JPH0560468B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel 1H-benzimidazole derivatives. The 1H-benzimidazole derivative of the present invention is
This is a new compound that has not been described in any literature and is represented by the general formula below. [In the formula, R ¹ and R ² are the same or different,
Each represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, or a halogen atom. R ³ , R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, a lower alkoxy group or a lower alkyl group. R ⁶ represents a phenyl lower alkyl group which may have a lower alkoxy group or a halogen atom on the phenyl ring. l represents an integer of 0 or 1. ] 1H-benzimidazole derivatives represented by the above general formula and salts thereof have anti-ulcer effects,
For example, it is useful as a therapeutic agent for gastrointestinal 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. recent years,
It was discovered that ATPase, which is activated by H ⁺ and K ⁺ , is responsible for acid production in gastric parietal cells. This enzyme exists specifically in gastric parietal cells and plays the role of a key enzyme in proton pumps, and inhibitors of this enzyme can serve as useful acid secretion inhibitors. In particular, the compound of the present invention has both acid secretion suppressing action and cell protective action, suppresses ulcer factors from both the attacking and defensive factors, has low toxicity and side effects, and has a long duration of acid secretion suppressing action. It has the characteristic of being long. Specific examples of each group defined by R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ in the above general formula (1) are shown below. Examples of lower alkyl groups include linear or branched alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl groups. Examples of lower alkoxy groups include those having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, and hexyloxy groups.
straight-chain or branched-chain alkoxy groups. Examples of the phenyl lower alkyl group which may have a lower alkoxy group or a halogen atom on the phenyl ring include benzyl, 2-phenylethyl, 1
-Phenylethyl, 3-phenylpropyl, 4-
Phenylbutyl, 1,1-dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl, 2-methyl-3-phenylpropyl,
2-chlorobenzyl, 2-(3-chlorophenyl)
Ethyl, 1-(4-chlorophenyl)-3-(2-
fluorophenyl)propyl, 4-(3-fluorophenyl)butyl, 1,1-dimethyl-2-
(4-fluorophenyl)ethyl, 5-(2-bromophenyl)pentyl, 6-(3-bromophenyl)hexyl, 2-methyl-3-(4-bromophenyl)propyl, 2-iodobenzyl, 4-iodobenzyl, 3,5-dichlorobenzyl, 2,
6-dichlorobenzyl, 3,4-dichlorobenzyl, 3,4-difluorobenzyl, 3,5-dibromobenzyl, 3,4,5-trichlorobenzyl, 2-methoxybenzyl, 2-(3-methoxyphenyl)ethyl , 1-(4-methoxyphenyl)
ethyl, 3-(2-ethoxyphenyl)propyl,
4-(3-ethoxyphenyl)butyl, 1,1-
dimethyl-2-(4-ethoxyphenyl)ethyl,
5-(4-isopropoxyphenyl)pentyl,
6-(4-hexyloxyphenyl)hexyl,
Even if it has an alkoxy group having 1 to 6 carbon atoms or 1 to 3 halogen atoms on the phenyl ring such as 3,4-dimethoxybenzyl, 3,4,5-trimethoxybenzyl, 2,5-dimethoxybenzyl, etc. A good example is a phenyl alkyl group, which is a linear or branched alkyl group in which the alkyl moiety has 1 to 6 carbon atoms. The compound of general formula (1) can be produced by various methods, and for example, can be produced by the method shown in Reaction Formula-1 below. [Reaction formula 1] [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same as above. X ¹ and X ² each represent a mercapto group, a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group, or an aralkylsulfonyloxy group. However, X ¹
When is a mercapto group, X ² is a halogen atom,
Indicates a lower alkanesulfonyloxy group, arylsulfonyloxy group, or aralkylsulfonyloxy group, and when X ² is a mercapto group, X ¹
represents a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group, or an aralkylsulfonyloxy group] In general formulas (2) and (3), the halogen atom represented by X ¹ and/or X ² is fluorine, chlorine,
Examples of lower alkanesulfonyloxy groups include methanesulfonyloxy, ethanesulfonyloxy, isopropanesulfonyloxy, propanesulfonyloxy, butanesulfonyloxy, tert-butanesulfonyloxy, pentanesulfonyloxy, and hexane. Examples include sulfonyloxy groups, and specific examples of rillelsulfonyloxy groups include phenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy,
Examples include substituted or unsubstituted arylsulfonyloxy groups such as 4-methoxyphenylsulfonyloxy, 3-chlorophenylsulfonyloxy, and α-naphthylsulfonyloxy, and specific examples of aralkylsulfonyloxy groups include benzylsulfonyloxy, 2-phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-
Examples include substituted or unsubstituted aralkylsulfonyloxy groups such as methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy, 4-methoxybenzylsulfonyloxy, 3-chlorobenzylsulfonyloxy, and α-naphthylmethylsulfonyloxy. The reaction between the compounds of general formula (2) and general formula (3) can be carried out in an appropriate solvent in the presence of a basic compound. Any solvent can be used as long as it does not affect the reaction, such as water, alcohols such as methanol, ethanol, and isopropyl alcohol, and aromatic hydrocarbons such as benzene, toluene, and xylene. , diethyl ether, tetrahydrofuran, dioxane,
Examples include ethers such as monoglyme and diglyme, Kents such as acetone, esters such as methyl acetate and ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide, hexamethyl phosphoric triamide, and mixed solvents thereof. Basic compounds used include sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate,
Inorganic bases such as silver carbonate, alkali metals such as metallic sodium and metallic potassium, 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), and 1,4-diazabicyclo[2.2.2]octane (DABCO). In addition, in the reaction, 18-crown-6 (i.e., 1,4,7,10,13,16-hexaoxacyclooctadecane), 12-crown-4
(i.e., 1,4,7,10-tetraoxacyclododecane), 15-crown-5 (i.e., 1,4,7,
Crown ethers such as 10,13-pentaoxacycloopentadecane) may also be added. The reaction is usually carried out at a temperature of 0 to 150°C, preferably 0 to 150°C.
It completes in about 1 to 10 hours at around 100℃. The amount of the compound of general formula (2) to be used is usually at least an equimolar amount, preferably an equimolar to 1.5 times the molar amount of the compound of general formula (3). [Reaction formula 2] [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same as above, and X ³ and X ⁴ each represent a halogen atom] Compound of general formula (2a) and thiourea (4) The reaction with is carried out in the presence of a solvent or without a solvent. Examples of solvents used include alcohols such as methanol, ethanol, and propanol, ethers such as diethyl ether, tetrahydrofuran, dioxane, and ethylene glycol monomethyl ether, aromatic hydrocarbons such as benzene, toluene, and xylene, acetone, Examples include ketones such as methyl ethyl ketone, dimethyl formamide, dimethyl sulfoxide, and hexamethyl phosphoric acid triamide (HMPA). The amount of thiourea (4) to be used is usually at least 1 mol, preferably 1 to 2 times the amount of the compound of general formula (2a). Further, the reaction is usually completed at room temperature to 200°C, preferably 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 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 range of known basic compounds can be used, including inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and silver carbonate, and alkali metals such as sodium and potassium. , alcoholates such as sodium methylate and sodium ethylate, triethylamine, pyridine, N,N-dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, DBN,
Examples include organic bases such as DBU and DABCO.
The reaction can be carried out in the absence of a solvent or in the presence of a solvent, and all inert solvents that do not adversely affect the reaction can be used, such as water, alcohols such as methanol, ethanol, propanol, butanol, and ethylene glycol. ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, and diglyme; Kents such as acetone and methyl ethyl Kent; aromatic hydrocarbons such as benzene, toluene, and xylene; esters such as methyl acetate and ethyl acetate;
Examples include aprotic polar solvents such as DMF, DMSO, and HMPA, and mixed solvents thereof.
Moreover, the reaction is advantageously carried out in the presence of a metal iodide such as sodium iodide or potassium iodide. The ratio of compound (3a) to compound (2a) in the above method is not particularly limited,
Although it is appropriately selected from a wide range of moles, it is usually desirable to use the latter in an amount of about 0.5 to 5 times the former, preferably 0.5 to 2 times by mole. In addition, the reaction temperature is not particularly limited, but usually -
The temperature is about 30 to 200°C, preferably 0 to 160°C, and the reaction is usually completed in about 1 to 30 hours. [Reaction formula 3] [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same as above] The reaction between the compound of general formula (5) and the compound of general formula (6) can be carried out using an appropriate acid. The reaction can be carried out in the presence of a solvent, in the absence of a solvent, or in an appropriate solvent. As the solvent used here, for example, the solvent used in the reaction of the compound of general formula (2) and the compound of general formula (3) in the above-mentioned reaction formula-1 can be exemplified. Further, examples of acids that can be used include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, and organic acids such as benzenesulfonic acid, p-toluenesulfonic acid, and methanesulfonic acid. The amount of the compound of general formula (6) to be used is
The amount should be at least equimolar, preferably equimolar to 1.5 times the molar amount of the compound. Also,
The reaction is usually carried out at room temperature to 150°C, preferably 50 to 120°C.
The reaction is completed in about 10 minutes to 5 hours at around ℃. [Reaction formula 4] [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same as above] The oxidation reaction of the compound of general formula (1a) is carried out in an appropriate solvent in the presence of an oxidizing agent. It will be done. Any solvent can be used as long as it does not affect the reaction, such as water, organic acids such as formic acid, acetic acid, and trifluoroacetic acid, and alcohols such as methanol, ethanol, and isopropyl alcohol. Examples 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, such as performic acid, peracetic acid,
Peracids such as trifluoroperacetic acid, perbenzoic acid, m-chloroperbenzoic acid, and 0-carboxyperbenzoic acid, hydrogen peroxide, chromates such as chromic acid, sodium chromate, and potassium chromate, permanganic acid Examples include permanganates such as sodium permanganate and potassium permanganate, iodates such as sodium metaperiodate, and selenium compounds such as selenium dioxide. The amount of the oxidizing agent to be used is at least equimolar, preferably equimolar to 1.5 times the molar amount of the compound of general formula (1a). The reaction is
The process is usually completed in about 5 minutes to 3 hours at a temperature of -70 to 40°C, preferably -70°C to around room temperature. [Reaction formula 5] [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same as above, R ⁷ and R ⁸ are halogen atoms or groups: -CH-M | R ⁶ (In the formula, R ⁶ is the same as above, M is sodium,
(Represents a metal selected from the group consisting of potassium and lithium) However, when R ⁷ represents the group -CH(R ⁶ )-M, R ⁸ represents a halogen atom, and when R ⁷ represents a halogen atom, , ^R8 represents a group: -CH( ^R6 )-M] The compound of the present invention represented by general formula (1b) is a compound of general formula (7) and a compound of general formula (8). It can be obtained by reacting with in a suitable solvent. 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, and mixed solvents thereof. The amount of the compound of general formula (8) to be used is usually at least an equimolar amount, preferably 1.5 times the molar amount of the compound of general formula (7). The reaction is usually carried out at room temperature to 150°C, preferably around room temperature to 120°C.
It will be completed in about 1 to 5 hours. In addition, the compound of general formula (3) which is a starting material can be manufactured according to the method of the following reaction formula-6, for example. [Reaction formula 6] [In the formula, R ³ , R ⁴ , R ⁵ , R ⁶ and X ⁴ are the same as above. X ⁵ represents a halogen atom. ] The reaction between the compounds of general formula (9) and general formula (10) is generally called the Grignard reaction, and can be carried out under normal Grignard reaction conditions. carried out in the presence of Examples of the solvent used here include ethers such as diethyl ether, tetrahydrofuran, dioxane, diglyme, and monoglyme, and aromatic hydrocarbons such as benzene, toluene, and xylene. Furthermore, examples of the metal used include magnesium. The reaction is usually carried out at -20 to 100°C, preferably at -20°C.
The process is completed in about 30 minutes to 5 hours at ~70°C. The amounts of general formula (10) and metal to be used are at least equimolar, preferably equimolar to twice the molar amount of the compound of general formula (9). The halogenation reaction of the compound of general formula (11) can be carried out in the presence of a halogenating agent, either in a suitable solvent or in the absence. Examples of the solvent used here include ethers such as dioxane, tetrahydrofuran, and diethyl ether, and hydrocarbon halides such as chloroform, dichloromethane, and carbon tetrachloride. As a halogenating agent,
Acids such as hydrochloric acid and hydrobromic acid, N,N-diethyl-
Examples include 1,2,2-trichlorovinylamide, phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, and thionyl chloride. The proportion of the halogenating agent to be used is preferably at least equimolar to the compound of general formula (11), usually in large excess. The reaction is usually carried out at room temperature to 150°C, preferably at room temperature to 150°C.
It completes in about 30 minutes to 6 hours at around 80℃. The compound represented by general formula (1) can easily form a salt with a common pharmacologically acceptable acid. Examples of such acids include inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, and hydrobromic acid, acetic acid, p-toluenesulfonic acid, ethanesulfonic acid, oxalic acid, maleic acid,
Examples include organic acids such as succinic acid and benzoic acid. The compound of the present invention produced by the above method can be easily isolated from the reaction system by conventional separation methods such as distillation, recrystallization, column chromatography, preparative thin layer chromatography, and solvent extraction. Can be separated and purified. The compounds of the present invention naturally include stereoisomers and optically active forms, and these isomers include, for example,
It can be separated by conventional separation means such as using a resolving agent. The compounds of the present invention are useful as anti-ulcer agents and are usually used in the form of common pharmaceutical preparations. The formulation is prepared using commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, and lubricants. Various forms of this pharmaceutical preparation can be selected depending on the therapeutic purpose, and typical examples include tablets, pills, powders,
Examples include solutions, suspensions, emulsions, granules, capsules, suppositories, and injections (solutions, suspensions, etc.). When forming tablets, a wide variety of carriers conventionally known in this field can be used, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc. Excipients, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binders such as polyvinylpyrolinde, dry starch, sodium alginate, agar, laminaran. disintegrants such as sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, etc. quaternary ammonium base,
Absorption enhancers such as sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid, and lubricants such as purified talc, stearate, boric acid powder, and polyethylene glycol. Examples include brighteners. Furthermore, the tablets can be made into tablets with conventional coatings, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double tablets, or multilayer tablets, if necessary. When forming into a pill form, a wide variety of carriers conventionally known in this field can be used, such as excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, gum arabic powder, etc. ,
Examples include binders such as tragacanth powder, gelatin, and ethanol, and disintegrants such as laminaran and agar. When forming into a suppository, a wide variety of conventionally known carriers can be used, such as polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides. When prepared as injections, solutions, emulsions and suspensions are preferably sterilized and isotonic with blood, and when formed into the form of solutions, emulsions and suspensions, diluents are added. Any of those commonly used in this field can be used, and examples thereof include water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. In this case, the antiulcer agent may contain a sufficient amount of salt, glucose, or glycerin to adjust the isotonicity of the solution, and may also contain conventional solubilizers, buffers, soothing agents, etc. Furthermore, if necessary, the therapeutic agent may contain colorants, preservatives, fragrances, flavoring agents, sweeteners, and other pharmaceuticals. 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 is usually 1 to 70% by weight, preferably 5 to 50% by weight of the total composition. Weight%. There are no particular restrictions on the method of administering the anti-ulcer agent using the compound of the present invention, and administration may be carried out in a manner depending on various formulation forms, age, sex and other conditions of the patient, degree of disease, etc. For example, tablets, pills, solutions, suspensions, emulsions, granules, and capsules are administered orally. In the case of an injection, it is administered intravenously alone or mixed with a normal replacement fluid such as glucose or amino acids, and furthermore, if necessary, it is administered alone intramuscularly, intradermally, subcutaneously, or intraperitoneally. Suppositories are administered rectally. The dosage of the anti-ulcer agent using the compound of the present invention is appropriately selected depending on the usage, age, sex and other conditions of the patient, degree of disease, etc., but the amount of the compound of the present invention is usually 0.6 to 1 kg body weight per day. 50mg, and the dosage unit form contains 10 to 10 mg of the active ingredient.
It is better to contain 1000 mg. <Examples> Next, the present invention will be explained in more detail by giving formulation examples, examples, and test examples. Formulation example 1 2-[(2-pyridyl)-(4-fluorobenzyl)-methylsulfinyl]-1H-benzimidazole 150g Avicel (trade name, manufactured by Asahi Kasei Corporation) 40g Cornstarch 30g Magnesium stearate 2g Hydroxypropyl Methylcellulose 10g Polyethylene glycol-6000 3g Castor oil 40g Ethanol 40g After mixing and polishing the compound of the present invention, Avicel, cornstarch and magnesium stearate, sugar coating
Compress the tablets with an R10mm kine. The obtained tablets are coated with a film coating agent consisting of hydroxypropyl methylcellulose, polyethylene glycol-6000, castor oil, and ethanol to produce film-coated tablets. Formulation example 2 2-[(2-pyridyl)-(4-fluorobenzyl)-methylsulfinyl]-1H-benzimidazole 150g citric acid 1.0g lactose 33.5g dicalcium phosphate 70.0g Pluronic F-68 30.0g lauryl Sodium sulfate 15.0g Polyvinylpyrrolidone 15.0g Polyethylene glycol (Carbowax 1500) 4.5g Polyethylene glycol (Carbowax 6000) 45.0g Cornstarch 30.0g Dry sodium lauryl sulfate 3.0g Dry magnesium stearate 3.0g Ethanol Appropriate amount Compound of the present invention, citric acid, lactose, Mix dicalcium phosphate, Pluronic F-68 and sodium lauryl sulfate. The above mixture was sieved through a No. 60 screen, and polyvinylpyrrolidone, Carbowax 1500 and 6000 were added.
wet granulation in an alcoholic solution containing Add alcohol if necessary to make the powder into a pasty mass. Add cornstarch and continue mixing until uniform particles are formed. Pass it through a No. 10 screen, put it in a tray and put it in an oven at 100 degrees for 12 minutes.
Dry for ~14 hours. The dry particles are sieved through a No. 16 screen, dried sodium lauryl sulfate and dry magnesium stearate are added and mixed, and compressed into the desired shape using a tablet machine. The core is treated with varnish and sprinkled with talc to prevent moisture absorption. A subbing layer is applied around the core. Apply varnish a sufficient number of times for internal use. A subbing layer and a smooth coating are applied to make the tablet completely round and smooth. Pigmented coatings are applied until the desired shade is obtained. After drying, the coated tablets are polished to a uniform gloss. Formulation example 3 2-[(4-methoxy-2-pyridyl) (benzyl)methylsulfinyl]-5-fluoro-1H-benzimidazole 5g Polyethylene glycol (molecular weight: 4000) 0.3g Sodium chloride 0.9g Polyoxyethylene- Sorbitan monooleate 0.4g Sodium metabisulfite 0.1g Methyl-paraben 0.18g Propyl-paraben 0.02g Distilled water for injection 10.0ml The above parabens, sodium metabisulfite and sodium chloride were heated at 80°C with stirring to approximately half the above amount. Dissolve in distilled water. The resulting solution is cooled to 40°C, and the compound of the present invention, followed by polyethylene glycol and polyoxyethylene sorbitan monooleate, are dissolved in the solution. The solution was then adjusted to the final volume by adding distilled water for injection.
The injection is prepared by sterilization by sterile filtration using a suitable filter paper. Reference examples and examples are shown below. Reference example 1 0.47g of magnesium in 15ml of tetrahydrofuran
4-fluorobenzyl chloride 2.78
5 ml of tetrahydrofuran solution was slowly added dropwise. A solution of 1.98 g of 3,5-dimethyl-4-methoxy-2-pyridinecarboxaldehyde in 20 ml of tetrahydrofuran was added dropwise under ice cooling. After dropping, stir at room temperature for 1 hour. After the reaction, tetrahydrofuran is distilled off under reduced pressure, an aqueous ammonium chloride solution is added to the resulting residue, and the mixture is extracted with chloroform. After drying over magnesium sulfate, chloroform is distilled off. Chloroform 20 to the resulting residue
ml and 2 ml of thionyl chloride were added, and the mixture was heated under reflux for 1 hour. After the reaction is completed, the reaction solution is distilled off under reduced pressure, water and sodium carbonate are added to the resulting residue to make it alkaline, and the mixture is extracted with chloroform. After drying with magnesium sulfate, chloroform is distilled off. The obtained residue was subjected to silica gel column chromatography (eluent: methylene chloride:methanol = 100:1)
to give 2.98 g of 2-[1-chloro-2-(4
-fluorophenyl)ethyl-3,5-dimethyl-4-methoxypyridine is obtained. Pale yellow oil NMR (CDCl ₃ ) δ: 2.13 (3H, s), 2.25 (3H,
S), 3.50-3.70 (2H, m), 3.70 (3H, s), 5.10
−5.30 (1H, m), 6.70−7.30 (4H, m), 8.33
(1H, s) Example 1 Dissolve 0.12g of 60% sodium hydride in 8ml of dithylformamide, add 0.46g of 5-fluoro-2-mercapto-1H-benzimidazole and 66mg of 18-crown-6, and heat to 50°C. Heat and stir for 20 minutes. Then, 2-[1-chloro-2-(4-fluorophenyl)ethyl]-3,5-dimethyl-
A solution of 0.69 g of 4-methoxypyridine in 8 ml of dimethylformamide is added, and the mixture is heated and stirred at 80 to 90°C for 4 hours. After the reaction is complete, dimethylformamide is distilled off under reduced pressure, water is added to the resulting residue, and the mixture is extracted with a mixed solvent of ethyl acetate and toluene (4:1).
After drying with magnesium sulfate, the solvent is distilled off. The obtained residue was subjected to silica gel column chromatography (eluent: n-hexane: ethyl acetate = 3:
1) to obtain 0.51 g of 2-[(4-fluorobenzyl)(3,5-dimethyl-4-methoxy-2
-pyridyl)methylthio]-5-fluoro-1H-
Obtain benzimidazole. Yellow oil NMR (CDCl ₃ ) δ: 1.97 (3H, s), 2.25 (3H,
s), 3.42 (2H, d), 3.63 (3H, s), 5.03 (1H,
t), 6.70-7.20 (5H, m), 7.20-7.30 (1H, m),
7.30-7.60 (1H, m), 8.33 (1H, s) In the same manner as in Example 1, using appropriate starting materials, a compound represented by the following general formula (1a) is obtained.

【table】

【table】

[Table] 1 NMR (CDCl ₃ ) δ: 3.47 (2H, d), 3.83
(3H, s), 4.80 (1H, t), 6.70−7.40 (9H,
m), 7.40−7.70 (2H, m), 8.67 (1H, dd) 2 NMR (CDCl ₃ ) δ: 3.47 (2H, d), 3.78
(1H, t), 6.70-7.80 (11H, m), 8.67 (1H,
dd) 3 NMR (CDCl ₃ ) δ: 2.37 (6H, s), 3.43
(2H, d), 5.83 (1H, t), 6.80−7.70 (10H,
m), 8.63 (1H, dd) 4 NMR (CDCl ₃ ) δ: 3.12 (2H, d), 4.87
(1H, t), 6.90-7.30 (9H, m), 7.30-7.70
(2H, m), 8.62 (1H, dd) 5 NMR (CDCl ₃ ) δ: 3.38 (2H, d), 3.70
(3H, s), 3.83 (3H, s), 4.77 (1H, t),
6.83 (4H, q), 6.50−7.30 (4H, m), 7.30−
7.70 (2H, m), 8.63 (1H, dd) 6 NMR (CDCl ₃ ) δ: 3.37 (2H, d), 3.67
(3H, s), 4.80 (1H, t), 6.77 (4H, q),
6.50−7.80 (6H, m), 8.63 (1H, dd) 7 NMR (CDCl ₃ ) δ: 2.33 (6H, s), 3.37
(2H, d), 3.70 (3H, s), 4.72 (1H, t),
6.80 (4H, q), 6.80−7.70 (5H, m), 8.63
(1H, dd) 8 NMR (CDCl ₃ ) δ: 3.37 (2H, d), 3.72
(3H, s), 4.73 (1H, d), 6.83 (4H, q),
7.00−7.80 (6H, m), 8.65 (1H, dd) 9 NMR (CDCl ₃ ) δ: 3.45 (2H, d), 4.85
(1H, t), 6.70-7.40 (9H, m), 7.40-7.80
(2H, m), 8.63 (1H, dd) 10 NMR (CDCl ₃ ) δ: 3.43 (2H, d), 4.80
(1H, t), 6.70-7.80 (10H, m), 8.67 (1H,
dd) 11 NMR (CDCl ₃ ) δ: 2.33 (6H, s), 3.40
(2H, d), 4.87 (1H, t), 6.60−7.60 (9H,
m), 8.60 (1H, dd) 12 NMR (CDCl ₃ ) δ: 3.43 (2H, d), 3.23
(3H, s), 4.93 (1H, t), 6.50−6.70 (2H,
m), 6.80-7.30 (7H, m), 7.40-7.70 (2H,
m), 8.37 (1H, d) 13 NMR (CDCl ₃ ) δ: 3.53 (3H, s), 3.50−
3.70 (2H, m) 4.65 (1H, t), 6.43 (1H, d),
6.60-6.80 (1H, m), 6.80-7.80 (8H, m),
8.23 (1H, d) 14 NMR (CDCl ₃ ) δ: 1.93 (3H, s), 2.17
(3H, s), 3.40 (2H, d), 3.53 (3H, s),
3.63 (3H, s), 5.20 (1H, t), 6.73 (4H, q),
7.00−7.30 (2H, m), 7.30−7.90 (2H, bs),
8.30 (1H, s) 15 NMR (CDCl ₃ ) δ: 1.97 (3H, s), 2.23
(3H, s), 3.40 (2H, d), 3.63 (3H, s),
3.70 (3H, s), 4.93 (1H, t), 6.73 (4H, q),
7.00−7.70 (3H, m), 8.33 (1H, s) 16 NMR (CDCl ₃ ) δ: 1.97 (3H, s), 2.23
(3H, s), 3.43 (2H, d), 3.60 (3H, s),
5.07 (1H, t), 6.60−7.00 (4H, m), 7.00−
7.30 (2H, m), 7.40-7.70 (2H, m), 8.33
(1H,s) Example 25 2-[(4-fluorobenzyl)(3,5-dimethyl-4-methoxy-2-pyridyl)methylthio]-5-fluoro-1H-benzimidazole
Dissolve 0.23g in 10ml of methylene chloride and heat at -60℃.
A solution of 0.12 g of m-chloroperbenzoic acid (80%) in 5 ml of methylene chloride was added dropwise, and the mixture was stirred at the same temperature for 15 minutes. After the reaction is completed, an aqueous sodium carbonate solution is added to the reaction solution, and the mixture is extracted with methylene chloride. After drying over magnesium sulfate, methylene chloride is distilled off. Recrystallized from diethyl ether-n-hexyne, 0.18g
2-[(4-fluorobenzyl)(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-5-fluoro-1H-benzimidazole is obtained. White powder mp 108-111°C (decomposition) In the same manner as in Example 25, using appropriate starting materials, a compound represented by the following general formula (1b) is obtained.

【table】

【table】

[Table] Example 46 2-[(3,5-dimethyl-4-methoxy-2-
pyridyl)(4-fluorobenzyl)methylthio]
34.5 g of formic acid and 12.6 g of 5-fluoro-o-phenylenediamine are heated under reflux for 40 minutes in 100 ml of 4N hydrochloric acid. After cooling the reaction mixture, it is neutralized with aqueous ammonia and extracted with chloroform. After drying the extract over magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 4.5 g of 2-[(3,5-dimethyl-4-methoxy- 2-pyridyl)(4-fluorobenzyl)methylthio]-5-fluoro-1H-benzimidazole is obtained. Yellow oil NMR (CDCl ₃ ) δ: 1.97 (3H, s), 2.25 (3H,
s), 3.42 (2H, d), 3.63 (3H, s), 5.03 (1H,
t), 6.70-7.20 (5H, m), 7.20-7.30 (1H, m),
7.30-7.60 (1H, m), 8.33 (1H, s) In the same manner as in Example 46, using appropriate starting materials, the compounds of Examples 2 to 24 are obtained. Example 47 818 mg of 2-chloro-5-fluoro-1H-benzimidazole and 0.4 g of thiourea are added to 20 ml of ethanol and heated under reflux for 2 hours. 2-
[(chloro)(4-fluorobenzyl)methyl]-
3,5-dimethyl-4-methoxypyridine hydrochloride
Add 1.05g and heat under reflux for 5 hours. After the reaction is complete, ethanol is distilled off, water is added to the resulting residue, and the mixture is extracted with chloroform. After drying the extract over magnesium sulfate, chloroform is distilled off. The obtained residue was purified by silica gel column chromatography to obtain 520 g of 2-[(3,5-dimethyl-4-methoxy-2-pyridyl)(4-fluorobenzyl)methylthio]-5-1H-benzimidazole. get. Yellow oil NMR (CDCl ₃ ) δ: 1.97 (3H, s), 2.25 (3H,
s), 3.42 (2H, d), 3.63 (3H, s), 5.03 (1H,
t), 6.70-7.20 (5H, m), 7.20-7.30 (1H, m),
7.30-7.60 (1H, m), 8.33 (1H, s) In the same manner as in Example 47, using appropriate starting materials, the compounds of Examples 2 to 24 are obtained. Example 48 [(5-fluoro-1H-benzimidazole-
31.2 g of 2-yl)sulfinyl](4-fluorobenzyl)methyllithium are dissolved in 150 ml of benzene. 2-chloro-3,5-dimethyl-4-
After adding 17.2 g of methoxypyridine, the mixture was heated under reflux for 2 hours. The generated lithium chloride is filtered off, and the filtrate is concentrated under reduced pressure. The obtained residue was recrystallized from diethyl ether-n-hexane to give 27 g of 2-
[(3,5-dimethyl-4-methoxy-2-pyridyl)(4-fluorobenzyl)methylsulfinyl]-5-fluoro-1H-benzimidazole is obtained. White powder mp 108-111°C (decomposition) In the same manner as in Example 48, using appropriate starting materials, the compounds of Examples 26-45 are obtained. Pharmacological test 1 H ⁺ + K ⁺ APTase (adenosine triphosphatase) prepared from pig stomach (protein amount: 10 μ
g) in Pipes-Tris buffer (2-amino-2-(hydroxymethyl)-1,3-propanediol) (PH6) containing 2mM piperazine N,N'-bis(2-ethanesulfonic acid). .1)
and leave it at room temperature. The test compound is dissolved in dimethylformamide, added to the above H ⁺ +K ⁺ APTase buffer to a final concentration of 1%, and allowed to react at room temperature for 30 minutes. Next, 1 ml of 75 mM Pipes-Tris buffer (PH7.4) (4 mM MgCl ₂ ,
4 mM Na ₂ ATP, and 20 mM KCl) and 1 ml of 75 mM Pipes-Tris buffer (PH
7.4) (4mM _MgCl2 and 4mM Na2ATP
(containing) were added separately to make two types of samples, and each was allowed to react at 37°C for 30 minutes. Add 0.3 ml of 40% trichloroacetic acid to each to terminate the reaction. Next, centrifuge for 10 minutes (3000 rpm),
Take the supernatant liquid and collect the inorganic phosphoric acid produced by Fiske.
and Subbarow's method [J.Biok.Chem.vol.66,
375 (1925)]. The amount of inorganic phosphoric acid determined from the Pipes-Tris buffer containing 20 mM KCl minus the amount of inorganic phosphoric acid determined from the Pipes-Tris buffer containing no 20 mM KCl is converted to per unit protein and unit time. It was expressed as an enzyme activity value. The inhibition value (%) of each dose was determined from the control value and the enzyme activity value at each dose.
IC ₅₀ (the dose of each test compound that inhibits 50%) was calculated from the obtained inhibition value (%). Test compound 1 2-[(4-fluorobenzyl)(3,5-dimethyl-4-methoxy-2-biridyl)methylsulfinyl]-5-fluoro-1H-benzimidazole 2 2-[(benzyl)( 2-pyridyl)methylsulfinyl]1H-benzimidazole3 2-[(4-methoxybenzyl)(2-pyridyl)methylsulfinyl]-5,6-dimethyl-1H-benzimidazole4 2-[(4 -methoxybenzyl)(2-pyridyl)methylsulfinyl]-5-chloro-1H-
Benzimidazole 5 2-[(4-fluorobenzyl)(2-pyridyl)methylsulfinyl]-1H-benzimidazole 6 2-[(4-fluorobenzyl)(2-pyridyl)methylsulfinyl]-5, 6-dimethyl-1H-benzimidazole 7 2-[(benzyl)(4-methoxy-2-pyridyl)methylsulfinyl]-5-fluoro-
1H-benzimidazole 8 2-[(methoxybenzyl)(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-5-fluoro-1H-benzimidazole 9 2-[(4-methoxybenzyl) )(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-5,6-dimethyl-1H-benzimidazole The test results are shown in the table below.

【table】

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ and R ² are the same or different,
Each represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, or a halogen atom. R ³ , R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, a lower alkoxy group or a lower alkyl group. R ⁶ represents a phenyl lower alkyl group which may have a lower alkoxy group or a halogen atom on the phenyl ring. l represents an integer of 0 or 1. ] A 1H-benzimidazole derivative and a salt thereof.