SK282473B6 - Benzimidazole compound, its production method, stable crystal, pharmaceutical preparation and intermediate - Google Patents

Abstract

Benzimidazole derivatives of general formula (I) and their pharmaceutically usable salts, which have significant anti-hypertensive and antagonistic effect against angiotensine II thus they are usable as therapeutic agents for treatment of circulatory diseases, such as hypertension and cardiac diseases; their production methods, intermediate for their production and pharmaceutical preparation containing them.

Description

Technical field

The invention relates to benzimidazole compounds with excellent pharmacological activity, intermediates thereof, processes for their preparation and pharmaceutical compositions containing them. In particular, the invention provides compounds having valuable antihypertensive activity and potent angiotensin II antagonist activity, which compounds are useful as therapeutic agents for treating circulatory diseases such as high blood pressure, heart diseases such as hypercardia, heart failure, heart attack and heart attack. etc., stroke, cerebral apoplexy, nephritis and the like.

BACKGROUND OF THE INVENTION

The renin-angiotensin system is used in the homeostatic function to regulate systemic blood pressure, body fluid volume, electrolyte balance, and the like, in conjunction with the aldosterone system. The development of angiotensin II converting enzyme inhibitors (ACE inhibitors) (an enzyme that produces angiotensin II with strong vasoconstrictor efficacy) has elucidated the relationship between the renin-angiotensin system and hypertension. Since angiotensin II contracts blood vessels and thereby increases blood pressure via angiotensin II receptors in cell membranes, angiotensin II antagonists, as an ACE inhibitor, may be useful in the treatment of angiotensin-induced hypertension.

Various analogues of angotensin II, such as saralasin (Sar ¹ , clay ⁸ / A II, etc.), have been reported to act as potent angiotensin II antagonists.

However, it has also been reported that, when administered parenterally, they do not have long-term effects and are ineffective when administered orally (M.A. Ondetti and D.W. Cushman, Annual Reports in Medicinal Chemistry, B, 82-91, 1978).

Thus, there is a great need for the development of non-peptide angiotensin II antagonists that do not have these disadvantages. In accordance with recent work in this field, imidazole derivatives acting as angiotensin II antagonists have been described in Japanese patent applications no. 71073/1981, 71074/1981, 92270/1982, 157768/1983, U.S. Pat. 4,355,040, 4,340,598 and the like. Improved imidazole derivatives are described in European patent applications no. 0253310, 0291969, 0324377 and 117876/1989. Pyrrole, pyrazole and triazole derivatives as angiotensin II antagonists are described in European patent application no. No. 0323841 and in Japanese application no. 287071/1989.

U.S. Pat. No. 4,880,804 discloses benzimidazole derivatives acting as angiotensin II receptor antagonists, which are effective in vivo when administered intravenously to hypertensive rats. Examples of such imidazole derivatives are compounds of general interest

wherein the substituents, e.g. at the 5- and / or 6-position are hydroxymethyl, methoxy, formyl, chlorine or carboxyl. Although most of these compounds are orally inactive, only the 6-hydroxymethyl and 6-chloro compounds have been said to be effective when administered orally (100 mg / kg or less). However, the efficacy of all these compounds is insufficient for clinical use.

SUMMARY OF THE INVENTION

The invention relates to novel benzimidazole derivatives having excellent antihypertensive activity and potent angiotensin II antagonist activity, which are of practical importance in clinical use as therapeutic agents.

The inventors have taken into account that compounds intended to act as regulators of the renin-angiotensin system and to be clinically useful in the treatment of cardiac diseases such as hytertension, cardiac diseases, e.g. hypercardia, heart failure, heart attack, etc., stroke, cerebral apoplexy, etc. must act as potent and long-acting angiotensin II receptor antagonists and have potent and long-term angiotensin II antagonist effects when administered orally. Based on these assumptions, extensive research has been conducted to show that the authors have synthesized novel 2-substituted benzimidazole derivatives of formula (I) which act as potent angiotensin II receptor antagonists and have potent and long-term angiotensin II antagonist activity and antihypertensive activity in oral administration.

The invention relates to a benzimidazole compound of formula (I)

in which

R ¹ is hydrogen or an optionally substituted hydrocarbon radical,

R ² is carboxyl, tetrazolyl, trifluoromethanesulfonic acid amide, phosphoric acid, sulfonic acid, cyano or lower alkoxycarbonyl, C _M, which may be protected by an optionally substituted lower alkyl or acyl,

X is a direct bond or a group between a phenylene group and a phenyl group,

R is a group of the formula -CO-D 'wherein D' is hydroxyl, optionally substituted with amino or alkoxy,

R is halogen, nitro, cyano, optionally substituted amino, and -WR ¹³ wherein W is a chemical bond, -O-, -S- or -CO- and

R ¹³ is hydrogen or optionally substituted lower alkyl, - (CH ₂ ) _p -CO-D wherein D is hydrogen, hydroxyl, optionally substituted amino or alkoxy and p is 0 or 1, tetrazolyl optionally protected with substituted lower an alkyl or acyl group, trifluoromethanesulfonic acid amide, phosphoric acid or sulfonic acid,

Y is -O-, -S (O) _m - or -N (R ⁴ ) wherein m is an integer of 0, 1 or 2 and R ⁴ is hydrogen or an optionally substituted alkyl group and n is an integer of 1 or 2, or a pharmaceutically acceptable salt thereof.

In the compound R ¹ is an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl or aralkyl group, which may be substituted with a hydroxyl group, an optionally substituted amino group, a halogen or a lower C _1-4 alkoxy group.

SK 282473 Β6

In the compound R ¹ is lower C 1-4 alkyl or lower C ₂ . ₃ alkenyl group which may be substituted by hydroxyl, amino, halogen or lower C _M alkoxy, preferably wherein the alkyl group is lower alkyl of 1 to 8 carbon atoms which may be straight or branched. Preferably lower alkyl is unsubstituted or substituted with hydroxy, optionally substituted amino, halogen or lower alkoxy group _of C.

In a compound, an aryl group means a phenyl group which may be substituted by halogen, nitro, lower C ₁₄ alkoxy or lower alkyl, and aralkyl means phenyl-lower C 1-4 alkyl which may be substituted by halogen, nitro, lower C 1-4 alkoxy or lower C _1-6 alkyl.

R ² in said compound of formula (I) represents a tetrazolyl group, a protected optionally substituted lower alkyl or acyl group, a carboxyl group, a protected optionally substituted lower alkyl group or a carboxylic ester.

R in said compound of formula (I) represents a group of the formula -CO-D ', wherein D ^- represents a hydroxyl group, a lower C 1-4 alkoxy group optionally substituted by hydroxy, amino, halogen, lower alkoxy group, lower C 1-4 alkylthio group or optionally substituted a dioxolenyl group on the alkyl moiety, or a group of the formula -OCH (R ⁷ ) OCOR ⁸ wherein R ⁷ is hydrogen, straight or branched (C 1 -C 6) alkyl, (C 5 -C 7) cycloalkyl and R ⁸ is straight or branched; a branched lower alkyl group having 1 to 6 carbon atoms, a straight or branched lower alkenyl group having 2 to 8 carbon atoms, a cycloalkyl having 5 to 7 carbon atoms, a lower C 1-4 alkyl group which is substituted with an optionally substituted aryl or cycloalkyl having 5 to 7 atoms carbon, lower C2. _An alkenyl group which is substituted with an optionally substituted aryl or cycloalkyl of 5 to 7 carbon atoms, an optionally substituted aryl, a straight or branched lower alkoxy group of 1 to 6 carbon atoms, a straight or branched lower alkenyloxy group of 2 to 8 carbon atoms, a cycloalkoxy group C 1 -C 3 alkoxy substituted with optionally substituted C 5 -C 7 aryl or cycloalkyl, C ₂ -C 7 lower alkoxy; _{3 is an} alkenyloxy group which is substituted with an optionally substituted aryl or cycloalkyl of 5 to 7 carbon atoms, or an optionally substituted aryloxy group.

R is also a group capable of forming the remainder of the formula -COCl 3 or a convertible group thereof, a salt thereof or an anion thereof.

In the compound R is also a group of the formula -CO-OCH (R ⁷ ) OCOR ⁸ wherein R ⁷ is hydrogen or a straight or branched alkyl group having 1 to 6 carbon atoms and R ⁸ is a straight or branched alkyl group having 1 to 6 atoms C 5 -C 7 cycloalkyl, optionally substituted phenyl, straight or branched C 1 -C 6 lower alkoxy or C 5 -C 7 cycloalkoxy, or a tetrazolyl group optionally protected by an optionally substituted lower alkyl or acyl group, acid amide trifluoromethanesulfonic acid, phosphoric acid or sulfonic acid.

X in the compound of formula (I) represents a chemical bond, a lower C 1-4 alkylene group, a group -CO-, -O-, -S-, -NH-, -CONH-, -OCH ₂ -, -SCH ₂ - or -CH = CH-, wherein the chemical bond is between a phenylene and a phenyl group.

Y in the compound of formula (I) is -O-, -S (O) _m -, wherein m is 0, 1 or 2, or -N (R ⁴ ) -, wherein R ⁴ is hydrogen or optionally substituted lower C 1-4 alkyl group.

YR ¹ is -N (R ⁴ ) -R *, wherein R ¹ and R ⁴ together with the nitrogen atom form a heterocyclic ring attached thereto.

Preferably, the compound of formula (I) is a derivative thereof, a compound of formula (I ')

wherein R ¹ 'is lower C 1-5 alkyl optionally substituted by hydroxy, amino, halogen or lower C 1-4 alkoxy, R ^b represents -CO-D ^1a , wherein D ^1a represents hydroxy, amino, N-lower C 1-4 alkylamino, N, N- di-lower C 1-4 alkyl amino or lower C 1-4 alkoxy optionally substituted by hydroxy, amino, halogen, lower C 1-4 alkoxy, lower C ₂₆ alkanoyloxy or 1-lower C _1-4 alkoxycarbonyloxy on the alkyl moiety or optionally substituted C 5-6 alkyl or optionally substituted acyl or C 1-6 alkoxycarbonyloxy; R ^2a represents a tetrazolyl group optionally protected by an optionally substituted lower C 1-4 alkyl or acyl group, or a carboxyl group optionally protected by an optionally substituted lower C 1-4 alkyl group, R represents hydrogen, halogen, a lower C 1-4 alkyl or alkoxy group, a nitro group or a group -CO-D ^a , wherein D ^a is hydroxy or lower C 1. ₂ alkoxy optionally substituted by hydroxy, lower C1-4 alkoxy, lower C1-4 alkoxycarbonyloxy optionally substituted by lower C1-4 alkyl, Y ^a is -O-, -S- or -N ( ^R4a ) -, wherein ^R49 is hydrogen or lower C1-4 an alkyl group or a pharmaceutically acceptable salt thereof.

In the compound of formula (I), R ^b is -CO-D ^1a , wherein D ^1a is hydroxyl or a lower C _1-4 alkoxy group optionally substituted by a hydroxy group, a lower C 1-4 alkoxy group, a lower C ₂ alkoxy group. ₆ alkanoyloxy or 1-lower alkoxycarbonyloxy, C _W at the alkyl or tetrazolyl group optionally protected substituted lower alkyl C _M C or less _{second 3} alkanoyl.

In said compound, R ²⁴ is a tetrazolyl group, optionally protected by a lower C 1-4 alkyl group, a lower C 1-4 alkoxy lower alkyl, triphenylmethyl, p-methoxybenzyl, p-nitrobenzyl, lower C ₂ . ₃ alkanoyl, benzoyl, or carboxyl optionally protected lower C _M alkyl, lower alkoxy, lower C _M C _M alkyl group, a triphenylmethyl group, a p-methoxybenzyl or p-nitrabenzylskupinou.

R 'in said compound is hydrogen, lower C 1-4 alkyl or halogen.

The compound of formula (I) or a pharmaceutically acceptable salt thereof may be in the form of a stable crystal with well-defined lattice distances.

The invention also relates to a pharmaceutical composition for eliciting an angiotensin II antagonist effect comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier, excipient or diluent.

A process for the preparation of a compound of formula (I) in which all substituents have the meanings given above is by (i) reacting a compound of formula (II)

R

wherein R ¹ , R, R, A and Y are as defined herein, with a compound of formula (III)

wherein R ² , X and n are as defined above and Z is halogen, (ii) reacting a compound of formula (IIV)

(IV) wherein each group is as defined above, with an alkyl carbonate, carbonylating or thiocarbonylating agent, or an isothiocyanate, (iii) reacting the compound of general formula (V ¹ )

wherein each group is as defined above with a nucleophilic reagent, and optionally, mixing concentrated residues, amorphous powders or crystals with the exception of a stable type C crystal in a suitable solvent to form a stable type C crystal, optionally converting the product obtained by processes (i) to (iii) to a compound of formula (I) by azidation, hydrolysis, reduction, halogenation, O-, N- or S-alkylation, nucleophilic reaction, ring closure, acylation, esterification, oxidation and / or deprotection, optionally a compound of formula (I) is converted into a pharmaceutically acceptable salt thereof.

The invention also provides an intermediate for the preparation of a compound of formula (I) which is a compound of formula

where

R ¹ is hydrogen or an optionally substituted hydrocarbon radical,

R ² is carboxyl, tetrazolyl, trifluoromethanesulfonic acid amide, phosphoric acid, sulfonic acid, cyano or lower alkoxycarbonyl, C _M, which may be protected by an optionally substituted lower alkyl or acyl,

X is a direct bond or a group between a phenylene group and a phenyl group,

R is a group of the formula -CO-D 'wherein D' is hydroxyl, optionally substituted with amino or alkoxy,

R ¹¹ is halogen, nitro, cyano, optionally substituted amino, and -WR ¹³ wherein W is a chemical bond, -O-, -S- or -CO- and

R ¹³ is hydrogen or optionally substituted lower alkyl, - (CH ² ) _p -CO-D wherein D is hydrogen, hydroxyl, optionally substituted amino or alkoxy and p is 0 or 1, tetrazolyl optionally protected with substituted lower alkyl or acyl, trifluoromethanesulfonic acid amide, phosphoric acid or sulfonic acid, n is an integer of 1 or 2,

Q ² is -NO ₂ or -NH ₂ when Q ¹ is hydrogen, or

Q ² is -NO 2 when Q ¹ is -COOR ³ , wherein R ³ is C 1-4 alkyl or salts thereof.

The compounds of the invention are valuable angiotensin II antagonists and are useful in the treatment of circulatory diseases, e.g. hypertension, heart disease, stroke, nephthids and the like.

In FIG. 1 is a x-ray of the product obtained in Experimental Example 1; FIG. 2 is an IR spectrum of the product obtained in Experimental Example 1 and FIG. 3 is a differential calorimetry record of the product obtained also in Example 1.

The invention relates to the benzimidazole compounds of formula (I) and their pharmaceutically usable salts, which act as potent angiotensin II antagonists and are useful in the treatment of circulatory diseases, e.g. hypertension, heart disease, stroke, cerebral disease, nephritis and the like, pharmaceutical compositions comprising an effective amount of a benzimidazole derivative of formula (I), and pharmaceutically acceptable carriers suitable for the treatment of said diseases, and a process for making such compounds and compositions.

The invention further relates to a method of treating diseases of the circulatory system of animals by administering to the animal an effective amount of a benzimidazole derivative of formula (I) or a pharmaceutical mixture thereof.

An important group of compounds of the invention are compounds of formula (I ^'1)

wherein A represents a benzene ring which may optionally contain other substituents in addition to R ¹ , R ¹ represents hydrogen or an optionally substituted hydrocarbon radical, R ² represents a group capable of forming an anion or a convertible group thereof, X represents a direct bond or a group between a phenylene group and a phenyl group with an atomic length of max. 2, ^and R is carboxyl, an ester or amide, Y is -0-, -S (0) _m - or -N (R ⁴⁾ -, wherein m is O, 1 or 2 and R ⁴ is hydrogen or optionally substituted alkyl, n is 1 or 2, and pharmaceutically acceptable salts thereof.

With respect to the preceding formulas, the hydrocarbon radical R * comprises e.g. alkyl, alkenyl, alkynyl, cycloalkyl, aryl and aralkyl, preferably alkyl, alkenyl and cycloalkyl.

The alkyl groups in R ¹ are lower alkyl groups having 1 to 8 carbon atoms, which may be straight or branched chain and include e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. butyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl, octyl and the like.

Alkenyl groups in R * are lower alkenyl groups having 2 to 8 carbon atoms, which may be straight or branched chain and include e.g. vinyl, propenyl, 2-butenyl, 3-butenyl, isobutenyl, octenyl and the like.

Alkynyl groups in R ¹ are lower alkynyl groups having 2 to 8 carbon atoms, which may be straight or branched chain and include e.g. ethynyl, 2-propynyl, 2-butynyl, 2-pentynyl, 2-octynyl and the like.

The cycloalkyl groups in R ¹ are lower cycloalkyl groups having 3 to 6 carbon atoms and include e.g. cyclopropyl, cyclobutyl, cyclopentyl and the like.

Said alkyl, alkenyl, alkynyl and cycloalkyl groups may be substituted by hydroxyl, optionally substituted amino (e.g., amino, methylamino, etc.), halogen, lower C 1 -C ₅ -alkoxy and the like.

Aralkyl groups in R ¹ are, for example, phenyl-lower (C _1-4 ) -alkyl such as benzyl, phenethyl and the like. and the aralkyl group may be substituted e.g. halogen such as e.g. fluorine, chlorine, bromine, and the like, nitro, lower (C _1-4 ) alkoxy, e.g. methoxy, ethoxy, and the like, lower (C _1-4 ) alkyl, e.g. methyl, ethyl, and the like. or the like at various positions in the benzene ring.

The aryl group of R ¹ is e.g. phenyl, wherein the aryl group may be substituted e.g. halogen (F, Cl, Br, etc.) nitro, lower (C _M) alkoxy, e.g. methoxy, ethoxy, and the like, lower (C _M ) alkyl, e.g. methyl, ethyl, and the like, or the like, at various positions in the benzene ring.

Preferred are examples wherein R ¹ represents an optionally substituted alkyl or alkenyl group, such as e.g. lower (0_ ₅₎ alkyl or lower _{(C2. 5)} alkenyl optionally substituted by hydroxy, amino, halogen or lower (C _w) alkoxy.

Examples of groups capable of forming an anion and groups convertible thereto in R ² are carboxyl, tetrazolyl, trifluoromethanesulfonic acid amide (-NHSO ₂ CF ₃ ), orthophosphoric acid, sulfonic acid, cyano, lower (C 1-4) alkocarbonyl and the like. These groups may be protected e.g. optionally substituted lower alkyl, e.g. lower (C 1-4) alkoxymethyl, optionally substituted arylmethyl, etc.), or acyl, e.g. a lower _{(C2. 5)} alkanoyl, optionally substituted benzoyl. These groups are capable of forming anions or are changeable to them by a chemical method, or by biological and / or physiological conditions, e.g. an in vivo reaction, such as an in vivo redox reaction or hydrolysis.

Compounds wherein R ² represents a group capable of forming anion or a group convertible into it for the chemical method, e.g. by oxidation, reduction or hydrolysis (e.g. an optionally protected tetrazolyl group, e.g. a group of formula II) wherein R ^p is methyl, triphenylmethyl, 2-tetrahydropyranyl, tert-butyl, methoxymethyl, ethoxymethyl or optionally substituted benzyl such as p- methoxybenzyl and p-nitrobenzyl, cyano and the like are suitable as synthetic intermediates.

Preferred are examples wherein R ² is tetrazolyl groups optionally protected by substituted lower alkyl or acyl groups, carboxyl groups optionally protected by substituted lower alkyl groups, and the trifluoromethanesulfonic acid amide group.

Examples of the carboxyl group, its esters or amides R and R ^a are mentioned e.g. -CO-D wherein D is hydroxyl, optionally substituted amino (e.g., amino, N-lower (C 1-4) alkylamino, N, N-di (C 1-4) alkylamino, etc.), or optionally substituted alkoxy, e.g. lower (C 1-6) alkoxy optionally substituted by hydroxy, amino, such as e.g. amino, dimethylamino, diethylamino, piperidino, morpholino, halogen, lower (C 1-4) alkoxy, lower (C 1-4) alkylthio or optionally substituted dioxolenyl such as 5-methyl-2-oxo-1,3,3-dioxolen-4-yl and Come. at the alkyl moiety and a group of the formula -OCH (R *) OCOR ⁸ , wherein R ⁷ is hydrogen, straight or branched lower alkyl having 1 to 6 carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert, butyl, n-pentyl, isopentyl, neopentyl and other or cycloalkyl of 5 to 7 carbon atoms such as cyclopentyl, cyclohexyl, cycloheptyl and others and R ⁸ is straight or branched alkyl having 1 to 6 carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. butyl, tert-butyl, n-pentyl, isopentyl, neopentyl and other branched or unbranched lower alkenyl containing 2 to 8 carbon atoms, e.g. vinyl, propenyl, 2-butenyl, 3-butenyl, isobutenyl, octenyl and others, C 5 -C 7 cycloalkyl such as cyclopentyl, cyclohexyl, cycloheptyl and other lower (C _1-3 ) alkyl such as methyl, ethyl, n- propyl, isopropyl and others substituted with optionally substituted C 5 -C 7 aryl or cycloalkyl such as e.g. benzyl, p-chlorobenzyl, phenethyl, cyclopentylmethyl, cyclohexylmethyl and the like., a lower _{(C2. 3)} alkenyl, such as vinyl, propenyl, allyl, isopropenyl, and the like., substituted by optionally substituted aryl or cycloalkyl having 5 to 7 carbon atoms, is e.g. cinnamyl and the like, optionally substituted aryl, such as phenyl, p-tolyl, naphthyl and the like, straight or branched lower alkoxy having 1 to 6 carbon atoms such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, check. butoxy, tert, butoxy, n-pentyloxy, isopentyloxy, C 2 -C 8 neopentyloxy such as allyloxy, isobutenyloxy and others, C 5 -C 7 cycloalkyloxy such as cyclo5

EN 282 473 Β6 pentyloxy, cyclohexyloxy, cycloheptyloxy etc., lower C _b3 alkoxy, methoxy, ethoxy, n-propoxy, isopropoxy etc., of allyl-substituted by optionally substituted or cycloalkyl containing 5 to 7 carbon atoms, such as, e.g. benzyloxy, phenethyloxy, cyclopentylmethoxy, cyclohexylmethoxy etc., lower _{(C2. 3)} alkenyloxy, e.g. vinyloxy, propenyloxy, allyloxy, isopropenyloxy, etc., substituted with optionally substituted aryl or C 5 -C 7 cycloalkyl such as cinnamyloxy and the like, optionally substituted aryloxy, e.g. phenoxy, p-nitrophenoxy, naphthoxy, etc. Examples of groups capable of forming an anion and groups convertible therein in the radical R are e.g. tetrazolyl groups optionally protected with optionally substituted lower alkyl, such as lower (C ₄₎ alkyl and lower (C _M) alkoxy- (C _M) alkyl or acyl such as lower (C _{2nd 5)} alkanoyl and optionally substituted benzoyl, an amide group trifluoromethanesulfonic acid, phosphoric acid, sulfonic acid and the like. Examples of substituents in the radical R are -COOH and its salts, -COOMe, -COOEt, -COOtBu, -COOPr, pivaloyloxymethoxycarbonyl, 1 (cyclohexyloxycarbonyloxyethoxycarbonyl, 5-methyl-2-oxo-1,3-dioxolen-4-ylmethoxycarbonyloxy, carbonyloxycarbonyl) propionyloxymethoxycarbonyl, n-butyryloxymethoxycarbonyl, isobutyryloxymethoxycarbonyl, 1- (ethoxycarbonyloxyethoxycarbonyl, 1- (acetyloxy) ethoxycarbonyl, 1- (isobutyryloxyethoxycarbonyl, cyclohexylcarbonyloxymethoxycarbonyl, cyclohexylcarbonyloxymethoxycarbonyl, benzoyloxymethoxycarbonyl, benzoyloxymethoxycarbonyl, benzoyloxymethoxycarbonyl; or are convertible into them by a chemical method, or by biological, and / or physiological conditions, e.g., in vivo reactions, such as redox reactions or enzymes catalyzed in vivo.

The benzene ring A may optionally contain other substituents besides R, e.g. halogen such as fluoro, bromo, chloro etc., nitro, cyano, optionally substituted amino, such as amino, N-lower (C _w) alkyl, e.g. methylamino and ethylamino, N, N-di (C _1-4 ) alkylamino, e.g. dimethyl, - and diethylamino, N-arylalkylamino, such as benzylamino and naphthylmethylamino, and alicyclic amino, such as morpholino, piperidino, piperazino and N-phenylpiperazino, of the formula -W-R ¹³ where -O- is a chemical bond, or -CO- and R ¹³ is hydrogen or optionally substituted lower alkyl, e.g. lower (C _{i. 4)} alkyl, optionally substituted with hydroxy, such as e.g. amino, dimethylamino, diethylamino, piperidino, morpholino and the like, halogen or lower (C ₁₄ ) alkoxy, - (CH ₂ ) _p -CO-D, wherein D is hydrogen, hydroxy, optionally substituted amino (e.g. . amino, N-lower _(C14) alkylamino, N, N-di (C | _ ₄₎ alkylamino etc.) or optionally substituted alkoxy, e.g. a lower (C _1-6 ) alkoxy group, optionally substituted with a hydroxy group, an amino group such as e.g. amino, dimethylamino, diethylamino, piperidino, morpholino, halogen, lower (C _1-6 ) alkoxy, lower (C _1-6 ) alkylthio or optionally substituted dioxolenyl such as 5-methyl-2-oxo-1,3-dioxolen-4-yl group and the like. at the alkyl moiety and a group of the formula -OCH (R ⁹ ) OCOR ¹⁰ , wherein R ⁹ is hydrogen, straight or branched lower alkyl having 1 to 6 carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl and others, or C 5 -C 7 cycloalkyl such as cyclopentyl, cyclohexyl, cycloheptyl and others and R ¹⁰ is a straight or branched alkyl of 1 to 6 carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. butyl, tert-butyl, n-pentyl, isopentyl, neopentyl and other branched or unbranched lower alkenyl containing 2 to 8 carbon atoms, e.g. vinyl, propenyl, 2-butenyl, 3-butenyl, isobutenyl, octenyl and others, C 5 -C 7 cycloalkyl such as cyclopentyl, cyclohexyl, cycloheptyl and other lower (C _1-3 ) alkyl such as methyl, ethyl, n-propyl , isopropyl and others, substituted with optionally substituted aryl or cycloalkyl of 5 to 7 carbon atoms, such as e.g. benzyl, p-chlorobenzyl, phenethyl, cyclopentylmethyl, cyclohexylmethyl and the like., a lower _{(C2. 3)} alkenyl, such as vinyl, propenyl, allyl, isopropenyl, and the like., substituted with optionally substituted aryl or cycloalkyl having 5 to 7 carbon atoms, is e.g. cinnamyl and the like, optionally substituted aryl, such as phenyl, p-tolyl, naphthyl and the like, straight or branched lower alkoxy having 1 to 6 carbon atoms such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, check. butoxy, tert-butoxy, n-pentyloxy group, isopentyloxy group, neopentyloxy group having 2 to 8 carbon atoms, such as allyloxy, isobutenyloxy, and others, cycloalkyloxy having 5 to 7 carbon atoms such as cyclopentyloxy, cyclohexyloxy, cycloheptyloxy etc., below a C ₃ alkoxy, methoxy, , ethoxy, n-propoxy, isopropoxy, etc., substituted with optionally substituted C 5 -C 7 aryl or cycloalkyl such as e.g. benzyloxy, phenethyloxy, cyclopentylmethoxy, cyclohexylmethoxy etc., lower _{(C2. 3)} alkenyloxy, e.g. vinyloxy, propenyloxy, allyloxy, isopropenyloxy, etc., substituted with optionally substituted C 5 -C 7 aryl or cycloalkyl such as cinnamyloxy and the like, optionally substituted aryloxy, e.g. phenoxy, p-nitrophenoxy, naphthoxy, etc. and p is 0 or 1, tetrazolyl, optionally protected e.g. optionally substituted lower alkyl such as e.g. lower (C _1-4 ) alkoxymethyl, optionally substituted arylmethyl, etc. or an acyl group such as e.g. a lower _{(C2. 5)} alkanoyl, optionally substituted benzoyl and the other ester group, phosphoric, sulfonic etc.

One or two of these substituents may be substituted at different positions of the benzene ring. When two substituents are present at the 4th and 5th or at the 5th and 6th positions of ring A, they may form a ring (e.g., benzene, etc.). These rings may be substituted with the same substituents as in ring A.

X means that the adjacent phenylene moiety is attached to the phenyl group either directly or via a bridge of 2 or fewer atoms. An example of such a bridge is a divalent chain, the straight part of which consists of one or two atoms and which may also contain a side chain.

Examples of such groups include lower (C _M) alkylene, -C0-, -0-, -5-, -NH-, -C0NH-, -0CH _r, -SCH ₂ -, -CH = CH-, etc. Most preferably in R, a chemical bond between the phenylene group and the phenyl group is preferred.

The group Y indicates that R ¹ is attached at the 2-position of the benzimidazole ring via a heteroatom. Examples of Y are -O-, -S (O) _m -, wherein m is 0, 1 or

2, -N (R ⁴ ) -, wherein R ⁴ is hydrogen or optionally lower (C _1-4 ) alkyl and the like, preferably -O-, -S- and -NH-, more preferably -O- and -S-, most preferably -O-. R ¹ and R ⁴ may together

To form a heterocyclic ring, e.g. piperidine, morpholine and the like.

In the case where R-H, the compounds of formula (I) may exist in two tautomeric forms.

Where the compounds of the invention contain several asymmetric carbon atoms, they may exist in several stereochemical forms. The invention includes both mixtures of isomers and individual stereoisomers. It is to be understood that the invention encompasses geometric isomers, rotational isomers, enantiomers, racemates, and diasteromers.

The compounds of the invention in which R is a carboxyl group or an anion thereof may exist in any form of prodrug.

Of the compounds represented by the above formula (I), the compounds of the general formula are preferred

wherein R ^la is lower (Ci_s) alkyl, optionally substituted with hydroxy, amino, halogen or lower (C 1-4) alkoxy, oinižší (C2J) alkyl, R ^b is -CO-D ^where D ¹ 'represents a hydroxyl, amino , N-lower (Cl-4) alkylamino, N, N-di (C _M) alkylamino or lower (C _M) alkoxy, optionally substituted with hydroxy, amino, halogen, lower (C _M) or lower alkoxy (C _{2nd 6} alkanoyloxy, such as e.g. acetyloxy, pivaloyloxy and the like. or lower (C _1-6 ) alkoxycarbonyloxy, such as methoxycarbonyloxy, ethoxycarbonyloxy, cyclohexylcarbonyloxy and the like. on an alkyl moiety or tetrazolyl, optionally protected with an optionally substituted lower (C _1-4 ) alkyl or acyl group, e.g. R ²¹ is tetrazolyl, optionally protected with an optionally substituted lower (C 1-4) alkyl group such as, e.g., lower (C 2-5) alkanoyl, benzoyl, R ²¹ is tetrazolyl. methyl, triphenylmethyl, methoxymethyl, ethoxymethyl, p-methoxybenzyl, p-nitrobenzyl and the like. or an acyl group such as lower (C2-5) alkanoyloxy, benzoyl, and the like. or a carboxy group, optionally protected by an optionally substituted lower (Cu) alkyl group such as e.g. methyl, triphenylmethyl, methoxymethyl, ethoxymethyl, p-methoxybenzyl, p-nitrobenzyl and the like, R is hydrogen, halogen, lower (C 1-4) alkyl or alkoxy, nitro or -CO-D ", wherein D ^a is hydroxy or N -lower (2alkyl) alkoxy, optionally substituted by hydroxy, lower (C. ₂₎ alkoxy or lower (C ₂ _ ₆₎ alkanoyloxy group such as e.g. acetyloxy, pivaloyloxy and the like, or lower (C _1-6 ) alkoxycarbonyloxy, such as methoxycarbonyloxy, ethoxycarbonyloxy, cyclohexylcarbonyloxy and the like. on an alkyl moiety or amino group optionally substituted by a lower (C _1-4 ) alkyl or halogen and in particular hydrogen, Y ^a represents -O-, -S- or -N (R ^4a ), wherein R ^4a represents hydrogen or a lower (C 1-4) alkyl group and pharmaceutically acceptable salts thereof.

The compounds (I) of the invention can be prepared according to several reaction schemes. By way of illustration, schemes for preferred compounds of the invention are set forth below.

and R, R ¹ , R ² , R 1, A, X and n are as defined above and Z is halogen.

in which each group is as defined above.

Sch * M C

COOR ⁶

wherein R, R ¹ , A, X, Y and n are as defined above and R 0 is optionally substituted lower (C _1-6 ) alkyl

ScMu D

in which each group is as defined above.

SK 282473 Β6

SoMm E

in which each group is as defined above.

wherein each group is as defined above.

in which each group is as defined above.

9 <ih4iu «

in which each group is as defined above.

in which each group is as defined above.

in which each group is as defined above.

SK 282473 Β6

in which each group is as defined above.

lehtti L

in which A, R ^p, R ^1, R ^11, X, Y n as defined above and R ⁶ is lower (C |. ₆₎ alkyl, optionally substituted lower _{(C2. 6)} alkanoyloxy, 1-lower (C. ₆ ) alkoxycarbonyloxy and the like as defined for R.

The reaction shown in Reaction Scheme A represents alkylation using an alkylating agent in the presence of a base. One molar portion of compound (U) is used with about 1 to 3 moles of base and 1 to 3 moles of alkylating agent. The reaction is usually carried out in solvents such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran, acetone, ethylmethylketone and the like. Examples of the base include sodium hydroxide, potassium tert-butoxide, sodium potassium carbonate and the like. Examples of alkylating agents include substituted halides, e.g. chlorides, bromides, iodides and the like, substituted sulfonates, e.g. p-toluenesulfonates, etc. The reaction conditions vary depending on the combination of the base and the alkylating agent. Preferably, the reaction is carried out with ice cooling to a temperature corresponding to room temperature for 1 to 10 hours.

In said alkylation, a mixture of the two isomers (1) and (Γ) is obtained depending on the position of the nitrogen atom to be alkylated. Although the production ratio of compound (I) and compound (I ') varies depending on the reaction conditions and substituents on the benzimidazole ring, both compounds can be obtained simply as pure materials by conventional methods used for isolation and / or purification (e.g., recrystallization) , column chromatography, etc.)

The nitrile of compound (Ia) is reacted with various azides to give tetrazal (fh) as shown in Scheme B. One molar portion of compound (Ia) is used with 1 to 5 moles of azide. The reaction is usually carried out in solvents such as dimethylformamide, dimethylacetamide, toluene, benzene and the like. Examples of azides are trialkyltin azide, e.g. trimethyltin azide, tributyltin azide, triphenyltin azide and the like, hydrazoic acid and its ammonium salts and the like. When organocinazide is used, 1 to 4 moles of azide are used per compound (Ia) and the reaction is carried out in toluene or benzene with heating under reflux for 1 to 4 days. If hydrochloric acid or its ammonium salt is used, 1 to 5 moles of sodium azide and ammonium chloride or tertiary amine, e.g. triethylamine, tributylamine and the like, to compound (Ia) and the reaction is carried out in dimethylformamide at a temperature of 100 to 120 ° C for 1 to 4 days. During this reaction, it is appropriate to support the reaction by adding an appropriate amount of sodium azide and ammonium chloride. In this case, an improvement in reaction time and yield was observed in some cases.

The ester (Ic) is hydrolyzed in the presence of a base to give the carboxylic acid (Id) as shown in Scheme C. The reaction is usually carried out in solvents such as aqueous alcohol, e.g. methanol, ethanol, methyl-2-ethoxyethanol and i. using an alkali in an amount of about 1 to 3 moles based on 1 mole of compound (Ic). Examples of alkali are sodium, potassium and the like. The reaction is carried out at temperatures ranging from room temperature to 100 ° C for 1 to 10 hours, preferably at a temperature corresponding to the boiling point of the solvent used for 2 to 5 hours.

The 2-alkoxy derivative (Ie) is obtained by reacting phenylenediamine (IV) with an orthocarbonate as shown in Scheme D. The reaction is carried out in the presence of an acid using an orthocarbonate in an amount of 1 to 3 moles based on compound (IV). Examples of orthocarbonates are methyl orthocarbonate, ethyl orthocarbonate, propyl orthocarbonate, isopropyl orthocarbonate, butyl orthocarbonate, and the like. When using e.g. of acetic acid or p-toluenesulfonic acid, the reaction is accelerated to give the cyclic compound in good yield. Halogenated hydrocarbons or ethers are used as the reaction solvent, but the reaction can be carried out without the use of a solvent. The reaction is carried out at 70 to 100 ° C for 1 to 5 hours. In this reaction, a dialkoxyimine compound is obtained as the reaction intermediate, which is then cyclized in the presence of an acid to give the 2-alkoxy compound (Ie). The reaction product can also be isolated and then cyclized in the presence of an acid to the 2-alkoxy compound (Ie).

The phenylenediamine compound (IV) is reacted with various reagents to form the 2-keto compound (or 2-hydroxy compound) as shown in Scheme E. This reaction is carried out using a carbonylating agent such as e.g. urea, diethyl carbonate, bis (1-imidazolyl) ketone, etc. in an amount of 1 to 5 moles, based on 1 mole of compound (IV), and usually using halogenated hydrocarbons such as e.g. methylene chloride, chloroform and others, alcohols such as methanol, ethanol, or amides such as e.g. dimethylformamide, dimethylacetamide and others.

The 2-hydroxy compound (If) is selectively O-alkylated using Meerwein's reagent to give the 2-alkoxy compound (Ig) as shown in Scheme F.

SK 282473-6 discloses using a Meerwein reagent in an amount of 1 to 3 moles based on compound (II), usually using a halogenated hydrocarbon solvent, e.g. methyl ester, ethyl ester, etc. Examples of Meerwein reagent include trimethyloxoiumfluoroborate (Me ₃ O ⁺ BF ₄ -), triethyloxoniumfluoroborate (Et ₃ O + BF ₄ -), etc. They are preferably used in in situ reactions according to methods described in the literature [H.Meerwein, Org. A son. 46, 113 and 120 (1966)]. The reaction is usually carried out at a temperature ranging from room temperature to the boiling point of the solvent used for 2 to 20 hours.

The phenylenediamine compound (IV) is reacted with various reagents in an organic solvent to give the 2-mercapto compound (Ih) as shown in Scheme G. 1 to 3 moles of a thiocarbonylating agent such as e.g. carbon disulfide, thiourea, potassium xanthate and the like, or isothiocyanate such as methyl isothiocyanate, ethyl isothiocyanate. As reaction solvents, alcohols such as methanol, ethanol and the like, amides such as dimethylformamide, dimethylacetamide or others can be used. The reaction is preferably carried out at a temperature ranging from room temperature to the boiling point of the solvent used for a period of 5 to 20 hours.

The 2-mercapto compound (Ih) is alkylated in the presence of a base in an organic solvent to form the alkylthio compound (Ii) as shown in Scheme H. For 1 mole of compound (Ih) is used 1 to 3 moles of base and 1 to 3 moles of alkylation. agents, typically in a solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, acetone, ethylmethylketone, ethanol, methanol, and water. As the base, sodium, potassium, potassium carbonate, sodium, sodium hydride, tert-butoxide and the like are used. As the alkylating agent, e.g. halide (methyl iodide, ethyl iodide, propyl iodide, butyl iodide and their bromide or chloride). The reaction is usually carried out at a temperature ranging from the temperature obtained by ice cooling to the boiling point of the solvent used, the reaction conditions varying according to the base used, the alkylating agent and the solvent.

Phenylenediamine (IV) reacts with isothiocyanate to form thiourea (V), which is then allowed to desulfurize to cyclize to form the 2-substituted amino compound (Ij) as shown in Scheme I. The reaction is carried out using 1 to 3 moles of isocyanate relative to compound (IV), usually in halogenated hydrocarbons, e.g. in chloroform, methylene chloride, in ethers, e.g. tetrahydrofuran, dioxane, in aromatic hydrocarbons, e.g. in benzene, toluene, in alcohols, e.g. in methanol, ethanol and the like, acetonitrile, dimethylformamide or the like. The reaction can be carried out without these solvents.

Examples of isothiocyanates are methylisothiocyanate, ethylisothiocyanate, propylisothiocyanate, isopropylthiocyanate, butylisothiocyanate and the like. The reaction is carried out at a temperature ranging from room temperature to about 50 ° C for 10 to 60 hours. The desulfurization cyclization can be carried out as described.

The reaction is carried out in halogenated hydrocarbons using 1 to 3 moles of metal halide, e.g. HgCl3, based on 1 mole of thiourea (V) obtained by the process. The reaction is preferably carried out at a temperature ranging from room temperature to the boiling point of the solvent used for 3 to 10 hours. The reaction can also be carried out using 1 to 3 moles of methyl iodide based on 1 mole of thiourea (IV) in alcohols, e.g. methanol, ethanol, preferably at a temperature ranging from room temperature to the boiling point of the solvent used for 3 to 15 hours.

The 2-halo compound (V '), readily prepared from compound (If), reacts with various nucleophilic reagents to form compound (I) as shown in Scheme I'. The reaction may be carried out according to procedures described in the literature, e.g. D. Harrison and J.J. Ralph, J. Chem. Soc., 1965, 236. Compound (If) reacts with a halogenating agent such as e.g. phosphorus oxychloride, phosphorus trichloride and the like. to form a 2-halo compound (V ') that reacts with various nucleophilic agents, e.g. with alcohols, mercaptans, amines and the like. in a suitable organic solvent to give compound (I). The reaction conditions depend on the nucleophilic reagent used. Preference is given to using alcohols and sodium alcoholates, e.g. sodium methoxide, sodium ethoxide, sodium propxide, etc., derived from alcohols and sodium metal. Alcohols are used as the reaction solvent for the nucleophilic reagents. 2 to 5 moles of alcoholate are used per mole of compound (V '). The reaction is preferably carried out at a temperature corresponding to the boiling point of the solvent used for 1 to 3 hours. In the reaction with amines, 3 to 10 moles of amine per 1 mol of compound (V ') are used. The reaction solvents used are alcohols, e.g. ethanol, but an excess of amines may be used. The reaction is preferably carried out at a temperature corresponding to the boiling point of the solvent used, to temperatures of 150 ° C for 1 to 10 hours. In the reaction with mercaptans, 2 to 5 moles of mercaptan are used per mole of compound (V '). The reaction is preferably carried out in the presence of 1 to 3 moles of a base such as e.g. sodium, potassium carbonate, based on compound (IV). Examples of solvents are acetonitrile, alcohols, halogenated hydrocarbons, e.g. chloroform, dichloroethane, ethers, e.g. tetrahydrofuran, dioxane, or amides, e.g. dimethylformamide, dimethylacetamide and the like. The reaction is preferably carried out at a temperature ranging from 50 ° C to a temperature corresponding to the boiling point of the solvent used for 1 to 5 hours.

Compound (Ih) is reacted with an oxidizing agent, e.g. m-chlorobenzoic acid, to form a sulfoxide or sulfone of compound (Ih '), which reacts with various nucleophilic agents, e.g. alcohols, amines, mercaptans to give compound (I) as shown in Scheme I '. The oxidation of the compound to the sulfoxide or sulfone (Ih ') is preferably carried out in solvents such as halogenated hydrocarbons, e.g. dichloromethane, chloroform, dichloroethane and the like, ethers, e.g. tetrahydrofuran, dioxane and the like. Exemplary oxidizing agents include organic peracids such as m-chloroperbenzoic acid, N-halosuccinimides, such as N-bromosuccinimide, and the like. Generally, the oxidizing agent is used in a slight excess relative to compound (Ih). Sulfoxides are obtained using 1 mole of oxidizing agent and sulfones (lh ') using 2 moles. The reaction is preferably carried out at a temperature ranging from the temperature reached by ice cooling to a temperature corresponding to room temperature for 3 to 10 hours.

The reaction of compound (Ih ') to compound (I) is carried out in essentially the same manner as shown in Scheme I'.

The carboxylic acid (Ik) is obtained by alkaline hydrolysis of the carboxylic acid ester (Ij) as shown in Scheme J. The reaction is carried out using 1 to 3 moles of base relative to 1 mole of compound (Ij), usually in a solvent such as aqueous alcohol, e.g. methanol, ethanol, methyl-2-ethoxyethanol and the like. Examples of bases are sodium, potassium or the like. The reaction is carried out at a temperature corresponding to room temperature to about 100 ° C for 1 to 10 hours, preferably at a temperature corresponding to the boiling point of the solvent used for 3 to 5 hours.

The protecting groups in the tetrazole derivatives (II) are removed to give compound (Im) as shown in Scheme K. The deprotection conditions depend on the protecting group (R ^p ). When the group is triphenylmethyl, 2-tetrahydropyranyl, methoxymethyl or the like, the reaction may be carried out in an aqueous alcohol such as methanol, ethanol and the like containing 0.5 N to 2 N hydrochloric acid or acetic acid at room temperature. for 1 to 10 hours.

Compound (Iq) is obtained by protecting the tetrazole group in the presence of a base and then converting the carboxyl group with an ester of compound (Ip) followed by deprotection in an acidic environment as shown in Scheme L. When converting compound (In) to compound (Io) the agent is used in an amount of 1 to 1.5 mole based on 1 mole of compound (In). Exemplary solvents include halogenated hydrocarbons such as chloroform, methylene chloride and ethylene chloride, esters such as dioxane and tetrahydrofuran, acetonitrile, pyridine and the like. Examples of bases are potassium, sodium, triethylamine, pyridine and the like. Examples of alkylating agents are halides such as triphenylmethyl chloride, methoxymethyl chloride and the like. Although the reaction conditions vary depending on the combination of the base and reagent used, the reaction is preferably carried out using triphenylmethyl chloride at a temperature ranging from ice cooling to room temperature for 1-3 hours in methylene chloride in the presence of triethylamine. In the reaction to obtain compound (Ip) from compound (Io), the alkylating agent is used in an amount of 1 to 3 moles, based on 1 mole of compound (Io). Examples of reaction solvents are amides such as dimethylformamide and dimethylacetamide, acetonitrile, dimethylsulfoxide, acetone, ethylmethylketone and the like. Examples of bases are potassium carbonate, sodium carbonate, sodium hydride, tertiary, potassium butoxide and the like. Exemplary alkylating agents include halides such as cyclohexyl 1-iodoethyl carbonate, ethyl 1-iodoethyl carbonate, pivaloyloxymethyl iodide and the like. Although the reaction conditions vary depending on the combination of base and alkylating agent, preferably compound (Io) is reacted in DMF, the alkylating agent is added in the presence of potassium carbonate, and the reaction is carried out at a temperature corresponding to room temperature for 30 minutes to 5 hours.

The deprotection reaction of the thus obtained compound (Ip) is carried out in the same manner as reaction (K). Where a trityl group is used as the tetrazole protecting group, it is preferred to carry out the reaction in methanol or ethanol with addition of 1N HCl and at room temperature for 30 minutes to 1 hour.

The reaction products obtained by the above reaction procedures (A) to (L) can be readily isolated and / or purified by known methods, such as evaporation of solvents, extraction with water or organic solvents, concentration, neutralization, recrystallization, distillation, column chromatography and the like. The compounds (1) thus obtained can be isolated and / or purified from the reaction mixture by known methods, e.g., recrystallization and column chromatography to obtain crystalline products.

The compounds obtained by processes (A) to (L) may be in the form of solvates or salts, including addition salts, derived from pharmaceutically or physiologically acceptable acids or bases. The following salts are given by way of illustration only, and are not intended to limit the invention in any way: salts with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric, phosphoric, salts with organic acids such as oxalic acid, oxalic acid, amber, lemon, ascorbic, milk, p-toluenesulfonic, methanesulfonic, fumar, wine and maleic. As other salts, salts with ammonia, alkali metals or alkaline earth metals such as sodium, potassium, calcium, magnesium or with organic bases such as e.g. trialkylamines, dibenzylamine, ethanolamine, triethanolamine, N-methylmorpholine and the like.

The compounds (I) can be converted into salts by known methods with non-toxic, physiologically or pharmaceutically acceptable acids or bases, e.g. to salts with inorganic acids such as hydrochloride, sulfate or nitrate, and further to salts with organic acids such as acetate, oxalate, succinate or maleate, to salts with alkaline earth metals such as calcium salts.

The starting compounds (II) and (IV) for the preparation of compounds (I) can be synthesized according to the methods described e.g. in the following literature or by methods analogous to reactions (M), (N), (O) and (P) as described.

(1) P.N. Preston, The Chemistry of Heterocyclic Compounds, Vol. 40, vyd. P. N. Preston, John Wiley & Sons Inc., New York, (1981) p. 1-286. (2) E.S. Schipper and A.R. Day, Heterocyclic Compounds, Vol. 5, vyd. R.C. Elderfield, John Wiley & Sons Inc., New York, 11965), p. (3) N.J. Leonard, D.Y. Curtin & K. M. Beck, J. Am. Chem. Soc. 69,2459 (1947), (4) S. Weiss, H. Michaud, H. Prietzel & H. Kromer, Angew. Chem. 85, 866 (1973), (5) by W.B. Wright, J. Heterocycl. Chem. 2.41 (1965), (6) A.M.E. Omar, Synthesis, 1974, 41, (7) D.J.Brown & R.K. Lynn, J. Chem. Soc. (Perkin I), 1974,349, (8) J.A. Van Allan & B.D. Deacon, Org. A son. 30, 56 (1950), (9), S.P. Singh, S.S. Parmar & B.R. Pandey, J. Heterocycl. Chem. 14.1093 (1977), (10) S. nakajima, I. Tanaka, T. Saki & T. Anmo, Yakugaku Zasshi, 78,1378 (1959), (11) K. Seno, S. Hagishita, T. Sato & K. Kuriyama, J. Chem. Soc. Perkin Trans. 1984, 2013, (12) D. R. Bude et al., J. Med. Chem., 30, 2216 (1987), (13) R.P. Gupta, C.A. Larroquette & K.C. Agrawal, J. Med. Chem., 25, 1342 (1982), etc.

wherein R ² , R, A, X and n are as defined above and R ³ is lower (C _{1 H} ) alkyl

SK 282473 Β6

BchM * h '

wherein R ² , R ³ , R, A, Z, X and n are as defined above

Scheme M and M 'illustrate the preparation of important intermediates useful in the preparation of compounds (I) of the invention.

These compounds may be prepared according to the references cited. Compound (VI) is converted to carbamic acid by compound (X) by a Curtius reaction followed by alkylation followed by reduction to give the diamino compound (IV). Switching compound (VI) to compound (X) yields compound (X) in high yield, with the Gurti rearrangement being carried out in the usual ways:

acid chloride (VII) → acid azide (VIII) → isocyanate (IX) → compound (X). Compound (VI) is usually heated with diphenylphosphoryl azide (DPPA) in the presence of triethylamine in DMF to form the isocyanate (IX) via the acid azide (VIII) and subsequent reaction with an alcohol to give compound (X) in high yield. The compound (X) thus obtained is alkylated in the same manner as in Scheme A to give compound (XI). In the reaction, the reaction mixture is refluxed for 4-6 hours in the presence of potassium carbonate in acetonitrile. Compound (XI) is refluxed in an alcohol containing a mineral acid (e.g. hydrochloric, sulfuric and the like) or an organic acid (e.g. trifluoroacetic acid, etc.) for 1-2 hours to give compound (XII). Various reducing agents are used to reduce the nitro compound (XII) to the diamino compound (IV), e.g. Raney nickel, tin tetrachloride and the like. Of these, the combination of ferric chloride and hydrazine hydrate in alcohol is most suitable. Compound (IV) can also be prepared by methods other than those listed above.

Compound (X '), commercially available or readily prepared by known methods, is preferably reacted with an amine (IIIb) in the presence of a base, e.g. potassium carbonate, sodium, amines, etc. in an organic solvent, e.g. in alcohol, ether, halogenated hydrocarbons, amides, and the like, at a temperature ranging from the boiling point of the solvent to 100 ° C for 5 to 20 hours.

Compound (X), readily obtained by acid treatment of compound (X), is subjected to condensation under dehydration conditions including azeotropic removal of water or in the presence of a dehydration agent in an organic solvent, e.g. in ethers, halogenated hydrocarbons, aromatic hydrocarbons and the like. and subsequent reaction with a reducing agent, e.g. NaCNBH ₃ gives compound (XII). Condensation under dehydration conditions can be accelerated using conventional acidic or basic catalysts.

Compound (X) is reacted with an acid chloride (IIId), preferably in the presence of a base, e.g. pyridine, triethylamine, dimethylaminopyridine and the like. in an organic solvent, e.g. in halogenated hydrocarbons, pyridine and the like. at a temperature ranging from room temperature to the boiling point of the solvent for 2 to 20 hours to give the amide (X '). The resulting amide (XI ') is reacted with a reducing agent, e.g. with sodium tetrahydroaluminate, sodium bis (2-methoxyethoxy) tetrahydroaluminate and the like. to form the diamine (IV).

ScMm N

wherein each group has a defined meaning.

Schtfma O

(IIb) wherein each group has a defined meaning.

wherein each group has a defined meaning.

Among the starting compounds of formula (III) are those compounds of formula (III) wherein n = 1, i. the compounds (IIIa) are readily available or can also be prepared by subjecting the compounds to halomethylation according to methods described in the literature, e.g.

(1) J.R.E. Hoover, A.W. Chow, R.J. Stedman, N.M. Halí,

H.S. Greenberg, M. M. Dolan and R.J. Feriauto, J. Med. Chem. 7, 245 (1964); (2) R.J. Stedman, J.R.E. Hoover, A.W. Chow, M.M. Dolan, N.M. Halí and R.J. Feriauto, J. Med. Chem. 7, 251 (1964), (3) by H. Gilman and R.D. Gorsich, J. Am. Chem. Soc., 78, 2217 (1956), (4) M. Orchin and E. Oscar Woolfolk, J. Am. Chem. Soc., 67, 122 (1945), and the like.

ScMm Q

(iv) wherein each group is as defined above.

Compounds (IIa) are readily prepared according to the methods described in L. N. Pridgen, L. Snyoler and J. Prol., Jr., J. Org.

Chem., 54, 1523 (1989), as shown in Scheme R by the following halogenation ^(l2 R = Me) or halomethylation (R ¹² = H).

ScMm * λ

---------- --------- < «! .-) l ⁿ⁾ wherein R ¹² is hydrogen or methyl.

Starting compounds of formula (III) may be those compounds of formula (III) wherein n = 2, i. compounds (IIIb) obtained from compounds (IIIa) by the reactions outlined in Scheme S.

SCMM 8 <t ^<ni ·) (m)

wherein each group is as defined above.

The compounds obtained and their salts are less toxic, strongly inhibit the vasoconstrictive and hypertensive effects of angiotensin II, have a hypotensive effect in animals, particularly in certain mammals, e.g. in humans. Dogs, rabbits, rats and the like. and therefore are useful as therapeutics not only for hypertensive but also for circulatory diseases such as heart failure, e.g. heart hypertrophy, cardiac insufficiency, heart attack and the like, stroke, cerebral apoplexy, nephropathy and nephritis. The compounds (I) and their salts of the invention strongly inhibit the vasoconstriction and hypertension caused by angiotensin II and therefore have valuable antihypertensive effects on animals, especially mammals. Furthermore, the compounds (I) and their salts of the invention have a fairly low toxicity and are clinically useful not only for the treatment of hypertension, but also for circulatory diseases such as heart and brain diseases, stroke, renal failure, nephritis and the like.

For therapeutic use, the compounds (I) and their salts may be administered orally, parenterally, by inhalation spray, rectally or topically in the form of pharmaceutical compositions or preparations, e.g. powders, granules, tablets, pills, capsules, injections, syrups, emulsions, elixirs, suspensions, solutions and the like, containing at least one of this compound alone or in admixture with pharmaceutically acceptable carriers, adjuvants, vehicles, excipients and / or diluents. The pharmaceutical compositions may be formulated in conventional manner. The term "parenteral" is used herein to include subcutaneous injections, intravenous, intramuscular, intraperitoneal injections, or infusion techniques. Injectable preparations, e.g. sterile injectable aqueous or oleaginous suspensions may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be in the form of a sterile injectable solution or suspension in a non-toxic parenterally employed diluent or solvent, e.g. such as a solution in water. Useful vehicles or solvents include water, Ringer's solution, and isotonic sodium chloride. In addition, sterile solid oils may also be employed as a solvent or suspending medium. For this purpose, any mixture of a solid oil or a fatty acid, including natural, synthetic or semi-synthetic fatty oils, or acids and natural, synthetic or semi-synthetic mono- or triglycerides may be used.

Suppositories for rectal administration of drugs can be prepared by mixing the drug with a suitable non-irritating carrier such as cocoa butter and polyethylene glycols that are solid at ordinary temperature but are liquid at rectal temperature and will therefore melt in the rectum to release the drug. The solid, solid dosage formulations for oral administration may be in the form of powders, granules, tablets, pills, capsules, as mentioned above. In such solid dosage forms, the active compound may be admixed with at least one additive such as sucrose, lactose, cellulose, mannitol, maltitol, dextran, starches, agar, alginates, chitins, chitosans, pectins, gum tragacanth, gum arabic, gelatin , collagens, caseins, albumins and synthetic or semisynthetic polymers, or glycerides.

Such dosage forms may also contain other substances, such as diluents, e.g. lubricants such as magnesium stearate, preservatives such as parabens and sorbic acid, antioxidants such as ascorbic acid, α-tocopherol and cysteine, disrupters, binders, thickeners, buffers, sweeteners, flavoring agents and perfumes. Tablets and pills may additionally be coated. Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, solutions containing inert diluents commonly used in the art, such as water.

Specific dosage levels for individual patients will depend on various factors, including the activity of the compound specifically employed, age, body weight, health, sex, diet, time of administration, route of administration, elimination rate, drug combination and severity of the disease being treated. The dose is dependent on the diseases to be treated, the symptoms, the subjects and the routes of administration, and it is desirable that a daily dose of 1-50 mg for oral administration or 1-30 mg for intravenous injections be administered at once or divided into two to two. three doses when used to treat adults. For example, for the treatment of adult idiopathic hypertension, the active ingredient will preferably be administered in an appropriate amount, e.g. 10 to 100 mg per day orally and 5 to 50 mg per day intravenously, the active ingredient preferably being administered in equal doses two to three times a day.

The invention is illustrated by the following non-limiting examples.

DETAILED DESCRIPTION OF THE INVENTION

The following formulation examples, working examples, experimental examples and reference examples are given

However, they do not limit the scope of the invention in any way.

Abbreviations used in the description of the invention have the following meanings:

Me: methyl, Et: ethyl, Tet: tetrazolyl, cycl: cyclo, Pr: propyl, Bu: butyl, Pen: pentyl, Hex: hexyl, Hep: heptyl, Ph: phenyl, DMF: dimethylformamide and THP: tetrahydrofuran.

Formulation examples

When Compound (I) of the invention is used as a therapeutic agent for the treatment of circulatory disorders such as hypertension, heart disease, stroke, kidney disease and the like, it can be used in the following formulations.

(1) 2-Ethoxy-1 - [(2 '- (2' - (1H-tetrazol-5-yl) biphenyl-4-yl) methyl) benzimidazole-7-carboxylic acid capsule10 mg (2) lactose 90mg (3) finely crystalline cellulose 70mg (4) magnesium stearate 10mg one capsule 180mg

1. 2, 3 and half 4 are mixed and granulated. The residue 4 is added to the granules and the whole is filled into gelatin capsules.

2. Tablets of (1) 2-ethoxy-1 - [(2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] benzimidazole-7-carboxylic acid 10 mg (2) lactose 35mg (3) ) corn starch 150 mg (4) fine crystalline cellulose 30mg (5) magnesium stearate 5mg one tablet 230mg

1, 2, 3, two thirds 4 and half 5 are mixed and granulated. Residues 4 and 5 are added to the granules and then the granules are subjected to compression molding.

3. Injection (1) 2-methylthio-1 - [(2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] benzimidazole-7-carboxylic acid disodium salt 10 mg (2) inazitol 100 mg (3) benzyl alcohol 20 mg one ampoule 130 mg

1, 2, and 3 are dissolved in distilled water to give a total volume of 2 ml for injection which is filled into ampoules. The entire procedure is carried out under sterile conditions.

4. (1) 1- (Cyclohexyloxycarbonyloxy) ethyl-2-ethoxy-1 - [(2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] benzimidazole-7-carboxylate capsule10 mg ( 2) lactose 90mg (3) fine crystalline cellulose 70mg (4) magnesium stearate10 mg one capsule 180mg

1, 2, 3 and half 4 are mixed and granulated. The residue 4 is added to the granules and the whole is filled into gelatin capsules.

5. Tablets of (1) 1- (cyclohexyloxycarbonyloxyxy) 1-2-ethoxy-1 - [(2 '- (1H-

-tetrazol-5-yl) biphenyl-4-yl) methyl] benzimidazole-7 carboxylate 10 mg (2) lactose 35mg (3) corn starch 150mg (4) fine crystalline cellulose 30mg (5) magnesium stearate 5mg one tablet 230 mg

1, 2, 3 and two thirds 4 and half 5 are mixed and granulated. Residues 4 and 5 are added to the granules and then the granules are subjected to compression molding.

Injection (1) 2-ethoxy-1 - [(2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] benzimidazole-7-carboxylic acid disodium salt 10 mg (2) inositol 100 mg (3) 20 mg benzyl alcohol per vial of 130 mg

1, 2 and 3 are dissolved in distilled water to give a total volume of 2 ml for injection, which is then filled into ampoules. The entire procedure is carried out under sterile conditions.

Reference Example 1 2-Propoxybenzimidazole

To a solution of o-phenylenediamine (2 g) in propyl orthocarbonate (5 mL) was added acetic acid (1.1 mL) and the solution was stirred at 80 ° C for 3 hours. Ethyl acetate was added to the reaction mixture, the solution was washed with aqueous sodium bicarbonate solution and water, then dried over Na ₂ SO ₄ and evaporated to dryness. The concentrate was purified by silica gel column chromatography to give crystals. Recrystallization from ethyl acetate-benzene gave colorless crystals (1.54 g, 47%), mp 163-164 ° C.

Reference Example 2 Ethyl 2-carboxy-3-nitrobenzoate

A mixture of 3-nitrophthalic acid (35 g) in ethanol (300 mL) containing horses, sulfuric acid (20 mL) was heated under reflux for 24 hours. The solvent was evaporated in vacuo and the residue was poured into cold water (700 mL). The mixture was extracted with ethyl acetate. The organic layer was washed with water and shaken with aqueous potassium carbonate solution. The aqueous layer was acidified with hydrochloric acid and the mixture was extracted with methylene chloride. The organic layer was washed with water, dried and then the solvent was evaporated. The obtained solid (29 g, 74%) was used for the next reaction without purification. 1 H-NMR (90 MHz, CDCl 3), δ: 1.43 (3H, t), 4.47 (2H, q), 7.70 (1H, t) 8.40 (2H, d), q, 87 (1H, br s) IR (Nujol) cm -1: 1725, 1535, 1359, 13300, 1270

Reference Example 3 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 under reflux for 3 hours. The reaction mixture was evaporated to dryness. The resulting acid chloride (26 g, quantitative) was dissolved in methylene chloride (20 mL). The solution was added dropwise to a mixture of sodium azide (9.75 g) in dimethylformamide (DMF) (20 mL) with vigorous stirring. The reaction mixture was poured into a mixture of ether and hexane (3: 1, 200 mL) and water (250 mL) to give two layers. The organic layer was washed with water, dried and the solvent was evaporated. The residue was dissolved in t-butanol (200 mL) and the solution was gradually warmed with stirring and then heated under reflux for 2 hours. The reaction mixture was evaporated in vacuo to give an oily product (30 g). 1 H-NMR (90 MHz, CDCl 3): 1.40 (3H, t), 1.53 (9H, s), 4.43 (2H) , q), 1.23 (1H, t), 8.03-8.21 (2H, m), 9.70 (1H, br s) IR (neat ¹ : 3320, 2980, 1740, 1585, 1535, 1500, 1440, 1375, 1265, 1115

Working Example 1 Ethyl 2 - '[[2'-cyanobiphenyl-4-yl) methyl] amino] 3-nitrobenzoate

To a solution of ethyl 2-t-butoxycarbonylamino-3-nitro-benzoate (20 g) in tetrahydrofuran (50 mL) was added sodium hydride (60% dispersion in mineral oil, 2.8 g) with stirring and ice cooling. The mixture was stirred at room temperature for 20 minutes and then 4- (2-cyanophenyl) benzyl bromide (18 g) and potassium iodide (360 mg) were added and the mixture was heated under reflux for 10 hours. The solvent was evaporated to dryness and the residue was partitioned between water (250 mL) and ether (200 mL). The organic layer was washed with water, dried and concentrated to a yellow syrup by evaporation. The syrup was dissolved in a mixture of trifluoroacetic acid (60 ml) and methylene chloride (40 ml) and the solution was stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness and ethyl ether (200 mL) was added to the residue to give crystals. The crystals were filtered off, washed with ether to give pale yellow crystals (22.1 g, 85%), mp 118-119 ° C.

1 H-NMR (90 MHz, CDCl ₃ ) δ: 1.37 (3H, t), 4.23 (2H, s), 4.37 (2H, q), 6.37 (1H, t), 7 33-7.83 (9H, m), 7.97-8.20 (2H, m) IR (Nujol) cm -1: 3280, 2220, 1690, 1575, 1530, 1480, 1450, 1255, 1105, 755

Working Example 2 Ethyl 3-amino-2 - [[(2'-cyanobiphenyl-4-yl) methyl] amino] benzoate

To a solution of ethyl 2 - [(2'-cyanobiphenyl-4-yl) methylamino] nitrobenzoate (10.4 g) in ethanol (50 mL) was added stannous chloride dihydrate (28.1 g) and the mixture was stirred at 80 ° C. ° C for two hours. The solvent was evaporated to dryness and 2N NaOH (500 mL) was added dropwise with stirring to a mixture of the residue in ice-cooled ethyl acetate (300 mL). The aqueous layer was extracted with ethyl acetate (200 mL x 2). The organic layers were combined, washed with water and dried. The solvent was evaporated to dryness and the residue was purified by silica gel column chromatography to give crystals. Recrystallization from ethyl acetate-hexane gave colorless crystals (7.3 g, 79%), mp 104-105 ° C.

1 H-NMR (200 MHz, CDCl 3) δ: 1.33 (3H, t), 4.23 (2H, s), 4.27 (2H, q), 6.83-6.93 (2H, m) 7.35-7.55 (7H, m);

7.64 (1H, dt), 7.76 (dd)

IR (KBr) m: 3445, 3350, 2220, 1680, 1470, 1280, 1240, 1185,1160,1070,1050,1020,805,750.

Working Example 3 Ethyl 1 - [(2'-cyanbiphenyl-4-yl) methyl] -2-methoxybenzimidazole-7-carboxylate

Acetic acid (0.2 g) was added to a solution of ethyl 3-amino-2 - [(2'-anobiphenyl-4-yl) methyl] aminobenzoate (1.1 g) in methyl carbonate (5 ml). The mixture was stirred at 80 ° C for 1 hour. The reaction mixture was concentrated and the concentrate was extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate solution and water. The solvent was evaporated in vacuo to give crystals. Recrystallization from ethyl acetate-benzene gave colorless crystals (1.09 g, 90%), mp 160-161 ° C.

1 H-NMR (200 MHz, CDCl ₃ ) δ: 1.23 (3H, t), 4.23 (2H, q), 4.26 (3H, s), 5.72 (2H, s), 7 09 (2H, d), 7.20 (1H, t), 7.38-7.48 (4H, m), 7.58-7.66 (2H, m), 7.73-7.79 (2H, m) IR (KBr) cm -1: 3000, 2220, 1725, 1560, 1465, 1440, 1415, 1285.1250, 1220.1040, 760, 750.740

Acetic acid (0.2 g) was added to a solution of ethyl 3-amino-2-N - [(2'-cyanobiphenyl-4-yl) methyl] aminobenzoate (1.0 g) in ethyl carbonate (5 mL). The mixture was stirred at 80 ° C for 1 hour. The reaction mixture was concentrated and the concentrate was dissolved in ethyl acetate. The solution was washed with aqueous sodium bicarbonate and water. The solvent was evaporated in vacuo to give crystals. Recrystallization from ethyl acetate-benzene gave colorless crystals (0.79 g, 69%), mp 131-132 ° C.

1 H-NMR (200 MHz, CDCl 3) δ: 1.24 (3H, t), 1.49 (3H, t), 4.24 (2H, q), 4.68 (2H, q), 5, 72 (2H, s), 7.10 (2H, d), 7.19 (1H, t), 7.38-7.46 (4H, m), 7.56-7.66 (2H, m) 7.73-7.77 (2H, m) IR (KBr) cm -1: 2220, 1720, 1550, 1480, 1430, 1280, 1245, 1215, 1040, 760, 740

Working Example 5 Ethyl 1 - [(2'-cyanbiphenyl-4-yl) methyl] -2-propoxybenzimidazole-7-carboxylate

Acetic acid (0.2 g) was added to a solution of ethyl 3-amino-2-N - [(2'-cyanabiphenyl-4-yl) methylaminobenzoate (0.9 g) in propyl carbonate (5 mL). The mixture was stirred at 80 ° C for 1 hour. The reaction mixture was concentrated and the concentrate was dissolved in ethyl acetate. The solution was washed with aqueous sodium bicarbonate. The solvent was evaporated to give crystals. Recrystallization from ethyl acetate-benzene gave colorless crystals (0.72 g, 68%), mp 90-92 ° C. Elemental analysis for C ₂₇ H ₂₅ N ₃ O ₃ calculated C 73.79, H 5.73, N 9.56, found C 73.84, H 5.79, N 9.5% -NMR (200 MHz, CDCl 3) δ: 1.01 (3H, t), 1.25 (3H, t), 1.80-1.97 (2H, m), 4.24 (2H, q), 4.57 (2H, q); 5.72 (2H, s);

7.1 (2H, d), 7.19 (1H, t), 7.38-7.46 (4H, m), 7.56-7.66 (2H, m), 7.73-7, 79 (2H, m)

IR (KBr) cm ^-1 : 2220, 1725, 1560, 1480, 1460, 1430, 1370, 1280.1245, 1210.1115, 1040.760, 750, 740

Working Example 6 Ethyl 1 - [(2'-cyanobiphenyl-4-yl) methyl] -2-mercaptobenzimidazole-7-carboxylate

A mixture of ethyl 3-amino-2-N - [(2'-cyanobiphenyl-4-yl) methyl] aminobenzoate (5.6 g) and sodium O-ethyldithiocarbonate (7.3 g) in ethanol (50 mL) was heated. 8 hours under reflux. The reaction mixture was concentrated and the residue was dissolved in ether. The pH of the solution was adjusted to 3-4 with hydrochloric acid. The precipitated crystals are filtered off and recrystallized from ethanol to give yellow crystals (5.0 g, 80%), mp 225-227 ° C.

1 H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.08 (3H, t), 4.12 (2H, q), 5.90 (2H, br s), 7.08 (2H, d) 7.27 (1H, t), 7.38-7.59 (6H, m), 7.76 (1H, dt), 7.92 (1H, dd)

IR (KBr) cm ^-1 : 2210, 1720, 1460, 1440, 1420, 1375, 1335, 1265, 1180, 1135, 1115, 1100,985,760,740

Reference Example 4 Methyl 2 - [[2'-cyanobiphenyl-4-yl) methyl] amino-3-nitrobenzoate

A mixture of ethyl 2 - [[2'-cyanobiphenyl-4-yl) methyl] amino] -3-nitrobenzoate (5 g) and sodium hydride (60% dispersion in mineral oil, 1.62 g) in methanol (50 mL) was added. Stir at room temperature for one day. The reaction mixture was concentrated and the residue was poured into saturated sodium bicarbonate solution (100 mL) and then extracted with chloroform. The organic layer was washed with water, dried and concentrated to dryness to give crystals. Recrystallization from ethanol

Pure yellow crystals (3.98 g, 83%), mp 106-108 ° C.

1 H-NMR (200 MHz, CDCl ₃ ) δ: 3.81 (3H, s), 3.97 (2H, br s), 4.23 (2H, s), 6.4O (1H, br s) 6.88-6.91 (2H, m), 7.34-7.55 (7H, m), 7.65 (1H, dt,> 1.2, 7.7Hz), 7.77 (1H) , dd,> 1.4, 8.0 Hz)

IR (KBr) cm ': 3410, 3350, 2225, 1695, 1485, 1470, 1290, 1200, 780,760

Working Example 7 Methyl 1 - [[2'-cyanobiphenyl-4-yl) methyl] -2-ethoxybenzimidazole-7-carboxylate

Acetic acid (0.37 g) was added to a solution of methyl 3-amino-2 - [[2'-cyanobiphenyl-4-yl) methyl] amino] benzoate (2.03 g) in ethyl carbonate (5 mL) and the mixture is stirred at 80 ° C for one hour. The reaction mixture was concentrated to dryness and the residue was dissolved in ethyl acetate. The solution was washed with aqueous sodium bicarbonate solution and water. The solvent was evaporated in vacuo to give crystals. Recrystallization from ethyl acetate-hexane gave colorless crystals (2.01 g, 86%), mp 168.5-169.5 ° C.

Elemental analysis: calculated 72.98% C, 5.14% H, 10.21% N, found 72.71% C, 5.12% H, 9.97% N 1 H-NMR (200 MHz, CDCl ₃₎ δ: 1.42 (3H, t,> 7, 1Hz), 3.71 (3H, s), 4.63 (2H, q,> 7, 1Hz), 5.59 (2H (2H, s)) 7.09 (2H, d, J = 8.4Hz), 7.20 (1H, t, J = 7.9Hz), 7.45-7.59 (5H, m), 7.69-7, 80 (2H, m), 7.92 (, dd, J = 1.4.7, 8Hz) IR (KBr) cm -1: 2225, 1725, 1550, 1480, 1430, 1350, 1280,

1250.1040.780.750

Reference Example 5 Ethyl 2 - [[2'-cyanobiphenyl-4-yl) methyl] amino] -3- (3-ethylthioureido) benzoate

A mixture of ethyl 3-amino-2 - [[2'-cyanobiphenyl-4-yl) methyl] aminobenzoate (1.61 g), ethyl isothiocyanate (1.5 mL) and ethanol (1 mL) was stirred at room temperature for three days. The reaction mixture was dissolved in ethyl acetate and the solution was washed with water, dried and concentrated to dryness to give crystals. Recrystallization from ethyl acetate-hexane gave pale yellow crystals (1.92 g, 91%), mp 108-110 ° C. 1 H-NMR (200 MHz, CDCl 3) δ: 1.15 (3H, t), 1.40 (3H, t), 3.50-3.70 (2H, br s), 4.37 (2H, q), 4.56 (2H, d), 6.07 (1H, t), 6.78 (1H, t), 7.19-7.24 (1H, m), 7.38-7.53 (6H, m),

7.63 (1H, dt), 7.72-7.76 (1H, m), 7.99 (1H, dd), 8.29 (1H br s) IR (KBr) cm -1: 3375, 3320 , 3150, 2975, 2220, 1740,

1540.1510.1450.1300.1225.1180.1150.760.750

Reference Example 6 Ethyl 2 - [[2'-cyanobiphenyl-4-yl) methyl] amino-3- (3-propylthioureido) benzoate

By essentially the same procedure described in Reference Example 5, the desired light yellow syrup (2.0 g, 98%) was obtained from ethyl 3-amino-2 - [[2'-cyanobiphenyl-4-yl) methyl] amino] benzoate (1). , 6 g), propylisothiocyanate (1.5 ml) and ethanol (1 ml).

1 H-NMR (200 MHz, CDCl ₃ ) δ: 0.88 (3H, t), 1.40 (3H, t), 1.48-1.67 (2H, m), 3.42-3, 68 (2H, br s), 4.37 (2H, q), 4.56 (2H, d), 6.13 (1H, t), 6.78 (1H, t), 7.21-7, 25 (1H, m), 7.36-7.53 (6H, m), 7.64 (1H, dt), 7.73-7.77 (1H, m), 7.99 (1H, dd) , 8.2O-8.4O (1H, brs)

IR (neat) cm ^-1 : 3325, 3175, 2960, 2930, 2875, 2220, 1710, 1690, 1590, 1475, 1360, 1175, 1140, 1090, 1020, 6060

Working Example 8 Ethyl 1 - [[2-cyanobiphenyl-4-ylmethyl] -2-ethylaminobenzimidazole] -7-carboxylate

Methyl iodide (4.5 g) was added to a solution of ethyl 2 - [(2'-cyanobiphenyl-4-yl) methyl] amino] -3- (ethylthioureido) benzoate (1.8 g) in ethanol and the mixture was heated under reflux for 12 hours. To the reaction mixture was added 1N HCl (60 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated to dryness and the concentrate was dissolved in ethyl acetate. The solution was washed with aqueous sodium bicarbonate solution and dried. The solvent was evaporated to dryness and the residue was purified by silica gel column chromatography to give a yellow syrup (0.96 g, 58%). 1 H-NMR (200 MHz, CDCl ₃ ) δ: 1.23 (6H, t), 3 48-3.62 (2H, m), 4.09 (1H, t), 4.23 (2H, q), 5.57 (2H, s),

7.15 (1H, t), 7.25 (2H, d), 7.40-7.77 (8H, m)

IR (neat) cm ^-1 : 3400,3225,2975,2930,2210,1710, 1610, 1570, 1480, 1425, 1365, 1320, 1270, 1250, 1210, 1130, 1100,1060,770,750

Working Example 9 Ethyl 1 - [[2'-cyanobiphenyl-4-yl) methyl] -2-propylaminobenzimidazole-7-carboxylate

In essentially the same manner as described in Working Example 8, the desired yellow syrup (1.2 g, 65%) was obtained from a solution of ethyl 2 - [[2'-cyanobiphenyl-4-yl) methyl] amino] -3- (3-propylthioureido) benzoate (2.0 g) and methyl iodide (4.8 g) in ethanol (50 mL).

¹ H-NMR (200 MHz, CDCl 3) δ: 0.87 (3H, t), 1.25 (6H, t), 1.52-1.70 (2H, m), 3.42-3.52 (2H, m), 4.12 (1H, t), 4.25 (2H, q), 5.58 (2H, s), 7.16 (1H, t), 7.29 (2H, d) 7.41-7.78 (8 H, m)

IR (neat) cm ^-1 : 3400, 3250, 2975, 2950, 2890, 2225, 1715, 1620, 1590, 1570, 1480, 1430, 1370, 1285, 1220, 1135, 1070, 760

Working Example 10 Methyl 1 - [[2'-cyanobiphenyl-4-yl) methyl] -2-methoxybenzimidazole-7-carboxylate

A solution of 5.2 M sodium methoxide in methanol (0.5 mL) was added to a solution of 1 - [[2'-cyanobiphenyl-4-yl] methyl] methoxy-benzimidazole-7-carboxylate (1.3 g) in methanol (50 mL). ). The reaction mixture was concentrated and the precipitated crystals were filtered off. Recrystallization from methanol gave colorless prisms.

Elemental Analysis Found: C, 72.53; H, 82; N, 10.57. Found: C, 72.38; H, 4.93; N, 10.44. CDC1 ₃₎ δ: 3.75 (3H, s), 4.26 (3H, s), 5.69 (2H, s), 7.09 (2H, d), 7.23 (H, t), 7.37-7.46 (3H, m), 7.55-7.65 (2H, m), 7.72-7.78 (2H, m)

Reference Example 7 Methyl 2 - [[(2'-cyanobiphenyl-4-yl) methyl] amino-3- (3-methylthioureido) -1-benzoate

The title compound was prepared in 86% yield in essentially the same manner as in Reference Example 5. Mp 152-155 ° C.

1 H-NMR (200 MHz, CDCl ₃ ) δ: 3.1 (3H, d), 3.73 (3H, s),

4.22 (1H, q), 5.54 (2H, s), 7.17 (1H, t), 7.27 (2H, d), 7.41-7.79 (8H, m)

IR (neat) cm ^-1 : 3400, 3250, 3, 2950, 2220, 1720,

1625 1610 1680 1480 1410 1340 1240 1240 1210

1130,1060,750

SK 282473 Β6

Reference example 8

2-Prapoxy-1 - [[2 '(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole

Sodium hydride (60% dispersion in mineral oil, 0.24 g) was added to a stirred solution of 2-propoxybenzimidazole (0.71 g) in dimethylformamide (10 mL) under ice-cooling. The mixture was stirred for 20 min, N-triphenylmethyl-5- (4'-bromomethylbiphenyl-2-yl) tetrazole (2.3 g) was added and then stirred at room temperature for 5 hours. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated to dryness. The concentrate was dissolved in methanol (50 mL), to which was added 1 N HCl (15 mL), and the mixture was further stirred at 60 ° C for two hours. The reaction mixture was concentrated, water (15 mL) and ethyl acetate (15 mL) were added. The mixture was basified with 1N NaOH and stirred. The aqueous layer was adjusted to pH 3-4 with 1N HCl and then extracted with chloroform. The organic layer was washed with water, dried and concentrated to dryness. The concentrate was purified by silica gel column chromatography to give crystals. Recrystallization from ethyl acetate-methanol gave colorless crystals (0.58 g, 35%), mp 177-179 ° C (dec.).

Elemental analysis for C24H22N6O: calculated C 70.23, H 5.40, N 20.47 found 69.93% C, 5.43% H, 20.22% N 1 H-NMR (200 MHz, DMSO) -d ₆ ) δ: 0.95 (3H, t), 1.70-1.88 (2H, m), 4.46 (2H, t), 5.23 (2H, s), 7.04- 7.10 (4H, m), 7.20 (2H, d), 7.38-7.43 (2H, m), 7.48-7.70 (4H, m)

IR (KBr) cm ^-1 : 1540, 1535, 1485, 1475, 1450, 1425, 1385,

1285,1270,1040,980,755,745

Working Example 12 Methyl-2. butylamino-1 - [(2'-cyanobiphenyl 1-4-yl) methyl] benzimidazole-7-carboxylate

The title compound was prepared from methyl [/ (2'-cyanobiphenyl-4-yl) methyl] amino] -3- (butylureido) benzoate in essentially the same manner as in Working Example 8. The yield was quantitative.

1 H-NMR (200 MHz, CDCl 3) δ: 0.89 (3H, t), 1.21-1.39 (2H, m), 1.45-1.60 (2H, m), 3.50 -3.65 (3H, br s), 3.92 (3H, s), 4.56 (2H, d), 6.08 (1H, t), 6.78 (1H, t), 7.21 -7.30 (1H, m), 7.39-7.54 (6H, m), 7.64 (1H, dt), 7.75 (1H, dd), 7.98 (1H, dd) 8.26 (1H, br s).

Working example 13

Methyl 2- (N-ethylmethylamino) -1 - [(2'-cyanobiphenyl-4-yl) methyl] benzimidazole-7-carboxylate

A mixture of sodium hydride (60% dispersion in mineral oil, 0.13 g) in DMF (5 mL) was stirred under ice-cooling for 5 minutes, and methyl-2-ethylamino-1- (2'-cyanobiphenyl-4) was added to this mixture. methyl-benzimidazole-7-carboxylate (0.95 g) and then stirred for 10 minutes. Methyl iodide (0.2 ml) was added and the mixture was stirred for 20 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and evaporated to dryness. The residue was purified by silica gel column chromatography, and the obtained crude crystals were recrystallized from ethyl acetate-hexane to give colorless needles (0.88 g, 82%), mp 66-69 ° C.

1 H-NMR (200 MHz, CDCl ₃ ) δ: 1.25 (3H, t), 3.03 (3H, s), 3.36 (2H, q), 3.73 (3H, s), 5 60 (2H, s), 6.88 (2H, d), 7.16 (1H, t), 7.34-7.49 (5H, m), 7.59 (1H, dt), 73 (1H, dd), 7.78 (1H, dd) IR (KBr) cm ^-1 : 2210, 1710, 1540, 153e, 1435, 1420, 1385, 1300,1275,1250,1005,760

Reference Example 9 Methyl 1 - [(2'-cyanobiphenyl-4-yl) methyl] -2-oxo-2,3-dihydrobenzimidazole-7-carboxylate

To a solution of methyl 2 - [(2'-cyanobiphenyl-4-yl) methylamino] -3-methoxycarbonylaminobenzoate (10.5 g) in methanol (100 mL) was added NaOMe (10 g) and the mixture was heated under reflux for 20 hours . The reaction mixture was neutralized with 1N HCl and concentrated to dryness. The residue was extracted with chloroform-water. The organic layer was washed with water, dried and evaporated to dryness. The resulting crystals were recrystallized from chloroform-methanol to give colorless needles (8.67 g, 89%), mp 250-253 ° C. 1 H-NMR (200 MHz, DMSO-d ₆ ) δ: 3.65 (H, s), 5.35 (2H, s), 7.04-7.16 (3H, m), 7.24- 7.28 (2H, m); 7.48-7.59 (4H, m);

7.76 (1H, dt), 7.92 (1H, dd)

IR (KBr) cm ^-1 : 2210, 1720, 1690, 1635, 1430, 1390, 1270, 1255,760,750,730,690

Reference Example 10 Methyl 3-chloro-1- [(2'-cyanobiphenyl-4-yl) methyl] benzimidazole-7-carboxylate

A mixture of methyl 1 - [(2'-cyanobiphenyl-4-yl) methyl] -2-oxo-2,3-dihydrobenzimidazole-7-carboxylate (8.02 g) in phosphorus oxychloride (30 mL) was heated to reflux. hours. The reaction mixture was concentrated and the resulting residue was poured into ice water. The mixture was extracted with chloroform. The extract was washed with water, dried and evaporated. The residue was purified by silica gel column chromatography, and the obtained crystals were recrystallized from chloroform-water to give colorless needles (2.2 g, 28%), mp 154-157 ° C.

1 H-NMR (200 MHz, CDCl 3) δ: 3.78 (3H, s), 5.95 (2H, s), 7.06 (2H, d), 7.31 (1H, t), 7, 39-7.48 (4H, m), 7.58-7.66 (1H, m), 7.71-7.77 (2H, m), 7.93 (1H, dd)

IR (KBr) cm ^-1 : 2240, 1720, 1480, 1450, 1440, 1425, 1370,

1350,1290,1270,1200,1150,1120,1000,775,760,750

Reference Example 11 Methyl 2 - [(2'-cyanobiphenyl-4-yl) methylamino] -3-methoxycarbonylamino benzoate

To a stirred solution of methyl 3-amino-2 - [(2'-cyanobiphenyl-4-yl) methylamino] benzoate (10 g) in pyridine (50 mL) was added methyl chloroformate (9.0 mL) dropwise with ice-cooling. The mixture was stirred at room temperature for 3 hours and concentrated. The residue was extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The residue was recrystallized from ethyl acetate-hexane to give pale yellow needles (10.5 g, 90%), mp 113-115 ° C. 1 H-NMR (200 MHz, CDCl 3) δ: 3.8O (3H, s), 3.83 (3H, s), 4.1 (2H, d), 6.29 (1H br s), 7, 09 (1H, t), 7.40-7.80 (10H, m), 8.19 (1H, d)

Working Example 14 Methyl 1 - [(2'-cyanobiphenyl-4-yl) methyl] -2-morpholinobenzimidazole-7-carboxylate

A mixture of methyl 2-chloro-1- (2'-cyanobiphenyl-1-yl) methyl benzimidazole-7-carboxylate (0.8 g) in morpholine (15 mL) was stirred at room temperature at 100 ° C for two hours and the reaction mixture was concentrated to dryness. The residue was extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The resulting crystals were recrystallized from ethyl acetate-hexane to give colorless prisms (0.69 g, 77%).

1 H-NMR (200 MHz, CDCl 3) δ: 3.38 (4H, t), 3.72 (3H, s), 3.90 (4H, t), 5.63 (2H, s), 6, 89 (2H, d), 7.20 (1H, t), 7.37-7.65 (6H, m), 7.74 (1H, dd), 7.82 (1H, dd)

IR (KBr) cm ^-1 : 2225, 1715, 1520, 1440, 1415, 1280, 1260, 1220, 1130, 1120, 1010, 860, 770, 760, 750

Working Example 15 Methyl 1 - [(2'-cyanobiphenyl-4-yl) methyl] -2-morpholinobenzimidazole-7-carboxylate

The title compound was prepared in essentially the same manner as in Working Example 14. Yield: 81%, mp 119-121 ° C.

1 H-NMR (200 MHz, CDCl 3) δ: 1.62-1.77 (6H, m), 3.31-3.36 (4H, m), 3.73 (3H, s), 5.58 (2H, s), 6.88 (2H, d);

7.15 (1H, t), 7.35-7.49 (5H, m), 7.56-7.64 (1H, m), 7.73 (1H, dd), 7.79 (1H) , d)

IR (KBr) cm ^-1 : 2225, 1720, 1530, 1445, 1410, 1385, 1305, 1285, 1265, 1250, 1130, 1110, 770, 750

Reference Example 12 Methyl 2 - [(2'-methoxycarbonylbiphenyl-4-yl) methylamino] -3-nitrobenzoate

To a solution of methyl 2-tert-butoxycarbonylamino-3-nitrobenzoate (1.84 g) in acetonitrile (10 mL) was added a solution of 4- (2'-methoxycarbonylbiphenyl-4-yl) methyl bromide (1.9 g) in acetonitrile ( 5 ml) and potassium carbonate (0.86 g) and the reaction mixture was heated under reflux for 20 hours. The reaction mixture was concentrated to dryness and the resulting residue was extracted with ethyl acetate and water. The organic layer was washed with water, dried and evaporated. The residue was purified by silica gel column chromatography to give a pale yellow syrup. The syrup was dissolved in ethanol (10 mL) and 20% hydrochloric acid in ethanol (4 mL) was added. The reaction mixture was stirred at room temperature for 22 hours and concentrated to dryness. The residue was dissolved in ethyl acetate, washed with a saturated aqueous solution of bicarbonate and water, dried and evaporated to give a yellow syrup (1.39 g, 53%). 1 H-NMR (200 MHz, CDCl 3) δ: 3.61 (3H, s), 3.89 (3H, s), 4.21 (2H, d), 6.72 (1H, t), 7, 30 (4H, d), 7.36 (1H, dd),

7.42 (1H, dd), 7.53 (1H, dd), 7.82 (1H, dd), 8.00 (1H, dd), 8.10 (1H, dd)

Reference Example 13 Methyl 3-amino-2 - [(2'-methoxycarbonylbiphenyl-4-yl) methylamino] benzoate

The title compound was prepared as a light yellow syrup from methyl 2 - [(2'-methoxycarbonylbiphenyl-4-yl) methylamino] -3-nitrobenzoate in essentially the same manner as in Working Example 2.

Yield: 79%. 1 H-NMR (200 MHz, CDCl 3) δ: 3.63 (3H, s), 3.80 (3H, s), 3.97 (2H br s), 4.22 (2H, d), 6, 40 (1H, br s), 6.82-6.92 (2H, m), 7.23-7.44 (7H, m), 7.53 (1H, dt), 7.79-7.83 (1 H, m)

IR (neat) cm ⁴ : 3450,3360, 2970, 1730,1700,1470, 1460,1450,1440,1290,1250,1200, 770, 750

Working Example 16 Methyl 2-ethoxy-1 - [(2'-methoxycarbonylbiphenyl-4-yl) methyl] benzimidazole-7-carboxylate

The title compound was prepared as colorless needles from methyl 3-amino-2 - [(2'-methoxycarbonylbiphenyl-4-yl) methylamino] benzoate in essentially the same manner described in Working Example 7.

Yield: 72%, mp 112-113 ° C. 1 H-NMR (200 MHz, CDCl 3) δ: 1.5O (3H, t), 3.55 (3H, s), 3.77 (3H, s), 4.68 (2H, q), 5, 65 (2H, s), 6.99 (2H, d), 7.17 (2H, d), 7.17 (1H, t), 7.31-7.55 (4H, m), 7.73 (1H, dd), 7.77 (1H, dd)

IR (neat) cm ⁴ : 1730, 1710, 1545, 1470, 1430, 1380, 1340, 1320, 1270, 1250, 1235, 1210, 1120, 1080, 1030, 750, 740,710

Working Example 17 Methyl 2-butoxy-1- (2'-cyanobiphenyl-4-yl) methylbenzimidazole-7-carboxylate

The title compound is prepared as colorless needles in essentially the same manner described in Working Example 7.

Yield: 75%, mp 74-75 ° C.

1 H-NMR (200 MHz, CDCl 3) δ: 0.95 (3H, t), 1.35-1.54 (2H, m), 1.77-1.90 (2H, m), 3.76 (3H, s), 4.60 (2H, t), 5.69 (2H, s), 7.10 (2H, d), 7.17 (1H, t), 7.43 (4H, d) 7.54-7.65 (2 H, m), 7.74 (2 H, dd)

IR (KBr) cm ⁴ : 2220, 1725, 1560, 1490, 1470, 1440, 1395, 1320, 1295, 1265, 1245, 1120, 1050, 1020, 7070

Working Example 18 Methyl 2-allyloxy-1 - [(2'-cyanobiphenyl-4-yl) methyl] benzimidazole-7-carboxylate

The title compound is prepared as colorless needles in essentially the same manner described in Working Example 7.

Yield: 73%, mp 118-119 ° C. 1 H-NMR (200 MHz, CDCl 3) δ: 3.76 (3H, s), 5.12 (2H, m), 5.33 (1H, m), 5.43 (1H, m), 5, 72 (2H, s), 6.02-6.21 (1H, m), 7.1 (2H, d), 7.19 (1H, t), 7.44 (4H, d), 7.56 -7.66 (2 H, m), 7.75 (2 H, dd)

IR (KBr) cm ⁴ : 2220, 1705, 1540, 1470, 1460, 1425, 1410, 1400, 1330, 1300, 1270, 1250, 1225, 1205, 1100, 1015, 995,760,750, 740,730

Working Example 19 Methyl 2-ethylamino-1- [(2'-cyanobiphenyl-4-yl) methyl] benzimidazole-7-carboxylate

The title compound was prepared as colorless crystals (3.2 g, 32%) according to the procedure described in Working Example 8 from methyl 2 - [[(2'-cyanobiphenyl-4-yl) methyl] amino] -3- ( 3-ethylthioureido) benzoate (10.5 g), which was prepared from methyl 3-amino-2 - [[(2'-cyanobiphenyl-4-yl) methyl] amino] benzoate by essentially the same procedure described in Reference Example 5 .

1 H-NMR (200 MHz, CDCl 3) δ: 1.24 (3H, t), 3.49-3.63 (2H, m), 4.06 (1H, t), 5.55 (2H, s) 7.16 (1H, t),

7.27 (2H, d); 7.41-7.79 (8H, m)

IR (KBr) cm ^-1 : 3275, 2225, 1720, 1620, 1610, 1580, 1570, 1480, 1350, 1275, 1240, 1212, 1100, 1070, 770, 760

Working Example 20 2-Cyano-4'-methylbiphenyl-N- (2-methoxyphenyl) methylidenecyclohexylamine

A solution of anisaldehyde (21 g) and cyclohexylamine (15 g) in chloroform (100 ml) was stirred at room temperature for 2 hours and then evaporated to give a brown syrup (35 g, quantitative).

1 H-NMR (200 MHz, CDCl 3) δ: 1.21-1.17 (10H, m), 3.14-3.28 (1H, m), 3.86 (3H, s), 6.88 -7.00 (2H, m), 7.36 (1H, m), 7.95 (2H, dd), 8.75 (1H, s) 1-Methyl-2-biphenylcarbaldehyde

To a suspension of magnesium metal (1.1 g) in THF (3 mL) was added dropwise a solution of 4-bromotoluene (7.7 g) in THF (10 mL) under gentle reflux. The resulting Grignard reagent solution was added dropwise to an ice-cooled stirred solution of N- (2-methoxyphenyl) methylidene-cyclohexamine (4.3 g) in THF (30 mL). The reaction mixture was stirred at room temperature for 1.5 hours and then heated under reflux for 7 hours. After addition of ice water, the reaction mixture was acidified with concentrated hydrochloric acid. The reaction mixture was extracted with ethyl acetate and the extract was washed with 1N HCl and water, dried and evaporated to dryness. The residue was purified by silica gel column chromatography to give a pale yellow syrup (2.0 g, 51%).

1 H-NMR (200 MHz, CDCl 3) δ: 2.43 (3H, s), 7.28 (4H, s), 7.42-7.51 (2H, m), 7.63 (1H, t) ), 8.02 (1H, d), 10.00 (1H, s)

2-Cyan-4'-methylbiphenyls

A mixture of 4'-methyl-2-biphenylcarbaldehyde (2.0 g) and hydroxyamine hydrochloride, g) in pyridine (10 ml) was stirred at room temperature for 15 minutes and then acetic anhydride (4.1 g) was added. The reaction mixture was stirred at 90-100 ° C for one hour and concentrated to dryness. After adding water to the residue, the precipitated crystals are filtered off. Recrystallization from hexane gave colorless needles (1.5 g, 79%).

1 H-NMR (200 MHz, CDCl 3) δ: 2.40 (3H, s), 7.2-7.8 (8H, m)

The title compound can be readily converted to the compound (IIIa ') according to known references.

Working Example 21 Methyl 2-carboxy-3-nitrobenzzoate

To a suspension of 3-nitrophthalic acid (211 g) and methyl orthoformate (127 g) in methanol (420 ml) was added concentrated sulfuric acid (20 ml) dropwise with stirring. The reaction mixture was heated to reflux for 18 hours and concentrated to dryness. Water (30 mL) was added to the residue and the mixture was stirred at 3-10 ° C for one hour. The precipitated crystals were recrystallized from ethyl acetate-hexane to give pale yellow prisms (185 g, 82%) mp 166-168 ° C.

1 H-NMR (200 MHz, CDCl 3) δ: 4.03 (3H, s), 7.74 (1H, t), 8.39 (1H, dd), 8.42 (1H, dd)

Working Example 22 Methyl 2-tert-butoxycarbonylamino-3-nitrobenzoate

To a solution of methyl 2-carboxy-3-nitrobenzoate (7.23 g) in DMF (50 mL) was added diphenylphosphoryl azide (11.3 g) at room temperature and then triethylamine was added dropwise to the stirred reaction mixture: 6.7 ml). The mixture was stirred at room temperature for 3 hours and tert-butanol (54 mL) was added to the stirred reaction mixture. After stirring at room temperature for 30 minutes, the reaction mixture was gradually warmed and then heated to reflux for 1 hour before being evaporated to dryness. The resulting residue was dissolved in ethyl acetate, washed with dilute hydrochloric acid, aqueous sodium bicarbonate, water, and then dried. After evaporation of the solvent, methanol was added to the residue and the mixture was cooled to give color crystals (6.7 g, 70%). 1 H-NMR (200 MHz, CDCl 3) δ: 1.50 (9H, s), 3.96 (3H, s), 7.23 (1H, t), 8.10 (1H, dd), 8.17 (1H, dd)

IR (KBr) cm ^-1 : 3360, 1730, 1705, 1580, 1520, 1490, 1440, 1365, 1355, 1310, 1270, 1240, 1150, 870, 835, 770, 725, 705

Working Example 23 Methyl 2 - [(N-tert-butoxycarbonyl-N- (2'-cyanobiphenyl-4-yl) methyl) amino] -3-benzoate

A solution of methyl 2-tert-butoxycarbonylamino-3-nitrobenzoate (0.6 g), 2- (4-bromomethylphenyl) benzonitrile (0.54 g) and K ₂ CO 3 (0.28 g) in acetonitrile (10 mL) was added. Heat at reflux for 4 hours and concentrate to dryness. Water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and evaporated to dryness. The residue was purified by silica gel column chromatography, and the obtained crystals were recrystallized from ethyl acetate-hexane to give colorless prisms (0.83 g, 85%), mp 153-154 ° C.

1 H-NMR (200 MHz, CDCl 3) δ: 1.35 (9H, s), 3.70 (3H, s), 4.63 (1H, d), 4.80 (1H, d), 7, 23-7.29 (3H, m), 7.39-7.53 (6H, m), 7.59-7.67 (1H, m), 7.75 (1H, dd), 7.93 ( 1 H, dd), 8.05 (1H, dd), 8.1 (1H, dd)

ID (KBr) cm ': 2220, 1700, 1530, 1390, 1360, 1315, 1290, 1160,765

Working Example 24 Methyl 2 - [[(2'-cyanobiphenyl-4-yl-5-methyl) amino] -3-nitrobenzoate

A mixture of methyl 2 - [[N-tert-butoxycarbonal-N- (2'-cyanobiphenyl-4-yl) methyl] amino] -3-nitrobenzate (0.49 g) in 20% HCl-ethanol (3 mL) and ethyl acetate (3 mL) was stirred at room temperature for 1 hour. After evaporation of the solvent, methanol and saturated aqueous sodium bicarbonate solution were added to the residue to give crystals. The crystals were filtered off and recrystallized from chloroform-methanol to give pale yellow crystals (0.3 g, 77%), mp 140-141 ° C.

1 H-NMR (200 MHz, CDCl 3) δ: 3.84 (3H, s), 4.26 (2H, m), 6.86 (1H, t), 7.46 (2H, d), 7, 54-7.65 (4H, m), 7.79 (1H, d), 7.95 (dd), 8.05-8.11 (2H, m), 8.67 (1H, t)

Working Example 25 Methyl 3-amino-2 - [[(2-cyanobiphenyl-4-yl) methyl] amino] benzoate

A mixture of methyl 2 - [[(2'-cyanobiphenyl-4-yl) methyl] amino] -3-nitrobenzoate (10 g), FeCl 3 .6H ₂ O (0.1 g), activated charcoal (1 g) in a mixture of methanol (100 mL) and THF (50 mL) was heated under reflux for 30 minutes. Hydrazine hydrate (7.2 mL) was added dropwise to the reaction mixture and the mixture was heated under reflux for 14 hours. Insoluble matter was filtered from the reaction mixture and the filtrate was concentrated to dryness. Aqueous sodium bicarbonate was added to the resulting residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and evaporated to dryness. The residue was purified by silica gel column chromatography, and the obtained crystals were recrystallized from isopropyl ether to give pale yellow needles (6.0 g, 64%), mp 110-111 ° C. 1 H-NMR (200 MHz, CDCl 3) δ: 3.81 (3H, s), 3.97 (2H, br s), 4.23 (2H, d), 6.39 (1H, t), 6 84.6.93 (2H, m), 7.26-7.55 (8H, m), 7.64 (1H, dt), 7.77 (1H, dd)

Working Example 26 Methyl 1- [(2'-cyanobiphenyl-4-yl) methyl] -2- (2,2,2-trifluoroethoxy) benzimidazole-7-carboxylate

The title compound was prepared as light yellow crystals from methyl 3-amino-2 - [[(2'-cyanobiphenyl-4-yl) methyl] amino] benzoate and 2,2,2-trifluoromethyl carbonate according to the procedure of Working Example 3. Yield: 25%, mp 143-145 ° C. Elemental analysis for C ₂₅ H ₁₈ F ₃ N ₃ O ₃ calculated C 64.52, H 3.90, N 9.03 found C 64.35, H 3.95, N 8.98% 1 H-NMR (200 MHz, CDCl 3) δ: 3.80 (3H, s), 5.01 (2H, q), 5.74 (2H, s), 7.13 (2H, d), 7.23 (1H, t), 7.38-7.47 (4H, m), 7.58-7.66 (2H, m), 7.72-7.78 (2H, m)

IR (KBr) cm ^-1 : 2225, 1735, 1550, 1465, 1430, 1305, 1280,

1270,1250,1170,1060,770,750,745

Working Example 27 Ethyl 1 - [(2'-cyanobiphenyl-4-yl) methyl] -2-ethoxybenzimidazole-7-carboxylate

To a solution of ethyl 2-chloro-1- [(2'-cyanobiphenyl-4-yl) methyl] benzimidazole-7-carboxylate (1.0 g) in ethanol (30 mL) was added NaOEt (17 g) and the mixture was heated under reflux for an hour. The reaction mixture was concentrated to dryness. The residue is dissolved in ethyl acetate and the solution is washed with water and then dried. After evaporation of the solvent, the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.37 g, 70%).

&Lt; 1 &gt; H-NMR and IR spectra show that the product prepared according to this working example is entirely identical to the product obtained in Working Example 4.

Reference Example 14 2- (4-Formylphenyl) benzonitrile

A mixture of 2- (4-bromomethylphenyl) benzonitrile (12 g) and sodium bicarbonate (26 g) in dimethylsulfoxide (150 mL) was heated with stirring at 120 ° C for five hours. Water was then added and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated to dryness. The residue was purified by silica gel column chromatography, and the obtained crystals were recrystallized from chloroform-isopropyl ether to give colorless needles (5.777 g, 63%).

1 H-NMR (200 MHz, CDCl 3) δ: 7.49-7.58 (2H, m), 7.67-7.84 (4H, m), 8.00-8.05 (2H, m) , 10.10 (1H, s)

Reference Example 15 2- (4-Aminomethylphenyl) benzonitrile

A mixture of 2- (4-bromomethylphenyl) benzonitrile (12 g) and potassium phthalimide (15 g) in DMF (200 mL) was stirred at 70 ° C for five hours. Water is then added and the mixture is extracted with methylene chloride. The extract was washed with water, dried and concentrated to dryness and the crystals obtained were recrystallized from ethyl acetate-isopropyl ether to give colorless crystals. To a suspension of crystals in methanol (500 mL) was added hydrazine hydrate (10 mL) and the mixture was refluxed for 12 hours. After evaporation of the solvent, the residue was dissolved in ethyl acetate and the solution was washed with 1N NaOH and water. The organic layer was dried and concentrated to dryness to give crystals (14.2 g, 93%). 1 H-NMR (200 MHz, CDCl ₃ ) δ: 1.56 (2H, br s), 3.88 (2H, s), 7.27-7.78 (8Hm)

Working Example 28 Ethyl 2-ethoxy-1- [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate

A mixture of ethyl 1 - [[2 ') cyanobiphenyl (4-yl) methyl] -2-ethoxy] benzimidazole-7-carboxylate (0.7 g) and trimethylezinide (0.7 g) in toluene (15 mL) was heated. under reflux for 4 days. The reaction mixture was concentrated to dryness and methanol (20 mL) and 1N HCl (10 mL) were added to the residue. The mixture was stirred at room temperature for 30 minutes and the pH was adjusted to pH 1 with NaOH

3-4. After removal of the solvent, the residue was partitioned between chloroform and water. The organic layer was washed with water, dried and the solvent was evaporated to dryness to give a syrup. The syrup was purified by silica gel column chromatography and the obtained crystals were recrystallized from ethyl acetate-benzene to give colorless crystals (0.35 g, 45%), m.p. 158-159 ° C.

H, C 6 H ₂ and N ₂ O _{6 3rd} found: C, 66.61; H, 5.05; N, 17.84.

1 H-NMR (200 MHz, CDCl ₃ ) δ: 1.10 (3H, t), 1.43 (3H, t), 4.02 (2H, q), 4.30 (2H, q), 5 57 (2H, s), 6.71 (2H, d), 6.83-6.96 (4H, m), 7.27-7.31 (1H, m), 7.40 (1H, m, dd), 7.55-7.66 (2H, m), 8.04-8.09 (1H, m)

IR (KBr) cm ^-1 : 1720, 1605, 1540, 1470, 1430, 1250, 1040, 750

Working example 29

2-Ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid

A solution of ethyl 2-ethoxy-1- [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate (0.24 g) and 1N NaOH (1.5) in ethanol (4 mL) was stirred at 80 ° C for one hour. The reaction mixture was concentrated and the concentrate was extracted with water and ethyl acetate. The aqueous layer was adjusted to pH 1 with 1N HCl

3-4 and the obtained crystals were recrystallized from ethyl acetate-methanol to give colorless crystals (0.15 g, 67%), mp 183-185 ° C.

H, C ^ H ^ N ₆ O ₃ .1 / 5 _H2O: Calcd 64.91% C, 4.63% H, 18.93% N Found 65.04% C, 4.51% H, 18.77% N 1 H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.38 (3H, t), 4.58 (2H, q), 5.63 (2H, s), 6.97 (4H, q), 7.17 (1H, t), 7.47-7.68 (6H, m) IR (KBr) cm ⁴ : 1710, 1550, 1480, 1430, 1280, 1240, 1040, 760

Working Example 30 Ethyl 2-propoxy-1- [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate

A mixture of ethyl 1 - [(2'-cyanobiphenyl-4-yl) methyl] -2-propoxybenzimidazole-7-carboxylate (0.69 g) and trimethyleinazide (0.7 g) in toluene (15 mL) was heated for 4 days. under reflux. The reaction mixture was concentrated to dryness and methanol (20 mL) and 1N HCl (10 mL) were added to the mixture. The mixture was then stirred for 30 minutes and adjusted to pH 3-4 with 1N NaOH. After removal of the solvent, the residue was extracted with chloroform-water. The organic layer was washed with water, dried and the solvent was evaporated to dryness to give a syrup. The syrup was purified by silica gel column chromatography, and the obtained crystals were recrystallized from ethyl acetate-benzene to give colorless crystals (0.31 g, 43%), mp 157-159 ° C. Elemental analysis for C 7 H ₂₆ N ₂ O _{6 3:} calculated 67.21% C, 5.43% H, 17.42% N Found 67.26% C, 5.45% H, 17.28% N H -NMR (200 MHz, CDCl 3) δ; 1.033 (3H, t), 1.13 (3H, t), 1.75-1.92 (2H, m), 4.05 (2H, q), 4.23 (2H, q), 5 57 (2H, s), 6.75 (2H, d), 6.90 (2H, d), 6.96 (2H, d), 7.28-7.33 (1H, m), 7.39 -7.44 (2H, m), 7.57-7.62 (2H, m), 8.07-8.1 L (1H, m) IR (KBr) cm -1: 1720, 1540, 1470, 1430 , 1250, 1250, 1130,

1020.750

Working Example 31 2-Propoxy-1- [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid

A solution of ethyl 2-propoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-ylZ-methyl] -benzimidazole-7-carboxylate (0.23 g) in ethanol (4 ml) containing IN NaOH (1.5 mL) was heated at 80 ° C for two hours. The reaction mixture was concentrated to dryness and the residue was extracted with water and ethyl acetate. The pH of the aqueous layer was adjusted to 3-4 with 1N HCl, and the obtained crystals were recrystallized from ethyl acetate-methanol to give colorless crystals (0.15 g, 69%), mp 174-175 ° C.

1 H-NMR (200 MHz, DMSO-d 6): 0.92 (3H, t), 1.70-1.77 (2H, m), 4.47 (2H, q), 5.63 (2H, s), 6.96 (4H, dd), 7.16 (1H, t), 7.42-7.67 (6H, m)

IR (KBr) cm ^-1 : 1700, 1550, 1430, 1212, 1240, 765

Working Example 32 Ethyl 2-mercapto-1- [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate

A mixture of ethyl [1- (2'-cyanobiphenyl-4-yl) methyl] -2-mercaptobenzimidatol-7-carboxylate (4.1 g) and trimethyltin azide (8.0 g) in toluene (100 mL) was heated for 4 days. under reflux. The solvent was evaporated to dryness and the residue was stirred with a mixture of horse, hydrochloric acid (2 ml) and methanol (20 ml) at room temperature for 20 minutes. 1N NaOH was added to adjust the pH to about 4, and the mixture was then extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated to dryness. The obtained crystals were recrystallized from chloroform to give colorless crystals (5.0 g, 89%), mp 263-264 ° C (dec.).

Elemental analysis for C ₂₄ H ₂₀ N ₆ O2S .1 / 2H ₂ O: Calculated 61.92% C, 4.55% H, 18.05% N Found 61.99% C, 4.30% H, 17 86% N 1 H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.10 (3H, t), 4.09 (2H, q), 5.82 (2H, br s), 6.87 (2H, d), 7.00 (2H, d), 7.26 (1H, t), 7.37-7.69 (6H, m)

IR (KBr) cm ^-1 : 1720, 1460, 1440, 1365, 1340, 1260, 1180,

1145,1150,1110,990,745

Working Example 33 Ethyl 2-methylthio-1- [2 '- (1H-tetrazol-5-yl) biphenyl-4-yl / methyl] benzimidazole-7-carboxylate

To a solution of ethyl 2-mercapto-1- [[2 '- (1H-tetrazol-5-yl) -biphenyl-4-yl] methyl] benzimidazole-7-carboxylate (0.68 g) in ethanol (10 mL) containing 1N NaOH (3.0 mL) was added methyl iodide (0.24 g) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was neutralized with dilute hydrochloric acid to obtain crystals. The crystals were purified by column chromatography on silica gel and recrystallized from ethyl acetate to give colorless prisms (0.31 g, 44%), mp 207-208 ° C (dec.). Elemental analysis for C ₂₅ H ₂₂ N ₆ O ₂ S: calculated 63.81% C, 4.71% H, 17.86% N found 63.55% C, 4.81% H, 17.50% N ' 1 H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.13 (3H, t), 2.77 (3H, s), 4.14 (2H, q), 5.62 (2H, s), 6.84 (1H, d), 7.26 (1H, t), 7.46-7.70 (5H, m)

IR (KBr) cm -1: 1705, 1480, 1450, 1420, 1360, 1340, 1275,

1255,1190,1140,1100,1025,990,770,750

Working Example 34 Ethyl 2-ethylthio-1- [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate

To a solution of ethyl 2-mercapto-1- [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate (0.91 g) in ethanol (13 mL) containing 1 N NaOH (4 mL) was added ethyl iodide (0.34 g) and the mixture was stirred at room temperature for 4 hours, the pH of the reaction mixture was adjusted to 4 with dilute hydrochloric acid to give crystals. The crystals were filtered, purified by silica gel column chromatography and recrystallized from ethyl acetate to give colorless prisms (0.55 g, 57%), mp 153-154 ° C.

Elemental Analysis Found C, 64.44; H, 4.99; N, 17.34. Found: C, 64.37; H, 5.05; N, 17.20. 200 MHz, CDCl 3 δ: 1.19 (3H, t), 1.37 (3H, t), 3.20 (2H, q), 4.12 (2H, q), 5.67 (2H, s) 6.75 (2H, d);

6.92 (2H, d), 7.05 (1H, t), 7.26-7.34 (2H, m), 7.50 (1H, dd), 7.53-7.63 (2H , m), 8.05-8.11 (1 H, m)

IR (KBr) cm -1: 1715, 1450, 1420, 1365, 1343, 1280, 1195, 1145.1110, 1035.1015, 990, 760.745

Working Example 35 Ethyl 2-propylthio-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate

To a solution of ethyl 2-mercapto-1- [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate (0.91 g) in ethanol (13 mL) containing 1 N NaOH (4.0 mL) was added propyl iodide (0.37) and the mixture was stirred at room temperature for 5 hours. The pH of the reaction mixture is adjusted to about 4 with dilute hydrochloric acid to obtain crystals. The crystals were filtered off, purified by silica gel column chromatography and recrystallized from ethyl acetate-hexane to give colorless prisms (0.4 g, 40%), m.p. 177-178 ° C (dec.). H, C 2 -C ₇ H ₂₆ N ₆ O ₂ S: calculated 65.04% C, 5.26% H, 16.85% N Found 64.88% C, 5.25% H, 16.78% N 1 H-NMR (200 MHz, CDCl 3) δ: 1.04 (3H, t), 1.19 (3H, t), 1.76 (2H, m), 3.18 (2H, t), 4.12 (2H, q), 5.69 (2H, s);

6.75 (2H, d), 6.93 (2H, d), 7.05 (1H, t), 7.27-7.34 (2H, m), 7.50 (1H, dd), 7 54-7.63 (2H, m), 8.07-8.12 (1H, m) IR (KBr) cm -1: 1715, 1450, 1420, 1380, 1365, 1350, 1280,

1260,1190,1145,1035,1020,990,760,745

Working Example 36 2-Methylthio-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid

A solution of methylthio-1- [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate (0.2 g) in a solution of methanol (5 mL) containing 1N NaOH (1). (3 mL) was heated at reflux for 2 hours. The pH of the reaction mixture is adjusted to about 4 with dilute hydrochloric acid to obtain crystals. The crystals were filtered off, purified by silica gel column chromatography and recrystallized from ethyl acetate-hexane to give colorless crystals (0.17 g, 81%), mp 223-225 ° C (dec.).

SK 282473 Β6

Elemental analysis for C ₂₃ H ₁₈ N ₆ O ₂ S · 1/2 C ₄ H ₈ O ₂ : calculated C 61.72, H 4.56, N 17.27% Found C 61.59, 54% H, 17.54% N 1 H-NMR (200 MHz, DMSO-d ₆ ) δ: 2.75 (3H, s), 5.76 (2H, s), 6.88 (2H, d) 7.01 (2H, d), 7.25 (1H, t), 7.47-7.66 (5H, m), 7.82 (1H, d)

IR (KBr) cm -1: 1710, 1485, 1450, 1420, 1370, 1345, 1320, 1280,1245,1195,1150,990,780,760

Working example 37

2-Ethylthio - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid

A solution of ethyl 2-ethylthio-1- [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate (0.35 g) in a methanol solution (7 mL) containing 1N NaOH (2.2 mL) was heated at reflux for 2 hours. After evaporation of the solvent, the pH of the aqueous residue is adjusted to about 3-4 with 1N hydrochloric acid to obtain crystals. The crystals were filtered and recrystallized from ethyl acetate-methanol to give colorless crystals (0.21 g, 64%), mp 209-210 ° C (dec.).

Elemental analysis for C ₂₄ H ₂₀ N ₆ O ² S: Calculated, 63.14% C, 4.42% H, 18.41% N Found 62.89% G, 4.35% H, 18.15% N H-NMR (200 MHz, _DMSO-D) δ: l, 39 (3H, t);

3.36 (2H, q), 5.82 (1H, dd), 76 (2H, s), 6.87 (2H, d),

7.01 (2H, d), 7.25 (1H, t), 7.47-7.69 (5H, m), 7.82 (1H, dd) IR (KBr) cm ^-1 : 1695, 1450 , 1415, 1350, 1275, 1225, 1190, 1180, 1145,755,740

Working Example 38 2-Propylthio-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid

A solution of ethyl 2-propylthio-1- [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate (0.25 g) in methanol containing 1N NaOH (1). (5 ml) was heated under reflux for 2 hours. After evaporation of the solvent, the pH of the aqueous residue is adjusted to about 3-4 with 1N hydrochloric acid to obtain crystals. The crystals were filtered off and recrystallized from ethyl acetate-hexane to give colorless crystals (0.21 g, 91%), mp 222-223 ° C (dec.).

Elemental analysis for C ₂₅ H ₂₂ N ₆ O ₂ S: calculated 63.95% C, 4.51% H, 17.90% N found 63.78% C, 4.85% H, 17.59% N ' H-NMA (200 MHz, DMSO-d6) δ 0.99 (3H, t), 1.67-1.85 (2H, m), 3.35 (2H, t), 5.77 (2H, s) 6.87 (2H, d);

7.01 (2H, d), 7.25 (1H, t), 7.46-7.70 (5H, m), 7.82 (1H, dd) IR (KBr) cm ^-1 : 1700, 1450 , 1280, 1240, 1195, 1145, 755,740

Working Example 39 Methyl 2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate

A mixture of methyl 1 - [(2'-cyanobiphenyl-4-yl) methyl] -2-ethoxybenzimidazole-7-carboxylate (1.85 g) and trimethylezinide (2.80 g) in toluene (15 mL) was heated under reflux. one day. The reaction mixture was concentrated to dryness. To the residue was added methanol (50 mL) and 1N HCl (20 mL), and the mixture was stirred at room temperature for 30 minutes. The pH of the reaction mixture was adjusted to about 3-4 with 1N NaOH. After removal of the solvent, the remaining syrup is purified by silica gel chromatography, and the obtained crystals are recrystallized from ethyl acetate.

-benzene to give colorless crystals (1.16 g, 56%), mp 191-193 ° C (dec.).

Elemental analysis for C ₂₅ H ₂₂ N ₆ O ₃ .1 / 5 H ₂ O calculated C 65.58, H 4.75, 18.53% N found C 65.55, H 4.93, 18 35% N 1 H-NMR (200 MHz, CDCl 3) δ: 1.43 (3H, t, J = 7.0Hz), 3.57 (3H, s), 4.30 (2H, q, J = 7.80Hz, 5.54 (2H, s), 6.72 (2H, d, J = 8.2), 6.84-6.97 (4H, m), 7.28-7.33 (1H, m), 7.40 (1H, dd, J = 1.8,7.0Hz), 7.57-7.62 (2H, m), 8.03-8.07 (1H, m)

ID (KBr) cm · 17 1720, 1550, 1475, 1430, 1280, 1250, 1040, 755,735

Working Example 40 Ethyl 2-ethylamino-1- [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazal-7-carboxylate

A mixture of ethyl 1- [[2'-cyanobiphenyl-4-yl] methyl] -2-ethylaminobenzimidazole-7-carboxylate (1.23 g) and trimethylezinide (2.80 g) in toluene (15 mL) was heated for 40 hours under reflux. The precipitate was filtered off and suspended in methanol (50 ml). 1N HCl (15 mL) was added to the suspension, and the mixture was stirred at room temperature for 10 minutes. The pH of the reaction mixture was adjusted to about 5 with 1N NaOH and then extracted with chloroform. The organic layer was washed with water, dried and concentrated to dryness. The residue was purified by silica gel column chromatography, and the obtained crystals were recrystallized from methanol-ethyl acetate to give colorless crystals (0.83 g, 61%), mp 166-168 ° C. 1 H-NMR (200 MHz, CDCl ₃ ) δ: 1.13 (3H, t), 1.21 (3H, t), 3.43 (2H, q), 4.13 (2H, q), 5 48 (2H, s), 6.78 (2H, d);

6.99 (2H, d), 7.07 (1H, t), 7.22 (1H, dd), 7.42-7.49 (2H, m), 7.54-7.69 (3H, m)

IR (KBr) cm -1: 1720, 1650, 1310, 1285, 765,755,750

Working Example 41 Ethyl 2-propylamino-1- [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate

A solution of ethyl 1- [[2'-cyanobiphenyl-4-yl] methyl] -2-propylaminobenzimidazole-7-carboxylate (1.20 g) and trimethylezinide (2.7 g) in toluene (15 mL) was heated for 40 hours. under reflux. The precipitate was filtered off and suspended in methanol (20 ml). 1N HCl (15 mL) was added to the suspension, and the mixture was stirred at room temperature for 10 minutes. The pH of the reaction mixture was adjusted to about 5 with 1N NaOH, and then extracted with chlorophonic acid. The organic layer was washed with water, dried and concentrated to dryness. The residue was purified by silica gel column chromatography, and the obtained crystals were recrystallized from methanol-ethyl acetate to give colorless crystals (10 g, 77%), mp 170-172 ° C.

1 H-NMR (200 MHz, CDCl ₃ ) δ: 0.89 (3H, t), 1.14 (3H, t), 1.52-1.70 (2H, m), 3.35 (2H, t, t), 4.14 (2H, q), 5.49 (2H, s), 6.77 (2H, d), 6.99 (2H, d), 7.05 (1H, t), 7, 21 (1H, dd), 7.39-7.47 (2H, m), 7.50-7.65 (3H, m)

ID (KBr) cm ': 1720,1670,1660,1290,1270, 760

Working Example 42 2-Ethoxy-1 - [[2 '- (N-triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid

To a solution of 2 ethoxy - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl / methyl] benzimidazole-7-carboxylic acid (2.07 g) in methylene chloride (10 mL) was added trityl chloride (1 mL). , 59 g) and triethylamine (0.8 mL). The mixture was stirred at room temperature for 1 hour. The reaction mixture is washed with water, dried and concentrated to dryness. The residue was purified by silica gel column chromatography and recrystallization of the obtained crude crystals from ethyl acetate-benzene gave colorless crystals (2.2 g, 66%), m.p. 168-170 ° C.

H, € ₄₃ Η3 _{4 6} Ν Ο ₃ calculated 75.64% C, 5.02% H, 12.31% N Found 75.37% C, 4.96% H, 12.20% N H NMR (200 MHz, CDCl 3) δ: 1.40 (3H, t), 4.61 (2H, q), 5.58 (2H, s), 6.76 (2H, d), 6.91-6 96 (8H, m), 7.12 (1H, t), 7.17-7.41 (12H, m) 7.60 (1H, dd), 7.73-7.82 (2H, m)

Working Example 43 Pivaloyloxymethyl-2-ethoxy-1- [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxlyate

To a solution of 2-ethoxy-1- [[2 '- (N-triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid (2.2 g) in DMF (10 mL) was added potassium carbonate (0.53 g) and pivaloyloxymethyl iodide (0.94 g) and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried. After removal of the solvent, the residue was dissolved in methanol (30 mL) and 1N HCl (6 mL) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to dryness and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water and dried. After removal of the solvent, the residue was purified by silica gel column chromatography, and the obtained crystals were recrystallized from ethyl acetate-hexane to give colorless crystals (1.13 g, 63%), mp 104-106 ° C.

Elemental analysis for C 10 H ₃₀ N ₆ O ₅ 1/4 C ₄ H ₈ O,. C 6 H ₁₄ 05.01 65.06 Calculated% C, 5.90% H, 14.32% N Found 64.79% C, 5.85% H, 14.43% N H-NMR (200 MHz, CDCl ) δ: 1.13 (9H, s), 1.44 (3H, t), 4.37 (2H, q), 5.61 (2H, s), 5.68 (2H, s), 6, 80 (2H, d), 6.93 (2H, d), 6.99-7.11 (2H, m), 7.33-7.37 (1H, m), 7.49-7.54 ( 1H, m), 7.59-7.62 (2H, m) 8.03-8.07 (1H, m)

Working Example 44 1-Cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl 7-benzimidazole-7-carboxylate

To a solution of 2-ethoxy-1- [[2 '- (N-triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid (0.5 g) in DMF (5 mL) was added potassium carbonate (0.12 g) and cyclohexyl-1-iodoethyl carbonate (0.26 g). The mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried. After removal of the solvent, the residue was dissolved in methanol (10 mL) and 1N HCl (2 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water and dried. After removal of the solvent, the residue was purified by silica gel column chromatography to give a colorless powder (0.21 g, 47%), mp 103-106 ° C. Elemental Analysis Found: C, 64.94; H, 5.71; N, 13.66. Found: C, 64.91; H, 5.61; N, 13.76.

To the prepared powder (1 g) was added ethanol (6 ml). The mixture was stirred at room temperature for 3 hours and then allowed to stand under ice-cooling. The mixture is then stirred for an hour at a temperature not exceeding 10 ° C. The crystals formed are filtered off and washed with cold ethanol. The crystals were dried at 25 ° C for 9 hours under reduced pressure and then at 35 ° C for an additional 18 hours to give white, powdered crystals (0.94 g), mp 18-166 ° C (decomposition). H, ₃ C 3 H ₃₄ N ₆ O _6: Calculated, 64.91% C, 5.61% H, 13.76% N Found 64.73% C, 5.66% H, 13.64% N H 1 H-NMR (200 MHz, CDCl 3) δ: 1.13-1.84 (16H, m), 4.28-4.55 (3H, m), 5.65 (2H, d), 6.72 (1H) , q), 6.81 (2H, d), 6.93 (2H, d), 7.03 (1H, t) 7.22-7.23 (1H; m), 7.31-7.36 (1H, m), 7.52-7.60 (3H, m), 8.02-8.07 (1H, m)

IR (KBr) cm -1: 2942, 1754, 1717, 1549, 1476, 1431, 1076,

1034.750

MS (m / z): 611 [M + H] &lt; ⁺ &gt; ^.

Working example 45

Methyl 2-methoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate

Methyl [1- (2'-cyanobiphenyl-4-yl) methyl] -2-methoxybenzimidazole-7-carboxylate (0.60 g) and trimethyltin azide (1.5 g) in toluene (15 mL) was heated for 40 hours under reflux. The precipitated crystals were dissolved in methanol (10 mL) and 1N HCl (3 mL) was added. The mixture was stirred at room temperature for 10 minutes and the methanol was evaporated, the pH of the aqueous residue was adjusted to about 3-4 with 1N NaOH and then extracted with ethyl acetate. The organic layer was washed with water and dried. is. After removal of the solvent, the residue was purified by silica gel column chromatography, and the obtained crystals were not crystallized from ethyl acetate to give colorless prisms (0.65 g, 65%), mp 165-166 ° C. Elemental analysis for C ₂₄ H ₂₀ N _with O 1/10 H ₂ O: calculated C 65.18, H 4.60, N 19.00 Found% C 64.91, H 4.49, 18 99% N 1 H-NMR (200 MHz, CDCl 3) δ: 3.64 (3H, s), 3.93 (3H, s), 5.55 (2H, s), 6.75 (2H, d) 6.90-7.01 (4H, m), 7.31-7.36 (1H, m), 7.49 (1H, dd), 7.55-7.64 (2H, m) , 8, O3-8, O7 (1H, m)

Working Example 46 2-Methoxy-1- [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid

To a solution of methyl 2-methoxy-1- [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate (0.22 g) in methanol (10 mL) was added. IN NaOH (1.5 mL) was added. The mixture was heated under reflux for 6 hours. The reaction mixture was concentrated to dryness and water was added to the residue. The pH of the mixture was adjusted to 3-4 with 1N HCl and the obtained crystals were not crystallized from methanol-chloroform to give colorless needles (0.17 g, 77%), mp 208-209 ° C. Elemental Analysis for C ₂₁ H ₁₈ N ₆ O 3. 0. 7 _H2O: Calculated 62.92% C, 4.45% H, 19.14% N Found 62.81% C, 4.08% H, 19.19% N H-NMR (200 MHz CDCl3): 4.15 (3H, s), 5.63 (2H, s), 6.90 (2H, d), 7.00 (2H, d), 7.18 (1H, t) 7.46-7.70 (6H, m)

Working example

2-Ethylamino-1 - [[2 '- (1H-tetrazal-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid

SK 282473 Β6

To a solution of ethyl 2-ethylamino-1- [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate (0.52 g) in ethanol (5 mL) was added. IN NaOH (4 mL) was added and the mixture was stirred at 80 ° C for 2 h. The reaction mixture was concentrated to dryness and the aqueous residue was adjusted to pH 1 with 1N HCl

4-5 to obtain crystals. The crystals were filtered and recrystallized from methanol-chloroform to give colorless crystals (0.3 g, 63.4%), mp 240-242 ° C.

Elemental analysis for C ₂₄ H ₂ O ₂ and ₇ .1.1 H ₂ O: Calculated 62.76% C, 5.09% H, 21.35% N Found 62.65% C, 5.15% H, 21.23% N 1 H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.20 (3H, t), 3.43 (2H, q), 5.62 (2H, s), 6.85 (2H, d), 6.99 (2H, d), 7.10 (1H, t), 7.34 (1H, d). 7.44 to 7.68 (5H, m)

Working Example 48 2-Propylamino-1- [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid

The compound was prepared in essentially the same manner as in Working Example 47.

Yield 73%, mp 244-246 ° C. Elemental analysis for C ₂₅ H ₂₃ N ₇ O ₂ .1 / 2 H ₂ O: C 64.92%, H 5.23%, N 21.20 Found: C 64.79%, H 5.27%, 21.08% N

The following compounds (Working Examples 49-53) were prepared essentially as in Working Example 43.

Working Example 49 (5-Methyl-oxo-1,3-dioxolen-4-yl) methyl-2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate

Yield. M.p. 122 DEG-125 DEG C. (decomposition). CHC1 _3: calculated 53.63% C, 3.75% H, 12.51% N Found 53.32% C, 3.58% H, 12.24% N H-NMR (200 MHz, CDC1 ₃₎ δ: 1.43 (3H, t), 2.1 L (3H, s), 4.40 (2H, q), 4.80 (2H, s), 5.58 (2H, s), 6, 79 (2H, d), 6.94 (2H, d), 7.02 (1H, t), 7.15 (1H, dd), 7.35-7.39 (1H, m), 7, 49-7.63 (3 H, m), 8.00-8.04 (1H, m)

Working Example 50 Acetoxymethyl-2-ethoxy-1- [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate

Yield: 38%, mp 152-154 ° C (dec.) Elemental analysis for C ₂₇ H ₂₄ N ₆ O ₅ :

calculated: 63.27%, 4.72% H, 16.40% N found 63.55% C, 4.70% H, 16.18% N 1 H-NMR (200 MHz, CDCl ₃ ) δ: 1 43 (3H, t), 2.01 (3H, s), 4.33 (2H, q), 5.61 (2H, s), 5.69 (2H, s), 6.81 (2H, s), d), 6.93 (2H, d), 7.01 (1H, t), 7.13 (1H, d), 7.33-7.38 (1H, m), 7.53-7.62 (3H, m), 8.03-8.07 (1H, m)

Working Example 51 Propionyloxymethyl-2-ethoxy-1- [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate

Yield: 60%, mp 145-150 DEG C. (with decomposition) Analysis for C ₂₆ H, _{2 g} of N ₆ O _p. 0.2 C ₇ H ₈ :

calculated: 64.79% C, 5.10% H, 15.42% N found: 64.70% C, 5.10% H, 15.44% N 1 H-NMR (200 MHz, CDCl ₃ ) δ: 1 0.04 (3H, t), 1.44 (3H, t), 2.29 (2H, q), 4.40 (2H, q), 5.61 (2H, s), 5.71 (2H, s), 6.82 (2H, d), 6.92-7.14 (3H, m), 7.20 (1H, m), 7.33-7.38 (1H, m), 7.53 -7.61 (3H, m), 8.03-8.08 (1H, m)

Working Example 52 Butyryloxymethyl-2-ethoxy-1- [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate

Yield: 36%, mp 96-100 ° C.

Elemental analysis for C 9 H ₂₈ N ₂ O ₆ .0.4 ₅ C ₇ H _8: Calculated 66.15% C, 5.45% H, 14.55% N Found 66.11% C, 5.44% H 14.65% N 1 H-NMR (200 MHz, CDCl 3) δ: 0.58 (3H, t), 1.44 (3H, t), 1.55 (2H, m), 2.24 (2H , q), 4.38 (2H, q), 5.61 (2H, s), 5.70 (2H, s), 6.81 (2H, d), 6.93 (2H, d), 7 .00 (1H, t), 7.20 (1H, m), 7.33-7.38 (1H, m), 7.52-7.61 (3H, m), 8.01-8.10 (lH, m)

Working Example 53 Isobutyryloxymethyl-2-ethoxy-1- [[2 '(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate

Yield: 53%, mp 143-145 ° C. Elemental analysis for C ₂₉ H ₂₈ N ₆ O ₅ .0.1 C ₇ H ₈ : Calculated: C, 64.88; H, 5.28; N, 15.29. Found: C, 65.04; H, 5.25. N, 1 H-NMR (200 MHz, CDCl ₃ ) δ: 1.10 (6H, d), 1.44 (3H, t), 2.50 (1H, m), 4.38 (2H, q), 5.61 (2H, s), 5.70 (2H, s), 6.81 (2H, d), 6.91-7.00 (3H, m), 7.19 ( 1H, m), 7.33-7.37 (1H, m), 7.51-7.63 (3H, m), 8.02-8.07 (1H, m)

The following compounds (Working Examples 54-56) were prepared in essentially the same manner as in Working Example 44.

Working Example 54 1- (Ethoxycarbonyloxy) ethyl 2-ethoxy-1- [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate

Yield: 44%, mp 85-87 ° C. Elemental analysis for C ₂₉ H ₂₈ N ₆ O ₆ .0.3 H ₂ O calculated C 61.98%, H 5.13%, N 14.95% found C 62.11%, H 5.02% 69% N 1 H-NMR (200 MHz, CDCl ₃ ) δ: 1.20 (3H, t), 1.30 (3H, d), 1.41 (3H, t), 4.03-4, 22 (3H, m), 4.31-4.47 (1H, m), 5.61 (2H, s), 6.62-6.72 (3H, m), 6.80-6.95 ( 4H, m), 7.29-7.32 (1H, m),

7.47 (1H, dd), 7.54-7.64 (2H, m), 7.97-8.01 (1H, m)

Working Example 55 1-Acetoxyethyl 2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate

Yield: 31%, mp 105-107 ° C Elemental analysis for C ₂₈ H ₂₆ N ₆ O ₅ .0.5 H ₂ O calculated C 62.80%, H 5.08%, N 15.69% found 62 77% C, 4.69% H, 15.85% N 1 H-NMR (200 MHz, CDCl ₃ ) δ: 1.46 (3H, t), 1.49 (3H, d), 4.47 -4.62 (2H, m), 5.59 (1H, d), 5.83 (1H, d), 6.84 (1H, q),

6.90 (2H, d), 7.03 (2H, d), 7.1 (1H, t), 7.34-7.39 (1H, m),

7.49 (1H, d), 7.53-7.61 (3H, m), 8.07-8.1 L (1H, m)

Working example

1- (Isopropoxycarbiyloxy) ethyl 2-ethoxy-1- [2 '- (1H-tetrazol-5-yl) biphenyl-4-yl / methyl] benzimidazole-7-carboxylate

Yield: 33%, mp 74-76 ° C. Elemental analysis for C ₃₀ H ₃₀ N ₆ O ₅ .1.5 H ₂ O calculated C 61.95%, H 5.72, N 14.45% Found C 62.02, H 5.43, 14 20% N 1 H-NMR (200 MHz, CDCl ₃ ) δ: 1.20 (3H, d), 1.21 (3H, d), 1.30 (3H, d), 1.42 (3H, d) t), 4.08-4.24 (1H, m), 4.34-4.50 (1H, n1), 4.79 (1H, m), 5.61 (2H, s), 6, 62-6.75 (3H, m), 7.27-7.32 (1H, m), 7.48 (1H, dd) 7.54-7.64 (2H, m), 7.98- 8.03 (lH, m)

Working example

2-Methylamino-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid

The title compound was prepared in essentially the same manner as in Working Examples 40 and 47. Yield: 40%, mp 247-250 ° C (dec.) Elemental analysis for C ₂₃ H 19 N ₇ O ₂ · _2.0 H ₂ O calculated 59, 68% G, 5.02% H, 21.25% N found 59.99% C, 4.89% H, 21.36% N H-NMR (200 MHz, CDC1 ₃₎ δ: 2.94 ( 3H, s), 5.64 (2H, s), 6.82 (2H, d), 6.99 (2H, d), 7.02 (1H, t), 7.31 (1H, d), 7.42-7.63 (5H, m)

The following compounds (Working Examples 58-60) were prepared in essentially the same manner as in Working Example 43.

Working Example 58 Cyclohexylcarbonylmethyl-2-ethoxy-1- [1 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate

Yield: 54%, mp 140-142 ° C. Elemental analysis for C ₃₂ H ₃₂ N ₆ O ₅ calculated 66.19% G, 5.55% H, 14.47% N found 65.93% C, 5.46% H, 14.39% N 1 H- NMR (200 MHz, CDCl ₃ ) δ: 1.21-1.17 (13H, m), 2.20-2.32 (1H, m), 4.47 (2H, q), 5.60 (2H , s), 6.86 (2H, d), 7.07 (1H, t), 7.27-7.40 (3H, m), 7.54-7.61 (2H, m), 8, 05 to 8.09 (lH, m)

Working Example 59 Benzoyloxymethyl-2-ethoxy-1- [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate

Yield: 47%, mp 138-142 ° C.

Elemental analysis for C ₃₂ H ₂₆ N ₆ O ₅ . 0.5 H ₂ O. 0, 1 0> Η ₈ 0 ₂

calculated 65.67% C, 4.76% H, 14.18% N Found 65.71% C, 4.66% H, 13.96% N H-NMR (200 MHz, CDC1 ₃₎ δ: l 43 (3H, t), 4.36 (2H, q), 5.60 (2H, s), 5.98 (2H, s), 6.74 (4H, s), 6.99 (1H, s), t), 7.09-7.14 (1H, m), 7.21-7.36 (3H, m), 7.50-7.59 (4H, m), 7.90 (2H, d) , 8.02-8.06 (1H, m)

Working Example 60 (E) -Cinnamoyloxymethyl-2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] benzimidazole-7-carboxylate

Yield: 56%, mp 146-147 ° C. Elemental analysis for C ₃₄ H ₂₈ N ₆ O ₅ .0,4 C ₄ H ₈ O ₂ :

calculated 67.16% C, 5.07% H, 13.20% Found 66.97 LV% C, 4.86% H, 13.28% N H-NMR (200 MHz, CDC1 ₃₎ δ: l 44 (3H, t), 4.45 (2H, q), 5.61 (2H, s), 5.87 (2H, s), 6.33 (1H, d), 6.84 (2H, s), d), 6.96 (2H, d), 7.05 (1H, t), 7.31-7.57 (10H, m), 7.65 (1H, d), 8.00-8.04 (lH, m)

The following compounds (Working Examples 61-63) were prepared in essentially the same manner as in Working Examples 43 and 44.

Working Example 61 Cyclopentylcarbonyloxymethyl-2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate

Yield. M.p. 136-138 ° C. Elemental analysis for C ₃₁ H ₃₀ N ₆ O ₅ : calculated C 65.71, H 5.34, N 14.83 found C 65.59, H 5.33, N 14.77% -NMR (200 MHz, CDCl ₃ ) δ: 1.41-1.84 (11H, m), 2.61-2.76 (1H, m), 4.43 (2H, q), 5.61 (2H, s), 6.84 (2H, d), 6.96 (2H, d), 7.05 (1H, t), 7.22-7.26 (1H, m), 7.35- 7.39 (1H, m), 7.53-7.61 (3H, m), 8.03-8.08 (1H, m)

Working Example 62 Pivaloyloxymethyl-2-ethylamino-1- [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate

Yield: 59%, mp 130-135 ° C.

Elemental analysis for C ₃₀ H ₃ and H _{4 7} .0.4 CHC1 ₃ .0,2 H ₂ O calculated 60.36% C, 5.30% H, 16.21% N Found 60.20% C, 5 20% H, 16.08% N 1 H-NMR (200 MHz, CDCl 3) δ: 1.22 (9H, s), 1.20 (3H, t), 3.43 (2H, q), 5 52 (2H, s), 5.81 (2H, s), 6.80 (2H, d), 6.99 (2H, d), 7.08 (1H, t), 7.24 (1H, dd) , 7.43-7.68 (5 H, m)

Working Example 63 1- (Cyclohexyloxycarbonyloxy) ethyl 2-ethylamino-1- [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate

Yield: 76%, mp 149-152 ° C: Elemental analysis for C ₃₃ H ₃₅ N ₇ O ₅ · _0.5 H ₂ O requires C, 64.06; H, 5.86; N, 15.85. Found: C, 64.27; H, 6.02; N, 15.86. 1 H-NMR (200 MHz, CDCl ₃ ) δ: 1.12-1.88 (16H, m), 3.383.47 (2H, m), 4.48-4.59 (1H, m), 5.51 (2H, s), 6.75-6.88 (5H, m), 7.04 (1H, t), 7.29 -7.40 (2H, m), 7.47-7.51 (3N, m), 7.91-7.95 (1H, m)

Working example

Methyl 2-allyloxy-1- [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate

The title compound was prepared as colorless crystals from methyl 2-allyloxy-1- [[2'-cyanobiphenyl-4-yl] methyl] benzimidazole-7-carboxylate according to the procedure of Working Example 28.

Yield: 30%, mp 154-156 ° C. Elemental Analysis for ΰ ^ Η ^ Ν ^. 0.5 _H2O: Calculated 65.67% C, 4.88% H, 17.67% N Found 65.63% C, 4.71% H, 17.68% N H-NMR (200 MHz , CDC1 ₃₎ δ: 3.75 (3H, d), 4.58-4.61 (lH, m), 4.92 to 4.95 (1H, m), 5.18 to 5.48 ( 2H, m), 5.52 (2H, d),

SK 282473 Β6

5.83-6.15 (1H, m), 6.98-7.05 (2H, m), 7.09-7.17 (2H, m), 7.35-7.44 (2H, m) 7.47-7.60 (3H, m), 8.09-8.19 (1H, m)

IR (KBr) cm ^-1 ; 1720, 1670, 1550, 1470, 1430, 1280, 1250, 1025, 760, 735

Working Example 65 Methyl 2-butoxy-1- [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate

The title compound was prepared as colorless needles from methyl 2-butoxy-1- [[2'-cyanobiphenyl-4-yl] methyl] benzimidazole-7-carboxylate according to the procedure of Working Example 28.

Yield: 91%, mp 146-148 ° C.

H, C 27 H ₂₆ N ₆ O 3: Calcd 67.21% C, 5.43% H, 17.42% N Found 67.00% C, 5.45% H, 17.49% N H-NMR ( 200 MHz, CDCl3) δ: 0.99 (3H, t), 1.37-1.55 (2H, m), 1.74-1.88 (2H, m), 3.61 (3H, s) 4.27 (2H, t); 5.53 (2H, s);

6.75 (2H, d), 6.90 (2H, d), 6.97 (2H, d), 7.30-7.34 (1H, m), 7.41 (2H, dd), 7.57-7.61 (2H, m), 8.04-8.08 (1H, m)

IR (KBr) cm ^-1 : 1720, 1600, 1540, 1470, 1430, 1270, 1250,

1020.750

Working Example 66 Methyl 2-butylamino-1- [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate

The title compound was prepared as colorless crystals from methyl 2-butylamino - [(2'-cyanobiphenyl-4-yl) methyl] benzimidazole-7-carboxylate according to the procedure of Working Example 41.

Yield: 42%, mp 216-218 ° C.

Elemental analysis for C ₂₇ H 7 N ₂ O 2 _{7. H2O} Calc'd 64, 91% C, 5% H, 85, 19, 63% N Found 64, 86% C, 5.68% H, 19.41% N H-NMR (200 MHz, DMSO-d ₆ ) δ: 0.91 (3H, t), 1.25-1.43 (2H, m), 1.52-1.67 (2H, m), 3.65 (3H, s), 5, 47 (2H, s), 6.79 (2H, d), 6.98-7.05 (3H, m), 7.18 (1H, dd), 7.42-7.64 (5H, m) IR (KBr) cm -1: 1720, 1665, 1660, 1650, 1430, 1260, 745

Working Example 67 Methyl 1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -2-morpholinobenzimidazole-7-carboxylate

The title compound was prepared as colorless crystals from methyl 1- [[2'-cyanobiphenyl-4-yl] methyl] -2-morpholinobenzimidazole-7-carboxylate according to the procedure of Working Example 41.

Yield: 62%, mp 163-167 ° C. H, C27H25N7O3.0,6 CHC1 _3: calculated 58.45% C, 4.55% H, 17.29% N Found 58.66% C, 4.36% H, 17.54% N H NMR (200 MHz, CDCl ₃ ) δ: 3.33 (4H, t), 3.73 (3H, s), 3.90 (4H, t), 5.44 (2H, s), 6.62 ( 2H, d), 6.97 (2H, d), 7.17 (1H, t), 7.33-7.38 (1H, m), 7.43-7.50 (2H, m), 7 55-7.61 (2 H, m), 8.08-8.13 (1 H, m)

IR (KBr) cm ^-1 : 1730, 1600, 1530, 1455, 1420, 1405, 1280, 1260, 1120, 1110, 1000, 760, 750, 740

Working Example 68 Methyl 1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -2-piperidinobenzimidazole-7-carboxylate

The title compound was prepared as colorless crystals from methyl 1- [[2'-cyanobiphenyl-4-yl] methyl] -2-piperidinobenzimidazole-7-carboxylate according to the procedure of Working Example 41. Yield: 47%, temperature mp 146-150 ° C. Elemental analysis for C ₂₈ H ₂₇ N ₇ O ₂ .0.8 CHCl ₃ . calculated: 58.72% C, 4.76% H, 16.64% N found: 58.69% C, 4.66% H, 16.75% N 1 H-NMR (200 MHz, CDCl 3) δ: 1, 72 (6H, br s), 3.1 (4H, m), 3.61 (3H, s), 5.38 (2H, s), 6.45 (2H, d), 6.80 (2H, d), 6.89-6.96 (2H, m), 7.28-7.37 (2H, m), 7.56-7.64 (2H, m), 8.01-8.06 ( H, m)

IR (KBr) cm ': 1715, 1600, 1530, 1450, 1420, 1415, 1405, 1300, 1280, 1260, 1240, 1215, 1130, 770, 760, 750

Working Example 69 Methyl-2-ethylmethylamino-1- [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate

The title compound was prepared as colorless crystals from methyl 2-ethylmethylamino-1- [[2'-cyanobiphenyl-4-yl] methyl] benzimidazole-7-carbaxylate according to the procedure of Working Example 41.

Yield: 54%, mp 130-136 ° C. H, C26H25N7O2.0,6 H ₂ O calculated 59.26% C, 4.79% H, 18.19% N Found 59, 04% C 4, 95% H, 18.05% N H -NMR (200 MHz, CDCl 3) δ: 1.19 (3H, t), 2.57 (3H, s), 3.22 (2H, m), 3.62 (3H, s), 5.40 ( 2H, s), 6.43 (2H, d), 6.78-6.94 (4H, m), 7.30-7.34 (1H, m), 7.57 (1H, dd), 7.59-7.63 (2H, m); 7.99-8.04 (1H, m)

IR (KBr) cm ^-1 : 1720, 1600, 1540, 1435, 1400, 1300, 1280, 1255, 1015,750,740

Working Example 70 2-Piperdino-1- [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid

The title compound was prepared as colorless crystals from methyl 1- [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -2-piperidinobenzimidazole-7-carboxylate according to the procedure described in Example 29.

Yield: 91%, mp 215-218 ° C (dec.). H, 0.5 CHC1 ₃ C27H25N7O2: Calculated 61.25% C 4, 77% K H, 18.18% N Found 60, 95% C 4, 70% H, 17, 90% N H-NMR (200 MHz, _DMSO-ds) δ: 1.65 (6H, br s), 3.24 (4H, br s), 5.48 (2H, s), 6.71 (2H, d), 6 92 (2H, d), 7.17 (1H, t), 7.42-7.48 (2H, m), 7.54-7.67 (2H, m)

IR (KBr) cm ': 1685, 1530, 1450, 1440, 1420, 1400, 1285, 1270,1245,750,730

Working example 71

2-Morpholino-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid

The title compound was prepared as colorless crystals from 2-morpholino-1- [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate according to the procedure of Working Example. 29th

Yield: 59%, mp 202-206 ° C (dec.). Elemental analysis for C ₂₆ H ₂₃ N ₇ O ₃ · 0.6 CHCl ₃ : calculated C 57.76, H 4.30, N 17.73 found C 57.55, H 4.25, 17 66% N 1 H-NMR (200 MHz, DMSO-d ₆ ) δ: 3.24 (4H, br s), 3.76 (4H, br s), 5.56 (2H, s), 6, 72 (2H, d), 6.93 (2H, d), 7.16 (1H, t), 7.417.70 (6H, m)

IR (KBr) cm · 16 1690, 1535, 1460, 1450, 1420, 1410, 1290, 1260,1245,1120,760,740

Working Example 72 2- (N-Ethylmethylamino) -1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid

The title compound is prepared as colorless crystals from 2-methyl-2- (N-ethylmethylamino) -1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7 carboxylate according to the procedure of Working Example 47.

Yield: 66% mp 204-206 ° C (dec.). Elemental analysis for C 5 H ₂₃ N ₂ O _{7 2} Dilute 0.5 _H2O Calc'd C, 64.92%, 5.23% H, 21.20% N Found 65.22% C, 5.31% H, 21 11% N 1 H-NMR (200 MHz, CDCl 3) δ: 1.13 (3H, t), 2.93 (3H, s), 3.27 (2H, m), 5.54 (2H, s) ), 6.68 (2H, d), 6.92 (2H, d), 7.13 (1H, t), 7.43-7.48 (2H, m), 7.53-7.67 ( 2H, m)

IR (KBr) cm ^-1 : 1725, 1620, 1550, 1540, 1460, 1440, 1420, 1300, 1250, 775

Working Example 73 2-Butylamino-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid

The title compound was prepared as colorless crystals from methyl 2-butylamino-1- [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate according to the procedure described in working example 47.

Yield: 67%, mp 213-216 ° C (dec.). Elemental Analysis for C25H57N7O2. _H2O: Calculated 64.32% C, 5.60% H, 20.19% N Found 64.07% C, 5, 77% H, 20% N 6 H-NMR (200 MHz, DMSO- d ₆ ) δ: 0.89 (3H, t), 1.22-1.41 (2H, m), 1.51-1.66 (2H, m), 3.34-3.43 (2H, m), 5.65 (2H, s), 6.83 (2H, d), 6.97-7.05 (3H, m), 7.29 (1H, dd), 7.40-7.67 (5H, m) IR (KBr) cm -1: 1660, 1580, 1540, 1485, 1440, 1380, 1340, 1215,850,810,780, 760,750

Working Example 74 2-Ethoxy-1- [(2'-carboxybiphenyl-4-yl) methyl] benzimidazole-7-carboxylic acid

To a solution of methyl 2-ethoxy-1- [(2'-methoxycarbonylbiphenyl-4-yl) methyl) benzimidazole-7-carboxylate (0.7 g) in methanol (10 mL) was added 1 N NaOH (5 mL) and the mixture was stirred at 80 ° C for three hours. After evaporation of the methanol, the aqueous residue was neutralized with 1N hydrochloric acid to give crystals. The crystals were recrystallized from methanol-chloroform to give colorless crystals (0.54 g, 83%), mp 213-215 ° C.

Elemental Analysis Found C, 69.22; H, 4.84; N, 6.73. Found: C, 68.98; H, 4.89; N, 6.71%. MHz, _DMSO-d6) δ: l, 42 (3H, t), 4.61 (2H, q), 5.68 (2H, s), 7.01 (2H, d), 7.13 to 7 , 56 (7H, m), 7.64-7.71 (2H, m) IR (in substance) cm -1: 1725.1545, 1460, 1420, 1380, 1280, 1260.1230, 1205.1120.1030 , 750

Working Example 75 Methyl 2-ethylamino-1- [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate

The title compound was prepared as colorless crystals from methyl 2-ethylamino-1- [[2'-cyanobiphenyl-4-yl] methyl] benzimidazole-7-carboxylate according to the procedure of Working Example 41.

Yield: 63%, mp 256-258 ° C. Elemental analysis for C ₂₅ H ₂₃ N ₇ O ₂ . _H2O: Calculated 63.68% C, 5.34% H, 20.79% N Found 63.99% C, 5.09% H, 20.68% N H-NMR (200 MHz, DMSO- d ₆ ) δ: 1.21 (3H, t), 3.40-3.60 (2H, m), 3.63 (3H, s), 5.47 (2H, s), 6.78 (2H , d), 6.98-7.05 (3H, m), 7.18 (1H, dd), 7.42-7.66 (5H, m)

ID (in substance) cm '. 1710, 1660, 1650, 1645, 1430, 1340, 1300, 1280, 1250, 1050,740

Working Example 76 Methyl 1 - [[2 '' - (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -2- (2,2,2-trifluoroethoxy) benzimidazole-7-carboxylate

The title compound was prepared as colorless needles (0.37 g, 77%) from methyl 1 - [(2'-cyanobiphenyl-4-yl) methyl] -2- (2,2,2, -trifluoroethoxy) benzimidazole-7-carboxylate (0.48 g) as described in Working Example 28. Melting point 210-212 ° C. Elemental Analysis Found C, 59.02; H, 3.71; N, 16.36. Found: C, 59.06; H, 3.77; N, 16.53. (200 MHz, CDCl ₁₃₎ δ: 3.82 (3H, s), 5.01 (2H, q), 5.64 (2H, s), 6.99 (2H, d), 7.14 (2H , d), 7.25 (1H, t), 7.37-7.41 (1H, m), 7.51-7.63 (3H, m), 7.71 (1H, dd), 8, 17-8.22 (1H, m) IR (KBr) cm ^-1 : 1710, 1550, 1425, 1275, 1240, 1180, 1160,

1055.750

Working Example 77 1- [/ 2 '- (1H-Tetrazol-5-yl) biphenyl-4-yl / methyl] -2- (2,2,2-trifluoroethoxy) benzimidazole-7-carboxylic acid

The title compound was prepared as colorless crystals (0.23 g, 88%) from methyl 1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -2- (2 2,2,2-trifluoroethoxy) benzimidazole-7-carboxylate (0.27 g) according to the procedure described in Working Example 47. Mp 204-206 ° C. Elemental analysis for C ₂₄ H ₁₈ Cl 2 O _{3 7} F ₃ N ₆ O ₃ . _H2O: Calculated 57.26% C, 3.60% H, 16.69% N Found 57.09% C, 3.59% H, 16.72% N

EN 282 473 Β6 H-NMR (200 MHz, _DMSO-ds) δ: 5.28 (2H, q), 5.66 (2H, s), 6.98 (4H, d), 7.23 (H t, 7.44-7.68 (5H, m), 7.72 (1H, dd) IR (KBr) m / z ¹ : 1690, 1540, 1470, 1430, 1270, 1225, 1210, 1160, 1050.740

The following compounds listed in Table I were prepared according to the procedures set forth in the Reference and Working Examples described herein.

Z * tauXka_JL

Z1Ečeni na β. B ¹ * t * a

H ··

OEt

OEt

OBt

CBt cet

OBt oet oet

C £ t cet

CBt eet (JBt cet

OEt

CBT

CBT

CBT

OBt

CBT

CEt

100 OEt

MeH

OM · H

NHMeH

FH

ClH

OPEN

CFiH

HME

HOH ·

HNMNi

KF

HCl

HBr

HCFi

HH

HH

HH

HH

HW

HN

WH

F · H

H No.

H Tet

H Tet

H Tet

H Tet

H Tat

H Tat

H Tet

K Tat

H Tat

K Tet

H Tat

H Tet

H Tet

H Tat

Ha Tat

OMe Tat

NHMe Tet

F Tet

Cl Tet

Br Tet

CF »Tet

H COOH

H COOH

COOH

COOH

COOH

COOH

COOH

COOH

COOH

COOH

COOH

COOH

COOH

COOH

COOH

COOH

COOH

COOH

COOH

COOH

COOH COOH

COOH

COOH

COOH

Table * í (continued)

Compound fi. £ s B> e B * e R »« B · · 113 OBt The H H Tet Tet 113 oet no M Tet Tet ) = ( 114 OBt H from \ Tet COOH 5 ) = L 115 OBt ) H Tet COOH 11 « CBT H H H Tet COOCH, OCO-cyclo-Pr 117 OEt H H N Tet COOCfeOCO-eek.-Bu 118 OEt H H N Tet COOCH, OCO-n-Bu 119 OEt M M H Tet COOCJW OCO-Cyclo-Bu 120 OBt H H H Tet COOCH, OCO-n-Pen 131 OEt H H H Tet COOCHtOCO-l-Pen 122 OEt The H The Tet COOClfa OCO-eek-Pen 123 OBt H H H Tet COOCH, OCO-n-Hex 124 CBT H M N Tet COOCH, OCO-AEK-Hex 126 OBt H H H Tet COOCHiOCO-n-Kept 12 « OBt H H H Tet COOCH, OCOCH, Ph 127 OBt H H N Tet C00CH (No) -0C08t 128 OBt H H H Tet COOCH (No) -OCO-n-Pr 129 «t H H H Tet CQ0CH (Me) -6C0-l-Pr L3O OBt H H The Tet COOCH (No) -OCO-cycle-Pr 131 OEt H H The Tet COOCH (No) -OCO-n-Bu 133 OEt H H The Tet COOCH (Sun) -OCO-i-Bu 133 OBt H H H Tet COOCH (Sun) -OCO-eek-Bu 134 OBt H H H Tet COOCM (Me) -OCO-tore-Bu L35 OBt N H H T «t COOCH (He) -OCO-cyclo-Bu 13 « OEt H H H Tet COOCH (He) -OCO-n-Pen 137 OBt M H H Tet COOCH (He) -OCO-i-Pen 138 Mt H H H Tet COOCH (Sun) -OCO-eek-Pen 139 OEt W H H Tet COOCH (He) -OCO-cyclo-Pen

101 OBt

102 OBt

103 OBt

104 (Bt

106 OBt

106 SBt

107 NHMe

108 ONe

109 OPr

110 SNa

111 OMe

HH

HH

ClH

HCl

HCL

NEH

HHV

HH

HW

NEH

HH

no

H H

H

H

H

H

ha

H

H

H

COOH COOH COOH COOH COOH Tet Tet Tet Tet

Tet

Tet

COOH COOH COOH COOH COOH COOH

TabuZka 1 (continued) Zioeenlna tí. D »· B · ® P ' 140 OEt H H H Tet COOCH (He) -OCO-n-Bex 141 CBT H H H Tet COOCH (He) --C-l-Hex 142 CBT H N H Tet COOCH (Ne) -OCO-aek-Hex 143 CBT H The H Tet COOCH (He) -OCO-evk1-Hex 144 OEt H H H Tet COOCH (Ho) -OCO-n-Hep 14 « OBt H H H Tet COOCH (Et) -OCO-n-pr 144 OBt H H H Tet COOCH (Pr) -OCO-n »in 147 Mt H H H Tet COOCH (Pr) -OCO-n-Pr 148 CBT H H H Tet COOCH (Me) -OCO-O-Sun 149 OBt H H H Tet COOCH (No) -OCO-0-n-Pr 15C OEt H H H Tet COOCH (No} -OCO-O-i-Bu 191 OBt H H H Tet COOCH (Sun) -OCO-O-eek-Bu 153 <Bt H H H Tet COOCHc} -OCO-O-n-Pen LB3 CBT H H H Tet COOCH (He) -OCO-0-i-Pen 164 CBT H H H Tet COOCH (Sun) -OCO-O-cyclo-Per 155 OEt H H H Tet COOCH (He) -OCO-0-n-Hex 15 « CBT H M H Tet COOCH (He) -OCO-O-cyclohex 167 OBt H H H Tet COOCH (He) -OCO-O-MOP-cycle 198 fire H H N Tet COOCH, OCO-tert-Bu 159 OPr H H N Tet COOCH OCO-t-Bu 160 OMe H H H Tet COOCH (Ne) -OCO - <> - Cycl- Hex 161 OPr H H H Tet C00CH (Sun) -0C0-0-cymene-Hex 142 NHeT H H H Tet COOCH, OCQ-tert-Bu 163 NHBt H H The Tet COOCH, OCO-O-cyclic-Kex

The following compounds (Working Examples 164-169) were prepared according to the procedure of Working Example 44.

Working Example 164

Cyclohexyloxycarbonyloxymethyl-2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methylbenzimidazole-7-carboxylate

Yield: 64%, mp 176-177 ° C (dec.). Analysis for C ₃₂ H ₃₂ N ₆ · ₆ of the calculated 64.42% C, 5.41% H, 14.09% N Found 64.16% C, 5.42% H, 13.95% N H -NMR (200 MHz, CDCl ₃ ) δ: 1.14-1.86 (13H, m), 4.48-4.58 (3H, m), 5.63 (2H, s), 5.78 ( 2H, s), 6.88 (2H, d), 7.01 (2H, d), 7.12 (1H, t), 7.37-7.44 (2H, m), 7.52-7 64 (3H, m), 8.05-8.09 (1H, m)

IR (KBr) cm ⁴ : 1750, 1730, 1550, 1480, 1430, 1280, 1235, 1210, 1030, 1000, 995, 960,750

Working Example 165 Cyclopentyloxycarbonyloxymethyl-2-ethoxy-1- [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate

Yield: 63%, mp 142-144 ° C. Elemental analysis for C ₃₁ H ₃₀ N ₆ O ₆ .

calculated 63.91% C, 5.19% H, 14.42% N found 63.63% C, 5.13% H, 14.41% N 1 H-NMR (200 MHz, CDCl ₃ ) δ 1, 43-1.80 (1H, m), 4.52 (2H, q), 4.94-5.00 (1H, m), 5.62 (2H, s), 6.87 (2H, d) ), 7.00 (2H, d),

7.12 (1H, t), 7.37-7.46 (2H, m), 7.55-7.62 (3H, m), 8.05-8.09 (1H, m)

IR (KBr) cm ⁴ : 1750, 1730, 1550, 1480, 1430, 1280, 1240, 1210, 1035, 1011, 1000, 960, 750

Working Example 166 Cyclopropylmethyloxycarbonyloxymethyl-2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methylbenzimidazole-7-carboxylate

Yield: 69%, mp 147-148 ° C (dec.). Elemental Analysis for C ₃₀ H ₂₈ N ₆ O ₆ .0.1 H ₂ O.

calculated: 63.17% C, 4.98% H, 14.73% N 1 H-NMR (200 MHz, CDCl 3) δ 0.17-0.24 (2H, m), 0.47-0.56 ( 2H, m), 0.93-1.09 (1H, m), 1.46 (3H, t), 3.86 (2H, d),

4.46 (2H, q), 5.62 (2H, s), 5.77 (2H, s), 6.84 (2H, d), 6.97 (2H, d), 7.06 (1H) t, 7.31-7.40 (2H, m), 7.55-7.60 (3H, m), 8.03-8.08 (1H, m)

Ic (KBr) cm ⁴ : 1760, 1730, 1550, 1475, 1430, 1280, 1260,

1240.1230.1200.1030.1020.950.750

Working Example 167 Isopropyloxycarbonyloxymethyl-2-ethoxy-1 - [[2 '(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate

Yield: 68%, mp 142-144 ° C (dec.). Elemental analysis for C ₂₉ H ₂₈ N ₆ O ₆ :

calculated: C, 61.59; H, 5.17; N, 14.86. Found: C, 61.82; H, 5.17; N, 14.69. @ 1 H-NMR (200 MHz, CDCl3) .delta .: 1, 19 (6H, d), 1.46 (3H, t), 4.49 (2H, q), 4.73-4.86 (1H, m), 5.62 (2H, s), 5.76 (2H, s),

6.86 (2H, d), 6.99 (2H, d), 7.09 (1H, t), 7.35-7.41 (2H, m), 7.55-7.61 (3H, m), 8.04-8.09 (1H, m)

IR (KBr) cm -1: 1760, 1745, 1550, 1480, 1460, 1430, 1280,

1240.1210.1090.1035.1010.750

Working Example 168 1- (Cyclobutyloxycarbonyloxy) ethyl 2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate

Yield: 37%, mp 95-97 ° C (dec.).

Elemental analysis for C ₃₁ H _F N ₆ O ₆ .0 5 _H2O: Calcd 62.94% C, 5.28% H, 14.21% N Found 63.18% C 9, 5.29% H 13.89% N 1 H-NMR (200 MHz, CDCl ₃ ) δ: 1.42-1.49 (12H, m), 4.31-4.54 (2H, m), 4.71-4 86 (1H, m), 5.55-5.75 (2H, m), 6.71 (1H, q), 6.80 (2H, d), 6.93 (2H, d), 7 03 (1H, t), 7.20-7.24 (1H, m), 7.32-7.39 (1H, m), 7.52-7.63 (3H, m), 8, 01 to 8.08 (lH, m)

IR (KBr) cm -1: 1760, 1730, 1550, 1470, 1430, 1280, 1240, 1070, 1035,990,750

Working Example 169 1- (3-pentyloxycarbonyloxy) ethyl-2-ethoxy-1- [2 '- (1H-tetrazol-5-yl) biphenyl-4-yl / methyl] benzimidazole-7-carboxylate

Yield: 45%, mp 86-88 ° C (dec.). Elemental Analysis for C ₃₂ H ₃₄ N _{E S} 0 3 H ₂ O: Calculated 63.63% C, 5.77% H, 13.91% N Found 63.56% C, 5.73% H, 14.01% N H-NMR (200 MHz CDCl ₃ ) δ: 0.75-0.87 (6H, m), 1.39-1.61 (10H, m), 4.27-4.57 (3H, m), 5.65 (2H s), 6.73 (1H, q), 6.81 (2H, d), 6.93 (2H, d), 7.01 (1H, t), 7.17-7.21 (1H, m), 7.31-7.37 (1H, m) 7.51-7.62 (3H, m), 8.03-8.08 (1H, m)

IR (KBr) cm ⁴ : 1760, 1730, 1550, 1480, 1460, 1430, 1390, 1350, 1280, 1240, 1070, 1035, 990,900, 750

Experimental Example 1

Stable crystalline 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1- [2 '- (1H-tetrazol-5-yl) biphenyl-4-yl / methyl] benzimidazole-7-carboxylate type C and process for its preparation

- (Cyclohexyloxycarbonyloxy) ethyl 1-2-ethoxy-1- [[2- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate was purified by silica gel column chromatography and eluted the fraction was concentrated to dryness to give an amorphous powder. The powder is thermally unstable and not suitable for manufacture. To solve this problem, therefore, extensive attempts have been made to crystallize this compound, and a type C crystal form has been found. The type C crystal is unexpectedly stable to temperature and usable for production. The type C crystal of the title compound has approximately

following grid distances 3,5.10.10 'm middle 3,7.10.10 Å weak 3.8.10.10 ⁴ ° m middle 4.0.10.10 ⁴⁰ m middle 4,1.10.10 Å weak 4.3.10.10 ⁴⁰ m weak 4.4.10.10 ¹⁰ m middle 4,6.10.10 Å middle 4.8.10.10 ⁴⁰ m middle 5.1.10.10 ⁴ ° m middle 5.2.10.10 ⁴ ° m weak 6.9.10.10 ⁴ ° m weak 7.6.10.10 ⁴ ° m weak 8.8.10.10 ⁴⁰ m middle 9.0.10.10 ⁴⁰ m thick 15.9.10.10 ⁴ ° m - weak

The IR spectrum (KBr technique) of the type C crystal is shown in Figure 2 and contains significant absorption maxima at 294, 1754, 1717, 1615, 1549, 1476, and 750 cm ^-1 and melts at 158-166 ° C. (decomposition). Representative X-ray, IR spectra (KBr technique) and differential calorimetry curves are shown in Figures 1 to 3.

The 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1- [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methylbenzimidazole-7-carboxylate crystal of type C has advantages such as e.g.

1. Improves thermal stability and practical use.

2. It is possible to minimize the content of solvent residue in the crystals.

3. It can achieve industrial and clinical development and favorable economic benefits

Concentrated residues, amorphous powders and / or crystals, with the exception of the type C crystal, to obtain the subject compound are stirred in a suitable solvent to form the desired type C crystal. seed crystal to initiate crystallization. Examples of such solvents are not limited to these solvents, but include lower alcohols (e.g. methanol, ethanol isopropyl alcohol, etc.), a mixture of a lower alcohol and water, and a mixture of a lower alkyl ketone (e.g. acetone) and water. The amount of solvents is also not limited, but in practice 2-30 times the weight of the crystal is used. The ratio of lower alcohols to water and lower ketones to water is not limited, but preferably 4: 1 to 1: 1 is used. The mixing temperatures are also not limited, but preferably temperatures from -5 ° C to 40 ° C, preferably from 0 ° C to 25 ° C are used.

Experimental Example 2 Inhibition of Angiotensin II Binding to Angiotensin Receptor (Methodology)

The angiotensin II (A II) binding inhibition assay for the A II receptor is performed by a modified method of Douglas et al. (Endocrinology, 102, 685-696 (1978). Membrane receptor A II fraction is prepared from the adrenal cortex.

The compound of the invention (10 ' ⁶ or 10' ⁷ M) and ¹²⁵ I-angiotensin II ( ¹²⁵ IA II) (1.85 kBq / 50 μ 1,8) were added to the membrane receptor fraction and incubated for one hour at room temperature. Using a filter (Whatman GF / B filter), the receptor bound and free ¹²⁵ IA II are separated and the radioactivity of ¹²⁵ IA II bound to the receptor is measured.

The results of this test for the individual compounds of the invention are shown in Table 2.

Experimental Example 3

Inhibitory effect of compounds of the invention on regulatory activity A II (Methodology)

Male Jcl: SD rats at 9 weeks of age were used for the test. The day before the start of the test, the test animals are anesthetized with sodium pentobarbital in the femoral artery and cannula force. Animals are not fed until the start of the test, but water intake is unlimited. On the day of the start of the test, the arterial cannulae are connected and the average blood pressure is recorded using a pressure gauge using polygraphy. Before administration of the test substance, the controlled effect of intravenous administration of A II (100 ng / kg) is measured as a control value. Test substances are administered orally, A II is always intravenously administered prior to each measurement and the regulatory effect is measured analogously. By comparing the regulatory effects before and after administration of the test substance, the percentage of inhibitory activity of the test substance on the regulatory effect of AII is evaluated.

(The results)

The results of this test for the individual compounds of the invention are shown in Table 2 below.

Signal shapes in NMR spectra are indicated by the following common abbreviations: s = singlet d = doublet t = triplet q = quartet m = multiplet br = broad signal dt = doublet triplet

Table 2

Compounds * In work, prlkl.

Inhibition of Rajrula Saj activity AII at an oral pedant dose of 3 W / M

28 It 0 tat ooon 46 82 +++ 1) 29 It 0 flight óoor 61 H • M4 · 30 FTI 0 tat OOOI 16 48 +++ 3X n 0 tat OOOE- 40 79 +++ 33 m 8 tat OOOI 2 86 ♦ 3 * I * 8 tat COOL 17 54 ♦♦♦ 35 8 flight COOL 7 32 n 3 ' la 8 tat COOEt 51 82 +++ 37 It WITH tat COOEt «1 ep 38 ?> B tat OOOl 6 50 ♦♦♦ 39 It 0 tat 0001a 58 89 ++ ♦ 40 It n tat Odoi 54 8J +++ 41 IS A tat COOL 45 57 IT (b) 43 n ABOUT tat OOOCHgOCtBa 74 »4 ++ ♦ 44 It 0 Tat. Oooch -OCO - ^^ 32 77 ++ ♦ 45 no 0 tat 0001a 17 67 +++ 46 Ka 0 tat COOB ó 66 W +++ 47 It H tat oooa í 84 96 48 go IH tat 67 92 ++ 49 It 0 tat = 00008 (01 ^ 66 91 5 ' It ABOUT tat OOOa ^ OOQOB. ' 63 92 n 0 tat OTOC ^ OCOIt 44 BA + ♦ + 52 It 0 tat oooágow ». 48 84 +++ 53 It 0 tat oooäuocoita 0. 55 85 ++ ♦ 54 It about:; tat OBoarófart 42 81 +++

Table ä (continued)

21 «· nin * in work, ex. a. R * Y r> Inhibition of anaR Bondho R II per roeoptor 1x10- »H lxiO-» M Inhibition of both fasting and AII activity by oral administration —dose 3 55 It 0 Set ooogroSatj OOOCĽOÓOlPí 63 91 +4+ 56 It 0 Set 31 76 +++ 57 Xa n Set oooa 41 79 The 5 ' It 0 Set 55 B4 '444 $ 9 II about Set 000 (8, 000 - ^ - ^ 3T 69 4 ++ 60 » 0 tot < »-« SOCOCSM3i-Q at 81 44f 61 II 0 Set OOO OOOC ^ - ^ - j 54 69 ♦ 44 62 It n Set OOOOHjOOOtSa 48 87 ♦ 4 + It ra Set "b 19 61 ♦ ++

a) '70'> i M 'j +> SOK> -

b) NT «nvoMMand

It is to be understood that the foregoing examples may be varied within the scope of the claims.

In a number of other different embodiments of the invention, changes may be made without departing from the scope of the invention, as the invention is not limited to the specific embodiments disclosed and the only limitation is the claims.

Claims (76)

PATENT CLAIMS A benzimidazole compound of general formula (I) wherein R ¹ represents an alkyl, alkenyl, alkynyl or cycloalkyl group, each of which may be substituted with a hydroxyl group, an optionally substituted amino group, a halogen or a lower alkoxy group, an aryl group which may be substituted with a halogen, nitro group. , lower C _1-4 alkoxy or lower C _1-4 alkyl, and aralkyl which means phenyl-lower C 1-4 alkyl, which may be substituted by halogen, nitro, lower C _1-4 alkoxy or lower C _1-4 alkyl, R ² represents carboxyl a tetrazolyl group, a trifluoromethanesulfonic acid amide group, a phosphoric acid group, a sulfonic acid group, a cyano group or a lower C 1-4 alkoxycarbonyl group, each of which may be protected by an optionally substituted lower alkyl or acyl group, X is a chemical bond, a lower C _1-4 alkylene group or 2 or fewer groups between a phenylene group and a phenyl group selected from the group H H -j-, -o-, -s-. -n-, -fi-iy-. -o-TJ-. -s-ι · -jj - (j-c 0 H 0 H H H H H R is a group of the formula -CO-D 'wherein D' is hydroxyl group, a lower C m alkoxy, optionally substituted by hydroxy, amino, N-lower alkylamino, C _M, N, _{N-di-lower-C] i (alkylamino} group, a lower C _{second three} substitutable alkenyloxy group or an optionally substituted aryl group of the alkenylcarbonyl, optionally substituted amino, halogen, lower alkoxy, C _w, C _d6 lower alkylthio group, a lower C _{2nd 6} alkanoyloxy, lower alkoxycarbonyloxy or C _w optionally substituted dioxolenyl on the alkyl moiety or -OCH (R ⁷ ) OCOR ⁸ wherein R ⁷ is hydrogen, straight or branched (C 1 -C 6) alkyl, (C 5 -C 7) cycloalkyl and R ⁸ is straight or branched lower alkyl containing C 1 -C 6, straight or branched lower alkenyl having 2 to 8 carbon atoms, cy (C 5 -C 7) C 1 -C 5 alkyl, lower C _1-3 alkyl substituted with optionally substituted C 5 -C 7 aryl or cycloalkyl, lower C ₂ . _An alkenyl group which is substituted with an optionally substituted aryl or cycloalkyl of 5 to 7 carbon atoms, an optionally substituted aryl, a straight or branched lower alkoxy group of 1 to 6 carbon atoms, a straight or branched lower alkenyloxy group of 2 to 8 carbon atoms, a cycloalkoxy group C ₁ -C ₇ alkoxy substituted with optionally substituted C 5 -C 7 aryl or cycloalkyl, C ₂ -C 7 lower alkoxy; _An alkenyloxy group which is substituted with an optionally substituted C 5 -C 7 aryl or cycloalkyl, or an optionally substituted aryloxy, tetrazolyl group, optionally protected with an optionally substituted lower alkyl or acyl group, a trifluoromethanesulfonic acid amide group, a phosphoric acid group or a sulfonic acid group, R is halogen, nitro, cyano, optionally substituted amino, -WR ¹³ wherein W is a chemical bond, -O-, -S- or -what and R ¹³ is hydrogen, or an optionally substituted lower alkyl group, - (CH ₂ ) _p -CO-D, wherein D is hydrogen, hydroxy, optionally substituted amino, or optionally substituted alkoxy, and p is 0 or 1, tetrazolyl optionally protected with optionally substituted lower alkyl or acyl, trifluoromethanesulfonic amide, phosphoric or sulfonic acid, Y is -O-, -S (O) _m - or -N (R ⁴ ) -, wherein m is an integer of 0, 1 or 2 and R ⁴ is hydrogen or optionally substituted alkyl, or YR ¹ is -N (R ⁴ ) -R ', wherein R ¹ and R ⁴ together with the nitrogen atom form to them a heterocyclic ring and n is an integer of 1 or 2, or a pharmaceutically acceptable salt thereof. A compound according to claim 1, wherein R ¹ is lower C 1. _{A 5} -alkyl or lower C 2-5 alkenyl group which may be substituted by a hydroxyl group, an amino group, a halogen or a lower C 1-4 alkoxy group. 3.8.10.10 ^{- 1} ° m; middle 3.7.10.10 · '° m; weak 3.5.10.10- 'm; middle A compound according to claim 1, wherein R ¹ represents a lower alkyl group having 1 to 8 carbon atoms, which may be straight or branched chain and which is unsubstituted or substituted by a hydroxyl group, an optionally substituted amino group, a halogen or a lower C 1-4 alkoxy group . 4.8.10.10 ^{- 1} ° m; middle 4.6.10.10 ^{- 1} ° m; middle 4.4.10.10 ^{- 1} ° m; middle 4.3.10.10 ^{- 1} ° m; weak 4.1.10.10 ^{- 1} ° m; weak 4.0.10.10 ^-1 ° m; middle A compound according to claim 1, wherein R ¹ represents a lower alkyl group having 1 to 8 carbon atoms. 5.2.10.10 ^{- 1} ° m; weak 1/1/10 ^{- 1} ° m; middle -5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate or a pharmaceutically acceptable salt thereof. 5. The compound according to claim 1, wherein R ¹ is a phenyl group which may be substituted with halogen, nitro, lower C _M alkoxy or lower alkyl group, C _M. 6.9.10.10 ^{- 1} 'm; weak A compound according to claim 1, wherein R ¹ represents a phenyl-lower C _1-4 alkyl group which may be substituted by halogen, nitro, lower C _1-4 alkoxy or lower C _1-4 alkyl. 7.6.10.10 ^{- 1} ° m; weak The compound of claim 1, wherein R ² is a tetrazolyl group protected with an optionally substituted lower alkyl or acyl group, a carboxyl group, an optionally substituted lower alkyl group, or a trifluoromethanesulfonic acid amide group. 8.8.10.10 ^{- 1} ° m; middle The compound of claim 1, wherein R ² is a tetrazolyl group. 9.0.10.10 ^-1 ° m; thick The compound of claim 1, wherein D 1 is a hydroxyl group, lower C 1. _An alkoxy group optionally substituted by a hydroxyl group, a lower C _1-4 alkoxy group or an optionally substituted dioxolenyl group on the alkyl moiety, a lower C ₂ . ₃ alkenyloxy optionally substituted with optionally substituted aryl on the alkenyl moiety or -OCH (R ⁷ ) OCOR ⁸ wherein R ⁷ is hydrogen or straight or branched lower alkyl of 1 to 6 carbon atoms and R ⁸ is straight or branched lower alkyl having 1 to 6 carbon atoms, cycloalkyl having 5 to 7 carbon atoms, a lower C _H, alkyl substituted with optionally substituted aryl or cycloalkyl having 6-7 carbon atoms, optionally substituted aryl, straight or branched lower alkoxy group having 1 to C 5-C cyk-cycloalkoxy, lower Cj-C.; ₃ alkoxy which is substituted with an optionally substituted C 5 -C 7 aryl or cycloalkyl or an optionally substituted aryloxy group. A compound according to claim 1, wherein R represents a carboxyl group or a salt thereof, or an anion thereof. A compound according to claim 1 wherein R is -CO-OCH (R ⁷ ) OCOR ⁸ wherein R ⁷ is hydrogen or straight or branched (C 1 -C 6) alkyl and R ⁸ is straight or branched. C 1 -C 6 -alkyl, C 5 -C 7 -cycloalkyl, optionally substituted phenyl, straight or branched C 1 -C 6 -alkoxy or C 5 -C 7 -cycloalkoxy. The compound of claim 1, wherein R is hydrogen. The compound of claim 1, wherein X is a chemical bond between a phenylene and a phenyl group. A compound according to claim 1, which is a compound of formula (I ') wherein R ^1a is lower C 1-5 alkyl optionally substituted by hydroxy, amino, halogen or lower C 1-4 alkoxy, R ^b is -CO-D ^1a , wherein D ^1a represents hydroxy, amino, N-lower C 1-4 alkylamino, N, N-di-lower C _1-4 alkylamino or lower C _1-4 alkoxy optionally substituted by hydroxy, amino, halogen, lower C 1-4 alkoxy, lower C ₂ . ₆ alkanoyloxy or 1-lower m alkoxycarbonyloxy on the alkyl moiety, or tetrazolyl optionally protected with an optionally substituted lower Cm alkyl or acyl group, R ²⁸ is a tetrazolyl group optionally protected by an optionally substituted lower Cm alkyl or acyl group, or a carboxyl group optionally protected by an optionally substituted lower C 1-4 alkyl, R represents hydrogen, halogen, lower C 1-4 alkyl or alkoxy, nitro or -CO-D ^a , wherein D ^a represents hydroxy or lower C 1-2 alkoxy optionally substituted by hydroxy, lower C 1-4 alkoxy, lower C 1-4 alkoxycarbonyloxy optionally substituted with a lower C 1-4 alkyl group, Y "represents -O-, -S- or -N (R ⁴ ") -, wherein R ^4a represents hydrogen or a lower C 1-4 alkyl group, or a pharmaceutically acceptable salt thereof. 15/09/10 ^{- 1} ° m; weak. The compound of claim 14, wherein R ^1a is lower C 1. ₅ alkyl. 16. The compound of claim 14, wherein R ^b is -CO-D ^{a, I a} wherein D is a hydroxy group or a lower alkoxy group Cm optionally substituted by hydroxy, lower C _M alkoxy, lower C ₂ .6 alkanoyloxy or 1-lower alkoxycarbonyloxy the C _M alkyl or tetrazolyl group optionally protected substituted lower alkyl C _M C or less _{second 5} alkanoyl. A compound according to claim 14, wherein R ^2a is a tetrazolyl group optionally protected by a lower C 1-4 alkyl group, a lower C 1-4 alkoxy lower C _1-4 alkyl, triphenylmethyl, p-methoxybenzyl, p-nitrobenzyl, lower C 2-5 alkanoyl or benzoyl or carboxyl optionally protected lower m alkyl, lower alkoxy, lower C _M C _S alkyl, triphenylmethyl, p-methoxybenzyl or p-nitrobenzyl. A compound according to claim 14, wherein R is hydrogen, lower C 1-4 alkyl or halogen. SK 282473 Β6 The compound of claim 14, wherein R is hydrogen. The compound of claim 14, wherein Y ^a is -O-. The compound of Claim 1 which is ethyl 2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate or a pharmaceutically acceptable salt thereof . The compound of claim 1 which is 2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is 2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is ethyl 2-propoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is 2-propoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is ethyl 2-methylthio-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is ethyl 2-ethylthio-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate or a pharmaceutically acceptable salt thereof. A compound according to claim 1 which is ethyl 2-propylthio-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate or a pharmaceutically acceptable salt thereof . The compound of claim 1 which is 2-methylthio-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is 2-ethylthio-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is 2-propylthio-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is methyl 2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is ethyl 2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate or a pharmaceutically acceptable salt thereof, The compound of claim 1 which is ethyl 2-propylamino-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate or a pharmaceutically acceptable salt thereof. A compound according to claim 1 which is pivaloyloxymethyl-2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate or a pharmaceutically acceptable salt thereof . The compound of claim 1 which is methyl 2-methoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is 2-methoxy-1 - [[2 '(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is 2-ethylamino-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is 2-propylamino-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl-2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl)] biphenyl-4-yl] methyl] benzimidazole-7-carboxylate or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is acetoxymethyl 2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate or a pharmaceutically acceptable salt thereof . A compound according to claim 1 which is propionyloxymethyl-2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate or a pharmaceutically acceptable compound thereof salt. The compound of claim 1 which is butyryloxymethyl 2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is isobutyryloxymethyl-2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate or a pharmaceutically acceptable salt thereof . The compound of claim 1 which is 1- (ethoxycarbonyloxy) ethyl 2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate or a pharmaceutically acceptable salt thereof. A compound according to claim 1 which is 1-acetoxyethyl 2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate or a pharmaceutically acceptable compound thereof salt. The compound of claim 1 which is 1- (isopropyloxycarbonyloxy) ethyl 2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate or a pharmaceutically acceptable salt thereof. A compound according to claim 1 which is cyclohexylcarbonyloxymethyl-2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate or a pharmaceutically acceptable salt thereof . The compound of claim 1 which is benzoyloxymethyl-2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is (E) -cinnamoyloxymethyl-2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate or a pharmaceutically acceptable salt thereof. A compound according to claim 1 which is cyclopentylcarbonyloxymethyl-2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate or a pharmaceutically acceptable salt thereof . A compound according to claim 1 which is pivaloyloxymethyl-2-ethyl-amino-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate or a pharmaceutically acceptable compound thereof salt. 53. A compound according to claim 1 which is 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethylamino-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate. or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is 1- (cyclohexyloxycarbonyloxy) ethyl-2-ethoxy-1 - [[2 '- (1H-tetrazole) 33]. SK 282473 Β6 A stable crystal of the compound of claim 1 which is 1- (cyclohexyloxycarbonyloxy) ethyl-2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazol-7- carboxylate. The stable crystal of claim 55, having the following lattice distances A pharmaceutical composition for antagonizing angiotensin II, comprising a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable carrier, excipient, or diluent. A pharmaceutical composition for antagonizing angiotensin II, comprising a therapeutically effective amount of a compound of claim 14, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable carrier, excipient, or diluent. A pharmaceutical composition for antagonizing angiotensin II, characterized in that ¹ 'comprises a therapeutically effective amount of a compound of claim 22, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable carrier, excipient, or diluent. 60. A pharmaceutical composition for antagonizing angiotensin II comprising a therapeutically effective amount of a compound of claim 23 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier, excipient or diluent. 61. A pharmaceutical composition for antagonizing angiotensin II, comprising a therapeutically effective amount of a compound of claim 54, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable carrier, excipient, or diluent. 62. A pharmaceutical composition for antagonizing angiotensin II, comprising a therapeutically effective amount of the crystal of claim 55 in admixture with a pharmaceutically acceptable carrier, excipient, or diluent. 63. A pharmaceutical composition for antagonizing angiotensin II, comprising a therapeutically effective amount of the crystal of claim 56 in admixture with a pharmaceutically acceptable carrier, excipient, or diluent. 64. A process for the preparation of a compound of formula (I) wherein each symbol is as defined in claim 1, or a pharmaceutically acceptable salt thereof, wherein: i) reacting a compound of formula (II) wherein R ¹ , R, R and Y are as defined above with a compound of formula (III) R ¹ Z- (CH, X (ΙΠ) wherein R ^2, X and n are as defined above and Z is halo, ii) a compound of formula (IV) wherein the substituents are as defined above, with alkylortouhličitanom, or thiocarbonylation carbonylating agent, or iii) reacting a compound of formula V wherein the substituents are as defined above with a nucleophilic reagent and, if desired, combining concentrated residues, amorphous powders or crystals with the exception of a stable type C crystal in a suitable solvent to form a stable crystal of type C, optionally converting the product obtained by processes i) to iii) to a compound of formula (I) by azidation, hydrolysis, reduction, halogenation, O-, A- or S-alkylation, nucleophilic reaction, ring closure, acylation, esterification , oxidizing and / or deprotecting and optionally converting the compound of formula (I) to its own a pharmaceutically acceptable salt. A process according to claim 64 for the preparation of a compound of formula (Ik) Wherein R ¹ , R ² , R, X, Y and n are the same as in claim 64, characterized in that the compound of formula (Ij) «· Wherein the general substituents R ¹ , R ² , R, X, Y and n are as defined above and R ⁵ is optionally substituted C 1-6 alkyl, prepared by methods i) to iii), is subjected to alkaline hydrolysis. A process according to claim 64, for the preparation of a compound of formula (Im), characterized in that the compound of formula (In) wherein the general substituents R ¹ , R ¹ , X, Y and n are as defined above, prepared by methods i) to ii) , is reacted with an alkylating agent. A process according to claim 64 for the preparation of a compound of formula (Ib) wherein the general substituents R ¹ , R, X, Y and n are as defined above, and R ^p is as defined above, prepared by methods i) to iii). agent. n \ .NH (Ib) The process of claim 64, for the preparation of a compound of formula (Io) (Io) wherein Q ² is -NO ² or -NH 2 when Q ¹ is hydrogen or Q ² is -NO 2 when Q ¹ is -COOR ³ , R ³ is C _(C4 alkyl, the other symbols are as defined in claim 1 or a salt thereof, as an intermediate for the preparation of a compound of of claim 1. A process according to claim 64, for the preparation of a compound of general formula (Ip) (n ¹ ) wherein R ¹ , R, R, X, Y and n are the same characterized in that of general formula (II) as in claim 64, ii) wherein R ¹ , R, X, Y and n are as defined above and R ^p is methyl, triphenylmethyl, 2-tetrahydropyranyl, tert-butyl, methoxymethyl, ethoxymethyl or optionally substituted benzyl and R ⁶ is alkyl of 1 to 6 carbon atoms optionally substituted with 2-6C alkanoyloxy or 1-6C-1alkoxycarbonyloxy, characterized in that the compound of formula (Io) wherein R ¹ , R, R ", X, Y and n are as defined above and R ^p is methyl, triphenylmethyl, 2-tetrahydropyranyl, tert-butyl, methoxymethyl, ethoxymethyl or optionally substituted benzyl, prepared by methods i) to iii), is deblocked. 70. A compound of formula (1) wherein R & apos ^; , R, R &apos;, X, Y and n having the formula (Ia) are as defined above, CN (Ia) wherein the general substituents R ¹ , R, R, X, Y and n are as defined above, prepared by methods i) to iii), is reacted with various ring-closing azides. A compound of formula (1) according to claim 70, wherein Q ² is -NO ₂ and wherein Q ¹ is -COOR ³ , wherein R ³ is C 1-6 alkyl. A compound of formula (1) according to claim 70, wherein Q ² is -NO ₂ and Q ¹ is hydrogen. A compound of formula (1) according to claim 70, wherein Q ² is -NH ₂ and Q ¹ is hydrogen. A compound of formula (1) according to claim 70 which is methyl 2 - [[N-tert-butoxycarbonyl-N- (2'-cyanobiphenyl-4-yl) methyl] amino] -3-nitrobenzoate. A compound of formula (1) according to claim 70 which is methyl 2 - [[2'-cyanobiphenyl-4-yl) methyl] amino] -3-nitrobenzoate. A compound of formula (1) according to claim 70 which is methyl 3-amino-2 - [[2'-cyanobiphenyl-4-yl) methyl] amino] benzoate.