CN1784386A

CN1784386A - 1,2-diarylimidazoles useful as inhibitors of COX

Info

Publication number: CN1784386A
Application number: CN 200480012372
Authority: CN
Inventors: 高桥史江; 寺坂忠嗣; 森田真正; 小西信清; 中村克哉
Original assignee: Yamanouchi Pharmaceutical Co Ltd
Current assignee: Astellas Pharma Inc; Yamanouchi Pharmaceutical Co Ltd
Priority date: 2003-05-08
Filing date: 2004-04-26
Publication date: 2006-06-07
Also published as: AU2003902208A0

Abstract

A compound of the formula (I) : wherein R<1> is cyano, and the like; R<2> is hydroxy, and the like; R<3> is (lower)alkoxy, and the like; X and Y are each CH or N; or pharmaceutically acceptable salts thereof, which are useful as a medicament.

Description

As 1 of COX inhibitor, 2-diaryl imidazole

Technical field

The present invention relates to have the imidazolium compounds and the drug acceptable salt thereof of pharmacological activity.

In addition, the present invention also relates to comprise above-mentioned imidazolium compounds and drug acceptable salt thereof medicine or pharmaceutical composition as activeconstituents.

Background technology

Known some imdazole derivatives has anti-inflammatory and/or analgesic activity, for example, and WO96/03388.But, all compounds disclosed herein are all replaced by alkylsulfonyl on imidazole ring.And disclosed compound selective suppresses cyclo-oxygenase-II (COX-II) and not at cyclo-oxygenase-I (COX-I) among the WO96/03388.

Disclosure of the Invention

As the result of study to the synthetic and pharmacologically active of imidazolium compounds, the present inventor finds that imidazolium compounds of the present invention has outstanding COX to suppress active (particularly COX-I suppresses active).Therefore, the present invention relates to have pharmaceutical activity such as COX and suppress active imidazolium compounds, and the medicine and the pharmaceutical composition that contain imidazolium compounds.

Therefore, an object of the present invention is to provide and have COX and suppress active imidazolium compounds.

Another object of the present invention provides the method that treats and/or prevents the COX relative disease and is used for the imidazolium compounds that this treats and/or prevents.

Another purpose of the present invention provides the purposes of this imidazolium compounds in production for treating or prophylactic medicine, and the pain killer that contains the imidazolium compounds that can be used for treating and/or preventing pain is provided.

Another purpose of the present invention provides the commodity package that comprises pharmaceutical composition, and this pharmaceutical composition contains new compound.

Imidazolium compounds of the present invention and drug acceptable salt thereof can be represented with following general formula (I) or its drug acceptable salt:

Wherein

R ¹For (rudimentary) alkyl, cycloalkyl, carbamyl, N-[(that (rudimentary) alkyl, halo (rudimentary) alkyl, hydroxyl replace rudimentary) alkyl] carbamyl, N, N-two [(rudimentary) alkyl] carbamyl, formyl radical, (rudimentary) alkyloyl, carboxyl, [(rudimentary) alkoxyl group] carbonyl, cyano group, naphthene base carbonyl or heterocycle carbonyl;

R ²Be halogen, cyano group, hydroxyl, (rudimentary) alkoxyl group, aryl [(rudimentary) alkyl] oxygen base, [(rudimentary) alkoxyl group] carbonyl, carbamyl, formyl radical oxygen base, (rudimentary) alkyloyl oxygen base, [(rudimentary) alkyl] sulfonyloxy, [halo (rudimentary) alkyl] sulfonyloxy or carboxyl;

R ³Be (rudimentary) alkoxyl group, hydroxyl, amino, [(rudimentary) alkyl] amino or two [(rudimentary) alkyl] amino;

X and Y respectively do for oneself CH or N.

More than this specification sheets and in the description subsequently, the suitable example of the various definition that are included in the scope of the present invention is explained as follows in detail.

Unless otherwise indicated, term " rudimentary " is meant the group that contains 1-6 carbon atom.

Accordingly, " (rudimentary) alkyl " is meant the straight or branched aliphatic hydrocrbon, for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, hexyl etc., preferred (C1-C4) alkyl, more preferably (C1-C2) alkyl, most preferable.

" halogen " can comprise fluorine atom, chlorine atom, bromine atoms and iodine atom, preferred fluorine atom or chlorine atom, more preferably fluorine atom.

" halo (rudimentary) alkyl " is meant the low alkyl group that is replaced by above-mentioned halogen atom, for example methyl fluoride, chloromethyl, difluoromethyl, dichloromethyl, two brooethyls, trifluoromethyl, trichloromethyl, fluoro ethyl, chloroethyl, 2,2,2-trifluoroethyl, 2,2,2-three chloroethyls, 2,2,3,3,3-pentafluoroethyl group, fluoropropyl, fluorine butyl, fluorine hexyl etc., preferred halo (C1-C4) alkyl, more preferably halo (C1-C2) alkyl, more preferably fluoro (C1-C2) alkyl, more preferably fluoro methyl, most preferably difluoromethyl or trifluoromethyl.

" hydroxyl replace (rudimentary) alkyl " refers to above-mentioned (rudimentary) alkyl of being replaced by the OH group, for example methylol, hydroxyethyl, hydroxypropyl, 1-hydroxyl sec.-propyl, 2-hydroxyl sec.-propyl, hydroxyl butyl, hydroxyl isobutyl-, hydroxyl-tertiary butyl, hydroxyl hexyl etc., (C1-C4) alkyl that preferred hydroxyl replaces, more preferably (C1-C2) alkyl of replacing of hydroxyl, most preferably methylol.

" cycloalkyl " refers to (C3-C10) cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, norcamphyl, adamantyl etc., preferably (C3-C6) cycloalkyl, more preferably (C3-C5) cycloalkyl, most preferably cyclopropyl.

Therefore, " naphthene base carbonyl " refers to by the carbonyl of above-mentioned cycloalkyl substituted, for example cyclopropyl carbonyl, cyclobutyl carbonyl, cyclopentylcarbonyl, cyclohexyl-carbonyl, suberyl carbonyl, norcamphyl carbonyl, adamantyl carbonyl etc., preferably [(C3-C6) cycloalkyl] carbonyl, more preferably [(C3-C5) cycloalkyl] carbonyl.

" N-[(is rudimentary) alkyl] carbamyl " refer on nitrogen-atoms by the carbamyl of above-mentioned (rudimentary) alkyl replacement; for example methyl carbamyl, ethyl carbamyl, propyl group carbamyl, sec.-propyl carbamyl, butyl carbamyl, isobutyl-carbamyl, tertiary butyl carbamyl, amyl group carbamyl, hexyl carbamyl etc.; preferred N-[(C1-C4) alkyl] carbamyl, more preferably N-[(C1-C2) alkyl] carbamyl.

" N; N-two [(rudimentary) alkyl] carbamyl " refers on nitrogen-atoms by the carbamyl of two identical or different above-mentioned (rudimentary) alkyl replacements; dimethylamino formyl radical for example; the diethyl amino formyl radical; the dipropyl carbamyl; the di-isopropyl carbamyl; the dibutylamine formyl radical; the diisobutyl carbamyl; the diamyl carbamyl; the dihexyl carbamyl; the ethyl-methyl carbamyl; the methyl-propyl carbamyl; the butyl methyl carbamyl; ethyl propyl carbamyl and butyl ethyl carbamyl etc.; preferred two [(C1-C4) alkyl] carbamyl, more preferably two [(C1-C2) alkyl] carbamyl.

" (rudimentary) alkyloyl " refers to by the carbonyl of above-mentioned (rudimentary) alkyl replacement; for example ethanoyl, propionyl (ethyl carbonyl), butyryl radicals, isobutyryl (sec.-propyl carbonyl), valeryl, pentanoyl, isovaleryl, caproyl etc.; preferably (C2-C5) alkyloyl, more preferably (C2-C4) alkyloyl.

Therefore, " (rudimentary) alkanoyloxy " can be exemplified as acetoxyl group, propionyloxy (ethyl ketonic oxygen base), butyryl acyloxy, isobutyl acyloxy (isopropyl carbonyl oxygen base), new pentane acyloxy, penta acyloxy, isoamyl acyloxy, hexylyloxy etc., preferably (C2-C5) alkanoyloxy, more preferably (C2-C4) alkanoyloxy.

" (rudimentary) alkoxyl group " refers to the aliphatic-oxyl of straight or branched, for example methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, pentyloxy, hexyloxy etc., preferably (C1-C4) alkoxyl group, more preferably (C1-C2) alkoxyl group, most preferably methoxyl group.

Therefore, " [(rudimentary) alkoxyl group] carbonyl " refers to-CO ₂-[(rudimentary) alkyl] group, for example methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl, butoxy carbonyl, isobutoxy carbonyl, tert-butoxycarbonyl, pentyloxy carbonyl, hexyloxy carbonyl etc., preferred [(C1-C4) alkoxyl group] carbonyl, more preferably ethoxy carbonyl.

" heterocycle " refers to contain five yuan or hexa-atomic saturated heterocyclic group of at least one heteroatoms such as nitrogen, oxygen, sulphur atom." heterocycle " can comprise five-membered ring group such as pyrrolidyl, imidazolidyl, pyrazolidyl, tetrahydro-thienyl, tetrahydrofuran base, oxazolidinyl, isoxazole alkyl, thiazolyl, isothiazolyl etc.; Also comprise hexa-member heterocycle group such as piperidyl, piperazinyl, morpholinyl and thio-morpholinyl or the like.

Therefore, " heterocycle carbonyl " can be exemplified as five-membered ring carbonyl such as pyrrolidyl carbonyl, imidazolidyl carbonyl, pyrazolidyl carbonyl, tetrahydro-thienyl carbonyl, tetrahydrofuran base carbonyl, oxazolidinyl carbonyl, isoxazole alkyl carbonyl, thiazolidyl carbonyl; Hexa-member heterocycle carbonyl such as piperidino carbonyl, piperazinyl carbonyl, morpholinyl carbonyl and thio-morpholinyl carbonyl.This group is preferably (nitrogen atom heterocycle) carbonyl or hexa-member heterocycle carbonyl, more preferably piperidino carbonyl.

" aryl [(rudimentary) alkyl] oxygen base " refers to above-mentioned (rudimentary) alkoxyl group of being replaced by aryl, as benzyloxy, naphthyl methoxyl group, indenyl methoxyl group, phenelyl, naphthalene ethyl, hydrocinnamyl, benzene butyl, benzene hexyl etc., preferred aryl groups [(C1-C2) alkyl] oxygen base, more preferably aryl methoxy, most preferably benzyloxy.

" [(rudimentary) alkyl] alkylsulfonyl " refers to by the alkylsulfonyl of above-mentioned (rudimentary) alkyl replacement; as methylsulfonyl, ethylsulfonyl, different third alkylsulfonyl, uncle's fourth alkylsulfonyl etc.; preferably (C1-C4) alkyl sulphonyl, more preferably (C1-C2) alkyl sulphonyl, most preferably methylsulfonyl.

Therefore, " [(rudimentary) alkyl] sulfonyloxy " can be exemplified as sulfonyloxy methyl oxygen base, ethyl sulfonyloxy, different third sulfonyloxy, uncle's fourth sulfonyloxy etc., preferably (C1-C4) alkylsulfonyloxy, more preferably (C1-C2) alkylsulfonyloxy, most preferably mesyloxy.

" [halo (rudimentary) alkyl] alkylsulfonyl " refers to by the alkylsulfonyl of above-mentioned halo (rudimentary) alkyl replacement; as trifyl etc.; preferably [halo (C1-C4) alkyl] alkylsulfonyl, more preferably [halo (C1-C2) alkyl] alkylsulfonyl, most preferably trifyl.

Therefore, " [halo (rudimentary) alkyl] sulfonyloxy " can be exemplified as trifluoro-methanesulfonyl oxy etc., preferred [halo (C1-C4) alkyl] sulfonyloxy, more preferably [halo (C1-C2) alkyl] sulfonyloxy, most preferably trifluoro-methanesulfonyl oxy.

" [(rudimentary) alkyl] amino " refers to by the amino of an above-mentioned low alkyl group replacement, as methylamino-, ethylamino, third amino, sec.-propyl amino, fourth amino, isobutylamino, tertiary butyl amino, amyl group amino and hexyl amino etc., preferably [(C1-C4) alkyl] amino, more preferably [(C1-C2) alkyl] amino.

" two [(rudimentary) alkyl] amino " refers to by the amino of two identical or different above-mentioned (rudimentary) alkyl replacements, as dimethylamino, diethylamino, dipropyl amino, diisopropylaminoethyl, dibutylamino, diisobutyl amino, diamyl amino, dihexyl amino, ethylmethylamino, methyl-propyl amino, butyl methyl amino, ethyl propyl amino and butyl ethyl amino etc., preferred two [(C1-C4) alkyl] amino, more preferably two [(C1-C2) alkyl] amino.

The combination of X and Y is, respectively do for oneself CH, X of X and Y is that N and Y are that CH, X are that CH and Y are N, X and the Y N that respectively does for oneself, and being preferably X and Y, to be CH, X be that N and Y are that CH or X are that CH and Y are N, preferred any these three kinds of combinations.

Formula (I) compound can comprise one or more asymmetric centers, so they can exist enantiomer and diastereomer.The present invention had both comprised that mixture also comprised isolating independent enantiomer.

Formula (I) compound also can exist with the form of tautomer, and the present invention had both comprised that mixture also comprised isolating independent tautomer.

Formula (I) compound and its salt can be solvate forms, and this form is included within the scope of the invention.This solvate preferably includes hydrate.

The radio-labeling derivative of formula (I) compound is also included within the scope of the invention, and it is applicable to biological study.

Imidazolium compounds of the present invention can be converted into salt with ordinary method.The acceptable acid addition salts of compound (I) is the acceptable non-toxic salt commonly used of medicine, comprises metal-salt such as an alkali metal salt (sodium salt for example, sylvite etc.) and alkaline earth salt (calcium salt for example, magnesium salts etc.), ammonium salt, organic alkali salt (front three amine salt for example, triethylamine salt, pyridinium salt, picoline salt and dicyclohexyl amine salt etc.), organic acid salt (acetate for example, maleate, tartrate, mesylate, benzene sulfonate, formate, tosylate and trifluoroacetate etc.), inorganic acid salt (hydrochloride for example, hydrobromate, vitriol and phosphoric acid salt etc.), amino acid salts (arginic acid salt for example, aspartate and glutaminate etc.) etc.

Imidazolium compounds (I) can preferably include

Wherein

R ¹Be (rudimentary) alkyl, halo (rudimentary) alkyl, cycloalkyl, N, N-two [(rudimentary) alkyl] carbamyl, (rudimentary) alkyloyl or cyano group;

R ²Be halogen, cyano group, hydroxyl or (rudimentary) alkoxyl group;

R ³Be lower alkoxy;

Respectively do for oneself CH, X of X and Y is that N and Y are that CH or X are that CH and Y are N.

In each definition of formula (I) compound, preferred

(1) R ¹Be (rudimentary) alkyl, halo (rudimentary) alkyl, cycloalkyl, carbamyl, N, N-two [(rudimentary) alkyl] carbamyl, (rudimentary) alkyloyl or cyano group,

(2) R ¹Be (rudimentary) alkyl, halo (rudimentary) alkyl, cycloalkyl,

(3) R ¹Be (C1-C4) alkyl, halo (C1-C4) alkyl or (C3-C6) cycloalkyl,

(4) R ¹Be (C1-C2) alkyl, halo (C1-C2) alkyl or (C3-C5) cycloalkyl,

(5) R ¹Be carbamyl or N, N-two [(C1-C4) alkyl] carbamyl,

(6) R ¹Be carbamyl or N, N-two [(C1-C2) alkyl] carbamyl,

(7) R ¹Be (C2-C4) alkyloyl or cyano group,

(8) R ²Be halogen, cyano group, hydroxyl, (rudimentary) alkoxyl group, aryl [(rudimentary) alkyl] oxygen base, [(rudimentary) alkoxyl group] carbonyl, carbamyl or [halo (rudimentary) alkyl)] sulfonyloxy,

(9) R ²Be halogen, cyano group, hydroxyl, (C1-C4) alkoxyl group, aryl methoxy, [(C1-C4) alkoxyl group] carbonyl, carbamyl or [halo (C1-C4) alkyl] sulfonyloxy,

(10) R ²Be halogen, cyano group, hydroxyl or (C1-C2) alkoxyl group,

(11) R ²Be hydroxyl or (C1-C2) alkoxyl group,

(12) R ³Be (rudimentary) alkoxyl group or hydroxyl,

(13) R ³Be (C1-C4) alkoxyl group,

(14) R ³Be (C1-C2) alkoxyl group,

(15) X and the Y CH that respectively does for oneself,

(16) X is that N and Y are CH,

(17) X is that CH and Y are N,

(18) X and the Y N that respectively does for oneself.

Formula of the present invention (I) compound can prepare by the following method.

Method A (1)

In following formula, X and Y represent meaning same as described above.R ¹(a), R ²(a) and R ³(a) represent R respectively ¹, R ²And R ³Definition in group, they do not influence present method.Particularly, R ¹(a) representative (rudimentary) alkyl, halo (rudimentary) alkyl, cycloalkyl, N, N-two [(rudimentary) alkyl] carbamyl, formyl radical, (rudimentary) alkyloyl, [(rudimentary) alkoxyl group] carbonyl, cyano group or naphthene base carbonyl; R ²(a) represent halogen, cyano group, (rudimentary) alkoxyl group, aryl [(rudimentary) alkyl] oxygen base, [(rudimentary) alkoxyl group] carbonyl, formyl radical oxygen base, (rudimentary) alkyloyl oxygen base, [(rudimentary) alkyl] sulfonyloxy or [halo (rudimentary) alkyl] sulfonyloxy; R ³(a) represent lower alkoxy." Hal " represents halogen atom, particularly chlorine atom or bromine atoms.

Method A (1) is the method for preparing compound (Ia), and its correspondence is R wherein ¹To R ³Group is not formula (I) compound of reactive group.

Present method is by in the presence of alkali formula (II) compound and formula (III) compound reaction formation imidazole ring being carried out.

If commercialization can have been bought formula (II) compound, perhaps become from the commodity compounds according to aftermentioned method B or other ordinary method.If commercialization can have been bought formula (III) compound, perhaps synthetic according to a conventional method with commodity compound, because formula (III) compound has simple relatively structure as the initial compounds of synthetic compound (Ia).

The spendable solvent of present method does not have particular restriction, as long as be inert in this reaction, can comprise that alcohol is as methyl alcohol, ethanol, 2-propyl alcohol; Ether such as Di Iso Propyl Ether, tetrahydrofuran (THF), diox and mixed solvent thereof.

The alkali that can be used for producing alkaline environment in present method does not have particular restriction, as long as it can quicken this reaction, can comprise alkali-metal supercarbonate such as lithium bicarbonate, sodium bicarbonate and saleratus; Alkaline carbonate such as Quilonum Retard, yellow soda ash and salt of wormwood; Alkaline earth metal carbonate such as magnesiumcarbonate and lime carbonate; Alkali metal hydroxide such as lithium hydroxide, sodium hydroxide and potassium hydroxide; Preferred as alkali supercarbonate, especially sodium bicarbonate.

Temperature of reaction is according to variations such as raw material and solvents, but usually from 50 ℃ to 150 ℃, preferred 60 ℃ to 100 ℃ or reflux conditions.

Reaction times is according to variations such as raw material, solvent, temperature of reaction, but usually from 1 hour to 1 day, preferred 2 to 12 hours.

After the reaction, reaction mixture is cooled to room temperature, and vacuum-evaporation adds water then and uses and the immiscible organic solvent of water ethyl acetate extraction for example.Washings such as organic phase water, anhydrous magnesium sulfate or anhydrous sodium sulfate drying, vacuum-evaporation is by ordinary method purification of target compounds such as silica gel column chromatography, recrystallizations.

According to raw material, can form heterocycle sometimes but do not form imidazole ring.In this case, need processed to form imidazole ring.

Processed is carried out under heating and sour environment.

The employed solvent of this method is not particularly limited, but for example acetate, sulfuric acid etc. can be used as the solvent use in acid.

Temperature of reaction is with variations such as raw material, solvents, but it is usually from 50 ℃ to 200 ℃, is preferably 80 ℃ to 150 ℃.

Reaction times is with variations such as raw material, solvent, temperature of reaction, but it is usually from 30 minutes to 5 hours, preferred 1 hour to 3 hours.

The reaction finish after, mixture is poured in the buck, and with immiscible organic solvent of water such as ethyl acetate extraction.Washings such as this organic phase water, anhydrous magnesium sulfate or anhydrous sodium sulfate drying, vacuum-evaporation is by ordinary method purification of target compounds such as silica gel column chromatography, recrystallizations.

Compound (Ia) also can synthesize by the following method.

Method A (2)

In above reaction formula, R ¹(a), R ²(a), R ³(a), X, Y and the Hal representative meaning identical with above definition.

Method A (2) is used to prepare compound (Ia), and it is corresponding to R wherein ¹To R ³It or not the compound (I) of active group.

In this method, at first with compound (II) and compound (IV) condensation, synthetic compound (V) (method A (2)-1).

Method A (2)-1 can carry out under Hunig alkali (N, N-diisopropylethylamine) exists.

If commercialization can have been bought compound (IV), perhaps synthetic according to a conventional method with commodity compound, because compound (IV) has simple relatively structure.

The spendable solvent of present method does not have particular restriction, as long as it is inert in this reaction, can comprise ether such as Di Iso Propyl Ether, tetrahydrofuran (THF), diox, preferred tetrahydrofuran (THF).

Temperature of reaction is with variations such as raw material and solvents, but usually from 50 ℃ to 200 ℃, is preferably 50 ℃ to 120 ℃ or reflux conditions.

Reaction times is with variations such as raw material, solvent, temperature of reaction, but usually from 1 hour to 2 days, and preferred 1 hour to 5 hours or spend the night.

Carry out if react insufficient, can additionally add compound (IV).

After the reaction, from reaction mixture, collect target compound (V) according to a conventional method.For example, be cooled to room temperature and vacuum-evaporation after, in the reaction mixture impouring water, use and immiscible organic solvent of water such as ethyl acetate extraction.Organic phase after washing such as water, anhydrous magnesium sulfate or dried over sodium sulfate, vacuum-evaporation is by ordinary method purification of target compounds such as silica gel column chromatography, recrystallizations.

Method A (2)-the 2nd, the oxidising process in the presence of catalyzer is used to form imidazole ring.

Adoptable oxide catalyst does not have particular restriction in present method, needs only its energy catalysis from 4, and 5-dihydro-imidazol-derivative (V) can comprise manganese oxide (IV) (MnO to the reaction of imdazole derivatives ₂).

Spendable solvent does not have particular restriction in this method, as long as it is inert in this reaction, can comprise acid amides such as N, N-dimethylformamide, N,N-DIMETHYLACETAMIDE, hexamethyl phosphoric triamide; Aromatic hydrocarbons such as benzene, toluene etc.

Temperature of reaction is with variations such as raw material, solvents, but usually from 50 ℃ to 200 ℃, preferred 80 ℃ to 120 ℃ or reflux conditions.

Reaction times is with variations such as raw material, solvent, temperature of reaction, but usually from 1 hour to 24 hours, is preferably 2 hours to 12 hours.

Carry out if react insufficient, can additionally add catalyzer.

After the reaction, mixture is cooled to room temperature and removes by filter catalyzer.The organic moiety vacuum concentration, or pour in the buck and use and immiscible organic solvent of water such as ethyl acetate extraction.Washings such as organic phase water, with anhydrous magnesium sulfate or anhydrous sodium sulfate drying, vacuum-evaporation.By ordinary method purification of target compounds such as silica gel column chromatography, recrystallizations.

Compound (Ia) can change into compound (I) by functional group, and this technician for organic chemistry filed is conspicuous.For example, this reaction can be described as follows.

Method A (3)

In above reaction formula, R represents hydrogen, (rudimentary) alkyl or aryl [(rudimentary) alkyl], and it does not specify." TF " representative is as the trifyl of blocking group.

4,5-glyoxalidine compound (V) transforms by above-mentioned functional group can be converted into compound (IX).

Method A (4)

Compound (IX) or its drug acceptable salt also have the activity of inhibition to COX.Therefore compound (IX) or its salt also can be used as medicine.

Except buying, compound (II) can also be by compound (VI) and (VII) synthetic as follows.

Method B (1)

In above reaction formula, R ²(a), R ³(a), X and the Y representative meaning identical with above-mentioned definition.

Method B (1) is for preparing the method for compound (II), and compound (II) is the raw material of method A (1) and A (2).

If commercialization can have been bought compound (VI) and (VII), perhaps the useful commercial compound is synthetic according to a conventional method, because these compounds have simple relatively structure as the raw material of synthetic compound (II).

In the method, at first in the solution of compound (VII), add highly basic.

Spendable highly basic does not have particular restriction, can comprise alkalimetal hydride such as lithium hydride, sodium hydride; Alkali metal alcoholates such as lithium methoxide, sodium methylate, sodium ethylate and potassium tert.-butoxide etc.

Spendable solvent does not have particular restriction in this method, as long as it is inert in this reaction, can comprise ether such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox; Acid amides such as N, N-dimethylformamide, N,N-DIMETHYLACETAMIDE, hexamethyl phosphoric triamide; Sulfoxide such as methyl-sulphoxide etc.

Temperature of reaction is with variations such as raw material, solvents, but usually from-10 ℃ to room temperature, be preferably room temperature.

Reaction times is with variations such as raw material, solvent, temperature of reaction, but usually from 5 minutes to 1 hour, preferred 10 minutes to 40 minutes.

Preferred present method is carried out in rare gas element such as nitrogen.

In the method, in reaction mixture, add compound (VI) then.

The reaction temperature with variations such as raw material and solvents, but, usually from-10 ℃ to room temperature, be preferably room temperature.

The time of reaction is with variations such as raw material, solvent, temperature of reaction, but usually between 1 hour to 24 hours, is preferably 2 hours to spending the night.

After the reaction, pour in the frozen water reaction mixture into highly basic with decomposing excessive.Collect as sedimentary target compound by filtering then.If necessary, can wash with solvent such as Di Iso Propyl Ether.Target compound can also be further purified with ordinary methods such as silica gel column chromatography, recrystallizations, and but, it just need not to be further purified and can be used for next step.

Except that buying, compound (II) also can be by compound (VII) and (VIII) synthetic as follows.

Method B (2)

In above reaction formula, R ²(a), R ³(a), X and the Y representative meaning identical with above definition.

Method B (2) is the another kind of method of preparation compound (II).At R ²(a) be that it is than the easier nucleophillic attack that is subjected to of cyano group under the situation of groups such as [(rudimentary) alkoxyl group] carbonyl.

In the method, compound (VII) and (VIII) condensation under acidic conditions.

If it is commercialization can be bought compound (VII), perhaps synthetic according to a conventional method from commodity compound.

Compound (VIII) can synthesize according to a conventional method, that is, at first by thioacetamide nitrile compound is converted into thioamide compound, and then methylates.

The spendable solvent of present method does not have particular restriction, as long as it is inert in this reaction, can comprise alcohol for example methyl alcohol, ethanol, 2-propyl alcohol; Ether is Di Iso Propyl Ether, tetrahydrofuran (THF) ， diox and mixed solvent thereof etc. for example.

The acid that is used to make sour environment in present method does not have particular restriction, as long as it is used as acid catalyst in common reactant, can comprise mineral acid for example hydrochloric acid, Hydrogen bromide, sulfuric acid etc.

Temperature of reaction is with variations such as raw material and solvents, but usually from 50 ℃ to 150 ℃, preferred reflux temperature.

Reaction times is with variations such as raw material, solvent, temperature of reaction, but usually from 30 minutes to 5 hours, preferably from 2 hours to 4 hours.

After the reaction, reaction mixture is poured in the buck, and used and the immiscible organic solvent of water ethyl acetate extraction for example.Organic layer is with anhydrous magnesium sulfate or anhydrous sodium sulfate drying, vacuum-evaporation.If necessary, can be with for example Di Iso Propyl Ether washing of solvent.In addition, target compound can be used the further purifying of ordinary method such as silica gel column chromatography, recrystallization, and but, it just need not to be further purified and can be used for next step.

In the above reaction method (method A and B), all raw materials and product can be salt.Compound in the above method can be converted into salt according to a conventional method.

In above compound, what contain reactive group can be protected on group at the fixed time, and go protection at the fixed time.In these reactions (protecting or go to protect step), about blocking group kind and reaction conditions, can be referring to " PROTECTIVE GROUPS INORGANIC SYNTHESIS second edition ", T.W.Green and P.G.M.Wuts, JohnWiley ﹠amp; Sons, Inc.

For therapeutic purpose, compound of the present invention (I) and drug acceptable salt thereof can use with the form of pharmaceutical composition, this pharmaceutical composition contains a kind of described compound as activeconstituents, this compound mixes with drug acceptable carrier, carrier is the solid or the liquid excipients of organic or inorganic for example, is suitable for oral, administered parenterally or external application.Pharmaceutical preparation can be capsule, tablet, coated tablet, granule, inhalation, suppository, solution, washing lotion, suspension agent, emulsion, ointment, gelifying agent, ointment etc.If desired, can also comprise auxiliary material, stablizer, wetting agent or emulsifying agent, buffer reagent and other typical additives in these preparations.

In addition, the commodity package of written material that comprises aforementioned pharmaceutical compositions and the above-mentioned effect of explanation also is useful.

Though the treatment effective dose of compound (I) changes with each individual patient's age and condition, the average single dose of about 0.01mg, 0.1mg, 1mg, 10mg, 50mg, 100mg, 250mg, 500mg and 1000mg compound (I) can effectively be treated aforementioned diseases.In general, can give 0.01mg/ people every day to the dosage between about 1000mg/ people.

Best Implementation Modes of the present invention

Provide following examples just in order more at large to illustrate the present invention.

Although the form by embodiment is described in detail the present invention, it should be understood that various variations and modification it will be apparent to those skilled in the art that.Therefore, except having departed from the hereinafter variation and the modification of the scope of the invention of definition, they all are construed as and comprise within the scope of the invention.

Embodiment 1-1

N ¹-(4-bromophenyl)-4-methoxyl group benzamidine

Under nitrogen, (568mg, (3.88g is in methyl-sulphoxide 22.5mmol) (30ml) solution 23.7mmol) to be added to the 4-bromaniline with NaH under the room temperature.After stirring the mixture 30 minutes, and adding 4-HOMOVERATRONITRILE (3.0g, 22.5mmol).

Reaction mixture is poured in the 300ml frozen water after stirring and spending the night.Filter collecting precipitation and, obtain the target compound that 5.53g is a white solid (80.4%) with the isopropyl ether washing.

IR(KBr，cm ^-1)：3473，3357，2958，1612，1249，1174，1103，1074，1030，837。

NMR(DMSO-d ₆，δ)：3.80(3H，s)，6.32(2H，brs)，6.78(2H，d，J＝9Hz)，6.96(2H，d，J＝9Hz)，7.42(1H，d，J＝8Hz)，7.92(2H，d，J＝8Hz)。

MS：305(M+H) ⁺( ⁷⁹Br)，307(M+H) ⁺( ⁸¹Br)。

Embodiment 1-2

1-(4-bromophenyl)-2-(4-p-methoxy-phenyl)-4-Trifluoromethyl-1 H-imidazoles

N1-(4-the bromophenyl)-4-methoxyl group benzamidine that obtains from embodiment 1-1 (2.0g, 6.55mmol) and sodium bicarbonate (add 3-bromo-1,1 among the 826mg, isopropyl alcohol mixture 9.83mmol) (20ml), 1-three fluoro-2-acetone (2.0g, 10.5mmol).This reaction mixture was 80 ℃ of heating 2 hours.

Reaction mixture is cooled to room temperature and filtration.The vacuum-evaporation organic layer.Residue was dissolved in acetate (20ml), 110 ℃ of heating 2.5 hours.

This reaction mixture is poured in the frozen water (100ml) and with the aqueous sodium hydroxide solution neutralization, is used ethyl acetate (50ml) extraction again.Organic layer evaporates with salt water washing, dried over mgso final vacuum.Residue uses silica gel column chromatography (20g) purifying, with n-hexane/ethyl acetate (10/1) wash-out, with the Di Iso Propyl Ether washing, obtains 660mg target compound (25.4%) again.

MP：140-141℃。

IR(KBr，cm ^-1)：3140，2970，1487，1294，1252，1149，1122，1026，833。

NMR(DMSO-d ₆，δ)：3.75(3H，s)，6.92(2H，d，J＝9Hz)，7.27(2H，d，J＝9Hz)，7.36(2H，d，J＝9Hz)，7.71(2H，d，J＝2Hz)，8.18(1H，s)。

MS：397(M+H) ⁺( ⁷⁹Br)，399(M+H) ⁺( ⁸¹Br)。

Embodiment 2-1

4-methoxyl group-N ¹-(2-methoxyl group-5-pyridyl) benzamidine

Reaction is carried out in the mode of similar embodiment 1-1, uses 4-HOMOVERATRONITRILE and 5-amino-2-methoxypyridine, obtains 4.57g target compound (78.8%).

IR(KBr，cm ^-1)：3452，3334，3205，2946，1606，1483，1273，1246，1176，1028，841。

NMR(DMSO-d ₆，δ)：3.80(3H，s)，3.82(3H，s)，6.36(2H，brs)，6.76(1H，d，J＝9Hz)，6.96(2H，d，J＝9Hz)，7.20(1H，dd，J＝9Hz and 3Hz)，7.67(1H，d，J＝3Hz)，7.94(2H，d，J＝9Hz)。

MS：258(M+H) ⁺。

Embodiment 2-2

Hydrochloric acid 2-(4-p-methoxy-phenyl)-1-(2-methoxyl group-5-pyridyl)-4-Trifluoromethyl-1 H-imidazoles

Reaction is carried out in the mode that is similar to embodiment 1-2, uses the 4-methoxyl group-N that obtains among the embodiment 2-1 ¹-(2-methoxyl group-5-pyridyl) benzamidine obtains 2-(4-p-methoxy-phenyl)-1-(2-methoxyl group-5-pyridyl)-4-Trifluoromethyl-1 H-imidazoles.

Then, the product that obtains is dissolved in ethyl acetate and uses the hydrochloric ethyl acetate solution-treated of 4M, obtains the target product (14.7%) of 399mg white amorphous solid.

NMR(DMSO-d ₆，δ)：3.75(3H，s)，3.89(3H，s)，6.80-7.05(3H，m)，7.31(2H，d，J＝9Hz)，7.43(1H，d，J＝9Hz)，7.74(1H，dd，J＝9Hz and 2Hz)，8.17(1H，s)，8.27(1H，s)。

MS:350 (M+H) ⁺(dissociating)

Embodiment 3-1

N ¹-(4-p-methoxy-phenyl)-2-methoxyl group-5-amidino groups pyridine

Under room temperature nitrogen, (23.5ml, 23.5mmol) drips of solution adds Para-Anisidine (2.75g is in tetrahydrofuran (THF) 22.4mmol) (15ml) solution with the tetrahydrofuran (THF) of 1.0M two (trimethyl silyl) acid amides sodium.After this mixture stirring 20 minutes, and adding 6-methoxyl group nicotinoyl nitrile (3.0g, 22.4mmol).

This reaction mixture was stirred 4 hours, pour into subsequently in the 300ml frozen water.Filter collecting precipitation,, obtain 3.36g target compound (58.4%) (mixture) with the Di Iso Propyl Ether washing.

This material just need not to be further purified and can use.

NMR(DMSO-d ₆，δ)：3.73(3H，s)，3.90(3H，s)，6.27(2H，brs)，6.70-7.00(5H，m)，8.24(1H，dd，J＝9Hz and 2Hz)，8.72(1H，d，J＝2Hz)。

MS：258(M+H) ⁺。

Embodiment 3-2

1-(4-p-methoxy-phenyl)-2-(2-methoxyl group-5-pyridyl)-4-Trifluoromethyl-1 H-imidazoles

Reaction is carried out in the mode of similar embodiment 1-2, uses the N that obtains among the embodiment 3-1 ¹-4-methoxyl group-2-methoxyl group-5-amidino groups pyridine, the clear crystal (21.5%) of acquisition 526.6mg target compound.

MP：90-92℃。

IR(KBr，cm ^-1)：3141，3107，1604，1518，1294，1248，1159，1118，835。

NMR(DMSO-d ₆，δ)：3.81(3H，s)，3.83(3H，s)，6.81(1H，d，J＝9Hz)，7.05(2H，d，J＝9Hz)，7.38(2H，d，J＝9Hz)，7.65(1H，dd，J＝9Hz and 2Hz)，8.08(1H，d，J＝2Hz)，8.17(1H，s)。

MS：350(M+H) ⁺。

Embodiment 4-1

4-cyano group-4,5-dihydro-1-(4-p-methoxy-phenyl)-2-(2-methoxyl group-5-pyridyl)-1H-imidazoles

The N that obtains to embodiment 3-1 ¹In the tetrahydrofuran (THF) suspension (20ml) of-4-methoxyl group-2-methoxyl group-5-amidino groups pyridine, add 2-chloroacrylonitrile and diisopropylethylamine successively.Heat this reaction mixture down at 70 ℃.After 5 hours, add 1.07ml 2-chloroacrylonitrile again, backflow is spent the night.

This reactant is cooled to room temperature, filters solvent removed in vacuo.Crude mixture uses silica gel column chromatography (24g) purifying, obtains 460mg target compound (54.9%) through eluent ethyl acetate.

This material need not to be further purified promptly and uses in embodiment 4-2.

Embodiment 4-2

4-cyano group-1-(4-p-methoxy-phenyl)-2-(2-methoxyl group-5-pyridyl)-1H-imidazoles

The residue and Manganse Dioxide (the IV) (MnO that obtain by embodiment 4-1 ₂) (1.3g, toluene suspension (10ml) 10eq) heated 5.5 hours down at 85 ℃.(0.65g 5eq) and in 110 ℃ heated 3 hours to add Manganse Dioxide (IV) to this mixture.

After the cooling, use the Celite filtering mixt.Concentrate organic phase (396mg).Crude mixture is with silica gel column chromatography (12g) purifying, and with chloroform/methanol (50/1 → 15/1) wash-out, through the Di Iso Propyl Ether washing, obtaining 200.8mg is the target compound (24.1%, through embodiment 4-1 and 4-2) of colorless solid.

MP：130-132℃。

IR(KBr，cm ^-1)：3132，2949，2233，1604，1516，1466，1292，1254，1024，835。

NMR(DMSO-d ₆，δ)：3.81(3H，s)，3.84(3H，s)，6.81(1H，d，J＝9Hz)，7.06(2H，d，J＝9Hz)，7.37(2H，d，J＝9Hz)，7.62(1H，dd，J＝9Hz and 2Hz)，8.10(1H，d，J＝2Hz)，8.47(1H，s)。

MS：307(M+H) ⁺。

Embodiment 5-1

N ¹-(4-benzyloxy phenyl)-2-methoxyl group-5-amidino groups pyridine

Reaction is carried out in the mode of similar embodiment 3-1, uses hydrochloric acid 4-benzyloxy-aniline, obtains 8.7g target compound (71.7%).

IR(KBr，cm ^-1)：3488，3396，3031，2958，1635，1502，1373，1236，1103，1020，840。

NMR(DMSO-d ₆，δ)：3.90(3H，s)，5.06(2H，s)，6.28(2H，brs)，6.70-7.05(5H，m)，7.25-7.60(5H，m)，8.24(1H，dd，J＝9Hz and 2Hz)，8.72(1H，d，J＝2Hz)。

MS：334(M+H) ⁺。

Embodiment 5-2

1-(4-benzyloxy phenyl)-2-(2-methoxyl group-5-pyridyl)-4-Trifluoromethyl-1 H-imidazoles

Reaction is carried out in the mode of similar embodiment 1-2, uses the N that obtains among the embodiment 5-1 ¹-(4-benzyloxy phenyl)-2-methoxyl group-5-amidino groups pyridine obtains 2.27g target compound (44.5%).

IR(KBr，cm ^-1)：3064，2950，1290，1244，1157，1122，1022，835。

NMR(DMSO-d ₆，δ)：3.84(3H，s)，5.16(2H，s)，6.81(1H，d，J＝9Hz)，7.05-7.58(9H，m)，7.65(1H，dd，J＝9Hz and 2Hz)，8.08(1H，d，J＝2Hz)，8.17(1H，s)。

MS：426(M+H) ⁺。

Embodiment 6

1-(4-hydroxy phenyl)-2-(2-methoxyl group-5-pyridyl)-4-Trifluoromethyl-1 H-imidazoles

(2.25g, the carbon of adding 20% carries palladium hydroxide (550mg) to 1-(4-benzyloxy phenyl)-2-(2-methoxyl group-5-the pyridyl)-4-Trifluoromethyl-1 H-imidazoles that obtains to embodiment 5-2 in tetrahydrobenzene solution (22ml) 5.29mmol) and the ethanol (45ml).The gained mixture stirs down and refluxed 2 hours.

After mixture is cooled to room temperature, filter and use washing with alcohol with Celite.The filtrate vacuum concentration, residue washs with Di Iso Propyl Ether subsequently, obtains the target compound 1.31g (73.9%) into white solid.

MP：198-200℃。

IR(KBr，cm ^-1)：3600-2600，1469，1292，1247，1159，1126，833。

NMR(CDCl ₃，δ)：3.91(3H，s)，6.67(1H，brs)，6.73(1H，d，J＝9Hz)，6.87(2H，d，J＝9Hz)，7.11(2H，d，J＝9Hz)，7.43(1H，s)，7.86(1H，dd，J＝9Hz and 2Hz)，8.03(1H，d，J＝2Hz)。

MS：336(M+H) ⁺。

Embodiment 7

2-(2-methoxyl group-5-pyridyl)-1-(4-trifluoro-methanesulfonyl oxy phenyl)-4-Trifluoromethyl-1 H-imidazoles

Under the ice bath temperature, 1-(4-hydroxy phenyl)-2-(2-methoxyl group-5-pyridyl)-4-Trifluoromethyl-1 H-imidazoles (600mg to embodiment 6 acquisitions, 1.79mmol) and triethylamine (190mg, 1.88mmol) drip trifluoromethanesulfanhydride anhydride in the mixture in chloroform (12ml), stirred 4.5 hours.

The aqueous solution (10ml) the quencher reaction that adds sodium bicarbonate.This reaction mixture distributes between chloroform and water.Organic layer water and salt water washing, through dried over mgso, vacuum-evaporation.

Residue with n-hexane/ethyl acetate (10/1) wash-out, obtains 593mg target compound (70.9%) with silica gel column chromatography (10g) purifying.

IR(KBr，cm ^-1)：3118，3062，1421，1255，1219，1136，891。

NMR(CDCl ₃，δ)：3.92(3H，s)，6.71(1H，d，J＝9Hz)，7.30-7.48(4H，m)，7.50(1H，s)，7.66(1H，dd，J＝9Hz and 2Hz)，8.08(1H，d，J＝2Hz)。

MS：467(M+H) ⁺。

Embodiment 8

1-(4-cyano-phenyl)-2-(2-methoxyl group-5-pyridyl)-4-Trifluoromethyl-1 H-imidazoles

At room temperature in the nitrogen gas stream, 2-(2-methoxyl group-5-pyridyl)-1-(4-trifluoromethyl sulfonyloxy phenyl)-4-Trifluoromethyl-1 H-imidazoles (150mg to embodiment 7 acquisitions, 0.321mmol) N, add zinc cyanide (Zn (CN) in the dinethylformamide solution (7.5ml) ₂)) (38mg 0.321mmol) closes palladium (Pd (PPh with four (triphenylphosphines) ₃) ₄) (185mg, 0.16mmol).Under 85 ℃, this mixture was stirred 2 days.

Mixture is cooled to room temperature, distributes between ethyl acetate (50ml) and water (50ml).Organic layer water and salt water washing are used dried over mgso, vacuum-evaporation subsequently.Residue with toluene/ethyl acetate (10: 1) wash-out, with the Di Iso Propyl Ether washing, obtains the target compound that 57.2mg is a white solid (51.8%) with silica gel column chromatography (20g) purifying.

MP：155-158℃。

IR(KBr，cm ^-1)：3120，2250，1606，1250，1122，822。

NMR(DMSO-d ₆，δ)：3.85(3H，s)，6.82(1H，d，J＝9Hz)，7.61(1H，dd，J＝9Hzand 2Hz)，7.65(2H，d，J＝9Hz)，8.03(2H，d，J＝9Hz)，8.12(1H，d，J＝2Hz)，8.36(1H，s)。

MS：345(M+H) ⁺。

Embodiment 9

4-ethoxy carbonyl-1-(4-p-methoxy-phenyl)-2-(4-p-methoxy-phenyl)-1H-imidazoles

N ¹-(4-p-methoxy-phenyl)-4-methoxyl group benzamidine (0.65g), ethyl bromide acetone (0.64ml) and the mixture of sodium bicarbonate (0.85g) in ethanol (7ml) under refluxad stir and spend the night.

After being cooled to room temperature, reaction mixture is filtered and vacuum concentration.With in the residue impouring water, use ethyl acetate extraction then, dried over mgso is vacuum-evaporation again.Residue uses purification by silica gel column chromatography, with n-hexane/ethyl acetate (5/1 → 2/1) wash-out, obtains 244mg oily target compound (27.3%).

IR (clean, cm ^-1): 3437,3392,3367,3217,3140,3072,2966,2843,1803,1699,1651,1614.

NMR(DMSO-d ₆，δ)：1.29(3H，t，J＝7.1Hz)，3.74(3H，s)，3.80(3H，s)，4.27(2H，q，J＝7.1Hz)，6.88(2H，dd，J＝6.8Hz and2.1Hz)，7.02(2H，dd，J＝6.7Hz and2.1Hz)，7.26(2H，dd，J＝5.0Hz and 2.1Hz)，7.28(2H，dd，J＝6.7Hz and2.1Hz)，8.02(1H，s)。

MS：353(M+H) ⁺。

Embodiment 10

4-carbamyl-1-(4-p-methoxy-phenyl)-2-(4-p-methoxy-phenyl)-1H-imidazoles

4-ethoxy carbonyl-1-that embodiment 9 obtains (4-p-methoxy-phenyl)-2-(4-p-methoxy-phenyl)-1H-imidazoles (244mg) and the mixture of sodium methylate (112mg) in methane amide (2ml) stirred 2 hours down at 100 ℃.

After being cooled to room temperature, in the reaction mixture impouring water, use ethyl acetate extraction, dried over mgso, vacuum-evaporation.The residue purification by silica gel column chromatography with n-hexane/ethyl acetate (1/1 → 0/1) wash-out, obtains 73mg target compound (32.6%).

MP：167-169℃。

IR(KBr，cm ^-1)：3427，3342，3276，3155，2964，2841，1672，1610。

NMR(DMSO-d ₆，δ)：3.74(3H，s)，3.80(3H，s)，6.87-6.89(2H，m)，7.00-7.03(2H，m)，7.20(1H，s)，7.26-7.29(4H，m)，7.43(1H，s)，7.77(1H，s)。

MS：324(M+H) ⁺。

Embodiment 11

Hydrochloric acid 4-cyano group-1-(4-p-methoxy-phenyl)-2-(4-p-methoxy-phenyl)-1H-imidazoles

4-carbamyl-1-that embodiment 10 obtains (4-p-methoxy-phenyl)-2-(4-p-methoxy-phenyl)-1H-imidazoles (73mg) and phosphoryl chloride (63 μ l) are at N, and the mixture in the dinethylformamide (1ml) at room temperature stirred 1 hour.

In this reaction mixture impouring saturated sodium bicarbonate aqueous solution, use ethyl acetate extraction, dried over mgso, vacuum-evaporation.The residue purification by silica gel column chromatography is with n-hexane/ethyl acetate (2/1) wash-out.

After collecting fraction, evaporation removes and desolvates, and residue is dissolved in ethyl acetate (1ml).The hydrogenchloride ethyl acetate solution (56ml) of 4N is added to above-mentioned solution.Filter and collect the gained precipitation,, obtain 38mg target compound (49.2%) with the isopropyl ether washing.

MP：142-143℃。

IR(KBr，cm ^-1)：3425，3407，3132，3076，3043，3026，2962，2929，2835，2231，1608。

NMR(DMSO-d ₆，δ)：3.74(3H，s)，3.80(3H，s)，6.55(1H，s)，6.88-6.91(2H，m)，7.03-7.05(2H，m)，7.25-7.32(4H，m)，8.39(1H，s)。

MS:306 (dissociating) (M+H) ⁺

Embodiment 12-1

4-cyano group-4,5-dihydro-1-(4-p-methoxy-phenyl)-2-(4-p-methoxy-phenyl)-1H-imidazoles

N ¹-(4-p-methoxy-phenyl)-4-methoxyl group benzamidine (5g), 2-chlorine cyano group ethene (2.01ml) and N stirred 6 hours under the mixture reflux conditions of N-diisopropylethylamine (4.38ml) in tetrahydrofuran (THF) (100ml).Add 2-chlorine cyano group ethene (2.01ml) again, this mixture refluxes and spends the night.

After being cooled to room temperature, reaction mixture vacuum-evaporation.The residue purification by silica gel column chromatography with n-hexane/ethyl acetate (1/1) wash-out, obtains 3.28g buttery target compound (63.7%).

IR (clean, cm- ¹): 3283,3217,3114,3055,3003,2958,2839,2243,2048,1896,1732,1606.

NMR(DMSO-d ₆，δ)：3.70(3H，s)，3.74(3H，s)，4.11-4.19(2H，m)，5.20(1H，dd，J＝10.5Hz and 8.2Hz)，6.81-6.97(6H，m)，7.32-7.37(2H，m)。

MS：308(M+H) ⁺。

Embodiment 12-2

4-cyano group-1-(4-p-methoxy-phenyl)-2-(4-p-methoxy-phenyl)-1H-imidazoles

The 4-cyano group-4 that embodiment 12-1 obtains, 5-dihydro-1-(4-p-methoxy-phenyl)-2-(4-p-methoxy-phenyl)-1H-imidazoles (2.7g) and Manganse Dioxide (IV) (MnO ₂) (3.82g) at N, the suspension in the dinethylformamide (30ml) stirred 4 hours down at 100 ℃.

After the filtration, in the reaction mixture impouring water, use ethyl acetate extraction, dried over mgso and vacuum-evaporation.To the N of residue, add phosphoryl chloride (2.46ml) in the dinethylformamide solution (30ml) under 0 ℃ of stirring.

After at room temperature stirring 1 hour, reaction mixture is poured in the saturated sodium bicarbonate aqueous solution, uses ethyl acetate extraction, dried over mgso, and vacuum-evaporation obtains 2.11g target compound (78.7%).

MP：132-134℃。

NMR(DMSO-d ₆，δ)：3.74(3H，s)，3.80(3H，s)，6.87-6.93(2H，m)，7.02-7.08(2H，m)，7.23-7.34(4H，m)，8.39(1H，s)。

MS：306(M+H) ⁺。

Embodiment 13

Hydrogenchloride/ethyl acetate (254 μ l) of 4N is added in the ethyl acetate solution (1ml) of 4-cyano group-1-(4-p-methoxy-phenyl)-2-(4-the p-methoxy-phenyl)-1H-imidazoles (300mg) that is obtained by embodiment 12-2.Filter and collect the gained precipitation,, obtain 300mg target compound (86.4%) with the isopropyl ether washing.

MP：142-143℃。

MS:306 (dissociating) (M+H) ⁺

Embodiment 14

4-ethoxy carbonyl-1-(4-p-methoxy-phenyl)-2-(4-p-methoxy-phenyl)-1H-imidazoles

The mixture of 4-cyano group-1-(4-p-methoxy-phenyl)-2-(4-p-methoxy-phenyl)-1H-imidazoles (315mg) and 4N hydrogenchloride/ethanol (6.2ml) under refluxad stirred 1 hour.

After the question response mixture is cooled to room temperature, pour in the saturated sodium bicarbonate aqueous solution, use ethyl acetate extraction, dried over mgso, vacuum-evaporation.The residue purification by silica gel column chromatography with n-hexane/ethyl acetate (1/1) wash-out, obtains 0.26g target compound (71.5%).

MP：142-143℃。

NMR(DMSO-d ₆，δ)：1.29(3H，t，J＝7.1Hz)，3.74(3H，s)，3.80(3H，s)，4.27(2H，q，J＝7.1Hz)，6.88(2H，dd，J＝6.8Hz and 2.1Hz)，7.02(2H，dd，J＝6.7Hz and2.1Hz)，7.26(2H，dd，J＝5.0Hz and 2.1Hz)，7.28(2H，dd，J＝6.7Hz and 2.1Hz)，8.02(1H，s)。

MS：353(M+H) ⁺。

Embodiment 15

4-methylol-1-(4-p-methoxy-phenyl)-2-(4-p-methoxy-phenyl)-1H-imidazoles

While be added drop-wise in 4-ethoxy carbonyl-1-(4-p-methoxy-phenyl)-2-(4-the p-methoxy-phenyl)-1H-imidazoles solution (5ml) of embodiment 14 acquisitions at-78 ℃ of toluene solutions (3.76ml) that stir down 1N hydrogenation di-isopropyl aluminium, and stirred 2 hours down at-78 ℃.

With saturated aqueous ammonium chloride quencher reaction mixture, add hydrochloric acid and the water extraction of 1N subsequently.The water layer that merges neutralizes ethyl acetate extraction, dried over mgso with saturated sodium bicarbonate aqueous solution.Behind the evaporating solns, the residue purification by silica gel column chromatography with n-hexane/ethyl acetate (1/1) wash-out, obtains 0.14g target compound (30%).

IR (clean, cm ^-1): 3369,3307,3224,3076,3006,2939,2837,1676,1608.

NMR(DMSO-d ₆，δ)：3.73(3H，s)，3.79(3H，s)，4.42(2H，d，J＝5.6Hz)，4.96(1H，t，J＝5.6Hz)，6.85(2H，d，J＝8.8Hz)，7.00(2H，d，J＝8.9Hz)，7.15-7.25(5H，m)。

MS：311(M+H) ⁺。

Embodiment 16

4-formyl radical-1-(4-p-methoxy-phenyl)-2-(4-p-methoxy-phenyl)-1H-imidazoles

While in-78 ℃ of dichloromethane solutions (2ml) that stir down methyl-sulphoxide (125 μ l) adding oxalyl chloride (118 μ l).After stirring 10 minutes under-78 ℃, the dichloromethane solution (2ml) of 4-methylol-1-(4-p-methoxy-phenyl)-2-(4-p-methoxy-phenyl)-1H-imidazoles (0.21g) that adding embodiment 15 obtains ,-78 ℃ were stirred 1 hour down.Triethylamine (0.66ml) is added reaction mixture, and stirred 20 minutes down at 0 ℃.

Miscellany saturated aqueous ammonium chloride quencher, ethyl acetate extraction, dried over mgso, vacuum-evaporation obtains 120mg buttery target compound (57.5%).

IR (clean, cm ^-1): 3126,3057,3005,2960,2837,2760,2551,2048,1685,1610.

NMR(CDCl ₃，δ)：3.83(3H，s)，3.86(3H，s)，6.81(2H，dd，J＝6.9Hz and2.0Hz)，6.94(2H，dd，J＝6.8Hz and 2.1Hz)，7.16(2H，dd，J＝6.7Hz and 2.2Hz)，7.36(2H，dd，J＝6.7Hz and 2.1Hz)，7.16(1H，s)，9.98(1H，s)。

MS：309(M+H) ⁺。

Embodiment 17

Hydrochloric acid 4-difluoromethyl-1-(4-p-methoxy-phenyl)-2-(4-p-methoxy-phenyl)-1H-imidazoles

Stirs down on one side at 0 ℃ and to fluoridize in the dichloromethane solution (2ml) of 4-formyl radical-1-(4-p-methoxy-phenyl)-2-(4-p-methoxy-phenyl)-1H-imidazoles (120mg) of (diethylin) sulphur (154 μ l) adding embodiment 16 acquisitions three.

After stirring was spent the night under the room temperature, reaction mixture was poured saturated sodium bicarbonate aqueous solution into, uses ethyl acetate extraction, dried over mgso, vacuum-evaporation.The residue purification by silica gel column chromatography is with n-hexane/ethyl acetate (1/1) wash-out.After collecting fraction, evaporation removes and desolvates, and residue is dissolved in ethyl acetate (1ml).Hydrogenchloride/the ethyl acetate (97 μ l) that adds 4N.Filter and collect the gained precipitation,, obtain 24mg target compound (16.8%) with the isopropyl ether washing.

MP：150-153℃。

IR(KBr，cm ^-1)：3454，3433，3265，3101，3060，2958，2837，2735，2659，2563，1606。

NMR(DMSO-d ₆，δ)：3.76(3H，s)，3.80(3H，s)，6.84(1H，t，J＝56.2Hz)，6.91-6.97(2H，s)，7.02-7.08(2H，m)，7.28-7.38(4H，m)，7.93(1H，t，J＝2.2Hz)。

MS:331 (dissociating) (M+H) ⁺

Embodiment 18

4-carbonyl-1-(4-p-methoxy-phenyl)-2-(4-p-methoxy-phenyl)-1H-imidazoles

The mixture of 4-cyano group-1-(4-p-methoxy-phenyl)-2-(4-p-methoxy-phenyl)-1H-imidazoles (1.5g) and 50% sulfuric acid (16ml) under refluxad stirred 1 hour.

After the question response mixture is cooled to room temperature, pour it into 6% aqueous sodium hydroxide solution (100ml), wash with ethyl acetate.Water layer concentrated hydrochloric acid acidifying, ethyl acetate extraction, dried over mgso is vacuum-evaporation again.Filter and collect the gained precipitation,, obtain 1.18g target compound (74.1%) with the isopropyl ether washing.

MP：102-105℃。

IR(KBr，cm ^-1)：3427，3269，3174，3141，3086，3005，2965，2910，2839，1678，1610。

NMR(DMSO-d ₆，δ)：3.76(3H，s)，3.813(3H，s)，6.89(2H，dt，J＝7.0Hzand 2.0Hz)，7.03(2H，dt，J＝7.2Hz and 2.0Hz)，7.26-7.32(4H，m)，7.97(1H，s)。

MS：325(M+H) ⁺。

Embodiment 19

4-ethyl-methyl carbamyl-1-(4-p-methoxy-phenyl)-2-(4-p-methoxy-phenyl)-1H-imidazoles

4-carboxyl-1-(4-p-methoxy-phenyl)-2-(4-the p-methoxy-phenyl)-1H-imidazoles (170mg), N-ethyl dimethylamine (45 μ l), I-hydroxybenzotriazole (71mg) and hydrochloric acid 1-(3-the dimethylamino-propyl)-3-ethyl carbodiimide (100mg) that are obtained by embodiment 18 are at N, mixture in the dinethylformamide (5ml) stirs under the room temperature and spends the night.

Reaction mixture is poured in the water, used ethyl acetate extraction, dried over mgso, vacuum-evaporation.The residue purification by silica gel column chromatography is with n-hexane/ethyl acetate (1/1) wash-out.Filter and collect the gained precipitation,, obtain 72mg target compound (37.6%) with the isopropyl ether washing.

MP：138-139℃。

IR(KBr，cm ^-1)：3124，3068，3006，2966，2929，2841，1603。

NMR(DMSO-d ₆，δ)：1.05-1.29(3H，m)，2.91-3.03(2H，m)，3.33-3.56(2H，m)，3.74(3H，s)，3.80(3H，s)，3.91-4.06(1H，m)，6.88(2H，dt，J＝8.8Hzand 1.8Hz)，7.02(2H，dt，J＝8.8Hz and 2.0Hz)，7.23-7.30(4H，m)，7.72(1H，s)。

MS：366(M+H) ⁺。

Embodiment 20

Hydrochloric acid 4-cyclopropyl-1-(4-p-methoxy-phenyl)-2-(4-p-methoxy-phenyl)-1H-imidazoles

N ¹-(4-p-methoxy-phenyl)-4-methoxyl group benzamidine (1g), 2-bromo-1-cyclopropyl ethyl ketone (1.27g) and sodium bicarbonate (656mg) under refluxad stir at the middle mixture of 2-propyl alcohol (10ml) and spend the night.

After being cooled to room temperature, filter reaction mixture, vacuum-evaporation.Subsequently residue is poured in the water, used ethyl acetate extraction, dried over mgso, vacuum-evaporation.Residue is dissolved in acetate (10ml), refluxes 1 hour.

After being cooled to room temperature, reaction mixture is poured saturated sodium bicarbonate aqueous solution into, uses ethyl acetate extraction, dried over mgso, vacuum-evaporation.The residue purification by silica gel column chromatography is with n-hexane/ethyl acetate (3/1) wash-out.After collecting fraction, evaporation removes and desolvates, and residue is dissolved in ethyl acetate (5ml).Hydrogenchloride/the ethyl acetate (175 μ l) that adds 4N.Filter and collect the gained precipitation,, obtain 200mg target compound (14.4%) with the isopropyl ether washing.

MP：180-181℃。

IR(KBr，cm ^-1)：3273，3051，2966，2935，2906，2835，2740，2640，2592，1610。

NMR(DMSO-d ₆，δ)：0.88-0.96(2H，m)，1.00-1.07(2H，m)，2.02-2.11(2H，m)，3.79(3H，s)，3.80(3H，s)，7.00-7.11(4H，m)，7.35-7.41(4H，m)，7.67(1H，s)。

MS:321 (dissociating) (M+H) ⁺

Embodiment 21

Hydrochloric acid 1-(4-p-methoxy-phenyl)-2-(4-p-methoxy-phenyl)-4-methyl isophthalic acid H-imidazoles

In the mode of similar embodiment 20, by N ¹-(4-p-methoxy-phenyl)-4-methoxyl group benzamidine (200mg) and 1-martonite (204 μ l) obtain the 85mg target compound.

MP：203-205℃。

IR(KBr，cm ^-1)：3400，3114，3055，2966，2929，2833，2804，2711，2650，2578，2426，1612。

NMR(DMSO-d ₆，δ)：2.39(3H，s)，3.79(3H，s)，3.81(3H，s)，7.02-7.12(4H，m)，7.36-7.66(4H，m)，7.66(1H，s)，14.6-15.5(1H，br)。

MS:295 (dissociating) (M+H) ⁺

Embodiment 22-1

N ¹-(4-ethoxy carbonyl phenyl)-4-methoxyl group benzamidine

Hydroiodic acid HI 4-methoxyl group thio phenyl first imido acid methyl esters (3.9g), 4-subcutin (2.08g) and the mixture of acetate (2ml) in 2-propyl alcohol (40ml) under refluxad stirred 2 hours.

After being cooled to room temperature, reactant is poured saturated sodium bicarbonate aqueous solution into, uses ethyl acetate extraction, dried over mgso, vacuum-evaporation.Filter and collect the gained precipitation,, obtain 2.35g target compound (62.4%) with the isopropyl ether washing.

MP：128-132℃。

IR(KBr，cm ^-1)：3456，3305，3251，3178，2976，2933，2850，1711，1626。

NMR(DMSO-d ₆，δ)：1.31(3H，t，J＝7.1Hz)，3.81(3H，s)，4.28(2H，q，J＝7.1Hz)，6.46(2H，s)，6.90-7.01(4H，m)，7.86-7.91(4H，m)。

MS：299(M+H) ⁺。

Embodiment 22-2

1-(4-ethoxy carbonyl phenyl)-2-(4-p-methoxy-phenyl)-4-Trifluoromethyl-1 H-imidazoles

From N1-(4-ethoxy carbonyl phenyl)-4-methoxyl group benzamidine (0.5g), 3-bromo-1,1 that embodiment 22-1 obtains, 1-three fluoro-2-acetone (0.35ml) and the mixture of sodium bicarbonate (563mg) in 2-propyl alcohol (5ml) under refluxad stirred 4 hours.

After being cooled to room temperature, pour reactant into saturated sodium bicarbonate aqueous solution, use ethyl acetate extraction, dried over mgso, vacuum-evaporation.The residue purification by silica gel column chromatography with n-hexane/ethyl acetate (3/1) wash-out, obtains 0.53g buttery target compound (81%).

IR (clean, cm ^-1): 3745,3610,3435,3396,3365,3298,3280,3236,3130,2962,2927,2856,1693,1649.

NMR(DMSO-d ₆，δ)：1.33(3H，t，J＝7.1Hz)，3.75(3H，s)，4.34(2H，q，J＝7.1Hz)，6.91(2H，dd，J＝6.9Hz and 1.9Hz)，7.26(2H，dd，J＝6.8Hz and 2.0Hz)，7.53(2H，dd，J＝6.8Hz and 1.7Hz)，8.04(2H，dd，J＝6.7Hz and 1.8Hz)，8.25(1H，d，J＝1.2Hz)。

MS：391(M+H) ⁺。

Embodiment 23

1-(4-carbamyl phenyl)-2-(4-p-methoxy-phenyl)-4-Trifluoromethyl-1 H-imidazoles

In the mode of similar embodiment 10,1-(4-ethoxy carbonyl phenyl)-2-(4-the p-methoxy-phenyl)-4-Trifluoromethyl-1 H-imidazoles (710mg) that obtains from embodiment 22-2 obtains the 255mg target compound.

IR(KBr，cm ^-1)：3410，3303，3190，3122，2960，2841，1655，1614。

NMR(DMSO-d ₆，δ)：3.77(3H，s)，6.90(2H，dt，J＝8.8Hz and 2.0Hz)，7.26(2H，dt，J＝8.8Hz and 2.1Hz)，7.46(2H，d，J＝8.5Hz)，7.52(1H，s)，7.96(2H，d，J＝8.5Hz)，8.10(1H，s)，8.21(1H，d，J＝1.2Hz)。

MS：362(M+H) ⁺。

Embodiment 24

1-(4-cyano-phenyl)-2-(4-p-methoxy-phenyl)-4-Trifluoromethyl-1 H-imidazoles

1-(4-carbamyl phenyl)-2-(4-p-methoxy-phenyl)-4-Trifluoromethyl-1 H-imidazoles (200mg) that embodiment 23 obtains and phosphoryl chloride (0.16ml) are at N, and the mixture in the dinethylformamide (2ml) at room temperature stirred 1 hour.

Reaction mixture is poured in the saturated sodium bicarbonate aqueous solution, used ethyl acetate extraction, dried over mgso, vacuum-evaporation.Filter and collect the gained precipitation,, obtain 171mg target compound (90%) with the isopropyl ether washing.

MP：146-148℃。

IR(KBr，cm ^-1)：3415，3163，3118，3064，3012，2968，2906，2839，2229，1608。

NMR(DMSO-d ₆，δ)：3.76(3H，s)，6.92(2H，dt，J＝8.9Hz and 1.9Hz)，7.25(2H，dt，J＝8.7Hz and 2.0Hz)，7.60(2H，dt，J＝8.5Hz and 1.8Hz)，8.00(2H，dt，J＝8.6Hz and 1.7Hz)，8.27(1H，d，J＝1.1Hz)。

MS：344(M+H) ⁺。

Embodiment 25-1

4-cyano group-4,5-dihydro-1-(4-ethoxy carbonyl phenyl)-2-(4-p-methoxy-phenyl)-1H-imidazoles

In the mode of similar embodiment 12-1, from N ¹-(4-ethoxy carbonyl phenyl)-4-methoxyl group benzamidine (500mg) obtains the 265mg target compound.

IR (clean, cm ^-1): 3417,3253,3217,3068,2974,2902,2841,1711,1603.

NMR(DMSO-d ₆，δ)：1.28(3H，t，J＝7.1Hz)，3.78(3H，s)，4.26(2H，q，J＝7.1Hz)，4.31-4.46(2H，m)，5.27(1H，t，J＝9.9Hz)，6.88-6.97(4H，m)，7.37(2H，dt，J＝8.8Hz and 1.9Hz)，7.79(2H，dt，J＝8.7Hz and 1.9Hz)。

MS：350(M+H) ⁺。

Embodiment 25-2

4-cyano group-1-(4-ethoxy carbonyl phenyl)-2-(4-p-methoxy-phenyl)-1H-imidazoles

The 4-cyano group-4 that embodiment 25-1 obtains, 5-dihydro-1-(4-ethoxy carbonyl phenyl)-2-(4-p-methoxy-phenyl)-1H-imidazoles (0.26g) and Manganse Dioxide (IV) (MnO ₂) (259mg) mixture in ethyl acetate (5ml) under refluxad stir and spend the night.

After the filtration, reaction mixture is poured in the water, uses ethyl acetate extraction, dried over mgso, vacuum-evaporation.The residue purification by silica gel column chromatography with n-hexane/ethyl acetate (5/1) wash-out, obtains 117mg target compound (45.3%).

MP：139-140℃。

IR(KBr，cm ^-1)：3425，3143，3060，2979，2947，2902，2839，2235，1718，1606。

NMR(DMSO-d ₆，δ)：1.33(3H，t，J＝7.1Hz)，3.75(3H，s)，4.34(2H，q，J＝7.1Hz)，6.90(2H，dt，J＝8.8Hz and 1.9Hz)，7.25(2H，dt，J＝8.8Hz and 1.9Hz)，7.52(2H，dt，J＝8.5Hz and 1.7Hz)，8.05(2H，dt，J＝8.5Hz and 1.7Hz)，8.55(1H，s)。

MS：348(M+H) ⁺。

Embodiment 26

1-(4-carbamyl phenyl)-4-cyano group-2-(4-p-methoxy-phenyl)-1H-imidazoles

In the mode of similar embodiment 10,4-cyano group-1-(4-ethoxy carbonyl phenyl)-2-(4-the p-methoxy-phenyl)-1H-imidazoles (100mg) that obtains from embodiment 25-2 obtains 49mg target compound (53.5%).

MP：228-290℃。

IR(KBr，cm ^-1)：3456，3396，3354，3292，3172，3113，3051，2970，2837，2227，1682，1612。

NMR(DMSO-d ₆，δ)：3.75(3H，s)，6.91(2H，d，J＝8.8Hz)，7.26(2H，d，J＝8.8Hz)，7.46(2H，d，J＝8.5Hz)，7.54(1H，s)，7.97(2H，d，J＝8.5Hz)，8.11(1H，s)，8.52(1H，s)。

MS：319(M+H) ⁺。

Embodiment 27

4-cyano group-1-(4-cyano-phenyl)-2-(4-p-methoxy-phenyl)-1H-imidazoles

In the mode of similar embodiment 26,1-(4-carbamyl phenyl)-4-cyano group-2-(4-the p-methoxy-phenyl)-1H-imidazoles (40mg) that obtains from embodiment 26 obtains 24mg target compound (63.6%).

MP：185-186℃

IR(KBr，cm ^-1)：3419，3219，3132，3091，3057，3012，2968，2935，2837，2229，1608。

NMR(DMSO-d ₆，δ)：3。76(3H，s)，6.92(2H，d，J＝8.8Hz)，7.25(2H，d，J＝8.7Hz)，7.59(2H，d，J＝8.5Hz)，8.02(2H，d，J＝8.5Hz)，8.56(1H，s)。

MS：301(M+H) ⁺。

Embodiment 28

4-ethanoyl-1-(4-p-methoxy-phenyl)-2-(4-p-methoxy-phenyl)-1H-imidazoles

The diethyl ether solution (1.17ml) of 3N methylmagnesium-bromide is added in the tetrahydrofuran solution (5ml) of 4-cyano group-1-(4-p-methoxy-phenyl)-2-(4-p-methoxy-phenyl)-1H-imidazoles (357mg).

After at room temperature stirring 2 hours, reaction mixture is poured in the hydrochloric acid, uses ethyl acetate extraction, washing, dried over mgso, vacuum-evaporation.The residue purification by silica gel column chromatography with n-hexane/ethyl acetate (5/1) wash-out, obtains 258mg target compound (68.5%).

MP：116-117℃

IR(KBr，cm ^-1)：3431，3118，3066，3008，2964，2929，2837，1668，1610。

NMR(DMSO-d ₆，δ)：2.48(3H，s)，3.74(3H，s)，3.80(3H，s)，6.89(2H，d，J＝8.6Hz )，7.03(2H，d，J＝8.8Hz)，7.26-7.31(4H，m)，8.12(1H，s)。

MS：323(M+H) ⁺。

Embodiment 29-1

4-ethoxy carbonyl-4,5-dihydro-1-(4-benzyloxy phenyl)-2-(4-p-methoxy-phenyl)-1H-imidazoles

N ¹-(4-benzyloxy phenyl)-4-methoxyl group benzamidine (1.25g), 2-chloracrylic acid ethyl ester (0.76g) and N, the mixture of N-diisopropylethylamine (0.98ml) in tetrahydrofuran (THF) (12ml) under refluxad stirred 2 hours.

After being cooled to room temperature, filter reaction mixture, filtrate is poured in the water, uses ethyl acetate extraction, dried over mgso, vacuum-evaporation.

This material need not to be further purified and just is used for next step reaction.

Embodiment 29-2

4-ethoxy carbonyl-1-(4-benzyloxy phenyl)-2-(4-p-methoxy-phenyl)-1H-imidazoles

The residue of embodiment 29-1 is dissolved in N, and dinethylformamide (10ml) adds Manganse Dioxide (IV) (1.63g) in solution.

Stirring is after 4 hours down at 100 ℃, and reaction mixture is cooled to room temperature, pours in water and the ethyl acetate.After the filtration, mixture ethyl acetate extraction, dried over mgso, vacuum-evaporation.The residue purification by silica gel column chromatography with n-hexane/ethyl acetate (1/1) wash-out, obtains 1.5g buttery target compound (93.1%).

IR (clean, cm ^-1): 3433,3253,3224,3140,3064,2966,2843,1722,1712,1606.

NMR(DMSO-d ₆，δ)：1.29(3H，t，J＝7.1Hz)，3.75(3H，s)，4.27(2H，d，J＝7.1Hz)，5.15(2H，s)，6.88(2H，dt，J＝8.9Hz and 1.9Hz)，7.10(2H，dt，J＝8.9Hz and1.9Hz)，7.24-7.49(9H，m)，8.04(1H，8)。

MS：429(M+H) ⁺。

Embodiment 30

1-(4-benzyloxy phenyl)-4-formyl radical-2-(4-p-methoxy-phenyl)-1H-imidazoles

Under-78 ℃, while stirring the dichloromethane solution (5ml) that toluene solution (6.49ml) with the hydrogenation di-isopropyl aluminium of 0.95N is added dropwise to 4-ethoxy carbonyl-1-(4-benzyloxy phenyl)-2-(4-p-methoxy-phenyl)-1H-imidazoles (0.88g) that embodiment 29-2 obtains, and stirred 2 hours down at-78 ℃.

The saturated aqueous ammonium chloride quencher is used in the reaction mixture reaction, adds the hydrochloric acid of 1N then, water extraction again.After adding aqueous sodium hydroxide solution, use ethyl acetate extraction, dried over mgso, vacuum-evaporation.

Residue is dissolved in N, and dinethylformamide (10ml) adds Manganse Dioxide (IV) (1.79g) again.

After 1 hour, reaction mixture is cooled to room temperature, pours in water and the ethyl acetate 100 ℃ of stirrings.After the filtration, mixture ethyl acetate extraction, dried over mgso, vacuum-evaporation.The residue purification by silica gel column chromatography with n-hexane/ethyl acetate (1/1) wash-out, obtains 0.77g buttery target compound (97.5%).

IR (clean, cm ^-1): 3440,3361,3219,3124,3062,2937,2837,2760,1732,1684,1610.

NMR(DMSO-d ₆，δ)：3.75(3H，s)，5.16(2H，s)，6.89(2H，dt，J＝8.9Hz and1.9Hz)，7.12(2H，dt，J＝8.9Hz and 2.1Hz)，7.27-7.49(9H，m)，8.28(1H，s)，9.82(1H，s)。

MS：385(M+H) ⁺。

Embodiment 31

1-(4-benzyloxy phenyl)-4-difluoromethyl-2-(4-p-methoxy-phenyl)-1H-imidazoles

Stirs down on one side at 0 ℃ and to fluoridize in the dichloromethane solution (5ml) of 1-(4-benzyloxy phenyl)-4-formyl radical-2-(4-p-methoxy-phenyl)-1H-imidazoles (0.45g) of (diethylin) sulphur (0.46ml) adding embodiment 30 acquisitions three.

After at room temperature stirring was spent the night, reaction mixture was poured in the saturated sodium bicarbonate aqueous solution, uses ethyl acetate extraction, dried over mgso, vacuum-evaporation.The residue purification by silica gel column chromatography with n-hexane/ethyl acetate (1/1) wash-out, obtains 0.38g buttery target compound (79.9%).

IR (clean, cm ^-1): 3433,3155,3113,3066,3041,2964,2841,1732,1610.

NMR(DMSO-d ₆，δ)：3.74(3H，s)，5.15(2H，s)，6.87(2H，d，J＝8.9Hz)，7.08(1H，t，J＝55.0Hz)，7.10(2H，d，J＝8.9Hz)，7.24-7.45(9H，m)，7.73(1H，t，J＝2.3Hz)。

MS：407(M+H) ⁺。

Embodiment 32

4-difluoromethyl-1-(4-hydroxy phenyl)-2-(4-p-methoxy-phenyl)-1H-imidazoles

1-(4-benzyloxy phenyl)-4-difluoromethyl-2-(4-p-methoxy-phenyl)-1H-imidazoles (0.38g), anhydrous 20% carbon that embodiment 31 is obtained carry palladium hydroxide (Pd (OH) ₂/ C) (100mg) mixture in ethanol (8ml) and tetrahydrobenzene (4ml) under refluxad stirred 1 hour, was cooled to room temperature then.

After the filtration, reaction mixture vacuum-evaporation obtains 0.3g target compound (about 100%).

MP：143-145℃

IR(KBr，cm ^-1)：3149，3111，3003，2966，2837，2804，2679，2602，1610。

NMR(DMSO-d ₆，δ)：3.74(3H，s)，6.80-6.91(4H，m)，6.96(1H，t，J＝55.0Hz)，7.14(2H，dt，J＝8.7Hz and 1.9Hz)，7.27(2H，dt，J＝8.9Hz and 1.9Hz)，7.68(1H，t，J＝2.2Hz)，9.90(1H，s)。

MS：317(M+H) ⁺。

Embodiment 33

4-difluoromethyl-2-(4-p-methoxy-phenyl)-1-(4-trifluoro-methanesulfonyl oxy phenyl)-1H-imidazoles

In 0 ℃ of chloroformic solution (5ml) that stirs down on one side 4-difluoromethyl-1-(4-hydroxy phenyl)-2-(4-the p-methoxy-phenyl)-1H-imidazoles (300mg) of triethylamine (0.15ml) and trifluoromethanesulfanhydride anhydride (0.18ml) adding embodiment 32 acquisitions.

After 4 hours, reaction mixture is poured in the saturated sodium bicarbonate aqueous solution, uses ethyl acetate extraction, dried over mgso, vacuum-evaporation 0 ℃ of stirring.The residue purification by silica gel column chromatography with n-hexane/ethyl acetate (1/1) wash-out, obtains 0.24g buttery target compound (56.4%).

IR (clean, cm ^-1): 3159,3118,3078,3006,2939,2848,1610.

NMR(DMSO-d ₆，δ)：3.74(3H，s)，6.89(2H，dt，J＝8.9Hz and 1.9Hz)，7.01(1H，t，J＝54.8Hz)7.23(2H，dt，J＝8.9Hz and 2.0Hz)，7.54-7.69(4H，m)，7.92(1H，t，J＝2.3Hz)。

MS：449(M+H) ⁺。

Embodiment 34

1-(4-cyano-phenyl)-4-difluoromethyl-2-(4-p-methoxy-phenyl)-1H-imidazoles

Under the nitrogen atmosphere, 4-difluoromethyl-2-(4-p-methoxy-phenyl)-1-(4-trifluoro-methanesulfonyl oxy phenyl)-1H-imidazoles (0.2g), zinc cyanide (Zn (CN) that embodiment 33 obtains ₂) (55mg) close palladium (Pd (PPh with four (triphenyl phosphorus) ₃) ₄) (272mg) at N, the suspension in the dinethylformamide (1ml) stirs down at 85 ℃ and spends the night, and is cooled to room temperature then.

After the filtration, reaction mixture is poured in the water, uses ethyl acetate extraction, dried over mgso, vacuum-evaporation.The residue purification by silica gel column chromatography with n-hexane/ethyl acetate (1/1) wash-out, obtains 83mg target compound (47.7%).

MP：131-132℃。

IR(KBr，cm ^-1)：3222，3157，3114，2966，2839，2231，1610。

NMR(DMSO-d ₆，δ)：3.75(3H，s)，6.91(2H，dt，J＝8.9Hz and 1.9Hz)，7.02(1H，t，J＝54.8Hz)，7.24(2H，dt，J＝8.8Hz and 2.0Hz)，7.55(2H，dt，J＝8.7Hzand 1.7Hz)，7.93(1H，t，J＝2.2Hz)，7.95(2H，dt，J＝8.5Hz and 2.0Hz)。

MS：326(M+H) ⁺。

Embodiment 35-1

1-(4-benzyloxy phenyl)-4,5-dihydro-4-ethoxy carbonyl-2-(2-methoxyl group-5-pyridyl)-1H-imidazoles

In the mode of similar embodiment 12-1, from N ¹The mixture of-(4-benzyloxy phenyl)-2-methoxyl group-5-amidino groups pyridine (2.57g) and 2-nitrogen ethyl propenoate (1.56g) obtains 2.67g target compound (80.3%).

IR (clean, cm ^-1): 3448,3411,3378,3037,2981,2949,2902,1734,1608.

NMR(DMSO-d ₆，δ)：1.24(3H，t，J＝7.1Hz)，3.83(3H，s)，4.06(2H，d，J＝9.9Hz)，4.17(2H，q，J＝7.1Hz)，4.81(1H，t，J＝9.8Hz)，5.04(2H，s)，6.77(1H，d，J＝8.6Hz)，6.93(4H，s)，7.29-7.44(5H，m)，7.68(1H，dd，J＝8.6Hz and 2.4Hz)，8.18(1H，d，J＝2.4Hz)。

MS：432(M+H) ⁺。

Embodiment 35-2

1-(4-benzyloxy phenyl)-4-ethoxy carbonyl-2-(2-methoxyl group-5-pyridyl)-1H-imidazoles

Mode with similar embodiment 25-2, the 1-(4-benzyloxy phenyl)-4 that obtains from embodiment 35-1, the N of 5-dihydro-4-ethoxy carbonyl-2-(2-methoxyl group-5-pyridyl)-1H-imidazoles (2.67g), dinethylformamide suspension (27ml) obtains 1.74g target compound (65.5%).

MP：109-110℃.

IR(KBr，cm ^-1)：3433，3390，3136，3070，2976，2941，2841，1693，1608。

NMR(DMSO-d ₆，δ)：1.29(3H，t，J＝7.1Hz)，3.84(3H，s)，4.28(2H，q，J＝7.1Hz)，5.15(2H，s)，6.80(1H，d，J＝8.6Hz)，7.12(2H，d，J＝8.9Hz)，7.32-7.49(7H，m)，7.65(1H，dd，J＝8.6Hz and 2.4Hz)，8.06(1H，d，J＝2.4Hz)，8.12(1H，s)。

MS：430(M+H) ⁺。

Embodiment 36

1-(4-benzyloxy phenyl)-4-formyl radical-2-(2-methoxyl group-5-pyridyl)-1H-imidazoles

In the mode of similar embodiment 30, obtain 0.83g target compound (63.3%) from 1-(4-benzyloxy phenyl)-4-ethoxy carbonyl-2-(2-methoxyl group-5-pyridyl)-1H-imidazoles (1.46g).

IR (clean, cm ^-1): 3217,3126,3059,2947,2831,2760,1687,1606.

NMR(DMSO-d ₆，δ)：3.84(3H，s)，5.16(2H，s)，6.82(1H，d，J＝8.5Hz)，7.14(2H，dt，J＝8.9Hz and 2.0Hz)，7.35-7.50(7H，m)，7.66(1H，dd，J＝8.6Hzand 2.5Hz)，8.11(1H，d，2.3Hz)，8.35(1H，s)，9.84(1H，s)。

MS：386(M+H) ⁺。

Embodiment 37

1-(4-benzyloxy phenyl)-4-difluoromethyl-2-(2-methoxyl group-5-pyridyl)-1H-imidazoles

In the mode of similar embodiment 29-1,1-(4-benzyloxy phenyl)-4-formyl radical-2-(2-methoxyl group-5-the pyridyl)-1H-imidazoles that obtains from embodiment 36 obtains 0.48g target compound (54.7%).

IR (clean, cm ^-1): 3429,3209,3151,3064,3028,2979,2949,2875,2549,1734,1604.

NMR(DMSO-d ₆，δ)：3.84(3H，s)，5.15(2H，s)，6.80(1H，d，J＝8.5Hz)，7.00(1H，t，J＝54.8Hz)，7.12(2H，d，J＝9.0Hz)，7.27-7.49(7H，m)，7.63(1H，dd，J＝8.6Hz and 2.5Hz)，7.81(1H，t，J＝2.2Hz)，8.07(1H，d，J＝1.8Hz)。

MS：408(M+H) ⁺。

Embodiment 38

4-difluoromethyl-1-(4-hydroxy phenyl)-2-(2-methoxyl group-5-pyridyl)-1H-imidazoles

In the mode of similar embodiment 32,1-(4-benzyloxy phenyl)-4-difluoromethyl-2-(2-methoxyl group-5-the pyridyl)-1H-imidazoles (0.48g) that obtains from embodiment 37 obtains 0.48g target compound (about 100%).

MP：155-156℃。

IR(KBr，cm ^-1)：3012，2962，2808，2681，2603，1603。

NMR(DMSO-d ₆，δ)：3.83(3H，s)，6.77-6.86(3H，m)，6.99(1H，t，J＝54.9Hz)，7.19(2H，d，J＝8.8Hz)，7.63(1H，dd，J＝8.7Hz and 2.5Hz)，7.76(1H，t，J＝2.2Hz)，8.06(1H，d，J＝2.4Hz)，10.06(1H，br)。

MS：318(M+H) ⁺。

Embodiment 39

4-difluoromethyl-2-(2-methoxyl group-5-pyridyl)-1-(4-trifluoro-methanesulfonyl oxy phenyl)-1H-imidazoles

In the mode of similar embodiment 33,4-difluoromethyl-1-(4-hydroxy phenyl)-2-(2-methoxyl group-5-the pyridyl)-1H-imidazoles (0.17g) that obtains from embodiment 38 obtains 0.2g target compound (83.1%).

IR (clean, cm ^-1): 3429,3224,3165,3084,3020,2958,2860,1724,1664,1604.

NMR(DMSO-d ₆，δ)：3.84(3H，s)，6.80(2H，d，J＝8.4Hz)，7.03(1H，t，J＝54.8Hz)，7.56-7.71(4H，m)，7.99(1H，t，J＝2.2Hz)，8.09(1H，d，J＝2.4Hz)。

MS：450(M+H) ⁺。

Embodiment 40

1-(4-cyano-phenyl)-4-difluoromethyl-2-(2-methoxyl group-5-pyridyl)-1H-imidazoles

In the mode of similar embodiment 34,4-difluoromethyl-2-(2-methoxyl group-5-pyridyl)-1-(4-trifluoro-methanesulfonyl oxy the phenyl)-1H-imidazoles (0.2g) that obtains from embodiment 39 obtains 62mg target compound (42.7%).

MP：160-161℃。

IR(KBr，cm ^-1)：3219，3140，3101，3051，3005，2985，2954，2241，1608。

NMR(DMSO-d ₆，δ)：3.85(3H，s)，6.82(1H，d，J＝8.6Hz)，7.04(1H，t，J＝54.7Hz)，7.57-7.63(3H，m)，7.99-8.03(3H，m)，8.11(1H，d，J＝2.3Hz)。

MS：327(M+H) ⁺。

Embodiment 41-1

4-ethoxy carbonyl-4,5-dihydro-1-(4-p-methoxy-phenyl)-2-(2-methoxyl group-5-pyridyl)-1H-imidazoles

In the mode of similar embodiment 12-1, from N ¹The mixture of-(4-p-methoxy-phenyl)-2-methoxyl group-5-amidino groups pyridine (5g) and 2-chloracrylic acid ethyl ester (3.92g) obtains 5.41g target compound (78.3%).

IR (clean, cm ^-1): 3448,3429,3411,3381,3047,2981,2951,2904,2841,1736,1608.

NMR(DMSO-d ₆，δ)：1.24(3H，t，J＝7.1Hz)，3.73(3H，s)，3.83(3H，s)，4.05(2H，d，J＝9.5Hz)，4.17(2H，q，J＝7.1Hz)，4.81(1H，t，J＝9.5Hz)，6.77(1H，d，J＝8.5Hz)，6.79-6.96(4H，m)，7.67(1H，dd，J＝8.6Hz and 2.4Hz)，8.17(1H，d，J＝2.3Hz)。

MS：356(M+H) ⁺。

Embodiment 41-2

4-ethoxy carbonyl-1-(4-p-methoxy-phenyl)-2-(2-methoxyl group-5-pyridyl)-1H-imidazoles

Mode with similar embodiment 25-2,4-ethoxy carbonyl-4 from embodiment 41-1 acquisition, the N of 5-dihydro-1-(4-p-methoxy-phenyl)-2-(2-methoxyl group-5-pyridyl)-1H-imidazoles, dinethylformamide suspension (54ml) obtains 3.71g target compound (69%).

MP：135-137℃。

IR(KBr，cm ^-1)：3413，3224，3145，3070，2949，2902，2837，1703，1610。

NMR(DMSO-d ₆，δ)：1.29(3H，t，J＝7.1Hz)，3.81(3H，s)，3.83(3H，s)，4.28(2H，q，J＝7.1Hz)，6.80(1H，d，J＝8.6Hz)，7.04(2H，dt，J＝8.9Hz and2.0Hz)，7.34(2H，dt，J＝8.9Hz and 2.2Hz)，7.64(1H，dd，J＝8.6Hz and 2.5Hz)，8.06(1H，d，J＝2.4Hz)，8.11(1H，s)。

MS：354(M+H) ⁺。

Embodiment 42

4-formyl radical-1-(4-p-methoxy-phenyl)-2-(2-methoxyl group-5-pyridyl)-1H-imidazoles

In the mode of similar embodiment 30,4-ethoxy carbonyl-1-(4-p-methoxy-phenyl)-2-(2-methoxyl group-5-the pyridyl)-1H-imidazoles (1.7g) that obtains from embodiment 41-2 obtains 0.88g target compound (59.1%).

IR (clean, cm ^-1): 3435,3367,3134,3074,3006,2960,2846,1682,1608.

NMR(DMSO-d ₆，δ)：3.81(3H，s)，3.84(3H，s)，6.82(1H，d，J＝8.5Hz)，7.06(2H，dt，J＝8.9Hz and 1.9Hz)，7.37(2H，dt，J＝8.9Hz and 1.9Hz)，7.65(1H，dd，J＝8.6Hz and 2.5Hz)，8.11(1H，d，J＝2.1Hz)，8.34(1H，s)，9.84(1H，s)。

MS：310(M+H) ⁺。

Embodiment 43

4-difluoromethyl-1-(4-p-methoxy-phenyl)-2-(2-methoxyl group-5-pyridyl)-1H-imidazoles

In the mode of similar embodiment 31,4-formyl radical-1-(4-p-methoxy-phenyl)-2-(2-methoxyl group-5-the pyridyl)-1H-imidazoles (0.83g) that obtains from embodiment 42 obtains 332mg target compound (36.5%).

MP：106-107℃。

IR(KBr，cm ^-1)：3398，3153，3114，2997，2947，2844，1606。

NMP(DMSO-d ₆，δ)：3.81(3H，s)，3.83(3H，s)，6.80(1H，d，J＝8.8Hz)，7.00(1H，t，J＝54.9Hz)，7.04(2H，dt，J＝8.9Hz and 2.1Hz)，7.33(2H，dt，J＝8.8Hz and 2.1Hz)，7.63(1H，dd，J＝8.6Hz and 2.5Hz)，7.80(1H，t，J＝2.3Hz)，8.07(1H，d，J＝2.4Hz)。

MS：332(M+H) ⁺。

Embodiment 44

In the mode of similar embodiment 9, from N ¹The 2-propanol suspension (10ml) of-(4-p-methoxy-phenyl)-2-methoxyl group-5-amidino groups pyridine (1.5g) obtains 1.5g target compound (72.8%).

Embodiment 45

1-(4-benzyloxy phenyl)-4-carboxyl-2-(4-p-methoxy-phenyl)-1H-imidazoles

The aqueous sodium hydroxide solution (6.81ml) of adding 1N in the ethanol (10ml) of 4-ethoxy carbonyl-1-(4-benzyloxy phenyl)-2-(4-p-methoxy-phenyl)-1H-imidazoles that embodiment 29-2 obtains and tetrahydrofuran (THF) (10ml) solution.

After at room temperature stirring was spent the night, reaction mixture was poured in water and the ethyl acetate, the water extraction.Subsequently, water layer is used ethyl acetate extraction, dried over mgso, vacuum-evaporation with the hcl acidifying of 1N.Filter and collect the gained precipitation,, obtain target compound (1.1g) with the diisopropyl ether washing.

MP：113-115℃。

1H NMR(200MHz，DMSO-d ₆，δ)：3.75(3H，s)，5.15(2H，s)，6.88(2H，d，J＝8.8Hz)，7.10(2H，d，J＝8.9Hz)，7.24-7.45(9H，m)，7.96(1H，s)，11.0-12.5(1H，br)。

IR(KBr，cm ^-1)：3392，3224，3145，3076，2972，2935，2893，1701，1610。

Embodiment 46

1-(4-benzyloxy phenyl)-4-(N-ethyl-N-methyl carbamyl)-2-(4-p-methoxy-phenyl)-1H-imidazoles

1-(4-benzyloxy phenyl)-4-carboxyl-2-(4-p-methoxy-phenyl)-1H-imidazoles (0.44g), ethyl dimethylamine (118ml), I-hydroxybenzotriazole (186mg) and hydrochloric acid 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (263mg) that embodiment 45 obtains are at N, and the mixture in the dinethylformamide (5ml) at room temperature stirs and spends the night.

Reaction mixture is poured in the water, used ethyl acetate extraction, dried over mgso, vacuum-evaporation.The residue purification by silica gel column chromatography is with (n-hexane/ethyl acetate=1/1) wash-out.Filter and collect the gained precipitation,, obtain target compound (0.44g) with the diisopropyl ether washing.

MP：118-119℃。

1H NMR(DMSO-d ₆，δ)：1.06-1.28(3H，m)，2.91-3.02(2H，m)，3.40-3.54(2H，m)，3.74(3H，s)，3.93-4.07(1H，m)，5.15(2H，s)，6.88(2H，d，J＝8.8Hz)，7.10(2H，d，J＝8.9Hz)，7.24-7.30(4H，m)，7.36-7.49(5H，m)，7.73(1H，s)。IR(KBr，cm ^-1)：3124，3066，2958，2935，2839，1608。

Mass m/e：442(M ⁺+1)。

Embodiment 47

4-(N-ethyl-N-methyl carbamyl)-1-(4-hydroxy phenyl)-2-(4-p-methoxy-phenyl)-1H-imidazoles

In the mode of similar aftermentioned embodiment 62,1-(4-benzyloxy phenyl)-4-(N-ethyl-N-methyl carbamyl)-2-(4-the p-methoxy-phenyl)-1H-imidazoles that obtains from embodiment 46 obtains target compound.

1H NMR(DMSO-d ₆，δ)：1.10-1.28(3H，m)，2.90-3.02(2H，m)，3.40-3.50(2H，m)，3.74(3H，s)，3.91-4.03(1H，m)，6.82(2H，d，J＝8.7Hz)，6.88(2H，d，J＝8.9Hz)，7.11(1H，s)，7.14(2H，d，J＝8.7Hz)，7.27(2H，d，J＝8.7Hz)，7.67(1H，s)，

IR(KBr，cm ^-1)：3126，3091，3018，2968，2933，2831，2738，2677，2600，2476，1612。

MS m/e：352(M ⁺+1)。

Embodiment 48

1-(4-benzyloxy phenyl)-4-(N, N-diethyl amino formyl radical)-2-(4-p-methoxy-phenyl)-1H-imidazoles

In the mode of similar embodiment 46, from 1-(4-benzyloxy phenyl)-4-carboxyl-2-(4-p-methoxy-phenyl)-1H-imidazoles and N that embodiment 45 obtains, N dimethylamine obtains target compound.

MP：146-147℃。

1H NMR(DMSO-d ₆，δ)：1.10-1.30(6H，m)，3.38-3.50(2H，m)，3.74(3H，s)，3.85-4.02(2H，m)，5.15(2H，s)，6.88(2H，d，J＝8.8Hz)，7.10(2H，d，J＝8.9Hz)，7.24-7.30(4H，m)，7.36-7.49(5H，m)，7.72(1H，s)。

IR(KBr，cm ^-1)：3113，2972，2929，1593。

MS m/e：456(M ⁺+1)。

Embodiment 49

4-(N, N-diethyl amino formyl radical)-1-(4-hydroxy phenyl)-2-(4-p-methoxy-phenyl)-1H-imidazoles

In the mode of similar aftermentioned embodiment 62,1-(4-benzyloxy phenyl)-4-(N, N-diethyl amino formyl radical)-2-(4-the p-methoxy-phenyl)-1H-imidazoles that obtains from embodiment 48 obtains target compound.

1H NMR(DMSO-d ₆，δ)：1.02-1.30(6H，m)，3.22-3.48(2H，m)，3.73(3H，s)，3.83-4.02(2H，m)，6.81-6.92(4H，m)，7.14(2H，dd，J＝6.7Hz，2.0Hz)，7.27(2H，dt，J＝9.4Hz，2.5Hz)，7.66(1H，s)。

IR(KBr，cm ^-1)：3145，3030，2970，2937，2833，1693，1606。

MS m/e：366(M ⁺+1)。

Embodiment 50

1-(4-benzyloxy phenyl)-2-(4-p-methoxy-phenyl)-4-(1-piperidinyl carbonyl)-1H-imidazoles

In the mode of similar embodiment 46,1-(4-benzyloxy phenyl)-4-carboxyl-2-(4-the p-methoxy-phenyl)-1H-imidazoles and the piperidines that obtain from embodiment 45 obtain target compound (0.5g).

1H NMR(200MHz，DMSO-d ₆，δ)：1.507-1.572(4H，m)，1.605-1.67(2H，m)，3.462-3.644(2H，m)，3.74(3H，s)，3.918-4.244(2H，m)，5.144(2H，s)，6.879(2H，d，J＝4.5Hz)，7.096(2H，d，J＝4.5Hz)，7.251(2H，d，J＝4.3Hz)，7.278(2H，d，J＝4.3Hz)，7.348-7.478(5H，m)，7.721(1H，s)。

IR(KBr，cm ^-1)：3116，3033，2931，2850。

MS m/e：468(M+H) ⁺。

Embodiment 51

1-(4-hydroxy phenyl)-2-(4-p-methoxy-phenyl)-4-(1-piperidinyl carbonyl)-1H-imidazoles

In the mode of similar aftermentioned embodiment 62,1-(4-benzyloxy phenyl)-2-(4-p-methoxy-phenyl)-4-(1-the piperidinyl carbonyl)-1H-imidazoles that obtains from embodiment 50 obtains target compound (0.41g).

1H NMR(200MHz，DMSO-d ₆，δ)：1.509-1.577(4H，m)，1.611-1.674(2H，m)，3.51-3.657(2H，m)，3.734(3H，s)，4.035-4.224(2H，m)，6.814(2H，d，J＝4.4Hz)，6.881(2H，d，J＝4.3Hz)，7.136(2H，d，J＝4.4Hz)，7.256(2H，d，J＝4.4Hz)，7.668(1H，s)，9.908(1H，bs)。

IR(KBr，cm ^-1)：3151，3035，2935，2852，1606。

MS m/e：378(M+H) ⁺。

Embodiment 52-1

N ¹-(4-benzyloxy phenyl)-4-methoxyl group benzamidine

At room temperature, in the tetrahydrofuran solution (15ml) of hydrochloric acid 4-benzyloxy-aniline (3g), drip the tetrahydrofuran solution (26.7ml) of two (trimethyl silyl) acid amides sodium of 1.0M.After stirring the mixture 20 minutes, add aubepine nitrile (1.69g).

Reaction mixture stirred 4 hours, poured into then in the 300ml frozen water.Filter collecting precipitation,, finally obtain target compound (3.3g) with the diisopropyl ether washing.

1H NMR(200MHz，DMSO-d ₆，δ)：3.8(3H，s)，5.05(2H，s)，6.09(2H，bs)，6.74-6.8(2H，m)，6.96(4H，d，J＝8.5Hz)，7.29-7.49(5H，m)，7.92(2H，d，J＝8.9Hz)。

MS m/e：333(M+H) ⁺。

Embodiment 52-2

4-cyano group-4,5-dihydro-1-(4-benzyloxy phenyl)-2-(4-p-methoxy-phenyl)-1H-imidazoles

N1-(4-benzyloxy phenyl)-4-methoxyl group benzamidine (2g), 2-chlorine acrylonitrile (0.36ml) and N that embodiment 52-1 obtains, the mixture of N-diisopropylethylamine (0.79ml) in tetrahydrofuran (THF) (10ml) under refluxad stirs and spends the night.

After being cooled to room temperature, reaction mixture is poured in the water, uses ethyl acetate extraction.Organic layer water and salt water washing, dried over mgso, vacuum-evaporation.The residue purification by silica gel column chromatography with (n-hexane/ethyl acetate=1/1) wash-out, obtains target compound (0.82g).

MP：121-122℃。

1H NMR(200MHz，DMSO-d ₆，δ)：3.74(3H，s)，4.11-4.19(2H，m)，5.03(2H，s)，5.16-5.25(1H，m)，6.87(2H，d，J＝9Hz)，6.93(4H，s)，7.29-7.44(7H，m)。

MS(ESI ⁺)m/e：384(M+H) ⁺。

Embodiment 52-3

4-cyano group-1-(4-benzyloxy phenyl)-2-(4-p-methoxy-phenyl)-1H-imidazoles

The 4-cyano group-4 that embodiment 52-2 obtains, 5-dihydro-1-(4-benzyloxy phenyl)-2-(4-p-methoxy-phenyl)-1H-imidazoles (0.8g) and Manganse Dioxide (IV) are (0.91g) at N, and the suspension in the dinethylformamide (8ml) stirred 4 hours down at 100 ℃.

After the filtration, reaction mixture is poured in the water, used ethyl acetate extraction, dried over mgso, vacuum-evaporation.Under 0 ℃,, add phosphoryl chloride (0.58ml) in the dinethylformamide solution (8ml) while the N that stirs to residue.

After at room temperature stirring 2 hours, reaction mixture is poured in the saturated sodium bicarbonate aqueous solution, uses ethyl acetate extraction, dried over mgso, vacuum-evaporation.The residue purification by silica gel column chromatography with (n-hexane/ethyl acetate=3/1 → 1/1) wash-out, obtains buttery target compound (0.74g).

1H NMR(200MHz，DMSO-d ₆，δ)：3.75(3H，s)，5.16(2H，s)，6.89(2H，d，J＝8.5Hz)，7.12(2H，d，J＝9Hz)，7.25-7.48(9H，m)，8.4(1H，s)。

MS(ESI ⁺)m/e：382(M+H) ⁺。

Embodiment 53

4-cyano group-1-(4-hydroxy phenyl)-2-(4-p-methoxy-phenyl)-1H-imidazoles

In the mode of similar aftermentioned embodiment 62,4-cyano group-1-(4-benzyloxy phenyl)-2-(4-the p-methoxy-phenyl)-1H-imidazoles that obtains from embodiment 52-3 obtains target compound.

1H NMR(CDCl ₃，δ)：3.74(3H，s)，6.75-6.95(4H，m)，7.10-7.35(4H，m)，8.36(1H，s)，9.98(1H，bs)。

MS(ESI，m/e)：292(M+1)。

Embodiment 54-1

1-(4-benzyloxy phenyl)-4-cyano group-4,5-dihydro-2-(2-methoxyl group-5-pyridyl)-1H-imidazoles

In the mode of similar embodiment 52-2, from N ¹-(4-benzyloxy phenyl)-2-methoxyl group-5-pyridyl amidine obtains target compound.

1H NMR(200MHz，DMSO-d ₆，δ)：3.84(3H，s)，4.15-4.21(2H，m)，5.05(2H，s)，5.25(1H，dd，J＝8.8，10.5Hz)，6.78(1H，d，J＝8.5Hz)，6.92-7.04(4H，m)，7.32-7.45(5H，m)，7.66(1H，dd，J＝2.5，8.5Hz)，8.19(1H，d，J＝2Hz)。

MS(ESI ⁺)m/e：385(M+H) ⁺。

Embodiment 54-2

1-(4-benzyloxy phenyl)-4-cyano group-2-(2-methoxyl group-5-pyridyl)-1H-imidazoles

In the mode of similar embodiment 52-3, from 1-(4-benzyloxy phenyl)-4-cyano group-4 that embodiment 54-1 obtains, 5-dihydro-2-(2-methoxyl group-5-pyridyl)-1H-imidazoles obtains target compound.

1H NMR(200MHz，DMSO-d ₆，δ)：3.84(3H，s)，5.16(2H，s)，6.81(1H，d，J＝8Hz)，7.14(2H，d，J＝9Hz)，7.316-7.5(7H，m)，7.63(1H，dd，J＝2.3，8.5Hz)，8.1(1H，dd，J＝2.5Hz)，8.47(1H，s)。

MS(ESI ⁺)m/e：383(M+H) ⁺。

Embodiment 55

1-(4-benzyloxy phenyl)-4-ethyl carbonyl-2-(2-methoxyl group-5-pyridyl)-1H-imidazoles

In the tetrahydrofuran solution (10ml) of 1-(4-benzyloxy phenyl)-4-cyano group-2-(2-methoxyl group-5-pyridyl)-1H-imidazoles (1.1g) that 0 ℃ of tetrahydrofuran solution (8.63ml) adding embodiment 54-2 that stirs down on one side the 1N ethyl-magnesium-bromide obtains.

After at room temperature stirring 1 hour, reactant is poured in 10% the aqueous potassium hydrogen sulfate, at room temperature stirs 30 minutes.This mixture alkalizes with saturated sodium bicarbonate aqueous solution, uses ethyl acetate extraction, washes dried over mgso, vacuum-evaporation with water.Filter and collect the gained precipitation,, obtain target compound (1.07g) with the diisopropyl ether washing.

MP：126-128℃。

1HNMR(DMSO-d ₆，δ)：1.10(3H，t，J＝7.4Hz)，2.95(2H，q，J＝7.4Hz)，3.84(3H，s)，5.16(2H，s)，6.81(1H，d，J＝8.6Hz)，7.12(2H，d，J＝8.9Hz)，7.32-7.49(7H，m)，7.66(1H，dd，J＝8.6Hz，2.4Hz)，8.08(1H，d，J＝2.4Hz)，8.17(1H，s)。

IR(KBr，cm ^-1)：3217，3126，3066，3030，2972，2939，2883，1666，1610。

MS m/e：414(M ⁺+1)。

Embodiment 56

4-ethyl carbonyl-1-(4-hydroxy phenyl)-2-(2-methoxyl group-5-pyridyl)-1H-imidazoles

In the mode of similar aftermentioned embodiment 62,1-(4-benzyloxy phenyl)-4-ethyl carbonyl-2-(2-methoxyl group-5-the pyridyl)-1H-imidazoles that obtains from embodiment 55 obtains target compound.

MP：221-223℃。

1H NMR(DMSO-d ₆，δ)：1.10(3H，t，J＝7.3Hz)，2.95(2H，q，J＝7.3Hz)，3.84(3H，s)，6.79-6.88(3H，m)，7.20(2H，dt，J＝9.6Hz，2.7Hz)，7.66(1H，dd，J＝8.7Hz，2.4Hz)，8.07(1H，d，J＝2.4Hz)，9.97(1H，s)。

IR(KBr，cm ^-1)：3215，3136，3053，2978，2947，2900，1676，1603。

MS m/e：324(M ⁺+1)。

Embodiment 57

1-(4-benzyloxy phenyl)-4-sec.-propyl carbonyl-2-(2-methoxyl group-5-pyridyl)-1H-imidazoles

In the mode of similar embodiment 55,1-(4-benzyloxy phenyl)-4-cyano group-2-(2-methoxyl group-5-the pyridyl)-1H-imidazoles that obtains from embodiment 54-2 obtains target compound (1.04g).

MP：118-120℃。

1H NMR(DMSO-d ₆，δ)：1.14(6H，d，J＝6.8Hz)，3.56-3.70(1H，m)，3.84(3H，s)，5.16(2H，s)，6.81(1H，d，J＝8.5Hz)，7.13(2H，dd，J＝9.1Hz，2.3Hz)，7.32-7.49(7H，m)，7.67(1H，dd，J＝8.5Hz，2.4Hz)，8.08(1H，d，J＝2.4Hz)，8.19(1H，s)。

IR(KBr，cm ^-1)：3126，3064，3033，2968，2875，1660，1608。

MS m/e：428(M ⁺+1)。

Embodiment 58

4-sec.-propyl carbonyl-1-(4-hydroxy phenyl)-2-(2-methoxyl group-5-pyridyl)-1H-imidazoles

In the mode of similar aftermentioned embodiment 62,1-(4-benzyloxy phenyl)-4-sec.-propyl carbonyl-2-(2-methoxyl group-5-the pyridyl)-1H-imidazoles that obtains from embodiment 57 obtains target compound.

MP：185-187℃。

1H NMR(DMSO-d ₆，δ)：1.14(6H，d，J＝6.8Hz)，3.56-3.69(1H，m)，3.84(3H，s)，6.79-6.86(3H，m)，7.17-7.25(2H，m)，7.67(1H，dd，J＝8.8Hz，2.4Hz)，8.07(1H，d，J＝2.4Hz)，8.14(1H，s)，9.98(1H，s)。

IR(KBr，cm ^-1)：3134，2972，2891，2812，2744，2681，2607，1676，1612。

MS m/e：338(M ⁺+1)。

Embodiment 59

1-(4-benzyloxy phenyl)-4-cyclopentylcarbonyl-2-(2-methoxyl group-5-pyridyl)-1H-imidazoles

Following at 0 ℃ while stirring the tetrahydrofuran solution (8ml) that the tetrahydrofuran solution (3.14ml) of 2N chlorination cyclopentyl magnesium is added 1-(4-benzyloxy phenyl)-4-cyano group-2-(2-methoxyl group-5-the pyridyl)-1H-imidazoles (0.8g) of embodiment 54-2 acquisition.

After at room temperature stirring 2 hours, reaction mixture is poured in 10% the aqueous potassium hydrogen sulfate, at room temperature stirs 30 minutes.This mixture alkalizes with saturated sodium bicarbonate aqueous solution, uses ethyl acetate extraction, washes dried over mgso, vacuum-evaporation with water.Filter and collect the gained precipitation,, obtain target compound (0.82g) with the diisopropyl ether washing.

1H NMR(200MHz，DMSO-d ₆，δ)：1.57-1.949(m，8H)，3.764(1H，t，J＝7.9Hz)，3.84(3H，s)，5.156(2H，s)，6.81(1H，d，J＝8.5Hz)，7.12(2H，d，J＝9Hz)，7.328-7.501(7H，m)，7.669(1H，dd，J＝8.5Hz，2.5Hz)，8.078(1H，d，J＝1Hz)，8.188(1H，s)。

IR(KBr，cm ^-1)：3122，2947，2868，1658，1608。

MS(ESI ⁺，m/e)：454(M+H)。

Embodiment 60

4-cyclopentylcarbonyl-1-(4-hydroxy phenyl)-2-(2-methoxyl group-5-pyridyl)-1H-imidazoles

In the mode of similar aftermentioned embodiment 62,1-(4-benzyloxy phenyl)-4-cyclopentylcarbonyl-2-(2-methoxyl group-5-the pyridyl)-1H-imidazoles that obtains from embodiment 59 obtains target compound.

1H NMR(200MHz，DMSO-d ₆，δ)：1.577-1.968(8H，m)，3.761(1H，t，J＝8Hz)，3.836(3H，s)，6.793-6.859(3H，m)，7.21(2H，d，J＝7Hz)，7.667(1H，dd，J＝9Hz，2.5Hz)，8.069(1H，d，J＝1.5Hz)，8.143(1H，s)。

IR(KBr，cm ^-1)：3220，3124，2960，1674，1608。

MS(ESI ⁺，m/e)：364(M+H)。

Embodiment 61

1-(4-benzyloxy phenyl)-2-(4-p-methoxy-phenyl)-4-Trifluoromethyl-1 H-imidazoles

N ¹-(4-benzyloxy phenyl)-4-methoxyl group benzamidine (1g), 3-bromo-1,1,1-trifluoroacetone (0.47ml) and the mixture of sodium bicarbonate (506mg) in Virahol (10ml) under refluxad stir and spend the night.

After being cooled to room temperature, filter reaction mixture, vacuum-evaporation.Subsequently residue is poured in the water, used ethyl acetate extraction, dried over mgso, vacuum-evaporation.The residue purification by silica gel column chromatography with (n-hexane/ethyl acetate=1/1) wash-out, obtains oily target compound (0.55g).

1H NMR(DMSO-d ₆，δ)：3.75(3H，s)，5.16(2H，s)，6.86-6.92(2H，m)，7.09-7.13(2H，m)，7.25-7.50(9H，m)，8.08(1H，d，J＝1.4Hz)。

IR(Neat，cm ^-1)：3120，3068，2973，2843，1610。

MS m/e：425(M ⁺+1)。

Embodiment 62

1-(4-hydroxy phenyl)-2-(4-p-methoxy-phenyl)-4-Trifluoromethyl-1 H-imidazoles

1-(4-benzyloxy phenyl)-2-(4-p-methoxy-phenyl)-4-Trifluoromethyl-1 H-imidazoles (0.55g), anhydrous 20%Pd (OH) that embodiment 61 in ethanol (10ml) and the tetrahydrobenzene (5ml) obtains ₂/ C (200mg) under refluxad stirred 2 hours, was cooled to room temperature then.

After the filtration, the vacuum-evaporation reaction mixture obtains target compound (0.44g).

MP：215-216℃。

1H NMR(DMSO-d ₆，δ)：3.74(3H，s)，6.81-6，92(4H，m)，7.16-7.30(4H，m)，8.03(1H，d，J＝1.3Hz)。

IR(KBr，cm ^-1)：3149，3103，3037，2964，2910，2829，2690，2611，1649，1614。

Ms m/e：335(M ⁺+1)。

[A] analgesic effect:

Effect to adjuvant arthritis rats:

(i) test method:

Studied the analgesic effect of single-dose preparations to rats with arthritis.

To contain 0.5mg Mycobacterium tuberculosis (Mycobacterium tuberculosis) (DifcoLaboratories, Detroit, whiteruss 50 μ l Mich.) be expelled to 7 age in week the Lewis rat right back sufficient sole of the foot portion, induce sacroiliitis.The 22nd day with the threshold of pain and the body weight random packet (n=10) of rats with arthritis based on left back sufficient sole of the foot portion, be used for pharmacological agent.

Give medicine (test-compound), measure the threshold of pain after 2 hours.Assess hyperalgesic intensity with the Randall-Selitto method.By (Italy) the compressing ankle joint is measured the mechanical pain threshold value of left back foot (not injecting metapedes) for Ugo Basile Co.Ltd., Varese with the equilibrium pressure instrument.Rat cries or the threshold pressure when struggling is represented with gram.With the threshold pressure of administration rat and not the administration rat compare.The dosage of ratio 1.5 is considered to effective dose.

(ii) test-results:

Test-compound (embodiment number)	Dosage (mg/kg)	The pain relieving coefficient
Test-compound (embodiment number)	Dosage (mg/kg)	The pain relieving coefficient	3-2 11 24 28 40 43	3.2 3.2 3.2 3.2 3.2 3.2	＞1.5 ＞1.5 ＞1.5 ＞1.5 ＞1.5 ＞1.5

[B] is to the inhibition activity of COX-I and COX-II

(whole blood check):

(i) test method:

Whole blood check at COX-I

Take a blood sample to the volunteer with the syringe that does not contain antithrombotics.These research objects do not have tangible inflammatory diseases, and do not take any medicine with interior at least 7 days before the blood sampling.

At once 500 μ l people whole bloods and 2 μ l methyl-sulphoxide vehicle or final concentration test-compound were hatched 1 hour at 37 ℃, allow blood coagulation.Use suitable processing (not hatching) as blank.Hatch when finishing, the indomethacin (5 μ l) that adds 250mM is with termination reaction.Blood sample 6000 * g under 4 ℃ obtained serum in centrifugal 5 minutes.Get 100 μ l serum and 400 μ l methanol mixed with protein precipitation.6000 * g obtained supernatant in centrifugal 5 minutes under 4 ℃, and adopted enzyme linked immunological kit to detect TXB according to manufacturer's operation instruction ₂For test-compound, the result be expressed as with the contrast that contains the methyl-sulphoxide vehicle hatch the group compare thromboxan B ₂(TXB ₂) the inhibition per-cent that generates.

By being logarithmic value with concentration conversion shown in the test-compound and carrying out simple linear regression, analytical data.Calculate IC by method of least squares ₅₀Value.

Whole blood check at COX-II

Collect fresh blood by syringe to the heparinization test tube from the volunteer.Before having tangible inflammatory diseases and get blood, these research objects do not take any medicine with interior at least 7 days.

The test-compound of 500 μ l people whole bloods and 2 μ l methyl-sulphoxide vehicle or 2 μ l final concentrations was hatched 15 minutes at 37 ℃.Subsequently the 5mg/ml lipopolysaccharides of blood and 10 μ l was hatched 24 hours in 37 ℃, to induce COX-II.Adopt suitable substance P BS to handle (not containing lipopolysaccharides) as blank.Hatch when finishing, with blood sample centrifugal 5 minutes, obtain blood plasma under 4 ℃ with 6000 * g.Get 100 μ l blood plasma and 400 μ l methanol mixed, with protein precipitation.6000 * g obtained supernatant in centrifugal 5 minutes under 4 ℃, used the radioimmunity test kit, illustrated PGE according to manufacturer ₂After being converted into its oxime acid methyl ester derivation, measure PGE ₂(PGE ₂).

The test-results of test-compound group be expressed as with the contrast that contains the methyl-sulphoxide vehicle hatch the group compare PGE ₂The inhibition per-cent that generates.By being logarithmic value with concentration conversion shown in the test-compound and carrying out simple linear regression, analytical data.Calculate IC by method of least squares ₅₀Value.

(ii) test-results

Test-compound (embodiment number)	COX-I IC ₅₀(μM)	COX-II IC ₅₀(μM)
Test-compound (embodiment number)	COX-I IC ₅₀(μM)	COX-II IC ₅₀(μM)	1-2 3-2 4-2 8 11 17 20 21 24 34 40 43	＜0.01 ＜0.01 ＜0.01 ＜0.01 ＜0.01 ＜0.01 ＜0.01 ＜0.01 ＜0.01 ＜0.01 ＜0.01 ＜0.01	≥0.1 ≥0.1 ≥0.1 ≥0.1 ≥0.1 ≥0.1 ≥0.1 ≥0.1 ≥0.1 ≥0.1 ≥0.1 ≥0.1

Above test-results shows that The compounds of this invention (I) and drug acceptable salt thereof have the inhibition activity of anti-COX, have the selective inhibitory activity of anti-COX-I especially.

In addition, confirmed that also compound of the present invention (I) does not have the adverse side effect of non-selective NSAID, for example gastrointestinal disturbance, hemorrhage, renal toxicity, cardiovascular effect etc.Therefore, compound (I) and salt thereof are expected to as medicine.

Compound of the present invention (I) and drug acceptable salt thereof have COX and suppress active, and have strong anti-inflammatory, bring down a fever, pain relieving, antithrombotic and antitumour activity etc.

Therefore, by whole body or topical, compound (I) and drug acceptable salt thereof be used for the treatment of and/or prevent that COX in the mankind or the animal is disease mediated, inflammatory diseases, various pain, collagen diseases, autoimmune disease, various Immunological diseases, thrombosis, cancer and nerve degenerative diseases.

More particularly, target compound (I) and drug acceptable salt is used for the treatment of and/or preventing inflammation and acute or chronic joint and myalgia (for example, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, urarthritis, adolescent arthritis etc.), inflammatory dermatosis (for example, sunburn, burn, eczema, dermatitis etc.), inflammatory eye disease (for example conjunctivitis etc.), the tuberculosis that relates to inflammation (for example, asthma, bronchitis, raise dove person disease, farmer lung etc.), the gastrointestinal tract disease relevant (for example, aphthous ulcer with inflammation, the Chrohn disease, atopy gastritis (atopic gastritis), alastrim gastritis (gastritis varialoforme), ulcerative colitis, coeliac disease, Crohn disease and irritable bowel syndrome etc.), oulitis, inflammation, postoperative or wound pain and swelling, the heating relevant with inflammation, pain and other illness are the symptom of factor with lipoxygenase and cyclo-oxygenase products particularly, systemic lupus erythematosus, scleroderma, polymyositis, tendonitis, bursitis, arteritis nodosa, rheumatic fever, Sjogren syndrome, the Behcet disease, thyroiditis, type i diabetes, nephrotic syndrome, aplastic anemia, myasthenia gravis, contact uveitis (uveitis contact dermatitis), psoriasis, mucocutaneous lymphnode syndrome, sarcoidosis, Hodgkin, alzheimer's disease etc.

In addition, scheduled target compound (I) and salt thereof can be used as and treats and/or prevents medicine, are used for disease cardiovascular or that cerebrovascular disease, hyperglycemia and hyperlipemia cause.

In addition, expected compound (I) and salt thereof are as pain killer, be used for the treatment of or prophylaxis of acute or chronic inflammatory diseases pain that cause or that be correlated with, for example rheumatoid arthritis, osteoarthritis, lumbar rheumatism, rheumatoid spondylitis, urarthritis, juvenile arthritis; Pain and swelling etc. after pain in the back, neck-shoulder-arm syndromes, scapulohumeral periarthritis, postoperative or the wound.

The patent that this paper quoted, patent application and publication are attached to herein by reference.

The application is based on the Australian provisional application 2003904068 of Australian provisional application application August 1 in 2003903861,2003 of Australian provisional application application July 24 in 2003902208,2003 of application on May 8th, 2003, and its content is attached to herein by reference.

Claims

1. formula (I) compound or its drug acceptable salt:

Wherein

R ¹For (rudimentary) alkyl, cycloalkyl, formamyl, N-[(that (rudimentary) alkyl, halo (rudimentary) alkyl, hydroxyl replace rudimentary) alkyl] formamyl, N, N-two [(rudimentary) alkyl] formamyl, formyl radical, (rudimentary) alkyloyl, carboxyl, [(rudimentary) alkoxyl group] carbonyl, cyano group, naphthene base carbonyl or heterocycle carbonyl;

R ²Be halogen, cyano group, hydroxyl, (rudimentary) alkoxyl group, aryl [(rudimentary) alkyl] oxygen base, [(rudimentary) alkoxyl group] carbonyl, formamyl, formyl radical oxygen base, (rudimentary) alkanoyloxy, [(rudimentary) alkyl] sulfonyloxy, [halo (rudimentary) alkyl] sulfonyloxy or carboxyl;

R ³For (rudimentary) alkoxyl group, hydroxyl, amino, [(rudimentary) alkyl) amino or two [(rudimentary) alkyl] amino;

X and Y respectively do for oneself CH or N.

2. the compound of claim 1 or its drug acceptable salt:

Wherein

R ¹Be (rudimentary) alkyl, halo (rudimentary) alkyl, cycloalkyl, N, N-two [(rudimentary) alkyl] formamyl, (rudimentary) alkyloyl or cyano group;

R ²Be halogen, cyano group, hydroxyl or lower alkoxy;

R ³Be lower alkoxy;

3. medicine, described pharmaceutical pack contain right and require 1 or 2 compounds as activeconstituents.

4. pharmaceutical composition, described pharmaceutical composition comprise claim 1 or 2 compounds as activeconstituents, described compound and drug acceptable carrier or excipient composition.

5. method that treats and/or prevents following disease: inflammatory diseases, various pain, collagen diseases, autoimmune disease, various Immunological diseases, thrombosis, cancer or nerve degenerative diseases, described method comprise claim 1 or 2 compounds that give the mankind or animal effective dose.

6. claim 1 or 2 the purposes of compound in treating and/or preventing the following disease of the mankind or animal: inflammatory diseases, various pain, collagen diseases, autoimmune disease, various Immunological diseases, thrombosis, cancer or nerve degenerative diseases.

7. claim 1 or 2 compound treat and/or prevent purposes in the medicine of the mankind or the following disease of animal in preparation: inflammatory diseases, various pain, collagen diseases, autoimmune disease, various Immunological diseases, thrombosis, cancer or nerve degenerative diseases.

8. pain killer, described pain killer comprises claim 1 or 2 compounds, and described pain killer can be used for treating and/or preventing by acute or that chronic inflammatory diseases causes or relative pain.

9. the pain killer of claim 8, described pain killer can be used for treating or prevent pain that caused by following disease or relative: rheumatoid arthritis, osteoarthritis, lumbar rheumatism, rheumatoid spondylitis, urarthritis, juvenile arthritis; Pain in the back; Neck-shoulder-arm syndromes; Scapulohumeral periarthritis; Operation or damage back pain and swelling.

10. commodity package that comprises pharmaceutical composition, described pharmaceutical composition contains the compound (I) and the relative printed instructions of claim 1 or 2, and wherein said printed instructions has illustrated that compound (I) can maybe should be used for prevention or treatment inflammatory diseases, various pain, collagen diseases, autoimmune disease, various Immunological diseases, pain relieving, thrombosis, cancer or nerve degenerative diseases.