KR0160771B1 - Benzimidazole derivatives, their production and use - Google Patents

Abstract

Novel amidazole derivatives of the general formula (I) and salts thereof:

(Wherein R ¹ is an optionally substituted alkyl group, R ² and R ³ are independently a group capable of forming an anion or a group which may be changed thereto, and ring A is a substituent other than R ² in some cases, Is a benzene ring, and X represents a direct phenylene group and a phenyl group binding through a spacer having an atomic chain of 2 or less.) The compound exhibits an antagonistic action against angiotensin II, thus treating a cardiovascular disease Useful as

Description

Benzimidazole Derivatives, Preparations and Uses thereof

The present invention relates to novel benzimidazole derivatives having excellent pharmacological activity and intermediates for their synthesis.

More specifically, the present invention relates to compounds of the general formula and salts thereof:

(Wherein R ¹ is an optionally substituted alkyl group, R ² and R ³ are independently a group capable of forming an anion or a group which may be changed thereto, and ring A is a substituent other than R ² in some cases, X is a benzene ring and X has a spacer having an atomic chain of 2 or less, or shows a direct bond of a phenylene group and a phenyl group.The compound exhibits angiotensine II antagonism and hypotensive activity. It is useful as a therapeutic agent for circulatory diseases such as hypertension, heart disease, stroke and the like.

The linin-angiotensin system is involved in homeostasis and, together with the aldosterone system, regulates the balance between body blood pressure, body volume and electrolyte. The relationship between linin-angiotensin-based and hypertension is evident based on the fact that inhibitors (ACE inhibitors) for angiotensin II (AII) converting enzymes that produce angiotensin II with vasoconstrictive action have been identified. Become. Since angiotensin II raises blood pressure through the angiotensin II receptor on the cell membrane, antagonists of angiotensin II, such as ACE inhibitors, can be used for the treatment of hypertension. Many angiotensin II-associated substances such as saralcin and (Sar ¹ , Ala ⁸ ) AII have been reported to have potent angiotensin II antagonists. However, it has been reported that peptide antagonists have a short duration of action after parenteral administration and are ineffective for oral administration (MA Ondetti and DW Cushman, Annual Reports in Medicinal Chemistry, 13, 82--91 (1978)). )

On the other hand, non-peptide angiotensin II antagonists were studied to solve the problems found in peptide antagonists. As one of the earliest studies in this area, imidazole derivatives having angiotensin II antagonists are disclosed in Japanese Patent Laid-Open Nos. 71073/1981, 71074/1981, 92270/1982 and 157768/1983, US Pat. Nos. 4,355,040 and 4,340,598. Later, improved imidazole derivatives have been disclosed in EP-0253310, EP-0291969, EP-0324377, JP 23863/1988 and 117876/1989. And pyrrole, pyrazole and triazole derivatives are disclosed as angiotensin II antagonists in EP-0323841 and Japanese Patent Laid-Open No. 287071/1989.

The inventors have found that a compound useful for the treatment of circulatory diseases such as hypertension, heart disease and stroke should have angiotensin II receptor antagonism and potent angiotensin II antagonism and hypotension by oral administration of the compound. Was considered, and they focused on non-peptidic angiotensin II receptor antagonists based on these considerations.

In addition, US Pat. No. 4,880,804 discloses benzimidazole derivatives, such as hydroxymethyl at the 5-or / and 6-positions, having angiotensin II receptor antagonism and effective against rats suffering from renal hypertension by intravenous administration. A compound (A) having a methoxy, formyl, chloro or carboxyl group (expressed by the general formula (A) below) is disclosed. However, most compounds (A) are described as inert when administered orally whereas only 6-hydroxy methyl compound and 6-chloro compound are described as effective when administered orally (up to 100 mg / kg). . However, compounds that exhibit only this level of potency are not satisfactory for their practical use as pharmaceutical products.

And, in the above-mentioned US patent, the compounds specifically expressed, including the above-mentioned compound (A), are defined as benzimidazoles having substituents at the 5- or / and 6-positions on the benzene ring, and 4- or 7- The publication of benzimidazole derivatives having substituents at positions is not found.

The inventors have found that certain compounds, such as the 7-substituted benzimidazole derivatives (not specifically described in US Pat. No. 4,880,804), have potent angiotensin II receptor antagonism and are unexpectedly 5 when administered orally. It was found that it exhibits potent AII antagonism and antihypertensive activity not found in derivatives substituted at the 6- and / or 6-positions. The present inventors further developed their research to complete the present invention.

More specifically, the present invention relates to compounds of the general formula and salts thereof:

(Wherein R ¹ is an optionally substituted alkyl group, R ² and R ³ are independently a group capable of forming an anion or a group which may be changed therein, and Ring A optionally substitutes for substituents other than R ² groups). Is a benzene ring, and X represents a direct linkage of a phenylene group and a phenyl group through a spacer having an atomic chain of 2 or less.)

With reference to general formula (I) mentioned above, the alkyl group represented by R ¹ is a C ₁ to C ₈ straight or branched lower alkyl group, ie methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- Butyl, t-butyl, pentyl, i-pentyl, hexyl, heptyl, octyl and the like. The alkyl group may doelsudo substituted with a hydroxyl group, an optionally substituted amino group, a halogen, a lower (C _{1 ~ 4)} alkylthio or lower (C _{1 ~ 4)} alkoxy. Preferred groups represented by R ¹ groups are lower (C _2-5 ) alkyl groups optionally substituted with hydroxyl groups, amino groups, halogens or lower (C _1-4 ) alkoxy groups.

An example of a group capable of forming an anion or a group capable of changing into an anion, represented by R ^2, is a general formula

Groups represented by, cyano, optionally protected (eg protected with alkyl or acyl groups) tetrazolyl, phosphoric acid, sulfonic acid, phenolhydroxyl groups, optionally substituted alkoxy groups, trifluoromethanesulfonic acid amides and hydroxyl groups Or lower (C _1-3 ) alkyl groups optionally substituted with optionally substituted amino groups.

(Wherein D is hydrogen, a hydroxyl group, an optionally substituted amino group, a halogen or an optionally substituted alkoxy group, (e.g., its alkyl moiety is a hydroxyl group, an optionally substituted amino group, a halogen, a general formula Wherein R 'is hydrogen, a straight or branched lower (C _1-6 ) alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t- Butyl, n-pentyl, isopentyl, neopentyl, etc.) or a C _5-7 cycloalkyl group (e.g. cyclopentyl, cyclohexyl, cycloheptyl, etc.), R is a straight or branched lower (C _1-6 ) alkyl group ( Eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, etc., C _5-7 cycloalkyl groups (e.g. Cyclopentyl, cyclohexyl, cycloheptyl, etc. C _5-7 cycloalkyl (e.g. cyclopentyl, cyclohexyl, cycloheptyl, etc.) or lower (C _1-3 ) alkyl substituted by phenyl group (e.g. methyl , ethyl, n- propyl, isopropyl, etc.) or a lower (C _{2 ~ 3)} an alkenyl group (eg, vinyl, propenyl, alkyl, isopropenyl, etc.), an optionally substituted phenyl group (such as phenyl, etc.), linear Or a lower chain (C _1-6 ) alkoxy group ( Eg methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, etc.) C _5-7 cycloalkyloxy group (e.g. cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, etc.), C _5-7 cycloalkyl (e.g. cyclopentyl, cyclohexyl, cycloheptyl etc.) or phenyl group A substituted lower (C _1-3 ) alkoxy group (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, etc.), an optionally substituted phenoxy group (e.g., phenoxy, etc.), or an optionally substituted a benzyloxy group (e.g. benzyloxy, etc.) a.) a lower (C _{1 ~ 6)} alkoxy group, a lower (C _{1 ~ 6)} alkylthio or optionally substituted dioxo alkylenyl (eg, 5-methyl-2 Oxo-1,3-dioxolen-4-yl, etc.), preferably its alkyl moiety is a hydroxyl group, an optionally substituted amino group, a halogen, a lower (C _2-6 ) alkanoyloxy, 1-lower ( C _1-6 ) alkoxy group, lower (C _1-6 ) egg A lower (C _1-6 ) alkoxy group which may be substituted with a chelthio or lower (C _1-6 ) alkoxycarbonyloxy group), n is 0 or 1.) A group capable of forming an anion, or biologically (e. g., by performing the physiological metabolism) or chemical group that (e.g., by oxidation, reduction or hydrolysis) vary the anion also that belonging to the meaning of R ^2, R ² may form an anion Compounds (I) which are characterized by representing groups or groups which can be converted into them chemically are useful as intermediates for synthesis.

Preferred R ² groups are those represented by the general formula-(CH ₂ ) _n CO-D, wherein D is hydrogen, a hydroxyl group, amino, N-lower (C _1-4 ) alkylamino, N, N-di-lower (C _1-4 ) alkylamido or lower (C _1-6 ) alkoxy, the alkyl moiety of which is optionally a hydroxyl group, amino, halogen, lower (C _2-6 ) alkanoyloxy, 1-lower (C _1-6 ) alkoxy, lower (C _1-6 ) alkylthio or lower (C _1-6 ) alkoxycarbonyloxy, n is 0 or 1), or optionally alkyl (eg lower (C _{1-6) 4} ) alkylazol) or tetrazolyl protected with acyl (eg lower (C _2-5 ) alkanoyl or benzoyl). Further preferred groups are those represented by the general formula -CO-D '(wherein D' is a hydroxyl group, amino, N-lower (C _1-4 ) alkylamino, N, N-di lower (C _1-4 ) Alkylamino or lower (C _1-6 ) alkoxy and its alkyl moiety is optionally hydroxyl group, amino, halogen, lower (C _2-6 ) alkanoyloxy, 1-lower (C _1-6 ) alkoxy, lower ( C _1-6 ) alkylthio or lower (C _1-6 ) alkoxycarbonyl oxy), or tetrazolyl, optionally protected with alkyl or acyl groups.

Examples of groups capable of forming anions or groups represented by R ³ , which may be represented by R ³ , include carboxyl, tetrazolyl, trifluoromethanesulfonateamide (-NHSO ₂ CF ₃ ), phosphoric acid, sulfonic acid, cyano and lower (C _1-4 ) alkoxycarbonyl is included and as long as these groups can form groups that can form anions or can be converted to anions under biological (eg physiological) conditions or chemically Optionally protected with an optionally substituted lower alkyl or acyl group.

Compounds characterized in that R ³ represents a group capable of forming an anion or a group which can be converted to an anion (eg cyano) by chemical means (eg by oxidation, reduction or hydrolysis) (I ) Is useful as an intermediate for synthesis.

Preferred R ³ groups are carboxyl or tetrazolyl.

Examples of substituents on the benzene ring A in addition to the R ² group include halogen (eg F, Cl, Br, etc.), nitro, cyano, optionally substituted amino groups (eg amino, N-lower (C _1-4 ) alkyl Amino (e.g. methyl amino, etc.), N, N-di-substituted (C _1-4 ) alkyl amino (e.g. methyl amino, etc.), N-arylamino (e.g. phenylamino, etc.), cycloaliphatic amino (e.g., mor Polyno, piperidino, piperazino, N-phenyl piperazino, etc.), a group represented by the general formula -YR (wherein Y is a bond -O-, -S-, or A denotes, R is (alkyl, for example, an optionally hydroxyl group, an optionally substituted amino group, a halogen, a lower (C _{1 ~ 4)} alkoxy group such as substituted lower (C _{1 ~ 4))} hydrogen, optionally substituted lower alkyl group Or a group represented by -CO-D '', wherein D '' is hydrogen, an optionally substituted alkoxy group (e.g., an optionally substituted amino group, a hydroxyl group, hydrogen, a lower (C _1-4 ) alkoxy, etc.) Lower (C _1-4 ) alkoxy optionally substituted with) an optionally substituted amino group (eg, amino, N-lower (C _1-4 ) alkylamino (eg methylamino), N, N-disubstituted ( C _1-4 ) alkylamino (eg dimethylamino), N-arylamino (eg phenylamino), cycloaliphatic amino (eg morpholino, piperidino, piperazino or N-phenylpiperazino) Etc.), such as halogen (e.g., chlorine) or hydroxyl group). Among them, a group represented by hydrogen, lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy, nitro and general formula —CO-D ′: wherein D ′ represents a hydroxyl group or a lower (C _1-2) shows an alkoxy), or amino, and optionally is preferably substituted by lower (C _{1 ~ 4)} alkyl, a halogen and lower (C _{1 ~ 4)} alkyl is more preferred.

X represents a phenylene group bonded to a phenyl group either directly or through a spacer having up to 2 atomic chains. The spacer may be any bivalent chain having one or two atoms constituting a straight chain, and may have a side chain. More specifically, lower (C _1-4 ) alkylene,

Can be exemplified.

Among the compounds of the general formula (I), compounds of the following general formula (I ') are preferred.

Wherein R ¹ represents lower (C _2-5 ) alkyl optionally substituted with a hydroxyl group, an amino group, a halogen or a lower (C _1-4 ) alkoxy group, and R ² is represented by the formula -CO-D ′ Wherein D 'is a hydroxyl group, amino, N-lower (C _1-4 ) alkylamino, N, N-di lower (C _1-4 ) alkylamino or lower (C _1-4 ) alkoxy and Alkyl portion of which is optionally substituted with a hydroxyl group, amino, halogen or lower (C _1-4 ) alkoxy), or a tetrazolyl group optionally protected with an alkyl or acyl group, R ³ is a carr optionally protected with an alkyl or acyl group Group represented by a compound represented by a compound represented by the formula -CO-D ', wherein R ¹ represents hydrogen, halogen, lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy, nitro, Is a hydroxyl group or lower (C _{1 -2} ) alkoxy) or optionally lower (C _1-4 ) alkyl (preferably hydrogen, lower (C _1-4 ) alkyl, halogen, more preferably Substituting amino)

The compounds of the general formula (I) mentioned above may be prepared by the process shown below.

Wherein R ¹ , R ² , R ³ , A and X have the same meanings as defined above, W represents a hydrogen atom, R ⁵ represents an optionally substituted lower (C _1-4 ) alkyl, and R ⁶ represents lower alkoxy, lower alkylthio, optionally substituted amino or cyano group, R ⁷ represents lower alkyl group, Y represents iminoether, iminothioether, carboxyl, amidine, cyano group and the like, n represents 0 or 1.)

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

Using about 1 to about 3 moles of base and about 1 to about 3 moles of alkylating agent (III) per mole of compound (III), dimethylformamide, dimethylacetamide, dimethyl sulfoxide, acetonitrile, The reaction is carried out in a solvent such as acetone or ethyl methyl ketone.

As the base, for example, sodium hydride, t-butoxy potassium, potassium carbonate or sodium carbonate is used.

The alkylating agent (III) is used in the form of substituted halides (e.g. chloride, bromide and iodide), but can also be used in the form of substituted sulfonic acid esters (e.g. methyl p-toluenesulfonate). have.

The reaction conditions may vary depending on the combination of base and alkylating agent (III) used, but are preferably carried out for about 1 to 10 hours at temperatures ranging from ice-cold to room temperature.

Reaction (b) is to react the cyano group substituted in the benzene ring of compound (Ia) with various azide to obtain tetrazole compound (Ib).

The reaction is usually carried out in a solvent such as dimethylformamide, dimethylacetamide, toluene or benzene, using about 1 to about 3 moles of azide compound per mole of compound (la).

Examples of azide are trialkyltin azide, triphenyltin azide or hydroazic acid.

When using organotin azide, the reaction is carried out under reflux in toluene or benzene for 10 to 30 hours. When using azide hydrochloric acid, sodium azide and ammonium chloride are used at about twice the moles relative to compound (la), and the reaction proceeds in dimethylformamide at about 100 to about 130 ° C. for about 1 to 3 days. In order to accelerate the reaction, it is preferred to add appropriate amounts of sodium azide and ammonium chloride to the reaction system.

Reaction (c) is to obtain carboxylic acid (Id) by hydrolysis of ester (Ic) in the presence of an alkali. The reaction proceeds in aqueous alcohol (e.g. methanol, ethanol or methylcellosolve) using about 1 to about 3 moles of alkali per mole of compound (Ic). Preferably, the reaction proceeds for about 1 to about 10 hours at a temperature in the range from room temperature to about 100 ° C.

Reaction (d) is to prepare a benzimidazole derivative (I) by reducing the nitro group followed by intramolecular dehydration cyclization.

The reaction is carried out by using about 2 to about 10 moles of reducing agent per mole of compound (IV). As the reducing agent, mention may be made of metals such as iron, zinc or tin, and the reaction can usually be carried out under acidic or alkaline conditions. As the solvent, alcohols (e.g., methanol and ethanol), ethers (e.g., dioxane and tetrahydrofuran) and acetic acid or hydrochloric acid can be used alone or in a mixed solution.

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

In order to complete the dehydration cyclization reaction after the reduction reaction, it is preferable to heat at about 50 ° C to about 100 ° C for about 2 to 3 hours under acidic conditions.

Reaction (e) is a cyclization reaction of diamino compound (V) to benzimidazole compound (I) using various compounds in an organic solvent.

Examples of the various compounds mentioned above are carboxylic acids, aldehydes, ortho esters, iminoethers and iminorioethers.

These reagents typically use from about 1 to about 10 moles per mole of compound (V), and the reaction proceeds in an organic solvent, but the reagent can be used as a solvent in duplicate.

The organic solvents vary depending on the reagents used, for example alcohols (methanol, ethanol, etc.), cellosolves (methyl cellosolve, ethyl cellosolves, etc.), halogenated hydrocarbons (chloroform, methylene chloride, etc.), ethers (dioxane, tetrahydro). Furan, etc.), aromatic hydrocarbons (benzene, toluene), acetonitrile and dimethylformamide.

To accelerate the reaction, acid (hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, etc.) or base (triethylamine, pyridine, sodium methoxide, sodium ethoxide, potassium carbonate, etc.) may be added to the reactor.

The reaction conditions vary depending on the reagent used, but are preferably carried out for from about 1 hour to about 10 hours in the temperature range typically between room temperature and the boiling point of the solvent used.

Reaction (f) is to prepare carboxylic acid (If) by hydrolysis of ester (Ie) in the presence of alkali.

About 1 to 3 moles of alkali are used per mole of compound (Ie), and the reaction is usually carried out in an aqueous alcohol (e.g., methanol, ethanol, methylcellosolve, etc.). As the alkali, sodium hydroxide and potassium hydroxide are used.

Preferably, the reaction is carried out at a temperature from room temperature to about 100 ° C. for about 1 to about 10 hours.

Reaction (g) manufactures a hydroxymethyl compound (Ig) by reduction of carboxylic acid ester (Ie).

The reaction is carried out by using about 1 to about 5 moles of reducing agent per mole of compound (Ie). As the reducing agent, for example, lithium aluminum hydride or sodium borohydride can be mentioned. When using lithium aluminum hydride, ether (tetrahydrofuran, dioxane, ethyl ether, etc.) is usually used as a solvent, and the reaction proceeds for about 1 to about 20 hours at room temperature to the boiling point of the solvent used. Let's do it. When using sodium borohydride, it is common to use ether (tetrahydrofuran and dioxane) or alcohol (ethanol, propanol, butanol, etc.) as a solvent, and to add the appropriate amount of methanol to the reactor to speed up the reaction. desirable. The reaction proceeds for about 1 to about 20 hours at room temperature to the boiling point of the solvent used, preferably from about 50 ° C. to the boiling point of the solvent.

Reaction (h) produces compound (Ih) by halogenating compound (Ig) with a halogenating agent in an organic solvent.

Examples of organic solvents are halogenated hydrocarbons such as dichloromethane, chloroform or dichloroethane and ethers such as ethylether tetrahydrofuran or dioxane. As the halogenating agent, thionyl chloride and phosphorus oxychloride are used. Among them, thionyl chloride is preferred in that the post-treatment of the reaction is easy. Preferably, the reaction is carried out for from about 1 hour to about 10 hours, typically at room temperature to the boiling point of the solvent used.

Reaction (i) produces methyl compound (Ii) by reducing halogen compound (Ih).

As the reducing agent, metal hydrides (e.g. organotin hydrides), metal hydride complex compounds (e.g. sodium hydride or sodium borohydride), metals and salts thereof (e.g. zinc, copper, sodium or lithium) are carried out. . Among them, when using a metal hydride (e.g. Ph ₃ SnH or Bu ₃ SnH), about 1 to about 3 times mole of the tin hydride compound is used to determine the solvent used in an aromatic hydrocarbon solvent (e.g. benzene or toluene). It is preferable to carry out the reaction for about 3 to about 10 hours at the boiling point. While the reaction proceeds rapidly when using iodide or bromide, it is desirable to add peroxides (eg perbenzoic acid) or azobisisobutyronitrile (AIBN) to the reaction system to accelerate the reaction when using chlorine compounds. Do.

Reaction (j) is to prepare a substituted compound (Ik) by substitution reaction of a halogen compound (Ih) using a nucleophilic reagent in an organic solvent. Examples of organic solvents include alcohols (e.g. methanol, ethanol, propanol and butanol), ethers (e.g. tetrahydrofuran and dioxane), halogenated hydrocarbons (e.g. dichloromethane, chloroform and dichloromethane), acetonitrile and dimethylformamide. have. The solvent used is preferably appropriately selected depending on the nucleophilic reagent used. Examples of nucleophilic reagents include alcohols (e.g. methanol, ethanol, etc.), thiols (e.g. methyl mercaptan, etc.), amines (e.g. alkylamines, aralkylamines, etc.) and cyanides (e.g. potassium cyanide, etc.) .

Preferably the reaction is carried out in the presence of a suitable base (eg potassium carbonate, sodium carbonate, sodium hydride, sodium alkoxide, etc.).

Preferred reaction times typically range from about 1 hour to about 10 hours at a temperature ranging from ice-cold to about 50 ° C., but vary depending on the combination of reagent and solvent.

Reaction (k) is to convert nitrile (Ik) to ester (Il).

In alcohols containing about 3 to 10 times the molar excess of hydrogen chloride gas (e.g. methanol, ethanol, propanol, butanol, etc.), the nitrile (for about 3 to about 20 hours in the temperature range of the boiling point of the solvent used It is preferable and convenient to heat Ik). The alcohol used at this time acts as a solvent and as a reaction reagent. Although iminoether is prepared as an intermediate during the reaction, it is preferred to obtain an ester compound without separating the intermediate.

Reaction (l) is to prepare ester (Im) by esterifying carboxylic acid (If) with alcohol.

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

Preferably, the reaction is carried out for about 5 to about 20 hours at approximately the boiling point of the solvent.

The reaction product obtained in reactions (a) to (l) can be easily separated by conventional separation and purification methods, such as column chromatography and recrystallization.

Compounds (I) are salts of physiologically acceptable acids or bases by conventional methods, for example salts of inorganic acids such as hydrochlorides, sulfates and nitrates, such as acetates, oxalates, citrates and maleates. Salts of organic acids, salts of alkali metals such as sodium and potassium salts, and salts of alkaline earth metals such as calcium salts.

Among the above compounds and the like, the starting compounds (II), (III), (IV) and (V) can be synthesized by, for example, the methods described in the following references or similar methods.

Starting compounds (IV) are also described, for example, in K. Seno, S. Hagishita, T. Sato and K. Kuriyama, J. Chem. Soc., Perkin Trans. 1. By alkylating compound (VI) synthesized by the method described in 1984, 2013 or a similar method, or by reacting compound (VI) with reaction (a) or with similar reactions (e.g., reactions shown in m)).

Starting compounds (V) can be prepared by the reactions indicated by the scheme (n) below or similar reactions.

Starting compounds (XIV) and (XV) can be prepared by the reactions indicated by the scheme (o) below or similar reactions.

Wherein A, R ¹ , R ² , R ³ , X and n have the same meanings as defined above, W represents a halogen atom and R ⁸ represents a carboxylic acid ester, cyano or optionally protected tetrazolyl Z is optionally -O-, -NH- or -S-.)

Reaction (m) is to prepare N-alkyl compound (IV) by alkylating compound (VI) by a method similar to reaction (a).

In reaction (n), o-nitrobenzoate derivative (VII) is reacted with a halogenating agent (e.g., thionyl chloride, phosphorus oxychloride, etc.) to obtain an acid chloride (VIII) which is then azide compound ( For example, the acid azide (IX) produced by reacting with sodium azide, etc.) can be easily converted to isocyanate (X), and the carbamic acid ester (XI) is heated by heating the isocyanate (X) and t-butanol It is produced in high yield. On the other hand, carbamic acid ester (XI) is prepared by heating a mixture of benzoate derivative (VII) and diphenylphosphoryl azide (DPPA) in t-butanol. The diamino compound (V) alkylates the carbamic acid ester (XI) obtained in a similar manner to reaction (m) to afford compound (XII), which is then deprotected and reduced to a reducing agent (e.g. Raney nickel, stannic chloride, Iron-hydrochloric acid, hydrazine-ferric chloride, etc.) to produce a high yield.

In reaction (o), benzimidazole derivatives (XIV) are diamino compounds (V) and acid chlorides (eg chloroacetate chloride, 2-chloropropionate) in the presence of a base (eg triethylamine, pyridine, etc.). Chloride, etc.) to obtain a diacylamino compound, which is then produced in high yield by heating the diacylamino compound and acid (e.g. hydrochloric acid-ethanol, etc.). It is prepared in high yield by reacting with a nucleophilic reagent (eg sodium methoxide, sodium ethoxide, methylamine, ethylamine, sodium thiomethoxide, sodium thioethoxide, etc.). Desired compound (I) can be prepared by subjecting the obtained compound (XV) to reactions (b), (c) and the like.

Compound (I) and the salts thereof prepared are less toxic and strongly inhibit the vasoconstriction and blood pressure-boosting action of angiotensin II, and blood pressure in animals, particularly mammals (eg, humans, dogs, rabbits, mice, etc.) It exhibits a lowering effect, and therefore compound (I) and salts thereof are useful as therapeutic agents for hypertension as well as circulatory diseases such as heart disease and stroke. When used as a medicament as mentioned above, Compound (I) and its salts are in dosage form, such as powders, granules, tablets, capsules, injections, etc., which are prepared by themselves or by mixing with pharmaceutically acceptable carriers, excipients or diluents. It can be administered orally or parenterally.

Dosages vary depending on the disease, condition, patient and route of administration, and when used as a treatment for essential hypertension in adults, a daily dose of 1-50 mg for oral administration or 1-30 mg for intravenous injection. It is preferable to divide the daily dose of 2 to 3 times.

EXAMPLE

Although the present invention is described in more detail by the following Preparation Examples, Examples, Experimental Examples and Reference Examples, this is not to be construed as limiting the present invention.

Examples of abbreviations in the present specification are as follows.

Me: methyl, Et: ethyl, Pr: propyl, Bu: butyl, Pen: pentyl, Tet: tetrazolyl, THF: tetrahydrofuran, DMF: dimethylformamide, Ph: phenyl, Ac: acetyl

[Production example]

When the compound (I) of the present invention is used as a therapeutic agent for circulatory diseases such as hypertension, heart disease, stroke, and the like, it can be used, for example, according to the following prescription.

1. Capsule

(1), (2), (3) and 1/2 (4) are mixed and granulated. The remainder of (4) is added to the granules and the whole is filled into gelatin capsules.

2. Tablet

(1), (2), (3), 2/3 times (4) and 1/2 (5) are mixed and granulated. To the granules are added the remainder of (4) and (5) and then the granules are compression molded.

3. Injection

Dissolve (1), (2) and (3) in distilled water for injection to make a total volume of 2 ml and fill it with ampoules. The whole process is carried out under sterile conditions.

4. Capsule

(1), (2), (3) and 1/2 (4) are mixed and granulated. The remainder of (4) is added to the granules and the whole is filled into gelatin capsules.

5. Tablet

(1), (2), (3), 2/3 (4) and 1/2 (5) are mixed and granulated. To the granules is added the remainder of (4) and (5), and then the granules are compression molded.

6. Capsule

(1), (2), (3) and 1/2 (4) are mixed and granulated. The rest of (4) is added to the granules and the whole is filled into gelatin capsules.

7. Tablet

(1), (2), (3), 2/3 (4) and 1/2 (5) are mixed and granulated. To the granules is added the remainder of (4) and (5), and then the granules are compression molded.

Reference Example 1

[2-Butyl-5-methoxybenzimidazole]

To a solution of 4-methoxy-o-phenylenediamine (4.4 g) and ethylvaleroimidate hydrochloride (4.6 g) in ethanol (50 mL) was added triethylamine (5.7 g) and the mixture was allowed to come to room temperature. Stir for 2.5 hours. After removal of the solvent by evaporation, the resulting residue is dissolved in ethyl acetate and water, the organic layer is washed with water, dried and concentrated. The concentrate is purified by silica gel column chromatography to afford crystalline product. Recrystallization from isopropyl ether gives needle-like crystals (2.7 g, 53%, melting point 95-96 ° C).

In a similar manner as in Reference Example 1, the following compound was synthesized.

Reference Example 2

[2-Butyl-5-chlorobenzimidazole]

Colorless acicular crystal, elemental analysis of yield 78% C ₁₁ H ₁₃ ClN _{2 with} melting point of 149-150 ° C .:

Reference Example 3

[2-Butyl-5-nitrobenzimidazole]

Colorless crystals, Melting point 140-141 ° C, yield 77%

Reference Example 4

[2-propylbenzimidazole]

A mixture of o-phenylenediamine (2.2 g) in butyr anhydride (4.7 g) is stirred at 110 ° C. for 4 hours. Water is added to the reaction mixture, which is extracted with ethyl acetate. The organic layer is washed with an aqueous solution of sodium bicarbonate, water, silver hydrochloric acid and water and then dried. The solvent is evaporated to dryness and the residue is refluxed in 3N-HCl (35 mL) for 1.5 h. The reaction mixture is basified with 6N NaOH. The crystals are recrystallized from ethyl acetate-hexane to give colorless flaky crystals (0.98 g, 38%, melting point 160 to 162 캜).

Reference Example 5

[2-pentylbenzimidazole]

To a solution of o-phenylenediamine (2.2 g) and triethylamine (2.0 g) in methylene chloride (20 mL) is added dropwise caproyl chloride (2.3 g) with stirring under ice cooling. The mixture is stirred at room temperature for 3 hours, which is washed with a saturated aqueous solution of sodium bicarbonate and water and then dried. Evaporate the solvent. 3N-HCl is added to the residue and the mixture is heated at reflux for 1.5 h. The reaction mixture is basified with 6N NaOH. The precipitated crystals are recrystallized from ethyl acetate-hexane to give colorless needles (1.5 g, 47%, melting point 161 to 162 DEG C).

Reference Example 6

[2-butyl-1-[(2'-cyanobiphenyl-4-yl) methyl] benzimidazole]

To a solution of 2-butylbenzimidazole (0.87 g) in dimethylformamide (DMF) (5 mL) is added sodium hydride (60% oil, 0.24 g) under ice cooling and the mixture is stirred for 10 minutes. 4- (2-cyanophenyl) benzyl chloride (1.1 g) is added to the resulting mixture, which is stirred for 1.5 hours. Water is added to the reaction mixture, which is extracted with ethyl acetate. The extract is washed with water and condensed under reduced pressure. The twill is purified by silica gel column chromatography to give a colorless oil (quantitatively 1.8 g).

The following compounds (preparation examples 7 to 16) were prepared according to the method of Reference Example 6.

Reference Example 7

[2-butyl-1-[(2'-cyanobiphenyl-4-yl) methyl] -6-methoxybenzimidazole]

Oil (yield 48%)

Reference Example 8

[2-butyl-1-[(2'-cyanobiphenyl-4-yl) methyl] -5-methoxybenzimidazole]

Oil (yield 44%)

Reference Example 9

[2-butyl-5-chloro-1-[(2'-cyanobiphenyl-4-yl) methyl] benzimidazole]

Oil (yield 48%)

Reference Example 10

[2-butyl-6-chloro-1-[(2'-cyanobiphenyl-4-yl) methyl] benzimidazole

Melting Point: 124 ~ 125 ℃ (35% Yield)

Reference Example 11

[2-butyl-1-[(2'-cyanobiphenyl-4-yl) methyl] -5-nitrobenzimidazole]

Oil (yield 45%)

Reference Example 12

[2-Butyl-1- (2'-cyanobiphenyl-4-yl) methyl-6-nitrobenzimidazole]

Oil (yield 43%)

Reference Example 13

[1-[(2'-cyanobiphenyl-4-yl) methyl] -2-propylbenzimidazole]

Oil (quantitative yield)

Reference Example 14

[1-[(2'-cyanobiphenyl-4-yl) methyl] -2-pentylbenzimidazole]

Oil (quantitative yield)

Reference Example 15

[1-[(2'-cyanobiphenyl-4-yl) methyl] benzimidazole]

Oil (quantitative yield)

Reference Example 16

[2-butyl-1-[(2'-cyanobiphenyl-4-yl) methyl] benzimidazole]

Oil (quantitative yield)

Reference Example 17

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

2-butyl-1-((2'-cyanobiphenyl-4-yl) methyl) benzimidazole, supplementing the reaction system with sodium azide (1.6 g), ammonium chloride (1.3 g) and DMF (5 mL). (1.8 g), a mixture of sodium azide (0.98 g) and ammonium chloride (0.80 g) is stirred in DMF (6 mL) at 110 ° C. for 5 days. Water and ethyl acetate are added to the reaction mixture and the precipitated crystals are collected by filtration. The organic layer of the filtrate is washed with water, dried and concentrated under reduced pressure to give crude crystals. These crystals are combined with the previously obtained crystals and then recrystallized from ethyl acetate-methanol to give a colorless prism (0.82 g, 41%, melting point 235-236 ° C.).

The following compounds were prepared according to the method of Reference Example 17.

Reference Example 18

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

Melting Point: 146 ~ 149 ℃ (Decomposition)

Reference Example 19

[2-butyl-6-methoxy-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole]

Melting Point 243 ~ 244 ° C (Decomposition)

Reference Example 20

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

Melting Point 249 ~ 250 ℃ (Decomposition)

Reference Example 21

[2-butyl-6-chloro-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole]

Melting Point 216 ~ 217 ℃

Reference Example 22

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

Yield: 51%, melting point 238 ~ 239 ° C

Reference Example 23

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

Yield: 70%, Melting Point 239 ~ 240 ℃ (Decomposition)

Reference Example 24

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

Yield 41%, Melting point 208-209 degreeC

Reference Example 25

[Methyl 2- [4- (2-butylbenzimidazol-1-yl) methylphenyl] benzoate]

To a solution of 2-butylbenzimidazole (0.52 g) in DMF (4 mL) is added sodium hydride (60% oil, 0.13 g) under ice cooling and then the mixture is stirred for 20 minutes. Methyl 2- (4-bromomethylphenyl) benzoate (1.0 g) is added to the resulting mixture, which is stirred for 1.5 hours at room temperature. Water is added to the mixture, which is then extracted with ethyl acetate. The solvent is evaporated to dryness to give an oily residue. The oil is purified by silica gel column chromatography to give a colorless oil (quantitatively 1.2 g).

Reference Example 26

[2- [4- (2-butylbenzimidazol-1-yl) methylphenyl] benzoic acid]

Methyl 2- [4- (2-butylbenzimidazol-1-yl) methylphenyl] benzoate (1.2 g) is heated under reflux for 3 hours in a mixture of 1N NaOH solution (4.5 mL) and methanol (10 mL). . The reaction mixture is concentrated, the concentrate is dissolved in water, washed with ether and acidified with 1N-HCl to give crystals. The crystals are collected by filtration and recrystallized from ethyl acetate-methanol to give colorless crystals (0.64 g, 53%).

Reference Example 27

[Methyl 2-butylbenzimidazole-4-carboxylate]

To a mixture of concentrated HCl (5.3 mL) and methanol (35 mL) was added methyl 3-nitro-2- (N-valerylamino) benzoate (2.8 g), and iron powder (1.7 g) was stirred at room temperature. ) In small portions. The resulting mixture is heated under reflux for 8 hours. Insoluble material is filtered off and the filtrate is concentrated. To the concentrate is added water and ethyl acetate. The water layer is basified with 6N NaOH, which is extracted with ethyl acetate. The organic layer is combined, washed with water and dried. The solvent is evaporated and the residue is purified by silica gel column chromatography. The obtained crystals are recrystallized from isopropyl ether to give colorless acicular crystals (1.6 g, 70%, melting point 97-98 DEG C).

Reference Example 28

[Methyl-2-butyl-1-[(2'-cyanobiphenyl-4-yl) methyl] benzimidazole-4-carboxylate]

To a solution of methyl 2-butylbenzimidazole-7-carboxylate (1.5 g) in DMF (15 mL) is added sodium hydride (60% oil, 0.13 g) under ice cooling. The mixture is stirred for 20 minutes, to which 4- (2-cyanophenyl) benzyl chloride (1.5 g) is added. The resulting mixture is further stirred at room temperature for 5 hours, to which water is added and then extracted with ethyl acetate. The organic layer is washed with water and dried. The solvent is evaporated to dryness and the residue is purified by silica gel column chromatography to give a pale yellow oil (2.3 g, 82%).

Reference Example 29

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

Methyl 2-butyl-1-[(2'-cyanobiphenyl-4-yl) methyl] benzimidazole-4-carboxylate (2.3 g), sodium azide (5.3 g) and ammonium chloride (4.4 g) The mixture of was stirred for 26 h at 110-120 ° C. in DMF (20 mL). Water and ethyl acetate are added to the reaction mixture, which is acidified with concentrated hydrochloric acid. The precipitated crystals are collected by filtration and recrystallized from methanol to give colorless needle-like crystals (0.22 g, 9%, melting point 223-224 DEG C (decomposition)).

Reference Example 30

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

Substantially the same reaction as in Reference Example 29 was carried out. Water and ethyl acetate are added to the reaction mixture, which is acidified with 6N-HCl. The precipitated crystals are collected by filtration. The organic layer is separated from the filtrate, washed with water, dried and concentrated to dryness. The residue is purified by silica gel column chromatography. The crystals thus obtained were recrystallized from methanol-chloroform to give a colorless prism (0.37 g, 15%, melting point 235-236 ° C.).

Reference Example 31

[Methyl 3-nitro-2-valerylaminobenzoate]

Fuming nitric acid (7.0 ml) was added dropwise to acetic anhydride (60 ml) under ice cooling, and a dark yellow phase (0.2 ml) was added thereto. Methyl 2-valerylaminobenzodate (12 g) is added to the mixture, which is stirred at room temperature for 1 hour. Ice water is added to the obtained mixture, which is extracted with ethyl acetate. The organic layer is washed with water, dried and concentrated. The concentrate is purified by silica gel column chromatography to give crude crystals which are then recrystallized from isopropyl ether to give colorless acicular crystals (3.9 g, 28%, melting point 61-62 ° C.).

Reference Example 32

[Methyl 2- [N- (2'-cyanobiphenyl-4-yl) methyl-N-valeryl] amino-3-nitrobenzoate]

A mixture of methyl 3-nitro-2-valerylaminobenzoate (3.9 g), 4- (2-cyanophenyl) benzyl bromide (3.8 g) and K ₂ CO ₃ (2.1 g) in DMF (30 mL) was prepared. Stir at room temperature for 15 hours. Water is added to the reaction mixture, which is extracted with ethyl acetate. The organic layer is washed with water and dried. The solvent is evaporated to dryness and the residue is purified by silica gel column chromatography. The obtained crude crystals are recrystallized from ethyl acetate-hexane to give colorless crystals (5.1 g, 78%, melting point 129-130 ° C).

Reference Example 33

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

Of methyl 2- [N- (2'-cyanobiphenyl-4-yl) methyl-N-valeryl] amino-3-nitrobenzoate (5.14 g) in concentrated HCl (4.0 mL) and methanol (10 mL) Iron powder (1.9 g) is added in portions to the mixture with stirring. The mixture is stirred at 70-80 ° C. for 3 hours, then the insolubles are filtered off and the filtrate is concentrated. To the concentrate is added ethyl acetate and saturated aqueous sodium bicarbonate solution. The precipitated insoluble material is filtered off. The water layer is separated from the filtrate and extracted with ethyl acetate. The organic layer is combined, dried and concentrated to give crystalline residue. Recrystallization from ethyl acetate gives colorless needles (4.15 g, 90%, melting point 123-124 ° C).

The following compounds were prepared according to the method of Reference Example 31.

Reference Example 34

[Methyl 2-butyryl amino-3-nitrobenzoate]

Melting point 64 ~ 65 ℃

Reference Example 35

[Methyl 2-hexanoylamino-3-nitrobenzoate]

Melting point 74 ~ 75 ℃

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

Reference Example 36

[Methyl 2- [N-butyryl-N- (2'-cyanobiphenyl-4-yl) methyl] amino-3-nitrobenzoate]

Melting Point 150 ~ 151 ℃ (78% Yield)

Reference Example 37

[Methyl 2- [N- (2'-cyanobiphenyl-4-yl) methyl-N-hexanoyl] amino-3-nitrobenzoate]

Melting Point 85 ~ 86 ℃ (75% Yield)

In substantially the same manner as in Reference Example 33, the following compounds were obtained.

Reference Example 38

[Methyl 1-[(2'-cyanobiphenyl-4-yl) methyl] -2-propylbenzimidazole-7-carboxylate]

Melting Point 130 ~ 131 ° C (yield 78%)

Reference Example 39

[Methyl 1-[(2'-cyanobiphenyl-4-yl) methyl] -2-pentylbenzimidazole-7-carboxylate]

Melting Point 109 ~ 110 ° C (Yield 75)

Reference Example 40

[Methyl 3-nitro-4-valerylamino benzoate]

Fuming nitric acid (1.4 mL) was added dropwise to acetic anhydride (12 mL) under ice-cooling, and concentrated sulfuric acid (0.1 mL) was added thereto. To the stirred mixture is added methyl 4-valeryl aminobenzoate (2.3 g) under ice cooling, which is stirred for 1 hour. Ice water is added to the resulting mixture, the crystals are separated and then recrystallized from ethyl acetate-hexane to give a yellow prism (2.14 g, 76%, melting point 106-107 ° C.).

Reference Example 41

[Methyl 4- [N- (2'-cyanobiphenyl-4-yl) methyl-N-valerylamino] -3-nitrobenzoate]

A mixture of methyl 4-valerylamino-3-nitrobenzoate (2.1 g), 4- (2-cyanophenyl) benzylbromide (2.0 g) and K ₂ CO ₃ (1.1 g) in DMF (20 mL) was prepared. Stir at room temperature for 4 hours. Water is added to the reaction mixture, which is extracted with ethyl acetate and the organic layer is washed with water. The resulting solution is dried and concentrated to give a syrup which is purified by silica gel column chromatography to give a yellow syrup (quantitatively 3.5 g).

Reference Example 42

[Methyl 2-butyl-1-[(2'-cyanobiphenyl-4-yl) methyl] benzimidazole-5-carboxylate]

To a mixture of concentrated HCl (4.0 mL) and methanol (10 mL) methyl 4- [N- (2'-cyanobiphenyl-4-yl) methyl-N-valerylamino] -3-nitrobenzoate (3.5 g Add). Iron powder (1.3 g) was added to the obtained mixture little by little with stirring, and this was stirred at 70 to 80 ° C. for 1 hour, and then the insoluble substance was filtered off. The filtrate is concentrated, it is dissolved in ethyl acetate, washed with water, dried and concentrated to dryness. The resulting syrup is purified by silica gel column chromatography to yield a yellow syrup (1.7 g, 53%).

Reference Example 43

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

Methyl 4- [N- (2'-cyanobiphenyl-4-yl) methyl-N-valerylamino] -3-nitrobenzoate (1.7 g) in DMF (17 mL), sodium azide (3.9 g) And a mixture of ammonium chloride (3.2 g) is stirred at 115 ° C. for 5 days. Water is added to the reaction mixture, which is neutralized with 1N-HCl and then extracted with ethyl acetate. The organic layer is washed with water, dried and concentrated to dryness. The concentrate is purified by silica gel column chromatography to give crude crystals. Recrystallization from ethyl acetate gives colorless needles (0.67 g, 34%, melting point 134-136 DEG C).

Reference Example 44

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

Methyl 2-butyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole- in methanol (3 ml) containing 2N NaOH (1 ml) The mixture of 5-carboxylate (0.3 g) is heated under reflux for two hours. The reaction mixture is concentrated to dryness and dissolved in water. The aqueous solution is acidified with 1H-HCl to give crystals. Recrystallization from acetonitrile-methanol affords colorless crystals (0.23 g, 83%, melting point 180-182 ° C.).

Reference Example 45

[Methyl 3- valeryl amino benzoate]

To a solution of methyl 3-amino benzoate (6.0 g) and triethylamine (4.5 g) in methylene chloride (90 mL) is added dropwise with valeryl chloride (4.8 g) with stirring under ice-cooling. The mixture is stirred for 1 hour. The reaction mixture is washed with an aqueous solution of sodium bicarbonate, dilute hydrochloric acid and water, then dried and concentrated to dryness. The concentrate was recrystallized from ethyl acetate-hexane to give a colorless prism (8.1 g, 87%, melting point 101-120 ° C.).

Reference Example 46

[Methyl 4-nitro-3- valeryl amino benzoate]

To a solution of methyl 3- valeryl amino benzoate (2.3 g) in acet anhydride (12 mL) was added dropwise with fuming nitric acid (1.4 mL) stirring under ice cooling. One drop of concentrated sulfuric acid is added to the mixture, which is stirred for 2 hours. Ice water is added to the reaction mixture, which is extracted with ethyl acetate. The organic layer is washed with aqueous sodium bicarbonate solution and water, and it is dried. The solvent is evaporated to dryness and the residue is purified by silica gel column chromatography to give a brown oil (1.0 g, 35%).

Reference Example 47

[Methyl 3- [N- (2'-cyanobiphenyl-4-yl) methyl-N-valerylamino] -4-nitrobenzoate]

A mixture of methyl 4-nitro-3-valeryl amino benzoate (1.0 g), 4- (2-cyanophenyl) benzyl bromide (0.97 g) and potassium carbonate (0.55 g) in DMF (10 mL) was added at room temperature. Stir for 2 days. Water is added to the reaction mixture, which is extracted with ethyl acetate. The organic layer is washed with water and dried. The solvent is distilled off and the residue is purified by silica gel column chromatography to give a pale yellow oil (1.24 g, 73%).

Reference Example 48

[Methyl 2-butyl-1-[(2'-cyanobiphenyl-4-yl) methyl] benzimidazole-6-carboxylate]

Methyl 3- [N- (2'-cyanobiphenyl-4-yl) methyl-N-valerylamino] -4-nitrobenzoate (1.2 g) in methanol (10 mL) containing concentrated HCl (1.3 mL) To the solution of) iron powder (0.45 g) is added little by little with stirring at room temperature. The mixture is stirred at 70-80 ° C. for 3 hours. Water and ethyl acetate are added to the reaction mixture, which is basified with aqueous sodium bicarbonate solution. At this time, the separated precipitate is filtered off. The organic layer separated from the filtrate is washed with water and dried. The solvent is evaporated to dryness and the residue is purified by silica gel column chromatography. The crude crystal thus obtained is recrystallized from ethyl acetate to give a colorless needle-like crystal (0.5 g, 45%, melting point 166 ~ 167 ℃).

Reference Example 49

[Methyl 2-butyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-6-carboxylate]

Methyl 2-butyl-1- [2 '-(cyano biphenyl-4-yl) methyl] benzimidazole-6-carboxylate (0.5 g), sodium azide and ammonium chloride in DMF (5 mL) ( 1.15 g) is stirred at 115 ° C. for 3.5 days. Water is added to the reaction mixture, which is acidified with 1N-HCl and then extracted with ethyl acetate. The organic layer is washed with water, dried and concentrated to dryness. The concentrate is purified by silica gel column chromatography. The crude crystals thus obtained are recrystallized from ethyl acetate-methanol to give colorless crystals (0.23 g, 41%, melting point 224-225 ° C.).

Reference Example 50

[2-butyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl] benzimidazole-6-carboxylic acid]

Methyl 2-butyl-1- [2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl] benzimidazole-5 in methanol (5 mL) containing 1N NaOH (0.5 mL) The solution of carboxylate (0.1 g) is heated under reflux for 5 hours. The solvent is evaporated to dryness and 1N-HCl (0.5 mL) is added to the residue, which is extracted with chloroform. The organic layer is washed with water, dried and concentrated to dryness. The crude crystal thus obtained is recrystallized from methanol-ethyl acetate to give colorless crystals (60 mg, 58%, melting point 258-259 ° C. (decomposition)).

Reference Example 51

[Methyl 2-amino-5-methylbenzoate]

A mixture of 2-amino-5-methyl benzoic acid (10 g) in methanol (50 mL) containing concentrated sulfuric acid (5.5 mL) is heated under reflux for 19 h. The solvent is distilled off and the residue is dissolved in water. The solution is neutralized with aqueous sodium hydroxide solution and then extracted with ethyl acetate. The organic layer is dried and concentrated to give a pale yellow oil (8.1 g, 74%).

Reference Example 52

[Methyl 5-methyl-2-valeryl amino benzoate]

Valeryl chloride (6.5 g) is added dropwise while stirring under ice cooling to a solution of methyl-2-amino-5-methylbenzoate (8.1 g) and triethylamine (6.0 g) in methylene chloride (50 mL). The reaction is carried out with stirring for 2 hours, and then the reaction mixture is washed with aqueous sodium carbonate solution, dilute hydrochloric acid and water and then dried. The solvent is evaporated to dryness to afford a pale yellow oil (12.8 g, 99%).

Reference Example 53

[Methyl 5-methyl-3-nitro-2-valeryl amino benzoate]

To the mixture of methyl 5-methyl-2-valeryl amino benzoate (12.8 g) in acet anhydride (5.9 g) was added dropwise with stirring nitric acid (6.7 ml) under ice-cooling, followed by stirring for 3 hours. Ice water is added to the reaction mixture, which is extracted with ethyl acetate. The extract is washed with aqueous sodium bicarbonate solution and water and then dried. The solvent is evaporated to dryness and the residue is purified by silica gel column chromatography. The crystals thus obtained are recrystallized from isopropyl ether to give colorless crystals (8.5 g, 60%, melting point 59-60 ° C).

Reference Example 54

[Methyl 2-[[N- (2'-cyanobiphenyl-4-yl) methyl-N-valeryl] amino] -5-methyl-3-nitrobenzoate]

Methyl 5-methyl-3-nitro-2-valeryl amino benzoate (5.89 g), 4- (2-cyanophenyl) benzyl bromide (5.44 g) in DMF (50 mL), and potassium carbonate (3.0 g) ) Mixture is stirred at 50 ° C. for 15 h. Water is added to the reaction mixture, which is extracted with ethyl acetate and the organic layer is dried. The solvent is distilled off and the residue is purified by silica gel column chromatography. The crystals thus obtained are recrystallized from ethyl acetate-hexane to give colorless crystals (3.1 g, 32%, melting point 141-142 DEG C).

Reference Example 55

[Methyl 2-butyl-1-[(2'-cyanobiphenyl-4-yl) methyl] -5-methylbenzimidazole-7-carboxylate]

Methyl 2-[[N- (2'-cyanobiphenyl-4-yl) methyl-N-valeryl] amino] -5-methyl-3- in a mixture of concentrated HCl (4.4 mL) and methanol (22 mL) To the nitrobenzoate (3.1 g) solution, add iron powder (1.6 g) little by little with stirring. The mixture is heated at reflux for 7 hours. Insoluble material is filtered off and the filtrate is concentrated. Water is added to the concentrate, which is extracted with ethyl acetate. The organic layer is washed with aqueous sodium bicarbonate solution and water and then dried. The solvent is distilled off and the residue is purified by silica gel column chromatography to give a pale brown oil (quantitatively 2.8 g).

Reference Example 56

[Ethyl 2-amino-6-methylbenzoate]

The compound is prepared according to the method of Reference Example 51.

Oil (yield 82%)

Reference Example 57

[Ethyl 6-methyl-2- valeryl amino benzoate]

The compound is prepared according to the method of Reference Example 52.

Melting Point 56 ~ 57 ℃ (70% Yield)

Reference Example 58

[Ethyl 6-methyl-3-nitro-2-valeryl amino benzoate]

The compound is prepared according to the method of Reference Example 53.

Melting point 103-104 degreeC (yield 52%)

Reference Example 59

[Ethyl 6-methyl-3-nitro-2-[[2 '-(N-triphenylmethyl-1H-tetrazol-5-yl) biphenyl-4-yl] methyl-N-valeryl] amino benzoate ]

The compound is prepared according to the method of Reference Example 54.

Oil yield (80%)

Reference Example 60

[Methyl 2-amino-5-chlorobenzoate]

Concentrated sulfuric acid (12 mL) is added to a solution of 2-amino-5-benzoic acid (25.5 g) in methanol (300 mL). The mixture is heated at reflux for 24 h. The reaction mixture is concentrated, to which water (300 mL) is added and then neutralized with potassium carbonate. The mixture is extracted with ethyl acetate. The organic layer is washed with water and dried and then the solvent is distilled off to give crude crystals. Recrystallization from i-propyl ether-benzene affords pale yellow crystals (17.1 g, 63%, melting point 68-70 ° C).

Reference Example 61

[Methyl 5-chloro-2-valeryl amino benzoate]

To a solution of methyl 2-amino-5-chlorobenzoate (15 g) and triethylamine (12 mL) in methylene chloride (150 mL) is added dropwise valeryl chloride (10 mL) with stirring under ice cooling. The mixture is stirred at room temperature for 2 hours. The reaction mixture is washed with aqueous sodium bicarbonate solution and water and then dried. The solvent was distilled off to obtain pale yellow crystals (13.4 g, 61%, melting point 48 ~ 49 ℃).

Reference Example 62

[Methyl 5-chloro-3-nitro-2-valeryl amino benzoate]

To the solution of methyl 5-chloro-2-valeryl amino benzoate (13.4 g) in acet anhydride (10 mL) was added dropwise while stirring nitric acid under ice cooling. The mixture is stirred for 1 hour at room temperature, to which ice water is added. The mixture is left to yield crystals. Recrystallization from isopropyl ether yields pale yellow crystals (9.5 g, 61%, melting point 84-85 ° C.).

Reference Example 63

[Methyl 5-chloro-2-[[N- (2'-cyanobiphenyl-4-yl) methyl-N-valeryl] amino] -3-nitro benzoate]

Of methyl 5-chloro-3-nitro-2-valeryl amino benzoate (3.15 g), 4- (2-cyanophenyl) benzylbromide (2.8 g) and potassium carbonate (1.8 g) in DMF (50 mL) The mixture is stirred at room temperature for 3 hours. The reaction mixture is concentrated to dryness and the concentrate is extracted with ethyl acetate and H ₂ O. The organic layer is washed with water and dried. The solvent is distilled off to obtain crystals. Recrystallization from ethyl acetate-benzene gives colorless crystals (4.0 g, 79%, 137-138 ° C).

Reference Example 64

[Methyl 5-chloro-3-nitro-2-[[2 '-(N-triphenylmethyl-1H-tetrazol-5-yl) biphenyl-4-yl] methyl-N-valeryl] aminobenzoate ]

To a solution of methyl 5-chloro-3-nitro-2-valeryl amino benzoate (0.93 g) in DMF (10 mL) was added potassium carbonate (0.5 g) and N-triphenylmethyl-5- [2 '-(4 -Bromomethyl) biphenylmethyl] tetrazole (1.84 g) is added. The mixture is stirred at rt for 19 h. Water (50 mL) is added to the reaction mixture, which is extracted with ethyl acetate. The organic layer is washed with water, dried and the solvent is distilled off. The residue (3.8 g) was purified by silica gel column chromatography to give pale yellow crystals (1.89 g, 82%).

Reference Example 65

[Methyl 2-butyl-5-chloro-1-[(2'-cyanobiphenyl-4-yl) methyl] benzimidazole-7-carboxylate]

Methyl 5-chloro-2- [N- (2'-cyanobiphenyl-4-yl) methyl-N-valeryl] amino-3-nitro in a mixture of concentrated HCl (4 mL) and methanol (50 mL). To a solution of benzoate (3.33 g) is added iron powder (95% purity, 1.1 g) little by little with stirring at room temperature. The mixture is stirred at 80 ° C. for 24 h. The insolubles are then filtered off and the filtrate is concentrated to dryness. The concentrate is extracted with ethyl acetate-water. The organic layer is washed with aqueous sodium bicarbonate solution and water, which is dried and concentrated. The solvent is distilled off and the residue is purified by silica gel column chromatography to give colorless needles (1.83 g, 61%).

Reference Example 66

[Ethyl 2-carboxy-3-nitrobenzoate]

A solution of 3-nitrophthalic acid (35 g) in ethanol (300 mL) containing concentrated sulfuric acid (20 mL) is heated under reflux for 24 h. The solvent is distilled off and the residue is poured into ice water (700 mL) and it is extracted with ethyl acetate. The organic layer is washed with water and extracted with aqueous potassium carbonate solution. The water layer is acidified with hydrochloric acid and then extracted with methylene chloride. The organic layer is washed with water and dried. The solvent is distilled off to give a solid product (29 g, 74%) which is then used for the next reaction without purification.

Reference Example 67

[Ethyl 2-t-butoxycarbonylamino-3-nitrobenzoate]

A mixture of ethyl 2-carboxy-3-nitrobenzoate (23.9 g) and thionyl chloride (12 mL) in benzene (150 mL) is heated under reflux for 3 hours. The resulting solution is concentrated to dryness to give acid chloride (quantitatively 26 g), which is dissolved in methylene chloride (20 mL). The solution is added dropwise to a mixture of sodium azide (9.75 g) in DMF (20 mL) with vigorous stirring. The reaction mixture is poured into a mixture of ether-hexane (3 mL: 1200 mL) and water (250 mL) and the whole mixture is shaken. The organic layer is washed with water, dried and the solvent is distilled off. The residue is dissolved in t-butanol (200 mL), stirred gradually and heated at reflux for 2 hours, raising the temperature of the solution. The reaction mixture is concentrated under reduced pressure to give an oil (30 g).

Reference Example 68

[Ethyl 2-[(2'-cyanobiphenyl-4-yl) methyl] amino-3-nitrobenzoate]

To a solution of ethyl 2-t-butoxycarbonylamino-3-nitrobenzoate (20 g) in THF (50 mL) is added sodium hydride (60% oil, 2.8 g) with stirring under ice cooling. 4- (2-cyanobiphenyl) methyl bromide (18 g) and potassium iodide (0.36 g) are then added to the mixture, which is then stirred for 15 hours at room temperature. The reaction mixture is heated at reflux for 4 hours. The solvent is distilled off and the residue is extracted with water (250 mL) and ether (200 mL). The organic layer is concentrated to give a yellow oil which is dissolved in a mixture of trifluoroacetic acid (60 mL) and methylene chloride (40 mL) and the solution is stirred at room temperature for 1 hour. The reaction mixture is concentrated to dryness and ethyl ether (200 mL) is added to the concentrate to give crystals. The crystals are collected by filtration, washed with ether and dried to give pale yellow crystals (22.1 g, 85%, melting point 119-120 ° C.).

Reference Example 69

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

Raney nickel (5 g) is added to a solution of ethyl 2-[(2'-cyanobiphenyl-4-yl) methyl] amino-3-nitrobenzoate (5.5 g) in THF (50 mL). The catalytic reduction is carried out at room temperature under atmospheric pressure. The catalyst is filtered off and the filtrate is concentrated to give a yellow oil (quantitatively 5 g).

Reference Example 70

[Ethyl 2-butyl-1-[(2'-cyanobiphenyl-4-yl) methyl] benzimidazole-7-carboxylate]

A solution of ethyl 3-amino-2-[(2'-cyanobiphenyl-4-yl) methyl] benzoate (0.31 g) and ethyl butyronimidate (0.18 g) in ethanol (2 mL) was added at 70 ° C. Stir for 2 hours. The reaction mixture is concentrated to dryness and the concentrate is extracted with an aqueous solution of ethyl acetate and sodium bicarbonate. The organic layer is washed with water, dried and concentrated to give crystals. Recrystallization from ethyl acetate-hexane gave pale yellow needle-like crystals (0.22 g, 60%, melting point 112-114 ° C).

Reference Example 71

[2-butyl-1-[(2'-cyanobiphenyl-4-yl) methyl] -7- (hydroxymethyl) benzimidazole]

Of methyl 2-butyl-1-[(2'-cyanobiphenyl-4-yl) methyl] benzimidazole-7-carboxylate (10 g) and NaBH ₄ (2.2 g) in tetrahydrofuran (100 mL) Methanol (19 mL) was added dropwise to the solution over 80 minutes. The mixture is heated at reflux for 27 hours and the reaction mixture is concentrated to dryness. Water is added to the concentrate, which is neutralized with concentrated HCl. The separated crystals are collected by filtration. Recrystallization from methanol yields colorless needle-like crystals (8.8 g, 93%, melting point 203-204 DEG C).

Reference Example 72

[2-butyl-1-[(2'-cyanobiphenyl-4-yl) methyl] -7- (chloromethyl) benzimidazole

A solution of 2-butyl-1-[(2'-cyanobiphenyl-4-yl) methyl] -7-hydroxymethylbenzimidazole (5.4 g) and thionyl chloride (8.3 g) in chloroform (80 mL) A catalytic amount of DMF (1 drop) is added to the mixture, and the mixture is then heated under reflux for 1 hour. The reaction mixture is washed with aqueous sodium bicarbonate solution and water, then dried and concentrated to dryness. The concentrate is crystallized from ethyl acetate-hexane to give colorless needles (5.3 g, 92%, melting point 144-145 ° C 1).

Reference Example 73

[2-butyl-1-[(2'-cyanobiphenyl-4-yl) methyl] -7- (cyanomethyl) benzimidazole]

A mixture of 2-butyl-1-[(2'-cyanobiphenyl-4-yl) methyl] -7-chloromethylbenzimidazole (0.83 g) and sodium cyanide (0.12 g) in DMF (10 mL) was cooled to room temperature. Stir for 22 hours. Water is added to the reaction mixture, which is extracted with ethyl acetate. The organic layer is washed with water and dried. The solvent is distilled off and the residue is crystallized from ethyl acetate to give a colorless prism (0.76 g, 94%, melting point 180-181 ° C.).

Reference Example 74

[Ethyl [[2-butyl-1- (2'-cyanobiphenyl-4-yl) methyl] benzimidazol-7-yl] acetate]

A mixture of 2-butyl-1-[(2'-cyanobiphenyl-4-yl) methyl] -7-cyanomethylbenzimidazole (0.76 g) in 3,5N-hydrochloride in ethanol (10 mL) Heated at reflux for 2.5 h. The reaction mixture is diluted with water, which is basified with an aqueous solution of sodium bicarbonate and then extracted with ethyl acetate. The organic layer is washed with water and then dried. The solvent is distilled off and the residue is purified by silica gel column chromatography to give a colorless oil (quantitatively 0.9 g).

Reference Example 75

[2-butyl-1-[(2'-cyanobiphenyl-4-yl) methyl] -7-methylbenzimidazole]

2-butyl-1-[(2'-cyanobiphenyl-4-yl) methyl] -7-chloromethylbenzimidazole (0.62 g) in toluene (20 mL), tributyltin hydride (3.0 g) and The mixture of perbenzoic acid (catalyst amount) is heated under reflux under a nitrogen atmosphere for 5.5 h. The reaction mixture is concentrated, purified by silica gel column chromatography and recrystallized from ethyl acetate-hexane to give colorless crystals (0.5 g, 88%, melting point 115-116 ° C).

Reference Example 76

[2-butyl-1-[(2'-cyanobiphenyl-4-yl) methyl] -7-hydroxybenzimidazole]

To a solution of 2-butyl-1-[(2'-cyanobiphenyl-4-yl) methyl] -7-methoxybenzimidazole (1.2 g) in methylene chloride (5 mL) Boron bromide (1.7 g) is added. The mixture is stirred at room temperature for 8 hours, to which water is added and then further stirred for 1 hour. The reaction is basified with 6N-NaOH and then extracted with ethyl acetate. The organic layer is washed with water, dried and concentrated. The concentrate is purified by silica gel column chromatography. The obtained crude crystals were recrystallized from ethyl acetate-hexane to give a colorless prism (0.69, 63%, melting point 185 to 186 ° C).

Reference Example 77

[2-methoxy-6-nitroaniline]

A mixture of 2-amino-2-nitrophenol (7.7 g) and potassium carbonate (7.6 g) in DMF (15 mL) is stirred at room temperature for 30 minutes, to which methyl iodide (7.8 g) is added. The mixture is stirred at room temperature for 5 hours. Water is added to the reaction mixture and it is extracted with ethyl acetate. The organic layer is washed with water and then dried. The solvent is distilled off to give crude crystals and recrystallized from isopropyl ether to give an orange prism (6.9 g, 82%, melting point 76-77 ° C).

Reference Example 78

[N- (2-methoxy-6-nitrophenyl) valeroamide]

A catalytic amount of concentrated sulfuric acid is added to a mixture of 2-methoxy-6-nitroaniline (5.9 g) in valeric anhydride (14 g), which is stirred at 130 to 140 ° C. for 1.5 hours. Water is added to the reaction mixture, which is basified with 6N NaOH. The reaction mixture is extracted with ethyl acetate. The organic layer is washed with water and dried. The solvent is distilled off. The residue is purified by silica gel column chromatography. The obtained crude crystals were recrystallized from ethyl acetate-hexane to give colorless crystals (3.2 g, 36%, melting point 113 to 114 DEG C).

Reference Example 79

[N- (2'-cyanobiphenyl-4-yl) methyl-N- (2-methoxy-6-nitrophenyl) valeramide]

To a solution of N- (2-methoxy-6-nitrophenyl) valeramide (3.2 g) in DMF (15 mL) is added sodium hydride (60% oil, 0.61 g) under ice cooling. The mixture is stirred for 20 minutes, to which 4- (2-cyanophenyl) benzyl bromide (3.5 g) is added, followed by stirring at room temperature for 1 hour. Water is added to the reaction mixture, which is extracted with ethyl acetate. The organic layer is washed with water and dried. The solvent is distilled off and the residue is purified by silica gel column chromatography to give a yellow oil (quantitatively 5.8 g).

Reference Example 80

[2-butyl-1-[(2'-cyanobiphenyl-4-yl) methyl] -7-methoxybenzimidazole]

N-[(2'-cyanobiphenyl-4-yl) methyl] -N- (2-methoxy-6-nitrophenyl) valeramide (5.8 g) in methanol (50 mL) and concentrated HCl (7 mL) To the solution of was added iron powder (2.3 g) little by little with stirring at room temperature. The reaction mixture is heated at reflux for 5 hours and then the solvent is distilled off. To the residue is added ethyl acetate and water, which is basified with 6N NaOH. The insoluble material is filtered off and the filtrate forms two layers. The organic layer is washed with water, dried and the solvent is removed. The residue is recrystallized from ethyl acetate-hexane to give a colorless prism (4.1 g, 80%, melting point 127-128 ° C).

Reference Example 81

[2-butyl-1-[(2'-cyanobiphenyl-4-yl) methyl] -7-methoxymethylbenzimidazole]

2-butyl-1-[(2'-cyanobiphenyl-4-yl) methyl] -7-hydroxymethylbenzimidazole (0.79 g), thionyl chloride (0.36 g) and DMF in chloroform (20 mL) The mixture of (catalyst amount) is heated under reflux for 1 hour. The solvent is distilled off and the residue is dissolved in methanol (15 mL). To the solution is added sodium methoxide (4.9 M methanol solution, 2 ml) and then heated under reflux for 6 hours. The solvent is distilled off. Water is added to the residue, followed by extraction with ethyl acetate. The organic layer is washed with water, dried and the solvent is evaporated. The residue is purified by silica gel column chromatography to give an oil (0.48 g, 59%).

The following compounds (Reference Examples 82 to 84) were prepared according to the method of Reference Example 32.

Reference Example 82

[Ethyl 2- [N-acetyl-N- (2'-cyanobiphenyl-4-yl) methyl] amino-3-nitrobenzoate]

oil

Reference Example 83

[Ethyl 2- [N-propionyl-N- (2'-cyanobiphenyl-4-yl) methyl] amino-3-nitrobenzoate]

oil

Reference Example 84

[Ethyl 2- [N-isobutyryl-N- (2'-cyanobiphenyl-4-yl) methyl] amino-3-nitrobenzoate]

oil

The following compounds (Reference Examples 85 to 87) were prepared according to the method of Reference Example 33.

Reference Example 85

[Ethyl 1-[(2'-cyanobiphenyl-4-yl) methyl] -2-methylbenzimidazole-7-carboxylate]

Melting point 167-168 degreeC (yield 81%)

Reference Example 86

[Ethyl 1-[(2'-cyanobiphenyl-4-yl) methyl] -2-ethylbenzimidazole-7-carboxylate]

Melting Point 163 ~ 164 ° C (Yield 76%)

Reference Example 87

[Ethyl 1-[(2'-cyanobiphenyl-4-yl) methyl] -2-isopropyl benzimidazole-7-carboxylate]

Melting point 107 ~ 108 ℃ (77% yield)

Reference Example 88

[Ethyl 2-chloromethyl-1-[(2'-cyanobiphenyl-4-yl) methyl] benzimidazole-7-carboxylate]

Chloroacetyl in an ice cold solution of ethyl 3-amino-2-[(2'-cyanobiphenyl-4-yl) methyl] aminobenzoate (1.0 g) and triethylamine (0.3 g) in methylene chloride (10 mL) Chloride (0.24 mL) is added in portions. The mixture is stirred for 13 hours and then evaporated to dryness to give a residue. The residue is washed with H ₂ O, dried and dissolved in EtOH (10 mL). To the solution was added concentrated HCl (1 mL) and the solution was refluxed for 6 hours. The reaction solution is evaporated to dryness to afford a residue. The residue is dissolved in methylene chloride and water. The solution is basified with 1N-NaOH and the organic layer is washed with water, dried and evaporated to dryness to yield crystals. Recrystallization from ethyl acetate-isopropylether gave colorless crystals (0.88 g, 76%).

Reference Example 89

[Ethyl 1-[(2'-cyanobiphenyl-4-yl) methyl] -2-methoxymethylbenzimidazole-7-carboxylate]

Ethyl-2-chloromethyl-1-[(2'-cyanobiphenyl-4-yl) methyl] -benzimidazole-7-carboxylate (0.8 g) and NaOMe (1.08 g, in methanol (15 mL) A 28% solution in methanol) is refluxed for 2 hours. The reaction solution is evaporated to dryness to afford a residue, which is dissolved in CH ₂ Cl ₂ -H ₂ O. The organic layer is washed with water, dried and evaporated to dryness to give a syrup. The syrup is purified by silica gel column chromatography to give a yellow syrup (0.4 g, 52%).

Following compounds similar to Reference Example 89 were prepared the following compounds (Reference Examples 90-93).

Reference Example 90

[Ethyl 1-[(2'-cyanobiphenyl-4-yl) methyl] -2-ethoxymethylbenzimidazole-7-carboxylate]

Light Brown Syrup (92%)

Reference Example 91

[Ethyl 1-[(2'-cyanobiphenyl-4-yl) methyl] -2-methylthiomethylbenzimidazole-7-carboxylate]

Pale yellow syrup (72%)

Reference Example 92

[Ethyl 1-[(2'-cyanobiphenyl-4-yl) methyl] -2-ethylthiomethylbenzimidazole-7-carboxylate]

Light Brown Syrup (88%)

Reference Example 93

Ethyl 2-acetoxymethyl-1-[(2'-cyanobiphenyl-4-yl) methyl] benzimidazole-7-carboxylate

Light Brown Syrup (99%)

Reference Example 94

[Methyl 3-amino-2-[(2'-cyanobiphenyl-4-yl) methyl] aminobenzoate]

A mixture of ethyl 3-amino-2-[(2'-cyanobiphenyl-4-yl) methyl] aminobenzoate (5 g) and NaH (60% oil, 1.62 g) in methanol (50 mL) was added at room temperature. Stir for time. The reaction mixture is concentrated to dryness to give a syrup, which is poured into saturated aqueous NaHCO ₃ (100 mL). The mixture is extracted with chloroform and the organic layer is washed with H ₂ O, dried and evaporated to dryness to give crystalline product. Recrystallization from ethyl acetate-hexane gave colorless crystals (3.9 g, 82%, melting point 106-108 DEG C).

Reference Example 95

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

3-chloropropionyl chloride (0.15) in a cold solution of methyl 3-amino-2-[(2'-cyanobiphenyl-4-yl) methyl] aminobenzoate (0.5 g) in CH ₂ Cl ₂ (5 mL). Ml) is added dropwise. The reaction mixture is stirred at room temperature for 30 minutes and then concentrated to dryness to afford a residue. The residue is dissolved in methanol (5 mL) containing concentrated HCl (0.5 mL) and the solution is stirred for 16 h at room temperature. The reaction solution is concentrated to dryness to afford a residue, which is dissolved in CH ₂ Cl ₂ -H ₂ O. The water layer is basified and then extracted. The organic layer was washed with H ₂ O, dried and evaporated to dryness to give a pale brown syrup (0.7 g, 100%).

Reference Example 96

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

Methyl 2- (2-chloroethyl) -1-[(2'-cyanobiphenyl-4-yl) methyl] benzimidazole-7-carboxylate (1.0 g) and K ₂ CO in methanol (30 mL) The mixture of ₃ (0.25 g) is refluxed for 2 hours. The reaction mixture is concentrated to dryness to afford a residue. The residue is dissolved in CH ₂ Cl ₂ and the insoluble material is filtered off. The filtrate is concentrated to dryness and the resulting syrup is purified by silica gel column chromatography to yield a pale yellow syrup (0.45 g, 59%).

Reference Example 97

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

The compound is prepared by a method similar to Reference Example 96.

Colorless powder (1.1 g, 93%)

Reference Example 98

[2-butyl-1-[(2'-cyanobiphenyl-4-yl) methyl] -7- (N, N-dimethylaminomethyl) benzimidazole]

2-butyl-1-[(2'-cyanobiphenyl-4-yl) methyl] -7-chloromethylbenzimidazole (0.65 g) and dimethylamine (50% aqueous solution, 1.5 mL) in ethanol (3 mL) Is heated in a closed tube for 5 hours. The reaction solution is concentrated to dryness and the resulting syrup is dissolved in ethyl acetate. The solution was washed with water, dried and evaporated to dryness to give a syrup, which was purified by silica gel column chromatography to give a colorless syrup (0.4 g, 63%).

Reference Example 99

[Ethyl 1-[(2'-cyanobiphenyl-4-yl) methyl] -2-sec-butylbenzimidazole-7-carboxylate]

A mixture of ethyl 3-amino-2-[(2'-cyanobiphenyl-4-yl) methyl] aminobenzoate (1.1 g) and 2-methylbutyr anhydride (0.56 g) in pyridine (2 mL) was charged. Heat 15 ° C. The reaction mixture is immersed in ethyl acetate (50 mL) and the solution is washed with water, dried and evaporated to dryness to give syrup. The syrup is dissolved in ethanol (15 mL) containing concentrated HCl (0.5 mL) and the solution is refluxed for 3 hours. After removal of the solvent, the resulting syrup is purified by silica gel column chromatography to yield a pale yellow syrup (1.2 g, 92%).

Reference Example 100

[Ethyl 1-[(2'-cyanobiphenyl-4-yl) methyl] -2-isobutylbenzimidazole-7-carboxylate]

The compound is obtained by a method similar to Reference Example 99.

Pale yellow syrup (quantitative)

Reference Example 101

[2-butyl-1-[[2 '-(N-triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid]

₂ -Butyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid in CH ₂ Cl ₂ (20 mL) (3.0 g), a mixture of triphenylmethylchloride (1.96 g) and triethylamine (1.0 mL) are stirred at room temperature for 16 hours. The reaction solution is washed with H ₂ O, dried over Na ₂ SO ₄ and concentrated to dryness to give a solid residue. The residue is purified by silica gel column chromatography to give a colorless powder (4.25 g, 91%, melting point 120 ~ 123 ° C).

Example 1

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

Methyl 2-butyl-1-[(2'-cyanobiphenyl-4-yl) methyl] benzimidazole-7-carboxylate (3.2 g) in DMF (30 mL), sodium azide (7.4 g) and The mixture of ammonium chloride (6.1 g) is stirred at 115 ° C. for 4 days. Water is added to the reaction mixture, which is adjusted to pH 3-4 with 1N-HCl. The obtained crude crystal (1) is purified by silica gel column chromatography. The obtained crystals were recrystallized from ethyl acetate-methanol to give a colorless prism (2.27 g, 63%, melting point 168-169 DEG C).

Example 2

[2-butyl-1-[[2 '-(N-methyltetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid]

The crude crystal (1) obtained in Example 1 was purified by silica gel column chromatography, and then recrystallized from ethyl acetate-hexane to give a colorless acicular crystal (0.17 g, 4.7%, melting point 133-135 DEG C).

Example 3

[2-butyl-N-isopropyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxamide]

2-butyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid (0.71 g) in DMF (6 mL) and A solution of diethylcyanophosphate (purity 90%, 0.82 g) is stirred under ice cooling for 1 hour. Isopropylamine hydrochloride (0.14 g) and triethylamine (0.61 g) are then added to the solution and the mixture is stirred at room temperature for 2 hours. Water is added to the reaction mixture, which is neutralized with 1N-HCl and extracted with ethyl acetate. The organic layer is washed with water, dried and concentrated to dryness. The resulting crude crystals were recrystallized from methanol-ethyl acetate to give a colorless prism (0.31 g, 41%, melting point 247-249 ° C.).

Example 4

[2-butyl-l-[[2 '-(lH-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid 2-sodium salt]

Methanol (15 mL) containing NaOMe (46 mg) 2-butyl-1- [2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methylbenzimidazole-7-carboxyl Acid (0.2 g) is added and the mixture is stirred at rt for 15 h. Toluene (30 mL) is added to the reaction mixture, which is concentrated under reduced pressure to give crystals. The separated crystals are collected by filtration to give colorless powdery crystals (0.14 g, 62%, melting point 255-257 ° C. (decomposition)).

Example 5

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

2-Butyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methylbenzimidazole-7-carboxylic acid (0.47 g) in butanol (10 mL) and concentrated The mixture of sulfuric acid (0.1 mL) is heated under reflux for 66 h. The solvent is removed by evaporation. Water is added to the residue and the mixture is adjusted to pH 3-4 with 1N-NaOH and then extracted with ethyl acetate. The organic layer is washed with water and dried. After removal of the solvent, the residue is purified by silica gel column chromatography. Recrystallization from ethyl acetate-hexane gave a colorless prism (0.15 g, 29%, melting point 192-193 ° C).

Example 6

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

(4-pyridine) methyl2-butyl-1-[(2'-cyanobiphenyl-4-yl) methyl] benzimidazole-7-carboxylate (0.61 g) and trimethyltin in toluene (10 mL) The solution of zide (0.75 g) is heated for 4 days under reflux under a nitrogen atmosphere. After removal of the solvent, the resulting solvent residue is dissolved in ethanol (5 mL). 1N-HCl (8 mL) is added to the solution and the mixture is stirred at room temperature for 5 minutes, which is neutralized with 1N NaOH and extracted with ethyl acetate. The extract is washed with water, dried and evaporated to dryness. The residue obtained is purified by silica gel column chromatography to yield crystals. Recrystallization from ethyl acetate-hexane yields a colorless prism (0.54 g, 83%, melting point 179-180 ° C.).

Example 7

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

Methyl 2-propyl-1-[(2'-cyanobiphenyl-4-yl) methyl] benzimidazole-7-carboxylate (2.5 g) in DMF (30 mL), sodium azide (3.9 g) and The mixture of ammonium chloride (3.2 g) is stirred at 110 ° C.-120 ° C. for 5 days. Water is added to the reaction mixture, the solution is acidified (pH 3-4) and extracted with ethyl acetate. The organic layer is washed with water and dried. After removal of the solvent, the residue is purified by silica gel column chromatography to give crystals. Recrystallization from DMF-ethanol yields colorless crystals (0.8 g, 23%, melting point 275-276 DEG C (decomposition)).

Example 8

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

Methyl 1-[(2'-cyanobiphenyl-4-yl) methyl] -2-pentylbenzimidazole-7-carboxylate (3.25 g) in DMF (20 mL), sodium azide (2.6 g) and The mixture of ammonium chloride (2.1 g) is stirred at 110-120 ° C. for 5 days. Water is added to the reaction mixture, which is acidified (pH 3-4) with 1N-HCl and then extracted with ethyl acetate. The organic layer is washed with water and dried. After removal of the solvent, the residue is purified by silica gel column chromatography to give crystals. Recrystallization from ethyl acetate-ethanol followed by treatment with hot water gives colorless powdery crystals (1.0 g, 29%, melting point 205-207 DEG C. (decomposition)).

Example 9

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

Methyl 2-butyl-1-[(2'-cyanobiphenyl-4-yl) biphenyl-4-yl] methyl] -5-methylbenzimidazole-7-carboxylate (2.8 in DMF (25 mL) g), a mixture of sodium azide (6.2 g) and ammonium chloride (5.1 g) is stirred at 110-120 ° C. for 3 days. The reaction mixture is diluted with water, acidified with 1N HCl (pH 3-4) and extracted with ethyl acetate. The organic layer is washed with water and dried. After removal of the solvent, the residue is purified by silica gel column chromatography to give crystals. Recrystallization from ethyl acetate-methanol yields a colorless prism (0.72 g, 24%, melting point 144-145 ° C.).

Example 10

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

Methyl 2-butyl-5-methyl-1-[[2 '-(1H- tetrazol-5-yl) biphenyl-4-yl] methyl] benzimi in 1N NaOH (1.2 mL) and methanol (2 mL) The mixture of dazol-7-carboxylate (0.15 g) is heated under reflux for 2 hours. The reaction mixture is diluted with water, washed with ether and acidified (pH 3-4) with 1N-HCl. The separated crystals are collected by filtration and recrystallized from ethyl acetate to give colorless crystals (0.1 g, 71%, melting point 175-178 ° C. (decomposition)).

Example 11

[Ethyl 2-butyl-6-methyl-1-[[2 '-(1H- tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate]

Ethyl 6-methyl-3-nitro- [N- [2 '-(N-triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methyl in concentrated HCl (2.1 mL) and ethanol (10 mL) A mixture of -N-valeroyl] anthranilate (2.1 g) and iron powder (0.73 g) is heated under reflux for 18 hours. Insoluble matter in the reaction mixture is filtered off. The filtrate is then concentrated to dryness. The residue is dissolved in 1N-NaOH and the precipitate obtained is filtered off through celite. The filtrate is acidified with concentrated HCl. The oil product is separated and extracted with methylene chloride. The extract is washed with water and concentrated to dryness. The syrup product thus obtained is purified by silica gel column chromatography to give crystalline product. Recrystallization from ethyl acetate-isopropyl ether gives a pale brown prism (0.8 g, 59%, melting point 164-165 ° C.).

Example 12

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

Methyl 5-chloro-3-nitro-2- [N- [2 '-(N-triphenylmethyl-1H-tetrazol-5-yl) biphenyl-4-yl) methyl]-in methanol (15 mL) A mixture of N-valerylanthranilate (1.26 g), concentrated HCl (1.6 mL) and iron powder (95% purity, 0.45 g) is heated under reflux for 20 hours. Insoluble material is filtered off and the filtrate is concentrated. The concentrate is extracted with ethyl acetate and water. An aqueous sodium bicarbonate solution is added to the organic layer, and the insoluble matter formed is filtered off. The filtrate is washed with water, dried and concentrated. The concentrate was purified by silica gel column chromatography to give crystals which were recrystallized from ethyl acetate-benzene to give colorless crystals (0.59 g, 74%, melting point 132-133 ° C.).

Example 13

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

Methyl 2-butyl-5-chloro-1-[[2 '-(1H- tetrazol-5-yl) biphenyl-4-yl] methyl] benzimi in 1N NaOH (2 mL) and methanol (4 mL) A solution of dazol-7-carboxylate (0.28 g) is stirred at room temperature for 16 hours. The reaction mixture is concentrated and the concentrate is dissolved in water (10 mL) and it is acidified with 1N-HCl. The separated crystals are collected by filtration and recrystallized from methanol-chloroform to give colorless crystals (0.2 g, 72%). Melting Point 232 ~ 234 ℃

Example 14

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

Ethyl 2-butyl-1-[(2'-cyanobiphenyl-4-yl) methyl] benzimidazole-7-carboxylate (0.21 g), sodium azide (1.3 g) in DMF (8 mL) and The mixture of ammonium chloride (1.07 g) is stirred at 110-120 ° C. for 60 hours. Water is added to the mixture, the mixture is acidified with 1N-HCl (pH 3-4) and extracted with ethyl acetate. The organic layer is washed with water, dried and concentrated to dryness. Ether was added to the concentrate, and the obtained crude crystals were collected by filtration and then recrystallized from ethanol to give colorless crystals (0.95 mg, 41%).

Melting Point 138 ~ 139 ℃

Example 15

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

Ethyl 2-butyl-1-[[2 '-(1H- tetrazol-5-yl) biphenyl-4-yl] methyl] benzimi in 2-methoxyethanol (1.5 mL) and 2N NaOH (1.5 mL) Dazol-7-carboxylate (80 mg) is stirred at 110-120 ° C. for 1 hour. The reaction mixture is neutralized with 2N-HCl and then concentrated to dryness. The concentrate is dissolved in chloroform. The insoluble matter is removed by filtration, and then the filtrate is concentrated to dryness. The obtained crude crystals were recrystallized from an aqueous ethanol solution to give colorless crystals (60 mg, 77%).

Melting point, ¹ H-NMR and IR data are consistent with the data observed in Example 1.

Example 16

[2-butyl-7-hydroxymethyl-1-[[2 '-(1H- tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole]

2-butyl-1-[(2'-cyanobiphenyl-4-yl) methyl] -7-hydroxymethylbenzimidazole (0.4 g), sodium azide (0.98 g) and ammonium in DMF (4 mL) The mixture of chloride (0.8 g) is stirred at 110-120 ° C. for 4 days. Water is added to the reaction mixture, which is extracted with ethyl acetate. The extract is washed with water and dried. After removal of the solvent, the residue is crystallized from ethyl acetate-methanol to give colorless acicular crystals (melting point 152-153 ° C.).

Example 17

[Ethyl [[2-butyl-1- [2 '-(1H- tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazol-7-yl] acetate]

Ethyl 2-butyl-1-[(2'-cyanobiphenyl-4-yl) methyl] benzimidazole-7-carboxylate (0.86 g), sodium azide (0.5 g) in DMF (10 mL) and The mixture of ammonium chloride (1.6 g) is stirred in DMF at 110-120 ° C. for 4.5 days. Water is added to the reaction mixture, which is acidified with 1N-HCl (pH 3-4) and extracted with ethyl acetate. The organic layer is washed with water and dried, then the solvent is distilled off. The residue is purified by silica gel column chromatography to give crude crystals. Recrystallization from ethyl acetate gives colorless needles (0.53 g, 56%, melting point 129-130 DEG C).

Example 18

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

Ethyl 2-butyl-1-[[2 '-(1H- tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7- in 1N NaOH (1.5 mL) and methanol (5 mL) The mixture of acetate (0.28 g) is heated under reflux for 2 hours. The reaction mixture is concentrated and neutralized with 1N-HCl. The separated crystals are collected by filtration and purified by silica gel column chromatography to give colorless crystals (0.12 g, 46%, melting point 170 ~ 171 ℃).

Example 19

[2-butyl-7-methoxymethyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole sodium salt]

Of 2-butyl-1-[(2'-cyanobiphenyl-4-yl) methyl] -7-methoxymethylbenzimidazole (0.6 g) and trimethyltin azide (1.2 g) in toluene (12 mL) The mixture is heated for 3 days under reflux in toluene (12 mL). The solvent is distilled off. 1N-HCl (8 mL) is added to the residue, the mixture is stirred briefly and then extracted with ethyl acetate. The organic layer is washed with water, dried and the solvent is distilled off. The residue is purified by silica gel column chromatography to give an oil. The product is dissolved in ethyl acetate, and thereto is added a sodium column methanol solution of 2-ethylhexanoic acid (0.25 g). The mixture is concentrated. The separated crystals are recrystallized from toluene-ethyl acetate to give colorless crystals (0.22 g, 31%, melting point 175-178 ° C.).

Example 20

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

A mixture of 2-butyl-1-[(2'-cyanobiphenyl-4-yl) methyl] -7-methoxybenzimidazole (0.8 g) and trimethyltin azide (1.6 g) in toluene (15 mL) Heated at reflux for 44 h. The separated crystals are collected by filtration and dissolved in methanol (20 mL). 1N-HCl (8 mL) is added to the solution and the mixture is stirred at room temperature for 5 minutes. Water is added to the reaction mixture, which is then extracted with ethyl acetate. The organic layer is washed with water and dried. The solvent is distilled off and the residue is purified by silica gel column chromatography to give crude crystals. Recrystallization from ethyl acetate-methanol yields a colorless prism (0.83 g, 87%, melting point 189-190 ° C.).

Example 21

[2-butyl-6-methyl-1-[[2 '-(1H- tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid]

5 N aqueous sodium hydroxide solution (5 mL) and ethyl 2-butyl-6-methyl-1-[[2 '-(1H- tetrazol-5-yl) biphenyl-4-yl] methyl] in ethanol (10 mL)] The mixture of benzimidazole-7-carboxylate (0.55 g) is heated under reflux for 100 hours. The reaction mixture is concentrated to dryness, which is dissolved in water and the solution is acidified with concentrated HCl. The separated precipitate is collected by filtration and washed with a mixture of dichloromethane and methanol. The precipitate is dissolved in a saturated aqueous solution of sodium bicarbonate. After the insoluble matter is removed by filtration, the filtrate is acidified with concentrated HCl. The separated precipitate is collected by filtration and crystallized from dimethylformamide-H ₂ O to give colorless crystals (0.22 g, 42%, melting point 298-299 ° C.).

Example 22

[2-butyl-1-[[2 '-(1H- tetrazol-5-yl) biphenyl-4-yl] methyl] -7-methylbenzimidazole]

2-butyl-1-[(2'-cyanobiphenyl-4-yl) methyl] -7-methylbenzimidazole (0.5 g), sodium azide (1.3 g) and ammonium chloride in DMF (5 mL) 1.1 g) is stirred at 110-120 ° C. for 3.5 days. Water is added to the reaction mixture, which is acidified with 1N-HCl (pH 3-4) and extracted with ethyl acetate. The organic layer is washed with water and dried. The solvent is distilled off and the residue is purified by silica gel column chromatography to give crystals. Recrystallization from ethyl acetate-methanol affords colorless crystals (0.36 g, 62%, melting point 222-224 ° C.).

Example 23

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

Ethyl-1-[(2'-cyanobiphenyl-4-yl) methyl] -2-isopropylbenzimidazole-7-carboxylate (2.12 g) in DMF (5 mL), sodium azide (3.9 g) ) And ammonium chloride (3.2 g) are stirred at 110-120 ° C. for 5 days. Water (150 mL) is added to the reaction mixture, which is acidified with diluted hydrochloric acid (pH 3-4) and extracted with ethyl acetate. The organic layer is washed with water, dried and concentrated to dryness. The concentrate is crystallized from ethanol to give a colorless prism (1.2 g, 52%, melting point 144-146 ° C).

Example 24

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

Ethyl 1-[(2'-cyanobiphenyl-4-yl) methyl] -2-methylbenzimidazole-7-carboxylate (2.5 g) in DMF (30 mL), sodium azide (3.9 g) and The mixture of ammonium chloride (3.2 g) is stirred at 110-120 ° C. for 4 days. The reaction mixture is treated according to the method described in Example 23 to obtain crystals. Recrystallization from ethanol yields a colorless prism (1.36 g, 49%, melting point 205-206 ° C).

Example 25

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

Ethyl 1-[(2'-cyanobiphenyl-4-yl) methyl] -2-ethylbenzimidazole-7-carboxylate (1.55 g), sodium azide (2.6 g) in DMF (15 mL) and The mixture of ammonium chloride (2.14 g) is stirred at 110-120 ° C. for 5 days. The reaction mixture is treated according to the method described in Example 23 to obtain crystals. Recrystallization from ethanol yields a colorless prism (0.68 g, 40%, melting point 188-189 ° C.).

Example 26

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

Ethyl 2-methyl-1-[[2 '-(1H- tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate (0.64 g) in methanol (10 mL) And heated to reflux for 24 hours in a mixture of 2N NaOH. The reaction mixture is concentrated to dryness and the concentrate is dissolved in water and neutralized with 1N-HCl to give crystals. Recrystallization from DMF-EtOH-H ₂ O affords a colorless prism (0.3 g, 49%, melting point 283-284 ° C. (decomposition)).

Example 27

[2-ethyl-1-[[2 '-(1H- tetrazol-5-yl) biphenyl-4-yl] methylbenzimidazole-7-carboxylic acid]

Ethyl 2-ethyl-1-[[2 '-(1H- tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate (0.5 g) in methanol (10 mL) And heated to reflux for 4 hours in a mixture of 2N NaOH. The reaction mixture is concentrated to dryness. The concentrate is dissolved in water and then neutralized with 1N-HCl to give crystals. Recrystallization from DMF-ethanol-water gives a colorless prism (0.27 g, 58%, melting point 261-262 ° C.).

Example 28

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

Ethyl 2-isopropyl-1-[[2 '-(1H- tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7 in methanol (5 mL) and 2N NaOH (5 mL) The carboxylate (1.2 g) mixture is heated at reflux for 4 hours. The reaction mixture is concentrated to dryness, dissolved in water and neutralized with 1N-HCl to give crystals. Recrystallization from DMF-50% EtOH gives a colorless prism (0.8 g, 71%, melting point 265-267 ° C. (decomposition)).

Example 29

[2-Butyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid dibasic potassium salt]

2-butyl-1-[[2 '-(1H- tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid (1.2 g) in ethanol (50 mL) and Toluene (50 mL) is added to a solution of potassium 2-ethylhexanoate (1.3 g), and ethanol is distilled off. The separated crystals are collected by filtration and washed with ether to give colorless crystals (1.1 g, 79%, melting point 355-358 ° C. (decomposition)).

Example 30

[2-butyl-7-hydroxy-1-[[2 '-(1H- tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole]

A mixture of 2-butyl-1-[(2'-cyanobiphenyl-4-yl) methyl] -7-hydroxybenzimidazole (0.69 g) and trimethyltin azide (1.1 g) in toluene (15 mL) Is heated under reflux for 4 days. The separated crystals are collected by filtration and stirred for 10 minutes at room temperature in a mixture of 1N-HCl (10 mL) and methanol (15 mL). 1N NaOH was added to the obtained solution to adjust the pH to 3-4 to obtain crystals. The crude crystals are purified by silica gel column chromatography to yield crystals. Recrystallization from acetone gives colorless crystals (melting point 186-188C).

Example 31

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

2-propyl-1-[[2 '-(1H- tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid (465 mg) in methanol (60 mL) and The mixture of concentrated sulfuric acid (7.2 g) is heated at reflux for 24 h. After removal of the solvent, the residue is suspended with water, adjusted to pH 3-4 by the addition of 1N-NaOH to it and extracted with ethyl acetate. The organic layer is washed with water, dried and the solvent is evaporated. The residue is purified by silica gel column chromatography. Recrystallization from ethanol yields a colorless prism (310 ml, melting point: 195-196 ° C.).

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

Example 32

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

Melting Point 185 ~ 186 ℃

Example 33

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

Example 34

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

2-butyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-car in methanol (18 mL) and deep sulfur phase (14.4 g) The mixture of acids (1.8 g) is heated at reflux for 24 h. After removal of the solvent by evaporation, the residue is suspended with water, adjusted to pH 3-4 by the addition of 1N-NaOH to it and extracted with ethyl acetate. The organic layer is washed with water and dried. The solvent is evaporated off and the residue is purified by silica gel column chromatography. Recrystallization from ethanol yields a colorless prism (1.05 g, melting point 153-155 ° C.).

Reference Example 35

[Ethyl 2-sec-butyl-1-[[2 '-(1H- tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate]

The compound is prepared according to the method described in Example 14.

Melting Point: 128 ~ 130 ℃

Example 36

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

2-butyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid (3.0 g) in methylene chloride (20 mL) A solution of triphenylmethylchloride (1.96 g) and triethylamine (1.0 mL) is stirred for 16 hours at room temperature. The reaction mixture is washed with water and dried. After removal of the solvent, the residue is purified by silica gel column chromatography to give a colorless powder (4.25 g). The N-trityl compound obtained is dissolved in DMF (5 mL). Potassium carbonate (0.2 g) and pivaloyloxymethyl iodide (0.35 g) are added to the solution and the mixture is stirred at room temperature for 2 hours. The reaction mixture is concentrated. Water and ethyl acetate are added to the concentrate, which is extracted. The organic layer is washed with water and dried. After removal of the solvent by distillation, the residue is dissolved in methanol (10 mL). 1N-HCl (3 mL) is added to the solution and the mixture is stirred at RT for 1.5 h. The reaction mixture is concentrated to dryness and the concentrate is purified by silica gel column chromatography to give colorless powdery crystals (0.43 g, 74%, melting point 102-105 ° C).

According to the method of Example 36, the following compounds were synthesized.

Example 37

[1- (Cyclohexyloxycarbonyloxy) ethyl 2-butyl-1-[[2 '-(1H- tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-car Carboxylate]

Yield: 74%

Melting Point: 102 ~ 105 ℃

Example 38

[1- (ethoxycarbonyloxy) ethyl 2-butyl-1-[[2 '-(1H- tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate ]

Yield: 75%

Melting Point: 92 ~ 95 ℃

Example 39

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

Yield: 71%

Melting Point: 123 ~ 125 ℃

Example 40

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

Ethyl 2-butyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate (0.72 g in ethylene glycol (15 mL) To the solution of) sodium hydride (60% oil, 0.25 g) is added with stirring at room temperature and the mixture is stirred at room temperature for 15 hours. Ice water (100 mL) is added to the reaction mixture, which is acidified with formic acid. The precipitate formed is dissolved in ethyl acetate (100 mL) and the solution is washed with water, dried and concentrated to dryness to afford crystalline product. The crystals are recrystallized from acetone to give colorless crystals (0.49 g, 66%, melting point 145-147 캜).

Example 41

[2- (4-morpholino) ethyl 2-butyl-1-[[2 '-(1H- tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate ]

2-butyl-1-[[2 '-(N-triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid in DMF (2 mL) (0.4 g), a cold solution of 4- (2-hydroxyethyl) morpholine (0.15 g) and diethyl phosphocyanidate (0.1 g) was added a solution of triethylamine (0.06 g) in DMF (1 mL) and The mixture is stirred for 30 hours at room temperature. The reaction mixture is concentrated to dryness to give a residue which is purified by silica gel column chromatography to give a colorless powder (0.3 g, 65%). The product is dissolved in methanol (7 mL) and 1N-HCl (1.2 mL) is added to the solution. After stirring for 2 hours at room temperature, the reaction solution is concentrated to dryness to give a residue. The residue is dissolved in CH ₂ Cl ₂ -H ₂ O and the water layer is basified with aqueous NaHCO ₃ solution. The water layer is extracted with CH ₂ Cl ₂ and the combined CH ₂ Cl ₂ solution is washed with H ₂ O, dried and evaporated to dryness to give a residue. The residue is purified by silica gel column chromatography to give colorless fine crystals (0.19 g, 87%, melting point 98-110 ° C.).

Example 42

[2- (1-piperidino) ethyl 2-butyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate ]

Colorless powder (55%)

Melting Point 210 ~ 213 ℃

Example 43

[2- (dimethylamino) ethyl 2-butyl-1-[[2 '-(1H- tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate]

Colorless powder (91%)

Melting Point 206 ~ 208 ℃

Example 44

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

Methyl 1-[(2'-cyanobiphenyl-4-yl) methyl] -2-methoxymethylbenzimidazole-7-carboxylate (0.4 g) and trimethyltin azide (1.0 g) in toluene (10 mL) The mixture of g) is refluxed for 49 hours. The reaction solution is concentrated to dryness to give a residue, which is dissolved in methanol (6 mL) and 1N-HCl (6 mL). The solution is stirred for 3 hours and concentrated to dryness to afford a residue. The residue is dissolved in CH ₂ Cl ₂ -H ₂ O and the mixture is neutralized with 1N-NaOH. The organic layer is washed with H ₂ O, dried and concentrated to dryness to give a residue, which is purified by silica gel column chromatography to give crystalline product. Recrystallization from ethyl acetate-isopropyl ether gives colorless needles (0.3 g, 68%).

Melting Point 191 ~ 194 ℃

The following compounds (Examples 45-47) were prepared following methods analogous to those of Example 44.

Example 45

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

Colorless powder

Example 46

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

Colorless powder (75%)

Example 47

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

Colorless powder (56%)

Example 48

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

By a method similar to Example 44, ethyl 2-acetoxymethyl-1-[[2 '-(1H- tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxyl The compound is prepared from the rate.

Pale yellow powder (80%)

Example 49

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

Methyl 2-methoxymethyl-1-[[2 '-(1H- tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole in methanol (10 mL) and 1N-NaOH (1.5 mL) The solution of -7-carboxylate (0.2 g) is heated at 80 ° C. for 20 hours. The solution is concentrated to dryness to afford a residue. The residue is dissolved in H ₂ O and acidified to give crystalline product. Recrystallization from DMF-MeOH-H ₂ O affords a colorless prism (0.16 g, 80%, melting point 272-274 ° C.).

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

Example 50

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

Colorless powder (80%), Melting point 243 ~ 245 ℃

Example 51

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

Colorless powder (82%), melting point 270-272 degreeC

Example 52

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

Colorless powder (65%), melting point 292-294 ℃

Example 53

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

Colorless crystals (76%), Melting point 157-160 ℃

Example 54

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

Colorless powder (48%)

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

Example 55

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

Colorless powder (54%), Melting point 186 ~ 188 ℃

Example 56

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

Pale yellow powder (49%)

Example 57

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

Colorless powder (30%)

Example 58

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

Colorless needle-like crystal (61%), melting point 214-217 ℃

Example 59

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

Ethyl 2-hydroxymethyl-1-[[2 '-(1H- tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxyl in CH ₂ Cl ₂ (3 mL) Thionylchloride (0.3 mL) is added dropwise to the solution of rate (0.2 g) and the mixture is refluxed for 3 hours. The reaction solution was poured into ice water, the organic layer was washed with water, dried and evaporated to dryness to give a pale yellow amorphous powder (0.2 g, 0.6%).

Example 60

[Ethyl 2-methylaminomethyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimadazole-7-carboxylate]

Ethyl 2-chloromethyl-1-[[2 '-(1H- tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate in acetonitrile (5 mL) (0.2 To the solution of g) is added 40% methylamine solution in methanol (0.33 g) and the mixture is heated for 60 ° C. to 77 hours. Cool the reaction solution to give a pale yellow prism (0.12 g, 61%, melting point 248 ~ 250 ℃).

The following compounds (Examples 61-62) were prepared by methods similar to those of Example 1.

Example 61

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

Colorless Prism (71%)

Example 62

[Ethyl 2-sec-butyl-1-[[2 '-(1H- tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate]

Colorless prism (43%), melting point 128-130 degreeC

The following compounds (Examples 63-64) were prepared by methods analogous to those of Example 49.

Example 63

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

Colorless powder (62%), Melting point 205-207 ° C (decomposition)

Example 64

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

Colorless Prism (79%), Melting Point 184 ~ 186 ℃

The following compounds (Examples 65-66) were prepared by methods analogous to those of Example 19.

Example 65

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

Pale yellow powder (35%)

Example 66

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

Pale yellow powder (16%)

Example 67

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

2-butyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid (2.0 g) in DMF (10 mL), A mixture of NaHCO ₃ (1.1 g) and methyl iodide (1.5 g) is stirred at room temperature for 15 hours. The reaction mixture is diluted with water and then the mixture is extracted with ethyl acetate. The organic layer is washed with water, dried and concentrated to dryness. The obtained residue is purified by silica gel column chromatography to give 1-methyl derivative (0.95 g, 45%) and 2-methyl derivative (0.36 g, 17%).

Example 68

[2-butyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -7-formylaminobenzimidazole and 2-butyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -7-ethoxycarbonylaminovanzimidazole]

2-butyl-1-[[2 '-(1H- tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid (0.94 g) in DMF (6 mL), The mixture of diphenylphosphoryl azide (0.61 g) and triethyl amine (0.61 g) is stirred at room temperature for 7 hours and then the reaction mixture is concentrated to dryness to give a crystalline residue. The residue is purified by silica gel column chromatography to give two colorless crystalline products 68a and 68b.

Example 69

[2-butyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -7- (N, N-dimethylaminomethyl) benzimidazole]

The compound is prepared by a method similar to that of Example 44.

Colorless crystals (56%), Melting point 178-180 ° C (distribution)

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

Example 70

[2-butyl-1-[[2 '-(1-methyltetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid]

Colorless prism (78%), melting point 213-214 degrees Celsius

Example 71

[2-butyl-1-[[2 '-(2-methyltetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid]

Colorless needle-like crystal (71%), melting point 226-228 ° C (decomposition)

Example 72

[2-Butyl-1-[[2 '-(N-pivaloyloxymethyltetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid]

2-butyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid (0.71 g) in DMF (2 mL), A mixture of K ₂ CO ₃ (0.21 g) and iodinemethylpivalate (0.36 g) is stirred at room temperature for 17 hours. The reaction mixture is immersed in water and acidified (pH 3-4) with 1N-HCl. The mixture is extracted with ethyl acetate and the organic layer is washed with H ₂ O, dried and evaporated to dryness to give a residue. The residue is purified by silica gel column chromatography to give a colorless powder (0.2 g, 23%, melting point 188-191 ° C. (decomposition)).

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

Example 73

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

Example 74

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

Example 75

[1- (Cyclohexyloxycarbonyloxy) ethyl 2-propyl-1-[[2 '-(1H- tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-car Carboxylate]

Example 76

[1- (Cyclohexyloxycarbonyloxy) ethyl 2-ethyl-1-[[2 '-(1H- tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-car Carboxylate]

Experimental Example 1

Inhibition of binding of angiotensin-II to angiotensin receptor.

[Way]

Experiments that inhibit the binding of angiotensin II (A-II) to A-II-receptors are performed by modifying Douglas et al. [Endocrinology, 102, 685-696 (1978)]. A-II receptors are prepared from bovine adrenal membrane fragments.

Compound (10 ^-6 M or 10 ^-5 M) and ^{125 IA-II (1.85kBq / 50㎕} ) a wherein for one hour, and the mixture to the receptor membrane fragments at room temperature of the present invention addresses. Receptor-binding and liberated ¹²⁵ IA-II are separated through a filter (Whatman GF / B filter) and the radioactivity of ¹²⁵ IA-II bound to the receptor is measured.

[result]

Table 1 shows the results for the compounds of the present invention.

Experimental Example 2

Inhibitory effect of the compound of the present invention on the blood pressure promoting action of A-II

[Way]

Jcl: SD rats (9 weeks old, males) are used. The day before the experiment, the animals were inserted in the arteries and veins of the femur under conditions anesthetized with pentobarbitalsodium. Until the experiment begins, the animals are fasted but the water is free to drink. On the day of the experiment, the kale is connected to the blood pressure transducer and the average blood pressure is recorded by the blood pressure recorder. Prior to drug administration, blood pressure enhancing action due to intravenous administration of A-II (100 ng / kg) is measured as a control. Following oral administration of the drug, A-II is administered intravenously and the blood pressure enhancing action is measured at each time point measured. The percent inhibition of the drug to A-II induced blood pressure promoting action is calculated by comparing the blood pressure enhancing action before and after the drug is administered.

[result]

Table 1 shows the results for the compounds of the present invention.

Toxicity Test Results

The compound of Example 1 was prepared at a concentration of 2.5% (w / v) and injected intravenously in a predetermined amount (62.5-1000 mg / kg) in 4-week-old Jcl: ICR male mice and 5-week-old male Jcl: Wistar rats. Lethality (death / dosage) was observed for 14 days after administration.

the results are as follow.

That is, in mice and rats, no mortality was observed even at the dose of 500 mg / kg, and therefore, the LD value was 500-1000 mg / kg.

Claims (38)

Compounds of the general formula [Wherein, R ¹ represents a hydroxyl group, an amino group, an N-lower (C _1-4 ) alkyl amino, an N, N-di lower (C _1-4 ) alkylamino, halogen, lower (C _1-4 ) alkyl tea C _1-8 straight or branched chain lower alkyl which may be substituted with an thio or lower (C _1-4 ) alkoxy group; R ² is a group of the general formula-(CH ₂ ) _n -CO-D- (wherein D is hydrogen, a hydroxyl group, an amino group, an N-lower (C _1-4 ) alkyl amino, N, N-diserial ( C _1-4 ) alkylamino, halogen, or hydroxyl group, amino, N-lower (C _1-4 ) alkylamino, N, N-di lower (C _1-4 ) alkylamino, halogen, lower (C _{2 1-6)} alkanoyloxy, lower (C _{1 - 6)} alkoxy, lower (C _{1 - 6)} alkylthio or lower (C _{1 - 6)} alkoxycarbonyloxy lower with the alkyl moiety which may be substituted with (C _{1 6} ) an alkoxy group, n is 0 or 1); Cyano; Tetrazolyl, which may be protected by alkyl or acyl; Phosphoric acid; Sulfonic acid; Phenolic hydroxyl groups; Hydroxyl group, amino, N-lower (C _1-4 ) alkyl amino, N, N-di lower (C _1-4 ) alkylamino, halogen, lower (C _2-6 ) alkanoyloxy or lower (C _{1 6} ) lower (C _1-6 ) alkoxy group having an alkyl moiety which may be substituted with alkoxycarbonyloxy; Trifluoromethanesulfonic acid amide; Or a hydroxyl, amino, N- lower (C _{1 ~ 4)} alkylamino or N, N- di-lower (C _{1 ~ 4)} linking may be substituted by a lower alkyl amino (C _{1 ~ 3)} represents an alkyl group; R ³ represents a carboxyl, tetrazolyl, trifluoromethanesulfonic acid amide, phosphoric acid, sulfonic acid, cyano or lower (C _1-4 ) alkoxycarbonyl group, which may each be protected by an alkyl or acyl group; Ring A is a group R ² in addition to, halogen, nitro, cyano, amino, N- lower (C _{1 ~ 4)} alkylamino, N, N- di-lower (C _{1 ~ 4)} alkylamino, N- arylamino, alicyclic A group amino, and a group of the formula -YR wherein Y is a bond, -O-, -S- or Represents; R is hydrogen, a hydroxyl group, an amino group, N-lower (C _1-4 ) alkyl amino, N, N-di lower (C _1-4 ) alkylamino, N-aryl amino, alicyclic amino, halogen or lower ( C _1-4 ) lower (C _1-4 ) alkyl group which may be substituted with alkoxy, or a group of the formula -CO-D (wherein D is hydrogen; hydroxyl group, amino group, N-lower (C _1-4 ) Lower amino (C _1-4 ) alkoxy which may be substituted by alkyl amino, N, N-di lower (C _1-4 ) alkylamino, N-aryl amino, alicyclic amino, halogen or lower (C _1-4 ) alkoxy Amino group; N-lower (C _1-4 ) alkyl amino; N, N-di-lower (C _1-4 ) alkylamino; N-arylamino; cycloaliphatic amino; halogen; or represents a hydroxyl group Benzene ring further having one or more other substituents; X represents a bond of a phenylene group and a phenyl group directly or through a spacer having up to 2 atomic chains.] According to claim 1, characterized in that the compound R ¹ is a hydroxyl group, an amino group, halogen or lower (C _{1 ~ 4)} alkoxy groups may be substituted by lower (C _{1 ~ 5)} alkyl group. The compound according to claim 1, wherein in the definition of R ² , alkyl which is a protecting group of tetrazolyl is lower (C _1-4 ) alkyl. The compound according to claim 1, wherein in the definition of R ² , acyl, which is a protecting group of tetrazolyl, is lower (C _2-5 ) alkanoyl or benzoyl. The compound of claim 1, wherein R ² is a group of the formula — (CH ₂ ) _n —CO—D—, wherein D is hydrogen, a hydroxyl group, amino, N-lower (C _1-4 ) alkylamino, N , N-di lower (C _1-4 ) alkylamino or lower (C _1-6 ) alkoxy group, the alkyl moiety of which is hydroxyl group, amino, halogen, lower (C _2-6 ) alkanoyloxy, lower Or (C _1-6 ) alkoxy, lower (C _1-6 ) alkylthio, or lower (C _1-6 ) alkoxycarbonyloxy, n is an integer 0 or 1.], or lower (C _{1) 4} ) A compound characterized in that it is tetrazolyl which may be protected by alkyl, lower (C _2-5 ) alkanoyl or benzoyl. 2. A group according to claim 1, wherein R ² is a group of the formula —CO—D ′ wherein D ′ is a hydroxyl group, amino, N-lower (C _1-4 ) alkylamino, N, N-diserial (C _1-4 ) alkylamino or lower (C _1-6 ) alkoxy group, the alkyl moiety of which is hydroxyl group, amino, halogen, lower (C _2-6 ) alkanoyloxy, lower (C _1-6 ) alkoxy Or lower (C _1-6 ) alkylthio or lower (C _1-6 ) alkoxycarbonyloxy.], Or lower (C _1-4 ) alkyl, lower (C _2-5 ) alkanoyl or Tetrazolyl, which may be protected with benzoyl. 7. A compound according to claim 6, wherein D 'is a hydroxyl group, amino, N-lower (C _1-4 ) alkylamino, N, N-di lower (C _1-4 ) alkylamino or lower (C _1-4 ) alkoxy Group, the alkyl moiety of which may be substituted by a hydroxyl group, an amino, a halogen, a lower (C _1-4 ) alkoxy group. The compound of claim 1, wherein in the definition of R ³ , alkyl which is a protecting group is lower (C _1-4 ) alkyl. A compound according to claim 1, wherein in the definition of R ³ , acyl, which is a protecting group, is lower (C _2-5 ) alkanoyl or benzoyl. The compound of claim 1, wherein R ³ is carboxyl or tetrazolyl. A compound according to claim 1, wherein N-arylamino which is a substituent of Ring A is phenylamino. A compound according to claim 1, wherein the cycloaliphatic amino which is a substituent of ring A is morpholino, piperidino or N-phenylpiperazino. The substituent of ring A is a halogen, lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy, nitro, group of the formula -CO-D'- wherein D ' Hydroxy group or lower (C _{1 -2} ) alkyl], and amino, which may be substituted with lower (C _1-4 ) alkyl. The compound of claim 1, wherein the substituent of ring A is selected from the group consisting of halogen and lower (C _1-4 ) alkyl. A compound according to claim 1, wherein the substituent of ring A is a group of the formula -Y-R wherein Y is a bond and R is hydrogen. The method of claim 1, wherein the spacer having an atomic chain of 2 or less is lower (C _1-4 ) alkylene, Compound characterized in that the two chains selected from the group consisting of. The compound of claim 1, wherein X represents a direct bond of phenylene and phenyl. The compound according to claim 1, represented by the following general formula: [Wherein R ¹ is lower (C _2-5 ) alkyl which may be substituted by hydroxyl, amino, halogen or lower (C _1-4 ) alkoxy, and R ² is a group of the formula -CO-D ' Wherein D ′ is hydroxyl, amino, N-lower (C _1-4 ) alkyl amino, N, N-di-lower (C _1-4 ) alkyl amino or hydroxyl, amino, halogen or lower (C _{1 ~ 4)} and is optionally substituted lower alkoxy (C _{1 ~ 4)} alkoxy), or lower (C _{1 ~ 4)} tetra which may be protected by alkyl, lower (C _{2 ~ 5)} alkanoyl or benzoyl group, the R ³ is carboxyl or tetrazolyl which may be protected by lower (C _1-4 ) alkyl, lower (C _2-5 ) alkanoyl or benzoyl, R ′ is hydrogen, halogen, lower (C _1-4 ) Alkyl, lower (C _1-4 ) alkoxy, nitro, group of the formula -CO-D '(wherein D' is hydroxyl or lower (C _1-2 ) alkoxy), or lower (C _1-4) Amino which may be substituted by alkyl.] _19. A compound according to claim 18, wherein R 'is hydrogen, lower (Ci _{. 4} ) alkyl or halogen. 19. The compound of claim 18, wherein R 'is hydrogen. 19. The method of claim 18 wherein, R ² is 'a group [wherein, D' the formula -CO-D is hydroxyl, amino, N- lower (C _{1 ~ 4)} alkylamino, N, N- di-lower (C _{1 4} ) alkylamino, or lower (C _1-4 ) alkoxy which may be substituted by hydroxyl, amino, halogen or lower (C _1-4 ) alkoxy. The compound of claim 1, wherein R ³ is tetrazolyl. The compound of claim 1, wherein the salt is a pharmaceutically acceptable salt. The compound of claim 1, which is 2-butyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid. The compound of claim 1, wherein pivalooxyoxymethyl 2-butyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate Phosphorus compounds. The compound according to claim 1, wherein 1- (cyclohexyloxycarbonyloxy) ethyl 2-butyl-1-[[2 '-(1H- tetrazol-5-yl) biphenyl-4-yl] methyl] benzimi Compound that is dozol-7-carboxylate. The compound of claim 1, which is methyl 2-butyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid. The compound of claim 1, which is 2-propyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid. Angiotensin, characterized in that it contains (a) an effective amount for antagonizing angiotensin II of a compound according to claim 1 or a salt thereof, and (b) a pharmaceutically acceptable carrier, excipient or diluent. Pharmaceutical compositions suitable for antagonizing II. A compound according to claim 1 and salts thereof for use in the manufacture of a medicament for the treatment of cardiovascular diseases. A compound of formula (I) consisting of reacting a compound of formula (II) with a compound of formula (III) and possibly converting the obtained compound of formula (I) to a salt thereof Process for the preparation of compounds and salts thereof: [Wherein R ¹ , R ² , R ³ , A and X are as defined in claim 1 and W represents a halogen atom.] A compound of formula (I) and salts thereof, characterized by intramolecular dehydration cyclization of a compound of formula (IV), wherein the obtained compound of formula (I) is capable of converting its salt Method of manufacture: [Wherein R ¹ , R ² , R ³ , A and X are as defined in claim 1.] A compound of formula (I), characterized by reacting a compound of formula (V) with a compound of formula R ¹ -Y and possibly converting the obtained compound of formula (I) to a salt thereof Method for preparing compounds and salts thereof [Wherein R ¹ , R ² , R ³ , A and X are as defined in claim 1 and Y represents carboxyl, aldehyde, iminoether, iminothioether, amidine or cyano.] Compounds of the general formula [Wherein R ² is a group of the formula-(CH ₂ ) _n -CO-D- (wherein D is hydrogen, a hydroxyl group, an amino group, an N-lower (C _1-4 ) alkyl amino, N, N- Lower (C _1-4 ) alkylamino, halogen, or hydroxyl group, amino, N-lower (C _1-4 ) alkyl amino, N, N-di lower (C _1-4 ) alkylamino, halogen, lower (C _{2 ~ 6)} alkanoyloxy or lower (C _{1 ~ 6)} alkoxycarbonyloxy represents a group having an alkyl moiety which may be substituted with a lower (C _{1 ~ 6)} alkoxy, n is 0 or 1); Cyano; Tetrazolyl, which may be protected by alkyl or acyl; Phosphoric acid; Sulfonic acid; Phenolic hydroxyl groups; Hydroxyl group, amino, N-lower (C _1-4 ) alkyl amino, N, N-di lower (C _1-4 ) alkylamino, halogen, lower (C _2-6 ) alkanoyloxy or lower (C _{1 6} ) lower (C _1-6 ) alkoxy group having an alkyl moiety which may be substituted with alkoxycarbonyloxy; Trifluoromethanesulfonic acid amide; Or lower (C _1-3 ) alkyl group which may be substituted by hydroxyl, amino group, N-lower (C _1-4 ) alkyl amino or N, N-di-lower (C _1-4 ) alkylamino; R ³ represents a carboxyl, tetrazolyl, trifluoromethanesulfonic acid amide, phosphoric acid, sulfonic acid, cyano or lower (C _1-4 ) alkoxycarbonyl group, which may each be protected by an alkyl or acyl group; Ring A is a group R ² in addition to, halogen, nitro, cyano, amino, N- lower (C _{1 ~ 4)} alkylamino, N, N- di-lower (C _{1 ~ 4)} alkylamino, N- arylamino, alicyclic A group amino, and a group of the formula -YR wherein Y is a bond, -O-, -S- or Represents; R is hydrogen, hydroxyl group, amino group, N-lower (C _1-4 ) alkylamino, N, N-di-lower (C 1-4) alkylamino, N-aryl amino, alicyclic amino, halogen or lower (C _1-4 ) a lower (C _1-4 ) alkyl group which may be substituted with alkoxy, or a group of the formula -CO-D wherein D is hydrogen; a hydroxyl group, an amino group, an N-lower (C _1-4 ) alkyl Lower (C _1-4 ) alkoxy which may be substituted by amino, N, N-di lower (C _1-4 ) alkylamino, N-arylamino, cycloaliphatic amino, halogen or lower (C _1-4 ) alkoxy; Amino group; N-lower (C _1-4 ) alkyl amino; N, N-di lower (C _1-4 ) alkylamino; halogen; N-arylamino; cycloaliphatic amino; or hydroxyl group. Benzene ring further having one or more other substituents; X represents a bond of a phenylene group and a phenyl group directly or through a spacer having up to 2 atomic chains; Q ² is —NO ₂ or —NH ₂ when Q ¹ is H; Or Q ² is -NO ₂ when Q ¹ is -COO ^t Bu.] Methyl 3-amino-2-[[(2'-cyanobiphenyl-4-yl) methyl] amino] benzoate. A process for preparing a compound of formula (XII) characterized by alkylating a compound of formula (XI) with an alkylating agent of formula (III): [Wherein R ² , R ³ , A and X are as defined in claim 46c and W represents a halogen atom.] A process for preparing a compound of formula (XIII) characterized by deprotecting a compound of formula (XII) Wherein R ² , R ³ , A and X are as defined in claim 34. A process for preparing a compound of formula (V) characterized in that for reducing the compound of formula (XIII) with a reducing agent: Wherein R ² , R ³ , A and X are as defined in claim 34.