the intermediate obtained in the above reaction and the compound of the general formula (3a) is usually carried out in the presence of a condensing agent. A basic compound is usually used as the condensing agent. A wide variety of known basic compounds can be used, such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,
Inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate and silver carbonate, alkali metals such as sodium and potassium,
Examples thereof include alcoholates such as sodium methylate and sodium ethylate, organic bases such as triethylamine, pyridine, N, N-dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, DBN, DBU and DABCO. The reaction is carried out without solvent or in the presence of a solvent. As the solvent, any inert one which does not adversely influence the reaction is used, and examples thereof include water, methanol, ethanol, propanol, butanol, and ethylene glycol. Ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, acetone, kents such as methylethyl kent, aromatic hydrocarbons such as benzene, tonell and xylene, esters such as methyl acetate and ethyl acetate, DMF,
Examples include aprotic polar solvents such as DMSO and HMPA, and mixed solvents thereof. Further, it is advantageous to carry out the reaction in the presence of a metal iodide such as sodium iodide or potassium iodide. The ratio of the compound (3a) to the compound (2a) used in the above method is not particularly limited and is appropriately selected from a wide range, but the latter is usually about 0.5 to 5 times by mole, preferably 0.5 to the former. It is desirable to use it in a molar amount to 2 times the molar amount. The reaction temperature is not particularly limited, but is usually about -30 to 200 ° C, preferably 0 to 160 ° C, and the reaction is usually completed in about 1 to 30 hours.

The compounds of the general formulas (3) and (3a) used as starting materials in the above reaction formulas -1 and -3 include some novel compounds, for example, by the methods of the following reaction formulas -4 and -5. Manufactured.

[Reaction Formula-4] [Wherein, R ¹ and R ² are the same as defined above. R ⁵ represents a lower alkanoyl group, and X ⁵ and X ⁶ each represent a halogen atom.] The reaction of the general formula (5) with the compound of the general formula (6) or (7) is performed in the presence or absence of a suitable solvent. Done below. Any solvent can be used as long as it does not affect the reaction, for example, dichloromethane,
Examples thereof include halogenated hydrocarbons such as dichloroethane, chloroform and carbon tetrachloride, aromatic hydrocarbons such as benzene, Tonell and xylene, ethers such as diethyl ether, tetrahydrofuran and dioxane, and pyridine. The compound of the general formula (6) or (7) is usually used at least equimolar to the compound of the general formula (5), preferably in large excess. The reaction is usually 0 to 150 ° C., preferably around 0 to 100 ° C.,
It takes about 1 to 5 hours to finish.

The hydrolysis reaction of the compound of the general formula (8) is carried out by using a suitable hydrolysis catalyst such as hydrohalic acid such as hydrochloric acid and hydrobromic acid, inorganic acids such as sulfuric acid and phosphoric acid, sodium hydroxide and potassium hydroxide. In the presence of an inorganic alkali compound such as a metal carbonate or bicarbonate such as an alkali metal hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate or the like, in the absence of a solvent or in a suitable solvent (for example, water, methanol, ethanol, etc.). Alcohols or mixed solvents thereof) at room temperature to 150 ° C., preferably 50 to 100 ° C.
Minutes to 24 hours.

The halogenation reaction of the compound of the general formula (9) is carried out using a usual halogenating agent in the presence or absence of a solvent. As the halogenating agent to be used, known ones can be widely used, for example, halogen molecules such as bromine and chlorine, hydrogen bromide, hydrohalic acids such as hydrochloric acid,
Examples thereof include phosphorus halide compounds such as thionyl chloride, phosphorus pentachloride, phosphorus tribromide and phosphorus oxychloride.
The halogenating agent is used in an amount of at least 1 equivalent, preferably 1 equivalent to a large excess based on the compound of the general formula (9). The solvent used in the reaction is, for example,
Examples thereof include halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride, acetic acid, propionic acid, sulfuric acid and water. The reaction is usually 0 to
Finish at 150 ° C, preferably 0 to 100 ° C, in about 1 to 24 hours.

Alternatively, the compound of formula (5) can be directly converted to the compound (3b) by reacting a halogenating agent in the absence of solvent or in a suitable solvent. As the solvent used, the above-mentioned general formula
The solvent used for the halogenation reaction of the compound of (9) can be exemplified. Examples of the halogenating agent include alkanes such as methanesulfonyl chloride, p-toluenesulfonyl chloride and benzenesulfonyl chloride, or arylsulfonyl halides. The amount of the halogenating agent used is at least equimolar, preferably equimolar to 2 times the molar amount of the compound of the general formula (5). The reaction is usually completed at 0 to 150 ° C., preferably at 0 to 100 ° C. for about 1 to 10 hours.

[Reaction Formula-5] [Wherein R ¹ , R ² and X ⁶ are the same as those defined above] The reduction reaction of the compound of the general formula (10) is carried out using a conventional hydrogenating / reducing agent. Examples of the hydride reducing agent include sodium borohydride, lithium aluminum hydride,
Dialkyl aluminum hydride such as diisobutylaluminum hydride (DIBAL), diborane, and the like, and the amount thereof is usually 0.1 to 10 with respect to the compound of the general formula (10).
It is preferable to use a 3-fold molar amount, preferably 0.5 to 2-fold molar amount. This reduction reaction is usually carried out in a suitable solvent, for example, water, methanol, ethanol, lower alcohols such as isopropanol, tetrahydrofuran, diethyl ether,
Ethers such as diglyme, aromatic hydrocarbons such as benzene, toluene, xylene, etc., usually -60 to 50
C., preferably -40.degree. C. to room temperature, about 10 minutes to 5 hours. When lithium aluminum hydride, dialkylaluminum hydride or diborane is used as the reducing agent, it is preferable to use an anhydrous solvent such as diethyl ether, tetrahydrofuran, diglyme, benzene, toluene or xylene.

The halogenation reaction of the compound of the general formula (11) is
It is carried out under the same conditions as the halogenation reaction of the compound of (9).

[Reaction Formula-6] [Wherein, R ¹ , R ² , R ⁵ and X ⁶ are the same as defined above. R
⁶ represents a lower alkyl group] The reaction of the compound of the general formula (12) with the compound of the general formula (6) or (7) is carried out by the compound of the general formula (5) and the general formula (6) or (7). The reaction is performed under the same conditions as the reaction with.

Hydrolysis reaction of the compound of the general formula (13), the general formula (8)
It is carried out under the same conditions as the hydrolysis reaction of the compound of.
The halogenation reaction of the compound of general formula (14) is carried out under the same conditions as the halogenation reaction of the compound of general formula (9).

[Reaction formula-7] [Wherein, m and X ⁶ are the same as defined above. R ⁷ represents a lower alkyl group and D represents a lower alkylene group. However, the group- (D)
_m CH ₂ − does not exceed 6 carbon atoms] As the esterification reaction of the general formula (15), a general esterification reaction is applied, for example, a method of performing it in the presence of a dehydrating agent in a suitable solvent; There is a method of performing it in the presence of an acid or a basic compound in a solvent.

As the solvent used in the method, dichloromethane, chloroform, dichloroethane, halogenated hydrocarbons such as carbon tetrachloride, benzene, toluene, aromatic hydrocarbons such as xylene, diethyl ether, tedrahydrofuran, dioxane, Examples thereof include ethers such as ethylene glycol monomethyl ether and dimethoethane, polar solvents such as dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide.
Examples of the dehydrating agent used include dicyclohexylcarbodiimide and carbonyldiimidazole. The amount of alcohol of the general formula (16) is
It is usually at least equimolar, preferably equimolar to 1.5 times the molar amount of the compound of 5). The amount of the dehydrating agent used is usually at least equimolar to the compound (15),
It is preferable that the molar amount is from equimolar to 1.5 times. The reaction is usually completed at room temperature to 150 ° C, preferably 50 to 100 ° C for about 1 to 10 hours.

Examples of the acid used in the method include hydrochloric acid gas, sulfuric acid, phosphoric acid, polyphosphoric acid, boron trifluoride, inorganic acids such as perchloric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, p-toluene. Examples thereof include organic acids such as sulfonic acid, benzenesulfonic acid and ethanesulfonic acid, acid anhydrides such as trichloromethanesulfonic acid anhydride and trifluoromethanesulfonic acid anhydride, thionyl chloride and acetone dimethyl acetal. Furthermore, an acidic ion exchange resin can also be used. Examples of the basic compound include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium carbonate or silver carbonate, and alcoholates such as sodium methylate and sodium ethylate. The reaction can be carried out in the absence of a solvent, but it is advantageously carried out using the solvent exemplified in the above method. Furthermore, this reaction advantageously proceeds using a desiccant such as anhydrous calcium chloride, anhydrous copper sulfate, anhydrous calcium sulfate, and phosphorus pentoxide. The amount of the alcohol of the general formula (16), with respect to the compound of the general formula (15), in the absence of solvent, it is usually good to use a large excess amount, and in the presence of the solvent, usually 1 to It is preferable to use a 5-fold molar amount, preferably 1- to 2-fold molar amount. The reaction is usually carried out at -20 to 200 ° C, preferably 0 to 150 ° C and completed in about 1 to 20 hours.

The reduction reaction of the compound of the general formula (15) or (17) is carried out in the presence of a hydrogenation reducing agent in a suitable solvent. Examples of the reducing agent used include sodium borohydride, lithium aluminum hydride, diborane and the like. The amount of reducing agent used, relative to the compound of the general formula (15) or (17),
At least equimolar, preferably equimolar to 3-fold molar is used. When lithium aluminum hydride is used as the reducing agent, it is preferably represented by the general formula (15) or (1
It is preferable to use an equal weight of the compound of 7). Examples of the solvent used include water, alcohols such as methanol, ethanol and isopropanol, and ethers such as tetrahydrofuran, diethyl ether and diglyme. The reaction is completed usually at -60 to 50 ° C, preferably at -30 ° C to around room temperature in about 10 minutes to 5 hours. When lithium aluminum hydride or diborane is used as the reducing agent, it is preferable to use an anhydrous solvent such as diethyl ether, tetrahydrofuran or diglyme.

The halogenation reaction of the compound of the general formula (18) is
It is carried out under the same conditions as in the halogenation reaction of (9).

The carboxylic acid (15) as a starting material and the homocarboxylic acid compound thereof in the above reaction scheme-7 are produced by the method shown in the following reaction scheme-8.

[Reaction formula-8] [Wherein D, m and X ⁶ are the same as defined above. R ⁸ represents a lower alkyl group] The reaction of the compound of general formula (19) with the compound of general formula (20) can be carried out in a suitable solvent. Here, as the MCN, for example, potassium cyanide, sodium cyanide,
Examples of cyanides include silver cyanide, copper cyanide, and calcium cyanide. The solvent used is water,
Examples thereof include alcohols such as methanol, ethanol and isopropanol, and mixed solvents thereof. The amount of the compound (20) used is at least equimolar, preferably equimolar to 1.5 times the molar amount of the compound of the general formula (19). The reaction is usually completed at room temperature to 150 ° C., preferably at 50 to 120 ° C. in about 30 to 10 hours.

Hydrolysis reaction of the compound of the general formula (21), hydrohalic acid such as hydrochloric acid, hydrobromic acid, mineral acid such as sulfuric acid, phosphoric acid,
In the presence of a hydrolysis catalyst such as alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates or hydrogen carbonates such as sodium carbonate, potassium carbonate and sodium hydrogen carbonate, in a suitable solvent or without solvent. Will be held in. As the solvent used, for example,
Examples thereof include water, alcohols such as methanol and ethanol, and mixed solvents thereof. The reaction is usually 50-15
At 0 ° C, preferably 70 to 100 ° C, the process is completed in about 1 to 24 hours.

The reaction of the compound of the general formula (19) with the compound of the general formula (22) is carried out in the presence of a basic compound in a suitable solvent, usually at room temperature to 200.
C., preferably 60 to 120.degree. C., for about 1 to 24 hours. Examples of the solvent used include ethers such as dioxane, tetrahydrofuran, ethylene glycol dimethyl ether and diethyl ether, aromatic hydrocarbons such as benzene, toluene and xylene, lower alcohols such as methanol, ethanol and isopropanol, and dimethylformamide. Examples thereof include polar solvents such as dimethyl sulfoxide and the like. Examples of the basic compound used include calcium carbonate, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium amide, sodium hydride, potassium hydride, sodium methylate, sodium ethylate and the like. Examples thereof include inorganic bases, amines such as triethylamine, tripropylamine, pirudine and quinoline. The reaction advantageously proceeds by using an alkali metal iodide such as potassium iodide or sodium iodide. The amount of the compound of the general formula (22) used is
The compound (19) is usually equimolar to large excess amount, preferably equimolar to 5-fold molar amount, more preferably equimolar to 1.2.
It is a double molar amount. The hydrolysis of the compound (23) is carried out by
The hydrolysis is carried out in the same manner as in 1).

In the reaction formula-4, the compound of the general formula (5) used as a starting material partially contains a novel compound, and can be produced, for example, by the following reaction formula-9.

[Reaction formula-9] [In the formula, R ¹ is the same as above, and R ⁵ is a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a lower alkoxy lower alkyl group. However, the substitution position of R ¹ is the 2 or 3 position of the tetrahydroquinoline skeleton. The oxidation reaction of the compound of general formula (25) is carried out in the presence of an oxidizing agent in a suitable solvent. As the solvent and the oxidizing agent used, any of the solvent and the oxidizing agent exemplified in the oxidation reaction of the compound of the general formula (1a) in the reaction formula-2 can be used. The amount of the oxidizing agent used is at least equimolar, preferably equimolar to 1.5 times the molar amount of the compound of the general formula (25). The reaction is usually at -20 to 120 ° C,
Preferably, it is completed at about -20 to 100 ° C in about 5 minutes to 5 hours.

The nitration reaction of the compound of the general formula (26) is carried out under ordinary aromatic compound nitration reaction conditions, for example, using a nitrating agent without solvent or in a suitable inert solvent. Examples of the inert solvent include acetic acid, acetic anhydride, concentrated sulfuric acid, etc., and examples of the nitrating agent include fuming nitric acid, concentrated nitric acid, mixed acid (mixed solution of nitric acid and sulfuric acid, fuming sulfuric acid, phosphoric acid or acetic anhydride). ), Potassium nitrate, sodium nitrate, and other alkali metal nitrates and a mixture of sulfuric acid and the like. The amount of the nitrating agent used may be an equimolar amount or more and usually an excess amount with respect to the raw material compound, and the reaction is advantageous.
It is carried out at 0 ° C to 100 ° C for 1 to 6 hours.

The reaction between the compound of general formula (27) and the compound of general formula (28) can be carried out without solvent or in a suitable solvent in the presence of a basic compound. Examples of the solvent used here include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme, ketones such as acetone, methyl acetate and ethyl acetate. And the like, aprotic polar solvents such as N, N-dimethylformamide, dimethylsulfoside, and hexamethylphosphoric triamide, or mixed solvents thereof. As the basic compound used, the above reaction formula-
Any of the basic compounds exemplified in 1 can be used.
The amount of the compound of the general formula (28) to be used may be an equimolar amount or more, usually an excess amount with respect to the compound of the general formula (27), and the reaction is usually 0 to 150 ° C., preferably room temperature to 100. Around ℃,
It ends in 1 to 5 hours.

In the compound of the general formula (1), a compound in which at least one of R ¹ to R ⁴ is a halogen atom is hydrolyzed under the same conditions as the hydrolysis of the compound (8) in the reaction formula-4. In the compound of general formula (1), R ¹ to R
^At least one of ⁴ can lead to a compound having a hydroxyl group.

Among the compounds represented by the general formula (1), the compound having an acidic group can form a salt with a pharmacologically acceptable basic compound. Examples of such basic compounds include metal hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide, alkali metal carbonates or bicarbonates such as sodium carbonate and sodium hydrogen carbonate, sodium methylate and potassium ethyl carbonate. Examples thereof include alkali metal alcoholates such as lath. Further, among the compounds represented by the general formula (1), the compound having a basic group can easily form a salt with a usual pharmacologically acceptable acid. Examples of such an acid include inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid and hydrobromic acid, and organic acids such as acetic acid, p-toluenesulfonic acid, ethanesulfonic acid, oxalic acid, maleic acid, succinic acid and benzoic acid. Can be mentioned.

The compounds of the present invention naturally include stereoisomers and optically active forms.

The compound of the present invention produced by the above method is easily isolated and purified from the reaction system by a conventional separation means such as distillation, recrystallization, column chromatography, preparative thin layer chromatography, and solvent extraction. it can.

The compound of the present invention is useful as an anti-ulcer agent and is usually used in the form of a general pharmaceutical preparation. The preparation is prepared by using diluents or excipients which are usually used such as fillers, fillers, binders, moisturizers, disintegrants, surfactants and lubricants. Various forms of this pharmaceutical preparation can be selected according to the therapeutic purpose, and typical examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories,
Examples include injections (solutions, suspensions, etc.). In the case of molding in the form of tablets, those conventionally known in this field can be widely used as carriers, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate,
Kaolin, crystalline cellulose, excipients such as silicic acid, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binders such as polyvinylpyrroind, Dry starch, sodium alginate, agar, no laminaran, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate,
Disintegrators such as stearic acid monoglyceride, starch and lactose, sucrose, stearin, cocoa butter, disintegration inhibitors such as hydrogenated oil, quaternary ammonium base, absorption promoters such as sodium lauryl sulfate, humectants such as glycerin and starch. , Starch, lactose, kaolin, bentonite, adsorbents such as colloidal silicic acid, purified talc, stearates, boric acid, and lubricants such as polyethylene glycol. Further, the tablet may be a tablet which is coated with a usual coating, if necessary, such as a sugar coating, a gelatin-coated tablet, an enteric coated tablet, a film-coated tablet, a double tablet or a multilayer tablet. When forming into the form of pills, those conventionally known in this field can be widely used as carriers, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, and gum arabic. Examples thereof include tragacanth-free, gelatin, binders such as ethanol, disintegrators such as laminaran and agar. In the case of molding in the form of suppositories, conventionally known carriers can be widely used, and examples thereof include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semisynthetic glycerides. When prepared as an injection, the solution and suspension are preferably sterilized and isotonic with blood, and when formed into the form of these solution, emulsion and suspension, as a diluent All those customary in the field can be used, for example water,
Examples thereof include ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. In this case,
A sufficient amount of salt, glucose or glycerin to prepare an isotonic solution may be contained in the anti-ulcer agent,
Further, a usual solubilizing agent, buffering agent, soothing agent and the like may be added to the therapeutic agent, and if necessary, coloring agents, preservatives, flavors, flavors, sweeteners and other pharmaceutical agents.

The amount of the compound of the present invention to be contained in the anti-ulcer agent using the compound of the present invention is not particularly limited and can be selected within a wide range, but it is usually 1 to 70% by weight, preferably 5 to 50% in the total composition.
% By weight.

The administration method of the anti-ulcer agent using the compound of the present invention is not particularly limited, and it may be administered according to various dosage forms, patient's age, sex and other conditions, degree of disease and the like. For example, tablets, pills, solutions, suspensions, emulsions, granules, and capsules are orally administered. In the case of an injection, it may be administered intravenously alone or in a mixture with a normal replacement fluid such as glucose or amino acid, and if necessary, may be administered intramuscularly, intradermally, subcutaneously or intraperitoneally alone. In the case of suppositories, it will be administered rectally.

The dose of the anti-ulcer agent using the compound of the present invention is appropriately selected depending on the usage, the age of the patient, sex and other conditions, the degree of disease, etc. Usually, the amount of the compound of the present invention is 1 body weight per day.
The dosage is preferably 0.6 to 50 mg per 1 kg, and the active ingredient is preferably contained in the dosage unit form in the range of 10 to 1000 mg.

<Example> Next, the present invention will be described more specifically with reference to formulation examples, examples and test examples.

Formulation Example 1 5- (5-Methoxy-2-benzimidazolyl) -sulfinyl-5,6,7,8-tetrahydroquinoline 150 g Avicel (trade name, manufactured by Asahi Kasei Corporation) 40 g Corn starch 30 g Magnesium stearate 2 g Hydroxypropyl methylcellulose 10 g polyethylene glycol-6000 3 g castor oil 40 g ethanol 40 g After mixing and polishing the active ingredient compound of the present invention, Avicel, corn starch and magnesium stearate, sugar coating 10 mm
Tablet with kine. The obtained tablets are coated with a film coating agent consisting of hydroxypropylmethyl cellulose, polyethylene glycol-6000, castor oil and ethanol to produce film coated tablets.

Formulation Example 2 5- (5-Methoxy-2-benzimidazolyl) -sulfinyl-3-methyl-5,6,7,8-tetrahydroquinoline 150g Citric acid 1.0g Lactose 33.5g Dicalcium phosphate 70.0g Pluronic F-68 30.0g Sodium lauryl sulfate 15.0g Polyvinylpyrrolidone 15.0g Polyethylene glycol (Carbowax 1500) 4.5g Polyethylene glycol (Carbowax 6000) 45.0g Corn starch 30.0g Dry sodium lauryl sulfate 3.0g Dry magnesium stearate 3.0g Ethanol The active ingredient compound, citric acid, lactose, dicalcium phosphate, Pluronic F-68 and sodium lauryl sulfate are mixed.

The above mixture is sieved through a No. 60 screen and wet granulated with an alcoholic solution containing polyvinylpyrrolidone, Carbowax 1500 and 6000. Alcohol is added as needed to make the powder a pasty mass. Add corn starch and continue mixing until uniform particles are formed.
Pass through a No. 10 screen, put in a tray and dry in a 100 degree oven for 12-14 hours. The dry particles are screened through a No. 16 screen, dry sodium lauryl sulfate and dry magnesium stearate are added and mixed and compressed into the desired shape on a tablet machine.

The core is treated with a varnish and sprinkled with talc to prevent moisture absorption. The undercoat layer is coated around the core. Apply varnish a sufficient number of times for internal use. Further subbing layers and smooth coatings are applied to make the tablets completely round and smooth. Color coating is applied until the desired shade is obtained. After drying, the coated tablets are polished into tablets of uniform gloss.

Formulation Example 3 8- (5-methoxy-2-benzimidazolyl) -sulfinyl-5,6,7,8-tetrahydroquinoline 5 g polyethylene glycol (molecular weight: 4000) 0.3 g sodium chloride 0.9 g polyoxyethylene-sorbitan monooleate 0.4 g Sodium metabisulfite 0.1 g Methyl-paraben 0.18 g Propyl-paraben 0.02 g Distilled water for injection 10.0 ml While stirring the parabens, sodium metabisulfite and sodium chloride at 80 ° C into about half of the above distilled water. Dissolve. The obtained solution is cooled to 40 ° C., and the active ingredient compound of the present invention, then polyethylene glycol and polyoxyethylene sorbitan monooleate are dissolved in the solution. Next, distilled water for injection is added to the solution to make a final volume, and the solution is sterilized by sterilizing filtration using an appropriate filter paper to prepare an injection.

Formulation Example 4 4-Allyloxy-8- (2-benzimidazolyl) sulfinyl-3-methyl-5,6,7,8-tetrahydroquinoline 150g Avicel (trade name, manufactured by Asahi Kasei Corporation) 40g Corn starch 30g Magnesium stearate 2g Hydroxypropyl methylcellulose 10 g Polyethylene glycol-6000 3 g Castor oil 40 g Ethanol 40 g The compound of the present invention, Avicel, corn starch and magnesium stearate are mixed and ground, and then tableted with a sugar coated R10 mm kine. The obtained tablets are coated with a film coating agent consisting of hydroxypropylmethyl cellulose, polyethylene glycol-6000, castor oil and ethanol to produce film coated tablets.

Formulation Example 5 4-allyloxy-8- (5,6-dimethyl-2-benzimidazolyl) sulfinyl-3-methyl-5,6,7,8-tetrahydroquinoline 150 g citric acid 1.0 g lactose 33.5 g dicalcium phosphate 70.0 g Pluronic F-68 30.0g Sodium lauryl sulfate 15.0g Polyvinylpyrrolidone 15.0g Polyethylene glycol (Carbowax 1500) 4.5g Polyethylene glycol (Carbowax 6000) 45.0g Corn starch 30.0g Dry sodium lauryl sulfate 3.0g Dry magnesium stearate 3.0g Ethanol An appropriate amount of the compound of the present invention, citric acid, lactose, dicalcium phosphate, Pluronic F-68 and sodium lauryl sulfate are mixed.

The above mixture is sieved through a No. 60 screen and wet granulated with an alcoholic solution containing polyvinylpyrrolidone, Carbowax 1500 and 6000. Alcohol is added as needed to make the powder a pasty mass. Add corn starch and continue mixing until uniform particles are formed.
Pass through a No. 10 screen, place in a tray and dry in a 100 degree oven for 12-14 hours. The dry particles are screened through a No. 16 screen, dry sodium lauryl sulfate and dry magnesium stearate are added and mixed and compressed into the desired shape on a tablet machine.

The core is treated with a varnish and sprinkled with talc to prevent moisture absorption. The undercoat layer is coated around the core. Apply varnish a sufficient number of times for internal use. Further subbing layers and smooth coatings are applied to make the tablets completely round and smooth. Color coating is applied until the desired shade is obtained. After drying, the coated tablets are polished into tablets of uniform gloss.

Formulation Example 6 4-allyloxy-8- (2-benzimidazolyl) sulfinyl-3-methyl-5,6,7,8-tetrahydroquinoline 5 g polyethylene glycol (molecular weight: 4000) 0.3 g sodium chloride 0.9 g polyoxyethylene- Sorbitan monooleate 0.4 g Sodium metabisulfite 0.1 g Methyl-paraben 0.18 g Propyl-paraben 0.02 g Distilled water for injection 10.0 ml While stirring the parabens, sodium metabisulfite and sodium chloride at 80 ° C, about half of the above amount is added. Dissolve in distilled water. The resulting solution is cooled to 40 ° C. and the compound of the present invention, then polyethylene glycol and polyoxyethylene sorbitan monooleate are dissolved in the solution. Next, distilled water for injection is added to the solution to make a final volume, and the solution is sterilized by sterilizing filtration using an appropriate filter paper to prepare an injection.

Hereinafter, reference examples and examples will be shown.

Reference Example 1 3-Methyl-5,6,7,8-tetrahydroquinoline-
Dissolve 7.02 g of N-oxide in acetic anhydride and heat and stir at 90 ° C. for 3.5 hours. After acetic anhydride was distilled off under reduced pressure, an aqueous sodium carbonate solution was added to make it alkaline, and the chloroform layer extracted with chloroform was washed with saturated brine and dried over magnesium sulfate, and then the solvent was distilled off. The obtained residue is purified by silica gel column chromatography (eluent: dichloromethane) to give 3-methyl-8-acetoxy-5,5.
7.18 g of 6,7,8-tetrahydroquinoline are obtained.

NMR (CDCl ₃ ) δ: 1.6-2.3 (m, 4H), 2.10 (s, 3H), 2.30 (s, 3H), 2.6-2.9 (m, 2H), 5.92 (t, 1H), 7.26 (d, 1H), 8.33 (d, 1H) Reference example 2 1.50 g of 3-methyl-8-hydroxy-5,6,7,8-tetrahydroquinoline was dissolved in 20 ml of chloroform, and 1.35 g of phosphorus tribromide was dissolved under ice cooling. A 5 ml solution of chloroform is added dropwise, and the mixture is stirred under ice cooling for 2 hours and at room temperature overnight. 5 in the reaction solution
% Aqueous sodium hydroxide solution, and extracted with chloroform. The chloroform layer is washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off to give 3-methyl-8.
-Bromo-5,6,7,8-tetrahydroquinoline 1.80
get g.

NMR (CDCl ₃ ) δ: 1.8-2.6 (m, 4H), 2.28 (s, 3H), 2.6-3.0 (m, 2H), 5.5-5.6 (m, 1H), 7.23 (d, 1H), 8.30 ( d, 1H) Reference Example 3 4.11 g of 3-methyl-8-acetoxy-5,6,7,8-tetrahydroquinoline was added to 15 m of a 30% aqueous sodium hydroxide solution.
1 and methanol (15 ml), and the mixture is heated with stirring at 65 ° C. for 3 hours. The solution was evaporated, and the obtained residue was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 5: 1), 3-methyl-8-hydroxy-5,6,7,8-tetrahydro. I get 1.50 g of quinoline.

NMR (CDCl ₃ ) δ: 1.5-2.5 (m, 4H), 2.27 (s, 3H), 2.73 (t, 2H), 4.65 (t, 1H), 7.23 (d, 1H), 8.25 (d, 1H) Reference Example 4 3-Methyl-5,6,7,8-tetrahydroquinoline-
7.02 g of N-oxide under ice cooling with methanesulfonyl chloride
9.62 g are added dropwise. Stir under ice cooling for 2 hours, then at 80 ℃
Stir for 3 hours. Water is added to this reaction solution, which is made alkaline with sodium carbonate, and the ether layer extracted with ether is washed with saturated saline and dried over magnesium sulfate. The solvent was evaporated, the obtained residue was purified by silica gel column chromatography (extract; dichloromethane: methanol = 100: 1), and 3-methyl-8-chloro-
2.74 g of 5,6,7,8-tetrahydroquinoline are obtained.

NMR (CDCl ₃ ) δ: 1.70-2.50 (m, 4H), 2.30 (s, 3H), 2.50-3.00 (m, 2H), 5.28 (t, 1H), 7.23 (d, 1H), 8.32 (d, 1H) Reference Example 5 7,8-Dihydro-3-methylquinoline-5 (6H)-
0.97 g of ON was dissolved in 20 ml of methanol, 0.23 g of sodium borohydride was added under ice cooling, and the mixture was stirred at room temperature for 3 hours. Water is added to the reaction solution, methanol is distilled off, the mixture is extracted with chloroform and dried over magnesium sulfate. The solvent was distilled off to give colorless methyl 3-methyl-5-hydroxy-5,6,6.
0.98 g of 7,8-tetrahydroquinoline is obtained.

NMR (CDCl ₃ ) δ: 1.60-2.20 (m, 4H), 2.27 (s, 3H), 2.83 (t, 2H), 3.28 (bs, 1H), 4.7-4.8 (m, 1H), 7.57 (d, 1H), 8.15 (d, 1H) Reference Example 6 In the same manner as in Reference Example 2, using the appropriate starting materials, the following compound was obtained.

3-methyl-5-bromo-5,6,7,8-tetrahydroquinoline _{NMR (CDCl 3) δ: 1.80-2.50} (m, 4H), 2.28 (s, 3H), 2.80-3.20 (m, 2H), 5.43 (t, 1H), 7.43 (bs, 1H), 8.25 (bs, 1H) Reference Example 7 3-Methyl-5,6,7,8-tetrahydroquinoline-
6.5 g of N-oxide was added dropwise to a mixed solution of 7 ml of fuming nitric acid and 7 ml of concentrated sulfuric acid while stirring under ice cooling. 2 hours at 40 ℃,
It is further stirred at 60 ° C. for 2 hours. The reaction solution is poured into cold aqueous sodium hydroxide solution and extracted with chloroform.
The chloroform layer is washed with saturated brine and dried over magnesium sulfate. After distilling off chloroform, the obtained residue was recrystallized from ethyl acetate-ethanol-n-hexane,
5.3 g of 3-methyl-4-nitro-5,6,7,8-tetrahydroquinoline-N-oxide are obtained.

m. p. 140-142 ° C Reference Example 8 2.0 g of 3-methyl-4-nitro 5,6,7,8-tetrahydroquinoline-N-oxide is dissolved in allyl alcohol. To this, add sodium hydroxide 0.6g, 70-8
Stir at 0 ° C. for 3 hours. After completion of the reaction, the reaction solution is concentrated under reduced pressure, water is added to the residue, and the mixture is extracted with chloroform. The chloroform layer is washed with saturated brine and dried over magnesium sulfate. Chloroform was distilled off to obtain 1.4 g of brown oily 4-allyloxy-3-methyl-5,6,7,8-tetrahydroquinoline-N-oxide.

NMR (CDCl ₃ ) δ: 1.50-2.10 (m, 4H), 2.21 (s, 3H), 2.80 (t, 2H), 2.89 (t, 2H), 4.00-4.50 (m, 2H), 4.90-5.50 ( m, 2H), 5.80-6.30 (m, 1H), 8.00 (s, 1H), Reference Example 9 4-allyloxy-3-methyl-5,6,7,8-tetrahydroquinoline-n-oxide anhydrous in 4.8 g Add 50 ml of acetic acid and stir at 90 ° C. for 5 hours. After completion of the reaction, acetic anhydride is concentrated under reduced pressure, water is added to the obtained residue, and the mixture is extracted with chloroform. The chloroform layer is washed with aqueous sodium hydroxide solution and saturated saline, and dried over magnesium sulfate. Chloroform was distilled off, and brown oily 8-acetoxy-4-allyloxy-3-methyl-5,6,7,8-
5.0 g of tetrahydroquinoline are obtained.

NMR (CDCl ₃ ) δ: 1.70-2.20 (m, 4H), 2.25 (s, 3H), 2.50-3.00 (m, 2H), 4.30-4.50 (m, 2H), 5.20-5.
60 (m, 2H), 5.91 (t, 1H), 5.80-6.40 (m, 1H), 8.30 (s, 1H) Reference Example 10 8-acetoxy-4-allyloxy-3-methyl-5,
5.0 g of 6,7,8-tetrahydroquinoline was added to methanol 20
Dissolve in ml. Add 2.3 g of sodium hydroxide to 20 ml of water.
Add the solution dissolved in and heat to reflux for 1 hour. After completion of the reaction, methanol was distilled off, water was added to the obtained residue,
Extract with chloroform. The chloroform layer is washed with saturated saline and then dried over magnesium sulfate. Chloroform was distilled off to obtain 3.5 g of brown oily 4-allyloxy-8-hydroxy-3-methyl-5,6,7,8-tetrahydroquinoline.

NMR (CDCl ₃ ) δ: 1.50-2.50 (m, 4H), 2.21 (s, 3H), 2.73 (t, 2H), 4.30-4.50 (m, 2H), 4.67 (t, 1H),
5.10-5.60 (m, 2H), 5.80-6.30 (m, 1H), 8.21 (s, 1H) Reference Example 11 4-allyloxy-8-hydroxy-3-methyl-5,
Chloroform of 3.5 g of 6,7,8-tetrahydroquinoline
It is dissolved in 40 ml, and a solution of 2.8 g of phosphorus tribromide in 5 ml of chloroform is added dropwise thereto while stirring with ice cooling. The mixture is stirred under ice cooling for 2 hours and further at room temperature for 2 hours. The reaction solution is poured into cold aqueous sodium hydroxide solution and extracted with chloroform. The chloroform extract is washed with saturated saline and dried over magnesium sulfate. Chloroform was distilled off, and the obtained residue was purified by silica gel column chromatography (eluent; methylene chloride: methanol = 100: 1) to give 4-allyloxy-8-bromo-3-methyl-5,6,7,8. -1.3 g of tetrahydroquinoline are obtained.

NMR (CDCl ₃ ) δ: 1.60-3.20 (m, 6H), 2.23 (s, 3H), 4.30-4.50 (m, 2H), 5.20-5.60 (m, 3H), 5.80-6.
30 (m, 1H), 8.29 (s, 1H) Example 1 2.80 g of sodium hydroxide in 15 ml of water and 200 ml of methanol
Was dissolved in the solution, 10.63 g of 2-mercapto-5-methoxybenzimidazole was added thereto, and the mixture was heated with stirring at 55 ° C. for 30 minutes. Next, 3-methyl-8-bromo-5,6,7,8-
Add 13.33 g of tetrahydroquinoline and heat and stir for 2.5 hours. After completion of the reaction, the solvent is distilled off under reduced pressure, a small amount of 30% aqueous sodium hydroxide solution is added to the residue, and the mixture is extracted with chloroform. The chloroform layer is washed with saturated brine and dried over magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; dichloromethane: methanol = 100: 1) to give colorless caramelized 3-methyl-8- (5-methoxy-2-benzimidazolyl) thio-5,6. 18.80 g of 7,8-tetrahydroquinoline are obtained.

NMR (CDCl ₃ ) δ: 1.60-2.00 (m, 2H), 2.00-2.40 (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) Using appropriate starting materials in the same manner as in Example 1. Thus, the compound of the general formula (1a) shown in the following table is obtained.

1) NMR (CDCl ₃ ) δ: 1.50-2.10 (m, 2H), 2.10-2.50 (m, 2H), 2.50-3.00 (m, 2H), 3.80 (s, 3H), 4.90 (t, 1H), 6.70- 7.60 (m, 5H), 8.33 (dd, 1H) 2) NMR (CDCl ₃ ) δ: 1.70-2.20 (m, 2H), 2.20-2.50 (m, 2H), 2.83 (t, 2H), 4.90 (t, 1H), 7.00-7.70 (m, 4H), 7.80 (bs, 1H), 8.47 (dd, 1H) 3) NMR (CDCl ₃ ) δ: 1.70-2.20 (m, 2H), 2.20-2.60 ( m, 2H), 2.47 (s, 3H), 2.87 (t, 2H), 4.77 (t, 1H), 6.90-7.70 (m, 5H), 8.50 (dd, 1H), 4) NMR (CDCl ₃ ) δ : 1.70-2.10 (m, 2H), 2.20-2.50 (m, 2H), 2.86 (t, 2H), 4.80 (t, 1H), 7.00-7.70 (m, 5H), 8.44 (dd, 1H) 5) NMR (CDCl ₃ ) δ: 1.60-2.20 (m, 2H), 2.20-2.60 (m, 2H), 2.30 (s, 3H), 2.47 (s, 3H), 2.80 (t, 2H), 4.77 (t, 1H), 7.00 (dd, 1H), 7.30-7.60 (m, 3H), 8.30 (d, 1H) 6) NMR (CDCl ₃ ) δ: 1.60-2.20 (m, 2H), 2.20-2.60 (m, 2H ), 2.37 (s, 3H), 2.67 (s, 3H), 2.87 (t, 2H), 4.83 (t, 1H), 7.37 (d, 1H), 7.57 (d, 1H), 7.90 (dd, 1H) , 8.20 (d, 1H), 8.33 (d, 1H) 7) NMR (CDCl ₃ ) δ: 1.70-2.50 (m, 4H), 2.27 (s, 3H), 2.50-2.80 (m, 2H), 3.83 ( s, 3H), 4.73 (t, 1H), 6.80 (dd, 1H), 6.90-7.10 (m, 2H), 7.40 (d, 1H), 8.33 (d, 1H) 8) NMR (CDCl ₃ ) δ: 1.70-2.10 (m, 2H), 2.10-2.40 (m, 2H), 2.57 (s, 3H), 2.73 (t, 2H), 3.82 (s, 3H), 4.70 (t, 1H), 6.70 -7.10 (m, 3H), 7.20-7.50 (m, 2H) 9) NMR (CDCl ₃ ) δ: 1.60-2.20 (m, 2H), 2.20-2.50 (m, 2H), 2.50-3.10 (m, 2H) ), 3.83 (s, 3H), 3.90 (s, 3H), 4.70 (t, 1H), 6.50-6.90 (m, 2H), 7.03 (bs, 1H), 7.43 (d, 1H), 8.40 (d, 1H) 10) NMR (CDCl ₃ ) δ: 1.70-2.10 (m, 2H), 2.10-2.40 (m, 2H), 2.40-2.80 (m, 2H), 3.87 (s, 3H), 4.87 (t, 1H ), 6.97 (d, 1H), 7.33 (dd, 1H), 7.53 (d, 1H), 7.77 (bs, 1H), 8.30 (d, 1H) 11) NMR (CDCl ₃ ) δ: 1.70-2.10 (m , 2H), 2.20-2.50 (m, 2H), 2.35 (s, 3H), 2.77 (t, 2H), 4.54 (t, 1H), 6.82 (dd, 1H), 7.05 (d, 1H), 7.33 ( s, 1H), 7.46 (d, 1H) 12) NMR (CDCl ₃ ) δ: 1.70-2.10 (m, 2H), 2.20-2.50 (m, 2H), 2.27 (s, 3H), 2.73 (t, 2H ), 4.93 (t, 1H), 7.20- 7.60 (m, 3H), 7.77 (bs, 1H), 8.23 (d, 1H) 13) NMR (CDCl ₃ ) δ: 1.80-2.20 (m, 2H), 2.20 -2.50 (m, 2H), 2.62 (s, 3H), 2.87 (t, 2H), 4.78 (t, 1H), 6.90-7.60 (m, 5H), 8.48 (dd, 1H) 14) NMR (CDCl ₃ ) δ: 1.70-2.10 (m, 2H), 2.20-2.50 (m, 2H), 2.85 (t, 2H), 4.82 (t, 1H), 6.75-7.55 (m, 5H), 8.47 (dd , 1H) 15) NMR (CDCl ₃ ) δ: 1.60-2.40 (m, 4H), 2.13 (s, 3H), 2.70-3.10 (m, 2H), 3.83 (s, 3H), 5.10-5.30 (m, 1H), 6.87 (dd, 2H), 7.10-7.50 (m, 2H), 8.20 (d, 1H), 12.00 (brod, 1H) 16) NMR (CDCl ₃ ) δ: 1.60-2.50 (m, 4H), 2.22 (s, 3H), 2.70-3.10 (m, 2H), 5.30-5.50 (m, 1H), 7.30-8.00 (m, 4H), 8.27 (d, 1H), 17) NMR (CDCl ₃ ) δ: 1.70-2.10 (m, 2H), 2.10-2.40 (m, 2H), 2.24 (s, 3H), 2.60-2.90 (m, 2H), 3.78 (s, 3H), 4.80 (t, 1H), 6.70- 7.50 (m, 3H), 8.25 (s, 1H), 18) NMR (CDCl ₃ ) δ: 1.70-2.10 (m, 2H), 2.10-2.40 (m, 2H), 2.23 (s, 3H), 2.60- 2.90 (m, 2H), 3.77 (s, 3H), 4.80 (t, 1H), 7.00-7.60 (m, 4H), 8.27 (s, 1H) 19) NMR (CDCl ₃ ) δ: 1.50 (t, 3H) ), 1.80-2.00 (m, 2H), 2.10-2.70 (m, 2H), 2.74 (t, 2H), 4.13 (q, 2H), 4.88 (t, 1H), 7.00-7.40 (m, 4H), 8.33 (dd, 1H) 20) NMR (CDCl ₃ ) δ: 1.70-2.10 (m, 2H), 2.10-2.50 (m, 2H), 2.82 (t, 2H), 4.92 (t, 1H), 7.00-7.50 (m, 4H), 8.42 (dd, 1H) 21) NMR (CDCl ₃ ) δ: 1.70-2.10 (m, 2H), 2.10-2.60 (m, 2H), 2.27 (s, 3H), 2.75 (t, 2H), 4.82 (t, 1H), 6.70-7.60 (m, 3H), 7.24 (d, 1H), 8.25 (d, 1H) 22) NMR (CDCl ₃ ) δ : 1.70-2.10 (m, 2H), 2.10-2.50 (m, 2H), 2.25 (s, 3H), 2.60-2.90 (m, 2H), 3.80 (s, 3H), 4.84 (t, 1H), 7.53 (s, 2H), 8.23 (s, 1H) 23) NMR (CDCl ₃ ) δ: 1.43 (t, 3H), 1.70-2.10 (m, 2H), 2.10-2.50 (m, 2H), 2.26 (s, 3H), 2.60-2.90 (m, 2H), 3.80 (s, 3H), 4.08 (q, 2H), 4.76 (t, 1H), 7.10 (d, 1H), 7.20 (d, 1H), 8.27 (s , 1H) 24) NMR (CDCl ₃ ) δ: 1.70-2.10 (m, 2H), 2.10-2.50 (m, 2H), 2.26 (s, 3H), 2.60-2.90 (m, 2H), 3.80 (s, 3H), 4.82 (t, 1H), 7.20 (d, 1H), 7.20 (d, 1H), 8.25 (s, 1H) 25) NMR (CDCl ₃ ) δ: 1.70-2.10 (m, 2H), 2.27 ( s, 3H), 2.10-2.50 (m, 2H), 2.60-2.90 (m, 2H), 3.80 (s, 3H), 3.88 (s, 3H), 4.78 (t, 1H), 7.13 (d, 1H) , 7.26 (d, 1H), 8.28 (s, 1H) 26) NMR (CDCl ₃ ) δ: 1.70-2.10 (m, 2H), 2.27 (s, 3H), 2.10-2.40 (m, 2H), 2.60- 2.90 (m, 2H), 3.80 (s, 6H), 4.75 (t, 1H), 6.78 (dd, 1H), 7.02 (d, 1H), 7.42 (d, 1H), 8.28 (s, 1H) 27) NMR (CDCl ₃ ) δ: 1.70-2.10 (m, 2H), 2.27 (s, 3H), 2.10-2.50 (m, 2H), 2.60-2.90 (m, 2H), 3.80 (s, 3H), 4.78 ( t, 1H), 7.08 (dd, 1H), 7.42 (d, 1H), 7.48 (d, 1H), 8.27 (s, 1H) 28) NMR (CDCl ₃ ) δ: 1.70-2.10 (m, 2H), 2 .20-2.50 (m, 2H), 2.50-3.00 (m, 2H), 3.90 (s, 3H), 4.72 (t, 1H), 6.72 (d, 1H), 6.70-7.60 (m, 3H), 8.39 (d, 1H) 29) NMR (CDCl ₃ ) δ: 1.70-2.10 (m, 2H), 2.27 (s, 3H), 2.32 (s, 6H), 2.10-2.40 (m, 2H), 2.73 (t, 2H), 4.76 (t, 1H), 7.20 (d, 1H), 7.30 (s, 2H), 8.26 (d, 1H) 30) NMR (DMSO-d ₆ ) δ: 1.5-2.2 (m, 4H), 2.23 (s, 3H), 2.70 (t, 2H), 3.0-4.1 (m, 3H), 6.73 (dd, 1H), 6.97 (d, 1H), 7.30 (s, 1H), 7.33 (d, 1H) , 8.27 (dd, 1H) Example 44 2-chloro-5-methoxybenzimidazole 0.55 g,
0.2 g of thiourea and 10 ml of ethanol are heated under reflux for 2 hours. To this, 3-methyl-8-bromo-5,6,7,
0.5 g of 8-tetrahydroquinoline and sodium hydroxide
Add 5 g of 0.3 g of an aqueous solution and heat to reflux for 5 hours. After completion of the reaction, ethanol was distilled off, water was added to the obtained residue,
Extract with black form. After drying over magnesium sulfate, chloroform is distilled off. The obtained residue was purified by silica gel column chromatography (eluent; dichloromethane: methanol = 100: 1) to give colorless caramelized 8- (5
0.5 g of -methoxy-2-benzimidazolyl) thio-3-methyl-5,6,7,8-tetrahydroquinoline are obtained.

NMR (CDCl ₃ ) δ: 1.60-2.00 (m, 2H), 2.00-2.40 (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) In the same manner as in Example 44, suitable starting materials were prepared. Use to obtain the compounds of Examples 2-43 above.

Example 45 2-Chloro-8-[(5-methoxy-2-benzimidazolyl) thio] -5,6,7,8-tetrahydroquinoline (0.8 g) was added with 20% hydrochloric acid (20 ml), and the mixture was heated at 70-80 ° C for 1 hour. Stir. After cooling, the precipitated crystals were collected by filtration and recrystallized from ethanol to give white powdery 2-hydroxy-8-[(5-methoxy-2-benzimidazolyl) thio] -5,6,7,
0.4 g of 8-tetrahydroquinoline is obtained.

mp.217-218 ° C. (decomposition) Example 46 2-mercaptobenzimidazole 0.5 g methanol 30
Dissolve in ml. Add 0.2 g of sodium hydroxide to 10 ml of water.
And 4-allyloxy-8-bromo-
3-Methyl-5,6,7,8-tetrahydroquinoline 0.
Add 6 g and heat to reflux for 2 hours. After distilling off the methanol,
Water is added to the residue and extracted with chloroform. After drying over magnesium sulfate, chloroform was distilled off, and the resulting residue was subjected to silica gel column chromatography (after elution;
Purification with methylene chloride: methanol = 100: 1) gives 0.7 g of 4-allyloxy-8- (2-benzimidazolyl) thio-3-methyl-5,6,7,8-tetrahydroquinoline as a light brown oil.

NMR (CDCl ₃ ) δ: 1.70-2.10 (m, 2H), 2.10-2.50 (m, 2H), 2.29
(s, 3H), 2.60-3.10 (m, 2H), 4.30-4.50 (m, 2H), 4.77 (t, 1H),
5.20-5.60 (m, 2H), 5.80-6.50 (m, 1H), 7.10-7.30 (m, 2H), 7.
40-7.70 (m, 2H), 8.33 (s, 1H) In the same manner as in Example 46, using appropriate starting materials, the compound of the general formula (1a) shown in the following table is obtained.

1) NMR (CDCl ₃ ) δ: 1.50-2.20 (m, 2H), 2.20-2.50 (m, 2H), 2.30 (s, 3H), 2.60-3.00 (m, 2H), 4.30-4.50 (m, 2H) ), 4.73 (t, 1H), 5.20-5.60 (m, 2H), 5.80-6.40 ((m, 1H), 6.70-
7.10 (m, 1H), 7.10-7.60 (m, 2H), 8.33 (s, 1H) 2) NMR (CDCl ₃ ) δ: 1.70-2.10 (m, 2H), 2.10-2.50 (m, 2H), 2.27 (s, 3H), 2.33 (s, 6H), 2.60-3.10 (m,
2H), 4.30-4.50 (m, 2H), 4.70 (t, 1H), 5.20-5.60 (m, 2H), 5.8
0-6.40 (m, 1H), 7.33 (s, 2H), 8.33 (s, 1H) 3) NMR (CDCl ₃ ) δ: 1.60-2.10 (m, 2H), 2.10-2.50 (m, 2H), 2.30 (s, 3H), 2.63 (s, 3H), 2.60-3.10 (m, 2H), 4.30-4.50 (m, 2H), 4.73 (t,
1H), 5.20-5.60 (m, 2H), 5.70-6.50 (m, 1H), 6.90-7.30 (m, 2
H), 7.30-7.60 (m, 1H), 8.33 (s, 1H) 4) NMR (CDCl ₃ ) δ: 1.60-2.10 (m, 2H), 2.10-2.50 (m, 2H), 2.30 (s, 3H) ), 2.60-3.10 (m, 2H), 3.92 (s,
3H), 4.30-4.50 (m, 2H), 4.87 (t, 1H), 5.20-5.60 (m, 2H), 5.8
0-6.40 (m, 1H), 7.10 (d, 1H), 7.30 (d, 1H), 8.33 (s, 1H) 5) NMR (CDCl ₃ ) δ: 1.60-2.10 (m, 2H), 2.10-2.50 (m, 2H), 2.30 (s, 3H), 2.60-3.10 (m, 2H), 4.40-4.50 (m, 2H), 4.38 (t, 1H), 5.20-5.60 (m, 2H), 5.80-6.40 (m, 1H), 7.10-7.
50 (m, 2H), 8.30 (s, 1H) 6) NMR (CDCl ₃ ) δ: 1.80-2.04 (m, 2H), 2.16-2.48 (m, 2H), 2.31 (s, 3H), 2.60-3.06 (m, 2H), 3.46 (s, 3H), 3.66-3.80 (m, 2H), 4.00-4.
14 (m, 2H), 4.76 (t, 1H), 6.94 (dt, 1H), 7.24 (dd, 1H), 7.46 (d
d, 1H), 8.32 (s, 1H) 7) NMR (CDCl ₃ ) δ: 1.80-2.04 (m, 2H), 2.20-2.44 (m, 2H), 2.32 (s, 3H), 2.55 (t, 1H) ), 2.64-3.12 (m, 2H), 4.65 (d, 2H), 4.80 (t, 1H),
7.12-7.28 (m, 2H), 7.48-7.64 (m, 2H), 8.34 (s, 1H) 8) NMR (CDCl ₃ ) δ: 1.80-2.07 (m, 2H), 2.23-2.50 (m, 2H) , 2.31 (s, 3H), 2.56 (t, 1H), 2.63-3.10 (m, 2H), 4.64 (d, 2H), 4.81 (t, 1H),
6.91 (dt, 1H), 7.25 (dd, 1H), 7.43 (dd, 1H), 8.32 (s, 1H) 9) NMR (CDCl ₃ ) δ: 1.71-1.94 (m, 2H), 2.14-2.37 (m , 2H), 2.
25 (s, 3H), 2.30 (s, 6H), 2.54 (t, 1H), 2.57-3.00 (m, 2H), 4.5
5 (d, 2H), 4.80 (t, 1H), 7.30 (s, 2H), 8.27 (s, 1H) 10) NMR (CDCl ₃ ) δ: 1.80-2.00 (m, 2H), 2.20-2.48 (m , 2H),
2.30 (s, 3H), 2.60-3.04 (m, 2H), 3.45 (s, 3H), 3.64-3.80 (m,
2H), 3.96-4.20 (m, 2H), 4.76 (t, 1H), 7.08-7.28 (m, 2H), 7.4
4-7.68 (brs, 2H), 8.33 (s, 1H) 11) NMR (CDCl ₃ ) δ: 1.70-2.10 (m, 2H), 2.10-2.50 (m, 2H),
2.30 (s, 3H), 2.70-3.00 (m, 2H), 4.40-4.50 (m, 2H), 4.77 (t,
1H), 5.20-5.60 (m, 2H), 5.80-6.30 (d, 1H), 7.60 (s, 2H), 8.3
0 (s, 1H) 12) NMR (CDCl ₃ ) δ: 1.72-2.16 (m, 2H), 2.24-2.48 (m, 2H),
2.34 (s, 3H), 2.57 (t, 1H), 2.60-3.08 (m, 2H), 4.68 (d, 2H),
4.80 (t, 1H), 7.63 (s, 2H), 8.33 (s, 1H) 13) NMR (CDCl ₃ ) δ: 1.70-2.10 (m, 2H), 2.20-2.50 (m, 2H),
2.50-2.90 (m, 3H), 4.60-4.90 (m, 2H), 6.60-7.50 (m, 3H), 6.
83 (d, 1H), 8.38 (d, 1H) Example 60 2-chlorobenzimidazole 0.46 g, thiourea 0.2 g
And 10 ml of ethanol are heated to reflux for 2 hours. to this,
4-allyloxy-8-bromo-3-methyl-5,6,6
0.68 g of 7,8-tetrahydroquinoline and 0.3 g of sodium hydroxide are added, and the mixture is heated under reflux for 5 hours. After the reaction,
Ethanol is distilled off, water is added to the obtained residue, and the mixture is extracted with chloroform. After drying over magnesium sulfate, chloroform is distilled off. The obtained residue was purified by silica gel column chromatography (eluent; methylene chloride: methanol = 100: 1) to give 4-allyloxy-8- (2-benzimidazolyl) thio-3-methyl-5 as a light brown oil. 0.5 g of 6,7,8-tetrahydroquinoline is obtained.

NMR (CDCl ₃ ) δ: 1.70-2.10 (m, 2H), 2.10-2.50 (m, 2H), 2.29
(s, 3H), 2.60-3.10 (m, 2H), 4.30-4.50 (m, 2H), 4.77 (t, 1H),
5.20-5.60 (m, 2H), 5.80-6.50 (m, 1H), 7.10-7.30 (m, 2H), 7.
40-7.70 (m, 2H), 8.33 (s, 1H) In the same manner as in Example 60, using appropriate starting materials, the compounds of the above Examples 47-59 are obtained.

Example 61 3-Methyl-8- (5-methoxy-2-benzimidazolyl) thio-5,6,7,8-tetrahydroquinoline 4.
Dissolve 00 g in 80 ml of dichloromethane, and slowly add a solution of 2.37 g of metachloroperbenzoic acid (85%) in 30 ml of dichloromethane at -10 ° C. After dripping, 15 at -10 ° to -4 ° C
It is stirred for a minute, water is added to the reaction solution, made alkaline with sodium carbonate, and extracted with diethyl ether. The ether layer is washed with saturated brine and dried over magnesium sulfate, and the solvent is evaporated. Recrystallization from dichloromethane-diethyl ether gave white powdery 3-methyl-8- (5-methoxy-2-benzimidazolyl) sulfinyl-5,6,6.
2.30 g of 7,8-tetrahydroquinoline are obtained.

mp.114-114.5 ° C (decomposition) In the same manner as in Example 61 above, using appropriate starting materials, compounds of the general formula (1b) shown in the following table are obtained.

1) NMR (CDCl ₃ ) δ: 1.70-2.10 (m, 2H), 2.10-2.60 (m, 2H), 2.70 (t, 2H), 4.90 (t, 1H), 6.90-7.70 (m, 4H), 7.83 (bs, 1H), 8.23 (dd, 1H) 2) NMR (CDCl ₃ ) δ: 1.70-2.20 (m, 2H), 2.20-2.50 (m, 2H), 2.20 (s, 3H), 2.70 (t , 2H), 4.83 (t, 1H), 7.10-7.50 (m, 2H), 7.20-7.80 (m, 2H), 8.18 (d, 1H) 3) NMR (CDCl ₃ ) δ: 1.70-2.60 (m, 4H), 2.20 (s, 3H), 2.47 (s, 3H), 2.70 (t, 2H), 4.80 (t, 1H), 7.20-7.30 (m, 2H), 7.40 (bs, 1H), 7.53 (d , 1H), 8.20 (d, 1H) 4) NMR (CDCl ₃ ) δ: 1.70-2.10 (m, 2H), 2.10-2.50 (m, 2H), 2.20 (s, 3H), 2.50-2.90 (m, 2H), 2.67 (s, 3H), 4.87 (t, 1H), 7.17 (bs, 1H), 7.63 (d, 1H), 7.97 (dd, 1H), 8.17 (d, 1H), 8.28 (d, 1H) ) 5) NMR (CDCl ₃ ) δ: 1.70-3.00 (m, 6H), 2.10 (s, 3H), 3.83 (s, 3H), 4.80 (t, 1H), 6.70-7.10 (m, 3H), 7.30 -7.70 (m, 1H), 8.28 (d, 1H) 6) NMR (CDCl ₃ ) δ: 1.60-3.00 (m, 4H), 2.33 (s, 3H), 2.70 (t, 2H), 3.87 (s, 3H), 4.73 (t, 1H), 6.80-7.10 (m, 3H), 7.10-7.30 (m, 1H), 7.53 (dd, 1H) 7) NMR (CDCl ₃ ) δ: 1.50-3.00 (m, 6H) ), 3.84 (s, 3H), 3.87 (s, 3H), 4.78 (t, 1H), 6.60-6.80 (m, 1H), 6.90-7.20 (m, 2H), 7.40-7.80 (m, 1H), 8.41 (d, 1H) 8) NMR (CDCl ₃ ) δ: 1.60-2.60 (m, 4H), 2.12 (s, 3H), 2.67 (t, 2H), 4.87 (t, 1H), 7.00 (d, 1H) ), 7.50 (dd, 1H), 7.66 (d, 1H), 8.85 (bs, 1H), 8.04 (d, 1H) 9) NMR (CDCl ₃ ) δ: 1.60-2.50 (m, 4H), 2.27 (s , 3H), 2.70-3.10 (m, 2H), 4.50-5.00 (m, 1H), 6.80-7.70 (m, 4H) 8.30 (dd, 1H) 10) NMR (CDCl ₃ ) δ: 1.60-2.70 (m , 4H), 2.27 (s, 3H), 2.70-3.10 (m, 2H), 4.50-4.80 (m, 1H), 6.75 (d, 1H) 7.57 (bs, 1H) 7.60 (d, 1H), 7.93 ( bs, 1H), 8.30 (dd, 1H) Example 104 4-allyloxy-8- (2-benzimidazolyl) thio-3-methyl-5,6,7,8-tetrahydroquinoline 0.7 g was dissolved in methylene chloride 30 ml. And this is -50-
After cooling to 60 ° C., a solution of 0.43 g of 80% metachloroperbenzoic acid in 10 ml of methylene chloride was added dropwise, and the mixture was stirred at the same temperature for 20 minutes. After completion of the reaction, the reaction solution is washed with an aqueous sodium carbonate solution and dried over magnesium sulfate. Methylene chloride was distilled off under reduced pressure, the obtained residue was recrystallized from diethyl ether, and 0.4 g of 4-allyloxy-8- (2-benzimidazolyl) sulfinyl-3-methyl-5,6,7,8-
Obtain tetrahydroquinoline.

mp.100 to 102 ° C. (decomposition) white powder form In the same manner as in Example 104, using appropriate starting materials,
The compounds of general formula (1b) shown in the table below are obtained.

Pharmacological test 1 H ⁺ K ⁺ ATPase (adenosine triphosphatase) (protein amount: 10 μg) prepared from pig stomach containing 2 mM piperazine N, N′-bis (2-ethanesulfonic acid) Pipes-Tris [2-amino] -2- (Hydroxymethyl) -1,3-propanediol buffer (Pipes-Trisbuf
fer) (pH 6.1) and leave at room temperature. Dissolve the test compound in dimethylformamide, add it to the above H ⁺ + K ⁺ ATPase buffer solution to a final concentration of 1%, and mix at room temperature for 3
Let react for 0 minutes. Next, 1 ml of 75 mM Pipes-Tris buffer (pH 7.4) (4 mM MgCl ₂ , 4 mM Na ₂ ATP, and 20 mM KC) was added.
l) and 1 ml of 75 mM Pipes-Tris buffer (pH 7.
4) (containing 4 mM MgCl ₂ and 4 mM Na ₂ ATP) separately,
Make two kinds of samples and incubate them at 37 ℃ for 30 minutes. Terminate the reaction by adding 0.3 ml of 40% trichloroacetic acid to each. Then centrifuge for 10 minutes (3,000 rpm),
The supernatant is taken and the produced inorganic phosphoric acid is treated with Fiske and Subb
arow's method [J. Biol.Chem.vol.66, 375 (1925)]. Pipes containing 20mM KCl-Pipes containing no 20mM KCl depending on the amount of inorganic phosphate obtained from Tris buffer
The value obtained by subtracting the amount of inorganic phosphate obtained from the Tris buffer was converted into unit protein and per unit time and expressed as the enzyme activity value. The inhibition value (%) of each dose was determined from the control value and the enzyme activity value at each dose, and the IC ₅₀ (the dose of each test compound that inhibits ₅₀ %) was determined from the obtained inhibition value (%).

Test compound 1.8- (2-benzimidazolyl) sulfinyl-
5,6,7,8-Tetrahydroquinoline 2.4-Methyl-8- (5-methoxy-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline 3.2-Methyl-8- (5 -Methoxy-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline 4.3-Methyl-8- (2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline 5.3- Methyl-8- (5-methyl-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline 6.8- (5-methyl-2-benzimidazolyl) sulfinyl-5,6,7,8- Tetrahydroquinoline 7.3-methyl-8- (5-acetyl-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquino 8.3-Methyl-8- (5,6-dimethoxy-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline 9.8- (5-chloro-2-benzimidazolyl) sulfinyl-5 , 6,7,8-Tetrahydroquinoline 10.2-chloro-8- (5-methoxy-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline 11.2-chloro-3-methyl-8 -(5-methoxy-2
-Benzimidazolyl) sulfinyl-5,6,7,8
-Tetrahydroquinoline 12.8- (5-methoxy-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline 13.4-methoxy-8- (5-methoxy-2-benzimidazolyl) sulfinyl-5 , 6,7,8-Tetrahydroquinoline 14.4-methoxy-8- (5-trifluoromethyl-2
-Benzimidazolyl) sulfinyl-5,6,7,8
-Tetrahydroquinoline 15.3-Methyl-8- (5-methoxy-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline 16.3-Methyl-8- (5-trifluoromethyl-2-
Benzimidazolyl) sulfinyl-5,6,7,8-
Tetrahydroquinoline 17.8- (5-trifluoromethyl-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline 18.2-hydroxy-8- (5-methoxy-2-benzimidazolyl) sulfinyl- 5,6,7,8-Tetrahydroquinoline 19.8- (5,6-dimethoxy-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline 20.8- (5-nitro-2-benz Imidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline 21.8- (5-fluoro-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline 22.8- (4-methyl-2) -Benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline 23.3-methyl-4-methoxy-8- (5- Fluoro-
2-benzimidazolyl) sulfinyl-5,6,7,
8-Tetrahydroquinoline 24.3-Methyl-4-methoxy-8- (2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline 25.8- (5,6-dichloro-2-benzimidazolyl) Sulfinyl-5,6,7,8-tetrahydroquinoline 26.8- (5-ethoxy-6-fluoro-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline 27.3-methyl-4- Methoxy-8- (5,6-dimethyl-2-benzimidazolyl) sulfinyl-5,6
7,8-Tetrahydroquinoline 28.3-methyl-5- (5-trifluoromethyl-2-
Benzimidazolyl) sulfinyl-5,6,7,8-
Tetrahydroquinoline 29.3-methyl-8- (5-fluoro-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline 30.3-methyl-4-methoxy-8- (5,6-dichloro -2-benzimidazolyl) sulfinyl-5,6
7,8-Tetrahydroquinoline 31.3-methyl-4-methoxy-8- (5-ethoxy-
6-Fluoro-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline 32.3-methyl-4-methoxy-8- (5,6-difluoro-2-benzimidazolyl) sulfinyl-5
6,7,8-Tetrahydroquinoline 33.3-methyl-5 (5-trifluoromethyl-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline 34.3-methyl-4-methoxy-8 -(5-fluoro-
6-Methoxy-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline 35.3-methyl-4-methoxy-8- (5-methoxy-
2-benzimidazolyl) sulfinyl-5,6,7,
8-Tetrahydroquinoline 36.3-Methyl-4-methoxy-8- (5-chloro-2
-Benzimidazolyl) sulfinyl-5,6,7,8
-Tetrahydroquinoline 37.4-methoxy-8- (5-fluoro-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline 38.3-methyl-8- (5,6-dichloro-2- Benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline 39.3-methyl-8- (5,6-dimethyl-2-benzimidazolyl) sulfinyl-5,6,7,8-tetrahydroquinoline 40.4 -Allyloxy-8- (2-benzimidazolyl) sulfinyl-3-methyl-5,6,7,8-tetrahydroquinoline 41.4-allyloxy-8- (5,6-difluoro-2)
-Benzimidazolyl) sulfinyl-3-methyl-
5,6,7,8-Tetrahydroquinoline 42.8- (5-Fluoro-2-benzimidazolyl) sulfinyl-3-methyl-4-propargyloxy-
5,6,7,8-Tetrahydroquinoline 43.4-allyloxy-8- (5,6-dimethyl-2-
Benzimidazolyl) sulfinyl-3-methyl-5,
6,7,8-Tetrahydroquinoline 44.4-allyloxy-8- (5,6-dichloro-2-
Benzimidazolyl) sulfinyl-3-methyl-5,
6,7,8-Tetrahydroquinoline 45.8- (5,6-Dimethyl-2-benzimidazolyl) sulfinyl-3-methyl-4-propargyloxy-5,6,7,8-tetrahydroquinoline 46.8- ( 2-benzimidazolyl) sulfinyl-3
-Methyl-4-propargyloxy-5,6,7,8-
Tetrahydroquinoline 47.8- (5,6-dichloro-2-benzimidazolyl) sulfinyl-3-methyl-4-propargyloxy-5,6,7,8-tetrahydroquinoline 48.8- (2-benzimidazolyl) sulfinyl -4
-(2-Methoxyethoxy) -3-methyl-5,6,
7,8-Tetrahydroquinoline 49.8- (5-Fluoro-2-benzimidazolyl) sulfinyl-4- (2-methoxyethoxy) -3-methyl-5,6,7,8-tetrahydroquinoline 50.4-allyloxy -8- (5-Fluoro-2-benzimidazolyl) sulfinyl-3-methyl-5,6
The results of 7,8-tetrahydroquinoline test are shown in the following table.

Pharmacological test 2 Male Witer rats were fasted for 24 hours, and then urethane (1.5 g
/ Kg SC) Under anesthesia, the pylorus was ligated and a gastric perfusion cannula was inserted into the stomach. Gastric acid secretion was measured by perfusing the stomach with physiological saline through an oral catheter and titrating the pH and total acidity of the perfusate. As an acid secretion stimulant, histamine dihydrochloride 1 mg / kg / hr was continuously infused through the femoral vein to enhance acid secretion, and then the effects of various compounds were examined. The test compound was dissolved in dimethylformamide, and each dose (up to 30 mg / kg) was intraduodenally administered.

The acid secretion before administration of the test compound was used as a control, and the percent inhibition of acid secretion was calculated. The ED ₅₀ value was calculated by the probit method from the value of percent inhibition for each dose.

The test results are shown in the following table.

Claims (1)

[Claims] 1. A general formula [In the formula, R ¹ and R ² are the same or different and each represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a hydroxyl group, a lower alkenyloxy group, a lower alkynyloxy group or a lower alkoxy lower alkoxy group. , R ³ and R ⁴ are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group optionally substituted with a halogen atom, a lower alkoxy group, a nitro group or a lower alkanoyl group, and A and B are Represents a lower alkylene group, and m and n each represent 0 or 1. In addition, the substituent The substitution position of may be any of positions 2 to 8 of the tetrahydroquinoline skeleton. However, R ¹ and R ² are both hydrogen atoms, and m is 1, n
Is 0. R ³ and R ⁴ are not a hydrogen atom, a lower alkoxy group and a lower alkanoyl group, or R ³ and R ⁴ are substituted at the 5- and 6-positions, respectively. ^{When one of 3} and R ^{4 is} a lower alkyl group optionally substituted with a halogen atom, the other is a hydrogen atom, a lower alkoxy group, a lower alkanoyl group or a lower alkyl group optionally substituted with a halogen atom. , R ¹ and R ² are both hydrogen atoms, m is assumed not to be a 1, n is 0. ] The tetrahydroquinoline derivative represented by these, and its salt.