JPH0574589B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Field of Application] The present invention relates to a novel and pharmaceutically useful imizole derivative or a pharmaceutically acceptable salt thereof. [Prior art] Japanese Patent Application Laid-open No. 58-150566 describes thromboxane
Imidazole derivatives have been described that have _A2 synthesis inhibitory effects, platelet aggregation inhibitory effects, and the like. [Problems to be Solved by the Invention] The present inventors have conducted extensive studies in order to develop a compound that has excellent thromboxane A ₂ synthesis inhibiting activity, platelet aggregation inhibiting activity, and the like. [Means for Solving the Problems] As a result of these studies, the present inventors have discovered that a novel imidazole derivative has excellent effects, and have completed the present invention. That is, the present invention is based on the general formula

The present invention relates to an imidazole derivative represented by the following formula or a pharmaceutically acceptable salt thereof. In the formula, R ¹ and R ² are hydrogen and lower alkyl, respectively, X is hydrogen, halogen, and lower alkyl, Y is formyl, and the formula -CH(R ³ )-Z, -AN(R ⁴ )(R ^Five )
Indicates a group represented by Here, R ³ is hydrogen or lower alkyl, Z is a hydroxyl group, lower alkoxy, acyloxy, or phenoxy, R ⁴ and R ⁵ are hydrogen, lower alkyl, hydroxyalkyl, carboxyalkyl, acyl, and the nitrogen at the 1st position is aralkyl. represents piperidine substituted with , or a group in which R ⁴ and R ⁵ combine with adjacent nitrogen atoms to form a heterocycle,
A represents carbonyl or methylene. In this invention, halogen refers to chlorine, bromine,
Fluorine, iodine, lower alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, etc., lower alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary Butoxy etc., hydroxyalkyl means hydroxymethyl, hydroxyethyl, hydroxypropyl, carboxyalkyl means carboxymethyl,
Carboxyethyl, carboxypropyl, etc.
Aralkyl refers to benzyl, phenylethyl, phenylpropyl, etc. Acyl refers to acetyl, propionyl, butyryl, isobutyryl, pivaloyl, benzoyl, nicotinoyl, etc. Acyloxy refers to acetoxy, propionyloxy, isobutyryloxy, pivaloyloxy, benzoyloxy, etc. Nicotinoyloxy, etc., and the heterocycle may further have nitrogen or oxygen, such as pyrrolidinyl, piperidino, morpholino, piperazinyl,
It means a 5- to 7-membered ring such as homopiperazinyl and imidazolyl. The compound of general formula () of the present invention is produced, for example, by the following method. Method 1 General formula

A method of reacting a compound represented by the formula (wherein Q represents halogen and the other symbols have the same meanings as above) with imidazole. This reaction generally involves combining the imidazole in the presence of a base (sodium hydride, sodium ethoxide, sodium methoxide, potassium carbonate, etc.) in a suitable solvent (dimethylformamide, hexatylphosphorotriamide, nitrobenzene, isoamyl alcohol, etc.). Then, the mixture is reacted with a compound of general formula () under heating for 1 to 24 hours. In this reaction, if a catalyst (copper powder, cuprous iodide, cuprous bromide, etc.) is used, the reaction will proceed more conveniently. Method 2 General formula

A method for reducing a compound represented by [Chemical formula] (In the formula, each symbol has the same meaning as above.) As the reducing agent used in the reduction reaction, a well-known reducing agent having the ability to reduce a carbonyl group to a hydroxyl group may be used, and the type thereof is not particularly limited, but sodium borohydride, lithium aluminum hydride, hydrogen The reduction is most commonly carried out with metal complex compounds such as sodium bis(2-methoxyethyl)aluminum chloride. Furthermore, in the compound of general formula (), Y is -
CH(R ³ )-Z, and when Z is a hydroxyl group, the general formula

[ka]

It can also be obtained by reducing a compound represented by the following formula: (wherein R represents hydrogen or lower alkyl, and the other symbols have the same meanings as above). Method 3 In the compound of general formula (), Y is -CH
(R ³ )-Z, and when Z is acyloxy,
It can also be obtained by acylating the compound obtained in Method 2. The reaction is carried out using a deoxidizing agent (sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, triethylamine, N-methyl morpholine, etc.) and the corresponding acid chloride, acid anhydride, etc. Method 4 If Y is aminomethyl in the general formula (), the general formula

It can be obtained by reducing the compound represented by the following formula in the same manner as in Method 2. Compounds of general formula () in which Y is a formyl compound can be obtained by hydrolyzing an imino compound, which is an intermediate produced by method 4, and compounds in which Y is acylaminomethyl can be obtained by hydrolyzing an intermediate imino compound produced by method 4. It is produced by acylating the compound as in Method 3. The imidazole derivative of the general formula () produced in this manner can be prepared using an inorganic acid such as hydrochloric acid, hydrobromic acid, or sulfuric acid, and oxalic acid, fumaric acid, maleic acid, mandelic acid, citric acid, tartaric acid, or salicylic acid. It can be made into an acid addition salt with an organic acid such as. The compound of the present invention has optical isomers, and the present invention includes both these individual isomers and mixtures thereof. When it is necessary to resolve a racemic compound, known means such as fractional crystallization and various chromatography methods can be used. The raw material compound of general formula () is produced by the following method. (1) General formula

The general formula obtained by oxidizing the compound represented by [Formula] (R ⁸ represents lower alkyl)

For example, by reacting a compound represented by the formula with ethanol in the presence of concentrated sulfuric acid, the compound represented by the general formula

By obtaining a compound represented by [formula] and reducing it, the general formula

A compound represented by the following formula is obtained. Compound d is also produced by reducing compound b. (2) reacting compound b with a halogenating agent such as thionyl chloride to form the corresponding acid halide compound e;
This is the general formula

[Formula] (In the formula, R ⁹ represents hydrogen or lower alkyl.) By reacting the compound represented by the formula and performing hydrolysis and decarboxylation reactions, the general formula

By obtaining a compound represented by [chemical formula] and reducing it, the general formula

[ka] A compound represented by is obtained. (3) General formula

【formula】 Compound and general formula represented by

[ka] (Hal indicates halogen.) A compound represented by or

[ka] Obtained by reacting with the compound represented by

[ka] The general formula is obtained by hydrolyzing the compound represented by

By obtaining a compound represented by [chemical formula] and reducing it, the general formula

[ka] A compound represented by is obtained. (4) Compound e is amidated to give the general formula

By obtaining a compound represented by [chemical formula] and reducing it, the general formula

A compound represented by the following formula is obtained. (5) Compound e is reduced with sodium borohydride etc. to form the general formula

Obtain a compound represented by

A compound represented by [chemical formula] is reacted with an amine compound to obtain the general formula

By obtaining a compound represented by [chemical formula] and reducing it, the general formula

A compound represented by the following formula is obtained. (6) Compound p and the general formula R ¹⁰ -OM (wherein R ¹⁰ is lower alkyl, phenyl which may have at least one halogen, lower alkyl, lower alkoxy, trifluoromethyl, or nitro as a substituent) , M represents a metal such as sodium) to form a compound represented by the general formula

By obtaining a compound represented by [chemical formula] and reducing it, the general formula

A compound represented by the following formula is obtained. (7) By reacting compound p and imidazole, the general formula

By obtaining a compound represented by [chemical formula] and reducing it, the general formula

A compound represented by the following formula is obtained. In these (1) to (7), the oxidizing agents used in the oxidation reaction include chromic acid, potassium permanganate, nitric acid, etc., and the reducing agents used in the reduction reaction include sodium borohydride, lithium aluminum hydride, Examples include bis(2-methoxyethoxy)aluminum hydride. (8) As another method, when the symbol R ⁸ of compound a is isopropyl, when oxidized with dilute nitric acid,
The corresponding acetyl compound [compound w] is obtained, and when this is subjected to a haloform reaction, compound b is obtained. Also, when compound w is reduced, the general formula

A compound represented by the following formula is obtained. The starting compounds of general formulas (), () and () are the above compounds b, c, f, k, m, o, a, s,
u, and w and imidazole are prepared as described in Method 1. The raw material compound of the general formula () can be obtained by reacting compound e with ammonium hydroxide to obtain the raw material compound of the general formula ().

A compound represented by

[Action and effect of the invention]

Imidazole derivatives of general formula () and their acid addition salts have pharmacological effects such as inhibiting the biosynthesis of thromboxane _A2 , inhibiting platelet aggregation, and dilating blood vessels, and are effective against thrombosis, stroke, myocardial infarction, etc.
It is useful for preventing and treating acute cardiac death, angina pectoris, hypertension, asthma, nephritis, etc., and is also useful for preventing cancer metastasis. Furthermore, the compound of the present invention exhibits a high protective effect against liver damage in animals caused by carbon tetrachloride, etc., and is effective against acute and chronic hepatitis, liver cirrhosis, fatty liver, or ethanol, organophosphorus insecticides, chloroform, and carbon tetrachloride. It is useful for the treatment of liver dysfunction such as toxic hepatitis caused by. When used as a medicine, the compound of the present invention can be administered orally by itself or mixed with appropriate pharmacologically acceptable carriers, excipients, diluents, etc. in the form of powder, granules, tablets, capsules, injections, etc. Or it can be administered parenterally. The dosage may vary depending on the target disease and symptoms, but 1 kg of human body weight
per day, preferably in the range of 0.01 to 50 mg/day. The present invention will be described in more detail with reference to reference examples and examples below, but the present invention is not limited thereto. Reference Example 1 5-iodo-2,2',4 obtained by a general Friedel-Crafts reaction of 2-methyl-5-iodobenzoic acid chloride and mesitylene in dichloroethane using anhydrous ferric chloride as a catalyst. ′,6′-tetramethylbenzophenone 200g 20% nitric acid 1.3
Then, heat under reflux for 48 hours with vigorous stirring. After the reaction is completed, it is cooled, toluene is added, and the precipitated crystals are collected by filtration to give 5-iodo 2,2',4'-trimethyl-6'-carboxybenzophenone with a melting point of 246-249.
Obtained as white crystals at ℃. Reference example 2 (1) 5-iodo-2,2',6'-trimethyl-4'-
34g of isopropylbenzophenone in 20% nitric acid
Heat and reflux 210 ml for 5 hours while stirring vigorously. After cooling, extract with toluene, wash with dilute aqueous sodium hydroxide solution, wash with water and dry, then distill off the toluene and purify the residue using 250 g of silica gel to obtain 5-iodo-2,2'-
6'-trimethyl-4'-acetylbenzophenone is obtained as white needles. Melting point 114-116
℃. (2) Dissolve 34.1g of sodium hydroxide in 225ml of water,
Slowly add 49.6 g of bromine while cooling on ice. Add 5-iodo-2,2',6'-trimethyl- to this solution.
18.6g of 4′-acelbenzophenone and dioxane
Add 110ml and heat to 35℃ while stirring.
It slowly heats up. After stirring at 40°C for 2 hours, the mixture is left at room temperature overnight, and the carboxylic acid sodium salt precipitates out as white crystals. This was collected by filtration, dried, suspended in 450 ml of ethanol, and stirred.
Add 16 ml of concentrated sulfuric acid and stir and reflux for 4 hours.
After the reaction is complete, ethanol is distilled off under reduced pressure, water is added to the residue, and the mixture is extracted with toluene. The extract was washed successively with a dilute aqueous sodium hydroxide solution and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to yield 5-iodo-2,2',6'-trimethyl-4'-ethoxycarbonylbenzophenone. Obtained in quantitative yield as white needles. melting point
115-118℃. Reference Example 3 15.3 g of 5-iodo-2,2',6'-trimethyl-4'-ethoxycarbonylbenzophenone, 3.0 g of imidazole and 6.4 g of potassium carbonate were suspended in 50 ml of dimethylformamide, and 0.3 g of copper powder was added to this. Add 0.3 g of potassium fluoride and heat with stirring at 140°C for 4 hours. After the reaction is complete, dimethylformamide is distilled off under reduced pressure, water is added to the residue, and the precipitated crystals are extracted with ethyl acetate. Insoluble copper compounds are removed by filtration, and the organic layer is separated, dried, and concentrated. A small amount of ethyl acetate was added to the residue, and after cooling on ice, the precipitated crystals were collected by filtration to give 5-(1-imidazolyl)-2,2'-
6'-trimethyl-4'-ethoxycarbonylbenzophenone is obtained as white crystals in high yield. Melting point 167-169℃. Reference Example 4 (1) 51 g of 3-bromobenzaldehyde diethyl acetal is dissolved in 200 ml of dry ether, and 141 ml of a hexane solution of n-butyllithium is slowly added dropwise at -35 to -45°C while stirring. −30〜−
After stirring at 40°C for 50 minutes, the mixture was cooled to -60°C, and 24 g of 3-fluorobenzonitrile was added dropwise. Thereafter, the cooling bath is removed and the temperature is slowly raised to room temperature. After the reaction is completed, water is added, 60 ml of concentrated hydrochloric acid is added, and the ether is distilled off by heating, and heating is continued until the internal temperature reaches 50°C. The oil that separates is extracted with toluene, dried and concentrated. Distill the residue under reduced pressure to 150-155℃/0.08mm
Collect the Hg fraction. When this fraction was recrystallized from isopropyl ether, 3-fluoro-
3'-Formylbenzophenone is obtained as needle-shaped crystals. Melting point 67-69℃. (2) 3-fluoro-3'-formylbenzophenone
18g and 23g of ethyl orthoformate in ethanol
Dissolve in 110ml, add a small amount of ammonium chloride,
Heat under reflux for 2 hours. After the reaction, ethanol was distilled off under reduced pressure, n-hexane was added to the residue, the ammonium chloride separated was filtered off, and concentrated to give 3
-Fluoro-3'-formylbenzophenone diethyl acetal is obtained as a colorless transparent oil. Next, 3.5g of 50% oil-based sodium hydride
is suspended in 75 ml of hexamethylphosphorotriamide, and 6.4 g of imidazole is added little by little while stirring. After the addition was complete, stirring was continued for 1 hour at room temperature, the above acetal was added, and the mixture was stirred at 70℃ for 22 hours.
Stir for an hour. After cooling, water is added and the oily substance that separates is extracted with toluene. Add dilute hydrochloric acid to the oil, stir at 40-50°C for 1 hour, and separate the aqueous layer. The mixture is made alkaline with a 30% aqueous sodium hydroxide solution, and the separated oil is extracted from ethyl acetate, washed with water, dried, and concentrated. Recrystallization of the residue from isopropyl ether containing a small amount of ethyl acetate yields 3-(1-imidazolyl)-3'-formylbenzophenone as white needles. Melting point 110-112℃. Reference example 5 4.5 g of 5-iodo-2,2',6'-trimethyl-4'-carboxybenzophenone was dissolved in dichloroethane.
Suspend in 35 ml, add 2.8 g of thionyl chloride, and stir under heating under reflux for 6 hours. After the reaction, excess thionyl chloride and dichloroethane are distilled off. Dissolve the residue in 50 ml of dichloroethane and stir under ice cooling. After adding 2.5 g of piperidine to this, at room temperature
Stir for 30 minutes. After the reaction is completed, the mixture is washed successively with water, dilute hydrochloric acid, dilute aqueous sodium hydroxide solution, and water, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue is dissolved in 30 ml of dimethylformamide, 2.2 g of imidazole, 3 g of potassium carbonate and 1 g of cuprous bromide are added thereto, and the mixture is stirred at 120-125°C for 4.5 hours. After the reaction is complete, pour into ice water and extract with ethyl acetate. At this time, unnecessary catalyst is filtered off. The ethyl acetate layer is separated, washed with water, dried over anhydrous magnesium sulfate, and concentrated. When the residue is recrystallized from toluene, 5-(1-imidazolyl)-2,2',6'-trimethyl-4'-piperidinocarbonylbenzophenone is obtained as pale yellow crystals in high yield. . melting point
119-122℃. Reference example 6 5-iodo- obtained by the same method as reference example 5
15 g of 4-chlorocarbonyl 2,2',6'-trimethylbenzophenone is added little by little under ice cooling to a mixed solution of 3.4 g of sodium borohydride, 30 ml of water and 150 ml of ethanol with stirring. After adding the entire amount, stir at room temperature for 1.5 hours. After the reaction is complete,
Pour into water and extract the precipitate with chloroform. The chloroform layer is washed with water, dried, and concentrated. When the residue is recrystallized from toluene, 5-iodo-4'-hydroxymethyl-2,2',6'-trimethylbenzophenone is obtained almost quantitatively as white crystals with a melting point of 157-160°C. 13 g of the obtained crystals were suspended in 65 ml of dichloroethane, and 6.1 g of thionyl chloride was added to the suspension at room temperature.
Drop g. After dropping the entire amount, reflux for 1.5 hours and concentrate. The residue was added to a solution of 1 g of sodium metal and 40 ml of methanol, and the mixture was stirred under reflux for 1.5 hours.
After the reaction is complete, pour into water and extract with chloroform.
The chloroform layer is dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography to produce 5-iodo-4'-methoxymethyl-
10.5 g of 2,2',6'-trimethylbenzophenone are obtained. Dissolve this in 50 ml of dimethylformamide, add 2.7 g of imidazole, and 5.6 g of potassium carbonate.
g, 0.3 g of copper powder and 0.3 g of potassium fluoride are added, and the mixture is stirred at 120 to 130°C for 4 hours. After the reaction is complete,
Add ethyl acetate and filter off insoluble matter. Then,
The ethyl acetate solution is washed twice with water, dried over anhydrous magnesium acetate, and concentrated. Recrystallization of the residue from toluene yields 8 g of 5-(1-imidazolyl)-4'-methoxymethyl-2,2',6'-trimethylbenzophenone as pale yellow crystals with a melting point of 149-151°C. Reference example 7 5-iodo- obtained by the same method as reference example 5
When 4'-chlorocarbonyl-2,2',6'-trimethylbenzophenone is reacted with aqueous ammonia, quantitatively 5-iodo-2,2',6'-trimethyl-
4'-carbamoylbenzophenone is obtained. 10 g of this carbamoyl compound and 15 ml of phosphorus oxychloride were stirred under reflux. After 30 minutes, pour the reaction mixture into ice water and stir for a while. The precipitated crystals were collected by filtration, thoroughly washed with water, and then washed with a small amount of ethanol and dried.
-Iodo-4'-cyano-2,2',6'-trimethylbenzophenone is obtained quantitatively. This is dissolved in 60 ml of dimethylformamide, and then 3.5 g of imidazole, 5.3 g of potassium carbonate, 0.5 g of copper powder and 0.5 g of potassium fluoride are added and reacted at 140°C for 3 hours. After the reaction is complete, pour into ice and extract with ethyl acetate. Insoluble matter precipitated at this time is filtered off. The ethyl acetate layer is separated, washed with water, dried, and concentrated. Recrystallization of the residue from toluene gives 7 g of 5-(1-imidazolyl)-4'-cyano-2,2',6'-trimethylbenzophenone as a pale yellow color with a melting point of 160-165°C. Example 1 0.7 g of lithium aluminum hydride was dissolved in 40 ml of dry ether and mixed with 4.5 g of 5-(1-imidazolyl)-2,2',6'-trimethyl-4'-ethoxycarbonylbenzophenone while stirring. A solution consisting of 50 ml of tetrahydrofuran is slowly added dropwise. After the dropwise addition is completed, stirring is performed at room temperature for 30 minutes to complete the reaction. After cooling on ice, excess lithium aluminum hydride is decomposed by carefully adding water dropwise. The organic layer is separated, and the aqueous layer is extracted with chloroform containing a small amount of methanol. The extracts are collected, dried over anhydrous magnesium sulfate, and concentrated. Residual toluene:dimethylformamide=
Recrystallization from a 3:1 solvent mixture gives 5-(1-imidazolyl)-2-methyl-α-(4-hydroxymethyl-
2,6-dimethylphenyl)benzene methanol is obtained. Melting point 189-191℃. Example 2 5-(1-imidazolyl)-4'-cabamoyl-
3 g of 2,2',6'-trimethylbenzophenone is suspended in 18 ml of ethanol, and a solution of 0.5 g of sodium borohydride and 5 ml of water is added thereto. After stirring under reflux for 1 hour, pour into ice water. The precipitated crystals were collected by filtration and recrystallized from methanol to give 5-
2.5 g of (1-imidazolyl)-2-methyl-α-(4-carbamoyl-2,6-dimethylphenyl)benzene methanol are obtained as white crystals with a melting point of 247-249°C. Example 3 5-(1-imidazolyl)-4'-diethylaminomethyl-2,2',6'-trimethylbenzophenone
Dissolve 4.6 g in 25 ml of ethanol and add 0.93 g of sodium borohydride and 10 ml of water.
After stirring under reflux for 2 hours, it was poured into ice water. The precipitated oil is extracted with chloroform, dried and concentrated. Dissolve the residue in 40 ml of isopropyl alcohol, add hydrochloric acid-isopropyl alcohol solution to make it acidic, and cool on ice. The precipitated crystals were collected by filtration and recrystallized from ethanol to give 5-(1-
3.6 g of benzene methanol dihydrochloride has a melting point of 244-245
Obtained as white crystals at ℃ (decomposition). Example 4 7 g of 5-(1-imidazolyl)-4'-phenoxymethyl-2,2',6'-trimethylbenzophenone
was dissolved in 50 ml of ethanol, 1 g of sodium borohydride and 5 ml of water were added thereto, and the mixture was stirred under reflux for 4.5 hours. After the reaction is complete, pour into ice water,
The deposited precipitate is extracted with chloroform. Separate the chloroform layer, wash with water, dry, and concentrate.
When the obtained residue is recrystallized from toluene, 5-
(1-Imidazolyl)-2-methyl-α-(4-phenoxymethyl-2,6-dimethylphenyl)benzene methanol is obtained in high yield as white crystals with a melting point of 81-85°C. Example 5 (1) 1.7 g of lithium aluminum hydroxide is suspended in 100 ml of tetrahydrofuran and stirred under water cooling. Then, to this, 5-(1-imidazolyl)-
A solution of 9.2 g of 4'-cyano-2,2',6'-trimethylbenzophenone in 100 ml of tetrahydrofuran was added.
Drip over 30 minutes. After dropping the entire amount, leave at room temperature for 40 minutes.
Stir for a minute. After the reaction is complete, add 50 ml of water for hydrolysis. The deposited precipitate is extracted with chloroform, and at this time, insoluble matter is filtered off. Separate the chloroform layer, wash with water, dry, and concentrate. When the obtained residue was recrystallized from a mixed solvent of ethanol and chloroform, 5-(1-imidazolyl)-2-
Melting point of 7.6 g of methyl-α-(4-formyl-2,6-dimethylphenyl)benzene methanol
Obtained as white crystals at 227-231°C. (2) Suspend 0.9 g of lithium aluminum hydride in 30 ml of tetrahydrofuran, and add 5-(1-imidazolyl)-4'-cyano-2,2',6'-trimethylbenzophenone to the suspension while stirring under water cooling. A solution of 3 g in 40 ml of tetrahydrofuran is added dropwise over 15 minutes. After dropping the entire amount, stir at 50°C for 7 hours. After the reaction is completed, the reaction mixture is cooled on ice, and 20 ml of water is added to it. Filter off the insoluble solution and wash thoroughly with methanol. Combine the filtrate and washings and concentrate. The obtained oil was purified by column chromatography, converted into a fumarate salt in ethanol, and further recrystallized from methanol, yielding 5
-(1-imidazolyl)-2-methyl-α-(4
-aminomethyl-2,6-dimethylphenyl)
Benzene methanol fumarate monohydrate
2.8 g are obtained as white crystals with a melting point of 140-142°C (decomposed). Example 6 5-(1-imidazolyl)-2-chloro-α-
Dissolve 1.5 g of (4-hydroxymethyl-2,6-dimethylphenyl)benzene methanol in 30 ml of dimethylformamide, and dissolve 0.53 g of triethylamine.
g and cooled to -50°C. Add 0.56 g of isobutyryl chloride to this at once. Thereafter, the mixture was stirred at room temperature for 1 hour and then poured into water. The deposited precipitate is extracted with ethyl acetate. The ethyl acetate layer is separated, washed successively with an aqueous sodium bicarbonate solution and water, dried over anhydrous magnesium sulfate, and then concentrated. When the obtained residue is recrystallized from ethanol, 5-
(1-Imidazolyl)-2-methyl-α-(4-isobutyryloxymethyl-2,6-dimethylphenyl)benzene methanol is obtained in high yield as white crystals with a melting point of 160-162°C. Example 7 10 g of 2-chloro-5-iodo-α-[4-(1-hydroxyethyl)-2,6-dimethylphenyl]benzene methanol, 2.1 g of imidazole and 4.6 g of potassium carbonate were added to 35 g of dimethylformamide.
ml, add 0.2 g of copper powder and 0.2 g of potassium fluoride, and stir and heat at 140°C for 5 to 6 hours. After the reaction is completed, the same treatment as in Reference Example 3 is carried out, and recrystallization from toluene containing a small amount of dimethylformamide yields 5-(1-
imidazolyl)-2-chloro-α-[4-(1-hydroxyethyl)-2,6-dimethylphenyl]
Benzene methanol is obtained. The following compounds are obtained in the same manner. (8) 5-(1-imidazolyl)-2-methyl-α-
[4-(1-hydroxyethyl)-2,6-dimethylphenyl]benzene methanol, melting point 165
~168℃ (9) 3-(1-imidazolyl)-α-(3-hydroxymethylphenyl)benzene methanol, colorless oil H-NMR (CDCl ₃ + small amount of CD ₃ OD): - CH ₂ -
OH (4.56ppm, 2H, singlet)

[Formula] (5.8ppm, 2H, singlet) (10) 5-(1-imidazolyl)-2-chloro-α-
(4-hydroxymethyl-2,6-dimethylphenyl)benzene methanol, melting point 199-201℃ (11) 5-(1-imidazolyl)-2-methyl-α-
(6-hydroxymethyl)-2,4-dimethylphenyl)benzene methanol, melting point 194-196℃ (12) 5-(1-imidazolyl)-2-methyl-α-
(4-Methoxymethyl-2,6-dimethylphenyl)benzene methanol, melting point 132-135℃ (11) 5-(1-imidazolyl)-2-methyl-α-
(4-isopropoxymethyl-2,6-dimethylphenyl)benzene methanol, melting point 138~
140℃ (14) 5-(1-imidazolyl)-2-methyl-α-
(4-acetoxymethyl-2,6-dimethylphenyl)benzene methanol, melting point 143-145℃ (15) 5-(1-imidazolyl)-2-methyl-α-
(4-isobutyryloxymethyl-2,6-dimethylphenyl)benzene methanol, melting point
123-124.5℃ (16) 5-(1-imidazolyl)-2-chloro-α-
(4-nicotinoyloxymethyl-2,6-dimethylphenyl)benzene methanol, melting point
204～205℃ (17) 5-(1-imidazolyl)-2-methyl-α-
(4-nicotinoyloxymethyl-2,6-dimethylphenyl)benzene methanol, melting point
211～213℃ (18) 5-(1-imidazolyl)-2-methyl-α-
(4-diethylcarbamoyl-2,6-dimethylphenyl)benzene methanol, melting point 182~
183℃ (19) 5-(1-imidazolyl)-2-methyl-α-
(4-Methylcarbamoyl-2,6-dimethylphenyl)benzene methanol monohydrate, melting point 137-139℃ (20) 5-(1-imidazolyl)-2-methyl-α-
(4-piperidinocarbonyl-2,6-dimethylphenyl)benzene methanol, melting point 236~
238℃ (21) 5-(1-imidazolyl)-2-methyl-α
-(4-isopropylcarbamoyl-2,6-
(dimethylphenyl)benzene methanol monohydrate, melting point 141-143℃ (decomposition) (22) 5-(1-imidazolyl)-2-methyl-α
-(4-octylcarbamoyl-2,6-dimethylphenyl)benzene methanol, pale yellow amorphous crystal H-NMR (CDCl ₃ )

[Formula] (6.22ppm, 1H, singlet)

[ka] (2.02ppm, 3H, singlet)

[Chem] (2.22ppm, 6H, singlet) (23) 5-(1-imidazolyl)-2-methyl-α
-[4-(1-2-phenylethyl)-4-piperidyl)carbamoyl-2,6-dimethylphenyl]benzene methanol 3/2 oxalate, melting point 198-199℃ (decomposition) (24) 5-( 1-imidazolyl)-2-methyl-α
-[4-(2-hydroxyethyl)carbamoyl-2,6-dimethylphenyl]benzene methanol monohydrate, melting point 125-130℃ (25) 5-(1-imidazolyl)-2-methyl-α
-(4-carboxymethylcarbamoyl-2,
6-dimethylphenyl)benzene methanol
Monohydrate, melting point 170-171℃ (decomposed) (26) 5-(1-imidazolyl)-2-methyl-α
-[4-(1-imidazolyl)methyl-2,6-
dimethylphenyl)benzene methanol, melting point
193～195℃ (27) 5-(1-imidazolyl)-2-methyl-α
-(4-acetylaminomethyl-2,6-dimethylphenyl)benzene methanol, pale yellow amorphous crystal H-NMR (CDCl ₃ )

[Formula] (6.24ppm, 1H, singlet)

[C] (4.3ppm, 2H, doublet) CH ₃ CONH− (2.12ppm, 3H, singlet)

Claims (1)

[Claims] 1. An imidazole derivative represented by the general formula [Formula] or a pharmaceutically acceptable salt thereof. In the formula, R ¹ and R ² are hydrogen and lower alkyl, respectively, X is hydrogen, halogen, and lower alkyl, Y is formyl, and the formula -CH(R ³ )-Z, -AN(R ⁴ )(R ^Five )
Indicates a group represented by Here, R ³ is hydrogen or a lower alkyl group, Z is a hydroxyl group, lower alkoxy, acyloxy, or phenoxy, and R ⁴ and R ⁵ are hydrogen, lower alkyl, hydroxyalkyl, carboxyalkyl, acyl, or nitrogen at the 1st position, respectively. It represents piperidine substituted with aralkyl, or a group in which R ⁴ and R ⁵ combine with adjacent nitrogen atoms to form a heterocycle, and A represents carbonyl or methylene.