DERIVES D'IMIDAZOLE

IMIDAZOLE DERIVATIVES

Abrégé anglais

ABSTRACT
An imidazole derivative of the formula:
<IMG>
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.

Revendications

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)
<IMG> (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
23

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:
<IMG>
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
24

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:
<IMG>
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:
<IMG>

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:
<IMG>
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
26

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. Process (a) of claim 1.
4. The imidazole derivative claimed in claim 2 when
prepared by the process of claim 3 or an obvious chemical
equivalent.
5. Process (b) of claim 1.
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. Process (c) of claim 1.
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. 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.
27

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. 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. ?-(2,4,6-Trimethylphenyl)-3-(1-imidazolyl)-
benzenemethanol when prepared by the process of claim 11 or
an obvious chemical equivalent.
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. ?-(2,4,6-Trimethylphenyl)-2-methyl-3-(1-
imidazolyl)benzenemethanol when prepared by the process of
claim 13 or an obvious chemical equivalent.
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.
28

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. 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. ?-(2,4,6-Trimethylphenyl)-2-chloro-5-(1-
imidazolyl)benzenemethabol when prepared by the process of
claim 17 or an obvious chemical equivalent.
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. ?-(2,4,6 Trimethylphenyl)-2-methyl-5-(1-
imidazolyl)benzenemethanol when prepared by the process of
claim 19 or an obvious chemical equivalent.
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.
29

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. 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. ?-(2,4,6-Trimethylphenyl)-3-chloro-5-(1-
imidazolyl)benzenemethanol when prepared by the process of
claim 23 or an obvious chemical equivalent.
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. ?-(2,4,6-Trimethylphenyl)-2-hydroxy-5-(1-
imidazolyl)-benzenemethanol when prepared by the process of
claim 25 or an obvious chemical equivalent.

27. An imidazole derivative of the general formula
(I) as defined in claim 1 and the pharmaceutically
acceptable acid addition salts thereof.
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. 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. ?-(2,4,6-Trimethylphenyl)-3-chloro-4-(1-
imidazolyl)benzenemthanol.
31. ?-(2,4,6-Trimethylphenyl)-3-(1-imidazolyl)-
benzenemethanol.
32. ?-(2,4,6-Trimethylphenyl)-2-methyl-3-(1-
imidazolyl)benzenemethanol.
31

33. ?-(2,4,6-Trimethylphenyl)-4-methyl-3-(1-
imidazolyl)benzenemethanol.
34. ?-(2,4,6-Trimethylphenyl)-2-chloro-5-(1-
imidazolyl)benzenemethanol.
35. ?-(2,4,6-Trimethylphenyl)-2-methyl-5-(1-
imidazolyl)benzenemethanol.
36. ?-(2,4,6-Trimethylphenyl)-2-methoxy-5-(1-
imidazolyl)benzenemethanol.
37. ?-(2,4,6-Trimethylphenyl)-3-chloro-5-(1-
imidazolyl)benzenemethanol,
38. ?-(2,4,6-Trimethylphenyl)-2-hydroxy-5-(1-
imidazolyl)benzenemethanol.
32

Description

1 S P E C I F I C A T I O N
.
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:
R I R 2
C =
R 3
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)
-- 2

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:
R I R2
~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)
R3 Z
~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~)
R3
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
- 6 - -

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
-- 10

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.
- 12

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
- 13

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
- 16

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
- 17

~f~
1 (18) a-(4-Nitrophenyl)-4-(l-imidazolyl)benzenemethanol~ melting at
176-178C
(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
131-133C
(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-
109C
(28) -(2-Methoey-3-pyridyl)-4-(1-imidazolyl)benzenemethanol~ melting
at 162-164C
(29) a-(2-Furyl)-4-(1-imidazolyl)benzenemethanol~ melting at 136-
138C
(30) a_(2_rhienyl)-2-(1-imidazolyl)benzenemethanol~ melting at 143-
14-4C
- 18

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-
146C
(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
- 20

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,
- 22