JPS61145182A - Imidazopyridine derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (either one of X and Y is =CH- and the other is =N-; R<1> and R<2> are H, lower alkoxycarbonyl, halogen atom, lower alkyl, NH2 or OH; R<3>, R<4> and R<5> are H, lower alkoxyl or lower alkyl; A is lower alkylene; l is 1 or 0) and its salt. EXAMPLE:2-[(3,5-Dimethyl-4-methoxy-2-pyridyl)methylthio]-imidazo-[4,5-b] pyridine. USE:An anticulcer agent. PREPARATION:A compound expressed by formula II is reacted with a compound expressed by formula III in an appropriate solvent in the presence of a basic compound (example; NaOH or triethylamine) at 0-100 deg.C for 1-10hr to obtain the compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel imidazopyridine derivatives, more specifically, the general formula [wherein X and Y are one -CH- group and the other one =N
- group, R1 and R2 are the same or different, and each represents a hydrogen atom, a lower alkoxycarbonyl group, a halogen atom, a lower alkyl group, an amino group or a hydroxyl group,
R3, R' and R5 are the same or different and each represents a hydrogen atom, a lower alkoke group or a lower alkyl group,
A is a lower alkylene group,! indicates O or 1. However, if Y is -CH- group, X or -N- group, and K is 0, R
3, R4 and R5 are not hydrogen atoms at the same time] and a salt thereof.

The imidazopyridine derivative of the present invention represented by the above general formula (1) has an anti-ulcer effect and 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. In recent years, it has been discovered that ATPase, which has the property of being activated by H+ and ni+, 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 the proton pump, and a blinding agent for this enzyme can be a useful acid secretion inhibitor. In particular, the compound of the present invention has both acid secretion suppressing action and cell protective action, inhibits ulcer factors from both the attacking and defensive factors, has low toxicity, and has a long duration of acid secretion suppressing action. It has characteristics.

Prior art UK Patent No. 1,234,058' describes the following general formula [wherein A is C+-S alkylene or straight chain, X is N
H, 0 or S, Y is S or 0, Z is CH or N,
R, is H or CH3, R, is Hl (4, Now or CH3, n is an integer from 1 to 3) The compound has antituberculosis, insecticidal, antifungal, antiviral, anthelmintic and It is stated that it exhibits anti-inflammatory effects.

The above compounds include those similar in chemical structure to the compounds of the present invention, but unlike anti-ulcer agents such as the compounds of the present invention,
As shown in the pharmacological tests described later, even compounds with the most similar structure have extremely weak antiulcer effects.

Structure and Effects of the Invention In this specification, lower alkoxy groups include linear or branched alkoxy groups having 1 to 6 carbon atoms, such as methquine, ethoxy, propoxy, isopropoxy,
Examples include butoxy, isobutquine, benzyloxy, and hexyloxy groups. Halogen atoms include fluorine, chlorine, bromine and iodine. 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, pentyl, and hexyl groups. The lower alkylene group includes a straight chain or branched alkylene group having 1 to 6 carbon atoms, such as methylene,
Ethylene, trimethylene, methylmethylene, ethylmethylene, 2-methyltrimethylene, 2,2-nomethyltrimethylene, ■-methyltrimethylene, tetramethylene,
Examples include pentamethylene and hexamethylene groups.

The compound of the present invention can be produced by various methods, and for example, it can be produced by the method shown in the reaction formula below.

[Reaction formula-1] [In the formula, R', R'', R', R', R5, X, Y.

and A are the same as above. R8 and R7 each represent a mercapto group, a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxo group, or an aralkylsulfonyloxy group.

However, when R11 is a mercapto group, R7 represents a halogen atom, a lower alkanesulfonyloquine group, an arylsulfonyloxy group, or an aralkylsulfonyloxy group, and when R7 is a mercapto group, R@ represents a halogen atom, a lower represents an alkanesulfonyloxy group, an arylsulfonyloxy group, or an aralkylsulfonyloxy group] In general formulas (2) and (3), R1'
The halogen atom represented by and/or R7 is the same as mentioned above, and examples of the lower alkanesulfonyloxy group include methanesulfonyloxy, ethanesulfonyloxy, isopropanesulfonyloxy, propanesulfonyloxy, butanesulfonyloxy, ter
Examples include t-butanesulfonyloxy, pentanesulfonyloxy, and hexanesulfonyloxy groups, and specific examples of arylsulfonyloxy groups include phenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, and 4-methylphenylsulfonyloxy. Examples include substituted or unsubstituted arylsulfonyloxy groups such as nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy, 3-chlorophenylsulfonyloxy, and α-naphthylsulfonyloxy groups, and specific examples of aralkylsulfonyloxy groups include Specifically, benzylsulfonyloxy, 2-phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy,
Examples include substituted or unsubstituted aralkylsulfonyloxy groups such as 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 a suitable solvent in the presence of a basic compound.

Any solvent can be used as long as it does not affect the reaction; for example, water, alcohols such as methanol, ethanol, isopropanol,
Aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme, ketones such as acetone, esters such as methyl acetate and ethyl acetate, N, Examples include N-dimethylformamide, dimethylsulfoquine, hexamethylphosphoric acid triamide, or a mixed solvent thereof. Basic compounds used include inorganic bases such as sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, silver carbonate, and alkalis such as metallic sodium and metallic potassium. metals, alcoholades such as sodium methylate, sodium ethylate,
Triethylamine, pyridine, N,N-dimethylaminopyridine, 1,5-diazavinchlo[4,3,0]nonene-5 (DBN), 1,8-diazabicyclo[5,4
,0]undecene-7 (DBU), l,4-diazabicyclo[2,2,2]octane (DABCO), and other organic bases.

The reaction is usually carried out at 0 to 150°C, preferably 0 to 100°C.
It will be completed in about 1-10 hours at a nearby location.

The amount of the compound of general formula (3) to be used is as follows:
The amount is usually at least equimolar, preferably equimolar to 1.5 times the molar amount of the compound.

[Reaction formula-21 (1b) [In the formula, R', R', R', R', R', A, X and Y are the same as above] The oxidation reaction of the compound of general formula (1a) in a solvent,
It is carried out in the presence of an oxidizing agent. 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, alcohols such as methanol and ethanol, chloroform, Examples include halogenated hydrocarbons such as dichloromethane. As the oxidizing agent, any oxidizing agent that normally oxidizes a mercapto group to a sulfoxide can be used, such as performic acid, peracetic acid, trifluoroperacetic acid, perbenzoic acid, m-chloroperbenzoic acid, and 0-carboxylic acid. Peracids such as perbenzoic acid, hydrogen peroxide, chromates such as chromic acid, sodium chromate, and potassium chromate, permanganates such as permanganic acid, sodium permanganate, and potassium permanganate. can be exemplified. The amount of the oxidizing agent to be used is at least equimolar, preferably equimolar to 1.
It is better to use 5 times the molar amount. The reaction is usually carried out at a temperature of -20° to 40°C, preferably -20° to room temperature, and is completed in about 5 minutes to 3 hours.

Reaction formula-3] "In the formula, R', R2, R', R', R", A, X.

and Y are the same as the face notes. R8 and R9 each represent a halogen atom] The reaction between the compound of general formula (2a) and thiourea (4) is carried out in the presence of a solvent or without a solvent.

Examples of solvents used include alcohols such as methanol, ethanol, and propatool, ethers such as diethyl ether, tetrahydrofuran, dioxane, and ethylene glycol monomethyl ether, benzene,
Aromatic hydrocarbons such as toluene and kiln, acetone,
Examples include ketones such as methyl ethyl ketone, dimethyl formamide, dimethyl sulfoxide, and hexamethyl phosphate triamide (HMPA). Thiourea (4
) is usually used in an amount of at least 1 mol, preferably 1 to 2 times the amount of the compound of general formula (2a). The reaction is usually carried out at room temperature to 200°C.
The process is completed in about 1 to 5 hours, preferably at room temperature to about 150°C.

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. , sodium methylate, sodium ethylate and other alcoholades, triethylamine, pyridine, N,N-nomethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, DBN, DBU, D
Examples include organic bases such as ABGO. The reaction can be carried out without a solvent or in the presence of a solvent; any inert solvent that does not adversely affect the reaction can be used as the solvent, such as water, methanol, ethanol, propatool, butanol, etc. , alcohols such as ethylene glycol, diethyl ether, THF, dioxane, monoglyme,
Ethers such as Nobulime, ketones such as acetone and methyl ethyl ketone, aromatic hydrocarbons such as benzene, toluene, and quinolene, esters such as methyl acetate and ethyl acetate, aprotic polar solvents such as DMF, DMSO, HMPA, etc. Examples include mixed solvents thereof. It is also advantageous to carry out the reaction in the presence of a metal iodide such as sodium iodide or potassium iodide.

Compound (3a) for compound (2a) in the above method
) is not particularly limited and is appropriately selected from a wide range, but usually the latter is 0.5 mol to 0.5 mol to the former.
It is desirable to use it in an amount of about 5 times the mole, preferably 0.5 to 2 times the mole. Further, 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 compound of general formula (2) includes some new compounds, and can be produced, for example, by the method shown in Reaction Scheme-4 below.

[Reaction formula-4] In formula 1, R', R2, X, and Y are the same as above.

The amination reaction of general formula (5) in which R10 represents a halogen atom is carried out by reacting with an aminating agent in a suitable solvent.

Examples of solvents used include ethers such as diethyl ether, tetrahydrofuran, and dioxane, aromatic hydrocarbons such as benzene, toluene, and xylene, alcohols such as methanol, ethanol, and isopropanol, dimethylformamide, dimethyl sulfoxide, Examples include polar solvents such as HMPA.

Examples of the aminating agent used include ammonia gas, aqueous ammonia, and sodium amide. The amount of the aminating agent to be used is preferably at least equimolar to the compound of general formula (5), usually in a large amount.

The reaction is usually carried out at 0 to 2°C, preferably at room temperature to 150°C.
The process is completed in about 5 minutes to 10 hours at around ℃.

The reduction reaction of the compound of general formula (6) can be carried out, for example, by: (1) reduction using a catalytic reduction catalyst in a suitable solvent, or (2) reduction with a metal salt and an acid in a suitable inert solvent, or a metal salt and an acid in a suitable inert solvent. The reduction is carried out by using a mixture of and an alkali metal hydroxide, sulfide, ammonium salt, etc. as a reducing agent.

When using the catalytic reduction described in (■), the solvent used is:
For example, water, alcohols such as acetic acid, methanol, ethanol, and isopropanol, hydrocarbons such as hexane and cyclohexane, ethers such as noethylene glycol dimethyl ether, dioxane, THF', and diethyl ether, ethyl acetate, and methyl acetate. esters such as DMF.

Examples include aprotic polar solvents such as and mixed solvents thereof. As a catalytic reduction catalyst, palladium,
Palladium-black, palladium-carbon, platinum, platinum oxide,
Copper chromite, Raney nickel, etc. are used. The amount of catalyst used is 0.02 to 1 per compound (6).
It is better to have ゜00 times the weight. The reaction is -20 to 10
The process is generally completed in about 0.5 to IO hours at 0°C, preferably 0 to 70°C, and a hydrogen pressure of 1 to 10 atm.

When using the method (2), iron, zinc, and tin can be treated with stannous chloride and a mineral acid such as hydrochloric acid or sulfuric acid, or with iron, ferrous sulfate, zinc or tin, or tin and an alkali metal hydroxide such as sodium hydroxide. A mixture of ammonium salts such as ammonium salts, sulfides such as ammonium sulfide, aqueous ammonia, and ammonium chloride is used as the reducing agent. Examples of the inert solvent used include water, acetic acid, methanol, ethanol, and dioxane. The conditions for the above reduction reaction may be appropriately selected depending on the reducing agent used, and are usually -50
The reaction proceeds at ~100°C and is completed for about 0.5 to 10 hours. For example, when stannous chloride and hydrochloric acid are used as reducing agents, the reaction is preferably carried out at around -20 to 70°C. The amount of the reducing agent to be used is preferably at least equimolar, usually equimolar to 3 times the molar amount of the raw material compound.

The reaction between the compound of general formula (7) and carbon dioxide of general formula (8) is carried out in a suitable solvent. Examples of solvents include alcohols such as methanol, ethanol, and isopropanol, aromatic hydrocarbons such as benzene, toluene, and xylene, halogenated hydrocarbons such as chloroform, dichloromethane, and carbon tetrachloride, diethyl ether, and tetrahydrofuran. , ethers such as dioxane,
Tsumethylporumamide, Tsumethylsulfokid, HMP
Examples include polar solvents such as A. The reaction is usually 0 to 1
00° C. Preferably at around 0 to 50° C. for about 1 to 24 hours.

In the compound of general formula (1), at least one of R1 and R2 in the compound of general formula (1) has a hydroxyl group by noazotization. This can lead to the compound shown.

The diazotization reaction is achieved by reacting with a diazotization agent in the presence of an acid in a suitable solvent. Examples of the solvent include water, dioxane, ethers such as tetrahydrofuran, and mixed solvents thereof. The acids used include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, and organic acids such as acetic acid and propionic acid. Examples of the diazotizing agent include alkyl nitrites such as sodium nitrite, ethyl nitrite, and inamyl nitrite. The amount of the diazotizing agent to be used is at least equimolar, preferably 1-1.5 times the molar amount of the starting material. The reaction is completed in about 5 minutes to 3 hours at around 0 to 5°C.

Among the compounds represented by the general formula (1), those having an acidic group can form a salt with a pharmacologically acceptable basic compound. Such basic compounds include, for example, metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, alkali metal carbonates or bicarbonates such as sodium carbonate, sodium bicarbonate, sodium methylate, potassium ethylate, etc. Examples include alkali metal alcolades such as. Further, among the compounds represented by the general formula (1), those having a basic group 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, 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 compound of the present invention produced by the above method can be easily isolated and purified from the reaction system by conventional separation methods such as distillation, recrystallization, column chromatography, preparative thin layer chromatography, and solvent extraction. .

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, fillers, binders, wetting agents, disintegrants, surfactants, and lubricants. Various forms of this pharmaceutical preparation can be selected depending on the therapeutic purpose, and representative examples include tablets, gunpowder, powders, liquids, layered preparations, emulsions, granules, capsules, suppositories, and
Examples include injections (solutions, suspensions, etc.). When forming into a tablet, a wide variety of carriers conventionally known in this field can be used, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate,
Excipients such as kaolin, crystalline cellulose, and silicic acid, water,
Ethanol, propatool, simple syrup, glucose solution,
Starch liquid, gelatin solution, binders such as carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, dried starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoquinoethylene sorbitan fatty acid esters , sodium lauryl sulfate,
Disintegrants such as stearic acid monoglyceride, starch, and lactose; disintegration inhibitors such as sucrose, stearin, cocoa butter, and hydrogenated oil; absorption enhancers such as quaternary ammonium bases and sodium lauryl sulfate; and humectants such as glycerin and starch. Examples include adsorbents such as , starch, lactose, kaolin, bentonite, and colloidal silicic acid, and lubricants such as purified talc, stearate, boric acid powder, and polyethylene glycol. Furthermore, tablets may be coated with conventional coatings, such as sugar-coated tablets, gelatin tablets,
It can be enteric-coated, film-coated, double-layered, or multilayered. When molding into the form of gunpowder, a wide variety of carriers conventionally known in this field can be used, such as glucose, lactose, starch, cocoa butter,
Examples include excipients such as hydrogenated vegetable oil, kaolin and talc, binders such as gum arabic powder, tragacanth powder, gelatin and ethanol, and disintegrants such as laminaran and agar. When forming into a suppository, a wide variety of conventionally known materials can be used as carriers, such as polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides. When prepared as injections, solutions and suspensions are preferably sterile and isotonic with blood, and when formed into solutions, emulsions, and suspensions, diluents may be used. All those commonly used in this field can be used, including water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like. In this case, the anti-ulcer agent may contain a sufficient amount of salt, glucose, or glycerin to prepare an isotonic solution, and may also contain conventional solubilizing agents, buffers, soothing agents, etc. Colorants, preservatives, fragrances, flavoring agents, sweeteners, and other pharmaceutical agents may be included in the therapeutic agent, if necessary.

The amount of the compound of the present invention to be contained in the anti-ulcer agent 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.

There are no particular restrictions on the method of administering the anti-ulcer agent of the present invention, and it can be administered in a manner depending on various formulation forms, age, sex and other conditions of the patient, degree of disease, etc.

For example, tablets, emulsions, 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 of the present invention is appropriately selected depending on the usage, patient's age, sex and other conditions, degree of disease, etc.
Usually, the amount of the compound of the present invention is 0.00000000000000000000 per kg body weight per day.
The dosage is preferably 6 to 50 mg, and the dosage unit preferably contains 10 to 1000 mg of the active ingredient.

Next, the present invention will be explained in more detail with reference to formulation examples, working examples, and experimental examples.

Formulation Example 1 1[(3,5-dimethyl-4-meth)
°゛・xy-2-pyridyl)methylthiokoimidazo[4,5-bl pyridine 150 g Avicel (trade name, manufactured by Asahi Kasei Corporation) 40 g Corn starch 30 g Magnesium stearate 2 g Hydroxypropyl methyl cellulose 10 g Polyethylene glycol 6000 3 g Castor oil
40g ethanol
After mixing and polishing 40 g of the compound of the present invention, Avicel, cornstarch and magnesium stearate, the mixture is tableted using a sugar coating R10n+m machine. 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 5-Methyl-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylthio]imidazo[4,5-b]
Pyridine 150 g citric acid
1.0 g lactose
33.5 g dicalcium phosphate
70.0g Bluronic F-68
30.0 g Sodium lauryl sulfate
15.0g polyvinylpyrrolidone 1
5.0g polyethylene glycol (Carbowax 1500) 4.5
g Polyethylene glycol (Carbowax 6000) 45.0
g Cornstarch 30.0g Dry sodium lauryl sulfate 3.0g Dry magnesium stearate 3.0g Ethanol suitable Kumiki invention compound,
Mix citric acid, lactose, dicalcium phosphate, Pluronic F-68 and sodium lauryl sulfate.

The above mixture was sieved with No. 60 screen, polyvinylpyrrolidone, carbowax 1500 and 6000.
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. No.

10 screen, placed in a tray and dried in an oven at 100°C for 12 to 14 hours. Dry particles No. 1
Sieve through 6 screens, add dry sodium lauryl sulfate and dry magnesium stearate, mix, and compress into desired shape with 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. Further subbing layers and smooth coatings are applied to make the tablet perfectly round and smooth.

Pigmented coatings are applied until the desired shade is obtained. After drying,
Polish the coated tablet to give it a uniform luster.

Formulation Example 3 5-chloro-2-[(3,5-dimethyl-.1-methquin-2-pyrinol)methylthio]imidazo[4,5-b
]Pyridine 5g Polyethylene glycol (molecule @: 4000) 0.3g Sodium chloride 0.9g Polyoxyethylene sorbitan monooleate 0.4
g Sodium metabisulfite 01 g
Methyl-paraben 0.18 g Propyl-paraben 0.02 g Distilled water for injection 10.0 m The above parabens, sodium metabisulfite and sodium chloride are dissolved in about half the amount of distilled water above at 80°C with stirring. The obtained solution was cooled to 40°C, and the compound of the present invention,
Polyethylene glycol and polyoxyethylene sorbitan monooleate are then dissolved in the solution.

The solution is then adjusted to the final volume by adding distilled water for injection, and sterilized by sterile filtration using a suitable filter paper to prepare an injection.

Reference example 1 6-chloro-5-nitronicotinic acid methyl ester 23
Dissolve g in 200 mfl dioxane.

Ammonia gas is introduced into this while stirring at room temperature.

After 10 minutes, the precipitated crystals were collected and recrystallized from dimethylformamide (DMF) to give yellow needle-like 6-amino-5-
18 g of nitronicotinic acid methyl ester are obtained. +++
p195-196°C Reference example 2 6-amino-5-nitronicotinic acid methyl ester Ig
Dissolve in methanol IOmJ. 5%Pd-CO,I
g to absorb hydrogen gas at room temperature and normal pressure. When the theoretical amount of hydrogen has been absorbed, the catalyst is removed and the solvent is distilled off. The residue was recrystallized from ethanol to give yellow needle-like 5.
0.8 g of 6-diamitnicodinic acid methyl ester is obtained. mp154-155°C Reference Example 3 0.2 g of 5.6-diamitnicotinic acid methyl ester is dissolved in DMF5J. To this, Vε carbon dioxide 1.2
ml and stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from DMF to give a yellow powder of 2-mercapto-5-methquine carbonylimidazo[4,5-b
] Obtain 02 g of pyridine. mp233-234°C Reference Examples 4-9 Compounds of the following formulas shown in the table below are obtained in the same manner as in Reference Example 3 using appropriate starting materials.

Example 1 2-mercapto-imidazo[4,5-b]pyridine
1.5 g was dissolved in 50 m of DMF, and 0.88 g of 60% oily sodium hydride was added thereto while stirring under water cooling, and the mixture was stirred at the same temperature for 30 minutes. Next, 2-chloromethyl-
3,5-dimethyl-4-methoquinopyridine hydrochloride 2.2
g and stirred while heating at 70 to 80°C for 3 hours. After the reaction is complete, DMF is distilled off, water is added to the resulting residue, and the mixture is extracted with chloroform. After washing the chloroform solution with water, dry it with magnesium sulfate. After distilling off the chloroform, the residue was recrystallized from ethanol to obtain 2-[(
1.3 g of 3,5-dimethyl-4-methoxy-2-pyridyl)methylthiokoimidazo[4,5-b]pyridine are obtained. mp186-188°C Examples 2-15 In the same manner as in Example 1, using appropriate starting materials, compounds of the general formula (IX4=0) shown in the table below are obtained.

Example 15 2-[(3,5-dimethyl-4-methoxy-2-pyrinol)methylthio]imidazo[4,sb;pyrinone
Dissolve 0.4 g in 40 m chloroform. To this was added 0.27 g of m-chloroperbenzoic acid (85%) while cooling with water and stirring.
and stirred at the same temperature for 20 minutes. After the reaction is completed, the reaction solution is concentrated under reduced pressure, and the residue is washed with ether. 2-[(3,5-
15 g of trimethyl-4-methoxy-2-pyridyl)methylsulfinyl coimigzoC4,5-b''JJ birinone is obtained. m9 169-170°C Examples 16-26 Proceed in the same manner as in Example I5 using appropriate starting materials. Compounds of the general formula (IX4=1) shown in the table below are used.

Example 27 2-chloro-imidazo[4,5-b]pyridine 737m
g, 0.4 g of thiourea and 20 J of ethanol
Heat to reflux for an hour. To this, 2-chloromethyl-3,5
Add 666 mg of -dimethyl-4-methoxypyridine hydrochloride 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 with magnesium sulfate, chloroform is distilled off. The obtained residue was recrystallized from ethanol to obtain a white powder of 2-[(3,5-trimethyl-4-methquine-2).
450 mg of -pyridyl)methylthio]imidazo[4,5-b]pyridine are obtained. mp186-188°C The compound of Example 2-14 is obtained in the same manner as in Example 27 above using appropriate starting materials.

Example 28 6-amino-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylthio]imidazo[4,5-b]
0.2 g of pyridine, 3 mal of water and 0.1 mi of concentrated sulfuric acid,
Dissolve in a mixture with. Add 59 mg of sodium nitrite while stirring at 0°C, and stir at the same temperature for 1 hour. Neutralize with 4N sodium hydroxide aqueous solution and precipitate crystals? take. Recrystallization from ethanol yields a yellow powder of 6-hydroxy-2-[(3,5-dimethyl-4-methoxy-2-
0.2 g of pyridyl)methylthio]imidazo[4,5-b]pyridine is obtained. 1llp178-179.5℃
Pharmacological test H++ prepared from pig stomach + ATPase (adenosine triphosphatase) (protein amount: 10 μg)
Vibsutris [2-amino-2-
(Hydroxymethyl)1,3-propanediol buffer (P1pas-'l'risbufTer Xp
Add to H6, 1) and leave at room temperature.

The test compound is dissolved in dimethylformamide, added to the above H+++ATPase buffer to a final concentration of 1%, and allowed to react at room temperature for 30 minutes.

Next, IJ's 75mM Pipes-Tris buffer (
+)H7,4) (4mM MgCL, 4mM N
atATP, and 20mM KCf) and IJ's 75mM Pipes Tris-buffered tL (pH 7,4) (4
(containing mM Mgc, et and 4 mM Na2ATP) were added separately to form two samples, each of which was reacted for 30 minutes at 37°C. Add 0.3 mjij of 40% trichloroacetic acid to each to terminate the reaction.

Next, it was centrifuged for 10 minutes (3,000 rpi), the supernatant liquid was taken, and the produced inorganic phosphoric acid was
d Subbarow's method [J, Biol, Ch.
Em,.

vol, 66.375 (1925)].

The value obtained by subtracting the amount of inorganic phosphate determined from the Pipes-Tris buffer containing 20 mM KC, 9 from the amount of inorganic phosphate determined from the Pipes-Tris buffer containing 20 mM KC, 9 is calculated per unit protein and unit time. It was expressed in terms of 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, from the obtained inhibition value (%). (Dose of each test compound that inhibits 50%) values were determined. The results are shown in the table below.

Test compound: 1,5-bromo-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]imidazo[
4,5-b] Pyridine 2,2- [(3,5-dimethyl-4-methoquino-2-pyridyl)methylsulfinylcoimidazo[4,5-c] Pyrinone 3,2-(2-pyridylmethylthio)imidazo [4,5
-b] Pyridine (compound disclosed in British Patent No. 1,234゜058) Procedural amendment (spontaneous, May 1985 IO, 1985 Patent Application No. 267061 2, Title of Invention: Imidazopyridine Derivatives 3, Relationship with the case of the person making the amendment Patent Applicant Address 2-9 Kanda Tsukasamachi, Chiyoda-ku, Tokyo Name Otsuka Pharmaceutical Co., Ltd. 4, Agent The following parts of the book will be corrected.

(1) Correct page 33 as shown in the attached sheet (Example 14°
Add).

that's all

Claims (1)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, X and Y are one =CH- group and the other =N
- group, R^1 and R^2 are the same or different and each represents a hydrogen atom, a lower alkoxycarbonyl group,
Halogen atom, lower alkyl group, amino group or hydroxyl group, R^3, R^4 and R^5 are the same or different and each is a hydrogen atom, lower alkoxy group or lower alkyl group, A is a lower alkylene group, l is Indicates 0 or 1. However, when Y is =CH- group, X is =N- group, and l is 0, R^3, R^4, and R^5 are not hydrogen atoms at the same time.] Imidazopyridine derivatives represented by and its salt.