JPH07291936A - Novel imidazole derivative and method for producing the same - Google Patents

Abstract

(57) [Summary] (Modified) [Objective] To provide an imidazole derivative as a selective muscarinic antagonist. [Structure] Useful as a cholinergic receptor antagonist containing the imidazole derivative represented by the general formula (1), a pharmaceutically acceptable salt thereof, a process for producing them, and the compound or a pharmaceutically acceptable salt thereof Pharmaceutical composition. Wherein, R ₁ represents a phenyl group or a thienyl group; R ₂ is -
CN, —OH, —COOR ₉ (R ₉ is hydrogen atom, lower alkyl group) or —CONR ₇ R ₈ (R ₇ , R ₈ are hydrogen atom, lower alkyl, or NR ₇ R ₈ is a nitrogen-containing ring. R ₃ represents a hydrogen atom or a lower alkyl group;
R ₄ , R ₅ and R ₆ each represent a hydrogen atom, a lower alkyl group or a cycloalkyl group; or may be condensed with a benzene ring at the positions of R ₅ and R ₆ . m is an integer of 1 to 6]

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel imidazole derivative useful as a drug, and more specifically, an anticholinergic drug, especially an imidazole derivative which is a selective muscarinic receptor antagonist, a method for producing the same and a method for containing the same. Related to drugs.

[0002]

2. Description of the Related Art Anticholinergics have antispasmodic and antisecretory actions and are useful as therapeutic agents for functional disorders such as intestine and bladder. Currently, as anticholinergics, alkaloids such as atropine, aminoalkanol esters such as oxybutynin and propantheline bromide, and their quaternary ammonium salts are known, and these block muscarinic acetylcholine receptors. It is a medicine. However, the antagonism of these compounds is poor in organ selectivity, so that the occurrence of side effects is a problem. Therefore, development of highly selective anticholinergic drugs is desired in clinical settings.

Further, as a muscarinic receptor antagonist having an imidazole group as a substituent, a 5- [1 (imidazole) methyl] -3,3-disubstituted-2 (3H) -furanone derivative has been reported (Japanese Patent Laid-Open No. Hei 4) -103581 publication),
The compound of the present invention has a different structure from that of the compound of the present invention and is not satisfactory in terms of efficacy.

[0004]

DISCLOSURE OF THE INVENTION The present invention is intended to provide a drug having a strong antagonism against the muscarinic receptor of the smooth muscle, which is more selective than the muscarinic receptor of the heart.

[0005]

Means for Solving the Problems The present inventor has focused his attention on imidazole derivatives for the above-mentioned purpose, and as a result of earnest research, the results of the general formula (1) [In the formula, R ₁ represents a phenyl group or a thienyl group which may have a substituent, R ₂ represents a cyano group, a hydroxyl group, a carboxyl group, a CONR ₇ R ₈ group (in the formula, R ₇ , R ₈ are The same or different, each represents a hydrogen atom or a lower alkyl group,
Or R ₇ and R ₈ represent a alkylene chain which may contain a hetero atom to form a ring) or a COOR ₉ group (in the formula, R ₉ represents a lower alkyl group), and R ₃ represents hydrogen. Represents an atom or a lower alkyl group, R ₄ , R ₅ and R ₆ are the same or different and represent a hydrogen atom, a lower alkyl group which may have a substituent or a cycloalkyl group, or R ₅ , R ₅ ; _The imidazole derivative, which may be condensed with a benzene ring at the position ₆ and m represents an integer of 1 to 6, has a strong anticholinergic effect, especially muscarine of smooth muscle such as digestive tract, trachea and bladder. The inventors have found that they have a selective and strong antagonism to the receptor, and completed the present invention.

Therefore, the compound of the present invention is used for the treatment of gastrointestinal motility disorder such as irritable bowel syndrome, diverticulum disease, functional diarrhea, esophageal insufficiency, cardia spasm, biliary tract, urethral spasm, urinary incontinence and the like. It is useful for medical use such as treatment of chronic airway obstructive disease.

The "substituent" of the phenyl group shown in the present invention includes halogen, lower alkyl group, lower alkoxy group and the like. “Halogen” includes fluorine, chlorine, bromine and iodine.

"Lower alkyl group" means methyl, ethyl,
Examples thereof include linear or branched ones having 1 to 6 carbon atoms such as isopropyl.

Examples of the "lower alkoxy group" include a methoxy group, an ethoxy group, an isopropoxy group and the like, in which a linear or branched alkyl group having 1 to 6 carbon atoms is bonded to an oxygen atom.

Examples of the "substituent of the lower alkyl group" include halogen, lower alkoxy group, hydroxyl group, phenyl group and the like.

Examples of the "cycloalkyl group" include alicyclic hydrocarbons having 3 to 8 carbon atoms such as cyclopropyl and cyclohexyl.

Examples of the "aralkyl group" include a benzene ring such as benzyl and phenylethyl to which a linear or branched alkylene group having 1 to 6 carbon atoms is bonded.

Examples of the "hetero atom" include oxygen atom, sulfur atom and nitrogen atom.

In the present invention, the general formula (2) (In the formula, R ₁ , R ₃ , R ₄ , R ₅ , R ₆ and m are as described above) and the compound represented by the general formula (3) [Wherein R ₁ , R ₃ and m are as described above and X represents a leaving group] and the compound represented by the general formula (4) It can be produced by reacting a compound represented by the formula [wherein R ₄ , R ₅ and R ₆ are as described above], preferably in the presence of a base.

Examples of the “leaving group” include halogen, an aliphatic sulfonyloxy group such as methanesulfonyloxy group, and an arylsulfonyloxy group such as toluenesulfonyloxy group.

The reaction is carried out by dimethylformamide, N-methylpyrrolidone, N, N'-dimethylimidazolidinone,
0 to 200 in an organic solvent such as dimethyl sulfoxide or xylene in the presence of an inorganic base such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate or potassium carbonate or an organic base such as triethylamine or pyridine as a base. C., preferably 60 to 150.degree.

In the present invention, the general formula (5) [Wherein R ₁ , R ₃ , R ₄ , R ₅ , R ₆ and m are as described above] are represented by the general formula (2) [Wherein R ₁ , R ₃ , R ₄ , R ₅ , R ₆ and m are as described above] can be produced by hydrolysis.

The reaction can be carried out in a hydrous acidic solution such as sulfuric acid, polyphosphoric acid, etc. at 0 to 150 ° C, preferably 100 to 150 ° C.

Further, in the present invention, the general formula (6) [Wherein R ₁ , R ₃ , R ₄ , R ₅ , R ₆ and m are as described above] is a compound represented by the general formula (2) [Wherein R ₁ , R ₃ , R ₄ , R ₅ , R ₆ and m are as described above] can be produced by hydrolysis.

The reaction is carried out at 0 to 150 ° C. in the presence of an inorganic acid such as sulfuric acid or hydrochloric acid or an organic acid such as p-toluenesulfonic acid,
It may preferably be carried out at 100 to 150 ° C.

In the present invention, the general formula (6) [Wherein R ₁ , R ₃ , R ₄ , R ₅ , R ₆ and m are as described above] are represented by the general formula (5) [Wherein R ₁ , R ₃ , R ₄ , R ₅ , R ₆ and m are as described above] can be produced by hydrolysis.

The reaction is carried out in an acidic solvent such as sulfuric acid or hydrobromic acid.
To 200 ° C, preferably 100 to 150 ° C.

Further, in the present invention, the general formula (7) [Wherein R ₁ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and m are as described above] is a compound represented by the general formula (6) [Wherein R ₁ , R ₃ , R ₄ , R ₅ , R ₆ and m are as described above] is used as a reactive derivative of a carboxylic acid, and then the compound represented by the general formula (8) It can be produced by reacting a compound represented by the formula [wherein R ₇ and R ₈ are as described above].

Examples of the reactive derivative of carboxylic acid include acid chloride, acid bromide, acid anhydride, active ester and the like. In the reaction, carboxylic acid is reacted with reactive derivative using thionyl chloride, thionyl bromide and the like. After that, it can be produced by reacting with the compound of the general formula (8) in the presence of a base if necessary.

The reaction is carried out by using sodium hydroxide as a base in an inert organic solvent such as chloroform, dimethylformamide, N-methylpyrrolidone, N, N'-dimethylimidazolidinone, dimethylsulfoxide, benzene, toluene and xylene. At −20 to 200 ° C. in the presence or absence of an alkali metal hydroxide such as potassium hydroxide, sodium carbonate, an inorganic base such as a metal carbonate such as potassium carbonate, or an organic base such as triethylamine or pyridine,
Preferably, it may be carried out at 0 to 150 ° C.

In the present invention, the general formula (9) [Wherein R ₁ , R ₃ , R ₄ , R ₅ , R ₆ , R ₉ and m are as described above] are represented by the general formula (6) [Wherein R ₁ , R ₃ , R ₄ , R ₅ , R ₆ and m are as described above] is used as a reactive derivative of carboxylic acid, and then the compound represented by the general formula (10) R ₉ —OH (10) It can be produced by reacting with a compound represented by the formula [wherein R ₉ is as described above].

Examples of the reactive derivative of carboxylic acid include acid chloride, acid bromide, acid anhydride, active ester and the like. In the reaction, carboxylic acid is reacted with reactive derivative using thionyl chloride, thionyl bromide and the like. After that, it can be produced by reacting with the compound of the general formula (10) in the presence of a base if necessary.

The reaction is carried out by using sodium hydroxide as a base in an inert organic solvent such as chloroform, dimethylformamide, N-methylpyrrolidone, N, N'-dimethylimidazolidinone, dimethylsulfoxide, benzene, toluene and xylene. At −20 to 200 ° C. in the presence or absence of an alkali metal hydroxide such as potassium hydroxide, sodium carbonate, an inorganic base such as a metal carbonate such as potassium carbonate, or an organic base such as triethylamine or pyridine,
It may preferably be carried out at 0 to 150 ° C.

In the imidazole derivative of the present invention, optical isomers exist for those having an asymmetric carbon, and these isomers and mixtures are included in the present invention.

The novel compounds of the present invention are pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, or organic acids such as maleic acid, fumaric acid, acetic acid, oxalic acid, tartaric acid, benzene. An acid addition salt can be obtained by reacting sulfonic acid or the like according to a conventional method.

Further, the administration form of the novel compound of the present invention includes oral administration by tablets, capsules, granules, powders, syrups and the like, or parenteral administration by injections, suppositories and the like.

[0032]

EXAMPLES The present invention will be described in detail below with reference to examples.

Example 1 4- (2-Methyl-1-imidazolyl) -2,2-diphenylbutyric acid hydrochloride

4- (2-methyl-1-imidazolyl)-
2,2-diphenylbutyramide (5.00g, 15.7mmo
l) and concentrated hydrochloric acid (250 ml) were placed in 500 ml eggplant-type Kolben, refluxed for 18 hours and left overnight, and the precipitated crystals were collected by filtration.
After washing with acetone and drying, 4.70 g of the title compound was obtained as a colorless powder. Yield 84%.

Melting point: 237 ° C. (decomposition) Elemental analysis value (%) C ₂₀ H ₂₀ N ₂ O ₂ .HCl calculated value C: 67.32 H: 5.93 N: 7.85 Actual value C: 67.22 H: 5.97 N: 7.81

¹ H-NMR (400 MHz, d ₆ -DMSO,
δ) 7.55 (1H, s), 7.51 (1H, s), 7.28 to 7.39
(10H, m), 3.77-3.81 (2H, m), 2.80-2.84
(2H, m), 2.38 (3H, s)

(Example 2) 4- (4,5-dimethyl-1-imidazolyl) -2,2
-Diphenylbutyric acid / hydrochloride

According to the method of Example 1, the title compound was synthesized from 4- (4,5-dimethyl-1-imidazolyl) -2,2-diphenylbutyramide. Melting point: 218 to 220 ° C. Elemental analysis value (%) C ₂₁ H ₂₂ N ₂ O ₂ · HCl calculated value C: 68.01 H: 6.25 N: 7.55 Actual value C: 67.73 H: 6.22 N: 7.56

(Example 3) 4- (4,5-diethyl-1-imidazolyl) -2,2
-Diphenylbutyronitrile

4-Bromo-2,2-diphenylbutyronitrile (5.00 g, 16.7 mmol), 4,5-diethylimidazole (6.22 g, 50.1 mmol), triethylamine (1.69)
g, 16.7 mmol) and dimethylformamide (50 ml) were placed in an eggplant-type Kolven and heated and stirred at 150 ° C. for 30 hours. Next, the reaction solution was transferred into water and extracted with benzene. The extract was dried with anhydrous sodium sulfate and then concentrated. The residue was purified by silica gel chromatography (developing solvent; dichloromethane: ethanol = 10: 1) to obtain 4.00 g of the title compound as a brown oil. Yield 70%

¹ H-NMR (400 MHz, CDCl ₃ , δ)
7.27 ~ 7.41 (11 H, m), 3.86 ~ 3.91 (2 H, m), 2.
76 to 2.81 (2H, m), 2.49 (2H, q, J = 7.6Hz),
2.42 (2H, q, J = 7.6Hz), 1.20 (3H, t, J = 7.
6Hz), 1.02 (3H, t, J = 7.6Hz)

(Example 4) 4- (4,5-diethyl-1-imidazolyl) -2,2
-Diphenylbutyramide

4- (4,5-diethyl-1-imidazolyl) -2,2-diphenylbutyronitrile (4.00 g, 1
1.6 mmol) and 70% sulfuric acid (20.0 ml) were placed in an eggplant-type Kolben and stirred at 150 ° C for 30 minutes. The reaction solution is made alkaline and a mixed solvent of chloroform and ethanol (5: 1)
The extract was dried over anhydrous sodium sulfate and then concentrated. The residue was recrystallized from ethyl acetate-ethanol to give 1.15 g of the title compound as colorless needle crystals.
Yield 27%

Melting point: 194 to 196 ° C. Elemental analysis value (%) C ₂₃ H ₂₇ N ₃ O Calculated value C: 76.42 H: 7.53 N: 11.62 Measured value C: 76.25 H: 7.64 N: 11.48

Mass M / Z 361 (M ⁺ ) ¹ H-NMR (400 MHz, CDCl ₃ , δ) 7.32 to 7.41 (1
0H, m), 7.21 (1H, s), 5.58 (1H, br
s), 5.34 (1H, brs), 3.74 to 3.78 (2H,
m), 2.71 to 2.75 (2H, m), 2.47 (2H, q, J =
7.6Hz), 2.43 (2H, q, J = 7.6Hz), 1.19 (3H,
t, J = 7.6Hz), 0.99 (3H, t, J = 7.6Hz)

(Example 5) 4- (4,5-diethyl-1-imidazolyl) -2,2
-Diphenylbutyric acid / hydrochloride

4- (4,5-diethyl-1-imidazolyl) -2,2-diphenylbutyramide (0.50 g, 1.38)
mmol) and concentrated hydrochloric acid (50 ml) in an eggplant type Kolben,
After refluxing for 15 hours and standing overnight, the reaction solution was concentrated, ethanol was added, and the precipitated crystals were collected by filtration, washed with acetone and dried,
Obtained mg of the title compound as a colorless powder. Yield 86%

Melting point: 203 to 206 ° C. Elemental analysis value (%) C ₂₃ H ₂₆ N ₂ O ₂ .HCl. 1/10
H ₂ O calculated value C: 68.94 H: 6.84 N: 6.99 Actual value C: 68.70 H: 6.75 N: 7.25

Mass M / Z 362 (M ⁺ ) ¹ H-NMR (400 MHz, d ₆ -DMSO, δ) 9.00 (1
H, s), 7.30 to 7.40 (10H, m), 3.81 to 3.85 (2
H, m), 2.81 to 2.84 (2H, m), 2.57 (2H, q,
J = 7.6Hz), 2.42 (2H, q, J = 7.6Hz), 1.15 (3
H, t, J = 7.6Hz), 0.89 (3H, t, J = 7.6Hz)

Example 6 N-Ethyl-4- (2-methyl-1-imidazolyl)-
2,2-diphenylbutyramide

4- (2-methyl-1-imidazolyl)-
2,2-Diphenylbutyric acid / hydrochloride (1.00g, 2.80mmo
l) and thionyl chloride (20 ml) were mixed, refluxed for 4 hours and then concentrated under reduced pressure. Dissolve the residue in dichloromethane and cool with ice.
% Ethylamine aqueous solution (30 ml) was added, and the mixture was stirred at the same temperature for 6 hours and left overnight. After making the reaction solution alkaline,
Dichloromethane was separated, and the aqueous layer was extracted with dichloromethane. The organic layers are combined and concentrated, and silica gel chromatography (developing solvent; dichloromethane: ethanol = 1)
It was purified by 0: 1) and recrystallized from ethyl acetate-ethanol to obtain 520 mg of the title compound as a colorless powder. Yield 54%

Melting point: 167 to 169 ° C. Elemental analysis value (%) C ₂₂ H ₂₅ N ₃ O / 1 / 10H ₂ O Calculated value C: 75.66 H: 7.27 N: 12.03 Actual value C: 75.59 H: 7.29 N: 11.97

¹ H-NMR (CDCl ₃ , δ) 7.31-7.4
0 (6H, m), 7.24 to 7.27 (4H, m), 6.86 (1
H, s), 6.74 (1H, s), 5.31 (1H, brs),
3.82 to 3.87 (2H, m), 3.24 to 3.31 (2H, m), 2.
68 to 2.72 (2H, m), 2.26 (3H, s), 1.04 (3
(H, t, J = 7.3Hz)

(Examples 7 to 12) According to the method of Example 6,
The following compounds were synthesized (Table 1).

[0055]

[Table 1]

Example 13 Methyl 4- (2-methyl-1-imidazolyl) -2,
2-Diphenylbutyrate 4- (2-Methyl-1-imidazolyl) -2,2-diphenylbutyric acid / hydrochloride (2.00 g, 5.60 mmol) and thionyl chloride (20 ml) were mixed, refluxed for 4 hours and concentrated under reduced pressure. . Methanol (100 ml) was added to the residue under ice cooling, and the mixture was refluxed for 18 hours. The reaction solution was concentrated, purified by silica gel chromatography (developing solvent; dichloromethane: ethanol = 10: 1), recrystallized from n-hexane-ethyl acetate,
250 mg of the title compound was obtained as a colorless powder. Yield 13%

[0057] mp: 84 to 86 ° C. Elemental analysis _{(%) C 21 H 22 N} 2 O 2 · 1 / 10H 2 O Calculated C: 75.02 H: 6.66 N: 8.33 Found C: 75.00 H: 6.80 N: 8.36

¹ H-NMR (CDCl ₃ , δ) 7.24 to 7.3
7 (10H, m), 6.87 (1H, s), 6.71 (1H,
s), 3.75 (3H, s), 3.58 to 3.62 (2H, m), 2.
69 to 2.73 (2H, m), 2.20 (3H, s)

[0059]

【The invention's effect】

Experimental example 1. Effect on Rhythmic Bladder Contraction Male Wistar rats were fixed in the dorsal position under halothane anesthesia, a catheter with a balloon was inserted from the apex of the bladder exposed by a midline abdominal incision, and purse string suture was performed. A catheter was pulled out from the sutured upper abdomen, and a three-way stopcock was connected, one side was connected with a syringe, and the other side was connected with a pressure transducer for measuring intravesical pressure. About 0.1-0.3m in the balloon
After injecting 1 l of distilled water and confirming that the induced rhythmic bladder contraction showed a stable amplitude, the test compound was administered into the duodenum via a catheter previously placed.
The inhibitory effect was evaluated from the decrease in the amplitude of rhythmic bladder contraction.
The compound of the present invention showed an inhibitory effect at 0.03 mg / kg or more.

2. Effect on Bezanecol-induced diarrhea The test compound was orally administered to ICR male mice, and 0.5 hours later, 20 mg / kg of besanecol was subcutaneously administered.
The diarrhea that developed at this time was observed until 0.5 hours later. The compound of the present invention suppressed the expression of diarrhea at 0.06 mg / kg or more.

From the above, the compound of the present invention is useful for medicinal use such as treatment of irritable bowel syndrome, frequent urination, urinary incontinence and chronic airway obstructive disease.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/415 ACV C07D 233/61 103 233/64 235/08 409/06 233 // (C07D 409 / 06 233: 56 333: 10) (72) Inventor Hisao Kusuma 5-7-15 Nishi Takanodai, Sugito-cho, Kitakatsushika-gun, Saitama

Claims (15)

[Claims] 1. The general formula (1) [In the formula, R ₁ represents a phenyl group or a thienyl group which may have a substituent, R ₂ represents a cyano group, a hydroxyl group, a carboxyl group, a CONR ₇ R ₈ group (in the formula, R ₇ and R ₈ are The same or different, each represents a hydrogen atom or a lower alkyl group,
Or R ₇ and R ₈ represent a alkylene chain which may contain a hetero atom to form a ring) or a COOR ₉ group (in the formula, R ₉ represents a lower alkyl group), and R ₃ represents hydrogen. Represents an atom or a lower alkyl group, R ₄ , R ₅ and R ₆ are the same or different and represent a hydrogen atom, a lower alkyl group which may have a substituent or a cycloalkyl group, or R ₅ , R ₅ ; _The imidazole derivative may be condensed with a benzene ring at the _6- position, m is an integer of 1 to 6, and a pharmaceutically acceptable salt thereof. 2. The imidazole derivative according to claim 1, wherein R ₁ is a phenyl group, and a pharmaceutically acceptable salt thereof. 3. The imidazole derivative according to claim 1, wherein R ₄ is a lower alkyl group, and a pharmaceutically acceptable salt thereof. 4. The imidazole derivative and the pharmaceutically acceptable salt thereof according to claim 1, wherein R ₂ is a carboxyl group. 5. 4- (2-Methyl-1-imidazolyl)
2. The imidazole derivative according to claim 1, which is 2,2-diphenylbutyric acid, and a pharmaceutically acceptable salt thereof. 6. The general formula (2) [In the formula, R ₁ represents a phenyl group or a thienyl group which may have a substituent, R ₃ represents a hydrogen atom or a lower alkyl group, and R ₄ , R ₅ and R ₆ are the same or different. It may represent a hydrogen atom, a lower alkyl group which may have a substituent or a cycloalkyl group, or may be condensed with a benzene ring at the positions of R ₅ and R ₆ , and m is an integer of 1 to 6. In the production of the compound represented by the formula] and salts thereof, the compound represented by the general formula (3) [Wherein R ₁ , R ₃ and m are as described above and X represents a leaving group], and the compound represented by the general formula (4) [Wherein R ₄ , R ₅ and R ₆ are as described above], and the reaction is carried out. 7. The general formula (5) [In the formula, R ₁ represents a phenyl group or a thienyl group which may have a substituent, R ₃ represents a hydrogen atom or a lower alkyl group, and R ₄ , R ₅ and R ₆ are the same or different. It may represent a hydrogen atom, a lower alkyl group which may have a substituent or a cycloalkyl group, or may be condensed with a benzene ring at the positions of R ₅ and R ₆ , and m is an integer of 1 to 6. The compound represented by the formula [2] [Wherein R ₁ , R ₃ , R ₄ , R ₅ . R ₆ and m are as described above], the compound represented by the formula is hydrolyzed. 8. The general formula (6) [In the formula, R ₁ represents a phenyl group or a thienyl group which may have a substituent, R ₃ represents a hydrogen atom or a lower alkyl group, and R ₄ , R ₅ and R ₆ are the same or different. It may represent a hydrogen atom, a lower alkyl group which may have a substituent or a cycloalkyl group, or may be condensed with a benzene ring at the positions of R ₅ and R ₆ , and m is an integer of 1 to 6. In the production of the compound represented by the general formula (2) [Wherein R ₁ , R ₃ , R ₄ , R ₅ . R ₆ and m are as described above], the compound represented by the formula is hydrolyzed. 9. The general formula (6) [In the formula, R ₁ represents a phenyl group or a thienyl group which may have a substituent, R ₃ represents a hydrogen atom or a lower alkyl group, and R ₄ , R ₅ and R ₆ are the same or different. It may represent a hydrogen atom, a lower alkyl group which may have a substituent or a cycloalkyl group, or may be condensed with a benzene ring at the positions of R ₅ and R ₆ , and m is an integer of 1 to 6. In the production of the compound represented by the formula] and salts thereof, the compound represented by the general formula (5) [Wherein R ₁ , R ₃ , R ₄ , R ₅ , R ₆ and m are as described above] is hydrolyzed. 10. The general formula (7) [In the formula, R ₁ represents a phenyl group or a thienyl group which may have a substituent, R ₃ represents a hydrogen atom or a lower alkyl group, and R ₄ , R ₅ and R ₆ are the same or different. It represents a hydrogen atom, a lower alkyl group which may have a substituent or a cycloalkyl group, or may be condensed with a benzene ring at the positions of R ₅ and R ₆ , and R ₇ and R ₈ are the same or Each independently represent a hydrogen atom or a lower alkyl group, or R ₇
And R ₈ may form a ring with an alkylene chain which may contain a hetero atom, and m represents an integer of 1 to 6]. 6) [Wherein R ₁ , R ₃ , R ₄ , R ₅ , R ₆ and m are as described above], the compound represented by the general formula (8) [Wherein R ₇ and R ₈ are as described above], and the reaction is carried out. 11. A general formula (9) [In the formula, R ₁ represents a phenyl group or a thienyl group which may have a substituent, R ₃ represents a hydrogen atom or a lower alkyl group, and R ₄ , R ₅ and R ₆ are the same or different. It represents a hydrogen atom, a lower alkyl group which may have a substituent or a cycloalkyl group, or may be condensed with a benzene ring at the positions of R ₅ and R ₆ , and R ₉ represents a lower alkyl group. , M represents an integer of 1 to 6], in the production of the compound represented by [In the formula, R ₁ , R ₃ , R ₄ , R ₅ , R ₆ and m are as described above], the compound represented by the general formula (10) R ₉ —OH (10) [in the formula, R ₉ Is as described above]. 12. The general formula (1) [In the formula, R ₁ represents a phenyl group or a thienyl group which may have a substituent, R ₂ represents a cyano group, a hydroxyl group, a carboxyl group, a CONR ₇ R ₈ group (in the formula, R ₇ and R ₈ are The same or different, each represents a hydrogen atom or a lower alkyl group,
Or R ₇ and R ₈ represent a alkylene chain which may contain a hetero atom to form a ring) or a COOR ₉ group (in the formula, R ₉ represents a lower alkyl group), and R ₃ represents hydrogen. Represents an atom or a lower alkyl group, R ₄ , R ₅ and R ₆ are the same or different and represent a hydrogen atom, a lower alkyl group which may have a substituent or a cycloalkyl group, or R ₅ , R ₅ ; A cholinergic compound containing an imidazole derivative and a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, which may be condensed with a benzene ring at the position ₆ and m represents an integer of 1 to 6] A pharmaceutical composition useful as a sex receptor antagonist. 13. The general formula (1) [In the formula, R ₁ represents a phenyl group or a thienyl group which may have a substituent, R ₂ represents a cyano group, a hydroxyl group, a carboxyl group, a CONR ₇ R ₈ group (in the formula, R ₇ and R ₈ are The same or different, each represents a hydrogen atom or a lower alkyl group,
Or R ₇ and R ₈ represent a alkylene chain which may contain a hetero atom to form a ring) or a COOR ₉ group (in the formula, R ₉ represents a lower alkyl group), and R ₃ represents hydrogen. Represents an atom or a lower alkyl group, R ₄ , R ₅ and R ₆ are the same or different and represent a hydrogen atom, a lower alkyl group which may have a substituent or a cycloalkyl group, or R ₅ , R ₅ ; Urinary disorders containing an imidazole derivative represented by the formula (6) may be condensed with a benzene ring at the position ₆ and m represents an integer of 1 to 6, a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. A therapeutic pharmaceutical composition. 14. The general formula (1) [In the formula, R ₁ represents a phenyl group or a thienyl group which may have a substituent, R ₂ represents a cyano group, a hydroxyl group, a carboxyl group, a CONR ₇ R ₈ group (in the formula, R ₇ and R ₈ are The same or different, each represents a hydrogen atom or a lower alkyl group,
Or R ₇ and R ₈ represent a alkylene chain which may contain a hetero atom to form a ring) or a COOR ₉ group (in the formula, R ₉ represents a lower alkyl group), and R ₃ represents hydrogen. Represents an atom or a lower alkyl group, R ₄ , R ₅ and R ₆ are the same or different and represent a hydrogen atom, a lower alkyl group which may have a substituent or a cycloalkyl group, or R ₅ , R ₅ ; _A benzene ring may be condensed with the benzene ring at the _6- position, and m represents an integer of 1 to 6], and the hypersensitivity containing the imidazole derivative and a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. A pharmaceutical composition for treating intestinal syndrome. 15. The general formula (1) [In the formula, R ₁ represents a phenyl group or a thienyl group which may have a substituent, R ₂ represents a cyano group, a hydroxyl group, a carboxyl group, a CONR ₇ R ₈ group (in the formula, R ₇ and R ₈ are The same or different, each represents a hydrogen atom or a lower alkyl group,
Or R ₇ and R ₈ represent a alkylene chain which may contain a hetero atom to form a ring) or a COOR ₉ group (in the formula, R ₉ represents a lower alkyl group), and R ₃ represents hydrogen. Represents an atom or a lower alkyl group, R ₄ , R ₅ and R ₆ are the same or different and represent a hydrogen atom, a lower alkyl group which may have a substituent or a cycloalkyl group, or R ₅ , R ₅ ; may be condensed with a benzene ring at a position _6, chronic airway m contain imidazole derivatives and their pharmaceutical acceptable salts and pharmaceutical acceptable carrier represented by 'represents an integer of 1 to 6 A pharmaceutical composition for treating an obstructive disease.