IL115437A - N-benzyl- 2-alkylbenzimidazole derivatives, their production and pharmaceutical compositions containing them - Google Patents

Description

N-BENZYL-2-ALKYLBENZIMIDAZOLE DERIVATIVES, THEIR PRODUCTION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM inix D^'.nn ηιπ]7η 'τκαηι inx? ,"7i TNTI_->T:I:.-,7'7,7N-2-,7->T-I:I- Ϊ) nn^i TAKEDA CHEMICAL INDUSTRIES LTD.

C: 23130 1 15437/3 FIELD AND BACKGROUND OF THE INVENTION This application is a divisional of Israel Patent Application No. 95975. The invention it describes concerns intermediates of formula XVII, that are used to prepare the l-benzyl-2-alkylbenzimidazoles that are the subject of the invention in Israel Patent Application No. 95975 The renin-angiotensin system is involved in "the homeostasis controlling_systemic blood pressure, body fluid volume, and balance among the electrolytes, together with the aldosterone system. The relation between the renin-angiotensin system and hypertension has been clarified based on the fact that an inhibitor of an angiotensin II (All) converting enzyme (ACE inhibitor) which produces angiotensin II havinga -potent vasoconstrictive action has been developed, Since angiotensin II elevates blood pressure via the angiotensin II receptors on the cellular membrane, the antagonists of angiotensin II, like ACE inhibitors, can be used for the treatment of hypertension. Host angiotensin-II related substances, such as saralasin and [Sar^, Ala^]AII, have been reported to have potent angiotensin II antagonism. However, the peptide antagonists have been reported to be of short duration of the action after parenteral administration and to be ineffective in oral administration [M.A. Ondetti and D.W. Cushman, Annual Reports in Medicinal Chemistry, 11 . 82-91 ( 1978) .

On the other hand, for solving the problems observed in these peptide antagonists, non-peptide angiotensin II antagonists have been investigated. As one of the earliest studies in this field, imidazole derivatives having angiotensin II antagonism were disclosed in Japanese Patent Unexamined Publication Nos . 71073/ 1981 , 71074/1981 , 92270/1982 and 157768/1 83 , USP 4 .355 , 040 and USP 4 , 340 , 5 8. Later, improved imidazole derivatives were disclosed in EP 0253310 (corresponding to' IL 83153 ) , EP O2 1969 (corresponding to IL 86456 ) . EP 0324377 , Japanese Patent Unexamined 1 1 5437/2 Publication Nos. 23863/1988 and H7876/I989 . Also, pyrrole, pyrazole and triazole derivatives were disclosed in EP 0323841 (corresponding to IL 889OI ) and Japanese Patent Unexamined Publication No. 287071/1989 as angiotensin II antagonists.

The present inventors have 'concluded 1. at clinically useful compounds for the therapy of circulatory diseases such as hypertension, cardiac diseases and cerebral apoplexy require angiotensin II receptor antagonism and should show a strong angiotensin II antagonism and hypotensive action on oral administration thereof .and .therefore have been intensively investigating non-peptidic angiotensin II receptor antagonists on the basis of such considerations.

Further, in USP 4 , 880 , 8o4 , benzimidazole derivatives having angiotensin II receptor antagonism and effective on rats by intravenous administration, for example, 1- ( 4 ' -phenyl-2-R3 ' )benzyl-2-Ri ' -5-R2-6-R" - 2 2" benzimidazoles, where R and R are selected from hydroxymethyl , methoxy, formyl, chloro or carboxy, and R1 and R^' having defined radical entities are disclosed. However, most of such compounds are described as inactive, when administered orally, while only 6-hydroxymethyl compounds and 6-chloro compounds are described as effective when administered orally ( 100 mg/kg or less) . Moreover, compounds showing only this limited degree of potency are not satisfactory for putting them into practical use as medicinal products. Furthermore, the compounds specifically disclosed in this US Patent are limited to 5" and/or 6-substituted benzimidazoles; no 4- or 7~substituted benzimidazoles are disclosed. The present inventors have found that certain 7-substituted benzimidazole derivatives, which are not specifically disclosed in USP 4 , 880 , 804 , have strong angiotensin II receptor antagonism, and also, when administered orally .show an unexpectedly strong All antagonism and antihypertensive action, which were not observed in the 5" and/or 6-substituted derivatives of the US Patent.

IL 9^(3^9. which was cited under Section 9 of the Patents Law, relates to 7~substituted benziraidazole derivatives in which the substituents in the^-position are different from those in the present compounds.

SUMMARY OF THE-*INVENTION The present invention accordingly provides a compound of the formula (I) , wherein R1 is a straight or branched lower alkyl group having 1 to 8 carbon atoms, which may be substituted by (1) hydroxyl, (2) amino, (3) N-lower- (Cj__ Zj) -alkylamino, (4) N,N-dilower- (C-j^) -alkylamino, (5) halo, (6) lower- (C-j^)- alkylthio, or (7) lower- (C^_^) -alkoxy , R2 is a group of the formula -CO-D' , wherein D' is (1) hydroxyl, (2) lower- (Cj__g) -alkoxy, the alkyl portion of which may be substituted by (i) hydroxyl, (ii) amino, (iii) halo, (iv) lower- (C2-5) -alkanoyloxy , (v) lower- (C^_g)-alkoxy, (vi) lower- (C^.g) -alkylthio , (vii) lower- (C^_g) - alkoxycarbonyloxy, (viii) C^_y-cycloalkoxycarbonylox , (ix) 5~nethyl-2-oxo- l,3-dioxyolen-4-yl, (x) N,N-dilower- (C^/j) -alkylamino , ^ is (1) carboxyl, (2) tetrazolyl, (3) trifluoromethanesulfonic acid amido, (4) phosphoryl, (5) sulfonyl, (6) cyano, or (7) lower- (C-^) - alkoxycarbonyl , each of which may be protected by (i) lower- (Cj__{j) -alkyl, (ii) lower- (02-5) -alkanoyl, (iii) benzoyl, or (iv) pivaloyloxymethyl , ring A is a benzene ring having a substituent other than that defined by R2, said substituent being selected from (1) halo, (2) nitro, (3) cyano, (4) amino, (5) N-lower- (C^.^) -alkylamino , (6) Ν,Ν-dilower- (C^.^) -alkylamino, (7) N-arylamino, (8) alicyclic amino, (9) a group of the formula -Y-R where Y is a direct bond or is -0-, -S- or -C(=0)-, and R is as defined below, (1G) lower- (C^) -alkyl, (11) lower- (C^i^-alkoxy or (12) a group of the formula -C0-D" , wherein D" is (1) hydroxyl, (2) lower- (C^^-alkoxy, the alkyl portion of which may be substituted by (i) hydroxyl, (ii) amino, (iii) N-lower- (C^_^) -alkylamino, (iv) N,N-dilower-"(C^_^) -alkylamino, (v) N-arylamino, (vi) alicyclic amino, (vii) halo, or (viii) lower- (C^_ij) -alkoxy, and R is: _ (i}- hydrogen; (ii) a lower- (C^.ij.) -alkyl group which may be substituted by (1) hydroxyl, (2) amino, (3) N-lower- (C1_it) -alkylamino, (4) N.^dilower-^-Zj) -alkylamino, (5) N-arylamino, (6) alicyclic amino, (7) halo, or (8) lower- (C^_^)-alkoxy; (iii) amino; (iv) N-lower- (C^..^) -alkylamino; (v) alicyclic amino; (vi) halo; or (vii) hydroxyl; and X is (1) a direct bond or (2) a divalent spacer linking the depicted unfused benzene rings by 1 or 2 atoms, selected from lower- (C^_^) -alkylene, -C(=0)-, -0-, -S-, -NH-, -C(=0)-NH-, -0GH2~, -SCH2- and -CH-CH-, or a salt thereof.

NOTICE UNDER THE REGISTRAR'S CIRCULAR NO. 23 (P) OF APRIL 5, 1992 Since the invention is defined in the appended claims, it will be apparent that the passages of the present specification which fall outside the scope of the claims do not relate directly to the invention.

More specifically, the present invention relates to i'corapounds of the formula: wherein 1 is an optionally substituted alkyl group, R2 and R3 are independently a group capable of forming anion or a group which can be changed thereinto, ring A is benzene ring optionally having, besides the group shown by R2, further substituents , and X shews linkage of phenylene group and phenyl group directly or through a spacer whose atomic chain is not more than 2 or salts thereof .

Referring.±o the above-mentioned general formul ( I ) , the alkyl group shown by R1 includes straight chain or branched lower alkyl groups having about 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, i-pentyl, hexyl, heptyl , octyl, etc. The alkyl groups may be substituted with hydroxyl group', optionally substituted amino group, halogen, lower (Ci,.4) alkylthio group or a lower (Ci_4) alkoxy group. Preferable groups shown by Rl are lower(C2-5) alkyl croups optionally substituted with hydroxyl group, amino group, halogen or a lower (Ct_4) alkoxy group.

Examples of a group capable of forming anion or a group which can be changed thereinto shown by R2 include a group shown by the formula: -(CH2).CO-D [wherein D stands for hydrogen, hydroxyl group, optionally substituted amino group, halogen or optionally substituted alkoxy group (e.g. lower ( C^) alkoxy group whose alkyl portion may be substituted with hydroxyl group, optionally substituted amino group, halogen, a group of the formula: I -OCHOCOR"" [wherein P.1 " is hydrogen, a straight or branched lower (Cl.i) alkyl group (e.g. methyl, ethyl, n-propyl , isopropyi, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, etc.), or C«_7 cycloalkyl group (e.g. cyclopentyl, cyclohexyl, cycloheptyl, etc.), and R" " is a straight or branched lower (C^) alkyl group (e.g. methyl, ethyl, n-propyl, isopropyi, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, etc.), C3_7 cycloalkyl croup (e.g. cyclopentyl, cyclohexyl, cycloheptyl, .etc.), lower (C^. 3) alkyl (e.g. methyl, ethyl, n-propyl, isopropyi, etc.) or lower (C2.3) alkenyl group (e.g. vinyl, propenyl, allyl, isopropenyl, etc.) substituted by.C5_7 cycloalkyl (e.g. cyclopentyl, cyclohexyl, cycloheptyl, etc.) or phenyl group, optionally substituted phenyl group (e.g. phenyl, etc.), a straight or branched lower (Ci,_e) alkoxy group (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, etc.), C5_7 cycloalkyioxy group (e.g. cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, etc.), lower (C^) alkoxy group (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, etc.) substituted by C3_ cycloalkyl (e.g. cyclopentyl, cyclohexyl, cycloheptyl., etc.) or phenyl group, optionally substituted phenoxy group (e.g. phenoxy, etc.), or optionally substituted benzyloxy group (e.g. benzyloxy, etc.)], lower (C,.6) alkoxy group, lower (Ci_6) alkylthio group or optionally substituted dioxolenyl (e.g. 5-methyl-2-oxo-l , 3-dioxolen-4-yl etc.), preferably lowertC^) alkoxy group whose alkyl portion may be substituted with hydroxyl group, optionally substituted amino group, halogen, lower(C2.i) alkanoyloxy, 1-lower (Ct.6 ) alkoxy group, lower (CL.6) alkyl hio or lower (C^) alkoxycarbonyloxy group), and n denotes 0 or 1], cyano , optionally protected (with e.g. alkyl or acyl group) tetrazolyl, phosphoric acid, sulfonic acid, phenolic hydroxyl group, optionally substituted alkoxy group, trifluoromethanesulfonic acid amide and lower (C^) alkyl group optionally substituted with hydroxyl group or optionally substituted amino group. Groups capable o£r,.forming anion or those which can be changed into such groups biologically, i.e. by being subjected to metabolism physiologically, or chemically (e.g. by oxidation, reduction or hydrolysis) are also within the meaning of R2, and the compound (I), wherein R2 stands for a group capable of forming anion or a group which can be changed thereinto chemically, is useful also as an intermediate for synthesis .

Preferable groups shown by R2 include those represented by the formula, -(CH2)uCO-D [wherein D stands for hydrogen, hydroxyl group, amino, N-lower- (C^i) alkylamino, N^-diloweriC^ ) alkylamino or lower (Ci_6) alkoxy whose alkyl portion is optionally substituted with hydroxyl group, amino, halogen, lower (C2_6) alkanoyloxy, l-lowertC^) alkoxy, lower (C^) alkylthio or lower (C^s) alkoxycarbonyloxy, and n denotes 0 or 1] or tetrazolyl optionally protected with alkyl (e.g. lower (C:_4) alkyl, etc.) or acyl (e.g. lower (C2-5) alkanoyl or benzoyl. Further preferable groups are those represented by the formula, -CO-D' [wherein D' stands for hydroxyl group, amino, N-lower C^) alkylamino, Ν,Ν-dilower (C^ ) alkylamino or lower (Ci.s) alkoxy whose alkyl portion, is optionally substituted with hydroxyl group, amino, halogen, lower (C2.6) alkanoyloxy, l-lower(C1.6) alkoxy, lower (C^) alkylthio or lower (C^) alkoxycarbonyloxy] or tetrazolyl optionally protected with alkyl or acyl group .

Examples of groups capable of forming anion or groups which can be changed thereinto, shown by R3, .· include carboxyl, tetrazolyl, trifluoromethanesulfonic acid amido . (-NHS02CF3), phosphoryl, sulfonyl, cyano, and lower(C^) alkoxycarbonyl , and these groups are optionally protected with optionally substituted lower alkyl group or acyl group, so long as they are capable of forming anion or groups which can be changed thereinto under biological,' i.e. physiological conditions or chemically.

And, the compounds (I), wherein R3 stands for a group capable of forming anion or a group which can be changed thereinto (e.g. cyano) chemically (e:g. by oxidation, reduction or hydrolysis), are useful as intermediates for synthesis.

Preferable groups shown by R3 are carboxyl or tetrazolyl.

Examples of substituents on the benzene ring A other than the groups shown by R2 include halo . . (e.g. F, CI, Br, etc.), nitro, cyano, optionally substituted amino groups [e.g. amino, N-loweriC^) alkylamino (e.g. methylamino, etc.), N,N-dilower(C!. ) alkylamino (e.g. dimethylamino, etc.), N-arylamino (e.g. phenylamino, etc.), alicyclic amino (e.g. morpholino, piperidino, piperazino, N-phenylpiperazino, etc.)], groups represented by the formula -Y-R [wherein Y stands for a direct "bond, -0-, -S- or -C-, and I o R stands for hydrogen, optionally substituted lower alkyl group (e.g. lower(Ct.A) alkyl group optionally substituted with hydroxyl group, optionally substituted amino group, halo, lower(Ct_4) alkoxy, etc.), or groups represented by the formula -CO-D" : [wherein D" stands for hydrogen, optionally substituted alkoxy group [e.g. lower (C^) alkoxy -optionally substituted with optionally substituted amino group, hydroxyl group, hale? , lower (Ct.A) aikoxy, etc.], optionally substituted amino group [e.g. amino, N-lower(CL_<) alkylamino (e.g. methylamino ) , N,N-di lower (C^) alkylamino (e.g. dimethylamino) , N-arylamino (e.g. phenylamino ) , alicyclic amino (e.g. morpholino, p'iperidino, piperazino or N-phenylpiperazino), etc.], halo. , (e.g. chloro, # etc.) or hydroxyl group].

Among them, halo1., ', lower(C^) alkyl, lower(Cj.*) aikoxy, nitro, and groups represented by the formula: -CO-D"' [wherein D"' stands for hydroxyl group or lower(C]._2 aikoxy] or amino optionally substituted with lower (Cj.4) alkyl are preferable, and halo · and lower (Ci_4) alkyl are more preferable.

X shows that adjacent phenylene group is bonded to phenyl group directly or through a spacer whose atomic chain is 2 or less. ""As~the spacer, any one can be exemplified, so long as it is divalent chain in which the number of atoms constituting the straight chain is 1 or 2, and it may have side chain. More specifically, it is exemplified by lower(C^) alkylene, -C-, -0-, -S-, -N-, -C- -, I I I I 0 H O H H H -0-C-, -S-C-, and -C=C- H H H H .

Among the compounds of the above 'formula (I), those of the formula (Ι') [wherein R1 stands for lower(C2.3) alkyl optionally substituted with hydroxyl group, amino group, halo' , , or lower(C^A) alkoxy group, R2 stands for a group represented by the formula: -CO-D' [wherein D' stands for hydroxyl group, amino, N-lower(CJ.A ) alkylamino, Ν,Ν-dilower(C^A) alkylamino or lower(C^) alkoxy whose alkyl portion is optionally substituted with hydroxyl group, amino, halo . or lower(C^) alkoxy] or te€razolyl group optionally protected with alkyl or acyl group, R3 stands for carboxyl or tetrazolyl group optionally protected with alkyl or acyl group and R' stands for hydrogen, halo, ' lower(CI_ ) alkyl, lower(C^) alkoxy, nitro, a group represented by the formula: -CO-D"' [wherein D" ' stands for hydroxyl group or lower(C^) alkoxy] or amino optionally substituted with lower(C^A) alkyl (preferably hydrogen,- lower(CJ. ) alkyl, halo, more preferably hydrogen)] are preferable.

Production Method The compounds of the above-mentioned general formula (I) can be produced by, for example, the methods as shown below.

Reaction (a) [wherein Rl, R2, R3, A and X are of the same meaning as defined above, and W stands for halogen atom] .

Reaction (b) [wherein each symbol is of the same meaning as defined above] .

Reaction (c) [wherein R1, R2, A and X are of the same meaning as defined above, and R3 stands for optionally substituted lower (C^) alkyl] .

Reaction (d) [wherein each symbol is of the same meaning as defined abov ] .

Reaction (e) [wherein R1, R2, R3, A and X are of the same meaning as defined above, and Y stands for iminoether, iminothioether, carboxyl, amidine, cyano group, etc.].

Reaction (f) [wherein R1, R3, R3, A and X are of the same meaning as defined above, and n denotes 0 or 1].

Reaction (g) [wherein each symbol is of the same meaning as defined above] .

Reaction (h) [wherein R1, R3, A and X are of the same meaning as defined above, and W stands for halogen atom].

Reaction (i) [wherein R1, R3, A, X and are of the same meaning defined above] .

Reaction ( j ) [wherein R1, R3, A, X and W are of the same meaning as defined above, and Re stands for lower alkoxy, lower alkylthio, optionally substituted amino group, or cyano group] .

Reaction (k) [wherein Rl, R3, A and X are of the same meaning as defined above, R7 stands for lower alkyl group] .

Reaction ( 1 ) I f [wherein R , R , R , A and X are of the same meaning as defined above, and n denotes 0 or 1].

The above-mentioned reaction (a) is alkylation by using the alkylating agent (III) in an organic solvent in the presence of a base.

Using about 1 to about 3 mol. of a base and about 1 to about 3 mol. of the alkylating agent (III) relative to 1 mol. of the compound (II), the reaction is conducted usually in a solvent such as dimethylformamide , dimethylacetamide , dimethylsulfoxide, acetonitrile, acetone, or ethyl methyl ketone.

As the base, use is made of e.g. sodium hydride, t-butoxy potassium, potassium carbonate or sodium carbonate .

The alkylating agent (III) is used in the form of a substituted halide (e.g. chloride, bromide and iodide), but it may be used in the form of a substituted sulfonic acid ester (e.g. methyl p-toluenesulfonate) .

While reaction conditions vary with the combination of a base and the alkylating agent (III) to be employed, usually the reaction is conducted preferably at temperatures ranging from ice-cooling to room temperatures for about 1 to about 10 hours.

The reaction (b-) is to allow the cyano group substituted on the benzene ring of the compound ( a) to react with various azides to give the tetrazole compound ( lb ) .

Using about 1 to about 3 mol. of an azide compound relative to 1 mol. of the compound (la), the reaction is carried out usually. in a solvent e.g. dimethylformamide, dimethylacetamide , toluene or benzene .

Examples of these azides include trialkyltin azide, triphenyltin azide or hydrazoic acid.

When an organotin azide is employed, the reaction is conducted in toluene or benzene under reflux for 10 to 30 hours. When hydrazoic acid is employed, sodium azide and ammonium chloride are used about 2 times mol. relative to the compound (la), and the reaction is allowed to proceed in dimethylformamide at about 100 to about 130°C for about 1 to 3 days. It is preferable to add to the reaction system an appropriate amount of sodium azide and ammonium chloride to accelerate the reaction .

The reaction (c) is to obtain the carboxylic acid (Id) by hydrolysis of the ester (Ic) in the presence of alkali. Using about 1 to about 3 mol. of alkali relative to 1 mol. of the compound (Ic), the reaction is allowed to proceed in an aqueous alcohol (e.g. methanol, ethanol or methyl cellosolve) . As the alkali, use is made of, among others, sodium hydroxide and potassium hydroxide. The reaction is allowed to proceed preferably at temperatures ranging from room temperatures to about 100°C for about 1 to about 10 hours .

The reaction (d) is to produce a benzimidazole derivative (I) by reduction of nitro group, followed by intramolecular dehydrative cyclization.

The reaction is conducted by using about 2 to about 10 mol. of a reducing agent relative to 1 mol. of the compound (IV). As the reducing agent, mention is made of a metal such as iron, zinc or tin, and the reaction can be conducted usually under acid or alkaline conditions. As the solvent, use is made of alcohols (e.g. methanol and ethanol), ethers (e.g. dioxane and tetrahydrofuran ) and acetic acid or hydrochloric acid singly or as a mixture solution.

The reaction conditions vary with a combination of a reducing agent, a solvent and acid (or alkali), and the reaction is usually allowed to proceed at temperatures ranging from room temperatures to about 100°C for about 1 to about 5 hours.

For the completion of dehydrative cyclization after reduction reaction, it is preferable to heat for about 2 to about 3 hours at about 50°C to about 100°C under acidic conditions .

The reaction (e) comprises cyclization reaction of a diamino compound (V) with various compounds in an organic solvent into a benzimidazole compound (I).

The above-mentioned various compounds are exemplified by carboxylic acid, aldehyde, ortho ester, imino ether and imino thioether.

These reagents are used usually 1 to about 10 mol. relative to 1 mol. of the compound (V), and the reaction is allowed to proceed in an organic solvent, but the reagent can be used dually as the solvent.

The organic solvent are, varying with the reagent then employed, exemplified by alcohols (methanol, ethanol, etc . ) , cellosolves (methyl cellosolve, ethyl cellosolve, etc.), halogenated hydrocarbons (chloroform, methylene chloride, etc.), ethers (dioxane, tetrahydrofuran, etc.), aromatic hydrocarbons (benzene, toluene), acetonitrile and dimethylformamide, among others .

For accelerating the reaction, an acid (hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, etc.) or a base (triethylamine, pyridine, sodium methoxide, sodium ethoxide, potassium carbonate, etc.) can be added to the reaction system.

While the reaction conditions vary with reagents then employed, the reaction is conducted preferably at temperatures usually ranging from room temperatures to about the boiling point of the solvent then employed for about 1 hour to about 10 hours.

The reaction (f) is to produce the carboxylic acid (If) by hydrolysis of the ester (Ie) in the presence of alkali .

Using about 1 to 3 mol. of alkali relative to 1 mol. of the compound (Ie), the reaction is carried out usually in an aqueous alcohol (e.g. methanol, ethanol, methyl cellosolve, etc.). As the alkali, use is made of sodium hydroxide and potassium hydroxide.

The reaction is conducted preferably at temperatures ranging from room temperatures to about 100°C for about 1 to about 10 hours.

The reaction (g) is to produce the hydroxymethyl compound (Ig) by reduction of the caroxylic acid ester (ie).

=The reaction is carried out by using about 1 to about 5 mol. of a reducing agent relative to 1 mol. of the compound (Ie). As the reducing agent, mention is made of, for example, lithium aluminum hydride or sodium borohydride. When the former is used, usually ether ( tetrahydrofuran, dioxane, ethyl ether, etc.) is employed as the solvent, and the reaction is allowed to proceed for about 1 to about 20 hours at temperatures ranging from room temperatures to about the boiling point of the solvent then employed. And, when the latter is used, usually ether (tetrahydrofuran and dioxane) or alcohol (ethanol, propanol, butanol, etc.) is employed as the solvent, and it is preferable to add a suitable amount of methanol to the reaction system to accelerate the reaction. The reaction is allowed to proceed for about 1 to about 20 hours at temperatures ranging from room temperature to about the boiling point of the solvent then employed, preferably from about 50°C to about the boiling point of the solvent.

The reaction (h) is to produce the compound (Ih) by halogenation of the compound (Ig) with a halogenating reagent in an organic solvent.

Examples of the organic solvent include, among others , halogenated hydrocarbons such as dichloromethane, chloroform or dichloroethane and ethers such as ethyl ether, tetrahydrofuran or dioxane. As the halogenating reagent, use is made of, among others, thionyl chloride and phosphorus oxychloride. Among them thionyl chloride is preferable from the viewpoint of convenience of post-treatment of the reaction. The reaction is preferably carried out usually for about 1 to about 10 hours at temperatures ranging from room temperature to about the boiling point of the solvent then employed.

The reaction (i) is to produce the methyl compound (li) by reducing the halogenated compound (Ih).

As the reducing agent, use is made of metal hydrides (e.g. organotin hydride), metal hydride complex compounds (e.g. sodium aluminum hydride or sodium borohydride ) , metals and salts thereof (e.g. zinc, copper, sodium or lithium). When, among them, a metal hydride (e.g. Ph3SnH or Bu3SnH) is employed, the reaction is carried out preferably in an aromatic hydrocarbon solvent (e.g. benzene or toluene) by using about 1 to about 3 times mol. of a tin hydride compound for about 3 to about 10 hours at about the boiling point of the solvent then employed. While the reaction proceeds rapidly when an iodide or bromide is employed, it is preferable to add peroxide (e.g. perbenzoic acid) or azobisisobutyronitrile (AIBN) to the reaction system to accelerate the reaction, when a chlorine compound is em loyed .

The reaction ( j ) is to produce the substituted compound (Ik) by a substitution reaction of the halogen compound (Ih) with a nucleophilic .agent in an organic solvent. Examples of the organic solvent include alcohols (e.g. methanol, ethanol, propanol, and butanol), ethers (e.g. tetrahydrofuran and dioxane), halogenated hydrocarbons (e.g. dichloromethane, chloroform and dichioroethane ) , acetonitrile and cimethylformamide . The solvent to be employed is preferably selected in accordance with; . the nucleophilic .agent then employed. Examples of the nucleophilic agent include alcohols such as methanol, ethanol, etc., thiols such as methyl mercaptan, etc., amines such as alkylamine, aralkylamine , etc., and cyanides such as potassium cyanide, etc.

The reaction is carried out preferably in the presence of a suitable base (e.g. potassium carbonate, sodium carbonate, sodium hydride, sodium alkoxide, etc . ) .

Preferable reaction time is usually within the range from about one hoiir to about 10 hours at temperatures ranging from ice-cooling to about 50 °C, but it varies with combination of the reagent and the solvent .

The reaction (k) is to convert the nitrile (Ik) to the ester ( 12 ) .

· It is convenient and preferable that the nitrile (Ik) is heated at temperatures ranging from about 50 °C to the boiling point of the solvent then employed for about 3 to about 20 hours in an alcohol (e.g. methanol, ethanol/ propanol, butanol, etc.) containing about 3 to 10 times mol. of excess hydrogen chloride gas. The alcohol then employed acts as the solvent and also as the reaction reagent. While, during the reaction, imino ether is produced as intermediate, it is preferable to obtain the ester compound without isolating the intermediate.

The reaction (2) is to produce the ester (Im) by esterification of the carboxylic acid (If) with an alcohol.

The reaction is usually carried out by using a reactive alcohol (e.g. methanol, ethanol, propanol or butanol) in the presence of an acid catalyst. Examples of the catalyst include a mineral acid such as hydrochloric acid and sulfuric acid or an organic acid such as p-toluenesulfonic acid.

The reaction is preferably carried out for about 5 to about 20 hours at around the boiling point of the solvent.

The reaction products obtained by the reactions (a) to (2) can be easily isolated by conventional isolation and purification processes, for example, column chromatography and recrystallization.

These compounds (I) can be led, by a conventional method, to salts with a physiologically acceptable acid or base, for example, salts with an inorganic acid such as hydrochloride, sulfate and nitrate, salts with an organic acid such as acetate, oxalate, citrate and maleate, salts with an alkali metal such as sodium salt and potassium salt, and salts with an alkaline earth metal such as calcium salt.

Among these compounds, the starting compounds (II), (III), (IV) and (V) can be synthesized by, for example, the methods described in the following literature references or methods analogous thereto. (1) P.N.Preston, "The Chemistry of Heterocyclic Compounds " Vol. 40, ed. by P.N.Preston, Tohn Wiley & Sons, New York (1981), pp. 1-286, (2) A.Hunger, J. ebrle, A.Rossi ..and K.Hottmann, Helv. Chim. Acta. 43., 1032 (1960), (3) R.C.De Selms, J . Org . Chem . , 27., 2163 (1962), (4) A. F. Casy and J.Wrigit, J.Chem.Soc. (C), 1966 , 1511, (5) O.Meth-Cohn, H.Suschitzky and M.E.Sutton, J.Chem.Soc. (C), 1968 , 1722, (6) A.A. Shazhenov, Ch. Sh. Kadyrov and P. urbanov, him. Geterotsikl. Soedin., 1972, 641, (7) N.Vinot, Bull . Soc . Chim . Fr. 1966 , 3989, (8) M.W. Partridge and H.A.Turner, J.Chem.Soc, 1958 , 2086, (9) R.E.Lyle and J .L . Lamattina , J. Org. Chem., 40 , 438(1975) , (10) S.H.Dandegaonker and C .R.Revankar, J. arnatak Univ., 6., 25(1961) (cf. CA, 59., 10023b), (11) Y. anaoka, O.Yonemitsu, K.Tanizawa and Y.Ban, Chem. Pharm. Bull., 12., 773 (1964), (12) J.Preston, W.F.Dewinter and. W.L.Hofferbert, Jr., J.Hetercycl. Chem., 6., 119(1969), (13) B.C. Bishop, A.S.Jones and J.C.Tatlow, - 20 - J. Chem. , Soc. , 1964, 3076, ( I4j H. Depoorter, G.G. Van Mierlo. M.J. Libeer and J. M. Nys, Belg. 595, 327, Mar. 23, I96 l ( cf. CA, 58, 9085a ( 1963 ) ), ( 15) Godeitoi, J*. Org. Chem. , 38, 3495 ( 1973 ), ( 16) and Y. Izawa, 353 ( 1976), ( 17) V. J. Grerda, . E. Jones, G. Gal and M. Sletzinser, J. Org. Chem 30 ">59 ( 1965), ~ ( 18) M. Itaya, Yakugaku Zasshi, 82, 1 ( 1965), ( 19) 1. Ganea and R. Taranu, Stud. Univ. Babes -Bolyai.

Ser. Chem. , 1966. 95 ( cf. CA, 67, 32648s ( 1967 ) ), (20) D. Jerchel, H. Fischer and M. Kracht, Ann. Chem. , 162 ( 1952 ), (21) N. S. Kozlov and . N. Tovshrein, Vestsi Akad. Navuk Belaras. SSR, Ser. Khim. Navuk 1967. 89 ( cf. CA, 69, 49507p ) , (22) J. B. Wright, Chem. Rev. , 48, 397 ( 1951 ).

And, the starring compound (IV) can easily be produced by alkyiarion of the compound vT) synthesized for exam le' bvthe method described in "K. Seno, S. Hagishita, T. Sato and K. Kuriyama. J. Chem. Soc. , Perkin Trans. 1. 1984. 20 3" or an analogous method thereto, or by subjecting the compound (VT) to a reaction similar to the reaction (a) or a reaction analogous thereto ( e.g. the reaction shown by the following scheme (m) ).

Reaction (m) [wherein A. Rl , R". R'\ X and n are of the same meaning as defined above, and W stands for halog atom] The reaction (m) is to produce an N-alk l compound ( [V) by alkylating the compound (VT) by a method similar to that of the reaction (a).

The starting compound (V) can be produced by the reaction shown by the following scheme (n) or a reaction analogous thereto.

Reaction (n) [wherein A, R2, RJ and X are of the same meaning as defined above, and W stands for halogen atom] In the reaction (n), the acid azide (ΓΧ) which is produced by reacting the o-nitrobenzoate derivative (VII) with a halogenating reagent (e.g. thionyl chloride, phosphorus oxychloride, etc.) to give the acid chloride (VTII), followed by reaction with an azide compound (e.g. sodium azide, etc.) can be easily convened into the isocyanate (X), and the carbamic acid ester (XI) is produced in a high yield by heating the isocyanate (X) and t-butanol. On the other hand, the carbamic acid ester (XI) is produced by heating a mixture of the benzoate derivative (VII) and diphenyl phosphoryl azide (DPPA) in t-butanol. The diamino compound (V) is produced in a high yield by alkylating the obtained carbamic acid ester (XI) in a method similar to that of the reaction ( m) to give the compound ^Xll), followed by deprotection and reaction with a reducing agent (e.g. raney nickel, stannic chloride, iron-hydrochloric acid, hydrazine-ferric chloride, etc.).

The starting compounds (XIV) and (XV) can be produced by the reaction shown by the following scheme (o) or a reaction analogous thereto.

Reaction (o) T X IV X T I [wherein A, Rl , R2, R", R3 and X are of the same meaning as defined above, R8 stands for carboxylic acid ester, cyano or optionally protected tetrazolyl, and Z is -0-, - H- or -S-] In the reaction (o), the benzimidazole derivative (XTV) is produced in a high yield by heating the diamino compound (V) and an acid chloride (e.g. chloroacetate chloride, 2-chloropropionate chloride, etc. ) in the presence of a base (e.g. triethylamine, pyridine, etc.) to give a diacylamino compound, followed by heating the diacylamino compound and an acid (e.g. hydrochloric acid -ethanol, etc. ), and the substituted compound (XV) is produced in a high yield by reacting the chloride (XTV) with a various nucleophilic reagent (e.g. sodium methoxide, sodium ethoxide, methylamine, ethylamine, sodium thiomethoxide, sodium thioethoxide, etc. ) . The desired compound (I) can be produced by subjecting the obtained compound (XV) to the reaction (b), (c) or the like.

The compounds (I) and the salts thereof thus produced are less toxic, strongly inhibit the vasoconstrictive and hypertensive actions of angiotensin II, exert a hypotensive effect in animals, in particular mammals (e.g. human, dog, rabbit, rat, etc.) , and therefore they are useful as therapeutics for not only hypertension but also cardiovascular diseases such as heart failure and cerebral stroke. The compounds (I) and salts thereof, when used as medicines as mentioned above, can be orally or non-orally administered as they are or in such dosage forms as powders, granules, tablets, capsules, injections, etc. prepared by mixing with appropriate pharmacologically acceptable carriers, excipients or diluents.

The dose varies with the diseases to be treated, 115437/2 symptoms, subjects and administration routes, and it i desirable that a daily dose of 1 to 50 mg for oral administration or 1 to 30 mg for intravenous injection be divided into 2 to 3 doses when used as an agent for the therapy of essential hypertension in adults.

(Examples) By the following formulation examples, working examples , experimental examples and reference examples the present invention will be explained more concretely, but they should not be interpreted as limiting the invention in any manner.

Examples of abbreviations in this specification are as follows: Me: methyl, Et: ethyl, Pr: propyl, Bu: butyl, Pen: pentyl, Tet: tetrazolyl, THF : tetrahydrofuran, ΌΚΞ : dimethylformamide, Ph: phenyl, Ac: acetyl Formulation Examples When the compound (I) of the present invention is used as a therapeutic agent for circulatory failures such as hypertension, heart failure, cerebral apoplexy etc., it can be used in accordance with, for example, the following recipies . 1. Capsules (1) 2-butyl-l-[ [ 2 ' -( lK-tetrazol-5-yl)biphenyl-■4- yl ]methyl]benzimidazole-7-carboxylic acid 10 mg (2) lactose 90 mg (3) fine crystalline cellulose 70 mg (4) magnesium stearate 10 mg one capsule 180 mg (1), (2), (3) and a half of (4) are mixed and granulated. To the granules is added the remainder of (4), and the whole is filled into gelatin capsules. 2. Tablets ( 1 ) 2-butyl-l-[ [ 2' -( lH-tetrazol-5-yl ) biphenyl-4-yl ] methyl ] benzimidazole-7-carboxylic acid 10 mg (2) lactose 35 mg (3) corn starch 150 mg (4) fine crystalline cellulose 30 mg (5) magnesium stearate 5 mg one tablet 230 mg (1)/ (2), (3), two thirds of (4) and a half of (5) are mixed and granulated. To the granules are added the remainders of (4) and (5), followed by subjecting the granules to compression molding. 3 Injections ( 1 ) 2-butyl-l-[ [ 2 ' - ( lH-tetrazol-5-yl )biphenyl-4- yl ]methyl ]benzimidazole-7-carboxylic acid disodium salt 10 mg (2) inositol 100 mg (3) benzyl alcohol 20 mg one ampoule 130 mg (1), (2) and (3) are dissolved in distilled water for injection to make the whole volume 2 ml, which is filled into an ampoule. The whole process is conducted under sterile conditions . 4. Capsules (1) l-( eyelohexyloxycarbonyloxy) ethyl 2-butyl-l-[ [ 2 ' - ( lH-tetrazol-5-yl ) biphenyl-4-yl ]methyl ] - benzimidazole-7-carboxylate 10 mg (2) lactose 90 mg (3) fine crystalline cellulose 70 mg (4) magnesium stearate 10 mg one capsule 180 mg (1), (2), (3) and a half of (4) are mixed and granulated. To the granules is added the remainder of (4), and the whole is filled into gelatin capsules. 5. Tablets (1) l-( eyelohexyloxycarbonyloxy) ethyl 2-butyl-l-[ [ 2 ' - ( lH-tetrazol-5-yl ) biphenyl-4-yl ] - methyl]benzimidazole-7-carboxylate 10 mg (2) lactose 35 mg (3) corn starch 150 mg (5) magnesium stearate 5 ng : one tablet 230 mg (1), (2), (3), two t irds cf (4) and a half cf (5) are nixed and grar.ulated. To the granules are added the remainders cf (4) and (5), followed by subjecting the granules to compression molding. 6. Capsules (1) pivaloyioxymeth i 2-butyl-l-[ [ 2 ' - ( lH-tetrazoi-5- yl )biphenyl-4-yl ]methyl ]benzimidazoie-7- — carboxylase 10 mg (2) lactose SO rag (3) fine crystalline cellulose 70 mg (4) magnesium stearate 10 mg one capsule ISO mg (1), (2), (3) and a half of (4) are mixed and granulated. To the granules is added the remainder (4), and the whole is filled into gelatin capsules. 7. Tablets (1) pivaicyioxymethyi 2-butyi-i- Γ [ 2 ' - ( lH-tetrazoi-5 yi ) biphenyl-4-yi Imethyi ] benzimidazole-7- carbcxyiate 10 mg (2) lactase 35 mg (3) corn starch 150 mg (4) fine crystalline cellulose 30 mg (5) magnesium stearate 5 mg one tablet 230 mg (1), (2), (3), o thirds of (4) and a half cf ( are mixed and granulated . To the granules are added the remainders of (4) and (5), followed by subjecting the granules to compression molding. Reference Example 1 2-5utyl-5-m5thox-^benoimidazcle To a solution of 4-methcxy-o-phenylenediamine (4 g) and ethyl vaieroimidate hydrochloride (4.5 g) in ethane1 (50 ml) was added triethyiamine (5.7 c) , and the mixture vas stirred far 2.5 hours at room temperature. After removal of the solvent bv evaporation, the resulting residue was dissolved in ethyl acetate and water , and the organic layer was washed with water, cried and concentrated. The concentrate was purified by column chromatography on silica gel to give a crystalline product. Rscrystallization from iscpropyl ether gave needles (2.7 g, 53%), m.p. 95- Elemental Analysis for C.2K,5N20 : C(%) H(%) N(¾) Calcd : 70.56; 7.89; 13.71 Found : 70.o=; 7.95; 13.72 5: 0.93(3H,t), 1.2-2.0 ( 4K,m) , 2.89(2H,t), 3.8i(3H,s), 6.84(11-1,0), 7.02(lH,d), 7.42 ( lH,d) .

In a manner similar to Reference Example 1, the following compounds were synthesized.

Reference Example 2 2-3utvl-5-chlorobenzimidazole Colorless needles, m.p. 149-150aC, yield 73% ' Elemental Analysis for C..Hi3Cl 2 : C(%) H(%) N(%) Calcd : 63.31; 6.23; 13.42 Found : €3.35; 6.46; 13.30 'H-N!-!P^CDCi,) 5: 0.90 ( 3K , t ) , 1.20-1.60 ( 2H,m) , l.S7-2.00(2>:, m), 1.67-2.00 ( 2H,m) , 2.92(2H,t), 7.17 ( lH, ) , 7.33-7.52( 2H,m) .

Preference Example 3 2-But--l-5--i robenzimidazole Colorless crystals, m.p. 140-14i°C, yield 77% Reference Example 4 2-Proovlbenzimidazole A mixture of o-phenylenediamine (2.2 g) in butyric anhydride (4.7 g) was stirred for 4 hours at 110°C. To the reaction mixture was added water, which was extracted with ethyl acetate. The organic layer was washed with an aqueous solution cf sodium bicarbonate, dilute hydrochloric acid and water, which was then dried. The solvent was evaporated to dryness, and the residue was refluxed for 1.5 hour in 3N-KC1 (35 ml).

The reaction mixture was made basic with a cN MaOH .

The crystals were recrystaiiized from ethyl acetate -hexane tc give colorless plates (0.9 g, 33%), m.o. 150-152°C. lH-.iMR( 902iHs,CDCl3) S: 1.00(3H,t), 1.83 ( 2K,se(hexapiet) ) , 2.91(2H,t), 2.91 ( 2H, t ) , 7.10-7.35(2H,m) , 7.45-7.70 ( 2:-I,m) , 3.30 ( IK, br s ) .

Reference Example 5 2-?entvlbenzimidazole To a solution of o -phenyler.ediamine (2.2 g) and trietliyianine (2.0 g) in methylene chloride (20 ml) was added dropwise caproyi chloride (2.3 g) with stirring under ice-ccoiing. The mixture was stirred for 3 hours at room temperature , was then washed with a saturated aqueous sodium, bicarbonate followed by water and then dried. The solvent was evaporated. To the residue was added 3N-HCl, a d the mixture was heated for 1.5 hour under reflux. The reaction mixture was made basic with 6 aCK. Then precipitating crys-ais were recrystailizad from ethyl acetate - exane to give colorless needles (1.5 g, 47%), .p. 161-152°C. l~-lWR(SQXr.zf CDClj ) c : 0.35 ( 3Ξ , t ) , 1.1-1. c ( 4H,m) , 1.7-2.0(2H, iti) , 2.92( 2H,t) , 7.1-7.3 ( 2H,m) , 7.5- 7.7 ( 2E, rr. ) .

Reference Example 6 2-5utyl-l- r 2' -cvanobi-henyl-4-yllmethyl 1 benzimidazo le To a solution of 2-butylbenzimidazole (0.87 g) in dimethylformamiide ( Di-iF ) (5 mi ) was added sodium hydride (60% oil, 0.24 g) under ice-cooling, and the mixture was stirred for 10 minutes. To the resultant mixture was added 4- ( 2-cyanophenyi ) benzyl chloride (1.1 g) , which was stirred for 1.5 hour.' "' To the reaction mixture was added water, which was extracted with ethyl acetate . The extract was washed with water and concentrated under reduced pressure. The concentrate was purified by column chromatography on silica gel to give a colorless oil (1.8 g, quantitatively). 1H-N R( 90MHz, CDC13) S: 0.90(3H,t), 1.2-1.6 (2H,m) , 1.65-2.00(2H,m) , 2.85(2H,t), 5.37(2H,s), 7.0- γ- 7.9(12H,m).

The following compounds (Reference Examples 7-16) were prepared according to the procedure for Reference Example 6.

Reference Example 7 2-Butyl-l- Γ ( 2 ' -cvanobiphenyl-4-vHmethyl 1 -6-methoxybenzimidazole Oil (Yield 48%) .. ~ .

^-NM i 200MHz, CDC13) δ: 0.93(3H,t), 1.14-1.53 ( 2H,m) , 1.76-1.91(2H,m) , 2.83(2H,t), 3.81(3H,s), 5.37(2H,s), 6.70(lH,d), 6.89(lH,dd), 7.17(2H,d), 7.41-7.53(4H,m) , 7.61-7.68 ( 2H,m) , 7.77(lH,dd).

IR(neat)cm"1: 2220, 1620, 1595, 1520, 1485, 1460, 1415, 1350, 1275, 1260, .1215, 1175, 1135, 1105, 1025, 930, 815, 765.

Reference Example 8 2-Butyl-l-r ( 2 ' -cyanobiphenyl-4-yl lmethyl 1 -5-methoxybenziiidazole Oil (Yield 44%) 1H-NMR(200MKz,CDCl3) S: 0.93(3H,t), 1.35-1.53 ( 2H,m) , 1.76-1.92(2H,m) , 2.85(2H,t), 3.86(3H,s), 5.38(2H,s), 6.86(lH,dd), 7.11(lH,d), 7.15(2H,d), 7.29(lH,d), 7.41-7.53(3H,m) , 7.64(lH,dt), 7.77(lH,dd) .

IR(neat)cm_1: 2220, 1620, 1595, 1485, 1440, 1415, 1345, 1275, 1200, 1160, 1030, 835, 800, 765.

Reference Example 9 2-Butyl-5-chloro-l-r ( 2 ' -cvanobiphenyl-4- yl ^methyl 1 benzimidazole Oil (Yield 43%) lH- R( 200MHz, CDCl) S: 0.94(3H,t), 1.35-1.5 ( 2H,m) , 1.77-1.92(2H,m) , 2.87(2H,t), 5.40(2H,s), 7.12- 7.27(4H,m), 7.42-7.55 ( 4H,m) , 7.65(lH,q), 7.75- 7.80(2H,m) .

IR( neat Jem"1: 2220, 1510, 1460, 1400, 760.

Reference Example 10 2-*Butyl-6-chloro-l-r ( 2 ' -cvanobiphenyl-4-yl ^methyllbenzimidazole m.p. 124-125°C (yield 35%). 1H-NMR( 200MHz, CDCI3) S: 0.94(3H,t), 1.35-1.54 ( 2H,m) , 1.77-1.92(2H,m) , 2.85(2H,t), 5.37(2H,s), 7.14(2H,d), 7.20-7.25(2H,m) , 7.41-7.55 ( 4H,m) , 7.61-7.70(2H,m) , .7.77(lH,d) .

IR( Br)cirfl: 2220, 1620, 1595, 1485, 14.40, 1415, 1345, 1275, 1200, 1160, 1030, 835, 765.

Reference Example 11 2-Butyl-l-r ( 2 ' -cyanobiohenyl-4-yl ^methyl] -5-nitrobenzimidazole Oil (Yield 45%) Reference Example 12 2-Butyl-l- ( 2 ' -cvanobiphenyl-4-yl methyl-6-nitrobenzimidazole .

Oil (Yield 43%) Reference Example 13 1- Γ ( 2 ' -Cyanobiphenyl-4-yHmethyl 1 -2-propylbenzimidazole Oil (Yield quantitative) 1H-NMR(200MKz,CDCl3) S: 1.04(3H,t), 1.82-2.00 ( 2H,m) , 2.86(2H,t), 5.42(2H,s), 7.15(2H,d), 7.21- 7.29(3H,m), 7.40-7.53 ( 4H,m) , 7.59-7.68 ( lH,m) , 7.73-7.81(2H,m) .

IR(neat)cm_1: 2220, 1510, 1480, 1455, 1410, 760, 740.

Reference Example 14 1-r ( 2 ' -Cyanobiphenyl-4-yl ^methyl 1 -2-pentylbenzimidazole Oil (Yield quantitative) 1H-NliR(200MK2,CDCl3) S: 0.88 ( 3H, t ) , 1.23-1.44 ( 4H/m) , 1.80-1.95(2H,m) , 2.87(2H,t), 5.43(2H,s), : 7.16(2H,d), 7.21-7.29(3H,m), 7.41-7.53 ( 4H,m) , 7.60-7.68(lH,m) , 7.74-7.82 ( 2H/m) .

IR(neat Jem"1: 2220, 1510, 1480, 1455, 1410, 760, 740.

Reference Example 15 1- Γ ( 2 ' -Cvanobiphenyl-4-yl methyl1benzimidazole Oil (Yield quantitative) 1H-NMR(200MHz,CDCl3) S: 5.44(2H,s), 7.26-7.3 ( 4H,m) , 7.41-7.55(4H,m) , 7.60-7.68 ( lH,m) , 7.76(lH,dd), 7.83-7.87(lH,m) , 8.01(lH,s).

IR(neat)cm"1: 2220, 1500, 1480, 1460, 1440, 1365, 1285, 760, 740.

Reference Example 16 2-Butyl-l-r ( 2 ' -cvanobjphenyl-4-yl lmethyl lbenzimidazole Oil (Yield quantitative) lH- KR( 90MHz ,CDCl3 ) S: 0.90(3H,t), 1.2-1.6 ( 2H,m) , 1.65-2.00(2H,m) , 2.85(2H,t), 5.37(2H,s), 7.0- 7.9(12H,m).

Reference Example 17 2-Butyl-l- Γ Γ 2 ' - ( lH-tetrazol-5-yl ) biphenyl-4-yl Imethyl 1 benzimidazole A mixture of 2-butyl-l-[ ( 2 ' -cyanobiphenyl-4-yl)methyl]benzimidazole (1.8 g), sodium azide (0.98 g) and ammonium chloride (0.80 g) was stirred in DUF (6 ml) at 110° C for 5 days , while supplementing sodium azide (1.6 g), ammonium chloride (1.3 g) and DMF (5 ml) to the reaction system. To the reaction mixture were added water and ethyl acetate, and precipitating crystals were collected by filtration. The organic layer of the filtrate was washed with water, dried and concentrated under reduced pressure to give crude crystals . These crystals were combined with the crystals obtained previously, followed by recrystallization from ethyl acetate - methanol to afford colorless prisms (0.82 g, 41%), m.p. 235-236°C.

Elemental Analysis for C2jH2£( 5 : , C(%) E(%) · N(%) Calcd : 73.51; 5.92; 20.57 Found : 73.42; 5.90; 20.87 lH-NMR(200MKz,DMSO-d«) S: 0.87(3K,t), 1.26-1.45 ( 2K,m) , 1.62-1.77(2H,m) , 2.82(2K,t), 5.49(2H,s), 7.05(4E,s), 7.13-7.22(2H,m) , 7.46-7.71 ( 6H,m) .

IR( Br ) cm-1 : 1510, 1460, 1415, 775, 760, 745.

The following compounds were prepared according to the procedure for Reference Example 17.

Reference Example 18 2-Butyl-5 -inethoxy- 1 - Γ Γ 2 ' - ( IH-tetrazol-5 -yl ) bichsnyl-4 -yllmethyl Ibenzimidazole m.p. 145-149°C (decomp.) Elemental : Calcd : 70.06; 6.06; 18.85 Found : 70.27; 6.03; 18.42 iH-iI¾R(200MHz,DMSO-ds) S: 0.87(3H,t), 1.25-1.44 ( 2H,m) , 1.60-1.75(2H,m) , 2.78(2H,t), 3.77(3H,s), 5.45(2H,s), 6.80(lH,q), 7.01(2H,d), 7.06(2H,d), 7.13(lE,c), 7.35(lE,d), 7.47-7.70 ( 4H,m) .

IR( Br ) cm"1 : 1490, 1450', 1440, 1195, 1155, 1020, 825, 755.

Reference Example 19 2-5utyl-6-msthoxy-l- r 2 ' - f lK-tetrazol-5-yl ) bicher.yl-4- ylTmethyl 1 benzimidazole m.p. 2 3-244°C (decomp.) Elemental Analysis for C2≤E25NsO : C(¾) H(%) N(%) Calcd : 71.21; 5.98; 19.16 Found : · 70.98; 5.96; 19.41 lH-NMR(200MHz,DMSO-d6) 6: 0.86(3H,t), 1.24-1.43 ( 2H,m) , 1.58-1.73(2H,m) , 2.75(2H,t), 3.75(3H,s), 5.45(2E,s), 6.78(lH,q), 7.05(5K,m), 7.43- 7.70(5H,m).

IR(KBr)cm"1: 1615, 1490, 1450, 1260, 1220, 1020, 825, 810, 745.

Reference Example 20 2-Butyl-5-chloro-l- Γ Γ 2 ' - ( lH-tetrazol-5-yl )biphenyl-4-yl Imethyl Ibenzimidazole m.p. 249-250°C (decomp.) Elemental Analysis for C23H23C1N6 · 1/2H20 : C(%) H(%) N(%) Calcd : 66.44; 5.35; 18.59 Found-: 66.55; 5.13; 18.37 ^-NMRf 200MHz ,ϋΜβΟ-άβ) δ: 0.87(3H,t), 1.26-1.44 ( 2H,m) , 1.61-1.76(2H,m) , 2.81(2H,t), 5.50(2H,s), 6.99-7.09(4H,m) , 7.20(lH,q), 7.47-7.70 ( 7H,m) .

IR(KBr)cm~l: 1500, 1450, 1410, 1000, 785, 760.

Reference Example 21 2-Butyl-6-chloro-l-r Γ 2 ' - ( lH-tetrazol-5-yl ^biphenyl-4-yllmethyl 1 benzimidazole m.p. 216-217°C Elemental Analysis for C25H23C1N6: C(%) H(%) N(%) Calcd : 67.79; 5.23; 18.97 Found : 67.41; 5.19; 19.02 1H-NMR(200MHz,DMSO-d6) S: 0.86(3H,t), 1.25-1.43 ( 2H,m) , 1.60-1.75(2H,m) , 2.79(2H,t), 5.51(2H,s), 7.01(2H,d), 7.08(2H,d), 7.18(lH,g), 7.49- 7.72(6H,m) .

IRtKBrJcm"1: 1460, 1410, 755.

Reference Example 22 1- Γ Γ 2 ' - { lH-Tetrazol-5-yl ^biDhenyl-4-yl Imethyl Ibenzimidazole Yield: 51% m.p. 238-239°C Elemental Analysis for C2iH16H6-l/5H20: C(%) H(%) N(%) Calcd : 70.85; 4.64; 23.61 Found : 70.75; 4.40; 23.41 1H-NMR(200MHz,DMSO-d6) S: 5.51(2H,s), 7.07(2H,d), 7.19-7.28(4H,m), 7.49-7.71 ( 6H,m) , 8.42(lH,s).

IR( Br)cm_1: 1505, 1460, 1375, 1290, 1265, 1230, 1195, 1145, 1035, 965, 945, 820, 775, 760, 750, 740.

Reference Example 23 2-Propyl-l- Γ Γ 2 ' - ( lH-tetrazol-5 -yl ) biphenyl-4-yllmethyl Ibenzimidazole Yield: 70% m.p. 239-240°C (decomp.) Elemental Analysis for C2I>K22K&- l/2MeOH- 3/5H20: C(%) H(%) N(%) Calcd : 69.85; 6.03; 19.95 Found : 69.88; 6.01; 19.79 1H-NMR(200MHz,DMSO-ds) S: 0.96(3H t), 1.67-1.85 ( 2H,m) , 3.05(2H,t), 5.68(2H,s), 7.09(2H,d), 7.17(2H,d), 7.40-7.77(8H,m) .

IR( Br)cm_l: 1505, 1480, 1460, 1415, 1405, 760, 745.

Reference Example 24 2-Pentyl-l- Γ Γ 2 ' - ( lH-tetrazol-5-yl ) biohenyl-4-yllmethyl 1 benzimidazole Yield: 41% m.p. 208-209°C Elemental Analysis for C26H2SN6: C(%) H(%) N(%) Calcd : 73.91; . 6.20; 19.89 Found : 73.67; 6.19; 20.00 1H- MR(200MHz,DMSO-ds) S: 0.84(3H,t), 1.27-1.34 ( 4H,m) , 1.64-1.78(2H,m), 2.81(2H,t), 5.49(2H,s), 7.04(4K,s), 7.12-7.20(2H,m) , 7.46-7.69 ( 6H,m) .

IRi BrJcm"1: 1510, 1460, 1410, 745.

Reference Example 25 Methyl 2- Γ 4- ( 2-butylbenzimidazol-l-yl ^methylphenyl 1 benzoate To a solution of 2-butylbenzimidazole (0.52 g) in DMF (4 ml) was added, under cooling with ice, sodium hydride (60% oil, 0.13 g), and then the mixture was. stirred for 20 minutes . To the resultant mixture was added methyl 2- ( 4-bromomethylphenyl ) benzoate (1.0 g) , which was stirred for 1.5 hour at room temperature. To the mixture was added water, followed by extraction with ethyl acetate. The solvent was evaporated to dryness to give an oily residue. The oil : was purified by column chromatography on silica gel to obtain a colorless oil (1.2 g, quantitatively). lH-NMR (90MHz, CDC13) S: 0.92(3H,t), 1.25-2.00 ( H,m) , 2.87(2H,t), 3.60(3H,s), 5.36(2H,s), 7.05(2H,d), 7.15-7.60(8H,m) , 7.65-7.9 ( 2H,m) .

IR(neat)cirfl: 1725, 1455, 1405, 1280, 1245, 780, 755, 740.

Reference Example 26 2-Γ 4- ( 2-Butylbenzimidazol-l-yl methylohenyl 1 benzoic acid In a mixture of IN NaOH solution (4.5 ml) and methanol (10 ml), methyl 2-[ 4- ( 2-butylbenz*imidazol-l-yl)methylphenyl]benzoate Jl .2 g) was heated for 3 hours under reflux. The reaction mixture was concentrated, and the concentrate was dissolved in water, washed with ether, then acidified with 1N-HC1 to afford crystals. The crystals were collected by filtration and recrystallized from ethyl acetate - methanol to afford colorless crystals (0.64 g, 53%).

Elemental Analysis for C23H24 202: C(%) H(%) N(%) Calcd : 78.10; 6.29; 7.29 Found : 77.99; 6.36; 7.22 1H-NMR(200MKz,CDCl3) S: 0.63(3H,t), 0.99-1.17 ( 2K,m) , 1.34-1.49(2H,m) , 2.62(2H,t), 5.32(2H,s), 7.04(2H,d), 7.18-7.55(8H,m), 7.66(lH,dd), 7.92(lH,dd).

IR( Br)cm_l : 1690, 1610, 1600, 1515, 1465, 1420, 1300, 1250, 1140, 1090, 1005, 820, 765, 750.

Reference Example 27 Methyl 2-butylbenzimidazole-4-carboxylate To a mixture of cone. HC1 (5.3 ml) and methanol (35 ml) was added methyl 3-nitro-2- (N- valerylamino ) benzoate (2.8 g), to which was added iron powder (1.7 g) in portions while stirring at room temperature. The resultant mixture was heated for 8 hours under reflux. Insoluble material was filtered off, and the filtrate was concentrated. To the concentrate were added water and ethyl acetate. The aqueous layer was made basic with 6N NaOH, which was extracted with ethyl acetate. Organic layers were combined, washed with water and dried. The solvent was evaporated, and the residue was purified by column chromatography on silica gel . The crystals thus obtained were recrystallized from isopropyl ether to give colorless needles (1.6 g, 70%), m.p. 97-98°C. 1H-NMR( 200MHz ,CDCI3 ) S: 0.93(3H,t), 1.37-1.56 ( 2H,m) , 1.80-1.95(2H,m) , 2.96(2H,t), 4.00(3H,s), 7.26(lH,t), 7.85(lH,dd), 7.91(lH,d), 10.13(lH,br s).

Reference Example 28 Methyl 2-butyl-l-r ( 2 ' -cyanobiohenyl-4-yl )methyl!benzimidazole-4-carboxylate To a solution of methyl 2-butylbenzimidazole-7- -carboxylate (1.5 g) in . DMF (15 ml) was added sodium hydride (60% oil, 0.13 g) under ice-cooling. The mixture was stirred for 20 minutes, to which was added 4- (2-cyanophenyl)benzyl chloride (1.5 g) .

The resultant mixture was stirred for further 5 hours at room temperature, to which was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and dried. The solvent was evaporated to dryness, and the residue was purified by column chromatography on silica gel to give a pale yellow oil (2.3 g, 82%).

^-N R( 90MHz,CDCI3) S: 0.94(3H,t), 1.37-1.55 ( 2H,m) , 1.78-1.93(2H,m) , 2.96(2H,m), 4.05(3H,s), 5.46(2H,s), 7.12(2H,d), 7.25(lH,t), 7.39- 7.52(5H,m), 7.64(lH,dt), 7.76(lH,d), 7.95(lH,dd).

IR( neat Jem"1: 2220, 1710, 1510, 14S0, 1435, 1405, 1350, 1290, 1245, 1215, 1190, 1130, 760.

Reference Example 29 Methyl 2-butyl-l-r Γ 2 ' - f lH-tetrazol-5-vH biphenyl-4-vL Imethyl 1 benzimidazole-4-carboxylate A mixture of methyl 2-butyl-l- [ ( 2 ' -cyanobiphenyl-4-yl )methyl]benzimidazole-4-carboxylate (2.3 g), sodium azide (5.3 g) and ammonium chloride (4.4 g) was stirred in DMT (20 nil) at 110-120 C for 26 hours. To the reaction mixture were added water and ethyl acetate, which was then made acidic with concentrated hydrochloric acid. Precipitating crystals were collected by filtration and recrystallized frcin methanol to give colorless needles (0.22 g, 9%), m.p. 223-224°C (cecomp.).

Elemental Analysis for C27H2SNS02 · 0.3H20 : C(%) K(%) N(%) Calcd : 68.72; 5.68; 17.81 Found : 68.69; 5.68; 17.57 ^-NM (20 OMKz , DMSO-d3 ) S: 0.88(3H,t), 1.28-1. 7 ( 2H,m) , 1.60-1.75(2H,m) , 2.88(2H,t), 3.89(3H,s), 5.56(2H,s), 7.01(2H,d), 7.07(2H,d), 7.27(lE,t), 7.47-7.65(4H,m) , 7.72-7.77 ( 2K,m) .

IR BrJcm*1: 1710, 1460, 1435, 1420, 1295, 1140, 765.

Reference Example 30 2-3utyl-l-r Γ 2 ' -( lH-tetrazol-5-yl ^blohenyl-4- yl Imethyl lber.-imidazole-4-carboxamide The reaction was conducted using substantially the same reaction s described in Reference Example 29. To the reaction mixture were added water and ethyl acetate, which was acidified with 6N-HC1. Precipitating crystals were collected by filtration. From the filtrate was separated the organic layer, which was washed with water, dried and concentrated to dryness. The residue was purified by - column chromatography on silica gel. Crystals obtained thus above were recrystallized from methanol-chloroform to afford colorless prisms (0.37 g, 15%), m.p. 235-236°C.

Elemental Analysis for C2SH25N70 · 1 / 2H20 : C(%) H(%) (%) Calcd : 67.81; 5.69; 21.29 Found : 67.64; 5.68; 21.05 1H- MR(200MHz,DMSO-d6) S: 0.89(3H,t), 1.30-1.48 ( 2H,m) , 1.65-1.80(2H,m) , 2.90(2H,t), 5.58(2H,s), 7.06(4H,s), 7.30(lH,t), 7.48-7.74 ( 5H,m) , 7.84(lH,dd), 9.28(2H,s).

IR( Br)cm'1: 1660, 1610, 1565, 1500, 1465, 1420, 1390, 1350, 1255, 1080, 1070, 1015, 885, 800, 775, 750. Reference Example 31 Methyl 3-nitro-2-valerylaminobenzoate Fuming nitric acid (7.0 ml) was added dropwise to acetic anhydride (60 ml) under ice-cooling, to which" was added cone, sulfuric acid (0.2 ml). To the mixture was added methyl 2-valerylaminobenzoate (12 g), which was stirred for one hour at room temperature. To the resultant mixture was added ice-water, which was then extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated. The concentrate was purified by column chromatography on silica gel to give crude crystals, followed by recrystallization from isopropyl ether to afford colorless needles (3.9 g, 28%), m.p. 61-62°C.

Elemental Analysis for Cl3H16N503: C(%) H(%) N(%) Calcd : 55.71; 5.75; 9.99 Found : 55.72; 5.79; 9.83 1H-NMR(CDC13) S: 0.95(3H,t), 1.30-1.50 ( 2H,m) , 1.65-1.80(2H,m) , 2.46(2H,t), 3.97(3H,s), 7.30(lH,t), 8.10(lH,dd), 8.22(lH,dd).

Reference Example 32 Methyl 2- Γ - ( 2 ' -cvanobiphenyl-4-yl ^methyl-N- valeryl 1 amino-3-nitrobenzoate A mixture of methyl 3-nitro-2-valerylaminobenzoate (3.9 g), 4- (2-cyanophenyl) benzyl bromide (3.8 g) and K2C03 (2.1 g) in DMF (30 ml) was stirred for 15 hours at room temperature. To the reaction mixture was added water, which was extracted with ethyl acetate. The organic layer was washed with water and dried. The solvent was evaporated to dryness, and the residue was purified by column chromatography on silica gel. The resultant crude crystals were recrystallized from ethyl acetate - hexane to afford colorless crystals (5.1 g, 78%), m.p. 129-130°C.

Elemental Analysis for C27I½N305: C(%) H(%) N(%) Calcd : 68.78; 5.34; 8.91 Found : 68.84; 5.43; 8.87 lH-NMR( 200MHz, CDC13) S: 0.85(3Ji,t), 1.18-1.36 ( 2H,m) , 1.61-1.76 (2H,m) , 2.08-2.16 ( 2H,m) , 3.67(3H,s), 4.65(lH,d), 4.96(lH,d), 7.20(2H,d), 7.38- 7.50(4H,m), 7.56-7.68 ( 2H,m) , 7.75(lH,d), 7.98(lH,dd), 8.10(lH,dd).

Reference Example 33 Methyl 2-butyl-l-i ( 2 ' -cvanobiphenyl-4-yl methyl 1benzimidazole-7-carboxylate To a mixture of methyl 2-[N- ( 2 ' -cyanobiphenyl-4-yl)methyl-N-valeryl]ainino-3-riitrobenzoate (5.14 g) in cone. HC1 (4.0 ml) and methanol (10 ml) was added iron powder (1.9 g) in portions with stirring. The mixture was stirred for 3 hours at 70-80°C, then insoluble material was filtered off, and the filtrate was concentrated. To the concentrate were added ethyl acetate and saturated aqueous sodium bicarbonate.

Precipitating insoluble material was filtered off.

From the filtrate was separated the aqueous layer, which was extracted with ethyl acetate. The organic layers were combined, dried and concentrated to give a crystalline residue. Recrystallization from ethyl acetate afforded colorless needles (4.15 g, 90%), m.p. 123-124°C.

Elemental Analysis for Cz7H25N302: ' C(%) H(%) N(%) Calcd : 76.57; 5.95; 9.92 Found : 76.44; 6.03; 9.67 lH-NMR( 200MHz ,CDCl3) S: 0.96(3H,t), 1.38-1.57 ( 2H,ra) , 1.82-1.97(2H,m) , 2.92(2H,t), 3.72(3H,s), 5.82(2H,s), 6.97(2H,d), 7.26(lH,t), 7.39- * 7.46(4H,m), 7.58-7.66 ( 2H,m) , 7.75(lH,dd), 7.97(lH,dd) .

IR(KBr) cm"1 : 2220, 1725, 1480, 1440, 1420, 1400, 1280, 1260, 1195, 1140, 1115, 765, 750, 745.

The following compounds were prepared according to the procedure for Reference Example 31.

Reference Example 34 Methyl 2-butyrylamino-3-nitrobenzoate m.p. 64-65°C. 1H-NMR(90MHz,CDCl3) S: 1.03(3H,t), 1.57-1.97 ( 2H,m) , 2.43(2H,t), 3.97(3H,s), 7.20-7.43 ( lH,m) , 8.07-8.27(2H,m) , 10.50 ( lH,br s ) .

IR(Nujol)citfl: 3300, 1725, 1690, 1585, 1535, 1510, 1445, 1355, 1265, 1210, 1115.

Reference Example 35 Methyl 2-hexanoylamino-3-nitrobenzoate m.p. 74-75°C.

^- MR^OMKz^DClj) S: 0.90(3H,t), 1.23-1.90 ( 6H,m) , 2.43(2H,t), 3.93(3H,s), 7.27(lH,t), 8.03- 8.27(2H,m), 10.30 ( lH,br s ) .

IR(Nujol)cm"1: 3320, 1725, 1675, 1535, 1505, 1270.

In substantially the same manner as in Reference Example 32, the following compounds were obtained.

Reference Example 36 Methyl 2-rN-butyryl-N-f 2 ' -cyanobiphenyl-4- yl ^methyl 1 amino-3-nitrobenzoate m.p. 150-151°C (yield 78%). lH- MR(90MHz,CDCl3) S: 0.87(3H,t), 1.50-1.90 ( 2H,m) , 2.10(2H,t), 3.67(3H,s), 4.83(2H,q), 7.17- 7.80(9H,m)', 7.93-8.17 ( 2H,m) .

IR(Nujal)ciTfl: 2220, 1740, 1670, 1530, 1445, 1430, 1390, 1345, 1290, 1280, 1250, 1125, 770.

Reference Example 37 Methyl 2-TN-f 2 ' -cyanobiphenyl-4-yl Tmethyl-N-hexanoyl 1 mino-3-nitrobenzoate nwp. 85-86°C (yield 75%). 1H- MR(90MHz,CDCl3) S: 0.83(3H,t), 1.07-1.37 ( H,m) , 1.50-1.83(2H,m) , 2.10(2H,t), 3.67(3H,s), 4.83(2H,q), 7.17-7.80 ( 9H,m) , 7.93-8.17 ( 2H,m) .

IR(Nujol)cm"1: 2220, 1735, 1670, 1530, 1480, 1445, 1430, 1390, 1375, 1345, 1290, 1270, 1260, 1200, 1130, 775.

In substantially the same manner as in Reference Example 33, the following compounds were obtained. Reference Example 38 Methyl l-Γ ( 2 ' -cvanobiphenyl-4-yl ^methyl 1-2-prooylbenzimidazole-7-carboxylate m.p. 130-131°C (yield 78%).

^- M ( 90MHz , CDCI3 ) S : .1.07 ( 3H, t ) , 1.93 ( 2H,br s ) , 2.90(2H,br s), 3.70(3H,s), 5.83(2H,br s), 6.93-8.07(llH,m) .

IR(Nu ol)cm*1: 2220, 1710, 1450, 1400, 1290, 1270, 1265, 1200, 1125, 760.

Reference Example 39 Methyl 1-r ( 2 ' -cyanobiphenyl-4-yl ^methyll -2- pentylbenzimidazole-7-carboxylate m.p. 109-110°C (yield 75%).

^-N ( 90MHz , CDCI3 ) S: 0.90(3H,t), 1.17-2.10 ( 6H,m) , 2.90(2H,t), 3.70(3H,s), 5.83(2H,s), 6.97(2H,d), 7.13-8.00(9H,m) .

IRiNujolJcm"1: 2220, 1710, 1450, 1430, 1280, 1260, 1190, 1120, 750.

Reference Example 40 Me hyl 3-nitro-4-valerylaminobenzoate Fuming nitric acid (1.4 ml) was added dropwise to acetic anhydride (12 ml) under ice-cooling, to which was added cone, sulfuric acid (0.1 ml). To the stirred mixture was added methyl 4-valerylaminobenzoate (2.3 g) under ice-cooling, which was stirred for one hour. To the r sultant mixture was added ice water, and the 'crystals that separated out were recrystallized from ethyl acetate - hexane to give yellow prisms (2.14 g, 76%), m.p. 10S-107°C.

Elemental Analysis for C,3H1SN205: C(%) H(%) N(%) Calcd : 55.71; 5.75; 9.99 Found : 55.84; 5.80; 10.01 lH-NMR(CDCl3) S: 0.98(3H,t), 1.20-1.60 ( 2H,m) , 1.70-1.85(2K,m) , 2.53(2H,t), 3.96(3H,s), 8.28(lH,dd), 8.91(lK,d), 8.96(lH,d), 10.60(lH,br · s) .

Reference Example 41 Methyl 4- Γ - ( 2 ' -cvanobiohenyl-4-yl ^methyl-N-valerylamino 1 -3-nitrobenzoate A mixture of methyl 4-valerylamino-3-nitrobenzoate (2.1 g), 4- ( 2-cyanophenyl ) benzyl bromide (2.0 g) and ?C03 (1.1 g) in DMF (20 ml) was stirred for 4 hours at room temperature. To the reaction mixture was added water, which was extracted with ethyl acetate, and the organic layer was washed with water. The resultant solution was dried and concentrated to give a syrup, which was purified by column chromatography on silica gel to afford a yellow syrup (3.5 g, quantitatively). 1H-NH ( 200MHz,CDCl3) S: 0.83(3H,t), 1.15-1.33 ( 2H,m) , 1.55-1.70(2H,m) , 1.99-2.08 ( 2H,m) , 3.98(3H,s), 4.27(lH,d), 5.55(lH,dJ, 7.07(lH,d), 7.27(2H,d), 7.42-7.56(4H,m) , 7.62-7.70 ( lH,m) , 7.77(lH,d), 8.19(lH,q), 8.61(lH,d).

IR(Neat)cm"1: 2220, 1730, 1610, 1535, 1480, 1435, 1390, 1 5«37/2 1345, 1285, 1240, 765.

Reference Example 42 Methyl 2-butyl-l- r ( 2 ' -cvanobiohenyl-4-yl ^methyl 1 benzimidazole-5-carboxylate To a mixture of cone. HCl (4.0 ml) and methanol (10 ml) was added methyl 4- [N- ( 2 ' -cyanobiphenyl-4-yi)methyl-N-valerylainino] -3-nitrobenzoate (3.5 g) . To the resultant mixture was added, with stirring, iron powder (1.3 g) in portions, which was stirred for one hour at 70-80 °C, followed by filtering off an insoluble material. The filtrate was concentrated, dissolved in ethyl acetate, washed with water, dried and concentrated to dryness. The resultant syrup was purified by column chromatography on silica gel to afford a yellow syrup (1.7 g, 53%). 1H-NM (200MHz,CDCl3) S: 0.94(3H,t), 1.45(2H,se), 1.79-1.94 ( 2H,m) , 2.89(2H,t), 3.94(3H,s), 5.44(2H,s), 7.15(2H,d), 7.27(lH,d), 7.42- 7.54(4H,m), 7.65(lH,dt), 7.77(lH,dd), 7.97 ( lH,dd) , 8.50(lH,dd) .

IR(neat)cm*1 : 2220, 1720, 1615 , 1480, 1440, 1400, 1335, 1300, 1280, 1210, 755.

Reference Example 43 Methyl 2-butyl-l- r Γ 2 ' - ( lK-tetrazol-5-yl 'ibiDhenyl-4-yl Imethyl 1 benzimidazole-5-carboxylate A mixture of methyl 4- [N- ( 2 ' -cyanobiphenyl-4-yl )methyl-N-valerylamino j -3-nitrobenzoate (1.7 g), sodium azide (3.9 g) and ammonium chloride (3.2 g) in DMT (17 ml) was stirred at 115 °C for 5 days. To the reaction mixture was added water, which was neutralized with 1N-KC1, followed by extraction with ethyl acetate.

The organic layer was washed with water, dried and concentrated to dryness. The concentrate was purified by column chromatography on silica gel to give crude crystals . Recrystallization from ethyl acetate gave colorless needles (0.67 g, 34%), m.p. 134-136°C. 115437/2 Elemental Analysis for C27H2sN50: . ι/2Κ·,0 : C(%) K(%) N(%) Calcd : 68.19; 5.72; 17.67 ":' Found : 63.46; 5.77; 17.31 1H-NMR(200MKz/CDCl3) S: 0.83(3K,t), 1.18-1.37 ( 2H,m) , 1.50-1.65(2H,m) , 2.33(2H,t), 3.90(3H,s), 5.24(2H,s), 6.68(2H,d), 6.91(2K,d), 7.06(lH,d), 7.28-7.33(lK,m) , 7.54-7.69 ( 3H,m) , 7.87(lH,dd), 8.00(lE,dd).

IR ( Br ) cm"1 : 1720, 1615, 1515, 1435, 1410, 1340, 1300, 1280, 1220, 1085, 770, 750.

Reference Example 44 2-Butyl-l-r Γ 2 ' -{ lH-tetrazol-5-vHbiphenyl-4-yl Imethyl 1benzimidazole-5-carboxylic acid A mixture of methyl 2-butyl-l- [ [ 2 ' - ( lH-tetrazol-5-yl )biphenyl-4-yl jmethyl ]benzimidazole-5-carboxylate (0.3 g) in methanol (3 ml) containing 2N NaOH (1 ml)' was heated under reflux for two hours. The reaction mixture was concentrated to dryness, and was then dissolved in water. The aqueous solution was made acidic with 1N-HC1 to give crystals. Recrystallization from acetonitriie-methanol afforded colorless crystals (0.23 g, 83%), ra.p. 180-182°C.

Elemental Analysis for C2sK24N602: C(%) H(%) N(%) Calcd : 68.16; 5.49; 19.08 Found : 68.43; 5.27; 18.88 1K-NIiR(200MK2,DMSO-ds) S: 0.8S(3K,t), 1.28-1.46 ( 2H,m) , 1.63-1.78 ( 2H,m) , 2.89(2K,t), 5.58(2H,s), 7.07 (4H,s), 7.47-7.70(5H,m) , 7.86(lH,dd), 8.18 (lH,s) .

Reference Example 45 Met yl 3-valerylaminobenzoate To a solution of methyl 3-aminobenzoate (6.0 g) and triethylamine (4.5 g) in methylene chloride (90 ml) was added dropwise, while stirring under ice-cooling, valeryl chloride (4.8 g). The mixture was stirred for one hour. The reaction mixture was washed with an aqueous solution of sodium bicarbonate, dilute hydrochloric acid and water, followed by drying and concentration to dryness. The concentrate was crystallized from ethyl acetate - hexane to afford colorless prisms (8.1 g, 87%), m.p. 101-102°C. lH*?NMR(90MHz,CDCl3) S: 0.93(3H,t), 1.2-1.9 ( 4H,m) , 2.37(2H,t), 3.90(3H,s), 7.36(lH,t), 7.5(lH,br s), 7.70-7.95(2H,m), 8.03(lH,t).

Reference Example 46 Methyl 4-nitro-3-valerylaminobenzoate To a solution of methyl 3-valerylaminobenzoate (2.3 g) in acetic anhydride (12 ml) was added dropwise fuming nitric acid (1.4 ml) while stirring undgr ice- cooling. To the mixture was added one drop of cone, sulfuric acid, which was stirred for two hours. To the reaction mixture was added ice-water, which was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium bicarbonate and water, which was then dried. The solvent was evaporated to dryness, and the residue was purified by column chromatography on silica gel to afford a brown oil (1.0 g, 36%) .

^-NM ( 9 OMHz , CDC13 ) 5: 0.96(3H,t), 1.1-1.9 ( 4H,m) , 2.51(2H,t), 3.96(3H,s), 7.80(lH,dd), 8.26(lH,d) ,9.41(lH,d) , 10.23(lH,br s).

IR(neat)cm_1: 3380, 1730. 1615, 1590, 1535, 1500, 1440, 1420, 1325, 1310, 1280, 1250, 1210, 1160, 1110, 1070, 845, 775, 740.

Reference Example 47 Methyl 3-ΓΝ- ( 2 ' -cvanobiphenyl-4-yl Tmethyl-N- valerylamino 1 -4-nitrobenzoate A mixture of methyl 4-nitro-3-valerylaminobenzoate (1.0 g), 4-( 2-cyanophenyl)benzyl bromide (0.97 g) and potassium carbonate (0.55 g) in DMF (10 ml) was stirred for two days at room temperature. To the reaction mixture was added water, which was extracted with ethyl acetate. The organic layer was washed with water and dried. The solvent was distilled off, and the residue was purified by column chromatography on silica gel to afford a pale yellow oil (1.24 g, 73%). 1H-NMR( 200MHz , CDC13) S: 0.84(3H,t), 1.17-1.30 ( 2H,m) , ^ 1.56-1.71(2H,m) , 1.80-2.08 ( 2H,m) , 3.92(3H,s) ,4.43(lH,d) , 5.37(lH,d), 7.26(2H,d), 7.40-7.51(4H,m) , 7.60-7.69 ( 2H,m) , 7.75(lH,d), 7.97(lH,d), 8.16(lH,dd).

IR(neat)cm_1: 2220, 1735, 1675, 1600, 1580, 1530, 1480, 1435, 1420, 1390, 1350, 1285, 1220, 1200, 1115, 1090, 825, 775, 765.

Reference Example 48 Methyl 2-butyl-l- Γ ( 2 ' -cvanobiphenyl-4-vHmethyl 1 benzimidazole-6-carboxylate To a solution of methyl 3-[N- ( 2 ' -cyanobiphenyl-4- yl)methyl-N-valerylamino]-4-nitrobenzoate (1.2 g) in methanol (10 ml) containing cone. HCl (1.3 ml), was added, while stirring at room temperature, iron powder (0.45 g) in portions. The mixture was stirred for 3 hours at 70-80°C. To the reaction mixture were added water and ethyl acetate, which was made basic with an aqueous solution of sodium bicarbonate. Precipitates then separated were filtered off . The organic layer separated from the filtrate was washed with water and dried. The solvent was evaporated to dryness, and the residue was purified by column chromatography on silica gel. Crude crystals thus obtained were recrystallized from ethyl acetate to give colorless needles (0.5. g, 45%) , m.p. 166-167°C.

Elemental Analysis for C27H25N302: C(%) H(%) N(%) Calcd : 76.57; 5.95; 9.92 •Found : 76.39; 6.05; 9.79 1H- MR(200MHz,CDCl3) δ: 0.94(3H,t), 1.35-1.5 ( 2H,m) , 1.79-1.94(2H,m) , 2.88(2H,t), 3.92(3H,s), 5.47(2H,s), 7.14(2H,d),: 7.40-7.53 ( 4H,m) , 7.60- 7.68(lH,m), 7.74-7.80 ( 2H,m) , 7.96-8.02 ( 2H,m) .

IR(KBr)cm_1: 2210, 1715, 1620, 1580, 1510, 1480, 1460, 1425, 1410, 1340, 1325, 1280, 1270, 1250, 1230, 1185, 1105, 1080, 770, 760, 745.

Reference Example 49 Methyl 2-butyl-l- Γ Γ 2 ' - ( lH-tetrazol-5-yl ) biphenyl-4-yllmethyl 1 benzimidazole-6-carboxylate A mixture of methyl 2-butyl-l-[ 2 ' - ( cyanobiphenyl-4-yl)methyl]benzimidazole-6-carboxylate (0.5 g), sodium azide and ammonium chloride (1.15 g) in DKF (5 ml) was stirred at 115°C for 3.5 days.. o the reaction mixture was added water, which was made acidic with 1N-HC1, followed by extraction with ethyl acetate. The organic layer was washed with water, dried and concentrated to dryness. The concentrate was purified by column chromatography on silica gel. Crude crystals thus obtained were recrystallized from ethyl acetate -methanol to afford colorless crystals (0.23 g, 41%), m.p. 224-225°C.

Elemental Analysis for C27H26H602: C(%) H(%) N(%) Calcd : 68.98; 5.66; 17.88 Found : 68.89; 5.68; 17.66 1H-NMR( 200MHz , DMSO-d6 ) S: 0.87(3H,t), 1.26-1.45 ( 2H,m) , 1.63-1.78(2H,m) , 2.85(2H,t), 3.85(3H,s), 5.62(2H,s), 7.00(2H,d), 7.07(2H,d), 7.48- 7.70(5H,m), 7.82(lH,dd), 8.14(lH,s).

IR( Br)cm_I: 1725, 1460, 1450, 1435, 1340, 1265, 1235, 775, 760, 745. - Reference Example 50 2-Butyl-l- Γ Γ 2 / - ( lH-tetrazol-5-yl Tbiphenyl-4- yl ^methyl 1 benzimidazole-6-carboxylic acid A solution of methyl 2-butyl-l-[2'-(lH-tetrazol-5- yl )bipheny1- -yl )methyl ]benzimidazole-5-carboxylate (0.1 g) in methanol (5 ml) containing 1 N NaOH (0.5 ml) was heated for 5 hours under reflux. The solvent was evaporated to dryness and to the residue was added 1N-HC1 (0.5 ml), which was extracted with chloroform. The organic layer was washed with water, dried and concentrated to dryness. Crude crystals thus obtained were recrystallized from methanol - ethyl acetate to afford colorless crystals (60 mg, 58%), m.p. 258-259°C (decomp . ) .

Elemental Analysis for C26H24N602- l/2EtOAc : C(%) H(%) N(%) Calcd : 67.73; 5.68; 16.92 Found : 67.79; 5.50; 16.89 1H-NMR(200MHz,DMSO-ds) S: 0.87(3H,t), 1.27-1.45 ( 2H,m) l".63-"l.79(2H,m), 2.85(2H,t), 5.60(2H s)/ 7.00(2H,d), 7.08(2H,d), 7.48(5H,m), 7.84(lH,dd), 8.11(lH,s) .

IR( Br)cm_1: 1730, 1460, 1410, 1335, 1285, 1265, 1225, 780, 760.

Reference Example 51 Methyl 2-amino-5-methyibenzoate A mixture of 2-amino-5-methyl benzoic acid (10 g) in methanol (50 ml) containing cone, sulfuric acid (5.5 ml) was heated for 19 hours under reflux. The solvent was distilled off, and the residue was dissolved in water. The solution was neutralized with an aqueous sodium hydroxide, followed by extraction with ethyl acetate. The organic layer was dried and concentrated to afford a pale brown oil (8.1 g, 74%).

^-NMR( 90MHz ,CDC13 ) 5: 2.24(3H,s), 3.89(3H,s), 5.55(2H/s), 6.59(lH,d), 7.10(lH,dd), 7.68(lH,d).

Reference Example 52 Methyl 5-methyl-2-valerylaminobenzoate To a solution of methyl 2-amino-5-methylbenzoate (8.1 g) and triethylamine (6.0 g) in methylene chloride - 49 - 115437/2 (50 ml) was added dropwise, while stirring under ice-cooling, valeryl chloride (6.5 g) . The reaction mixture was allowed to stir for two hours, washed with an aqueous solution of sodium carbonate, dilute hydrochloric acid and water, followed by drying. The solvent was evaporated to dryness to give a pale brown oil (12.8 g, 99%). lH- KR(90MKz,CDCl3) S: 0.95(3H,t), 1.2-1.9 ( H,m) , 2.33(3H,s), 2.43(2K,t), 3.93(3H,s), 7.34(lH,dd), .7.82(lH,d) , 8.62(lH,d) .

Reference Example 53 Methyl 5-methyl-3-nitro-2-valerylaminobenzoate To a mixture of methyl 5-methyl-2-valerylaminobanzoate (12.8 g) in acetic anhydride (5.9 g) was added dropwise, while stirring under ice-cooling, fuming nitric acid (6.7 ml), followed by stirring for 3 hours . To the reaction mixture was added ice water, which was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium bicarbonate and water, which was then dried. The solvent was evaporated to dryness, and the residue was purified by column chromatography on silica gel. Crystals thus obtained were recrystallized from isopropyl ether gave colorless crystals (8.5 g, 60%), m.p. 59-60°C. lE-NMR( 200MHz ,CDC13) : 0.94(3K,t), 1.31-1.50 ( 2H,m) , 1.63-1.78(2H,m) , 2.43(2H,t), 3.95(3H,s), 7.90(lK,d), 8.00(lH,d), 10.16(1K,S).

Reference Example 54 Methyl 2-Γ Γ N- ( 2 ' -cvanobiphenyl-4-yl ^methyl-N-valeryl 1 amino 1 -5-methyl-3-nitrobenzoate A mixture of methyl 5-methyl-3-nitro-2-valeryla inobenzoate (5.89 g), 4- ( 2-cyanophenyl)benzyl bromide (5.44 g) and potassium carbonate (3.0 g) in DMF (50 ml) was stirred for 15 hours at 50 °C. To the reaction mixture was added water, which was extracted with ethyl acetate, and the organic layer was dried. The solvent was distilled off, and the residue was purified by column chromatography on silica gel.

Crystals thus obtained were recrystallized from ethyl acetate - hexane to afford colorless crystals (3.1 g, 32%) , m.p. 141-142°C. lH-NMR( 200MHz,CDC13) S: 0.85(3H,t), 1.17-1.36 ( 2H,m) , ^ 1.60-1.75(2H,m) , 2.05-2.15 ( 2H,m) , 2.49(3H,s), 3.64(3H,s), 4.62(lH,d), 4.94(lH,d), 7.21(2H,d), 7.38-7.50(4H,m) , 7.59-7.68 ( lH,m) , 7.73-7.77 ( 3H,m) , 7.89(lH,m) .

Reference Example 55 Methyl 2-butyl-l-r ( 2 ' -cvanobiphenyl-4-yl ^methyl 1 -5-methylbenzimidazole-7-carboxylate To a solution of methyl 2-[ [N- ( 2 ' -cyanobiphenyl-4-yl )methyl-N-valeryl ]amino] -5-methyl-3-nitrobenzoate (3.1 g) in a mixture of cone. HCl (4.4 ml) and methanol (22 ml) was added, while stirring, iron powder (1.6 g) in portions . The mixture was heated for 7 hours under reflux. Insoluble materials were filtered off, and the filtrate was concentrated. To the concentrate was added water, which was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium bicarbonate and water, followed by drying. The solvent was distilled off and the residue was purified by column chromatography on silica gel to afford a pale brown oil (2.8 g, quantitatively) . 1H-NMR(200MHz,CDCl3) δ: 0.95(3H,t), 1.37-1.56 ( 2H,m) , 1.79-1.94(2H,m) , 2.47(3H,s), 2.90(2H,t), 3.71(3H,s), 5.79(2H,s), 6.96(2H,d), 7.39- 7.46(5H,m), 7.58-7.66 ( lH,m) , 7.73-7.77 ( 2H,m) .

IR(neat)cm_1: 2220, 1720, 1520, 1480, 1435, 1410, 1305, 1245, 1215, 1195, 1110, 1040, 780, 760.

Reference Example 56 Ethyl 2-amino-6-methylbenzoate This compound was prepared according to the procedure for Reference Example 51.

Oil (yield 82%) .

^-N ( 90MHz , CDC13) δ: 1.34(3H,t), 2.43(3H,s), 4.35(2H,q), 5.06(2H,br s), 6.50(2H,d), 7.07(lH,t) Reference Example 57 Ethyl 6-methyl-2-valerylaminobenzoate This compound was prepared according to the procedure for Reference Example 52. m. . 56-57°C (yield 70%). lH-NMR(90MHz,CDCl3) δ: 0.93(3H,t), 1.39(3H,t), 1.18-1.87(4H,m) , 2.37(2H,t), 2.46(3H,s), 4.41(2H,q), 6.94(lH,d), 8.27(lH,d), 7.32(lH,t), 9.69(lH,br s) .

Reference Example 58 Ethyl 6-methyl-3-nitro-2-valerylaminobenzoate This compound was prepared according to the procedure for Reference Example 53. m.p. 103-104°C (yield 52%).

^-N R( 90MHz , CDCI3 ) S: 0.93(3H,t), 1.35(3H,t), 1.17-1.85(4H,m) , 2.38(2H,t), 2.49(3H,s), 4.38(2H,q), 7.14(lH,d), 7.97(lH,d).

Reference Example 59 Ethyl 6-methyl-3-nitro-2-r Γ 2 ' - ( N-triphenylmethyl-lH- tetrazol-5-yl ^biphenyl-4-yl1methyl-N- valeryl 1 aminobenzoate This compound was prepared according to the procedure for Reference Example 54.

Oil (yield 80%) . lH-NMR( 200MHz ,CDC13) 5: 0.86(3H,t), 1.34(3H,t), 1.20-1.45(2H,m), 1.60-1.78 ( 2H,m) , 2.14(2H,t), 2.40(3H,s), 4.09(lH,d), 5.28(lH,d), 4.23- 4.42(2H,m), 6.81-6.96(10H,m) , 7.19-7.53 ( 13H,m) , . 7.69(lH,d), 7.88(lH/dd).

Reference Example 60 Methyl 2-amino-5-chlorobenzoate To a solution of 2-amino-5-benzoic acid (25.5 g) in methanol (300 ml) was added cone, sulfuric acid (12 ml). The mixture was heated for 24 hours under reflux. The reaction mixture was concentrated, to which was added water (300 ml), followed by neutralization with potassium carbonate. The mixture was extracted with ethyl acetate . The organic layer was washed with water and dried, then the solvent was distilled off to give crude crystals. Recrystallization from isopropyl ether - benzene gave pale yellow crystals (17.1 g, 63%), m.p. 68-70°C Reference Example 61 Hethyl 5-chloro-2-valerylaminobenzoate To a solution of methyl 2-amino-5-chlorobenzoate (15 g) and triethyiamine (12 ml) in methylene chloride (150 ml) was added dropwise, while stirring under ice- cooling, valeryl chloride (10 ml). The mixture was stirred at room temperature for further two hours . The reaction mixture was washed with an aqueous solution of sodium bicarbonate and water, followed by drying. The solvent was distilled off to afford a pale yellow crystals (13.4 g, 61%), m.p. 48-49°C.

Reference Example 62 Hethyl 5-chloro-3-nitro-2-valerylaminobenzoate To a solution of methyl 5-chloro-2- valerylaminobenzoate (13.4 g) in acetic anhydride (10 ml) was added dropwise, while stirring under ice- cooling, fuming nitric acid. The mixture was stirred for one hour at room temperature, to which was added ice. water. The mixture was allowed to stand to give crystals. Recrystallization from isopropyl ether afforded pale yellow crystals (9.5 g, 61%), m.p. 84- 85°C.

Reference Example 63 ethyl 5-chloro-2-r ΓΝ-ί 2 ' -cvanobiohenyl-4-yl ^methyl-N- valeryl 1 amino 1 -3-nitrobenzoate A mixture of methyl 5-chloro-3-nitro-2- - - valerylaminobenzoate (3.15 g), 4- ( 2-cyanopher.yl ) benzyl bromide (2.8 g) and potassium carbonate (1.8 g) in DMF (50 ml) was stirred for 3 hours at room temperature. The reaction mixture was concentrated to dryness, and the concentrate was extracted with ethyl acetate and H20. The organic layer was washed with water and dried. The solvent was distilled off to give crystals. Recrystallization from ethyl acetate - benzene afforded colorless crystals (4.0 g, 79%), 137-138°C.

Reference Example 64 Methyl 5-chloro-3-nitro-2-f Γ 2 ' - ( N-triDhenylmethyl-lH-tetrazol-5-yl ^biDhenyl-4-yllmethyl-N-valeryl T aminobenzoate To a solution of methyl 5-chloro-3-nitro-2-valerylaminobenzoate (0.93 g) in DMF (10 ml) were added potassium carbonate (0.5 g) and N-triphenylmethyl-5-[ 2 ' - ( 4-bromomethyl ) biphenylmethyl ] tetrazole (1.84 g). The mixture was stirred for 19 hours at room temperature . To the reaction mixture was added water (50 ml), whic'rwas then extracted with ethyl acetate. The organic layer was washed with water, dried and . the solvent was distilled off. The residue (3.8 g) was purified by column chromatography on silica gel to give pale yellow crystals (1.89 g, 82%).

^-NM ( 200MHz , CDC13 ) 5: 0.8o(3H,t), 1.17-1.35 ( 2K,m) , 1.56-1.80(2H,m), 2.03-2.10 ( 2H,m) , 3.63(3K,s), 4.41(lH,d), 4.82(IK,d), 6.76-S .98 ( 10H,m) , 7.20-7.54(12H,m) , 7.88(lH,d), 7.90-7.93 ( lH,m) , 7.98(lH,d) .

IR(XBr)cm" :: 1750, 1690, 1555, 1295, 1270, 1225, 760, 710.

Reference Example 65 Methyl 2-butyl-5-chloro-l- Γ ( 2 ' -cvanobiohenyl-4-yl methyl 1 benzimidazole-7-carboxylate To a solution of methyl 5-chloro-2- [ - ( 2 ' -cyanobiphenyl-4-yl )methyl-N-valeryl ] amino-3- 5437/2 nitrobenzoate (3.33 g) in a mixture of cone. HC1 (4 ml) and methanol (50 ml) was added, while stirring at room temperature, iron powder (95% purity, 1.1 g) in portions. The mixture was stirred for 24 hours at 80 °C. Then, insoluble materials were filtered off, and the filtrate was concentrated to dryness . The concentrate was subjected to extraction with ethyl acetate - water. The organic layer was washed with an aqueous solution of sodium bicarbonate and water, which was then dried and concentrated. The solvent was distilled off, and the residue was purified by column chromatography on silica gel to afford colorless needles (1.83 g, 61%). lH- MR( 200MHz, CDC13) 5: 0.96(3H,t), 1.38-1.57 ( 2H,m) , 1.80-1.95(2H,m) , 2.92(2H,t), 3.72(3H,s), 5.79(2H,s), 6.94(2H,d), 7.41-7.49 ( H,m) , 7.59- 7.63(lH,m), 7.73-7.78 ( lH,m) , 7.61(lH,d), 7.91(lH,d).

Reference Example 56 Ethyl 2-carboxy-3-nitrobenzoate A solution of 3-nitrophthalic acid (35 g) in ethanol (300 ml) containing cone, sulfuric acid (20 ml) was heated for 24 hours under reflux. The solvent was distilled off, and the residue was poured into ice- water (700 ml), which was extracted with ethyl acetate.

The organic layer was washed with water, and then extracted with an aqueous solution of potassium carbonate . The aqueous layer was made acidic with hydrochloric acid, followed by extraction with methylene chloride. The organic layer was washed with water and dried. The solvent was distilled off to give a solid product (29 g, 74%), which was used to the subsequent reaction without purification.

:H-NMR(90MKz,CDCl3) S: 1.43(3H,t), 4.47(2H,q), 7.70(lH,t), 8.40(2K,d), 9.87 ( lH,br s ) .

IR(Nujol)cm"1: 1725, 1535, 1350, 1300, 1270.

Reference Example 67 Ethyl 2-t-butoxycarbonylamino-3-nitrobenzoate A mixture of ethyl 2-carboxy-3-nitrobenzoate (23.9 g) and thionyl chloride (12 ml) in benzene (150 ml) was heated for 3 hours under reflux. The resultant solution was concentrated to dryness to give acid chloride (26 g, quantitatively), which was dissolved in methylene chloride (20 ml). The solution was added dropwise to a mixture of sodium azide (9.75 g) in DMF (20 ml) while stirring vigorously. The reaction mixture was poured into a mixture of ether-hexane (3 ml : 1,200 ml) and water (250 ml), and the whole mixture was shaken. The organic layer was washed with water and dried, followed by distilling off the solvent. The residue was dissolved in t-butanol (200 ml), and the temperature of the solution was raised, while stirring gradually, followed by heating for two hours under reflux. The reaction mixture was concentrated under reduced pressure to obtain an oil (30 g) . 1H-NMR( 90MHz , CDC13 ) S: 1.40(3H,t), 1.53(9H,s), 4.43(2H,q), 7.23(lH,t), 8.03-8.27 ( 2H,m) , 9.70(lH,br s) .

IR NeatJcm-1: 3320, 2980, 1740, 1700, 1585, 1535, 1500, 1440, 1375, 1265, 1155.

Reference Example 68 Ethyl 2-Γ ( 2 ' -cvanobiOhenyl-4-yl methyl lamino-3- nitrobenzoate To a solution of ethyl 2-t-butoxycarbonylamino-3- nitrobenzoate (20 g) in THF (50- ml) was added, while stirring under ice-cooling, sodium hydride (60% oil, 2.8 g). To the mixture were then added 4- (2- cyanobiphenyl )methyl bromide (18 g) and potassium iodide (0.36 g), followed by stirring for 15 hours at room temperature. The reaction mixture was heated for further 4 hours under reflux. The solvent was distilled off, and the residue was extracted with water (250 ml) and ether (200 ml). The organic layer was concentrated to give a yellow oil, which was dissolved in a mixture of trifluoroacetic acid (60 ml) and methylene chloride (40 ml), and the solution was stirred for one hour at room temperature . The reaction mixture was concentrated to dryness and to the concentrate was added ethyl ether (200 ml) to give crystals. The crystals were collected by filtration, washed with ether and dried to afford pale yellow crystals (22.1 g, 85%), m.p. 119-120°C. 1H-NMR(90MHz,CDCl3) S: 1.37(3H,t), 4.23(2H,s), 4.37(2H,q), 6.37(lH,t), 7.33-7.83 ( 9H,m) , 7.97- 8.20(2H,m) .

IR NujolJcm"1: 3280, 2220, 1690, 1575, 1530, 1480, 1450, 1255, 1125, 1105, 755.

Reference Example 69 Ethyl 3-amino-2-r ( 2 ' -cvanobiOhenyl-4-yl methyl 1 amino benzoate To a solution of ethyl 2-[ ( 2 ' -cyanobiphenyl-4-yl)methyl]amino-3-nitrobenzoate (5.5 g) in THF (50 ml) was added Raney nickel (5 g). Catalytic reduction was conducted at room temperature under atmospheric pressure. The catalyst was filtered off, and the filtrate was concentrated to give a yellow oil (5 g, quantitatively) .

S: 1.30(3H,t), 4.23(2H,s), 4.27(2H,q), 6.87-7.03 ( 2H,m) , 7.33-7.87 ( 9H,m) .

IR(Neat)cm_1: 3435, 3350, 2980, 1690, 1615, 1465, 1365, 1280, 1240, 1215, 1190, 1065, 755.

Reference Example 70 Ethyl 2-butyl-l-r ( 2 ' -cvanobiphenyl-4- yl )methyl lbenzimidazole-7-carboxylate A solution of ethyl 3-amino-2-[ ( 2 ' -cyanobiphenyl- 4-yl)methyl]benzoate (0.31 g) and ethyl butyroimidate (0.18 g) in ethanol (2 ml) was stirred for 2 hours at 70°C. The reaction mixture was concentrated to dryness, and the concentrate was extracted with ethyl acetate and an aqueous solution of sodium bicarbonate. The organic layer was washed with water, dried and concentrated to give crystals. Recrystallization from ethyl acetate - hexane afforded pale yellow needles (0.22 g, 60%), m.p. 112-114°C. lH-NMR(90MHz,CDCl3) S: 0.93(3H,t), 1.20(3H,t), 1.33-2.07(4H,m) , 2.90(2H,t), 4.20(2H,q), 5.87(2H,s), 7.00(2H,d), 7.17-8.03 ( 9H,m) .

IR(Nujol)cm"1: 2220, 1725, 1480, 1450, 1420, 1400, 1285, 1255, 1245, 1190, 1110, 750.

Reference Example 71 2-Butyl-l- Γ ( 2 ' -cvanobiOhenyl-4-yl ^methyl 1 -7- hvdroxymethylbenzimidazole To a solution of methyl 2-butyl-l-[ ( 2 ' - cyanobiphenyl-4-yl )methyl]benzimidazole-7-carboxylate (10 g) and NaBH4 (2.2 g) in tetrahydrofuran (100 ml) was added dropwise methanol (19 ml) during 80 minutes. The mixture was heated for further 27 hours under reflux, and the reaction mixture was concentrated to dryness. To the concentrate was added water, which was neutralized with cone. HC1. Crystals thus separated were collected by filtration. Recrystallization from methanol afforded colorless needles (8.8 g, 93%), m.p. 203-204°C.

Elemental Analysis for C^H^^O: C(%) H(%) N(%) Calcd : 78.96; 6.37; 10.62 . Found : 79.24; 6.36; 10.69 NMR(200MKz,CDCl3) S: 0.94(3H,t), 1.36-1.55 ( 2H,m) , 1.79-1.95(2H,m) , 2.85(2H,t), 4.66(2H,d), 5.82(2H,s), 7.04(2H,d), 7.10(lH,dd), 7.18- 7.26(lH,m), 7.40-7.52(4H,m) , 7.64(lH,dt).

IR ( Br) cm"1 : 3200, 2210, 1510, 1480, 1455, 1425, 1410, 1280, 1015, 765, 750.

Reference Example 72 ¾ chloromethylbenzimidazole To a solution of 2-butyl-l- [ ( 2 ' -cyanobiphenyl-4-yl )methyl ] -7-hydroxybenzimidazole (5.4 g) and thionyl chloride (8.3 g) in chloroform (80 ml) was added a catalytic amount of DMF (one drop), then the mixture was heated for one hour under reflux. The reaction mixture was washed with an aqueous solution of sodium bicarbonate and water, followed by drying and concentration to dryness. The concentrate was crystallized from ethyl acetate - hexane to afford colorless needles (5.3 g, 92%), m.p. 144-145°C.

Elemental Analysis for C26H24C1 3: C(%) H(%) N(%) Calcd : 75.44; 5.84; 10.15 Found : 75.29; 5.87; 10.04 NJiR( 200MHz ,CDC13 ) S: 0.96(3K,t), 1.38-1.57 ( 2H,m) , 1.82-1.97(2H,m) , 2.88(2H,t), 4.60(2H,s), 5.78(2H,s), 7.07(2H,d), 7.14(lH,dd), 7.21(lH,d), 7.41-7.54(4K,m) , 7.60-7.69 ( lH,m) , 7.75-7.8 ( 2H,m) .

IRi BrJcm-1: 2210, 1515, 1480, 1450, 1425, 1400, 1350, 1280, 760, 745, 690.

Reference Example 73 2-Sutyl-l-r f 2 ' -cvanobiphenyl-4-yl ^methyl 1 -7-cvanomethylbenzimidazole A mixture of 2-butyl-l- [( 2 ' -cyanobiphenyl-4-yl )methyl ] -7-chloromethylbenzimidazole (0.83 g) and sodium cyanide (0.12 g) in DMF (10 ml) was stirred for 22 hours at room temperature. To the- eaction mixture was added water, was then extracted with ethyl acetate. The organic layer was washed with water and dried. The solvent was distilled off, and the residue was crystallized from ethyl acetate to give colorless prisms (0.76 g, 94%), m.p. 180-181°C.

Elemental Analysis for C27H24N4: C(%) H(%) N(%) - 59 - Λ5437/2 Calcd : 80.17; 5.98; 13.85 Found : 80.22; 6.17; 13.69 Reference Example 74 Ethylf Γ 2-butyl-l-i' 2 ' -cvanobiahenyl-4-yl Tmethyl 1benzimidazol-7-yl1 acetate A mixture of 2-butyl-l-[ ( 2 ' -cyanobiphenyl-4-yl)methyl] -7-cyanomethylbenzimidazol (0.76 g) in 3.5N-hydrochloride in ethanol (10 ml) was heated for 2.5. hours under reflux. The reaction mixture was diluted with water, made basic with an aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was washed with water and dried. The solvent was distilled off, and the residue was purified by column chromatography on silica gel to give a colorless oil (0.9 g, quantitatively) .

NMR( 200MHz ,CDC13) S: 0.94(3H,t), 1.23(3H,t), 1.37-1.55(2H,m) , 1.80-1.95 ( 2H,m)-, 2.85(2H,t), 3.65(2H,s), 4.10(2K,q), 5.73(2H,s), 7.01- 7.07(3K,m), 7.21(lH,t), 7.74-7.68 (5H,m) , 7.71- 7.78 ( 2H,m) .

IR(neat)cm_1: 2210, 1730, 1510, 1475, 1435, 1400, 1365, 1350, 1275, 1040, 760, 735.

Reference Example 75 methylbenzimidazole A mixture of 2-butyl-l- [ ( 2 ' -cyanobiphenyl-4-yl )methyl ] -7-chloromethylbenzimidazole (0.62 g), tributyltin hydride (3.0 g) and perbenzoic acid (catalytic amount) in toluene (20 ml) was heated for 5.5 hours under reflux in nitrogen atmosphere . The reaction mixture was concentrated, purified by column chromatography on silica gel and recrystallized from ethyl acetate - hexane to give colorless crystals (0.5 g, 88%), m.p. 115-116°C.

Elemental Analysis for C25K25N1: C(¾) K(%) (¾) ' 1 75437/2 Calcd : 82.29; 5.64 11.07 Found :: 82.30 ; 5.74; 10.94 Mi?.( 200ME2,CDClj) S: 0.93(3H,t), 1.35-1.53 ( 2H/m) , 1.77-1.92(2H,m) , 2.51(3E/s), 2.82(2H,t), 5.64(2H,s), 5.94(iH,d), 7.05 ( 2H,d) , 7.15 ( 1H, t ) , 7.41-7.53(4H, m) , 7.60-7.68 ( 2K,m) , 7.75(lH,d).

IR(: Reference Example 76 hvdroxyben-imidazols o a solution cf 2-butyi-l-[ ( 2 ' -cyanobipher.yi-4-yi )methyi ] -7-methoxy-benzimidazoie (1.2 g) in ir.ethylene chloride (5 ml) was added boron tribromide (1.7 g) at -72 °C in nitrocen atmosphere. The mixture was stirred for 8 hours at rccm temperature, to which was added water, followed by stirring for a further one hour. The reaction mixture was made basic with 6 NaOH, followed by extraction with ethyl acetate. The organic layer was washed with water, dried and concentrated. The concentrate was purified by column chromatography on silica gel.

Crude crystals thus obtained were recrystallizsd from ethyl acetate - hexar.e to give colorless prisms (0.69, 63%), m.p. iS5-i35°C.

Elemental Analysis for CxH::N:0: C(%) H(%) N(%) Calcd : 78.71; 6.03; 11.02 Fc r.c : 73.70 ; 5.07; 11.01 1H-^-i (200JiH-:,CDCl3) S: 0.81(3H,t), 1.22-1.42 ( 2H,m) , 1.65-l.Sl(2H,ra) , 2.80(2H,t), 5.8i(2H,s), 6.7i(lH,c), 7.00 ( lH,t) , 7.19-7.26 ( 3H,m) , 7.38- 7.50(4H,m), 7.6i(lK,m), 7.74(4H,d).

IR( 3r)cm-L: 2210, 1615, 15S0, 1500, 1475, 1440, 1410, 1355, 1290, 1195, 1150, 1055, 780, 755, 725.

Reference Example 77 2-Methoxy-6-nitroanilir.e A mixture of 2-amino-3-nitrophenol (7.7 g) and potassium carbonate (7.6 g) in DMT (15 ml) was stirred for 30 minutes at room temperature, to which was then added methyl iodide (7.8 g) . The mixture was stirred for a further- 5 hours at room temperature.- To the reaction mixture was added water, was then extracted with ethyl acetate . The organic layer was washed with water and, then, dried. The solvent was distilled off to give crude crystals and recrystallization from isopropyl ether gave orange prisms (6.9 g, 82%), m.p. 76-77°C.

Reference Example 78 N- ( 2-Methoxy-6-nitroohenyl ) valeroamide To a mixture of 2-methoxy-6-nitroaniline (5.9 g) in valeric anhydride (14 g) was added a catalytic amount of cone, sulfuric acid, which was stirred for 1.5 hour at 130-140°C. To the reaction mixture was added water, which was made basic with 6N NaOH . The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and dried. The solvent was distilled off. The residue was . purified by column chromatography on silica gel. Crude crystals thus obtained were recrystallized from ethyl acetate -hexane to give colorless crystals (3.2 g, 36%), m.p. 113-114°C.

^-NMRi 90MHz, CDC13) S: 0.95(3H,t), 1.33-1.51 ( 2H,m) , 1.64-1.79(2H,m) , 2.42(2H,t), 3.94(3K,s), 7.14(lH,dd), 7.26 ( lH,t) , 7.51(lK,dd), 7.64(lE,brs) · IR( 3r)cm"1: 3300, 1670, 1600, 1590, 1545, 1520, 1485, 1460, 1430, 1360, 1275, 1055, 800, 735.

Reference Example 79 N-f 2 ' -CyanobiDhenyl-4-yl 'imethyl-N- ( 2-methoxy-6-nitroohenyl valeramide To a solution of N- ( 2-methoxy-6-nitrophenyl ) valeramide (3.2 g) in DMF (15 ml) was added, under ice-cooling,' sodium hydride (60% oil, 0.61 g) . The mixture was stirred for 20 minutes , was then was added 4- ( 2-cyanophenyl ) benzyl bromide (3.5 g), followed by stirring for one hour at room temperature. To the reaction mixture was added water, which was extracted with ethyl acetate. The organic layer was washed with water and dried. The solvent was distilled off, and the residue was purified by column chromatography on silica gel to give a yellow oil (5.8 g, quantitatively) . 1H- MR(90lfflz,CDCl3) S: 0.84(3H,t), 1.12-1.35 ( 2H,m) , 1.56-1.70(2H,m) , 1.91-2.23 ( 2H,m) , 3.61(3H,s), 4.42(lH,d), 5.20(lH,d), 7.03-7.12 ( lK,m) , 7.22(2K,d), 7.34-7.49(6H,m) , 7.63(lH,m), 7.74(lH,d).

IR(Neat)cm"1: 2220, 1670, 1535, 1480, 1390, 1275, 1050, 800, 760, 730.

Reference Example 80 2-Butyl-l- Γ ( 2 ' -cvanobjphenyl-4-yl ^methyl 1-7-rnethoxybenzimid zole To a solution of N- [ ( 2 ' -cyanobiphenyl-4-yl )methyl ] -N- ( 2-methoxy-6-nitrophenyl )valeramide (5.8 g) in methanol (50 ml) and cone. HCl (7 ml) was added, while stirring at room temperature, iron powder (2.3 g) in portions . The reaction mixture was heated for 5 hours under reflux, then the solvent was distilled off. To the residue were added ethyl acetate and water, which was made basic with 6N NaOK. Insoluble materials were filtered off, and the filtrate was allowed to form two layers . The organic layer was washed with water and dried, followed by removal of the solvent. The residue was recrystallized from ethyl acetate - hexane to afford colorless prisms (4.1 g, 80%), m.p. 127-128°C. 1H-NMR ( 20 OMHz , CDClj ) S: 0.91(3H,t), 1.32-1.51 ( 2H,m) , 1.73-1.89 (2H,m) , 2.79(2H/t) 3.83(3H,s), 5.71(2H,s), 6.69(lH,d), 7.11-7.19 ( 3H,m) , 7.38- 7.51(5H/m)/ 7.63 ( ΙΗ,πι) , 7.76(lH,d).

IR(KBr)cm'1: 2210, 1605, 1585, 1505, 1480, 1460, 1445, 1420, 1400, 1280, 1255, 1090, 770, 720.

Reference Example 81 2-Butyl-l-r ( 2 ' -cvanobjphenyl-4-yl ^methyl 1-7-methoxymethylbenzimidazole A mixture of 2-butyl-l-[ ( 2 ' -cyanobiphenyl-4-yl )methyl ] -7-hydroxymethylbenzimidazole (0.79 g), thionyl chloride (0.36 g) and DMF (catalytic amount) in chloroform (20 ml) was heated for one hour under reflux. The solvent was distilled off and the residue wars dissolved in methanol (15 ml). To the solution was added sodium methoxide (4.9 M methanol solution, 2 ml), followed by heating for 6 hours under reflux. The solvent was distilled off. To the residue was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and dried, followed by evaporation of the solvent. The residue was purified by column chromatography on silica gel to give an oil (0.48 g, 59%) . 1H-NMR( 90MHz , CDC13 ) S: 0.92(3H,t), 1.20-2.05 ( 4H,m) , 2.84(2H,t), 3.30(3H,s), 4.34 ( 2H, s ) , 5.7 ( 2H, s ) , 6.90-7.90(llH,m) .

IR(neat)cm"1: 2220, 1520, 1480, 1460, 1440, 1425, 1280, 1190, 760.

The following compounds (Reference Examples 82-84) were prepared according to the procedure for Reference Example 32.

Reference Example 82 Ethyl 2- Γ -acetyl-N- ( 2 ' -cvanobiphenyl-4- yl Imethyl 1 amino-3-nitrobenzoate Oil lH-NHR(90MHz,CDCl3) S: 1.30(3H,t), 1.97(3H,s), - 64 - 4.17(lH,d), 4.83(lH,d), 7.17-8.17 ( llH,m) .

IR(Neat)cm_1: 2985, 2230, 1730, 1675, 1600, 1540, 1390, 1365, 1285, 770.

Reference Example 83 Ethyl 2-rN-propionyl-N-( 2,-cyanobiphe yl-4-yl πιethyl 1 amino-3-nitrobenzoate Oil 1HTNMR( 90MHZ ,CDCl3) S: 1.13(3H,t), 1.27(3H,t), 2.17(2H,q), 4.13(2H,q), 4.77(lH,d), 4.83(lH,d), 7.10-8.17(llH,m) .

IR(Neat)cm_1: 2985, 2220, 1730, 1675, 1600, 1535, 1480, 1445, 1390, 1350, 1290, 1265, 1210, 770.

Reference Example 84 Ethyl 2- ΓΝ-isobutylyl-N- ( 2 ' -cyanobiphenyl-4-yl ^methyl 1 amino-3-hitrobenzoate Oil S: 1.07 ( 3H,d) , · 1.13 ( 3H,d) , 1.30(3H,t), 2.03-2.47(lH,m) , 4.20(2H,q), 4.70(lH,d), 5.13(lH,d), 7.17-8.27 ( lH,m) .

IR( Neat Jem"1: 2980, 2220, 1730, 1670, 1590, 1530, 1480, 1390, 1350, 1285, 1260, 1240, 1205, 765.

The following compounds (Reference Examples 85-87) were prepared according to the procedure for Reference Example 33.

Reference Example 85 Ethyl 1- Γ ( 2 ' -cvanobiphenyl-4-yl 1methyl 1 -2-methylbenzimidazole-7-carboxylate m.p. 167-168°C (yield 81%). 1H-NM ( 90MHz , CDCI3 ) δ: 1.20(3H,t), 2.63(3H,s), 4.20(2H,q), 5.83(2H,s), 7.00(2H,d), 7.17- 7.97(9H,m) .

IR(Neat)cm_1: 2220, 1705, 1395, 1280, 1265, 1210.

Reference Example 86 Ethyl 1-Γ ( 2 ' -cyanobiphenyl-4-yl Tmethyll-2- ethylbenzimidazole-7-carboxylate m.p. 163-164°C (yield 76%). 1H- MR(90MH2,CDC13) δ: 1.20(3H,t), 1.47(3H,t), 2.93(2H,q), 4.20(2K,q), 5.83(2H/s)/ 6.97(2H,d), 7.17-3.00(9H,m) .

IR(Nujol)c-n"1: 2220, 1720, 1480, 1450, 1420, 1400, 1380, 1280, 1250, 1200, 1145, 1110.

Reference Example 87 Ethyl 1-Γ ( 2 ' -cvanobiohenyl-4-yl ^methyll-2-isooroOylbenzimidazole-7-carboxylate . m.p. 107-108°C (yield 77%). 1H-NMR( 9 OMKz , CDC13 ) S: 1.17(3H,t), 1.43(6H,d), 3.03-""""" 3.47(lH,m), 4.17(2H,q), 5.87(2H,s), 6.93(2H,d), 7.17-7.80(8K,m), 7.97(lH,d).

IRiNujolJcm"1: 2220, 1730, 1440, 1400, 1280, 1250, 1205, 1140, 1110, 765, 740.

Reference Example 88 -- ~— ■ Ethyl 2-chloroms hyl-l- Γ ( 2 ' -cvanobiOhenyl-4- To a ice-ccoled solution of ethyl 3-amino-2-[ ( 2' -cyanobiphenyl-4-yl )methyl ]aminobenzoate (1.0 g) and triethylamine (0.3 g) in methylene chloride.. (10 ml) was added chloroacetyl chloride (0.24 ml) in portions. The mixture was allowed to stir for 13 hours and then evaporated to dryness to give a residue. The residue was washed with K20, dried and dissolved in EtOH (10 ml). To the solution was added conc-HCl (1 ml) and the solution was refluxed for 6 hours . The reaction solution was evaporated to dryness to give a residue and the residue was dissolved in methylene.'chloride and water. The solution was made basic with lN-NaOH and the organic layer was washed with water, dried and evaporated to dryness to give crystals.

Recrystallization from ethyl acetate-isopropyl ether gave colorless crystals. (0.88 g, 76%) 1H-NMR( 200MHz, CDClj) S: 1.21(3K,t), 4.21(2H,q), 4.83(2K,s), 6.02(2H,s), 7.02(2K,d), 7.29- 7.49(5H,m), 7.53-7.79 ( 3H,m) , 8.00 (lH,dd).

Reference Example 89 Ethyl 1- Γ ( 2 ' -cvanobiphenyl-4-yl ^methyl 1 -2-methoxymethylbenzimidazole-7-carboxylate A solution of ethyl 2-chloromethyl-l-[ ( 2 ' -cyanobiphenyl-4-yl)methyl]-benzimidazole-7-carboxylate (0.8 g) and NaOMe (1.08 g, 28% solution in methanol) in methanol (15 ml) was refluxed for 2 hours. The reaction solution was evaporated to dryness to give a residue and the residue was dissolved in CH2C12-H20.

The organic layer was washed with H20, dried and evaporated to dryness to give a syrup. The syrup was purified by column chromatography on silica gel to give a yellow syrup (0.4 g, 52%).

^-NMR(200MHz , CDC13 ) S: 3.43(3H,s), 3.72(3H,s), 4.78(2H,s), 5.97(2H,s), 6.99(2H,d)~, 7.25- 7.49(5H,m), 7.55-7.77(3H,m) , 7.99(lH,dd).

The following compounds " (Reference Examples 90-93) were prepared by a method similar to that of Reference Example 89.

Reference Example 90 Ethyl 1- Γ ( 2 ' -cyanobiphenyl-4-yl ^methyl 1 -2- ethoxymethylbenzimidazole-7-carboxylate pale brown syrup (92%) 1H- MR(200MHz,CDCl3) 5: 1.16{3ilf .) r 1.23(3H,t)f 3.59(2H,q), 4.21(2H,q), 4.82(2H,s), 5.99(2H/s), 6.99(2H/d)/ 7.24-7.45(5H,m) , 7.55-7.75 ( 3H,m) , 7.98(lH,dd).

Reference Example 91 Ethyl 1-Γ ( 2,-cvanobiphenyl-4-yl')methvn-2- methylthiomethylbenzimidazole-7-carboxylate pale yellow syrup (72%) 1H-NMR( 200MHz , CDC13 ) 5: 1.20(3H,t), 2.18(3H,s)/ 3.90(2H,s), 4.20(2H,q)/ 5.96(2H,s), 7.01(2H,d), 7.23-7.35( ^ , 11» ) , 7.37-7.50 ( 4H,m) , 7.59-7.80 (3H,m) , 7.97(lH,dd).

Reference Example 92 ethyl hiome~hylbe z imid z le-7 -carboxylate pale brow, syrup (S3%) lK-.NHR( 200MHz,CDCl3) δ: 1.20(3K,t), 1.27(3H,t), 2.62(2Η,ς), 3.96(2K,s), 4.20(2Κ,ς), 6.00 ( 2Ξ, s ) , 7.01(2H,c), 7.29(lH,t), 7.38-7.4 ( 4H,m) , 7.57- 7.78(3H,m), 7.96 ( lK,cd) .

Reference Example 93 ½-NMR(CDCl3 ) δ: 1.20 (3H, t), 1.94 (3H, s), 4.21 (2H, q) 5.43 (2H, s), 5.94 (2H, s), 6.98 (2H, d) , 7.33 (1H, t), 7:;.39-7.48 (4H, m) , 7.57-7.79 ( 3H, m) , 8.02 (1H, dd) Ethyl 2-acetoxymethyl-l-r ( 2 ' -cvanobiohenyl-4- pale brown syrup ( %) Reference Example 94 Methyl 3-a ino-2-r ( 2 ' -cvanobiohenyl-4-vHme hvnaminobenzoate A mixture of ethyl 3-amino-2-[ ( 2 ' -cyanobi?henyl-4- yl)methyl ja inobenzcate (5g) and NaH (60% oil, 1.62 g) in methanol (50 ml) was stirred at room temperature for 24 hours . The reaction mixture was concentrated to dryness to give a syrup, which was poured into saturated aqueous NaHC03 solution (100 ml). The mixture was extracted ■ with chloroform and the organic layer was washed with KzO, dried and evaporated to dryness to give a crystalline product.

Recry stallization from ethyl acetate-hexane gave colorless crystals (3.9 c, 82%), m.p. 106-108SC. lE-N2£R( 200MH2,CDClj) S: 3.8i(3H,s), 3.97(2H,b s) 4.23(2H,s) , 6.40(lH,br s) , 6.88-6.91 (2H,m), 7.34- 7.55(7H,m), 7.64(lH,dt), 7.77(lH,dd).

IR ( 3r) cm"1: 3410 , 3350, 2225, 1695, 1485, 1470, 1290, 1200, 780, 760.

Reference Example 95 Kethyl 2- ( 2-chloroethyl ) -1-Γ ( 2 ' -cvanobiphenyl-4- To a cold solution of methyl 3 -amino-2- [ ( 2 ' - cyanobiohenyi-4-yl)methyi]aminobenzoate (0.5 g) in CK,Cli (5 ml) was added 3-chloropropionyl chloride (0.15 ml) dropwise. The reaction mixture was stirred at room temperature for 30 minutes and then concentrated to dryness to give a residue. The residue was dissolved in methanol (5 ml) containing cone. HC1 (0.5 ml) and the solution was stirred at room temperature for 16 hours. The reaction solution was concentrated to dryness to give a residue, which was dissolved in CH2C12-H20. The aqueous layer was made basic and then extracted. The organic layer was washed with H20, dried and evaporated to dryness to give a pale brown syrup (0.7 g, 100%). lHrNMR(200MHz,CDCl3) S: 3.37(2H,t), 3.74(3H,s), 4.09(2H,t), 5.87(2H,s), 7.00(2H,d), 7.29(lH,t), 7.39-7.81(7H,m) , 7.97(lH,dd).

Reference Example 96 Methyl 1-r f 2'-cvanobiOhenyl-4-yl'tmethyl1-2-(2-methoxyethyl ) benzimidazole-7-carboxylate A mixture of methyl 2-(2-chloroethyl)-l-[ (2'~ cyanobiphenyl-4-yl )methyl ]benzimidazole-7-carboxylate (1.0 g) and 2C03 (0.25 g) in methanol (30 ml) was refluxed for 2 hours . The reaction mixture was concentrated to dryness to give a residue. The residue was dissolved in CH2C12 and an insoluble material was filtered off. The filtrate was concentrated to dryness and a resulting syrup was purified by column chromatography on silica gel to give a pale yellow ■ syrup (0.45 g, 59%) . 1H-NMR( 200MHz , CDCI3 ) S: 3.19(2H,t), 3.34(3H,s), 3.72(3H,s), 3.92(2H,t), 5.88(2H,s), 7.00(2H,d), 7.26(lH,t), 7.40-7.48(4H,m) , 7.56-7.76 ( 3H,m) , 7.95(lH/dd).

Reference Example 97 Methyl 1-Γ ( 2,-cvanobiOhenyl-4-yl^methyl T-2- ( 2- methylthiomethyl benzimidazole-7-carboxylate This compound was prepared by a method similar to that of Reference Example 96. colorless powder (1.1 g, 93%) lH-NMR( 200MHz, CDClj) S: 2.14(3H,s), 3.02-3.11 ( 2H,m) , 3.16-3.25(2H,m) , 3.74(3H,s), 5.86(2H,s), 7.00(2H,d), 7.28(lH,t), 7.39-7.49 ( 4H,m) , 7.58- 7.78(3H,m), 7.97(lH,dd).

Reference Example 98 2-But l-1- Γ ( 2 ' -cvanobiphenyl-4-yl )methyl 1 -7- ( ,N-dimethylaminoethyl^benzimidazole ;" A mixture of 2-butyl-l-[ ( 2 ' -cyanobiphenyl-4-yl)methyl] -7-chloromethylbenzimidazole (0.65 g) and dimethylamine (50% aqueous solution, 1.5 ml) in ethanol (3 ml) was heated in a. sealed tube for 5 hours. The reaction solution was concentrated to dryness and a resulting syrup was dissolved in ethyl acetate. The solution was washed with water, dried and evaporated to dryness to give a syrup, which was purified by column chromatography on silica gel to give a colorless syrup (0.4 g, 63%) . 1H-NMR(200MHz,CDCl3) δ: 0.92(3H,t), 1.35-1.53 ( 2H,m) , 1.81-1.94(2H,m) , 2.16(6H,s), 2.80(2H,t), 3.34(2H,s), 6.00(2H,s), 6.95-7.01 ( 3H,m) , 7.16(lH,t), 7.39-7.50(4H,m) , 7.62(lH,m), 7.73- 7.77(2H,m) .

IR (Neat) cm"1: 2210, 1515, 1480, 1460, 1440, 1405, 1360, 1330, 1275, 1005, 840, 785, 760.

Reference Example 99 Ethyl 1-r f 2 ' -cvanobiphenyl-4-yl ^methyl 1-2-sec- butylbenzimidazole-7-carboxylate A mixture of ethyl 3-amino-2-[ ( 2 ' -cyanobiphenyl-4- yl)methyl]aminobenzoate (1.1 g) and 2-methylbutyric anhydride (0.56 g) in pyridine (2 ml) was heated at 115°C for 15 hours. The reaction mixture was digested with ethylacetate (50 ml) and the solution was washed with water, dried and evaporated to dryness to give a syrup. The syrup was dissolved in ethanol (15 ml) containing cone. HC1 (0.5 ml) and the solution was refluxed for 3 hours. After removal of the solvent, the resulting syrup was purified by column chromatography on silica gel to afford a pale yellow syrup (1.2 g, 92%) . lH-NMR( 90MHz ,CDC13) δ: 0.90(3H,t), 1.20(3H,t), 1.40(3H,d), 1.50-2.10(lH,m) , 4.17(2H,q), 5.87(2H,s), 6.97(2H,d), 7.17-8.03 ( 9H,m) .

IR (Neat) cm"1: 2975, 2930, 2875, 2220, 1480, 1445, 1410, 1370, 1280, 1260, 1200, 1140, 1110, 1035, 760.

Reference Example 100 Ethyl 1-Γ ( 2,-cvanobiphenyl-4-yl^methyl 1-2-isobutylbenzimidazole-7-carboxylate This compound was prepared by a method similar to that of Reference Example 99. a pale yellow syrup (quant.) 1H-NMR( 90MHz , CDC13 ) S: 1.03(6H,d), 1.20(3H,t), 2.07-2.53(lH,m) , 2.80(2H,d), 4.17(2H,q), 5,83(2H,s), 6.93(2H,d), 7.13-8.00 ( 9H,m) .

IR (Neat) cm"1: 2960, 2215, 1710, 1480, 1400, 1280, 1255, 1200, 1120, 760.

Reference Example 101 2-Butyl-l-r Γ 2' -fN-triphenylmethyltetrazol-5-yl ) biphenyl-4-yl 1methyl1benzimidazole-7-carboxylic acid A mixture of 2-butyl-l.-[ [ 2 ' - ( lH-tetrazol-5- yl ) biphenyl-4-yl jmethyl ]benzimidazole-7-carboxylic acid (3.0 g), triphenylmethyl chloride (1.96 g) and triethylamine (1.0 ml) in CH2C12 (20 ml) was stirred at room temperature for 16 hours. The reaction solution was washed with H20, dried over Na2SO« and concentrated to dryness to give a solid residue. The residue was purified by column chromatography on silica gel to give a colorless powder (4.25 g, 91%), m.p. 120-123°C. 1H-NMR(200MHz,CDCl3) 5: 0.88 (3H,t), 1.26-1.45 ( 2H,m) , 1.72-1.88(2H,m) , 2.81(2H,t), 5.72(2H,s), 6.63(2H,d), 6.92-6.97(8H,m) , 7.12-7.43 ( 13H,m) , 1 15437/2 7.68(lH,d), 7.78-7.83(lH,m) , 7.92(lH,d).

IR (Neat) cm'1: 3050, 2950, 2925, 1690, 1595, 1510, 1490, 1440, 1405, 1275, 1240, 1180, 740, 690.

Working Example 1 2-Butyl-l-r Γ 2 ' - f lH-tetrazol-5-yl ^biphenyl-4-yl Imethyl 1 benziitiidazole-7-carboxylic acid A mixture of methyl 2-butyl-l- [ ( 2 ' -cyanobiphenyl-4-yl )methyl]benzimidazole-7-carboxylate (3.2 g), sodium azide (7.4 g) and ammonium chloride (6.1 g) in DMT (30 ml)' was stirred for 4 days at 115°C. To the reaction mixture was added water, which was adjusted to pH - 4 with 1N-HC1. Resulting crude crystals (1) were purified by column chromatography on silica gel. The crystals thus obtained were recrystallized from ethyl acetate - methanol to afford colorless prisms (2.27 g, 63%) , m.p. 168-169°C.

Elemental Analysis for C26H24N602 · H20 : C(%) H(%) N(%) Calcd : 66.37; 5.57; 17.86 Found : 65.04; 5.69; 17.58 'Η-ΝΗΡ. 200MKz,DMSO-d6) S: 0.88(3H,t), 1.28-1.46 ( 2H,m) , 1.65-1.80(2H,m) , 2.82(2H,t), 5.85(2H,s), 6.79(2H,d), 7.00(2H,d), 7.24(lH,t), 7.45(5H,m), 7.83(lH,dd).

IR ( X3r ) cm"1 : 1720, 1600, 1510, 1455, 1285, 1255, 1240, 775, 755, 745.

Working Example 2 2-Butvi-l-r Γ 2 ' - ( N-methyltetrazol-5-yl ^biDhenyl-4-yl 1methvnbenzimidazole-7-carboxylic acid The crude crystal (1) obtained in Working Example 1 was purified by column chromatography on silica gel, followed by recrystallization from ethyl acetate -hexane to give colorless needles (0.17 g, 4.7%), m.p. 133-135°C.

Elemental Analysis for C27H26N502: C(%) H(%) N(%) Calcd : 69.51; 5.62; 18.01 Found : 69.47; 5.66; 17.92 lH-NMR( 200MHz, CDC13) δ: 0.94(3H,t), 1.35-1.55 ( 2H,m) , 1.78-1.93(2H,m) , 2.96(2H/t), 3.15(3H,s), 5.82(2H,s), 6.81(2H,d) ,.6.97(2H,d) , 7.25(lH,t), 7.48-7.67(4H,m) , 7.80(lH,dd), 7.95(lH,dd).

IRiKBrJcm"1: 1715, 1520, 1415, 1290, 1260, 1200, 1125, : 780, 750.

Working Example 3 2-Butyl-N-isoproDyl-l-r Γ 2 ' - ( lH-tetrazol-5-yl ^biphenyl-4-yllmet.hyl 1 benzimidazole-7-carboxamide A solution of 2-butyl-l-[ [ 2 ' - ( lH-tetrazol-5-yl )biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (0.71 g) and diethyl cyanophosphate (purity 90%, 0.82 g) in DMF (6 ml) was stirred for one hour under ice-cooling. To the solution were then added isopropylamine hydrochloride (0.14 g) and triethylamine (0.61 g), and the mixture was stirred for 2 hours at room temperature. To the reaction mixture was added water, which was neutralized with 1N-HC1, followed by extraction with ethyl acetate. The organic layer was washed with water, dried and, then concentrated to dryness. Recrystallization of thus-obtained crude crystals from methanol - ethyl acetate gave colorless prisms (0.31 g, 41%), m.p. 247-249°C Elemental Analysis for C2H32N7O · 1/5H20: C(%)) H(%) N(%) Calcd : 69.91; 6.55; 19.68 Found : 69.91; 6.30; 19.87 1H-NMR(200MHz,D SO-d6) 6: 0.87(3H,t), 0.93(6H,d), 1.26-1.44(2H,m) , 1.62-1.77 ( 2H,m) , 2.80(2H,t), 3.85-3.95(lH,m) , 5.67(2H,s), 6.84(2H,d), ' 6.99(2H,d), 7.16-7.24(2H,m), 7.44(lH,d), 7.51- 7.72(4H,m), 8.27(lH,d).

IR(KBr)cm"1: 1640, 1540, 1510, 1455, 1415, 755, 740.

Working Example 4 2-Butyl-l-r Γ 2' -( lH-tetrazol-5-vHbiphenyl-4-yllmethyl 1 benzimidazole-7-carboxylic acid 2-sodium: salt 2-Butyl-l- [ 2 ' - ( lH-tetrazol-5-yl )biphenyl-4-yl]methylbenzimidazole-7-carboxylic acid (0.2 g) was added to methanol (15 ml) containing NaOMe (46 mg), and the mixture was stirred for 15 minutes at room temperature. To the reaction mixture was added toluene (30 ml), which was concentrated under reduced pressure to give crystals . The crystals separated out were collected by filtration to give colorless powdery crystals (0.14 g, 62%), m.p. 255-257 °C (decomp.).

Elemental Analysis for C26H22N6Na202 · 2H20 : C(%) H(%) N(%) Calcd : 58.64; 4.92; 15.78 Found : 58.98; 4.60; 15.66 1H-NMR( 200MHz , DMSO-d6 ) S: 0.85(3H,t), 1.27-1.39 ( 2H,m) , 1.59-1.74(2H,m) , 2.69(2H,t), 6.lO(2H,s), 6.81(2H,d), 6.98-7.07(3H,m) , 7.19-7.53 ( 6H,m) .

IR( Br)cm_1: 1610, 1410, 1360, 760.

Working Example 5 But l 2-butyl-l-r Γ 2' -( lH-tetrazol-5-yl ^biphenyl-4- yllmethyl 1 benzimidazole-7-carboxylate A mixture of 2-butyl-l-[ [ 2 ' - ( lH-tetrazol-5- yl )biphenyl-4-yl ]methylbenzimidazole-7-carboxylic acid (0.47 g) and cone, sulfuric acid (0.1 ml) in butanol (10 ml) were heated for 66 hours under reflux. The solvent was removed by evaporation. To the residue was added water and the mixture was adjusted to pH 3 to 4 with IN-NaOH, followed by extraction with ethyl acetate. The organic layer was washed with water and dried. After removal of the solvent, the residue was purified by column chromatography on silica gel.

Recrystallization from ethyl acetate - hexane afforded colorless prisms (0.15 g, 29%), m.p. 192-193°C.

Elemental Analysis for C3oH32N602: C(%) H(%) N(%) Calcd : 70.84; 6.34; 16.52 Found : 70.99; 6.46; 16.25 lH-NMR( 200MHz, CDC13) S: 0.83(3H,t), 0.85(3H,t), 1.18-1.39(4H/m) , 1.45-1.64 ( 4H,m) , 2.38(2H,t), 3.99(2H,t), 5.50(2H,s), 6.47(2H,d), 6.79(2H,d), 6.93(lH,d), 7.04(lH,t)/ 7.27-7.32 ( lH,m) , 7.50(lH,dd), 7.56-7.68(2H,m) , 7.97-8.01 ( lH,m) .

IR(KBr)cm"1: 1710, 1465, 1455, 1415, 1280, 1265, 1125, 760.

Working Example 6 ( 4-PyridvHmethyl 2-butyl-l-r Γ 2 ' - ( lH-tetrazol-5-yl ) biphenyl-4-yl 1methyl 1 benzimidazole-7-carboxylate A solution of ( 4-pyridyl )methyl 2-butyl-l-[ ( 2 ' - . cyanobiphenyl-4-yl)methyl]benzmidazole-7-carboxylate (0.61 g) and trimethy!tin azide (0.75 g) in toluene (10 ml) was heated for 4 days under reflux in nitrogen atmosphere. After removal of the solvent, the resulting solvent residue was dissolved in ethanol (5 ml). To the solution was added 1N-HC1 (8 ml), and the mixture was stirred for 5 minutes at room temperature, which was neutralized with IN NaOH, followed by extraction with ethyl acetate. The extract was washed with water, dried, and evaporated to dryness. The resulting residue was purified by column chromatography on silica gel to give crystals. Recrystallization from ethyl acetate - hexane afforded colorless prisms (0.54 g, 83%), m.p. 179-180°C.

Elemental Analysis for 032Η29 702: C(%) H(%) N(%) Calcd : 70.70: 5.38; 18.04 Found : 70.96; 5.45; 18.02 6: 0.80(3H,t), 1.18-1.36 ( 2H,m) , 1.53-1.68(2H,m) , 2.49(2H,t), 5.19(2H,s), 5.51(2H,s), 6.44(2H,d), 6.79(2H,d), 7.15- 7.31(4H,m), 7.47-7.61 ( 3H,m) , 7.67(lH,dd), 7.92(lH,dd), 8.35(2H,d).

IR(KBr)cm_1: 1720, 1600, 1410, 1280, 1250, 1120, 760, 750, 740.

Working Example 7 2—Propyl—1— Γ Γ2'-( lH-tetrazol-5-yl ^biphenyl-4-yl Imethyl 1 benzimidazole-7-carboxylic acid A mixture of methyl 2-propyl-l-[ ( 2 ' -cyanobiphenyl-4-.yl)methyl]benzimidazole-7-carboxylate (2.5 g), sodium azide (3.9 g) and ammonium chloride (3.2 g) in DMF (30 ml) was stirred for 5 days at 110°C-120°C. To the reaction mixture was added, water and the solution was made acidic (pH 3 - 4), followed by extraction with ethyl acetate. The organic layer was washed with water and dried. After removal of the solvent, the residue was purified by column chromatography on silica gel to give crystals . Recrystallization from DMF-ethanol afforded colorless crystals (0.8 g, 23%), m.p. 275- 276°C (decomp . ) .

Elemental Analysis for C25H22N602' 1/2H20: C(%) H(%) N(%) Calcd : 67.10; 5.18; 18.78 Found : 67.19; 4.95; 18.84 1H-NMR(90MHz,CDCl3-CF3COOH) S: 1.10(3H,t), 1.70-2.20(2H,m) , 3.23(2H,t), 5.97(2H,s), 6.90(2H,d), 7.13(2H,d), 7.47-7.80 ( 5H,m) , 8.03- 8.17(2H,m) .

IR( Br)cm_1: 3070, 2720, 2440, 1700, 1450, 1410, 1405, 1285, 1235, 1200, 1190, 1120, 755.

Working Example 8 2-Pentyl-l-r Γ 2 " — f lH-tetravol-5-yl ^bjphenyl-4- vnmethyllbenzimidazole-7-carboxylic acid A mixture of methyl l-[ ( 2 ' -cyanobiphenyl-4- yl )methyl ] -2-pentylbenzimidazole-7-carboxylate (3.25 g), sodium azide (2.6 g) and ammonium chloride (2.1 g) in DMF (20 ml) was stirred for 5 days at 110 - 120 °C.

To the reaction mixture was added water, which was made acidic, ( H 3 - 4) with 1N-KC1, followed by extraction with ethyl acetate. The organic layer was washed with water and dried. After removal of the solvent, the residue was purified by column chromatography on silica gel to give crystals . Recrystallization f om ethyl acetate - ethanol, followed by treatment with hot water, afforded colorless powdery crystals (1.0 g, 29%), m.p. 205-207°C (decomp.).

Elemental Analysis for C27H26 602' 1/5H20: C(%) H(%) N(%) Calcd : 68.98; 5.66; 17.88 Found : 69.14; 5.60; 17.90 ½-NMR(90MHz,CDCl3-CF3COOH) S: 0.87(3H,t), 1.13-1.53(4H,m) , 1.67-2.10 ( 2H,m) , 3.27(2H,t), 6.00(2H,s), 6.93(2H,d), 7.17(2H,d), 7.47- 7.90(5H,m), 8.07-8.20 ( 2H,m) .

IR(Nujol)cm_l: 3040, 2775, 1695, 1485, 1450, 1425, 1410, 1290, 1240, 1200, 755.

Working Example 9 Methyl 2-butyl-5-methyl-1- Γ Γ 2 ' - ( lH-tetrazol-5-yl ) bjphenyl-4-yl ^methyl 1 benzimidazole-7-carboxylate A mixture of methyl 2-butyl-l- [ ( 2 ' -cyanobiphenyl-4-yl)methyl]-5-methylbenzimidazole-7-carboxylate (2.8 g), sodium azide (6.2 g) and ammonium chloride (5.1 g) in DMF (25 ml) was stirred for 3 days at 110-120 °C. The reaction mixture was diluted with water, which was made acidic (pH 3 - 4) with IN HCl, followed by extraction with ethyl acetate. The organic layer was washed with water and dried. After removal of the solvent, the residue was purified by column chromatography on silica gel to give crystals . Recrystallization from ethyl acetate - methanol afforded colorless prisms (0.72 g, 24%), m.p. 144-145°C.

Elemental Analysis for C28H28Ns02 · 0.1H20 : C(%) H(%) N(%) Calcd : 69.72; 5.89; 17.42 Found : 69.58; 5.89; 17.28 Ή-ΝΜΚ( 200MHz,CDCl3) S: 0.82(3H,t), 1.17-1.37 ( 2H,m) , 1.45-1.60(2H,m), 2.26(3H,s), 2.34(2H,t), 3.56(3H,s), 5.23(2H,s), 6.43(2H,d), 6.60(lH,s), 6.76(2H,d), 7.28-7.32 ( 2H,m) , 7.59-7.69 ( 2H,m) , 7.96-8.00(lH,m) .

IR( Br)cm_1: 1715, 1515, 1455, 1440, 1410, 1315, 1255, 1225, 1050, 785, 765.

Working Example 10 2-Butyl-5-methyl-1-Γ Γ 2 ' -( lH-tetrazol-5-yl ^biphenyl-4-yl Imethyl lbenzimidazole-7-carboxylic acid A mixture of methyl 2-butyl-5-methyl-l-[ [ 2' -( 1H-tetrazol-5-yl )biphenyl-4-yl ]methyl ] benzimidazole-7-carboxylate (0.15 g) in IN NaOH (1.2 ml) and methanol (2 ml) was heated for 2 hours under reflux. The reaction mixture was diluted with water, washed with ether and made acidic (pH 3 - 4) with 1N-HC1. Crystals separated were collected by filtration and recrystallized from ethyl acetate to afford colorless crystals (0.1 g, 71%), m.p. 175-178°C (decomp.).

Elemental Analysis for C27H26N602 · 1/2H20: C(%) H(%) N(%) Calcd : 68.19; 5.72; 17.67 Found : 68.25; 5.66; 17.59 1H-NMR(200MHz,DMSO-d5) S: 0.87(3H,t), 1.25-1.44 ( 2H,m) , 1.63-1.77(2H,m), 2.41(3H,s), 2.79(2H,t), 5.82(2H,s), 6.76(2H,d), 6.99(2H,d), 7.45-7.49 ( 2H,m) , 7.55-7.69(4H,m) .

IRi BrJcm"1: 3440, 1700, 1600, 1515, 1450, 1410, .1310, 1240, 765.

Working Example 11 Ethyl 2-butyl-6-methyl-l-r Γ 2 ' - ( lH-tetrazol-5- yl^biphenyl-4-yl Imethyl Tbenzimidazole-7-carboxylate A mixture of ethyl 6-methyl-3-nitro-[N-[2'-(N- triphenylmethyltetrazol-5-yl)bipheny-4-yl]methyl-N- valeroyl]anthranylate (2.1 g) and iron powder (0.73 g) in cone. HC1 (2.1 ml) and ethanol (10 ml) was heated for 18 hours under reflux. Insoluble materials in the reaction mixture were filtered off. The filtrate vas then concentrated to dryness. The residue was dissolved in ΙΝ-NaOH, and the resulting precipitates were filtered off through celite. The filtrate was made acidic with cone. HCl. The oily product was separated and extracted with methylene chloride. The extract was washed with water and concentrated to dryness. The syrupy product thus obtained was purified by column chromatography on silica gel to give a crystalline product. Recrystallization from ethyl acetate - isopropyl ether afforded pale brown prisms (0.8 g, 59%), m.p. 164-165°C. lH-NMR(200MHz,CDCl3) S: 0.84, 1.06(each 3H,t), 1.20-1.39(2H,m), 1. 8-1.63 ( 2H,m) , 2.32(3H,s), 2.38(2H,t), 3.88(2H,q), 5.28(2H,s), 6.56(2H,d), 6.74(lH,d), 6.86(3H,dd), 7.28-7.33 ( lH,m) , 7.58- 7.63(2H,m), 7.91-7.97 ( lH,m) .

Working Example 12 Methyl 2-butyl-5-chloro-l- Γ Γ 2 ' - ( lH-tetrazol-5- yl biphenyl-4-yl1methyl1benzimidazole-7-carboxylate To a mixture of methyl 5-chloro-3-nitro-2-[N-[ 2 ' - (N-triphenylmethyl-lH-tetrazol-5-yl)biphenyl-4- yl]methyl ] -N-valerylanthranylate (1.26 g) , cone. HCl (1.6 ml) and iron powder (95% purity, 0.45 g) in methanol (15 ml) was heated for 20 hours under reflux. Insoluble materials were filtered off, and the filtrate was concentrated. The concentrate was extracted with ethyl acetate and water. To the organic layer was added an aqueous solution of sodium bicarbonate and insoluble materials formed were filtered off. The filtrate was washed with water, dried and concentrated. The concentrate was purified by column chromatography on silica gel to give crystals, which were recrystallized from ethyl acetate - benzene to afford colorless crystals (0.59 g, 74%), m.p. 132-133°C.

Elemental Analysis for C27H25N602C1 : C(%) H(%) N(%) Calcd : 64.73; 5.03; 16.77 Found : 64.49; 5.06; 16.50 1H-NMR( 200MHz , CDC13 ) δ: 0.84(3H,t), 1.23-1.41 ( 2H,m) , 1.52-1.68(2H,m) , 2.50(2H,t), 3.62(3H,s), 5.48(2H,s), 6.46(2H,d), 6.83(2H,d), 6.93(lH,m), 7.31-7.36(lH,m), 7.49(lH,d)/ 7.63-7.68 ( 2H,m) , 7.96-8.00(lH,m) .

IR(KBr)cm_1: 2960, 2875, 1720, 1510, 1460, 1430, 1400, 1280, 1230, 1190, 750.

Working Example 13 2-Butyl-5-chloro-l- Γ Γ 2 ' - ( lH-tetrazol-5-yl ^biphenyl-4-yl ^methyl 1benzimidazole-7-carboxylic acid A solution of methyl 2-butyl-5-chloro-l-[ [ 2' -( 1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazol-7-carboxylate (0.28 g) in IN NaOH (2 ml) and methanol (4 ml) was stirred for 16 hours at room temperature. The reaction mixture was concentrated, and the concentrate was dissolved in water (10 ml), which was made acidic with 1N-HC1. Crystals thus separated were collected by filtration, recrystallized from methanol-chloroform to afford colorless crystals (0.2 g, 72%), m.p. 232-234°C. Elemental Analysis for C26H23N602C1.1/2H20: C(%) H(%) N(%) Calcd : 62.96; 4.88; 16.94 Found : 63.01; 4.81; 16.87 1H-NMR(200MHz,DMSO-d6) S: 0.87(3H,t), 1.26-1.45 ( 2H,m) , 1.64-1.79(2H,m) , 2.82(2H,t), 5.81(2H/s), 6.78(2H,d), 7.00(2H,d), 7.45-7.69 ( 5H,m) , 7.91(lH,d).

IR( Br)cm_1: 2975, 2930, 2875, 1705, 1480, 1460, 1400, 1270, 1240, 1220, 1190, 870, 760, 740.

Working Example 14 Ethyl 2-butyl-l- Γ Γ 2 ' - ( lH-tetrazol-5-yl Tbiphenyl-4- - 80 - yllmethyl 1 benzimidazcle-7-carboxylate A mixture of ethyl 2-butyl-l- [( 2 ' -cyanobiphenyl-4-yl )methyl ]benzimidazole-7-carboxylate (0.21 g), sodium azide (1.3 g) and ammonium chloride (1.07 g) in DMF (8 ml) was stirred for 60 hours at 110-120°C. To the mixture was added water and the mixture was made acidic (pH 3 - 4) with 1N-KC1, followed by extraction with ethyl acetate. The organic layer was washed with water, dried and concentrated to dryness. To the concentrate was added ether, and the resulting crude crystals were collected by filtration, followed by recrystallization from ethanol to afford colorless crystals (0.95 mg, 41%), m.p. 138-139°C. lH-N (90MHz,CDCl3) 5: 0.80(3H,t), 1.07-1.77 ( 7H,m) , 2.37 (2H,t), 4.07(21-1,0), 5.50(2H,s), 6.47(2H,d), 6.80(2H,d), 7.00-7.10(2H,m) , 7.23-7.73 ( 4H,m) , 7.90-8.10(lK,m) .

IRfNujolJcm"1: 1715, 1410, 1290, 1260, 1125, 1040, 750. Working Example 15 2-Butyl-l-r Γ 2 ' - f lK-tetrazol-5-yl ) biOhenyl-4-yl Imethyl 1benzimidazole-7-carboxylic acid A mixture of ethyl 2-butyl-l-[ [ 2 ' - ( lH-tetrazol-5-yl )biphenyl- -yl]methyl ]benzimidazole-7-carboxylate ( 80 mg) in 2-me hoxyethanol (1.5 ml) and 2N NaOH (1.5 ml) was stirred for one hour at 110-120°C. The reaction mixture was neutralized with 2N-HC1, and then concentrated to dryness. The concentrate was dissolved in chloroform. After removal of insoluble materials by filteration, the filtrate was concentrated to dryness. Crude crystals thus obtained were recrystallized from aqueous ethanol to give colorless crystals (60 mg, 77%) .

The melting point, ^- MR and IR data are in good agreement with those observed in Working Example 1. Working Example 16 2-3utyl-7-hvdroxymethyl-l-r Γ 2 ' - ! lH-tetrazol-5- yl biphenyl-4-yl Imethyl Ibenzimidazole A mixture of 2-butyl-l-[ ( 2 ' -cyanobiphenyl-4-yl)methyl]-7-hydroxymethylbenzimidazole f'0.4 g), sodium azide (0.98 g) and ammonium chloride (0.8 g) in DMF (4 ml) was stirred for 4 days at 110-120 °C. To the reaction mixture was added water, which was extracted with ethyl acetate. The extract was washed with water and dried. After removal of the solvent, the residue was crystallized from ethyl acetate - methanol to give colorless needles, m.p. 152-153°C.

Elemental Analysis for C26H26N60 · l/2C4Ha02- 1/10H20: C(%) H(%) N(%) Calcd : 69.43; 6.28; 17.35 Found : 69.14; 6.22; 17.59 ¾-NMR(200MHz,DMSO-d6) S: 0.86(3H,t), 1.26-1.44 ( 2H,m) , 1.63-1.78(2H,m) , 2.76(2H,t), 4.47(2H,s), 5.47(lH,br s) , 5.76(2H,s), 6.81(2H,d), 7.04(2H,d), 7.08-7.16(2H,m), 7.49-7.70 ( 5H,m) .

IR(KBr)cnfl: 1510, 1450, 1405, 1020, 755, 740.

Working Example 17 Ethyl Γ r2-butyl-l-r2,-f lH-tetrazol-5-vUbiphenyl-4-yl Imethyl 1 benzimidazol-7-yl 1 acetate A mixture of ethyl 2-butyl-l-[ ( 2 ' -cyanobiphenyl-4- yl)methyl]benzimidazole-7-carboxylate (0.86 g), sodium azide (0.5 g) and ammonium chloride (1.6 g) in DMF (10 ml) was stirred in DMF for 4.5 days at 110-120°C. To the reaction mixture was added water, which was made acidic (pH 3 - 4) with 1N-HC1, followed by extraction with ethyl acetate . The organic layer was washed with water and dried, then the solvent was distilled off. The residue was purified by column chromatography on silica gel to give crude crystals . Recrystallization from ethyl acetate afforded colorless needles (0.53 g, 56%), m.p. 129-130°C.

Elemental Analysis for C29H3o 602 · 0.4H20 : C(%) H(%) N(%) 1 15437/2 Calcd : 69.41; 6.19; 16.75 Found : 69.50; 5.94; 17.03 i- MR( 200MHz,CDCl3) S: 0.83(3K,t), 1.12-1.33 ( 5H,m) , 1.48-1.63(2H,m) , 2.24(2H/t)/ 3.41(2H,s), 4.03(2H,q), 5.46(2H,s), 6.55-6.66 ( 3H,m) , 6.87 ( 2H,d) , 6.93-6.99 ( 2H/m)/ 7.28-7.32 ( lH,m) , 7.55-7.68 ( 2H,m) , 7.95-7.99(lH,m) .

IR(X3r)cm"1: 1740, 1720, 1510, 1410, 1280, 1255, 1145, 755, 740.

Working Example 18 2-Butyl-l-r Γ 2 ' - ( lH-tetrazol-5-vi biohenyl-4- vnmethyl1benzimida2ole-7-acetic acid A mixture of ethyl 2-butyl-l- [[ 2 '-( lH-tetrazol-5- yl)biphenyl-4-yl)methyl]benzimidazole-7-acetate (0.28 g) in IN NaOH (1.5 ml) and methanol (5 ml) was heated for two hours under reflux. The reaction mixture was concentrated, and , neutralized with 1N-HC1.

Crystals which separated out were collected by filtration and purified by column chromatography on silica gel to afford colorless crystals (0.12 g, 46%), m.p. 170- 171°C.

Elemental Analysis for C27K2S S02: C(%) H(%) N(%) Calcd : 69.51; 5.62; 18.01 Found : 69.60; 5.78; 17.90 1K-NK (200MKz,DMSO-d5) S: 0.87(3E,t), 1.27-1.4 ( 2H,m) , 1.64-1.75(2H,m) , 2.79(2H,t), 3.58(2H,s), 5.62(2H,s), 6.80(2H,d), 6. 8-7.16 ( H,m) , 7.49- 7.71(5H,m).

IR(K3r)cm"1: 3430 , 1720 , 750.

Working Example 19 2-Butyl-7-methoxymethyl-l-r Γ 2 ' - ( lH-tetrazol-5- yl)biphenyl-4-yllmethvnbenzimidazole sodium salt A mixture of 2-butyl-l- [( 2 ' -cyanobiphenyl-4- yl )rnethyl ] -7-methoxymethylbenzimidazole (0.6 g) and trimethyltin azide (1.2 g) in toluene (12 ml) was heated for 3 days under reflux in toluene (12 ml). The solvent was distilled off. To the residue was added 1N-HC1 (8 ml) and the mixture was stirred for a while, followed by extraction with ethyl acetate. The organic layer was washed with water, dried and then the solvent was distilled off. The residue was purified by column chromatography on silica gel to give an oil. The product was dissolved in ethyl acetate, to which was added a methanol solution of sodium salt of 2-ethyl hexanoic acid (0.25 g) . The mixture was concentrated. Crystals separated out were recrystallized from toluene - ethyl acetate to afford colorless crystals (0.22 g, 31%), m.p.l75-178°C.

Elemental Analysis for C27H27NsONa · H20 : C(%) H(%) N(%) Calcd: 65.84; 5.93; 17.06 Found : 65.94; 5.81; 17.06 :K-NKR(200MHz,CDCl3) S: 0.70(3H,t), 1.06-1.25 ( 2H,m) , 1.50-1.65 ( 2H,m) , 2.49(2H,t), 2.86(3H,s), 4.21(2K,s), 5.27(2H,s), 6.41(2H,d), 6.73- 6.77(3H,m), 6.92-7.00 ( 2H,m) , 7.19-7.30 ( 2K,m) , 7.37(lH,d), 7.62(lH,d).

IR XBrJcm"1: 1510, 1455, 1420, 1405, 1350, 1280, 1080, 740.

Working Example 20 2-3utyl-7-methoxy-l-r Γ 2 ' - ! lH-tetrazol-5-yl ) biohenyl-4- yl Imethyl 1 benzimidazole hydrochloride A mixture of 2-butyl-l- [ ( 2 ' -cyanobiphenyl-4- yl )methyl ] -7-methoxybenzimidazole (0.8 g) and trimethyltin azide (1.6 g) in toluene (15 ml) was heated for 44 hours under reflux. Crystals then separated out which were collected by filtration, and were dissolved in methanol (20 ml). To the solution was added 1N-KC1 (8 ml), and the mixture was stirred for 5 minutes at room temperature. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and dried. The solvent was distilled off, and the residue was purified by column chromatography on silica gel to give crude crystals. Recrystallization from ethyl acetate - methanol afforded colorless prisms (0.83 g, 87%) , m.p. 189-190°C.

Elemental Analysis for C2sH2SNsO · HCl : C(%) H(%) N(%) Calcd : 65.75; 5.73; 17.69 Found : 65.46; 5.85; 17.44 1K-NMR(200MHz, DMSO-d6) S : 0.87(3H,t), 1.26-1. 4 ( 2H,m) , 1.61-1.76 ( 2H,m) , 3.14(2H,t), 3.83(3H,s), 5.82(2H,s), 7.07-7.18(5H,m) , 7.38(lH,d), 7.45- 7.73(5H,m).

IR(KBr)cm_1: 1615, 1550, 1490, 1455, 1440, 1355, 1275, 1260, 1130, 1100, 1060, 990, 870, 850, 775, 750, ' 730.

Working Example 21 2-Butyl-6-methyl-l- r Γ 2 ' - f lH-tetrazol-5-yl 1 bjphenyl-4-yllmethyl 1 benzimidazole-7-carboxylic acid A mixture of ethyl 2-butyl-6-methyl-1- [ [ 2 ' - ( 1H-tetrazol-5-yl ) biphenyl-4-yl ]methyl ] benzimidazole-7-carboxylate (0.55 g) in 5N aqueous sodium hydroxide (5 ml) and ethanol (10 ml) was heated for 100 hours under reflux. The reaction mixture was concentrated to dryness,. dissolved in water, and the solution was made acidic with cone. HCl. Precipitates separated out were collected by filtration and washed with a mixture of dichloromethane and methanol. The precipitates were dissolved in saturated aqueous sodium bicarbonate. After removal of insoluble materials by falteration, the filtrate was made acidic with cone. HCl. Precipitates then separated out were collected by filtration'- and crystallized from dimethylformamide -H20 to afford colorless crystals (0.22 g, 42%), m.p. 298- 299°C. 1H-NMR(200MHz,CDCl3) S: 0.85(3H,t), 1.23-1.43 ( 2H,m) , 1.58-1.75(2H,m) , 2.38(3H,s), 2.70(2H,t), 5.47(2H,s), 6.87, 7.02 (each 2H,d), 7.07(lH,d), 7.45-7.71(5H,m) .

Elemental Analysis for 027Η26Ν602 · l/10H2O: C(%) H(%) N(%) Calcd : 69.24; 5.64; 17.94 Found : 68.97; 5.85; 17.81 Working Example 22 2-Butyl-l- Γ Γ 2 ' - ( lH-tetrazol-5-yl ) biphenyl-4-yl Imethyl 1 -7-methylbenzimidazole A mixture of 2-butyl-l-[ ( 2 ' -cyanobiphenyl-4-yl)methyl]-7-methylbenzimidazole (0,5 g) , sodium azide (1.3 g) and ammonium chloride (1.1 g) in DMF (5 ml) was stirred for 3.5 days at nO-120°C. To the reaction mixture was added water, which was made acidic (pH 3 -4) with 1N-HC1, followed by extraction with ethyl acetate. The organic layer was washed with water and dried. The solvent was distilled off, and the residue was purified by column chromatography on silica gel to give crystals . Recrystallization from ethyl acetate -methanol afforded colorless crystals (0.36 g, 62%), m.p. 222-224°C.

Elemental Analysis for C2SH26N6 · 1/4C4H802: C(%) H(%) N(%) Calcd : 72.95; 6.35; 18.90 Found : 72.80; 6.35; 19.02 1H-NHR( 200MHz , CDC13 ) S: 0.80(3H,t), 1.14-1.32 ( 2H,m) , 1.44-1.59(2H,m) , 2.14(2H,t), 2.26(3H,s), 5.32(2H,s), 6.48-6.56(3H,m) , 6.83-6.89 ( 4H,m) , 7.29-7.34(lH,m) , 7.55-7.68 ( 2H,m) , 7.92-7.97 ( lH,m) . IR( Br)cm_1: 1510, 1450, 1410, 780, 750, 740.

Working Example 23 Ethyl 2-isoOropyl-l- Γ Γ 2 ' - f lH-tetrazol-5-vUbiphenyl-4- vnmethyllbenzimidazole-7-carboxylate A mixture of ethyl l-[ ( 2 ' -cyanobiphenyl-4-yi )methyl ] -2-isopropyibenzimidazole-7-carboxylate (2.12 g), sodium azide (3.9 g) and ammonium chloride (3.2 g) in DI4F (15 ml) was stirred for 5 days at 110-120°C. To the reaction mixture was added water (150 ml), which was made acidic (pE 3 - 4) with dilute hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with water, dried and concentrated to dryness. The concentrate was crystallized from ethanol to afford colorless prisms (1.2 g, 52%), m.p. 144-146°C.

Elemental Analysis for C27H26N502 · l/4C2H5OE · H20 : C(%) H(%) N(%) Calcd : 66.58; 5.99; 16.94 Found : 66.38; 5.74; 16.69 1E-MK (90iiHz,CDCl3-CF3COOH) : 1.30(3E,t), 1.53(6H,d), 3.37-3.80(lK,m) , 4.30(2H,q), 5.97 ( 2E,. s-J, 6.90(2E,d), 7.13(2E,d), 7. 3-8.10 ( 7E,m) .

IR(Nujoi)cm"1: 1730, 1450, 1285, 1270, 750.

Working Example 24 Ethyl 2-methyl-l-r Γ 2 ' -( lH-tetrazoL-5-yl ^ biohenyl-4-yl lmethyl 1benzimidazol-7-carboxylate A mixture of ethyl l-[ ( 2 ' -cyanobiphenyl-4-yl )methyl ] -2-methylbenzisiidazole-7-carboxylate (2.5 g), sodium azide (3.9 g) and ammonium chloride (3.2 g) in DZ-i? (30 ml) was stirred for 4 days at 110-120°C. The reaction mixture was worked up according to the procedure described in Working Example 23 to give crystals . Recrystaliization from ethanol afforded colorless prisms (1.36 g, 49%), m.p. 205-206°C.

Elemental Analysis for C25H22N602* 2/5EtOE: C(%) H(%) N(%) Calcd : 67.82; 5.38; 18.39 Found : 67.64; 5.38; 18.24 5: 1.27(4E,t). 2.90(3H,s), 3.87(lE,c), 4.30(2E,c), 5.93(2E,s), 6.93(2H,d), 7.10(2H,G), 7.40-7.80(5H,m) , 8.00(2H,d).

I?.(Nujol)cm"L: 1725 , 1410 , 1290 , "1260 , 1220 , 1115, 1040, 750.

Working Example 25 Ethyl 2-ethyl-l-r Γ 2 ' - ( lH-tet.razol-5-vUbiohenyl-4-yl Imethyl lbenzimidazole-7-carbo: Elemental Analysis for C2SK24N602- 2/5K20: - - C(%) H(%) N(%) Calcd : 67.93; 5.44; 18.28 Found : 67.76; 5.36; 18.54 S: 1.33(3H,t), 1.50 (3H,t) , 3.27(2Η,ς), 4.33(2Κ,ς), 5.97(2H,s), 6.93(2H,d), 7.17(2K,c), 7.40-8.07(7H,m) .

IR(Nujol)cm"1: 1710, 1285, 1265, 755.

Working Example 26 2-Methyl-l-r Γ 2' -( lH-tetrazol-5-yl 1 biphenyl-4-yl Tmethyl lbenzi:nidazole-7-carboxylic acid Ethyl 2-methyl-l-[ [ 2 ' - ( lH-tetrazol-5-yl )biphenyl- 4-yl]methyllber.zimidazole-7-carbcxylata (0.64 g) was heated under reflux for 4 hours in a mixture of methanol (10 ml) and 2 NaOH. The reaction mixture was concentrated to dryness, and the concentrate was dissolved in water, followed by neutralization with 1N- HC1 to afford crystals . Recrystallization from DMT- EtOH-H20 gave colorless prisms (0.3 g, 49%), m.p. 283- 284°C (decomp.).

Elemental Analysis for C23HISNS02 · 1/5H20 : C(%) K(%) N(%) Calcd : 65.72; 4.48; 20.30 Found : 66.96; 4.40; 20.25 lH-NMR(90 ~:z,CDCl3-CF3COOH) 5: 2.97(3H,s), 5.97(2H,s), 6.97(2H,d), 7.17(2H,d), 7.50-7. 0 ( 5H,m) , 8.lO(lH,d), 8.20(lH,d).

IR NujolJcm-1: 2470, 1700, 1455, 1410, 1240, 1220, 990, 750.

Working Example 27 2-Ethyl-l- Γ Γ 2 ' - ( lH-tetrazol-5-yl )biOhenyl-4-yl 1methylbenzimldazole-7-carboxylic acid A mixture of ethyl 2-ethyl-l-[ [ 2 ' - ( lH-tetrazol-5-yl )biphenyl-4-yl ]methyl ]benzimidazole-7-carboxylate (0.5 g) in methanol (10 ml) and 2N NaOH was heated under reflux for 4 hours. The reaction mixture was concentrated to dryness. The concentrate was dissolved in water, followed by neutralization with IN-HCl to give crystals. Recrystallization from DMF-ethanol- , water afforded colorless prisms (0.27 g, 58%), ra.p. 261-262°C.

Elemental Analysis for C:4H2oN502: C(%) H(%) N(%) Calcd : 67.63; 4.70; 19.45 Found : 67.91; 4.75; 19.80 ^- MRi 90MHz ,CDCl3-CF3COOH) δ: 1.50(3H,t), 3.20(2H,q), 5.97(2H,s), 6.93(2H,d), 7.l3(2H,d), 7.37- 8.17 ( 7H,m) .

IR(Nujol)cm"1: 3070, 2720, 1700, 1450, 1410, 1290, 1250, 1210, 755.

Working Example 28 2-IsoproOyl-l- r Γ 2 ' - ( lH-tstrazol-5-yl 1 biohenyl-4-yl "Imethyl 1 benzimidazole-7-carboxylic acid A mixture of ethyl 2-isopropyl-l-[ [ 2 ' - ( 1H-tetrazol-5-yl ) biphenyl-4-yl ]methyl ] benzimidazole-7-carboxylate (1.2 g) in methanol (5 ml) and 2N NaOH (5 ml) was heated for 4 hours under reflux. The reaction mixture was concentrated to dryness, and then 2 dissolved in water, followed by neutralization with 1N-HCl to give crystals. Recrystallization from DMF - 50% EtOH afforded colorless prisms (0.8 g, 71%), m.p. 265-267°C (decomp. ) .

Elemental Analysis for ^Η22Ν602 · 3/10H2O : C(%) H(%) N(%) Calcd : 67.55; 5.13; 18.93 Found : 67.64; 5.07; 19.00 lH-NMR(90-ffiz,CDCl3-CF3COOH) 5: 1.67(6H,d), 3. 0-3 - 83 ( lH,m) , 6.00(2H,s), 6.90(2H,d), • 7.13(2H,d), 7.43-7.83(5H,m) , 8.07(2H,d).

IR(Nujol)cm"1: 2620, 1695, 1285, 1260, 1245, 1205, 760. Working Example 29 2-Butyl-l- Γ Γ 2 ' - ( lH-tetrazol-5-yl biDhenyl-4-vnmethvnbenzimidazole-7-carboxylic acid 2. potassium salt To a solution of 2-butyl-l-[ [ 2 ' -( lH-tetrazol-5-yl )biphenyl-4-yl]methyl ]benzimidazole-7-carboxylic acid (1.2 g) and potassium 2-ethyl hexanoate (1.3 g) in ethanol (50 ml) was added toluene (50 ml) and the ethanol was removed by evaporation. Crystals then separated out which were collected by filtration and washed with ether to give colorless crystals (1.1 g, 79%), m.p. 355-358°C (decomp . ) Elemental Analysis for C2sH22 2N602 Ή20 : C(%). H(%) N(%) Calcd : 57.12; 4.42; 15.37 Found : 56.93; 4.26; 15.01 1H-Nld( 200MHz , DMSO-d6) S: 0.86(3K,t), 1.22-1.43 ( 2H,m) , 1.60-1.76(2H,m) , 2.70(2H,t), 6.06(2H,s), 6.79(2H,d), 6.94-7.03(3H,m) , 7.20-7.34 ( 4H,m) , 7.40(lH,dd), 7.53-7.58(lH,m) .

IR Karicm"1: 3350, 1600, 1570, 1515, 1460, 1400, 1360, 1315, 1280, 1005, 825, 785, 760.

Working Example 30 2-Butvl-7-hvdroxv-l-r Γ 2 ' - ( lH-tetrazol-5-vl ) biohenvl-4-yllme hyl 1 benzimidazole A mixture of 2-butyl-l- [( 2 ' -cyanobiphenyl-4-yl)methyl] -7-hydroxybenzimidazole (0.69 g) and trimethyltin azide (1.1 g) in toluene (15 ml) was heated for 4 days under reflux. Crystals then separated out and were collected by filtration, which were stirred in a mixture of 1N-HC1 (10 ml) and methanol (15 ml) for 10 minutes at room temperature. To the resultant solution was added IN NaOH to adjust the pH to 3 - 4 to give crystals . The crude crystals were purified by column chromatography on silica gel to give purified crystals. Recrystallization from acetone afforded colorless crystals, m.p. 186-188 °C.

Elemental Analysis for C23H24NsO · 1/2H20 : C(%) H(%) N(%) Calcd : 69.27; 5.81; 19.39 Found : 69.60; 5.69; 19.26 1K- MR(200MHz,DMSO-ds) S: 0.84(3H,t), 1.23-1.41 ( 2H,m) , 1.55-1.70 (2K,m) , 2.71(2H,t), 5.68(2H, s ) , 6.60(lH,d), 6.95(lH,t), 7.02-7.06 ( 5H,m) , 7.48- 7.70(4H,m), 10.00(lH,s).

IR(K3r)cm"1: 1620, 1490, 1460, 1350, 1295, 780, 755, 730.

Working Example 31 Methyl 2-orooyl-l-r Γ 2 ' - ( lK-tetrazol-5-yl ) biphenyl-4-yl Imethyl 1 benzimidazole-7-carboxylate A mixture of 2-propyl-l-[ [ 2 ' - ( lH-tetrazol-5-yl ) biphenyl-4-yl jmethyl ]benzimidazole-7-carboxylic acid (465 mg) and cone, sulfuric acid (7.2 g) in methanol (60 ml) was heated for 24 hours under reflux. After removal of solvent, the residue was. suspended m water, to which was added ΙΝ-NaOH to adjust the pH to 3 -4, followed by extraction with ethyl acetate. The organic layer was washed with water and dried, followed by evaporation of the solvent. The residue was - 91 · - purified by column chromatographyon silica gel.

Recrystallization from ethanol afforded colorless prisms (310 mg), m.p. 195-196°C.

Elemental Analysis for C25H24N607 · 2/5K20 : C(%) H(%) N(%) Calcd : 67.93; 5.44; 18.28 Found : 68.02; 5.33 18.33 ^-NMRC 90MHz, CDClj) S: 0.87(3H,t), 1.37-1.80 ( 2H,m) , 2.30(2H,t), 3.60(3H,s), 5.47(2H,s), 6.47(2H,d), . 6.80(2H,d), 6.93-8.00(7H,m) .

IR(Nujol)cm"i: 1730, 1440, 1290, 1280, 1270, 760.

The following compounds (Working Examples 32-33) were prepared according to the procedure described in Working Example 5.

Working Example 32 Methyl 2-ethyl-l-r Γ 2 ' - flH-tetrazol-5-yl )biohenyl-4-yl Imethyl 1 benzimidazole-7-carboxylate m.p.: 185-186°C Elemental Analysis for C^H^NsC 1/2C4H802-H20: C(%) H(%) N(%) Calcd : 66.70; . 5.47; 17.29 Found : 66.70; 5.26 17.49 Working Example 33 Methyl 2-isoorooyl-l- Γ f 2 ' - ( lH-tetrazol-5-yl VDiohenyl-4-yl imethyl lbenzimidazole-7-carboxylate Working Example 34 Methyl 2-butyl-l-r Γ 2 ' - ( lH-tetrazol-5-yl \ biohenyl-4-yl Imethyl 1benzimidazole-7-carboxylate A mixture of 2-butyl-l- [ [ 2 ' - ( lH-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (1.8 g) in methanol (18 ml) and cone, sulfuric acid (14.4 g) was heated for 24 hours under reflux.

After removal of the solvent by evaporation, the residue was suspended in water, whose pK was adjusted to 3 - 4 with ΙΝ-NaOH, followed by extraction with ethyl acetate . The organic layer was washed with water - 92 - and dried. The solvent was removed by evaporation and the residue was purified by column chromatography on silica gel. Recrystallization from ethanol afforded colorless prisms (1.05 g), m.p. 153-155°C.

Elemental Analysis for C27H26N602' 2/5H20: C(%) H(%) N(%) Calcd : 68.45; 5.70; 17.74 Found : 68.63; 5.61; 17.72 1H- MR ( 90MHz , CDC13 ) S: 0.80(3H,t), 1.00-1.73 (4H,m) , 2.37(2H,t), 3.60(3H,s), 5.47(2H,s), 6.47(2H,d), 6.80(2H,d), 6.97-8.00(7H,m) .

IR(Nujol)cm_l: 1720, 1450, 1430, 1290, 1280, 1270, 755. Working Example 35 Ethyl 2-sec-butyl-l-r Γ~2 ' - ( lH-tetrazol-5-yl ) biphenyl-4-yllmethyl Tbenzimida2ole-7-carboxylate This compound was prepared according to the procedure described in Working Example 14.

Melting point : 128-130°C Elemental Analysis for C28H28N602- 2/5C_,He02' 2/5H20: C(%) H(%) N(%) Calcd : 67.98; 6.06; 16.07 Found : 68.10; 6.07; 15.94 Working Example 36 Pivaloyloxymethyl 2-butyl-l-T Γ 2 ' - 1 lH-tetrazol-5-yl ^biphenyl-4-yl1methyl1benzimidazole-7-carboxylate A solution of 2-butyl-l- [ [ 2 ' - ( lH-tetrazol-5-yl )biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (3.0 g), triphenylmethyl chloride (1.96 g) and triethylamine (1.0 ml) in methylene chloride (20 ml) was stirred for 16 hours at room temperature. The reaction mixture was washed with water and dried.

After removal of the solvent, the residue was purified by column chromatography on silica gel to give colorless powder (4.25 g). The N-trityl compound thus obtained was dissolved in DMF (5 ml). To the solution were added potassium carbonate (0.2 g) and pivaroyloxymethyl iodide (0.35 g), and the mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated. To the concentrate were added water and ethyl acetate, which was subjected to extraction. The organic layer was washed with water and dried. After removal of the solvent by evaporation, the residue was dissolved in methanol (10 ml). To the solution was added 1N-HC1 (3 ml), and the mixture was stirred for 1.5 hour at room temperature. The reaction mixture was concentrated to dryness, and the concentrate was purified by column chromatography on silica gel to give colorless powdery crystals (0.43 g, 74%), m.p. 102-105°C.

Elemental Analysis for C32H34N604 · 1/2H20: C(%) H(%) N(%) Calcd : 66.77; 6.13; 14.60 Found : 66,76; 6.09; 14.45 1H- MR( 200MHz ,CDC13) 5: 0.87(3H,t), 1.16(9H,s), 1.23-1.42(2H,m) , 1.57-1.72 ( 2H,m) , 2.53(2H,t), 5.60(2H,s), 5.70(2H,s), 6.60(2K,d), 6.89(2H,d), 7.11(lH,t), 7.25-7.27(lH,m) , 7.33-7.38 ( lH,m) , 7.58-7.63(3H,m) , 7.97-8.02 ( lH,m) .

IR( Br)cm_l: 2975, 1750, 1730, 1480, 1450, 1410, 1280, 1260, 1150, 1100, 1010, 950, 760, 750.

In accordance with the method of Working Example 36, the fpi-idwing compounds were synthesized.

Working Example 37 1-r.Cvclohexyloxycarbonylox ) ethyl 2-butyl-1-Γ Γ 2 ' - ( lH-tetrazol-5-yl)biphenyl-4-yl1methyl1benzimidazole-7 carboxylate Yield : 74% Melting point : 102-105°C Elemental Analysis for C33H38N605- 1/5CHC13: C(%) H(%) N(%) Calcd : 65.39; 5.95; 13.00 Found : 65.18; 5.99; 12.86 lH-NMR(200MHz,CDCl3) : 0.87(3H,t), 1.17-1.87 ( 18H,m) , 2.53(2H,t), 4.45-4.58(lH,m) , 5.52-5.75 ( 2H,m) , 6.60(2H,d), 6.73(lH,q), 6.89(2H,d), 7.12(lH,t), 7.27-7.35(2H,m), 7.57-7.66 ( 3H,m) , 7.98-8.03 ( lH,m) .

IR(KBr)cm_1: 2950, 2875, 1760, 1740, 1450, 1420, 1280, 1250, 1080, 1000, 910, 760.

Working Example 38 1-f EthoxycarbonyloxyMethyl 2-butyl-l-r Γ 2 r — f 1H-tetrazol-5-yl ^biphenyl-4-yl1methyl1benzimidazole-7-carboxylate Yield : 75% Melting point : 92-95°C Elemental Analysis : C(%) H(%) N(%) Calcd : 64.46; 5.76; 14.55 Found : 64.56; 5.69; 14.52 1H-NMR(200MHz,CDCl3) δ: 0.86(3H,t), 1.21(3H,t), 1.27-1.43(2H/ra) , 1.42(3H,d), 1.46-1.69 ( 2H,m) , 2.50(2H,t), 4.13(2H,dq), 5.48-5.73 ( 2H,m) , 6.56(2H,d), 6.72(lH,q), 6.86(2H,d), 7.09(lH,t), 7.19-7.23(lH,m) , 7.29-7.34 ( lH,m) , 7.55-7.64 ( 3H,m) , 7.97-8.01(lH,m) .

IR( Br)cm_1: 1760, 1730, 1410, 1375, 1275, 1245, 1070, 990, 760.

Working Example 39 f 5-Methyl-2-oxo-l , 3-dioxolen-4-yl )methyl 2-butyl- 1- Γ Γ 2 ' - ( lH-tetrazol-5-yl ) biphenyl-4-yl Imethyl Ibenz-imidazole-7-carboxylate Yield : 71% Melting point : 123-125°C Elemental Analysis for C31H2aN605- 1/2H20: C(%) H(%) N(%) Calcd : - 64.91; 5.10; 14.65 Found : 64.79; ' 4.82; 14.34 1H-NMR(200MHz,CDCl3) 8: 0.84(3H,t), 1.22-1.40 ( 2H,m) , 1.53-1.68(2H,m) , 2.16(3H,s), 2.46(2H,t), - 95 4.81(2H,s), 5.54(2H,s), 6.53(2H,d), 6.86(2H/d)/ 7.08-7.22(2H,m), 7.43-7.38 ( lH,m) , '' 7.58-7.65 ( 3H,m) , 7.95-8.00(lH,m) .

I ( Br ) cm"1 : 1820, 1720 , 1400, 1300, 1275, 1250, 1220, 1185, 1105, 1000, 745.

Working Example 40 2-Kvdroxyethyl 2-butyl-l-r Γ 2 ' - ( lH-tetrazol-5- yl 1 biphenyl-4-yl Imethyl 1 benzimidazole-7-carboxylate To a solution of ethyl 2-butyl-l- [ [ 2 ' - ( 1H- tetrazo1-5-yl )biphenyl-4-yl ]methyl ]benzimidazole-7- carboxylate (0.72 g) in ethylene glycol (15 ml) was added, while stirring at room temperature, sodium hydride (60% oil, 0.25 g) and the mixture was stirred at room temperature for 15 hours . To the reaction mixture was added ice-water (100 ml), which was made acidic with formic acid. Precipitates then formed were dissolved in ethyl acetate (100 ml) and the solutio was w shed , with water, dried and concentrated to dryness to give a crystalline product. The crystals were recrystallized from acetone to afford colorless crystals (0.49 g, 66%), m.p. 145-147°C.

Elemental Analysis for C23H23N603 · 1/2C3H50 : C(%) K(%) N(%) Calcd : 67.41; 5.94; 15.99 Found : 67.19; 5.84; 15.79 K-NliR( 200MHz, CDCl3) S: 0.93(3H,t), 1.23-1.97 ( 4K,m) , 2.l3(3K,s), 2.87(2H,t), 3.77(2H,t), 4.23(2H,t), 5.73(2K,s), 6.77(2H,d), 7.00(2H,d), 7.20(lH,t),7.43-7.93(6H,m).

IR(Nujol)cm"1: 3340, 1715, 1410, 1290, 1265, 1035, 755. Working Example 41 2- ( 4-Mornholino)ethyl 2-butyl-l-r Γ 2 ' - flH-tetrazol- 5-yl lbiahenyl-4-yl Imethyl 1 benzimidazole-7 -carboxylate To a cold solution of 2-butyl-l- [[ 2 '- (N- triphenyimethyitetrazol-5-yl ) iphenyi-4- 115437/2 - 96 - yl ]met ylber.zimidazole-7-carbaxylic acid (0.4 g), 4_(2-hydrcxyethyl )morpholine (0.15 g) and diethyl phosphocyanidate (0.1 g) in DMF (2 ml) was added a solution of triethylamine (0.06 g) in DMF ( 1 ml ) and the mixture was stirred at room temperature for 30 hours . The reaction mixture was concentrated to dryness to give a residue, which was purified by column chromatography on silica gel to afford a colorless powder (0.3 g, 65%). The product was dissolved in methanol (7 ml) and to. the solution was added 1N-HC1 (1.2 ml). After stirring at room temperature for 2 hours, the reaction solution was concentrated to dryness to give a residue. The residue was dissolved in CH2C12-H20 and the aqueous layer was made basic with aqueous NaHC03 solution. The aqueous layer was extracted · with CH2C12 and the combined CH2C12 solution was washed with H20, dried and evaporated to dryness to give a residue. The residue was purified by column chromatography on silica gel to give colorless fine crystals (0.19 g, 87%), m.p. 98-110°C.

Elemental Analysis for C32K35N703 · 3/5 H20: C(%) H(%) N(%) Calcd : 66.67; 6.33; 17.01 Found : 66.41; 6.15; 16.89 ιΗ-ΝΜ?.(200ΜΚζ,Οθαΐ3) S: 0.93(3H,t), 1.34-1.52 ( 2K,m) , 1.71-1.88(2H,m) , 2.58 ( 4H,br t ) , 2.85(2H,t), 2.94(2H,br t), 3.39(2K,br t), 4.10(2K,br t), 5.65(2K,s), 6.63(2H,d), 6.96(2H,d), 7.25(lH,t), 7.40-7.61(4H,m), 7.77(lH,dd), 7.83(lH,d).

The following compounds (Working Examples 42-43) were prepared by a method similar to that of Working Example 41.

Working Example 42 2- ! l-Pioeridino ethyl 2-butyl-l-r Γ 2 ' - ( IH-tetrazol- 5-yl biohenyl-4-yl Imethyl 1 benzimidazole-7-carboxylate colorless powder (55%), m.p. 210-213°C Elemental Analysis for C^H^^C^- 3/5 H20: C(%) H(%) N(%) Calcd : 68.99; 6.70; 17.07 Found : 68.93; 6.59; 16.94 lH-NMR( 200MHz,CDClj) δ: 0.96(3H,t), 1.27-1.58 ( 8H,m) , 1.79-1.94(2H,m) , 2.72-2.85 ( 4H,m) , 2.93(2H,t), 3.20-3.31(2H,m) , 4.10-4.27 ( 2H,m) , 5.63 ( 2H,br s ) , 6.59-6.70(2H,m) , 7.04(2H,d), 7.26(lH,t), 7.36- 7.50(4H,m), 7.72-7.77(lH,m) , 7.98(lH,dd).

Working Example 43 2-fDimethylaminolethyl 2-butyl-l- Γ Γ 2 ' - ( 1H-tetrazol-5-yl biphenyl-4-ylImethyl1benzimidazole-7-carboxylate colorless powder (91%), m.p. 206-208°C Elemental Analysis for Ο30Η33Ν7Ο2· 2.1 H20: C(%) H(%) N(%) Calcd : 64.18; 6.68; 17.46 Found : 64.31; 6.40; 17.16 1H-NMR( 200MHz ,CDC13 ) S: 0.96(3H,t), 1.39-1.57 ( 2H,m) , 1.79-1.94(2H,m) , 2.34(6H,s), 2.94(2H,t), 3.10(2H,br t), 4.19(2H,br t), 5.66(2H,s), 6.63(2H,d), 7.03(2H,d), 7.27(lH,t), 7.39- 7.54(4H,m), 7.73-7.78 ( lH,m) , 7.97(lH,dd).

Working Example 44 Methyl 2-methoxymethyl-l- Γ Γ 2 ' -( lH-tetrazol-5-yl biphenyl-4-yl Imethyl lbenziinidazole-7-carboxylate A mixture of methyl l-[ ( 2 ' -cyanobiphenyl-4-yl)methyl] -2-methoxymethylbenzimidazole-7-carboxylate (0.4 g) and trimethyltin azide (1.0 g) in toluene (10 ml) was refluxed for 49 hours. The reaction solution was concentrated to dryness to give a residue and the residue was dissolved in methanol (6 ml) and IN-HCl (6 ml). The solution was allowed to stir for 3 hours and concentrated to dryness to give a residue. The residue was dissolved in CH2C12-H20 and the mixture was made neutral with ΙΝ-NaOH. The organic layer was washed - 98 with K:0, cried and concentrated to dryness to give a residue, which was purified by column chromatography on silica gel to give a crystalline product.

Recrystallization from ethyl acetate-isopropyl ether gave colorless needles (0.3g, 68%). m.p. 191-194°C Elemental Analysis for C25H22 S03 · 3 /5 H20: C(%) H(%) N(%) Ca^cd : 64.53; 5.03; 18.06 Found : 64.57; 4.94; 17.97 lH-NMR( 200MHz, CDC13) S: 3.27(3H,s), 3.55(3H,s), 4.21(2H,s), 5.62(2H,s), 6.59(2H,d), 6.87(2H,d), 7.1o(lH,t), 7.3~0-7.36(2H,m) , 7.55-7.63 ( 3H,m) , 7.93-7.99(lH,m) .

The following compounds (Working Examples 45-47) were prepared by a method similar to that of Working Example 44.

Working Example 45 Ethyl 2-ethcxymethyl-l-r Γ 2 ' - f lH-tetrazol-5-yl ) bip'ner.yl-4-yl Imethyl 1 benzimidazole-7-carboxylate colorless powder 1H- MR(200M:-:Z,CDC13) S: 1.14(3K/t) 1.21(3H,t), 3.45(2E,q), 4.20(2H,q), 4.85(2H,s), 5.89(2H,s), 6.95(2H,d), 7.10-7.40 ( 3H,m)., 7.56-7.70 ( 3H,m) , 7.96(lH,dd).

Working Example 46 Ethyl 2-ethylthiomethyl-l- Γ Γ 2 ' - ( lH-tetrazol-5-yl biohenyl-4-vnmethyl 1 benzimidazole-7-carboxylate colorless powder (75%) lK- MR( 200MHz ,CDC13) 5: 1.12 (3H,t), 1.23(3H,t), 2.46(2H,q), 4.11(2H,q), 3.36(2H/s)/ 5.63(2H,s), 6.58(2K/d)/ 6.87(2H,d), 7.10-7.36 ( 3H,m) , 7.56- 7.64(3H,m), 7.97 -8.04 ( lH,m) .

Working Example 47 Ethyl 2-methylthiomethyl-l-r r 2 ' - ( lK-tetrazol-5-yl ^ bio"nenyl-4-yllmethyl 1 benzimidazole-7-carboxylate colorless powder (56%) XH-N R( 200MHz, CDC13) δ: 1.21(3H,t), 2.03(3H,s), 4.11(2H,q), 5.63(2H,s), 6.60(2H,d), 6.91(2H/d)/ 7.15-7.40(3H,m) , 7.55-7.68(3H,m) , 8.00-8.10 ( lH,m) . Working Example 48 Ethyl 2-hvdroxymethyl-l-r 2 ' - I lH-tetrazol-5-yl ^biohenyl-4-yl1methvnbenzimidazole-7-carboxylate The compound was prepared by a method similar to that of Working Example 44 from ethyl 2-acetoxymethyl-l-[ [2'-(lH-tetrazol-5-yl)biphenyl-4-yl ]methyl ]benzimidazole-7-carboxylate . pale yellow powder (80%) 1H-NMR(200llHz,CDCl3) S: 1.20(313, t), 4.17(2H,q), 4.82(2H,br s) , 5.56 ( 2H,br s ) , 6.65(2H,d), 6.86(2H,d), 6.82-6.95 ( lH,m) , 7.21-7.54 ( 4H,m) , 7.62(lH,d), 7.75-7.82(lH,m) .

Working Example 49 2-Methoxymethyl-l- Γ Γ 2 ' - ( lH-tetrazol-5-yl ^biphenyl-4-yllmethyl 1 benzimidazole-7-carboxylic acid A solution of methyl 2-methoxymethyl-l- [[ 2 '-( 1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (0.2 g) in methanol (10 ml) and IN-NaOH (1.5 ml) was heated at 80 °C for 20 hours. The solution was concentrated to dryness to give a residue. The residue was dissolved in H20 and made acidic to give a crystalline product. Recrystallization from DMF-MeOH-H20 gave colorless prisms (0.16 g, 80%). m.p. 272-274°C Elemental Analysis for C24H20N6O3 (Mw. 440.46): C(%) H(%) N(%) Calcd : 65.45; 4.58; 19.08 Found : 65.32; 4.47; 18.95 1H-NMR(200MHz,DMSO-d6) 5: 3.28(3H,S), 4.68(2H,s), 5.87(2H,s), 6.80(2H,d), 6.98(2H,d), 7.29(lH,t), 7.45-7.70(5H,m) , 7.91(lH,dd).

The following compounds (Working Examples 50-54) - 100 - were prepared by a method similar to that of Working Example 49.

Working Example 50 2-Ethoxymethyl-l-Γ Γ 2 · -( lH-tetrazol-5-yl )biphenyl-4-yl Imethyl 1benzimidazole-7-carboxylic acid colorless powder (80%) , m.p. 243-245°C Elemental Analysis for C2jH22N603 · 1/2H20 (Mw. 463.50): C(%) H(%) N(%) Calcd : 64.78; 5.00; 18.13 Found : 64.99; 4.97; 18.26 1H-NMR(200MHz,DMSO-d6) 5: 1.01(3H,t), 3.48(2H,q), 4.72(2H,s), 5.89(2H,s)/ 6.81(2H,d), 6.99(2H,d), 7.29(lH,t), 7.44-7.70(5H,m) , 7.91(lH,dd).

Working Example 51 2-Methylthiomethyl-l-r Γ 2 ' -( lH-tetrazol-5-yl^biphenyl-4-yllmethyl 1benzimidazole-7-carboxylic acid colorless powder (82%), m.p. 270-272°C Elemental Analysis for C24H2oN602S · 1/2H20 (Mw. 465.54): C(%) H(%) N(%) Calcd : 61.92; 4.55; 18.05 Found : 61.94; 4.44; 18.20 1H- MR( 200MHz , DMS0-d6 ) S: 2.09(3H,s), 3.98(2H,s), 5.89(2H,s), 6.80(2H,d), 7.00(2H,d), 7.27(lH,t), 7.45-7.69(5K,m) , 7.87(lH,dd).

Working Example 52 2-Hvdroxymethyl-l- Γ Γ 2 ' -( lH-tetrazol-5-yl )biphenyl-4-yllmethyl 1benzimidazole-7-carboxylic acid colorless powder (65%), m.p. 292-294°C Elemental Analysis for Ο^Η^Ν^ · 3/10 H20 (Mw. 431.84): C(%) H(%) N(%) Calcd : 63.97; 4.34; 19.46 Found : 64.01; 4.29; 19.49 ^-N R( 200MHz , DMS0-d6 ) δ: 4.72(2H,s), 5.92(2H,s), 6.83(2H,d), 6.98(2H,d), 7.27(lH,t), 7.45-7.68 (5H,m), 7.88(lH,dd).

Working Example 53 - 101 - 2-Ethylthiomethyl-l-r Γ2'-( lH-tetrazol-5-yl biOhenyl-4-yl Imethyl 1benzimidazole-7-carboxylic acid colorless crystals (76%), m.p. 157-160°C Elemental Analysis for C^I^ eC^S · 9/10 H20: C(%) H(%) N(%) Calcd : 61.69; 4.93; 17.26 Found : 61.75;. 4.91; 17.26 lH-NMR( 200MHz,DMSO-d6) S: 1.18(3H,t), 2.54(2H,q), 4.01(2H,s), 5.89(2H,s), 6.80(2H,d), 7.00(2H,d), 7.27(lH,t), 7.45-7.68(5H,m), 7.87 ( lH,dd) .

Working Example 54 2-Methylaminomethyl-l-r Γ 2 ' - ( lH-tetrazol-5-yl ^biOhenyl-4-ylImethyl lbenzimidazole-7-carboxylic acid colorless powder (4¾%) 1H-NMR(200MHz,DMSO-d6) S: 2.66(3H,s), 4.42(2H,s) 5.84(2H,s), 6.79(2H,d), 7.00(2H,d), 7.27- 7.68(6H,m), 7.87(lH,d).

The following compounds (Working Examples 55-58) were prepared by a method similar to that of Working Example 31.

Working Example 55 Methyl 2-methylthiomethyl-1-Γ Γ 2 ' - ( lH-tetrazol-5-yl )biphenyl-4-yl Imethyl 1benzimidazole-7-carboxylate colorless powder (54%), m.p. 186-188°C Elemental Analysis for C2sH22N602S-l/2 H20: C(%) H(%) N(%) Calcd : 62.61; 4.83; 17.52 Found : 62.82; 4.63; 17.69 1H-NMR(200MHz,CDCl3) S: 2.03(3H,s), 3.70(3H,s), 3.36(2H,s), 5.63(2H,s), 6.64(2H,d), 6.94(2H,d), 7.18(lH,t), 7.30-7.40(2H,m) , 7.57-7.66 ( 3H,m) , 8.02-8.07(lH,m) .

Working Example 56 Methyl 2-ethylthiomethyl-l- Γ Γ 2 ' - ( lH-tetrazol-5-yl ^biphenyl-4-yl1methyl1benzimidazole-7-carboxylate pale yellow powder (49%) - 102 - Elemental Analysis for C26H24N602S .1/2 H20: C(%) H(%) N(%) Calcd : 63.27; 5.11; 17.03 Found : 63.42; 4.87; 16.92 lH-NMR(200MHz,CDCl3) δ: 1.09(3H,t), 2.42(2H,q), 3.22(2H,s), 3.64(3H,s), 5.57(2H,s), 6.53(2H,d), 6.84(2H,d), 7.13(2H,d), 7.31-7.38 ( lH,m) , 7.56- 7.65(3H,m), 7.89-7.98 ( lH,m) .

Working Example 57 Methyl 2-hvdroxymethyl-l-r Γ 2 ' - ( lH-tetrazol-5-yl ^biphenyl-4-yl1methyl1benzimidazole-7-carboxylate colorless powder (30%) ^-NMRf 200MHz, CDCI3) δ: 3.63(3H,s), 4.77(2H,s= , . 5.75(2H,s), 6.76(2H,d), 6.99(2H,d), 7.23(lH,t), 7.39-7.62(5H,m)/ 7.90(lH,dd).

Working Example 58 Methyl 2-ethoxymethyl-l-r Γ 2 ' - I lH-tetrazol-5-yl ) biphenyl-4-yl Imethyl 1benzimidazole-7-carboxylate colorless needles (61%), m.p. 214-217°C Elemental Analysis for C26H2«N603-l/5 H20: C(%) H(%) N(%) Calcd : 66.08; 5.18; 17.87 Found : 66.15; 5.21; 17.80 lH-NMR(200MKz,CDCl3) S: 1.14(3H,t), 3.44(2H,q), 3.68(3K,s), 4.13(2H,s), 5.63(2K,s), 6.61(2H,d), 6.89(2H,d), 7.16(lH,t), 7.19-7.39 ( 2H,m) , 7.57- 7.64(3H,m), 7.97-8.02 ( lH,m) .

Working Example 59 Ethyl 2-chloromethyl-l-r ϊ 2 ' - ( lH-tetrazol-5-yl biphenyl-4-vnmethyl1benzimidazole-7-carboxylate To a solution of ethyl 2-hydroxymethyl-l-[ [2'-(lH-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (0.2 g) iri CH2C12 (3 ml) was added thionyl chloride (0.3 ml) dropwise and the mixture was refluxed for 3 hours . The reaction solution was poured into ice-water and the organic layer was washed with water, - 103 - dried and evaporated to dryness to give a pale yellow amorphous powder (0.2 g, 96%). 1H- MR( 200MHz , CDC13 ) S: 1.29(3H,t), 4.19(2H,q), 4.63(2H,s), 5.77(2H,s), 6.75(2H,d), 7.03(2H,d), 7.28(lH,t), 7.35-7.39(lH,m) , 7.56-7.72 ( 4H,m) , 8.06-8.11(lH,m) .

Working Example 60 Ethyl 2-methylaminomethyl-l- Γ Γ 2 ' - ( lH-tetrazol-5-yl biohenyl-4-yl 1methyl! benzimidazole-7-carboxylate To a solution of ethyl 2-chloromethyl-l-[ [ 2' - ( 1H-tetrazol-5-yl )biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (0.2 g) in acetonitrile (5 ml) was added a solution of 40% methylamine in methanol (0.33 g) and the mixture was heated at 60°C for 77 hours. The reaction solution was cooled to give pale yellow prisms (0.12 g, 61%), m.p. 248-250°C.

^-NMR 200MHz, DMS0-d6) S: r:i4(3H,t), 2.62(3H,s), 4.16(2H,q), 4.39(2H,s), 5.71(2H,s), 6.73(2H,d), 7.03(2H,d), 7.27-7.46(4H,m) , 7.54-7.63 ( 2H,m) , 7.94(lH,dd).

The following compounds (Working Examples 61-62) were prepared by a method similar to that of Working Example 1.

Working Example 61 " Ethyl 2-isobutyl-l-r Γ 2 ' - ( lH-tetrazol-5-yl ^biohenyl-4-yl1methyl1benzimidazole-7-carboxylate colorless prism (71%) !H- MR ( 90MHz , CDC13 ) S: 0.87(6H,d), 1.13(3H,t), 1.23(lH,t), 1.83-2.40(lH,m) , 2.00(lH,s), 2.27(2H,d), 4.03(2H,q), 4.13(lH,g), 5.47(2H,s), 6.43(2H,d), 6.73(2H,d), 6.87-7.70 ( 6H,m) , 7.90- 8.00(lH,m) .

Working Example 62 Ethyl 2-sec-butyl-l-r F2'-f lH-tetrazol-5-yl biphenyl-4-yl lmethvnbenzimidazole-7-carboxylate colorless prism (43%), m.p. 128-130°C 104 - lH-NMR( 90MHz ,CDC13) S: 0.87(3H,t), 1.00-1.17 ( 6H,m) , 1.23(lH,t), 1.50-1.90(2H,m) , 2.03(lH,s), 2.63- 3.03 ( lH,m) , 4.00(2H,q), 4.13(lH,q), 5.57(lH,d), 5.77(lH,d), 6.50(2H,d), 6.77(2H,d).

IR(Nujol)cm_1: 2720, 1730, 1450, 1280, 1265, 1200, 760, 765.

• The following compounds (Working Examples 63-64) were prepared by a method similar to that of Working Example 49.

Working Example 63 2-Isobutyl-l-r Γ 2 ' - ( lH-tetrazol-5-yl ^biphenyl-4-yllmethvnbenzimidazole-7-carboxylic acid colorless powder (62%), m.p. 205-207°C(d) Elemental Analysis for C26H24Ns02* 2/5 H20: C(%) H(%) N(%) Calcd : 67.93; 5.44; 18.23 Found : 67.98; 5.63; 18.43 lH- MR( 90MHz ,CDCI3) 5: 1.57(6H,d), 3.40-3.83 ( lH,m) , 6.00(2H,s), 6.90(2H,d), 7.13(2H,d), 7.43- 7.83(5H,m), 7.97-8.12 ( 2H,m) .

IR(Nujol)cm_1: 2460, 1690, 1410, 1290, 1245, 1200, 1120, 760.

Working Example 64 2-sec-Butyl-l-r Γ 2 ' - ( lH-tetrazol-5-yl 1biOhenyl-4-yl 1methvnbenzimidazole-7-carboxylic acid colorless prism (79%), m.p. 184-186°C Elemental Analysis for C26H24N602- 1/2 EtOH: C(%) H(%) N(%) Calcd : 68.20; 5.72; 17.67 Found : 67.96; 5.71; 17.46 1H-NMR( 90MHz ,DMS0-d6 ) δ: 0.83(3H,t), 1.17(lH,t), 1.30(3H,d), 1.53-2.13(2H,m) , 2.77-3.13 ( lH,m) , 3.63(lH,q), 5.90(2H,s), 6.80(2H,d), 7.03(2H,d), 7.23(lH,t), 7.33-7.97(7H,m) .

IR NujolJcirT1: 2600, 1700, 1450, 1410, 1275, 1230, 1200, 1140, 750. - 105 - The following compounds (Working ..Examples 65-66) were prepared by a method similar to that of Working Example 19.

Working Example 65 Methyl 2-( 2-methoxyethv -l-r Γ 2 · -( lH-tetrazol-5-yl biOhenyl-4-yl Imethyl lbenzimidazole-7-carboxylate ; pale yellow powder (35%) lH-NMR( 200MHz, CDC13) 6: 2.60(2H,t), 3.61(2H,t), 3.19(3H,t), 3.63(3H,t), 5.60(2H,s), 6.56(2H,d), 6.85(2H,d), 7.07-7.12(2H,m) , 7.30-7.35 ( lH,m) , 7.51-7.65(3H,m) , 7.96(lH,dd).

Working Example 66 Methyl 2- f 2-methylthioethyl \ -1-Γ Γ 2 ' - ( lH-tetrazol-5-yl ^biphenyl-4-yl 1methyl 1benzimidazole-7-carboxylate pale yellow powder (16%) 1H- MR( 200MHz , CDC13 ) S: 2.09(3H,t), 3.63(3H,s), 2.72- 2.96(4H,m), 5.65(2H,s), 6.60(2H,d), 6.87(2H,d)/ 7.06-7.20(2H,m) , 7.29-7.34 ( lH,m) , 7.54-7.63 ( 3K,m) , 7.99-8.05(lH,m) .

Working Example 67 Methyl 2-butyl-l-r Γ 2 ' - < l-methyltetrazol-5- methyl 2-butyl-l-r Γ 2 ' - ( 2-methyltetrazole-5-yl biphenyl-4-yl Imethyl 1benzimidazole-7-carboxylate A mixture of 2-butyl-l- [ 2 ' - ( lH-tetrazol-5-yl )biphenyl- -yl]methyl ]benzimidazole-7-carboxylic acid (2.0 g), NaHC03 (1.1 g) and methyl iodide (1.5 g) in DME (10 ml) was stirred at room temperature for 15 hours . The reaction mixture was diluted with water and then the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated to dryness. The resulting residue was purified by column chromatography on silica gel to give 1-methyl derivative (0.95 g, 45%) and 2-methyl derivative (0.36 g, 17%). 1-Methyl derivative (67a): - 106 - m.p. 200-201°C Elemental Analysis for C28H28 602: C(%) H(%) N(%) Calcd : 69.98; 5.87; 17.49 Found : 69.67; 5.80; 17.36 S: 0.97(3H,t), 1.39-1.58 ( 2H,m) , 1.81-1.97(2H,m), 2.91(2H/t), 3.16(3H,s), 3.74(3H,s), 5.72(2H,s), 6.77(2H,d), 7.00(2H,d), 7.25(lH,t), 7.48-7.69(5H,m) , 7.95(lH,dd). 2-Methyl derivative (67b): pale yellow syrup 1H-NMR(200MHz,CDCl3) δ: 0.96(3H,t), 1.38-1.57 ( 2H,m) , 1.80-1.96(2H,m) , 2.92(2H,t), 3.71(313,8) , 4.18(3H,s), 5.J3(2H,s), 6.77(2H,d), 7.06(2H,d), 7.24(lH,t), 7^35-7.55(3H,m) , 7.59 ( lH,dd) , 7.80(lH,dd), 7.94(lH,dd).

IRiNeatJcm"1: 1725, 1520, 1460, 1435, 1400, 1360, 1280, 1265, 1220, 1200, 1125, 760.

Working Example 68 2-Butyl-l- Γ Γ 2 ' - ( lH-tetrazol-5-yl ^biphenyl-4-yllmethyll -7-formylaminobenzimidazole and 2-butyl-l-Γ Γ 2 / - ( lH-tetrazol-5-yl )biphenyl-4-yl Imethyl 1 -7-ethoxycarbonylaminobenzimidazole A mixture of 2-butyl-l-[ [ 2 ' -( lH-tetrazol-5-yl )biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (0.94 g) , diphenylphosphoryl azide (0.61 g) and triethylamine (0.61 g) in DMF (6 ml) was stirred at room temperature for 7 hours and then the reaction mixture was concentrated to dryness to give a crystalline residue. The residue was chromatographed on silica gel column to give two colorless crystalline products (68a and 68b).

Formylamino derivative (68a): colorless crystals (0.26 g, 29%), m.p. 290- 292°C(d) Elemental Analysis for C26H25 70: - 107 - C(%) H(%) N(%) Calcd : 69.16; 5.58; 21.71 Found : 69.29; 5.51; 21.94 1H-NMR(200MHz,CDCl3) S: 0.84(3H,t), 1.22-1.40 ( 2H/m) , 1.56-1.71(2H,m) , 2.70(2H,t), 5.55(2H,s), 6.79(lH,d), 6.89(2H,d), 6.98-7.07 ( 3H,m) , ■ 7.43(2H,d),.7.51-7.70(3H,m), 8.27(lH,s).

IR(KBr)cm_1: 3340, 1630, 1530, 1510, 1420, 1400, 750, 730.

Ethoxycarbonylami.no derivative (68b): colorless crystals (0.31 g, 31%), m.p. 190- 194°C(d) Elemental Analysis for C28H2N7O2· 0.1 H20: C(%) H(%) N(%) Calcd : 67.62; 5.92; 19.71 Found : 67.43; 5.81; 19.70 1H-NMR(200 Hz,CDCl3) S: 0.87(3H,t), l.l8(3H,t), 1.25- 1.39(3H,m), 1.56-1.71 ( 2H,m) , 2.50(2H,t), 3.99(2H,q), 5.37(2H,s), 6.07(lH,s), 6.66(2H,d), 6.90-7.05(5H,m) , 7.34 ( lH,dd) , 7.55-7.64 ( 2H,m) , 8.00(lH,dd) .

IR(KBr)cm_1: 1700, 1520, 1250, 750.

Working Example 69 2-Butyl-l-Γ Γ 2 ' - ( lH-tetrazol-5-yl ^biOhenyl-4-yl Irnethyl 1 -7- { ,Ν-dimethylaitiinomethyl ^benzimidazole This compound was prepared by a method similar to that of Working Example 44. colorless crystals (56%), m.p. 178-180°C(d) Elemental Analysis for C2_H31N7- 2HC1 · 2Η20· 1/2 AcOEt: C(%) H(%) N(%) Calcd : 58.25; 6.68 15.85 Found : 58.42; 6.42 15.61 1H-NMR(200i4Hz,DMSO-d6) S .91(3H,t), 1.33-1.51(2H, 1,71-1.86(2H,m) , 2.50(6H,s), 3.17(2H,t), 4.32(2H,s), 5.92(2H,s), 7.07(2H,d), 7.14(2H,d), 7.49-7.72(5H,m) , 7.80(lH,d), 7.92(lH,d). - 108 - IR(KBr)cm"1: 340Q, 1500, 1470, 1435, 1420, 750.

The following compounds (Working Examples 70-71) were prepared by a method similar to that of Working Example 44.

Working Example 70 yl Imethyl "lbenziniidazole-7-carboxylic acid colorless prism (78%), m.p. 213-214°C Elemental Analysis for C27H26N602- 1/2 H20: C(%) H(%) N(%) Calcd : 68.19; 5.72; 17.67 Found : 68.52; 5.55; 17.62 lH-NMR( 200MHz ,CDC13) 5: 0.95(3H,t), 1.38-1.57 ( 2H,m) , 1.80-1.95 (2H,m) , 2.99(2H,t), 3.18(3H,s), 5.82(2H,s), 6.80(2H,d)/ 6.97(2H,d), 7.27(lH,t), 7.48-7.68(4H,m) , 7.80(lH,d), 7.98(lH,d).

IRi BrJcm'1: 1700, 1520, 1470, 1445, 1435, 1410, 1290, 1280, 1230, 1185, 1145, 1120, 1100, 820, 770, 760, 745, 730.

Working Example 71 2-Butyl-l-r Γ 2 ' - ( 2-methyltetrazol-5-yl ^biphenyl-4-yl Imethyl 1 benzimidazole-7-carboxylic acid colorless needles (71%), m.p. 226-228°C(d) Elemental Analysis for C27H26N602 · 0. H20: C(%) H(%) N(%) Calcd : 67.68; 5.76; 17.54 Found : 67.48; 5.51; 17.26 1H- MR(200MHz,CDCl3) 5: 0.94(3H,t), 1.38-1.56 ( 2H,m) , 1.79-1.94(2H,m) , 3.07(2H,t), 4.22(3H,s), 5.84(2H,s), 6.81(2H,d), 7.06(2H,d), 7.25- 7.55(4H,m), 7.74(lH,d), 7.81(lH,dd), 8.00(lH,d). IR(KBr)cm_1: 1700, 1510, 1450, 1430, 1410, 1360, 1290, 1240, 1190, 1150, 1120, 1100, 1060, 1035, 1000, 820, 760, 750, 740, 720.

Working Example 72 2-Butyl-l- Γ Γ 2 ' - ( N-pivaloyloxymethyltetrazol-5- - 109 - yl )biphenyl-4-yl Imethyl 1benzimidazole-7-carboxylic acid A mixture of 2-butyl-l-[ [ 2 ' - ( lH-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (0.71 g), K2C03 (0.21 g) and iodomethylpivalate (0.36 g) in DMF (2 ml) was stirred at room temperature for 17 hours . The reaction mixture was digested with water and made acidic (pH 3-4) with 1N-HC1. The mixture was extracted with ethyl acetate and the organic layer was washed with H20, dried and evaporated to dryness to give a residue. The residue was purified by column chromatography on silica gel to afford colorless powder (0.2 g, 23%), m.p. 188-191°C(d) .

Elemental. Analysis for C32H34N604 · 0.6 H20: C(%) H(%) N(%) Calcd : 66.56; 6.14; 14.55 Found : 66.82; 6.28; 14.13 lH-N R( 200MHz , CDC13 ) S: 0.94(3H,t), 0.96 and l.l8(9H,s), 1.36-1.55(2H,m) , 1.77-1.93 ( 2H,m) , 2.90-2.97(2H,m) , 5.39 ( 1.5H, s ) , 5.81(2H,s), 6.36(0.5H,s), 6.76-6.83 ( 2H,m) , 6.96-7.03 ( 2H,m) , 7.20-7.29(lH,m), 7.38-7.97 ( 6H,m) .

IR KBrJcm"1: 1760, 1600, 1460, 1410, 1275, 1240, 1125, 1100, 760.

The following compounds (Working Examples 73-76) were prepared according to the procedure described in Working Example 36.

Working Example 73 Pivaloyloxymethyl 2-ethyl-l- Γ Γ 2 ' - ( lH-tetrazol-5-vHbiphenyl-4-vnmethyl 1benzimidazole-7-carboxylate Working Example 74 Pivaloyloxymethyl 2-propyl-l- Γ Γ 2 ' - ( lH-tetrazol-5-yl )biphenyl-4-yl Imethyl lbenzimidazole-7-carboxylate Working Example 75 1- f Cyclohexyloxycarbonyloxy Methyl 2-proPyl-l-r Γ 2 ' - C lH-tetrazol-5-yl 1biphenyl-4-yl1methyl1benzimidazole-7-carboxylate - no - 1 1 5437/2 Working Example 76 ;· 1- ( Cvclohexyloxycarbonyloxyl ethyl 2-ethyl-l-r Γ 2 ' - ! lK-tetrazol-5-yl bip'nenyl-4-yl Im thyl "lbenzimidazole-7- carboxylate Experimental Example 1 Inhibition of binding of angiotensin-II to angiotensin receptor [.Method] .An experiment of inhibition on the binding of angiotensin II (A-II) to A-II-receptor was conducted by modifying the method of Douglas et al.

[Endocrinology, 102 , 685-595 (1978)]. An A-II receptor was prepared from the membrane fraction of bovine adrenal cortex.

The compound of this invention (10_iM or 10"¾) and. 125I-A-II (1.85 kBq/50 μΐ) were added to the receptor membrane fraction , and the mixture was incubated for one hour at room temperature. The receptor-bound and free l25I-A-II were separated through a filter (Whatman GF/B filter) , and the radioactivity of 125I-A-II bound to the receptor was measured.

[Results ] The results relating to the compounds of this invention are shown in Table 1.

Experimental Example 2 Inhibitory effect of the compound of this invention on pressor action of A-II [Method] Jcl : SO rats (9 week old, male) were used. On the previous day of the experiment, these animals were were injected with pentobarbital Na into the femoral artery and , vein under anesthesia ' The animals were fasted but allowed to access freely to drinking water until the experiment was started, only" on the day of the experiment, the artery cannula was connected with a blood-pressure transducer, 115437 - Ill - and the average blood pressure was recorded by means of a polygraph. Before administration of the drug, the pressor action due to intravenous administration of A-II (100 ng/kg) as the control was measured. The drugs were orally administered, and then, at each point of the measurement, A-II was administered intravenously, and the pressor action was similarly measured. By comparing the pressor action before and after administration of the drug, the percent inhibition by the drug on A-II-induced pressor action was evaluated. [Results ] The results relating to the compounds of this invention are shown in Table 1.

Table 1 *1 NT= not tested *2

Claims (4)

1. CLAIMS compound of the formula (XVII) or a salt thereof, wherein R2 is a group of the formula -CO-D1 , wherein D* is (1) hydroxyl, (2) lower-fC^.gJ-alkoxy, the alkyl portion of which may be substituted by (i) hydroxyl, (ii) amino, (iii) halo, (iv) lower- ^ gj-alkanoylo y, (v) lower- (C-j^g) -alkoxy, (vi) lower- (C1_g) -alkylthio, Lvii) lower- (C^.g) -alkoxycarbonylox , (viii) C^_y-cycloalkoxycarbonyloxy , (ix) 5-methyl-2-oxo-1.S-dioxyolen-'i-yl, (x) is (1) carboxyl, (2) tetrazolyl, (3) trifluoromethanesulfonic acid amido, (4) phosphoryl, (5) sulfonyl, (6) cyano, or (7) lower- (C^_[|) -alkoxycarbonyl , each of which may be protected by (i) lower- (C^..^ ) -alkyl , (ii) lower- (02-5) -alkanoyl , (iii) benzoyl, or (iv) pivaloyloxyme hyl , ring A is a benzene ring having a substituent other than that defined by R , said substituent being selected from (1) halo, (2) nitro, (3)· cyano, (4) amino, (5) N-lower-(C^_ij)-alkylamino, (6) N,N-dilower-(C^_ i| ) -alkylamino , (7) N-arylamino, (8) alicyclic amino, (9) a group of the formula -Y-R where Y is a direct bond or is -0-, -S- or -C(=0)-, and R is as defined below, (10) lower- (C^_/j ) -alkyl , (11) lower- (C^_/j ) -alkoxy or (12) a group of the formula -CO-D", wherein D" is (1) hydroxyl, (2) lower- (C-^_ (j) -alkoxy, the alkyl portion of which may be substituted by (i) hydroxyl, (ii) amino, (iii) N-lower-^.^) -alkylamino, (iv) N,N-dilower-(C1_/ )-alkylamino, (v) N-arylauiino, (vi) alicyclic amino, (vii) halo, or (viii) lower- (Cj^tj) -alkoxy, and R is: 114 115437/2 ( i ) hydrogen ; (ii) a lower- (C-^_^) -alkyl group which may be substituted by (1) hydroxyl, (2) amino, (3) N-lower-(C-^_ij) -alkylamino, (4) Ν,Ν-dilower- (C^. /j) -alkylamino, (5) N-arylamino, (6) alicyclic amino, (7) halo, or (8) lower-(C1_ij)-alkoxy; (iii) amino; (iv) N-lower-(C^_ij) -alkylamino; (v) alicyclic amino; (vi) halo; or (vii) hydroxyl; X is (1) a direct bond or (2) a divalent spacer linking the depicted unfused benzene rings by 1 or 2 atoms, selected from lower- (C-j^)-alkylene, -C(=0)-, -0-, -S-, -NH-, -C(=0)-NH-, -0CH2-, -SCH2~ and -CH=CH-; and either Q1 is H and Q2 is -N02 or NH2; or is -COR^, where is a straight or branched lower alkyl grou having 1 to 8 carbon atoms, which may be substituted by (1) hydroxyl, (2) amino, (3) N-lower- -alkylamino, (5) halo, (6) lower- (C^.^) -alkylthio, or (7) lower- (C^/j) -alkoxy, and Q2 is N02.

2. A compound according to claim 1, which is selected from methyl 2- [ [N-tert . -butoxycarbonyl] -N- (2 * -cyanobiphenyl-4-yl ) methyl]amino]~3~ nitrobenzoate , ethyl 2-[ [N-tert . -butoxycarbonyl] -N- (2 ' -cyanobiphenyl-4-yl)methyl]amino]-3_nitrobenzoate, methyl 2-[[ (2' -cyanobiphenyl-4-yl)methyl]amino]-3-nitrobenzoate, ethyl 2-[[ (2' -cyanobiphenyl-4-yl) methyl]amino]-3-nitrobenzoate, methyl 3~aniino-2-[[ (2* -cyanobiphenyl-4-yl)methyl]amino]benzoate and ethyl 3~amino-2-[[ (21 -cyanobiphenyl-4-yl ) methyl]amino]benzoate . 115 115437/2

3. A process for the preparation of a compound of formula (XVII) as 1 1 defined in claim 1 or claim 2, when Q is -COR , which comprises reacting a compound of formula (XI) with a compound of formula (XVI), where W is a halogen atom and the other symbols in these formulae are as defined in claim 1.

4. A process for the preparation of a compound of formula (XVII) as 1 P defined in claim 1 or claim 2, when Q is H and Q is NC^, which comprises removing the protecting group = -COO^u from the analogous protected secondary amino-compound of formula (XVII) where is -COO^u. 5· A process according to claim 4, wherein said analogous protected secondary amino-compound has been prepared by a process according to claim 3· 6. A process for the preparation of a compound of formula (XVII) as defined in claim 1 or claim 2, when Q is H and Q is H2, which comprises reducing to NH2, the group Q"'" = -NO2 in the analogous nitro-compound of formula (XVII) where Q1 is Ν02· 7· A process according to claim 6, wherein said analogous nitrocompound has been prepared by a process according to claim 4. 8. A process according to claim 7i wherein said analogous protected secondary amino-compound has been prepared by a process according to claim 3· 9· Compounds according to either claim 1 or claim 2, which have been prepared by a process according to any of claims 3 to 8. For the Applicants, Sanford T. Colb & Co. C: 2313O I-1225B 116