JPH01258670A - Imidazole compound - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I [R<1> is pyridyl; R<2> is lower alkyl or aryl; R<3> is lower alkyl which may contain substituent group (lower alkoxycarbonyl or COOH), NH2 acylamino, OH or SH: R<4> and R<5> are H, lower alkyl, lower alkoxy or halogen; S is O, S or NR<6> (R<6> is H or lower alkyl)] and a salt thereof. EXAMPLE:2-(2-Methyl-5-methoxy-6-benzimidazolyl)-4-methyl-5-(3-pyridyl) imidazole. USE:A drug having antiplatelet action useful for thrombosis. PREPARATION:A compound shown by formula II or a salt thereof is reduced to give a compound shown by formula I or a salt thereof. Or a compound shown by formula IIIa (Ra<3> is R<3> except OH and SH) or a salt thereof is subjected to ring formation or a compound shown by formula IIIb is a salt thereof is reacted with a compound shown by formula IV to give a compound shown by formula Ia or a salt thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION This invention relates to novel imidazole compounds and pharmaceutically acceptable salts thereof.

More specifically, the present invention relates to novel imidazole compounds having pharmacological effects and pharmaceutically acceptable salts thereof;
The present invention relates to a method for producing the same, a pharmaceutical composition containing the same, and a drug therapy using the same.

One object of this invention is to provide new and useful imidazole compounds and pharmaceutically acceptable salts thereof having antiplatelet activity.

Another object of this invention is to provide a method for producing imidazole compounds and salts thereof.

Yet another object of the present invention is to provide a pharmaceutical composition containing the imidazole compound or a pharmaceutically acceptable salt thereof as an active ingredient.

Another object of this invention is to provide a pharmacotherapy for large or veterinary thrombosis by administering said imidazole compound or a pharmaceutically acceptable salt thereof.

Certain imidazole compounds having a substituted or unsubstituted phenyl group at the 2-position of the imidazole ring are known as described in U.S. Pat. be.

The imidazole compound targeted by this invention is novel and can be represented by the following formula [I].

[In the formula, R1 is a pyridyl group, R2 is a lower alkyl group or an aryl group, R3 is a lower alkyl group optionally substituted with alkoxycarbonyl or carboxy, an amine group, an acylamino group, a hydroxy group or a mercapto group, R and R5 each represent hydrogen, a lower alkyl group, a lower alkoxy group, or a halogen, and X represents a group represented by O, S, or NR (in the formula, R6 means hydrogen or a lower alkyl group).

What should be noted about target compound [1F is that when R3 is an amine group, acylamino group, hydroxy group or mercapto group, compound [I] can exist in the following tautomeric form. That's what it means.

(In the formula, Y means an amine group, an acylamino group, a hydroxy group or a mercapto group, Y' means an imino group, an acylimino group, an oxo group or a thioxo group, and R1, R2, R3, R4, R5 and X are has the same meaning).

Although both the above tautomers, namely benzazole type (A) and benzazolidine type (B), are included within the scope of the present invention, in this specification and claims, the formula of the target compound [I] For convenience, it will be expressed as benzazole type (A).

The target compound [I] or a salt thereof can be produced by a production method that can be explained by the following reaction formula.

Production method 1 or its salt or its salt production method 2 or its salt or its salt production method 3 R3-COOH[]V] or its salt or its salt production method 4 or its salt or its salt production method 5 or its salt or A salt thereof or a salt thereof or a method for producing a salt thereof 7 or a salt thereof or a method for producing a salt thereof 8 or a salt thereof or a salt thereof (in the above formula, R7 is an acyl group, R3 is substituted with lower alkoxycarbonyl or carboxy) R4 is a halogen, R5 is hydrogen, a lower alkyl group or a lower alkyl group, and R1, R2, R3, R4, R5, R6 and x are respectively have the same meaning).

In the foregoing and following description of this specification, preferred examples of the various definitions falling within the scope of this invention are explained in detail below.

``Lower ``, unless otherwise specified, shall mean a group having from 1 to 6 carbon atoms.

Suitable lower alkyl groups include straight or branched chain alkyl groups such as methyl, ethyl, propyl, isopropyl, isobutyl, tertiary butyl, pentyl, hexyl, etc., among which are preferred. is C
1-C, alkyl group, most preferably a methyl group or an ethyl group.

Suitable "aryl groups" include phenyl, naphthyl,
Examples include groups such as tolyl, xylyl, mesityl, cumenyl, etc., and among them, phenyl group is preferred.

Suitable mono-lower alkoxycarbonyl groups include straight chain or branched groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, impropoxycarbonyl, butquincarbonyl, tertiary butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc. Examples include chain alkoxycarbonyl groups, and preferred among them are lower alkoxycarbonyl groups having 2 to 4 carbon atoms.

suitable acyl groups, and 1 acylamino group and 1
Suitable acyl moieties of the acylimino group include, for example, lower alkanoyl groups such as formyl, acetyl, propionyl, hexanoyl, pivaloyl, etc., such as benzoyl,
Substituted or unsubstituted aroyl groups such as 3-nitrobenzoyl, 4-chlorobenzoyl, such as methoxycarbonyl, propoxycarbonyl, tertiary butoxycarbonyl, tertiary pentyloxycarbonyl, hexyloxycarbonyl, etc. Examples include lower alkyl dicarbonyl groups, such as al(lower) alkyl dicarbonyl groups such as benzyloxycarbonyl, lower alkanesulfonyl groups such as mesyl and ethanesulfonyl, and arenesulfonyl groups such as benzenesulfonyl and tosyl.

Suitable lower alkoxy groups include straight or branched alkoxy groups such as methoxy, ethoxy, propoxy, impropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, etc. Among them, preferred is C1-C, alkoxy group, and most preferred is methoxy group.

Suitable halogens include fluorine, chlorine, bromine and iodine.

Suitable pharmaceutically acceptable salts of the target compound [I] are conventional non-toxic salts, such as formates, acetates, trifluoroacetates, maleates, tartrates, methanesulfonates, benzenesulfonates. , organic acid addition salts such as toluene sulfonate, inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, phosphate, etc., salts with acidic amino acids such as aspartate, glutamate, etc. Can be mentioned.

Regarding the compounds [Ial to [Ig] of Production Methods 2 to 8, these compounds are included within the scope of compound [I]. Therefore, suitable examples of salts of these compounds are Reference may be made to the salts exemplified for compound [I].

The method for producing the object compound [11] of the present invention will be described in detail below.

Preparation jI The target compound [I] or a salt thereof can be produced by reducing the compound [I] or a salt thereof.

Reduction is carried out by conventional methods, ie chemical reduction or Tsuji catalytic reduction.

Suitable reducing agents that can be used in the chemical reduction include aluminum hydride compounds such as lithium aluminum hydride, sodium aluminum hydride, aluminum hydride, lithium trimethoxyaluminum hydride, lithium tritert-butoxyaluminum hydride, etc. borohydride compounds such as sodium borohydride, lithium borohydride, sodium cyanoborohydride, tetramethylammonium borohydride, borane, diborane, aluminum halides such as aluminum chloride, For example, phosphorous trihalides such as trichloride, phosphorus tribromide, tri(lower) alkyl phosphites such as triethyl phosphite, ferrous iron, metals such as tin, zinc, iron or such as chromium chloride, Examples include a combination of a metal compound such as chromium acetate and an organic or inorganic acid such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, salt 9, or hydrobromic acid.

Suitable catalysts used for catalytic reduction are platinum catalysts such as platinum plates, platinum sponges, platinum black, colloidal platinum, platinum oxide, platinum wires, e.g. palladium sponges, palladium black, palladium oxide, palladium-carbon, colloidal palladium. ,
Palladium catalysts such as palladium-barium sulfate, palladium-barium carbonate, nickel catalysts such as reduced nickel, nickel oxide, Raney nickel, cobalt catalysts such as reduced cobalt, Raney cobalt, iron catalysts such as reduced iron, Raney iron, etc. Commonly used materials include copper catalysts such as reduced steel and Ullmann steel.

The reaction of this production method is usually water, an alcohol such as methanol, ethanol, propatool, acetic acid, diethyl ether, dioxane, tetrahydrofuran, methylene chloride, chloroform, N.

It is carried out in a solvent such as N-dimethylformamide, dimethyl sulfoxide, or any other organic solvent that does not adversely affect the reaction, or a mixture thereof.

The reaction is carried out under cooling, room temperature, heating or heating.

Production method 2 The target compound [Ial or its salt is the compound [11[a
] or a salt thereof can be produced by subjecting it to a cyclization reaction.

Suitable salts of compound [1[[a] include compound [1
] The same examples as those exemplified are listed.

This reaction is usually carried out in the presence of an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, or trifluoroacetic acid, water, an alcohol such as methanol or ethanol, acetic acid, dioxane, etc.
Tetrahydrofuran, N,N-dimethylformamide,
It is carried out in conventional solvents such as dimethyl sulfoxide, etc., or mixtures thereof. If the acids mentioned above are liquids, they can also be used as solvents.

Although the reaction temperature is not particularly limited, the reaction is usually carried out at room temperature, under heating, or under heating.

Production method 3 Target compound [Ia] or its salt is compound [I[[b
or a salt thereof with a compound [IVi or a reactive derivative thereof at the carboxy group or a salt thereof.

Suitable salts of compound [I[bl] include compound [I]
The same salts as those exemplified above can be mentioned.

Suitable reactive derivatives at the carboxy group of compound [11V,] include conventional acid halides such as acid chlorides and acid bromides; acid azides; acid anhydrides; activated amides, activated esters, and the like.

Suitable salts for compound [IV] include the same salts as exemplified for compound [I], as well as basic salts such as alkali metal salts such as lithium salts, sodium salts, and potassium salts.

This reaction can be carried out in substantially the same manner as in 7-,
Therefore, for the reaction method of this reaction and reaction conditions such as acid, solvent, reaction temperature, etc., please refer to the explanation of Production Method 2.

Production method 4 Target compound [Ib] or its salt is compound [1 [[b]
It can be produced by reacting 1 or a salt thereof with compound [V] or a salt thereof.

Suitable salts for compound ['/] include the same salts as exemplified for compound [I].

In this reaction, the imino group of compound [V] is usually
Compound [V] can be activated by reacting with an activating agent such as methyl σ roformate.

This reaction is usually carried out using water, e.g. methanol, ethanol,
Alcohol such as propatool, tetrahydrofuran, dioxane, chloroform, methylene chloride, acetic acid, N, N
- carried out in conventional solvents such as dimethylformamide, dimethylsulfoxide, etc., or mixtures thereof.

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling, at room temperature, under heating, or under heating.

Production method 5 The target compound [Ic] or its salt is the compound [Ill
It can be produced by subjecting bl or a salt thereof to a carbonyl group introduction reaction.

This reaction is performed using phosgene, a haloformate compound such as ethyl chloroformate, trichloromethyl chloroformate, etc.
N,N'-Carbonyldiimidazole, a metal carbonyl compound such as cobalt carbonylcarbonyl, a combination of carbon oxide and a catalyst such as palladium chloride, etc., is carried out in the presence of a reagent that introduces a carbonyl group. .

This reaction is typically carried out using dioxane, tetrahydrofuran, benzene, toluene, chloroform, methylene chloride, N.
Although the reaction is carried out in a solvent such as N-dimethylformamide, the reaction can be carried out in any other organic solvent that does not adversely affect the reaction.

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating.

1. The target compound [1d] or its salt is the compound [III
It can be produced by reacting cl or a salt thereof with ammonium thiocyanate.

Suitable salts of compound [11[cl] include compound [1
The same salts as those exemplified for 1 can be mentioned.

This reaction is carried out in the presence of a cyclizing agent.

Suitable examples of the cyclizing agent used in this reaction include halogens such as bromine, chlorine, and iodine, thionyl halides such as thionyl chloride and thionyl bromide, and halogens such as sulfuryl hachloride and sulfuryl bromide. Examples include sulfuryl chloride.

This reaction is usually carried out in conventional solvents that do not adversely affect the reaction, such as methylene chloride, dichloroethane, chloroform, carbon tetrachloride, acetic acid, propionic acid, or mixtures thereof.

When the cyclizing agent is a liquid, it can also be used as a solvent.

Although the reaction temperature is not particularly limited, the reaction is usually carried out at room temperature, under heating, or under heating.

Production method 7 The target compound [Ie] or its salt is the compound [I[[d
] or a salt thereof with carbon disulfide.

Suitable salts of compound [11[d] include compound [I
] The same salts as those exemplified can be mentioned.

This reaction is usually carried out using alkali metal hydrides such as sodium hydride, potassium hydride, alkaline metal hydrides such as calcium hydride, magnesium hydride, etc.
Alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium bicarbonate and potassium bicarbonate; e.g. sodium methoxide; It is carried out in the presence of a base such as an alkali metal alkoxide such as sodium ethoxide, potassium tert-butoxide, etc.

The reaction is usually carried out in water, an alcohol such as methanol, ethanol, propatool, a solvent such as tetrahydrofuran, dioxane, etc., or a mixture thereof.

Although the reaction temperature is not particularly limited, the reaction is usually carried out at room temperature, under heating, or under heating.

Production method 8 Target compound [1g] or its salt is compound [I f]
Alternatively, it can be produced by reducing its salt.

Reduction can be carried out by conventional methods, ie chemical reduction or catalytic reduction.

Suitable reducing agents that can be used in the chemical reduction include metals such as tin, zinc, iron or metal compounds such as chromium chloride, chromium acetate, and for example formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluene. combination with organic or inorganic acids such as sulfonic acid, hydrochloric acid, hydrobromic acid, etc.
Alkali metal borohydride such as lithium borohydride, sodium borohydride, potassium borohydride, alkali metal cyanoborohydride such as sodium cyanoborohydride, or alkali aluminum hydride such as lithium aluminum hydride Examples include metals.

For suitable catalysts used for catalytic reduction, refer to those exemplified with @.

The reactions in this process are usually carried out in water, alcohols such as methanol, ethanol, propatool, etc., solvents such as acetic acid, diethyl ether, dioxane, tetrahydrofuran, etc., or mixtures thereof.

The reaction is usually carried out under cooling or heating.

Raw material compounds [1[] and [I[[a] to [md]
Among them, some of these compounds are new, and such compounds can be produced by a production method that can be explained by the following reaction formula.

or its salt or its salt or its salt JILDAN or its salt or its salt or its salt or its salt or its salt manufacturing method C or its salt [wherein R8 is hydrogen, hydroxy group, amine group, lower alkylamino group, protected amine group or formula: %Formula% (wherein R3 has the same meaning as before), R8 is N
- protecting group, one of Q and Q2 means 0, the other one means hydroxyimino group, R1, R2, R3, R4, R5, R6 and X each have the same meaning as before.

Suitable "lower alkylamino groups" include straight chain or branched groups such as methylamino, ethylamino, propylamine, inpropylamine, butylamino, isobutylamino, tertiary butylamino, pentylamino, hexylamino, etc. Chain alkyl groups are mentioned.

Suitable rN-protecting groups include substituted or unsubstituted lower alkanoyl groups such as formyl, acetyl, propionyl, trifluoroacetyl, phthaloyl groups,
For example, lower alkoxycarbonyl groups such as tertiary butoxycarbonyl, tertiary amyloxycarbonyl, substituted or unsubstituted aralkoxycarbonyl groups such as benzyloxycarbonyl, p-benzyloxycarbonyl, etc., such as benzenesulfonyl, etc. Examples include substituted or unsubstituted arenesulfonyl groups such as tosyl, nitrophenylsulfenyl groups, and aralkyl groups such as hatrityl and benzyl.

The method for producing the raw material compounds [ff], [IIr] and [Xb] will be explained in detail below.

Manufactured aS capture Δ Compound [1 [] or a salt thereof can be produced by reacting compound [■] or a salt thereof with compound [■] or a salt thereof in the presence of ammonia or a reagent that liberates ammonia. can.

Suitable salts for compound [VI] include the same salts as exemplified for compound [1], and further basic salts such as alkali metal salts such as lithium salts, sodium salts, and potassium salts.

Suitable salts for compound [■] include the same salts as exemplified for compound [I].

This reaction is usually carried out using water, e.g. methanol, ethanol,
alcohols such as propyl alcohols, common solvents such as acetic acid, dioxane, tetrahydrofuran, methylene chloride, chloroform, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, or any other organic solvent that does not adversely affect the reaction; or in a mixture thereof.

Suitable reagents for liberating ammonia include, for example, ammonium formate, ammonium acetate, ammonium propionate, ammonium lower alkanoates such as ammonium butyrate, ammonium carbonate, ammonium hydrogen carbonate, ammonium carbamate, and the like.

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling, at room temperature, under heating, or under heating.

Production method B Kanyoko 1 Compound [IX] or its salt is produced by reacting compound [VI] or its salt with compound [■] or its salt in the presence of ammonia or a reagent that liberates ammonia. be able to.

Suitable salts for compounds [■] and [■] include the same salts as exemplified for compound [I].

This reaction can be carried out substantially in the same manner as Production Method A, therefore, for the reaction method of this reaction and reaction conditions such as reagents for liberating ammonia, solvents, reaction temperature, etc., see the explanation of 1. do it.

Second step Compound [Xl or a salt thereof can be produced by reducing compound [IX] or a salt thereof.

Suitable salts for compound [Xl include the same salts as exemplified for compound [I].

This reaction can be carried out in substantially the same manner as in 7, and therefore, the explanation at @ may be referred to for the reaction method of this reaction and reaction conditions such as solvent, reducing agent, catalyst, reaction temperature, etc.

Under these reaction conditions, nitro groups may also be reduced to amino groups.

Third step Compound [1[[] or a salt thereof can be produced by reducing compound [Xl or a salt thereof.

Suitable salts of compound [1111 include compound [I]
The same salts as those exemplified for are mentioned.

Reduction is carried out by conventional methods, ie chemical reduction or catalytic reduction.

Suitable reducing agents used in the chemical reduction include, for example, combinations of metals such as tin, zinc, iron and ammonium chloride or bases such as ammonia, sodium hydroxide; A combination of a metal compound such as formic acid, acetic acid, propionic acid, triple oroacetic acid, tri-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, or an organic acid, such as lithium borohydride, hydrogenated Examples include alkali metal borohydrides such as sodium boron and potassium borohydride, alkali metal cyanoborohydrides such as sodium cyanoborohydride, and alkali metal aluminum hydrides such as lithium aluminum hydride.

For suitable catalysts used in catalytic reduction, see Preparation Method 1
You can refer to the example given in .

The reactions in this process are usually carried out in water, alcohols such as methanol, ethanol, propatool, etc., solvents such as acetic acid, diethyl ether, dioxane, tetrahydrofuran, etc., or mixtures thereof.

The reaction is carried out under cooling or heating, or under heating.

Production method C Compound [Xb] or a salt thereof can be produced by subjecting compound [Xa] or a salt thereof to an amino-protecting group elimination reaction.

Suitable salts of compounds [Xa] and [Xb] include:
The same salts as those exemplified for compound [1] can be mentioned.

This elimination reaction can be carried out by a conventional method, and the reaction methods such as hydrolysis and reduction, as well as the reaction conditions such as acid, base, catalyst, solvent, and reaction temperature, are as follows: Refer to conventional reaction methods.

Among the raw material compounds [■] and [■], some of them are new, and such compounds can be produced by the methods of the production examples described below, or by the production field of compounds structurally similar to them. It can be manufactured by any method known in the art.

The compound obtained by the above production method can be isolated and purified by conventional methods such as pulverization, recrystallization, column chromatography, reprecipitation and the like.

The novel imidazole compound [I] and its pharmaceutically acceptable salts have antiplatelet effects and are useful in the drug treatment of thrombosis.

For therapeutic purposes, the compounds [I] of this invention and their pharmaceutically acceptable salts may be combined with pharmaceutically acceptable carriers such as organic or inorganic solid or liquid excipients suitable for oral, parenteral or topical administration. The mixture can be used in the form of a pharmaceutical preparation containing one of the compounds mentioned as active ingredient. Pharmaceutical preparations include capsules,
Examples include tablets, sugar-coated tablets, granules, solutions, suspensions, and emulsions. If desired, auxiliaries, stabilizers, wetting agents or emulsifiers, buffers and other commonly used additives may be included in these formulations.

The dosage of Compound [1] varies depending on the age and condition of the patient, but the average single dose of Compound [I] is approximately 0.1 m
g, 1 mg, 10 mg, 50 mg, 100 m
Administration of 250n+g, 500m&, 1000mg is effective in treating the above-mentioned diseases. Generally O,
An amount between 1 mg/individual and about 1000 mg/individual may be administered per day.

In order to explain the usefulness of the target compound [11], the compound [
The pharmacological test results for several of the 11 representative compounds are shown below.

2-(2-methyl-5-methoxy-6-benzimidazolyl)-4-methyl-5-(3-pyridyl)imidazole (hereinafter abbreviated as compound a).

2-(2-methyl-4-methoxy-7-chloro-5-benzimidazolyl)-4-methyl-5-(3-pyridyl)imidazole (hereinafter abbreviated as compound).

2-(5-methoxy-2-hydroxy-6-benzimidazolyl)-4-methyl-5-(3-pyridyl)imidazole (hereinafter abbreviated as compound C).

Platelet-rich plasma (PRP) containing 6-7 x 108 K violet platelets was prepared from rabbit blood. PRP2004
11 calcium chloride 54 and 120mM NaCl
25mM Tris-acetic acid (pH 7,4) containing 501
ali and test compound were added sequentially, then at 37°C.
The mixture was stirred for 2 minutes.

Collagen (2,54/all) 54 was added to this solution as an aggregation inducer. Agglomeration is measured using an ablebometer (N
KK, hair-), laser 1) was used for measurement.

The aggregation-inhibiting activity of the test compound was expressed as IC5-1, ie, the dose required to inhibit 50% of platelet aggregation.

Grave! Male Spragard Cree rats weighing 250 g were used after being fasted overnight. One hour after oral administration of test compound or test compound carrier (vs. WA), blood was collected into tubes containing 0.1 volume of 3.8% sodium citrate. Collagen (final concentration 5, 0Pd) in blood 0.4511112
I/N) 0.05- and then heated at 37°C under shaking.
Incubated for 5 minutes. 10mM phosphate buffered saline containing 11.5mM EDτA and 1% formalin 1
70Xg of the zero reaction mixture that was stopped by adding acupuncture needles
The platelets were centrifuged for 5 minutes, and the number of platelets in the upper phase was measured using a Technifun Auto Analyzer. Blood/J% plate aggregation was calculated according to the following formula.

Platelet aggregation (%) -"-X100 A: Number of platelets after addition of collagen carrier B: Number of platelets after addition of flagen Test The aggregation inhibition rate by the compound was calculated according to the following formula.

Inhibition (%) [--L toyou x 100 C: Platelet aggregation of control (%) D: Platelet aggregation of test compound (%) Blood was taken from the carotid artery of a domestic rabbit, and 0.1 volume of 3.8% sodium citrate was added. Collected in a plastic container containing Platelet-rich plasma (PRP) was prepared by centrifugation at 150 g for 15 minutes. Ablebometer (NKK) for platelet aggregation
Tested using the turbidity method with the Hemertracer 1). Add 25 drops of test compound solution to PRP2251J,
The mixture was then stirred at 37° C. and 11,000 rpm for 2 minutes. 9,11-azo PGH2 (final concentration 1.0 lM) 54 was added to the solution as an aggregation inducer.

Part j1 Kushu (hereinafter referred to as ♀i) This invention will be described below in accordance with the Production Examples and Examples.
This will be explained in more detail.

K Kei Yu
Medel Q4-acetylamino-5-chloro-2-methoxybenzoate (45 g) was dissolved in fuming nitric acid (specific gravity 1.42).
) (160 m) at -35°C to -20°C with stirring, and the mixture was stirred for 10 minutes at -25°C to -20°C. The reaction mixture was poured into ice water and the precipitate was dissolved. Collect by filtration. Dissolve the precipitate in ethyl acetate, wash with brine, and dry over magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is triturated with 1 l of diisopropylether. Methyl acedelamino-5-chloro 40-2-methoxy-3-nitrobenzoate (46.5 g) is obtained.

mp: 129-131℃ IR (streak rule): 3300. 1700.
1600. 1560°1540 am-1 NMR (DMSO-d6.δ): 2.10 (3H, s
), 3.95 (6H.

s), 8.17 (IH, s), 10.33 (I
H,5) 11 weeks 1 Iron (15,9 g) and ammonium chloride (1,7 g>
) 4-acetylamino-5-crogo 2
-Methoxy-3-nitrobenzoate] 15.1 g)
is added in small portions at 80°C to 90°C with stirring, and the mixture is refluxed with stirring for 1 hour. The reaction mixture was filtered, the solvent of the filtrate was distilled off under reduced pressure, and one residue was dissolved in ethanol. The solvent of the solution was distilled off under reduced pressure, and the residue was triturated with diethyl ether to give methyl 4-acetylamino-5-chloro-2-methoxy-3-aminobenzoate (13,
6g) obtained)・mp: 143-145℃ IR (streak seal): 3300 (sh),
3230. 3160 (sh).

1730, 1650.1600.1510 crn-'
NMR (DMSO-ds, 8)' 2-08 (3
H-s), 3-73 (3H1s), 3.83 (3
H, s), 6.95 (LH, s), 7.48 (2
H, br s), 9.52 (IH, br s) Production Example 3 In the same manner as in Production Example 2, 4-7'' tylamino- Methyl 2-chloro-5-aminobenzoate is obtained.

mp: 153-156°C IR (line silicon): 3425. 3355.
3240. 1700. 1655°1600, 15
75.1510.1490 cm'NMR (DMSO-
d6. δ)' 2.10 (3H,s), 3.81
(3) 1°s), 7.25 (LH,s), 7.
72 (IH, s), 9.50 (LH, br s) Production example 4 4-acedelamino-5-chloro-2-methoxy-3-
Methyl aminobenzoate (13,6 g) and sulfuric acid (LO
mQ) A solution of nomethanol (200 mu) is refluxed under stirring for 1 hour. The solvent of the reaction mixture is distilled off under reduced pressure and the residue is dissolved in a mixture of ethyl acetate and water. Add this solution to 20
% potassium carbonate aqueous solution to pH 8.0, and extracted with ethyl acetate. The extract is washed with brine and dried over magnesium sulfate. '/a medium was distilled off under reduced pressure, and the residue was ground with diethyl needles to give 2-methyl-4-methoxy-5-methoxycarbonyl-7-chlorobenzimidazole mp: 188-191°C IR (streak a). -L＞' 1730.17
10. 1625. 1540 am-INMR
(DMSO-d δ): 2.56 (3H.s
), 3.85 (3H.

6.

s), 4.17 (3H,br s), 7
. 53 (IH,s)Mass (M/Z) ' 2
54 (M-1)1 Keishi 1 In the same manner as in Production Example 4, 2-methyl-5-chloro-6-
Obtain medoxycarbonylbenzimidazole.

mp: 114 (18℃ IR (line 1-l)? 3380.17
25. 1700. 1630, 1580.

1535 cm-1 NMR (DMSOda.E)' 2.58 (3
H. s), 3. 92 (3H.

s), 7.65 (IH, s), 8.00 <IH
．． s), 8.36 (IH.s) ju1 iron (15.9g) and ammonium chloride (1.7g)
Methyl 2-methoxy-4-acetylamino-5-nitrobenzoate (13.4 g) was added to a mixture of ethanol (200111 fl') and water (40 cm) in a mixed solvent at 80°C to 90"C under stirring. The reaction mixture is filtered and the filtrate is evaporated under reduced pressure. The oily residue is dissolved in a mixture of chloroform and methanol (9:1, v/v). ) !=
Dissolve and dry over magnesium sulfate. The solvent is distilled off under reduced pressure to obtain a residue containing methyl 2-methoxy-4-acetylamino-5-aminobenzoate. Dissolve this residue in a mixture of methanol (200 mQ) and sulfuric acid (6-alpha). This solution is refluxed for 1 hour while stirring. The solvent of the reaction mixture is distilled off under reduced pressure, and the residue is dissolved in a mixture of ethyl acetate and water. Adjust this solution to 8.0 with a 20% aqueous potassium carbonate solution and extract with ethyl acetate. Dry the extract with magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was triturated with diethyl ether to give 2-methyl-5
-Methoxy-6-medoxycarponylbenzimidazole (5.64 g) is obtained.

mp: 167 (69℃ IR (Suji Meal) '1720.16
40, 1590. 1545 am-'NMR
(DMSO-ds,l; )' 2.50
(3) 1,s), 3.80 (3H.

s), 3.87 (3H.s), 7.13 (IH.s), 3.87 (3H.s), 7.13 (IH.
．． s), 7.97 (IH.s) Production Example 7 2-Methyl-
5-Methoxy-6-medoxycarponylbenzimidazole (11.3 g) is added portionwise at 50 DEG to 60 DEG C. with stirring and the mixture is refluxed with stirring for 5 hours. The reaction mixture was poured into a mixture of ethyl acetate and ice water and 10%
Adjust the pH to 7.0 with hydrochloric acid and filter. Dry the organic layer with magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixture of ethyl acetate and acetone to give 2-
Methyl-5-methoxy-6-hydroxymethylbenzimidazole (5.92 g) is obtained.

mp: 193-195℃ IR (streak seal): 1635. 1595.
1540 cm-”NMR (DMSO-9, S
)' 2.45 (34s), 3.97 (3B.

s), 4.62 (2H, s), 7.00 (I
H,s), 7.50(LH,5) 11yo1 The following compound is obtained in the same manner as in Production Example 7.

(1) 2-Methyl-4-methoxy-5-hydroquinemethyl-7-chlorobenzimidazole.

mp: 161-163'c IR (X Dit-R)' 1625. 1590.
1540 cm-'NMR (DMSO-ds, δ)
: 2.53 (31 (, s), 4.13 (3H.

s), 4.60 (2H, s), 7.22 (IH
, 5) (2) 2-Methyl-5-chloro-6-hydroxymethylbenzimidazole.

mp: 119-122℃ IR<Zjihot-L): 1625. 1535
c+m-m-1N (DMSO-ds, δ): 2
．． 45 (3H, s), 4.72 (2H.

s), 7.44 (1B, s), 7.60 (LH
,s>jli and lithium aluminum hydride (4.95g) in tetrahydrofuran (7oom) was added methyl 4-acetylamino-2-methoxy-5-nitrobenzoate (35
, 0g) was added in small portions at -30°C to -10°C with stirring, and the mixture was stirred for 3 hours at -20°C to -10°C. The reaction mixture was poured into a mixture of ethyl acetate and ice water, and the mixture was poured into a mixture of ethyl acetate and ice water. Acidify to pH 2.0 with 10% hydrochloric acid. 11JII was collected, washed with brine, and dried over magnesium sulfate. The solution was concentrated under reduced pressure and the crystalline residue was collected by filtration to obtain 4-acedelamino-2-methoxy-5-nitrobenzyl alcohol (17.2 g).

mp: 165-167℃ IR (Stripe 1-L)! 3480. 3350.
1700. 1625. 1595,)505 am
-1 NMR (DtfSO-ds, l; ) ” 2.13
(3H1s), 3°87 (3H.

s), 4.50 (2)1. d, J=6Hz>, 5
．． 30 (IH, t.

J:6)1z), 7.63 (1)t,s), 8.
07 (LH,s), 10.33(1)1. s) Methyl isobutyl ketone (zoomn) of 2-methyl-5-methoxy-6-hydroxymethylbenzimidazole (5.8 g) and activated manganese dioxide (30 g) manufactured by J.
The warm mixture is refluxed for 1 hour with stirring. Filter the reaction mixture and cool the filtrate. The precipitate was collected by filtration and 2-methyl-5-
Methoxy-6-formylbenzimidazole (4,46
g) is obtained.

mp: 208-210℃ IR (streak seal): 1665. 1625.
1585. 1540 am-INMR (DMSO
-ds, S>' 2.55 (3H1s), 3.9
7 (3t(.

s), 7.53 <LH, s), 7.83 (LH
,s), 10.43(LH,5) 11 Obtain the following compound in the same manner as in Preparation Example 10.

(1) 2-methyl-4-methoxy-5-formyl-7-
Chlorobenzimidazole.

mp: 239-240°C IR (streak tool): 3150. 165(]
, 1610. 1585°1550 cm-1 NMR (DMSO-ds, δ): 2.57 (3H
,s), 4.42 (3H.

s), 7.45 (LH, s), 10.33 (
IH, s) Mass (M/Z): 224

mp: 123 (25°C IR (X di++-): 3300. 1700.
1615. 1580. 1530°1505 cr
s-” NMR (DMSO-d, δ): 2.20 (3H
,s), 4.00 (3)1゜s), 7.75
(IH,s), 7.97 (IH,s),
10.20 (LH, s), 10.55 (LH, 5)
(3) 4-acetylamino-2-methylbenzaldehyde.

mp: 104 (07°C IR (X-J: 3425.3275.
3175. 3090. 1708°1650, 159
0.1515 am'(4>2-methyl-5-chloro-
6-Formylbenzimidazole.

mp + 180-184℃ IR (S9-11,) + 1680.1622.15
85.1540 am-1 NMR (CDCl2.S
): 2.20 (3H,s), 3.90 (6H
,s).

7.50-7.82 (2H, m), 8.02 (
LH, br s), 8.47 (IH, d, J=8H
z) Production of IM 4-acetylamino-2-methyl-5-nitrobenzaldehyde is obtained in the same manner as in Production Example 1.

mp: 98-102°C IR: 3320. 1695.
1615. 1565. 1535°1500 am
"" NMR (DMSO-d6.δ): 2.16 (3H
,s), 2.65 (3H.

s), 7.80 (IH, s), 8.41 (IH
,s), 10.15(18,s), 10.48(
IH,br s)Mass (M/Z)' 222
(M”) 1-hydroxyimino-1-(3-pyridyl)acetone (3,8 g), 2-methyl-5-methoxy-6-formylbenzimidazole (4,4 g) and ammonium acetate ( A solution of 17.8 g) in acetic acid (70 ml) was added to 10
The solvent of the reaction mixture, which is stirred at 0° C. to 110° C. for 2 hours, is distilled off under reduced pressure and the residue is dissolved in a mixture of ethyl acetate and dilute hydrochloric acid. The aqueous layer was separated, adjusted to pH 18.0 with 20% potassium carbonate, and extracted with a mixture of chloroform and methanol (9:1, v/v). Dry the extract with magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was crystallized from acetone to give 1-hydroxy-2-(2
-Methyl-5-methoxy-6-benzimidazolyl)-
4-methyl-5-(3-pyridyl)imidazole (8,
4g) is obtained.

IR (striped seal): 1630. 1585.
1560. 1530 cm-'NMR (D20+
DC1,8): 2.70 (3H,s),
3.07 (38°s), 4.20 (3H,s
), 7.70 <IH,s), 8.36-8.63
(LH, m>, 8.53 <IH, s), 8.83
-9.27 (2H, m).

9.37 (IH, !11> Jugeki Shi B 1-Hydroxyimino-1-(3-pyridyl)acetone (3, asg), 2-methoxy-4-acetylamino-
A solution of 5-nitrobenzaldehyde (5.0 g) and ammonium acetate (16.2 g) in acetic acid (70111+1) was stirred at 100°C to 110°C for 30 minutes.
The reaction mixture is evaporated under reduced pressure and the residue is dissolved in a mixture of water and ethyl acetate. This solution is acidified to pH 1.0 with 10% hydrochloric acid. The aqueous layer is separated, ethyl acetate is added, and the pH is adjusted to 7.0 with a 20% aqueous potassium carbonate solution. The precipitate was collected by filtration, washed with water and ethyl acetate, and dried to give 1-hydroxy-2-(2-methoxy-4-acetylamino-5-nitrophenyl)-4-methyl-5.
-(3-pyridyl)imidazole (5.17 g) is obtained.

mp: 182-183°C IR: 3470. 3350.
1700. 1620. 1590°1500 cm
-” NMR (DMSO-d6.δ): 2.43 <38
．． s), 2.63 (3H.

s), 4.12 (3H, s), 8.17 (LH
, s), 8.48 (LH, dd, J=5.8Hz),
8.83-9.27 (2H, m).

9.05 (IH, s), 9.33 (IH, d, J
:2Hz) Production Example January The following compound was obtained in the same manner as Production Example 13 or 14.

(1) 1-Hydroxy-2-(2-methyl-4-methoxy-7-chloro-5-benzimidazolyl)-4-methyl-5-(3-pyridyl)imidazole.

mp: 115-117°C (decomposition) IR (threshold): 1620. L530
cm-1(2)1-hydroxy-2-(2-methyl-
5-chloro-6-benzimidazolyl)-4-methyl-
5-(3-pyridyl)imidazole.

mp: 126-142℃ IR (streak seal): 1675. 1620.
1540 am-'NMR (DMSO-d6.δ)
: 2.28 (3)1. s), 2.50 (3H
.

s), 7.30-8.15 (4H, m), 8.4
0-8.85 (2H,m)(3)1-hydroxy-2
-(2-Methyl-4-acetylamino-5-nitrophenyl)-4-methyl-5-(3-pyridyl)imidazole.

mp: 125-153℃ IR (streak seal): 3340. 1690.
161g, 1568 cm-'NMR (DMS
O-d6. ε): 2.26 (3Ls), 2.3
8 (3H.

s), 2.56 (3H, s), 7.58 (LH
, dd, J=8Hz.

51(z), 7.80 (IH,s), 8.
05 (IH, ddd, J=8Hz.

21 (Z, 2Hz), 8.20 (LH, s),
8.55 (LH, dd.

J=5Hz, 2Hz), 8.83 (IH, d
J=2Hz>, 10.42<LH,'5) (4) 1-hydroxy-2-(4-hydroxy-3-nitrophenyl)-4-methyl-5-(3-pyridyl)imidazole.

mp: 175178°C (decomposition)-IR (7-dihin-L); 1620. 1575
．． 1540. 1510 am-1MMR (DzO
+DC1,6i) =2.67 (3H,s), 7
-44 (LH9d, C9Hz), 8.22 (IH
, dd, J=2Hz, 9)1z), 8.53(LH
, ddJ=5) 1z, 8Hz>, 8.80 (1M
, d, J=2Hz).

9.00-9.29 (2H, m), 9.40 (I
H, d, J = 2Hz) (5) 1-hydroxy-2-(4
-acetylamino-3-nitrophenyl)-4-methyl-5-(3-pyridyl)imidazole.

mp: 175 (79℃ (decomposition) IR (Sujiwor) i 3300. 1720.
1625. 1570. 1550°1500 cm
-1 NMR (D O + DC1, δ): 2.39 (3H
,s), 2.67 (3H.

s), 8.30 (2H, s), 8.50 (LH
, ddJ=5Hz.

8Hz), 8.83 <IH,s), 9.00-9
．． 30 (2t(,m).

9.36 (LH, d, J=2Hz) (6) 1-hydroxy-2-(6-medoxy1.2-
Dimethyl-5-benzimidazolyl)-4-methyl-5
-(3-pyridyl)imidazole mp: 178-1
85°C (decomposition) IR (streak*-4)' 1630. 1590.
1570. 1520 am-'(7)2-(7-
Chloro-4-methoxy-2-methyl-5-benzimidazolyl)-1-hydroxy-5-methyl-4-(4-pyridyl)imidazole mp: >250°C IR (strange 3-l): 1605. 1540
cm-1(8)2-(7-chloro-4-methoxy-2
-Methyl-5-benzimidazolyl)-1-hydroxy-4-phenyl-5-(3-pyridyl)imidazole mp: 204-209°C (decomposition) IR (streak 9-IL)' 1630. 1540
cm'-1MMR (DI'l5O-d δ)
: 2.56 (3H, s), 4.08 (3H.

6゜s), 7.20-8.80 (10H, m) (9)
2-(4-amino-3-chloro-2-methoxy-5-nitrophenyl)-1-hydroxy-4-methyl-5-(
3-pyridyl)imidazole mp: 145-150
°C (decomposition) IR (sujiwor): 1625. 1555.
1500 am-1 MMR (DMSO-ds, l;
)' 2.28 (3H-s), 3-75 (3H
9s), 7.30-7.70 (2H, m), 7.
98 (IH, dd, J=3°7Hz), 8.55
(IH, d, J=7Hz), 8.76 (IH, 5)
(10) 1-hydroxy-2-(5-methoxy-2-
Methyl-6-benzimidazolyl)-4-phenyl-5
-(3-pyridyl)imidazole mp: 207-2
11°C IR (X dit4): 1640. 1600.
1545 cm-1MMR (DMSO-dS)
: 2.60 (3H,s), 3.85 (34(
.

6゜s), 7.00-8.20 (11H, m) 11 1-hydroxy-2-C2-,,'t→C4-7cetylamino-5-nitrophenyl)-4-methyl-5 −
A solution of (3-pyridyl)imidazole (5,1 g) and triethyl phosphite (3,3 g) in N,N-dimethylformamide (4oma) is stirred at 80°C to 90°C for 1 hour.The reaction mixture is poured into water. This mixture is stirred for 30 minutes at room temperature. The precipitate was collected by filtration and recrystallized from a mixture of chloroform and methanol to give 2-(2-methoxy-4-acetylamino-5-nitrophenyl)-4.
-Methyl-5-(3-pyridyl)imidazole (2,6
5g).

mp: 220-221°C IR: 3350. 1700.
1620. 1585. 1580°1530 am
−' NMR (DMSO-ds, l; >' 2.20 (
3H,s), 2.58 (3H9s), 4.11 (
3H, s), 7.47 (IH, dd, J=5.8H
z).

7.90 (LH, +), 8.12 (LH, dt,
J=2.8Hz).

8.48 (LH, dd, , C2, 5Hz>, 8.7
7 (LH,s).

8.95 (LH, d, J=2Hz>, 10.42
(LH, br s).

11.70 <IH, m) Production example 17 The following compound is obtained in the same manner as in Production Example 16.

(1) 2-(2-methyl-4-acetylamino-5-nitrophenyl)-4-methyl-5-(3-pyridyl)imidazole.

mp: 234-238°C IR: 3305. 1675.
1620. 1600. 1570°1500cm
'NMR (DMSO-ds-8)' 2.15 (3)
1. s), 2.58 (3)1゜s), 2.76 (
3H, s), 7.48 (IH, dd, J=8Hz.

5Hz>, 7.75 (IH, 5>, 8.13 (
1)1. ddd, J=8Hz.

2) 1z, 2Hz), 8.32 <LH, r>,
8.49 <IH, d.

J=5Hz), 8.99 (LH,s), 10.3
5 (IH,s)<2) 2-(4-hydroxy-3-nitrophenyl)-4-methyl-5-(3-pyridyl)imidazole.

mp2 146-148°C (decomposition) IR (stainless steel): 1620. 1575.
1540. 1510 cm'(3) 2-(4-acetylamino-3-nitrophenyl)-4-methyl-5
-(3-pyridyl)imidazole.

mp: 260-265°C (decomposition) IR (streak 1-l): 3350. 1700.
1625. 1600. 1585°1540, 15
00 cm-1 NMR (DMSO-ds, 8)' 2.13 (3
H1s>, 2.50 (3H1s), 7.47 (L
H, dd, J: 5Hz, 8Hz), 7.83 (I
H.

d, J=9Hz), 8.00-8.63 (3H, m
), 8.55 (IH.

dJ=2Hz), 8.95 (IH, d, J=2Hz
), 10.37<LH,ri(4>2-(4-amino-3-chloro-2-methoxy-
5-nitrophenyl)-4-methyl-5-(3-pyridyl)imidazole mp: 216-222°C (decomposition) IR (sudital): 3490. 3400.
1620. 1550°1490 cm-' NMR (DMSO-da, 8)' 2-53 (3
H9s), 3,89 (3H9s), 7.30-7.
70 (2H, m), 8.08 (IH, d.

J=7Hz), 8.45 (IH, d, J-7Hz)
, 8.91 (LH,s)] Mouth weight ■ 2-(2-methoxy-4-acetylamino-5-2)・
lophenyl)-4-methyl-5-(3-pyridyl)imidazole (8.6 g) (7) 6N hydrochloric acid (100 mm
) m solution for 2 hours at 85°C to 90"C. Pour the reaction mixture into a mixture of ethyl acetate and water, and adjust the solution to 18.0% with 20% aqueous potassium subacid solution. Yes The m-layer was separated, washed with brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was triturated with diethyl ether to give 2-(2-methoxy-4-amino-
5-nitrophenyl)-4-methyl-5-(3-pyridyl)imidazole (7.6 g) is obtained.

mp: 245-248°C (decomposition) IR (19p-J: 3450.3360.
3280. 3150. 1630°1600, 157
0.1560 am-1 HMR (D20"DCl-1;
)' 2.57 (3H,s), 3.97 <3
H1S), 6.38 (LH,s), 8.30
(!H,s), 8.30 (IH.

dd, J: 5.8Hz), 8.77-9.18 (2
H, m>, 9.18 (IH, d, J = 2 Hz) Production example 19 Iron (3.2 g) and ammonium chloride (0.34 g)
Noetair (150mm) and water (20+111
) in a mixed solvent with 2-(2-methoxy-4-
Amino-5-nitrophenyl)-4-methyl-5-(3
-pyridyl)imidazole (3.25 g) under stirring
C. to 85.degree. C. in portions and the mixture is refluxed under stirring for 3 hours.The reaction mixture is filtered and the filtrate's solvent is distilled off under reduced pressure. The residue is dissolved in a mixture of chloroform and water (9:1, v/v) and dried over magnesium sulphate. The solvent was distilled off under reduced pressure to give 2-(2-methoxy-4,5-diaminophenyl)-4-methyl-5.
-(3-pyridyl)imidazole (2.5 g) is obtained.

mp: 102-105°C (decomposition) IR (sugital): 1625. 1580.
1510 cm-'NMR (DMSO-da, ε
): 2.57 (3H, m), 3.9
0 (3H.

m), 6.40 (5H, m), 7.47 (IH
, s), 7.47 (LH.

ddj=5.8Hz), 8.10 (IH, dt, J
=2.8Hz).

8.55 (IH, dd, J=2.5Hz), 8.9
3 <IH, d.

J=2H2) Rabbit jU milk 2-(4-hydroxy-3-nitrophenyl)-4-methyl-5-(3-pyridyl)imidazole (8.2g)
and 10% palladium-carbon (approximately 50% wet, 3 g)
A mixture of methanol (2001119) and tetrahydrofuran (100 mQ) in a mixed solvent was subjected to catalytic reduction in a hydrogen gas atmosphere at atmospheric pressure at room temperature for 5 hours. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel, eluting with a mixture of chloroform and methanol (9:1, v/v). Fractions containing the desired compound are combined and concentrated to give 2-
(4-hydroxy-3-aminophenyl)-4-methyl-5-(3-pyridyl)imidazole (19 g) is obtained.

mp: >280℃ IR (streak hole)! 1605. 1585.
1565. 1540°1505 am-" NMR (DMSO-ds, 8)' 2.47 (3
H9s), 6-73 (LH9d.

J=9Hz>, 7.10 (1B, dd, J=2Hz
, 9Hz>, 7.35 (IH, d, J=2Hz), 7.
47 (LH, ddJ=5Hz, 8Hz).

8.07 (1)1. dt, J=2Hz, 8)1
z), 8.43 (IH, dd.

J=2Hz, 5Hz), 8.93 (IH, d, J=
2Hz) Production Example 21 2-(2-methoxy-4-methylamino-5-nitrophenyl)-4-methyl-5-(
3-pyridyl)imidazole is obtained.

mp: >250℃ IR (Sujoor): 3380. 1620.
1565. 1535°1490 am-1 NMR (DMSO-d6+DC1, δ): 2.60
(3H,s>, 3.08<3H,s>, 4.1
1 (3)1. s), 6.42 (LH, s)
, 8.24 (LH, dd, J=6.9Hz>,
8.78-9.06 (3H, m).

9.30 (IH,s) 3% (1-hydroxy-2-(2-methyl-5-methquine-6)
-benzimidazolyl)-4-methyl-5-(3-pyridyl)imidazole (7,3 g) and triethyl phosphite (8,7 g) in N,N-dimethylformamide (70
m) Stir the solution at 80°C to 90°C for 1.5 hours. The reaction mixture is poured into water, the mixture is acidified to pH 1.0 with 10% hydrochloric acid and washed with chloroform.

Adjust the aqueous layer to pH 8.0 with 20% potassium carbonate! jl adjustment,
A mixture of chloroform and methanol (9:1, v/v
) to extract. Dry the extract with magnesium sulfate. The solvent is distilled off under reduced pressure and the residue is subjected to column chromatography using alumina, eluting with a mixture of chloroform and methanol (97:3, v/v). The eluate was concentrated under reduced pressure and the residue was recrystallized from a mixture of ethyl acetate and methanol to give 2-(2-methyl-5-methoxy-6-benzimidazolyl)-4-methyl-5-(
3-pyridyl)imidazole (4.0 g) is obtained.

mpi 202-204°C (decomposition) IR (streak 1-l): 3320. 1625.
1595. 1560 cm-IN MR (DMS
O-d s, 8)' 2-52 (3H, s)
, 2-53 (3H.

s), 3.97 (3H,s), 7.17 (
IH, s), 7.40 (1)! .

dd, J=5. 88Z), 8.09 (IH, d
t, J=2. 8Hz).

8.19 (1)! , s), 8.43 (IH,
dd, J=2. 5Hz).

8.98 (IH, d, J: 2i1z) 亥】J The following compound is obtained in the same manner as in Example 1.

(1) 2-(5-chloro-2-methyl-6-benzimidazolyl)-4-methyl-5-(3-pyridyl)imidazole.

mp 7189-194℃ IR (Sujoor): 1730. 1670,
1625. 1590°1560 cm-' NMR (DMSO-d6.δ): 2.51 (3H
,s), 2.54 (3H.

s), 7.43 (IH, dd, J=8Hz, 5H
z), 7.60 (IH.

s), 7.80 (LH, s), 8.07 (IH
, d, J=8Hz>.

8.45 (IH, d, 5Hz), 8.95 (I
H, s) Mass (M/Z) ' 323 (M”)
(2) 2-(2-methyl-4-methoxy-7-chloro-
5-benzimidazolyl)-4-methyl-5-(3-pyridyl)imidazole.

mpi 243°C (decomposition) IR (streak w-p): 1625. 1575.
1530 am-1HMR (DMSO-ds, 8 >
:2.57 (6H1s), 4.33 (3H1s)
, 7.43 (1B, dd, , C5, 8Hz>, 7
．． 93 (IH, s).

8°10 (IH, dt, J=2.8Hz), 8.4
7 (LH, dd, J=2°5Hz), 8.98 (I
H, d, J=2Hz) MaSs (M/Z): 35
3 (M”) (3) 2-(2-Methyl-5-benzimidazolyl)-4-methyl-5-(3-pyridyl)imidazole.

mp: >280℃ IR (line hair) '1630. 1595.
1570. 1520 am-1(4)2~(2,
5-dimethyl-6-benzimidazolyl)-4-methyl-5-(3-pyridyl)imidazole.

IR (line) = 1620. 1540
am-1Mass (M/Z) ' 303 (M”)
(5) 2-(2-ethyl-5-methoxy-6-benzimidazolyl)-4-methyl-5-(3-pyridyl)imidazole.

IR (Streak Standard): 1725. 1635.
1590 crn-1Mass (M/Z):
333 (M) (6) 2-(2-methoxycarbonylamino-5-methoxy-6-benzimidazolyl)-4
-Methyl-5-(3-pyridyl)imidazole.

mp: 211°C (decomposition) IR (sujione): 34B0. 3320.
1700. 1625. 1590°1520 am
-1 (7) 2-(5-methoxy-2-hydroxy-6-benzimidazolyl)-4-methyl-5-(3-pyridyl)
Imidazole.

mp: 249-251℃ (decomposition) IR (streak test): 3340. 1690.
1640. 1610°1570cI! 1-1 (8) 2-(2-amino-5-methoxy-6-benzthiazolyl)-4-methyl-5-(3-pyridyl)imidazole.

IR (Streak 1-L): 3420. 3300.
3150. 1620°1560 am' Mass (M/Z) ' 337 (M") <9>2
-(2-mercapto-5-benzoxasilyl)-4-
Methyl-5-(3-pyridyl)imidazole.

mp: 278-280°C (decomposition) IR (sudicol): 3400. 1600.
1582. 1565°1540 am-1 (10) 2-(7--chloro-4-methoxy-2-methyl-5-benzimidazolyl)-4-methyl-5-(4
-pyridyl)imidazole mp: 266-270°C IR (streak 11-4>' 3400. 1620
．． 1600. 1530 cm-INMR (DMS
O-ds + DC1-8) = 2.53 <3H-s),
274 (38,s), 4.00 (3H,s), 7
．． 93 (1)1. s), 8.17 (2H, d, J=
6) +z>, 8.70 (2H, d, J=I3Hz)
Mass (M/Z) ' 353 (M") (11)
2-(6-methoxy-1,2-dimethyl-5-benzimidazol)-4-methyl-5-(3-pyridyl)
Imidazole mp: 225-230°C (decomposition) IR (streak seal): 3430. 1630.
1595. 1550°1520 am' NMR (DMSO-ds, 8)" 2.50 (6
H1s), 3.71 (3H9s), 4.97 (3
H,s), 7.26 (IH,s), 7.35<L
H, dd, J=5.8Hz), 7.90-8.45
<3H, m).

8.87 (IH, s) Mass (M/Z) ' 333 (M ) (12)
2-(6-Medoxy2-methyl-5-benzimidazolyl)-4-phenyl-5-(3-pyridyl)imidazole mp: 1g4-189°C IR (stinyl): 1635. 1600
cm-'NMR (DMSO-ds, δ): 2.5
2 (3H,s), 3.95 (3H.

s), 7.00-8.80 (11H, m)Mass
(M/Z): 381 (M”) (13) 2-(7
-Chloro-4-methoxy)-2-methyl-5-benzimidazolyl)-4-phenyl-5-(3-pyridyl)imidazole mp: 243-245°C IR: 3440. 1670.
1625. 1600°1540 am-1 NMR (DMSO-d6.δ): 2.95 (3H
,s), 4.32 (3H.

S). 7.30-7.78 (5H, m), 8.0
5-8.32 (2H, m>.

8.66 (IH, d, J=8Hz>, 8.97
(LH, d, J: 5Hz).

9.18 (IH,s) Mass (M/Z): 415 (M”) Example 3 2-(2-methoxy-4-acetylamino-5-nitrophenyl)-4-methyl-5-(3- pyridyl)imidazole (2.1 g) and 10% palladium-carbon (approximately 50% wet, 0.8 g) in methanol (1501111
A mixture of 1) and tetrahydrofuran (80 mR) in a mixed solvent is subjected to catalytic reduction in a hydrogen gas atmosphere at atmospheric pressure and room temperature for 4 hours.The reaction mixture is filtered, and the filtrate is concentrated under reduced pressure.
An oily residue containing 2-(2-methoxy-4-acetylamino-5-aminophenyl)-4-methyl-5-(3-pyridyl)imidazole is obtained. The residue was dissolved in 17% hydrochloric acid (10
IIIQ ) and acetic acid (3QmQ ) and reflux for 2 hours with stirring. Pour this mixture into water,
Wash with ethyl acetate. The aqueous layer is adjusted to p) 18.0 with a 20% aqueous potassium carbonate solution and extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract is washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography using alumina.
, v/v). The eluate was concentrated under reduced pressure, and the residue was recrystallized from a mixture of ethyl acetate and methanol.
-(2-Methyl-5-methoxy-6-benzimidazolyl)-4-methyl-5-(3-pyridyl)imidazole (0°8 g) was obtained.

mp: 182-184℃ (decomposition) IR (sujiwor): 3300. 1625.
1590. 1600 cm-INMR (DMSO
-ds, 8)' 2.50 (3H1s), 2.5
3 (3H1s), 4.00 (3H,s), 7.
18 (IH, s), 7.45 (IH, dd, J=5
．． 8Hz), 8.10 (IH, dt, J=2°8H
z), 8.13 (IH,s), 8.45 (IH
, ddj=2゜5Hz>, 8.97 (IH, dJ=
2Hz>Mass (M/Z)' 319 (M
) in mM iron (3,2 g) and ammonium chloride (0,34 g)
of ethanol (3011LQ) and water (151111)
2-(4-acetylamino-
3-nitrophenyl)-4-methyl-5-(3-pyridyl)imidazole (3.37 g) is added portionwise at 70° C. with stirring and the mixture is refluxed for 1 hour while stirring. The reaction mixture was filtered and the solvent of the filtrate was distilled off under reduced pressure to give 2-(4-acetylamino-3-aminephenyl)-
A residue containing 4-methyl-5-(3-pyridyl)imidazole is obtained. This residue was dissolved in acetic acid (3omQ) and 17%
Dissolved in a mixture with hydrochloric acid and heated the solution at 100-110 °C for 2
Stir for an hour. The solvent of the reaction mixture is distilled off under reduced pressure and the residue is dissolved in water. The solution was adjusted to pH 7.0 with 20% aqueous potassium carbonate solution and extracted with a mixture of chloroform and methanol (9:1.v/v). The extract is washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography using alumina.
Elute at 7:3, v/v). The solvent of the eluate was distilled off under reduced pressure, and the residue was recrystallized from a mixture of ethyl acetate and methanol to give 2-(2-methyl-5-benzimidazolyl)-4-methyl-5-(3-pyridyl). ) Imidazole (1.28 g) is obtained.

mp: >280°C IR (Skyl): 1630. 1595.
1570. 1520 am-INMR (DMSO-
d6. δ): 2.53 (3H, s), 2.58
(3) 1°s), 7.50 (IH, dd, J:5
．． 8Hz), 7.60 (LH, d.

J=8Hz), 7.85 (LH, d, J: 2Hz)
, 7.96-8.33<28. m), 8.50 (
IH, dd, J=2.5Hz), 9.02 (18, d
, J=2H2) Mass (M/Z) ' 289 (M'') Example 5 The following compound is obtained in the same manner as in Example 3 or 4.

(1) 2-(2,5-dimethyl-6-benzimidazolyl)-4-methyl-5-(3-pyridyl)imidazole.

mp: 235-241°C ZR: 1620. 1540
cm-1HMR (DMSO-ds, δ): 2.6
5 (61 (, s), 2.76 (3H.

s), 7.31-7.68 (21(,+n),
7.80 (IH, s), 8.17<LH, dJ
=8Hz), s,so (18,d, J=5Hz)
, 9.02 (IH, s) Mass (M/Z): 303 (M”) (2) 2
-(5-chloro-2-methyl-6-benzimidazolyl)-4-methyl-5-(3-pyridyl)imidazole.

IR (Stripe 1-L): 1730. 1670.
1625. 1590゜1560CIIl-1 Mass (M/Z): 323 (M”) (3) 2
-(2-Methyl-4-methoxy-7-chloro-5-benzimidazolyl)-4-methyl-5-(3-pyridyl)
Imidazole.

IR (Streak Inscription): 1625. 1575.
1530 cm-1Mass (M/Z): 3
53 (M”) (4) 2-(2-ethyl-5-methoxy-6-benzimidazolyl)-4-methyl-5-(3-
pyridyl) imidazole.

IR (Stripe 1-L): 1725. 1635.
1590 am-1Mass (M/Z): 3
33 (M”) (5) 2-(4-chloro-5-methoxy-2-methyl-6-benzimidazolyl)-4-methyl-5-(3-pyridyl)imidazole mp: 214-215°C IR(X Jiun 4)' 1640. 1600.
1545 cm-1 HMR (DMSO-d δ)
' 2.50 (6H, s), 3.74 (3H.

6′ s), 7.32 (LH, dd, J=5.8Hz>,
7.80-8.10 (2H, m), 8.34 (L
H,dJ=5Hz), 8.86 (IH,s)Mas
s (M/Z) 7353 (M) 笈1孡1 2-(2-methoxy-4,5-diaminophenyl)-4
-Methyl-5-(3-pyridyl)imidazole (0,4
1 g) and propionic acid (1, somQ) in 35% hydrochloric acid (1011111) was refluxed under stirring for 2 days. The reaction mixture was poured into a mixture of chloroform and water and 4N
Tit to pH 9.5 with aqueous sodium hydroxide solution. Separate the organic layer and dry with magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was triturated with diethyl ether and diisopropyl ether to give 2-(2-ethyl-5
-methoxy-6-benzimidazolyl)-4-methyl-
5-(3-pyridyl)imidazole (0.21 g) is obtained.

mp: 158-163℃ IR (Streak*-1->: 1725. 1635
．． 1590 am-1HMR (DMSO-ds, 8
) :1-33 <3H, t, J=8)1z), 2
-83 (2H, q, J=8Hz), 3.97 (3H
, s), 7.18 (18°br s), 7.40
(LH, dd, J=8Hz, J:5Hz>, 7.
96-8.21 <2H, m), 8.42 (LH,
d,, C3Hz>, 8.93 (IH, s) Mass (M/Z); 333 (M)

(1) 2-(2-methyl-5-methoxy-6-benzimidazolyl)-4-methyl-5-(3-pyridyl)imidazole.

mp: 202-204°C (decomposition) IR (X div-4)' 3320. 1625.
1595. 1560 am-'(2)2-(5-
Chloro-2-methyl-6-benzimidazolyl)-4-
Methyl-5-(3-pyridyl)imidazole.

IR (Sujoor): 1730. 1670.
1625. 1590゜1560 cab-1 Mass (M/Z) ' 323 (M) (3) 2
-(2-Methyl-4-methoxy-7-lycoro-5-benzimidazolyl)-4-methyl-5-(3-pyridyl)
Imidazole.

IR (Streak 1-L): 1625. 1575.
1530 cm-1Mass (M/Z): 3
53 (M”) (4) 2-(2-Methyl-5-benzimidazolyl)-4-methyl-5-(3-pyridyl)imidazole.

mp: >280°C IR<Za-L')' 1630. 1595
．． 1570. 1520 cm-'(5)2-(2
,5-dimethyl-6-benzimidazolyl)-4-methyl-5-(3-pyridyl)imidazole.

IR: 1620. 1540
am-1Mass (M/Z)' 303 (M”
) Example 8 A mixture of S-methylisothiobase sulfate (1.4 g) and methyl chloroformate (0.95 g) in water (51) was heated to pH 7 with stirring at 10°C to 15°C with 20% aqueous sodium hydroxide solution. , 0 to 8.0, and the mixture is adjusted to pH 5.0 with acetic acid. 2-(2-methoxy-4,5-diaminophenyl)-4-methyl-5-(3
-Pyridyl)imidazole (1.5 g) (7) Add the above solution to an ethanol (20 mQ) solution at room temperature with stirring, and stir this mixture at room temperature for 9 hours. 6. Distill the solvent of the reaction mixture under reduced pressure, The residue is dissolved in a mixture of ethyl acetate and dilute hydrochloric acid.

Separate the aqueous layer and add 20% potassium carbonate aqueous solution to pH 8.0.
A mixture of chloroform and methanol C9:
1, v/v). The extract is dried over magnesium sulfate, and the solvent is distilled off under reduced pressure.

The residue was subjected to column chromatography using alumina, and a mixture of chloroform and methanol (97:3,
v/v). The solvent of the eluate was distilled off under reduced pressure, and the residue was recrystallized from a mixture of ethyl acetate and methanol to give 2-(2-methoxycarbonylamino-5-methoxy-6-benzimidazolyl)-4-methyl- 5-(
3-pyridyl)imidazole (0.3 g) is obtained.

mp; 211°C (decomposition) IR (suji meal): 3480. 3320.
1700. 1625. 1590°1520am
"" Example 9 2-(2-methoxy-4,5-diaminophenyl)-4
-Methyl-5-(3-pyridyl)imidazole (1,2
g) and N,N'-carbonyldiimidazole (1
,0g) of N,N-dimethylformamide (20111
9) Stir the solution at room temperature for 8 hours. The solvent of the reaction mixture is distilled off under reduced pressure and the residue is dissolved in a mixture of ethyl acetate and dilute hydrochloric acid. The aqueous layer is separated, adjusted to pH 8.0 with a 20% aqueous potassium carbonate solution, and extracted with a mixture of chloroform and methanol (9:1, v/v). Dry the extract with magnesium sulfate. The solution was concentrated under reduced pressure and the residue was crystallized from a mixture of chloroform and methanol.
2-(5-methoxy-2-hydroxy-6-benzimidazolyl)-4-methyl-5-(3-pyridyl)imidazole (0.38 g) is obtained.

mp: 249-254℃ (decomposition) IR (sujiwor): 3340. 1690.
1640. 1610°1570 am' NMR (C20"DCl, '5)' 2.57 (
3) I, s), 3.93 (3H9s), 6.63
(IH,s), 7.13 (18,s), 8.38
(IH.

dd, J=5.8Hz), 8.77-9.20 (2
H, m), 9.20(1)1. dJ=2Hz) A solution of bromine (0.68 g) in acetic acid (3sei) was mixed with 2-(4-
Amino-2-methoxyphenyl)-4-methyl-5-(
9. Add 3-pyridyl)imidazole (1.2 g) and ammonium thiocyanate (0.66 g) to an acetic acid (12-alcohol) solution at 10°C to 15°C with stirring, and stir the mixture at room temperature for 2 hours to form a reaction mixture. The solution was adjusted to pH 1.0 with 10% hydrochloric acid and washed with ethyl acetate. Separate the aqueous layer and add 20% potassium carbonate to pH 7.
, 0 and extracted with a mixture of ethyl acetate and tetrahydrofuran.

The extract is washed with brine and dried over magnesium sulfate. The solution was concentrated under reduced pressure and the crystalline residue was collected by filtration to give 2-(2
-amino-5-methoxy-6-benzdeazolyl)-4
-Methyl-5-(3-pyridyl)imidazole (0,4
2g) is obtained.

mp: 206-209°C IR: 3420. 3300.
3150. 1620°1560 cab-1 NMR (DMSO-9, S): 2.50 (3
H,s), 3.93 (3)t.

s), 6.22 (2H, s), 6.60 (IH
, s), 7.43 (IH.

dd, J=5.8Hz>, 8.07 (IH, dt,
J=2.8Hz>.

8.10 <LH, s), 8.43 (1B, dd,
C2,5Hz).

8.93 (IH, d, J=2Hz) Mass (M/Z) ' 337
32g) of ethanol-JL, (3QmQ) and water (1m
2-(3-amino-4-hydroxyphenyl)-4-methyl-5-(3-pyridyl)imidazole (0.94 g) was added to the mixture solution with 1 and the mixture was refluxed for 6 hours with stirring. The solvent of the mixture is evaporated under reduced pressure and the residue is dissolved in water. This solution was acidified with 10% hydrochloric acid to pH
Adjust to 1.0 and wash with ethyl acetate. Separate the aqueous layer 2
Adjust the pH to 6.0 with 0% potassium subacid, collect the precipitate by filtration,
Drying gives 2-(2-mercapto-5-benzoxasilyl)-4-methyl-5-(3-pyridyl)imidazole (0.82 g).

mp: 278-280°C (decomposition) IR (streak 1-l): 3400. 1660.
1582. 1565°1540 cm-1 Example 12 2-(2-methyl-4-methoxy-7-chloro-5-benzimidazolyl)-4-methyl-5-(3-pyridyl)imidazole (1.0 g), triethylamine ( 51
A mixture of 1111) and 10% palladium (about 50% wet, 1.0 g) in methanol < 150 mQ) was subjected to catalytic reduction in a hydrogen gas atmosphere at atmospheric pressure and room temperature for 7 hours. 6. The reaction mixture was filtered and the filtrate The solvent is distilled off under reduced pressure. The residue is dissolved in a mixture of chloroform and saturated aqueous sodium chloride solution and extracted with a mixture of chloroform and methanol (9:1, v/v). The extract is dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is dissolved in hydrochloric acid-ethanol solution. To this is added tetrahydrofuran and the mixture is heated to 60°C to 70°C for 10 minutes. The precipitate was collected by filtration to give 2-(2-methyl-4-methoxy-5-benzimidazolyl)-4-methyl-5-(
3-pyridyl)imidazole dihydrochloride (0.69g)
get.

mp: >290°C IR (striped tar): 3400. 3320.
1660. 1625°1570 cm' NMR (C20, δ): 2.70 (3H, s),
3.00 <3H, s).

4.20 (3H, s), 7.76 (LH, d, J
:8Hz), 8.01(LH, d, J:8Hz>,
8.35 (LH, dd, J=5.8!(z).

8.83-9.02 (2H, m), 9.22 (IH
, d, J = 2H2)]U>1 2-(5-methoxy-2-methyl-6-benzimidazolyl)-4-methyl-5-(3-pyridyl)imidazole (0.20 g) in ethanol (2 7N hydrochloric acid-ethanol solution (0, OgmA) is added to the solution at room temperature.

The resulting precipitate was triturated with ethanol and diethyl ether to give 2-(5-methoxy-2-methyl-6-benzimidazolyl)-4-methyl-5-(3-pyridyl)imidazole hydrochloride (0°13g). ).

mp: 262-265°C NMR (C20, δ): 1.96 (3H, s),
2.18 (3H, s).

3.75 <38. s), 6.57 <IH, s>,
7.10-7.25 (3H, m), 7.85 (1
1(,s), 8.15 (IH,s) Elemental analysis Cl
Calculated value as 8H18N50C1: C60,75,
H5, 18, N 19.41. C19,90 actual measurement value:
C59,75,H5,09,N 19.41. C.I.
9.32 x 1 d x The following compound was obtained in the same manner as in Example 13.

(1) 2-(5-methoxy-2-methyl-6-benzimidazolyl)-4-methyl-5-(3-pyridyl)imidazole dihydrochloride.

mp: 239-243℃ (decomposition) NMR (C20,S): 2.35 (3
H,s), 2.72 (3H,s).

3.98 (3)1. s), 7.17 (IH, s)
, 7.70-7.95 (2H, m), 8.20 (
LH, ddd, J=8) 1z, 2Hz, 2Hz).

8.51-8.75 (2H, m> Elemental analysis Cl8H19N50C1°・H2O,
Calculated value: C52,69, H5,15, N 17.06
゜C117,28 Actual value: C51,38, H5,17, N 16.84
°C116,87 (2) 2-(5-methoxy-2-methyl-6-benzimidazolyl)-4-methyl-5-(3-pyridyl)imidazole dihydrochloride.

mp: 239-243°C (decomposition) NMR (C20-8)' 2.65 (3H3s),
2.91 (3H1s).

4.19 (3H,s>, 7.66 (IH,
s), 8.30-8.49<2H,m>, 8.
82-9.28 <3H, n+) Elemental analysis Cl8H
Calculated value as 2oN50C13・H2O: C48,3
9,H4,96,N 15.67゜C123,80 Actual measurement: C47,09,H4,89,N 1
5.31°C122,99 (3) 2-(5-methoxy-2-hydroxy-6-benzimidazolyl)-4-methyl-5-(3-pyridyl)
Imidazole-hydrochloride.

mp: 255-257°C IR: 1718. 1645.
1607. 1597. 1560°1495 cm
' NMR (D20"DCl, 8) ' 2.50 (3
H1s), 3.89 (3H1s), 6.63 (1)
1. s), 7.13 (LH,s), 8.29 (
IH.

dd, J=8Hz, 5Hz), 8.70-9.16
(3H, m)Mass (M/Z): 321 (
M”) Elemental analysis Calculated value as C1□H16N202C1・H2O: C51,84,H5,63,N 17
．． 78. C19,00 Real Ill <nhif:
C52,12, H4,76, N 17.86.
CI 8.27 Example 15 In the same manner as in Production Example 19, 2-(3-amino-6-medoxy4-methylaminephenyl)-4-methyl-5-
After obtaining (3-pyridyl)imidazole, the following compound was obtained in the same manner as in Example 9.

2-(2-hydroxy-6-medoxy-1-methyl-5
-Benzimidazolyl)-4-methyl-5-(3-pyridyl)imidazole mp i 208-210°C IR (Steel training)' 3300. 1700.
1640. 1570°1500 cm' NMR (DMSO-ds+DC1,S): 2-11
(3H, s), 2.90 (3H, s), 3.58
(3H,s), 6.64 (IH,s), 7.1
0-7.48 (2H, m), 7.98 (I
H, d, J=8Hz), 8.30(LH, d, J=
5Hz), 8.58 (11(,s)Mass
(M/Z): 335 (W”) Example 16 In the same manner as in Production Example 19, 2-(3,4-diamino-5
-chloro-6-methoxyphenyl)-4-methyl-5-
After obtaining (3-pyridyl)imidazole, the following compound was obtained in the same manner as in Example 8 and 9.

2-(4-chloro-2-hydroxy-5-methquin-6
-benzimidazolyl)-4-methyl-5-(3-pyridyl)imidazole mp: >250°C IR: 1680. 1590
．． 1570. 1540 am-INMR (D20
"DCl-8) ' 2-80 (3H-s), 3.9
8 (3H9s), 7.58 (11(,s), 8
．． 45 (LH, dd, J=6.8Hz).

8.95-9.20 (2H, m), 9.33 (L
H, s) Mass (M/Z): 355 (M”)
Example 17 2-(3,4-diamino-5-chloro-2-methoxyphenyl)-4-methyl-5-(3-pyridyl)imidazole (1,5 g) and N,O-bis(trimethylsilyl)
Acetamide (3m) Tetrahydrofuran (50m)
Q) Add 15 g of ethyl succinyl chloride to the solution.
The mixture was stirred for 35 hours at a temperature of 1,000 yen. The reaction mixture is evaporated under vacuum and the residue is dissolved in a mixture of sulfuric acid (3 mu) and ethanol (50 mQ). This mixture solution is refluxed for 30 minutes while stirring.

The reaction mixture is evaporated under reduced pressure and the residue is dissolved in a mixture of ethyl acetate and water. The aqueous layer is separated, the pH of this solution is adjusted to 8.0 with a 20% aqueous potassium carbonate solution, and the mixture is extracted with ethyl acetate. The extract is washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixture of ethyl acetate and diethyl ether to give 2-[7-chloro-2-(2-ethoxycarbonylethyl-benzimidazolyl]-4-methyl-5 -(3-pyridyl)imidazole (x.asg) is obtained.

mp: 184-186℃ IR (streak accuracy): 3220. 17
40. 1650. 1540.

1520 cm-1 NMR (DMSO-C6.δ): 1.20 (3
)1. t. J=7Hz>, 2.57 (3H, s),
2.67 (4H.s), 3.75 (3H.s),
4. ], 7 (2H.q.J=7Hz), 7.33
-7.67 (1)1. m), 8, C7 (LH.s
), 8.00-9.10 (2H.nt),
9.37 (IH.s) and 2-[7-chloro-2-(2-ethoxycarbonylethyl)-4-methoxy-5-penzimidazolyl-4-
Methyl-5-(3-pyridyl)imi'Isol(0,
88 g ) (7) 6 Nm acid (20 mfl) tIH&O Stir at 80"C to 85°C for 4.5 hours. The solvent of the reaction mixture is evaporated under reduced pressure and the residue is reconstituted from a mixture of ethanol and acetone. Crystallized to give 2-[2-(2-carboxyethyl)-7-chloro-4-methoxy-5-henzimidazolyl-4-methyl-5-(3-pyridyl).
Imidazole dihydrochloride (0.45 g) is obtained.

mp: 230-233°C (decomposition) IR (streak 1-l): 3360. 1720.
1610. 1560 cm-INMR (D20.
δ): 2.73 (3H,s), 3.20 (2
H,t.

J=6Hz), 3.57 <28. t, J=6Hz)
, 4.25 (3H,s).

7.93 (LH,s), 8.39 (LH,ddj
=5.8Hz).

8.85-9.13 (2H, m), 9.28 (I
H, d, J = 2Hz) Patent applicant Fujisawa Pharmaceutical Co., Ltd.

Claims (1)

[Claims] 1. Formulas: ▲ Numerical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1 is a pyridyl group, R^2 is a lower alkyl group or aryl group, R^3 is lower alkoxycarbonyl or a lower alkyl group which may be substituted with carboxy, an amino group, an acylamino group, a hydroxy group or a mercapto group, R^4 and R^5 are each hydrogen, a lower alkyl group,
Lower alkoxy group or halogen, X means a group represented by O, S or NR^6 (wherein R^6 means hydrogen or a lower alkyl group)]
Compounds represented by and their salts.