GB2276166A - Benzimidazoles as angiotensin II antagonists - Google Patents

Abstract

Imidazole derivatives of the formula: <IMAGE> [wherein R<1> is C<1> to C<6> alkyl, R<2> is optionally esterified carboxy, R<3> is a group of the formula: <IMAGE> (in which R<4> is hydrogen or imino-protective group, and R<5>, R<6> and R<7> are each C1 to C6 alkyl), and A is C1 to C6 alkylene] and pharmaceutically acceptable salts thereof show angiotensin II antagonism and are useful for the treatment or prevention of diseases such as hypertension and heart failure in human beings and animals. Processes for preparing these compounds are also described, together with pharmaceutical compositions containing them.

Description

DESCRIPTION HETEROCYCLIC DERIVATIVES 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 II 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 Rl is lower alkyl, R2 is optionally esterified carboxy, R3 is a group of the formula:

in which R4 is hydrogen or imino-protective group, and R5, RS and R7 are each lower alkyl, and A is lower alkylene.

According to the present invention, the object compound (I) can be prepared by the following processes.

Process 1

(I-a) or a salt thereof Process 2

(I-b) or a salt thereof Process 3

Elimination of the ester moiety

(I-d) or a salt thereof Process 4

(I-f) or a salt thereof Process 5

Removal of the imino - protective group

or a salt thereof

(I-h) or a salt thereof Process 6

(I-d) or its reactive derivative at the carboxy group or a salt thereof

(I-c) or a salt thereof Process 7

(I-f) or a salt thereof

(I-e) or a salt thereof Process 8

(I-h) or a salt thereof

(I-g) or a salt thereof Process 9

Ring closure

(III) or a salt thereof

(I) or a salt thereof Process 10

(IV) (V) or a salt thereof or a salt thereof

(I) or a salt thereof Wherein R1 R2, R3, R4, R, R6, R7 and A are each as defined above, Ra2 is esterified carboxy, Rt is imino-protective group, 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" 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 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 "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, l-methoxyethyl ester, 1ethoxyethyl 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-butoxycarbonylmethyl ester, 2-tert-butoxycarbonyl-ethyl ester, 3-tert-butoxycarbonylpropyl ester, etc.),protected carboxysubstituted-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, 2,2,2trichloroethyl ester, etc.), lower alkanoyloxy(lower)alkyl ester [e.g.

acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1(or 2)-acetoxyethyl ester, 1(or 2 or 3)-acetoxypropyl ester, 1(or 2 or 3 or 4)-acetoxybutyl ester, 1(or 2)-propionyloxyethyl ester, 1(or 2 or 3)-propionyloxypropyl ester, 1(or 2)-butyryloxyethyl ester, 1(or 2)isobutyryloxyethyl ester, 1(or 2)-pivaloyloxyethyl ester, 1(or 2)hexanoyloxyethyl ester, isobutyryloxymethyl ester, 2ethylbutyryloxymethyl ester, 3, 3-dimethylbutyryloxymethyl ester, 1(or 2) -pentanoyloxyethyl ester, etc.J,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 ester1 heptadecanoyloxymethyl ester, stearoyloxymethyl ester, nonadecanoyloxymethyl ester, eicosanoyloxymethyl ester, 1(or 2) heptanoyloxyethyl ester, 1(or 2)-octanoyloxyethyl ester, 1(or 2)nonanoyloxyethyl ester, 1(or 2)-decanoyloxyethyl ester, l(or 2)undecanoyloxyethyl ester, l(or 2)-lauroyloxyethyl ester, 1(or 2)tridecanoyloxyethyl ester, l(or 2)-myristoyloxyethyl ester, 1(or 2)pentadecanoyloxyethyl ester, 1(or 2)-palmitoyloxyethyl ester, 1(or 2)heptadecanyloxyethyl ester, l(or 2)-stearoyloxyethyl ester, 1(or 2)nonadecanoyl-oxyethyl ester, 1(or 2)-eicosanoyloxyethyl ester, etc.], cycloalkylcarbonyloxy(lower)alkyl ester [e. g. cyclohexylcarbonyloxymethyl ester, 1(or 2) -cyclopentylcarbonyloxyethyl ester, 1 (or 2) cyclohexylcarbonyloxyethyl ester, etc, 3, aroyloxy (lower) alkyl ester such as benzoyloxy(lower)alkyl ester [e. g. 1 (or 2) -benzoyloxyethyl ester, etc, 3 heterocycliccarbonyloxy(lower)alkyl ester such as lower alkylpiperidylcarbonyloxy(lower)alkyl ester [e. g. 1 (or 2) -(1methylpiperidyl)carbonyloxyethyl, etc. 3, lower alkoxycarbonyloxy(lower) alkyl ester [e.g. methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, isopropoxycarbonyloxymethyl ester, tert-butoxycarbonyloxymethyl ester, 1(or 2)methoxycarbonyloxyethyl ester, 1(or 2)-ethoxycarbonyloxyethyl ester, 1(or 2)-propoxycarbonyloxyethyl ester, 1 (or 2)-isopropoxycarbonyloxyethyl ester, 1(or 2)-butoxycarbonyloxyethyl ester, 1(or 2)isobutoxycarbonyloxyethyl ester, 1(or 2)-tert-butoxycarbonyloxyethyl ester, 1(or 2)-hexyloxycarbonyloxy-ethyl ester, 1(or 2 or 3)methoxycarbonyloxypropyl ester, 1(or 2 or 3)-ethoxycarbonyloxypropyl ester, 1(or 2 or 3)-isopropoxycarbonyloxypropyl ester, 1(or 2 or 3 or 4) -ethoxycarbonyloxybutyl ester, 1(or 2 or 3 or 4)-butoxycarbonyloxybutyl ester, 1(or 2 or 3 or 4 or 5)-pentyloxycarbonyloxypentyl ester, 1(or 2 or 3 or 4 or 5)-neopentyloxycarbonyloxypentyl ester, 1(or 2 or 3 or 4 or 5 or 6)-ethoxycarbonyloxyhexyl ester, etc.], cycloalkyloxycarbonyloxy (lower)alkyl ester [e.g. cyclohexyloxycarbonyloxymethyl ester, 1(or 2)cyclopentyloxycarbonyloxyethyl ester, 1(or 2)cyclohexyloxycarbonyloxyethyl ester, etc. 3, (5-lower alkyl-2-oxo-1, 3 dioxol-4-yl) (lower)alkyl ester [e. g. (5-methyl-2-oxo-1, 3-dioxol-4-yl) methyl ester, (5-ethyl-2-oxo-1, 3-dioxol-4-yl)methyl ester, (5-propyl-2 oxo-l, 3-dioxol-4-yl)ethyl ester, etc.], (5-lower alkyl-2-oxo-1, 3-dioxolen -4-yl) (lower)alkyl ester [e. g. (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl ester, (5-tert-butyl-2-oxo-1, 3-dioxolen-4-yl)methyl ester, etc. ], (5 aryl-2-oxo-1, 3-dioxolen-4-yl) (lower)alkyl ester such as (5-phenyl-2-oxo1, 3-dioxolen-4-yl)(lower)alkyl ester [e.g. (5-phenyl-2-oxo-1, 3-dioxolen4-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, 1(or 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 dior tri-)phenyl(lower)alkyl (e.g.benzyl, benzhydryl, trityl, etc.), acyl such as lower alkoxycarbonyl (e.g.tert-butoxycarbonyl,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.

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-a) or a salt thereof can be prepared by subjecting the compound (II-a) 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 example, alkali metal azide(e.

g., potassium azide, sodium azide etc.), tri(lower)alkyltin azide(e.g.

trimethyltin 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.triethylamine, 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 (II-b) to the formation reaction of a tetrazole group.

This reaction can be carried out in substantially the same manner as Process 1.

Process 3 The object compound (I-d) or a salt thereof can be prepared by subjecting the compound (I-c) 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 4 The object compound (I-f) or a salt thereof can be prepared by subjecting the compound (I-e) 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, Nmethylpyrrolidine, N-methylmorpholine, 1, 5-diazabicyclo [4, 3, O]non-5-one, 1, 4-diazabicyclo [2, 2,2] octane, 1,5-diazabicyclo[5, 4, O]-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, sulfuric 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-h) or a salt thereof can be prepared by subjecting the compound (I-g) or a salt thereof to removal reaction of the imino-protective group.

This reaction can be carried out in substantially the same manner as Process4.

Process 6: The compound (I-c) or a salt thereof can be prepared by subjecting the compound (I-d) 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 -d) 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, sulfuric 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.

cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH3)2N+=CH-] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2, 4dinitrophenyl 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- (111)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, l-hydroxy-6- chloro-lll-benzotriazole, etc.), and the like.

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-1-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 react ion.

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

Process 7: The object compound (I-e) can be prepared by subjecting the compound (I-f) 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-f) 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,Ndimethylformamide 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 object compound (I-g) can be prepared by subjecting the compound (I-h) to introduction reaction of the imino protective group.

This reaction can be carried out in substantially the same manner as Process 7.

Process 9: The object compound (I) or a salt thereof can be prepared by subjecting the compound (III) 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-dimethylformamide 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.

Process 10: The object compound (I) or a salt thereof can be prepared by reacting the compound (IV) or a salt thereof with the compound (V) 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.

The starting compounds (II), (III) 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 purified in a conventional manner, for example, extraction 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 II antagonist and effective to various angiotensin II 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 andsor preventive agents for cardiopathy (e.g.angina pectoris, arrhythmia, myocardial 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 is 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, stearic 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 1-ethyl-2-(4methanesulfonyloxymethylphenyl) 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-1-ethyl-5- methyl-2-pyrrolyl)benzyl] amino]-3-nitrobenzoate (4.36g) as amorphous powder.

NMR(CDCl3, 6) : 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), 4.49(1H,d, J=14Hz), 4.94(1H,d,J=14Hz), 6.19(1H,s), 7.24(4H,s), 7.48(1H,t,J=8Hz), 7.87(1H,dd, J=8,2Hz), 8.09(1H,dd, J=8,2Hz) Preparation 2 To a solution of ethyl 2-[N-tert-butoxycarbonyl-[4-(3-cyano-1-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-1-ethyl-5-methyl -2-pyrrolyl)benzyl]amino]-3 -nitrobenzoate (3.18g) as yellow crystals.

mp:119-120 C NMR (CDCl3, #) : 1.20(3H,t,J=7Hz), 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), 6.21(1H,s), 6.74(1H, t, J=8Hz), 7.40(4H, s), 8.01(1H,dd,J=8.2Hz), 8.12(1H, dd, J=8.2Hz) Preparation 3 The following compound was obtained according to a similar manner to that of Preparation 1.

Ethyl 2-[N-[4-(2-cyano-4-methyl-1-pyrrolyl]benzyl]-N-tert- butoxycarbonyl-amino]-3-nitrobenzoate.

NMR (CDCl3, #) :1.33(3H, t, J=7.5Hz), 1.79(9H, s), 2.13(3H, s), 4.15 4.29(2H, M), 4.53(1H, d, J=14.5Hz), 4.88(1H, d, J=14.5Hz) 6.80(1H, d, J=0.

5Hz), 6.87(1H, d, J=0. 5Hz), 7.28(4H,s), 7.49(1H,t,J=8.OHz), 7.90(1H,dd,J= 8. 0, 0. 5Hz), 8. 09(111, dd, J=8. 0, 0. 5Hz) Preparation 4 The following compound was obtained according to a similar manner to that of Preparation 2.

Ethyl 2-[[4-(2-cyano-4-methyl-1-pyrrolyl)benzyl]amino]-3nitrobenzoate.

mp: 124.5-128 C NMR(CDCl3, # ) : 1. 1.39(3H,t,J=7.5Hz), 2.13(3H,s), 4.21(2H,s), 4. 35 (2H, q, J=7.5Hz), 6.75(1H, t, J=8.0Hz), 6.82(1H, d, J=0.5Hz), 6.88(1H, d, J=0.

5Hz), 7.41(4H,s), 8.00(111, dd, J=8. 0,1.0Hz), 8.14(1H, dd. J=8.0,1.OHz) Preparation 5 Ethyl 2-[[4-(3-cyano-1-ethyl-5-methyl-2-pyrrolyl)benzyl]amino]-3nitrobenzoate(2. 254g) was dissolved dimethylaniline(4.5ml) at 100 C under nitrogen atmosphere. Then butyryl chloride(0. 9ml) was added dropwise to the solution, and stirred at 100 C for 1.5 hours. After cooled to room temperature, ethyl acetate and water were added to the mixture. The organic layer was washed with water, and dried over magnesium sulfate, and evaporated in vacuo.The residue was purified by flash column chromatography (eluted by n-hexane~n-hexane-ethyl acetate=4:1 ~ 2:1) to afford ethyl 2-[N-butyryl-N-[4-(3-cyano-1-ethyl-5-methyl-2-pyrrolyl) benzyl]amino]-3-nitrobenzoate(2.722g) as a pale yellow oil.

NMR(CDCl3, #) : 0.90(3H, t, J=7Hz), 1.20(3H, t, J=7Hz), 1.32 (3H, t, J=7Hz), 1.

72(2H,m), 2.10(2H,m), 2.28(3H,s), 3.87(2H, q, J=7Hz), 4.20(2H,m), 4.52(1H, d,J=14Hz), 5.07(1H,d,J=14Hz), 6.20(1H,s), 7.17(2H,d,J=8Hz), 7.25(2H,d,J= 7Hz), 7.60(1H, t, J=8Hz), 7.90(1H, dd, J=8, 1Hz), 8.15(1H,dd, J=8, 1Hz) Preparation 6 Ethyl 2-[N-butyryl-N-[4-(3-cyano-1-ethyl-5-methyl-2-pyrrolyl)benzyl] amino]-3-nitrobenzoate(2.72g), iron(2.91g), acetic acid(6ml) and ethanol (12ml) were combined under nitrogen atmosphere, and refluxed for 6.5 hours. After cooled to room temperature, the mixture was filtered through a celite pad. The filtrate was concentrated in vacuo. Ethyl acetate and saturated sodium bicarbonate were added to the residue, and separated.

The organic layer was washed with water and brine, and dried over magnesium sulfate, and evaporated in vacuo. The solid was washed with diisopropyl ether to give ethyl 3-[4-(3-cyano-1-ethyl-5-methyl-2 pyrrolyl]benzyl] -2-propyl-4-benzimidazolecarboxylate(2. 174g) as white crystals.

mp : 130-132 C NMR(CDCl3, 6) : 1.08(3H, t, J=7Hz), 1.14(3H,t,J=7Hz), 1.20(3H,t,J=7Hz), 1.

95(2H, m), 2.27(3H, s), 2.98(2H, t, J=7Hz), 3.80(2H, q, J=7Hz), 4.20(2H, q, J= 7Hz), 5.87(2H,s), 6.20(1H,s), 6.94(2H,d,J=8Hz), 7.30(2H,d,J=8Hz), 7.32 (1H, t, J=7Hz), 7.70(1H, d, J=8Hz), 8.04(1H, d, J=8Hz) Preparation 7 The following compound was obtained according to a similar manner to that of Preparation 5.

Ethyl 2-[N-butyryl-N-[4-(2-cyano-4-methYS pyrrolyl)benzyl]amino] 3-nitrobenzoate NMR(CDCl3, #) : 0.88(3H, t, J=7.5Hz), 1.30(3H, t, J=7.5Hz), 1.52-1.84(2H, m), 1.99-2.17(2H, m), 2.12(3H, s), 4.06-4.25(2H, m), 4.62(1H, d, J=1.5Hz), 4.95 (1H, d, J=14.5Hz), 6.77(1H, d, J=0.5Hz), 6.85(1H, d, J=0.5Hz), 7.17(2H, d, J=9.

OHz), 7.28(2H, d, J=9.0Hz), 7.60(1H, t, J=8.0Hz), 7.93(1H, dd, J=8.0, 0.5Hz), 8.

13(1H, dd, J=8.0, 0.5Hz) Preparation 8 The following compound was obtained according to a similar manner to that of Preparation 6.

3-[4-(2-Cyano-4-methyl-1-pyrrolyl)benzyl]-2-propyl-4- benzimidazolecarboxylate mp : 154.5-159 C NMR(CDCl3, #) : 1.07(3H, t, J=7.5Hz), 1.21(3H, t, J=7.5Hz), 1.82-2.03(2H, m), 2.11(3H, s), 2.89(2H, t, J=7.5Hz), 4.19(2H, q, J=7.5Hz), 5.83(2H, s), 6.78(2H, s), 6.93(2H,d,J=9.OHz), 7.26(1H,t,J=8.OHz), 7.30(2H,d,J=9.OHz), 7.67(1H, dd, J=8. 0,0. 5Hz), 7. 96(1H, dd, 5=8. 0, 0. 5Hz) Example 1 Ethyl 3-[4-(3-cyano-1-ethyl-5-methyl-2-pyrrolyl]benzyl]-2-propyl-4 -benzimidazolecarboxylate(2.17g), trimethyltin azide (2. 95g) and xylene (22ml) were combined under nitrogen atmosphere, and stirred at 125 C for 60 hours.After cooled to room temperature, methanol(22ml), chloroform (llml) and silica gel(10. 9g) were added to the mixture. The mixture was stirred at room temperature for an hour, and filtered through a celite pad. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (eluted by dichloromethane-dichloromethane -methanol=50:1) to give ethyl 3-[4-[1-ethyl-5-methyl-3-(1H-tetrazol-5-yl) -2-pyrrolyl]benzyl]-2-propyl-4-benzimidazolecarboxylate(2.13g) as a white amorphous.

NMR(CDC13, 6) : 1.08(3H,t,J=7Hz), 1.10(3H,t,J=7Hz), 1.30(3H,t,J=7Hz), 1.

95(2H,m), 2.32(3H,s), 2.95(2H, t, J=7Hz), 3.73(2H,q,J=7Hz), 4.22(2H,q,J= 7Hz), 5.78(2H,s), 6.62(1H,s), 6.95(2H, dm J=8Hz), 7.24(2H,d,J=8Hz), 7. 26 (1H, J=8Hz), 7.62(1H, d, J=8Hz), 7.92(1H, d, J=8Hz) Example 2 Ethyl 3-[4-[1-ethyl-5-methyl-3-(1H-tetrazol-5-yl)-2-pyrrolyl]benzyl] -2-propyl-4-benzimidazolecarboxylate (995mg), 1N sodium hydroxide(6ml) and ethanol(l8ml) were combined and stirred under refluxing for 1. 5 hours.

After cooled to room temperature, concentrated in vacuo. The residue was dissolved in water. The pH value of the solution was adjusted to ~ 4 with 1N hydrochloric acid(6ml), and stirred at room temperature for 30 minutes. The solid was filtered off. The solid was washed with water, dried in vacuo at 60 C for an hour to give 3-[4-[l-ethyl-5-methyl-3-(1H- tetrazol-5-yl)-2-pyrrolyl]benzyl]-2-propyl-4-benzimidazolecarboxylic acid (856mg) as white crystals.

mp : 268-269"C (dec.) NMR(DMSO-d6, 6) : 0.95(3H,t,J=7Hz), 0.96(3H,t,J=7Hz), 1.77(2H,m), 2.29 (3H,s), 2.88(2H,t,J=7Hz), 3.68(2H,q,J=7Hz), 5.90(2H,s), 6.32(1H,s), 6. 90 (2H, d, J=8Hz), 7.17-7.30(3H), 7.60(1H, d, J=8Hz), 7.84(1H, d, J=8Hz) Example 3 3-[4-[1-Ethyl-5-methyl-3-(1H-tetrazol-5-yl)-2-pyrrolyl]benzyl]-2propyl-4-benzimidazolecarboxylic acid (376mg), 1N sodium hydroxide(1.6ml) and water(3ml) were combined, and dissolved. The mixture was filtered through milipore filter, and the filtrate was lyophilized to afford disodium salt of 3-[4-[1-ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2-pyrrolyl] benzyl]-2-propyl-4-benzimidazolecarboxylic acid (421mg) as a white powder.

NMR(D2O, #) : 0.92(3H, t, J=7Hz), 1.03(3H, t, J=7Hz), 1.76(2H, q), 2.30(3H, s), 2.92(2H, t, J=7Hz), 3.75(2H, q, J=7Hz), 5.80(2H, s), 6.37(1H, s), 6.97(2H, d, J =8Hz), 7.17(2H,d,J=8Hz), 7.26-7.38(2H), 7.71(1H, dd, J=8.2Hz) Example 4 The following compound was obtained according to a similar manner to that of Example 3.

Sodium salt of ethyl 3-[4-[1-ethyl-5-methyl-3-(1H-tetrazol-5-yl)-2- pyrrolyl]benzyl]-2-propyl-4-benzimidazolecarboxylate NMR(MSO-d6, #) : 0.64(3H, t, J=7Hz), 0.85(6H, t, J=7Hz), 1.63(2H, m), 2.08 (3H s), 2.74(2H, t, J=7Hz), 3.26(2H, q, J=7Hz), 3.87(2H, q, J=7Hz), 5.43(2H, s), 6.28(1H,s), 6.60(2H,d,J=8Hz), 6.84(2H,d,J=8Hz), 6.92(1H,t,J=8Hz), 7. 17 (1H, d, J=8Hz), 7.67(1H, d, J=8Hz) Example 5 The following compound was obtained according to a similar manner to that of Example 1.

Ethyl 3-[4-[4-methyl-2-(1H-tetrazol-5-yl)-1-pyrrolyl]benzyl]-2propyl-4-benzimidazolecarboxylate mp : 179-184 C NMR(CDCl3, #) : 0.96(3H, t, J=7.5Hz), 1.2093H, t, J=7.5Hz), 1.60-1.82(2H, m), 2.18(3H, s), 2.54(2H, T, J=7.5Hz), 4.11(2H, q, J=7.5Hz), 5.60(2H, s), 6.63(2H, d,J=9.OHz), 6.70(1H,d,J=0.5Hz), 6.86(2H, d, J=9.0Hz), 6.90(1H,d,J=0.5Hz), 7.19(1H, t, J=8.0Hz), 7.42(1H, dd, J=8.0, 0.5Hz), 7.59(1H, dd, J=8.0, 0.5Hz) Example 6 The following compound was obtained according to a similar manner to that of Example 2.

3-[4-[4-Methyl-2-(1H-tetrazol-5-yl)-1-pyrrolyl]benzyl]-2-propyl-4benzimidazolecarboxylic acid mp : 267-271 C NMR(DMSO-d6, 6) : 0.96(3H,t,J=7.5Hz), 1.62-1.91(2H,m), 2.08(3H,s), 2.83 (2H,t,J=7.5Hz), 5.90(2H,s), 6.70(1H, d, J=0.5Hz), 6.84(2H,d,J=9.OHz), 6. 98 (1H, d, J=0.5Hz), 7.13(2H,d,J=9.OHz), 7.23(1H,t,J=8.OHz), 7.62(1H,dd,J=8.0, 0. 5Hz), 7. 85(1H, dd, J=8. 0, 0. 5Hz) Example 7 The following compound was obtained according to a similar manner to that of Example 3.

Disodium salt of 3-[4-[4-methyl-2-(lH-tetrazol-5-yl)-1-pyrrolyl] benzyl]-2-propyl-4-benzimidazolecarboxylic acid NMR(DMSO-d6, 6) : 0.92(3H,t,J=7.5Hz), 1.62-1.83(2H,m), 2.04(3H,s), 2.67 (2H,t,J=7.5Hz), 6.11(2H,s), 6.16(1H,d,J=0.5Hz), 6.64(1H,d,J=0.5Hz), 6. 86 (2H,d,J=9.OHz), 6.97(2H,d,J=9.OHz), 7.03(1H,t,J=8.OHz), 7.38(1H, dd, J=8.0, 0. 5Hz), 7. 47(1H, dd, 5=8. 0, 0. 5Hz) Example 8 The following compound was obtained according to a similar manner to that of Example 3.

Sodium salt of ethyl 3-[4-[4-methyl-2-(lH-tetrazol-5-yl)-1-pyrrolyl] benzyl] -2-propyl-4-benzimidazolecarboxylate NMR(DMSO-d6, #) : 0.99(3H, t, J=7.5Hz), 1.13(3H, t, J=7.5Hz), 1.71-1.92(2H, m), 2.05(3H,s), 2.88(2H,t,J=7.5Hz), 4.13(2H, q, J=7.5Hz), 5.67(2H,s), 6. 15 (1H, d, J=0.5Hz), 6.63(1H,d,J=0.5Hz), 6.68(2H,d,J=9.OHz), 7.02(2H,d,J=9.

OHz), 7.24(1H, t, J=8.0Hz), 7. 50(111, dd, J=8. 0, 0. 5Hz), 7. 86(1H, dd, J=8. 0, 0.

5Hz) Example 9 3-[4-[4-Methyl-2-(1H-tetrazol-5-yl)-1-pyrrolyl]benzyl]-2-propyl-4benzimidazolecarboxylic acid(268. lmg), dichloromethane(3ml), triethylamine(109.4g 1) and trityl chloride(203.2mg) were combined under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 3 hours, poured into water and extracted with chloroform (twice). The combined organic layer was washed with brine, and dried over magnesium sulfate, and evaporated to give 3-[4-[4-methyl-2-(1-trityl-1H -tetrazol-5-yl)-1-pyrrolyl]benzyl]-2-propyl-4-benzimidazolecarboxylic acid (528.0mg) as white amorphous.

NMR(CDC13, 6) : 0.92(3H,t,J=7.5Hz), 1.69-1.91(2H,m), 2.13(3H,s), 2.66(2H, t,J=7.5Hz), 5.98(2H,s), 6.61(1H, d, J=0.5Hz), 6.73-6.83(3H,m), 6.84-7.07 (8H,m), 7. 10-7. 40(1011, m), 7. 66(111, dd, J=7. 5Hz), 7.80(1H, dd, J=7.5Hz) Example 10 3-[4-[4-Methyl-2-(1-trityl-1H-tetrazol-5-yl)-1-pyrrolyl]-benzyl]-2 -propyl-4-benzimidazolecarboxylic acid(523.2mg) was dissolved in dimethylformamide(5ml) under nitrogen atmosphere. Then potassium carbonate(338.4mg) and 1-(propionyloxy)ethyl chloride(261.3mg) in dimethylformamide(2. 5ml) were added to the solution at room temperature.

The reaction mixture was stirred at room temperature for 5 hours, and poured into water and extracted with ethyl acetate. The combined organic layer was washed with water(twice) and brine, dried over magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (eluted by ethyl acetate : n-hexane = 1:2) to give 1 (propionyloxy)ethyl 3-[4-[4-methyl-2-(1-trityl-lH-tetrazol-5-yl)-1- pyrrolyl]benzyl]-2-propyl-4-benzimidazolecarboxylate (344.1mg) as white amorphous.

NMR(CDCl3, 6) : 0.98(3H,t,J=7.5Hz), 1.11(3H,t,J=7.5Hz), 1.36(3H,d,J=5.

5Hz), 1.76-1.97(2H,m), 2.13(3H,s), 2.30(2H,q,J=7.5Hz), 2.76(2H,t,J=7.

5Hz), 5.60(1H, d, J=16.0Hz), 5.83(1H, d, J=16.0Hz), 6.59-6.69(3H, m), 6.83(1H, d, J=1.5Hz), 6.89-7.07(9H, m), 7.16-7.36(10H, m), 7.68(1H, dd, J=8.0, 0.5Hz), 7. 99(1H, dd, 5=8. 0, 0. 5Hz) Example 11 1-(Propionyloxy)ethyl 3-[4-[4-methyl-2-(1-trityl-1H-tetrazol-5-yl) -1-pyrrolyl]benzyl]-2-propyl-4-benzimidazolecarboxylate(338.0mg),acetic acid(4ml), tetrahydrofuran(2ml) and water(lml) were combined and stirred at 50 C for 2 hours. After cooled to room temperature, the mixture was concentrated in vacuo with toluene. The residue was purified by silica gel column chromatography (eluted by ethyl acetate : n-hexane = 1:1 then ethyl acetate : dichloromethane = 1:2) to give a colorless oil. The oil was solified with water to afford l-(propionyloxy)ethyl 3-[4-[4-methyl 2- (lH-tetrazol-5-yl)-1-py rrolyl] be nzyl] -2-propyl-4 - benzimidazolecarboxylate(173. 3mg) as white solid.

mp : 83-92 C NMR(CDCl3, #) : 1.00(3H, t, J=7.5Hz), 1.02(3H, t, J=7.5Hz), 1.50(3H, d, J=5.

OHz), 1.73-1.94(2H,m), 2.17(3H,s), 2.29(2H,q,J=7.5Hz), 2.76(2H,t,J=7.

5Hz), 5.63(1H, d, J=16.5Hz), 5.99(1H, d, J=16.5Hz), 6.75(1H, d, J=1.0Hz), 6.79 (2H,d,J=9.OHz), 6.87(1H,q,J=5.OHz), 6.93(1H, d, J=1.0Hz), 7.00(2H,d,J=9.

OHz), 7.28(1H, t, J=8.0Hz), 7.71(111, dd, J=8. 0,0.5Hz), 7.81(111, dd, J=8. 0,0.

5Hz) Example 12 The following compound was obtained according to a similar manner to that of Example 9.

3-[4-[1-Ethyl-5-methyl-3-(1-trityl-lH-tetrazol-5-yl)-2-pyrrolyl] benzyl]-2-propyl-4-benzimidazolecarboxylic acid NMR(CDCl3, #) : 0.90(3H, t, J=7.5Hz), 1.04(3H, t, J=7.5Hz), 1.67-1.86(2H, m), 2.29(3H, s), 2.71(2H, t, J=7.5Hz), 3.68(2H, q, J=7.5Hz), 6.05(2H, s), 6.44(1H, s), 6.91-7.08(9H, m), 7.12-7.39(11H, m), 7.68(1H, dd, J=7.5Hz), 7.76(1H, dd, J =7.5Hz) Example 13 The following compound was obtained according to a similar manner to that of Example 10.

1-(Propionyloxy)ethyl 3-[4-[1-ethyl-5-methyl-3-(1-trityl-1H-tetrazol -5-yl)-2-pyrrolyl]benzyl]-2-propyl-4-benzimidazolecarboxylate NMR(CDCl3, #) : 0.98(3H, t, J=7.5Hz), 1.06(3H, t, J=7.5Hz), 1.10(3H, t, J=7.

5Hz), 1.35(3H,d,J=5.5Hz), 1.73-1.96(2H, m), 2.29(3H,s), 2.30(2H,q,J=7.

5Hz), 2.78(2H, t, J=7.5Hz), 3.70(2H, q, J=7.5Hz), 5.61(1H, d, J=16.0Hz), 5.93 (1H, d, J=16.0Hz), 6.50(1H, s), 6.74(2H, d, J=8.0Hz), 6.91-7.08(7H, m), 7.13-7.

38(12H, m), 7.69(1H, dd, J=7.5, 0.5Hz), 7.99(1H, dd, J=7.5, 0.5Hz) Example 14 The following compound was obtained according to a similar manner to that of Example 11.

1-(Propionyloxy)ethyl 3-[4-[1-ethyl-5-methyl-3-(1H-tetrazol-5-yl)-2 -pyrrolyl]benzyl]-2-propyl-4-benzimidazolecarboxylate mp : 84-91 C NMR(CDCl3, 6) : 1.00(3H, t, J=7.5Hz), 1.06(3H,t,J=7.5Hz), 1.11(3H,t,J=7.

5Hz), 1.54(3H, d, J=5.5Hz), 1.83-2.04(2H, m), 2.27(2H, q, J=7.5Hz), 2.31(3H, s), 2.90(2H, T, J=7.5Hz), 3.71(2H, q, J=7.5Hz), 5.72(1H, d, J=16.0Hz), 6.07(1H, d, J=16.0Hz), 6.60(1H, s), 6.94(1H, Q, J=5.5Hz), 7.01(2H, d, J=9.0Hz), 7.23(2H, d, J=9.0Hz), 7.30(1H, t, J=8.0Hz), 7.73(1H, dd, J=8.0, 0.5Hz), 7.97(1H, dd, J=8.

0, 0. 5Hz)

Claims (9)

1. What we claim is 1. A compound of the formula

   wherein Rl is lower alkyl, R2 is optionally esterified carboxy, R3 is a group of the formula:

   in which R4 is hydrogen or imino-protective group, and R5, Rs and R7 are each lower alkyl, and A is lower alkylene, and pharmaceutically acceptable salt thereof.
2. 2. A process for preparing a compound of the formula

   wherein R' is lower alkyl, R2 is optionally esterified carboxy, R3 is a group of the formula:

   in which R4 is hydrogen or imino-protective group, and R5, RB and R7 are each lower alkyl, and A is lower alkylene, or a salt thereof, which comprises a) subjecting a compound of the formula

   wherein R1, R2, R5 and A are each as defined above, to formation reaction of a tetrazole group, to give a compound of the formula

   wherein Rl, R2, R4, R5 and A are each as defined above, or a salt thereof, or b) subjecting a compound of the formula::

   wherein Rl, R2, R6, R7 and A are each as defined above, to formation reaction of a tetrazole group, to give a compound of the formula

   wherein R', R2, R4, R6, R7 and A are each as defined above, or a salt thereof, or c) subjecting a compound of the formula:

   wherein Rl, R3 and A are each as defined above, and Ra2 is esterified carboxy, or a salt thereof, to elimination of the ester moiety, to give a compound of the formula

   wherein R', R3 and A are each as defined above, or a salt thereof, or d) subjecting a compound of the formula::

   wherein R', R2, R5 and A are each as defined above, and Ra4 is imino-protective group, or a salt thereof, to removal of the imino-protective group, to give a compound of the formula

   wherein Rl, R2, R5 and A are each as defined above, or a salt thereof, or e) subjecting a compound of the formula:

   wherein R, R2, RB, R7 and A are each as defined above, and R is imino-protective group, or a salt thereof, to removal of the imino-protective group, to give a compound of the formula

   wherein R', R2, R6, R7 and A are each as defined above, or a salt thereof, or f) subjecting a compound of the formula::

   wherein R', R3 and A 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 Rl, R3 and A are each as defined above, and Ra2 is esterified carboxy, or a salt thereof, or g) subjecting a compound of the formula:

   wherein R, R2, R5 and A 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, R5 and A are each as defined above, and R is imino-protective group, or a salt thereof, or h) subjecting a compound of the formula::

   wherein R', R2, R6, R7 and A are each as defined above, or a salt thereof, to introduction of the imino-protective group, to give a compound of the formula

   wherein Rl, R2, R6, R7 and A are each as defined above, and R is imino-protective group, or a salt thereof, or i) subjecting a compound of the formula::

   wherein R1, R2, R3 and A are each as defined above, or a salt thereof, to ring closure, to give a compound of the formula

   wherein R1, R2, R3 and A are each as defined above, or a salt thereof, or j) reacting a compound of the formula

   wherein R',and R2 are each as defined above, or a salt thereof, with a compound of the formula

   wherein R3 and A are each as defined above, and R8 is acid residue, or a salt thereof, to give a compound of the formula

   wherein Rl, R2, R3 and A are each as defined above, or a salt thereof.
3. 3. 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.
4. 4. 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.
5. 5. 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.
6. 6. A compound of claim 1 or pharmaceutically acceptable salt thereof for use as a medicament.
7. 7. A compound of claim 1 or pharmaceutically acceptable salt thereof for use as an angiotensin II antagonist.
8. 8. Use of a compound of claim 1 for manufacturing a medicament for treating or preventing angiotensin II mediated diseases.
9. 9. 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.