JPS63239274A - Novel imidazole derivative and salt thereof - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R<1> and R<2> are phenyl or heterocyclic group; R<3> is H, alkyl or cycloalkyl; R<4> is H, CN, alkyl, cycloalkyl, aryl or heterocyclic group; R<5> and R<6> are H, halogen, CN, NO2, acyl, alkoxy, aryloxy, alkylthio, alkyl, aryl, etc.; R<4> and R<6> together with C to which they are linked may form 5--7-membered cycloalkenyl ring; R<5> and R<6> together with C to which they are linked may form 3--8-membered cycloalkyl ring) and salt thereof. EXAMPLE:2-[(E)-2-Cyano-1-phenylvinyl]-4,5-bis(4-methoxyphenyl)-1H-imid azole. USE:An anti-inflammatory agent, antipyretic, analgesic agent and antiarthritic agent. PREPARATION:For example, a compound expressed by formula II (R<4a> is R<4> except CN) is subjected to the Wittig reaction to afford the corresponding compound expressed by formula I.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to a compound of the formula "wherein R and R2 are phenyl or a heterocyclic group which may be the same or different substituted; R3 is a hydrogen atom, a substituted an optionally substituted alkyl or cycloalkyl group: R4 is a hydrogen atom, a cyano group, an optionally substituted alkyl, cycloalkyl, aryl or heterocyclic group; R and R6 are the same or different and are a hydrogen atom,
Halogen atom, cyano group, nitro group, optionally substituted acyl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, ? R4 and R6 together with their adjacent carbon atoms optionally have a substituent 5-7 A membered cycloalkenyl ring may be formed, and R5 and R6 together with adjacent carbon atoms form a 3- to 8-membered cycloalkyl ring which may have a substituent. Good too. However, when R1 and R2 are phenyl groups, at least one of them is a substituted phenyl group. Moreover, when R4 is a hydrogen atom,
Excludes aryl and heterocyclic groups in which R and R6 may be identically or differently substituted. ” and its salts.

SUMMARY OF THE INVENTION An object of the present invention is to provide novel imidazole derivatives and salts thereof that have excellent anti-inflammatory, antipyretic and analgesic, and anti-arthritic effects and exhibit excellent therapeutic effects.

[Prior art] Substituted imidazoles are disclosed in, for example, Japanese Patent Application Laid-Open No. 47-1037.
No. 9, Special Publication No. 51-23506, No. 59-46605
Issue, Journal of Medicinal Chemistry [
Journal of )ledicinalChem
istry 28(9), 1188-1194 (198
5) 1 and the like, and the compounds described in these are also known to 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 effects and toxicity, and there has been a desire to develop even more excellent compounds.

[Means for Solving the Problems] Under such circumstances, the present inventors conducted intensive research and found that the 2nd position of imidazole is characterized by [wherein R4
, R5 and R6 have the same meanings as above. ] It was discovered that the compound of formula [I] to which a group represented by the following is bonded exhibits excellent pharmacological effects and low toxicity, and the present invention has been completed.

The compounds of the present invention will be explained in detail below.

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

Alkyl groups include, for example, C alkyl groups such as methyl, ethyl, n-propyl, 1so-propyl, n-butyl, 1so-butyl, 5ec-butyl, tert-butyl, and pentyl; alkoxy groups include 1 to 8 10-alkyl group; alkylthio group, -8-alkyl group, di-alkylamino group, for example, di-C alkylamino group such as dimethylamino, diethylamino, etc.; alkylsul 1-5 finyl: -8O-alkyl group: Alkylsulfonyl group refers to -802-alkyl group: Alkenyl group refers to, for example, vinyl, allyl, 1-propenyl, l5
C such as O-propenyl, 1-butenyl, 2-butenyl, etc.
alkenyl group; 2-6 chloroalkyl group, for example, C cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; aryl group 3-6, for example, group such as phenyl, naphthyl; Arylthio group refers to -S-aryl group; Aryloxy group refers to -0-aryl group; Arylsulfinyl refers to -5O-aryl group; Arylsulfonyl group refers to -5o2-aryl group. ;Acyl group is, for example,
formyl, acetyl, propionyl, butyryl, 1so
- C acyl groups such as butyryl; heterocyclic groups include nitrogen atoms, oxygen atoms or/and sulfur as heteroatoms such as furyl, chenyl, pyrrolyl, oxasilyl, thiazolyl, imidazolyl, pyridyl, etc. A 5- or 6-membered heterocyclic group containing one or more atoms; the halogen atom means fluorine, chlorine, bromine, iodine, and the like.

R1 and R2 represent phenyl or a heterocyclic group which may be substituted the same or differently, and examples of these substituents include a halogen atom, an alkyl group, a hydroxyl group, an alkoxy group, a mercapto group, an alkylthio group, and an aryl group. Examples include sulfonyl groups.

Next, R3 represents a hydrogen atom, an optionally substituted alkyl group, or a cycloalkyl group, and examples of such substituents include a halogen atom, a hydroxyl group, and an alkoxy group.

R4 represents a hydrogen atom, a cyano group, an optionally substituted alkyl, cycloalkyl, aryl, or a heterocyclic group; examples of these substituents include a halogen atom, an alkyl group, a hydroxyl group, an alkoxy group, Examples include mercapto group, alkylthio group, alkylsulfonyl group, dialkylamino group, nitro group, and cyano group.

Furthermore, R and R6 are the same or different and are hydrogen atom, halogen atom, cyano group, nitro group, optionally substituted acyl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl ,
It represents an alkyl, cycloalkyl, alkenyl, aryl or heterocyclic group, and substituents thereof include a halogen atom, an alkyl group, a hydroxyl group, a mercapto group, an alkylthio group, an alkylsulfonyl group, a dialkylamino group, a nitro group, Examples include cyan group.

In general, R and R6 may be combined with their adjacent carbon atoms to form a 5- to 7-membered cycloalkenyl ring that may have a substituent, and specifically, for example, Formula, 85°C82)- [where m represents 3 to 5, and R5 has the same meaning as above. ], and substituents on this 5- to 7-membered cycloalkenyl ring include groups such as acyl, hydroxyl, oxo, alkoxy, mercapto, alkylthio, alkylsulfonyl, arylsulfonyl, nitro, cyano, and dialkylamino. Can be mentioned. Further, R5 and R6 may be combined with adjacent carbon atoms to form a 3- to 8-membered cycloalkyl ring which may have a substituent, and specifically, for example, the formula: = Should be H2).

[In the formula, n represents 2 to 7. ], and substituents on this 3- to 8-membered cycloalkyl ring include acyl, hydroxyl, oxo-1. Examples include groups such as alkoxy, mercapto, alkylthio, alkylsulfonyl, arylsulfonyl, nitro, cyan, dialkylamino, and the like.

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

The compounds of the present invention further include all isomers (geometric isomers, optical isomers), hydrates, solvates, and crystal forms.

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

Chin visit d familiar b2 jaw deaf J fissure A LVIJ
LIGJ limb segment [wherein R, R and R3 have the above-mentioned meanings, R3
O is the same optionally substituted alkyl or cycloalkyl group as explained for R3, or a protecting group that is stable under strong basic conditions and is easily removed with an acidic reagent and replaced with a hydrogen atom: R4a is R4 A hydrogen atom similar to that explained in
An optionally substituted alkyl, cycloalkyl, aryl or heterocyclic group: R5a and R6O are the same or different and represent the same halogen atom, cyano group, or optionally substituted acyl group as explained for R and R6; , alkoxy, aryloxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, alkyl, cycloalkyl, alkenyl, aryl or heterocyclic group: R5b and R6b are the same or different and R and R
The same cya group, nitro group, optionally substituted acyl, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aryl, alkenyl or heterocyclic group as explained in 6: R50, R2O, R60 and R
6O is the same or different and represents the same hydrogen atom, optionally substituted alkyl, cycloalkyl, aryl or heterocyclic group as described for R5 and R6: R50 and R68 are the same or different and are the same as those described for R5 and R6 The same hydrogen atoms, optionally substituted alkyl,
Cycloalkyl or aryl group: A is phosphorus yl id, phosphonate anion
), phosphinate anion t'phosphrnat
e anion), phosphine oxyto anion (ph
X is a halogen atom; Y is a leaving group; B is a formyl group or an acetal. Roughly,
R4O and R6O may be combined with their adjacent carbon atoms to form a 5- to 7-membered cycloalkenyl ring which may have the same substituents as explained for R and R6, and , R5O and R6O, R50 and R
6O, R2O and R6O or R and R60 together with adjacent carbon atoms form a 3- to 8-membered cycloalkyl ring which may have the same substituents as explained for R5 and R6. It's okay. ” Formula [Ial, [I bl, [Icl, [Idl, [Ie
l, [Work month, [IC11, [II], [IV], [VI
], [XI] and [XI] can also be obtained as salts, and examples of these salts include those similar to the salts of formula [I].

Protective groups for R3a that are stable under strongly basic conditions and are easily eliminated by acidic reagents and replaced with hydrogen atoms include, for example, α-ethoxyethyl, 2-tetrahydropyranyl, benzyloxymethyl, p-methoxybenzyl. , trityl group, etc.

Further, as a leaving group for Y, for example, a halogen atom,
Examples include groups such as alkylsulfonyloxy and arylsulfonyloxy.

Furthermore, the formula [Ial~[Ial, [I[], [I[I]
, [l■], [V], [v1], [VI], [■], [
X], [XI], [X[] and [Kari] compounds, R1, R2, R3, R3a, R4a, R5b, R6
When C5R5d, R6C5R5d and R6d have a hydroxyl group, a mercapto group, etc. as a substituent, for example, Protective Groups in Org
anic 5 synthesis (T.

(W. Green, 1981) John Wi I
ey & 5ons, Inc.].

A compound of the formula [Ial] can be produced by subjecting the compound of the formula [I[] to the Witzteig reaction.

The Wittia reaction is, for example, the organic reaction [OrganicReac
tions (John Wi Iey &
5ons, Inc.)] 14th Liu, 270-4
90, Vol. 25, pp. 73-253, Ylid Chemistry (A.

)1. Acade (written by John SOn, 1966)
mic press InC, ], Organophosphorus Reagents in Organic Life Synthesis [
Organophosphorust agents
in organic 5 synthesis (J,
1. G. Cadogan, 1979) Academ
ic Press Inc. (London) LTD.
, ], Synthtake Communication [5ynt
het icCommunication 3(3),
197-200 (1973)] or by a method similar thereto;
n)”, phosphinate anion (phosphina
teanion), phosphine oxyto anion (
This shows a reaction in which a phosphorus compound such as phosphine oxide anion is reacted with an aldehyde or a ketone to obtain a compound having a double bond.

The phosphorus compound used in the Witteich reaction is
All those having R5a and R6a substituents that can produce a compound of formula [Ial are included.

The solvent used in this reaction may be any solvent that does not adversely affect the reaction, such as hydrocarbons such as benzene, toluene, xylene, n-hexane, and n-heptane; diethyl ether, tetrahydrofuran,
Ethers such as dioxane, 1,2-dimethoxyethane, diglyme; methylene chloride, chloroform, 1,
Hydrogen halides such as 2-dichloroethane; esters such as methyl acetate and ethyl acetate; alcohols such as methanol, ethanol, propatool, isopropanol, n-butanol, and tert-butanol;
Nitriles such as acetonitrile: N.

Examples include amides such as N-dimethylformamide and N,N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide; and water, and two or more of these solvents may be used in combination.

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

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

A compound of the formula [I bl] can be produced by reacting the old compound with an active methylene compound having b substituents R and R6b of the formula [I11] in the presence of a catalyst.

This method uses the so-called Knoevena gel.
el ) type, Thalaisen-Schmidt (C1aisen
-8chmidt) type and Perkin type reactions.

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

Catalysts used in this reaction include, for example, ammonia; primary amines such as n-butylamine; secondary amines such as piperidine, pyrrolidine, and morpholine; tertiary amines such as nitriethylamine and pyridine; The basic catalyst can be used alone or together with C lower fatty acids such as acetic acid, propionic acid, butyric acid, and valeric acid (1-5); alkali metals such as sodium hydroxide and potassium hydroxide. hydroxides of alcohols: alkali metal salts of alcohols such as sodium methylate, sodium ethylate, potassium tert-butoxy; alkali metal hydrogen compounds such as sodium hydride, potassium hydride; sodium bicarbonate, sodium carbonate, potassium carbonate alkali metal salts of carboxylic acids such as sodium acetate, potassium acetate; salts of carboxylic acids such as ammonium acetate, piperidine acetate; potassium fluoride, rubidium fluoride, cesium fluoride fluorides such as; Lewis acids such as titanium tetrachloride.

The amounts of the catalyst and the compound of formula [I[1] to be used are 0.1 to 5 times the mole and 1 to 5 times the mole of the compound of formula [old], respectively.
It is 10 times the molar amount.

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

A compound of formula [C] can be produced by reacting a compound of formula [IV] with a base and then reacting it with a compound of formula [V].

The solvent used in this reaction may be any solvent as long as it does not adversely affect the reaction, and includes, for example, the same solvents used in the Witzteig reaction as mentioned in Production Method 1.

Bases used in this reaction include, for example, alkali metal salts of carbonic acid such as sodium bicarbonate, sodium carbonate, potassium carbonate; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide; sodium methylate. , alkali metal salts of alcohols such as tert-butoxypotassium; alkali metal hydride compounds such as sodium hydride and potassium hydride; n-butyllithium, phenyllithium:sodium amide, lithium diisopropylamide, and the like.

The amount of the base and the compound of formula [V] to be used is 1 to 5 times the mole and 1 to 10 times the mole of the compound of formula [IV], respectively.
It is a mole.

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

A compound of formula [Idl] can be produced by reacting a compound of formula [VI] with a compound of formula [VI] in the presence of a catalyst.

The solvent used in this reaction may be any solvent as long as it does not adversely affect the reaction, and examples thereof include those described in Production Method 2.

Moreover, the compound of formula [W] can also be used as a solvent.

Catalysts used in this reaction include, for example, ammonia; primary amines such as n-butylamine; secondary amines such as piperidine, pyrrolidine, and morpholine; tertiary amines such as nitriethylamine and pyridine; The basic catalyst can be used alone or together with C1-5 lower fatty acids such as acetic acid, propionic acid, butyric acid, valeric acid.): Hydroxification of alkali metals such as sodium hydroxide and potassium hydroxide. alkali metal salts of alcohols such as sodium methylate, sodium ethylate, potassium tert-butoxy; alkali metal hydrogen compounds such as sodium hydride, potassium hydride; sodium bicarbonate, sodium carbonate, potassium carbonate; Alkali metal salts of carbonic acid: Alkali metal salts of carboxylic acids such as sodium acetate and potassium acetate:
Examples include salts of carboxylic acids such as ammonium acetate and piperidine acetate; fluorides such as potassium fluoride, rubidium fluoride, and cesium fluoride.

The amount of catalyst and compound of formula [VI] to be used is as follows: formula [vI]
of the compound, respectively, 0.1 to 5 times the mole and 1
~10 times the molar amount.

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

Production method 5 1) A compound of formula ['lX] can be produced by reacting a compound of formula [■] with a compound of formula ['lX] in the presence of ammonia or ammonium acetate.

The solvent used in this reaction may be any solvent that does not adversely affect the reaction; examples include alcohols such as methanol, ethanol, tert-butanol, and ethylene glycol; acetic acid; Two or more types may be mixed and used.

The amount of ammonia or ammonium acetate used in this reaction is 5 to 10 times the molar amount of the compound of formula [■]. In addition, the amount of the compound of formula [IX] to be used is the amount of compound of formula [■]
The molar amount is 1 to 2 times that of the compound.

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

Moreover, this reaction is similar to that of the Society [Soc, 49.
464° (1894)], Journal of Organic Chemistry [J, Ora, Chem, 2
, 319 (1937)].

2) A compound of formula [1] can be prepared by reacting a compound of formula [Iel with a compound of formula [XI] in the presence of a base.

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 listed in Production Method 2.

Bases used in this reaction include, for example, alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal salts of alcohols such as sodium methylate, sodium ethylate, and potassium tert-butoxy; potassium carbonate. Alkali metal salts of carbonic acid such as triethylamine, 1,8-diazabicyclo[5
,4,0]undec-7-ene (DBU>) and the like.

The amount of the compound of formula [XI and base to be used is 1 to 5 times the mole of the compound of formula [Iel] and 1 to 10 times the amount of the compound of formula [Iel], respectively.
It is twice the mole.

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

1) The compound of formula [XII] can be produced by reacting the compound of formula [XI] with n-butyllithium and then reacting it with the compound of formula [X[].

The solvent used in this reaction may be any solvent as long as it does not adversely affect the reaction, and examples thereof include ethers such as tetrahydrofuran, diethyl ether, and dioxane. Two or more of these solvents may be mixed together. You may also use it.

The amounts of lobetillithium and the compound of formula [XI[] to be used are 1 to 1.5%, respectively, relative to the compound of formula [X1].
5 times the mole and 0.5 to 2 times the mole.

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

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

The solvent used in this reaction may be any solvent that does not adversely affect the reaction, such as hydrocarbons such as benzene and toluene; alcohols such as methanol and ethanol; diethyl ether, tetrahydrofuran, and dioxane. Ethers: Halogenated hydrocarbons such as methylene chloride and chloroform; Nitriles such as acetonitrile; Amides such as N,N-dimethylformamide; Carboxylic acids such as acetic acid and formic acid:
and water, and two or more of these solvents may be used in combination. Moreover, you may use the acid mentioned later as a solvent.

Examples of acids used in this reaction include mineral acids such as hydrochloric acid and sulfuric acid, and sulfonic acids such as toluenesulfonic acid and metaxulfonic acid.

The amount of acid used is 1.1 for the compound of formula [Xl1l]
~5 times the molar amount.

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

The compound of formula [X[Il] can also be used as it is in the next reaction without being isolated.

In each of the above-described reactions, when an active group is present at a site other than the reaction site, the active group may be appropriately protected, subjected to the reaction, and the protecting group removed according to a conventional method.

Moreover, the object compound of the present invention obtained by the above-mentioned production method is
In addition, the compound of the present invention can also be obtained by subjecting it to commonly known oxidation reactions, reduction reactions, dehydration reactions, Witzteig reactions, and the like.

Next, the raw material compounds for each production method will be explained.

The compound of formula [I[] is disclosed in, for example, JP-A-56-118
It can be produced by the method described in No. 072 or a method similar thereto.

Further, the compound of formula [IV] can be, for example, manufactured by the following LIV
J LXvl” [
In the formula, R1, R2, R3, R3a, R4a, A and X
has the meaning given above. ] 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 any solvent as long as it does not adversely affect the reaction, such as methanol, ethanol, tert-butanol, alcohols such as ethylene glycol, diethyl ether, tetrahydrofuran, 1,2- Examples include ethers such as dimethoxyethane and diglyme, and two or more of these solvents may be used in combination.

Examples of the reducing agent used in this reaction include sodium borohydride cyanide (NaBH3CN), sodium borohydride (NaBH4), and lithium aluminum hydride (LiAlH4).

The amount of reducing agent used is 0.2 to 2
It is twice the mole.

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

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

The solvent used in this reaction may be any solvent as long as it does not adversely affect the reaction, and examples thereof include the same solvents as in Production Method 1. Further, a halogenating agent described below may be used as a solvent.

The halogenating agent used in this reaction is usually a reagent capable of converting a hydroxyl group into a halogen atom, such as thionyl chloride, thionyl bromide, phosphorous trichloride,
Phosphorus pentachloride, phosphorus tribromide, phosphorus oxychloride, hydrogen chloride,
Hydrogen bromide, hydrochloric acid, hydrobromic acid, hydroiodic acid, etc. are mentioned, and examples of halogenating agents generated and used in the reaction system include C(, triphenylphosphine dibromide, triphenylphosphine dibromide, triphenylphosphine dibromide, etc.). Examples include dichloride.

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

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

Furthermore, the reaction may be carried out by adding a distributing agent if necessary. Examples of deoxidizers include pyridine, 4-N, N-
Dimethylaminopyridine, triethylamine, N, N-
Major bases such as dimethylaniline, calcium carbonate,
Inorganic bases such as barium carbonate may be mentioned.

Further, the compound of formula [XV] can also be produced by reacting the compound of formula [XVI] with a halogenating agent. Examples of the halogenating agent used in this reaction include N-bromosuccinimide and N-chlorosuccinimide, and examples of the radical reaction initiator include azobisisobutyronitrile. Ru.

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 as long as it does not adversely affect the reaction, and examples thereof include the same solvents as mentioned in Production Method 1.

Examples of phosphorus compounds used in this reaction include:
Examples include trivalent phosphorus compounds, such as phosphines such as triphenylphosphine and tributylphosphine; and phosphites such as trimethylphosphite, triethylphosphite, and triethylphosphite.

The amount of phosphorus compound used is 0 for the compound of formula [XV].
．． It is 5 to 2 times the mole.

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

Further, by reacting the compound of formula [Xv] with a cyanide compound, a compound of formula [XV] in which the group corresponding to X is a nitrile group can be obtained.
] Compounds can also be produced.

The solvent used in this reaction may be any solvent that does not adversely affect the reaction, such as alcohols such as methanol, ethanol, tert-butanol, and ethylene glycol: N, N-dimethylformamide, N, N Examples include amides such as dimethylacetamide, sulfoxides such as dimethylsulfoxide, and water, and two or more of these solvents may be used in combination.

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

The amount of cyanide used is as follows for the compound of formula [XV]:
It is 0.5 to 5 times the mole.

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

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

The compound of the present invention represented by formula [I] can be prepared into capsules, powders, granules, gunpowders, tablets, suspensions, emulsions, solutions, poultices, ointments, injections, eye drops, and liniments by conventional methods. , can be administered orally or parenterally as syrups or suppositories.

In addition, the administration method, dose, and frequency of administration may be adjusted as appropriate depending on the age and symptoms of the patient.
About 5.0 mg to about 10,100 O per day may be administered in one to several divided doses.

[Effect of the invention] Sensitive food No. 1 2-[(E)-2-cyano-1-phenylvinyl]-4,5-bis(4-methoxyphenyl)-1
H-imidazole 2-[(E)-2-cyanovinyl]-4゜5-bis(4-methoxyphenyl)-1H-imidazole 2-[(E)-2-cyano-1-methylvinyl]
-4,5-bis(4-methoxyphenyl)-1)-1-
Imidazole No. 4 2-[(E)-2-chlorovinyl]-4゜5
-bis(4-methoxyphenyl)-1H-imidazole, 5' 2-[(E)-1-propenyl 4,5
-Bis(4-methoxyphenyl)-1H-imidazole No. 6 2-vinyl-4,5-bis(4-methoxyphenyl)-1 day-imidazole No. 72-(2,2-dichlorovinyl)-4, 5-bis(4-methoxyphenyl)-18-imidazole, 8 2-[(2E,4E)-4-cyano-1゜3-
2-cyclohexylidenemethyl-4,5-bis(
4-methoxyphenyl)-1 day-imidazole No, 102- [(Z)-2-cyano-1-phenylvinyl]-4,5-bis(4-fluorophenyl)-
18-imidazole No., 112-[(E)-1-pentenyl]-4,
5-bis(4-methoxyphenyl)-1d-imidazole No., 122-[(Z)-1-pentenyl]-4,5-
Bis(4-methoxyphenyl)-1H-imidazole NO, 132-cyclopentylidenemethyl-4,5-bis(4-methoxyphenyl)-1day-imidazole No., 142-[2-methyl-1-propenylco-4゜5-bis(4-methoxyphenyl)-1 day-imidazole No., 152-[(E)-2-methylthiovinyl]-
4,5-bis(4-methoxyphenyl)-11-1-imidazole No. 162-[(E)-2-chloro-1-methylvinyl]-4,5-bis(4-methoxyphenyl)-18-
Imidazole No., 172- [(E)-2-cyano-1-ethylvinyl]-4,5-bis(4-methoxyphenyl)-
1st-Imidazole No., 182- [(E)-2-cyano-1-methylvinyl]-4,5-bis(4-methoxyphenyl)-1
-Methyl-1 day-imidazole No., 192-[(E)-1-ethylvinyl]-4゜5-bis(4-methoxyphenyl)-1-methyl-IH
-imidazole No., 202O2-cyclohexenyl]-4,5-bis(4-methoxyphenyl)-1-methyl-1H-imidazole No., 212-[(E)-2-cyano-1-propenyl]-4,5 -bis(4-methoxyphenyl)-1-
Methyl-1 day-imidazole No., 222-[(E)-2-methylthio-1-propenyl]-4,5-bis(4-methoxyphenyl)-1
-Methyl-1 day-imidazole No., 232-[(E)-2-cyano-1-propenyl]-4,5-bis(4-methoxyphenyl)-1 day-
Imidazole No., 242- [(E) -2-methylthio-1-methylvinyl]-4,5-bis(4-methoxyphenyl)
-1-methyl-1 day-imidazole No., 252- [
(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 [-ship name: phenflumizole] 1. Prostarandin biosynthesis and harmful effects in vitro
) Prostaglandin biosynthesis inhibitory effect is produced by R.G.A. Flower (R,J.

Flower) et al.'s method [prostaglandins (Pr
ostaglandins) 4.325 (1973)]
Tested according to.

Prostaglandin biosynthesis inhibitory activity was determined in vitro by measuring the inhibitory effect of malondialdehyde (MDA) i produced after addition of arachidonic acid using rabbit kidney microsomal fraction as a prostaglandin biosynthesis system. I looked into it.

The MDA production inhibitory effect of the test compound was determined by varying the amount of the test compound solubilized in dimethyl sulfoxide (DMSO), and the concentration (x /rnl). Renal medullary microsomal fraction at protein concentration of 1 mFI/d, 501IIH Tris-HCl buffer containing 5mM glutathione and 5mM epinephrine (1) H8) 1
．． 0.02 mf of DM SO solution in which the test compound was dissolved in 98 precepts! Add and keep warm at 37℃. After 5 minutes, add arachidonic acid to a volume of 0.5 ml and incubate for 15 minutes.

The reaction was stopped by adding perchloric acid, and the produced MDA was turned red by reaction with thiobarbic acid (TBA reaction), then extracted with n-butanol and fixed colorimetrically. The results are shown in Table-1.

Table 1 (1) Carrageenin suppressing effect on foot edema The anti-inflammatory effect of carrageenan on suppressing foot edema was determined by the method of C. Experimental Biology and Medicine (PrOCeedin is of the Society
Ty for Experimental Biolo
gy and) 1edicine) 111,544
(1962)].

Volumetric male rats fasted overnight (body weight 90-1209>
Using 6 to 7 animals per group, 4% polyethylene glycol 30
A test compound dissolved or suspended in 0-5% Tween 80 solution was orally administered at a rate of 1 m/100 g body weight. One hour later, 1% carrageenan was injected 0.1 m subcutaneously into the kick of the left hind leg. The swollen volume of the hind paw and heel was measured 3 hours after the onset of inflammation, and the edema rate was determined from the volume before injection, and the inhibition rate was determined using the following formula.

The results were expressed in terms of the suppression effect described below based on the suppression rate.

10% or less (-) 10-15% (±) 15-20%
(+) 20~30% (++) 3Q~40% (10++
) 40% or more (・÷++) The results are shown in Table-2.

Table 2 (2) Adjuvant arthritis suppressing effect The adjuvant arthritis suppressing effect was determined by E.M. Glenn (E.
, H. Glenn) method [American Journal of Competition Research (AmeriCan)]
Journal of Veterinary Re
5earch) 27, 339 (1966)].

Wistar Lewis male rat (weight 190-230g)
) was added to liquid paraffin as an adjuvant.
6 dry killed bacteria of Losis)! The suspension at a ratio of n37ml was used and injected into O0'1ml at the base of the ridge. At 188 days after adjuvant treatment, the test compound was divided into groups according to the swelling volume of both hind limbs, and 0.5% of the test compound was administered once a day for 7 consecutive days.
A suspension in an aqueous carboxymethyl cellulose solution was orally administered at a rate of 1 mi/100!9 body weight. The swelling volume of both hind limbs was measured on the day after the final administration, and the suppressive effect was determined in the same manner as in (1). The results were expressed in terms of the suppression effect described below based on the suppression rate.

10% or less (-) 10-15% (±) 15-20%
(20-30% (++) 30-40% (++
10) 4Q~50% (+10++) 50% or more (++
+++) The results are shown in Table-3.

Table 3: Analgesic effect of Earl Costa (f?, KO3ter)
et al.'s method [Fede Lotion Proceedings (
Federation Proceedings) 1
8.412 (1959)].

Using 10 ICR male mice (body weight 20-30 g) per group, 0.1 ml of a test compound suspended in a 0.5% carboxymethylcellulose aqueous solution was added. /10y10
Administered orally at a rate of 0.

After 30 minutes, 0.5% acetic acid was intraperitoneally injected at a rate of 0.1 m/109 body weight, and the number of stretching events occurring in 15 minutes from 5 minutes later was measured. 3 for each test compound
~5 doses were studied, and the number of stretching sessions in the control group was 50.
% inhibiting dose E D50 Cm'J/Kg') was determined. The results are shown in Table 4.

(Margin below) Table 4 4. Ulcer-inducing effect 5-6 Wistar male rats per group (body weight 180~
After fasting for 24 hours (water was allowed ad libitum), the test compound suspended in a 0.5% carboxymethyl cellulose aqueous solution was orally administered at a ratio of Id/1009 body weight. After being left in a fasted state for 5 hours, the patient was killed by cervical dislocation, the stomach was removed, and the body was placed in a 1% formalin solution for 3 hours.
Fixed for 0 minutes. This stomach is cut open along the public view, and the length (#) of erosion and ulcers that have occurred on the gastric mucosa are measured under a stereomicroscope. It was taken as a coefficient.

Q: J<0.5.1:0.5≦, g<1, 2:1≦
J<23:2≦, g<3, 4:3≦1<5°5:5≦, g<7.5 near≦, j<10°7:10≦,
j<15. 8:15≦Jl<25°9:25≦, g<
40.10: i≧40 then the dose Lj D 50 (mg/
'l) was calculated.

The results are shown in Table-5.

Table 5 5. Acute toxicity 4-week-old ICR male mice (weight 20-25 g,
Oral acute toxicity was measured using 3 animals per group. A test compound suspended in a 0.5% carboxymethyl cellulose aqueous solution was orally administered at a rate of 0.2 d/109 body weight. Observe general symptoms for 2 weeks after administration, calculate the number of deaths/number of test cases, and calculate the 50% lethality IJLD 50
(my/Kg) was estimated. Test compound Nα1-Nα2
The oral acute toxicity of 5 and the control drug NαA was 1000 my/
It was over Kg.

From the results shown in Tables 1 to 5 above, it is clear that the compounds of the present invention have excellent pharmacological effects and high safety.

(Margin below) [Example] Next, the present invention will be explained by giving reference examples and examples.

Note that the symbols used in Reference Examples and Examples have the following meanings.

M'e: methyl, Et: ethyl, pr: n-propyl, 1-pro: isoprobyl, 3u: n-butyl,
t-Bu: tert-butyl, Pent: n-pentyl, AC niacetyl, THF: tetrahydrofuran,
DMSO dimethyl sulfoxide, ACOEt: ethyl acetate, IPA: isopropyl alcohol, IPE diisopropyl ether, Et20 dimethyl ether, and all solvent mixing ratios are volume ratios.

In addition, the carrier in column chromatography is silica gel manufactured by Merck & Co., Ltd. Kiesselgel 601 Art, 77
34 (ieselgel 60.Art, 7734)
] was used.

Reference example 1゜(1) 4.5-bis(4-methoxyphenyl)-1-(
1-ethoxyethyl)-1H-imidazole was dissolved in 35 (M) dry tetrahydrofuran and heated to -50'C.
Cool to A solution of n-butyllithium in n-hexane (1,6
Drop N>150m over 20 minutes. 1 at the same temperature
After stirring for an hour, N,N-dimethylformamide 70d
and raise the temperature to 25°C. After stirring for 2 hours at 25-30° C., 20 d of acetic acid are added. The reaction solution was introduced into a mixed solution of 300 rnl of ethyl acetate and 200 ml of saturated saline, and the organic layer was separated. After washing the organic layer with saturated brine, the solvent was distilled off under reduced pressure. Recrystallization of the resulting residue from ethanol gives 4,5-bis(4-methoxyphenyl)-1-(1
-ethoxyethyl)-2-formyl-1H-imidazole 64.2 g (yield 85%) are obtained.

IR(KBr)cIn-1: 1680.1435,1
410.1295.1252゜1175, 1108.1
025 N) IR (CDCl2) δ value: 1.14 (3H, t, J = 7Hz), 1.49 (3H
, d, J=7Hz).

3°48 (2M, Q, J=7Hz), 3.73
(3H,s), 3.85 (3H,S).

6, 37 (IH, Q, J=7Hz).

8.72, 7.27 (4H, ABQ, J=9H2).

6, 92.7.35 (4H, ABQ, J=9Hz)
, 9.95 (IH,5)(2)4.5-bis(4-
methoxyphenyl)-1-(1-ethoxyethyl)-2
- 60 g of formyl-1H-imidazole in 2 ethanol
00d, add 200 parts of 1N hydrochloric acid, and stir at air temperature for 2 hours.
Stir for an hour. After the reaction is completed, the pH is adjusted to 7 with a saturated aqueous sodium hydrogen carbonate solution. Collect the precipitated crystals by filtration and add 1 part of water.
After sequential washing with 00ml and diethyl ether 5C7, recrystallization from ethanol gives a melting point of 187-189°.
4,5-bis(4-methoxyphenyl)-2- showing C
Formyl-1 day-imidazole 42.3g (yield 87%)
).

IR (KBr) cm-1; 3250.1658.143
5.1255.1205.118ONHR(CDCl2
) δ value: 3, 78 (6) f, s), 8.72-6.95 (4
)1. m).

7.25-7.50 (4N, m), 9.71 (IH, S
).

11.07 (1H, bs).

Similarly, the compounds shown in Table 6 are obtained.

Reference example 2 4,5-bis(4-methoxyphenyl)-1-methyl-
1 day - 5 g of imidazole in dry tetrahydrofuran 30
Dissolve in water and cool to -50'C. under nitrogen atmosphere,
While maintaining the temperature at -50 to -40'C, 13.6 ml of a n-hexane solution (1,6N) of n-butyllithium was added dropwise over 10 minutes. After stirring at the same temperature for 1 hour, N,
Add 5 parts of N-dimethylformamide and raise the temperature to 25°C. After stirring for 2 hours at 25-30'C, 2N salt 11
Add 0d and separate the organic layer. The organic layer is washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. When the solvent is distilled off under reduced pressure and the resulting solid is washed with diisoprolether, 4,5-bis(4-methoxyphenyl)-2-formyl-1-methyl-1 having a melting point of 132-134°C is obtained. -imidazole 59 (yield 91.
2%).

IR (KBr) cm-1; 16B5.1600.143
5.1225.1172.1025N) IR(CDCl
2) δ value; 3.72 (3H, s), 3.77 (3H, s13.84
(3H, s).

8, 63-7.48 (8) 1. m), 9.82
(IH,s) In the same manner, the following compound is obtained.

04.5-Bis(4-methoxyphenyl)-2-formyl-1-isopropyl-1 day-imidazole Melting point: 174-175°C (recrystallized from IPA) IR (K
I3r) cm-1: 1685.1440.1250.
118ONHR (CDCl2) δ value: 1, 46 (6H, d, J=8.4H2), 3.7
1 (38,S).

3.84 (3H, S), 4.07-4.90 (IH, m
).

6, 62-7.39 (8H, m), 9.32 (I
H,5)04.5-bis(4-methoxyphenyl)-2
- Acetyl-1-isopropyl - 1 day - Imidazole Melting point: 125-127°C (recrystallized from IPA) IR (K
Br) cm-': 1B75.1600.1510.
1440.1245°1170.103O NHR (CDCl2) δ value: 1.44 (6M, d, J=7Hz), 2.74 (3
H,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 (4M, ABQ, J=9H2)
04.5-bis(4-methoxyphenyl)-2-acetyl-1-cyclopropyl-1 day-imidazole melting point = 115-117°C (recrystallized from ACOEt-n-hexane) IR (KBr) cm-1: 1B70.1600.15
10.1425.1280°1245, 1170.1
025 NHR (CDCl2) δ value; 0.20-0.65 (2H, m), 0.65-1.15
(2H, m).

2.70 (3H, s), 3.05-3.50 (IH, m
), 3.69 (3H, s).

3,79 (3M, S), 6.78 (4N, t,
J=9NZ).

7,26 (4H,t, J=9H2) Reference Example 3 4.5-bis(4-methoxyphenyl)-2-formyl-1H-imidazole 30.89 methylene chloride 300
mf! 70 d of a methylene chloride solution containing 100 g of boron tribromide was added dropwise over 30 minutes while cooling with water. After stirring at 15-20°C for 2 hours, the reaction solution was mixed with 90 g of sodium hydroxide and 300 InI of ice water. and separate the aqueous layer. The aqueous layer was diluted with methylene chloride 150
After washing with water, adjust the pH to 5 with concentrated hydrochloric acid while cooling with water. The precipitated crystals are collected by filtration, washed with 100 d of water, and then dried. If the obtained solid is purified by column chromatography (elution solvent: toluene:ethyl acetate = 2:1), 4゜5-bis(
4-Hydroxyphenyl)-2-formyl-1 day-imidazole 17.4 g (yield 62%) Melting point 288-290°C (recrystallized from methanol) IR (
KBr) cm-1; 3320.1660.1610.1
445.1250.119ONHR(d6-DMSO)
δ value; 6, 77, 7.31 (8H, ABq, J=8Hz)
, 9.50 (1M, bs).

9,63(IH,s), 9.70(IH,bs),
13.57(1N, bs) and 4(5)-(4-
3.49 (yield: 10%) of ethanol adduct of methoxyphenyl)-5(4>-(4-hydroxyphenyl)-2-formyl-1-day-imidazole) is obtained.

Melting point: 155-157°C (recrystallized from ethanol) IR
(to 8r) cm-': 3500.1660.160
5.1450.1250°1215.117O NHR (66-D) ISO) δ value; 1, 10 (3H, t, J=7H2), 3.52
(2M, q, J=7Hz).

3, 79 (3H, s), 6.73-6.98 (4H,
m), 7.26-7.51 (4H, m), 9.7
0(IH,s), 9.80(IH,bs) Reference Example 4 (1) 4.5-bis(4-methoxyphenyl)-2-formyl-1-day-imidazole 30. Dissolve EEF in a mixture of 300 ml of tetrahydrofuran and 50 d of methanol, and add 1.899 ml of sodium borohydride under water cooling.
is added at 10-15°C. After stirring at the same temperature for 30 minutes, the solvent was distilled off under reduced pressure. Water and ethyl acetate are sequentially added to the resulting residue, and the precipitated crystals are collected by filtration, washed with diethyl ether, and then recrystallized from isopropyl alcohol to give 4°5-bis(4- methoxyphenyl)-2-hydroxymethyl-1
24.6 g (yield 79.4%) of day-imidazole are obtained.

IR(KBr)cm-';1602.1510.14
50.1285.1245.117ONHR(d6-D
H3O) δ value; 3,73 (6tl, S), 4.48 (2N, S)
, 6.06 (IH, br).

6, 84.7.34 (8H, ABq, J=9Hz) (
2) Add 12.4 m of thionyl chloride to 3.19 mL of 4.5-bis(4-methoxyphenyl)-2-hydroxymethyl-1H-imidazole, reflux for 20 minutes, and then concentrate the reaction solution under reduced pressure.

50 farts of diethyl ether are added to the resulting residue, and the precipitated crystals are 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; 3000-2600.1
620.1603.1520゜1290, 1240.1
187.1025(3) 3.65 g of 4.5-bis(4-methoxyphenyl)-2-chloromethyl-1H-imidazole hydrochloride was mixed with 70 d of toluene containing 3.9,1 triphenylphosphine and N,N- Add to the mixture of dimethylformamide 19d and reflux for 3 hours. After the reaction, add 30d of toluene and heat at 25-30'C for 30 minutes.
Stir roughly for 1 hour at 5-10°C. The precipitated crystals were collected by filtration, washed sequentially with toluene and diethyl ether,
[4,5-bis(4-methoxyphenyl)-1d-imidazole-2] has a melting point of 238-242°C when dried.
-yl]methylenetriphenylphosphonium chloride
5.58 g (yield 88.9%) of hydrochloride is obtained.

IR(KBr)cm-'; 1605.1525.1
490.1435.1295゜1255, 1180.1
110.1025.840°750,685 Reference Example 5 4.5-bis(4-methoxyphenyl)-2-chloromethyl-1-day-imidazole hydrochloride 3.66y was mixed with N,N
- dissolved in 35 d of dimethylformamide, and under water cooling, 4 d of an aqueous solution containing 1.4 i of sodium cyanide was added dropwise;
Stir at 20-25°C for 1 hour. The reaction solution was introduced into 200 g of water, and the precipitate was collected by filtration and washed with water. 4.5 with a melting point of 172-174°C when recrystallized from benzene
-Bis-(4-methoxyphenyl)-2-cyanomethyl-1 day-imidazole 1.289 (yield 40%) is obtained.

IR(KBr)cm-';2250.1607.15
07.1288.1245°1170.1031 03ON d6-Q)lsO+cDc+3)δ value; 3,
77 (6H, S), 3.84 (2H, S).

6, 79.7.38 (8N, ABq, J=9Hz)
Reference Example 6 (1) 8.07 ml of 4.5-bis(4-methoxyphenyl)-2-formyl-1 day-imidazole was added to 40 ml of toluene.
f! 14.1 of ethyl 2-triphenylphosphoranylidenepropionate is added, and the mixture is stirred at 25 to 30°C for 1 hour. The solvent is distilled off under reduced pressure, and the resulting residue is purified by column chromatography (elution solvent: toluene:ethyl acetate = 20:1) to obtain 2-[(E)
-2-ethoxycarbonyl-1-propenyl]-4,5
-Bis(4-methoxyphenyl)-1H-imidazole 8.0g (yield 79%) Melting point: 221-223°C (recrystallized from ethanol) IR
(KBr) cm-1; 3250.1688.1620.
1502.1242NHR (CDCl2) δ value; 1, 27 (3H, t, J=7H2), 2.51 (
3H, d, J=1.5H2).

3.82 (68, S), 4.17 (2H, Q, J=7
H2).

6.87, 7.47 (8ti, ABq, J=9H2).

7.52 (IH, d, J = 1.5l-12) and 2-
[(Z)-2-ethoxycarbonyl-cyphenyl)-
1 day - Obtain 200 Ing of imidazole (2% yield).

Melting point: 141-143°C (recrystallized from Et20) IR
(KBr)cm-1: 1685, 1605, 14
92. 1243NHR (CDCl2 > δ value; 1, 35 (3H, t, J=7Hz), 2.
14 (3N, d, J=1.5Hz).

3, 82 (6H, s), 4. 29 (2M,
Q. J=7Hz).

8, 87, 7. 47 (8H, ABQ, J=9
Hz).

6, 97 (IN, d, J=1.5Hz) is obtained.

(2)'2-[(E)-2-ethoxycarbonyl-1-propenyl]-4.5-bis(4-methoxyphenyl)-1 day - 3.0 g of imidazole was added to 30 g of ethanol
Add 30 d of 2N 7kl aqueous solution, and reflux for 40 minutes. After the reaction is completed, the mixture is cooled to room temperature and adjusted to I)H3 with 2N hydrochloric acid. If the precipitated crystals are filtered, washed with water, and recrystallized from ethanol, the melting point is 2.
2-[(E)-2-carboxyl-1-propenyl]-4.5-bis(4-methoxyphenyl)-IH-imidazole showing 56-258°C 1.99 (yield 68%)
get.

IR (KBr) cm-1: 3300, 1665
．． 1605, 1507, 1285.

1243, 117O NI4R (d6-DHSO) δ value; 2, 50 (3H, S), 3.77 (6H, S).

6, 8γ, 7. 42 (8H, ABq, J=8H
z), 7. 40 (1N, s) (3) 2- [ (
E)-2-carboxyl-1-propenyl]-4.5-
Bis(4-methoxyphenyl)-1H-imidazole 1
．． 53 was dissolved in 15 ml of methylene chloride, 3d of thionyl chloride, 0.1 d of N,N-dimethylformamide was added, and the mixture was stirred at 25-30'C for 1 hour. The reaction solution was heated to -3
Concentrated ammonia aqueous solution (25% purity) cooled to 0'C3
It takes 20 minutes to drip during 0d. After dropping, the temperature is raised to room temperature, and the precipitated crystals are collected by filtration. When recrystallized from a mixed solvent of ethyl acetate-diisopropyl ether, 2-[(E)-2-carbamoyl-4,5-bis(4-methoxyphenyl)-1 day- exhibits a melting point of 211-213°C. 1.2 g of imidazole (yield 80%) is obtained.

IR (KBr)cm-1:3220, 1662,
1502, 1370, 1242. 1175N)
IR (d6-D)130) δ value; 2, 56 (3H,
S), 3. 77 (61-1, S).

6, 90, 743 (8H, ABq, J=9Hz
), 7. 21 (2H, bs).

7, 36 (1N, s) Example 1 3.08 g of 4,5-bis(4-methoxyphenyl)-2-formyl-1-day-imidazole was suspended in 50% of benzene, and triphenylphosphoranylideneacetonitrile 6. , OOy and stir at 25-30°C for 2 hours.

The solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography (elution solvent: benzene: ethyl acetate = 20
21), 2-[(E)-2-cyanovinyl]-4,5-bis(4-methoxyphenyl)-
18-imidazole 1.36g (yield 41%) Melting point: 2
05-208℃ (recrystallized from toluene) IR (KB
r) cm-1; 3275, 2210, 1605,
1460, 1255. 1185N)IR(d6-
DHSO+C[)C10) δ value: 3, 77 (6H, S)
, 6.17 (18, d, J = 17 Hz).

6, 79, 7.36 (8H, ABq, J=9Hz).

7, 14 (1) 1, d, J = 17 Hz) and 2- [
(Z)-2-cyanovinyl]-4,5-bis(4-methoxyphenyl)-18-imidazole 1.16 g (yield 35%) is obtained.

Melting point: 209-211°C (recrystallized from ethanol) I
R (KBr) cm-1: 3205, 2205,
1600, 1460, 1290.

1250, 1170 NMR (CDCl2-d6-D)IsO) δ1 direct;
3.75 (6H, s), 5.37 (18, d, J=12
Hz).

6, 79 (4H, ABq, J=9tlz), 7.
t4 (IH, d, J=12Hz).

7, 10-7.60 (4H, m), 12.44 (1
8, bs) Similarly, the compounds shown in Table 8 are obtained under the reaction conditions shown in Table 7.

(Left below) Example 2 Sodium hydride (purity 60% > 580 mg) and dimethyl sulfoxide (7.3 d) were mixed, and 7.3 d of dimethyl sulfoxide was mixed under a nitrogen atmosphere.
After stirring for 45 minutes at 0-so'c, cool. Under water cooling, 5.42 g of triphenylethylphosphonium bromide
15 ml of a dimethyl sulfoxide solution containing the above was added dropwise over a period of 5 minutes. After stirring for 10 minutes at 15-20'C,
10 d of a dimethyl sulfoxide solution containing 1.5 g of 4,5-bis(4-methoxyphenyl)-2-formyl-1 day-imidazole is added and stirred for 30 minutes at 20-25°C. The reaction solution was introduced into a mixture of ethyl acetate and water, and the organic layer was separated. The organic layer is washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The resulting residue was subjected to column chromatography (elution solvent; toluene:ethyl acetate = 10:1
), 2-[(E)-1-probenyl-4,5-bis(4-methoxyphenyl)-1H-imidazole 190/ffg (yield 12.2%) Melting point: 118-120°C ( Recrystallized from IPA) IR (
KBr) cm-1: 1505.1290, 1245.
1175.1030°NMR (CDCl2>δ value: 2, 18 (3H, d, J=7Hz), 3.77 (
6H,s).

5, 72-6.29 (2H, m), 6.69-7.44
(9H,m) and 2-[(Z)-1-propenyl]
370 mg (yield 23.7%) of -4°5-bis(4-methoxyphenyl)-1 day-imidazole is obtained.

Melting point: 185-187°C (recrystallized from IPA) IR (K
Br) cm-1: t505.1285.1245.1
175.103ON) IR (CDCl2>δ value; 1, 76 (3H, d, J=4.5Hz), 3.7
6 (6N, s).

6.15-6.32 (2H, m), 6.67-7.41
(9H, m) In the same manner, the compounds shown in Table 10 were obtained under the reaction conditions shown in Table 9.

(Left below) Example 3 3.939 cJ of triphenylphosphine and 1.68 cJ of tert-butyl-xypotassium were mixed with 4 cJ of dry n-heptane (
Suspended in M and cooled to O''C. At 0-5 °C a solution of 1.2 m chloroform and 10 m n-hebutane was diluted with 30 m
It takes a few minutes to drip. After stirring for 30 minutes at 20-25°C, N,N- containing 3.08 g of 4,5-bis(4-methoxyphenyl)-2-formyl-1-imidazole
10 parts of dimethylformamide solution was added dropwise over 10 minutes, and the mixture was stirred at the same temperature for 30 minutes. The reaction solution is introduced into a mixed solution of water and benzene, and the organic layer is separated. After washing the organic layer with saturated brine, the solvent was distilled off under reduced pressure. If the obtained residue is purified by column chromatography (elution solvent: toluene: ethyl acetate = 30: 1),
2-(2,2-dichlorovinyl)-4,5-bis(4-
methoxyphenyl) - 1 day - imidazole 1.63 g (
Yield: 43.5%).

Melting point: 128-129°C (IPE-recrystallized from n-hexane) IR (KBr) cm-1: 1610.1510.14
75.1290.1250°1175.103O 8MR103ON , l ) δ value; 3.77 (6M
, s), 6.80 (1H, s).

6.81, 7.35 (8H, ABQ, J=9NZ) Example 4 (1) 2-acetyl-4,5-bis(4-methoxyphenyl)-1-(1-ethoxyethyl)71-day-imidazole 500 mg and dibromodifluoromethane 400
Dissolve 5 mg in methylene chloride and add 5 mg under nitrogen atmosphere.
Cool to °C. After adding hexamethylphosphorustriamide 6201Q dropwise over 5 minutes at 5-10°C,
Stir at 20-25°C for 1 hour. After sequentially washing the reaction solution with water and saturated saline, drying with anhydrous magnesium acid,
The solvent is distilled off under reduced pressure. The resulting residue was subjected to column chromatography (elution solvent; toluene:ethyl acetate = 5
0:1), 2-(2,2-difluoro-1-methylvinyl)-1-ethoxyethyl-4,5
-Bis(4-methoxyphenyl)-1 day - 400 mg (yield 74%) of imidazole are obtained.

IR) cm-1; 1742.1610.15
15.1250.113ONMR (CCl2) δ value: 1.0g (3N, t, J=7Hz), 1.40 (3
)1. d, J=711z).

1,98 (3N, t, J=3Hz), 3.18(
2H, q, J=7Hz).

3,64 (3H, S), 3.79 (3N, S)
, 5.10 (IH, Q, J=7H2).

6.55, 7.18 (4H, ABQ, J=9H2).

6.82, 7.22 (4H, ABQ, J=9H2) (2
)2- (2,2-difluoro-1-methylvinyl)-
1-Ethoxyethyl-4,5-bis(4-methoxyphenyl)-1 day - 400 mg of imidazole was dissolved in methanol 4
Dissolve in a mixture of 2N hydrochloric acid and 2N hydrochloric acid,
Stir at 5°C for 2 hours. If the precipitated crystals are collected by filtration and washed with a mixture of methanol and water, the melting point is 213-21.
2-(2,2-difluoro-1-methylvinyl)-4,5-bis(4-methoxyphenyl)- showing 6 (decomposition)
1 day - Imidazole hydrochloride 230my (yield 62%)
get.

IR (KBr) cm-1: 1730.1625.16
00.1515.1490°1245, 1128.10
3O N)IR(d6-0)1sO)δ value: 2.30(3N,t,J=3t(z),3.80(68
,s).

6, 98 (41-1, A8 (1, J=9H1).

7,45 (4H, ABq, J=911z) Example 5 2-[(E)-2-formylvinyl]-4,5-bis(4-methoxyphenyl)-1d-imidazole 600
my was suspended in 10 mA of toluene, 1.19 g of triphenylphosphoranylidene acetonitrile was added, and the mixture was stirred at air temperature for 2.
Stir for an hour. If the reaction solution is purified by column chromatography (elution solvent; toluene:ethyl acetate = 1Q:1), 2-[(2E,4E)-4-cyanobutadienyl]
-4,5-bis(4-methoxyphenyl)-1H-imidazole (300 ml, yield 46.9%) is obtained.

Melting point: 130-133°C (recrystallized from IPE) IR (K
B(')cm-1: 2200.1605.1455.
1248 R (CI) CI3>δ value; 3, 73 (6H, S), 5.05 (IH, d, J
=14H2).

6.00-7.50 (11M, m) and 2-[(2E,4Z)-4-cyanobutadienyl]-4,5-bis(4-methoxyphenyl)-1d-imidazole'loomy (yield 15.6%).

Melting point: 245-246°C (recrystallized from AcOEt) IR
(KBr)cm-'”, 3250,2210.16
05.1460.1250 P, Cd6-0830 >
δ value: 3,76 (6N, s), 5.58 (IH, d, J
= 10Hz).

6.65-7.60 (11H, m) Example 6 2-[(E)-2-formylvinyl]-4,5-bis(
4-methoxyphenyl)-1 day-imidazole 5001
Suspend 11 g in ethanol 10- and heat at 10-15"C
Then, 20 yt of sodium borohydride was added over a period of 5 minutes. After stirring at the same temperature for 10 minutes, chloroform and water were sequentially added to the reaction solution, and the organic layer was separated. The organic layer is washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. When the resulting residue is recrystallized from ethyl acetate, it has a melting point of 169-171
2-[(E)-3-hydroxy-1nipropenyl]-4,5-bis(4-methoxyphenyl)-1 showing °C
400 mg (yield 80%) of day-imidazole are obtained.

IR(Br)cm-1: 1602.1500.12
45.1182.102ON)IR(d6-DMSO)
δ value; 3, 76 (6) 1. s), 4.02-4.28(
2N, m).

6.40-6.70 (2) 1. m), 6.88.7.3
8(8H, ABQ, J=9H2) Example 7 4.5-bis(4-methoxyphenyl)-2-[(E)
-2-methylthiovinyl]-1 day-imidazole'1.
009 was dissolved in 20 d of methylene chloride, and 1.35 g of 3-chloroperbenzoic acid was dissolved in 10 d of methylene chloride at 0 to 10°C.
A solution dissolved in the solution was added dropwise over a period of 10 minutes. 20～
After stirring at 25°C for 2 hours, precipitated crystals were collected by filtration.

The obtained crystals are dissolved in ethyl acetate, washed successively with a 10% aqueous potassium carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. When the resulting solid was recrystallized from ethyl acetate, it showed a melting point of 199-201°C. 1-4.5-bis(4-methoxyphenyl)-2-[(E)-2-methylsulfonylvinyl]-1 - 450 mg of imidazole (yield 41.3
%).

IR (KBr) cm-1; 3230.1605.15
05.1455.1280°1250, 1170.11
2O NHR (d6-DH30) δ value: 2,78 (3H,s), 3.10 (6H,s).

6.55, 7.45 (8H, ABQ, J=9H2), 7
゜37(2H,s) Example 8 4.5-bis(4-methoxyphenyl)-2-[(E)
-2-methylthiovinyl]-1 day-imidazole 1. O
Oy was dissolved in 10 m of methylene chloride, and a solution prepared by dissolving 1,640 m of 3-chlorobenzene in 5 m of methylene chloride at 0 to 10'C was added dropwise over 10 minutes. 30 at the same temperature
After stirring for a minute, add 2 ml of 10% potassium carbonate aqueous solution to the reaction solution.
Add 0m and separate the organic layer. After washing the organic layer with water,
Dry over anhydrous magnesium sulfate and remove the solvent under reduced pressure. If the obtained residue is purified by column chromatography (elution solvent: benzene:toluene-1:1), 4
,5-bis(4-methoxyphenyl)-2-[(E)-
1 q of 600 my (yield 57.1%) of 2-methylsulfinylvinyl]-IH-imidazole is obtained.

Melting point: 225-227°C (recrystallized from acetone) IR (
Br) cm-1; 1605.1505.1465.
1290, 1250° 1170, 1035 N) IR (66-D) ISO>δ value: 2, 71 (3H, s), 3.75 (6H, s)
.

6.85, 7.35 (8N, ABQ, J=9H2).

6, 90 (IH, d, J=15Hz), 7.47
(1 M, d, J = 15 Hz) Example 9 4.5-bis(4-methoxyphenyl)-2-formyl-1 day - 500 mrJ of imidazole and 110 my of malondinitrile were suspended in 5 d of ethanol and heated at 0 to 5°C.
Add 0.11 m of piperidine and stir at the same temperature for 30 minutes. The reaction solution was introduced into a mixture of ethyl acetate and water, and the organic layer was separated.

The organic layer was washed with 1N hydrochloric acid '15d, dried over anhydrous magnesium chloride, and the solvent was distilled off under reduced pressure. If the resulting residue is recrystallized from ethanol, it has a melting point of 221-222.
2-(2,2-dicyanovinyl)-4,5- showing °C
Bis(4-methoxyphenyl)-1H-imidazole 2
60 my (yield 44.8%) is obtained.

IR (KBr) cm-1; 3200, 2210.16
00.1580.1450°1435, 1295.12
50.1205.1175NHR(d, -0830)
δ value: 3.78 (6H, S), 6.93, 7.42 (8H, A
Bq, J=9H2).

7,64(IH,S) Example 10 6.28 g of [4,5-bis(4-methoxyphenyl)-1-imidazol-2-yl]methylenetriphenylphosphonium chloride hydrochloride was added to 126 g of dry tetrahydrofuran. Suspend and cool to -30'C. n-butyllithium while maintaining the same temperature under a nitrogen atmosphere.
Add hexane solution (1,6N>20d) dropwise over 10 minutes.

After stirring at -30 to -25°C for 15 minutes, add 2.09% of cyclohexanone and stir at the same temperature for 30 minutes, roughly stirring for 20 to 20 minutes.
Stir for 30 minutes at 25°C. The reaction solution was introduced into a mixture of ethyl acetate and water, and the organic layer was separated. After washing the organic layer with saturated brine, drying with anhydrous magnesium sulfate,
The solvent is distilled off under reduced pressure. The resulting residue was subjected to column chromatography (elution solvent: toluene:ethyl acetate = 1
0:1) and recrystallized from diisopropyl ether-〇-hexane to give 1.24y of 2-cyclohexylidenemethyl-4,5-bis(4-methoxyphenyl)-1H-imidazole (yield: 33 .1%). In addition,
The physical properties (melting point, IRlNHR) of this compound were consistent with those obtained in Example 2 (described in Table 10).

Similarly, the compounds shown in Table 11 are obtained.

(Leaving space below) Example 11 3.19 y of 4,5-bis(4-methoxyphenyl)-2-cyanmethyl-1 day-imidazole, 10.69 y of benzaldehyde, 20 m of acetic acid and 200 y of toluene were mixed, and further 1 d of piperidine. and reflux for 1 hour. After cooling, 200 d of water is added to the reaction solution, and the organic layer is separated. The organic layer was washed with 100 d of water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue is purified by column chromatography (elution solvent: toluene:ethyl acetate = 20:1) to obtain 2-[(E
) -1-cyano-2-phenylvinyl-4.5-bis(4-methoxyphenyl)-1H-imidazole2.
32 g (57% yield) are obtained.

Melting point: 210-211°C (recrystallized from toluene) IR
(KBr)cm-'; 3230,2220.160
2.1502.1465°1282, 1242.117
0.1022N) IR (CDCl2) δ value: 3, 77 (6H, s), 6.81 (4H, ABQ,
J=81-IZ), 7.15-7.60 (7H,
ml 7.70-7.95 (2H, m), 8.15 (
IH,s) Compounds shown in Table 12 are obtained in the same manner.

Example 12 Anisyl 1. ○09, crotonaldehyde 0.3r, f
fi, 2.58y of ammonium acetate and 7d of acetic acid are mixed and refluxed for 2 hours. After cooling, the solvent is distilled off under reduced pressure, 50 d of ethyl acetate and 50 ml of water are added to the resulting residue, the mixture is adjusted to p]17 with a saturated aqueous sodium carbonate 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 distilled off under reduced pressure. The resulting residue was subjected to column chromatography (elution solvent; toluene:ethyl acetate = 10
:1), 330 mg (yield 27.7%) of 2-[(E)-1-propenyl]-4,5-bis(4-methoxyphenyl)-1-day-imidazole is obtained. The physical properties (melting point, IR, N) of this compound were consistent with those obtained in Example 2.

Example 13 Under ice cooling, diethyl-cyanomethylphosphonate 1.95
485 mg of sodium hydride (purity 60%) was added to 60% solution of anhydrous tetrahydrofuran in No. 9, and the mixture was heated at the same temperature.
Stir for 0 minutes. Furthermore, at the same temperature, 4.5-bis(4-methoxyphenyl)-2-formyl-1 day-imidazole 3
．． Add 0.8 g of anhydrous tetrahydrofuran in 20 ml and stir at 20-25°C for 1 hour. The solvent was distilled off under reduced pressure, ethyl acetate and water were added to the residue, and the organic layer was separated. After washing with saturated saline, drying with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (elution solvent: benzene: ethyl acetate = 2
0:1), 2-[(E)-2-cyanovinyl-4,5-bis(4-methoxyphenyl)
-1 day - 1.59 g (yield 48%) of imidazole and 2-[(Z)-2-cyanovinyl]-4,5-bis(
4-methoxyphenyl)-1t-1-imidazole1.
06y (yield 32%) is obtained. Physical properties of these compounds (
The melting point, 'IR, NHR) was consistent with that obtained in Example 1.

Example 14 2-[(E)-2-cyano-1-methylvinyl]-4
,5-bis(4-methoxyphenyl)-1d-imidazole 3.45y was dissolved in N,N-dimethylformamide 5(M
dissolve in While cooling with water, 440 m of sodium hydride was added, and the mixture was stirred at the same temperature for 1 hour. Methyl iodide 1.569
After stirring at 20-25°C for 1 hour, ethyl acetate and water are added, and the organic layer is separated. After washing with saturated brine, drying over anhydrous magnesium sulfate, and evaporating the solvent under reduced pressure. Recrystallization of the resulting residue from isopropyl alcohol gives 2-[(
E) -2-cyano-1-methylvinyl]-4,5-bis(4-methoxyphenyl)-1-methyl-1-day-imidazole 2.669 <yield 74.1%) is obtained.

IR (KBr) cm-'; 2200.7600.
1490.1290.1250゜1175.103O N) IR (CDCl2>δ value; 2.63 (3N, S
), 3.48 (3N, S).

3.74 (3H, s), 3.85 (3N, s), 5.6
2 (1M, s).

6, 70.7.22 (4H, ABQ, J=9H2)
.

6, 92.7.36 (4H, ABq, J=9tiz)
Similarly, the compounds shown in Table 13 are obtained.

Example 15 4,5-bis(4-methoxyphenyl)-1-(1-ethoxyethyl)-1 day-imidazole 3.529 d is dissolved in 100 d of dry tetrahydrofuran and cooled to -50<0>C. Under a nitrogen atmosphere, while maintaining a temperature of =50 to -40'C, a solution of n-butyllithium in n-hexane (1,6N
Drop >6.9m over 20 minutes. After stirring at the same temperature for 1 hour, 1.03 cyclohexanone was added and 30
Stir for a minute. After raising the temperature of the reaction solution to 20'C, the solvent was 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 residue was dissolved in 20r111 of dioxane, 4 ml of concentrated hydrochloric acid was added, and the mixture was 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, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. If the obtained residue is purified by column chromatography (elution solvent: toluene:ethyl acetate = 10 = 1), 4,5-bis(4-methoxyphenyl)-2-(1-cyclohexenyl)-1 day −
Imidazole 2.12y (yield 58.8%) is obtained.

Melting point: 232-234°C (recrystallized from toluene) IR
'(KBr) cm''; 1605.1505.12
50.1170.103ONHR (CDCl2>δ value:
1.42-1.85 (41-1, m).

1.95-2.65 (4N, m), 3.74 (8H, s
), 6.50 (ltl, s).

6, 75.7.35 (8N, ABQ, J=9H2
) Compounds shown in Table 14 are obtained in the same manner.

(Left below) Example 16 (1) 4.5-bis(4-methoxyphenyl)-1-(
1-ethoxyethyl)-1 day-imidazole 3.529
was dissolved in dry tetrahydrofuran 10 (M, -50
Cool to 'C. A solution of n-butyllithium in n-hexane (1
, 6N>6.9d over a period of 20 minutes. After stirring at the same temperature for 1 hour, a tetrahydrofuran solution containing 1.82y of 3-pyrrolidinyl-2-cyclohexenone
Add m1 and stir for 30 minutes. After heating the reaction solution to 20° C., the solvent is distilled off under reduced pressure. Water and ethyl acetate are added to the resulting residue, and the organic layer is separated. After washing with saturated brine, the solvent is distilled off under reduced pressure. The resulting residue was dissolved in 30 d of tetrahydrofuran, and 20 d of 2N hydrochloric acid was added.
d and stirred at 40-50°C for 2 hours. After distilling off the solvent under reduced pressure, ethyl acetate was added, and the concentration was adjusted to 1) 87 with sodium hydrogen carbonate. The Yuho layer is separated, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The resulting residue was purified by column chromatography (elution solvent: toluene:ethyl acetate = 3:1) to obtain 4.5-bis(
1.57 g (42% yield) of 4-methoxyphenyl)-2-(3-oxo-1-cyclohexenyl)-1H-imidazole is obtained.

Melting point: 230-233°C (recrystallized from toluene-IPE) IR (KBr) cm”: 3280, 3225
．． 1635.1593.1457゜1250, 1182
．． 1175.103ONHR (CDCI3>δ value: 1
．． 9-2.6 (4H, m).

3.03 (2H, t, J=5Hz), 3.82 (6H,
s), 6.70 (1H, s).

6, 86.7.41 (4H, ABQ, J=9H2)
.

6, 86.7.48 (4H, ABQ, J=9Hz)
, 1o, 54(IH, bs) (2>4.5-bis(
4-Methoxyphenyl)-2-(3-oxo-1-cyclohexenyl)-1 day - Dissolve 3.749 of imidazole in 20 (M!) of dry tetrahydrofuran and add 50 d of methanol. Boron hydride at 25-30 °C Add 760 my of sodium and stir for 1 hour. The solvent is distilled off under reduced pressure, ethyl acetate and water are added to the resulting residue, and the pH is adjusted to 7 with 2N hydrochloric acid. The organic layer is separated and saturated brine is added. After washing with water, drying with anhydrous magnesium sulfate, and distilling off the solvent under reduced pressure. Recrystallization of the resulting residue from ethyl acetate gives 4,5-
Bis(4-methoxyphenyl)-2-(3-hydroxy-1-cyclohexenyl)-1H-imidazole 2.6
1 g (69.4% yield) is obtained.

IR (in Br) cm-1; 1610.1510.1
285.1245.1175°03O NHR (CDCI 3 ) δ (direct; 1.3-2.
1 (4H, m).

2, 2-2.7 (2H, m), 3.77 (6H, s
), 4.30 (tH, m).

4.9-5.8 (IH, m), 6.3t (IH, s).

6, 78.7.35 (8H, A[3q, J=91-
1z) Example 17 (1) 4.5-bis(4-methoxyphenyl)-2-(
4,5-bis(3-oxo-1-cyclohexenyl)-1 day-imidazole was used in the same manner as in Example 14.
4-Methoxyphenyl)-2-(3-oxo-1-cyclohexenyl)-1-methyl-1H-imidazole is obtained.

Melting point: 165-167 °C (recrystallized from IPE) IR (
KBr) cm-1: 1640.1605.1587
．． 1287.1243°1180,1027 (2>4.5-bis(4-methoxyphenyl)-2-(
3-oxo-1-cyclohexenyl)-1-methyl-1
4,5-bis(4-methoxyphenyl)-2-(
3-Hydroxy-1-cyclohexenyl)-1-methyl-1H-imidazole is obtained.

Melting point: 182-184°C (recrystallized from toluene) IR
(Br) cm”: 161'0.1515,15
00,1283.1245°1175.103O NMR (103ON>δ value; 1.42-2.2 (4H
, m).

2, 58 (2H, m), 3.39 (3H, s), 3
．． 72 (3H, s).

3.82 (3H, S), 4.39 (IH, m), 6.0
5 (IH, m).

6, 69.7.23 (4H, ABQ, J=9H2)
.

6, 93.7.38 (4N, ABq, J=9Hz)
.

Example 18 -2-[(E) -2-carleno5moyl-1-1daybenyl1-4.5-bis(4-methoxyphenyl)-1H
- Dissolve 1.19 of imidazole in 5d of thionyl chloride and stir at 25-30''C for 24 hours.

The reaction solution was added dropwise to a mixture of 50 ml of ethyl acetate, 50 ml of water, and 2 ml of sodium bicarbonate (EJ).

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. If the obtained residue is purified by column chromatography (elution solvent: toluene: ethyl acetate = 10:1),
2-[(E)-2-cyano-1-propenyl]-4,5
-Bis(4-methoxyphenyl)-1 day - 250 my of imidazole (yield 24%) is obtained.

Melting point: 211-212°C (recrystallized from AcOEt-IPE) IR (KBr) cm”: 3285, 2195.
1605.1455.1248.1172NHR(ds
-DH3O-CDCl2 > δ value: 2.55 (3H,
s), 3.79 (6H, s), 6.80.7.38
(81-1° ABq, J=9Hz), 6.88 (IH,
s) Example 19 (1) Diethyl-(1-cyanoethyl)phosphonate 2
．． 109 was dissolved in 20 parts of N,N-dimethylformamide and cooled. Aqueous sodium (purity 60%) 460
Add my and stir under water cooling until the generation of water-based gas stops. 1-(1-ethoxyethyl)-2-formyl-4,
Add 3.809 g of 5-bis(4-methoxyphenyl)-'IH-imitasol and stir at -5 to O'G for 2 hours.

After introducing the reaction solution into a mixture of water and ethyl acetate,
Separate the organic layer. After washing with saturated brine and drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The resulting residue was subjected to column chromatography (elution solvent;
If purified with toluene:ethyl acetate=20:1), 2-[(E)-2-cyano-1-propenyl]-1-
(1-ethoxyethyl)-4,5-bis(4-methoxyphenyl)-IH-imidazole 1.759 (yield 42
%).゛Melting point: 108-110°C (recrystallized from IPE) IR (
KBr) cm” :2205.1605.1515.
1457.1303゜1281.1245,1175,
1121,1105.1027NHR(CDCl2)δ
Value: 1, 12 (3H, t, J=7Hz), 1.58
(3H, d, J=6Hz).

2, 60 (3H, d, J=IH2), 3.31 (
2H,m), 3.72 (3H,S).

3,85 (3H,S), 5.11 (IH,Q,
J=6H2).

' 6.69.7.18 (4H, ABq, J=9Hz
).

6, 95.7.39 (4H, ABq, J=9Hz)
, 7.47 (IH, d, J=IHz) and 2-
[(Z)-2-cyano-1-propenyl]-1-(1-
2.09 (yield: 48%) of ethoxyethyl)-4,5-bis(4-methoxyphenyl)-1-day-imidazole is obtained.

Melting point: 179-181°C (recrystallized from ACOEt-IPE) IR (Br) cm-1: 2200,1605
．． 1513.14B3.1440°1300, 1242
．． 1175.1110.1025N)IR(CDCl2
>δ value: 1, 10 (3H, t, J=7Hz), 1.54 (
3N, d, J=7Hz).

2.19 (3H, d, J=IH2), 3.35 (2H,
m), 3.69 (3H,S).

3,83(3H,s), 5.06(IH,q,J
=7Hz).

6.67.7.17 (4N, 8Bq, J=9Hz)
.

6, 93.7.46 (4N, ABQ, J=9tlZ
), 7.23 (1H, d, J=IH2) (2>2-
[(E)-2-cyano-1-propenyl]-1-(1
-ethoxyethyl)-4,5-bis(4-methoxyphenyl)-1H-imidazole, 2-[(E)-2-cyano-1-propenyl]- 4゜5-bis(4-methoxyphenyl)-1H-
Obtain imidazole. The melting point, IR, and NHR of this product were consistent with those obtained in Example 18.

Example 20 Diethyl-(1-methylthioethyl)phosphonate2.
Dissolve 54 g in 100 g of anhydrous tetrahydrofuran,
Cool to -60°C. At the same temperature, n-butyllithium n
-Drop a hexane solution (1,6N>7.2%)-
After stirring for 4 hours at 60 to -50'C, an anhydrous tetrahydrofuran solution containing 3.8 g of 1-(1-ethoxyethyl)-2-formyl-4,5-bis(4-methoxyphenyl)-1H-imidazole 5077112 is added dropwise over a period of 10 minutes.

After stirring for 30 minutes at -60 to -50°C, 20 to 25°
C. and refluxed for an additional 2 hours. The solvent is distilled off under reduced pressure, water and ethyl acetate are added, and the M-containing layer is separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to column chromatography (elution solvent; toluene:ethyl acetate = 20:1) to obtain 1-(1-
ethoxyethyl)-2-[(E)-2-methylthio-1
-propenyl]-4,5-bis(4-methoxyphenyl)-1 day-imidazole 1.15 g (yield 25.5%)
get.

Melting point = 103-105°C (IPE-recrystallized from n-hexane) IR (KBr) cm”: 1605.1510.1
495.1295.1247゜1172, 1125.1
103.103ONHR (CDCl2>δ value; 1.11 (3H, t, J=7Hz), 1.55 (3N,
d, J=7Hz).

2, 34 (3H, s), 2.59 (3H, s), 3
．． 38 (2H, Q, J=7Hz).

3,71 (3N, s), 3.84 (3H, s),
5.08 (IH, Q, J=7Hz).

6, 60 (IH, s), 6.67, 7.18 (4N
, ABQ, J=9H2).

6, 91 (2H, d, J=9Hz), 7.34
(2H, dd, J = 7Hz, J = 9Hz) and 1-(1-ethoxyethyl)-2-[(Z)-2-methylthio-1-propenyl]-4°5-bis(4nimethoxyphenyl ) - 1 day - 2.72 g of imidazole (yield 6
0.3%).

Melting point: 145-147°C (recrystallized from Ac0Et-IPE) IR (KBr) cm-1: t602.158
2.1510.1495.1290°1280, 124
7.1122.1100.1033NHR(CDCl2
>δ value; t 10 (3H, t, J=7Hz), 1.55
(3H, d, J=7Hz).

2, 32 (3H, s), 2.38 (3H, s),
3.38 (2N, Q, J=7Hz).

3, 71 (3H, S), 3.83 (3H, S), 5
．． 55 (IH, q, J=7H2).

6, 67 (IH, S), 6.67, 7.16 (4H, A
BQ, J=9H2).

6, 89 (2H, d, J=9Hz), 7.37 (
2N, t, J = 9Hz) (2>1-(1-ethoxyethyl)-2-[(E)-2-methylthio-1-propenyl]-4,5-bis(4-methoxyphenyl)-1H
-imidazole and 2-[(E)-2-methylthio-1-propenyl]-4 in the same manner as in Example 4(2).
, 5-bis(4-methoxyphenyl)-IH-imidazole is obtained.

Melting point: 190-192°C (recrystallized from IPA-IPE) IR (Br) cm': 1610.1520.1
505.1290.1247.1175N) IR (CD
C1,) δ value: 2, 34 (3) 1. s), 2.50 (3H, s)
, 3.82 (6H,s).

5.94 (IH, s), 6.85.7.45 (8H,
Similarly to AB(1, J=9H2), 2-[(Z)-
2-methylthio-1-propenyl]-4,5-bis(4
-methoxyphenyl)-1H-imidazole is obtained.

Melting point: 134-136 °C (recrystallized from ethanol-IPE) 3340.1635.16 in IR (KBr) cm -
08.1520.1298°1250, 1180.10
25 Nl (R (CDCl2>δ value: 2.28 (3H, d, J = 1) 1z), 2.45 (3N
, s), 3.82 (6N, s).

6, 84 (IH, d, J=tHz), 6.89.
7.46 (8H, AB (1, J = 9) 1z) 8, 45
(II-1, bs)

Claims (1)

[Claims] (1) Formula ▲ Numerical formula, chemical formula, table, etc. ▼ “In the formula, R^1 and R^2 are phenyl or heterocyclic groups that may be the same or different substituted; R^3
represents a hydrogen atom, an optionally substituted alkyl or cycloalkyl group; R^4 represents a hydrogen atom, a cyano group, an optionally substituted alkyl, cycloalkyl, aryl or heterocyclic group; R^5 and R^6 is the same or different and is a hydrogen atom, a halogen atom, a cyano group, a nitro group,
Indicates an optionally substituted acyl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, alkyl, cycloalkyl, alkenyl, aryl or heterocyclic group, R^4 and R ^6 may be combined with adjacent carbon atoms to form a 5- to 7-membered cycloalkenyl ring that may have a substituent, and R^5 and R^6 are 3 which may have a substituent together with the carbon atom
A ~8-membered cycloalkyl ring may be formed. however,
When R^1 and R^2 are phenyl groups, at least one is a substituted phenyl group. Also,
When R^4 is a hydrogen atom, aryl and heterocyclic groups in which R^5 and R^6 may be substituted the same or differently are excluded. ” A novel imidazole derivative and its salt.