Note: Descriptions are shown in the official language in which they were submitted.
33
Technical Field
This invention relates to novel imidazole derivatives
having excellent pharmacological actions.
Background Art
There are known various imidazole derivatives having
diuretic and antihypertensive actions but none of the deriva-
tives so far reported have been clinically satisfactory.
The e~tensive research undertaken by the present in-
ventors resulted in the successful preparation of imidazole
derivatives possessing desirable diuretic an~ antihypertensive
actions, and consequently, in the development of this invention.
Disclosure of the Invention
This invention relates to novel imidazole derivatives
having excellent pharmacological actions.
The broadest scope of this invention provides a com-
pound of the formula: Cl
N -- ~
N , \ C~12CH (I-a)
C~2
R
1 111~
ORl
herein R is 10~7er alkyl and R is H or COR wherein R is
lo~,~er alkyl"~ pharmaceutically acceptable salt thereof with
a ba.se or a pharrnaceutically acceptable acid addition salt thereof.
One preferred embodiMent of this invention provides
a compound of the formula:
~,
, ,~,"
Cl
N ~
CH2COOH (I)
R
OH
wherein R is lower alkyl or a pharmaceutically acceptable salt
thereof with a base or a pharmaceutically acceptable acid addi-
tion salt thereof, ~Jhich has angiotensin II-antagoniziny, di-
uretic and antihypertensive activities and is useful as diure-
tics and antihypertensives.
Another preferred embodiment of the invention provides
a compound of the formula:
2CH (VI)
R
OCOR2
wherein R is lower alkyl and R2 is lower alkyl, or a pharmaceu-
tically a-ce~ptable sal-t thereof with a base or a pharmaceuti-
cally acceptable acid addition salt thereof.
Referriny to above formulas lower alkyl R is prefer-
abl~ of 1 to 3 carbon atoms, such a.s me-thyl, ethyl, propyl, i-
propyl, etc.
~' - 2 -
The present invention also provides a process for pro-
ducing the above-mentioned compounds, the process comprising
[1] when a compound of formula (I a) wherein Rl is H is
required,
(A) deprotecting a compound of the formula:
Cl
CH2COOH (II)
R
OR
wherein R is as defined above and Rl is a protective group
which is Cl 3 alkyl or benzyl which may be substituted by 1 to
3 of Cl_3 alkyl or Cl 3 alkoxy or
(B) hydrolyzing a compound of the formula:
Cl
N 1CH CN (III)
CH2
~3
R
OH
~,7herein R is as defined above, or
10(C) hydrolyzing a compound of the formula:
- 2~ -
CH2CH (~1 ' )
~2
\R
OR
wherein R is as defined above, and
R1 is lower alkyl, with an acid, and
[2] when a compound of formula (I-a) wherein Rl is COR
is required, acylating a compound of formula (I-a) wherein R1
is H obtained in step [1], with a carboxylic acid of the for-
mula:
R COOH (VII)
wherein R is as defined above,
or a reactive derivative thereof, and
if desired, converting the thus-obtained compound of formula
(I-a) into a pharmaceutically acceptable salt thereof with a
base or into a pharmaceutically acceptable acid addition salt
thereof.
Referring to the above formula (II), the protective
group R1 i5 a lo~,Jer (Cl 3) alkyl or a benzyl group which may be
substituted ~by 1 to 3 Cl 3 alkyl or Cl 3 alkoxy).
Any method of deprotection may be employed as far as it
'~
- 2b -
is capable of replacing Rl with a hydrogen atom, e.g.
solvolysis, hydrogenolysis or a suitable dealXylation
reaction.
When Rl is lower alkyl, there may be mentioned such
procedures as 1) heating in the presence of an aqueous
hydrogen halide, 2) reaction with trimethylsilyl iodide
and subsequent treatment with water, 3) reaction with
boron tribromide and subsequent treatment with water and
4) reaction in the copresence of a Lewis acid and a
sulfur-containing compound followed by treatment with water,
for instance.
In process 1), 1 to 10 hours of heating in 20 to
60~ hydrobromic acid at 50 to 150C is desirable. In
process 2), II is preferably reacted with 1 to 5 equivalents
of trimethylsilyl iodide in a solvent such as acetonitrile
at 50 to 90C for 10 to 50 hours and, then, water is added.
In process 3), II is reacted with 1 to 2 equivalents of
boron tribromide in a solvent such as dichloromethane at
10 to 30C for 1 to 10 hours, followed by treatment with
~ater. In process 4), II is preferably reacted with 3 to
5 equivalents of a Lewis acid and 3 to 30 equivalents of
a sulfur-containing compound in a solvent such as dichloro-
methane at b to 30C for 1 to 20 hours, followed by treat-
ment ~7ith ~,7ater. The Lewis acid mention_d above is
preferably aluminum chloride, ferric chloride or the like,
and the sulfur-containing compound is preferably 1,3-
ethanedithiol, thiophenol, thioglycolic acid, dimethyl
disulfide, diethyl disulfide or the like.
~hen Rl is said benzyl group whieh may be substituted,
there may be employed the process comprising heating (II)
in trifluoroacetic acid for 10 minutes to 1 hour or the
catalytic reduction reaction in hydrogen gas streams in
the presence of a suitable c~talyst such as palladium,
Raney nickel or the like.
The h~drolysis of said compound (III) is conducted
ad~an'cageou~ly in'chepresence of an alkali or an acid.
~3 ~ 3
The alkali is preferably a metal hydroxide such as
sodium hydroxide, potassium hydroxide, etc., while the
acid is preferably a mineral acid such as hydrochloric
acid, sulfuric acid, hydrobromic acid, etc. The solvent
is preferably aqueous alcohol. Generally, this reaction
is preferably conducted at 50 to 100C for 2 to 10 hours.
~ he resulting compound (I) can be easily isolated
by the conventional separation procedure such as aqueous
dilution, extraction, neutralization, recrystallization,
etc.
The compound (I) can also be obtained by administer-
ing a compound of the formula
N ~
~ N CH2COOH (IV)
lH2
~ R
OCH3
herein R is as defined hereinbefore to a rat and recover-
ing the compound (I) as a metabolic thereof.
The compound (I) can be obtained as salts with a
physiologically acceptable acid or base by utilizing the
per se con~entional procedure. Such salts include acid
addition salts e.g. salts with inorganic acids (hydro-
chloric acid, hydrobromic acid, sulfuric acid, etc.),
salts ~ h organic acids (acetic acid, propionic acid,
maleic acid, succinic acid, malic acid, etc.) depending
on substituents, and salts with bases such as ammonium
sal~s and salts with alkali metals ox alkaline earth
metals (e.g. sodiurn, potassium, calcium, etc.), etc.
The compound (I) and salts thereof, which can thus
be produced, are o~ low to~icity, have desirable diuretic
i - 5 -
actions, and antagonize the vasoconstrictive and hyper-
tensive actions of angiotensin II. Thus, these compounds
display excellent diuretic and antihyper-tensive effects
in animals and particularly in mammalian animals (e.g. dog,
rabbit, rat, man) and are therefore useful as drugs for
the treatment of edema and hypertension due to various
causes. When the compound (I) and a salt thereof is used
as a drug, it can be administerea orally or otherwise,
either as it is or as formulated with an appropriate
pharmaceutically acceptable carrier, excipient or diluent
in such dosage forms as powders, granules, tablets,
capsules, injections, etc. The dosage depends on the
disease to be treated, the condition and background of the
patient or recipient, administration route, etc. For the
treatment of essential hypertension in an dult human, for
instance, the preferred oral dosage is 10 to 100 mg daily
and the preferred intravenous dosage is 5 to 50 mg daily,
given in 2 to 3 divided doses.
Of the starting compounds used in the practice of
this invention, the compound (III) is a novel compound and
can be produced for example by deprotecting a compound of
the formula
Cl
~ I CH2CN ~V)
R
OR
1'
~lherein P. is as defined hereinbeore and R is a benzyl
~roup ~7hich may be substituted~ The deprotecting reaction
referred to above can be conducted in the same manner as
described hereinbefore.
The compound (I) can be produced by treating a
cornpound of the formula
N ~ CH2C~
R
OR
wherein R is as defined hereinhefore and Rl is lower alkyl,
with an acid, in which case both the deprotection of the pro-
cess (A) and the hydrolysis of the process (B) are accomplished
in one operation. In regard of the acid mentioned just above,
the one mentioned in 1) of the conditions of deprotection re-
action mentioned hereinbefore can be employed with advantage.
In using the compound (I) of this invention as a di-
uretic or antihypertensive drug, it can be used in the form of
a "masked compound", for example as a compound of the formula
N ~
N ~\CH2COOH (VI)
R
OCOR2
~7herein R is lo~,Jer alk~l and ~ is lower alk~l, or a pharma-
ceutically acceptable salt thereof with a base or a pharmaceu-
ticall~ acceptable ac.id addition salt thereof.
Referriny to the abo~e forrnula, lor,7er alk~l R2 is
preferably a group containing up to 5 carbon atoms, such as
methyl, ethyl, propyl, i-propyl, butyl, i-butyl, sec-butyl, t-
butyl, etc.
The compound (VI) can be produced for example by
6a -
8~
acylating the compound (I). ~hus, the compound (~JI) can
be easily produced by reacting the compound (I) T~Jith a
carboxylic acid of the fo~nula
R2COOH (VII)
~7herein R2 is as defined above, or a reactive derivative
thereof (e.g. acid halides, acid anhydrides, etc.).
This reaction is carried out in the presence or
absence of a solvent. The solvent that can be used includes
the common neutral organic solvents such as benzene,
chloroform, diethyl ether, etc., basic solvents such as
pyridine, picoline, lutidine, etc., and water. If
necessary, a dehydrating agent (DCC, p-toluenesulfonic
acid, etc.), an inorganic base (NaOH, KOH, K2CO3, etc.),
or an organic base (pyridine, collidine, etc.) may be
added.
The reaction proceeds satisfactorily at room tempera-
ture, although the reaction may be conducted at elevated
temperature (40 to 100C) or under cooling (-10 to +10C).
With respect to the compound (I), the compound (VII) is
generally used in a proportion of 1 to 5 molar equivalents.
Just as inthe case of compound (I), the product
compound (VI) can be easily isolated by the conven-tional
separation procedure and can also be obtained as a salt
~7ith a physiologically acceptable acid or base.
The compound (VI) and salt thereof, like the
compound (I), are of low toxicity, have desirable diuretic
actions and antagonize the vasoconstrictive and hyper-
tensive actions of angiotensin II 80 that they are of value
for the treatment of edema and hypertension of various
etiologie~. rrhe administration regimens and other conditions
o~ use for the cornpound (VI) may be similar to those men-
tioned for the compound (I).
~s~ mode for Carrying out the Invention
=
Example l
4-Chloro-1-(4-methoxy-3-methylbenzyl)-2-phenyl-
imidazole~5-acetic acid (2 g) ~1as suspended in 150 ml of
33
acetonitrile, and 4 ml of trimethylsilyl iodide was added
The mixture was stirred in an argon stream at 90C for 43
hours. The reaction mixture was concentrated to dryness
and the residue was shaken with 100 ml each of chloroforro
and water. The chloroform layer was washed with water and
dried under reduced pressure. The residue was purified by
column chromatography using 100 g of silica gel and
recrystallization from acetone-diethyl ether to give 1.1 g
of 4-chloro-1-(4-hydroxy-3-methylbenzyl)-2-phenylimidazole-
5-acetic acid as colorless needles, m.p. 193-195C
(decompn.).
Elemental analysis:
Calcd. fo 19 17 2 3
C, 63.96; H, 4.80; N, 7.85
Found: C, 64.06; H, 4.86; N, 7.88
Example 2
4-Chloro-1-(4-benzyloxy-3-methylbenzyl)-2-phenyl-
imidazole-5-acetic acid (20 g) was boiled in 200 ml of
trifluoroacetic acid for 30 minutes. The reaction mixture
was evapora~ed to dryness under reduced pressure and the
residue was dissolved in 300 ml of diethyl ether and
washed with two 300-ml portions of water. The diethyl
ether layer was extracted with six 150-ml portions of
0.3 N-sodiurn hydroxide. The aqueous layers containing
the desired product were combined, adjusted to p~l 2 with
hydrochloric acid and extracted with four 200-ml portions
of ethyl acetate. 'rhe ethyl acetate layer was evaporated
tG dr~ness under reduced pressure and the residue was
dissolved i~ 20 ml of acetone, ~ollowed by addition of
30 ml of diethyl ether to give 10 g or 4-chloro-1-(4-
h~dro~.y-3-methylbenzyl)-2-phenylimidazole-5-acetic acid
as colorless needles, m.p. 193-19SC (decompn.)
'rhe IR spectrum (KBr) of this product was in good
agre ment with that of the compound obtained in Example 1.
E~arnple 3
4-Chloro-1-(4-rnethoxy-3-methylbenzyl)-2-phenyl-
imidazole-5-acetic acid (2.2 g) T,~as stirred in 20 ml of
57~ hydrobromic acid at 100-110C for 2 hours. To the
reaction mixture ~as then added 80 ml of water and the
mixture was allowed to stand. The resulting syrupy
precipitate was dissolved in 50 ml of ethyl acetate and
washed with water. The ethyl acetate layer was evaporated
to dryness and the residue was purified by column chromato-
graphy using 50 g of silica gel. The desired fractions
were combined and crystallized from acetone-diethyl ether
to give 0.3 g of 4-chloro-1-(4-hydroxy-3-methylbenzyl)-2-
phenylimidazole-5-acetic acid as colorless needles, m.p.
190-193C (decompn.).
The IR spectrum (KBr) of this product was in good
agreement with that of the compound obtained in Example 1.
Example 4
4-Chloro-5-cyanomethyl-1-(4-hydroxy-3-methylbenzyl)-
2-phenylimidazole (1 g) was dissolved in 10 ml of ethanol,
and 10 ml of 2 N-sodium hydroxide was added. The mixture
was boiled for 4 hours and evaporated to dryness, and the
residue was shaken with 20 ml each of chloroform and water.
The aqueous layer was washed with chloroform and 10 ml of
2N-hydrochloric acid was added. The resulting syrupy
precipitate was recrystallized from aqueous ethanol to
give 0.5 g of 4-chloro-1-(4-hydroxy-3-methylbenzyl)-2-
phenylimidazole-5-acetic acid as colorless needles, m.p.
192-195C (decompn.).
Example 5
4-Chloro-1-(4-hydroxy-3-methylbenzyl)-2 phenyl-
imidazole-5-acetic acid (3.6 g) was dissolved in 20 ml of
ethanol, and 5 ml of 2N-sodium hydroxide and then 200 ml
o~ acetone ~ere added to give 3 g of the sodium salt of
the abo~e compound as colorle.ss sc~les, m.p. 195-200C
(decompn.).
Elemental analysis;
C~lcd- for C15H16N2 3Cl~la:
C, 60.25; H, 4~26; N, 7.39
-- 10 --
Found: C, 60,18; H, 4,34; N, 7.52
Example 6
4-Chloro-1-(4-ethoxy-3-methylbenzyl)-2-phenyl-
imidazole-5-acetic acid (10 gj was stirred in 90 ml o~
57% hydrobromic acid at 80-90C for 6 hours. The reaction
mixture was evaporated to dryness under reduced pressure
and the residue was dissolved in 200 ml of ethyl acetate
and washed three times with water, The ethyl acetate
layer was evaporated to dryness under reduced pressure
and the residue was purified by column chromatography using
210 g of silica gel. The desired fractions were recrystal-
lized from acetone-diethyl ether to give 3 g of 4-chloro-
1-(4-hydroxy-3-methylbenzyl)-2-phenylimidazole-5-acetic
acid as colorless needles, m.p. 190-192C (decompn.).
Example 7
4-Chloro-1-(4-methoxy-3-methylbenzyl)-2-phenyl-
imidazole-5-acetic acid (1.1 g) was suspended in 20 ml of
dichloromethane and 4 ml of a dichloromethane solution
containing 1 g of boron tribromide was added dropwise
under stirring at room temperature. A precipitate separated
out immediately after dissolution oE the starting material.
The mixture was allowed to stand for 6 hours, The super-
natant was discarded and the precipitate was stirred with
50 ml each of ethyl acetate and water. The ethyl acetate
layer was washed with water and evaporated to dryness
under reduced pressure. The residue was washed with a
small amount of acetone and recrystallized from aqueous
ethanol to give 0.8 g of 4-chloro~l-(4-hydroxy-3 methyl-
~enzyl)-2-phenylimidazole-5-acetic acid as colorless
scales, m.p. 193-195~C (decompn.).
Elernental analysis: '
CalCd~ for Cl9H17N2 3Cl
C, 63.96; H, 4.80; N, 7.85
Found: C, 64.03; H, 4.80; N, 7.93
E~ample 8
4-Chloro-1-(4-methoxy~3~meth~1benzyl)-2-phenylimidazole-
33
-- 11 --
5-acetic acid (15 g) was added to 270 ml of a dichloro-
methane solution containing 16.2 g of aluminum chloride
and 10 g of 1,3-ethanedithiol and the mixture was s'cirred
at room temperature, whereupon the starting material
dissolved once and then a precipitate separated out. The
mixture was allowed to stand at room temperature for 6
hours. The supernatant was then discarded, and50 ml of
acetone and 20 ml of water were added to the precipitate.
To the resulting solution was added 20 ml of lN-hydro-
chloric acid to give a precipitate, which was dissolved
in 150 ml of 75~ ethanol. The solution waspassed through
a column of 50 ml of Amberlite IRC-50 (trademark) (H-form)
and the colurnn was washed with 75~ ethanol. The effluent
and washings were combined and diluted with water to the
ethanol concentration of 50%. The above procedure gave
12 g of 4-chloro-1-(4-hydroxy-3-methylbenzyl)-2-phenyl-
imidazole-5-acetic acid as colorless scales, m.p. 190-192C
(decompn.).
Example 9
Aluminum chloride (1.2 g) and 0.8 ml of dimethyl
disulfide were dissolved in 20 ml of dichloromethane, then
1.1 g of 4-chloro-1-(4-methoxy-3-methylbenzyl)-2-phenyl-
imidazole-5-acetic acid was added, and the mixture was
stirred at room temperature. During this procedure, the
material dissolved once and then a precipitate separated
out. After the mixture was allowed to stand at room
ternperature for 3 hours, the supernatant was discarded and
the precipitate was further treated in accordance with the
procedure of Example 8 to yive 0.8 g of 4-chloro-1-(4-
h~droxy-3-rnethylbenzyl)-2-phen~limidazole-5-acetic acid
as colorless scales, m.p. 190-192C (decompn.).
Referring Example 1
o-Cresol (50 ~), 70 ~ of henzyl chloride and 38.5 g
of potassiurn hydroxide were boiled in a mixture of 100 ml
of r~7ater and 500 ml of ethanol for 4 hours. The solvent
was ~hen distilled off and the residue was shaken with
- 12 -
500 ml each of water and diethyl ether. The diethyl ether
layer was washed with 10% sodium hydroxide and water in
that order, and distilled under reduced pressure to give
70 g of an O-benzylcresol fraction boiling at 130-133C/
5 mmHg.
The above product (50 g) and 30.5 g of paraform-
aldehyde were stirred together in 130 ml of concentrated
hydrochloric acid at room temperature for 48 hours. The
reaction mixture was extracted with two 300-ml portions
of hexane and the hexane layer was washed with 10~
aqueous sodium hydrogen carbonate and water in that order
and evaporated to dryness under reduced pressure to give
59 g of crude 4-benzyloxy-3-methylbenzyl chloride as a
colorless oil
The above product (without purification) was mixed
with 31 gof 4-chloro-5-formyl-2-phenylimidazole, and20 g of
potassium carbonate was added. The whole mixture was
stirred in 230 ml of dimethylformamide at 100C for 5 hours.
The reaction mixture was poured into 2 liters of water
and extracted with two 500-ml portions of chloroform. The
chloroform layer was washed with water and evaporated to
dryness under reduced pressure, and the residue was
chromatographed on a column of silica gel (700 g) using
chloroform as an eluent. The desired fractions were
combined and evaporated to dryness under reduced pressure.
The residue was dissolved in methanol and the solution was
allowed to coolto give 37.5 g of le(4-benzyloxy-3-methyl-
benzyl)-4-chloro-5-formyl-2-phenylimidazole as colorless
prisms, m.p. 135-136C.
The abov product (37 g) was suspended in 300 ml of
ethanol, then 3 g of sodium borohydride was added, and the
mixture was stirred at 50-60~ for 6 hours, at the end
of "hich time it was evaporated to dryness under reduced
pressure~ The residue was washed with methanol to give
36.5 g of 1-(4-benzyloxy-3-methylbenzyl)-4-chloro-5-
hydro~ymeth~l-2-phenylimidazole as light-yellow prisms,
4~
- 13 -
m.p. 184-186C.
The above product (36.5 g) was suspended in 200 ml
of chloroforrn, then 14 ml of thionyl chloride was added
dropwise, and the mixture was allowed to stand at room
temperature for an hour and then evaporated to dryness
under reduced pressure. The residue was dissol~ed in
300 ml of chloroform and the solution was ice-cooled~
Sodium cyanide (20 g) and 3 g of tetrabutylammonium bromide
were dissolved in 150 ml of ice water and the solution was
stirred vigorously with the above-prepared chloroform
solution under ice-cooling for 2 hours and at room tempera-
ture for 15 hours. The aqueous layer was extracted with
chloroform, and the chloroform layers were combined, washed
with water and evaporated to dryness under reduced pressure.
The residue was chromatographed on a colurnn of silica gel
(500 g) using chloroform as an eluent. The desired frac-
tions were combined and evaporated to dryness under
reduced pressure. The residue was dissolved in methanol
and the solution was allowed to cool to give 35 g of 1-(4-
benzyloxy-3-methylben~y~)-4-chloro-5-cyanomethylimidazole
as light-yellow needles, m.p. 102-105C.
The above product (30 g) was dissolved in 200 ml of
ethanol, 200 ml of 2N-sodium hydroxide was added and the
mixture was boiled for 8 hours and then evaporated to
dryness under reduced pressure. The residue was dissolved
in 1 liter of water and washed with two 500-ml portions of
diefhyl ether, The aqueous layer was adjusted to pH 3
with hydrochloric acid and e~tracted with 500 ml of chloro-
form. The chloroform layer was washed with water and
e~Japorated 'co dryness under reduced pressure. The residue
was dissolve~ in 100 ml of acetone andthe solution was
allor,led to cool to gi~e 20 g of 1-~4-~enzyloxy-3-methyl-
benzyl)-4-chloro-2-phenylimidazole-5-acetic acid a~
colorless needles, which were washed with diethyl ether
and reco~ered by filtration, rn~p. 177-178C.
33
- 14 -
Elemental analysis
Calcd- for C26H23N23Cl
C, 69.87, H, 5.18; N, 6.26
Found; C, 69.61; H, 5.32; N, 6.01
Reference Example 2
1-(4-Benzyloxy-3-methylbenzyl)-4-chloro-5-cyano-
methylimidazole (10 g) was boiled in 100 ml of trifluoro-
acetic acid for 15 minutes. The reaction mixture was
then evaporated to dryness and the residue was chromato-
graphed on a column of silica gel (100 g) using chloroform
as an eluent. The desired fractions were combined and
concentrated to about 20 ml to give 3.7 g of 4-chloro-5-
cyanomethyl-l-(4-hydroxy-3-methylbenzyl)-2-phenylimidazole
as colorless prisms, m.p. 194~196C.
Elemental analysis:
19 16 3 Cl
C, 67.~5; H, 4.78; N, 12.42
Found: C, 67.10; H, 4.78; N, 12.10
Reference Example 3
4-Chloro-1-(4-hydroxy-3-methylbenzyl)-2-phenyl-
imidazole-5-acetic acid (1.1 g) was dissolved in 10 ml of
pyridine, then 2 ml of acetic anhydride was added, and the
miYture was stirred at room temperature for 2 hours and
evaporated to dryness under reduced pressure. The residue
was purified by column chromatography using 20 g of silica
gel. The lesired fractions were combined and evaporated
to dryness under reduced pressure and the residue was
recrystallized from aqueous ethanol to give 0.7 g of
4-chloro-1-(4-acetoY.y-3-methylbenzyl~-2-phenylimidazole-
5-acetic aci~ as colorless needles, m.p. 200-203C.
Elemental analysi.s:
Calcd. f~Jr C21H1gN2O4Cl /2H2:
C, 61.84; H, 4.94; N, 6.87
Found: C, 62.06; H, 4.69; N, 6.95
Refexence ~xample 4
4-Chloro~1-(4-hydroxy-3-methylbenzyl)-2-phenyl~
8~
imidazole-5-acetic acid (0.8 g) was dissolved in 10 ml
of pyridine, 2 ml of butyric anhydride was added, and
the mixture was stirred at room temperature for 15 hours
and then evaporated to dryness under reduced pressure.
The residue was purified by column chromatography using
30 g of silica gel. The desired fractions were combined
and evaporated to dryness under reduced pressure and the
residue was recrystallized from aqueous ethanol to give
0.75 g of 4-chloro-l-(4-n-butyryloxy-3-methylben~yl~-2-
phenylimidazole-5-acetic acid as colorless prisms, m.p.
165-170C.
Elemental analysis:
Calcd. 23 23 2 4
- C, 64.71; H, 5.43; M, 6.56
Found: C, 65.01; H, 5.31; N, 6.65
Experimental Example l
Angiotensin II (briefly, AII)-antagonizing activity of the
compound (I) of this invention (rabbit aortic vessel)
The method of preparing the aortic vessel specimens
and the reaction conditions employed were as described in
European Journal of Pharmacology 18, 316 (1972). AII
was used in a concentration of 4 x 10 9 M, and the change
in isometric tension of the untreated vessel specimen
was measured as control. As a test, the vessel was
treated with the test compound for 15 minutes and a
similar determination was made. The 'cwo results were
compared and the inhibition rate was calculated by means
of the following formula.
Inhibition rate (~)
/Change (g) in isometric tension of untreated\
~essel by AII - change (g) in isometric J
tension of treated vessel by AII
-- - - x 1 0 0
Change (g) in isometric tension of untreated
vessel by AII
5 The results are shown in Table 1.
8~33
- 16 -
Table l
Compound Concentration Inhibition !
(Example No.) (M) rate
10-5 100
Example l 10-6 75
4-Chloro-1-(4-hydroxyben~yl)-2-
phenylimidazole-5-acetic acid -5 46
(known compound)
Experimental Example 2
The diuretic action of the compound (I) of this
invention is shown in Table 2. The test was conducted
in rats and dogs, in accordance with the method of W. L.
Lipschitz [Journal of Pharmacology and Experimental
Therapeutics 79, 97, 1943]. The numerals in the table
denote the values for the treated groups with the value
for a control group being taken as 1.00.
Urine volume of animals in treated group
(ml/6 hrs./100 g body weight)
UV Urine volume of animals in control group
(ml/6 hrs./100 g body weight)
Excretion of sodium by animals in treated
group (~ equiv./6 hrs./100 g body weight)
UNaV Excretion of sodium by animals in control
group (~ equiv./6 hrs./100 g body weight)
Excretion of potassium by animals in treated
group (~ equiv./6 hrs./100 g body weight)
K Excretion of potassium ~y animals in control
group (~ equiv./6 hrs./100 g body weight)
Unable to recognize this page.
- 18 -
Experimental Example 3
,Antihypertensive action in doys with renal hypertension
Male adult beagle dogs were laparotomize~7 under
pentobarbital anesthesia and the left renal artery was
constricted with a silver clip so as to reduce the renal
blood flow to about 30%. After the operation, the animals
were kept for at least 2 months and the individuals ha~Jing
a systolic pressure of at least about 180 mmHg were used
in the test. The blood levels of renin were normal during
the time indicating that the dogs were in the chronic
phase of renal hypertension. Blood pressure determinations
were made using a plethysmograph (Narco, DE-300). Each
drug was sealed in a g~latin capsule and administered by
, the oral route. The blood pressure was monitored up to 8
hours after ad~inistration. The results are shown in
Table 3.
,,~, r~ p ~, ", f~
Unable to recognize this page.
83
- 20 ~
Industrial Applicability
4-Chloro-2-phenyimidazole-5-acetic acid deriva-
tives (I) provided by this invention have excellent
pharmacological actions and are of use as drugs.
