JPH0830063B2 - Novel imidazole derivative and its salt - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial field of application] “In the formula, R ¹ and R ² are the same or different and each is a phenyl group which may be substituted with a halogen atom, alkyl, hydroxyl, alkoxy, mercapto, alkylthio or alkylsulfonyl group; R ³ is a halogen atom, hydroxyl group Or an alkyl or cycloalkyl group which may be substituted with an alkoxy group or a hydrogen atom; R ⁴ is substituted with a halogen atom, alkyl, hydroxyl, alkoxy, mercapto, alkylthio, alkylsulfonyl, dialkylamino, nitro or cyano group. Optionally an alkyl or cycloalkyl group or a hydrogen atom, a cyano group or a furyl group; R ⁵ and R ⁶ are the same or different and are a hydrogen atom, a halogen atom,
A cyano group, a formyl group, an acetyl group, a nitro group, an aryl group or an alkylthio group; and R ⁵ and R ⁶ together with adjacent carbon atoms are acyl, hydroxyl, oxo, alkoxy, mercapto, alkylthio,
It may form a 3- to 8-membered cycloalkyl ring optionally substituted with an alkylsulfonyl, arylsulfonyl, nitro, cyano or dialkylamino group. However, when R ¹ and R ² are phenyl groups, at least one of them is a phenyl group substituted with a halogen atom, alkyl, hydroxyl, alkoxy, mercapto, alkylthio or alkylsulfonyl group. Also, R ⁴
When is a hydrogen atom, R ⁵ and R ⁶ are the same or different and are not an aryl group. ] Relating to a novel imidazole derivative and a salt thereof.

Therefore, an object of the present invention is to provide a novel imidazole derivative and a salt thereof which have excellent anti-inflammatory action, antipyretic analgesic action and anti-arthritic action and exert an excellent therapeutic effect.

[Prior Art] Substituted imidazoles are described, for example, in JP-A-47-10379,
Japanese Examined Japanese Patent Publication No. 51-23506, No. 59-46505, Journal of
Medical Chemistry [Journal of Medicinal C
hemistry 28 (9), 1188-1194 (1985)] and the like, and it is also known that the compounds described therein have anti-inflammatory and analgesic effects.

[Problems to be Solved by the Invention] However, these substituted imidazoles cannot be said to be sufficient in terms of both pharmacological effect and toxicity, and further excellent compounds have been desired to be developed.

[Means for Solving the Problems] Under these circumstances, the present inventors have conducted diligent research, and as a result, as a feature of the imidazole at the 2-position, the formula [In the formula, R ⁴ , R ⁵ and R ⁶ have the same meanings as described above. ] It was found that the compound of the formula [I] to which the group represented by the formula is bonded exhibits an excellent pharmacological effect and low toxicity, and has completed the present invention.

 Hereinafter, the compound of the present invention will be described in detail.

In the present invention, each term has the following meaning unless otherwise specified.

The alkyl group is, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or se.
a C _1-8 alkyl group such as c-butyl, tert-butyl, pentyl and the like; an alkoxy group means an —O-alkyl group;
The alkylthio group means an —S-alkyl group; the dialkylamino group means, for example, a diC _1-5 alkylamino group such as dimethylamino or diethylamino; the alkylsulfinyl means an —SO-alkyl group; an alkylsulfonyl group. The group is -SO ₂ -alkyl group; the alkenyl group is
For example, C _2-6 such as vinyl, allyl, 1-propenyl, iso-propenyl, 1-butenyl, 2-butenyl and the like.
An alkenyl group; a cycloalkyl group is, for example, a C _3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; an aryl group is a group such as phenyl and naphthyl; an arylthio group is , -S- aryl group; and aryloxy group, an -O- aryl group; and arylsulfinyl, -SO- aryl group a; and arylsulfonyl group, -SO ₂ - aryl groups; and acyl groups Is, for example, a C _1-4 acyl group such as formyl, acetyl, propionyl, butyryl, iso-butyryl; and the heterocyclic group is, for example, furyl, thienyl, pyrrolyl, oxazolyl,
A 5-membered or 6-membered heterocyclic group containing at least one nitrogen atom, oxygen atom and / or sulfur atom as a hetero atom such as thiazolyl, imidazolyl and pyridyl; a halogen atom is fluorine, chlorine or bromine. And iodine and the like.

R ¹ and R ² are the same or different and are phenyl groups which may be substituted with a halogen atom, alkyl, hydroxyl, alkoxy, mercapto, alkylthio or alkylsulfonyl group.

R ³ is a halogen atom, an alkyl or cycloalkyl group which may be substituted with a hydroxyl or alkoxy group, or a hydrogen atom.

R ⁴ is a halogen atom, alkyl, hydroxyl, alkoxy, mercapto, alkylthio, alkylsulfonyl, dialkylamino, alkyl or cycloalkyl group optionally substituted with nitro or cyano group, or a hydrogen atom, cyano group or furyl group. .

R ⁵ and R ⁶ are the same or different and each is a hydrogen atom, a halogen atom, a cyano group, a formyl group, an acetyl group, a nitro group,
It is an aryl group or an alkylthio group.

R ⁵ and R ⁶ together with adjacent carbon atoms may be substituted with an acyl, hydroxyl, oxo, alkoxy, mercapto, alkylthio, alkylsulfonyl, arylsulfonyl, nitro, cyano or dialkylamino group. A good 3- to 8-membered cycloalkyl ring may be formed, and specifically, for example, a formula, "In the formula, n shows 2-7."

The salt of the imidazole derivative of the formula [I] is a pharmaceutically acceptable salt, for example, a salt with a mineral acid such as hydrochloric acid, sulfuric acid, phosphoric acid; acetic acid, fumaric acid, maleic acid, malic acid, tartaric acid, citric acid. , Salts with organic carboxylic acids such as aspartic acid; salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid; salts with alkaline metals such as sodium and potassium.

The compound of the present invention further includes all isomers (geometric isomers,
Optical isomers), hydrates, solvates and crystalline forms.

The imidazole derivative of the formula [I] or a salt thereof can be produced, for example, by the method shown below.

`` In the formula, R ¹ , R ² and R ³ have the meanings described above, and R ^3a is R
Optionally substituted alkyl similar to that described in ^{3 above} ,
A cycloalkyl group or a protecting group that is stable under strongly basic conditions and is easily removed by an acidic reagent to replace a hydrogen atom; R ^4a is the same hydrogen atom as described for R ⁴ , which may be substituted. An alkyl, cycloalkyl, or furyl group; R ^5a and R ^6a are the same or different and are the same halogen atom, cyano group, and formyl group as described for R ⁵ and R ⁶ ;
Acetyl group, a nitro group, an aryl group or an alkylthio group; R ^5b and R ^6b are the same or different, R ⁵ and
A cyano group, a formyl group, an acetyl group, a nitro group, an aryl group or an alkylthio group similar to those described for R ⁶ ; R
^5c , R ^5d , R ^6c and R ^6d are the same or different and R ⁵ and R
Similar hydrogen atom and described in ^6, the aryl group; R ^5e and R ^6e are the same hydrogen atom and described in R ⁵ and R ⁶ identical or different, an aryl group; A is phosphate scan Hora Sui chloride (phosphorus ylid), phosphonate anion
nate anion), phosphinate
anion), phosphine oxide anion
Deanion) and other phosphorus compound residues; X is a halogen atom; Y is a leaving group; B is a formyl group or acetal. Further, R ^5a and R ^6a , R ^5c and R ^6c , R ^5d and R ^6d or R ^5e and R ^6e together with the adjacent carbon atom have the same substituents as those described for R ⁵ and R ^6. It may form a 3- to 8-membered optionally cycloalkyl ring. Expressions [Ia], [Ib], [Ic], [Id], [Ie], [I
The compounds of [f], [Ig], [II], [IV], [VI], [XI] and [XIII] can also be obtained as salts, which are salts of the compounds of formula [I]. The same thing as is mentioned.

Examples of the protecting group of R ^3a which is stable under strongly basic conditions and which is easily removed by an acidic reagent to replace a hydrogen atom include, for example, α-ethoxyethyl, 2-tetrahydropyranyl, benzyloxymethyl, p-methoxy. Examples thereof include benzyl and trityl groups.

Examples of the leaving group of Y include a halogen atom, an alkylsulfonyloxy group, an arylsulfonyloxy group and the like.

Furthermore, expressions [Ia] to [Ig], [II], [III], [I
V], [V], [VI], [VII], [VIII], [X],
In the compounds of [XI], [XII] and [XIII],
When R ¹ , R ² , R ³ , R ^3a , R ^4a , R ^5b , R ^6b , R ^5c , R ^6c , R ^5d and R ^6d have a hydroxyl group and a mercapto group as a substituent, for example, a protective group・ Groups in Organic Synthesis [Protecti
ve Groups in Organic Synthesis (TW Green, 1981
Years) John Wiley & Sons, Inc.].

Production Method 1 A compound of formula [Ia] can be produced by subjecting a compound of formula [II] to a Wittig reaction.

The Wittig reaction is, for example, Organic Reactions (John Wi
[ley & Sons, Inc.)] Vol. 14, 270-490, Vol. 25, pp. 73-253, Ylid Chemistry
(AW Johnson, 1966) Academic Press Inc.], Organophosphorus Reagents in Organ
ic Synthesis (JIG Cadogan, 1979) Academic Pr
ess Inc. (London) LTD.], Synthetic Communication [Synthetic Communication 3 (3) , 197-200 (19
73)]] or by a method analogous thereto,
ylid), phosphonate anio
n), phosphinate anion,
Phosphine oxide anion
It shows a reaction to obtain a compound having a double bond by a reaction with an aldehyde or a ketone using a phosphorus compound such as n).

Here, the phosphorus compound used in the Wittig reaction includes all those having a substituent of R ^5a and R ^6a which can produce the compound of the formula [Ia].

The solvent used in this reaction may be any solvent that does not adversely influence the reaction, and examples thereof include hydrocarbons such as benzene, toluene, xylene, n-hexane and n-heptane; diethyl ether, tetrahydrofuran, dioxane. Ethers such as 1,2-dimethoxyethane and diglyme; methylene chloride, chloroform, 1,
Hydrogen halides such as 2-dichloroethane; Esters such as methyl acetate and ethyl acetate; Alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol; Nitriles such as acetonitrile; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide;
Examples thereof include sulfoxides such as dimethyl sulfoxide; and water, and these solvents may be used as a mixture of two or more kinds.

The amount of the phosphorus compound used is usually 1 to 10 times mol, preferably 1 to 5 times mol, of the compound of the formula [II].

This reaction is usually performed under nitrogen atmosphere at -78 to 160 ° C for 10
It may be carried out for a minute to 72 hours.

Production Method 2 A compound of formula [Ib] can be produced by reacting a compound of formula [II] with an active methylene compound having substituents R ^5b and R ^6b of formula [III] in the presence of a catalyst.

This method is called the so-called Knoevenagel
Type, Claisen-Schmidt type,
It utilizes a Perkin type reaction.

The solvent used in this reaction may be any solvent which does not adversely influence the reaction, for example, hydrocarbons such as benzene, toluene and xylene; alcohols such as methanol, ethanol, tert-butanol and ethylene glycol. Amides such as N, N-dimethylformamide and N, N-dimethylacetamide; ethers such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane and diglyme; methylene chloride, chloroform and 1,2-dichloroethane Examples thereof include halogenated hydrocarbons; dimethyl sulfoxide; and water, and these solvents may be used as a mixture of two or more kinds. Moreover, you may use the catalyst mentioned later as a solvent.

Examples of the catalyst used in this reaction include ammonia; primary amines such as n-butylamine; secondary amines such as piperidine, pyrrolidine and morpholine;
Tertiary amines such as triethylamine and pyridine (these basic catalysts can be used alone or with a C _1-5 lower fatty acid such as acetic acid, propionic acid, butyric acid, and valeric acid); Alkali metal hydroxides such as sodium and potassium hydroxide; Alkali metal salts of alcohols such as sodium methylate, sodium ethylate and potassium tert-butoxide; Alkali metal hydrogen compounds such as sodium hydride and potassium hydride Alkali metal salts of carbonic acid such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate; sodium acetate,
Alkali metal salts of carboxylic acids such as potassium acetate; Salts of carboxylic acids such as ammonium acetate, piperidine acetate; Fluorides such as potassium fluoride, rubidium fluoride, cesium fluoride; Lewis such as titanium tetrachloride An acid is mentioned.

The amount of the catalyst and the compound of the formula [III] used is the formula [II]
0.1 to 5 times mol and 1 to 1 times, respectively, with respect to the compound of
It is 0 times the mole.

This reaction may be carried out at 0 to 200 ° C. for 10 minutes to 24 hours.

Production Method 3 The compound of formula [Ic] can be produced by reacting the compound of formula [IV] with a base and then reacting with the compound of formula [V].

The solvent used in this reaction may be any solvent that does not adversely influence the reaction, and examples thereof include the same solvents used in the Wittig reaction as those described in Production Method 1.

Examples of the base used in this reaction include alkali metal carbonates such as sodium hydrogen carbonate, sodium carbonate and potassium carbonate; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; sodium methylate. Alkali metal salts of alcohols such as potassium tert-butoxy; alkali metal hydrogen compounds such as sodium hydride and potassium hydride; n-butyllithium,
Phenyllithium; sodium amide, lithium diisoiipropylamide and the like.

The amounts of the base and the compound of the formula [V] used are 1 to 5 times mol and 1 to 10 mol, respectively, relative to the compound of the formula [IV].

The reaction with a base is usually -78 to 100 ° C for 30 minutes to 24 hours, and the reaction with a compound of the formula [V] is usually -78.
It may be carried out at ~ 160 ° C for 30 minutes to 24 hours.

Production Method 4 A compound of formula [Id] can be produced by reacting a compound of formula [VI] with a compound of formula [VII] in the presence of a catalyst.

As the solvent used in this reaction, any solvent may be used so long as it does not adversely influence the reaction, and examples thereof include the same solvents as those described in the production method 2.

Further, the compound of the formula [VII] can also be used as a solvent.

Examples of the catalyst used in this reaction include ammonia; primary amines such as n-butylamine; secondary amines such as piperidine, pyrrolidine and morpholine;
Tertiary amines such as triethylamine and pyridine (these basic catalysts can be used alone or with a C _1-5 lower fatty acid such as acetic acid, propionic acid, butyric acid, and valeric acid); Alkali metal hydroxides such as sodium and potassium hydroxide; Alkali metal salts of alcohols such as sodium methylate, sodium ethylate and potassium tert-butoxide; Alkali metal hydrogen compounds such as sodium hydride and potassium hydride Alkali metal salts of carbonic acid such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate; sodium acetate,
Examples thereof include alkali metal salts of carboxylic acids such as potassium acetate; salts of carboxylic acids such as ammonium acetate and piperidine acetate; fluorides such as potassium fluoride, rubidium fluoride and cesium fluoride.

The amount of the catalyst and the compound of the formula [VII] used is the same as that of the formula [VI]
0.1 to 5 times mol and 1 to 1 times, respectively, with respect to the compound of
It is 0 times the mole.

This reaction may be carried out at 0 to 200 ° C. for 10 minutes to 24 hours.

Production Method 5 1) A compound of the formula [Ie] can be produced by reacting a compound of the formula [VIII] with a compound of the formula [IX] in the presence of ammonia or ammonium acetate.

The solvent used in this reaction may be one that does not adversely affect the reaction, for example, methanol,
Examples thereof include alcohols such as ethanol, tert-butanol, and ethylene glycol; acetic acid, and the like. These solvents may be used as a mixture of two or more kinds.

The amount of ammonia or ammonium acetate used in this reaction is 5 to 10 times the mol of the compound of the formula [VIII]. The amount of the compound of the formula [IX] used is
It is 1-2 times the molar amount of the compound of [I].

This reaction may be carried out at 15 to 120 ° C. for 30 minutes to 24 hours.

In addition, this reaction was also reported by the Society [Soc., 49 , 464, (189
4)], Journal of Organic Chemistry [J.Org.Chem., 2, 319 (1937)] and the like.

2) The compound of formula [If] can be produced by reacting the compound of formula [Ie] with the compound of formula [X] in the presence of a base.

The solvent used in this reaction may be one that does not adversely affect the reaction, and examples thereof include the same solvents as those mentioned in the production method 2.

Examples of the base used in this reaction include alkali metal hydrogen compounds such as sodium hydride and potassium hydride; alkali metal salts of alcohols such as sodium methylate, sodium ethylate and potassium tert-butoxide; potassium carbonate. Alkali metal salts of carbonic acid such as: triethylamine, 1,8-diazabicyclo [5.4.0]
Examples include tertiary amines such as undec-7-ene (DBU).

The amounts of the compound of the formula [X] and the base to be used are 1 to 5 times and 1 to 10 times the mols of the compound of the formula [Ie], respectively.

This reaction may be carried out at 0 to 160 ° C. for 30 minutes to 24 hours.

Production Example 6 1) After reacting the compound of the formula [XI] with n-butyllithium, the compound of the formula [XII] is reacted.
III] can be produced.

The solvent used in this reaction may be one that does not adversely affect the reaction, and examples thereof include ethers such as tetrahydrofuran, diethyl ether, dioxane, and the like. May be used.

The amounts of the n-butyllithium and the compound of the formula [XII] used are 1 to 1.5 times mol and 0.5 to 2 times the mol of the compound of the formula [XI], respectively.

This reaction is usually performed under nitrogen atmosphere at -70 to 0 ° C for 10
It may be carried out for 1 minute to 1 hour.

2) A compound of formula [Ig] can be produced by reacting a compound of formula [XIII] with an acid.

The solvent used in this reaction may be any solvent that does not adversely influence the reaction, for example, hydrocarbons such as benzene and tonene; alcohols such as methanol and ethanol; diethyl ether, tetrahydrofuran, dioxane and the like. Ethers; methylene chloride,
Halogenated hydrocarbons such as chloroform; nitriles such as acetonitrile; amides such as N, N-dimethylformamide; carboxylic acids such as acetic acid and formic acid; and water. These solvents are two types. The above may be mixed and used. Moreover, you may use the acid mentioned later as a solvent.

Examples of the acid used in this reaction include hydrochloric acid,
Mineral acids such as sulfuric acid; sulfonic acids such as p-toluenesulfonic acid and methanesulfonic acid.

The amount of the acid used is 1.1 to 5 relative to the compound of the formula [XIII].
It is twice the mole.

This reaction may be carried out at 0 to 110 ° C for 10 minutes to 24 hours.

The compound of the formula [XIII] can be directly used in the next reaction without isolation.

In the case where each reaction described above has an active group at a site other than the reaction site, it may be appropriately protected, then subjected to the reaction, and the protecting group may be eliminated according to a conventional method.

Further, the object compound of the present invention obtained by the above-mentioned production method can be further led to the object compound of the present invention by subjecting it to, for example, a commonly known oxidation reaction, reduction reaction, dehydration reaction, Wittig reaction and the like. .

 Next, the raw material compound of each production method will be described.

The compound of the formula [II] can be produced, for example, by the method described in JP-A-56-118072 or a method analogous thereto.

In addition, the compound of the formula [IV] can be produced, for example, by the following production route.

[In the formula, R ¹ , R ² , R ³ , R ^3a , R ^4a , A and X have the above-mentioned meanings. 1) A compound of formula [XIV] can be produced by subjecting a compound of formula [II] to a reduction reaction.

The solvent used in this reaction may be one that does not adversely affect the reaction, for example, methanol,
Alcohols such as ethanol, tert-butanol, and ethylene glycol; ethers such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, and diglyme, and the like. These solvents are used as a mixture of two or more kinds. Good.

Examples of the reducing agent used in this reaction include sodium cyanoborohydride (NaBH ₃ CN) sodium borohydride (NaBH ₄ ), lithium aluminum hydride (LiAlH ₄ ), and the like.

The amount of the reducing agent used is 0.2 to the compound of the formula [II].
It is twice the mole.

This reaction is carried out at 0 to 100 ° C, preferably 0 to 25 ° C for 10
It may be carried out for 1 minute to 1 hour.

2) The compound of formula [XV] can be produced by reacting the compound of formula [XIV] with a halogenating agent.

The solvent used in this reaction may be any solvent that does not adversely affect the reaction, and examples thereof include the same solvents as those in Production Method 1. Moreover, you may use the halogenating agent mentioned later as a solvent.

The halogenating agent used in this reaction is usually a reagent capable of converting a hydroxyl group into a halogen atom, for example, thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus oxychloride, hydrogen chloride. , Hydrogen bromide, hydrochloric acid, hydrobromic acid, hydroiodic acid, and the like. Examples of the halogenating agent generated and used in the reaction system include triphenylphosphine dibromide, triphenylphosphine dichloride, etc. Is mentioned.

The amount of the halogenating agent used is 1 to 5 times mol the compound of the formula [XIV].

This reaction may be carried out at 0 to 100 ° C for 30 minutes to 24 hours.

If necessary, a deoxidizing agent may be added to carry out the reaction. Examples of the deoxidizing agent include pyridine and 4-N, N-
Examples thereof include organic bases such as dimethylaminopyridine, triethylamine, N, N-dimethylaniline, and inorganic bases such as calcium carbonate and barium carbonate.

In addition, the compound of formula [XV] can also be produced by reacting the compound of formula [XVI] with a halogenating agent. As the halogenating agent used in this reaction,
Examples thereof include N-bromosuccinimide, N-chlorosuccinimide, and the like, and as the radical reaction initiator, for example, azobisisobutyronitrile and the like are used.

3) The compound of formula [IV] can be produced by reacting the compound of formula [XV] with a phosphorus compound.

The solvent used in this reaction may be any solvent that does not adversely influence the reaction, and examples thereof include the same solvents as those mentioned in the production method 1.

Examples of the phosphorus compound used in this reaction include trivalent phosphorus compounds, for example, phosphines such as triphenylphosphine and tributylphosphine; phosphorous compounds such as trimethylphosphite, triethylphosphite and triphenylphosphite. Acid esters are mentioned.

The amount of the phosphorus compound used was 0. with respect to the compound of the formula [XV].
It is 5 to 2 times the molar amount.

This reaction may be carried out at 20 to 200 ° C. for 30 minutes to 24 hours.

Further, by reacting a compound of formula [XV] with a cyanide compound, a group of formula [XV] in which the group corresponding to X is a nitrile group
It is also possible to produce the compound of

The solvent used in this reaction may be one that does not adversely affect the reaction, for example, methanol,
Alcohols such as ethanol, tert-butanol, ethylene glycol; N, N-dimethylformamide, N, N
Examples include amides such as dimethylacetamide; sulfoxides such as dimethylsulfoxide; and water, and these solvents may be used as a mixture of two or more kinds.

Examples of the cyan compound used in this reaction include sodium cyanide and potassium cyanide.

The amount of cyanide compound used is based on the compound of formula [XV]
It is 0.5 to 5 times the molar amount.

This reaction may be carried out at 0 to 50 ° C for 30 minutes to 5 hours.

Further, the compounds of the formulas [VI], [VIII], [IX], [XI] and [XVI] can be produced by a known method or a method analogous thereto.

The compound of the present invention represented by the formula [I] can be prepared by a conventional method into capsules, powders, granules, pills, tablets, suspensions, emulsions,
It can be administered orally or parenterally as a liquid, poultice, ointment, injection, eye drop, liniment, syrup or suppository. The administration method, dose, and frequency of administration may be appropriately adjusted according to the age and symptoms of the patient. Normally, about 5.0 mg to about 1000 mg per day should be divided into 1 to several divided doses. Good.

[Effect of the invention] Test compound No. 1 2-[(E) -2-cyano-1-phenylvinyl] -4,5-bis (4-methoxyphenyl) -1H-imidazole No. 2 2-[(E ) -2-Cyanovinyl] -4,5-bis (4-methoxyphenyl) -1H-imidazole No.3 2-[(E) -2-Cyano-1-methylvinyl]
-4,5-bis (4-methoxyphenyl) -1H-imidazole No.4 2-[(E) -2-chlorovinyl] -4,5-bis (4-methoxyphenyl) -1H-imidazole No.5 2-[(E) -1-propenyl] -4,5-bis (4-methoxyphenyl) -1H-imidazole No. 6 2-vinyl-4,5-bis (4-methoxyphenyl) -1H-imidazole No. .7 2- (2,2-dichlorovinyl) -4,5-bis (4-
Methoxyphenyl) -1H-imidazole No.8 2-[(2E, 4E) -4-cyano-1,3-butadienyl] -4,5-bis (4-methoxyphenyl) -1H-imidazole No.9 2- Cyclohexylidenemethyl-4,5-bis (4
-Methoxyphenyl) -1H-imidazole No.10 2-[(Z) -2-cyano-1-phenylvinyl] -4,5-bis (4-fluorophenyl) -1H-imidazole No.11 2-[( E) -1-Pentenyl] -4,5-bis (4-methoxyphenyl) -1H-imidazole No. 12 2-[(Z) -1-pentenyl] -4,5-bis (4-methoxyphenyl)- 1H-imidazole No. 13 2-cyclopentylidenemethyl-4,5-bis (4
-Methoxyphenyl) -1H-imidazole No.14 2- [2-methyl-1-propenyl] -4,5-bis (4-methoxyphenyl) -1H-imidazole No.15 2-[(E) -2- Methylthiovinyl] -4,5-
Bis (4-methoxyphenyl) -1H-imidazole No.16 2-[(E) -2-chloro-1-methylvinyl] -4,5-bis (4-methoxyphenyl) -1H-imidazole No.172 -[(E) -2-Cyano-1-ethylvinyl] -4,5-bis (4-methoxyphenyl) -1H-imidazole No. 18 2-[(E) -2-Cyano-1-methylvinyl]- 4,5-bis (4-methoxyphenyl) -1-methyl-1H-imidazole No. 19 2-[(E) -1-ethylvinyl] -4,5-bis (4-methoxyphenyl) -1-methyl- 1H-imidazole No. 21 2-[(E) -2-cyano-1-propenyl]
-4,5-bis (4-methoxyphenyl) -1-methyl-1
H-imidazole No.22 2-[(E) -2-methylthio-1-propenyl] -4,5-bis (4-methoxyphenyl) -1-methyl-1H-imidazole No.23 2-[(E) 2-Cyano-1-propenyl]
-4,5-bis (4-methoxyphenyl) -1H-imidazole No. 24 2-[(E) -2-methylthio-1-methylvinyl] -4,5-bis (4-methoxyphenyl) -1- Methyl-1H-imidazole No.25 2-[(E) -2-methylthio-1-methylvinyl] -4,5-bis (4-methoxyphenyl) -1H-imidazole No.A 2- (2,4- Difluorophenyl) -4,5-bis (4-methoxyphenyl) -1H-imidazole [generic name; fenflumizole] 1. Prostaglandin biosynthesis inhibitory effect In vitro prostaglandin biosynthesis inhibitory effect R. J. Flower (RJFlower) et al method [prostaglandins lens (prostaglandins) 4, 325 (1
973)] and tested.

Using the rabbit kidney medulla microsome fraction as a prostaglandin biosynthesis system, the in vitro prostaglandin biosynthesis inhibitory activity was measured by measuring the inhibitory effect on the amount of malondialdehyde (MDA) produced after the addition of arachidonic acid. Examined.

The MDA production inhibitory effect of the test compound was obtained by changing the addition amount of the test compound solubilized in dimethyl sulfoxide (DMSO), and the MDA production amount of only DMSO added (control) was 50%.
Expressed as inhibitory concentration (μg / ml). DMSO solution in which the test compound was dissolved in 1.98 ml of 50 mM Tris-HCl buffer (pH 8) containing renal medulla microsome fraction of 1 mg / ml in protein concentration, 5 mM glutathione and 5 mM epinephrine 0.02 m
Add l and incubate at 37 ℃. Arachidonic acid 0.5 after 5 minutes
Add to mM and incubate for 15 minutes. The reaction was stopped by the addition of perchloric acid, and the produced MDA was turned red by the reaction with thiobarbituric acid (TBA reaction), and then extracted with n-butanol for colorimetric determination. The results are shown in Table-1.

2. Anti-inflammatory action (1) Carrageenin footpad edema inhibitory action The anti-inflammatory action of carrageenin footpad edema inhibitory action is the method of CAWinter et al. [Proceedings of the Society for Extracts]. Peripheral Biology and Medicine (Procee
dings of the Society for Experimental Biology and
Medicine) 111, 544 (1962)].

Group of 6-7 male Gouryu male rats (body weight 90-120g) fasted overnight 4% polyethylene glycol 300-5%
A test compound dissolved or suspended in a Tween 80 solution was orally administered at a rate of 1 ml / 100 g body weight. One hour later, 0.1 ml of 1% carrageenin was subcutaneously injected into the footpad of the left hind leg. The volume of hind footpad swelling was measured 3 hours after inflammation, and the edema rate was calculated from the volume before injection, and the suppression rate was calculated by the following formula.

Inhibition rate (%) = (1-edema rate of test compound-administered group / average edema rate of control group) × 100 In addition, the results are expressed by the inhibition rate and the inhibitory effect described below.

10% or less (-) 10 to 15% (±) 15 to 20% (+) 20 to 30% (++) 30 to 40% (+++) 40% or more (++++) The results are shown in Table-2.

(2) Adjuvant arthritis suppressive effect Adjuvant arthritis suppressive effect is the method of EMGlenn [American Journal of Vetenerary Research (American Journal of Vete
rinary Research) 27, 339 (tested in accordance with the 1966)].

Male Wistar Lewis rats (body weight 190-230 g) were used in groups of 5 and liquid paraffin was used as an adjuvant in which 6 mg of dead killed Mycobacterium tuberculosis was killed.
0.1 ml in the ridge skin using the suspension at the ratio of ml
I made an injection. On the 18th day after the adjuvant treatment, the test compound was divided into groups according to the volume of swelling of both hind limbs, and the test compound was administered once a day for 7 consecutive days.
The suspension in 5% carboxymethyl cellulose aqueous solution was orally administered at a ratio of 1 ml / 100 g body weight. On the day after the final administration, the swelling volumes of both hind limbs were measured, and the inhibitory effect was determined in the same manner as (1). The results are expressed by the suppression rate and the suppression effect described below.

10% or less (-) 10-15% (±) 15-20% (+) 20-30% (++) 30-40% (+++) 40-50%
(+++++) 50% or more (++++++) The results are shown in Table-3.

3. Analgesic action Analgesic action is performed by R. Koster et al. [Federation Proceedings (Federation
Proceedings) 18, 412 (1959)].

A group of 10 ICR male mice (body weight 20 to 30 g) was used, and a test compound suspended in a 0.5% carboxymethyl cellulose aqueous solution was orally administered at a rate of 0.1 ml / 10 g body weight.

After 30 minutes, 0.5% acetic acid was intraperitoneally injected at a rate of 0.1 ml / 10 g body weight, and the number of stretchings that occurred 15 minutes after 5 minutes was measured. 3 to 5 doses of each test compound are examined, and a dose that suppresses the frequency of stretching in the control group by 50%
The ED ₅₀ (mg / kg) was determined. The results are shown in Table-4.

4. Ulcer-inducing action Male Wistar rats (body weight: 180-2
30g) and fast for 24 hours (water is allowed freely)
Then, the test compound suspended in a 0.5% carboxymethylcellulose aqueous solution was orally administered at a rate of 1 ml / 100 g body weight.
After leaving it under fasting and dewatering for 5 hours, it was killed by bleaching the cervical spine, and the stomach was removed and fixed with a 1% formalin solution for 30 minutes. The stomach was cut open along the greater curvature and the length of erosion and ulcer on the gastric mucosa under a stereomicroscope (mm)
Was measured, the total l (mm) was determined, and the ulcer index was determined according to the following criteria.

0: l <0.5,1: 0.5 ≦ l <1,2: 1 ≦ l <2 3: 2 ≦ l <3,4: 3 ≦ l <5, 5: 5 ≦ l <7,6: 7 ≦ l <10, 7: 10 ≦ l <15, 8: 15 ≦ l <25, 9: 25 ≦ l <40, 10: l ≧ 40 Then, for each test compound, the dose that induces an ulcer index of 5 UD ₅₀ (mg / Kg).

The results are shown in Table-5.

5. Acute toxicity 4-week-old male ICR mice (body weight: 20-25g, 3 mice per group)
Was used to measure the oral acute toxicity. 0.5% test compound
What was suspended in carboxymethyl cellulose aqueous solution
It was orally administered at a ratio of 0.2 ml / 10 g body weight. The general symptoms were observed for 2 weeks after the administration, the number of dead cases / the number of test cases was calculated, and the 50% lethal dose LD ₅₀ (mg / Kg) was estimated. Test compound N
Oral acute toxicity of o.1 to No.25 and control drug No.A is 1000 mg / K
It was more than g.

As described above, it is clear from the results shown in Tables 1 to 5 that the compound of the present invention has an excellent pharmacological effect and high safety.

EXAMPLES Next, the present invention will be described with reference to reference examples and examples. The symbols used in Reference Examples and Examples have the following meanings.

Me: methyl, Et: ethyl, Pr: n-propyl, i-Pro: isopropyl, Bu: n-butyl, t-Bu: tert-butyl, Pent: n
- pentyl, Hep: heptyl, Ac: acetyl, THF: tetrahydrofuran, DMSO: dimethyl sulfoxide, AcOEt: ethyl acetate, IPA: isopropyl alcohol, IPE: diisopropyl ether, Et ₂ O: diethyl ether, and all mixing ratios of solvents are volume Is a ratio.

The carrier used in column chromatography is silica gel [Kieselgel 60, Art. 7734 (K
ieselgel 60, Art.7734)] was used.

Reference Example 1. (1) 4,5-bis (4-methoxyphenyl) -1- (1
70 g of -ethoxyethyl) -1H-imidazole are dissolved in 350 ml of dry tetrahydrofuran and cooled to -50 ° C.
Under nitrogen atmosphere, while maintaining the temperature at -50 to -40 ° C, 150 ml of n-butyllithium n-hexane solution (1.6N) is added dropwise over 20 minutes. After stirring at the same temperature for 1 hour, 70 ml of N, N-dimethylformamide is added and the temperature is raised to 25 ° C. twenty five~
After stirring for 2 hours at 30 ° C., 20 ml of acetic acid are added. The reaction solution is introduced into a mixed solution of 300 ml of ethyl acetate and 200 ml of saturated saline, and the organic layer is separated. The organic layer is washed with saturated saline, and then the solvent is distilled off under reduced pressure. If the obtained residue is recrystallized from ethanol, it has a melting point of 104-105 ° C.
64.2 g of bis (4-methoxyphenyl) -1- (1-ethoxyethyl) -2-formyl-1H-imidazole (yield 8
5%).

IR (KBr) cm ^-1 ; 1680,1435,1410,1295,1252,1175,1108,1
025 NMR (CDCl ₃ ) δ value; 1.14 (3H, t, J = 7Hz), 1.49 (3H, d, J = 7Hz), 3.46 (2
H, q, J = 7Hz), 3.73 (3H, s), 3.85 (3H, s), 6.37 (1H, q,
J = 7Hz), 6.72,7.27 (4H, ABq, J = 9Hz), 6.92,7.35 (4H,
ABq, J = 9Hz), 9.95 (1H, s) (2) 4,5-bis (4-methoxyphenyl) -1- (1
-Ethoxyethyl) -2-formyl-1H-imidazole
60 g is suspended in 200 ml of ethanol, 200 ml of 1N hydrochloric acid is added, and the mixture is stirred at room temperature for 2 hours. After completion of the reaction, the pH is adjusted to 7 with saturated aqueous sodium hydrogen carbonate solution. The precipitated crystals were collected by filtration, washed successively with 100 ml of water and 50 ml of diethyl ether, and recrystallized from ethanol to give 4,5-bis (4-methoxyphenyl) -2-formyl-1H having a melting point of 187-189 ° C. 42.3 g (87% yield) of imidazole are obtained.

IR (KBr) cm ^-1 ; 3250,1658,1435,1255,1205,1180 NMR (CDCl ₃ ) δ value; 3.78 (6H, s), 6.72 ~ 6.95 (4H, m), 7.25 ~ 7.50 (4H,
m), 9.71 (1H, s), 11.07 (1H, bs), and similarly, the compounds shown in Table 6 are obtained.

Reference Example 2 4.5-bis (4-methoxyphenyl) -1-methyl-1
5 g of H-imidazole are dissolved in 30 ml of dry tetrahydrofuran and cooled to -50 ° C. Under nitrogen atmosphere, -50 to -40
13.6 ml of n-hexane solution (1.6N) of n-butyllithium was added dropwise over 10 minutes while maintaining the temperature at ℃. 1 at the same temperature
After stirring for 5 hours, 5 ml of N, N-dimethylformamide is added and the temperature is raised to 25 ° C. After stirring for 2 hours at 25-30 ° C,
10 ml of 2N hydrochloric acid is added, and the organic layer is separated. The organic layer is washed successively with water and saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting solid was washed with diisopropyl ether to give 4,5-bis (4-methoxyphenyl) -2-formyl-1-methyl-1H-, which has a melting point of 132 to 134 ° C. 5 g of imidazole (91.2% yield) are obtained.

IR (KBr) cm ^-1 ; 1665,1600,1435,1225,1172,1025 NMR (CDCl ₃ ) δ value; 3.72 (3H, s), 3.77 (3H, s), 3.84 (3H, s), 6.63〜 7.4
8 (8H, m), 9.82 (1H, s) Similarly, the following compound is obtained.

○ 4,5-Bis (4-methoxyphenyl) -2-formyl-1-isopropyl-1H-imidazole Melting point: 174-175 ° C (recrystallized from IPA) IR (KBr) cm ^-1 ; 1685,1440,1250, 1180 NMR (CDCl ₃ ) δ value; 1.46 (6H, d, J = 8.4Hz), 3.71 (3H, s), 3.84 (3H, s),
4.07 to 4.90 (1H, m), 6.62 to 7.39 (8H, m), 9.32 (1H, s) ○ 4,5-bis (4-methoxyphenyl) -2-acetyl-1-isopropyl-1H-imidazole Melting point: 125-127 ℃ (Recrystallized from IPA) IR (KBr) cm ^-1 : 1675,1600,1510,1440,1245,1170,1030 NMR (CDCl ₃ ) δ value; 1.44 (6H, d, J = 7Hz), 2.74 (3H, s), 3.69 (3H, s), 3.
83 (3H, s), 4.73 (1H, m, J = 7Hz), 6.67,7.17 (4H, ABq, J
= 9Hz), 6.90,7.28 (4H, ABq, J = 9Hz) ○ 4,5-bis (4-methoxyphenyl) -2-acetyl-1-cyclopropyl-1H-imidazole Melting point: 115-117 ° C (AcOEt- Recrystallized from n-hexane) IR (KBr) cm ^-1 : 1670,1600,1510,1425,1280,1245,1170,1
025 NMR (CDCl ₃ ) δ value; 0.20 to 0.65 (2H, m), 0.65 to 1.15 (2H, m), 2.70 (3H,
s), 3.05 to 3.50 (1H, m), 3.69 (3H, s), 3.79 (3H, s),
6.78 (4H, t, J = 9Hz), 7.26 (4H, t, J = 9Hz) Reference Example 3 4,5-bis (4-methoxyphenyl) -2-formyl-1H-imidazole 30.8g in methylene chloride 300ml. Suspension and, under ice cooling, a methylene chloride solution containing 100 g of boron tribromide
70 ml is added dropwise over 30 minutes. After stirring at 15 to 20 ° C for 2 hours, the reaction solution was mixed with sodium hydroxide 90g and ice water 300ml.
It is introduced into the mixed solution of and the aqueous layer is separated. The aqueous layer is washed with 150 ml of methylene chloride and then adjusted to pH 5 with concentrated hydrochloric acid under ice cooling.
The precipitated crystals are collected by filtration, washed with 100 ml of water and dried. The resulting solid matter is purified by column chromatography (elution solvent; toluene: ethyl acetate = 2: 1) to give 4,5-bis (4-
(Hydroxyphenyl) -2-formyl-1H-imidazole 17.4 g (yield 62%) Melting point 288-290 ° C. (recrystallized from methanol) IR (KBr) cm ^-1 ; 3320,1660,1610,1445,1250,1190 NMR (D ₆ -DMSO) δ value; 6.77,7.31 (8H, ABq, J = 8Hz), 9.50 (1H, bs), 9.63 (1
H, s), 9.70 (1H, bs), 13.57 (1H, bs) and 4 (5)-(4-methoxyphenyl) -5 (4)
3.4 g (yield 10%) of an ethanol adduct of-(4-hydroxyphenyl) -2-formyl-1H-imidazole is obtained.

Melting point: 155 to 157 ° C (recrystallized from ethanol) IR (KBr) cm ^-1 ; 3500,1660,1605,1450,1250,1215,1170 NMR (d ₆ -DMSO) δ value; 1.10 (3H, t, J = 7Hz), 3.52 (2H, q, J = 7Hz), 3.79 (3
H, s), 6.73 ~ 6.98 (4H, m), 7.26 ~ 7.51 (4H, m), 9.70
(1H, s), 9.80 (1H, bs) Reference Example 4 (1) 30.8 g of 4,5-bis (4-methoxyphenyl) -2-formyl-1H-imidazole was added to tetrahydrofuran 300
ml and methanol 50 ml dissolved in a mixed solution, and under ice cooling,
1.89 g of sodium borohydride are added at 10-15 ° C.
After stirring at the same temperature for 30 minutes, the solvent is distilled off under reduced pressure.
Water and ethyl acetate were sequentially added to the obtained residue, and the precipitated crystals were collected by filtration, washed with diethyl ether and then recrystallized from isopropyl alcohol to give 4,5-bis (4- 24.6 g (yield 79.4%) of methoxyphenyl) -2-hydroxymethyl-1H-imidazole are obtained.

IR (KBr) cm ^-1 ; 1602,1510,1450,1285,1245,1170 NMR (d ₆ -DMSO) δ value; 3.73 (6H, s), 4.48 (2H, s), 6.06 (1H, br), 6.84,7.3
4 (8H, ABq, J = 9Hz) (2) 4,5-Bis (4-methoxyphenyl) -2-hydroxoxymethyl-1H-imidazole 3.1g to which thionyl chloride 12.4ml was added and refluxed for 20 minutes The reaction solution is concentrated under reduced pressure. 50 ml of diethyl ether was added to the obtained residue, and the precipitated crystals were collected by filtration, washed with diethyl ether, and dried to give 4,5-bis (4
3.2 g (yield 87.7%) of -methoxyphenyl) -2-chloromethyl-1H-imidazole hydrochloride is obtained.

IR (KBr) cm ^-1 ; 3000 ~ 2600,1620,1603,1520,1290,1240,
1187,1025 (3) 4,5-bis (4-methoxyphenyl) -2-chloromethyl-1H-imidazole hydrochloride 3.65 g of triphenylphosphine 3.93 g of toluene 70 ml and N, N-dimethylformamide 19 ml Add to the mixture and reflux for 3 hours. After completion of the reaction, 30 ml of toluene is added, and the mixture is stirred at 25 to 30 ° C for 30 minutes and further at 5 to 10 ° C for 1 hour. The precipitated crystals are collected by filtration, washed with toluene and diethyl ether successively, and dried to give a melting point of 238 to 242 ° C. [4,5-bis (4-methoxyphenyl) -1H-imidazol-2-yl] methylene. 5.58 g (yield 88.9%) of triphenylphosphonium chloride hydrochloride is obtained.

IR (KBr) cm ^-1 ; 1605,1525,1490,1435,1295,1255,1180,1
110,1025,840,750,685 Reference Example 5 4,5-bis (4-methoxyphenyl) -2-chloromethyl-1H-imidazole hydrochloride (3.66 g) was dissolved in 35 ml of N, N-dimethylformamide, and cooled under ice-cooling to give cyan. 4 ml of an aqueous solution containing 1.47 g of sodium chloride was added dropwise, and the mixture was stirred at 20 to 25 ° C for 1 hour. The reaction solution is introduced into 200 ml of water, and the precipitate is collected by filtration and washed with water. Recrystallized from benzene, melting point 17
4,5-bis- (4-methoxyphenyl) showing 2-174 ° C
2-Cyanomethyl-1H-imidazole 1.28 g (yield 40
%).

IR (KBr) cm ^-1 ; 2250,1607,1507,1288,1245,1170,1030 NMR (d ₆ -DMSO + CDCl ₃ ) δ value; 3.77 (6H, s), 3.84 (2H, s), 6.79, 7.38 (8H, ABq, J ＝ 9
Hz) Reference Example 6 (1) 8.0 g of 4,5-bis (4-methoxyphenyl) -2-formyl-1H-imidazole was suspended in 40 ml of toluene, and 14.1 g of ethyl 2-triphenylphosphoranylidenepropionate was added. Add and stir at 25-30 ° C. for 1 hour. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (elution solvent; toluene: ethyl acetate = 20: 1) to give 2-[(E) -2-ethoxycarbonyl-1.
-Propenyl] -4,5-bis (4-methoxyphenyl)
-1H-Imidazole 8.0 g (79% yield) Melting point: 221-223 ° C (recrystallized from ethanol) IR (KBr) cm ^-1 ; 3250,1688,1620,1502,1242 NMR (CDCl ₃ ) δ value; 1.27 (3H, t, J = 7Hz), 2.51 (3H, d, J = 1.5Hz), 3.82
(6H, s), 4.17 (2H, q, J = 7Hz), 6.87,7.47 (8H, ABq, J =
9Hz), 7.52 (1H, d, J = 1.5Hz) and 2-[(Z) -2-ethoxycarbonyl-1-
Propenyl] -4,5-bis (4-methoxyphenyl) -1
200 mg of H-imidazole (2% yield) are obtained.

Melting point: 141 to 143 ° C (recrystallized from Et ₂ O) IR (KBr) cm ^-1 : 1685,1605,1492,1243 NMR (CDCl ₃ ) δ value; 1.35 (3H, t, J = 7Hz), 2.14 ( 3H, d, J = 1.5Hz), 3.82
(6H, s), 4.29 (2H, q, J = 7Hz), 6.87,7.47 (8H, ABq, J =
9Hz), 6.97 (1H, d, J = 1.5Hz).

(2) 2-[(E) -2-ethoxycarbonyl-1-propenyl] -4,5-bis (4-methoxyphenyl) -1H
-Suspend 3.0 g of imidazole in 30 ml of ethanol, add 30 ml of 2N aqueous sodium hydroxide solution and reflux for 40 minutes. After the reaction is complete, cool to room temperature and adjust to pH 3 with 2N hydrochloric acid.
The precipitated crystals are collected by filtration, washed with water, and recrystallized from ethanol to give a melting point of 256 to 258 ° C. 2-[(E) -2-
Carboxyl-1-propenyl] -4,5-bis (4-methoxyphenyl) -1H-imidazole 1.9 g (yield 68%)
Get.

IR (KBr) cm ^-1 : 3300,1665,1605,1507,1285,1243,1170 NMR (d ₆ -DMSO) δ value; 2.50 (3H, s), 3.77 (6H, s), 6.87,7.42 (8H , ABq, J ＝ 8
Hz), 7.40 (1H, s) (3) 1.5 g of 2-[(E) -2-carboxyl-1-propenyl] -4,5-bis (4-methoxyphenyl) -1H-imidazole in 15 ml of methylene chloride. Dissolve, add thionyl chloride 3 ml, N, N-dimethylformamide 0.1 ml,
Stir at ~ 30 ° C for 1 hour. The reaction solution is added dropwise to 30 ml of concentrated aqueous ammonia solution (25% purity) cooled to -30 ° C over 20 minutes. After the dropping, the temperature is raised to room temperature, and the precipitated crystals are collected by filtration. Recrystallization from a mixed solvent of ethyl acetate-diisopropyl ether shows a melting point of 211-213 ° C.
[(E) -2-carbamoyl-1-propenyl] -4,5
-Bis (4-methoxyphenyl) -1H-imidazole 1.
2 g (yield 80%) are obtained.

IR (KBr) cm ^-1 ; 3220,1662,1502,1370,1242,1175 NMR (d ₆ -DMSO) δ value; 2.56 (3H, s), 3.77 (6H, s), 6.90,743 (8H, ABq , J ＝ 9H
z), 7.21 (2H, bs), 7.36 (1H, s) Example 1 3.08 g of 4,5-bis (4-methoxyphenyl) -2-formyl-1H-imidazole was suspended in 50 ml of benzene,
Triphenylphosphoranylideneacetonitrile (6.00 g) is added, and the mixture is stirred at 25 to 30 ° C for 2 hr. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (eluting solvent; benzene: ethyl acetate = 20: 1) to give 2
-[(E) -2-Cyanovinyl] -4,5-bis (4-methoxyphenyl) -1H-imidazole 1.36 g (yield 41
%) Melting point: 205 to 208 ° C. (recrystallized from toluene) IR (KBr) cm ⁻¹ ; 3275,2210,1605,1460,1255,1185 NMR (d ₆ -DMSO + CDCl ₃ ) δ value; 3.77 (6H, 6H, s), 6.17 (1H, d, J = 17Hz), 6.79, 7.36 (8H,
ABq, J = 9Hz), 7.14 (1H, d, J = 17Hz) and 2-[(Z) -2-cyanovinyl] -4,5-bis (4-methoxyphenyl) -1H-imidazole 1.16g
(Yield 35%) is obtained.

Melting point: 209 to 211 ° C (recrystallized from ethanol) IR (KBr) cm ^-1 : 3205,2205,1600,1460,1290,1250,1170 NMR (CDCl ₃ -d ₆ -DMSO) δ value; 3.75 (6H, 6H, s), 5.37 (1H, d, J = 12Hz), 6.79 (4H, ABq, J
= 9Hz), 7.14 (1H, d, J = 12Hz), 7.10 to 7.60 (4H, m), 1
2.44 (1H, bs) Similarly, the compounds of Table-8 are obtained under the reaction conditions shown in Table-7.

Example 2 580 mg of sodium hydride (purity 60%) and 7.3 ml of dimethyl sulfoxide were mixed, and under a nitrogen atmosphere, 70-80 ° C.
Stir for 45 minutes and cool. Under ice cooling, 15 ml of a dimethyl sulfoxide solution containing 5.42 g of triphenylethylphosphonium bromide was added dropwise over 5 minutes. 15 ~ 20 ℃
After 10 minutes of stirring, 10 ml of a dimethyl sulfoxide solution containing 1.5 g of 4,5-bis (4-methoxyphenyl) -2-formyl-1H-imidazole is added, and the mixture is stirred at 20 to 25 ° C for 30 minutes. The reaction solution is introduced into a mixed solution of ethyl acetate and water, and the organic layer is separated. The organic layer is washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue was purified by column chromatography (elution solvent; toluene: ethyl acetate = 10: 1) to give 2-[(E) -1-propenyl] -4,5-bis (4-methoxyphenyl)- 190 mg of 1H-imidazole
(Yield 12.2%) Melting point: 118-120 ° C (recrystallized from IPA) IR (KBr) cm ^-1 ; 1505,1290,1245,1175,1030 NMR (CDCl ₃ ) δ value; 2.18 (3H, d, J = 7Hz), 3.77 (6H, s), 5.72 ~ 6.29 (2H,
m), 6.69 to 7.44 (9H, m) and 2-[(Z) -1-propenyl] -4,5-bis (4-methoxyphenyl) -1H-imidazole 370mg
(Yield 23.7%) is obtained.

Melting point; 185 to 187 ° C (recrystallized from IPA) IR (KBr) cm ^-1 ; 1505,1285,1245,1175,1030 NMR (CDCl ₃ ) δ value; 1.76 (3H, d, J = 4.5Hz), 3.76 (6H, s), 6.15 ~ 6.32 (2
H, m), 6.67 to 7.41 (9H, m) Similarly, the compounds of Table-10 are obtained under the reaction conditions shown in Table-9.

Example 3 3.93 g of triphenylphosphine and 1.68 g of potassium tert-butoxide are suspended in 40 ml of dry n-heptane,
Cool to ° C. Chloroform 1.2 ml and n at 0-5 ° C
A solution of 10 ml heptane is added dropwise over a period of 30 minutes. 20 ~
After stirring at 25 ° C for 30 minutes, 10 ml of N, N-dimethylformamide solution containing 4,5-bis (4-methoxyphenyl) -2-formyl-1H-imidazole (3.08 g) was added dropwise over 10 minutes, Stir for 30 minutes at the same temperature. The reaction solution is introduced into a mixed solution of water and benzene, and the organic layer is separated. The organic layer is washed with saturated brine and the solvent is evaporated under reduced pressure. The obtained residue is subjected to column chromatography (elution solvent;
If purified with toluene: ethyl acetate = 30: 1), 2- (2,
1.63 g (yield 43.5%) of 2-dichlorovinyl) -4,5-bis (4-methoxyphenyl) -1H-imidazole are obtained.

Melting point: 128 to 129 ° C. (recrystallized from IPE-n-hexane) IR (KBr) cm ⁻¹ ; 1610,1510,1475,1290,1250,1175,1030 NMR (CDCl ₃ ) δ value; 3.77 (6H, s ), 6.80 (1H, s), 6.81,7.35 (8H, ABq, J = 9
Hz) Example 4 (1) 2-Acetyl-4,5-bis (4-methoxyphenyl) -1- (1-ethoxyethyl) -1H-imidazole
500 mg and 400 mg of dibromodifluoromethane are dissolved in 5 ml of methylene chloride and cooled to 5 ° C under a nitrogen atmosphere.
After 620 mg of hexamethylphosphorus triamide was added dropwise at 5 to 10 ° C over 5 minutes, the mixture was stirred at 20 to 25 ° C for 1 hour. The reaction solution is washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue is subjected to column chromatography (elution solvent;
If purified with toluene: ethyl acetate = 50: 1, 2- (2,
400 mg (74% yield) of 2-difluoro-1-methylvinyl) -1-ethoxyethyl-4,5-bis (4-methoxyphenyl) -1H-imidazole are obtained.

IR (neat) cm ^-1 ; 1742,1610,1515,1250,1130 NMR (CCl ₄ ) δ value; 1.08 (3H, t, J = 7Hz), 1.40 (3H, d, J = 7Hz), 1.98 (3
H, t, J = 3Hz), 3.18 (2H, q, J = 7Hz), 3.64 (3H, s), 3.79
(3H, s), 5.10 (1H, q, J = 7Hz), 6.55,7.18 (4H, ABq, J =
9Hz), 6.82, 7.22 (4H, ABq, J = 9Hz) (2) 2- (2,2-difluoro-1-methylvinyl)-
1-Ethoxyethyl-4,5-bis (4-methoxyphenyl) -1H-imidazole (400 mg) in methanol (4 ml) and 2N
It is dissolved in a mixed solution of 4 ml of hydrochloric acid and stirred at 20 to 25 ° C for 2 hours. Precipitated crystals are collected by filtration and washed with a mixed solution of methanol and water to give a melting point of 213 to 216 ° C. (decomposition).
(2,2-Difluoro-1-methylvinyl) -4,5-bis (4-methoxyphenyl) -1H-imidazole hydrochloride
230 mg (62% yield) are obtained.

IR (KBr) cm ^-1 ; 1730,1625,1600,1515,1490,1245,1128,1
030 NMR (d ₆ -DMSO) δ value; 2.30 (3H, t, J = 3Hz), 3.80 (6H, s), 6.98 (4H, ABq, J
= 9Hz), 7.45 (4H, ABq, J = 9Hz) Example 5 600 mg of 2-[(E) -2-formylvinyl] -4,5-bis (4-methoxyphenyl) -1H-imidazole in 10 ml of toluene. It is suspended, 1.1 g of triphenylphosphoranylideneacetonitrile is added, and the mixture is stirred at room temperature for 2 hours.
The reaction solution was purified by column chromatography (eluting solvent; toluene: ethyl acetate = 10: 1) to give 2-[(2E, 4
E) -4-Cyano-1,3-butadienyl] -4,5-bis (4-methoxyphenyl) -1H-imidazole 300 mg
(Yield 46.9%) is obtained.

Melting point; 130 to 133 ° C. (recrystallized from IPE) IR (KBr) cm ⁻¹ ; 2200,1605,1455,1248 NMR (CDCl ₃ ) δ value; 3.73 (6H, s), 5.05 (1H, d, J = 14Hz), 6.00 ~ 7.50 (11
H, m) and 2-[(2E, 4Z) -4-cyano-1,3-butadienyl] -4,5-bis (4-methoxyphenyl) -1H-imidazole (100 mg, yield 15.6%).

Melting point: 245 to 246 ° C (recrystallized from AcOEt) IR (KBr) cm ^-1 ; 3250,2210,1605,1460,1250 NMR (d ₆ -DMSO) δ value; 3.76 (6H, s), 5.58 (1H, d, J = 10Hz), 6.65 ~ 7.60 (11
H, m) Example 6 500 mg of 2-[(E) -2-formylvinyl] -4,5-bis (4-methoxyphenyl) -1H-imidazole was suspended in 10 ml of ethanol and hydrogenated at 10-15 ° C. 20 mg sodium borohydride are added over 5 minutes. After stirring at the same temperature for 10 minutes, chloroform and water are sequentially added to the reaction solution, and the organic layer is separated. The organic layer is washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The resulting residue was recrystallized from ethyl acetate to give 2-[(E) -3-hydroxy-1-propenyl] -4,5-bis (4-methoxyphenyl) -1H- which shows a melting point of 169-171 ° C. 400 mg (80% yield) of imidazole are obtained.

IR (KBr) cm ^-1 ; 1602,1500,1245,1182,1020 NMR (d ₆ -DMSO) δ value; 3.76 (6H, s), 4.02 to 4.28 (2H, m), 6.40 to 6.70 (2H,
m), 6.88, 7.38 (8H, ABq, J = 9Hz) Example 7 4,5-bis (4-methoxyphenyl) -2-[(E)
2-Methylthiovinyl] -1H-imidazole (1.00 g) was dissolved in methylene chloride (20 ml), and 3-chloroperbenzoic acid (1.35 g) was dissolved in methylene chloride (10 ml) at 0 to 10 ° C.
Drip in 0 minutes. After stirring for 2 hours at 20 to 25 ° C, the precipitated crystals are collected by filtration. The obtained crystals are dissolved in ethyl acetate, washed successively with 10% aqueous potassium carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained solid was recrystallized from ethyl acetate to give 4,5-bis (4-methoxyphenyl) -2-[(E) -2-methylsulfonylvinyl] -1H-imidazole (450 mg) having a melting point of 199-201 ° C. (Yield 4
1.3%).

IR (KBr) cm ^-1 ; 3230,1605,1505,1455,1280,1250,1170,1
120 NMR (d ₆ -DMSO) δ value; 2.78 (3H, s), 3.10 (6H, s), 6.55,7.45 (8H, ABq, J = 9)
Hz), 7.37 (2H, s) Example 8 4,5-bis (4-methoxyphenyl) -2-[(E)
2-Methylthiovinyl] -1H-imidazole (1.00 g) was dissolved in methylene chloride (10 ml), and a solution of 3-chloroperbenzoic acid (640 mg) in methylene chloride (5 ml) was added dropwise at 0-10 ° C over 10 minutes. . After stirring at the same temperature for 30 minutes, 20 ml of 10% aqueous potassium carbonate solution is added to the reaction solution, and the organic layer is separated. The organic layer is washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was subjected to column chromatography (elution solvent; benzene: toluene =
If purified by 1: 1), 4,5-bis (4-methoxyphenyl) -2-[(E) -2-methylsulfinylvinyl]
-1 H-imidazole 600 mg (yield 57.1%) is obtained.

Melting point; 225 to 227 ° C. (recrystallized from acetone) IR (KBr) cm ⁻¹ ; 1605,1505,1465,1290,1250,1170,1035 NMR (d ₆ -DMSO) δ value; 2.71 (3H, s), 3.75 (6H, s), 6.85,7.35 (8H, ABq, J = 9
Hz), 6.90 (1H, d, J = 15Hz), 7.47 (1H, d, J = 15Hz) Example 9 4,5-bis (4-methoxyphenyl) -2-formyl-1H-imidazole 500 mg and malondi Nitrile 110 mg
Was suspended in 5 ml of ethanol and piperidine 0.1 was added at 0-5 ° C.
Add 1 ml and stir at the same temperature for 30 minutes. The reaction solution is introduced into a mixed solution of ethyl acetate and water, and the organic layer is separated.
The organic layer is washed with 1N hydrochloric acid (15 ml), dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. If the obtained residue is recrystallized from ethanol, it has a melting point of 221-222 ° C.
260 mg of (2,2-dicyanovinyl) -4,5-bis (4-methoxyphenyl) -1H-imidazole (yield 44.8%) are obtained.

IR (KBr) cm ^-1 ; 3200,2210,1600,1580,1450,1435,1295,1
250,1205,1175 NMR (d ₆ -DMSO) δ value; 3.78 (6H, s), 6.93,7.42 (8H, ABq, J = 9Hz), 7.64 (1
H, s) Example 10 6.28 g of [4,5-bis (4-methoxyphenyl) -1H-imidazol-2-yl] methylenetriphenylphosphonium chloride.hydrochloride was dried with 126 ml of tetrahydrofuran.
And chill to -30 ° C. Under a nitrogen atmosphere, 20 ml of an n-hexane solution of n-butyllithium (1.6N) is added dropwise over 10 minutes while maintaining the same temperature. -30 to -25 ° C
After stirring for 15 minutes, 2.0 g of cyclohexanone is added, and the mixture is stirred at the same temperature for 30 minutes and further at 20 to 25 ° C for 30 minutes. The reaction solution is introduced into a mixed solution of ethyl acetate and water, and the organic layer is separated. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue was purified by column chromatography (elution solvent; toluene: ethyl acetate = 10: 1) and recrystallized from diisopropyl ether-n-hexane to give 2-cyclohexylidenemethyl-4,5-bis ( 4-methoxyphenyl)
-1H-imidazole (1.24 g, yield 33.1%) is obtained. The physical properties (melting point, IR, NMR) of this compound were the same as those obtained in Example 2 (described in Table-10).

 Similarly, the compounds of Table-11 are obtained.

Example 11 4,5-bis (4-methoxyphenyl) -2-cyanomethyl-1H-imidazole 3.19 g, benzaldehyde 10.6
g, 20 ml of acetic acid and 200 ml of toluene are mixed, 1 ml of piperidine is further added, and the mixture is refluxed for 1 hour. After cooling, 200 ml of water is added to the reaction solution, and the organic layer is separated. 100 ml of water for the organic layer
After washing with, dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography (elution solvent; toluene: ethyl acetate = 20: 1) to give 2-[(E) -1-cyano-2-phenylvinyl] -4,5-bis (4 2.32 g (yield 57%) of -methoxyphenyl) -1H-imidazole is obtained.

Melting point: 210 to 211 ° C (recrystallized from toluene) IR (KBr) cm ^-1 ; 3230,2220,1602,1502,1465,1282,1242,1
170,1022 NMR (CDCl ₃ ) δ value; 3.77 (6H, s), 6.81 (4H, ABq, J = 8Hz), 7.15 to 7.60 (7
H, m), 7.70 to 7.95 (2H, m), 8.15 (1H, s) Similarly, the compounds of Table-12 are obtained.

Example 12 Anisyl 1.00 g, crotonaldehyde 0.3 ml, ammonium acetate 2.58 g and acetic acid 7 ml are mixed and refluxed for 2 hours. After cooling, the solvent is distilled off under reduced pressure, 50 ml of ethyl acetate and 50 ml of water are added to the obtained residue, and the pH is adjusted to 7 with a saturated aqueous sodium hydrogen carbonate solution, and then the organic layer is separated.
The organic layer is washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue was purified by column chromatography (elution solvent; toluene: ethyl acetate = 10: 1) to give 2-[(E)
330 mg of -1-propenyl] -4,5-bis (4-methoxyphenyl) -1H-imidazole (yield 27.7%) are obtained.
The physical properties of this compound (melting point, IR, NMR) were in agreement with those obtained in Example 2.

Example 13 1.95 g of diethyl-cyanomethylphosphonate under ice cooling
485 mg of sodium hydride (purity 60%) was added to a solution of anhydrous tetrahydrofuran in 60 ml, and the mixture was stirred at the same temperature for 30 minutes. At the same temperature, 4,5-bis (4-methoxyphenyl)
A solution of 3.08 g of 2-formyl-1H-imidazole in 20 ml of anhydrous tetrahydrofuran is added, and the mixture is stirred at 20 to 25 ° C. for 1 hour. The solvent is distilled off under reduced pressure, ethyl acetate and water are added to the residue, and the organic layer is separated. The extract is washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (eluting solvent; benzene: ethyl acetate = 20: 1) to give 2-
[(E) -2-Cyanovinyl] -4,5-bis (4-methoxyphenyl) -1H-imidazole 1.59 g (yield 48%)
And 2-[(Z) -2-cyanovinyl] -4,5-bis (4-methoxyphenyl) -1H-imidazole 1.06 g
(Yield 32%) is obtained. Physical properties of these compounds (melting point, IR,
NMR) was in agreement with that obtained in Example 1.

Example 14 2-[(E) -2-Cyano-1-methylvinyl] -4,5
-Bis (4-methoxyphenyl) -1H-imidazole 3.
45 g are dissolved in 50 ml N, N-dimethylformamide. Under cooling with ice, 440 mg of sodium hydride is added, and the mixture is stirred at the same temperature for 1 hour. Methyl iodide (1.56 g) was added, the mixture was stirred at 20 to 25 ° C for 1 hr, ethyl acetate and water were added, and the organic layer was separated. The extract is washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. If the obtained residue is recrystallized from isopropyl alcohol, the melting point is 155-156 ° C.
2-[(E) -2-cyano-1-methylvinyl]
-4,5-bis (4-methoxyphenyl) -1-methyl-1
2.66 g of H-imidazole (74.1% yield) is obtained.

IR (KBr) cm ^-1 ; 2200,1600,1490,1290,1250,1175,1030 NMR (CDCl ₃ ) δ value; 2.63 (3H, s), 3.48 (3H, s), 3.74 (3
H, s), 3.85 (3H, s), 5.62 (1H, s), 6.70,7.22 (4H, ABq,
J = 9 Hz), 6.92, 7.36 (4H, ABq, J = 9 Hz) Similarly, the compounds shown in Table 13 are obtained.

Example 15 3.52 g of 4,5-bis (4-methoxyphenyl) -1- (1-ethoxyethyl) -1H-imidazole are dissolved in 100 ml of dry tetrahydrofuran and cooled to -50 ° C. In a nitrogen atmosphere, 6.9 ml of a 1.6N n-hexane solution of n-butyllithium is added dropwise over 20 minutes while maintaining -50 to -40 ° C. After stirring at the same temperature for 1 hour, 2,4-dimethyl-
Add 1.14 g of 3-pentane and stir for 30 minutes. 2 reaction solutions
After heating to 0 ° C., the solvent is distilled off under reduced pressure. Water and ethyl acetate are added to the residue, and the organic layer is separated. The solvent is distilled off under reduced pressure. The obtained residue is dissolved in 20 ml of dioxane, 4 ml of concentrated hydrochloric acid is added, and the mixture is refluxed for 1 hour. The solvent is distilled off under reduced pressure, water and ethyl acetate are added, and the pH is adjusted to 7 with sodium hydrogen carbonate. The organic layer is separated and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography [elution solvent; toluene: ethyl acetate = 10: 1] to give 4,5-bis (4-methoxyphenyl) -2- (1-isopropyl-
2-Methyl-1-propenyl) -1H-imidazole yield
Obtain 1.80 g (47.9%).

Melting point: 131-133 ° C (recrystallized from toluene-hexane) IR (KBr) cm ^-1 : 1610,1520,1505,1290,1250,1173,1073 NMR (CDCl ₃ ) δ value; 1.05 (6H, d, J = 7Hz), 1.65 (3Hs), 1.72 (3H, s), 3.0
5 (1H, m), 3.76 (6H, s), 6,79 (8H, ABq, J = 9Hz), 7.43
(8H, ABq, J = 9Hz), similarly, the compounds shown in Table-14 are obtained.

Example 16 2-[(E) -2-carbamoyl-1-propenyl]
1.1 g of -4,5-bis (4-methoxyphenyl) -1H-imidazole was dissolved in 5 ml of thionyl chloride, and the solution was added at 25-30 ° C for 24 hours.
Stir for hours. The reaction solution is added dropwise to a mixed solution of 50 ml of ethyl acetate, 50 ml of water and 20 g of sodium hydrogen carbonate. The organic layer is separated, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is subjected to column chromatography (elution solvent;
2-toluene: ethyl acetate = 10: 1)
[(E) -2-Cyano-1-propenyl] -4,5-bis (4-methoxyphenyl) -1H-imidazole 250 mg
(24% yield) is obtained.

Melting point; 211-212 ° C (recrystallized from AcOEt-IPE) IR (KBr) cm ^-1 : 3285,2195,1605,1455,1248,1172 NMR (d ₆ -DMSO-CDCl ₃ ) δ value; 2.55 (3H, 3H, s), 3.79 (6H, s), 6.80,7.38 (8H, ABq, J = 9
Hz), 6.88 (1H, s) Example 17 (1) Diethyl- (1-cyanoethyl) phosphonate 2.
10 g are dissolved in 20 ml N, N-dimethylformamide and cooled. Add 460 mg of sodium hydrogen (purity 60%) and stir under ice cooling until the generation of hydrogen gas stops. 1- (1-Ethoxyethyl) -2-formyl-4,5-bis (4-methoxyphenyl) -1H-imidazole (3.80 g) was added, and -5-
Stir at 0 ° C. for 2 hours. After introducing the reaction solution into a mixed solution of water and ethyl acetate, the organic layer is separated. The extract is washed with saturated saline and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography (elution solvent; toluene: ethyl acetate = 20: 1) to give 2-[(E) -2-cyano-1-propenyl] -1- (1-ethoxyethyl). -4,5-bis (4-
Methoxyphenyl) -1H-imidazole 1.75 g (yield 42
%).

Melting point: 108-110 ° C (recrystallized from IPE) IR (KBr) cm ^-1 : 2205,1605,1515,1457,1303,1281,1245,1
175,1121,1105,1027 NMR (CDCl ₃ ) δ value; 1.12 (3H, t, J = 7Hz), 1.58 (3H, d, J = 6Hz), 2.60 (3
H, d, J = 1Hz), 3.31 (2H, m), 3.72 (3H, s), 3.85 (3H,
s), 5.11 (1H, q, J = 6Hz), 6.69,7.18 (4H, ABq, J = 9H
z), 6.95, 7.39 (4H, ABq, J = 9Hz), 7.47 (1H, d, J = 1Hz) and 2-[(Z) -2-cyano-1-propenyl]
2.0 g of -1- (1-ethoxyethyl) -4,5-bis (4-methoxyphenyl) -1H-imidazole (48% yield) is obtained.

Melting point: 179-181 ° C (recrystallized from AcOEt-IPE) IR (KBr) cm ^-1 : 2200,1605,1513,1463,1440,1300,1242,1
175,1110,1025 NMR (CDCl ₃ ) δ value; 1.10 (3H, t, J = 7Hz), 1.54 (3H, d, J = 7Hz), 2.19 (3
H, d, J = 1Hz), 3.35 (2H, m), 3.69 (3H, s), 3.83 (3H,
s), 5.06 (1H, q, J = 7Hz), 6.67,7.17 (4H, ABq, J = 9H
z), 6.93, 7.46 (4H, ABq, J = 9Hz), 7.23 (1H, d, J = 1Hz) (2) 2-[(E) -2-cyano-1-propenyl]-
Example 4 using 1- (1-ethoxyethyl) -4,5-bis (4-methoxyphenyl) -1H-imidazole
In the same manner as in (2), 2-[(E) -2-cyano-1-
Propenyl] -4,5-bis (4-methoxyphenyl) -1
H-imidazole is obtained. The melting point, IR, and NMR of this product are
In agreement with that obtained in Example 16.

Example 18 Diethyl- (1-methylthioethyl) phosphonate 2.
Dissolve 54 g in anhydrous tetrahydrofuran 100 ml, -60 ℃
Cool to. At the same temperature, 7.2 ml of n-hexane solution (1.6N) of n-butyllithium was added dropwise. After stirring at -60 to -50 ° C for 4 hours, 50 ml of an anhydrous tetrahydrofuran solution containing 3.8 g of 1- (1-ethoxyethyl) -2-formyl-4,5-bis (4-methoxyphenyl) -1H-imidazole was added.
Drip over 10 minutes. After stirring at -60 to -50 ° C for 30 minutes, the temperature is raised to 20 to 25 ° C and the mixture is refluxed for 2 hours. The solvent is distilled off under reduced pressure, water and ethyl acetate are added, and the organic layer is separated. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue was purified by column chromatography (elution solvent; toluene: ethyl acetate = 20: 1) to give 1- (1-
Ethoxyethyl) -2-[(E) -2-methylthio-1
-Propenyl] -4,5-bis (4-methoxyphenyl)
-1H-imidazole 1.15 g (yield 25.5%) is obtained.

Melting point: 103 to 105 ° C (recrystallized from IPE-n-hexane) IR (KBr) cm ^-1 : 1605,1510,1495,1295,1247,1172,1125,1
103,1030 NMR (CDCl ₃ ) δ value; 1.11 (3H, t, J = 7Hz), 1.55 (3H, d, J = 7Hz), 2.34 (3
H, s9,2.59 (3H, s), 3.38 (2H, q, J = 7Hz), 3.71 (3H,
s), 3.84 (3H, s), 5.06 (1H, q, J = 7Hz), 6.60 (1H, s),
6.67,7.18 (4H, ABq, J = 9Hz), 6.91 (2H, d, J = 9Hz), 7.3
4 (2H, dd, J = 7Hz, J = 9Hz) and 1- (1-ethoxyethyl) -2-[(Z) -2
-Methylthio-1-propenyl] -4,5-bis (4-methoxyphenyl) -1H-imidazole 2.72 g (yield 60.3
%).

Melting point: 145 to 147 ° C (recrystallized from AcOEt-IPE) IR (KBr) cm ^-1 : 1602,1582,1510,1495,1290,1280,1247,1
122,1100,1033 NMR (CDCl ₃ ) δ value; 1.10 (3H, t, J = 7Hz), 1.55 (3H, d, J = 7Hz), 2.32 (3
H, s), 2.38 (3H, s), 3.38 (2H, q, J = 7Hz), 3.71 (3H,
s), 3.83 (3H, s), 5.55 (1H, q, J = 7Hz), 6.67 (1H, s),
6.67,7.16 (4H, ABq, J = 9Hz), 6.89 (2H, d, J = 9Hz), 7.3
7 (2H, t, J = 9Hz) (2) 1- (1-ethoxyethyl) -2-[(E) -2
-Methylthio-1-propenyl] -4,5-bis (4-methoxyphenyl) -1H-imidazole, Example 4
In the same manner as in (2), 2-[(E) -2-methylthio-
1-Propenyl] -4,5-bis (4-methoxyphenyl) -1H-imidazole is obtained.

Melting point: 190 to 192 ° C (recrystallized from IPA-IPE) IR (KBr) cm ^-1 : 1610,1520,1505,1290,1247,1175 NMR (CDCl ₃ ) δ value; 2.34 (3H, s), 2.50 ( 2H, s), 3.82 (6H, s), 5.94 (1H,
s), 6.85, 7.45 (8H, ABq, J = 9Hz) Similarly, 2-[(Z) -2-methylthio-1-propenyl] -4,5-bis (4-methoxyphenyl) -1H
-Obtaining imidazole.

Melting point: 134-136 ° C (recrystallized from ethanol-IPE) IR (KBr) cm ^-1 : 3340,1635,1608,1520,1298,1250,1180,1
025 NMR (CDCl ₃ ) δ value; 2.28 (3H, d, J = 1 Hz), 2.45 (3H, s), 3.82 (6H, s), 6.
84 (1H, d, J = 1Hz), 6.89,7.46 (8H, ABq, J = 9Hz) 8.45
(1H, bs)

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication C07D 233/64 106 // A61K 31/415 AAG AA AH ABE ABG C07D 405/06 233 (72) Inventor Shinji Makino 3490, Mikkaichi, Kurobe, Toyama Prefecture (72) Inventor Shuntaro Takano 3-8-44, Inarimoto-cho, Toyama City, Toyama Prefecture 56-56 Examiner Sano Norihiro Sano (56) Reference JP-A-57-56466 (JP, A) Kai 55-31065 (JP, A) JP 62-93278 (JP, A) Japanese Patent Sho 51-23506 (JP, B1)

Claims (1)

[Claims] 1. A general formula “In the formula, R ¹ and R ² are the same or different and each is a phenyl group which may be substituted with a halogen atom, alkyl, hydroxyl, alkoxy, mercapto, alkylthio or alkylsulfonyl group; R ³ is a halogen atom, hydroxyl group Or an alkyl or cycloalkyl group which may be substituted with an alkoxy group or a hydrogen atom; R ⁴ is substituted with a halogen atom, alkyl, hydroxyl, alkoxy, mercapto, alkylthio, alkylsulfonyl, dialkylamino, nitro or cyano group. Optionally an alkyl or cycloalkyl group or a hydrogen atom, a cyano group or a furyl group; R ⁵ and R ⁶ are the same or different and are a hydrogen atom, a halogen atom,
A cyano group, a formyl group, an acetyl group, a nitro group, an aryl group or an alkylthio group; and R ⁵ and R ⁶ together with adjacent carbon atoms are acyl, hydroxyl, oxo, alkoxy, mercapto, alkylthio,
It may form a 3- to 8-membered cycloalkyl ring optionally substituted with an alkylsulfonyl, arylsulfonyl, nitro, cyano or dialkylamino group. However, when R ¹ and R ² are phenyl groups, at least one of them is a phenyl group substituted with a halogen atom, alkyl, hydroxyl, alkoxy, mercapto, alkylthio or alkylsulfonyl group. Also, R ⁴
When is a hydrogen atom, R ⁵ and R ⁶ are the same or different and are not an aryl group. ] The novel imidazole derivative represented by these, and its salt.