CA1244032A - Imidazole derivatives - Google Patents

Abstract

ABSTRACT

An imidazole derivative of the formula:

wherein each of R1 and R4 is a hydrogen atom or a lower alkyl group; each of R2 and R3 is a nydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group an araIkyloxy group, a nitro group or an amino group; A is -O-, -S-, -CH=CH- pr -OH=N-; Z is an aryl group, a thienyl group, a pyridyl group or a furyl group, in which definition these aromatic (hetero-cyclio) rings may have 1 to 3 substituents, each substituent boing independently selected from a halogen atom, a lower alkyl group, a cyclic alkyl group, a lower alkoxy group, a hydroxyl group, a carboxyl group, a lower alkoxycarbonyl group, a carboxy-lower-alkoxy group, a di-lower-alkylamino-lower-alkoxy group and a nitro group; and a pharmaceutically acceptable acid addition salt thereof, a method for preparing the same and a pharmaceutical composition containing such compound.
Such compounds have inhibitory activities on biosynthesis of thromboxane A2, inhibitory activities on platelet aggregation, vasodilative activities and protective effects on liver disorders.

Description

.

Imidazole Deri7atives Technical Field Thi8 invention relates to novel imidazole derivatives and pharmaceutic211 acceptabla acid addition salts thereo~ useful a pbarmaceutical~, method~ for preparing the sa~e and pharmaceutical oompositions containing such compound~

Disclo6ure o~ the In~ention _ _ _ Imidazole derivatives of thi~ in~enti¢n are represented by tha formulas ~I R2 Ng ~ I--Of2 (I) ~3 Z

~herein each of Rl and R4 i~ a hydrogan atom or a lower alk~l group~ aach of R2 and R3 i~ a hydrogen atom~ a halogen atom~ a ~ydro~yl group~ a lGwer alkyl group~ a lo~er alko~y group~ an araLkylQ~y group~ a nitro group cr an amino group; A iB -0-~ -S-~ -CH=CH- ~r -CH ~-; Z is an aryl group~ a thienyl group~

a pyridyl group ar a furyl group~ in ~hich definiti~n these aromatio (~atero-cyclic) ring~ may have 1 to 3 ~ubstituants~ aaoh substituent being independontlyselected from a halogen atom, a lower aIk~l group~ a cy¢lic alkyl graup~ a lower alko~y group~ a b;ydro~r gro~p~ a ca:rbo:~l groul?, a l~er alkca;yca:rbon~1 ; -- 1 --1 group~ a carboTy-lower-alkory group~ a dilower-alkylami~o-lower-alko~y group snd a nitro group.
In the above defi~itions~ the lo~er alkyl grcup includes methyl~ e ~yl~
propyl, isopropyl, bu~yl~ isobu~yl, sec-butyl and tert-butyl; the cyclic zl~yl groIp includes cyclopropyl a~d cyclohe2yl; the lo~er alko~y group includes metho y~ ethoIy9propo~y~ i~opropo~y znd buto~y; ~he aralkylo~y group includes benzylo~y snd phenethylo~; the lower sl~o ycarbon~l group includes methozy-carbonyl~ etho~yc~rbo~yl~ propo~ycarbonyl~ isopropQ~yc2~bo~yl and bu~oxyczrbonyl;
the csrbo~y-lower-alko~y group includes carbc~ ~ tho~y~ carbo yethc~ carbo~y-propo~y s~d carborybuto~y; the d;lo~er~alkylamino-lower-al~c~y group includeo dimethylaminoethoxy~ dimethylaminopropo~y~ dim~thylaminobuto~y~ dietkylamino-etho2y~ dipropylaminoetho~y and dibutylaminoethory~ the h~logen atom includes fluorine~ ohlorine~ bromine and iodine; the aryl group inolude~ phenyl and naphthyl. . ~
According to this inventio~ the oompounds of fcrmula (I) can be prepa~ed by th~ following methods; for e~ample:
~ethod 1 ~his method comprises reaoting a oompound of the formula:

C =

wherein each sy~bol is as defined above9 ~ith an or~a~ometallio compound of the formula [ a Grignard reagent (III) or an organolit~ium compound (IV)~:
ZMgX (III) or ZLi (IV) 1 ~herein X is a halogen atom such as chlorine9 bromine or iodine and Z is as defined above ~ his invention is carried out in a non-an~uecus ~olvent (e.g. ether~
tetrahydrofuran~ dio~ane, bensene or toluene).
Method 2 ~ his method~ to be applied for the production of compounds of formula (I) wherein R4 is a hydrogen atom, comprises sub~ecting a compound of the formula:

~N ~ I =O (V) to reduction~ wherein each symbol i8 a~ defined above.
As a reduoing agent can be employed a conventional reagent having the ability to reduce a oarbonyl group to the seoondary alcohol.
IrhiB reaotion is carried out by treating a suspensionor a soluticn of the compound of formula (V) in a suitable solvent (e.g. wa-ter~ methanol~
ethanol, dioxane or a mi~ture thereof) with a oomple~ metal hydride such as sodium borohydride at a temperature of from room temperature to a boiling point of the solvent employed~ preferably from room temperat~8 to 100C~ for an hour to ?4 hours. This reaction is also carried out by reducing the compound of formula (V) uith a comple metal hydride such as lithium aluminum hydride or sodium bi~-(2-metho~yetho~y)aluminum hydride in a suitable non-aqueGus solvent (e.g. ether, tetrahydrofuran, dioxane or benzene) at a te~perature from room temperature to a boiling point of the solvent employed.

l Method 3 This method~ to be applied for the production of compounds of formulz (I) wherein R4 is a lower alkyl group~ comprises reacting the ~bove-mentioned compound of formula (V):

.` Rl R7 1~ ~C (~ (V) ~herein each symbol iB as defined abo~e, with a compound of the formula:
R5~5g (VI) whersin R5 i8 a lower alkyl group and X is as defined abc~e~
This reaotion is carried out in a non-~ueous solvent (e.g. ether~
tetrahydrofuran~ diorane~ ben~ene or toluene).
The starting oompounds of formula (V) can be prepared, for example~ by the follo~ing M~thod A or Method B:
~ethod A
This method oomprises reacting a oompound of the formula:

,, Rl ~ (VII) ~H

wherein Rl is as defined abo~e~ with a oompound of the formula:
R -~ C = ~ (VIII) R 3 A z ~C~ 3~

1 wherein Y is a halogen atom and R2~ R3, A a~d Z are as defined above.
~ his reaction is generally carried out by treating a metal salt of the compound of fcrmul2 (VII), which is obtained by treating the compound of formula (VII) with a base (e.g. sodium hydride~ sodium amide~ a sodium zlko~ide such as sodium metho~ide or sodium ethQxide~ or potassium carbonate) ~ith the compound of formula (VIII) at a temperature of from room temperature to a boiling point of the solvent employed for an hour to 24 hc~rs.
Method 3 This method comprise~ reacting a compound of the formula:
Rl R2 ~N ~ C N (I~) wherein each symbol is as defined above7 with the compound of for~ula (III) or the compou~d o~ formula (IV) in a non-aqueou~ solvent (aOgO ether~ tetra-hydrofuran~ dio~ane or benzene)~ and then subjecting the res~t.ing compound to hydrolysis.

The starting compounds of formula (II) aan be prepared by the same method for the production of compounds of formula (V)~ for e~mple~ by the follouing h~ethod C or Method D.
Method C
~hi6 method comprises reacting the compound of formula (VII) with a compound of the formula:
R

y ~ ~ C = O (~) l-~3 1 wherein each symbol is as defined above.
~ hi5 reaction is generall~ c~rried out by treating a metal salt of the compound of formula (VII), which i5 obtained by reacting the com~ound of formula (VII) with a base (e.g. sodium hydride? sodium amide, a sodium aIko~ide such as sodium methoOEide or sodium etho~ide or potassium carb~nate~, ~ith the compound of for~ula (~) at a temperature of from room temperature to a boiling point of the solvent e~ployed for an hcur to 24 hours.
Method D
~his method, to be ~lied for the production of compounds of formula (II) wherein R4 is a lo~er alkyl group~ comprises reacting the compound of formLla (I~) ~ith the c~mpound of formula (VI)~ and then subjecting the resulting compound to ~vdrolysis.
Furthermore~ the starting compounds of formNlas (VIII) and (~) can easil~ prepared in a conventional manner employed in the field of synthetic organio chemistry suoh as ~riedel-Crafts reaction.
~ he novel imidazole derivatives of formula (I) thus obtained can be converted into phzr~aoeutioally aooeptable acid addition salts by treating the oomp ~d ~ith ino~ga~io aoids suoh as hydroohlorio aoid~ hydrobromic aoid or sulfuric acid and organic acids such as o~alio acid~ f~umaric aoid~ maleic gcid, m2ndelic acid, citric acid~ tartario aoid and salicylio aoid~ if desIred.
~ he compound6 of formula (I) are prese~t in the form of opticPl isomers~
and this inTention embraces all classes of these indiTidual isomers a~d the mi tures thereof. When the resolution of racemic compounds iB necess~-y~
conventional manners such as fi~actional crystallizatio~s and various chromato-gra~hic techniaue~ are aYailable.
~ne imidazole derivatives of fo~mula (I) and acid additian salts thereof 1 h~ve ph~macological activities such as inhibitory ~ctivitieq cn biosyn~hesis of thromboxane A2, inhibitory activities on platelet ag~regation or v2sodilative activities, and these are useful for the prcphylaxis or ~he ther2py of thromDosi~
cerebral apople~y, myocardial infarction, acute heart death, zng_na pectoris~
hypertention, asthma or nephritis.
Furthermore, the compounds of this invention exhibit potent prot3ctive sffects on animal liver discrders induced by carbon tetrachloride, and are useful for treating hepatic insufficiencies such as acute and chranic hepatitis, hepatocirrihosis~ fa-tty liver or toxic hepatitis induced by ethanol~ a~ organo-phosphorus insecticide~ chloroform or carbon tetrachloride.
~ he following eYperimental data demonstrate ~he pharmaceutical utilitiesof the compounds of this invention.
(1) q~he inhibitory activities on pla-telet aggregation Accarding to the method described in Journal of Physiology~ vol. 162 page 67 (1962)~ the inhibitory aotivities of compounds of this invention an platelet ag~regation were measured from the ohanges in transmittance with an aggregometer (Rikadenki Eleotranics Co.~ Japan).
~efore and ane haur after the oral administration o~ test compaunds to rabbits, blood was colleoted. ~he blood was mixed with sodiu~ citrate in the ratio of 9:1 by volume. Platelet rich plasma (PRP) was prepared by centrifuging the citrated blood at lOO0 rpm far lO minutes~ and platelet poor plasma (PPP), by centrifuging the remaining citrat~d blood at 3OOO rpm ~or 10 minutes.
The transmittance of aggregometer was adjusted to O and lOO~o with PRP and PPP~ respectively. To 0.3 ml of a PRP sample was added 0.003 ml of arachidonic acid solution~ ~he changes in transmittance of the mi ture were 3~

1 measured using the aggregometer with stirring at 1200 rpm.
Lnhibitory activities on platelet aggregation were assessed 2S ~o inhibition by com~aring the rate of aggrsgation of treated PRP with thPt of blood collected before the oral administration of test compounds. The results are summerized in Table 1.
Table 1 Inh~bitory activities on platelet aggregation Test oompound Rate of Dose (mg/kg)inhibition (~) a-(2,4,6-~rimethylphanyl)-3-chloro-4-(1-imidazolyl)- 10 80 benzenemethanol a_(2,4~6-qrimethylphenyl)-3-(1-imidazolyl)benzene- 10 100 methanol a_(2~4~6-qrimethylphenyl)-

2-methyl-3~ imid~zolyl)- 10 68 benze~eme~noI
_ -(2~4~6-~rimethylphenyl)-4-methyl-3-(1-imidazolyl)- 10 88 benzenemethanol a_(2~4~6-Trimet~ylphenyl)-2-chloro-5-(1-imidazolyl)- 10 71 benzenemethanol -(2~4~6-Trimethylphenyl)-2-methyl-5-(l-imid2zolyl)- 10 100 benzenemethanol _ i 1 (2) Effect on arachidonic acid metabolism Effects of test ccmpounds on t~rombo~ane synthetase~ cyclo-o~y~en2se ~nd prostacyclin synthetase Nere e~amined in vitro by follswing methods:
(a) Inhibit~ry effect cn thrombosane synthetase According to the method described in Journal of Biological Chemisiry~
vol. 252, page S871 (1977), thrombo3ane was prcduced by incubating human platelet micrcsomes ~ith 4.3 ~ 14C-arachidonic acid at 25C for 5 minutes.
Since thromb~ane A2 i8 extrem01y short-lived~ thromboxane B2~ which iæ a stable degradation prod~ct of thromboxane A2, was assayed. The incubation mixture was e~tracted with ethyl acetate~ and thromb~ane B2 was separated on a thin-layer chromatogram. The zone of thrombo~ane ~2 on a silica gel plate was detected with a radiochromatoscanner and scraped off. The radio-activities were determired ~ith a liquid scintilation counter.
The inhibitory activities of test compounds on thrombo~ane synthetase were assessed by comparing the conten-ts of thrombo~ane formed in the presenoe and the absence of test compound~.
The re~ults are ~ummeri2ed in q'able 2. .
(b) Inhibitory effect on cyolo-oxygenase According to the method described in Proceedings of National Academy of Sciences~ ~.S.A., vol. 71~ page 3645 (1974)~ bovine seminal vesicle microsomes were incubated with 104.3 ~ M 14C-arachidonic acid at 25~C fcr 10 minutes.
Prostaglandin E2 thus formed was separated and assayed using tha same method as (a).
The inhibit~rr activities of test compounds on cyclo-o~ygenase were assessed by comparing the contents of prostaglandin E2 formed i~ the presence and absènce of test ccmpound The resul~s are summerized in Table 2.

33~

1 (c) Inhibito~y effect on prostacyclin synthetase According to the method described in ~ournal of P_armacology and perimental Therapeutics, vol. 215, page 240 (1980), prostacyclin was formed by incubating the rat arota ring ~ith 1.7)~M 14C-arachidonic acid at 37 C
for 20 minutes. Since prostacyclin is extremely short-lived~ 6-keto-prosta-glandin Fla, which is a stable degradation product of prostacyclin~ was separated and assayed using the same method as (a).
The inhibitory acti~ities of test compounds on prostacyclin synthetass were assessed by comparing the contents of 6-keto-prostaglandin Fl~ formed in the presence and the absence of test compounds.
The results are summerized in Table 2.
Table 2 _ ~ffeot on araohidonio acid metabolism (5 ~ inhibitory molar oonoentration) Test oom20und TnhibitOry I~hibitory Inhibitory effect on effect on effect on thromboxane cyolo-oxygenase prostacyclin synthetase synthetaae _ .
a_ (2~4~6-Trimethylphenyl)- -7 -4 -4

3~o~1cro~4~ imidazolyl)- 1.8 ~ 10 > 10 > 10 benzenemethanol a_ (2~4 ? 6-Trimethylphen~l)- -7 -3 -4 3-(1-imidazolyl)benzene- 3.4 x 10 > 10 > 10 methanol _ -(2~4~6 Trimethylphenyl)- -6 -3 -3 2-chloro-5~ imidazolyl)~ 2.3 ~ 10 ~ 10 > 10 benzenemethanol a_(2~4~6-lrimethylphenyl)- -7 2-methyl-5-(1-imidazolyl~- 8.2 ~ 10 ~ot tested ~ot tested benzenemethanol 1 (3) Acute to~icity According to the method described in Journal of Pharmacological 2nd E~perimantal Thera~eutics~ vol. 96~ ~age ~9 (1949), the tsst co~pounds were orally administered to a grouD consisting of six male ~istar rats. ~ne 5 ~o 5 lethal doses (LD50, mg/kg) ~ere determined. The result~ are summeri~ed in Table 3.
l'able 3 _ qest co~pound / 5 a_(2~4~6-lrimethylphenyl)-3-chloro-

4-(1-imidazolyl)benzenemethanol > 1~000 a_(2~4,6-qrimethylphenyl)-3-(l-imidazolyl)benzenemethanol ~ 1~000 -(2~4~6-Trimethylphenyl)-2-methyl-3-(1-imidazolyl)benaenemethanol . > 1~000 _ a-(2~4~6-lrimethylphenyl)-4-me ~4yl-3-(1-imidazolyl)benzenemethanol > 1~000 .
-(2~4~6-qrimethylphenyl)-2-chloro-

5-(1-imidazolyl)benzenemethanol > 1~000 -(2,4,6-~rimethylphenyl)-2-methyl-5-(1-imidazolyl)benzenemethanol > 1~000 3~
1 When the compounds of this invention are used as medicines~ they may be administered orzlly or oarenterally in the form of tablets~ c2psules~ granules~
powder or injectaole solutions by mi i~g with a pharmacologically acceptable carrier, e2cipient or diluent.
~he dose may vary depending upon the disease to be treated or the conditions of the patients to be treated~ but the daily dose preferably ranges from 0.01 to 50 mg per Kg of human body weight~ in 1 to 4 times divided doses.
The oresent invention will be more concretely explained ~y the following working and reference e~amples~ but they should not be thought to indicate the scope of the invention.
Reference Exam~le 1 A Grignard reagent which i~ prepared by reacting 1.9 g of magnesium with 15 g of p-chlorobromooenzene in 150 ml of anhydrous ether is added to a susoension of 10.2 g of 3-oyano-2-(1-imidazolyl)pyridine in 200 ml of be~zene at 30-35 C. After the addition is complete~ the whole mixture is stirred at room temoerature for 1.5 hours. The reaction mi~ture is treated with an aqueous ammonium chloride solution under ice cooling. To the benzene laysr oontaining the resulting 3-(4-ohloroben~imidoyl)-2-(1-imidazolyl)pyridine i8 added dilute hydrochloric soid and the mi~ture is stirred at 35 C for 10 minutesto hydrolize. The dilute hydroohloric aoid layer is separated and made alkaline with sodium hydro~ide and then e~tracted with ohloroform. The ohloroform lzyer is washed with water~ dried and oQnoentrat~sd to give 3-(4-ohlorobenzoyl)-2-(1-imidazolyl)pyridineas an oil in high yield. This oily product oan ba used in the ne~t reaction without isolation, but when the oil is treated with toluene~
crystallization takes plaoe. Upon reorystallization from toluene the produot is obt~ined as white orystals, ~slting at 118-120 C.

c~ 3~

1 ~eference E~am~le 2 To a suspension of 13 g of sodium hydride (6~o dispersion in minerzl oil) in 240 ml of dime~hylfcrmamide is added 20 g of imidazole ov~r a 15 minute period under occasional ice cooling. After the mixture is stirred at room temperzture for an hour~ 60 g of 2-chloro-5-(4-chloroben~oyl)pyridine is added.
The ~hole mistur~ is heated to 35C znd an e~othermic reaction stzrts. When the tem~erature rise6 at 60C, the mi~ture is ice-cooled and then stirred at room tem~erature for an hour. Th~ reaction mixture is poured into ice-cold water, the crystals precipitated are filtered off and recrystallized from ethanol to give 58 g cf 5-(4-chlorobenzoyl)-2-(1-imidazolyl)pyridine as ~hite crystals~ melting at 155-156C.
Reference Exam~le 3 To a suspension of 2.9 g of sodium hydride (6 ~ dis~ersion in mineral oil) in 50 ml of he~amethylphosphorio triamide is added 5~3 g of imidaæole over a 30 minute period under heating at 40 C. After the addition is complete~ the mixture i8 stirred at room t0mperature for an hour. To the reactio~ mixture is added 16.6 g of 3-fluoro-2',4'~6'-trimethylbenzophenone and the mi~ture is stirred at 70C for 24 hours The reaotion solution is poured into ice-oold water and extracted with ethyl acetate The ethyl acetate layer is ~ashed with wat0r, dried and concentrated The residue is recrystalli~ed from a mixture of toluene and isopropyl ether to give 16 g of 3-(l~imidazolyl)-2',4'~6'-tri-methylben~ophenone as ~hite crystals, melting at 134-136 C.
~eference Example 4 To a suspension of 2.3 g of sodium hydride (6 ~ dispersion in mineral oil) in 50 ml of dimethylformamide is added 4.2 g of imidazole over a 5 minute period under occasional ice oooling. After stirring at room temperature for 1 30 minutes, a solution of 14.2 g of 3-chlaro-4-fluoro-2~4'~6~-trimethylbenzo-phenone in 10 ml of dimethylformamide i5 added and the mi~ture is stirred at 50C for 3 hours. The reaction mixture is poured into ice-cold water and e~tracted with benzene. After benzene is distilled off~ vhe residue is purifisd column-cbromatographically to give 15.6 g of 3-chloro-4-(1-imidazoly1)-2'J4'~

6'-trimetnylbenzophenone as a colorless oil.
E~am~le To a suspension of 16 g of 3-(1-imidazolyl)-2'~4~61-trimet~ylbenzo-phenone in 90 ml of ethanol is added a solution of 3.4 g of ~odium borohydride in 30 ml of water. After stirring at 56C f~r 20 hours~ the reaction mi~ture is poured into ice-cold water. The precipitate is filtered off and recrystallized from a mi~ture of dio~ane and water to give 13.6 g of -(2~4,6-trimethylphenyl)-3-(1-imidazolyl)benzenemethanol as white orystal~:~ melting at 191-193 C.
E~am~le 2 In 100 ml of ethanol i8 dissolved 15.6 g of oily 3-chloro-4-(1-imida olyl)-2~4~6~-trimethylbenzophenone obtained in the referenoe example 4. To the ethanol solution is added a solution of 1.8 g of sodium borohydride in 20 ml of water. After the whole solution i~ stirred at 50C for 17 hours~ the reaction mi~ture is poured into ioe-cold water and extract~d with ohloroform.
The ohloroform is distilled off and the re~idue is reorystallized from toluene to give 14 g of a-(2~4~6-trimethylphenyl)-3-chloro-4~ imidazolyl)benzene methanol as white crystals~ melting at 156-15~ C.
E~am~le 3 To a suspen6ion of 10.9 g of 2 chloro-5-(1-imidazolyl)-2'~4~6'-tri-methylbenzophenone m 65 ml of ethanol is added a solution of 1.4 g of sodium borohydride in 14 ml of water. ~ne mi~ture is stirred at 50 C for 18 hcurs~

_ 14 1 and then the reaction mi~urs is poured into ice-cold water. ~he crystals precipitated are filtered off and recrystallized from ethanol to give 9.4 g of a-(2~4~6-trimethylphenyl)-2-chloro-5-(l-imidazolyl)benzenemethanol as white crystals, melting at 206-207C.
E~am~le 4 ~o a suspension of 7O3 g of 2-methyl-5-(1-imidazolyl)-2',4',6'-tri-methylbenzophenone in 50 ml of ethanol is added a solution of 1 g cf sodium borohydride in 10 ml of ~-ater. After the m;~ture is stirred at 50 C for 10 hours~ the reaction mirture is poured into ice-cold water ~he crystals precipitated are filtered off and recrystallized from ethanol to give 5.8 g of -(2~4~6-trimethylphenyl)-2-methyl-5-(1-imidaYolyl)benzenemethanol as white crystal6~ melting at 190-191C.
E~am~le ~
To a suspension of 4 g of 2-methQ~y-5-(1-imidazolyl)-2'~4'~6'-trimethyl-benzophenone in 20 ml of ethanol is added a solution of 0.9 g of sodium boro-hydride in 5 ml of water. After the whole mixtule is stirred at 70-75C for 1.5 hours~ the rsaction mi~ture is poured into ice-cold ~ater. ~he crystals precipi~3ted are filtered off and recrystallized from ethanol to give 2.9 g of -(2~4~6-trimethylphenyl)-2-methoxy-5-(1-imidazolyl)benzenemethanol as white crystals~ melting at 187-188C.
Exam~le 6 A Grignard reagent which is prepared by reaoting 1.9 g of magnesium with 15 g of p-chlorobromobenzene in 40 ml of ether is added to a ~uspension of 6.2 g of 4-(1-imidazolyl)benzaldehyde in 70 ml of ether at 0 C. After the mirture is stirred at room temperature for an hour, the reaotion mi~ture is poured into an aaue~us ammonium chloride solution with cauticn. The mi~ture ,.
~ ~ 15 ~c~

1 i~ e~tracted ~ith chloroform and the chlorofarm is distilled o~f. ~he residue is purified column-chromatographically and recrystallized from toluene to give 8.6 g of a-(4-chlorophenyl)-4~ imidazolyl)benzenemethanol as ~hite crystals~
melting at 148~5~149.5C.
E~ample 7 ~o a solution of 4.8 g of 3-(4-chlarobenzoyl)-2-(1-imidazolyl)pyridine in 35 ml of ethanol and 5 ml of water is add~d 0.64 g of sodium borohydride~
After the mi~turs i8 stirred at room temperature for an hour~ t~s re~ction mi~ture is poured into ~ater and e~tracted ~ith chlorofarm. ~he chlaroform is distill~d off and the residue iB recrystallized from toluene to give 4.3 g of a-(4-chlorophenyl)-2-(l-imidazolyl)-3-pyridinsm0thanol a~ white crystals~
melting at 133-134C.
Exam~le 8 ~o a ~olution of 7 g of 5-(4-chlarobenzoyl)-2-(1-imidazalyl)pyridine 15 in 60 ml of et~anol plu3 10 ml of ~ater is added 1 ~ of sodium barohydride.
After the mi~ture is stirred at room temperature far an haur~ the solvent is dietilled off. To th~ re~idue is added water and the mi~ture is e~tracted ~ith ohlorofarm. A~ter the ohlorofarm is distilled ofP~ the residue is recrg~
talliz0d from a m~rture of toluene and ethanol to give 605 g of -(4-chlaro-phenyl)-2-(1-imidanol~1)-5-pyridinemethanol a~ white crystals~ melting at 147 14~C.
E~am~le 2 ~ Grignard reagent which is prepared by reacting o.46 g of magnesium with 3 g of methyl ioaide in 30 ml of ethsr is added to a susp~nsion of 4.5 g of 2~ imidazolyl)-5-(4-ohlorobenzoyl)pyridine in 50 ml o~ e~her at -5C.
After the mi~ture is stirred at room temperature for an hour~ th~ reaction 1 mi~ture is poured into an aaueous ammonium chloride solution with caUtiQn.
~he precipitate is e2tracted ~ith chloroform and the chloroform is distilled off. ~he residue is recrystallized from toluene to giv~ 4.1 g of 1-[2-(1-imidazolyl)-5-pyridyl)-1-(4-chlorophenyl)etnanol in 90.3~o yields as wnite crystals, melting at 140-142C.
~he follo~ing com~ounds can be prepared in a simil~r manner men4icned in the above E~amples:
(10) a-(2,416~ kylphenyl)-2-met~yl-3--(l--imidazol~l)benzenemethanol, melting at 221-222C
(11) -(2,4,6-1rimethylphenyl)-4-me-thyl-3-(1-imidazo~l)benzenemethanol~
melting at 132-133C
(12) a-(2~4~6-Irimethylphenyl)-3-chlcro-5-(l-imidazolyl)benzenemethan melting at 194-196C
(13) a-(2~4~6-lrimethylphenyl)~2-hydroxy-5-(l-imidazolyl)benzene methanol~ melting at 188-lE39C (deoomposition) (14) a-(4-chloropherlyl)-3-nitro-4-(l-imidazolyl)benzenemethan semi-solid Elementary an~lysis:
C (~) ~ (%) ~ (%) Found : 58.31 3.63 12.83 Calculated : 58.28 3 67 12.74 tl5) -(2-Chlorophenyl)-4-(1-imidazolyl)benzenemethanol hydrochloride~
melting at 212-214C.
(16~ -(2,4,6-lrimethylphenyl)-4-(1-imidazolyl)benzenemethQnol, mel4ing at 155-157 C~ its hydrochloride~mme7ting at 234-235 C ~decomposition) (17) a-(4-chlorophen~l)-3-amino-4-(l-imidazolyl)benzenemethan melting at 202-203C

~f~

1 (18) a-(4-Nitrophenyl)-4-(l-imidazolyl)benzenemethanol~ melting at (19) a-(4-Chlorophenyl)-3-met~yl~4-(l~imidazolyl)benzenemethanol~
mel~ing at 144-145C
(20) -(2,4,6-lrimet~ylphenyl)-3-methyl-4-(1-imidazolyl)benzenemPthanol, melting at 8G-100C
(21) -Phenyl-3-(1-imidazolyl)benzenemethanol~ melting at 110-112 C
(22) -(4-Methylphenyl)-3-(1-imidazolyl)benzenemethanol~ melting at (23) a-(2-Meth~Iy-5-methylphenyl)-3-(l-imidazolyl)benzenemethan melting at 127-128C
(24) -(2-Methylphenyl)-4-methoxy-3-(1-imidazolyl)benzenemethanol~
a colorless oily product; ~MR (CDC13)~ (ppm): 2.20 (s~ 3H~ -C6E4-CH3), 3.72 ( 6 ~ 3H~ 0-CH3) (25) -(2,4~6-Trimathylphenyl)-2-(1-imidazolyl)benzenemethanol~
melting at 201-203C
(26) -(2~4,6-lrimethylphenyl)-2-chloro-4-(1-im;dazolyl)benzenemethanol, melting at 154-156C
(27) a-(2-~hienyl)-3_(1-imidazolyl)benzenemethanol~ meltir.g at 107-(28) -(2-Methoey-3-pyridyl)-4-(1-imidazolyl)benzenemethanol~ melting at 162-164C
(29) a-(2-Furyl)-4-(1-imidazolyl)benzenemethanol~ melting at 136-(30) a_(2_rhienyl)-2-(1-imidazolyl)benzenemethanol~ melting at 143-3~

1 (31) a-(2-Thienyl)-2~(2-methyl-l-imidazolyl)benzenemethan melting at 134-136C
(32) a-(3-Carboxyphenyl)-3-(l-imidazolyl)benzenemethanol~ melting at 162-164C
(33) -(2,4,6-Trimet~ylphenyl)-5-chloro-2-(l-imid2zolyl)benzenemethanol~
melting at 190-192C
(34) a-(4-ter~-~utyl-2~6-dimathylphenyl)-2-chloro-5-(l-imidazolyl) ben~enemethanol, melting at 171-173 C
(35) a-(2~4~6-lrimethylphen~ 3-amino-5-(l-imidazolyl)benzenemethan melting at 205-207C
(36) a-(2~4~6-qrimethylphenyl)-3-methoxy-5-(l-imidazolyl)benzene methanol~ melting at 149-151C
(37) a-(2~4?6-Trimethylphenyl)-2-isopropoxy-~-(l-imidazolyl)benzene methanol~ melting at 167-168C
(38) a-(2~4~6-Trimethylphenyl)-4-methQ~y-3-(l-imidazolyl)benzene methanol~ meltin at 118~119C
(39) a- (2~4~6-~rimsthylphenyl)-4-isopropRxy-3-(1-imidazolyl)benzene-methanol, melting at 167-168C
(40) a-(2~4~6-~rrimethylphenyl)-4-hydrQxy-3-(l-imidazolyl)benzene methanol~ melting at 205-206C (decompooition) (41) a-(2~4~6~Trimethylphenyl)-4-benzylQ~y-3-(l-imidazolyl)benzene methanol~ melting at 185-187C
(42) a-(2~4~6-Trimethylphenyl)-2-benzylo~y-5-(l-imidazolyl)benzene methanol~ melting at 189-190 C
(43) a-(3~5-Di-tert-butyl-4-hydro~yphenyl)-3-(1-imidazolyl)benzene-methanol -- lg 3~

1 (44) a-(2~4~6-~rimethylphenyl)-3-nitro-5-(l-imidazolyl)benzeneme~hanol (45) a-(2~4,6-r~rimethylphenyl)-2-nitro-5-(1-imidzzolyl)benzeneme~banol (46) a_(2~4~6-r~rimethylphenyl)-3-bromo-5-(1-imidazolyl)benzenemetn~nol (47) ~-(2,~,6-lrimethylphenyl)-2-chloro-3-(1-imidzzolyl)benzenemethznol (48) a-(2~4~6-lrimethylphenyl)-4-chloro-3-(1-imidazo~yl)benzenemethznol (49) a-(2~4~6-r~rimethylphenyl)-2 amino-5-(1-imidazolyl)benzenemethanol (50) a-(4_Chorophenyl)-2-(2-methyl-1-imidzzolyl)-3-pyridinemethznol~
melting at 203-210C
(5].) a-Phenyl-2-(1-imidazolyl)-5-pyridinsmethanol~ melting at 144-(52) a_(4 Pluorophenyl)-2-(1-imidazolyl)-5-pyridinemetbanol~ melting at 133-135C
(53) a-(4-E~lethylphenyl)-2-(l-imidazolyl)-5-pyridinemethanol~ mel~ing at 149-150C
(54) a-(3~4-Dimethylphenyl)-2-(l-i~idazolyl) 5-pyridinemeth2nol~
melting at 139-141C
(55) a-(4 Cyolohexylphenyl)-2-(1-i~idazolyl)-5-pyridinemethanol~
melting at 162-163C
(56) a-(2~4,6-l~imethylphenyl)-2-(1-imidazolyl)-5~pyridinemethanol.
hydroohloride~ melting at 237-238 C (decomposition) (57) a (4-Metho~yphenyl)-2-(1-imidazolyl)-5-pyridinemethanol~
mel~ing at 116-119C
(58) ~-(2-~etho~y-j-methylphenyl)-2-(l-imidazolyl)-5-pyridinemeth2nol~
melting at 141-143C
(59) a-(2-~ydroxy-5-methylphenyl)-2-(l-imidazolyl)-5-pyridinemethan melting at 164-166 C

3~

1 (60) a-(2-Metho~y-5-chlorophenyl)-2-(l-imid2zolyl)-5-pyridineme~r~n melting at 171-172 C
(61) a-(2,4-Dimetho~yphenyl)-2-(1-imidazolyl)-5-pyridinemetkanol~
melting at 138-140C
(62) a-(2,5-Dimethoxyphenyl)-2-(1-imidazolyl)-5-pyridinemet nol~
melting at 127-129C
(63) a-(3,4-Dimetho~yphenyl)-2-(1-imidazolyl)-5-pyridinemethanol~
meltin~ at 154-155C
(64) a-(4-Carbo~yphenyl)-2-(l-imidazolyl)-5-pyridinemethanol~ melting at 224-228C
(65) -(6-Metho~y-2-naphthyl)-2-(1-imidazolyl)-5-pyridinemethanol~
semi-solid ~lementary analysis:
C (%)~ (%~ N (~o) Found : 72.735.11 12.95 Calculated : 72 49 5.17 12068 (66) a-(2-carbo~ymethox~-5-methylphenyl)-2-(l-imidazolyl)-5-pyridine methano~ melting at 219-220C (deoompositio.n) (67) a- (2-Dimethylaminoethoey-5-methylphenyl)-2-(1-imidazolyl)-5-pyridinemetkænol o~alate, melting at 157-158C (decomposition) (68) a-(4-~etho~ycarbonylphenyl)-2-(l-imidaY.olyl)-5-p~ridinemethanol~
melting at 150C
(69) a-(4-chlorophenyl)-2-(2-metkyl-l-imida~olyl)-5-pyridinemethan melting at 106-110C
(70) a-(4-chlorophenyl)-5-(l-imidazolyl)-2-tkiophenemethanol hydro-chloride, melting at 176-177 C

1 (71) ~-(2,4,6-~rimethylphe~yl)-5-(1-imidazolyl)-2-furanme~hanol~
melting at 142-144 C
ormulztion ~xam~le 25 mg tablets are prepared from the follo~ing composition:
Compound of ~ample 3 25.0 mg Lactose 70.0 mg Starch 10.0 mg icrocrystalline cellulose10.~ mg ~alc 4.0 mg Magnesium stearate 0.5 mg 120.0 mg ~ hese tablets can be film-coated or sugar-coated~ if desired. Further~
capsules can be prepared by filling the above composition in a soft capsule.

~lthough this invention has been adequately discussed in the foregoing specification and examples included therein~ one readily recogniæes that various changes and modifications may be made ~ithout departing from the spirit and scope thereof,

Claims (38)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing an imidazole derivative of the formula (I) (I) wherein each of R1 and R4 is a hydrogen atom or a lower alkyl group; each of R2 and R3 is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, an aralkyloxy group, a nitro group or an amino group;
A is -O-, -S-, -CH=CH- or -CH=N-, Z is an aryl group, a thienyl group; a pyridyl group or a furyl group, in which definition these aromatic (heterocyclic) rings may have 1 to 3 substituents, each substituent being independently selected from a halogen atom, a lower alkyl group, a cyclic alkyl group, a lower alkoxy group, a hydroxyl group, a carboxyl group, a lower alkoxycarbonyl group, a carboxy-lower-alkoxy group, a di-lower-alkylamino-lower-alkoxy group and a nitro group, or a pharmaceutically acceptable acid Claim 1 continued...

addition salt thereof, comprising a process selected from the group of processes comprising:
(a) a process for preparing an imidazole derivative of the formula (I) above or a pharmaceutically acceptable acid addition salt thereof, wherein each of R1, R2, R3, R4, A and Z is as defined above which comprises reacting a compound of the formula:
with an organometallic compound of the formula:
ZMgX or ZLi wherein R1, R2, R3, R4, A and Z are as defined above and X
is a halogen atom;
(b) a process for preparing an imidazole derivative of the formula (I) above, or a pharmaceutically acceptable acid addition salt thereof, wherein each of Claim 1 (b) continued...

R1, R2, R3, A and Z is as defined above and R4 is hydrogen which comprises subjecting to reduction a compound of the formula:

wherein R1, R2, R3, A and Z are as defined above, and (c) a process for preparing an imidazole derivative of the formula (I) above, or a pharmaceutically acceptable acid addition salt thereof, wherein each of R1, R2, R3, A
and Z are as defined above and R4 is a lower alkyl group, which comprises reacting a compound of the formula:


1. Claim 1 (c) continued...
   
   wherein R1, R2, R3, A and Z are as defined above with a compound of the formula:
   R5MgX
   wherein R5 is a lower alkyl group.
   
   2. An imidazole derivative of the formula:
   
   wherein each of R1 and R4 is a hydrogen atom or a lower alkyl group; each of R2 and R3 is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, an aralkyloxy group, a nitro group or an amino group;
   A is -O-, -S-, -CH=CH- or -CH=N-; Z is an aryl group, a thienyl group; a pyridyl group or a furyl group, in which definition these aromatic (heterocyclic) rings may have 1 to 3 substituents, each substituent being independently selected from a halogen atom, a lower alkyl group, a cyclic alkyl group, a lower alkoxy group, a hydroxyl group, a
2. Claim 2 continued...
   
   carboxyl group, a lower alkoxycarbonyl group, a carboxy-lower-alkoxy group, a di-lower-alkylamino-lower-alkoxy group and a nitro group, or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 1 or an obvious chemical equivalent.
3. 3. Process (a) of claim 1.
4. 4. The imidazole derivative claimed in claim 2 when prepared by the process of claim 3 or an obvious chemical equivalent.
5. 5. Process (b) of claim 1.
6. 6. The imidazole derivative claimed in claim 2 wherein R4 is hydrogen when prepared by the process of claim 5 or an obvious chemical equivalent.
7. 7. Process (c) of claim 1.
8. 8. The imidazole derivative claimed in claim 2 wherein R4 is a lower alkyl group when prepared by the process of claim 7 or an obvious chemical equivalent.
9. 9. A process for preparing ?-(2,4,6-trimethylphenyl)-3-chloro-4-(1-imidazolyl)benzenemethanol which comprises subjecting 3-chloro-4-(1-imidazolyl)-2',4',6-trimethylbenzophenone to reduction with sodium borohydride.
10. 10. ?-(2,4,6-Trimethylphenyl)-3-chloro-4-(1-imidazolyl)benzenemethanol when prepared by the process of claim 9 or an obvious chemical equivalent.
11. 11. A process of preparing ?-(2,4,6-trimethylphenyl)-3-(1-imidazolyl)benzenemethanol which comprises subjecting 3-(1-imdazolyl)-2',4',6'-trimethylbenzophenone to reduction with sodium borohydride.
12. 12. ?-(2,4,6-Trimethylphenyl)-3-(1-imidazolyl)-benzenemethanol when prepared by the process of claim 11 or an obvious chemical equivalent.
13. 13. A process for preparing ?-(2,4,6-trimethylphenyl)-2-methyl-3-(1-imidazolyl)benzenemethanol which comprises reacting 2-methyl-3-(1-imidazolyl)-benzaldehyde with 2,4,6-trimethylphenylmagnesium bromide.
14. 14. ?-(2,4,6-Trimethylphenyl)-2-methyl-3-(1-imidazolyl)benzenemethanol when prepared by the process of claim 13 or an obvious chemical equivalent.
15. 15. A process for preparing ?-(2,4,6-trimethylphenyl)-4-methyl-3-(1-imidazolyl)benzenemethanol which comprises subjecting 4-methyl-3-(1-imidazolyl)-2',4',6'-trimethylphenyl benzophenone to reduction with sodium borohydride.
16. 16. ?-(2,4,6-Trimethylphenyl)-4-methyl-3-(1-imidazolyl)benzenemethanol when prepared by the process of claim 15 or an obvious chemical equivalent.
17. 17. A process for preparing ?-(2,4,6-trimethylphenyl)-2-chloro-5-(1-imidazolyl)benzenemethabol which comprises subjecting 2-chloro-5-(1-imidazolyl)-2,4,6-trimethylphenyl benzophenone to reduction with sodium borohydride.
18. 18. ?-(2,4,6-Trimethylphenyl)-2-chloro-5-(1-imidazolyl)benzenemethabol when prepared by the process of claim 17 or an obvious chemical equivalent.
19. 19. A process for preparing ?-(2,4,6-trimethylphenyl)-2-methyl-5-(1-imidazolyl)benzenemethanol which comprises subjecting 2-methyl-5-(1-imidazolyl)-2',4',6'-trimethylphenyl benzophenone to reduction with sodium borohydride.
20. 20. ?-(2,4,6 Trimethylphenyl)-2-methyl-5-(1-imidazolyl)benzenemethanol when prepared by the process of claim 19 or an obvious chemical equivalent.
21. 21. A process for preparing ?-(2,4,6-trimethylphenyl)-2-methoxy-5-(1-imidazolyl)benzenemethanol which comprises subjecting 2-methoxy-5-(1-imidazolyl)-2',4',6'-trimethylphenyl benzophenone to reduction with sodium borohydride.
22. 22. ?-(2,4,6-Trimethylphenyl)-2 methoxy-5-(1-imidazolyl)benzenemethanol when prepared by the process of claim 21 or an obvious chemical equivalent.
23. 23. A process for preparing ?-(2,4,6-trimethylphenyl)-3-chloro-5-(1-imidazolyl)benzenemethanol which comprises reacting 3-chloro-5-(1-imidazolyl)-benzaldehyde with 2,4,6-trimethylphenylmagnesium bromide.
24. 24. ?-(2,4,6-Trimethylphenyl)-3-chloro-5-(1-imidazolyl)benzenemethanol when prepared by the process of claim 23 or an obvious chemical equivalent.
25. 25. A process for preparing ?-(2,4,6-trimethylphenyl)-2-hydroxy-5-(1-imidazolyl)-benzenemethanol,which comprises subjecting 2-hydroxy-5-(1-imidazolyl)-2',4',6'-trimethyphenyl benzophenone to reduction with sodium borohydride.
26. 26. ?-(2,4,6-Trimethylphenyl)-2-hydroxy-5-(1-imidazolyl)-benzenemethanol when prepared by the process of claim 25 or an obvious chemical equivalent.
27. 27. An imidazole derivative of the general formula (I) as defined in claim 1 and the pharmaceutically acceptable acid addition salts thereof.
28. 28. An imidazole derivative of the general formula (I) as defined in claim 1 wherein R4 is hydrogen, and the pharmaceutically acceptable acid addition salts thereof.
29. 29. An imidazole derivative of the general formula (I) as defined in claim 1 wherein R4 is a lower alkyl group and the pharmaceutically acceptable acid addition salts thereof.
30. 30. ?-(2,4,6-Trimethylphenyl)-3-chloro-4-(1-imidazolyl)benzenemthanol.
31. 31. ?-(2,4,6-Trimethylphenyl)-3-(1-imidazolyl)-benzenemethanol.
32. 32. ?-(2,4,6-Trimethylphenyl)-2-methyl-3-(1-imidazolyl)benzenemethanol.
33. 33. ?-(2,4,6-Trimethylphenyl)-4-methyl-3-(1-imidazolyl)benzenemethanol.
34. 34. ?-(2,4,6-Trimethylphenyl)-2-chloro-5-(1-imidazolyl)benzenemethanol.
35. 35. ?-(2,4,6-Trimethylphenyl)-2-methyl-5-(1-imidazolyl)benzenemethanol.
36. 36. ?-(2,4,6-Trimethylphenyl)-2-methoxy-5-(1-imidazolyl)benzenemethanol.
37. 37. ?-(2,4,6-Trimethylphenyl)-3-chloro-5-(1-imidazolyl)benzenemethanol,
38. 38. ?-(2,4,6-Trimethylphenyl)-2-hydroxy-5-(1-imidazolyl)benzenemethanol.