CA1194883A - 4-chloro-2-phenylimidazole-5-acetic acid derivatives and production thereof - Google Patents

Abstract

Abstract of the Disclosure Compounds of the formula

Description

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

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) ~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

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

~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 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 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-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 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~

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.

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 Table l Compound Concentration Inhibition !
(Example No.) (M) rate 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.

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.

- 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.

Claims (21)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for producing a compound of the formula:

(I-a) wherein R is lower alkyl, and R1"' is H or COR2 wherein R2 is lower alkyl or a pharmaceutically acceptable salt thereof with a base or a pharmaceutically acceptable acid addition salt thereof, which process comprises:
[1] when a compound of formula (I-a) wherein R1"' is H is required, (A) deprotecting a compound of the formula (II) wherein R is as defined above and R1 is a protective group which is C1-3 alkyl or benzyl which may be substituted by 1 to 3 of C1-3 alkyl or C1-3 alkoxy, or (B) hydrolyzing a compound of the formula:

(III) wherein R is as defined above, or (C) hydrolyzing a compound of the formula:

(V') (V' ) wherein R is as defined above, and R1" is lower alkyl, with an acid, and [2] when a compound of formula (I-a) wherein R1'" is COR2 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:
R2COOH (VII) wherein R2 is as defined above, or a reactive derivative thereof, and if desired, converting the thus-obtained compound of for-mula (I-a) into a pharmaceutically acceptable salt thereof with a base or into a pharmaceutically acceptable acid addition salt thereof.

2. A process according to claim 1, wherein in the starting materials the lower alkyl is methyl.

3. A process according to claim 1, wherein the de-sired compound is obtained as an alkaline metal salt thereof.

4. A process for producing a compound of the formula:

(I) wherein R is lower alkyl or a pharmaceutically acceptable salt thereof with a base or a pharmaceutically acceptable acid addi-tion salt thereof, which process comprises:
(A) deprotecting a compound of the formula:

(II) wherein R is as defined above and R1 is a protective group which is C1-3 alkyl or benzyl which may be substituted by 1 to 3 of C1-3 alkyl or C1-3 alkoxy or (B) hydrolyzing a compound of the formula:

(III) wherein R is as defined above, or (C) hydrolyzing a compound of the formula:

(V') wherein R is as defined above, and R1" is lower alkyl, with an acid,and, if required, con-verting the thus-obtained compound of formula (I) into a phar-maceutically acceptable salt thereof with a base or into a pharmaceutically acceptable acid addition salt thereof.

5. A process according to claim 4, wherein in the starting materials the lower alkyl is methyl.

6. A process according to claim 4, wherein the de-sired compound is obtained as an alkaline metal salt thereof.

7. A process for producing a compound of the formula:

(VI) wherein R is lower alkyl and R2 is lower alkyl, or a pharma-ceutically acceptable salt thereof with a base or a pharmaceuti-cally acceptable acid addition salt thereof, which process com-prises acylating a compound of formula (I) prepared in claim 4, with a carboxylic acid of the formula:

R2COOH (VII) wherein R2 is as defined above, or a reactive derivative thereof.

8. A process for producing 4-chloro-1-(4-hydroxy-3-methylbenzyl)-2 phenylimidazole-5-acetic acid or a pharmaceuti-cally acceptable salt thereof with a base, which method com-prises:
(a) deprotecting the hydroxy-protective group in 4-chloro-1-(4-methoxy-3-methylbenzyl)-2-phenylimidazole-5-acetic acid, 4-chloro-1-(4-benzyloxy-3-methylbenzyl)-2-phenylimidazole-5-acetic acid or 4-chloro-1-(4-ethoxy-3-methylbenzyl)-2-phenyl-imidazole-5-acetic acid, or (b) hydrolyzing 4-chloro-5-cyanomethyl-1-(4-hydroxy-3-methylbenzyl)-2-phenylimidazole, and if desired, converting the thus-obtained compound into a pharmaceutically acceptable salt thereof with a base.

9. A process according to claim 8, wherein process al-ternative (a) is carried out by reacting a starting material wherein the hydroxy-protective group is methyl or ethyl, with trimethylsilyl iodide and subsequently treating with water.

10. A process according to claim 8, wherein process al-ternative (a) is carried out by heating a starting material wherein the hydroxy-protective group is methyl or ethyl, in the presence of hydrobromic acid.

11. A process according to claim 8, wherein process al-ternative (a) is carried out by reacting a starting material wherein the hydroxy-protective group is methyl or ethyl, with boron tribromide and subsequently treating with water.

12. A process according to claim 8, wherein process al-ternative (a) is carried out by reacting a starting material wherein the hydroxy-protective group is methyl or ethyl, with aluminum chloride and 1,2-ethanedithiol and subsequently treat-ing with water.

13. A process according to claim 8, wherein process al-ternative (a) is carried out by reacting a starting material wherein the hydroxy-protective group is methyl or ethyl, with aluminum chloride and dimethyl disulfide and subsequently treating with water.

14. A process according to claim 8, wherein process al-ternative (a) is carried out by heating the starting material wherein the hydroxy-protective group is benzyl, in trifluoro-acetic acid.

15. A process according to claim 8, wherein the hydroly-sis of process alternative (b) is carried out in the presence of sodium hydroxide.

16. A process according to claim 8, wherein the acid obtained in process alternative (a) or (b) is converted to the sodium salt thereof.

17. A compound of formula (I-a) as defined in claim 1, or a pharmaceutically acceptable salt thereof with a base or a pharmaceutically acceptable acid addition salt thereof, when-ever prepared or produced by the process of claim 1 or by an obvious chemical equivalent thereof.

18. A compound of formula (I) as defined in claim 4, or a pharmaceutically acceptable salt thereof with a base or a pharmaceutically acceptable acid addition salt thereof, whenever prepared or produced by the process of claim 4 or by an obvious chemical equivalent thereof.

19. A compound of formula (VI) as defined in claim 7, or a pharmaceutically acceptable salt thereof with a base or a pharmaceutically acceptable acid addition salt thereof, whenever prepared or produced by the process of claim 7 or by an obvious chemical equivalent thereof.

20. 4-Chloro-1-(4-hydroxy-3-methylbenzyl)-2-phenyl-imidazole-5-acetic acid or a pharmaceutically acceptable salt thereof with a base, whenever prepared or produced by the pro-cess of claim 8 or by an obvious chemical equivalent thereof.

21. A process according to claim 4, 5 or 6, wherein process alternative (B) is carried out using a compound of for-mula (III) which is prepared by deprotecting a compound of the formula:

(V) wherein R is as defined in claim 4 or 5, and R1' is a benzyl group which may be substituted by 1 to 3 of C1-3 alkyl or C1-3 alkoxy.