CA1152516A - Imidazole-5-acetic acid derivatives, their production and use - Google Patents

Imidazole-5-acetic acid derivatives, their production and use

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Publication number
CA1152516A
CA1152516A CA000364361A CA364361A CA1152516A CA 1152516 A CA1152516 A CA 1152516A CA 000364361 A CA000364361 A CA 000364361A CA 364361 A CA364361 A CA 364361A CA 1152516 A CA1152516 A CA 1152516A
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Prior art keywords
lower alkyl
amino
chloro
phenyl
compound
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CA000364361A
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French (fr)
Inventor
Kohei Nishikawa
Shoji Kishimoto
Yoshiyasu Furukawa
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Takeda Pharmaceutical Co Ltd
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Takeda Chemical Industries Ltd
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D233/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/68Halogen atoms
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/12Antihypertensives

Abstract

Abstract of the Disclosure Novel imidazole-5-acetic acid derivatives of the formula:

wherein R1 is lower alkyl, cycloalkyl or, phenyl which may be substituted with one to three of halogen, nitro, amino, mono(lower alkyl)amino, di(lower alkyl)amino, lower alkyl, lower alkoxyl, benzyloxyl or/and hydroxyl;
X1, X2 and X3 are each hydrogen, halogen, nitro, amino, lower alkyl, lower alkoxyl, benzyloxyl or hydroxyl;
Y is halogen and R2 is hydrogen or lower alkyl;
provided that X1 is halogen, lower alkyl, lower alkoxyl, benzyloxyl or hydroxyl when R1 is unsubstituted or substituted phenyl only with one halogen, di(lower alkyl)amino, lower alkyl or lower alkoxyl, and its salts have hypotensive activity.

Description

~5Z516 IMIDAZO~E-5-ACE~IC ACID D~RIVATIVES, THEIR
PRODUCTIO~ AND US~
The present invention relates to novel imidazole derivatives which are of value as medicines and to their production and use. More Particularly, the present invention provides compounds of the ~ormula (I):
~ Y

R,IJ~CH2C02R2 CH
~ X3 (I) xl X2 wherein Rl is lower alkyl, cycloalkyl or, phenyl which may be substituted with one to three of halogen, nitro, amino, mono(lower alkyl)amino, di(lower alkyl)amino, lower alkyl, lower alkoxyl, benzyloxyl or/and hydroxyl;
Xl, x2 and X3 are each hydrogen,:halogen, nitro, amino, lower alkyl, lower alkoxyl, benzyloxyl or hydroxyl;
Y is halogen and R is hydrogen or lower alkyl, provided ;
that Xl is halogen~ lower aIkyl, lower alkoxyl, benzyloxyl or hydroxyl when Rl is unsubstituted or substituted phenyl only with one halogen, di(lower alkyl)amino, lower alkyl or lower alkoxyl, and its salts which have :
the antagonistic effect on angiotensin II and the hypotensive activity, and are useful as a hypotensive agent.

~:
- . :: , ~. ,.
: : , :

~15Z~

Referring to the formula I, lower alkyl as R may be either straight-chain or branched, being exemplified by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl and heptyl, and those having 1 to 6 carbon atoms are particularly preferred; cycloalkyl as R includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., and in particular, those having 4 to 6 carbon atoms are preferable; and phenyl as R may have, as substituents in its optional positions, one to three, either the same or different, of halogen, nitro, amino, mono(lower alkyl)amino, di(lower alkyl)amino, lower alkyl, lower alkoxyl, benzyloxyl or/and hydroxyl. The halogen as such substituent is pre-ferably chlorine and bromine, while the lower alkyl in the mono(lower alkyl)-amino, di(lower alkyl)amino, lower alkyl and lower alkoxyl are preferably the same as the examples mentioned for the lower alkyl as R .
Halogen as X , X and X is preferably chlorine and bromine, while lower alkyl and lower alkyl in lower alkoxyl may be either straight-chain or branched and are in particular preferably those having 1 to 4 carbon atoms.
Halogen as Y is preferably chlorine and bromine and among them chlorine is most preferable.
Among the compounds I, preferable are the compounds where R is the lower alkyl having 1 to 6 carbon atoms, phenyl having only one nitro, amino or hydroxyl, or phenyl having two to three of halogen, lower alkyl, lower alkoxyl, mono(lower alkyl)amino, di(lower alkyl)amino, amino, nitro, benzyloxyl or/and hydroxyl.
The compound I can be advantageously produced, for example, by sub-jecting to solvolysis a compound of the formula II:

: . : ~ . :

1152S~6 ~Y , .
Rl ~ N ~ A
~H2 ~ X3 (II) xl ~ ~2 wherein Rl, Xl, x2 and X3 are as defined above and A
is cyanomethyl or ~ disubstituted vi~yl designated with one of the following formulaa (III a), (III b) and 10 (III c): ~
,SCH3 ~S ~ ,O~s ~1 -CH=C -CH=C ~ -CH=C
SCH3 \S ~ ~HCH0 ~s`~ :.
(III a) (III b) (III c) As the solvolysis, either of hydrolysis and alcoholysis may be employed. Hydrolysis produces the compound (I) where R2 is hydrogen, whereas alcoholysis affords the compound where R2 is lower alkyl~
The hydrolysis of compound (II) wherein A is cyanome-thyl is normally carried out in the presence of an acid or alkali. Among preferred examples of the acid are mineral acids such as sulfuric acid and hydrochloric acid. The concentration of such mineral acid in the reaction system is preferably about 40 to 60 % for sulfuric acid and about 10 to 30~Yo for hydrochloric acid~, and in cases in which the compound (I) is less soluble in these acids, about 30 to 50 %~of acetic acid is advantageously allowed to coexist. Desired examples of the alkali include alkali-metal hydroxides such as sodium hydroxide and potassium hydroxide, and the solvent which is advantageousIy used is for example aqueous methanol, aqueous ethanol, etc. ~he hydrolysis reaction proceeds under heating, and is normally conducted ~:

- . .~, -. ~ . . , :. ,- , ~iSZ5~6 desirably at a temperature of about 50 to 160C for 2 to 12 hours. The compound (I) where R2 is hydrogen, as obtained in this manner, can be derived -through esterification into the compound (I) having lower alkyl as R2. ~he esterification is conducted for example by heating the compound (I) where R2 is hydrogen in a solvent containing the alcohol corresponding to the desired alkyl in the presence of an acid catalyst (e.g. sulfuric acid, hydrogen chloride, methanesulfonic acid, etc.).
The alcoholysis of compound (II) wherein A is cyanomethyl is normally carried out by heating it in an absolute or aqueous alcohol corresponding to lower alkyl as R2 with addition of an acid, or further hydrolyzing, if necessary, an imino ether produced as an intermediate~
As preferable examples of such acid may be mentioned inorganic acids such as hydrogen chloride and hydrogen bromide and organic acids such as p-toluenesulfonic acid, and these are desirably used in the proportion of about l to lO the molar ratio af the compound (II). The reaction is preferably conducted under heating at about 50 to 100C Por l to lO hours. ~he resulting compound (I) where R2 is lower alkyl can also be derived through hydrolysis into the compound (I) where R2 is hydrogen.
The hydrolysis is accomplished preferably by heating, with use of an alkali such as sodium hydroxide and potassium hydroxide, in a solvent such as aqueous methanol and aqueous ethanol at 20 to 100C for 5 to 20 hours.
As the solvolysis procedure for compound (II) wherein A
is ~,~-disubstituted vinyl, either hydrolysis or alcoholysis may be employed. In the hydrolysis, hydrochloric acid, sulfuric acid of about lO to 40 /0 or p-toluene sulfonic acid of about 0.5 to lO the molar ratio of the compound (III) is used and, in cases in which (II) is less soluble in these solvents, acetic acid or 1,2-~5 dimethoxyethane is advantageously allowed to coexist inthe range of about 30 to 50 %. ~he alcoholysis is .

:; ~ , : :,.-. ;

:, .. .

~lSZ51~

normally carried out easily by passing hydrogen chloride through the compound (II), at a temperature of about 0 to 30C, in an alcohol corresponding to the lower alkyl group as R2.
In the solvolysis of the compounds (II), the substituents on the substituted phenyl as Rl, in some instances, undergo changes. For example, hydrolysis in hydrochloric acid of the compound (IIa) where Rl is a 4-dimethylamino-3,5-dinitrophenyl yields the compound (Ia) where nitrile is converted into the carboxyl, with the dimethylamino changed to chlorine.

(CE3 ~ CE2C~ ~ (CE3)2~ ~ ~N ~ 1i2CC2H Cl ~ _~ ~ E2CC2E

~ ~ ~ 2 (IIa) (Ia') (Ia) Starting from the compound (IIb) where Rl is a 4-acylamino- ;-phenyl, further, there is obtained the compound (Ib) having a 4-aminophenyl through hydrolysis with hydrochloric 25 acid as mentioned above C3H7CO~H ~ CH2CN ~ ~ ~ Cl (IIb) (Ib) ~ rom the resulting compound (I) where nitro and/or a benzyloxyl group are present on the phenyl as Rl and/or as ~1, x2 and X3, there can be derived the compound (I) having an amino and/or hydroxyl through reduction of , - . - ' ~ . , ~, . ,.. . :

~SZ~16 these groups. As examples of the reduetion procedure there may be mentioned the procedures normally employed such as the tin-hydrochloric acid, iron-hydro-ehloric aeid, zinc-aoetie acid and eatalytic reductions, and the catalysts for the catalytic reduction are preferably 5 to 10 % palladium-carkon, Raney nickel, platinum, ete.
From the resulting ccmpound (I) where there is benzyloxyl or lower alkoxyl on the phenyl as Rl and/or as Xl, X and X3, there ean ke derived the compound (I) having a hydroxyl through hydrolysis of sueh groups. The preferred example of the hydrolysis ineludes the procedure of heating under reflux in ethanol saturated with hydrochlorie aeid or 30 to 50 % hydrobromie aeid for 2 to 6 hours.
The co~pcund (I) produced in this manner can be easily isolated from the reaetion mixture by the conventional separation and purifieation prooedures sueh as dilution with water, extraetion, eonoentration, neutralization and reery-stallization. These eompounds (I) ean be obtained, by the pro oedures conven-tional per se, as physiologieally aeeeptable salts with aeids or bases. As examples of sueh salts there may be msntioned aeid addition salts formed with inorganie aeids (e.g. hydroehlorie acid, hydrobromie aeid, sulfurie aeid, ete.) and with organie aeids (e.g. aoetic aeid, propionie aeid, maleic aeid, suceinie acid, r~alic acid, etc.), salts with bases sueh as ammonium salt and salts formed with aLkali metals or alkaline earth metals (e.g. sodium, potassium, calcium, etc.).
The compounds (I) produoe d in this manner as well as their salts, keing low in toxicity and suppressing the vaso-constrietive and blood-pressure elevating aetions of angiotensin II, exhibit the exeellent hypotensive activity tcward animals, particularly mammals (e.g. dogs, rabbits, rats, men, etc.), and are of value as a treatment agent for hypertension. When one of the ccmpounds is ":
- . .
.~ , ~ . ' i .~
: ~ ': ' ' `.
: ,:

l~SZSllli employed as such a hypotensive agent, the compound I or its salts as mentioned above can be orally or parenterally administered, either as such or in the form of powder, granule, tablet, capsule, injection, etc., prepared by mixing with a suitable, pharmaceutically acceptable carrier, vehicle or diluent. Though the quantity of the compound to be administered varies depending upon the kinds of diseases to be treated, symptoms, subjects and routes of administration, etc., it is preferably given in a daily dose of 10 to 100 mg for oral administration and 5 to 50 mg Eor intravenous injection, 2 to 3 times a day, in case of admin-istration to adult humans as a treatment agent for essential hypertension.
The starting compounds II wherein A is cyanomethyl to be used in the present invention can be produced for example in accordance with the procedure of United States Patent No. 4,207,324 through the route given below.
Cl ~ NH2 Cl / N=CH-R
C = C \ + OHC - R > C = C
Cl CN Cl CN

(IV) (V) (VI) xl y yX ~CH2Z lJ~
HY ) > 1 ~ ~ CHO (VIII) CH2 (VHII) ~ X3 (IX) Y

1 N CH2OH R ~ CH CN
Reduction > R CH2 Chlorinatlon~ NaCN~ CH2 2 xl~x2 xl~x2X3 (X) (II') .

" ~
. : : ~ : . : :
:- :
: - : . :. -iiZS~

wherein Rl, Xl, X2, X3 and Y are as defined above; Z
is halogen~
On the other hand, the starting compounds (II) wherein A is ~ disubstituted vinyl can be produced from the corresponding aldehyde (IX) and following respective reagent in accordance with the method thereon;
Compound (II) : formaldehyde dimethylthioacetal wherein A is (III a) S-oxide by the ~AMSO method ~etrahedron ~etters, 1383(1972)) Compound (II): 1,3-dithian by the dithian method wherein A is (III b) ~J.Med. Chem., 15, 1297(1972)) Compound (II): p-toluenesulfonylmethylisocyanide by wherein A is (III c) the lOSMIC method ~Ang. Chem. Int.
~d., 11, 311 (1972)~
In addition, the intermediate (X) can be also produced by the route given below.
C\OC H HCl + CH020H NH~ ~ Halo~enation~
2 5 CH~OH H CH2 H
(XII) (XIII) Y
Rl ~CH20H > (X) H (VIII) (XIV) ~ ~ tion (VII) (XII) + NH2CH2CH(OCH3)2 Rl~ ~ (VIII)
3 (XV) H
(XVI) .
-: - ~ .. . - - :; : : .

: :: . . . -. , ,: ;

:. : : ;: ~

115;Z~5~6 , ~ ` . . ..

R~ D I CH2H Halogenation ~ (X) X ~x2 ~ X3 xl x2 (XVII) (XVIII) wherein each of the symbols in the formulas is as defined above.
The compound (XIII) is produced for example by the procedure described in "Archiv der Pharmazie", ~
470 (1974). ~he halogenation of the compound (XIII) is preferably accomplished by reacting with 1 to 2 equivalents of ~-halogenosuccinimide in a solvent such as dioxane and methylcellosolve at a temperature of about 40 to 100C for 1 to 10 hours. Reaction of the compound (XIV) obtained in this manner with benzyl halogenide is conducted in a solvent in the presence of acid acceptor. Examples of the acid acceptors which are useful include potassium carbonate, sodium carbonate, sodium hydride, sodium methylate and sodium ethylate, and in the case of the last three, it is recommended to treat in advance with (XIV) to form the sodium salts.
As preferred examples of the solvent may be mentioned dimethylformamide and dimethylsulfoxide. ~he reaction is preferably conducted under stirring at a temperature of about 20 to 100C for 1 to 10 hours. In the reaction, there is normally produced an isomer designated by (X'), in addition to the compound (X).
Xl Rl ~CH20H

(X') . : . .. . . .
: , : ,, . . .
'. . .
, -liSZ5~

~,eparation of (X) from (X') is carried out by the conventional chemical procedures such as recrystallization and chromatography. Oxidation of the compound (XIV) to the compound (VII) is conducted in tetrahydrofuran with 5 use of anhydrous chromic acid-silica gel.
The compound (XVI) can be produced for exa~nple by the procedure described in "The Journal of Chemical Society", 4225 (1957), while the compound (XVIII) can be produced for example in accordance with the procedure described 10 in "Recueil", 91, 1385 (1972). The compound (XVIII) obtained in this manner can be derived into (X) by the procedure similar to the halogenation reaction of (XIII)o In various synthesis routes as mentioned above, Rl, Xl, x2 and X3 do not necessarily remain the same 15 from the starting compound to the final objective compound, but they can be, as a matter of course, changed to appropriate ones through the known reactions in the intermediate steps. These are specifically exemplified below.

n C3 7 ~ ~CH20H ~iAlH4~ 4 9~ ~C~20H

~ ~D
(XIX) (XX) ~--I~CHO 3 2 4 > 2~ ~HO

H
(XXI) (XXII) , , ~

, - - , -- . .: . . . .

~.

~15Z516 2 ~ l~ OX2CN 3 - ~ R2N ~ ~ ~ CH2CN

5 (XXIII) \ ~ ~Z 2~ ~ 2 HN03-AcOH

2 ~ ~ ~ ~ ~ N~ ~ Y

~b (XXIV) C H O ~ ~ ~ HNO~-H2S04 2 ~ ~ OHO
H H
(XXVI) (XXVII) CH30 ~ CH30 ~Y CH30 ~ Y

~2C~ ~ H2C~ + Nr G~

(XXVIII) (XXIX) (~XX) 1' wherein Y is as defined above; R is lower alkyl; X is halogen or nitro).
The present invention is more specifically illustrated by the following Examples~ Experiment Examples and Reference Examples; however, it goes without saying that these are not intended to limit the - ~
:
; . . .
:- - .. .

:
- . ;..... : : .

; ~ .
.

~15Z51 present invention.

E~ample 1 7 g o~ 1-benzyl-4-chloro-5--cyanomethyl-2-(4-nitrophenyl)imidazole was boiled in 60 m~ o~ 6~-hydrochloric acid for 4 hours. ~he reaction solution was diluted with 150 me of water, and the deposited precipitate was dissolved by heating in 50 m~ of 90 % ethanol. Water was added little by little until cloudiness was developed, followed by allowing the solution to cool. ~here was obtained 5.6 g of 1-benzyl-4-chloro-2-(4-nitrophenyl)imidazole -5-acetic acid deposited as yellow, prism-formed crystals, m.p. 180-183C.
~lementary analysis, for C18H14N304Cl C (%) H (%) N (%) Cl (%) Calcd. 58.15 3.79 11.30 9.54 Found 58.29 3.77 11.11 9.77 _xample 2 1.9 g of 1-(2-chloro-5-nitrobenzyl)-4-chloro-5-cyanomethyl-2-phenylimidazole was boiled in a mixed solution of 12 m~ of concentrated hydrochloric acid and 12 m~ of glacial acetic acid for 3 hours. ~he reaction solution was concentrated to dryness under reduced pressure, and 50 m~ of water was added to the residue, resulting in the formation of a colorless powder.
The residue was dissolved in 30 m~ of heated ethanol, and 30 m~ of water was added. Upon cooling, there was obtained 1.7 g of 1-(2-chloro-5-nitrobenzyl)-4-chloro-2-phenylimidazole-5-acetic acid as colorless, prism-formed crystals. m.p. 200-205C.
Elementary analysis, for C18H13~304C12 C (%) H (%) ~ (%) C1 (%) Calcd. 53.22 3.23 10.34 17.44 35 Found 53.32 3.03 10.44 17.44 , :.: ,. ~ .

.. ..

. :: . , . : : , ." , ~ .. . .
. .. . .

Example 3 ~ .8 g of 1-(2,4-dichlorobenzyl)-4-chloro-2-phenyl-5-cyanomethylimidazole was boiled in 40 m~ of 6~-hydrochloric acid for 11 hours. After cooling, the crystals deposited from the solution were recrystallized from acetonitrile, thus yielding 3.5 g of 1-(2,4-dichlorobenzyl)-4-chloro-2-phenylimidazole-5-acetic acid hydrochloride as colorless, needle-formed crystals, m.p. 209-211C.
Elementary analysis, for C18H1~202Cl~ HCl H20 C (%) H (%~ ~ (%) Cl (%) Calcd. 48.02 3.58 6.22 31,50 Found 48.14 3.50 6.29 31.26 Examples 4 - 35 ~ y the procedures as described in Examples 1, 2 and 3, there were obtained the compounds given below.

~able 1 R ~ CH2C02H

~ X3 EXemple xl ~ x2 ~3 m.p. ( 3o 4 ~ 4-CH3 H H 100-105 ~ 2-CX3 H H 211-212 6 ~ 4-Cl H H (decomp.) 7 ~ 2-Cl H H 198-200 8 2-C1 H 6-Cl 185-186 . - ~ .~, .
.

~lSZS16 EXNmoPle¦ Rl ~ Xl x2 X3 m.p. ~C) 9 1 ~ _ 2-Cl E 6-~ 210-214 10 ' ~ 2-Cl 5-~H2 H (decomp.) 11 , ~ 2-Br H H (decomp.) 12 C4H9N _ ~ H H H 131-135 13 ~ N02 H H H (hydrochloride) 14 CH2 0 ~ H H H 175-177 (CH3)2N ~ H H H 187-190 16 02N ~ H H H 190-192 17 Cl H H H 165-170 (C2H5 ) 2N ~

18 ( 3)2 ~ H H H 202-204 19 (CH3)2N ~ H H H 205-207 CH30 ~ 2-Cl H H 147-148 21 Cl ~ 2-N0 ¦ H H (decomp,) Cl (potassium salt) 22 2~ ~ 2-No ¦ H H 102-105 3o 25 i-C3H7- H H H 181-182 26 n~C4H9~ H H H 151-152 27 n~C4H9~ 2-Cl H H 172-173 28 n~C4H9~ 2-N02 H H 188-190 29 n~C3H7~ H H H 189-191 t-C4H9- H H H 202-204 31 n-C5Hll- E H E 110-112 .- ,. - - :~

., . . :
., - - .. : . .: . : -~152516 Example Rl Xl X2 X3 m .p. (C) 32n-C5Hll 2-Cl H H 137-139 33n C6H13 2-Cl H H 157-159 34 ~ H H H 164-165 35 ¦ ~ ¦ H H H 117-119 Example 36 1.7 g of 4-chloro-1-(3-methoxybenzyl)-2-phenyl-5-cyanomethylimidazole was boiled in a mixed solution of 20 m~ of ethanol and 10 m~ of l~-sodium hydroxide for 10 hours. ~he reaction solution was evaporated to dryness under reduced pressure, and the residue was dissolved in 50 m~ of water. After washing with 50 m~
of chloroform, 10 m~ of lN-hydrochloric acid was added to the water layer, resulting in the precipitate deposited~
~he precipitate was dissolved in 20 m~ of 90 % ethanol, and water was added little by little, thus yielding 1.3 g of 4-chloro-1-(3-methoxybenzyl)-2-phenylimidazole-5-acetic acid as colorless, needle-formed crystals, m p 135-l38oc.
~lementary analysis, for C19H17N203Cl C (%) H (/0) N (%) Cl (%) Calcd. 63.95 4.80 7.85 9.93 ~ound 64.22 4.72 7.89 9.91 Ex~mple ~7-49 ~ here were obtained the following compounds in accordance with the procedure of Example ~6.

3 ~able 2 N ll,Cl R Nl CH2C2H

.
.

.
; ~

1~5;2 S~6 E~ampl~ xl X2 X3 (C) 37 ~ 2-CH30 H H 189-190 38 ~ 4-CH30 H H (decomp.) 539 ~ 4-C2E[50 H H 210-212 ~ 4-n-C4HgO H H 153-156 41 ~ 6 5 2 H H 209-211 1042 ~ 3-CH30 H 4-CH30 199-200 434 CH_0 3-CH3 H 4-CH30 (decomp.) ~ H H H 230-232 1545 CH33003 ~ H X H 199-200 46 ~ CHcHO ~ H H H 203-205 2047 ~ 3-CH304-CH30 5-CH30 161-162 48 n~C4H9~ H4-n-C4H90 H 102-103 2549 CH30 ~ HH ~ H l,'~ l~i Example 50 In lOO m~ of methanol was dissolved 1.8 g of
4-chloro-1-(4-methylbenzyl)-2-phenylimidazole-5-acetic ~
acid, and 0.5 m~ of concentrated sulfuric acid was added to the solution to boil for 2 hours. ~he reaction solution was evaporated to dryness under reduced pressure, and 50 m~ each of ethyl acetate and a 10 % aqueous sodium bicarbonate solution were added to the residue to shake. ~he ethyl acetate layer, after washing with water, was evaporated to dryness under reduced pressure.
~he residue was dissolved in a small amount of methanol ,: : :
. . ~ ' : , .~
, . - . - . . .. .

: ~ .
, . . .~ , - ' '~

`` 1:1525~6 and there was obtained, upon standing, 1.5 g of methyl 4-chloro-1-(4-methylbenzyl)-2-phenylimidazole-5-acetate as colorless, prism-formed crystals, m.p. 92-95C.
Elementary analysis, for C20H19N202Cl C (%) H (%) N (~O) Cl (%) Calcd. 67.70 5.39 7.89 9.99 Found 67.34 5.56 7.71 9.61 xample 51 1 g of 1-benzyl-2-n-butyl-4-chloro-5-cyano-- methylimidazole was heated in 20 m~ of ethanol containing 1 g of hydrogen chlo~ride in a sealed tube at 100C
for 2 hours. 0.5 m~ of water was added to the reaction solution, which was then boiled for 1 hour and evaporated to dryness under reduced pressure. ~he residue was dissolved in 50 m~ of ethyl acetate and, after washing with aqueous sodium bicarbonate, the ethyl acetate layer was evaporated to dryness, and chromatographed on a column of 30 g of silica gel ~he column was eluted with benzene-ethyl acetate (4 : 1), and the main fractions were evaporated to dryness. The residue was dissolved in 1 m~ ethanol saturated with hydrogen chloride, and crystallized by adding petroleum ether. After further adding ethyl acetate to separate out in the fully ;
25 crystallized condition, there was obtained 300 mg of ~ ~ ;
ethyl l-benzyl-2-n-butyl-4-chloroimidazole-5-acetate hydrochloride. m.p. 101-103C.
Elementary analysis, for C18H23~202C 2 C (%) H (%) N (%) Calcd. 56.85 6.62 7.36 ~ound 57.02 6.42 7.40 Example 52 In 5 m~ of tetrahydrofuran was dissolved 1.5 g of 4-chloro-1-(2-fluorobenzyl)-2-phenyl-5-formylimidazole, and the solution was stirred and refluxed. 1 m~ each -` ~lS2~ii6 of formaldehyde dimethylthioacetal S-oxide and 35 ~ methanol solution of kenzyl-trimethyl ammonium hydroxide were dissolved in 3 mQ of tetrahydrofuran to add dropwise to the above-mentioned solution over a 2-hour period. After adding was r~mpleted~ the reaction solution was boiled for further 5 hours and evaporated to dryness under reduoe d pressure. 50 mQ each of chloroform and water were added to the residue, and shaken to mix, followed by evaporating the chloroform layer to dryness to obtain a resinous material of l-methylsulfinyl-l-methylthio-2-~4-chloro-1-(2-fluorobenzyl)-2-phenylimidazol-5-yl]ethylene. 5 mQ of concen-trated hydrochloric acid and 5 mQ of glacial aoe tic acid were added to the mate-rial, and heated at 100C for 5 hours. me reaction solution was evap~rated to dryness under re & oed pressure, and 50 mQ each of chloroform and a 10 % aq~eoussodium OE bonate solution were added to the resi &e to shake to mix. me water layer was acidified by adding concentrated hydrochloric acid and extracted with 50 mQ of chloroform. After evaporating the chloroform layer to dryness under reduced pressure, re~rystallization of the residue from aqueous ethanol yielded 410 mg of 4-chloro-1-(2-fluorobenzyl)-2-phenylimidazole-5-aoetic acid as color-less, prism-formed crystals, m.p. 144-146 & .
Elementary analysis, for C18H14N202ClF
C (%) H (%) N (%) Calod. 62.71 4.09 8.12 Found 62.74 4.33 7.87 Example 53 In 30 mQ of tetrahydrofuran was dissolved 4.5 g of 4-chloro-1-(2-methylbenzyl)-2-phenyl-5-formylimidazole, and the solution was stirred and refluxed. 6 mQ of formaldehyde dimethylthioaoetal S-oxide and 6 mQ of a 35 %
methanol solution of benzyltrimethyl ammonium hydroxide were dissolved in 30 mQ
of tetrahydrofuran to add . . .

; ~ . .

.
.
: ~ ' : . .

~`152~6 dropwise to the above-mentioned solution over a period of 12 hours. After adding was completed, the solution was boiled for further 18 hours, and evaporated to dryness under reduced pressure. 200 m~ each of chloroform and water were added to the residue to sha~e for mixing, followed by evaporating the chloro~orm layer to dryness to obtain a resinous material of l-methylsulfinyl-l-methylthio-2-~4-chloro-1-(2-methylbenzyl)-2-phenylimidazol-
5-yl)ethylene. ~he material was dissolved in 100 m~
of ethanol sat~rated with hydrogen chloride and allowed to stand at room temperature for 40 hours. ~he reaction solution was evaporated to dryness under reduced pressure, and the residue was chromatographed on a column of 80 g of silica gel, followed by eluting with chloroform.
~he main fractions were collected to evaporate to dryness under reduced pressure, Recrystallization of the residue from methanol yielded 1.5 g of methyl 4-chloro-1-(2-methylbenzyl)-2-phenylimidazole-5-acetate, m.p., 102-105C.
Elementary analysis, for C20H19~202Cl C (%) H (%) ~ (%) Cl (%) Calcd. 67 70 5.39 7.89 9.99 Found 67.29 5.71 7.52 9.58 hxample 54 1.4 g of 1-benzyl-4-chloro-2-(4-dimethylamino-3~5-dinitrophenyl)-5-cyanomethylimidazole was stirred in 30 m~ of concentrated hydrochloric acid at 70C
for 40 hours. ~he deposited yellow crystals were 30 recovered by filtration, washed twice with concentrated - -hydrochloric acid and adequately with water, and recrystallized twice from 70 /0 ethanol, thus yielding 0.9 g of 1-benzyl-4-chloro-2-(4-chloro-3,5-dinitrophenyl)imidazole-5-acetic acid as yellow-orange, 35 needle-formed crystals, m.p. 100-105C.
Elementary analysis, for Cl~H12~405C12-C2H50H

- , - ; ~, '~
- : . -., ~ ~ , -C (%) H (~o) N (%) Cl (%) Calcd. 48.25 3.65 11.26 14.24 Found 48.28 3.56 11.36 14.15 - Example 55 1.7 g of 1-benzyl-4-chloro-2-(4-n-butyrylaminophenyl)-5-cyanomethylimidazole was stirred in a mixed solution of 9 mQ
each of concentrated hydrochloric acid, water and glacial acetic acid at 120C for 5 hours. The reaction solution was evaporated to dryness under reduced pressure, and the residue was dissolved in 20 mQ of water, followed by adjusting to pH 4 with sodium bicarbonate. The deposited precipitate was recrystallized from 80% ethanol, thus resulting in 1.3 g of 1-benzyl-4-chloro-2-(4-aminophenyl)imidazole-5-acetic acid as colorless, needle-formed crystals, m.p. 120-122C.
15 Elementary analysis, C (~) H (~o) N (%) Cl (%) or C18H16~32Cl H2o ~alcd, 60,09 5.04 11.66 9.85 Found 60.00 5.05 11.76 9.66 ExamplQ56 In 100 mQ of 80 % ethanol was dissolved 1.8 g of I-benzyl-4-chloro-2-(2-nitrophenyl)imidazole-5-acetic acid, and hydro-genated in the presence of 0.3 g of 10 ~o palladium - carbon.
The catalyst was filtered out and the filtrate, after adding 5 mQ of l~-hydrochloric acid, was evaporated to dryness under reduced pressure, resulting in 1.3 g of 1-benzyl-4-chloro-2-(2-aminophenyl)imidazole-5-acetic acid hydrochloride as colorless powder, m.p. 115-120~.
Elementary analysis, C (~o) H (%) ~ (%) Cl (%) for C18H16N302Cl HCl Calcd. 57.15 4.53 11.11 18.74 Eound 56.85 4.66 10.97 18.66 Example 57 2.8 g of 1-benzyl-4-chloro-2-(4-benzyloxy-3-methoxyphenyl)-5-cyanomethylimidazole was boiled in a mixed solution of 45 mQ
of 6~-hydrochloric acid and 10 mQ of glacial acetic acid for 3.5 hours. The reaction solu-tion was e~aporated to dryness under reduced pressure, and the residue was dissolved in 30 mQ of water.

-: . : . . . : :,: . - :: :- .: .: : : :: ~ - . . ; :
- . : :
, . , :: - ,. . . .

~, .. : ~ . ~ . : . ..
' - . ., , :':

~lSZS~6 When the solution was made to pH 3 with sodium bicarbonate, there deposited 2 g of l-benzyl-4-chloro-2-(4-hydroxy-3-methoxyphenyl)imidazole-5-aoetic acid as colorless, prism-formed crystals, which ~ere recovered by filtration, m.p. 179-181& .
Elementary analysis, for ClgH17N204Cl C (%) H (%) N (%) Calcd. 61.21 4.60 7.51 Found 61.06 4.51 7.56 Example 58 1 g of 1-benzyl-4-chloro-2-(4-n-butoxyphenyl)imidazole-5-acetic acid was boiled in 14 mQ of 48 % hydrobromic acid for 2 hours, and addition of 15 mQ
of water, followed by allowing the solution to stand, resulted in crystals de-posited. Recrystallization of the crystals from aqueous ethanol yielded 0.5 g of l-~enzyl-4-chloro-2-(4-hy~rcEyphenyl)imidazole-5-acetic acid as colorless, prism~formed crystals, m.p. 140-145C.
Elementary analysis, for C18~ 5N203Cl C (%) H (%) N (%) Cl (~) Calcd. 63.10 4.38 8.17 10.34 Found 62.76 4.61 8.01 9.77 Example 59 1 g of 1-benzyl-4-chloro-2-(3-methoxyphenyl)imidazole-5-acetic acid was boiled in 14 mQ of 48 ~ hydrobromic acid for 2 hours. The reaction solution was eva~orated to dryness and, when water was added to the residue, there separ-ated out white powder. The pawder was dissolved in 10 mQ of hot ethanol, and water was added to the solution until turbidity was developed. After allowing it to stand, there was obtained 0.8 g of 1-benzyl-4-chloro-2-(3-hydr~xyFhenyl)-imidazole-5-aoetic acid as colorless, prims-formed crystals, m.p. 220-222 &.

~ . . .
: , : ~ ' - , ' , - ~ . , .

` - : .' ' ' :

` ~525~

Elementary analysis, for C18H15N203Cl C (%) H (%) N (%) Cl (%) Calod. 63.10 4.38 8.17 10.34 Found 63.19 4.20 8.04 10.18 EXample 60-62 mere were obtained the following compounds in accordance with the pro-oe dures of Examples 58 and 59.

- 21a -.: ~ . . :

Table Z~

N Gl R ~CH2C02H

~}X3 xl x2 10E~cemple ~ x2 ~ m.p. (C) ~OH H H H 175-178 61 HHOO~ H H H 153-155 62 HO ~ H H H 197-199 Example 67j 1.3 g of 1-(4-benzyloxybenzyl)~-chloro-2-phenylimidazole-5-acetic acid was boiled in 50 m~ of ethanol saturated with hydrogen chloride for 7 hours. The reaction solution was evaporated to dryness under reduced pressure, and 50 m~ each of a 5 % aqueous sodium carbonate solution and 25 ethyl acetate were added to the residue to shake to mix. The ethyl acetate layer was washed and evaporated~
to dryness under reduced pressure. Recrystallization of the residue from 10 m~ of acetonitrile yielded 140 mg of l-(4-hydroxybenzyl)-4-chloro-2-phenylimidazole-5-~0 acetic acid as colorless crystals, m.p. 196-199C.
Elementary analysis, for C20HlgN203Gl C (%) ~ (%) ~ (%) Calcd. 64.77 5,16 7.56 ~ound 64.95 5.28 7.31 - -- - ~ . , :

::

1~ 6 Example 64 In 5 mQ of ethanol was dissolved 680 mg of 4-chloro-2-phenyl-1-(4-methylbenzyl)imidazole-5-acetic acid, and a solution of 80 mg of sodium hydro-xide in 1 mQ of water was added to the solution. me mLxed solution was evapor-ated to dryness under reduoe d pressure, and the residue was dissolved in 5 mQ of ethanol. Upon addition of 30 mQ of ether to the solution, there was obtained 0.5 g of sodium salt of the above-mentioned cc~pound as colorless crystalline powder, m.p. 287-290C.
EXample 65 To the solution of 6 g of 1,3-dithian in 66 mQ of tetrahydrofuran was added dropwise n-butyllithium in 30 mQ of hexane (1.6M) under nitrogen atmos-phere and cooling (-25C) during 15 minutes period. After the reaction mixture was stirred for 2 hours at -15C, was added under ice-cooling 13.6 g of l-benzyl-4-chloro-5-formy1-2-(4-nitrophenyl)imidazole in 215 mQ of tetrahydrofuran during 1 hour period, and then was stirred for 20 hours under ice-cool;ng. m e reac-tion mixture was evaporated to dryness under reduoe d pressure and 200 mQ of chloroform was added to the resulting residue and was washed with 5 % hydro-chloric acid, water and saturated aqueous NaCQ solution in this order. The solu-tion was dried over sodium sulfate and evaporated to dryness under reduoe d pres-sure and the residue was dissolved 200 mQ of benzene and was refluxed for 30 minutes after addition of 1.6 g p-toluenesulfonic acid using water separator to catch the resulting water. The reaction mixture was washed with 5 % sodium bicarbonate, water and saturated aqueous NaCQ solution in this or~er and evapor-ated to dryness under reduced pressure. m e resulting residue (20 g) of 2-[1-benzyl-4-chloro-2-(4-nitrophenyl)imidazol-5-yl methylidene]-1,3~dithiane was re-fluxed for tWD hours in 210 mQ of aoetic anhydride and 70 mQ of conoentrated hydrochloric acid and concentrated to dryness under reduoe d pressure~ me resi-~, ~
, _.
.

.

~52~6 due was dissolved in 200 mQ of chloroform and washed with water and then ex-tracted twice with 200 mQ portion of lN-NaCH.
The ccmbined extract was washed with chloroform and adjusted to pH 2 with hydrochloric acid and then extracted twice with 100 mQ portion of chloro-form. m e chloroform layer was washed with water and concentrated to dryness under reduced pressure. m e residue was recrystallized twice from 80 ~ ethanol to give 1.2 g of 1-benzyl-4-chloro-2-(4-nitrophenyl)imidazole-5-acetic acid as yellow prism crystal, m.p. 180-183C.
Example 66 In 35 mQ of t-butanol was dissolved 975 mg of potassium and conoen-trated to dryness under reduoe d pressure. me resulting residue was dissolved in 25 mQ of ~MSO and 0.5 mQ of t-butanol. me solution was added to ~MSO solu-tion of 2.92 g of p-toluenesulfonylmethylisocyanide and 1.7 g of 1-(4-chloro-benzyl)-4-chloro-5-formyl-2-phenylimidazole under i oe -oooling and then stirred for 1 hour under ice-cooling and 18 hours at room te~perature. The reaction mix-ture was poured into 150 mQ of water and extracted 3 tL~,es with 100 mQ portion of ether. Combined ether layer was washed with water and conoentrated to dryness under redu oe d pressure, the resulting residue was chromatographed on 60 g of silica gel and eluted with chloroform. me main fraction was concentrated to dryness under reduoed pressure and the residue (0.3 g) of l-formylamino-l-p-toluenesulfonyl-2-[1-(4-chlorobenzyl)-4-chloro-2-phenylimidazol-5-yl]ethylene was refluxed in 2 mQ each of glacial aoetic acid and conoe ntrated hydrochloric acid for 2 hours. The reaction mixture was conoe ntrated to dryness under re-duced pressure and the resulting residue was recrystallized from 5 mQ of 60 ':

~li5~ 6 ethanol to give 0.2 g of 1-(4-chlorobenzyl)-4-chloro-2-phenylimidazole-5-acetic acid as colorless needles.
m.p. 203-205C (decomp.).

Exam-~le 67 3.8 g of 4-chloro-1-(3-methyl-4-methoxybenzyl)-2-phenylimidazole-5-acetic acid was dissolved in 10.8 mQ
of l~-sodium hydroxide under heating and the solution was concentrated to dryness under reduced pressure.
The resultin~ residue was dissolved in 20 m~ of acetone and triturated with ether to precipitate 4 g of sodium salt of the above-mentioned compound as colorless needles. m.p. 272-274C (decomp.).
Elementary analysis, for C20Hl8~2o3clNa C (/0) H (%) ~ (%) Calcd. 61.15 4.62 7.13 ~ound 60.87 4.84 7.25 Example 68-74 There were obtained the following compounds in accordance with the procedures of Examples 1-67 ~able 3-II
Example Rl XlX2 ~3 m p (DG) 69 ~ 4-C2H503-CH3 H 188-189 n~C4H9~ 4-CH303-CH3 H 142-143 3o 71 n C4H9 2-C2H5 H H 160-162 72 n C6H13 4-n-C4~90 H H 137-139 73 n C6H13 4-CH30 3-CH3 H 98-101 (ammonium salt) 74 CHC3Ho3 ~ 4-CH303-CH3 ~ 220-222 .

: . .
: . :
`: . . ;
.

- -In accordance with the procedures of Examples 1 through 74, the following compounds can be synthesized:
2-Butyl-4-chloro-1-(2-methoxybenzyl)imidazole-5-acetic acid;
2-Isobutyl-4-chloro-1-(2-chlorobenzyl)lmidazole-5-acetic acid;
2-Butyl-4-chloro-1-(2-ethoxybenzyl)imidazole-5-acetic acid;
2-Butyl-4-chloro-1-(2-propoxybenzyl)imidazole-5-acetic acid;
2-3utyl-4-chloro-1-(2-butoxybenzyl)imidazole-5-acetic acid;
2-Butyl-4-chloro-1-(2-bromobenzyl)imidazole-5-acetic acid; and 2-Phenyl-4-bromo-1-(2-methoxybenzyl)imidazole-~-acetic acid.
Example 75 In cases in which the compound (I) of the present invention is employed as a treatmen-t agent for essential hypertension, for example, it is utilized by the following fo~mulation:
1. ~ablets (1) 1-Benzyl-2-n-butyl-4-chloroimidazole-5-acetic acid, 10 mg (2) ~actose, 35 mg (3) Corn starch, 150 mg 20 (4) Microcrystaline cellulose 30 mg (5) Magnesium stearate 5 mg One tablet230 mg (1), (2), (3) and two thirds of (4) were mixed with a half of (5) and granulated. ~he remainders of (4) and (5) were added to the granules and pressed into a tablet~
2. Capsules (1) 1-(4-~thoxybenzyl)-2-phenyl-5-chloroimidazole-5-acetic acid, 10 mg (2) ~actose 9O mg (3) Microcrystalline cellulose . 70 mg (4) Magnesium stearate 10 mg One capsule190 mg (1), (2) and (3) were mixed with one fourth of (4), .

,.... , : :
,. ; , : :: ~ .. . .

.... .
.: : ::: .

~52516 and granulated. ~he remainder of (4) was added to the granules and the mixture was fiLled in-to a gelatin capsule.
~. Injections (1) Sodium 1-(4-methylbenzyl)-2-phenyl-5-chloroimidazole-5-acetate 10 mg (2) Inosite 100 mg (3) Benzyl alcohol 20 mg One ampoule 130 mg (1), (2) and (3) were dissolved in distilled water for injection to make 2 m~ of the solution, and filIed into an ampoule. The whole preparation process was ~-conducted in the sterile condition, Reference Example 1 5.2 g of 2-phenyl-5-hydroxymethylimidazole and 4.43 g of ~-chlorosuccinimide were stirred in a mixture of 40 m~ of methyl cellosolve and 60 ml of dioxane at 50C for 8 hours. 50 m~ of ether was added to the reaction solution, and the crystals separated out were recrystallized from 100 m~ of ethanolt resulting in 4.6 g of 2-phenyl-4-chloro-5-hydrox~methylimidazole as colorless, prism-formed crystals, m.p 190-195C (decomp.).
Elementary analysis, for CloH9 OCl C (%) H (%) ~ (%) C1 (%) Calcd. 57.52 4.35 13.42 16.98 ~ound 57.89 4.30 13.39 16.98 Reference Examples 2 to 9 In accordance with the procedure of Reference ~xample 1, there were obtained the following compounds.
able 4 Rl~CH2H
H

- ~ - . .
. ~ . , : , - . , . : ", , , :~ . . .
.: . . .
, ~ 5 ~ 1 6 _ Reference Rl m.p (C) _ _ 2 n C4H9 147-148 3 n~C4H9 ~ 190-191 L~ CH3 - ~ 209-211 CH30 - ~ 191-193
6 Cl - ~ - 209-211
7 t-C4Hg- 170-174
8 3 7 172-175
9 ~ 185-186 Reference Example 10 1 g of 2-phenyl-4-chloro-5-hydroxymethylimidazole, together with 0.7 m~ of p-methylbenzyl bromide and 3 g of potassium carbonate, was stirred in 10 m~ of dimethylformamide at 30C for 2 days. ~he reaction solution was poured into 100 m~ o~ water, and the precipitate deposited was chromatographed on a column of 30 g of silica gel, followed by eluting with chloroform.
~he initially eluted fraction was collected, and recrystallization from aqueous methanol yielded 0.5 g of 2-phenyl-4-chloro-5-hydroxymethyl-1-(4-methylbenzyl)imidazole as colorless, needle-formed crystals, m.p. 173-175C.

30Reference Example 11 0.7 g of sodium was dissolved in 15 mR of methanol, and the solution was combined with 30 m~ of a methanol solution of 5.6 g of 2-cyclopentyl-4-chloro-5-hydroxymethylimidazole. ~he mixed solution was evaporated to dryness under reduced pressure, and the residue was dissolved in 20 m~ of dimethylformamide, followed by ', . .
. ~ . . , ~ . . : ":
.: : , ' :,, '' : : .
- ,-.
. : , : ~ : :

~l~Z~

adding 3.9 g of benzyl chloride to stir at 40 to 45C
for 3 hours. The reac-tion solution was poured into 300 m~
of water to extract with two 100 m~ portions of ethyl acetate.
The ethyl acetate layer was evapora-ted to dryness under reduced pressure, and the residue was chrom~tographed on a column of 200 g of silica gel to elute with ethyl acetate - benzene (1 : 3). The initially eluted fraction was collected to evaporate to dryness under reduced pressure. The residue was dissolved in ether, whereby there separated out crystals. Addition of petroleum ether, followed by recovery by filtration, yielded 2 g of 2-cyclopentyl-4-chloro-5-hydroxymethyl-1-benzylimidazole as slightly yellow, prism-formed crystals, m.p. 102-103C.
Elementary analysis, for C16H19N20Cl C (%) H (%) ~ (%) Calcd. 66.09 6.59 9.63 ~ound 66.37 6.55 9,59 Reference Example 12 5.8 g of 1-benzyl-2-cyclohexyl-5-hydroxymethylimidazole, together with ~.2 g of N-chlorosuccnimide, was stirred in 58 m~ of methyl cellosolve at 40C for 1 hour. The reaction solution was poured into 500 m~ of water and extract with two portions of 200 m~ of ether. The ether layer was evaporated to dryness under reduced pressure, and the residue was chromatographed on a column of 200 g of silica gel to elute with ethyl acetate - benzene (1 : 4).
The objective fractions were collected and evaporated to dryness under reduced pressure. Recrystallization of the residue from ether yielded 1.6 g of 1-benzyl-4-chloro-2-cyclohexyl-5-hydroxymethylimidazole as colorless, needle-formed crystals, m.p. 160-161C.
~lementary analysis, for C17H21~20Cl C (%) H (%) ~ (%) Calcd. 66.99 6.95 9.19 ~ound 66.90 6.87 9.25 :: , , :

5Z5:~6 - ~o -Reference Examples 13 to 23 In accordance with the procedures of Reference Examples 10, 11 and 12, there wcre obtained the following compounds:
5able 5 Rl~ l~CH2oH

xl X2 Reference Rl Xl X2 X3 m p, (C) Example No.
13 t C4H9 H H H160-163 n C4H9 H H H 65-67 16 n C4H9 2-Cl H H101-103 17 n C4H9 2-N02 H H107-108 22 5 11 2-Cl H H112-114 23 n C6H13 2-Cl H H 96-98 Reference Example 24 In 50 m~ of tetrahydrofuran:was dissolved 2.1 g of l-benzyl-2-(4-n-butyrylaminophenyl)-4-chloro-5-hydroxymethylimidazole. 300 mg of lithium aluminiumhydride was added to the solution, followed by boiling for 4 hours. The procedure was repeated twice. 1 m~ of water and 1.8 ml of 6~-hydrochloric acid were added to the reaction solution, which was shaken well, and insolubles were filtered out. ~he filtrate was evaporated to dryness under reduced pressure, and the residue was ,: : : ,.
. ~

l~:SZS~$

dissolved in 20 m~ of methanol to add water li-ttle by little.
There was obtained 1.5 g of 1-benzyl-2-(4-n-butylaminopheyl)-4-chloro-5-hydroxymethylimidazole separated out as colorless needle-formed crystals, m.p. 161-lS3C.
~lementary analysis, for C21X24N~OCl C (%) H (%) ~ (%) Cl (%) Calcd. 68.75 6.59 11.44 9.67 ~ound 68.45 6.59 11.26 9.32 Reference Example 25
10 g of 4-chloro-5-formyl-2-phenylimidazole was added little by little to a mixture of 25 me each of fuming nitric acid (specific gravity of 1.52) and concentrated sulfuric acid. After addition was completed, the mixture was stirred at room temperature for 1 hour, and poured into 400 m~ of ice-water. Recrystallization of the resultant precipitate from 100 m~ of dimethylformamide yielded 9 g of 4-chloro-5-formyl-2-(4-nitrophenyl)imidazole as slightly yellow, needle-formed crystals, m,p. o~ not lower than 300C.
~lementary analysis, for CloH6~303Cl C (%) H (%) ~ (%) Cl (%) Calcd. 47.73 2.40 16.70 14.08 ~ound 47.44 2.57 16.90 13 91 Reference Example 26 In 35 m~e of glacial acetic acid was dissolved 3.5 g of l-benzyl-4-chloro-5-cyanomethyl-2-(4-dimethylaminophenyl) imidazole, and 1 me of fuming nitric acid (specific gravity of 1.52) was added dropwise to the solution under cooling with water. The mixture was stirred at room temperature for 1 hour and poured into 500 m~ of ice-water. ~he resultant precipitate was chromatographed on a column of 60 g of silica gel, followed by eluting with chloroform.
~5 ~he objective fractions were collected and concentrated to about 5 m~. Addition of 10 m~ of ethanol yielded . . ; ;
~' '' '' ' ' '. ~ ' ' ,' , ~525~6 1.7 g of 1-benzyl-4-chloro-5-cyanomethyl-2-(4-dimethylamino-3,5-dinitrophenyl)imidazole as yellow prism-formed crystals, m.p. 173-175C.
~lementary analysis, for C20E17~60~Cl 5C (o/O) H (%) ~ (%) Cl (/0) Calcd. 54.45 3.89 19.04 8.05 Found 54~17 3.87 19.31 8.25 Reference Example 2Z
2 g of 1-benzyl-4-chloro-5-cyanomethyl-2-(4-dimethylaminophenyl)imidazole and 1 g of ~-chlorosuccinimide were stirred in 30 mQ of dioxane at 50C for 2 hours.
The reaction solution was evaporated to dryness under reduced pressure, and the residue was dissolved in 100 m~
of chloroform, followed by washing twice with water and evaporating to dryness under reduced pressure.
The residue was recrystallized twice from 20 m~ of methanol, thus yielding 1.4 g of 1-benzyl-4-chloro-5-cyanomethyl-2-(4-dimethylamino-3-chlorophenyl)imidazole assli~htly yello~, needle-formed crystals, m.p. 142-143C, ~lementary analysis, for C20H19~302C12 C (o/o) H (%) ~ (%) Cl (%) Calcd. 59.42 4.73 10.38 17.54 ~ound 59.64 4.61 10.37 17.43 Reference Example 28 In 40 me of chloroform was suspended 8.2 g of l-benzyl-4-chloro-2-(4-nitrophenyl)-5-hydroxymethylimidazole, and 3.7 m~ of thion~l chloride was added dropwise to the suspension. After allowing it to stand at room temperature for 2 hours, the reaction solution was evaporated to dryness under reduced pressure. 50 m~ of toluene was added to the residue, followed by evaporating to dryness under reduced pressure again. The residue was dissolved in 80 m~ of chloroform and cooled with ice. 7 g of sodium cyanide and 0.8 g of tetrabutyl ammonium bromide were . ..

, ,. , "
.: . . ~ . . , 1' : : i .
- .

dissolved in 25 m~ of ice water, and the solution was added to the chloroform solution mentioned above, followed by stirring vigorously at 0C for 2 hours and further at room temperature for 5 hours. The chloroform layer was washed with 50 m~ of water, and chromatographed on a column of 80 g of silica gel, followed by eluting with chloroform. The fractions of the objective compound were collected and evaporated to dryness under reduced pressure, followed by dissolvirg the residue in 50 m~
of methanol to allow to cool. ~here was obtained 7 g of l-benzyl-4-chloro-2-~4-nitropheryl)-5-cyanomethylimidazole resulted as slightly yellow, needle-formed crystals, m.p. 125-128C.
Elementary analysis, for C18H13~402C1 C (%) H (%) N (%) C1 (%) Calcd. 61.29 3.71 15.87 10.05 ~ound 61.14 3 . 65 15.74 9.95 Reference ExamPle 29 In 18 m~ of chloroform was dissolved 1.8 g of l-benzyl-4-chloro-2-cyclopentyl-5-hydroxymethylimidazole, and 2.2 m~ of thionyl chloride was added dropwise to the solution, followed by stirring at room temperature for 1 hour. ~he reaction solution was evaporated to dryness under reduced pressure, and 20 m~ of benzene was added to the residue to distill off the solvent.
The procedure was repeated twice. ~he residue was dissolved in 10 m~ of dimethylsulfoxide, and the solution was added dropwise to a suspension of 1.8 g of dried sodium cyanide in 10 m~ of dimethylsulfoxide at room temperature with stirring. After addition was completed, the solution was vigorously stirred at room temperature for 1 hour, followed by pouring into 200 m~ of water to extract with two 100 m~ portions of ethyl acetate. lhe ethyl acetate layer was evaporated to dryness under reduced pressure, and the residue was chromatographed on - ~
- , ~ . ~ : -:

.~ , ~15;~53L`~
_ 3l~ _ a column of 70 g of silica gel, followed by eluting with benzene - acetone (20 ~ he fractions of the objective compound were collected and evaporated to dryness under reduced pressure. ~he residue was dissolved in 50 m~ of ether, and 1.5 m~ o:E 20 % hydrogen chloride - ethanol was added to the solution. ~here was obtained 1.5 g of 1-benzyl-4-chloro-2-cyclopentyl-5-cyanomethylimidazole hydrochloride deposited as colorless, plate-formed crystals, m.p. 124-132C.
~lementary analysis, for C17H18~3Cl-HCl C (%) H (%) N (%) Calcd. 60.72 5.69 12.50 ~ound 60.67 5.70 12.35 Reference Examples 30 to 65 In accordance with the procedures of Reference Examples 28 and 29, there were obtained the following compounds:
~able 6 ~ Cl Rl ~aH2C~ :

~ X3 X X
:
Reference Rl Xl X2 X3 m p (C) 3o 30 ~ 2-Cl H 5-N02 150-151 31 ~ 4-CH2 H H 146-148 32 ~ 2-CH30 H H 112-113 _ 3-CH30 E H 65-70 :- , :
: . . . ;. .:, ,.
- . . . ~ , - . , ~ . , : .
. ~ ~ . , .. - .

IS2Sl~

~ 35 -Reference Rl I Xl x2 X3 ~-P- (C) Example No, __ _ _ _ ~ __ _ _ _ _ _ 34 ~ 4-CH30 H H 89-90 ~ 4-C2H50 H H 108-110 36 ~ 4-n-C4X90 H H 80-81 37 ~ 6 5 2 H 152~155 38 ~ 3-CH30 X 4-CH30 113-114 39 ~ 3-CH3 H 4-CH30 137-138 ~ 3-CH30 4-CH30 5-CH30 124-125 41 ~ 4-Cl H H 155-156 42 ~ 2-Cl H H 163-164 43 ~ 2-C1 4-Cl H 172-173 44 ~ 2-Cl 6-Cl H 189-190 ~ 2-Br H H 153 46 CH30~ ~2 H H H 157-159 47 CHCH030 ~ H H H 100-101 48 CH30 ~ ~ H H 147-149 49 CHC3Ho3 ~ H H H 110-112 3o 5 ClCH~0 ~ H H H 94-96 51 iCH3 H H H 114-115 53 i-C3H7 H E H 130-131 : , :, , - ~:
: . . .

S25~6 Reference _ _ x2 X3 m.p.(C) 54 n C4H9 H H H (hydrochloride) 5 55 n-C4Hg 2-Cl H H 117-118 56 n-C4Hg 2-~02 H H 82-84 57 n-C~H7 H H H (hydrochloride) . 58 t-C4Hg H H H (hydrochloride) 61 n C6H13 2-Cl H H 126-128 62 ~ H H H 117-118 63 n-C3H7CNH- ~ - H H H 152-154 64 Cl ~1 ~ H H H 188-190 .

n C4H9 4-n-C4H90 H H 120-122 66 ~ 2-C2H5 H H 110-112 67 ~ 4-C2H50 3-CH3 H 117-119 68 n C4H9 4-CH30 3-CH3 H IR(Nujol):2240cm 1 69 n C4H9 2-C:2H50 H H IR(~ujol):2240cm 1 n 6 13 4-n-C4HgO H H (hydrochlorlde) 3o 71 n-C6X13- ~4`-CH3C 3-CH3 H 126 127 72 CH30 ~ 4-CH30 3-CH3 H 85-90 .

- ;

:,. . .
~ ~ . .- , .
, . .: : . ~
.: - ~: - : : . : .. -,. .. . :
.. : ~ :: ;-~l~iZ516 Ex~eriment Example 1 - Antagonistic effect of the compound (I) of the present invention on angio-tensin II (hereinafter referred to briefly as "A II") (with aortic blood vessel of rabbits) -The blood-vessel preparation and reaction were done in accordance with the method as described in "~uropean Journal of Pharmacology", 18, 316 (1972).
While employing A II in the concentration of 4 x 10 9M, the potency of inhibition was calculated by the following equation from changes in isometric tension of the blood vessel brought about by A II and that found after treatment with a test drug substance for 15 minutes, respectively.
Potency of inhibition (o/o) = ~1 T T? x 100 where; :
Tl = Change in isometric tension of the blood vessel brought about by A II without a test drug substance (g) T2 = Change in tension found after treatment with a test drug substance (g) The results are shown in Table 7.
Table 7 . Rl ~ CH2C02H

~ X3 3o 1 ?Ound ~ ~ Concn of drug Inhibition (/0) R ~ Xl X X~ substance (M) :
~ 4-CH3 H H 10 5 80 ~ 2-CH3 H H 10 5 58 ~ 4-Cl H H 10 5 25 .

" . -... .. . . . . .... .

.: . . . :

Co~ pound 2 ¦ Concn of drug Inhibition (%) R __ _ X X - X3 subs tance (M) ~ 2-Cl H H 10-5 90 ~ 2-Cl 4-Cl H 10-5 30 2-Cl H 6-01 10 6 34 ~ 2-Cl H 6-F 10 6 64 10 e~ 2-Cl5-N02 H 10 6 34 2-Br H H 10-6 60 ~ 2-~ H H 10-6 23 15n-C4Eg~H~ H H H 10-5 63 ~N02 H H H 10 5 35 ~:
2 ~ H H H 10-5 50 20 ~H2 H H H 10-5 3 0 HO~ H H H 10-5 32 HO~ H H H 10-5 18 25H2Go_~ H H H 10-5 51 (CH3 ) 2~ H H H 10-5 73 22 ~ ~ ~
3o(CH3 ) 2N~ H H I 10-5 8~ : .

~~ H H H 10-6 82 35 Cl (C2H5)2~ H H H 10-6 25 ~OH H H H 10 5 _ ,. .- : .:
. .

.- ..

- " liSZSl6 Comp( und 2 Concn of dru Inhibition (%) R Xl X X3 substance (M~
___ _ _ ( 3)2 ~ H H H Io-6 33 5(CH3)2N ~ H H H 10-6 18 H0 ~ H H H 10-6 34 3 ~ 2-Cl H H 10-6 23 10CH30 ~ H H H 10-6 16 ~ 3-GH30 H H 10-5 73 ~ 4-CH30 H H 10-5 61 ~ 2-C2H5 H H 10-6 L~l ~ 4-C4HgO H H 10-6 56 4-C6H5cH2c H H 10-5 19 ~ 3-CH30 H ~ ~-CH30 10-6 38 ~ 3-CH3 H 41-CH30 10 6 80 CH~0 ~ 3-CH3 H 4-C2H50 10-6 81 3 ~ H H H 10-6 18 CH3H3 ~ H X H 10-6 32 3oCH30 ~ 3-CH3 4-CH3( ) H 10 6 54 ~ CH20 ~ H H H 10-6 18 C2H5- H H H lo~6- 36 i-C3H7- H H H 10 6 41 . ..
.
: . .. .

, .
'' .. : , . . .

: ~:

l:~SZS:16 C ompound 2 _ Concn.of dru~ Inhibition (%) Rl Xl X X3 substance (M) n C4H9 H H H 10 6 55 n C4H9 `2-Cl H H 10-7 75 ~ C4H9 2-~02 H H 10-8 30 n C4H9 3-CH3 4-CH30 H 10 6 99 n C4Hg 2-C2H5 H H 10 6 53 t C4Hg H H H 10-6 10 n-C5Hll- H H H 10-6 65: :~
n-C5Hll- 2-Cl H H 10-7 57 n C6H13 2-Cl H H 10-7 84 ~:
n C6H134-n-C4H9C H H 10 6 100 n C6H13 3-CH3 4-CH30 H 10-6 100 ~ H H H 10-6 34 ~ H H H 10-6 18 n~C4H9~ 4-n-C4HgC ~ H H 10 6 85 :

Experiment ExampIe 2 30 - Inhibitory activity of the compound (I) of the present invention against angiotensin II-induced elevation of blood pressure in rats -Male SD rats weighing~250 to 350 g, under anesthesiawith pentobarbital sodium (50 mg/kg, intraperitoneall~), 35 were operated on for c~nnulation in trachea, carotid and femoral arteries. In order to maintain the anesthesia, - . . . .

, .:

~5j~5~6 pentob~rbital dissolved in physiological saline was admunistered to the rats by continuous intravenous infusion (350 ~g/kg/min.). Pbout one hour after opera~
tion, when the blood pressure got stable, A II was given by contLnuous intraven-ous infusion at a rate of 20 ng/kg~min. 30 to 60 minutes later, the stable blood pressure was realized. The elevation of blood pressure after the infusion of A II, as ccmpared with the one before the infusion, was 45.5 ~ 2.1 mmHg (for 75 cases). Then, a test drug substance (dissolved in 500 ~Q physiological saline/
100 g body weight) was adm mistered intravenously to take measurements of blood pressure after 10, 30 and 90 minutes. m e potency of inhibition by a drug sub-stance was calculated by the following equation:

Pf Potency of inhibition (%) = Pe x 100 where;
Pf = Fall in blood pressure after admLnistration of a drug substanoe (mmHg) Pe = Elevation of blood pressure due to A II (mmHg) The results are shcwn in Table 8.

r ;~
~ .

` ~

~: : : : ~.. , ::: - ' . `' - :
' ~,` :' , ' ' ' : ~

~1`5Z51 ~

Table 8 Compound Doses Inhibition (~), ater;
_ .
R Xl x2 X3 (mg/kg) Cases 10 mm. 30 min. 90 min.
__ H~ H H H 0.3 310.7+1.824.3+2.311.7+6.0 0.5 414.8+1.836.0+3.035.0+3.9 2 ~ H H H 0.5 317.7+1.245.3+2.437.0+8.6 ~ 2-C1 H H 1.0 411.8+1.836.5+4.532.3+7.0 n-C H H H H 0.1 319.6+1.564.3+15.360.0+21.5 4 9 0.3 1 25 94 94 Cl~ H H H 0.1 422.5+3.255+7.5 55+7.5 2 0.3 2 18 72 72 ~ 4-n-C4HgO H H 3.0 1 20 40 O
n-C4Hg 2-Cl H H 0 03 2 1378 4160o5 86 3 - CH3 4 - C~3O H 0.5 4 33+15 60+18 62+7

Claims (19)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a compound of the formula I;

wherein R1 is lower alkyl, cycloalkyl or, phenyl which is unsubstituted or is substituted with one to three of halogen, nitro, amino, mono(lower alkyl)amino, di(lower alkyl)amino, lower alkyl, lower alkoxy, benzyloxy and hydroxyl; X1, X2 and X3 are each hydrogen, halogen, nitro, amino, lower alkyl, lower alkoxy, benzyloxy or hydroxyl; Y is halogen and R2 is hydrogen or lower alkyl, provided that X1 is halogen, lower alkyl, lower alkoxy, benzyloxy or hydroxyl when R1 is unsubstituted or substituted phenyl only with one halogen, di(lower alkyl)amino, lower alkyl or lower alkoxy, or its pharmaceutically acceptable salt, which pro-cess comprises subjecting to solvolysis a compound of the formula:

wherein X1, X2, X3 and Y are as defined above, R1' is the same as R1 defined above or is a group which is converted to R1 during the solvolysis and A is cyanomethyl or .beta.,.beta.-disubstituted vinyl designated with one of the following formulae:

-CH = , -CH = , -CH = and, if required, reducing an obtained compound of formula I in which a nitro group or a benzyloxy group is present to convert the nitro group to an amino group or to convert the benzyloxy group to a hydroxyl group or, if required, hydrolysing an obtained compound of formula I in which a benzyloxy or lower alkoxy group is present to convert the benzyloxy or lower alkoxy group to a hydroxyl group and, if required, converting a compound of formula I into a pharmaceutically acceptable salt thereof.
2. A process according to claim 1, wherein A is cyanomethyl and the solvolysis is hydrolysis.
3. A process according to claim 1, wherein Y is chlorine.
4. A process according to claim 1, wherein R1 is lower alkyl.
5. A process according to claim 1, wherein R1 is phenyl which is sub-stituted with only one nitro, amino or hydroxyl, or with two to three of halogen, nitro, amino, mono(lower alkyl)amino, di(lower alkyl) amino, lower alkyl, lower alkoxyl, benzyloxyl or hydroxyl.
6. A process according to claim 5, wherein R1 is phenyl substituted with two to three of halogen, mono(lower alkyl)amino, di(lower alkyl)amino, lower alkyl, lower alkoxyl, benzyloxy or hydroxyl, and X1, X2 and X3 are each hydrogen.
7. A process according to claim 1, wherein R1 is unsubstituted or phenyl monosubstituted with halogen, di(lower alkyl)amino, lower alkyl or lower alkoxyl, and X1 is halogen, lower alkyl, lower alkoxyl, benzyloxy or hydroxyl
8. A process according to claim 1, wherein R1 is unsubstituted phenyl, and X1 is C1-4 alkyl, X2 is C1-4 alkoxyl and X3 is hydrogen.
9. A compound according to claim 1, wherein R2 is hydrogen.
10. A compound of formula I as defined in claim 1, or a pharmaceutically acceptable salt thereof when prepared by a process according to claim 1 or an obvious chemical equivalent thereof.
11. A process according to claim 1, wherein X1 is chlorine in the 2-posi-tion of the phenyl ring, X2 and X3 are hydrogen R1 is n-butyl, Y is chlorine and R2 is hydrogen.
12. A process for preparing 1-(2-chlorobenzyl)-2-n-butyl-4-chloroimidazole -5-acetic acid which comprises hydrolyzing 1-(2-chlorobenzyl)-2-n-butyl-4-chloro -5-cyanomethylimidazole.
13. The compound 1-(2-chlorobenzyl)-2-n-butyl-4-chloroimidazole-5-acetic acid when prepared by a process according to claim 1 or an obvious chemical equivalent thereof.
14. A process according to claim 1, wherein X3 is methoxy in the 4-posi-tion and X1 is methyl in the 3-position of the phenyl ring and X2 is hydrogen, R1 is phenyl, Y is chlorine and R2 is hydrogen.
15. A process for preparing 4-chloro-1-(4-methoxy-3-methylbenzyl)-2-phenylimidazole-5-acetic acid which comprises hydrolysing 4-chloro-1-(4-methoxy-3-methylbenzyl)-2-phenyl-5-cyanomethylimidazole.
16. The compound 4-chloro-1-(4-methoxy-3-methylbenzyl)-2-phenylimidazole-5-acetic acid when prepared by a process according to claim 15 or an obvious chemical equivalent thereof.
17. A process according to claim 1, wherein X1 is ethoxy in the 4-position and X2 is methyl in the 3-position of the phenyl ring and X3 is hydrogen, R1 is phenyl, Y is chlorine and R2 is hydrogen.
18. A process for preparing 4-chloro-1-(4-ethoxy-3-methylbenzyl)-2-phenylimidazole-5-acetic acid which comprises hydrolyzing 4-chloro-1-(4-ethoxy-3-methylbenzyl)-2-phenyl-5-cyanomethylimidazole.
19. The compound 4-chloro-1-(4-ethoxy-3-methylbenzyl)-2-phenylimidazole-5-acetic acid when prepared by a process according to claim 18 or an obvious chemical equivalent thereof.
CA000364361A 1979-11-12 1980-11-10 Imidazole-5-acetic acid derivatives, their production and use Expired CA1152516A (en)

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