WO1993018030A1 - Benzimidazole derivatives as angiotensin ii antagonists - Google Patents

Abstract

The object compound of formula (I) wherein R1 is hydrogen, halogen, nitro, lower alkyl, lower alkoxy, amino or acylamino, R?2, R3 and R4¿ are each hydrogen, halogen, nitro, cyano, lower alkyl, lower alkenyl, lower alkylthio, mono or di or trihalo(lower)alkyl, oxo(lower)alkyl, hydroxy(lower)alkyl or optionally esterified carboxy; or R?2 and R3¿ are linked together to form 1,3-butadienylene, R5 is hydrogen or imino-protective group, R6 is lower alkyl, R7 is nitro, optionally esterified or amidated carboxy or optionally substituted amino, A is lower alkylen, Q is CH or N, X is N or CH, Y is NH, O or S, and Z is S, SO¿2? or 0, and pharmaceutically acceptable salts thereof which are useful as a medicament.

Description

BENZIMIDAZOLE DERIVATIVES AS ANGIOTENSIN II ANTAGONISTS

TECHNICAL FIELD The present invention relates to novel heterocyclic derivatives and a pharmaceutically acceptable salt thereof. More particularly, it relates to novel imidazole derivatives and a pharmaceutically acceptable salt thereof which have pharmaceutically activities such as angiotensin II antagonism and the like, to process for preparation thereof, to a pharmaceutical composition comprising the same and to a use of the same as a medicament.

Accordingly, one object of the present invention is to provide novel imidazole derivatives and a pharmaceutically acceptable salt thereof, which are useful as a potent and selective antagonist of angiotensin II receptor.

Another object of the present invention is to provide process for preparation of said imidazole derivatives or a salt thereof.

A further object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, said imidazole derivatives or a pharmaceutically acceptable salt thereof.

Still further object of the present invention is to provide a use of said imidazole derivatives or a pharmaceutically acceptable salt thereof as a medicament such as angiotensin II antagonist useful for treating or preventing angiotensin 11 mediated diseases, for example, hypertension (e.g. essential hypertension, renal hypertension, etc.), heart failure, and the like in human being or animals.

DISCLOSURE OF INVENTION

The imidazole derivatives of the present invention are novel and can be represented by the formula (I):

wherein R¹ is hydrogen, halogen, nitro, lower alkyl, lower alkoxy, amino or acylamino, R^ώ, R° and R are each hydrogen, halogen, nitro, cyano, lower alkyl, lower alkenyl, lower alkylthio, mono or di or trihalo(lower)alkyl, oxo(lower)alkyl, hydroxy(lower)alkyl or optionally esterified carboxy; or R^ and R^ are linked together to form 1, 3-butadienylene, R^ is hydrogen or imino-protective group,

R" is lower alkyl,

R⁷ is nitro, optionally esterified or amidated carboxy or optionally substituted amino, A is lower alkylene, Q is CH or N,

X is N or CH, Y is NH, 0 or S, and Z is S, S0₂ or 0. According to the present invention, the object compound (I) can be prepared by the following processes. Process 1

(π)

(I) or a salt thereof Process 2

Elimination of the ester moiety

(I-a) or a salt thereof

(I-TD) or a salt thereof Process 3

(III) (IV) or a salt thereof or a salt thereof

(I) or a salt thereof Process 4

Removal of the imino-protective group

(I-d) or a salt thereof Process 5

Amidation

or its reactive derivative at the carboxy group or a salt thereof

-

(I - e) or a salt thereof Process 6

Esterification

or its reactive derivative at the carboxy group or a salt thereof

or a salt thereof Process 7

(I-d) or a salt thereof

(I-c) or a salt thereof Process 8

Conversion of carboxy to lower alkoxycarbonylamino

or its reactive derivative at the carboxy group or a salt thereof

(i - f) or a salt thereof

(I) or a salt thereof Wherein R¹ R², R³, R⁴, R⁵, R^δ, R⁷, A, Q, X, Y and Z are each as defined above, R| is imino-protective group, R is esterified carboxy, RS is amidated carboxy,

K is lower alkoxycarbonylamino, and R⁸ is acid residue.

Suitable salts of the compound (I) are conventional non-toxic, pharmaceutically acceptable salt and may include a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e. g. sodium salt, potassium salt, cesium salt, etc.), an alkali earth metal salt (e. g. calcium salt, magnesium salt, etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g. triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'- dibenzylethylenediamine salt, etc. ), etc. ; an inorganic acid addition salt (e. g. hydrochloride, hydrobromide, sulfate, phosphate, etc. ) ; an organic carboxylic or sulfonic acid addition salt (e. g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.); a salt with a basic or acidic amino acid (e. g. arginine, aspartic acid, glutamic acid, etc. );and the like, and the preferable example thereof is an acid addition salt.

In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention include within the scope thereof are explained in detail as follows.

The term "lower" is intended to mean 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, unless otherwise indicated. Suitable "lower alkyl" and lower alkyl group in the term "lower alkylthio" may include straight or branched one, having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, preferably one having 1 to 5 carbon atoms, and the like. Suitable "lower alkenyl" may include vinyl, 1-propenyl, allyl, 1- butenyl, 2-butenyl, 2-pentenyl, and the like, preferably one having 2 to 4 carbon atoms, in which the most preferred one is vinyl.

Suitable "lower alkylene" is one having 1 to 6 carbon atom(s) and may include methylene, ethylene, trimethylene, propylene, tetramethylene, methyltrimethylene, dimethylethylene, hexamethylene, and the like, in which the preferred one is methylene.

Suitable "halogen" means fluoro, chloro, bromo and iodo. Suitable "lower alkoxy" may include straight or branched one such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy or the like, in which the preferable one is Cj-C^ alkoxy.

Suitable acyl group in the term "acylamino" may include carbamoyl, thiocarbamoyl, sulfamoyl, aliphatic acyl, aromatic acyl, heterocyclic acyl, in which the preferable one is aliphatic acyl such as lower alkanoyl (e. g. formyl, acetyl, propionyl, hexanoyl, etc. ), lower alkoxycarbonyl (methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, etc) and the like.

Suitable "mono or di or trihalo (lower) alkyl " may include chloromethyl, f luoromethyl, dif luoromethyl, dichloromethyl, trifluoromethyl, trifluoromethylpropyl, and the like. Suitable "hydroxy(lower)alkyl " may include hydroxymethyl, hydroxyethyl, and the like.

Suitable "oxo(lower)alkyl " may include formyl, formylmethyl, formylethyl, and the like.

Suitable "ester moiety" in "esterified carboxy group" may include pharmaceutically acceptable, easily removable one such as lower alkyl ester (e. g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, tert-pentyl ester, hexyl ester, etc. ), lower alkenyl ester (e. g. vinyl ester, allyl ester, etc. ), lower alkynyl ester (e. g. ethynyl ester, propynyl ester, etc. ), lower alkoxy(lower)alkyl ester (e. g. methoxymethyl ester, ethoxymethyl ester, isopropoxymethyl ester, 1-methoxyethyl ester, 1- ethoxyethyl ester, etc. ), lower alkylthio(lower)-alkyl ester (e. g. methylthiomethyl ester, ethylthiomethyl ester, ethylthioethyl ester, isopropylthiomethyl ester, etc. ), carboxy-substituted-lower alkyl ester (e. g. carboxymethyl ester, 2-carboxyethyl ester, 3-carboxypropyl ester, etc. ), protected carboxy-substituted-lower alkyl ester such as lower alkoxycarbonyl-substituted-lower alkyl ester (e. g. methoxycarbonylmethyl ester, tert-butoxycarbonyl ethyl ester, 2-tert-butoxycarbonyl-ethyl ester, 3-tert-butoxycarbonylpropyl ester, etc. ), protected carboxy- substituted-lower alkenyl ester such as lower alkoxycarbonyl-substituted -lower alkenyl ester (e. g. 2-isobutoxycarbonyl-2-pentenyl ester, etc. ), mono (or di or tri) halo (lower) alkyl ester (e. g. 2-iodoethyl ester, 2, 2, 2- trichloroethyl ester, etc. ), lower alkanoyloxy (lower) alkyl ester [e. g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, l(or 2)-acetoxyethyl ester, l(or 2 or 3)-acetoxypropyl ester, l(or 2 or

3 or 4)-acetoxybutyl ester, l(or 2)-propionyloxyethyl ester, l(or 2 or

3)-propionyloxypropyl ester, Kor 2)-butyryloxyethyl ester, Kor 2)- isobutyryloxyethyl ester, Kor 2)-pivaloyloxyethyl ester, Kor 2)- hexanoyloxyethyl es ter, i sobu tyryl oxyme thy l es ter, 2 - ethylbutyryloxymethyl ester, 3, 3-dimethylbutyryloxymethyl ester, 1 (or 2) -pentanoyloxyethyl ester, etc. ], higher alkanoyloxy (lower) -alkyl ester [e. g. heptanoyloxymethyl ester, octanoyloxymethyl ester, nonanoyloxymethyl ester, decanoyloxymethyl ester, undecanoyloxymethyl ester, lauroyloxymethyl ester, tridecanoyloxymethyl ester, myristoyloxymethyl ester, pentadecanoyloxymethyl ester, palmitoyloxymethyl ester, heptadecanoyloxymethy l es ter, s tearoy loxymethyl es ter , nonadecanoyloxymethyl ester, eicosanoyloxymethyl ester, Kor 2)- heptanoyloxyethyl ester, Kor 2)-octanoyloxyethyl ester, Kor 2)- nonanoyloxyethyl ester, Kor 2)-decanoyloxyethyl ester, Kor 2) - undecanoyloxyethyl ester, Kor 2)~lauroyloxyethyl ester, Kor 2)- tridecanoyloxyethyl ester, Kor 2)-myristoyloxyethyl ester, Kor 2)- pentadecanoyloxyethyl ester, Kor 2)-palmitoyloxyethyl ester, Kor 2)- heptadecanyloxyethyl ester, Kor 2)-stearoyloxyethyl ester, Kor 2)- nonadecanoyl-oxyethyl ester, Kor 2)-eicosanoyloxyethyl ester, etc. ], cycloalkylcarbonyloxy(lower)alkyl ester [e. g. cyclohexylcarbonyloxymethyl ester, Kor 2) -cyclopentylcarbonyloxyethyl ester, 1 (or 2) - cyclohexylcarbonyloxyethyl ester, etc, ], aroyloxy (lower) alkyl ester such as benzoyloxy (lower) alkyl ester [e. g. 1 (or 2) -benzoyloxyethyl ester, etc, ] heterocycliccarbonylox (lower) alkyl ester such as lower alkylpiperidylcarbonyloxy(lower)alkyl ester [e.g. 1 (or 2) -Q- methylpiperidyDcarbonyloxyethyl, etc.], lower alkoxycarbonyloxy (lower) alkyl ester [e.g. methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, isopropoxycarbonyl-oxymethyl ester, tert-butoxycarbony loxymethy 1 ester, Kor 2)- methoxycarbonyloxyethyl ester, Kor 2)-ethoxycarbonyloxyethyl ester, Kor

2)-propoxycarbonyloxyethyl ester, Kor 2)-isopropoxycarbonyloxyethyl ester, Kor 2)-butoxycarbonyloxyethyl ester, Kor 2)- isobutoxycarbonyloxyethyl ester, Kor 2)-tert-butoxycarbonyloxyethyl ester, Kor 2)-hexyloxycarbonyloxy-ethyl ester, Kor 2 or 3)- methoxycarbonyloxypropyl ester, Kor 2 or 3)-ethoxycarbonyloxypropy1 ester, Kor 2 or 3)-isopropoxycarbonyloxypropyl ester, Kor 2 or 3 or 4) -ethoxycarbonyloxybutyl ester, Kor 2 or 3 or 4)-butoxycarbonyloxybutyl ester, Kor 2 or 3 or 4 or 5)-pentyloxycarbonyloxypentyl ester, Kor 2 or 3 or 4 or 5)-neopentyloxycarbonyloxypentyl ester, Kor 2 or 3 or 4 or 5 or 6)-ethoxycarbonyloxyhexyl ester, ,etc.], cycloalkyloxycarbonyloxy

(lower)alkyl ester [e.g. cyclohexyloxycarbonyloxymethyl ester, Kor 2)- cyc 1 o pent y 1 oxy ca rbony 1 oxye t hy 1 ester, 1 (or 2)- cyclohexyloxycarbonyloxyethyl ester, etc.], (5-lower alkyl-2-oxo-l, 3- dioxol-4-yl)(lower)alkyl ester [e.g. (5-methyl-2-oxo-l, 3-dioxol-4-yl) methyl ester, (5-ethyl-2-oxo-l,3-dioxol-4-yl)methyl ester, (5-propyl-2- oxo-1,3-dioxol-4-yl)ethyl ester, etc.], (5-lower alkyl-2-oxo-l,3-dioxolen -4-yl)(lower)alkyl ester [e.g. (5-methyl-2-oxo-l, 3-dioxolen-4-yl)methyl ester, (5-tert-butyl-2-oxo-l, 3-dioxolen-4-yl)methyl ester, etc. ], (5- aryl-2-oxo-l,3-dioxolen-4-yl)(lower)alkyl ester such as (5-phenyl-2-oxo-

1,3-dioxolen-4-yl)(lower)alkyl ester [e.g. (5-phenyl-2-oxo-l,3-dioxolen-

4-yl)methyl ester, etc.], lower alkanesulfonyl(lower)alkyl ester (e.g. mesylmethyl ester, 2-mesylmethyl ester, etc. ), ar(lower)alkyl ester which may have one or more substituent(s) such as mono-(or di or tri)phenyl (lower)alkyl ester which may have one or more suitable substituent(s) (e. g. benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, benzhydryl ester, trityl ester, bis(methoxyphenyl)-methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3, 5-di-t-butylbenzyl ester, etc.), aryl ester which may have one or more suitable substituents (e.g. phenyl ester, tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, salicyl ester, etc. ), heterocyclic ester (e. g. phthalidyl ester, Kor 2)-phthalid-3-ylideneethyl ester, etc. ), and the like.

Suitable "imino-protective group" may include conventional one, and the preferable example thereof is ar(lower)alkyl such as mono-(or di- or tri-) phenyl (lower) alkyl (e. g. benzyl, benzhydryl, trityl, etc. ), acyl such as lower alkoxycarbonyl (e. g. tert-butoxycarbony 1, etc. ), lower alkanesulfonyl (e. g. mesyl, etc. ), arenesulfonyl (e. g. tosyl, etc. ), and the like, in which the most preferred one is trityl.

Suitable "acid residue" may include halogen (e. g. fluoro, chloro, bromo, iodo), acyloxy (e. g. acetoxy, tosyloxy, mesyloxy, etc. ) and the like.

Suitable "amidated carboxy" may carbamoyl which may have suitable substituent(s) and may include carbamoyl, mono or di (lower) alkylcarbamoyl (e. g. methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl, butylcarbamoyl, t-butylcarbamoyl, etc. ), lower alkylarylcarbamoyl (e. g. isobutylphenylcarbamoyl, etc. ), N-hydroxy-N-, (lower)alkylcarbamoyl(e. g. N-hydroxy-N-methylcarbamoyl, etc. ) and the like.

Suitable "substituted amino" is conventional one used in a pharmaceutical field and may include mono or di (lower) alky lamino (e. g. methy lamino, dimethylamino, ethylamino, butylamino, etc. ), lower alkenylamino (e. g. viny lamino, propenylamino, etc. ), lower alkynylamino (e. g. ethynylamino, propyny lamino, etc. ), hydroxy (lower) alkylamino (e. g. hydroxymethy lamino, hydroxyethylamino, hydroxypropy lamino etc. ), lower alkoxy (lower) alkylamino (e. g. methoxymethylamino, etc. ), mono or di (lower) alkylamino (lower) alkylamino (e. g. methy laminomethylamino, dimethylaminoethy lamino, etc. ), protected amino such as acylamino, in which acyl is as mentioned above.

Su itable " l ower a lkoxycarb ony lam ino " may inc lud e methoxycarbonylamino, ethoxycarbonylamino, butoxycarbonylamino, and the like.

The preferred embodiment of the heterocyclic derivatives (I) of the present invention can be represented by the following chemical formula:

(1-1)

(1-3)

wherein R⁵, R⁶, R⁷ and A are each as defined above, RI , Rb and Ri are each lower alkyl, and RE, Ri. and Ra are each hydrogen, halogen, or lower alkyl. Further, the preferred embodiment of the compound (I) can be represented by the following formula :

(I-⁴)

(1-6)

wherein R⁵, R⁶, R^τ and A are each as defined above, RI , RI and Ra are each lower alkyl, and Rb, Ro and Ra are each hydrogen, halogen, or lower alkyl.

Particularly, the preferred compound (I) of the present invention is represented by the following formula :

wherein R³ and R⁶ are each lower alkyl,

R⁷ is carboxy, lower alkoxycarbonyl, lower alkoxycarbonyl(lower)alkoxycarbonyl, lower alkoxycarbonyl(lower)alkenyloxycarbonyl, lower alkanoyloxy(lower)alkoxycarbonyl, cycloalkylcarbonyloxy(lower)alkoxycarbonyl, benzoyloxy(lower)alkoxycarbonyl, lower alkylpiperidylcarbonyloxy(lower)alkoxycarbonyl, lower alkoxycarbonyloxy(lower)alkoxycarbonyl, cycloalkyloxycarbonyloxy(lower)alkoxycarbonyl, (5-lower alkyl-2-oxo-l, 3-dioxolen-4-yl)(lower)- alkoxycarbonyl, (5-phenyl-2-oxo-l,3-dioxolen-4-yl)(lower)alkoxycarbonyl or phthalid-3-yϋdene(lower)alkoxycarbonyl.

The processes for preparing the object compound (I) of the present invention are explained in detail in the following. . Process 1 :

The object compound (I) or a salt thereof can be^' prepared by subjecting the compound (II) to the formation reaction of a tetrazole group. The agent to be used in the present reaction may include conventional ones which is capable of converting a cyano group to a tetrazolyl group such as metal azide, for examle, alkali metal azide(e. g. , potassium azide, sodium azide etc. ), tri(lower)alkyltin azide(e. g. tri ethyltin azide, etc.), triaryltin azide (e. g. triphenyltin azide, etc.), or the like.

The present reaction is usually carried out in the presence of a base such as tri(lower)alkylamine(e.g. triethyla ine, etc.), and the like, or 1, 3-dimethyl-2-imidazolidinone, and the like.

The present reaction is usually carried out in a solvent such as xylene, dioxane, chloroform, methylene chloride, 1, 2-dichloroethane, tetrahydrofuran, pyridine, acetonitrile, dimethylformamide or any other solvent which does not adversely affect the reaction.

The reaction temperature is not critical and the reaction is usually carried out under warming or heating, preferably under heating.

Process 2 :

The object compound (I-b) or a salt thereof can be prepared by subjecting the compound (I-a) or a salt thereof to the elimination reaction of the ester moiety. Suitable method for this reaction may include conventional one such as hydrolysis,and the like.

The hydrolysis is to be referred to those as explained in process 4.

Process 3 :

The object compound (I) or a salt thereof can be prepared by reacting the compound (III) or a salt thereof with the compound (IV) or a salt thereof.

The present reaction is usually carried out in the presence of a base such as alkyl lithium (e. g. n-butyl lithium, etc. ), alkali metal hydride (e. g. sodium hydride, potassium hydride, etc. ), di (lower) alkylamine (e. g. diisopropylamine, etc. ), tri(lower)alkylamine (e. g. trimethylamine, triethylamine, etc. ), pyridine or its derivative (e. g. picoline, lutidine, 4-dimethylaminopyridine, etc. ), or the like. The present reaction is usually carried out in a solvent such as dioxane, dimethyl sulfoxide, dimethylformamide, diethylformamide, dimethylacetamide, benzene, tetrahydrofuran, or any other solvent which does not adversely affect the reaction. In case that the base to be used is liquid, it can also be used as a solvent. The reaction temperature is not critical and the reaction is usually carried out under cooling, at ambient temperature or under heating.

Process 4 :

The object compound (I-d) or a salt thereof can be prepared by subjecting the compound (I-c) or a salt thereof to removal reaction of the imino-protective group.

Suitable method for this removal may include conventional one which is capable of removing an imino-protective group on a tetrazolyl group such as hydrolysis, reduction, or the like. The hydrolysis is preferably carried out in the presence of the base or an acid.

Suitable base may include, for example, an inorganic base such as alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc. ), alkaline earth metal hydroxide (e.g.magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonate, (e.g. sodium carbonate,potassium carbonate, etc.), alkaline earth metal carbonate (e. g. magnesium carbonate, calcium carbonate, etc.), alkali metal bicarbonate (e.g.sodium bicarbonate, potassium bicarbonate, etc.), alkali metal acetate (e.g. sodium acetate, potassium acetate, etc.), alkaline earth metal phosphate

(e. g. magnesium phosphate, calcium phosphate, etc.), alkali metal hydrogen phosphate (e.g.disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.), or the like, and an organic base such as trialkylamine

(e. g. trimethylamine, triethylamine, etc.), picoline, N- methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo[4,3, 0]non-5-one,

1,4-diazabicyclo[2,2,2]octane, 1,5-diazabicyclo[5,4,0]-undecene-5 or the like. The hydrolysis using a base is often carried out in water or a hydrophilic organic solvent or a mixed solvent thereof.

Suitable acid may include an organic acid (e. g. formic acid, acetic acid, propionic acid, etc. ) and an inorganic acid (e. g. hydrochloric acid, hydrobromic acid, sulfurie acid, etc.). The present hydrolysis is usually carried out in an organic solvent, water or a mixed solvent thereof.

The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating.

Process 5:

The object compound (I-e) or a salt thereof can be prepared by subjecting the compound (I-b) or its reactive derivative at the carboxy group or a salt thereof to amidation reaction.

Suitable salt of the compound (I-e) can be referred to the salt exemplified for the compound (I).

The amidating agent to be used in the present amidation reaction may include amine which may have suitable substituent(s). ■_

Suitable reactive derivative at the carboxy group of the compound (I -b) may include an acid halide, an acid anhydride, an activated ester, and the like. The suitable example may be an acid chloride, an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e. g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulforous acid, thiosulfuric acid, sulfurie acid, alkylcarbonic acid, aliphatic carboxylic acid (e.g. pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, or trichloroacetic acid, etc. ) or aromatic carboxylic acid (e. g. benzoic acid, etc.); a symmetrical acid anhydride; or an activated ester (e.g. cyano ethyl ester, methoxymethyl ester, dimethyliminomeihyl [(CH₃)₂N⁺=CH-] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2, 4- dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresylthioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc. ), or an ester with a N-hydroxy compound (e. g. N,N-dimethylhydroxylamine, l-hydroxy-2- (lH)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, l-hydroxy-6- chloro-lH-benzotriazole, etc. ), and the like.

When the compound (I-b) is used in a free acid form or its salt form in the reaction, the reaction is preferably carried out in the presence of a conventional condensing agent such as N, N' - dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N

-ethyl-N'-(3-dimethylaminopropyl) carbodiimide, 1, l'-carbonyldi- imidazole, thionyl chloride, oxalyl chloride, lower lower alkoxycarbonyl halide [e.g. ethyl chloroformate, isobutyl chloroformate, etc.], l-(p- chlorobenzenesulfonyloxy)-6-chloro-lH-benzotriazole, or the like.

The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction. Among these solvents, hydrophilic solvents may be used in a mixture with water.

The reaction in the presence of a condensing agent is usually carried out in an anhydrous, but not critical conditions.

The reaction may be carried out in the presence of an inorganic or an organic base such as an alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), an alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc. ), an alkali metal bicarbonate (e. g. sodium bicarbonate, potassium bicarbonate, etc. ), tri (lower) alkylamine

(e. g. trimethylamine, triethylamine, etc. ), pyridine or its derivative (e.g. picoline, lutidine, 4-dimethylaminopyridine, etc. ), or the like.

In case that the base or the condensing agent to be used is in liquid, it can be used also as a solvent.

The reaction temperature is not critical, and the reaction is usually carried out under heating or under warming, preferably under heating.

Process 6

The compound (I-a) or a salt thereof can be prepared by subjecting the compound (I-b) or its reactive derivative at the carboxy thereof, or a salt thereof to esterification. The reaction can be carried out by a conventional esterification. Suitable reactive derivative at the carboxy group of the compound (I -b) may be the same as those exemplified in Process 5.

Suitable esterifying agent used in this reaction may include alcohol or its conventional reactive derivative such as halide, sulfonate, and the like. Further, it may include di (lower) alkylsulfate (e. g. dimethylsulfate,etc. ), diazo (lower) alkanes (e.g. diazomethane, etc.), 3-lower alkyltriazenes (e.g. 3-methyl-l-tolyltriazene, etc.), and the like. This reaction is usually carried out_.in a conventional solvent such as alcohols(e.g. methanol, ethanol, etc.), dioxane, tetrahydrofuran, or any other organic solvent which does not adversely influence the reaction.

The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.

Process 7

The object compound (I-c) can be prepared by subjecting the compound (I-d) to introduction reaction of the imino protective group. The introduction reaction of the imino protective group in this step can be carried out by reacting the compound (I-d) with a suitable agent for introducing the imino protective group.

Suitable examples of said agent may be ar (lower) alkyl halide which may have a foresaid lower alkoxy such as phenyl (lower) alkyl halide which may have lower alkoxy (e. g. benzyl iodide, 3-methoxybenzyl iodide, benzyl bromide, 4-methoxybenzyl bromide, phenethyl chloride, etc. ), diphenyl (lower) alkyl halide (e. g. benzhydryl chloride, etc. ), triphenyl (lower)alkyl halide (e. g. tritylchloride, tritylbromide, etc. ) or the like. This introduction reaction may be carried out in a suitable solvent such as chloroform, acetonitrile, acetone, nitrobenzene, N, N- dimethylformamide or any other solvent which does not adversely affect the reaction.

The reaction temperature is not critical and usually carried out at room temperature, under warming or under heating. Process 8

The compound (I-f) or a salt thereof can be prepared by subjecting the compound (I-b) or its reactive derivative at the carboxy group or a salt thereof to the. conversion reaction of carboxy to lower alkoxycarbonylamino.

This reaction can be carried out in a conventional manner, for example, (1) azidation, (2)Curtius type rearrangement to an isocyanate, and then (3) addition of alcohol, the details of which are explained in the below example.

Process 9

The object compound (I) or a salt thereof can be prepared by subjecting the compound (V) or a salt thereof to ring closure. This reaction is usually carried out in the presence of acetic acid.

This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, alcohol (e. g. methanol, ethanol, etc. ), chloroform, acetonitrile, acetone, nitrobenzene, N, N-dimethylf ormamide or a mixture thereof.

The reaction temperature is not critical, and the reaction is usually carried out at room temperature, under warming or under heating.

The starting compounds (I I), (I I I) and (IV) are new and can be prepared by the methods of Preparations mentioned below or a similar manner thereto or a conventional manner.

The object compound (I) of the present invention can be isolated and puri fied in a conventional manner, for example, extract ion precipitation, fractional crystallization, recrystallization, chromatography, and the like.

The object compound (I) thus obtained can be converted to its salt by a conventional method.

The object compound (I ) of the present invention exhibits angiotensin antagonism such as vasodilating activity and is useful as an angiotensin I I antagonist and effective to various angiotensin I I mediated diseases such as hypertension (e. g. essential hypertension, renal hypertension, etc. ), heart failure, and the like.

Further, it is expected that the object compounds of the present invention are useful as therapeutical and/or preventive agents for cardiopathy (e. g. angina pectoris, arrhythmia, yocardial infarction, etc. ), hyperaldosteronism, cerebral vascular diseases, senile dementia, ophthalmic diseases (e. g. glaucoma, etc.), and the like; and diagnostic agents to test the renin angiotensin system.

For therapeutic or preventive administration, the object compound(I) of the present invention are used in the form of conventional pharmaceutical preparation which contains said compound as an active ingredient, in admixture with pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral, external and inhalant administration. The pharmaceutical preparation may be in solid form such as tablet, granule, powder, capsule, or liquid form such as solution, suspension, syrup, emulsion, lemonade and the like.

If needed, there may be included in the above preparations auxiliary substances, stabilizing agents, wetting agents and other commonly used additives such as lactose, citric acid, tartaric acid, s^'tearic acid, magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter, ethylene glycol, and the like.

While the dosage of the compound (I) may vary form and also depend upon the age, conditions of the patient, a kind of diseases or conditions, a kind of the compound (I) to be applied, etc. In general amounts between 0.01 mg and about 500 mg or even more per day may be administered to a patient. An average single dose of about 0.05 mg, 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 20 mg, 50 mg, 100 mg of the^" object compound (I) of the present invention may be used in treating diseases.

The following Preparations and Examples are given for the purpose of illustrating the present invention.

Preparation 1 To a solution of ethyl 2-tert-butoxycarbonylamino-3-nitro- benzoate(2. 94g) in dimethylformamide(30ml) was added sodium hydride (379mg, 60% in oil) in an ice-water bath, and the mixture was stirred at ambient temperature for 25 minutes. Therein l -ethyl-2- (4- methanesulfonyloxymethylphenyl) pyrrole-3-carbonitrile(2. 87g) was added. After stirring for 3 hours, the mixture was poured into brine and extracted with ethyl acetate twice. The organic layers were combined, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluted by n-hexane/ethyl acetate) to afford ethyl 2-[N-tert-butoxycarbonyl-[4-(3-cyano-l-ethyl-5- methyl-2-pyrrolyl)benzyl] amino] -3-nitrobenzoate (4. 36g) as amorphous powder.

NMR(CDClg, δ : 1. 19(3H, t, J=7Hz), 1. 33(3H, t, J=7Hz), 1. 34(9H, s), 2. 28(3H, s), 3. 87(2H, q, J=7Hz), 4. 23(2H, q, J=7Hz), 4.49QH, d, J=14Hz), 4. 94(lH, d, J=14Hz), 6. 19(lH, s), 7. 24(4H, s), 7. 48QH, t, J=8Hz), 7. 87(lH, dd, J=8, 2Hz), 8. 09(lH, dd, J=8, 2Hz)

Preparation 2

To a solution of ethyl 2-[N-tert-butoxycarbonyl-[4-(3-cyano-l-ethyl

-5-methyl-2-pyrrolyl)benzyl]amino] -3-nitrobenzoate (4. 36g) in dichloromethane (5ml) was added trifluoroacetic acid (7. 5ml). After

•standing at ambient temperature for 40 minutes, the reaction mixture was evaporated in vacuo. The residue was crystallized from methanol to afford ethyl 2-[[4-(3-cyano-l-ethyl-5-methyl -2-pyrrolyl) benzyl] amino] -3

-nitrobenzoate (3. 18g) as yellow crystals. mp: 119-120°C

NMR(CDClg, δ : 1. 20C3H, t, MHz), 1. 40(3H, t, J=7Hz), 2. 30(3H, s),

3.86(2H, q, J=7Hz), 4. 23(2H, s), 4. 37(2H, q, J=7Hz), 6. 2K1H, s),

6. 74(1H, t, J=8Hz), 7- 40(4H, s), 8. OKlH. dd, J=8. 2Hz), 8. 12(lH, dd, J=8. 2Hz)

Preparation 3

A mixture of ethyl 2-[[4-(3-cyano-l-ethyl-5-methyl -2-pyrrolyl) benzyl]amino]-3-nitrobenzoate (3.18g), 10% palladium on carbon (1. Og), methanol(20ml) and dioxane(20ml) was stirred at 40°C for 7 hours under hydrogen atmosphere (4atm). After removal of the catalyst by vacuum filtration, the filtrate was evaporated in vacuo. The residue was washed with diisopropyl ether to give ethyl 3-amino-2-[[4-(3-cyano-l-ethyl-5- methyl -2-pyrrolyl)benzyl]amino]benzoate (2.43g) as an amorphous powder.

NMR(CDC1₃, 5) : 1.19(3H,t, J=7Hz), 1.36(3H, t, J=7Hz), 2.29(3H,s), 3.87(2H,q,J=7Hz), 4.2K2H,s), 4.28(2H,q, J=7Hz), 6.21(lH,s), 6.86-6.94 (2H), 7.30-7.50(5©

Preparation 4

A mixture of ethyl 3-amino-2-[[4-(3-cyano-l-ethyl-5-methyl -2- pyrrolyl)benzyl]amino]benzoate (2.43g), tetraethoxymethaneQ.5ml), and acetic acid (24ml) was stirred at ambient temperature for 2 hours and evaporated in vacuo. The residue was crystallized from ethyl acetate-n- hexane to afford ethyl 3-[4-(3-cyanp-l-ethyl-5-methyl-2-pyrrolyl)benzyl] -2-ethoxy-4-benzimidazolecarboxylate (2.015g) as yellow crystals. mp:153-155O NHR(CDClg, 5) : 1.13C3H,t, J=7Hz), 1.24(3H,t, J=7Hz), 1.49(3H,t, J=7Hz), 2.26(3H,s), 3.80(2H,q,J=7Hz), 4.23(2H,q,J=7Hz), 4.67(2H,q_>J=7Hz), 5.70(2H,s), 6.19(1H,s), 7.08C2H,d,J=8Hz), ^*7.19QH, t,J=8Hz), 7.28(2H,d,J=8Hz), 7.58QH,dd,J=8, 1Hz), 7.73(lH,dd,J=8, 1Hz)

Preparation 5

The following compound was obtained according to a similar manner to that of Preparation 1.

Ethyl 2-[N-[4-(2-bromo-4-cyano-l-methyl-3-pyrrolyl)benzyl]-N-tert- butoxycarbonylamino]-3-nitrobenzoate. NMR(CDC1₃, 5) :1.29C3H,t,J=7.5Hz), 1.35(9H,s),3.70(3H,s),4.03-4.22(2H,m), 4.70(2H,s),7.22(2H,d,J=8.5Hz),7.30C1H,s), 7.4K2H,d, J=8.5Hz), 7.46(1H,t,J= 8.0Hz),7.9K1H,dd,J=8.0, 1.0Hz), 8.04QH,dd,J=8.0, 1.0Hz)

Preparation 6 The following compound was obtained according to a similar manner to that of Preparation 2.

Ethyl 2-[[4-(2-bromo-4-cyano-l-methyl-3-pyrrolyl)benzyl]amino]-3- nitrobenzoate. m.p.124-126.5°C NMR(CDC1₃, d) :1.39(3H, t, J=7.5Hz), 3.70C3H,s),4.20(2H,s),4.37C2H,q, J=7. 5Hz), 6. 73(1H, t, J=8. OHz), 7. 32(1H, s), 7. 39(2H, d, J=8. 5Hz), 7. 56(2H, d, J=8. 5Hz), 8. 02(1H, dd, J=8. 0, 1. OHz), 8. 12(1H, dd, J=8. 0, 1. OHz)

Preparation 7 The following compound was obtained according to a similar manner to that of Preparation 3.

Ethyl 3-amino-2-[[4-(2-bromo-4-cyano-l-methyl-3-pyrrolyl)benzyl] amino]-3-nitrobenzoate.

NMR(CDC1₃, δ ) :1.30(3H,t, J=7.5Hz), 3.70C3H, s),4.24(2H,q, J=7.5Hz),4.32(2H, s),6.90-7.0K2H,m),7.31-7.42(1H,m),7.33(1H,s),7.36(2H,d,J=8.5Hz),7.52(2H, d,J=8.5Hz)

Preparation 8

The following compound was obtained according to a similar manner to that of Preparation 4.

Ethyl 3-[4-(2-bromo-4-cyano-l-methy1-3-pyrrolyl)benzyl]-2-ethoxy-4- benzimidazolecarboxylate .

NMR(CDC1₃, 5) :1.22(3H,t,J=7.5Hz), 1.50(3H,t, J=7.5Hz), 3.68(3H,s),4.2K2H, q,J=7.5Hz),4.72(2H,q,J=7.5Hz),5.68C2H,s),7.05(2H,d, J=8.5Hz), 7.20(1H, t,J= 8.OHz), 7.30(1H,s),7.44(2H,d,J=8.5Hz), 7.58(1H,dd, J=8.0, 1.OHz),7.79(1H,dd, J=8.0, 1.OHz)

Preparation 9

The following compound was obtained according to.a similar manner to that of Preparation 1.

Ethyl 2-[N-tert-butoxycarbonyl-N-[4-(4-chloro-2-cyano-l-pyrrolyl) benzyl]amino]-3-nitrobenzoate.

NMR(CDClg, <5) :1.35(9H,s), 1.35(3H,t, J=7.5Hz),4.24(2H,q, J=7.5Hz),4.48C1H, d,J=14.5Hz),4.93(1H,d,J=14.5Hz),6.89(1H,d,J=l.OHz),7.02(1H,d,J=l.OHz),7. 3K4H,s), 7.50(1H, t,J=8.OHz),7.89(1H,dd, J=8.0, 1. OHz),8.09(1H,dd, J=8.0, 1. OHz)

Preparation 10

The following compound was obtained according to a similar manner to that of Preparation 2. Ethyl 2- [ [4-(4-chloro-2-cyano-l-pyrrolyl) benzyl] amino] -3- nitrobenzoate.

m. p. 131-133 NMR(CDC1₃, δ ) : 1. 39(3H, t, J=7. 5Hz)4. 23(2H, s), 4. 35(2H, q, J=7. 5Hz), 6. 75(1H, t, J=8. OHz), 6. 90QH, d, J=l. OHz), 7. 05QH, d, J=l. OHz), 7. 39(2H, d, J=8. 5Hz), 7. 48 (2H, d, J=8. 5Hz), 7. 99(1H, dd, J=8. 0, 1. OHz), 8. 16(1H, dd, J=8. 0, 1. OHz)

Preparation 11 The following compound was obtained according to a similar manner to that of Preparation 3.

Ethyl 3-amino-2- [[4-(4-chloro-2-cyano-l-pyrrolyl)benzyl] amino] nitrobenzoate.

NMR(CDC1₃, S) :1. 32(3H, t, J=7. 5Hz), 3. 92(2H, s), 4. 27 (2H, q, J=7. 5Hz), 6. 86-6. 94 (3H, m), 7.02QH, d, J=l. OHz), 7. 32-7. 42(1H, m), 7. 35(2H, d, J=9. OHz), 7. 47 (2H, d, J =9. OHz)

Preparation 12

The following compound was obtained according to a similar manner to that of Preparation 4.

Ethyl 3-[4-(4-chloro-2-cyano-l-pyrrolyl)benzyl]-2-ethoxy-4- benzi idazolecarboxylate . m.p.151-154'O

NHR(CDC1₃, S) : 1. 27 (3H, t, J=7. 5Hz), 1. 9(3H, t, J=7. 5Hz), 4. 23C2H, q, J=7. 5Hz), 4. 70(2H, q, J=7. 5Hz), 5. 72(2H, s), 6. 88(1H, d, J=l. 5Hz), 6. 97QH, d, J=l. 5Hz), 7. 14

(2H, d, J=9. OHz), 7. 2K1H, t, J=8. 5Hz), 7. 3K2H, d, J=9. OHz), 7. 62C1H, dd, J=8. 5, 1.

0Hz), 7. 77(lH, dd, J=8. 5, 1. 0Hz)

Preparation 13 The following compound was obtained according to a similar manner to that of Preparation 1.

Ethyl 2-[N-tert-butoxycarbonyl-N-[4-(2-cyano-5-methyl-l-pyrroly1) benzyl]amino]-3-nitrobenzoate.

NMR(CDC1₃, δ ) : 1.35(9H,s), 1.36(3H,t,J=8Hz), 2.15(3H,s), 4.28Q.5HX2, q 2, J=8Hz each), 4.45 (IH,d, J=15Hz), 5. OlQH.d,J=15Hz), 6.05C1H,d, J= 4Hz), 6. 48(lH, d, J=4Hz), 7. 15(2H, d, J=9Hz), 7. 29 (2H, d, J=9Hz), 7. 48( lH, t, J =7Hz), 7. 86(lH, dd, J=7, 1Hz), 8. 10(1H, dd, J=7, 1Hz)

Preparation 14 The following compound was obtained according to a similar manner to that of Preparation 2.

Ethyl 2-[[4-(2-cyano-5-methyl-l-pyrrolyl)benzyl]amino]-3- nitrobenzoate.

NMR(CDC1₃, δ ) : 1.39(3H, t,J=7.5Hz), 2.14(3H, s), 2.35(3H,s), 4.25 (2H,s), 4.37(2H,q,J=7.5Hz), 6.06( IH,d, J=5Hz), 6.76QH, t, J=8Hz), 6.86QH, d,J=5Hz), 7.28(2H,d,J=9Hz), 7.45(2H,d,J=9Hz), 7.99(lH,dd, J=8 and 1Hz), 8.13(1H,dd, J=8 and 1Hz) Preparation 15

The following compound was obtained according to a similar manner to that of Preparation.3.

Ethyl 3-amino-2-[[4-(2-cyano-5-methyl-l-pyrrolyl)benzyl]amino] benzoate.

NMR(CDC1₃, δ ) : 1.34(3H,t,J=7.5Hz), 2.12(3H,s), 3.97(2H,br,s), 4. 25(2H,br,s), 4.27(2H,q,J=7.5Hz), 6.07(lH,d,J=5Hz), 6.49(lH,br,s), 6.79-6. 96(3H,m), 7.25(2H,d, J=9Hz), 7.39(lH,dd, J=7 and 5Hz), 7,49(2H,s, J=9Hz) Preparation 16

The following compound was obtained according to a similar manner to that of Preparation 4.

Ethyl 3-[4-(2-cyano-5-methyl-l-pyrrolyl)benzyl]-2-ethoxy-4- benzimidazolecarboxylate.

NMR(CDC1₃, δ ) : 1.25(3H, t, J=7.5Hz), 1.48(3H,t, J=7.5Hz), 2.09(3H, s), 4.22(2H,q,J=7.5Hz), 4.66 (2H,q, J=7.5Hz), 5.74(2H,s), 6.04(lH,d,J= 5Hz), 6.84(lH,d,J=5Hz), 7.03-7.25(5H,m), 7.60C1H,dd, J=7.5 and 1Hz), 7.75 (IH,dd,J=7.5 and 1Hz)

Preparation 17

The following compound was obtained according to a similar manner to that of Preparation 1.

Ethyl 2-[N-[4-(2-cyano-4-methyl-l-pyrrolyl]benzyl]-N-tert- butoxycarbonyl-amino]-3-nitrobenzoate. NMR(CDC1₃, δ ) : 1.33(3H,t, J=7.5Hz), 1.79(9H,s), 2.13C3H, s), 4.15 -4.29(2H,m). 4.53QH,d, J=14.5Hz), 4.88QH, d, J=14.5Hz), 6.80(1H,d, J=0. 5Hz), 6.87QH, d,J=0.5Hz), 7.28(4H,s), 7.49QH,t, J=8.OHz). 7.90(lH,dd. J= 8.0.0.5Hz). 8.09(IH,dd, J=8.0,0.5Hz) Preparation 18

The following compound was obtained according to a similar manner to that of Preparation 2.

Ethyl 2-[[4-(2-cyano-4-methyl-l-pyrrolyl)benzyl]amino]-3- nitrobenzoate. mp:124.5-128

NMR(CDC1₃, δ ) : 1.39(3H,t,J=7.5Hz), 2.13(3H,s), 4.21(2H,s), 4.35 (2H,q,J=7.5Hz), 6.75(lH,t, J=8.0Hz), 6.82(1H,d, J=0.5Hz), 6.88QH,d, J=0. 5Hz), 7.41(4H,s), 8.OOQH.dd, J=8.0, 1. OHz), 8.14QH,dd, J=8.0,1.0Hz)

Preparation 19

The following compound was obtained according to a similar manner to that of Preparation 3.

Ethyl 3-amino-2-[[4-(2-cyano-4-methyl-l-pyrrolyl)benzyl]amino]-3- nitrobenzoate. NMR(CDC1₃, δ ) : 1.32C3H,t,J=7.5Hz), 2.13(3H,s), 3.94(2H,bs), 4.21 (2H,bs), 4.26(2H,q,J=7.5Hz), 6.45(lH,bs), 6.80(lH,d, J=0.5Hz), 6.84(lH,d, J=0.5Hz), 6.86-6.93(2H,m), 7.31-7.40(3H,m), 7.43(2H,d, J=8.5Hz)

Preparation 20 The following compound was obtained according to a similar manner to that of Preparation 4.

Ethyl 3-[4-(2-cyano-4-methyl-l-pyrrolyl)benzyl]-2- ethoxy-4- benzimidazolecarboxylate. mp:152.5-154.5 °C NHR(CDClg, δ ) : 1.26(3H,t,J=7.5Hz), 1.49(3H,t, J=7.5Hz), 2.1K3H, s), 4.24(2H,q,J=7.5Hz), 4.67C2H,q,J=7.5Hz), 5.70(2H,s), 6.79(2H,s), 7.09 (2H,d, J=8.5Hz), 7.19QH,t,J=8.0Hz), 7.3K2H, d,J=8.5Hz), 7.60(lH,dd, J=8. 0,0.5Hz), 7.74(lH,dd, J=8.0,0.5Hz)

Preparation 21 The following compound was obtained according to a similar manner to that of Preparation 1.

Ethyl 2-[N-[4-(2-bromo-5-cyano-l-pyrrolyl)benzyl]-N-tert- butoxycarbonylamino]-3-nitrobenzoate. N R(CDClg, δ ) : 1.34(3H, t, J=7.5Hz), 1.37(9H,s), 4.15-4.33(2H,m), 4.56(lH,d,J=14.5Hz), 4.91(lH,d, J=14.5Hz), 6.36QH,d, J=4.5Hz), 6.9K1H, d, J=4.5Hz), 7.19(2H,d,J=8.5Hz), 7.34(2H,d, J=8.5Hz), 7.49QH,t,J=8.OHz), 7.90(lH,^!dd, J=8.0, 0.5Hz), 8.09(1H,dd, J=8.0, 0.5Hz)

Preparation 22

The following compound was obtained according to a similar manner to that of Preparation 2.

Ethyl 2-[[4-(2-bromo-5-cyano-l-pyrrolyl)benzyl]amino]-3- nitrobenzoate. mp:105-109 V

NMR(CDClg, δ ) : 1.39(3H,t, J=7.5Hz), 4.29(2H,d, J=5. OHz), 4.35C2H, q,J=7.5Hz), 6.38(lH,d,J=4.5Hz), 6.76QH, t, J=8. OHz), 6.93(lH,d, J=4.5Hz), 7.34(2H, d,J=8.5Hz), 7.48C2H,d, J=8.5Hz), 8.01(IH,dd, J=8.0, 0.5Hz), 8.14 (IH,dd,J=8.0, 0.5Hz), 8.91(lH,bt, J=5. OHz)

Preparation 23

The following compound was obtained according to a similar manner to that of Preparation 3.

Ethyl 3-amino-2-[[4-(2-bromo-5-cyano-l-pyrrolyl)benzyl]amino] benzoate.

NMR(CDClg, δ ) : 1.34(3H,t,J=7.5Hz), 3.93(2H,bs), 4.24(2H,s), 4.27 (2H,q,J=7.5Hz), 6.37(lH,d, J=4.5Hz), 6.49(lH,bs), 6.84-6.95(3H,m),.7.29 (2H, d,J=8.5Hz), 7.40(lH,dd,J=5.5,4.5Hz), 7.51(2H,d, J=8.5Hz)

Preparation 24

The following compound was obtained according to a similar manner to that of Preparation 4.

Ethyl 3-[4-(2-bromo-5-cyano-l-pyrrolyl)benzyl]-2-ethoxy-4- benzimidazolecarboxylate. . NMR(CDC1₃, δ ) : 1.23(3H,t,J=7.5Hz), 1.46(3H,t, J=7.5Hz), 4.20(2H, q,J=7.5Hz), 4.64(2H,q, J=7.5Hz), 5.75(2H,s), 6.35(lH,d, J=4.5Hz), 6.89C1H, d, J=4.5Hz), 7.13C2H,d,J=8.5Hz), 7.23C2H,d, J=8.5Hz), 7.18-7.30(lH,m), 7. 61(IH.dd,J=8.0,0.5Hz),7.74(1H, dd,J=8.0,0.5Hz)

Preparation 25

The following compound was obtained according to a similar manner to that of Preparation 1.

Ethyl 2-[N-[4-(4-bromo-2-cyano-l-pyrrolyl)benzyl]-N- tert- butoxycarbonylamino]-3-nitrobenzoate. NMR(CDC1₃, δ ) : 1.35(3H.t,J=7.5Hz), 1.35(9H,s), 4.17-4.3K2H,m), 4.49QH,d,J=14.5Hz), 4.93(lH,d, J=14.5Hz), 6.94QH,d, J=0.5Hz), 7.07QH,d, J=0.5Hz), 7.28(2H,d,J=8.5Hz), 7.32(2H,d,J=8.5Hz), 7.50QH,t, J=8.0Hz), 7. 88(IH,dd, J=8.0, 0.5Hz), 8.09(IH,dd,J=8.0,0.5Hz)

Preparation 26

The following compound was obtained according to a similar manner to that of Preparation 2.

Ethyl 2-[[4-(4-bromό-2-cyano-l-pyrrolyl)benzyl]amino]-3- nitrobenzoate. mp:119-123

NMR(CDC1₃, δ ) : 1.39(3H, t, J=7.5Hz), 4.23(2H,s), 4.36(2H,q, J=7. 5Hz), 6.76QH,t,J=8.OHz). 6.97QH, d,J=0.5Hz), 7.09(lH.d,J=0.5Hz). 7.40 (2H.d. J=8.5Hz), 7.47(2H,d,J=8.5Hz), 7.99QH,dd,J=8.0, 0.5Hz), 8.16QH, dd,J=8.0,0.5Hz)

Preparation 27

The following compound was obtained according to a similar manner to that of Preparation 3.

Ethyl 3-amino-2-[[4-(4-bromo-2-cyano-l-pyrrolyl)- benzyl]amino]-3-nitrobenzoate.

NMR(CDC1₃, δ ) : 1.33(3H,t,J=7.5Hz), 3.93(2H,bs), 4.22(2H,bs), 4. 26(2H,q,J=7.5Hz). 6.48QH,bs). 6.82-6.93(2H,m), 6.94QH,d,J=0.5Hz), 7. 04QH,d, J=0.5Hz), 7.29-7.41(lH,m), 7.35(2H,d, J=8.5Hz), 7.47(2H,d. J=8. 5Hz) Preparation 28 The following compound was obtained according to a similar manner to that of Preparation 4.

Ethyl 3-[4-(4-bromo-2-cyano-l-pyrrolyl)benzyl]-2-ethoxy-4- benzimidazolecarboxylate. mp:148-152 °C

NMR(CDC1₃, δ ) : 1.27(3H, t,J=7.5Hz), 1.47(3H,t, J=7.5Hz), 4.23(2H, q,J=7.5Hz), 4.67(2H,q.J=7.5Hz), 5.72(2H,s), 6.95(lH,d, J=0.5Hz), 7. OKIH, d, J=0.5HZ), 7.13C2H,d,J=8.5Hz), 7.20QH,t,J=8.OHz), 7.3K2H,d,J=8.5Hz), 7.6K1H,dd, J=8.0, 0.5Hz), 7.76QH,dd, J=8.0, 0.5Hz)

Preparation 29

The following compound was obtained according to a similar manner to that of Preparation 1.

Ethyl 2-[N-tert-butoxycarbonyl-N-[4-(5-chloro-2-cyano-l-pyrrolyl) benzyl]amino]-3-nitrobenzoate.

NMR(CDC1₃, δ ) : 1.32(3H, t, J=7.5Hz), 1.35(9H,s). 4.06-4.35(2H,m), , 4.57(lH,d,J=14Hz), 4.89(lH,d, J=14Hz), 6.26(lH,d, J=5Hz), 6.90(lH,d,J= 5Hz), 7.2K2H.d,J=9Hz), 7.35(2H,d.J=9Hz), 7.49(lH,t, J=8Hz), 7.90(lH,dd, J=8,lflz), 8.09(lH,dd,J=8,lHz) Preparation 30

The following compound was obtained according to a similar manner to that of Preparation 2.

Ethyl 2-[[4-(5-chloro-2-cyano-l-pyrrolyl)benzyl]amino]-3- nitrobenzoate. (This product was used for the next step without further purification)

Preparation 31

The following compound was obtained according to a similar manner to that of Preparation 3. Ethyl 3-amino-2-[[4-(5-chloro-2-cyano-l-pyrrolyl)benzyl]amino] benzoate.

NMR(CDC1₃, δ ) : 1.32(3H,t,J=7.5Hz), 3.94(2H,br.s), 4.24(2H,s), 4. 27(2H,q,J=7.5Hz), 6.25(lH,d,J=5Hz), 6.50QH.br.s), 6.83-6.95(3H,m), 7.30 (2H,d,J=9Hz), 7.39QH,dd,J=6,5Hz), 7.50(2H,d,J=9Hz), Preparation 32

The following compound was obtained according to a similar manner to that of Preparation 4.

Ethyl 3-[4-(5-chloro-2-cyano-1-pyrroly1)benzyl]-2-ethoxy-4- benzimidazolecarboxylate. mp:102-104 °C

NMR(CDC1₃, δ ) : 1. 25(3H, t, J=7. 5Hz), 1.46(3H, t, J=7. 5Hz), 4. 20(2H, q, J=7.5Hz), 4. 65(2H, q, J=7. 5Hz), 5. 75(2H, s), 6. 24QH, d, J=5Hz), 6. 89(lH, d, J=5Hz), 7. 06-7. 30(5H, m), 7. 60QH, dd, J=8, 0. 5Hz), 7. 76QH, dd, J=8, 0. 5Hz).

Preparation 33

A mixture of ethyl 3-amino-2-[4-(3-cyano-l-ethyl-5-methyl-2- pyrrolyl)benzyl]aminobenzoate(937.4mg), trimethyltin azideQ.44g) and xylene (lθml)was stirred at 125 °C for 40 hours and concentrated in vacuo. The residue was dissolved in a mixture of methanol and chloroform Q:4v/v90(10ml).Then silica gel(2g) was added to the solution and the mixture was stirred at room temperature for an hour. The suspension was filtered through a celite pad,and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (methanol-chloroform)to give ethyl 3-amino-2-[[4-[l-ethyl-5-methyl-3-(lH

-tetrazol-5-yl)-2-pyrrolyl]benzyl]amino]benzoate (777.4mg)as pale brown amorphous.

NHR(CDC1₃, δ ) : 1. 13 (3H, t, J=7.5Hz), 1. 30(3H, t, J=7. 5Hz), 2. 33(3H. s), 3. 73(2H. q. J=7. 5Hz), 4. 21(2H, q, J=7. 5Hz), 4. 24(2H, s), 6. 67QH, s), 6.

90-6. 99(2H, m), 7. 19-7. 37(5H, )

Preparation 34

Ethyl 3-amino-2-[[4-[l-ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2-pyrrolyl] benzyl] amino] benzoa te (1. 38g), triethylamine(859. 0 μDand dichloromethane (14ml)were combined under nitrogen atmosphere. Then trityl chloride (906. 7mg)was added to the solution at 0 °C. The reaction mixture was stirred at room temperature for 1. 5 hours, and di luted in dichloromethane. The organic solution was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by a silica gel column chromatography(n-hexane-ethy acetate)to afford pale yellow amorphous which solidified with isopropyl ether to give ethyl 3- amino-2-[[4-[l-ethyl-5-methyl-3-(l-trityl-lH-tetrazol-5-yl)-2-pyrrolyl] benzyl]amino]benzoate(824. Omg) as pale yellow solid, mp:141-145 V NMR(CDC1₃, δ ) : 1.1K3H,t,J=7.5Hz), 1.33(3H, t, J=7.5Hz), 2.32C3H, s), 3.78(2H,q,J=7.5Hz), 3.92(2H,bs), 4.17(2H,bs), 4.30(2H,q,J=7.5Hz), 6.40(lH,bs), 6.53(lH,s), 6.87(1H,d,J=5. OHz), 6.88(1H,d,J=4.5Hz), 6.92- 7.04(6H,m), 7.16-7.34 (13H,m), 7.39QH,dd, J=5.0.4.5Hz)

Preparation 35

The following compound was obtained according to a similar manner to that of Preparation 4. Ethyl 3-[4-(3-cyano-l-ethyl-5-methyl-2-pyrrolyl)benzyl]-2-propyloxy-4 -benzimidazolecarboxylate. mp:168-169.5 V

NMR(CDC1₃, δ ) : 0.98C3H,t, J=7.5Hz). 1.13(3H. t, J=7.5Hz). 1.25(3H. t,J=7.0Hz), 1.85(2H,sextet, J=7.0Hz). 2.27(3H,s), 3.79(2H,q,J=7.5Hz), 4.

23(2H, q. J=7.5Hz). 4.56C2H, t, J=7. OHz). 5. 70(2H. s), 6. 19QH, s). 7. 09C2H, d. J=8. 5Hz), 7. 18(lH, t. J=8.0Hz), 7.27(2H, d, J=8. 5Hz), 7. 59(1H, dd, J=8. 0, 0. 5Hz), 7. 73(lH, dd, J=8. 0, 0. 5Hz)

Preparation 36

The following compound was obtained according to a similar manner to that of Preparation 1.

Ethyl 2-[N-tert-butoxycarbonyl-N-[4-(2-cyano-4, 5-dimethyl-l- pyrrolyl)benzyl]amino]-3-nitrobenzoate.

NMR (CDClg, δ : 1.36(9H,s), 1.36(3H, t, J=7.5Hz), 2.06(6H,s), 4.17-4.34 (2H,m), 4.45QH,d.J=14.5Hz). δ.OOQH.d.J=14.5Hz), 6.71(lH,s), 7.12(2H,d, J=8.0Hz), 7.29(2H,d,J=8.0Hz), 7.49C1H, t, J=7.5Hz), 7.87(1H, dd, J=7.5, 0. 5Hz), 8.11(lH,dd,J=7.5,0.5Hz)

Preparation 37

The following compound was obtained according to a similar manner to that of Preparation 2. Ethyl 2-[N-[4-(2-cyano-4, 5-dimethyl-l-pyrrolyl)benzyl]amino]-3- nitrobenzoate

NMR (CDClg, d) : 1.39(3H, t,J=7.5Hz), 2.06(6H,s), 4.25C2H,d, J=5.OHz), 4. 37(2H,q,J=7.5Hz), 6.73QH,s), 6.77QH.t, J=8.OHz), 7.26(2H,d, J=8.5Hz), 7. 44(2H,d,J=8.5Hz), 8.OKIH,dd,J=8.0,0.5Hz), 8.16(lH,dd,J=8.0,0.5Hz), 8.90 (IH,bt,J=5. OHz)

Preparation 38

The following compound was obtained according to a similar manner to that of Preparation 3.

Ethyl 3-amino-2-[N-[4-(2-cyano-4,5-dimethyl-l-pyrrolyl)benzyl]amino] benzoate

NMR (CDClg, 5) : 1.33(3H,t,J=7.5Hz), 2.03(3H,s), 2.06(3H,s), 4.25(2H,d,

J=4.0Hz), 4.28(2H,q,J=7.5Hz), 6.72(lH,s), 6.90(lH,d, J=5.5Hz), 6.91(lH,d, J=4.5Hz). 7.2K2H,d,J=8.5Hz), 7.39QH,dd,J=5.5,4.5Hz), 7.48C2H,d,J=8.5Hz)

Preparation 39

The following compound was obtained according to a similar manner to that of Preparation 4. Ethyl 3-[4-(2-cyano-4, 5-dimethyl-l-pyrrolyl)benzyl] 2-ethoxy-4- benzimidazolecarboxylate mp : 121-122.5°C

NMR (CDClg, 5) : 1.25(3H. t, J=7.5Hz), 1.48(3H. t, J=7.5Hz), 1.98(3H,s), 2.

04(3H,s). 4.22(2H.q.J=7.5Hz), 4.65(2H.q, J=7.5Hz). 5.73(2H,s), 6.71(lH,s). 7.10(2H.d.J=8.5Hz). 7.16(2H, d, J=8.5Hz), 7.20QH, t, J=8. OHz), 7.60(lH,dd,

J=8.0, 0.5Hz), 7.76(1H, dd, J=8.0, 0.5Hz)

Preparation 40

The following compound was obtained according to a similar manner to that of Preparation 1.

Ethyl 2-[N-tert-butoxycarbonyl-N-[4-(5-chloro-2-cyano-4-methyl-l- pyrrolyl)benzyl]amino]-3-nitrobenzoate

NMR (CDClg, 5) : 1.3K3H, t. J=7.5Hz). 1.37(9H,s). 2.09(3H.s). 4.09-4.30

(2H,m), 4.59QH, d, J=14.5Hz), 4.86QH, d, J=14.5Hz), 6.78(lH,s), 7.20(2H,d. J=&5Hz), 7.33(2H,d. J=8.5Hz), 7.49QH, t,J=8.0Hz), 7.90QH, dd, J=8.0, 0. 5Hz), 8. 09C1H, dd, J=8. 0, 0. 5Hz)

Preparation 41

The following compound was obtained according to a similar manner to that of Preparation 2.

Ethyl 2-[N-[4-(5-chloro-2-cyano-4-methyl-l-pyrrolyl)benzyl]amino]-3 -nitrobenzoate

NMR (CDClg, δ ) : 1.39(3H.t,J=7.5Hz), 2.10(3H, s), 4.27(2H,s), 4.36C2H,q, J=7.5Hz), 6.76GH,t, J=8.OHz), 6.79(lH,s), 7.33(2H,d, J=8.5Hz), 7.47(2H,d, J=8.5Hz), 8.02QH,dd, J=8.0, 0.5Hz), 8.16(lH,dd, J=8.0, 0.5Hz)

Preparation 42

The following compound was obtained according to a similar manner to that of Preparation 3. Ethyl 3-amino-2-[N-[4-(5-chloro-2-cyano-4-methyl-l-pyrrolyl)benzyl] amino]benzoate

NMR (CDClg, <5) : 1.34(3H,t.J=7.5Hz). 2.10(3H,s), 3.94(2H.bs). 4.24(2H, bs), 4.28(2H,q,J=7.5Hz), 6.47(lH,bs), 6.79(lH,s), 6.84-6.95(2H,m), 7.29 (2H,d,J=8.5Hz), 7.40(lH,dd,J=5.5,4.5Hz), 7.5K2H,d,J=8.5Hz)

Preparation 43

The following compound was obtained according to a similar manner to that of Preparation 4.

Ethyl 3-[4-(5-chloro-2-cyano-4-methyl-l-pyrrolyl)benzyl]-2-ethoxy-4 -benzimidazolecarboxylate

NMR (CDClg, <5) : 1.23(3H,t,J=7.5Hz), 1.47(3H, t, J=7.5Hz), 2.09(3H.s), 4. 20(2H,q,J=7.5Hz), 4.66(2H.q,J=7.5Hz), 5.75(2H,s). 6.77QH.s), 7.12(2H,d, J=8.5Hz), 7.19(lH,t, J=8. OHz), 7.2K2H, d, J=8.5Hz), 7.60(1H, dd. J=8.0, 0. 5Hz). 7.74(lH.dd.J=8.0,0.5Hz)

Preparation 44

The following compound was obtained according to a similar manner to that of Preparation 1.

Ethyl 2-[N-tert-butoxycarbonyl-N-[4-(4-chloro-2-cyano-5-methyl-l- pyrrolyDbenzyl]amino]-3-nitrobenzoate NMR (CDClg, δ^~) : 1.35(9H,s), 1.37(3H,t, J=7.5Hz), 2.13(3H,s), 4.21-4.38 (2H,m), 4.41(lH,d,J=14.5Hz), 5.OδQH.d,J=14.5Hz), 6.82QH,s), 7.13(2H,d, J=8.5Hz), 7.3K2H,d, J=8.5Hz), 7.50(1H, t, J=8. OHz), 7.87(1H,dd, J=8.0, 0. 5Hz), 8.12(lH,dd,J=8.0,0.5Hz)

Preparation 45

The following compound was obtained according to a similar manner to that of Preparation 2.

Ethyl 2-[N-[4-(4-chloro-2-cyano-5-methyl-l-ρyrroly1)benzyl]amino]-3 -nitrobenzoate

NMR (CDClg, S) : 1.39(3H. t,J=7.5Hz), 2.12(3H,s). 4.29(2H,d,J=5.OHz), 4. 36(2H,q,J=7.5Hz), 6.77QH,t, J=8.OHz), 6.85(lH,s), 7.29(2H,d, J=8.5Hz), 7. 49(2H,d,J=8.5Hz), 7.99(lH,dd,J=8.0, 0.5Hz), 8.16QH,dd, J=8.0,0.5Hz), 8.91 (IH,bt.J=5.OHz)

Preparation 46

The following compound was obtained according to a similar manner to that of Preparation 3.

Ethyl 3-amino-2-[N-[4-(4-chloro-2-cyano-5-methyl-l-pyrrolyl)benzyl] amino]benzoate

NMR (CDClg, 5) : 1.34C3H,t,J=7.5Hz), 2.10C3H,s), 3.95(2H,bs). 4.24(2H. s). 4.26(2H,q,J=7.5Hz), 6.84(lH,s), 6.90QH,d,J=5.5Hz), 6.9K1H,d, J=4. OHz), 7.22(2H,d. J=8.5Hz), 7.39(1H.dd,J=5.5,4. OHz), 7.50(2H,d,J=8.5Hz)

Preparation 47

The following compound was obtained according to a similar manner to that of Preparation 4.

Ethyl 3-[4-(4-chloro-2-cyano-5-methyl-l-pyrrolyl)benzyl]-2-ethoxy-4 -benzimidazolecarboxylate NMR (CDClg, 5) : 1.25(3H,t,J=7.5Hz), 1.48(3H,t,J=7.5Hz), 2.04(3H,s), 4. 22(2H,q,J=7.5Hz), 4.66(2H,q,J=7.5Hz), 5.74(2H,s), 6.81(lH,s), 7.14(4H,s), 7.20QH,t,J=8.OHz), 7.6K1H,d,J=8. OHz), 7.76(lH,d, J=8.OHz)

Preparation 48 . A mixture of ethyl 4-(2-cyano-4-vinyl-l-pyrrolyl)benzoate (864.6mg), platinum(IV) oxide(90mg) and ethyl acetate(8.6ml) was stirred at room temperature for 2 hours under hydrogen atmosphere (atmospheric pressure). After removal of the catalyst by vacuum filtration, the filtrate was evaporated in vacuo. The residue was purified by a silica gel column chromatography(ethyl acetate-hexane) to give ethyl 4-(2-cyano-4-ethyl-l- pyrrolyl)benzoate (833.6mg). mp : 64-69°C

NMR (CDClg, δ : 1.23(3H,t,J=7.5Hz), 1.42(3H, t,J=6.5Hz), 2.57(2H,q,J=7. 5Hz), 4.4K2H,q,J=6.5Hz), 6.90(lH,d, J=0.5Hz), 6.94(lH,d,J=0.5Hz), 7.53 (2H,d,J=9. OHz), 8, 18(2H,d, J=9.OHz)

Preparation 49

Ethyl 4-(2-cyano-4-ethyl-l-pyrrolyl)benzoate(830mg) , lithium borohydride (134. 6mg) and tetrahydrofuran (8. 3ml) were combined under nitrogen atmosphere. The reaction mixture was stirred at 90 °C for 2 hours. After cooled to room temperature, saturated aqueous ammonium chloride was added to the mixture at 0°C, and stirred at room temperature for 2 hours, and ethyl acetate and water were added to the mixture. The separated organic layer was washed with water and sodium bicarbonate, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluted by a mixture of ethy l ace ta te and n -hexane ( 1 : 2 ) t o g i ve 4-e thy l- l - ( 4 - hydroxymethylphenyl)-2-pyrrolecarbonitrile (644. 9mg). NMR (CDClg, 5 ) : 1. 23(3H, t, J=7. 5Hz), 1. 84(1H, t, J=5. 5Hz), 2. 53C2H, q, J=7. 5Hz), 4. 76(2H, d, J=5. 5Hz), 6. 84QH, d, J=0. 5Hz), 6. 89(1H, d, J=0. 5Hz), 7. 43 (2H, d, J=7. 5Hz), 7.50 (2H, d, J=9.5Hz)

Preparation 50

4-Ethyl-l-(4-hydroxymethylphenyl)-2-pyrrolecarbonitrile (622. 3mg) was dissolved in dichloromethane (6. 2ml) under nitrogen atmosphere. Triethylamine (460ml) was added to the mixture, and cooled to -30 °C. Then, methanesulfonyl chloride (223. 5 # 1) was added at -30^CC for 5 minutes. The reaction mixture was stirred at -10°C for 15 minutes and poured into water. The organic layer was washed with water (2 times), sodium bicarbonate and brine, dried over magnesium sulfate, and concentrated in vacuo to give 4-ethyl-l-(4- methanesulf onyloxymethylphenyl) -2-pyrrolecarbonitrile (860.9mg) . NMR (CDClg, δ) : 1.23(3H, t, J=7.5Hz), 2.53(2H, q, J=7.5Hz), 3.01(3H,s), 5. 29(2H,s), 6.86(lH,d,J=0.5Hz), 6.90(1H. d, J=0.5Hz), 7.49(2H, d, J=9.5Hz), 7.57 (2H, d, J=9.5Hz)

Preparation 51

The following compound was obtained according to a similar manner to that of Preparation 1. Ethyl 2-[N-tert-butoxycarbonyl-N-[4-(2-cyano-4-ethyl-l-pyrrolyl) benzyl]amino]-3-nitrobenzoate

NMR (CDClg, 5) : 1.2K3H,t, J=7.5Hz), 1.33(3H,t, J=7.5Hz), 1.36(6H,s), 1. 58(3H,s), 2.52(2H,q,J=7.5Hz), 4.14-4.32(2H,m), 4.53QH,d, J=14.5Hz), 4.90 QH,d,J=14.5Hz), 6.82QH,d,J=0.5Hz), 6.87QH,d, J=0.5Hz), 7.29(4H,s), 7.49 QH,d,J=0.5Hz), 7.90(lH,dd,J=7.5,0.5Hz), 8.09C1H,dd,J=7.5,0.5Hz)

Preparation 52

The following compound was obtained according to a similar manner to that of Preparation 2. Ethyl 2-[N-[4-(2-cyano-4-ethyl-l^~pyrrolyl)benzyl]amino]-3~ nitrobenzoate

NMR (DMSO-dg, 5) : 1.22C3H, t, J=7.5Hz), 1.39(3H, t, J=7.5Hz), 2.53(2H,q,J =7.5Hz), 4.21(2H,s), 4.37(2H,q, J=7.5Hz), 6.75QH, t, J=8. OHz), 6.85QH,d,J =0.5Hz), 6.89(lH,d,J=0.5Hz), 7.42(4H,s), 8.01(lH,dd, J=8.0, 0.5Hz), 8.13 (IH, dd, J=8.0, 0.5Hz)

Preparation 53

The following compound was obtained according to a similar manner to that of Preparation 3. Ethyl 3-amino-2-[N-[4-(2-cyano-4-ethyl-l-pyrrolyl)benzyl]amino] benzoate

NMR (CDClg, £) : 1.22C3H, t, J=7.5Hz), 1.33(3H,t,J=7.5Hz), 2.53(2H,q, J=7. 5Hz), 4.2K2H,bs), 4.27(2H,q, J=7.5Hz), 6.82-6.93(4H,m), 7.33-7.4K3H,m), 7.45(2H,d,J=9.0Hz) Preparation 54

The following compound was obtained according to a similar manner to that of Preparation 4.

Ethyl 3-[4-(2-cyano-4-ethyl-l-pyrrolyl)benzyl]-2-ethoxy-4- benzimidazole-4-carboxylate mp : 121-124°C

NMR (CDClg, 5) : 1.20C3H, t,J=7.5Hz), 1.26(3H, t, J=7.5Hz), 1.48(3H, t, J=7. 5Hz), 2.50(2H,q,J=7.5Hz), 4.27(2H,q, J=7.5Hz), 4.66(2H,q, J=7.5Hz), 5.70 (2H,s), 6.79(lH,d,J=0.5Hz), 6.8K1H,d, J=0.5Hz), 7.10(2H,d, J=9.5Hz), 7.20 (IH,t,J=7.5Hz), 7.3K2H,d,J=9.5Hz), 7.60(lH,dd, J=7.5Hz), 7.76(1H,dd, J=7. 5Hz)

Preparation 55

Bromo(ethyl)triphenylphosphorane(3.3g) was dissolved in dimethyl sulfoxide (20ml) under nitrogen atmosphere, and sodium hydride (355.5mg) was added to the solution at room temperature. The mixture was stirred at 50°C for an hour. After cooled to room temperature, ethyl 4-(2-cyano

-4-formyl-l-pyrrolyl)benzoate (2. Og) was added to the solution, and stirred at room temperature for 16 hours. Water and ethyl acetate were added to the mixture and separated. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water (2 times) and brine, and dried over magnesium sulfate, and concentrated in vacuo to give a mixture of ethyl 4-[2-cyano-4-[(Z)-l-propenyl]-l- pyrrolyl]benzoate and ethyl 4-[2-cyano-4-[(E)-l-propeηyl]-l-pyrrolyl] benzoate (1.42g).

NMR (CDClg, δ ) : 1.4K3H, t, J=7.5Hz), 1.82-1.97(3H,m), 4.42(2H,q, J=7. 5Hz), 5.63-6.29(2H,m), 7.01-7.17(2H,m), 7.49-7.6K2H,m), 8.12-8.25(2H,m)

Preparation 56 The following compound was obtained according to a similar manner to that of Preparation 48.

Ethyl 4-(2-cyano-4-propyl-l-pyrrolyl)benzoate NMR (CDClg, 5) : 0.97(3H,t, J=7.5Hz), 1.4K3H,t,J=7.5Hz), 1.62(2H, sextet, J=7.5Hz), 2.47(2H,t,J=7.5Hz), 4.41(2H,q,J=7.5Hz), 6.88QH,d,J=0.5Hz), 6. 94(lH,d,J=0.5Hz), 7.53(2H,d, J=9.5Hz), 8.19(2H,d,J=9.5Hz) Preparation 57

The following compound was obtained according to a similar manner to that of Preparation 49. 1-(4-Hydroxymethylpheny1)-4-propyl-2-pyrrolecarbonitrile

NMR (CDClg, <5) : 0.98(3H,t,J=7.5Hz), 1.62(2H,sextet, J=7.5Hz), 1.83(lH,t, J=5.5Hz), 2.46(2H,t,J=7.5Hz), 4.76(2H,d, J=5.5Hz), 6.83QH,d,J=0.5Hz), 6. 88C1H,d,J=0.5Hz), 7.42(2H,d,J=9.5Hz), 7.50(2H,d, J=9.5Hz)

Preparation 58

The following compound was obtained according to a similar manner to that of Preparation 50.

1-(4-Methanosulfonyloxy ethylphenyl)-4-propy1-2-pyrrolecarbonitrile NMR (CDClg, 5) : 0.97(3H,t,J=7.5Hz), 1.6K2H,sextet, J=7.5Hz), 2.47C2H, t,J=7.5Hz), 3.0K3H,t), 5.29(2H,s), 6.85QH,d, J=0.5Hz), 6.90QH,d, J=0. 5Hz), 7.49(2H,d,J=9.5Hz), 7.57(2H,d,J=9.5Hz)

Preparation 59

The following compound was obtained according to a similar manner to that of Preparation 1.

Ethyl 2-[N-tert-butoxycarbonyl-N-[4-(2-cyano-4-propyl-l-pyrrolyl) benzyl]amino]-3-nitrobenzoate

NMR (CDClg, δ : 0.97(3H,t,J=7.5Hz), 1.33(3H, t, J=7.5Hz), 1.36(6H,s), 1.

49-1.72(2H,m), 1.58(3H,s), 2.46(2H, t, J=7.5Hz), 4.13-4.31(2H,m), 4.53QH, d,J=14.5Hz), 4.89(lH,d,J=14.5Hz), 6.8K1H,d,J=0.5Hz), 6.86(lH,d,J=0.5Hz),

7.29(4H,s), 7.48C1H,t,J=7.5Hz), 7.89(1H,dd,J=7.5, 0.5Hz), 8.09(1H,dd,J=7.

5,0.5Hz)

Preparation 60 The following compound was obtained according to a similar manner to that of Preparation 2.

Ethyl 2-[N-[4-(2-cyano-4-propyl-l-pyrrolyl)benzyl]amino]-3- nitrobenzoate

NMR (CDClg, δ : 0.97(3H,t,J=7.5Hz), 1.40(3H,t,J=7.5Hz), 1.61(2H, sextet, J=7:5Hz), 2.47(2H,t,J=7.5Hz), 4.21(2H,s), 4.37(2H,q, J=7.5Hz), 6.75(lH,t, J=7. 5Hz), 6. 83C1H. d, J=0. 5Hz), 6. 89(1H, d, J=0. 5Hz), 7. 42(4H, s), 8. OOQH, dd, J=7. 5, 0. 5Hz), 8. 13(1H, dd, J=7. 5, 0. 5Hz)

Preparation 61 The following compound was obtained according to a similar manner to that of Preparation 3.

Ethyl 3-amino-2-[N-[4-(2-cyano-4-propy1-1-pyrrolyl)benzyl] aminobenzoate

NMR (CDClg, δ ) : 0.96(3H,t, J=7.5Hz), 1.32(3H,t, J=7.5Hz), 1.61(2H,sextet, J=7.5Hz), 2.47(2H,t, J=7.5Hz), 3.9K2H,bs), 4.2K2H,bs), 4.26(2H,q, J=7. 5Hz), 6.47(lH,bs), 6.80QH,d,J=0.5Hz), 6.85(1H,d, J=0.5Hz), 6.87-6.92C2H, m), 7.30-7.48(5H,m)

Preparation 62 The following compound was obtained according to a similar manner to that of Preparation 4.

Ethyl 3-[4-(2-cyano-4-propyl-l-pyrrolyl)benzyl]-2-ethoxy-4- benzimidazolecarboxylate mp : lOδ.δ-HO'C NMR (CDClg, 5) : 0.94(3H, t,J=7.5Hz), 1.27(3H, t, J=7.5Hz), 1.49(3H, t, J=7.

5Hz), 1.59(2H,sextet,J=7.5Hz), 2.43(2H,t,J=7.5Hz), 4.25(2H,q, J=7.5Hz), 5.

70(2H,s), 6.80(2H,s), 7.09(2H,d, J=9.5Hz), 7.19C1H,t, J=7.5Hz), 7.30(2H,d,

J=9.5Hz), 7.60QH,dd,J=7.5,0.5Hz), 7.74QH,dd,J=7.5,0.5Hz)

Preparation 63

The following compound was obtained according to a similar manner to that of Preparation 4.

Ethyl 3-[4-(2-cyano-4-methyl-l-pyrrolyl)benzyl]-2-propoxy-4- benzimidazolecarboxylate mp : 106-108°C

NMR (CDClg, δ : 0.99C3H, t, J=7.5Hz), 1.27(3H, t, J=7.5Hz), 1.77-1.98C2H, m), 2.10(3H,s), 4.24(2H,q, J=7.5Hz), 4.56(2H, t, J=7.5Hz), 5.7K2H,s), 6.78 (2H,s), 7.11(2H,d,J=9.0Hz), 7.19(1H,t, J=7.5Hz), 7.30(2H,d, J=9. OHz), 7.61 (IH,dd, J=7.5,0.5Hz), 7.75(1H,dd,J=7.5, 0.5Hz) Preparation 64

The following compound was obtained according to a similar manner to that of Preparation 4.

Ethyl 3-[4-(2-cyano-4-methyl-l-pyrrolyl)benzyl]-2-methoxy-4- benzimidazolecarboxylate

NMR (CDClg, _.,$) : 1.26(3H, t,J=7.5Hz), 2.12(3H,s), 4.23C2H,q, J=7.5Hz), 4. 25(3H,s), 5.70(2H,s), 6.79(2H,s). 7.10(2H,d.J=9.OHz), 7.20QH,t, J=8.OHz), 7.30(2H,d,J=9.OHz), 7.61(IH,dd,J=8.0,0.5Hz), 7.77(IH,dd, J=8.0, 0.5Hz)

Preparation 65

The following compound was obtained according to a similar manner to that of Example 3.

2-[N-tert-butoxycarbonyl-N-[4-(2-cyano-4-methyl-l-pyrrolyl)benzyl] amino]-3-nitrobenzoic acid

NMR (CDClg, δ : 1.29(6H,s), 1.53(3H,s), 2.09(3H,s), 4.45-5.00(2H,m), 6. 75(lH,s), 6.81(lH,s), 7.09-7.29(4H,m), 7.38(lH,bt,J=8.OHz), 7.83(lH,bd,J =8.OHz), 8.08QH,bd,J=8.0Hz)

Preparation 66

The following compound was obtained according to a similar manner to that of Example 7.

3-(tert-Butoxycarbon lamino)-2-[N-tert-butoxycarbonyl-N-[4-(2-cyano -4-methyl-l-pyrrolyl)benzyl]amino]-1-nitrobenzene NMR (CDClg, £) : 1.35(9H,s), 1.4K9H,s), 2.12(3H,s), 4.33QH,d, J=14. 5Hz). 5.04QH,d,J=14.5Hz), 6.59(lH,bs), 6.80(lH.d,J=0.5Hz), 6.84(lH,d,J= 0.5Hz), 7.19-7.46(lH,m), 7.34(4H,s), 7.60QH,dd, J=8.0,0.5Hz), 8.33QH,dd, J=8.0,0.5Hz)

Preparation 67

The following compound was obtained according to a similar manner to that of Preparation 2.

3-Amino-2-[N-[4-(2-cyano-4-methyl-l-pyrrolyl)benzyl]amino]-1- nitrobenzene NMR (CDClg, 5) : 2.13(3H,s), 4.10(2H,bs), 4.28(2H,d, J=8.OHz), 6.07(lH,t, J=8. 0Hz), 6. 80(lH, d, J=0. 5Hz), 6. 86(lH, d, J=0. 5Hz), 6. 89-7. 0K2H, m), 7. 37 (4H, s), 7. 40(1H, dd, J=6. 5, 2. OHz)

Preparation 68 The following compound was obtained according to a similar manner to that of Preparation 4.

3-[4-(2-cyano-4-methyl-l-pyrrolyl)benzyl]-2-ethoxy-4-nitro- benzimidazole mp : 166-169°C NMR (CDClg, 5) : 1.53(3H, t,J=7.5Hz), 2.12(3H, s), 4.72(2H,q, J=7.5Hz), 5. 57(2H,s), 6.78QH,d, J=0.5Hz), 6.81(lH,d,J=0.5Hz), 7.10(2H,d, J=9. OHz), 7. 23(1H, t, J=8. OHz), 7.3K2H,d, J=9. OHz), 7.73(1H,dd, J=8.0,0.5Hz), 8.82QH, dd, J=8.0, 0.5Hz)

Example 1

A mixture of ethyl 3- [4-(3-cyano.-l-ethyl-5-methyl-2-pyrrolyl) benzyl] -2-ethoxy-4-benzimidazolecarboxy late (2. 356g), trimethyltin azide (3. 19g) and xylene (24ml) was stirred at 120 °C for 39 hours and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluted by dichloromethane/methanol) twice to give ethyl 2-ethoxy-3-[4-[l-ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2-pyrrolyl]benzyl]- 4-benzimidazolecarboxylate(l. 87g) as an amorphous powder. NMR(CDClg, δ) : 1. 12C3H, t, J=7Hz), 1. 3K3H, t, J=7Hz), 1. 52(3H, t, J=7Hz), 2. 33(3H, s), 3. 73(2H, q, J=7Hz), 4. 24(2H, q, J=7Hz), 4. 70(2H, q, J=7Hz), 5. 69(2H, s), 6. 63(lH, s), 7. 10(2H, d, J=8Hz), 7. 1K1H, t, J=8Hz), 7. 16(2H, d, J=8Hz), 7. 56(lH, dd, J=8, 1Hz), 7. 73(1H, dd, J=8, 1Hz).

Example 2 Ethyl 2-ethoxy-3- [4- [l-ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2- pyrrolyl] benzyl] -4-benzimidazolecarboxylate(223mg) was dissolved in 0. IN aqueous solution of sodium hydroxide (4. 46ml). The solution was lyophilized to afford sodium salt of ethyl 2-ethoxy-3-[4- [l-ethyl-5- methyl-3-(lH-tetrazol-5-yl)-2-pyrrolyl]benzyl]-4-benzimidazolecarboxylate (217mg) as an amorphous powder. NMR(D₂0, δ : 0.76(3H, t,J=7Hz), 0.96C3H,t, J=7Hz), 1.37(3H, t,J=7Hz), 2.17(3H,s), 3.38(2H,q,J=7Hz), 3.98(2H,q, J=7Hz), 4.50(2H,q, J=7Hz), 5.35(2H,s), 6.30(lH,s), 6.79(2H,d, J=8Hz), 6.97(2H,d, J=8Hz), 7.03(lH,t, J=8Hz), 7.28(1H,d,J=8Hz), 7.58C1H,d,J=8Hz).

Example 3

A mixture of ethyl 2-ethoxy-3-[4-[l-ethyl-5-methyl-3-(lH-tetrazol- 5-yl)-2-pyrrolyl]benzyl]-4-benzimidazolecarboxylate (465mg), IN aqueous solution of sodium hydroxide (2.8ml) and ethanol (7.5ml) was stirred at 80 °C for 1 hour. The reaction mixture was evaporated in vacuo, and the residue was dissolved in water (6ml). The pH value of the solution was adjusted to 4 with IN hydrochloric acid. Resulting precipitate was collected, washed with water and recrystallized from ethanol to afford 2-ethoxy-3-[4-[l-ethyl-5-methyl-3-(lH-tetrazol-5- yl)-2-pyrrolyl]benzyl]-4-benzimidazolecarboxylic acid (330mg) as colorless crystals, mp 2U-212°C

NMR(DMS0-d₆, <5) : 0.98(3H,t, MHz), 1.39(3H,t, J=7Hz), 2.28(3H,s), 3.69(2H,q,J=7Hz), 4.60(2H,q, J=7Hz), 5.69(2H,s), 6.32(lH,s), 7.02(2H,d, J=8Hz), 7.18QH,t,J=8Hz), 7.24(2H,d, J=8Hz), 7.5K1H,dd, J=8, 1Hz). 7.68QH,dd,J=8,lHz).

Example 4

The following compound was obtained according to a similar manner to that of Example2.

Disodium salt of 2-ethoxy-3-[4-[l-ethyl-5-methyl-3-(lH-tetrazol-5- yl)-2-pyrrolyl]benzyl]-4-benzimidazolecarboxylie acid. NMR(D₂0, 5) : 1.0K3H,t,J=7Hz), 1.43(3H,t, J=7Hz), 2.32(3H,s), 3.74(2H,q,J=7Hz), 4.58(2H,q, J=7Hz), 5.60(2H,s), 6.37(lH,s), 7.10-7.33(6H), 7.54(lH,dd, J=8, 1Hz).

Example 5

To a mixture of 2-ethoxy-3-[4-[l-ethyl-5-methyl-3-(lH-tetrazol-5-yl)

-2-pyrrolyl]benzyl]-4-benzimidazolecarboxylic acid (47mg), triethylamine (0.3ml), and tetrahydrofuran(2ml) was added ethyl chloroformate(0.1ml) dropwise in an ice-water bath. The mixture was stirred for.15 minutes in an ice-water bath and then for 1 hour at ambient temperature. An 40% aqueous solution of methylamine (0.05ml) was added therein and stirring was continued for 3 hours at ambient temperature. After removal of the solvent, the residue was purified by preparative thin layer chromatography to afford N-methyl-2-ethoxy-3-[4-[l-ethyl-5-methyl-3-(lH- tetrazol-5-yl)pyrrolyl] benzyl] -4-benzimidazolecarboxamide (18mg) as colorless glass

NMR(CDClg-CDgOD) : _, 1.13(3H, t, MHz), 1.52(3H, t, MHz), 2.32(3H,s),

2.64(3H,s), 3.78(2H,q,MHz), 4.68(2H,q, MHz), 5.50(2H,s), 6.36(lH,s), 6.98(2H, d, J=8Hz), 7.10-7.23(4H), 7.60(1H, dd, J=8, 2Hz).

Example 6

N-Methyl-2-ethoxy-3-[4-[l-ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2- pyrrolyl] benzyl] -4-benzimidazolecarboxamide(16mg) was dissolved in 0. IN sodium hydroxide (0.33ml) and water (1ml). The solution was lyophilized to afford sodium salt of N-Methyl-2-ethoxy-3-[4-[l-ethyl-5-methyl-3-(lH -tetrazol-5-yl)-2-pyrrolyl] benzyl] -4-benzimidazolecarboxamide as amorphous powder. NMR(D₂0, <5):

0.78(3H, t, MHz), 1.45(3H, t, MHz), 2.13(3H, s), 2.47(3H,s), 3.58(2H,q,MHz), 4.6K2H, q, MHz), 5.42(2H,s), 5.80(lH,s), 6.81(2H,d, J=8Hz),

6.94(2H, d, J=8Hz), 7.17-7.31 (2H), 7.67C1H, dd, J=8, 2Hz).

Example 7 A mixture of 2-ethoxy-3-[4-[l-ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2- pyrrolyl]benzyl]-4-benzimidazolecarboxylic acid (85mg), diphenylphosphoryl azide (149mg), triethylamine (0.1ml), and ethanol

(2ml) was heated under reflux for 3 hours. After removal of the solvent under reduced pressure, the residue was purified by preparative thin layer chromategraphy to afford 2-ethoxy-4-ethoxycarbonylamino-3-[4-[l- ethyl-5-methyl-3-QH-tetrazol-5~yl)-2-pyrrolyl] benzyl] benzimidazole (41mg) as amorphous powder. NMR(CDClg, <5 ) :

1. 12(3H, t, J=7Hz), 1. 16(3H, t, MHz), 1. 51(3H, t, MHz), 2. 32(3H, s), 3. 65-3. 90 (4H),

4. 70(2H, q, MHz), 5. 47(2H, s), 6. 68(lH, s), 6. 93-7.40C6H), 7. 53QH, d, J=8Hz).

Example 8 2-Ethoxy-4-ethoxycarbonylamino-3-[4-[l-ethyl-5-methyl-3-(lH-tetrazol- 5-yl)-2-pyrrolyl]benzyl]benzimidazole (41mg) was dissolved in 0. IN sodium hydroxide (0.8ml) and water (1ml). The solution was filtered through a milipor filter and lyophilized to yield sodium salt of 2-ethoxy-4- ethoxycarbonylamino-3-[4-[l-ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2- pyrrolyl]benzyl]benzimidazole as amorphous powder. NMR(D₂0, 5):

0.85(3H,t,MHz), 1.10(3H,t, MHz), 1.32(3H,t,MHz), 2.19(3H,s), 3.5K2H,q,MHz), 3.90(2H,q,MHz), 4.48(2H,q,MHz), 5.2K2H,s), 6.31QH,s), 6.82-7.17(6H), 7.40(lH,d, J=8Hz).

Example 9

The following compound was obtained according to a similar manner to that of Example 5. N-Methyl-2-ethoxy-3-[4-[l-ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2- pyrrolyl]benzyl]-4-benzimidazolecarbohydroxamic acid. NMR(CDClg-CDgOD):

1.10(3H,t,MHz), 1.50(3H,t,MHz), 2.32(3H,s)„ 3.75C3H,t,MHz), 3.80(3H,s), 4.67(2H,q,MHz), 5.65(2H,s), 6.48(lH,s), 7.09(2H,d, J=8Hz), 7.17-7.33(3H), 7.59(1H,dd,J=8, 1Hz), 7.75(lH,dd,J=8,lHz).

Example 10 ^{' ■} N-Methyl-2-ethoxy-3-[4-[l-ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2- pyrrolyl]benzyl]-4-benzimidazolecarbohydroxamic acid (llmg) was dissolved in 0.01N sodium hydroxide (4ml) and lyophilized to afford disodium salt of N-methyl-2-ethoxy-3-[4-[l-ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2- pyrrolyl]benzyl]-4-benzimidazolecarbohydroxamic acid as white powder. NMR(D₂0, δ :

0.74(2.2H,t,MHz), 0.98(0.8H, t, MHz),

1.36(2.2H,t,MHz), 1.40(0.8H,t,MHz),

2.17(2.2H,s), 2.30(0.8H,s), 3.40(1.4H,q, MHz), 3.49(3H,s), 3.69(0.6H,q,MHz), 4.49(1.4H,q,MHz), 4.56(0.6H,q, MHz), 5.32(1.4H,s), 5.58(0.6H,s), 6.31(0.7H, s), 6.37(0.3H,s), 6.78(2H,d,J=8Hz), 6.96(2H,d, J=8Hz), 7.02C1H,t, J=8Hz), 7.13-7.33(2H), 7.51-7.6K1H).

Example 11

A mixture of 2-ethoxy-3-[4-[l-ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2- pyrrolyl]benzyl]-4-benzimidazolecarboxylic acid (158mg), triethylamine (0.06ml), trityl chloride (lOOmg), and dichloromethane (3ml) was stirred at ambient temperature for 3 hours. The mixture was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (ethyl acetate) to afford 2-ethoxy-3-[4-[l-ethyl-5-methyl-3-(l-trityl-lH-tetrazol-5-yl)-2- pyrrolyl]benzyl]-4-bezimidazolecarboxylic acid (121mg) as white solid. mp : 188-190°C NMP(CDC1₃, <5): 1.03(3H,t,MHz), 1.47(3H,t,MHz), 2.27(3H,s), 3.70(2H,q,MHz), 4.67(2H,q,MHz), 5.63(2H,s), 6.44(lH,s), 6.92(2H,d,J=8Hz), 6.96-7.34Q8H), 7.50(lH,dd,J=8,lHz), 7.73(1H,dd, J=8, 1Hz)

Example 12

A mixture of 2-ethoxy-3-[4-[l-ethyl-5-methyl-3-(l-trityl-lH-tetrazol-

5-yl)-2-pyrrolyl]benzyl]-4-benzimidazolecarboxylic acid (llδmg), cyclohexyl 1-iodoethyl carbonate (465mg), potassium carbonate (72mg), and dimethylformamide (3ml) was stirred at ambient temperature for 3 hours. The mixture was portioned into a mixture of ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over magnesium sultate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (n-hexane- ethyl acetate) to afford 1-cyclohexyloxycarbonyloxyethyl 2-ethoxy-3-[4-[l -ethyl-5-methyl-3-(l-trityl-lH-tetrazol-5-yl)-2-pyrrolyl]benzyl]-4- benzimidazolecarboxylate (74mg) as pale yellow oil. NMR(CDC1₃, 5): 0.82-2.00(19H), 2.29(3H,s), 3.68(2H,q,MHz), 4.54-4.72C3H), 5.58(lH,d,J=15Hz), 5.74QH,d,J=15Hz), 6.50(lH,s), 6.86-7.03(8H), 7.11-7.33Q2H), 7.60(1H,dd,J=8, 1Hz), 7.76(1H,dd, J=8, 1Hz)

Example 13

A mixture of 1-cyclohexyloxycarbony loxyethyl 2-ethoxy-3-[4-[l-ethyl-5

^' -methyl-3- (l-trityl-lH-tetrazol-5-yl) -2-pyrrolyl] benzyl] -4- benzimidazolecarboxylate (74mg), silica gel (370mg), and methanol (7.4ml) was heated under reflux for 18 hours. After removal of the silica gel by vacuum filtration, the filtrate was evaporated in vacuo. The residue was purified by preparative thin layer chromatography (dichloromathane - methanol) and pulverized with water to afford 1-

(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-3-[4-[l-ethyl-5-methyl-3-(lH- tetrazol-5-yl)-2-pyrrolyl]benzyl]-4-benzimidazolecarboxylate (39mg) as amorphous powder.

NMR(CDC1₃, 5) : 1. 05-1. 97Q9H), 2. 32(3H, s), 3. 73(2H, q, MHz), 4. 55QH, m), 4. 70(2H, q, MHz), 5. 68QH, d, M5Hz), 5. 80(lH, d, J=15Hz),

6. 63(lH, s), 6. 88QH, q, J=5Hz), 7. 10-7. 30 (5H), 7. 66(1H, dd, J=8, 1Hz), 7. 78(1H, dd, J=8, 1Hz)

Example 14 • The following compound was obtained according to a similar manner to that of Example 1.

Ethyl 3-[4-[2-bromo-l-methyl-4-(lH-tetrazol-5-yl)-3-pyrrolyl]benzyl] -2-ethoxy-4-benzimidazolecarboxylate. mp: 177-181°C NMR(DMS0-dg, δ ) : 1. 13(3H, t, M. 5Hz), 1. 4K3H, t, M. 5Hz), 3. 70(3H, s),

4. 19C2H, q, J=7. 5Hz), 4. 62C2H, q, J=7. 5Hz), 5. 53(2H, s), 6. 9K2H, q, J=7. 5Hz), 7. 16 (2H, d,J=8. 5Hz), 7. 18(1H, t, J=8. OHz), 7. 46(1H, dd, J=8. 0, 1. OHz), 7. 62(1H, s), 7. 70 (IH, dd, J=8. 0, 1. OHz)

Example 15

The following compound was obtained according to a similar manner to that of Example 2.

Sodium salt of ethyl 3-[4-[2-bromo-l-methyl-4-(lH-tetrazol-5-yl)-3- pyrrolyl]benzyl]-2-ethoxy-4-benzimidazolecarboxylate. NMR(DMS0-d₆, δ ) :1.17(3H,t,M.5Hz), 1.42(3H,t,M.5Hz),3.6K3H,s),

4.20(2H,q,M.5Hz),4.6K2H,q,J=7.5Hz),5.50(2H,s),6.80(2H,q,J=8.5Hz),7.18 (IH,t, J=8.OHz),7.18(1H,s),7.27(2H,d, J=8^*.5Hz),7.43(1H,dd,J=8.0,0.5Hz), 7.69 (IH,dd,J=8.0,0.5Hz)

Example 16

The following compound was obtained according to a similar manner to that of Example 3.

3-[4-[2-Bromo-l-methyl-4-(lH-tetrazol-5-yl)-3-pyrrolyl]benzyl]-2- ethoxy-4-benzimidazolecarboxylic acid. mp:178-180^<€

NMR(DMS0-d₆, δ ) :1.40(3H,t,M.5Hz),3.69(3H,s),4.59(2H,q,M.5Hz),

5.66(2H,s), 6.97(2H,d,J=8.5Hz), 7.16(2H,d, J=8.5Hz), 7.19(1H,t, J=8. OHz), 7.53 (IH,dd,J=8.0,0.5Hz),7.61(IH,s),7.67(1H,dd,J=8.0,0.5Hz),

Example 17

The following compound was obtained according to a similar manner to that of Example 2.

Disodium salt of 3-[4-[2-bromo-l-methyl-4-(lH-tetrazol-5-yl)-3- pyrrolyl]benzyl]-2-ethoxy-4-benzimidazolecarboxylic acid. • NMR(D₂0, δ) :1.40(3H, t, J=7.5Hz), 3.67C3H, s),4.53(2H,q,J=7.5Hz), 5.52 (2H, s), 7. 04(2H, d, J=8. 5Hz), 7. 12(2H, d, J=8. 5Hz), 7. 2K1H, t, J=8. OHz), 7. 24-7. 37 (2H, m), 7. 5K1H, dd, J=8. 0. 1. OHz)

Example 18 ..The following compound was obtained according to a similar manner to that of Example 1.

Ethyl 3-[4-[4-chloro-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-2- ethoxy-4-benzimidazolecarboxylate. mp:149-153°C NMR(DMS0-dg, δ ) :1.18(3H,t,M.5Hz), 1.4K3H, t, M.5Hz),4.19(2H,q, M.5Hz),4.6K2H,q,M.5Hz).5.56(2H,s),6.87(1H.d, J=l. OHz), 6.97(2H,d, J=9. OHz),7.20(IH,t,J=8.OHz),7.2K2H,d,J=9.OHz),7.39(IH,d, J=l.OHz),7.49(IH,dd, J=8.0,0.5Hz),7.70(IH,dd,J=8.0,0.5Hz)

Example 19

The following compound was obtained according to a similar manner to that of Example 2.

Sodium salt of ethyl 3-[4-[4-chloro-2-(lH-tetrazol-5-yl)-l-pyrrolyl] benzyl]-2-ethoxy-4-benzimidazolecarboxylate. NMR(DMSO-dg, δ ) :1.17(3H,t,M.5Hz), 1.4K3H,t,M.5Hz),4.19(2H,q, M.5Hz),4.6K2H,q,J=7.5Hz),5.5K2H,s),6.33(1H,d,J=l.OHz).6.85(2H,d,J=8. 5Hz),7.03(1H,d,J=l.OHz),7.09(2H,d,J=8.5Hz),7.20(1H,t,J=8.OHz),7.47(IH,dd, J=8.0,0.5Hz),7.69(IH,dd, J=8.0,0.5Hz)

Example 20

The following compound was obtained according to a similar manner to that of Example 3.

3-[4-[4-chloro-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-2-ethoxy-4- benzimidazolecarboxylic acid. mp:182-184^eO

NMR(DMS0-d₆, δ ) :1.38(3H,t,J=7.5Hz),4.59(2H,q,J=7.5Hz),5.69(2H,s), 6.90(IH,d,J=l.OHz), 7.04(2H,d, J=8.5Hz),7.18(IH, t,J=8.OHz), 7.23(2H,d, J=8. 5Hz).7.44(1H,d,J=l.OHz),7.56(IH,d,J=8.OHz).7.69(1H,d.J=8.OHz)

Example 21 The following compound was obtained according to a similar manner to that of Example 2.

Disodium salt of 3-[4-[4-chloro-2-(lH-tetrazol-5-yl)-l-pyrrolyl] benzyl]-2-ethoxy-4-benzimidazolecarboxylic acid. NMR(D₂0, δ ):1.40(3H, t,J=7.5Hz),4.56(2H,q, J=7.5Hz), 5.53(2H,s), 6.68(1H, d, J=l.OHz), 6.98(2H,d, J=8.5Hz), 7.06(2H,d, J=8.5Hz), 7.1K1H,d, J=l. OHz), 7.22 (IH,t,J=8. OHz), 7.28(1H,dd, J=8.0, 1. OHz), 7.53C1H,dd, J=8.0, 1. OHz)

Example 22 The following compound was obtained according to a similar manner to that of Example 1.

Ethyl 2-ethoxy-3-[4-[5-methyl-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl] -4-benzimidazolecarboxylate.

NMR(CDC1₃, δ ) : 1.30(3H, t,M.5Hz), 1.49(3H,t, M.5Hz), 2.07(3H,s), 4.22(2H,q, M.5Hz), 4.65 (2H,q,M.5Hz), 5.69(2H,s), 6.17(1H,d, J=5Hz), 6.99-7.25(6H,m), 7.55(1H,dd,M, 0.5Hz). 7.66QH, dd,M,0.5Hz)

Example 23 The following compound was obtained according to a similar manner to that of Example 2.

Sodium salt of ethyl 2-ethoxy-3-[4-[5-methyl-2-(lH-tetrazol-5-yl)-l -pyrrolyl]benzyl]-4-benzimidazolecarboxylate.

NMR(DMS0-d₆, δ ) : 1.15(3H,t,M.5Hz), 1.40(3H,t, M.5Hz), 1.92(3H,s), 4.14(2H,q,M.5Hz), 4.61 (2H,q,M.5Hz), 5.53(2H,s), 5.91(lH,d, J=5Hz), 6.21(lH,d,J=5Hz), 6.85(2H,d,J=9Hz), 7.04(2H,d, J=9Hz), 7.20(lH,d,M.5Hz), 7.44QH,dd,M.5, 1Hz), 7.70QH,dd, M.5, 1Hz)

Example 24

The following compound was obtained according to a similar manner to that of Example 3.

2-Ethoxy-3-[4-[5-methyl-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-4- benzimidazolecarboxylic acid. mp:141-144 °C

NMR(DMS0-d₆, δ ) : 1.38C3H, t,M.5Hz), 1.95(3H,s), 4.60(2H,q,M.5Hz), 5.70(2H,s), 6.66QH,d, J=5Hz), 6.80QH,d, J=5Hz), 7.04 (2H,d,J=9Hz), 7.16(2H,d, J=9Hz), 7.19(lH,d, J=8Hz), 7.52QH.dd,J=8, 0.5Hz), 7.69(IH,dd,J=8,0.5Hz)

Example 25

The following compound was obtained according to a similar manner to that of Example 2. Disodium salt of 2-ethoxy-3-[4-[5-methyl-2-(lH-tetrazol-5-yl)-l- pyrrolyl]benzyl]-4-benzimidazolecarboxylic acid. mp:>285°C(dec.)

NMR(DMS0-d₆, δ ) : 1.28(3H,t.J=7.5Hz). 1.9K3H.s). 4.47(2H.q.M.5Hz), 5.85-5.95(3H,m), 6.20(lH,d. J=5Hz). 6.96(lH.d.J=8Hz). 6.98(2H,d.J=9Hz),

7.11(2H,d.J=9Hz). 7.30QH,dd,J=8.0.5Hz), 7.35QH, dd,J=8,0.5Hz)

Example 26

The following compound was obtained according to a similar manner to that of Example 1.

Ethyl 3-[4-[4-methyl-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-2- ethoxy-4-benzimidazolecarboxylate. mp:161-162.5 °C

NMR(DMS0-dg, δ ) : 1.17(3H, t,M.5Hz), 1.4K3H,t, • J=7.5Hz), 2.10(3H,s), 4.19C2H,q,M.5Hz). 4.6K2H.q,M.5Hz). 5.56(2H.s). 6.69(lH.d, J=0.5Hz), 6.94(2H,d,J=8.5Hz), 6.97QH.d.J=0.5Hz). 7.13(2H,d,J=8.5Hz), 7. 19(IH,t,J=8.OHz), 7.48(IH, dd, J=8.0, 0.5Hz), 7.70(IH,dd, J=8.0, 0.5Hz)

Example 27

The following compound was obtained according to a similar manner to that of Example 3.

3-[4-[4-Methyl-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-2-ethoxy-4- benzimidazolecarboxylic acid. - mp:183-184 °C NMR(DMS0-dg, δ ) : 1.39C3H,t,M.5Hz), 2.09(3H,s), 4.59(2H,q,M.5Hz), 5.67(2H,s). 6.70(lH,d, J=0.5Hz), 6.99(lH,d,J=0.5Hz), 7.01(2H,d, J=8.5Hz), 7.15(2H,d, J=8.5Hz), 7. 19(1H,t, J=8.OHz), 7.54QH, dd, J=8.0, 0.5Hz), 7.68(lH,dd, J=8.0, 0.5Hz)

Example 28

The following compound was obtained according to a similar manner to that of Example 2.

Disodium salt of 3-[4-[4-methyl-2-(lH-tetrazol-5-yl)-l-pyrrolyl] benzyl]-2-ethoxy-4-benzimidazolecarboxylic acid. mp:>280°C

NMR(DMSO-dg, δ ) : 1.35(3H,t, M.5Hz), 2.03(3H,s), 4.48(2H,q,M.5Hz), 5.86(2H,s), 6.14(lH,d,

J=0.5Hz), 6.66(lH,d,J=0.5Hz), 6.95QH,t,J=8.OHz), 6.96(2H,d,J=8.5Hz), 7. 06(2H,d,J=8.5Hz). 7.28GH, dd, J=8.0, 0.5Hz), 7.3K1H,dd, J=8.0, 0.5Hz)

Example 29

The following compound was obtained according to a similar manner to that of Example 1. Ethyl 3-[4-[5-bromo-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-2-ethoxy -4-benzimidazolecarboxylate.

NMR(CDC1₃, δ ) : 1.29(3H,t, M.5Hz), 1.47(3H,t, M.5Hz), 4.21(2H,q,M.5Hz), 4.59(2H,q, M.5Hz), 5.68(2H,s), 6.48(lH,d, J=4.5Hz), 7.04(2H,d,

J=8.5Hz), 7.11-7.23(4H,m), 7.55(lH,dd, J=8.0, 0.5Hz), 7.63(lH,dd,J=8.0,0.5Hz)

Example 30 The following compound was obtained according to a similar manner to that of Example 3.

3-[4-[5-Bromo-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-2-ethoxy-4- benzimidazolecarboxylic acid, mp:172.5-177 °C ^• NMR(DMSO-dg, δ ) : 1.37(3H. t,J=7.5Hz), 4.59(2H,q, M.5Hz), 5.72(2H,s), 6.59QH,d, J=4.5Hz), 6.93 (IH,d, J=4.5Hz), 7.07(2H, d,J=8.5Hz), 7.14-7.28C3H, ), 7.56(1H,dd, J=8.0, 0.5Hz), 7.69(lH,dd, J=8.0, 0.5Hz)

Example 31

The following compound was obtained according to a similar manner to that of Example 2.

Disodium salt of 3-[4-[5-bromo-2-(lH-tetrazol-5-yl)-l-pyrrolyl] benzyl]-2-ethoxy-4-benzimidazolecarboxylic acid. mp:>280°C

NMR(DMS0-dg, δ ) : 1.29(3H,t,M.5Hz), 4.48(2H,q, J=7.5Hz), 5.93(2H,s), 6.30(lH.d.J=4.OHz).

6.40(lH,d,J=4.0Hz), 6.99QH, t.J=8.0Hz), 7.02(2H, d,J=8.5Hz), 7.16(2H,d, J=8.5Hz), 7.30QH,dd.J=8.0, 0.5Hz), 7.36(lH,dd,J=8.0,0.5Hz)

Example 32

The following compound was obtained according to a similar manner to that of Example 1.

Ethyl 3-[4-[4-bromo-2-(lH-tetrazol-5-yl)-1-pyrrolyl]benzyl]-2-ethoxy -4-benzimidazolecarboxylate. mp:157-160 °C NMR(DMS0-dg, δ ) : 1.17C3H, t,M.5Hz), 1.40(3H,t,

M.5Hz), 4.I9(2H,q,M.5Hz), 4.62(2H,q.M.5Hz), 5.57(2H,s), 6. 90QH,d,J=l.OHz), 6.97(2H,d, J=8.5Hz), 7.20QH,t,J=8.0Hz), 7.21(2H,d,J=8.5Hz), 7.42(lH,d, J=l.OHz), 7. 49QH,dd.J=8.0.0.5Hz), 7.71QH,dd.J=8.0,0.5Hz)

Example 33 The following compound was obtained according to a similar manner to that of Example 3.

3-[4-[4-Bromo-2-(lH-tetrazol-5-yD-1-pyrrolyl]benzyl]-2-ethoxy-4- benzimidazolecarboxylic acid, mp:176-180 - NMR(DMS0-d₆, δ ) : 1.39(3H,t,M.5Hz). 4.59(2H,q, M.5Hz), 5.68(2H,s), 6.83(lH,d,M.5Hz), 7.01(2H,d.J=8.5Hz), 7.18(1H,t,J=8. OHz), 7.20C2H, d,J=8.5Hz), 7.39(lH,d. M.5Hz), 7.55QH.dd,J=8.0, 0.5Hz), 7.69(lH,dd,J=8.0, 0.5Hz) Example 34 The following compound was obtained according to a similar manner to that of Example 2.

Disodium salt of 3-[4-[4-bromo-2-(lH-tetrazol-5-yl)-l-pyrrolyl] benzyl]-2-ethoxy-4-benzimidazolecarboxylic acid. mp:>280°C NMR(DMSO-dg, δ ) : 1.34(3H,t,M.5Hz), 4.48(2H,q, J=7.5Hz), 5.88(2H.s), 6.34(1H,d, J=0.5Hz),

6.96QH,t,J=8.OHz), 7.02(2H,d,J=8.5Hz), 7.07(1H, d,J=0.5Hz). 7.10(2H,d, J=8.5Hz). 7.29(lH,dd,J=8.0, 0.5Hz), 7.32QH,dd, J=8.0, 0.5Hz)

Example 35

The following compound was obtained according to a similar manner to that of Example 1. .

Ethyl 3-[4-[5-chloro-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-2-ethoxy -4-benzimidazolecarboxylate. NMR(DMSO-dg, δ ) : 1.13(3H,t, J=7.5Hz), 1.38(3H,t,

M.5Hz), 4.14(2H,q,M.5Hz), 4.60(2H,q, M.5Hz), 5.60(2H,s), 6. 50(1H,d, J=5Hz), 6.9K1H,d, J=5Hz),

7.00(2H,d.J=9Hz). 7.10-7.37(3H,m), 7.46(1H,d, J=8Hz). 7.70(lH,d.J=8Hz)

Example 36

The following compound was obtained according to a similar manner to that of Example 3.

3-[4-[5-Chloro-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-2-ethoxy-4- benzimidazolecarboxylic acid, mp:156-161 °C

NMR(DMSO-dg, δ ) : 1.46(3H.t,M.5Hz), 4.59(2H,q, M.5Hz), 5.71(2H,s), 6.5K1H,d, J=5Hz), 6.95QH, d, J=5Hz), 7.08(2H,d,J =9Hz), 7.14-7.30(3H,m), 7.56(1H,d,J=8Hz), 7.70(1H,d,J=8Hz) Example 37

The following compound was obtained according to a similar manner to that of Example 2. Disodium salt of 3-[4-[5-chloro-2-(lH-tetrazol-5-yl)-l-pyrrolyl] benzyl]-2-ethoxy-4-benzimidazolecarboxylic acid. mp:>280°C(dec.)

NMR(DMS0-dg, δ ) : 1.29(3H, t,J=7.5Hz), 4.47(2H,q, M.5Hz), 5.92(2H,s), 6.22(lH,d, J=5Hz), 6.46QH, d, J=5Hz), 6.98QH,t,J =8Hz). 7.04(2H,d,J=9Hz). 7.16C2H,d, J=9Hz), 7.31(lH,br.d.J=8Hz), 7.35QH, br.d,J=5Hz)

Example 38

A mixture of ethyl 3-amino-2-[[4-[l-ethyl-5-methyl-3~(l-trityl-lH- tetrazol-5-yl)-2-pyrrolyl]benzyl]amino]benzoate(803. Img),acetic acid (12ml) and tetramethyl orthocarbonate(186.5μl)was stirred at room temperature for 2 hours under nitrogen atmosphere. Then water(lml) and chloroform(6ml) were added to the mixture,and stirred at 50°C for 1.5 hours. The reaction mixture was concentrated in vacuo. The residue was purified by a silica gel column chromatography(ethyl acetate)to give ethyl 3-[4-[l-ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2- pyrrolyl]benzyl]-2-methoxy-4-benzimidazolecarboxylate (529.7mg)as pale orange amorphous

NMR(CDC1₃, δ ) : 1.1K3H,t, M.5Hz), 1.30(3H,t, M.5Hz), 2.32(3H,s), 3.72(2H,q, M.5Hz), 4.23(2H,q,J=7.5Hz), 4.29(3H,s), 5.68(2H,s). 6.64(lH,s), 7.08(2H.d,J=8.5Hz), 7.2KlH,t, J=7.5Hz), 7.26(2H,d, J=8.5Hz), 7.58(lH.dd, M.5. 0.5Hz). 7.76(lH.dd,J=7.5,0.5Hz)

Example 39

The following compound was obtained according to a similar manner to that of Example 3.

3-[4-[l-Ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2-pyrrolyl]benzyl]-2- methoxy-4-benzimidazolecarboxylic acid. mp:175-178 °C

NMR(DMS0-dg, δ ) : 0.98(3H,t,M.5Hz), 2.27(3H,s), 3.69(2H,q,M.5Hz), 4.18(3H,s), 5.70(2H,s), 6.32(lH,s), 7.00(2H.d,J=8.5Hz), 7.19(lH.t, J=8.0Hz), 7.25(2H,d,J=8.5Hz)_i 7.53(1H,dd, J=8.0, 0.5Hz), 7.69C1H.dd,J=8.0.0.5Hz)

Example 40

The following compound was obtained according to a similar manner to that of Example 2.

Disodium salt of 3-[4-[l-ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2- pyrrolyl]benzyl]-2-methoxy-4-benzimidazolecarboxylic acid. mp:>280°C

NMR(DMS0-dg. δ ) : 1.00(3H,t,J=7.5Hz), 2.29(3H,s), 3.73(2H,q,M.5Hz), 4.19(3H,s), 5.59(2H,s), 6.37(1H,s), 7.12(2H,d.J=8.5Hz), 7.19(2H.d, ^' J=8.5Hz), 7.23(lH,t,J=8.0Hz), 7.3K1H,dd, J=8.0, 0.5Hz), 7.56(IH,dd,J=8.0,0.5Hz)

Example 41

The following compound was obtained according to a similar manner to that of Example 1.

Ethyl 3-[4-[l-ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2-pyrrolyl]benzyl] -2-propyloxy-4-benzimidazolecarboxylate. NMR(CDC1₃, δ ) : 1.02(3H, t, M.5Hz), 1. ll(3H,t, M.5Hz), 1.3K3H,t, M.5Hz), 1.90(2H,sextet, M.5Hz). 2.3K3H.S), 3.7K2H,q, M.5Hz),

4.24(2H,q,J=7.5Hz), 4.57(2H, t, M.5Hz), 5.68(2H, s), _.6.6K1H,s), 7.10 (2H,d,J=8.5Hz), 7.20(lH,t, J=8.0Hz), 7.25(2H,d,J=8.5Hz), 7.56(lH,dd, J=8.0, 0.5Hz), 7.72(lH,dd,J=8.0,0.5Hz)

Example 42

The following compound was obtained according to a similar manner to that of Example 3. 3-[4-[l-Ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2-pyrrolyl]benzyl]-2- propyloxy-4-benzimidazolecarboxylic acid. mp:135-144 °C

NMR(DMSO-dg, δ ) : 0.89(3H, t,M.0Hz), 0.98(3H,t, M.5Hz), 1.76(2H,sextet, M.OHz), 2.28(3H,s),

3.69(2H,q,J=7.5Hz), 4.49(2H,t. M.OHz), 5.70C2H, s), 6.32(lH,s), 7.03 (2H,d,J=8.5Hz), 7.17(lH,t, J=8.OHz), 7.23(2H,d,J=8.5Hz), 7.52(1H,dd,J=8.0, 0.5Hz), 7.63(IH,dd,J=8.0, 0.5Hz)

Example 43

The following compound was obtained according to a similar manner to that of Example 2.

Disodium salt of 3-[4-[l-ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2- pyrrolyl]benzyl]-2-propyloxy-4-benzimidazolecarboxylic acid. mp:>266 °C(dec.)

NMR(DMSO-dg. δ ) : 0.82(3H,t,J=7.5Hz), 0.96(3H,t, J=7.5Hz), 1.69(2H,sextet,J=7.5Hz), 2.23(3H,s),

3.64(2H.q,M.5Hz), 4.39(2H, t, M.5Hz), 5.92C2H, s), 6.09(lH,s), 6.98 (IH,t,J=8.OHz), 7.08(2H,d, J=8.5Hz), 7.20(2H,d,J=8.5Hz), 7.30QH,dd,J=8. 0, 0.5Hz). 7.35(lH.dd.J=8.0.0.5Hz)

Example 44 The following compound was obtained according to a similar manner to that of Example 1.

Ethyl 3-[4-[4, 5-dimethyl-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-2- ethoxy-4-benzimidazolecarboxylate

NMR (CDClg, 5) : 1.30(3H,t,J=7.5Hz), 1.50(3H,t, M.5Hz), 1.98(3H,s), 2. ll(3H,s), 4.23(2H,q,M.5Hz), 4.66(2H,q,M.5Hz). 5.68(2H,s), 6.98(lH,s), 7.08(2H,d,J=8.5Hz), 7.14(2H,d,J=8.5Hz), 7.19QH,t, J=8.OHz), 7.57QH,dd, J=8.0,0.5Hz), 7.69(IH,dd,J=8.0, 0.5Hz)

Example 45 The following compound was obtained according to a similar manner to that of Example 3.

3-[4-[4, 5-Dimethyl-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-2-ethoxy -4-benzimidazolecarboxylic acid. mp:> 260°C NMR (DMSO-dg, 5) : 1.25(3H,t,M.5Hz), 1.8K3H,s), 1.98(3H,s), 4.49(2H, q,M.5Hz), 5.91(2H,s), 6.18(lH,s), 7.00(4H,s), 7.08(1H,t, J=8. OHz), 7.48 (IH,dd,J=8.0, 0.5Hz), 7.56(1H,dd, J=8.0, 0.5Hz)

Example 46 The following compound was obtained according to a similar manner to that of Example 1.

Ethyl 3-[4-[5-chloro-4-methyl-2-(lH-tetrazol-5-yl)-l-pyrrolyl] benzyl]-2-ethoxy-4-benzimidazolecarboxylate

NMR (CDClg, 5) : 1.27(3H, t.M.5Hz). 1.45(3H,t,M.5Hz), 2.13(3H,s), 4. 17(2H,q,M.5Hz), 4.57(2H,q,M.5Hz), 5.66(2H,s), 7.00(lH,s), 7.0K2H,d, J=8.5Hz), 7. ll(2H,d,J=8.5Hz), 7.18(1H, t, J=8. OHz), 7.53(1H, dd, J=8.0, 0. ^' 5Hz), 7.60(lH,dd,J=8.0,0.5Hz)

Example 47 The following compound was obtained according to a similar manner to that of Example 3.

3-[4-[5-Chloro-4-methyl-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-2- ethoxy-4-benzimidazolecarboxylic acid mp : lδO-lθO'C NMR (DMSO-dg, 5) : 1.35(3H,t, J=7.5Hz), 2.07(3H, s), 4.59(2H,q, J=7.5Hz), 5.70(2H,s), 6.82(lH,s), 7.04(2H,d,J=8.5Hz), 7.17(1H, t, J=8. OHz), 7.20(2H, d,J=8.5Hz), 7.55(lH,dd,J=8.0,0.5Hz), 7.68(1H,dd, J=8.0, 0.5Hz)

Example 48 The following compound was obtained according to a similar manner to that of Example 2.

Disodium salt of 3-[4-[5-chloro-4-methyl-2-(lH-tetrazol-5-yl)-l- pyrrolyl]benzyl]-2-ethoxy-4-benzimidazolecarboxylic acid mp:> 260°C NMR (DMSO-dg, δ ) : 1.30(3H,t,J=7.5Hz), 2.0K3H,s), 4.48(2H,q,J=7.5Hz), 5. 92(2H, s), 6. 29(lH, s), 6. 97QH, t, J=8. OHz), 7. 0K2H, d, J=8. 5Hz), 7. 14(2H, d, J=8. 5Hz), 7. 30(lH, dd, J=8. 0, 0. 5Hz), 7. 34QH, dd, J=8. 0, 0. 5Hz)

Example 49 The following compound was obtained according to a similar manner to that of Example 1.

Ethyl 3-[4-[4-chloro-5-methyl-2-(lH-tetrazol-5-yl)-l-pyrrolyl] benzyl]-2-ethoxy-4-benzimidazolecarboxylate

NMR (CDClg, 5) : 1.29(3H,t,M.5Hz), 1.45(3H,t,M.5Hz), 2.03(3H,s), 4. 21(2H,q,M.5Hz), 4.6K2H,q,M.5Hz), 5.67(2H,s), 7.05(lH,s), 7.08(2H,d, J=8.5Hz), 7.12(2H,d,J=8.5Hz), 7.20(1H, t, J=8.OHz), 7.57QH, dd, J=8.0, 0. 5Hz), 7.66QH,dd,J=8.0,0.5Hz)

Example 50 The following compound was obtained according to a similar manner to that of Example 3.

3-[4-[4-Chloro-5-methyl-2-(lH-tetrazol-5-yD-1-pyrrolyl]benzyl]-2- ethoxy-4-benzimidazolecarboxylic acid mp : 156-159X NMR (CDgOD-CDCl₃, δ : 1.47(3H, t, M.5Hz), 2.04(3H,s), 4.62(2H,q,M. -5Hz), 5.69(2H,s), 6.87(lH,s), 7.09(4H,s), 7.20QH,t,J=8.OHz), 7.64C1H,dd, J=8.0,0.5Hz), 7.72(1H,dd,J=8.0, 0.5Hz)

Example 51 The following compound was obtained according to a similar manner to that of Example 2.

Disodium salt of 3-[4-[4-chloro-5-methyl-2-(lH-tetrazol-5-yl)-l- pyrrolyl]benzyl]-2-ethoxy-4-benzimidazolecarboxylic acid mp:> 260 NMR (DMSO-dg, S) : 1.28(3H,t,J=7.5Hz), 1.88(3H,s), 4.48(2H,q,M.5Hz), 5.93(2H,s), 6.29QH,s), 6.98(lH,t,J=8.0Hz), 7.03(2H,d,J=8.5Hz), 7.15(2H, d,J=8.5Hz), 7.30(lH,dd,J=8.0,0.5Hz), 7.35QH,dd, J=8.0,0.5Hz)

Example 52 . The following compound was obtained according to a similar manner to that of Example 1.

Ethyl 2-ethoxy-3-[4-[4-ethyl-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl] -4-benzimidazolecarboxylate

NMR (CDClg, <5) : 1.19(3H, t,M.5Hz), 1.26(3H, t, M.5Hz), 1.46(3H, t, J=7. 5Hz), 2.58(2H,q,M.5Hz), 4.09(2H,q, J=7.5Hz), 4.43(2H,q, J=7.5Hz), 5.59 (2H,s), 6.71(lH,d,J=0.5Hz), 6.81(2H,d, J=9.5Hz), 6.90(2H,d, J=9.5Hz), 7.00 (IH,d,J=0.5Hz), 7.09C1H,t, J=8. OHz), 7.21(lH,dd, J=8.0, 0.5Hz), 7.48(lH,dd, J=8.0,0.5Hz)

Example 53

The following compound was obtained according to a similar manner to that of Example 3.

2-Ethoxy-3-[4-[4-ethyl-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-4- benzimidazolecarboxylic acid mp : 178.5-180.5

NMR (CDClg-CDgOD, <5) : 1.23(3H,t,J=7.5Hz), 1.48(3H,t, J=7.5Hz), 2.54(2H, q,M.5Hz), 4.62(2H,q,M.5Hz), 5.68(2H,s), 6.82(2H,s), 7.04(2H,d, J=9. 5Hz), 7.11(2H,d,J=9.5Hz), 7.2K1H,t, J=8.0Hz), 7.66(lH,dd,J=8.0,0.5Hz), 7. 70(lH,dd,J=8.0,0.5Hz)

Example 54

The following compound was obtained according to a similar manner to that of Example 2.

Disodium salt of 2-ethoxy-3-[4-[4-ethyl-2-(lH-tetrazol-5-yl)-l- pyrrolyl]benzyl]-4-benzimidazolecarboxylic acid τnp:> 250°C

NMR (DMSO-dg, δ) : 1.14(3H,t, J=7.5Hz), 1.34(3H, t,J=7.5Hz), 2.42(2H,q, J= 7.5Hz), 4.48(2H,q, M.5Hz), 5.84(2H,s), 6.19(1H,d,J=0.5Hz), 6.67(lH,d,J= 0.5Hz), 6.95QH,t, M.5Hz), 6.96C2H,d, J=9.5Hz), 7.06(2H,d, J=9.5Hz), 7.29 (lH,dd,M.5,0.5Hz), 7.32QH,dd, M.5, 0.5Hz)

Example 55

The following compound was obtained according to a similar manner to that of Example 1. • Ethyl 2-ethoxy-3-[4-[4-propyl-2-(lH-tetrazol-5-yl)-l-pyrrolyl] benzyl]-4-benzimidazolecarboxylate mp : 123-128°C

NMR (CDClg, δ ) : 1.00C3H,t,J=7.5Hz), 1.18C3H,t, M.5Hz), 1.46(3H,t,M. 5Hz), 1.67(2H,sextet, M.5Hz), 2.5K2H,t,M.5Hz), 4.09(2H,q, M.5Hz), 4. 40(2H,q,M.5Hz), 5.60(2H,s), 6.7K1H,d,J=0.5Hz), 6.80(2H,d,J=9.5Hz), 6. 92(2H,d,J=9.5Hz), 6.99(lH,d, J=0.5Hz), 7.07(IH,t,M.5Hz), 7.2K1H,dd, M. 5, 0.5Hz), 7.48C1H,dd,J=7.5, 0.5Hz)

Example 56 The following compound was obtained according to a similar manner to that of Example 3.

2-Ethoxy-3-[4-[4-propyl-2-(lH-tetrazol-5-yD-1-pyrrolyl]benzyl]-4- benzimidazolecarboxylic acid mp : 170.5-173O NMR (CDClg-CDgOD, δ > : 0.98(3H,t,J=7.5Hz), 1.49(3H,t, M.5Hz), 1.63C2H, sextet,M.5Hz), 2.49C2H,t,M.5Hz), 4.63(2H,q,M.5Hz), 5,68(2H,s), 6.80 (2H,s), 7.04(2H,d,J=9.0Hz), 7. ll(2H,d,J=90Hz), 7.2K1H,t, J=8.OHz), 7.64 (IH,dd,J=8.0,0.5Hz), 7.70C1H,dd,J=8.0,0.5Hz)

Example 57

The following compound was obtained according to a similar manner to that of Example 2.

Disodium salt of 2-ethoxy-3-[4-[4-propyl-2-(lH-tetrazol-5-yl)-l- pyrrolyl]benzyl]-4-benzimidazolecarboxylic acid mp:> 250^

NMR (DMSO-dg, <5) : 0.92(3H, t, J=7.5Hz), 1.34(3H, t, J=7.5Hz), 1.55C2H, sextet,M.5Hz), 2.37(2H,t,J=7.5Hz), 4.48C2H,q,J=7.5Hz), 5.85(2H,s),.6.17 (IH,d, J=0.5Hz), 6.66QH,d, J=0.5Hz), 6.95(1H,t, J=8. OHz), 6.96C2H,d, J=8. 5Hz),7.04(2H,d,J=8.5Hz), 7.29QH,d,J=8.OHz), 7.31(lH,d,J=8.OHz)

Example 58

A mixture of 2-ethoxy-3-[4-[4-methyl-2-(l-trityl-lH-tetrazol-5-yl)-

1-pyrrolyl] benzyl] -4-benzimidazolecarboxylic acid (500. Omg), 1, 1 '- carbonyldiimidazole (354. 6mg) and tetrahydrofuran (5mg) was stirred at room temperature for 23 hours under nitrogen atmosphere. Then triethylamine (650.3ml) and glycine ethyl ester hydrochloride (610.5ml) were added to the mixture. The resulting suspension was stirred at room temperature for 11.5 hours and concentrated in vacuo. The residue was purified by column chromatography eluting with ethyl acetate-n-hexane to give N-ethoxycarbonylmethyl-2-ethoxy-3-[4-[4-methyl-2-(l-trityl-lH- tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxamide(352.4mg) as a white amorphous.

NMR (CDClg, δ ) : 1.2K3H,t, J=7.5Hz), 1.49(3H, t, J=7.5Hz), 2.13(3H, s), 3. 83(2H,d,J=6.0Hz), 4.12(2H,q,M.5Hz), 4.67(2H,q,M.5Hz), 5.46(2H,s), 6. 12(lH,t,J=6.0Hz), 4.67(lH,d,J=0.5Hz), 6.78-6.83(3H,m), 6.91-7.00(9H,m), 7.07-7. ll(2H,m), 7.19-7.68(9H,m)

Example 59

The following compound was obtained according to a similar manner to that of Example 13.

N-Ethoxycarbonylmethyl-2-ethoxy-3-[4-[4-methyl-2-(lH-tetrazol-5-yl)

-l-pyrrolyl]benzyl]-4-benzimidazolecarboxamide mp : 178-180.5°C

NMR (DMSO-dg, 5) : 1.19(3H,t, J=7.5Hz), 1.40(3H,t, M.5Hz), 2.09(3H,s), 3.9K2H,d,J=5.5Hz), 4. ll(2H,q,M.5Hz), 4.59(2H,q,M.5Hz),^' 5.4K2H, s),

6.68(lH,d,J=0.5Hz), 6.97QH,d,J=0.5Hz), 7.05(2H,d,J=9. OHz), 7.09-7.26(2H, m), 7.12(2H,d,J=9.0Hz), 7.57C1H,dd,J=8.0,0.5Hz), 8.82QH,t,J=5.5Hz)

Example 60 The following compound was obtained according to a similar manner to that of Example 2.

Sodium salt of ethyl 2-ethoxy-3-[4-[4-methyl-2-(lH-tetrazol-5-yl)-l -pyrrolyl]benzyl]-4-benzimidazolecarboxylate mp : 184-194°C

NMR (DMSO-dg, δ : 1.17(3H,t, J=7.5Hz), 1.4K3H,t, M.5Hz), 2.05(3H,s), 4.19(2H,q,J=7.5Hz), 4.6K2H,q,J=7.5Hz), 5.48(2H,s), 6.16(1H, d, J=0.5Hz), 6.65(lH,d,J=0.5Hz), 6.80(2H,d,J=9.0Hz), 7.02(2H,d,J=9. OHz), 7.19(lH,t,J= 8.0Hz), 7.46(lH,dd,J=8.0,0.5Hz), 7.69(lH,dd,J=8.0, 0.5Hz)

Example 61 The following compound was obtained according to a similar manner to that of Example 1.

Ethyl 3-[4-[4-methy1-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-2- propoxy-4-benzimidazolecarboxylate mp : 156-157.5°C

NMR (DMSO-dg, δ) : 0.92(3H,t,M.5Hz), 1.17(3H,t,M.5Hz), 1.70-1.90(2H, m), 2.09(3H,s), 4.19C2H,q, M.5Hz), 4.5K2H, t, M.5Hz), 5.53(2H,s), 6.70 QH,d,J=0.5Hz), 6.96C2H,d, J=9. OHz), 6.97QH,d, J=0.5Hz), 7.14C2H,d, J=9. 0Hz, 7.20(1H, t, J=8. OHz), 7.49(1H,dd, J=8.0, 0.5Hz), 7.70QH,dd, J=8.0, 0. 5Hz)

Example 62

The following compound was obtained according to a similar manner to that of Example 3. 3-[4-[4-Methyl-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-2-propoxy-4- benzimidazolecarboxylic acid mp : 169-1711:

NMR (DMSO-dg, S) : 0.92C3H,t,M.5Hz), 1.69-1.90(2H,m), 2.08(3H,s), 4.49

(2H,t,M.5Hz), 5.68(2H,s), 6.70QH,d,J=0.5Hz), 6.99(lH,d,J=0.5Hz), 7.00 (2H,d,J=9.OHz), 7.16(2H,d,J=9.0Hz), 7.19QH, t,J=8.OHz), 7.56(lH,dd,J=8.0,

0.5Hz), 7.67(lH,dd,J=8.0,0.5Hz)

Example 63

The following compound was obtained according to a similar manner to that of Example 2.

Disodium salt of 3-[4-[4-methyl-2-(lH-tetrazol-5-yl)-l-pyrrolyl] benzyl]-2-propoxy-4-benzimidazolecarboxylic acid

NMR (DMSO-dg, 5) : 0.89C3H,t,M.5Hz), 1.64-1.85(2H,m), 2.04(3H,s), 4.39

(2H,t,M.5Hz), 5.85(2H,s), 6.14QH,d, J=0.5Hz), 6.64(lH,d,J=0.5Hz), 6.97 (IH,t, J=8.OHz), 6.97(2H,d,J=9.0Hz), 7.07(2H,d,J=9.OHz), 7.28QH,dd,J=8.0,

0.5Hz), 7.32(1H,dd,J=8.0,0.5Hz)

0.5Hz), 7.67(1H,dd,J=8.0, 0.5Hz)

Example 64 - The following compound was obtained according to a similar manner to that of Example 1.

^{■■ ■} Ethyl 2-methoxy-3- [4- [4-methyl-2-(lH-tetrazol-5-yl)-l-pyrrolyl] benzyl]-4-benzimidazolecarboxylate mp : 151-153°C NMR (DMSO-dg, δ : 1. 15(3H, t, M. 5Hz), 2. 08(3H, s), 4. 18(3H, s), 4. 18(2H, q, M. 5Hz), 5. 54(2H, s), 6. 68QH, d, J=0. 5Hz), 6. 93(2H, d, J=9. OHz), 6. 96(1H, d, J=0. 5Hz), 7. 14(2H, d, J=9. OHz), 7. 20(1H, t, J=8. OHz), 7. 48(1H, dd, J=8. 0, 0. 5Hz), 7. 7K1H, dd, J=8. 0, 0. 5Hz)

Example 65

The following compound was obtained according to a similar manner to that of Example 3.

2-Methoxy-3-[4-[4-methyl-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-4- benzimidazolecarboxylic acid mp : 181-184.5

NMR (DMSO-dg, <5) : 2.08(3H,s), 4.18(3H,s), 5.69(2H,s), 6.70C1H,d, J=0. 5Hz), 6.98(2H,d,J=9.0Hz), 7. OOQH, d, J=0.5Hz), 7.14(2H, d,J=9. OHz), 7.20 (IH,t,J=8.OHz), 7.57(1H,dd,J=8.0,0.5Hz), 7.70(1H,dd, J=8.0,0.5Hz)

Example 66

The following compound was obtained according to a similar manner to that of Example 2.

Disodium salt of 2-methoxy-3-[4-[4-methyl-2-(lH-tetrazol-5-yl)-l- pyrrolyl]benzyl]-4-benzimidazolecarboxylate NMR (DMSO-dg, <5) : 2.03(3H,s), 4.07(3H, s). 5.88(2H,s), 6.14QH,d, J=0. 5Hz). 6.65(lH,d,J=0.5Hz), 6.97QH.t, J=8.OHz), 6.98(4H,s), 7.30QH,dd, J=8. 0,0.5Hz), 7.32(lH,dd,J=8.0,0.5Hz)

Example 67 The following compound was obtained according to a similar manner to that of Example 12. l-(Cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-3-[4-[4-methyl-2-(l- trityl-lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate NMR (CDClg, δ) : 1.15-2. OOdOH,m), 1.43(3H,d,J=4Hz). 1.44(3H,t, J=7.5Hz), 2-12(3H,s), 4.57(lH.m), 4.62(2H,q, M.5Hz), 5.56QH,d, J=20Hz), 5.65(1H, d, J=20Hz), 6. 63QH. br, s), 6. 79-7. 42(21H, m), 7.49(lH, dd, J=7. 5 and 1Hz), 7. 75(lH, dd, J=8 and 1Hz)

Example 68 The following compound was obtained according to a similar manner to that of Example 13.

l-(Cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-3-[4-[4-methyl-2-(lH- tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate NMR (CDClg, 5) : 0.83-2.02(10H,m), 1.45(3H,t,M.5Hz), 1.54(3H,d,J=4Hz), 2.18(3H,s), 4.39-4.76(3H,m), 5.60QH,d, M7.5Hz), 5.72QH,d, M7.5Hz), 6.74(lH,m), 6.78(1H,q,J=4Hz), 6.94(lH,m), 6.95(2H,d, J=9Hz), 7.02(2H,d,J= 9Hz), 7.18(1H,t,M.5Hz), 7.58C1H,dd. M.5 and 0.5Hz), 7.62(1H.dd.J=7.5 and 0.5Hz)

Example 69

The following compound was obtained according to a similar manner to that of Example 2.

Sodium salt of l-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-3~[4-[4- methyl-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate NMR (DMSO-dg. δ ) : 1.11-1.9K16H.m), 2.03(3H.s), 4.37-4.62(lH.m). 4.62 (2H.q,M.5Hz). 5.49(2H.s), 6.17QH.d,J=0.5Hz). 6.64(lH.d,J=0.5Hz), 6.79 QH,q,J=5.0Hz), 6.82(2H,d,J=9. OHz), 7.02(2H,d, J=9.OHz), 7.20(1H, t, J=7. 5Hz), 7.46(lH,dd,M.5.0.5Hz). 7.73QH.dd, M.5, 0.5Hz) _:

Example 70

The following compound was obtained according to a similar manner to that of Example 12. l-(Ethoxycarbonyloxy)ethyl 2-ethoxy-3-[4-[4-methyi-2-(1-trityl-lH- tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate

NMR (CDClg, δ : 1.28C3H, t, J=7.5Hz), 1.45(3H, t,M.5Hz), 1.46C3H,d, J= 5Hz),2.12(3H,s), 4.19(2H,q, M.5Hz), 4.63(2H,q,M.5Hz). 5.50(s,0.8H), 5. 61(s,1.2H), 6.53-6.65(2H,m), 6.78-7.44(2IH,m), 7.60QH,dd, J=9, IHz), 7.76 (IH,dd,J=9, IHz) Example 71

The following compound was obtained according to a similar manner to that of Example 13. l-(Ethoxycarbonyloxy)ethyl 2-ethoxy-3-[4-[4-methyl-2-(lH-tetrazol-5-yl)- l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate

NMR (CDClg, δ) : 1.22(3H,t,M.5Hz), 1.47(3H,t,M.5Hz), 1.54(3H,d,

J=5.5Hz). 2.17(3H,s), 4.13(2H,q, M.5Hz), 4.57(2H,q, M.5Hz), 5.60(lH,d,

J=15.5Hz), 5.77(lH,d,M5.5Hz), 6.70-6.83(2H,m), 6.94(2H,d,J=9.OHz), 6.95

(lH,d,J=0.5Hz), 7.02(2H.d,J=9.OHz). 7.17(1H, t, M.5Hz), 7.59C1H,dd,M.5, 0.5Hz), 7.63(lH,dd.M.5.0.5Hz)

Example 72

The following compound was obtained according to a similar manner to that of Example 2. Sodium salt of l-(ethoxycarbonyloxy)ethyl 2-ethoxy-3-[4-[4-methyl-2 -(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate NMR (DMSO-dg, δ ) : 1.20(3H,t,J=7.5Hz), 'l.40(3H,d,J=5.5Hz), , 1.4K3H, t, J= 7.5Hz), 2.04(3H,s). 4.16(2H,q,M.5Hz), 4.6K2H,q,M.5Hz), 5.49(2H.s), 6.16(lH.d,J=0.5Hz), 6.63(lH,d,J=0.5Hz), 6.79(lH,q,J=5.5Hz), 6.8K2H,d,J= 8.5Hz), 7.00(2H,d,J=8.5Hz), 7.2K1H,t,M.5Hz), 7.47(lH,dd,M.5, 0.5Hz), 7.73(1H,dd,J=7.5, 0.5Hz)

Example 73

To a stirred suspension of 3-[4-[4-methyl-2-(lH-tetrazol-5-yl)-l- pyrrolyl]benzyl]-2-ethoxy-4-benzimidazolecarboxylic acid (400mg) in dichloromethane (5ml) was added triethylamine (150 μl) and trityl chloride (302mg) at ambient temperature and the resulting suspension was stirred for 12 hours at the same temperature. The mixture was diluted with dichloromethane and washed with water and saturated sodium chloride. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to afford 2-Ethoxy-3-[4-[4-methyl-2-(l-trityl-lH- tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylic acid (706mg) as a amorphous solid. This compound was used in the next step without further purification. NMR (CDClg, δ ) : 1.30(3H, t,M.5Hz), 2.07(3H,s), 4.5K2H,q, M.5Hz), 5. 65(2H. s), 6. 41-8. 00(24H, m)

Example 74

To a stirred solution of 2-ethoxy-3-[4-[4-methyl-2-(l-trityl-lH- tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylic acid (706mg) in N,N-dimethylformamide (10ml) was added potassium carbonate (373mg) and iodomethyl pivalate (327mg) at ambient temperature and the resulting heterogeneous mixture was stirred at the same temperature for 4 hours. The mixture was diluted with ethyl acetate and washed with saturated ammonium chloride and saturated sodium chloride. After dried over magnesium sulfate, the organic layer was concentrated in vacuo and the residue was purified by flash chromatography eluting with ethyl acetate- n-hexane (1:3→1:2V/V) to give pivaloyloxymethyl 2-ethoxy-3-[4-[4-methyl -2-(l-trityl-lH-tetrazol-5-yl) -l-pyrrolyl]benzyl]-4- benzimidazolecarboxylate (647mg) as a colorless amorphous.

NMR (CDClg. S : 1.18(9H,s), 1.33(3H.t, M.5Hz), 2.13(3H,s), 4.62(2H,d, . M.5Hz). 5.65(2H.br.s), 6.80(2H.s), 6.56-7.44(20H.m). 7.63QH.dd. J=8 and 0.5Hz), 7.77(1H,dd.J=8 and 0.5Hz)

Example 75

To a stirred solution of pivaloyloxymethyl 2-ethoxy-3-[4-[4-methyl-

2-(1-trityl-lH-tetrazol-5-yl)-l-pyrrolyl] benzyl] -4- benzimidazolecarboxylate (788mg) in a mixed solvent (tetrahydrofuran- acetic acid-water=2:4:1 14ml) was stirred at ambient temperature for three hours and then at 50°C for 2 hours. The solvent was evaporated in vacuo and the residual solvent was removed azeotropically with toluene.

The residue was purified by flash chromatography eluting with ethyl acetate-n-hexane (1:1V/V) -ethyl acetate (2 times) to afford an amorphous solid which was suspended in water (10ml) and stirred vigorously at ambient temperature for three hours. The solid was filtered and dried to give pivaloyloxymethyl 2-ethoxy-3-[4-[4-methyl-2-(lH-tetrazol-5-yl)-l- pyrrolyl]benzyl]-4-benzimidazolecarboxylate (216mg) as a pale brown amorphous solid. mp : 81-90.5 NMR- (CDClg, δ ) : 1.18(9H,s), 1.46QH,t, M.5Hz), 2.18(3H.s), 4.56(2H.q. M.5Hz), 5.6K2H,s), 5.79(2H,s), 6.78QH, br, s), 6.94(1H, s), 6.97(2H,d, J =9Hz), 7.05(2H,d,J=9Hz), 7.17(1H, t, MHz), 7.59(2H, d, MHz)

Example 76 The following compound was obtained according to a similar manner to that of Example 74.

(5-Methyl-2-oxo-l, 3-dioxolen-4-yl)methyl 2-ethoxy-3- [4- [4-methyl-2- (l-trityl-lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate

NMR (CDClg, δ : 1.45(3H, t, M.5Hz), 2.04(3H,s), 2.17(3H,s), 4.63(2H,q, M.5Hz), 4.81(2H,s), 5.63(2H,s), 6.69(lH,s), 6.77-6.85(2H,m), 6.93-7.09 (8H,m). 7.18-7.36C11H, m), 7.60<1H, dJ=7.5Hz), 7.80(lH,dM.5Hz)

Example 77 The following compound was obtained according to a similar manner to that of Example75.

(5-Methyl-2-oxo-l, 3-dioxolen-4-yl)methyl 2-ethoxy-3- [4- [4-methyl-2- (lH-tetrazol-5-yl)-l-pyrrolyl] benzyl] -4-benzimidazolecarboxylate NMR (CDClg, 5) : 1.43(3H, t, M.5Hz), 2.17(6H.s), 4.54(2H,q, J=7.5Hz), 4. 90(2H.s), 5.16(2H,s), 6.79(lH,d, J=0.5Hz), 6.91(lH,d, J=0.5Hz), 6.93(2H,d, J=8.5Hz), 7.04(2H, d, J=8.5Hz), 7.17(1H, t, M.5Hz), 7.56QH, d. M.5Hz), 7. 58(lH.d.M.5Hz)

Example 78 The following compound was obtained according to a similar manner to that of Example 2.

Sodium salt of (5-Methyl-2-oxo-l, 3-dioxolen-4-yl)methyl 2-ethoxy-3-

[4- [4-methy 1-2- (lH-tetrazol-5-yl)- l-pyrrolyl] benzyl] -4- benzimidazolecarboxylate mp : 153-174^<

NMR (DMSO-dg, 5) : 1.4K3H, t, M.5Hz), 2.06(3H,s), 2.18(3H,s), 4.62(2H, q,M.5Hz), 5.13(2H,s), 6.17QH, d, J=0.5Hz), 6.66(lH,d, J=0.5Hz), 6.8K2H, d,J=8.5Hz), 7.0K2H, d, J=8.5Hz), 7.20(1H, t, J=8. OHz), 7.48(1H, dd, J=8.0, 0.

5Hz), 7.72(lH,dd,J=8.0,0.5Hz) Example 79

The following compound was obtained according to a similar manner to that of Example 74.

2-(Cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-3-[4-[4-methyl-2-Q- trityl-lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate NMR (CDClg. δ : 1.29-1.96(13H.m). 2.13(3H.s). 4.22-4.38(2H.m). 4.48-4. 70(4H,m), 5.49(4/3H,s), 5.61(2/3H,s), 6.53-6.69(4H,m), 6.77-7.46C17H,m), 7.57-7.64(lH,m), 7.72-7.82(2H,m), 8.OKIH,dd,J=8.0,0.5Hz)

Example 80

The following compound was obtained according to a similar manner to that of Example 75.

2-(Cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-3-[4-[4-methyl-2-(lH- tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate mp : 81.5-90.5°C

NMR (CDC1₃, δ : 1.14-2.21(10H,m), 1.47C3H,t,M.5Hz), 2.16(3H,s), 4.23 -4.32(2H,m). 4.34-4.43(2H,m), 4.47-4.69(lH.m), 4.6K2H,q, M.5Hz), 5.61 (2H,s), 6.76QH,s), 6.92(lH,s), 6.98(2H,d,J=8.5Hz), 7.07(2H.d.J=8.5Hz), 7.19(1H,t,J=8.OHz), 7.57C1H,d,J=8.OHz), 7.68(1H,d.J=8.OHz)

Example 81

The following compound was obtained according to a similar manner to that of Example 74. l-(Propionyloxy)ethyl 2-ethoxy-3-[4-[4-methyl-2 l-trityl-lH- tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate

NMR (CDClg, δ : 1.1K3H,t,M.5Hz). 1.40(3H,d, J=5.5Hz), 1.43(3H,t,M. 5Hz), 2.13(3H,s), 2.30(2H,q.M.5Hz), 4.62(2H,q, M.5Hz), 5.50(2/5H,s). 5.6K8/5H.S). 6.55-6.64(lH,m). 6.78-7.04(llH.m). 7.10-7.42(llH.m), 7.58 (IH,dd,J=8.0,0.5Hz), 7.77C1H,dd,J=8.0,0.5Hz)

Example 82

The following compound was obtained according to a similar manner to that of Example 75. l-(Propionyloxy)ethyl 2-ethoxy-3-[4-[4-methyl-2-(lH-tetrazol-5-yl)- l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate mp : 88-96°C

NMR (CDClg, 5 ) : 1. 0K3H, t, M. 5Hz), 1. 47C3H, t, J=5. 5Hz), 1. 5K3H, d, J=5. 5Hz), 2. 17(3H, s), 2. 29(2H, q, M. 5Hz), 4. 58(2H, q, M. 5Hz), 5. 59QH, d, M6. 5Hz), 5. 83(lH, d, M6. 5Hz), 6. 74(lH, _.d, J=0. 5Hz), 6. 88QH, q, J=5. 5Hz), 6. 93 (lH, d, J=0. 5Hz), 6. 97(2H, d, J=9. 0Hz), 7. 04(2H, d, J=9. OHz), 7. 18(1H, t, J=8. OHz), 7. 56-7. 68(2H, m)

Example 83

The following compound was obtained according to a similar manner to that of Example 1.

2-Ethoxy-3-[4-[4-methyl-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-4- nitrobenzimidazole

NMR (CDClg, δ : 1.54(3H, t,M.5Hz). 2.13(3H,s), 4.70(2H.q, M.5Hz), 5. 52(2H,s), 6.77(lH.d,J=0.5Hz), 6.93QH,d, J=0.5Hz), 7.00(2H,d,J=9. OHz), 7. 12(2H,d,J=9.0Hz), 7,22(1H,t,J=8. OHz), 7.67(1H,dd, J=8.0,0.5Hz), 7.78QH, dd,J=8.0,0.5Hz)

Example 84

The following compound was obtained according to a similar manner to that of Example 2.

Sodium salt of 2-ethoxy-3-[4-[4-methyl-2-(lH-tetrazol-5-yl)-l- pyrrolyl]benzyl]-4-nitrobenzimidazole

NMR (DMSO-dg, <5) : 1.43(3H,t, M.5Hz), 2.04(3H,s), 4.65(2H,q, J=7.5Hz), 5.39(2H,s), 6.17(lH,d,J=0.5Hz), 6.69(lH,d,J=0.5Hz), 6.84(2H,d,J=9.OHz), 7.03(2H,d,J=9.0Hz), 7.30(1H,t,J=8.OHz), 7.74(lH,dd,J=8.0, 0.5Hz), 7.88(1H, dd, J=8.0,0.5Hz)

Example 85

The following compound was obtained according to a similar manner to that of Example 74. l-(Pivaloyloxy)ethyl 2-ethoxy-3-[4-[4-methyl-2-(l-trityl-lH-tetrazol -5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate NMR (CDClg, δ : 1.18(9H,s), 1.39(3H,d, J=5.5Hz), 1.43(3H, t, M.5Hz), 2. 12(3H,s), 4.63(2H.q.M.5Hz). 5.62(2H.s). 6.61(lH,s), 6.78-7.06(12H,m), 7.11-7.43(10H,m), 7.57(1H,dd,J=8.0,0.5Hz), 7.76(1H,dd, J=8.0, 0.5Hz) Example 86

The following compound was obtained according to a similar manner to that of Example 75. l-(Pivaloyloxy)ethyl 2-ethoxy-3-[4-[4-methyl-2-(lH-tetrazol-5-yl)-l -pyrrolyl]benzyl]-4-benzimidazolecarboxylate mp : 91-99

NMR (CDClg, 5) : 1.12C9H,s), 1.45(3H,t, M.5Hz), 1.47(3H,d, J=5.5Hz), 2. 17(3H,s), 4.43-4.65(2H,m), 5.60(lH,d,J=15.5Hz), 5.78(lH,d, 5.5Hz), 6.74 (IH,d,J=0.5Hz), 6.83(1H,g, J=5.5Hz), 6.93(1H,d,J=0.5Hz)6.96(2H,d, J=9.OHz), 7.02(2H,d,J=9.OHz),7.17(IH,t, J=7.5Hz), 7.56(IH,dd,M.5,0.5Hz),7.60(IH, dd,J=7.5,0.5Hz) Example 87

The following compound was obtained according to a similar manner to that of Example 74. l-(Cyclohexylcarbonyloxy)ethyl 2-ethoxy-3-[4-[4-methyl-2-(l-trityl- lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate NMR (CDClg, δ : 1.10-1.49(6H,m), 1.39(3H,d, J=5.5Hz), 1.43(3H, t, J=7. 5Hz), 1.54-1.96(4H,m), 2.12(3H,s), 2.20-2.38QH,m), 4.6K2H,q,J=7.5Hz), 5.60(2H,s), 6.60QH,d,J=0.5Hz), 6.80(2H,d, J=9.0Hz), 6.87-7.05(8H,m), 7.12 -7.43(12H.m), 7.56QH,dd,J=7.5.0.5Hz). 7.76(lH,dd,M.5,0.5Hz) Example 88

The following compound was obtained according to a similar manner to that of Example 75. l-(Cyclohexylcarbonyloxy)ethyl 2-ethoxy-3-[4-[4-methyl-2-(1H- tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate mp : 89-98°C

NMR (CDC1₃, δ : 1.05-1.36(6H,m), 1.47(3H,t,M.5Hz), 1.49(3H,d,J=5.5Hz), 1.53-1.89(4H,m),2.11-2.3K1H,m),2.16(3H,s),4.58C2H,q,M.5Hz), 5.59C1H,d. J=16.OHz),5.80(IH,d,M6.OHz), 6.76(1H,d,J=0,5Hz), 6.87(1H,q,J=5,5Hz), 6. 92C1H,d,J=0,5Hz), 6.94(2H,d, J=9. OHz), 7.02(2H,d,J=9.0Hz)7.18C1H, t, J=7. 5Hz), 7.60(IH,dd, M.5, 0.5Hz),7.61(IH,dd,J=7.5,0.5Hz) Example 89

The following compound was obtained according to a similar manner to that of Example 74. - l-(Isobutyryloxy)ethyl 2-ethoxy-3-[4-[4-methyl-2-(l-trityl-lH- tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate

NMR (CDClg, δ ) : 1.15(3H,d, J=6.5Hz), 1.17C3H, d, J=6.5Hz), 1.40(3H, d, J=5.

5Hz), 1.45(3H,t,M.5Hz), 2.13(3H,s),2.52QH,septet, J=6.5Hz), 4.6K2H,q,

M.5Hz), 5.61(2H,s), 6.60(lH,d, J=0..5Hz), 6.82(2H,d, J=9. OHz), 6.83(lH,d, J=0.5Hz),6.87-7.06(9H,m), 7.10-7.44C10H,m,), 7.59(lH,dd,J=8.0,0.5Hz),7.76

(IH,dd, J=8.0, 0.5Hz)

Example 90

The following compound was obtained according to a similar manner to that of Example 75. l-(Isobutyryloxy)ethyl 2-ethoxy-3-[4-[4-methyl-2-(lH-tetrazol-5-yl)

-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate mp : 79-83.5°C

NMR (CDClg, 5) : 1.08(3H,d, J=6.5Hz), 1.09(3H,d, J=6.5Hz), 1.45(3H, t, J=7.

5Hz), 1.48(3H.d,J=5.5Hz), 2.16(3H,s),2.50QH,septet,J=6.5Hz), 4.49-4.64 (2H.m). 5.59(lH,d.J=16.0Hz). 5.80(lH,d.M6.OHz). 6.74(1H,d, J=0.5Hz), 6.

86(lH,q,J=5.5Hz). 6.95(lH,d,J=0.5Hz), 6.96(2H.d,J=9.OHz). 7.03(2H,d,J=9.

OHz), 7.18QH,t, J=8.OHz), 7.61(2H,d.J=8. OHz)

Example 91

The following compound was obtained according to a similar manner to that of Example 74. l-(Acetoxy)ethyl 2-ethoxy-3-[4-[4-methyl-2-(l-trityl-lH-tetrazol-5- yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate

NMR (CDClg. δ : 1.40(3H,d. J=5.5Hz). 1.43(3H,t,M.5Hz).2.03C3H,s), 2.11

(3H,s), 4.62(2H,q,J=7.5Hz), 5.62(2H,s), 6.62(lH,d, J=0..5Hz), 6.78-7.06 (12H,m), 7.12-7.4K10H,m), 7.60QH,dd,M.5,0.5Hz), 7.77(1H,dd, M.5,0.

5Hz)

Example 92

The following compound was obtained according to a similar manner to that of Example 75. l-(Acetoxy)ethyl 2-ethoxy-3-[4-[4-methyl-2-(lH-tetrazol-5-yl)-l- pyrrolyl]benzyl]-4-benzimidazolecarboxylate mp : 85-93.5°C

NMR (CDClg. 5) : 1.46(3H.t.J=7.5Hz), 1.52(3H,d.J=5.5Hz), 2.00(3H,s), 2.

15(3H,s), 4.60(2H,q.M.5Hz). 5.59(1H,d, J=16. OHz), 5.88(lH,d, M6. OHz), 6.75(lH,d,J=0.5Hz), 6.83(lH,q,J=5.5Hz), 6.95(1H,d,J=0.5Hz), 6.95(2H,d,J= 9.OHz). 7.03(2H,d,J=9.OHz),7.19C1H,t,J=7.5Hz),7.6K1H,dd,J=7.5,0.5Hz), 7.

65(lH,dd,M.5,0.5Hz)

Example 93

The following compound was obtained according to a similar manner to that of Example 74. l-(Butytyloxy)ethyl 2-ethoxy-3-[4-[4-methyl-2-(l-trityl-lH-tetrazol -5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate NMR (CDClg, δ) : 0.91(3H,t, J=7.5Hz), 1.41(3H,d, J=5.5Hz), 1.43(3H,t, J=7. 5Hz), 1.53-1.75(2H,m), 2.12(3H, s), 2.29(2H, t, J=7.5Hz), 4.62(2H.q, J=7. 5Hz), 5.61(2H,s), 6.61(lH,d, J=0.5Hz), 6.76-7.07C12H,m), 7.10-7.43C10H,m), 7.58C1H,dd, J=7.5.0.5Hz). 7.77(IH,dd, J=7.5, 0.5Hz) Example 94

The following compound was obtained according to a similar manner to that of Example 75. l-(Butytyloxy) thyl 2-ethoxy-3-[4-[4-methyl-2-(lH-tetrazol-5-yD-1- pyrrolyl]benzyl]-4-benzimidazolecarboxylate mp : 77-81O

NMR (CDClg, δ) : 0.84(3H,t,M.5Hz), 1.41-1.62(2H,m).1.47(3H.t,J=7.5Hz), 1.5K3H,d,J=5.5Hz), 2.17(3H,s), 2.23(2H,t,J=7.5Hz), 4.58C2H,q,J=7.5Hz), 5.60(lH,d,J=16.0Hz),5.84(lH,d,J=16.0Hz), 6.76QH,d, J=0.5Hz), 6.87QH.q, J=5.5Hz), 6.95(2H,d.J=9.0Hz), 6.97QH,d, J=0.5Hz), 7.02(2H,d,J=9. OHz), 7. 18(1H,t,J=7.5Hz), 7.6K2H,d, J=7.5Hz) Example 95

The following compound was obtained according to a.similar manner to that of Example 74. l-(Benzoyloxy)ethyl 2-ethoxy-3-[4-[4-methyl-2-Q-trityl-lH-tetrazol -5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate NHR (CDClg, δ : 1.44(3H, t,M.5Hz), 1.57(3H,d, J=5.5Hz), 2.13(3H,s), 4. 63(2H,q,M.5Hz), 5.62(2H,s), 6.57(1H,d,J=0.5Hz), 6.77(2H,d,J=9. OHz). 6. 81-6.97(9H,m), 7.11-7.57(14H,m), 7.63QH.dd, M.S.0.5Hz), 7.76QH,dd, M. 5,0.5Hz), 8.00(2H,dd,M.5,0.5Hz) Example 96

The following compound was obtained according to a similar manner to that of Example 75. ^• l-(Benzoyloxy)ethyl 2-ethoxy-3-[4-[4-methyl-2-(lH-tetrazol-5-yl)-l- pyrrolyl]benzyl]-4-benzimidazolecarboxylate mp : 93-103.5°C

NMR (CDClg, δ ) : 1.44C3H, t, M.5Hz), 1.60C3H,d, J=5.5Hz), 2.20(3H,s), 4. 49(2H,q,J=7.5Hz). 5.57(1H,d,J=17.OHz),5.79(1H,d,J=17.OHz), 6.70(1H,d,J=0. 5Hz), 6.84(2H,d,J=8.5Hz).6.89(2H.d,J=8.5Hz), 6.95(1H,d, J=0.5Hz), 7.09-7. 22(2H,m), 7.29-7.41(2H,m) 7.47(1H,d, M.5Hz), 7.57QH, t, M.5Hz), 7.64QH, d,M.5Hz), 7.89(2H,d,M.5Hz) Example 97

The following compound was obtained according to a similar manner to that of Example 74.

Propionyloxymethyl 2-ethoxy-3-[4-[4-methyl-2-(l-trityl-lH-tetrazol- 5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate NMR (CDClg, δ : 1.1K3H,t,M.5Hz), 1.43(3H,t, M.5Hz), 2.12(3H,s), 2.31 (2H,q,M.5Hz),4.63(2H,q.M.5Hz). 5.62(2H,s), 5.80(2H,s), 6.56-7.06Q2H, m), 7.10-7.43(10H,m), 7.64(lH,dd,M.5,0.5Hz), 7.77C1H,dd,M.5,0.5Hz) Example 98

The following compound was obtained according to a similar manner to that of Example 75.

Propionyloxymethyl 2-ethoxy-3-[4-[4-methyl-2-(lH-tetrazol-5-yl)-l- pyrrolyl]benzyl]-4-benzimidazolecarboxylate

NMR (CDClg, <5) : 1.10(3H,t,M.5Hz), 1.47C3H,t,M.5Hz), 2.17(3H,s), 2. 37(2H.q,M.5Hz), 4.56(2H,q,M.5Hz), 5.62(2H,s), 5.79(2H,s), 6.77(lH,d, J=0.5Hz), 6.94(lH,d,J=0.5Hz), 6.96(2H,d,J=9. OHz), 7.06(2H,d,J=9. OHz). 7. 18C1H,t, J=7.5Hz). 7.60X1H,dd, J=7.5,0.5Hz), 7.62(1H,dd, J=7.5, 0.5Hz) Example 99

The following compound was obtained according to a similar manner to that of Example 74.

Cyclohexylcarbonyloxymethyl 2-ethoxy-3-[4-[4-methyl-2-(l-trityl-lH- tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate NMR (CDClg, δ : 1.12-1.51(6H,m), 1.43(3H, t,J=7.5Hz), 1.52-1.78(2H,m), 1.79-1.96C2H,m), 2.13(3H,s), 2.20-2.38(lH,m), 4.62(2H,q, M.5Hz), 5.62 (2H,s), 5.79(2H,s), 6.66(1H,d, J=0.5Hz), 6.8K2H,d,J=9. OHz), 6.83(lH,d,J= 0.5Hz), 6.87-6.99(6H,m), 7.03(2H,d, J=9.OHz), 7.12-7.44(10H.m), 7.630H, dd, M.5,0.5Hz), 7.78QH,dd, M.5, 0.5Hz) Example 100 The following compound was obtained according to a similar manner to that of Example 75.

Cyclohexylcarbonyloxymethyl 2-ethoxy-3-[4-[4-methyl-2-(lH-tetrazol- 5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate NMR (CDClg, S) : 1.08-1.52C4H,m), 1.44(3H,t,M.5Hz), 1.56-1.78(4H,m), 1.79-1.93(2H,m), 2.17(3H,s), 2.20-2.39(lH,m). 4.56(2H,q,M.5Hz), 5.61 (2H.s), 5.76(2H,s), 6.77(lH,d, J=0.5Hz), 6.93(lH,d,J=0.5Hz), 6.94(2H,d,J= 9.0Hz), 7.03(2H,d,J=9.OHz), 7.17QH, t,M.5Hz), 7.57(lH,dd,M.5,0.5Hz), 7.59QH,dd,M.5,0.5Hz) Example 101

The following compound can be obtained according to a similar manner to that of Example 74.

Cyclohexyloxycarbonyloxymethyl 2-ethoxy-3-[4-[4-methyl-2-Q-trityl- lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate Example 102

The following compound can be obtained according to a similar manner to that of Example 75.

Cyclohexyloxycarbonyloxymethyl 2-ethoxy-3-[4-[4-methyl-2-(lH- tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate Example 103

The following compound can be obtained according to a similar manner to that of Example 74.

Ethoxycarbonyloxymethyl 2-ethoxy-3~[4-[4-methyl-2-(l-trityl-lH- tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate Example 104

The following compound can be obtained according to a similar manner to that of Example 75.

Ethoxycarbonyloxymethyl 2-ethoxy-3-[4-[4-methyl-2-(lH-tetrazol-5-yl) -l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate Example 105

The following compound can be obtained according to a similar manner to that of Example 74. tert-Butoxycarbonyloxymethyl 2-ethoxy-3-[4-[4-methyl-2-Q-trityl-lH -tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate Example 106 The following compound can be obtained according to a similar manner to that of Example 75. tert-Butoxycarbonyloxymethyl 2-ethoxy-3-[4-[4-methyl-2-(lH-tetrazol -5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate Example 107

The following compound can be obtained according to a similar manner to that of Example 74.

2-(Phthalid-3-ylidene)ethyl 2-ethoxy-3-[4-[4-methyl-2-(l-trityl-lH- tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate Example 108

The following compound can be obtained according to a similar manner to that of Example 75.

2-(Phthalid-3-ylidene)ethyl 2-ethoxy-3-[4-[4-methyl-2-(lH-tetrazol- 5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate Example 109

The following compound can be obtained according to a similar manner to that of Example 74. l-(l-Methylpiperidyl)carbonyloxyethyl 2-ethoxy-3-[4-[4-methyl-2-(l- trityl-lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate Example 110

The following compound can be obtained according to a similar manner to that of Example 75. l-(l-Methylpiperidyl)carbonyloxyethyl 2-ethoxy-3-[4-[4-methyl-2-(lH -tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate Example 111

The following compound was obtained according to a similar manner to that of Example 74. l-(Cyclopentylcarbonyloxy)ethyl 2-ethoxy-3-[4-[4-methyl-2-(l-trityl -lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate NMR (CDClg, δ ) : 1.40(3H,d. J=5.5Hz), 1.44(3H.t, M.5Hz), 1.50-1.90C8H, m). 2.13(3H.s), 2.61-2.77(lH,m), 4.62(2H,q,M.5Hz), 5.62(2H, s), 6.63QH, d,J=0.5Hz). 6.77-7.05(12H,m). 7.11-7.43C10H,m), 7.59(lH,dd,M.5,0.5Hz), 7.77(lH,dd,M.5,0.5Hz) Example 112 The following compound was obtained according to a similar manner to that of Example 75. l-(Cyclopentylcarbonyloxy) ethyl 2-ethoxy-3- [4- [4-methyl-2-(lH- tetrazol-5-yl) -l-pyrrolyl] benzyl] -4-benzimidazolecarboxylate NHR (CDClg, S) : 1. 39-1. 9K8H, m), 1. 46(3H, t, M. 5Hz), 1. 50C3H, d, J=7. 5Hz), 2. 16(3H, s), 2. 57-2. 75(lH, m), 4. 57(2H, q, J=7. 5Hz), 5. 60QH, d, J=16. 5Hz), 5. 81(lH, d, M6. 5Hz), 6. 75QH, d, J=0. 5Hz), 6. 87(lH, q, J=5. 5Hz), 6. 94 (IH, d, J=0. 5Hz), 6. 96C2H. d, J=9. OHz), 7. 02(2H, d, J=9. OHz), 7. 18(1H, t, J=7. 5Hz), 7. 60 (IH, dd, J=7. 5, 0. 5Hz), 7. 62 (IH, dd. J=7. 5, 0. 5Hz) Example 113 The following compounds can be obtained according to a similar manner to that of Example 74.

(1) Isobutyryloxymethyl 2-ethoxy-3- [4-[4-methyl-2-(l-trityl-lH-tetrazol -5-yl)-l -pyrrolyl] benzyl] -4-benzimidazolecarboxylate

(2) Butyryloxymethyl 2-ethoxy-3- [4- [4-methyl-2-(l-trityl-lH-tetrazol-5- yl) -l-pyrrolyl] benzyl] -4-benzimidazolecarboxylate

(3) (5-tert-Butyl-2-oxo-l, 3-dioxolen-4-yl)methyl 2-ethoxy-3-[4-[4-methyl -2- ( l -tri tyl - l H-tet ra zol -5 -yl ) - l -pyrro ly l ] benzy l ] -4 - benzimidazolecarboxylate

(4) (5-Phenyl-2-oxo-l, 3-dioxolen-4-yl)methyl 2-ethoxy-3-[4-[4-methyl-2- (l-trityl-lH-tetrazol-5-yl) -l-pyrrolyl] benzyl] -4-benzimidazόlecarboxylate

(5) Hethoxycarbonylmethyl 2-ethoxy-3- [4- [4-methyl-2-(l-trityl-lH- tetrazol-5-yl) -l-pyrrolyl] benzyl] -4-benzimidazolecarboxylate

(6) 2-1 sobutoxycarbonyl-2-pentenyl 2-ethoxy-3- [4- [4-methyl-2-Q-trityl- lH-tetrazol-5-yl) -l-pyrrolyl] benzyl] -4-benzimidazolecarboxylate Example 114

The following compounds can be obtained according to a similar manner to that of Example 75.

(1) Isobutyryloxymethyl 2-ethoxy-3-[4-[4-methyl-2-(lH-tetrazol-5-yl)-l- pyrrolyl] benzyl] -4-benzimidazolecarboxylate (2) Butyryloxymethyl 2-ethoxy-3-[4-[4-methyl-~2-(lH-tetrazol-5-yl)-l- pyrrolyl] benzyl] -4-benzimidazolecarboxylate

(3) (5-tert-Butyl-2-oxo-l. 3-dioxolen-4-yl)methyl 2-ethoxy-3-[4-[4-methyl -2-(lH-tetrazol-5-yl) -l-pyrrolyl] benzyl] -4-benzimidazolecarboxylate

(4) (5-Pheny 1-2-oxo-l, 3-dioxolen-4-yl)methyl 2-ethoxy-3-[4-[4-methyl-2- (lH-tetrazol-5-yl) -l-pyrrolyl] benzyl] -4-benzimidazolecarboxylate (5) Methoxycarbonylmethyl 2-ethoxy-3- [4- [4-methyl-2-(lH-tetrazol-5-yl)- 1-pyrrolyl] benzyl] -4-benzimidazolecarboxylate

(6) 2- I sobutoxycarbonyl-2-penteny 1 2-ethoxy-3- [4- [4-methy 1-2- (1H- tetrazol-5-yl) -l-pyrrolyl] benzyl] -4-benzimidazolecarboxylate

Claims

What we claim is :

1. A compound of the formula

wherein R is hydrogen, halogen, nitro, lower alkyl, lower alkoxy, amino or acylamino, R , R3 and R^ are each hydrogen, halogen, nitro, cyano, lower alkyl, lower alkenyl, lower alkylthio, mono or di or trihalo(lower)alkyl, oxo(lower)alkyl, hydroxy(lower)alkyl or optionally esterified carboxy; or R^ and R^ are linked together to form

1,3-butadienylene, R^ is hydrogen or imino-protective group, R" is lower alkyl,

R⁷ is nitro,optionally esterified or amidated carboxy or optionally substituted amino, A is lower alkylene,

Q is CH or N,

X is N or CH, Y is NH, 0 or S, and Z is S, S0₂ or 0,

and pharmaceutically acceptable salt thereof.

2. A compound of claim 1, which is represented by the formula

wherein R⁶ and A are each as defined in claim 1, R⁷ is optionally esterified carboxy, R⁹ is a group of the formula :

in which R⁵ is as defined in claim 1,

RI, RI and RI are each lower alkyl, and

Rb , R? and RI are each hydrogen, halogen or lower alkyl.

3.A compound of claim 2, which is represented by the formula

wherein R⁶, R⁷ and R⁹ are each as defined in claim 2.

4.A compound of claim 3, which is R^τ is carboxy, lower alkoxycarbonyl, lower alkoxycarbonyl(lower)alkoxycarbonyl, lower alkoxycarbonyl(lower)alkenyloxycarbonyl, lower alkanoyloxy(lower)alkoxycarbonyl, cycloalkylcarbonyloxy(lower)alkoxycarbonyl, benzoyloxy(lower)alkoxycarbonyl, lower alkylpiperidylcarbonyloxy(lower)alkoxycarbonyl, lower alkoxycarbonyloxy(lower)alkoxycarbonyl, cycloalkyloxycarbonyloxy(lower)alkoxycarbonyl, (5-lower alkyl-2-oxo-l, 3-dioxolen-4-yl)(lower)alkoxycarbonyl, (5-phenyl-2-oxo-l,3-dioxolen-4-yl)(lower)alkoxycarbonyl, phthalid-3-ylidene(lower)alkoxycarbonyl.

5.A compound of claim 4, which is represented by the formula :

wherein R⁶ and R⁷ are each as defined in claim 4, and RI is lower alkyl.

6. A process for preparing a compound of formula :

wherein R^ is hydrogen, halogen, nitro, lower alkyl, lower alkoxy, amino or acylamino, R% R and R^ are each hydrogen, halogen, nitro, cyano, lower alkyl, lower alkenyl, lower alkylthio, mono or di or trihalo(lower)alkyl, oxo(lower)alkyl, hydroxy(lower)alkyl or optionally esterified carboxy; or R^ and R^ are linked together to form 1, 3-butadienylene, R^ is hydrogen or imino-protective group,

R^b is lower alkyl,

R⁷ is nitro, optionally esterified or amidated carboxy or optionally substituted amino, A is lower alkylene, Q is CH or N,

X is N or CH, Y is NH, 0 or S, and Z is S, S0₂ or 0, or a salt thereof, which comprises

a) subjecting a compound of formula :

wherein R¹, R², R³, R\ R⁶, R⁷, \,Q,X,Y and Z are each as defined above, to- formation reaction of a tetrazole group, to give a compound of the formula

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, A,Q,X,Y and Z are each as defined above, or a salt thereof, or b) subjecting a compound of the formula:

wherein R¹, R², R³, R⁴, R⁵, R⁶, A,Q,X,Y and Z are each as defined above, and RI is esterified carboxy, or a salt thereof, to elimination of the ester moiety, to give a compound of the formula :

wherein R¹, R², R³, R⁴, R⁵, R⁶, A,Q,X,Y and Z are each as defined above, or a salt thereof, or

C) reacting a compound of the formula :

wherein R^s, R⁷ and Z are each as defined above, or a salt thereof, with a compound of the formula :

wherein R\ R², R³, R⁴, R⁵, A,Q,X,and Y are each as defined above, and R⁸ is acid residue, or a salt thereof, to give a compound of the formula :

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, A,Q,X and Z are each as defined above, or a salt thereof, or d) subjecting a compound of the formula:

wherein R¹, R², R³, R⁴, R⁶, R⁷, A,Q,X,Y and Z are each as defined above, and RI is imino-protective group, or a salt thereof, to removal of the imino-protective group, to give a compound of the formula :

wherein R¹, R², R³, R⁴, R^B, R⁷, A,Q,X,Y and Z are each as defined above, or a salt thereof, or e) subjecting a compound of the formula:

wherein R¹, R², R³, R⁴, R⁵, R⁶, A,Q,X,Y and Z are each as defined above, or its reactive derivative at the carboxy group, or a salt thereof, to amidation, to give a compound of the formula :

wherein R¹, R², R³, R⁴, R⁵, R\ A,Q,X,Y and Z are each as defined above, and b is amidated carboxy, or a salt thereof, or f) subjecting a compound of the formula:

wherein R¹, R², R³, R⁴, R⁵, R^B, A,Q,X,Y and Z are each as defined above, or its reactive derivative at the carboxy group, or a salt thereof, to esterification, to give a compound of the formula

wherein R\ R². R³, R⁴. R⁵. R⁶, A,Q,X,Y and Z are each as defined above, and RI is esterified carboxy, or a salt thereof, or g) subjecting a compound of the formula:

wherein R¹, R², R³, R⁴, R⁶, R⁷,A,Q,X,Y and Z are each as defined above, or a salt thereof, to introduction of the imino-protective group, to give a compound of the formula :

wherein R¹, R², R³, R\ R⁶, R⁷,A,Q,X,Y and Z are each as defined above, and RI is imino-protective group, or a salt thereof, or h) subjecting a compound of the formula:

wherein R R², R³, R⁴, R⁵, R⁶, A,Q,X,Y and Z are each as defined above, or its reactive derivative at the carboxy group, or a salt thereof, to the conversion reaction of carboxy to lower alkoxycarbonylamino to give a compound of the formula :

wherein R¹, R², R³, R⁴, R⁵, R^a, A,Q,X.Y and Z are each as defined above, and RI is lower alkoxycarbonylamino, or a salt thereof, or i) subjecting a compound of the formula:

wherein R\ R², R³, R⁴, R⁵, R⁷,A,Q,X and Y are each as defined above, or a salt thereof, to ring closure, to give a compound of the formula

wherein R\ R², R³, R⁴, R⁵. R⁶, R⁷, A,Q,X,Y and Z are each as defined above, or a salt thereof.

7. A pharmaceutical composition comprising a compound of claim 1 or pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable, substantially non-toxic carrier or excipient.

8. A method for treating or preventing angiotensin II mediated diseases, which comprises administering a compound of claim 1 or pharmaceutically acceptable salt thereof to human being or ^• animals.

9. A method for treating or preventing hypertension or heart failure, which comprises administering a compound of claim 1 or pharmaceutically acceptable salt thereof to human being or animals.

10. A compound of-claim 1 or pharmaceutically acceptable salt thereof for use as a medicament.

11. A compound of claim 1 or pharmaceutically acceptable salt thereof for use as an angiotensin II antagonist.

12. Use of a compound of claim 1 for manufacturing a medicament for treating or preventing angiotensin II mediated diseases.

13. A process for preparing a pharmaceutical composition which comprises admixing a compound of claim 1 with a pharmaceutically acceptable substantially non-toxic carrier or excipient.