HUT74463A - Process for preparing new intermediates for producing benzimidazol derivatives - Google Patents

Abstract

SUMMARY OF THE INVENTION The present invention relates to a compound of formula (XVI) wherein R2 and R3 are a group capable of forming or converting an anion, A is a benzene ring which may optionally carry other substituents other than R2, X is phenylene. and the phenyl bond between the phenyl group or a linking chain of up to two members, Q1 is hydrogen or -COO-t-butyl, and Q2 is -NO2 or NH2 when Q1 is hydrogen and Q2 is - NO2 when Q1 is -COO-t-butyl and their salts. The compounds are useful intermediates for the preparation of certain angiotensin (II) inhibitors.

Description

The present invention relates to novel intermediates for the preparation of benzimidazole derivatives and to processes for their preparation.

The compounds of the invention are represented by the general formula (XVI) wherein

R ² and R ³ represent a group capable of forming or converting to an anion,

A is a benzene ring which may optionally carry substituents other than R ² ,

X is a bond or a bond of up to two members which is a bond between the phenylene and the phenyl group,

Q ¹ is hydrogen or -COO-t-butyl, and

Q ² is -NO 2 'or -NH ₂ when Q ¹ is hydrogen, and Q ² is -NO 2 - when Q ¹ is -COO-t-butyl.

The compounds of the invention may also exist in salt form.

The invention also relates to a process for the preparation of the compounds.

These compounds are important intermediates for the preparation of compounds of formula I wherein:

R ¹ is optionally substituted alkyl,

R ² and R ³ represent a group capable of forming or converting to an anion,

A is a benzene ring which may optionally carry substituents other than R ² ,

X is a bond or a bond of up to two members which is a bond between phenylene and phenyl. The compounds of formula I and their salts have potent angiotensin-3 (II) antagonism and have antihypertensive activity. Therefore, they can be used as drugs for the treatment of vascular diseases such as hypertension, heart disease, stroke.

The renin-angiotensin system plays a role in homeostasis, regulating systemic blood pressure, body fluid volume and electrolyte balance, along with the aldosterone system. The connection between the renin-angiotensin system and hypertension is known, based on the development of an angiotensin (II) (Ali) inhibitor that converts the enzyme (ACE inhibitor) that produces angiotensin (II), which has an effective vasoconstrictor effect. Because angiotensin (II) increases blood pressure through the angiotensin (II) receptors on the cell membrane, angiotensin (II) antagonists such as ACE inhibitors can be used to treat hypertension. Several angiotensin (II) -related substances are known to be potent angiotensin (II) antagonists, such as sararazine and (Sar ¹ , Al ⁸ ) Al. However, peptide antagonists are known to have a short duration of action after parenteral administration and to be ineffective when administered orally (see MA Ondetti and DW Cushman, Annual Reports in Medical Chemistry, 13, 82-91 (1978)).

On the other hand, certain non-peptide angiotensin (II) antagonists have also been developed to solve peptide antagonist problems.

The compounds of formula (I) are clinically useful compounds which are useful in the treatment of vascular diseases such as hypertension, heart disease and cerebral haemorrhage.

- 4 medications which are angiotensin (II) receptor antagonists and which have a potent angiotensin (II) antagonist and antihypertensive activity even after oral administration. These compounds are non-peptide angiotensin (II) receptor antagonists.

A number of processes for the preparation of compounds of formula I are known and possible. In some of these processes, new intermediates are also formed. The present invention relates in particular to these and novel processes for their preparation.

The present invention therefore relates to a process for the preparation of compounds of formula (XII) wherein R ² , R ³ and X are as defined above by reacting a compound of formula (XI) wherein R ² is as described above with a compound of formula (III). wherein R ³ and X are as defined above, and W is halogen.

The invention further relates to a process for the preparation of a compound of formula XIII wherein R ² , R ³ and X are as defined above by reacting a compound of formula XII wherein R ² , R ³ and X are as defined above. the protecting group is removed.

The invention further relates to a process for the preparation of compounds of formula V wherein R ² , R ³ and X are as defined above by reacting a compound of formula XIII wherein R ² , R ³ and X are as defined above. reduced.

According to the invention, alkyl is preferably a C1-8 linear or branched alkyl group in R ^1, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl -, pentyl, isopentyl, hexyl, heptyl,

- 5 groups. Alkyl groups may be substituted by hydroxy, optionally substituted amino, halogen, C 1-4 alkylthio or C 1-4 alkoxy. Particularly preferred substituents are C2-C5 alkyl, which may be optionally substituted by hydroxy, amino, halogen, or

It is substituted with C 1-4 alkoxy.

Suitable groups for the formation of the anion represented by R or which may be converted include: - (CH2) CO-D, wherein D is hydrogen, hydroxy, optionally substituted amino, halogen or optionally a substituted alkoxy group (for example, a C 1 -C 6 alkoxy group, the alkyl portion of which may be substituted by a hydroxy group, an optionally substituted amino group, a halogen atom, or a group of formula (1),

wherein R is hydrogen, straight or branched C 1 -C 6 alkyl such as methyl, ethyl, η-propyl, isopropyl, η-butyl, isobutyl, secondary butyl, tert-butyl, η- pentyl, isopentyl or neopentyl, or C 5-7 cycloalkyl, such as cyclopentyl, cyclohexyl, cycloheptyl, and

R 4 is a straight or branched C 1 -C 6 alkyl group such as methyl, ethyl, η-propyl, isopropyl, η-butyl, isobutyl, secondary butyl, tert-butyl, n-pentyl, isopentyl or neopentyl, or C 5 -C 7 cycloalkyl, such as cyclopentyl, cyclohexyl, cycloheptyl, C 1 -C 3 alkyl, such as methyl, ethyl, η-propyl, isopropyl, or C 2 -C 4 alkenyl, such as vinyl. -, propenyl, allyl, isopropenyl, which is substituted wherein the substituent is a C 5 -C 7 cycloalkyl group such as cyclopentyl, cyclohexyl, cycloheptyl, or phenyl, optionally substituted phenyl, straight or branched C 1 -C 6 alkoxy. such as methoxy, ethoxy, n-propoxy, isopropoxy, η-butoxy, isobutoxy, secondary butoxy, t-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, C 5 -C 7 cycloalkyloxy groups such as cyclo pentyloxy, cyclohexyloxy, cycloheptyloxy, lower C 1-3 alkoxy such as methoxy, ethoxy. n-propoxy, isopropoxy, substituted with C5-C7 cycloalkyl, such as cyclopentyl, cyclohexyl, cycloheptyl or phenyl, optionally substituted phenoxy, or optionally substituted benzyloxy-C1-6-lower alkoxy; A C 6 -C 6 alkylthio group or an optionally substituted dioxolenyl group such as 5-methyl-2-oxo-1,3-dioxolen-4-yl, preferably C 1 -C 6 alkoxy, the alkyl portion of which is hydroxy, optionally substituted amino, halogen, 2- Substituted with C 6 alkanoyloxy, C 1-6 alkoxy, C 1-6 alkylthio or C 1-6 alkoxycarbonyloxy, and n is 0 or 1 to 7

A cyanide group which may be optionally protected, such as an alkyl or acyl group, a tetrazolyl group, a phosphoric acid, a sulfonic acid, a phenolic hydroxy group, an optionally substituted alkoxy group, a trifluoromethanesulfonic acid amide and a C 1-3 alkyl group optionally substituted or hydroxy. optionally substituted amino. Groups which are capable of forming anion, or which can be biologically converted to such groups, such as those which are physiologically metabolized or chemically, such as by oxidation, reduction or hydrolysis, are also within the meaning of R.

Compounds of formula (I) wherein R is an anion-forming group or a group which may be chemically converted to such an are important intermediates for synthesis.

Preferred values for R are: -C0-0, wherein D is hydrogen, hydroxy, amino, N-lower C1-C4 alkylamino, N, N-di-C1-C4 alkylamino, or C 6 -C 6 alkoxy optionally substituted on alkyl, hydroxy, amino, halogen, C 2 -C 6 alkanoyloxy, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, or C 1 -C 6 alkoxycarbonyl; and n is 0 or 1; or tetrazolyl optionally substituted with alkyl, for example

C 1-4 alkyl, or acyl, for example

It may be protected by a C 2 -C 5 alkanoyl or benzoyl group.

Also preferred are -C0-0 'groups, wherein 0' is hydroxy, amino,

N-C 1 -C 4 alkylamino; N, N-di-C 1 -C 4 i

- 8 alkylamino or C 1-6 alkoxy optionally substituted in alkyl, where the substituent is hydroxy, amino, halo, C 2-6 alkanoyloxy, C 1-6 alkoxy, C 1-6 an alkylthio group, or a C 1 -C 6 alkoxycarbonyloxy group, or a tetrazolyl group which may be optionally protected by an alkyl or acyl group.

The meanings of the radicals represented by R 1 which may or may be converted to an anion include the carboxyl group, the tetrazolyl group, the trifluoromethanesulfonic acid amide (NHSC 4 CF 3) group, the phosphoric acid, the sulfonic acid group, the cyanide group, C 1 -C 4 alkoxycarbonyl groups, and these groups may be optionally protected by optionally substituted lower alkyl or acyl groups, provided that they are capable of forming anion or of converting it to a biological, physiological or chemical moiety.

Compounds of formula (I) wherein they are an anion forming group or a group which can be converted into one by chemical means such as oxidation, reduction or hydrolysis are important intermediates for synthesis.

r3 is preferably carboxyl or tetrazolyl.

Examples of substituents on ring (A) (other than R) are: halogen such as fluorine, chlorine, bromine, nitro, cyanide, optionally substituted amino groups such as amino, C 1-4 alkylamino such as methyl amino, N, N-di-C 1-4 alkylamino such as dimethylamino, N-arylamino such as phenylamino, alicyclic amino such as morpholino, piperidino, piperazino, N-phenyl- piperazino or a group of formula YR wherein Y is a bond, oxygen, sulfur, or carbonyl, and

R is hydrogen, optionally substituted lower alkyl, such as C 1 -C 4 alkyl, optionally substituted with hydroxy, optionally substituted amino, halo, C 1 -C 4 alkoxy, or a -CO-D group, wherein

D is hydrogen, optionally substituted alkoxy such as C 1-4 alkoxy optionally substituted with optionally substituted amino, hydroxy, halo, lower C 1-4 alkoxy, optionally substituted amino such as amino, N 1 -C 4 alkoxy; alkylamino. for example, methylamino, N, N-di-C 1-4 alkylamino, such as dimethylamino. N-arylamino such as phenylamino, alicyclic amino such as morpholino, piperidino, piperazino or N-phenylpiperazino, halogen or hydroxy.

Particularly preferred are: halogen,

C 1-4 alkyl, C 1-4 alkoxy, ß

Or an amino group optionally substituted with a C 1 -C 4 alkyl group.

Particularly preferred are halogen and C 1-4 alkyl.

X indicates that the adjacent phenyl moiety is attached directly to the phenyl moiety or by a linking chain of up to two members. This linking chain can be anything if it has two valencies and if it has 1 or 2 atoms. This linking chain may also contain side chains. Exemplary linkages include C 1-4 alkylene, carbonyl, oxygen. sulfur, -NH-, -C (O-NH) -, -O-CF 4 -, -S-CF 4 - and -CH = CH-.

Of the compounds of formula (I), those of the formula (I) are preferred, wherein

R ¹ is C 2 -C 5 alkyl optionally substituted by hydroxy, amino, halogen, or C 1 -C 4 alkoxy,

R is a group of the formula -CO-D ', wherein D' is hydroxy, amino, N-C 4 -alkylamino, N, N-di (C 1 -C 4) -alkylamino, or C 1 -C 4 -alkoxy, the alkyl portion of which may be optionally substituted by hydroxy, amino, hydrogen, or C 1-4 alkoxy, or

R may also be a tetrazolyl group which may be optionally protected by an alkyl or acyl group,

and

R 'is hydrogen, halo, C 1-4 alkyl, C 1-4 alkoxy, nitro, or a group -CO-D' 'wherein

0 '' 'is hydroxy or C 1-2 alkoxy, or

R 'may also be an amino group optionally substituted with C 1-4 alkyl.

Preferred values of R 'are: hydrogen, (C1-C4) -alkyl, halogen, particularly preferably hydrogen.

Various methods of preparing the compound of formula (I) are illustrated below.

The compound of formula (I) may be prepared, for example, according to Scheme (a). In the reaction scheme a

In the formulas 2 to 3, R, R, R and A are as defined above, W is halogen.

Reaction scheme b) may also be carried out wherein all substituents have the meanings given above.

Compounds of formula (Id) may be prepared according to Scheme c12, wherein R 1, R 6 -A are as defined above, R 1 is optionally substituted C 1 -C 4 alkyl.

Alternatively, Scheme d) wherein all substituents are as defined above.

Scheme (e) also provides the compounds of formula (I) wherein R, R, R A are as defined above, Y is imidine, thiolaldehyde,

- 12 carboxylic, amidine or cyano groups.

The compounds of formula (If) can be prepared by f) reaction scheme wherein R ^{1, RR?} fy is as defined above, n is 0 or 1.

Compounds of formula (Ig) may be prepared according to Scheme (g), wherein the substituents are as defined above.

The compounds of general formula (IFV) h) can be obtained by reakció1 3 Scheme ^1, wherein R, R 'is as defined above,

W is halogen.

Compounds of formula (II) are prepared according to Scheme (i), wherein R 1, R 1 A and ti are as defined above.

Compounds of formula (Ik) are prepared according to Scheme (j) wherein R ¹ , R ⁵ , A and W are as defined above, R 1 is lower alkoxy, lower alkyl thio, optionally substituted amino or cyanide.

Compounds of formula (Ib) may be prepared according to Scheme k) wherein R 1 - R 4 are as defined above, R ⁷ is lower alkyl.

Compounds of formula (1m) are obtained according to Scheme 1, wherein R 1, R 1, R ⁷ and a are as defined above and n is 0 or 1.

Scheme a) is carried out by alkylation using an alkylating agent of formula III in an organic solvent in the presence of a base.

In the reaction, 1-3 moles of base and 1-3 moles of alkylating agent (III) are used per mole of the compound of formula II (13). The reaction is usually carried out in a solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, acetone or ethyl-methyl ketone.

Suitable bases include sodium hydride, tertiary butoxide, potassium carbonate or sodium carbonate.

The alkylating agent of formula (III) is in the form of a substituted halide, such as chloride. in the form of the bromide or iodide, but may also be used in the form of a substituted sulfonic acid ester such as methyl paratoluene sulfonate.

The reaction conditions depend on the base used, the alkylating agent (III), however, the reaction temperature is usually between ice-cooling and room temperature and the reaction is carried out for 1 to 10 hours.

In Scheme b, the cyanide group on the benzene ring of the compound of formula (leu) is reacted with various azides to give the tetrazole derivative of formula (I0).

mole (Ιω) in general

1-3 mol of azide are used. The reaction is usually carried out in a solvent such as dimethylformamide, dimethylacetamide, toluene or benzene.

Examples of the azide include trialkyltin azide, triphenyltin azide, or hydrazinic acid.

When organic stannous azide is used, the reaction is carried out in toluene or benzene at reflux temperature · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- They cross for 10-30 hours. When hydrazinic acid is used, sodium azide and ammonium chloride are used in about twice the molar excess of compound (Ια) and the reaction is carried out in dimethylformamide at 100-130 ° C for 1-3 days. Preferably, sufficient amounts of sodium azide and ammonium chloride are added to the reaction mixture to accelerate the reaction.

In Scheme c), carboxylic acids of formula (let) are prepared by hydrolysis of an ester of formula (Io) in the presence of an alkali metal. 1-3 mol of alkali metal are used for 1 mol of compound (Ic) and the reaction is carried out in an aqueous alcohol such as methanol, ethanol or methylcellulose. The alkali metal may be used, for example, in the form of sodium hydroxide or potassium hydroxide. The reaction is carried out at up to 100 ° C for 1-10 hours.

In Scheme d), the benzimidazole derivative of formula (I) is prepared by reduction of the nitro group in a compound of formula (IV) followed by intramolecular dehydrative cyclization.

The reaction is carried out using 2-10 moles of reducing agent per mole of compound (IV). The reducing agent can be a metal such as iron, zinc or tin and the reaction is carried out under acidic or basic conditions. Solvents include alcohols, such as methanol or ethanol, ethers, such as dioxane or tetrahydrofuran, or acetic acid or hydrochloric acid, or mixtures of the solvents mentioned.

The reaction conditions depend on the reduI · · · · · · ··· ♦ * · i used

- 15 precipitants, solvents and acids or bases, the reaction is usually carried out at room temperature to 100 ° C

It is carried out for 1-5 hours.

Preferably, the reaction mixture is heated at 50-100 ° C for 2 to 3 hours under acidic conditions to complete the dehydrative ring closure after the reduction reaction.

In Scheme (e), a diamino compound of formula (V) is cyclized with various compounds in an organic solvent to a benzimidazole derivative of formula (I).

Carboxylic acid, aldehyde, orthoester, imidate ^{J can be used} as ring closure compounds. or thioimide.

1-10 moles of the compound of formula V are used, the reaction is carried out in an organic solvent, but the reagent may also serve as a solvent.

Organic solvents which may be used are, depending on the reagent, alcohols such as methanol, ethanol, cellosolvents (methylcellosolve, ethylcellosolve) or halogenated hydrocarbons such as chloroform, methylene chloride, ethers, dioxane, tetrahydrofuran or aromatic hydrocarbons, benzene, toluene, or dimethylformamide.

An acid such as hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, or a base such as diethylamine, pyridine, sodium methoxide, sodium ethoxide or potassium carbonate may be added to accelerate the reaction.

The reaction conditions will depend on the nature of the reagents used, however, the reaction is preferably carried out at room temperature to the reflux temperature of the solvent for 1-10 hours.

In Scheme f), carboxylic acids of formula III are prepared by hydrolysis of esters of formula Le in the presence of alkali.

1-3 moles of alkali per mole of the compound of formula (le) are generally carried out in an aqueous alcohol such as methanol, ethanol or methylcellulose. The alkali may be sodium hydroxide or potassium hydroxide.

The reaction is preferably carried out at room temperature to 100 ° C for 1-10 hours.

In Scheme g, a hydroxymethyl derivative of formula (Ig) is prepared by reduction of a carboxylic acid ester of formula (le). In the reaction, 1-5 moles of reducing agent are used per mole of the compound of formula (le). Suitable reducing agents are, for example, lithium aluminum hydride or sodium borohydride. When the first compound is used, the solvent is usually an ether, such as tetrahydrofuran, dioxane, diethyl ether, and the reaction is carried out for 1 to 20 hours at room temperature to reflux. . When the second compound is used, the solvent is usually an ether, such as tetrahydrofuran or dioxane, or an alcohol, such as ethanol, propanol or butanol, and an appropriate amount of methanol is preferably added to accelerate the reaction.

The reaction was carried out for 1 to 20 hours at room temperature and applied.

- 1? The reaction is carried out at a boiling point of the solvent, preferably between 50 ° C and the boiling point of the solvent.

In Scheme h, compounds of formula (Ifi) are prepared by halogenation of compounds of formula ($ 1) with a suitable halogenating agent in a solvent.

Suitable solvents are, for example, halogenated hydrocarbons such as dichloromethane, chloroform or dichloroethane, or ethers such as diethyl ether, tetrahydrofuran or dioxane.

Suitable halogenating agents include thionyl chloride or phosphorus oxychloride. The use of thionyl chloride is more advantageous for the processing of the reaction mixture. The reaction is preferably carried out at room temperature to the reflux temperature of the solvent for 1 to 10 hours.

In Scheme (i), the methyl derivatives of formula (II) are prepared (by reduction of the halogen derivatives of formula (ID).

Suitable reducing agents are metal hydrides, such as organic tin anhydride, ferric hydride complex compounds such as sodium aluminum hydride or sodium borohydride, metals or metal salts such as zinc, copper, sodium or lithium. When using a metal hydride as reducing agent, such as Ph 2 ShH or Bu 2 SnH, the reaction is preferably carried out in an aromatic hydrocarbon solvent, such as benzene or toluene, in an amount of 1 to 3 moles of tin hydride. The reaction

The reaction is carried out for 3 to 10 hours at about the boiling point of the solvent used. The reaction proceeds rapidly with iodide or bromide, but when chloride is used, it is · ·

Preferably, a peroxide such as perbenzoic acid or azobisisobutylonitrile (AIBN) is added to the reaction mixture to accelerate the reaction.

In Scheme (j), a substituted compound of formula (Ik) is prepared from a halogen derivative of formula (Ih) by substitution reaction with a nucleophilic reagent in an organic solvent. The organic solvent may be an alcohol such as methanol, ethanol, propanol or butanol, an ether such as tetrahydrofuran or dioxane. halogenated hydrocarbons such as dichloromethane, chloroform or dichloroethane, acetonitrile or dimethylformamide. The solvent is preferably selected according to the quality of the nucleophilic reagent used. Nucleophilic reagents include alcohols, such as methanol, ethanol, or amines, such as alkylamine, or cyanides, such as potassium cyanide.

The reaction is preferably carried out in the presence of a suitable base such as potassium carbonate, sodium carbonate, sodium hydride, sodium alkoxide.

The reaction is usually carried out for 1 to 10 hours at ice-cooling to 50 ° C, depending on the reagent and solvent used.

In Scheme k, nitriles of formula (Ik) are converted to esters of formula (IC).

Preferably the nitriles of formula (Ik)

I! Temperature between 50 ° C and the boiling point of the solvent used is heated at room temperature for 3 to 20 hours in an alcohol such as methanol, ethanol, propanol or butanol, which is 4 · 999 ς. _e i

It also contains 3 to 10 times the molar excess of hydrogen chloride gas. The alcohol used serves as both a solvent and a reagent. The reaction produces an imiolate intermediate, but it is preferable to prepare the ester compound without isolating the intermediate.

In Scheme 1, esters of formula (Im) are prepared by esterifying the carboxylic acids of formula (II) with alcohol.

The reaction is usually carried out with a reactive alcohol such as methanol, ethanol, propanol or butanol in the presence of an acid catalyst. The catalysts used are inorganic acids such as hydrochloric or sulfuric acid or organic acids such as p-toluenesulfonic acid.

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

The products of Schemes a) to l) may be readily isolated by known isolation and purification techniques, such as column chromatography or recrystallization.

The compound of formula (I) obtained by any of the above processes may be converted into a salt by reaction with a physiologically acceptable acid or base in a known manner. For example, salts with inorganic acids such as hydrochlorides, sulfates or nitrates, salts with organic acids such as acetates, oxalates, cifrates or maleate, salts with alkali metals such as sodium or potassium salts, or alkali metal salts, for example, calcium salts.

The starting compounds of formulas (II), (III), (IV) and (V) may be prepared, for example, by the methods described in the literature or analogous thereto:

(1) P.N. Preston, The Chemistry of Heterocyclic Compounds Vol 40, ed. by P.B. Preston, Tohn Wilcy and Sons,

New York (1981), 1-286. (2) A. Hunger, J. Kebrle, A. Rossi, and K. Hottmann, Helv. Chim.

Acta. 43, 1032 (1960), (3) R.C.De Selms, J. Org.Chem., 27, 2163 (1962), (4) A.F.Casy and J.Wrigit, J.Chem.Soc. (C), 1966, 1511, (5) O.Meth-Cohn, H.Suschitzky and M.E. Sutton,

J. Chem. (C), 1968), 1722, (6) A.A.Shazhenov, Ch. Kadyrov and P. Kurbanov,

Khim. Geterotsikl. Soedin., 1972, 641, (7) N.Vinot, Bull.Soc.Chim. Fr. 1966, 3989, (8) MWPartridge and HATurner, J.Chem.Soc., 1958, 2086 (9) RELyle and JLLamattina, J.Org.Chem., 40, 438 (1975), (10) ) SH. Andegaonker and CR. Revankar, J.Karnatak

Univ., 6, 25 (1961) (cf. CA, 59, 10012b), (11) Y.Kanaoka, O.Yonemitsu, K.Tanizawa and Y.Ban,

Chem. Pharm. Bull., 12, 773 (1964), (12) J. Preston, W.F.Dewinter and W.L.Hofferbert, Jr.

J.Heterocycl. Chem., 1969, 119, (13) B.C.Bishop, A.S.Jones and J.C.Tatlow,

J. Chem., Soc., 1964, 3076, (14) H. Depoorter, G. G. Van Mierlo, M. J. Libeer and J. M. Nys,

Belg. 595, 327, Mar. 23, 1961 (cf. CA 58, 9085a (1963)), (15) H.J.J.Loozen and E.F.Godefroi, J.Org.Chem., 21 »

3495 (1973), (16) N.Suzuki, T.Yamabayashi and Y.Izawa,

Bull.Che.Soc. Jpn., 49, 353 (1976), (17) V.J.Gerda, R.E.Jones, G.Gal and M.Sletzinger,

J. Org.Chem., 30, 259 (1965), (18) M.Itaya, Yakugaku Zasshi, 82, 1 (1965), (19) I.Ganea and R.Taranu, Stud. Univ. Babes-Bolyai

Ser.Chem., 1966, 95 (cf. CA, 67, 32648s (1967)), (20) O.Jerchel, H.Fischer and M.Kracht, Ann.Chem., 162 (1952), (21) NS. Kozlow and Μ.N.Tovshtein, Vestsi Akad. Nauk. Belorus.

SSR, Ser. Khim. Navuk 1967, B9 (cf.CA, 69, 49507p), (22) J.B.Wright, Chem. Rev., 48, 397 (1951).

In addition, the starting compound (IV) can be readily prepared by alkylation of the compound (VI). Examples of compounds of formula VI include K.Seno, S.Hagishita, T.Sato and K.Kuriyama, J.Chem.

Soc., Perkin Trans. 1. 1984, 2013, or analogous thereto.

Alternatively, the compound of formula (VI) may be reacted by a procedure similar to that described in Scheme a) or by an analogous procedure (for example Scheme m).

The starting compound (V) may be prepared, for example, according to Scheme n) or by an analogous process.

The starting compounds of formula (XIV) and (XV) may be prepared according to Scheme (o) or an analogous procedure.

3

In Scheme m), A, R, R, R and n are as defined above, W is halogen.

In Scheme n), A, R ² and R ³ are as defined above, W is halogen.

In Scheme (o), A, R ¹ , R ² , R ³ and R ⁵ are as defined above, R ⁸ is a carboxylic acid ester, cyanide or an optionally protected tetrazolyl group, and Z is oxygen, -NH-, or sulfur.

Scheme m) is a compound of formula IV. An N-alkyl compound is prepared by reacting a compound of formula (VI). Compound III is alkylated by a procedure similar to Scheme a).

The process of the invention is illustrated in Scheme n).

Scheme n): the orthonitrobenzoate derivative is reacted with a halogenating agent such as thionyl chloride or phosphorus oxychloride, and the resulting compound of formula (VIII) is obtained. the acid chloride is reacted with an azide compound such as sodium azide to give the acid azide of formula IX, which can be easily converted to the compound of formula X; isocyanate, which can be prepared in good yield by heating with tertiary butanol. carbamic acid ester. On the other hand, the general formula (XI)! The carbamic acid ester may also be prepared by reacting a compound of formula VII. the benzoate derivative is heated with diphenylphosphoryl azide (DPPA) in tert-butanol. The general formula (V)! The diamino derivative is obtained by reacting the resultant compound of formula XI. The carbamic acid ester is alkylated in a similar manner to that described in Scheme m to afford the deprotected compound (XII) followed by a reducing agent such as Raney nickel, tin (II) chloride, ferric hydrochloric acid. or hydrazine-iron (III) chloride.

In Scheme o), the benzimidazole derivative of formula (XIV) is prepared by reacting a diamino derivative of formula (V) with an acid chloride such as chloroacetate chloride, 2-chloropropionate chloride, a base, e.g. heated in the presence of triethylamine or pyridine, the resulting diacylamino derivative is heated with an acid such as hydrochloric acid-ethanol and the resulting chloride of formula XIV is reacted with a nucleophilic reagent such as sodium methoxide, sodium ethoxide, methylamine. with ethylamine, sodium thiomethoxide or sodium thioethoxide to give the substituted compound of formula (XV). The resulting compound of formula XV is converted to the compound of formula I by the process outlined in scheme b), c) or the like.

The invention is further illustrated by the following examples but is not intended to be limited thereto.

In the examples, the following abbreviations are used: Me: methyl, Et: ethyl, Pr: propyl, Bu: butyl, Pen: pentyl, Tet: tetrazolyl, THF: tetrahydrofuran, DMF: dimethylformamide, Ph: phenyl, Ac: acetylmethyl.

- 24 # -

Reference Example 1

2-butyl-5-methoxy-benzimidazole

To a solution of 4-methoxy-O-phenylenediamine (4.4 g) and ethyl valeroimidate hydrochloride (4.6 g) in ethanol (50 µL) was added triethylamine (5.7 g) and the reaction mixture was stirred at room temperature for 2.5 hours. The solvent was then distilled off and the residue was dissolved in ethyl acetate and water. The organic layer was washed with water, dried and the solvent was distilled off. The residue was purified by silica gel column chromatography to give a crystalline product. This crude product was recrystallized from isopropyl ether

2.7 g of the expected product are obtained. Yield: 53%, m.p. 95-96 ° C.

Elemental Analysis for Formula:

C (%) N (%) N (%) calculated: 70.50 7.89 13.71 Found: 70.68 7.95 13.72 1 H NMR (CDCl ₃ ); J S: 0.93 (3H, t); 1.2-2.0 (4H , m), 2.89 (2H, 3.81 (3H, s), 6.84 (1H, d), 7.42 (1H, d).

Following the procedure of Reference Example 1, the following compounds were prepared:

Reference Example 2

2-butyl-5-chloro-benzimidazole

Physical properties of the compound are as follows: Colorless needle crystals, m.p. 149-150 ° C, yield: 78%.

Elemental analysis for ^c u ^H u ^clN 2 ^total 9 ^{images :}

C (¾) H (%) N (%)

calculated: 63.31 6.28 13.42 Found: 63.35 6.46 13.30

¹ H-NMR (CDCl ₃ ): δ: 0.90 (3H, t), 1.20-1.60 (2H, m), 1-67-2.00 (2H, m), 1-67-. 2.00 (2H, m), 2.92 (2H, t),

7.17 (1H, m), 7.38-7.52 (2H, m).

REFERENCE EXAMPLE 3 2-Butyl-5-nitrobenzimidazole

Physical properties of the compound: colorless crystals, m.p. 140-141 ° C. The compound was prepared in 77% yield.

Reference Example 4

Preparation of 2-propylbenzimidazole

A mixture of 2.2 g of o-phenylene diamine and 4.7 g of butyric anhydride was heated at 110 ° C for 4 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic phase is washed with aqueous sodium bicarbonate solution, diluted with hydrochloric acid and water and dried. The solvent was distilled off and the residue was refluxed in 35 ml of 3N hydrochloric acid for 1.5 hours. The reaction mixture was then quenched with 6N sodium hydroxide. The resulting crystals were recrystallized from a mixture of ethyl acetate and hexane. 0.9 g of the desired compound is obtained in the form of colorless flat crystals. Yield: 38%, m.p. 160-162 ° C.

1 H-NMR (CDCl 3): $: 1.00 (3H, t), 1.88 (2H, se (hexaplet)),

2.91 (2H, t), 7.10-7.35 (2H, m), 7.45-7.70 (2H, m),

8.30 (1H, br s).

Reference Example 5

2-pentyl-benzimidazole

To a solution of 2.2 g of o-phenylene diamine and 2.0 g of triethylamine in ml of methylene chloride is added dropwise, while stirring and ice-cooling, 2.3 g of capric acid chloride. After stirring for 3 hours at room temperature, the reaction mixture was washed with saturated aqueous sodium bicarbonate solution and water, and then dried. The solvent was distilled off, to the residue was added 3N hydrochloric acid and the mixture was refluxed for 1.5 hours. The reaction mixture was then quenched with 6N sodium hydroxide. The precipitated crystals were recrystallized from ethyl acetate / hexane to give 1.5 g of colorless needles. Yield: 47%, m.p. 161-162 ° C.

¹ H-NMR (90MHz, CDCl 3: 0.86 (3H, t), 1.1-1.6 (4H, m),

1.7-2.0 (2H, m), 2.92 (2H, t), 7.1-7.3 (2H, m),

7.5-7.7 (2 H, m).

Reference Example 6

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

To a solution of 2-butylbenzimidazole (0.87 g) in dimethylformamide (5 ml) was added sodium hydride (0.24 g, 60% in oil) under ice-cooling, and the reaction mixture was stirred for 10 minutes. To the reaction mixture was then added 1.1 g of 4- (2-cyanophenyl) -benzyl chloride and the mixture was stirred for 1.5 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the title compound

1.8 g of a colorless oil are obtained. Yield: quantitative. 1 H NMR (90 MHz, CDCl 3): 0.90 (3H, t), 1.2-1.6 (2H, m),

1.65-2.00 (2H, m), 2.85 (2H, t), 5.37 (2H, s), 7.0-7.9 (12H, m).

7-16. The compound of Reference Example 6 was prepared as described in Reference Example 6.

Reference Example 7

2-butyl-l- / ~ (2'-cyanobiphenyl-4-yl) benzimidazole--metil_7-6metoxi

Physical properties of the compound: oil, yield: 48 ¹ H-NMR (200 MHz, COCl 3) δ: 0.93 (3H, t), 1.14-1.53 (2H, m),

1.76-1.91 (2H, m), 2.83 (2H, t), 3.81 (3H, s),

5.37 (2H, s), 6.70 (1H, d), 6.89 (1H, dd), 7.17 (2H, d),

7.41-7-53 (4H, m), 7.61-7.68 (2H, m), 7.77 (1H.dd).

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

Reference Example 8

Bút11-1-2 - // (2'-cyanobiphenyl-4-yl) -metil_7-5-methoxybenzimidazole

Physical properties of the compound: oil, yield 44%. 1 H NMR (300 MHz), COCl 3: 0.93 (3H, t), 1.35-1.53 (2H, m),

1.76-1.92 (2H, m), 2.85 (2H, t), 3.86 (3H, s), 5.38 (2H, s), 6.86 (1H dd), 7 , 11 (1H, d), 7.15 (2H, d), 7.29 (1H, d), 7.41-7.53 (3H, m), 7.64 (1H.dt), 7, 77 (1H, dd).

IR (cm ^-1 ): 2220, 1620, 1595, 1485, 1440, 1415, 1345, 1275,

1200, 1160, 1030, 835, 800, 765.

Reference Example 9

2-Butyl-5-chloro-1- [7- (2'-cyano-biphenyl-4-yl) -methyl] -benzimidazole Physical properties: oil, yield 48%.

¹ H-NMR (200 MHz, CDCl 3) δ: 0.94 (3H, t), 1.35-1.54 (2H, m),

1.77-1.92 (2H, m), 2.87 (2H, t), 5.40 (2H, s), 7.12-7.27

4H, m), 7.42-7.55 (4H, m), 7.65 (1H, q), 7.75-7.80 (2H, m).

IR (cm ^-1 ): 2220, 1510, 1460, 1400, 760.

Reference Example 10

2-butyl-6-chloro-l- / ~ (2'-cyanobiphenyl-4-yl) benzimidazole--metil_7

Physical properties: mp 124-125 ° C, yield 35%.

1 H-NMRCZOO MHz, COCl 3) δ: 0.94 (3H, t), 1.35-1.54 (2H, m),

1.77-1.92 (2H, m), 2.85 (2H, t), 5.37 (2H, s), 7.14 (2H, d), 7.20-7.25 (2H, m), 7.41-7.55 (4H, m), 7.61-.

7.70 (2H, m), 7.77 (1H, d). IR (KBr) cm ^-1 : 2220, 1620, 1595, 1485, 1440, 1415, 1345, 1275, 1200, 1160, 1030, 835, 765.

II. refereciapélda

2-Butyl-1 H - (2'-cyanobiphenyl-4-yl) methyl-7- (5-nitrobenzimidazole)

Physical properties: oil, yield: 45%.

Reference Example 12

2-butyl-l- / ~ (2'-cyanobiphenyl-4-yl) -metil_7-6-nitrobenzimidazole

Physical properties: oil, yield: 43

Reference Example 13

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

Physical properties: oil, yield: quantitative ¹ H-NMR (200 MHz, CDCl 3) δ: 1.04 (3H, t), 1.82-2.00 (2H, m),

2.86 (2H, t), 5.42 (2H, s), 7.15 (2H, d), 7.21-7.29 (3H, m), 7.40-7.53 (4H, m), 7.59-7.68 (1H, m), 7.73-.

7.81 (2 H, m).

IR cm ^-1 : 2220, 1510, 1480, 1455, 1410, 760, 740.

Reference Example 14

1 - // (2'-cyanobiphenyl-4-yl) benzimidazole-pentyl -metil_7-2

Physical properties: oil, yield: quantitative ¹ H-NMR (200 MHz, CDCl 3) δ: 0.88 (3H, t), 1.23-1.44 (4H, m),

1.80-1.95 (2H, m), 2.87 (2H, t), 5.43 (2H, s), 7.16 (2H, u),

7.21-7.29 (3H, m), 7.41-7.53 (4H, m), 7.60-7.68 (1H, m),

7.74-7.82 (2 H, m).

IR cm ^-1 : 2220, 1510, 1480, 1455, 1410, 760, 740.

Reference Example 15

1- / ~ (2'-cyanobiphenyl-4-yl) benzimidazole--metil_7

Physical properties: oil, yield: quantitative.

• ·

¹ H-NMR (200 MHz, CDCl 3): 5.44 (2H, s), 7.26-7.34 (4H, m),

7.41-7.55 (4H, m), 7.60-7.68 (1H m), 7.76 (1H, dd), 7.83-7.87 (1H, m), δ, 01 (1H, s).

IR cm ^-1 : 2220, 1500, 1480, 1460, 1440, 1365, 1285, 760, 740.

Reference Example 16

2-Butyl-1 H - (2'-cyano-biphenyl-4-yl) -methyl-7-benzimidazole

Physical properties: oil, yield: quantitative. 1 H-NMR 50 MHz, CDCl 3 (δ); 0.90 (3H, t), 1.2-1.6 (2H, m), 1.65-2.00 (2H, m), 2.85 (2H, t), 5.37 (2H, s), 7.0-7.9 (12H, m).

Reference Example 17

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

A mixture of 1.8 g of 2-butyl-1 - [(2'-cyanobiphenyl-4-yl) methyl] -benzimidazole, 0.98 g of sodium azide and 0.80 g of ammonium chloride in 6 ml of dimethylformamide. After stirring at 5 ° C for 5 days, another 1.6 g of sodium azide, 1.3 g of ammonium chloride and 5 ml of dimethylformamide were added. Water and ethyl acetate were added to the reaction mixture, and the precipitated crystals were filtered off. The filtrate was washed with water, dried and concentrated in vacuo. The crude crystals are obtained which are combined with the crystals obtained above and recrystallized from ethyl acetate / methanol.

0.82 g of colorless prism crystals are obtained. Yield: 41 V 0-p .: 235-236 ° C.

·· «· ·:

·· · ♦ · · ·

- 34 Elemental analysis for C ₂ 5 ^H 26 ^N 6:

C (O H (\) N (*) calculated: 73.51 5.92 20.57 Found: 73.42 5.90 20.87

(3H, t), 1.26-1.45 (2H, m), ¹ H NMR (200 MHz, DMSO-d 6) δ: 0.87

1.62-1.77 (2H, m), 2.82 (2H, t), 5.49 (2H, s), 7.05 (4H, s)

7.13-7.22 (2 H, m), 7.46-7.71 (6 H, m).

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

The following compounds were prepared as described in Reference Example 17:

Reference Example 18

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

Physical properties of the compound: mp 146-149 ° C (dec.)

Elemental analysis a ^ 26 ^Η 26 ^Ν 6θ H ₂ 0 H (%) N (%) C (%) calculated: 70.06 6.06 18.85 Found: 70.27 6.03 18.42 1 H-NMR (200 MHz, DMSO-d 6) : 0.87 (3H, t), 1.25-1.44 (2H, m),

1.60-1.75 (2H, m), 2.78 (2H, t), 3.77 (3H, s), 5.45 (2H, s),

6.80 (1H, q), 7.01 (2H, d), 7.06 (2H, d), 7.13 (1H, d),

7.35 (1H, d), 7.47-7.70 (4H, m).

IR (KBr) cm ^_1: 1490, 1450, 1440, 1195, 1155, 1020, 825, 755th

Reference Example 19

2-Butyl 1-6-methoxy-1 H, 2 '- (1H-tetrazol-5-yl) -biphenyl-4-yl-7-methyl-7-benzimidazole

- 32 Physical properties: mp 243-244 ° C (decomposition)

Analysis for ^C 26 ^H 26 ^N 6 ° ^{down from} 9 ^Ké * P ^from:

C (%) H (\) N (\) calculated: 71.21 5.98 19.16 Found: 70.98 5.96 19.41 1 H-NMR (200 MHz, DMSO-dg) S: 0.86 (3H, t); 1.24-1.43 (2 H, m),

1.58-1.73 (2H, m), 2.75 (2H, t), 3.75 (3H, s), 5.45 (2H, s), 6.78 (1H, q), 7 , 05 (5H, m), 7.43-7.70 (5H, m).

IR (KBr) cm ^_1: 1615, 1490, 1450, 1260, 1220, 1020, 825,

810, 745.

Reference Example 20

2-butyl-5-chloro-l - /// 2 '- (lH-tetrazol-5-yl) biphenyl-4-benzoimidazol ^ -metil_7

Physical Properties: mp 249-250 ° C (dec.)

Elemental analysis for C ^ jH ^ jClNg.1 / 2Η ₂ 0

C (%)

Calculated: 66.44

Found: 66.55 1 H-NMR (200 MHz, OMSO-d 6) δ

H (%) N (%) 5.35 18.59 5.13 18.37

0.87 (3H, t), 1.26-1.44 (2H, m),

1.61-1.76 (2H, m), 2.81 (2H, t), 5.50 (2H, s), 6.99-.

9.09 (4H, m), 7.20 (1H, q), 7.47-7.70 (7H, m). IR (KBr) cm ^-1 : 1500, 1450, 1410, 1000, 785, 760.

Reference Example 21

2-Butyl 1-6-chloro-1- [2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] -7-methyl-7-benzimidazole

Physical properties: mp 216-217 ° C.

Elemental analysis for ^C 25 ^H 23 ^ClN 6:

C (\) H (%) N (\) calculated 67.79 5.23 18.97 Found: 67.41 5.19 19.02

¹ H NMR (200 MHz, DMSO-d ₆ ) δ: 0.86 (3H, t), 1.25-1.43 (2H, m),

1.60-1.75 (2H, m), 2.79 (2H, t), 5.51 (2H, s), 7.01 (2H, d), 7.08 (2H, d), 7 , 18 (1H, q), 7.49-7.72 (6H, m). IR (KBr) cm ^_1: 1460, 1410, 755th

Reference Example 22

1 - /// 2 '- (δ-tetrazol-5-yl) -biphenyl-4-yl-7-methyl-7-benzimidazole

Yield: 51%.

Physical properties: 0 pp. 238-239 ° C. Elemental Analysis a ^ 21 ^ 16 ^ * 6 ' l / 5H ₂ O C (%) H (%) N (%) Calculated: 70.85 4.64 23.61 Found: 70.75 4.40 23.41

¹ H NMR (200 MHz, DMSO-d 6) 5.51 (2H, s), 7.07 (2H, d), 7.19-7.28 (4H, m), 7.49-7.71 (6H, m), 8.42 (1H, s).

IR (KBr) cm ^_1: 1505, 1460, 1375, 1290, 1265, 1230, 1195, 1145, 1035, 965, 945, 820, 775, 760, 750, 740th

Reference Example 23

2-Propyl-1H-2 '- (1H-tetrazol-5-yl) -biphenyl-4-yl-7-methyl-7-benzimidazole

Yield: 70 V

Physical properties: mp 239-240 ° C (decomposition)

Elemental analysis for ^C 24 ^H 22 ^N 6 Ί / ^2Με θ ^Η '^ ^Η 2θ:

C (%) H (%) N (\) calculated: 69.85 6.03 19.95 Found: 69.88 6.01 19.79 1 H-NMR (200 MHz, DMSO-dg) S: 0.96 (3H, t), 1.67-1.85 (2H, m),

3.05 (2H, t), 5.68 (2H, s), 7.09 (2H, d), 7.17 (2H, d),

7.40-7.77 (8 H, m).

IR (KBr) cm ^-1 : 1505, 1480, 1460, 1415, 1405, 760, 745.

Reference Example 24

2-pentyl-l- / ^- / 2 '- (tetrazol-5-yl) biphenyl-4-il_7 metil_7-benzimidazole

Yield: 41

Physical properties: mp: 208-209 ° C:

Elemental analysis ^{for C} 26 ^H 26 ^N 6

C (%) H (%) N (%) calculated: 73.91 6.20 19.89 Found: 73.67 6.19 20.00 1 H NMR (200 MHz, DMSO-d 6) 0.84 (3H, t);

1.27-1.34 (4 H, m),

1.64-1.78 (2H, m), 2.81 (2H, t), 5.49 (2H, s), 7.04 (4H, s), 7.12-7.20 (2H, m), 7.46-7.69 (6H, m).

IR (KBr) cm ^-1 : 1510, 1460, 1410, 745.

Reference Example 25

2- [4- (2-Butyl-benzimidazol-1-yl) -methyl-phenyl] -7-benzoic acid methyl ester

To a solution of 0.52 g of 2-butylbenzimidazole in 4 ml of dimethylformamide was added 0.13 g of 60% sodium hydride in oil under ice-cooling, and the mixture was stirred for 20 minutes. To the reaction mixture was then added 1.0 g of methyl 2- (4-bromomethylphenyl) benzoate and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The solvent was distilled off and the resulting oily residue was purified by silica gel column chromatography to give 1.2 g of a colorless oil. Yield: quantitative. 1 H-NMR (90 MHz, DMSO-d ₆ ) δ: 0.92 (3H, t), 1.25-2.00 (4H, m),

2.87 (2H, t), 3.60 (3H, s), 5.36 (2H, s), 7.05 (2H, d),

7.15-7.60 (8H, m), 7.65-7.9 (2H, m).

IR cm ^-1 : 1727, 1455, 1405, 1280, 1245, 780, 755, 740.

REFERENCE EXAMPLE 26 2- [4- (2-Butyl-benzimidazol-1-yl) -methyl-phenyl] -7-benzoic acid

A mixture of 4.5 ml of 1N sodium hydroxide solution, 10 ml of methanol and 1.2 g of methyl Z- [4- (2-butylbenzimidazol-1-yl) methylphenyl] benzoate was heated at reflux for 3 hours. The reaction mixture was concentrated and the residue was dissolved in water, washed with diethyl ether and acidified with 1N hydrochloric acid. The resulting crystals were filtered off and recrystallized from a mixture of ethyl acetate and methanol. 0.64 g of colorless crystals are obtained. Yield: 53%.

Analysis ^ 25 ^ 24 ° ^{Ν 2θ2 adder} 9 * ^<épletre:

2> G

C (%) H (%) N (%) Calculated: 78.10 6.29 7.29 Found: 77.99 6.36 7.22 1 H-NMR (200 MHz, CDCl 3) δ : 0.63 (3H, t), 0.99-1.17 (2H, m),

1.34-1.49 (2H, m), 2.62 (2H, t), 5.32 (2H, s), 7.04 (2H, d), 7.18-7.55 (8H, m), 7.66 (1H, dd), 7.92 (1H, dd). IR (KBr) cm ^-1 ; 1690, 1610, 1600, 1515, 1465, 1420, 1300, 1250, 1140, 1090, 1005, 820, 765, 750.

Reference Example 27 2-Butylbenzimidazole-4-carboxylic acid methyl ester

To a mixture of concentrated hydrochloric acid (5.3 ml) and methanol (35 ml) was added methyl 3-nitro-2- (N-valerylamino) benzoic acid (2.8 g) followed by small portions (1.7 g) of iron powder. The reaction mixture was stirred at room temperature and then heated under reflux for 8 hours. The insolubles were then filtered off and the filtrate was evaporated. Water and ethyl acetate were added to the residue. The aqueous phase was read with 6N sodium hydroxide solution and extracted with ethyl acetate. The organic layers were combined, washed with water and dried. The solvent was then distilled off and the residue was purified by silica gel column chromatography. The crystals thus obtained were recrystallized from isopropyl ether. 1.6 g of colorless needle-like crystals are obtained. Yield: 70% M.p .: 97-9B. 1 H-NMR (200 MHz, CDCl 3) δ: 0.93 (3H, t), 1.37-1.56 (2H, m),

1.80-1.95 (2H, m), 2.96 (2H, t), 4.00 (3H, s), 7.26 (1H, t), 7.85 (1H, dd), 7 , 91 (1H, d), 10.13 (1H, br, s).

Reference Example 28

Bút11-1-2 - // (2'-cyanobiphenyl-4-yl) benzimidazole--metil_7

4-carboxylic acid methyl ester

To a solution of 1.5 g of 2-butyl-benzimidazole-4-carboxylic acid methyl ester in 15 ml of dimethylformamide was added 0.13 g of sodium hydride as a 60% oil in ice-cooling. After stirring for 20 min, then was added 1.5 g of 4- ^(2-cyano> phenyl) -benzyl chloride. The resulting mixture was further stirred at room temperature for 5 hours, then water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried. The solvent was distilled off and the residue was purified by column chromatography on silica gel. 2.3 g of a pale yellow oil are obtained. Yield: 82%.

¹ H-NMR (90 MHz, CDCl 3) 0.94 (3H, t), 1.37-1.55 (2H, m),

1.78-1.93 (2H, m), 2.96 (2H, m), 4.05 (3H, s), 5.46 (2H, s), 7.12 (2H, d), 7 , 25 (1H, t), 7.39-7.52 (5H, m),

7.64 (1H, dt), 7.76 (1H, d), 7.95 (1H.dd).

IR cm ^-1 : 2220, 1710, 1510, 1480, 1435, 1405, 1350, 1290, 1245, 1215, 1190, 1130, 760.

Reference Example 29

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

2.3 g of methyl 2-butyl-1 H - (2'-cyanobiphenyl-4-yl) methyl-7-benzimidazole-4-carboxylic acid, 5.3 g of sodium azide and 4.4 g of ammonium chloride in 20 ml of dimethylformamide:

«· · · · · · · · · · · · · · ·

- 3S ι ί

Stir at 110-120 ° C for 26 hours. Water and ethyl acetate were added to the reaction mixture, followed by acidification with concentrated hydrochloric acid. The precipitated crystals are filtered off and recrystallized from methanol. 0.22 g of colorless needle-like crystals are obtained. Yield: 9%. 223-224 ° C (dec.).

Elemental analysis for C ₂₇ H ₂₆ N ₆ 0 ₂ .0, 3H ₂ 0: C (%) H (%) N (^) Calculated: 68.72 5.68 17.81 Found: 68.69 5.68 17.57 ¹ H-NMR (200 MHz, DMSO-d 6) δ : 0.88 (3H, t), 1.28-1.47 (2H, m); 1.60-1.75 (2 H, m), 2.88 (2H , t), 3.89 (3H, s), 5.56

(2H, s), 7.01 (2H, d), 7.07 (2H, d), 7.27 (1H, t),

7.47-7-66 (4H, m), 7.72-7.77 (2H, m).

IR (KBr) cm ^-1 : 1710, 1460, 1435, 1420, 1295, 1140, 765.

Reference Example 30

2-butyl-l- / ~ / 2 '- (lH-tetrazol-5-yl) biphenyl-4-il_7 metil_7benzimidazol-4-carboxamide

Essentially, the procedure described in Reference Example 29 is followed. Water and ethyl acetate were added to the reaction mixture, followed by acidification with 6N hydrochloric acid. The precipitated crystals are filtered off. The organic phase was separated from the filtrate, washed with water, dried and evaporated to dryness. The residue was purified by column chromatography over silica gel. The resulting crystals were recrystallized from methanol / chloroform to give colorless prism crystals (0.37 g). Yield: 15% M.p .: 235-236 ° C.

Elemental analysis for ^C 26 ^H 25 ^N 7 ^{01 / 2H} 2 °:

C (%) H (%) N (%) calculated: 67.81 5.69 21.29 Found: 67.64 5.68 21.05 1 H-NMR (200 MHz, DMS0- -d ₆ ) § = 0.89 (3H, t), 1.30-1.48 (2H, m),

1.65-1.80 (2H, m), 2.90 (2H, t), 5.58 (2H, s), 7.06

(4H, s), 7.30 (LH, t) , 7.48 -7.74 (5H, m), 7.84 (1H, dd), 9.28 (2 H, s). IR (KBr) cm ^-1 : 1660, 1610, 1565, 1500 1465, 1420, 1390, 1350, 1255, 1080 1070 1015, 885, 800, 775,

750th

Reference Example 31

3-nitro-2-valerilamino-benzoic acid methyl ester

Fuming nitric acid (7.0 ml) was added dropwise to 60 ml of acetic anhydride under ice-cooling and 0.2 ml of concentrated sulfuric acid was added to the reaction mixture. 12 g of 2-valerylaminobenzoic acid methyl ester are then added and the reaction mixture is stirred at room temperature for 1 hour, then ice-water is added and the mixture is extracted with ethyl acetate. The organic layer was washed with water, dried and evaporated. The residue was purified by column chromatography over silica gel. The resulting crude crystals were recrystallized from isopropyl ether. 3.9 g of colorless needle crystals are obtained. Yield: 28%, m.p. 61-62 ° C.

Analysis for ^C 13 ^H 16 ^N 5O5 calcd

C (%) H (%) N (%) calculated: 55.71 5.75 9.99 Found: 55.72 5.79 9.83.

· * ···················································································•

- 40 H-NMR (CDCl 3): δ: 0.95 (3H, t), 1.30-1.50 (2H, m), 1.65-1.80 (2H, m), 2.46 (2H, t), 3.97 (3H, s), 7.30 (1H, t), 8.10 (1H, dd), 8.22 (1H, dd).

Reference Example 32

Methyl 2- [N- (2'-cyanobiphenyl-4-yl) methyl] -7-valerylamino-3-nitrate / 6-benzoic acid

A mixture of 3.9 g of 3-nitro-2-valerylaminobenzoic acid methyl ester, 3.8 g of 4- (2-cyanophenyl) benzyl bromide and 2.1 g of potassium carbonate in 30 ml of dimethylformamide was stirred at room temperature for 15 hours. stirred. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried, and the solvent was evaporated. The residue was purified by column chromatography over silica gel. The resulting crude crystals were recrystallized from ethyl acetate / hexane. 5.1 g of colorless crystals are obtained. Yield: 78%, m.p. 129-130 ° C.

Analysis of 27 ^ 25 ^ ^Η 3θ5 ö ^k épletre ^adder 9: C (%) H (%) N (%) calculated: 68.78 5.34 8.91 Found: 68.84 5.43 8.87 1 H NMR (200 MHz, CDCl3) δ: 0.85 (3H, t), 1.18-1.36 (2H, m), 1.61 to 1 , 76 (2H, m), 2.08-2.16 (2H, m), 3.67 (3H, s),

4.65 (1H, d), 4.96 (1H, d), 7.20 (2H, d), 7.38-7.50 (4H, m),

7.56-7.68 (2H, m), 7.75 (1H, dd), 7.98 (1H, dd), 8.10 (1H, dd).

«· • ·

Reference Example 33

2-butyl 11-1 - [(2'-cyanobiphenyl-4-yl) methyl] -7-benzimidazole-7-carboxylic acid methyl ester

Slow stirring for 5.14 g of 2 - N - (2'-cyano-biphenyl-4-ylmethyl) -N-valeryl-7-amino-3-nitro (benzoic acid methyl ester, 4.0 mL of concentrated hydrochloric acid and 10 mL of methanol) 1.9 g of iron powder are added while stirring for 3 hours at 70-80 [deg.] C., the insolubles are filtered off and the filtrate is evaporated, to the residue are added ethyl acetate and saturated aqueous sodium bicarbonate solution.

The precipitated insoluble material is filtered off, the aqueous phase is separated from the filtrate and extracted with ethyl acetate.

The organic layers were combined, dried and evaporated. A crystalline residue is obtained, which is recrystallized from ethyl acetate. 4.15 g of colorless needle-like crystals are obtained. Yield: 90 p.p. Mp: 123-124 ° C.

Analysis for ^C 27 ^H 25 ^N 2 O 2 ^from 9 ^Ké P ^O:

calculated:

Found:

C (%) H (%) N (% 76.57 5.95 9.92 76.44 6.03 9.67

¹ H-NMR (200 MHz, COCl 3)

0.96 (3H, t), 1.38-1.57 (2H, m),

1.82-1.97 (2H, m), 2.92 (2H, t), 3.72 (3H, s), 5.82 (2H, s), 6.97 (2H, d), 7 , 26 (1H, t), 7.39-7.46 (4H, m),

7.58-7.66 (2H, m), 7.75 (1H, dd), 7.97 (1H, dd). -1.

2220, 1725, 1480, 1440, 1420, 1400, 1280,

1260, 1195, 1115, 765, 750, 745.

IR (KBr) cm -1

- 42 ····· «

V · · · Λ · »9 ··· ·· * ♦ · · ·

The following compounds were prepared as described in Reference Example 31:

Reference Example 34

2-butyrylamino-3-nitro-benzoic acid methyl ester

Physical constants: mp 64-65 ° C.

1 H-NMR (90MHz, COCl ₃ ) 1.03 (3H, t), 1.57-1.97 (2H, m),

2.43 (2H, t), 3.97 (3H, s), 7.20-7.43 (1H, m), 8.07-8.27 (2H, m), 10.50 (1H, br s).

IR (Nujol) cm ^-1 : 3300, 1725, 1690, 1585, 1510, 1445, 1355,

1265, 1210, 1115.

Reference Example 35

2-hexanoylamino-3-nitro-benzoic acid methyl ester

Physical constants: mp 74-75 ° C.

1 H-NMR (90MHz, CDCl 3) δ: 0.90 (3H, t), 1.23-1.90 (6H, m),

2.43 (2H, t), 3.93 (3H, s), 7.27 (1H, t), 8.03-8.27 (2H, m), 10.30 (1H, br, s) .

IRINNOjoDCnT ¹ : 3320, 1725, 1675, 1535, 1505, 1270.

Following the procedure of Reference Example 32, the following compounds were prepared:

Reference Example 36

Methyl 2-N-butyryl-N- (2'-cyanophenophenyl-4-ylmethyl) -7-amino-3-nitrobenzoic acid

Yield: 78%. Physical constants: mp 150-151 ° C.

• · · · · * ♦ · · · · · · · · · · · · · · · · · · · · NMR (90MHz, CDClj) δ: 0.87 (3H, t), 1.50-1.90 (2H, m),

2.10 (2H, t), 3.67 (3H, s), 4.83 (2H, q), 7.17-7.80 (9H, m), 7.93-8.17 (2H, m).

IRCNujoDcm ' ¹ : 2220, 1740, 1670, 1530, 1445, 1430, 1390, 1345, 1290, 1280, 1250, 1125, 770.

Reference Example 37

Methyl 2- [8- (2'-cyano-biphenyl-4-ylmethyl) -N-hexanoyl] -7-amino-3-nitrobenzoic acid

Yield: 75%, m.p. 85-86 ° C.

¹ H-NMR (90MHz, CDCl 3?: 0.83 (3H, t), 1.07-1.37 (4H, m),

1.50-1.83 (2H, m), 2.10 (2H, t), 3.67 (3H, s), 4.83 (2H, q), 7.17-7.80 (9H, m), 7.93-8.17 (2 H, m).

IRINujoDcm ' ¹ : 2220, 1735, 1670, 1530, 1480, 1445, 1430,

1390, 1375, 1290, 1260, 1200, 1130, 775.

In the same manner as in Reference Example 33, the following compounds were prepared:

Reference Example 38

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

Yield: 78%, m.p. 130-131 ° C.

1 H-NMR (90MHz, CDCl 3) δ: 1.07 (3H, t), 1.93 (2H, br s), 2.90 (2H, br s), 3.70 (3H, s), δ, 83 (2H, br s),

6.93-8.07 (11H, m).

IR (Nujol) cm ^_1: 2220, 1710, 1450, 1400, 1290, 1270, 1265,

1200, 1125, 760.

Reference Example 39 1- (2'-Cyano-biphenyl-4-yl) -methyl-7-2-pentyl-benzimidazole-7-carboxylic acid methyl ester

Yield: 75 p. 109-110 ° C.

¹ H-NMR (90MHz, CDCl 3) δ: 0.90 (3H, t), 1.17-2.10 (6H, m),

2.90 (2H, t), 3.70 (3H, s), 5.83 (2H, s9, 6.97 (2H, d),

7.13-8.00 (9 H, m).

IR (Nujol) cm ^_1: 2220, 1710, 1450, 1430, 1280, 1260, 1190, 1120, 750th

Reference Example 40

3-nitro-4-valerilamino-benzoic acid methyl ester

1.4 ml of fuming nitric acid was added dropwise to 12 ml of acetic anhydride under ice-cooling and 0.1 ml of concentrated sulfuric acid was added. To the reaction mixture was added 2.3 g of methyl 4-valerylaminobenzoic acid under ice-cooling and stirred for 1 hour. Ice water was added and the resulting crystals were recrystallized from a mixture of ethyl acetate and hexane. 2.14 g of a yellow prism crystal are obtained. Yield: 76%, m.p. 106-107 ° C.

calcd

Elemental analysis for C ₁₃ H ₁₆ N ₂ 0 ₅

• C (%) H (%) N (%) calculated: 55.71 5.75 9.99 Found: 55.84 5.80 10.01.

¹ H-NMR (CO 2 _{; j} ) δ: 0.98 (3H, t), 1.20-1.60 (2H, m), 1.70-1.85 (2H, m), 2.53 ( 2H, t), 3.96 (3H, s), 8.28 (1H.dd),

8.91 (1H, d), 8.96 (1H, d), 10.60 (1H, br s).

<.:. .:. · .. ·.:. ...

- ^ 5 _

Reference Example 41

4- N - (2'-Cyano-biphenyl-4-ylmethyl) -N-valeryl-amino-7-nitro-benzoic acid methyl ester

A mixture of 2.1 g of 4-valerylamino-3-nitrobenzoic acid methyl ester, 2.0 g of 4- (2-cyanophenyl) benzyl bromide and 1.1 g of potassium carbonate in 20 ml of dimethylformamide was stirred at room temperature for 4 hours. stirred. Water was added to the reaction mixture, extracted with ethyl acetate, and the organic layer was washed with water. The resulting solution was dried and evaporated. The remaining syrup-like material was purified by column chromatography on silica gel. 3.5 g of yellow syrup are obtained. Yield: quantitative.

¹ H-NMR (200MHz, CDCl 3) δ: 0.83 (3H, t), 1.15-1.33 (2H, m),

1.55-1.70 (2H, m), 1.99-2.08 (2H, m), 3.98 (3H, s),

4.27 (1H, d), 5.55 (1H, d), 7.07 (1H, d), 7.27 (2H, d),

7.42-7.56 (4H, m), 7.62-7.70 (1H, m), 7.77 (1H, d), 8.19 (1H, q), 8.61 (1H, d).

IR cm ^-1 : 2220, 1730, 1610, 1535, 1480, 1435, 1390, 1345, 1285, 1240, 765.

Reference Example 42

2-butyl-l- / ~ (2'-cyanobiphenyl-4-yl) benzimidazole--metil_7

To a mixture of 5-carboxylic acid methyl ester in ml of concentrated hydrochloric acid and 10 ml of methanol was added 3.5 g of 4- (N- (2'-cyanobiphenyl-4-ylmethyl) -N-valerylamino-7- (3-nitrobenzoic acid) methyl ester. To the resulting reaction mixture was added 1.3 g of iron powder in portions with stirring, followed by ϊ .... · .. ·.:. ...

The mixture was stirred at 70-80 ° C for 1 hour and the insolubles were filtered off. The filtrate was evaporated and the residue was dissolved in ethyl acetate, washed with water, dried and evaporated to dryness. The resulting syrup was purified by column chromatography on silica gel to give 1.7 g of a yellow syrup. Yield: 53%.

¹ H-NMR (200MHz, CDCl 3) δ: 0.94 (3H, t), 1.45 (2H, se), 1.791.94 (2H, m), 2.89 (2H, t), 3.94 (3H, s), 5.44 (2H, s),

7.15 (2H, d), 7.27 (1H, d), 7.42-7.54 (4H, m), 7.65 (1H, dt),

7.77 (1H, dd), 7.97 (1H, dd), 8.50 (1H, dd).

IR cm ^-1 : 2220, 1720, 1615, 1480, 1440, 1400, 1335, 1300, 1280, 1210, 755.

Reference Example 43

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

A mixture of 1.1% methyl 2-butyl-2'-cyano-biphenyl-4-yl) -methyl-benzenesulfonate-5-a-acetic acid, 3.9 g of sodium azide and 3.2 g of ammonium chloride It is stirred in 17 ml of dimethylformamide for 5 days at 115 ° C. The reaction mixture was diluted with water, then neutralized with 1 N hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water, dried and evaporated to dryness. The residue was purified by silica gel column chromatography to give crude crystals. The crystals were recrystallized from ethyl acetate to give 0.67 g of colorless needle-like crystals. Yield: 34%. Mp: 134-136 ° C.

- for the formula:

Elemental Analysis ^{for C} 27 ^H 26 ^N 6 ° 2 ' ¹ ^ ^{2 H} 2 °

C (\) H (%) N (%) calculated: 68.19 5.72 17.67 Found: 68.46 5.77 17.31

¹ H-NMR (200 MHz, CDCl 3) δ: 0.83 (3H, t), 1.18-1.37 (2H, m),

1.50-0.65 (2H, m), 2.38 (2H, t), 3.90 (3H, s), 5.24 (2H, s), 6.68 (2H, d), 6 , 91 (2H, d), 7.06 (1H, d),

7.28-7.33 (1H, m), 7.54-7.69 (3H, m), 7.87 (1H, dd), 8.00 (1H, dd).

IR (KBr) cm ^_1: 1720, 1615, 1515, 1435, 1410, 1340, 1300, 1280,

1220, 1085, 770, 750.

Reference Example 44

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

0.3 g of Y 2 -butyl-1 H - / 2 '- (1H-tetrazol-5-yl) biphenyl-4-yl-7-methyl-7-benzimidazole-5-carboxylate was refluxed for 2 hours with 1 ml of 2N sodium hydroxide. heated in methanol. The reaction mixture was dried and dissolved in water. The aqueous solution was acidified with IN hydrochloric acid to give crystals. Recrystallization from a mixture of acetonitrile and methanol gives colorless crystals. Yield:

0.23 g (83%) ) pp. 180-182 ° C. Analysis the * For 26 ^ 24 ^ 6θ2: C (%) H (%) N (%) calculated: 68.16 5.49 19.08 Found: 68.43 5.27 18.88 1 H-NMR (200 MHz , DMSO-d ₆ ) (µ: 0.88 (3H, t), 1.28-1.46 (2H, m),

1.63-1.78 (2H, m), 2.89 (2H, t), 5.58 (2H, s), 7.07 (4H, s),

7.47-7.70 (5H, mI, 7.86 (1H, dd), 8.18 (1H, s).

Reference Example 45

To a solution of methyl 3-valerylaminobenzoate mechl6 g-3-aminobenzoate and 4.5 g triethylamine in 90 ml methylene chloride was added dropwise with stirring and ice-cooling, 4.8 g of valeryl chloride. The mixture was stirred for one hour. The reaction mixture was washed with an aqueous solution of sodium bicarbonate and dilute hydrochloric acid, dried and evaporated. The residue was recrystallized from ethyl acetate / hexane to give colorless prism crystals. Yield: 8.1 g (87%), m.p. 101-102 ° C. ¹ H-NMR (90MHz, CDCl 3) δ: 0.93 (3H, t), 1.2-1.9 (4H, m), 2.37 (2H, t), 3.90 (3H, s), δ , 36 (1H, t), 7.5 (1H, br, s), 7.70-7-95 (2H, m), 8.03 (1H, t).

Reference Example 46 Methyl 4-nitro-3-valerylaminobenzoate

To a solution of 2.3 g of methyl 3-valerylaminobenzoate in 12 ml of acetic anhydride was added dropwise 1.4 ml of fuming nitric acid while stirring under ice-cooling. To the reaction mixture was added 1 drop of concentrated sulfuric acid and stirred for 2 hours. Ice water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate solution, then with water and finally dried. The solvent was distilled off and the residue was purified by silica gel column chromatography. 1.0 g of a brown oil are obtained. Yield: 36 V ^H} NMR (90 MHz, CDCl₃) ^: 0.96 (3H, t), 1.1-1.9 (4H, m), 2.51 (2H, t), 3.96 (3H, s), 7.80 (1H, dd), 8.26 (1H, d),

9.41 (1H, d), 10.23 (1H, br s).

3380, 1730, 1615, 1590, 1535, 1500 1440, 1420 1325, 1310, 1280, 1250, 1210, 1160, 1110, 1070 845, 775, 740th

Reference Example 47

Methyl 3 - / _ ^- N- (2'-cyanobiphenyl-4-yl-methyl) -N-valeryl amino_7-4-nitro-benzoic acid methyl ester

A mixture of 1.0 g of methyl 4-nitro-3-valerylaminobenzoate, 0.97 g of 4- (2-cyanophenyl) benzyl bromide and 0.55 g of potassium carbonate in 10 ml of dimethylformamide was added. Stir at room temperature for 2 days. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried. The solvent was distilled off and the residue was purified by column chromatography on silica gel.

1.24 g of a pale yellow oil are obtained. Yield: 73%. ¹ H NMR (200 MHz, CDCl 3) 0.84 (3H, t), 1.17-1.30 (2H, m),

1.56-1.71 (2H, m), 1.80-2.08 (2H, m), 3.92 (3H, s),

4.43 (1H, d), 5.37 (1H, d), 7.26 (2H, d), 7.40-7.51 (4H, m), 7.60-7.69 (2H, m), 7.75 (1H, d), 7.97 (1H, d),

8.16 (1H, dd).

IR cm ^-1 : 2220, 1735, 1675, 1600, 1580, 1530, 1480, 1435,

1420, 1390, 1350, 1285, 1220, 1200, 1115, 1090,

825, 775, 765.

Reference Example 48

Methyl 2-but11-1 -. / (2'-cyanobiphenyl-4-yl) benzimidazole--metil_7

6-carboxylic acid methyl ester

1,2 9 To a solution of 3- / 8- (2'-cyano-biphenyl-4-ylmethyl) -N-valerylamine-p7-4-nitrobenzoic acid methyl ester in 10 ml of methanol, containing 1.3 ml of concentrated hydrochloric acid 0.45 g of iron powder are added in portions while stirring at room temperature. After stirring for 3 hours at 70-80 ° C, water and ethyl acetate were added and the reaction mixture was quenched with aqueous sodium bicarbonate solution. The precipitate was filtered off. The organic layer was separated from the filtrate, washed with water and dried. The solvent was evaporated and the residue was purified by silica gel column chromatography. The resulting crude crystals were recrystallized from ethyl acetate to give 0.5 g of colorless needle-like crystals. Yield: 45%, m.p. 166-167 ° C.

Elemental analysis of ^ 27 ^Η 25 ^Ν 3θ2 ^with 9 ^k ^ Pl ^etre:

C (%) H (%) N (%) calculated: 76.57 5.95 9.92 Found: 76.39 6.05 9.79

¹ H-NMR (200MHz, COCl 3) 0.94 (3H, t), 1.35-1.54 (2H, m),

1.79-1.94 (2H, m), 2.88 (2H, t), 3.92 (3H, s), 5.47 (2H, s), 7.14 (2H, d), 7 , 40-7.53 (4H, m9? 7.60-7.68 (1H, m), 7.74-7.80 (2H, m9? 7.96-8.02 (2H, m)).

IR <KBr) cm ^_1: 2210, 1715, 1620, 1580, 1510, 1480, 1460, 1425,

1410, 1340, 1325, 1280, 1270, 1250, 1230, 1185,

1105, 1080, 770, 760, 745.

Reference Example 49

Methyl 2-butyl-l - // 2 '- (ΙΗ-tetrazol-5-yl) biphenyl-4-il_7 meti1_7benzimidazol-6-carboxylic acid methyl ester

A mixture of 0.5 g of 2-butyl-1- (2 '- (cyanobiphenyl-4-yl) methyl-7-benzimidazole-6-carboxylic acid methyl ester, sodium azide and 1.15 g of ammonium chloride in 5 ml of dimethylformamide is added.

After stirring at 115 ° C for 3.5 days, water was added to the reaction mixture and acidified with IN hydrochloric acid. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water, dried and evaporated to dryness. The residue was purified by column chromatography over silica gel. The resulting crude crystals were recrystallized from ethyl acetate / methanol. 0.23 g of colorless crystals are obtained. Yield: 41%. Mp 224-225 ° C.

Anal épletre a ^ ₂ 7 26 ^{Η Η 6θ2} ° ^adder 9 ^are:

C (%) H (%) N (%) calculated: 68.98 5.66 17.88 Found: 68.89 5.68 17.66

1.26 to 1.45 (2H, m), ¹ H-NMR (200MHz, DMSO) 5: 0.87 (3H, t);

1.63-1.78 (2H, m), 2.85 (2H, t), 3.85 (3H, s), 5.62 (2H, s), 7.00 (2H, d), 7 , 07 (2H, d), 7.48-7.70 (5H, m),

7.82 (1H, dd), 8.14 (1H, s).

IR (KBr) cm ^-1 : 1725, 1460, 1450, 1435, 1340, 1265, 1235, 775,

760, 745.

ι

Reference Example 50

2-butyl-l- / ~ / 2 '- (1H-tetrazol-5-yl) biphenyl-4-il_7 metil_7benzimidazol-6-carboxylic acid

0.1 g of 2-butyl-1- [2 '- (1H-tetrazol-5-yl) biphenyl]

A solution of 4-ylmethyl-7-benzimidazole-6-carboxylic acid methyl ester in 5 ml of methanol containing 0.5 ml of 1N sodium hydroxide was heated under reflux for 5 hours. The solvent was distilled off, 0.5 mL of IN hydrochloric acid was added and the mixture was extracted with chloroform. The organic phase is washed with water, dried and evaporated to dryness. The resulting crude crystals were recrystallized from methanol / ethyl acetate to give 60 mg of colorless crystals. Yield: 58 M.p .: 258-259 ° C (dec.).

for C ₂ 6 ^H 24 ^N 6 ° 2.l / 2Et0ac

Analysis

C (%) H (%) calculated: 67.73 5.68 Found: 67.79 5.50 ¹ H NMR (200MHz, DMSO) < §: 0.87

N (%)

16.92

16.89 (3H, t), 1.27-1.45 (2H, m),

1.63-1.79 (2H, m9? 2.85 (2H, t), 5.60 (2H, s), 7.00 (2H, d), 7.08 (2H, d), 7 48 (5H, m), 7.84 (1H, dd),

8.11 (1H, s).

IR (KBr) cm ^_1 1730, 1460, 1410, 1335, 1285, 1265, 1225,

780, 760.

Reference Example 51

Methyl 2-amino-5-methylbenzoate

53 A mixture of 10 g of 2-amino-5-methylbenzoic acid in 50 ml of methanol containing 5.5 ml of concentrated sulfuric acid was heated under reflux for 19 hours. The solvent was distilled off, the residue was dissolved in water, the solution was neutralized with aqueous sodium hydroxide and extracted with ethyl acetate. The organic phase is dried and evaporated.

8.1 g of a light brown oil are obtained. Yield: 74%. 1 H-NMR (90MHz, CDCl 3) δ: 2.24 (3H, s), 3.89 (3H, s), 5.55 (2H, s), 6.59 (1H, d), 7.10 ( 1H, dd), 7.68 (1H, d).

Reference Example 52

Methyl-5-meti1-2 -valerylamino benzoate

To a solution of 8.1 g of methyl 2-amino-5-methylbenzoate and 6.0 g of triethylamine in 50 ml of methylene chloride are added dropwise 6.5 g of valeryl chloride while stirring under ice-cooling. After stirring for 2 hours, the reaction mixture was washed with aqueous sodium carbonate solution, dilute hydrochloric acid solution, then water and dried. The solvent was distilled off and so on

12.8 g of a light brown oil are obtained. Yield: 99 H NMR (90 MHz, CDCl 3): 0.95 (3H, t), 1.2-1.9 (4H, m), 2.33 (3H, s), 2.43 (2H, t), 3.93 (3H, s), 7.34 (1H, dd),

7.82 (1H, d), 8.62 (1H, d).

Reference Example 53

5-Methyl-3-nitro-2-valeryl-amino-benzoic acid methyl ester

To a solution of 12.8 g of 5-methyl-2-valerylaminobenzoic acid methyl ester in 5.9 g of acetic anhydride is added dropwise 6.7 ml of fuming nitric acid under stirring and ice-cooling, and the reaction mixture is stirred for 3 hours. Ice water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate solution, then water and dried. The solvent was distilled off and the residue was purified by column chromatography on silica gel. The resulting crystals were recrystallized from isopropyl ether to give 8.5 g of a colorless crystal. Yield: 60%, m.p. 59-60 ° C.

1 H-NMR (200MHz, CDCl 3) δ: 0.94 (3H, t), 1.31-1.50 (2H, m),

1.63-1.78 (2H, m), 2.43 (2H, t), 3.95 (3H, s), 7.90 (1H, d), 8.00 (1H, d), 10 , 16 (1H, s).

Reference Example 54

1- ~ (2'-Cyano-biphenyl-4-yl) methyl-7-N-valeryl-7-amino-7- (5-methyl-3-nitrobenzoic acid methyl ester)

5.89 g of 5-methyl-3-nitro-2-valerylaminobenzoic acid methyl ester, 5.44 g of 4- (2-cyanophenyl) benzyl bromide and 3.0 g of potassium carbonate in 50 ml of dimethylformamide The mixture was stirred for 15 hours at 50 ° C. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic phase is dried and the solvent is distilled off and the residue is purified by silica gel column chromatography. The resulting crystals were recrystallized from a mixture of ethylhexane

3.1 g of colorless crystals are obtained. Yield: 32%. Mp: 141-142 ° C.

1 H-NMR (200MHz, CDCl 3) δ: 0.85 (3H, t), 1.17-1.36 (2H, m),

1.60-1.75 (2H, m), 2.05-2.15 (2H, m), 2.49 (3H, s),

3.64 (3H, s), 4.62 (1H, d), 4.94 (1H, d), 7.21 (2H, d),

7.38-7.50 (4H, m), 7.59-7.68 (1H, m), 7.73-7.77 (3H, m),

7.89 (1H, m).

Reference Example 55

Methyl 2-Butyl-1 - (2'-cyano-biphenyl-4-yl) -methyl-7- (5-methylbenzimidazole) -7-carboxylic acid

3.1 g 2-N- (2'-Cyano-biphenyl-4-yl) -methyl-7-N-valeryl-7-amino-7- (5-methyl-3-nitrobenzoic acid methyl ester)

To a solution of 4.4 ml of concentrated hydrochloric acid in 22 ml of methanol is added 1.6 g of iron powder in portions while stirring. The mixture was heated at reflux for 7 hours, then the insolubles were filtered off and the filtrate was evaporated. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate solution, then water and dried. The solvent was then distilled off and the residue was purified by column chromatography on silica gel. 2.8 g of a light brown oil are obtained. Yield: quantitative.

¹ H-NMR (200 MHz, CDCl 3) δ: 0.95 (3H, t), 1.37-1.56 (2H, m),

1.79-1.94 (2H, m), 2.47 (3H, s), 2.90 (2H, t), 3.71 (3H, s), 5.79 (2H, s), 6 , 96 (2H, d), 7.39-7.46 (5H, m),

7.58-7.66 (1H, m9? 7.73-7.77 (2H, m9).

IR cm ^-1 : 2220, 1720, 1520, 1480, 1435, 1410, 1305, 1245, 1215, 1195, 1110, 1040, 780, 760.

Reference Example 56

Ethyl 2-amino-6-methylbenzoate

This compound was prepared as described in Reference Example 51.

Physical constants: oil, yield 82 82 ¹ H NMR (90MHz, COCl 3) δ: 1.34 (3H, t), 2.43 (3H, s),

4.35 (2H, q), 5.06 (2H, br s), 6.50 (2H, d), 7.07 (1H, t).

Reference Example 57

6-methyl-2-valeryl-amino-benzoic acid ethyl ester

The compound was prepared as described in Reference Example 52. Yield: 70%.

Physical State: m.p. 56-57 ° C.

¹ H-NMR (90MHz, CDCl 3) δ: 0.93 (3H, t), 1.39 (3H, t), 1.18-1.87 (4H, m> 2.37 (2H, t), 2.46 (3H, s), 4.41 (2H, q), 6.94 (1H, d), 8.27 (1H, d), 7.32 (1H, t), 9, 69 (1H, br s).

Reference Example 58

6-methyl-3-nitro-2-valerylamino benoesav ethyl ester

The compound was prepared as described in Reference Example 53. Yield: 52%. Physical constants: mp 103-104 ° C.

¹ H-NMR (90MHz, CDCl 3): 0.93 (3H, t), 1.35 (3H, t), 1.17-1.85 (4H, m), 2.38 (2H, t), 2, 49 (3H, s), 4.38 (2H, q), 7.14 (1H, d), 7.97 (1H, d).

59. Reference mice

6-Methyl-3-nitro-2- [2 '- (N-triphenylmethyl-1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] -N-valeryl-amino} -benzoic acid methyl ester

The compound was prepared as described in Example 54. Yield: 80 Physical constants: oil.

¹ H-NMR (200NH 2, CDCl 3) δ: 0.86 (3H, t), 1.34 (3H, t), 1.20-1.45 (2H, m), 1.60-1.78 ( 2H, m), 2.14 (2H, t), 2.40 (3H, s), 4.09 (1H, d), 5.28 (1H, d), 4.23-4.42 (2H) , m), 6.81-6.96 10H, m), 7.19-7.53 (13H, m), 7.69 (1H, d), 7.88 (1H, dd).

Reference Example 60

Methyl 2-amino-5-chlorobenzoate clones—

To a solution of 25.5 g of 2-amino-5-benzoic acid in 300 ml of methanol is added 12 ml of concentrated formic acid. The reaction mixture was heated at reflux for 24 hours, evaporated, water (300 mL) was added and the mixture was neutralized with potassium carbonate. The reaction mixture was extracted with ethyl acetate, the organic phase was washed with water, dried and the solvent was distilled off. The resulting crude crystals were recrystallized from isopropyl ether / benzene to give 17.1 g of pale yellow crystals. Yield: 63%. Mp: 68-70 ° C.

Reference Example 61

Methyl 5-chloro-2-valerylaminobenzoic acid methyl ester To a solution of 2-amino-5-chlorobenzoic acid methyl ester g (12 ml) in triethylamine (150 ml) in methylene chloride was added dropwise 10 ml of valeryl chloride under ice-cooling. The reaction mixture was stirred at room temperature for an additional 2 hours, then washed with aqueous sodium bicarbonate solution and water and then dried. The solvent is distilled off,

SS to give 13.4 g of pale yellow crystals. Yield: 61 p. 48-49 ° C.

Reference Example 62 5-Chloro-3-nitro-2-valerylaminobenzoic acid methyl ester

To a solution of 13.4 g of methyl 5-chloro-2-valerylaminobenzoic acid in ml of acetic anhydride was added dropwise fuming nitric acid with stirring under ice-cooling. The reaction mixture was stirred for 1 hour at room temperature and then ice water was added. On standing, crystals precipitated which were recrystallized from isopropyl ether to give 9.5 g of a pale yellow crystal. Yield: 61 p. 84-85 ° C.

Reference Example 63

5-Chloro-2- (2 '-cyano-biphenyl-4-yl) -methyl] -N-valeryl-amino-7- (3-nitrobenzoic acid) methyl ester

A mixture of 3.15 g of 5-chloro-3-nitro-2-valerylaminobenzoic acid methyl ester, 2.8 g of 4- (2-cyanophenyl) benzyl bromide and 1.8 g of potassium carbonate in 50 ml of dimethylformamide Stir at room temperature for 3 hours. The reaction mixture was evaporated to dryness and the residue was extracted with ethyl acetate and water. The organic layer was washed with water and dried. The solvent was evaporated and the resulting crystals were recrystallized from ethyl acetate / benzene. 4.0 g of colorless crystals are obtained. Yield: 79%, m.p. 137-138 ° C.

Reference Example 64 j * · * «···· ···· *«

5-Chloro-3-nitro-2H-2 '- (N-triphenylmethyl-1H-tetrazol-5-yl) biphenyl-4-ylmethyl-N-valeri-7-amine- benzoic acid methyl ester space

To a solution of 0.93 g of methyl 5-chloro-3-nitro-2-valerylaminobenzoic acid in 10 ml of dimethylformamide

0.5 g of potassium carbonate and 1.84 g of N, 2 '- (4-bromomethyl) biphenylmethyl-7-tetrazole are added to M-tn' / en-L-methyl.

After stirring for 19 hours at room temperature, water (50 mL) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and the solvent was distilled off. 3.8 g of a residue are obtained, which is purified by column chromatography over silica gel.

1.89 g of a pale yellow crystal are obtained. Yield: 82%. ¹ H-NMR (200MHz, CDCl 3)? 0.86 (3H, t), 1.17-1.35 (2H, m),

1.56-1.80 (2H, m), 2.03-2.10 (2H, m), 3.63 (3H, s),

4.41 (1H, d), 4.82 (1H, d), 6.76-6.98 (10H, m), 7.20-7.54 (12H, m), 7.88 (1H, d), 7.90-7.93 (1H, m), 7.98 (1H, d). IR (KBr) cm ^_1: 1750, 1690, 1555, 1295, 1270, 1225, 760, 710th

Reference Example 65

2-Butyl 1-5-chloro-1 H - (2'-cyanobiphenyl-4-yl) methyl-7-benzimidazole

7-carboxylic acid methyl ester

3.33 g of 5-chloro-2- N - (2'-cyanobiphenyl-4-ylmethyl) -N-valeryl-7-amino-3-nitrobenzoic acid methyl ester in 4 ml of concentrated HCl and 50 ml of methanol To a stirred solution of the mixture (1.1 g) at room temperature was added 1.1 g of 95% pure iron powder in portions. and extracted with water.The organic layer aqueous sodium bicarbonate solution and water, dried and evaporated the solvent, the residue was purified by column chromatography on silica gel, 1.83 g of colorless needle-like crystals with a yield of.... 61 ^X H NMR ( 200 MHz, COCl 3): 0.96 (3H, t), 1.38-1.57 (2H, m),

1.80-1.95 (2H, m), 2.92 (2H, t), 3.72 (3H, s), 5.79 (2H, s), 6.94 (2H, d), 7 , 41-7.49 (4H, m), 7.59-7.63 (1H, m), 7.73-7.78 (1H, m), 7.61 (1H, d), 7.91 (lH, d).

Reference Example 66

A solution of ethyl 2-carboxy-3-nitrobenzoic acid ethyl ester in 3 ml of ethanol containing 300 ml of concentrated sulfuric acid was heated at reflux for 24 hours. The solvent was then distilled off and the residue was poured into 700 ml of ice water and extracted with ethyl acetate. The organic layer was washed with water and extracted with aqueous potassium carbonate solution. The aqueous phase is acidified with hydrochloric acid and extracted with methylene chloride. The organic phase is washed with water and dried. The solvent was distilled off to give 29 g of a solid which was used in the next step without further purification. Yield: 74 h.

¹ H-NMR (90MHz, COCl ₃ ) δ: 1.43 (3H, t), 4.47 (2H, q), 7.70 (1H, t), 8.40 (2H, d), δ , 87 (1H, br s).

IR (Nu joDcm ' ¹ : 1725, 1535, 1350, 1300, 1270.

4 «· • · * •« · ♦ · ··

Reference Example 67

Ethyl 2-t-butoxycarbonylamino-3-nitrobenzoate

A solution of 23.9 g of ethyl 2-carboxy-3-nitrobenzoic acid and 12 ml of thionyl chloride in 150 ml of benzene was heated under reflux for 3 hours. The resulting solution was evaporated to dryness, and the resulting acid chloride (26 g, quantitative) was dissolved in methylene chloride (20 mL) and added dropwise to a solution of sodium azide (9.75 g) in dimethylformamide (20 mL) with vigorous stirring. The reaction mixture was poured into a mixture of 3 ml of diethyl ether, 1200 ml of hexane and 250 ml of water, and the whole was shaken. The organic phase is washed with water, dried and the solvent is distilled off. The residue was dissolved in tert-butanol (200 mL) and the temperature of the solution was gradually raised while stirring. Finally, the reaction mixture was refluxed for 2 hours. The mixture was then concentrated in vacuo to give 30 g of an oil.

1 H-NMR (90MHz, CDCl 3: 1.40 (3H, t), 1.53 (9H, s), 4.43 (2H, q), 7.23 (1H, t), 8.03-8, 27 (2H, m), 9.70 (1H, br s).

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

Reference Example 68

To a solution of 2 - [(2'-cyano-biphenyl-4-yl) -methyl-amino] -3-nitrobenzoic acid ethyl ester in 2 g of 2-t-butoxycarbonylamino-3-nitrobenzoic acid ethyl ester in 50 ml of tetrahydrofuran. · »·«

With stirring at 6Z and cooling with ice, 2.8 g of sodium hydride were added in the form of a weight% oil solution. To the reaction mixture was added 4- (2-cyano-biphenyl) methyl bromide (18 g) and potassium iodide (0.36 g), and the mixture was stirred at room temperature for 15 hours. The reaction mixture was heated at reflux for 4 hours and the solvent was distilled off. The residue was extracted with water (250 mL) and diethyl ether (200 mL), and the organic phase was evaporated. A yellow oil is obtained which is dissolved in a mixture of 60 ml of trifluoroacetic acid and 40 ml of methylene chloride and the solution is stirred for 1 hour at room temperature. The reaction mixture was evaporated to dryness and diethyl ether (200 mL) was added to the residue. The resulting crystals were filtered off, washed with diethyl ether and dried. 22.1 g of pale yellow crystals are obtained. Yield: 85%. Mp: 119-120 ° C.

¹ H-NMR (90MHz, CDCl 3) δ: 1.37 (3H, t), 4.23 (2H, s), 4.37 (2H, q), 6.37 (1H, t), δ , 33-7.83 (9H, m), 7.97-8.20 (2H, m).

IR (Nujol) cm ^-1 : 3280, 2220, 1690, 1575, 1530, 1480, 1450, 1255, 1125, 1105, 755.

Reference Example 69

3-amino-2 - // (2 ^{1-cyano-biphenyl-4-yl)} -methyl-amino benzoate

5.5 g 2 - [(2- ^l- cyano-biphenyl-4-yl) -methyl-amino] -

To a solution of ethyl 3-nitrobenzoic acid in 50 ml of tetrahydrofuran was added 5 g of Raney nickel. The reaction mixture was subjected to catalytic reduction at room temperature under atmospheric pressure. The catalyst is then filtered off to give the filtrate as a tan oil (9 x * g). Yield: quantitative. 1 H-NMR (90MHz, COCl 3 -O 3 OS: 1.30 (3H, t), 4.23 (2H, s),

4.27 (2H, q), 6.87-7.03 (2H, m), 7.33-7.87 (9H, m).

IR cm ^-1 : 3435, 3350, 2980, 1690, 1615, 1465, 1365, 1280,

1240, 1215, 1190, 1065, 755.

Reference Example 70

2-Butyl-1- (2'-cyano-biphenyl-4-yl) -methyl-7-benzimidazole

7-carboxylic acid ethyl ester

0.31

3-amino-2- [3- (2'-cyano-biphenyl-4-yl)

-amfnO

A solution of ethyl D-methylbenzobenzoic acid and 0.18 g of ethyl tetravalimide in 2 ml of ethanol was stirred at 70 ° C for 2 hours, then the reaction mixture was evaporated to dryness and the residue was extracted with ethyl acetate and aqueous sodium bicarbonate. The organic layer was washed with water, dried and evaporated. The resulting crystals were recrystallized from ethyl acetate / hexane to give 0.22 g of a pale yellow needle-like crystal. Yield: 60%. Mp: 112-114 ° C.

¹ H NMR (90MHz, CDCl 3) δ: 0.93 (3H, t), 1.20 (3H, t), 5.87 (2H, s), 7.11 (3H, d), δ , 17-8.03 (9 H, m).

IR (Nujol) cm ^-1 : 2220, 1725, 1480, 1450, 1420, 1400, 1285,

1255, 1245, 1190, 1110, 750.

Reference Example 71

2-Butyl-1 H - (2'-cyanobiphenyl-4-yl) methyl-7- (7-hydroxymethylbenzimidazole) g-2-butyl-1 '- (2'-cyanobiphenyl-4-yl) - methyl-7-benzimidazole-7-carboxylic acid methyl ester and 2.2 g of sodium borohydride

To a solution of 100 ml of tetrahydrofuran is added dropwise 19 minutes of methanol. The reaction mixture was heated at reflux for a further 27 hours and then evaporated to dryness. Water was added to the residue, and the solution was neutralized with concentrated hydrochloric acid. The resulting crystals were filtered off and recrystallized from methanol. 8.8 g of colorless needle-like crystals are obtained. Mp: 203-204 ° C.

Elemental analysis for ^C 26 ^H 25 ^N 3 °: C (%) H (%) N (%) Calculated: 78.96 6.37 10.62 Found: 79.24 6.36 10.69 NMR (200MHz, CDCl3) δ: 0.94 (3H, t), 1.36-1.55 (2 H, m),

1.79-1.95 (2H, m), 2.85 (2H, t), 4.66 (2H, d), 5.82 (2H, s), 7.04 (2H, d), 7 , 10 (1H, dd), 7.18-7.26 (1H, m), 7.40-7.52 (4H, m), 7.64 (1H, dt).

IR (KBr) cm ^-1 : 3200, 2210, 1510, 1480, 1455, 1425, 1410, 1280, 1015, 765, 750.

Reference Example 72

2-butyl / ~ (2'-cyanobiphenyl-4-yl) -metil_7-7-klórmetilbenzimidazol

5.4 g of 2-butyl-1- (2'-cyano-biphenyl-4-yl) -methyl-7-methyl-

To a solution of 7-hydroxybenzimidazole (8.3 g) and thionyl chloride (8.3 g) in chloroform (80 ml) was added 1 drop, i.e. a catalytic amount of dimethylformamide, and the mixture was heated under reflux for 1 hour. The reaction mixture was washed with aqueous sodium bicarbonate solution, then with water, then dried and evaporated to dryness. The residue was crystallized from ethyl acetate / hexane to give 5.3 g of colorless needle-like crystals.

we get. Mp .: 144-145 ° C. Analysis a C ₂₆ H ₂₄ ClN ₃ calcd C (%) MONTH N (H) calculated: 75.44 5.84 10.15 Found: 75.29 5.87 10.04 NMR (200 MHz, cdci ₃ )? c. 0.96 (3H, t), 1.38

1.82-1.97 (2H, m), 2.88 (2H, t), 4.60 (2H, s),

5.78 (2H, s), 7.07 (2H, d), 7.14 (1H dd), 7.21 (1H, d),

7.41 -7.54 (4H, m), 7.60-7.69 (1H, m), 7.75-7.84 (2H, m). IR (K8r) cm ^-1 : 2210, 1515, 1480, 1450, 1425, 1400, 1350,

1280, 760, 745, 690.

Reference Example 73

2-Butyl 1 -1 (2'-cyanobiphenyl-4-yl) methyl-7- (7-cyanophenylethyl) benzimidazole

0, 3 g of 2-butyl-1 - [(2'-cyanobiphenyl-4-yl) methyl] -7-

A mixture of 7-chloromethylbenzimidazole and 0.12 g of sodium cyanide in 10 ml of dimethylformamide was stirred for 22 hours at room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and dried. The solvent was evaporated and the residue was crystallized from ethyl acetate to give 0.76 g of a colorless prism crystal. Yield: 94%. Mp: 180-181 ° C.

Elemental analysis for ^C 27 ^H 24 ^N 4

C (%)

Calculated: 80.17

Found: 80.22

Reference Example 74:

H (*) N (\)

5,9813,85

6,1713,69

Ethyl 2-butyl-1 - [(2 * -cyano-biphenyl-4-yl) -methyl-7-benzimidazol-7-yl] -acetic acid ester

0.76 g of 2-butyl-l - // ^(one 2-cyano-biphenyl-4-yl) ethanol in 10 ml of 3.5 N hydrochloric acid solution -metil_77-cyanomethyl-benzimidazole

Heat at reflux for 2.5 hours. The reaction mixture was diluted with water, then read with an aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with water and dried. The solvent was distilled off and the residue was purified by column chromatography on silica gel. 0.9 g of a colorless oil are obtained. Yield: quantitative.

NMR (200MHz, COCl 3) δ: 0.94 (3H, t), 1.23 (3H, t), 1.37-1.55 (2H, m), 1.80-1.95 (2H, m) ), 2.85 (2H, t), 3.65 (2H, q),

5.73 (2H, s), 7.01-7.07 (3H, m), 7.21 (1H, t), 7.74-7.68 (5H, m), 7.71-7, 78 (2 H, m).

IR cm ^-1 : 2210, 1730, 1510, 1475, 1435, 1400, 1365, 1350,

1275, 1040, 760, 735.

Reference Example 75

2-butyl-l - / * (2'-cyanobiphenyl-4-yl) methylbenzimidazole--metil_7-7

A mixture of 0.62 g of 2-butyl-1 - [(2'-cyanobiphenyl-4-yl) methyl] -77-chloromethylbenzimidazole, 3.0 g of tributyltin hydride and catalytic amount of perbenzoic acid in 20 ml of toluene was added.

Reflux under nitrogen for 5.5 hours. The reaction mixture was concentrated, purified by column chromatography and recrystallized from ethyl acetate / hexane. 0.5 g of colorless crystals are obtained. Yield: 88 M.p .: 115-116 ° C.

Analysis a C ₂₆ H ₂₅ N ₃ C (%) calcd H (*) N (%) calculated: 82.29 6.64 11.07 Found: 82.30 6.74 10.94 IR (KBr) cm ^_1: 2210, 1595, 1515, 1480, 1460, 1415, 1400, 1345, 1280, 780, 760, 740.

Reference Example 76

2-butyl-l- / ~ (2'-cyano-bifeni1-4-yl) -meti1_7-7-hidroxibenzimidazol

To a solution of 1.2 g of 2-butyl-1- (2'-cyanobiphenyl-4-yl) methyl-77-methoxybenzimidazole in 5 ml of methylene chloride was added 1.7 g of boron in a nitrogen atmosphere at 72 ° C. tribromide is added. After stirring for 8 hours at room temperature, water was added and stirring continued for an additional 1 hour. The mixture was read with 6N sodium hydroxide and extracted with ethyl acetate. The organic phase is washed with water, dried and concentrated. The residue was purified by column chromatography over silica gel. The crude crystals thus obtained were recrystallized from ethyl acetate / hexane to give 0.69 g of a colorless prism-like crystal.

we get. Yield: 63%. Mp : 185-186 ° C. Analysis the calcd C (%) H (%) N (%) calculated: 78.71 6.08 11.02 Found: 78.70 6.07 11.01 1 H-NMR (200MHz, CDCl 3) δ: 0.81 (3H, t), 1.22 -1.42 (2 H, m), 1.66 -1.81 (2 H, m), 2.80 (2H, t), 5.81 (2H, s), 6.71 (1H, d), 7.00 (1H, t), 7, 19-7.26 (3H, m), 7.38-7.50 (4H , m), 7.61 (1H, m), 7.74 (4H, d). IR (KBr) cm 2210, 1615, 1590, 1500, 1475, 1440, 1410, 1365, 1290, 1195, 1160, 1065, 780, 755, 725.

n

Reference Example 77

2-methoxy-6-nitroaniline

A mixture of 7.7 g of 2-amino-3-nitrophenyl and 7.6 g of potassium carbonate in 15 ml of dimethylformamide was stirred for 30 minutes at room temperature, and then 7.8 g of methyl iodide was added. The reaction mixture was stirred for an additional 5 hours at room temperature, then water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried. The solvent was distilled off and the resulting crude crystals were recrystallized from isopropyl ether. 6.9 g of an orange prism crystal are obtained. Yield: 82%. Melting point: IG-ΊΊ ° C.

78.referenciapélda

N- (2-methoxy-6-nitróíenil) -valeroamid

5.9 2-Methoxy-6-nitroaniline 14 g of valeric acid

A catalytic amount of concentrated sulfuric acid was added to the mixture of ¢ 9 anhydride and the mixture was stirred at 130-140 ° C for 1.5 hours. Water was added to the reaction mixture and then basified with 6N sodium hydroxide. The mixture was then extracted with ethyl acetate, and the organic phase was washed with water and dried. The solvent was distilled off and the residue was purified by column chromatography on silica gel. The resulting crude crystals were recrystallized from ethyl acetate / hexane

3.2 g of colorless crystals are obtained. Yield: 36 M.p .:

113-114 ° C.

1 H-NMR (90MHz, COCl ₃ ) δ: 0.95 (3H, t), 1.33-1.51 (2H, m),

1.64-1.79 (2H, m), 2.42 (2H, t), 3.94 (3H, s), 7.14 (1H, dd),

7.26 (1H, t), 7.51 (1H, dd), 7.64 (1H, brs).

IR (KBr) cm ^_1: 3300, 1670, 1590, 1545, 1520, 1485, 1460, 1430, 1360, 1275, 1055, 800, 735th

Reference Example 79 N- (2'-Cyano-biphenyl-4-ylmethyl) -N- (2-methoxy-6-nitrophenyl) valeramide

To a solution of N- (2-methoxy-6-nitrophenyl) -valeramide (3.2 g) in dimethylformamide (15 ml) was added 0.61 g of sodium hydride (60% w / w) under ice-cooling. After stirring for 20 minutes, 4- (2-cyanophenyl) -benzyl bromide (3.5 g) was added and the mixture was stirred at room temperature for another hour. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic phase is washed with water and dried, the solvent is distilled off and the residue is subjected to column chromatography.

ΊΟ Purify on silica gel. 5.8 g of a yellow oil are obtained. Yield: quantitative.

¹ H-NMR (90MHz, CDCl 3: 0.84 (3H, t), 1.12-1.35 (2H, m),

1.56-1.70 (2H, m), 1.91-2.23 (2H, m), 3.61 (3H, s),

4.42 (1H, d), 5.20 (1H, d), 7.03-7.12 (1H, m), 7.22 (2H, d), 7.34-7.49 (6H, m), 7.63 (1H, m), 7.74 (1H, d). IR cm ^-1 : 2220, 1670, 1535, 1480, 1390, 1275, 1050, 800,

760, 730.

Reference Example 80

2-Butyl 1-1- (2'-cyanobiphenyl-4-yl) methyl-7- (7-methoxybenzimidazole)

To a solution of 5.8 g of N- (2'-cyanobiphenyl-4-yl) methyl-7-N- (2-methoxy-6-nitr61phenyl) valeramide in 50 ml of methanol and 7 ml of concentrated hydrochloric acid at room temperature was added 2.3 g iron powder is given in more detail. The reaction mixture was refluxed for 5 hours and the solvent was evaporated. Ethyl acetate and water were added to the residue and the reaction was quenched with 6N sodium hydroxide. The insoluble material is filtered off and the filtrate is left to stand, thereby separating into two portions. The organic layer was washed with water, dried and the solvent was distilled off. The residue was recrystallized from ethyl acetate / hexane to give 4.1 g of a colorless prism crystal. Yield: 80%. Mp 127-128 ° C.

¹ H-NMR (200MHz, COCl 3 S: 0.91 (3H, t), 1.32-1.51 (2H, m),

1.73-1.89 (2H, m), 2.79 (2H, t), 3.83 (3H, s), 5.71 (2H, s), 6.69 (1H, d), 7 , 11-7.19 (3 H, m), 7.38-7.51

(5H, m), 7.63 (1H, m), 7.76 (1H, d).

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

Reference Example 81

2-Butyl-1- (2'-cyanobiphenyl-4-yl) methyl-7- (7-methoxymethylbenzimidazole)

0.79 g of 2-butyl-1- (2'-cyanobiphenyl-4-yl) methyl-77-hydroxymethylbenzimidazole, 0.36 g of thionyl chloride and a catalytic amount of dimethylformamide were prepared in 20 ml of chloroform. the mixture was refluxed for 1 hour. The solvent was then distilled off and the residue was dissolved in methanol (15 mL). To the solution was added 2 mL of a 4.9 M solution of sodium methoxide in methanol and the reaction mixture was heated under reflux for 6 hours. The solvent was then distilled off, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic phase is washed with water, dried and the solvent is distilled off. The residue was purified by column chromatography over silica gel. 0.48 g of an oil are obtained. Yield: 59%.

¹ H-NMR (90MHz, CDCl 3) δ: 0.92 (3H, t), 1.20-2.05 (4H, m),

2.84 (2H, t), 3.30 (3H, s), 4.34 (2H, s), 5.74 (2H, s),

6.90-7.90 (H H, m).

IR cm ^-1 : 2220, 1520, 1480, 1460, 1440, 1425, 1280, 1190, 760.

82-84. Reference Examples 32 are followed as described in Reference Example 32.

- 7Z -

Reference Example 82

Ethyl 2- [N-acetyl-N * (2'-cyanobiphenyl-4-yl) methylamino] -3-nitrobenzoic acid

Physical Properties: Oil 1 H-NMR (90MHz, CDCl 3) δ: 1.30 (3H, t), 1.97 (3H, s), 4.17 (1H, d),

4.83 (1H, d), 7.17-8.17 (HH, m).

IR cm ^-1 : 2985, 2230, 1730, 1675, 1600, 1540, 1390, 1365,

1285, 770.

Reference Example 83

2- N -propionium 1-N- (2'-cyanobiphenyl-4-yl) methylamino;

3-nitrobenzoic acid ethyl ester

Physical constants: oil ¹ H-NMR (90MHz, CDCl 3): 1.13 (3H, t), 1.27 (3H, t), 2.17 (2H, q), 4.13 (2H, q), 4 , 77 (1H, d), 4.83 (1H, d), 7.10-8.17 (HH, m).

IR cm ^-1 : 2985, 2220, 1730, 1675, 1600, 1535, 1480, 1445,

1390, 1350, 1290, 1265, 1210, 770.

Reference Example 84

2- N -isobutyryl-N- (2'-cyano-biphenyl-4-yl) -methyl-amino} -

3-Nitralenezoic acid ethyl ester

Physical constants: oil ¹ H-NMR (900MHz, CDCl 3) δ: 1.07 (3H, d), 1.13 (3H, d), 1.30 (3H, t), 2.03-2.47 ( 1H, m), 4.20 (2H, q), 4.70 (1H, d),

7.17-8.27 (1H, m).

IR cm ^-1 : 2980, 2220, 1730, 1670, 1590, 1530, 1480, 1390,

1350, 1285, 1260, 1240, 1205, 765.

- 73 A 85-87. Reference Example 33 is followed as described in Reference Example 33.

Reference Example 85 1-N '- (2'-Cyano-biphenyl-4-yl) -methyl-7-2-methyl-benzimidazole-7-carboxylic acid ethyl ester

Yield: 81%. Physical constants: mp 167-168 ° C.

¹ H NMR (90MHz, CDCl 3) δ: 1.20 (3H, t), 2.63 (3H, s), 4.20 (2H, q), 5.83 (2H, s), 7.00 (2H, d), 7.17-7.97 (9H, m).

IR cm ^-1 : 2220, 1705, 1395, 1280, 1265, 1210,

Reference Example 86

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

Yield: 76%, m.p. 163-164 ° C.

¹ H NMR (90MHz, CDCl 3) δ: 1.20 (3H, t), 1.47 (3H, t), 2.93 (2H, q), 4.20 (2H, q), 5.83 (2H, s), 6.97 (2H, d),

7.17-8.00 (9 H, m).

IR (Nujol) cm ^_1: 2220, 1720, 1480, 1450, 1420, 1400, 1380, 1280, 1250, 1200, 1145, 1110th

Reference Example 87

Ethyl 1 - [(2'-cyano-biphenyl-4-yl) -methyl] -2-isopropyl-benzimidazole-7-carboxylic acid

Yield: 77%, m.p. 107-108 ° C.

IR (NujoDcm ¹ : 2220, 1730, 1440, 1280, 1250, 1205, 1140,

1110, 765, 740.

Reference Example 88

2-Chloromethyl-1- (2'-cyano-biphenyl-4-yl) -methyl-7-benzimidazole-7-carboxylic acid ethyl ester

To a solution of 1.0 g of 3-amino-2- [7- (2'-cyano-biphenyl-4-yl) -methyl-amino] -benzoic acid and 0.3 g of triethylamine in 10 ml of methylene chloride was added in portions under ice-cooling. 0.24 mL of chloroacetyl chloride. The reaction mixture was stirred for 13 hours and then evaporated to dryness. The resulting residue was washed with water, dried and dissolved in 10 ml of ethyl alcohol. Concentrated hydrochloric acid (1 ml) was added to the solution and the solution was heated under reflux for 6 hours. The mixture was then evaporated to dryness and the resulting residue was dissolved in methylene chloride and water. The solution was basified with 1N sodium hydroxide and the organic layer was washed with water, dried and evaporated to dryness. The resulting crystals were recrystallized from ethyl acetate / isopropyl ether to give 0.88 g of a colorless crystal. Yield: 76%. ¹ H-NMR (200MHz, CDCl 3): 1.21 (3H, t), 4.21 (2H, q), 4.83 (2H, s), 6.02 (2H, s), 7. 02 (2H, d), 7.29-7.49 (5H, m),

7.58-7.79 (3H, m), 8.00 (1H, dd).

Reference Example 89

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

0.8 g of 2-chloromethyl-1 H - (2'-cyanobiphenyl-4-yl) methyl-7-benzimidazole-7-carboxylic acid ethyl ester and 1.08 g of 28% sodium methoxide in methanol 15 of methanol was heated under reflux for 2 hours. The reaction mixture was evaporated to dryness and the residue was dissolved in a mixture of methylene chloride and water. The organic phase is washed with water, dried and evaporated to dryness. The resulting syrup was purified by column chromatography over silica gel.

0.4 g of a yellow syrup are obtained. Yield: 52%.

1 H-NMR (200MHz, CDCl 3) δ: 3.43 (3H, s), 3.72 (3H, s), 4.78 (5H, m), 7.55-7.77 (3H, m), 7.99 (1H, dd).

90-93. Reference Example 89 is followed as described in Reference Example 89.

Reference Example 90

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

Light brown syrup.

1 H-NMR (200MHz, CDCl 3) δ: 1.16 (3H, t), 1.23 (3H, t), 3.59 (2H, q), 4.21 (2H, q), δ , 82 (2H, s), 5.99 (2H, s),

6.99 (2H, d), 7.22-7.45 (5H, m), 7.55-7.75 (3H, m), 7.98 (1H, dd).

Reference Example 91 v

Ethyl 1 - [(2'-cyano-biphenyl-4-yl) -methyl] -2- (methylthio) -benzimidazole-7-carboxylic acid

Yield: 72%.

Physical properties: pale yellow syrup.

i

¹ H-NMR (200MHz, COCl 3) δ: 1.20 (3H, t), 2.18 (3H, s), 3.90 (2H, s), 4.20 (2H, q), 5.96 (2H, s), 7.01 (2H, d),

7.23-7.35 (1H, m), 7.37-7.50 (4H, m), 7.59-7.80 (3H, m), 7.97 (1H, dd).

Reference Example 92

Ethyl 1- [2- (2'-cyano-biphenyl-4-yl) -methyl] -2- (ethylmethyl) -benzimidazole-7-carboxylic acid

Yield: 88%. Physical properties: light brown syrup. ¹ H-NMR (200MHz, CDCl 3) δ: 1.20 (3H, t), 1.27 (3H, t), 2.62 (2H, q), 3.96 (2H, s), 4.20 (2H, q), 6.00 (2H, s), 7.01 (2H, d), 7.29 (1H, t), 7.38-7.49 (4H, m), 7.57-. 7.78 (3Hm,), 7.96 (1H.dd).

Reference Example 93

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

Yield: 99%, light brown syrup.

Reference Example 94

3-Amino-2H - (2'-cyano-biphenyl-4-yl) -methyl-amino} -benzoic acid methyl ester g 3-amino-2H- (2'-cyano-biphenyl-4-yl) -methyl A mixture of ethyl aminobenzoic acid ethyl ester and 1.62 g of sodium hydride (60% w / w in oily solution) in methanol (50 ml) was stirred at room temperature for 24 hours. The reaction mixture was evaporated to dryness and the resulting syrup was saturated with water (100 mL)

- FI *

is poured into a solution of sodium bicarbonate. The mixture was extracted with chloroform, and the organic phase was washed with water, dried and evaporated to dryness. A crystalline product is obtained which is recrystallized from ethyl acetate / hexane. 3.9 g of colorless crystals are obtained. Yield: 82%. Mp: 106-108 ° C. ¹ H NMR (200MHz, CDCl 3) δ: 3.81 (3H, s), 3.97 (2H, br s),

4.23 (2H, s), 6.40 (1H, br s), 6.88-6.91 (2H, m), 7.34-7.55 (7H, m), 7.64 (1H) dd).

IR (KBr) cm ^-1 : 3410, 3350, 2225, 1695, 1485, 1470, 1290,

1200, 780. 760.

Reference Example 95

2- (2-chloroethyl) -l- / ~ (2'-cyanobiphenyl-4-yl) -metil_7-benzimidazole-7-carboxylic acid methyl ester

To a solution of 0.5 g of 3-amino-2H- (2'-cyanobiphenyl-4-yl) methyl-7-aminobenzoic acid methyl ester in 5 ml of methylene chloride is added 0.15 ml of 3-chloropropionyl chloride dropwise. The reaction mixture was stirred at room temperature for 30 minutes and then evaporated to dryness. The resulting residue was dissolved in methanol (5 ml) containing concentrated hydrochloric acid (0.5 ml) and stirred at room temperature for 16 hours. The reaction mixture was evaporated to dryness and the resulting residue was dissolved in methylene chloride / water. The aqueous phase was read and extracted. The organic phase is washed with water, dried and evaporated to dryness. 0.7 g of a light brown syrup is obtained. Yield: quantitative.

¹ H NMR (200MHz, CDCl 3) δ: 3.37 (2H, t), 3.74 (3H, s), 4.09 (2H, t), 5.87 (2H, s), 7.00 (2H, d), 7.29 (1H, t), 7.39-

7.81 (7H, m), 7.97 (1H.dd).

f

-? 8 * «

Reference Example 96

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

A mixture of 1.0 g of 2- (2-chloroethyl) -1 H - (2'-cyanobiphenyl-4-yl) methyl-7-benzimidazole-7-carboxylic acid methyl ester and 0.25 g of potassium carbonate in 30 ml of methanol was stirred for 2 hours. is refluxed. The reaction mixture was evaporated to dryness, the resulting residue was dissolved in methylene chloride and the insolubles were filtered off. The filtrate is evaporated to dryness and the residual syrup is purified by column chromatography over silica gel. 0.45 g of a pale yellow syrup are obtained. Yield: 59%.

¹ H NMR (200MHz, CDCl ₃ ) δ: 3.19 (2H, t), 3.34 (3H, s), 3.72 (3H, s), 3.92 (2H, t), δ 88 (3H, s), 7.00 (2H, d),

7.26 (1H, t), 7.40-7.48 (4H, m), 7.56-7.76 (3H, m),

7.95 (1H, dd).

Reference Example 97

1 - [(2'-Cyano-biphenyl-4-yl) -methyl] -2- (2-methyl-thidynyl) -benzimidazole-7-carboxylic acid methyl ester

Proceed as described in Reference Example 96.

1.1 g of a colorless powder are obtained. Yield: 93%. ¹ H NMR (200MHz, COCl 3) δ: 2.14 (3H, s), 3.02-3.11 (2H, m),

3.16-3.25 (2H, m), 3.74 (3H, s), 5.86 (2H, s), 7.00 (2H, d), 7.28 (1H, t), , 39-7.49 (4H, m), 7.58-7-78 (3H, m), 7.97 (1H.dd).

Reference Example 98

2-butyl-l- / ^- (2'-cyano-biphenyl-4-yl) -metil_7-7- (N, N-dimethyl amino4étil) benzimidazole

A mixture of 0.65 g of 2-butyl-1- (2'-cyanobiphenyl-4-yl) methyl-7-chloromethylbenzimidazole and 1.5 ml of a 50% aqueous solution of dimethylamine in 3 ml of ethanol was sealed. heat in a tube for 5 hours. The reaction solution was evaporated to dryness and the resulting syrup was dissolved in ethyl acetate. The solution was washed with water, dried and evaporated to dryness. A further syrup was obtained, which was purified by column chromatography on silica gel. 0.4 g thus obtained. Yield: 63%. 1 H-NMR (200MHz, CDCl 3: 0.92)

1.81-1.94 (2H, m), 2.16 (2H, s), 6.00 (2H, s), 6

7.39-7.50 (4H, m), 7.62 IR (Neat) cm ^_1: 2210, 1515, 1480 1330, 1275, 1005 was a colorless liquid (3H, t), 1.35-1.53 ( 2H, m), (6H, s), 2.80 (2H, t), 3.34 95-7.01 (3H, m), 7.16 (1H, t), (1H, m), 7 , 73-7.77 (2 H, m).

1460, 1440, 1405, 1360,

840, 785, 760.

Reference Example 99

Ethyl-2- (2'-cyano-biphenyl-4-yl) -methyl-7-2-sec-butyl-benzimidazole-7-carboxylic acid

A mixture of 1.1 g of 3-amino-2 - [(2'-cyanobiphenyl-4-yl) methyl] amino} benzoic acid ethyl ester and 0.56 g of 2-methylbutyric anhydride in ml of pyridine was heated for 15 hours 115 Heat at <RTI ID = 0.0> C </RTI>. The reaction mixture was triturated with ethyl acetate (50 mL), and the solution was washed with water, dried and evaporated to dryness (4 x ¹⁰ ).

U I »· ♦. ** ··· • · · - · ·

- 80 rolls. The resulting syrup was dissolved in ethanol (15 ml) containing concentrated hydrochloric acid (0.5 ml) and heated to reflux for 3 hours. The solvent was then distilled off and the residual syrup was purified by column chromatography on silica gel.

1.2 g of pale yellow syrup are obtained. Yield: 92%.

1 H-NMR (90MHz, CDCl 3?): 0.90 (3H, t), 1.20 (3H, t), 1.40 (3H, d),

1.50-2.10 (1H, m), 4.17 (2H, q), 5.87 (2H, s), 6.97 (2H, d),

7.17-8.03 (9 H, m).

IR (Neat) cm ^-1 : 2975, 2930, 2875, 2220, 1480, 1445, 1410,

1370, 1280, 1260, 1200, 1140, 1110, 1035, 760.

Reference Example 100

1- [(2'-Cyano-biphenyl-4-yl) -methyl] -7-2-isobutyl-benzimidazole

7-carboxylic acid ethyl ester

The compound was prepared as described in Reference Example 99. Yield: quantitative. Physical properties: pale yellow syrup.

¹ H-NMR (90MHz, CDCl ³ ) δ: 1.03 (6H, d), 1.20 (3H, t), 2.07-2.53 (1H, m), 2.80 (2H, d) , 4.17 (2H, q), 5.83 (2H, s), 6.93 (2H, d), 7.13-8.00 (9H, m).

IR cm ^-1 : 2960, 2215, 1710, 1480, 1400, 1280, 1255, 1200, 1120, 760.

Reference Example 101

2-Butyl-1- [2 '- (N-triphenylmethyl-tetrazol-5-yl) -biphenyl]

4 il_7 metil_7-benzimidazole-7-carboxylic acid

84 g of 2-butyl-1 H - [2 '- (1H-tetrazol-5-yl) -biphenyl-4-yl] -7-methyl-7-benzimidazole-7-carboxylic acid, 1.96 g of triphenylmethyl chloride and 1, A mixture of 0 ml triethylamine in 20 ml methylene chloride was stirred at room temperature for 16 hours. The reaction mixture was washed with water, dried over sodium sulfate and evaporated to dryness. The resulting solid residue was purified by column chromatography over silica gel.

4.25 g of a colorless powder are obtained. Yield: 91%. Mp: 120-123 ° C. ¹ H-NMR (200MHz, CDCl 3) δ: 0.88 (3H, t), 1.26-1.45 (2H, m),

1.72-1.88 (2H, m), 2.81 (2H, t), 5.72 (2H, s), 6.63 (2H, d), 6.92-6.97 (8H, m), 7.12-7.43 (13H, m), 7.68 (1H, d), 7.78-7.83 (1H, m), 7.92 (1H, d).

IR (Neat) cm ^-1 : 3050, 2950, 2925, 1690, 1595, 1510, 1490,

1440, 1405, 1275, 1240, 1180, 740, 690.

Reference Example 102

2- [N- (2'-methoxycarbonyl-biphenyl-4-yl) methyl-N-valeryl] amino-3-nitro-benzoic acid methyl ester

To a solution of 1.0 g of 3-nitro-2-valerylaminobenzoic acid methyl ester in 10 ml of dimethylformamide was added 0.17 g of 60% oily sodium hydride under ice-cooling for 20 minutes. To the resulting reaction mixture was added 1.1 g of 2- (4-bromomethyl-phenyl) -benzoic acid methyl ester, and the reaction mixture was stirred for 5 hours. The mixture was then diluted with water and extracted with ethyl acetate. The organic phase is washed with water,

After drying over anhydrous magnesium sulfate, the solvent was distilled off in vacuo and the residue was purified by column chromatography over silica gel. 1.2 g of a yellow oil are obtained. Yield: 76%.

1 H-NMR (200 MHz, CDCl ₃ ) δ: 0.85 (3H, t), 1.17-1.36 (2H, m), 1.59-1.76 (2H, m), 2.05 -2.17 (2H, m), 3.65 (3H, s), 3.69 (3H, s), 4.72 (1H, d), 4.83 (1H), 7.07-7, 18 (4H, m), 7.33 (1H, dd), 7.41 (1H, dd), 7.50 (1H, dd), 7.59 (1H, td), 7.79 (1H, dd) ), 7.96 (1H, dd), 8.12 (1H, dd).

IR (neat): 1730, 1675, 1600, 1540, 1455, 1440, 1395,

1355, 1290, 1210, 1130, 1090, 760, 710 cm ^-1 .

Example 1

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

3.2 g of 2-butyl-1 - [(2'-cyanobiphenyl) -1D-methyl-benzimidazole-1-carboxylic acid methyl ester, 7.4 g of sodium azide and 6.1 g of ammonium chloride (30 mL) was stirred at 115 DEG C. for 4 days, then water was added to the reaction mixture, and the pH was adjusted to 3-4 with 1N hydrochloric acid. The crystals thus obtained were recrystallized from ethyl acetate / methanol to give 2.27 g (63%) of a colorless prism crystal, mp 168-169 ° C.

- ΘΖ -

Elemental Analysis a ^C 26 ^H 24 ^N 6 ° 2 .h ₂ o calcd C (%) H (%) N (%) calculated: 66.37 5.57 17.86 Found: 66.04 5.69 17.58 ¹ H NMR (200MHz, CDCl3) S: 0.88 (3H, t), 1.28-1.46 (2H, m),

1.65-1.80 (2H, m), 2.82 (2H, t), 5.85 (2H, s), 6.79 (2H, d), 7.00 (2H, d), 7 , 24 (1H, t), 7.45 (5H, m),

7.83 (1H, dd).

IR (KBr) cm ^-1 : 1720, 1600, 1510, 1455, 1285, 1255, 1240, 775, 755, 745.

Example 2

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

The crude crystal (1) obtained in Example 1 was purified by column chromatography on silica gel and recrystallized from ethyl acetate / hexane. 0.17 g of colorless needle crystals are obtained. Yield:

4.7%. M.p .: 133-135 ° C. Elemental Analysis a ^C 27 ^H 26 ^N 6 ° 2 calcd 0 (¾) H (%) N (%) calculated: 69.51 5.62 18.01 Found: 69.47 5.66 17.92 ¹ H NMR (200MHz, CDClj) A: 0.94 (3H, t), 1.35-1.55 (2H, m),

1.78-1.93 (2H, m), 2.96 (2H, t), 3.15 (3H, s), 5.82 (2H, s), 6.81 (2H, d), δ , 97 (2H, d), 7.25 (1H, t), 7.4777.67 (4H, m), 7.80 (1H, dd), 7.95 (1H, dd).

IR (KBr) cm ^_1: 1715, 1520, 1415, 1290, 1260, 1200, 1125, 780,

750th

Example 3

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

- 83 0.71 g of 2-butyl-1 H - 2 '- (1H-tetrazol-5-yl) biphenyl-4-yl-7-methyl-7-benzimidazole-7-carboxylic acid and 0.82 g of 90% pure diethyl A solution of cyanophosphate in 6 ml of dimethylformamide was stirred for 1 hour under ice-cooling. Then, 0.14 g of isopropylamine hydrochloride and 0.61 g of triethylamine are added to the solution, and the reaction mixture is stirred for 2 hours at room temperature. Water was added to the reaction mixture, neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried and evaporated to dryness. The resulting crude crystals were recrystallized from methanol / ethyl acetate. 0.31 g of a colorless prism crystal is obtained. Yield: 41%. Mp: 247-249 ° C.

Elemental analysis for C ₂₉ H ₃₂ N ₇ 0 · 1 / 5H ₂ 0:

calculated:

Found:

C (%) H (%) N (%) 69.91 6.55 19.68 69.91 6.30 19.87

¹ H-NMR (200MHz, 0MSO-d ₆ ) δ: 0.87 (3H, t), 0.93 (6H, d),

1.26-1.44 (2H, m), 1.62-1.77 (2H, m), 2.80 (2H, t),

3.85-3.95 (1H, m), 5.67 (2H, s), 6.84 (2H, d), 6.99 (2H, d), 7.16-7.24 (2H, m), 7.44 (1H, d), 7.51-7.72 (4H, m), 8.27 (1H, d).

IR (KBr) cm ^-1 : 1640, 1540, 1521, 1455, 1415, 755, 740.

2-Butyl-l- / ~ / 2 '- (lH-tetrazol-5-yl) biphenyl-4-il_7 metil_7-

Example 4 Benzimidazole-7-carboxylic acid 2-sodium salt

0.2 g of 2-butyl-1 H - 2 '- (1H-tetrazol-5-yl) biphenyl-

4-yl-7-Methyl-benzimidazole-7-carboxylic acid was added to methanol (46 mg, 46 mg) and the reaction mixture was stirred at room temperature for 15 minutes. Toluene (30 mL) was added and the mixture was concentrated in vacuo. The resulting crystals are filtered off. 0.14 g of colorless powdery crystals are obtained. Yield: 62%. M.p. 255-257 ° C (dec.).

Elemental analysis for ^C 26 ^H 22 ^N 6 ^Na :

calculated:

Found:

₂ O ₂ .2H ₂ O

C (%) H (%) N (%) 58.64 4.92 15.78 58.98 4.60 15.66

¹ H-NMR (200MHz, OMSO-d 6): 0.85 (3H, t), 1.27-1.39 (2H, m),

1.59-1.74 (2H, m), 2.69 (2H, t), 6.10 (2H, s), 6.81 (2H, d), 6.98-7.07 (3H, m), 7.19-7.53 (6H, m).

IR (KBr) cm ^-1 : 1610, 1410, 1360, 760.

Example 5

2-butyl-l- / ^- / 2 '- (lH-tetrazol-5-yl) biphenyl-4-il_7 metil_7benzimidzaol-7-carboxylic acid butyl ester

A mixture of 0.47 g of 2-butyl-1 H - 2 '- (1H-tetrazol-5-yl) -biphenyl-4-yl-7-methyl-benzimidazole-7-carboxylic acid and 0.1 ml of concentrated sulfuric acid was refluxed with 10 ml of butanol heat to reflux for 66 hours. The solvent is then evaporated, water is added to the residue and the pH of the mixture is adjusted to 3-4.

- 35 ml with 1 N sodium hydroxide solution and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and dried, and the solvent was distilled off. The residue was purified by column chromatography over silica gel.

The product thus obtained was recrystallized from ethyl acetate / hexane to give 0.15 g of a colorless prism-like crystal. Yield: 29%. M.p .: 192-193 ° C.

Elemental analysis a ^ 39 ^ 32 ^ 6 ^ 2 calcd C (%) H (%) N (%) Calculated: 70.84 6.34 16.52 Found: 70.99 6.46 16.25 1 H-NMR (200MHz, CDCl 3)?: 0.83 (3H, t), 0.85 (3H, t); 1,18- 1.39 (4H, m), 1.45-1.64 (4H, m), 2.38 (2H, t); 3.99

(2H, t), 5.50 (2H, s), 6.47 (2H, d), 6.79 (2H, d),

6.93 (1H, d), 7.04 (1H, t), 7.27-7.32 (1H, m), 7.50 (1H, dd), 7.56-7.68 (2H, m), 7.97-8.01 (1H, m).

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

Example 6

2-Butyl-1 H - { ¹ - (1H-tetrazol-5-yl) -biphenyl-4-yl-7-methyl-7-benzimidazole-7-carboxylic acid (4-pyridyl) methyl ester

0.61 g of 2-butyl-1- (2'-cyanobiphenyl-4-yl) methyl-7-benzimidazole-7-carboxylic acid (4-pyridyl) methyl ester and 0.75 g of trimethyltin azide in 10 ml A solution of toluene in nitrogen was heated at reflux for 4 days.

The solvent was then distilled off, the residue was dissolved in ethanol (5 ml), 1N hydrochloric acid (8 ml) was added and the mixture was stirred at room temperature for one minute. The reaction mixture · ·

it is then neutralized with 1N sodium hydroxide and extracted with ethyl acetate. The extract was washed with water and evaporated to dryness. The residue was purified by column chromatography over silica gel. The resulting crystals were recrystallized from ethyl acetate / hexane to give 0.54 g of a colorless prism crystal. Yield: 83%, m.p. 179-180 ° C.

Analysis ^ J2 ^H 29 ^N 7 ^ 2 ^ ^k ° ^adder 9 Ex ^{e 'tre:}

C (%) H (%) N (%) calculated: 70.70 5.38 18.04 Found: 70.96 5.45 18.02 ¹ H NMR (200MHz, CDC1 ₃ ) He: 0.80 (3H, t), 1.18-1.36 (2H, m),

1.53-1.68 (2H, m), 2.49 (2H, t), 5.19 (2H, s), 5.51 (2H, s), 6.44 (2H, d), δ , 79 (2H, d), 7.15-7.31 (4H, m),

7.47-7.61 (3H, m), 7.67 (1H, dd), 7.92 (1H, dd, 8.35 (2H, dd)).

IR (KBr) cm ^-1 : 1720, 1600, 1410, 1280, 1250, 1120, 760, 750,

740th

Example 7

2-Propyl-l - / '/ 2' - (lH-tetrazol-5-yl) biphenyl-4-il_7 metil_7benzimidazol-7-carboxylic acid

2.5 g of 2-propyl-l- / ^- (2'-cyanobiphenyl-4-yl) -metil_7benzimidazol-7-carboxylic acid methyl ester, 3.9 g of sodium azide and

A mixture of 3.2 g of ammonium chloride in 30 ml of dimethylformamide was stirred at 110-120 ° C for 5 days.

Water is added to the reaction mixture and the mixture is acidified to pH 3-4. The mixture was extracted with ethyl acetate, the organic phase was washed with water, dried and the solvent was distilled off. The residue was subjected to column chromatography

- Purified on 37 silica gel. The resulting crystals are obtained as dimethyl crystals. Yield: 0.8 g colorless *, m.p. 275-276 ° C (dec), recrystallized from 23 formamide / ethanol.

calcd

Elemental analysis for C ₂₅ H ₂₂ N ₆ O ₂ .1 / 2H ₂ 0

C (%) H (\) N (%) calculated: 67.10 5.18 18.78 Found: 67.19 4.95 18.84

1 H-NMR (200MHz, (2H, m),

C0Cl ₃ -CF ₃ C00H)

3.23 (2H, t), 5.97

1.10 (3H, t), 1.70-2.20 (2H, s), 6.90 (2H, d), 7.13

7.47-7.80 (5 H, m),

8.03-8.17 (2 H, m).

(2H, d);

IR (KBr) cm ^-1 : 3070, 2720, 2440, 1700, 1450, 1410, 1405,

1285, 1235, 1200, 1190, 1120, 755,

Example 8

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

3.25 g of 1 - [(2'-cyano-biphenyl-4-yl) methyl] -7-pentylbenzimidazole-7-carboxylic acid methyl ester, 2.6 g of sodium urea azide and 2.1 g of ammonium chloride in 20 ml of dimethyl- formamide was stirred at 110-120 ° C for 5 days. Water was added to the reaction mixture, and the pH was adjusted to 3-4 with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and dried, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography. The crystals thus obtained were recrystallized from ethyl acetate / ethanol and treated with hot water. 1.0 g of a colorless crystalline powder are obtained. Yield: 29%. M.p .: 205-207 ° C (dec.).

Analysis a C ₂₇ H 26 ^N 6 ° 2 ^{, 1 / 5H} 2 ° calcd N (%) C (%) H (\) calculated: 68.98 5.66 17.88 Found: 69.14 5.60 17.90

¹ H-NMR (90MHz, CDCl 3 - CF 3 COOH) δ: 0.87 (3H, t), 1.13-1.53 (4H, m), 1.67-2.10 (2H, m), 3, 27 (2H, t), 6.00 (2H, s), 6.93 (2H, d),

7.47-7.90 (5H, m), 8.07-8.20 (2H, m).

IR (NujoDcm ' ¹ : 3040, 2775, 1695, 1485, 1450, 1425, 1410,

1290, 1240, 1200, 755.

Example 9

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

2.8 g of 2-butyl-l -. / ~ ⁽¹ 2 -cyanobiphenyl-4-yl) -metil_7-

A mixture of 5-methylbenzimidazole-7-carboxylic acid methyl ester, 6.2 g of sodium azide and 5.1 g of ammonium chloride in 25 ml of dimethylformamide is stirred at 110-120 ° C for 3 days. The reaction mixture was diluted with water and adjusted to pH 3-4 with 1N hydrochloric acid. The mixture was then extracted with ethyl acetate, the organic phase was washed with water, dried and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography. The crystals thus obtained were recrystallized from ethyl acetate / methanol to give 0.72 g of a colorless prism crystal. Yield: 24%, m.p. 144-145 ° C.

Elemental Analysis a ^C 28 ^H 28 ^N 6 ° 2 ° '° ^{together 1H} 2 ^O 9 P ^Ké: C (%) H (%) N (%) calculated: 69.72 5.89 17.42 Found: 69.58 5.89 17.28

¹ H-NMR (200MHz, CDCl 3) δ: 0.82 (3H, t), 1.17-1.37 (2H, m),

1.45-1.60 (2H, m), 2.26 (3H, s), 2.34 (2H, t), 3.56 (3H, s), 5.23 (2H, s), δ , 43 (2H, d), 6.60 (1H, s),

6.76 (2H, d), 7.28-7.32 (2H, m), 7.59-7.69 (2H, m),

7.96-8.00 (1H, m).

IR (KBr) cm ^-1 : 1715, 1515, 1455, 1440, 1410, 1315, 1255, 1225, 1050, 785, 765.

Example 10

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

0.15 g of 2-butyl-5-methyl-l- / ^- / 2 '- (lH-tetrazol-5-yl) biphenyl-4-il_7metil_7-benzimidazole-7-carboxylic acid methyl ester in 1.2 ml IN sodium of hydroxide and 2 ml of methanol was heated under reflux for 2 hours. The reaction mixture was diluted with water, washed with diethyl ether and acidified to pH 3-4 with IN hydrochloric acid. The precipitated crystals were removed by filtration and recrystallized from ethyl acetate.

0.1 g of colorless crystals 175-178 ° C (dec.). we get. Yield: 71%. Mp .: Elemental Analysis a ^C 27 ^H 26 ^N 6 ° 2 .l / 2H ₂ 0 calcd C (%) H (%) N (%) calculated: 68.19 5.72 17.67 Found: 68.25 5.66 17.59 1 H NMR (200MHz, DMSO-dg) § : 0.87 (3H, t), 1.25-1.44 (2H, m);

1.63-1.77 (2H, m), 2.41 (3H, s), 2.79 (2H, t), 5.82 (2H, s), 6.76 (2H, d), δ , 99 (2H, d), 7.45-7.49 (2H, m),

7.55-7.69 (4 H, m).

Example 11

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

2.1 g of 6-methyl-3-nitro-N-N-2 '- (N-triphenylmethyl-tetrazol-5-yl) -biphenyl-4-ylmethyl] -N-1 A mixture of ethyl ester and 0.73 g of iron powder in 2.1 ml of concentrated hydrochloric acid and 10 ml of ethanol was heated under reflux for 18 hours. Insoluble matters are filtered off from the reaction mixture. The filtrate is evaporated to dryness, the residue is dissolved in 1 N sodium hydroxide solution and the precipitated solid is filtered through a celite filter. The filtrate was acidified with concentrated hydrochloric acid. The oily product was separated off and extracted with methylene chloride. The extract was washed with water and evaporated to dryness. The syrup-like product was purified by column chromatography over silica gel.

A crystalline product is obtained which is recrystallized from ethyl acetate / isopropyl ether to give 0.8 g of a light brown prism crystal. Yield: 59%, m.p. 164165 ° C.

1 H-NMR (200MHz, COCl 3) δ: 0.84, 1.06 (each 3H, t),

1.20-1.39 (2H, m), 1.48-1.63 (2H, m), 2.32 (3H, s),

2.38 (2H, t), 3.88 (2H, q), 5.28 (2H, s), 6.56 (2H, d),

6.74 (1H, d), 6.86 (3H, dd), 7.28-7.33 (1H, m), 7.58-7.63 (2H, m), 7.91-7, 97 (1H, m).

Example 12

2-Butyl-5-chloro-1 H, 2 '- (1 H -tetrazol-5-yl) -biphenyl-4-yl] -7-methyl-zimidazole-7-carboxylic acid methyl ester

1.26 g of 5-chloro-3-nitro-2H-N '- {2' - (N-triphenylmethyl-1H-tetrazol-5-yl) -biphenyl-4-yl-7-methyl-7- N -valeryl anthranilic acid A mixture of methyl ester, 1.6 ml of concentrated hydrochloric acid and 0.45 g of 95% pure iron powder in 15 ml of methanol was heated under reflux for 20 hours. The insoluble material is filtered off and the filtrate is evaporated. The residue was extracted with ethyl acetate and water. The organic layer was filtered with an aqueous sodium bicarbonate solution and the resulting insoluble material. The filtrate was washed with water, dried and evaporated. The residue was purified by silica gel column chromatography and the resulting crystals were recrystallized from ethyl acetate / benzene. 0.59 g of colorless crystals are obtained. Yield: 74%. Mp 132-133 ° C.

Elemental analysis for ^C 27 ^H 25 ^N 6 ° 2 ^C1 :

C (%) H (%) H (%) Calculated: 64.73 5.03 16.77 Found: 64.49 5.06 16.5 ¹ H-NMR (200MHz, CDCl 3) δ: 0.84 (3H, t), 1.23-1.41 (2H, m),

1.52-1.68 (2H, m), 2.50 (2H, t), 3.62 (3H, s), 5.48 (2H, s), 6.46 (2H, d), δ , 83 (2H, d), 6.93 (1H, m),

7.31-7.36 (1H, m), 7.49 (1H, d), 7.63-7.68 (2H, m),

7.96-8.00 (1H, m).

IR (KBr) cm ^_1 2960, 2875, 1720, 1510, 1460, 1430, 1400,

1280, 1230, 1190, 750.

Example 13

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

- 92 - 0.28 g of methyl 2-butyl-5-chloro-1 '- (2' - (1H-tetrazol-5-yl) biphenyl) methyl] -benzimidazole-7-carboxylate in 2 ml of 1N sodium hydroxide and 4 ml of methanol are stirred for one hour at room temperature. The reaction mixture was evaporated and the residue was dissolved in water (10 ml)

It is acidified with N hydrochloric acid. The precipitated crystals were filtered off and recrystallized from methanol / chloroform. 0.2 g of colorless crystals are obtained. Yield: 72%. Mp: 232-234 ° C.

Elemental analysis for ^ε 26 ^Η 23 ^Ν 6θ2 ^Ε1 ' ^X ^ ^2H 2 °: C (%) H (%) N (%) calculated: 62.96 4.88 16.94 Found: 63.01 4.81 16.87 ¹ H NMR (200MHz, DMSO-dg) δ: 0.87 (3H, t), 1.26-1.45 (2H, m),

1.64-1.79 (2H, m), 2.82 (2H, t), 5.81 (2H, s), 6.78 (2H, d), 7.00 (2H, d), 7 , 45.7.69 (5H, m), 7.91 (1H, d). IR (KBr) cm ^_1: 2975, 2930, 2875, 1705, 1480, 1460, 1400, 1270, 1240, 1220, 1190, 870, 760, 740th

Example 14

2-butyl-l- / ^- / 2 '- (lH-tetrazol-5-yl) biphenyl-4-il_7 metil_7benzimidazol-7-carboxylic acid ethyl ester

0.21 g of ethyl 2-butyl-1 H - (2'-cyanobiphenyl-4-yl) methyl-7-benzimidazole-7-carboxylic acid, 1.3 g of sodium azide and 1.07 g of ammonium chloride. of dimethylformamide (60 ml) was stirred at 110-120 ° C for 60 hours. Water was added to the reaction mixture and acidified to pH 3-4 with 1N hydrochloric acid. The mixture was extracted with ethyl acetate and the organic layer was washed with water, dried

-93 and evaporate to dryness. Diethyl ether was added to the residue. The crude crystals thus obtained are filtered off and recrystallized from ethanol. 0.95 mg of colorless crystals are obtained. Yield: 41%. Mp 138-139 ° C.

¹ H NMR (90 MHz, CDCl₃) £ 0.80 (3H, t), 1.07 to 1.77 (7H, m);

2.37 (2H, t), 4.07 (2H, q), 5.50 (2H, s), 6.47 (2H, d),

6.80 (2H, d), 7.00-7.10 (2H, m), 7.23-7.73 (4H, m),

7.90-8.10 (1H, m).

IR (NujoDcm ^-1 : 1715, 1410, 1290, 1260, 1125, 1040, 750).

Example 15

Mg of 2-Butyl-1-1 / 2 '- (1H-tetrazol-5-yl) -biphenyl-4-yl-7-methyl-7-benzimidazole-7-carboxylic acid 2-butyl-1', 2 '- (1H- A mixture of tetrazol-5-yl) -biphenyl-4-yl-7-methyl-7-benzimidazole-7-carboxylic acid ethyl ester in 1.5 ml of 2-methoxyethanol and 1.5 ml of 2N sodium hydroxide was stirred at 110-120 ° C for 1 hour. . The reaction mixture was neutralized with 2N hydrochloric acid and evaporated to dryness.

The residue was dissolved in chloroform and insoluble materials were filtered off. The filtrate was evaporated to dryness and the resulting crude crystals were recrystallized from aqueous ethanol. 60 mg of colorless crystals are obtained. Yield: 77%. M.p., IR and NMR are in good agreement with the compound prepared in Example 1.

• 4 »· ·

Example 16

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

0.4 g of 2-butyl-1 - [(2'-cyanobiphenyl-4-yl) methyl] -77-hydroxymethylbenzimidazole, 0.98 g of sodium azide and 0.8 g of ammonium chloride in 4 ml of dimethyl -formamide mixture was stirred at 110-120 ° C for 4 days. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was washed with water, then dried and the solvent was distilled off. The residue was crystallized from ethyl acetate / methanol to give colorless needle crystals. Mp: 152-153 ° C.

Elemental analysis a ^ 26 ^Η 26 ^Ν 6θ '^^ HqOj C (%) H (%) Calculated: 69.43 6.28 Found: 69.14 6.22 ¹ H-NMR (200MHz, DMSO-d ₆ ) _δ : 0.86 (

1.63-1.78 (2H, m), 2.76 (2H,

5.76 (6.81 (2H, d), 7.04 (2H, I / 10H2 O):

N (%)

17.35

17.59

H, t), 1.26-1.44 (2H, m), 4.47 (2H, s), 5.47 (1H.br s),

d), 7.08-7.16 (2 H, m), 7.49-

7.70 (5 H, m).

IR (KBr) cm ^-1 : 1510, 1405, 1020, 755, 740.

Example 17

Γ1-Butyl 1-1- [2 '- (1H-tetrazol-5-yl) -biphenyl-4-yl] -7-methyl-7-benzimidazole-7-acetic acid ethyl ester

0.86 g of ethyl 2-butyl-1- (2'-cyanobiphenyl-4-yl) methyl-7-benzimidazole-7-acetic acid, 0.5 g of sodium azide and 1.6 g of ammonium chloride in 10 ml. dimethylformamide '

Stir for 4.5 days at 110-120 ° C. Water was added to the reaction mixture, which was then acidified to pH 3-4 with 1N hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic phase was washed with water, dried and the solvent was distilled off. The residue was purified by column chromatography on silica gel. The crude crystals obtained were recrystallized from ethyl acetate to give 0.53 g of colorless needle-crystalline yield: 56%, m.p. 129-130 ° C.

we get a bowl.

Analysis a C ₂₉ H _3Q N ₆ 0 ₂ .0.4H ₂ 0 összegké C (%) H (%) N (%) calculated: 69.41 6.19 16.75 Found: 69.50 5.94 17.03

(3H, t);

0.83 ¹ H-NMR (200MHz, CDCl 3) δ:

1.48-1.63 (2 H, m),

1.12-1.33 (5 H, m),

2.24 (2H, t),

3.41

4.03 (2H, q),

5.46 (2H, s), 6.55-6.66 (3H, m),

6.87 (2H, d),

6.93-6.99 (2H, m), 7.28-7.32 (1H, m), 7.55-7.68 (1H, m).

IR (KBr) cm ^_1 1740, 1720, 1510, 1410, 1280,

7.95-7.99

1255, 1145, 755,

740th

Example 18

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

A mixture of 2-butyl-1- [2 '- (1H-tetrazol-5-yl) -biphenyl-4-phenyl] methyl] -7-benzimidazole-acetic acid in ethyl acetate (0.28 g) was stirred under reflux for 2 hours. heated. The reaction mixture was concentrated and neutralized with IN hydrochloric acid.

The precipitated crystals are filtered off and subjected to column chromatography

Purification on silica gel. 0.12 g

mp 170-171 ° C.

colorless crystals are obtained. Yield: 46

Elemental analysis a θ ₂ 7 ^Η 26 ^Ν 6θ2

For C (%):

H (%)

N (\)

calculated:

69.51

5.62

18.01

69.60

5.78

17.90

Found:

1 H-NMR (200MHz, DMSO-dg)

1.64-1.75 (2H, m), 2.79 (2H, t), 3.58 (2H, s), 5.62 (2H, s), 0.87 (3H, t), 1.27-1.44 (2 H, m),

6.80 (2H, d), 6.98-7.16 (4H, m), 7.49-7.71 (5H, m). IR (KBr) cm ^-1 : 3430, 1720, 750.

Example 19

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

A mixture of 0.6 g of 2-butyl-1 H - (2'-cyanobiphenyl-4-yl) methyl-77-methoxymethylbenzimidazole and 1.2 g of trimethyltin azide in 12 ml of toluene was heated under reflux for 3 days. under. The solvent was then distilled off, 8 ml of 1N hydrochloric acid was added and the mixture was stirred further. The mixture was extracted with ethyl acetate, the organic phase was washed with water, dried and the solvent was distilled off. The residue was purified by column chromatography over silica gel. The oil was dissolved in ethyl acetate and a solution of 0.25 g of sodium salt of 2-ethylhexanoic acid in ethanol was added. The mixture was then concentrated. The precipitated crystals were recrystallized from toluene / ethyl acetate. 0.22 g of colorless crystals are obtained. Yield: 31%. Mp: 175-178 ° C.

Elemental analysis for formula 02 ^ 27 ^ 0 ^^ 0:

· 4 ' ^w ::. ·· ί "

...... ·· .s. . .

- 9Τ -

C (%) H (%) N (*) calculated: 65.84 5.93 17.06 Found: 65.94 5.81 17.06

1 H-NMR (200MHz, CDCl 3) δ: 0.70 (3H, t), 1.06-1.25 (2H, m),

1.50-1.65 (2H, m), 2.49 (2H, t), 2.86 (3H, s), 4.21 (2H, s), 5.27 (2H, s), 6 , 41 (2H, d), 6.73-6.77 (3H, m), 6.92-7.00 (2H, m), 7.19-7.30 (2H, m), 7.37 (1H, d), 7.62 (1H, d).

IR (KBr) cm ^-1 : 1510, 1455, 1420, 1405, 1350, 1280, 1080, 740.

Example 20

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

A mixture of 0.8 g of 2-butyl-1- (3'-cyanobiphenyl-4-yl) methyl-7'-methoxybenzimidazole and 1.6 g of trimethyltin azide in 15 ml of toluene was refluxed for 44 hours. heat. The crystals were then filtered and dissolved in methanol (20 mL). To the solution was added 1N hydrochloric acid (8 mL), and the mixture was stirred at room temperature for 5 minutes, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and the solvent was distilled off. The residue was purified by column chromatography over silica gel. The crude crystals were recrystallized from ethyl acetate / methanol to give 0.83 g of a colorless prism-like crystal. Yield 87: 189-190 ° C.

Elemental analysis for Οζ ^ Ηζ ^ Ν ^ Ο.ΗΟΙ:

C (%) H (%) N (%) calculated: 65.75 5.73 17.69 Found: 65.46 5.85 17.44

·· '·. »·. *.? .:. 1 H NMR (200MHz, DMSO-d 6) δ: 0.87 (3H, t), 1.26-1.44 (2H, m),

1.61-1.76 (2H, m), 3.14 (2H, t), 3.83 (3H, s), 5.82 (2H, s), 7.07-7.18 (5H, m), 7.38 (1H, d), 7.45-7.73 (5H, m).

IR (KBr) cm -1: 1615, 1550, 1490, 1455, 1440, 1355, 1275, 1260,

1130, 1100, 1060, 990, 870, 850, 775, 750, 730.

Example 21

2-Butyl-6-methyl-l-Γ / J. '- (1H-Tetrazol-5-yl) -biphenyl-4-yl-7-methyl-7-benzimidazole-7-carboxylic acid

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

A mixture of N anhydrous sodium hydroxide and 10 ml of ethanol was heated at reflux for 100 hours. The reaction mixture was evaporated to dryness, the residue was dissolved in water and the solution was acidified with concentrated hydrochloric acid. The precipitate was filtered off and washed with dichloromethane / methanol.

The precipitate was then dissolved in a saturated aqueous solution of sodium bicarbonate and the insolubles were filtered off. The filtrate was acidified with concentrated hydrochloric acid. The resulting precipitate was filtered off and crystallized from dimethylformamide / water. 0.22 g of colorless crystals are obtained. Yield: 42%.

Mp 298-299 ° C.

¹ H-NMR (200MHz, CDCl 3: 0.85 (3H, t), 1.23-1.43 (2H, m),

1.58-1.75 (2H, m), 2.38 (3H, s), 2.70 (2H, t), 5.47 (2H, s),

6.87, 7.02 (both 2H, d), 7.07 (1H, d), 7.45-7.71 (5H, m).

Elemental Analysis a

for l / lOHzO:

C (\) H (%) N (%) calculated: 69.24 5.64 17.94 Found: 68.97 5.85 17.81

Example 22

2 Buti1-1 - /// 2 '- (lH-tetrazol-5-yl) biphenyl-4-il_7 metil_7-7metil-benzimidazole

0.5 g of 2-butyl-l - // ^(one 2-cyano-biphenyl-4-yl) -metil_77-methylbenzimidazole, 1.3 g of sodium azide and 1.1 g of ammonium chloride with 5 ml of dimethylformamide the mixture was stirred at 110-120 ° C for 3.5 days. Water was added to the reaction mixture, acidified to pH 3-4 with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and dried, and the solvent was distilled off. The residue was purified by column chromatography over silica gel. The resulting crystals were recrystallized from diethyl acetate / methanol to give colorless crystals (0.36 g). Yield: 62%, m.p. 222-224 ° C.

Elemental Analysis ^{3 C} 26 ^H 26 ^N 6 · ^{1 / 40.1 Hq0}

C (%) '4 8 2

For H (%):

N (%)

calculated:

72.95

6.35

18.90

72.80

Found:

1 H-NMR (200MHz, CDCl 3) δ:

1.59 (2 H, m), 2.14

6.35

19.02

0.80 (3H, t);

1.14-1.32 (2H, m), 1.44 (2H, t), 2.26 (3H, s), 5.32 (2H, s),

6.48-6.56 (3H, m), 6.83-6.89 (4H, m), 7.29-7.34 (1H, m),

7.55-7.68 (2 H, m), 7.92-7.97 (1H, m).

IR (KBr) cm ^_1: 1510, 1450, 1410, 780, 750.740.

- 100 -

Example 23

2-Isopropyl-1H-2 '- (1H-tetrazol-5-yl) -biphenyl-4-yl-7-methyl-7-benzimidazole-7-carboxylic acid ethyl ester

2.12 g of ethyl 1 - [(2'-cyanobiphenyl-4-yl) methyl] -2-isopropylbenzimidazole-7-carboxylic acid, 3.9 g of sodium azide and 3.2 g of ammonium chloride in 15 ml of dimethylformamide was stirred at 110-120 ° C for 5 days.

To the reaction mixture was added water (150 mL) and acidified to pH 3-4 with dilute hydrochloric acid. The reaction mixture was then extracted with ethyl acetate, and the organic phase was washed with water, dried and evaporated to dryness. The residue was crystallized from ethanol

1.2 g of a colorless prism crystal are obtained. Yield:

52%. Mp .: 144 -146 ° C. Elemental Analysis a ^C 27 ^H 26 ° 2- ^{1 / 4C} 2 ^H 5 ^0H .H ₂ 0: C (%) H (%) N (%) calculated: 66.58 5.99 16.94 Found: 66.38 5.74 16.69 1 H-NMR (90MHz, cdci ₃ -cf ₃ cooh) δ: 1.30 (3H, t), 1.53 (6H, d), 3,37- 3.80 (1H, m), 4.30 (2H, q), 5.97 (2H, s), 6.90

(2H, d), 7.13 (2H, d), 7.43-8.10 (7H, m).

IR (Nujol) cm ^-1 : 1730, 1450, 1285, 1270, 750.

Example 24

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

2.5 g of ethyl 1 - [(2'-cyanobiphenyl-4-yl) methyl] -2-methylbenzimidazole-7-carboxylic acid, 3.9 g of sodium azide and • ·

A mixture of 104 g (32 g) of ammonium chloride in 30 ml of dimethylformamide was stirred at 110-120 ° C for one day. The reaction mixture was worked up as described in Example 23 and the resulting crystals were recrystallized from ethanol. 1.36 g (49%) of colorless prism-like crystals are obtained. M.p .: 205-206 ° C.

Elemental analysis for C ₂₅ H _{2 2} gO 2 · 2 / 5EtOH: 0 (¾) H (%) N (%) calculated: 67.82 5.38 18.39 Found: 67.64 5.38 18.24 ¹ H-NMR (90MHz, CDCl ₃ -CF ₃ C00H) δ: 1 , 27 (4H, t), 2.90 (3H, s)

3.87 (1H, q), 4.30 (2H, q), 5.93 (2H, s), 6.93 (2H, d),

7.10 (2H, d), 7.40-7.80 (5H, m), 8.00 (2H, d).

IR (Nu joDcm ^-1 : 1725, 1410, 1290, 1260, 1220, 1115, 1040, 750).

Example 25

2-Ethyl-1 H - 2 '- (1H-tetrazol-5-yl) -biphenyl-4-yl-7-methyl-7-benzimidazole-7-carboxylic acid ethyl ester

1.55 g of 1- (2'-cyano-biphenyl-4-yl) methyl-7-2-ethylbenzimidazole-7-carboxylic acid ethyl ester, 2.6 g of sodium azide and

A mixture of ammonium chloride (2.14 g) in dimethylformamide (15 ml) was stirred at 110-120 ° C for 5 days. The reaction mixture is a

After working up as described in Example 23, the resulting crystals were recrystallized from ethanol. 0.68 g of a colorless prism crystal is obtained. Yield: 40%, m.p. 188-189 ° C.

Elemental analysis a ⁽ -'26 ^Η 24 ^Ν 6θ2 .2 / 5H ₂ O calcd 0 (¾) H ( "). N (%) Calculated: 67.93 5.44 18.28 Found: 67.76 5.365 18.54

102 H-NMR (90MHz, CDCl3-CF-1COOH) 3: 1.33 (3H, t), 1.50 (3H, t),

3.27 (2H, q), 4.33 (2H, q), 5.97 (2H, s), 6.93 (2H, d),

7.17 (2H, d), 7.40-8.07 (7H, m).

IRNujoDcm ' ¹ : 1710, 1285, 1265, 755.

Example 26

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

0.64 g of ethyl 2-methyl 1-1 - [(2 ') - (1H-tetrazol-5-yl) -biphenyl-4-yl] -7-methyl-7-benzimidazole-7-carboxylic acid prepared in 10 ml of methanol and 2 N sodium hydroxide the mixture was heated under reflux for 4 hours. The reaction mixture was evaporated to dryness, dissolved in water and neutralized with 1N hydrochloric acid. The resulting crystals were recrystallized from a mixture of dimethylformamide / ethyl alcohol / water

0.3 g colorless, prism-shaped ° C (dec.).

crystals are obtained. Yield: 49

pp. 283-284

Analysis a C ₂₃ H ₁₈ N ₆ 0 ₂ .l / 5H ₂ 0 calcd C (%) H (%) N (%) calculated: 66.72 4.48 20,30 Found: 66.96 4.40 20.25 ¹ H-NMR (90MHz, .CDCl-j-CF-jCOOH) S: 2.97 (3H, s), 5.97

(2H, s),

6.97 (2H, d), 7.17 (2H, d), 7.50-7.90 (5H, m), 8.10 (1H, d),

8.20 (1H, d).

IR (Nu joDcm ¹ : 2470, 1700, 1455, 1410, 1240,

1220, 990, 750.

Example 27

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

103 0.5 g of ethyl 2-ethyl-1H-2 '- (1H-tetrazol-5-yl) -biphenyl-4-yl-7-methyl-7-benzimidazole-7-carboxylic acid in 10 ml of methanol and

A mixture of N sodium hydroxide was heated under reflux for 4 hours. The reaction mixture was evaporated to dryness and the residue was dissolved in water and neutralized with 1N hydrochloric acid. The resulting crystals were recrystallized from dimethylformamide / ethanol / water. 0.27 g of a colorless prism crystal is obtained. Mp: 261-262 ° C.

Elemental analysis a ^ ₂₄ Η ₂ θΝ ₆ 0 ₂ calcd C (%) H (%) N (%) calculated: 67.63 4.70 19.45 Found: 67.91 4.75 19.80 ¹ H-NMR (90MHz, _CF3 C00H _CDCl3) S: 1.50 (3H, t), 3.20 (2H, q), 5.97 (2H, s) , 6.93 (2H, d), 7.13 (2H. , d), 7.37-8.17 (7H, m) • AND (Well joDcrn ” ¹ : 3070, 2720, 1700, 1450, 1410, 1290, 1250, 1210,

755th

28.példa

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

1.2 g of ethyl 2-isopropyl-1H-2 '- (1H-tetrazol-5-yl) -biphenyl-4-yl-7-methyl-7-benzimidazole-7-carboxylic acid in 5 ml of methanol and 5 ml of 2 N sodium hydroxide The mixture was heated under reflux for 4 hours. The reaction mixture was evaporated to dryness, dissolved in water and neutralized with 1N hydrochloric acid. The resulting crystals were recrystallized from a 50:50 (v / v) mixture of dimethylformamide / ethanol to give 0.8 g of a colorless prism crystal. Yield: 71%,

104

mp 265-267 ° C (dec.). Elemental Analysis a ^C 25 ^H 22 ^H 6 ° 2 - 3 / 10H ₂ For 0: C (%) H (%) N (\) calculated: 67.65 5.13 18.93 Found: 67.64 5.07 19.00 ¹ H-NMR (90MHz, CDCl ₃ -CF ₃ C00H) δ: 1.67 (6H, d), 3.40-

6.00 (2H, s), 6.90 (2H, d), 7.13 (2H, d), 7.43-7.83 (5H, m),

8.07 (2H, d), 7.13 (2H, d), 7.43-7.83 (5H, m), 8.07 (2H, d).

IR (Nujol) cm ^_1: 2620, 1695, 1285, 1260, 1245, 1205, 760th

Example 29

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

1.2 g of 2-butyl-l- / ^- / 2 '- (tetrazol-5-yl) -bifeni1-4il_7 metil_7-benzimidazole-7-carboxylic acid and 1.3 g of potassium 2-ethylhexanoate in 50 ml of ethanol 50 ml of toluene are added and the ethanol is distilled off. The resulting crystals were filtered off and washed with diethyl ether. 1.1 g of colorless crystals are obtained. Yield: 79%, m.p. 355-358 ° C (dec.).

Elemental analysis for C ₂₆ H ₂₂ K ₂ N 6 ° 2 ' ^H 2 ° calcd C (%) H (%) N (%) Calculated: 57.12 4.42 15.37 Found: 56.93 4.26 15.01 ¹ H-NMR (200MHz, DMSO-dg) S, 0.86 (3H, t), 1.22-1.43 (2H, m),

1.60-1.76 (2H, m), 2.70 (2H, t), 6.06 (2H, s), 6.79 (2H, d),

6.94-7.03 (3H, m), 7.20-7.34 (4H, m), 7.40 (1H, dd),

7.53-7.58 (1H, m).

IR (KBr) cm ^_1: 3350, 1600, 1570, 1515, 1460, 1400, 1360, 1315,

1280, 1005, 825, 785, 760.

105 -

Example 30

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

A mixture of 0.69 g of 2-butyl-1 H - (2'-cyanobiphenyl-4-yl) methyl-77-hydroxybenzimidazole and 1.1 g of trimethyltin azide in 15 ml of toluene was heated at reflux for 4 days. under. The resulting crystals were filtered and stirred in 10 mL of IN hydrochloric acid and 15 mL of methanol for 10 minutes at room temperature.

To the resulting solution was added 1N sodium hydroxide until the pH reached 3-4. The resulting crystals were purified by column chromatography on silica gel. The resulting crystalline crystals were recrystallized from acetone to give colorless crystals. Mp: 186-188 ° C.

Elemental analysis a 0 ₂ 5Η ₂ ^ Ν ^ 0.l / 2H ₂ 0 calcd N (%) C (%) H (%) calculated: 69.27 5.81 19.39 Found: 69.60 5.69 19.26 1 H-NMR (200MHz, DMSO-d 6) δ : 0.84 (3H, t), 1.23-1.41 (2H, m), 1.55 -1.70 (2 H, m), 2.71 (2H, t), 5.68 (2H, s), 6.60 (1H, d), 6.95 (1H, t), 7.02 -7.06 (5H, m), 7.48-7.70 (4H, m),

10.00 (1H, s).

IR (KBr) cm ^-1 : 1620, 1490, 1460, 1350, 1295, 780, 755, 730.

Example 31

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

A mixture of 465 mg of 2-propyl-1- [2 '- (1H-tetrazol-5-yl) biphenyl4-yl] -7-methyl-7-benzimidazole-7-carboxylic acid and 7.2 g of concentrated sulfuric acid in methanol was heated for 24 hours. yl

106 under reflux. The solvent was distilled off, the residue was suspended in water and 1N sodium hydroxide was added until pH = 3-4, and the reaction mixture was extracted with ethyl acetate. The organic phase is washed with water, dried and the solvent is distilled off. The residue was purified by column chromatography over silica gel. The resulting crystals were recrystallized from ethanol to give 310 mg of a colorless prism

crystals are obtained. Mp : 195-196 ° C. Elemental analysis for C ₂ H 4 ^H 24 ^N 6 ° i ₂ .2 / 5H ₂ 0 calcd C (%) H (%) N (%) calculated: 67.93 5.44 18.28 Found: 68.02 5.33 18.33 ¹ H-NMR (90MHz, CDCl 3)? ₃ ) δ: 0.87 (3H , t), 1.37-1.80 (2 H, m), 2.30 (2H, t); 3.60 (3H, s), 5.47 (2H, s), 6.47 (2H, d), 6.80

(2H, d), 6.93-8.00 (7H, m).

IR (NujoDcm ^-1 : 1730, 1440, 1290, 1280, 1270, 760).

32 to the 33rd example

Example 5 was followed.

Example 32

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

benzimidazole-7-carboxylic acid methyl ester Mp .: 185-186 Elemental Analysis a ° C. ^C 25 ^H 22 ^N 6 ° 2 ll / 2C ₄ HgO ₂ .H ₂ 0 C (%) H (%) N (%) calculated: 66.70 5.47 17.29 Found: 66.70 4.26 17.49

- 10? -

Example 33

2-isopropyl-1 - /// 2 '- (lH-tetrazol-5-yl) biphenyl-4-il_7 metil_7benzimidazol-7-carboxylic acid methyl ester

Example 34

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

A mixture of 1.8 g of 2-butyl-1 H - [2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] -7-methyl-7-benzimidazole-7-carboxylic acid in 18 ml of methanol and 14.4 g of concentrated sulfuric acid It is heated under reflux for 24 hours. The solvent is then distilled off, the residue is suspended in water and the pH is adjusted to 3-4 with 1N sodium hydroxide. The reaction mixture was then extracted with ethyl acetate, and the organic layer was washed with water and dried. The solvent was distilled off and the residue was purified by column chromatography on silica gel. The residue was recrystallized from ethanol to give 1.5 g of a colorless prism crystal. Mp 153-155 ° C.

Elemental Analysis a ^ 27 ^ * 26 ^ 6 ^ 2 ' , 2 / 5H ₂ 0 calcd C (%) H (%) N (%) Calculated: 68.45 5.70 17.74 Found: 68.63 5.61 17.72 ¹ H NMR (90MHz, CDCl 3) δ: 0.80 (3H, t) , 1.00-1.73 (4 H, m), 2.37

(2H, t), 3.60 (3H, s), 5.47 (2H, s), 6.47 (2H, d), 6.80 (2H, d), 6.97-8.00 ( 7H, m).

IR (Nu Jo Dcm ¹ : 1720, 1450, 1430, 1290, 1280, 1270, 755).

• «V ·« ·

- 103 -

Example 35

2-sec.-butyl-l - / '/ 2' - (lH-tetrazol-5-yl) biphenyl-4-il_7 metil_7benzimidazol-7-carboxylic acid ethyl ester

Example 14 was followed.

Mp 128-130 ° C.

Analysis a C ₂₈ ^h ₂₈ N ₆ 0 ₂ . , 2 / 5H ₂ 0 calcd C (%) H (%) N (%) calculated: 67.98 6.06 16.07 Found: 68.10 6.07 15.94 Example 36

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

3.0 g of 2-butyl-1 - /. ^- 2 '- (1H-Tetrazol-5-yl) -biphenyl-4-yl-7-methyl-7-benzimidazole-7-carboxylic acid, 1.96 g of triphenylmethyl chloride and 1.0 ml of triethylamine in 20 ml of methylene chloride for 16 hours. stir at room temperature. The reaction mixture was washed with water and dried. The solvent was distilled off and the residue was purified by column chromatography on silica gel. 4.25 g of a colorless powder are obtained. The N-trityl compound thus obtained is dissolved in 5 ml of dimethylformamide, 0.2 g of potassium carbonate and 0.35 g of pivaloyloxymethyl iodide are added and the mixture is stirred for 2 hours at room temperature. The reaction mixture was concentrated and the residue was extracted with water and ethyl acetate, and the organic phase was washed with water and dried. The solvent was distilled off, the residue was dissolved in methanol (10 mL), and 1N HCl (109 mL) was added and the mixture was stirred at room temperature for 1.5 h. The reaction mixture was evaporated to dryness and the residue was purified by column chromatography on silica gel. Yield: 0.43 g (74%), m.p. 102-105 ° C.

Elemental Analysis a. 1/2 1 ^ 0 calcd N (%) C (%) H (%) calculated: 66.77 6.13 14.60 Found: 66.76 6.09 14.45 ¹ H NMR (200MHz, COC1 ₃ ) 5: 0.87 (3H, t), 1.16 (9H, s), 1.23-1.42 (2H, m); 1.57-1.72 (2H, m); 2.53 (2H, t), 5.60 (2H, s), 5.70 (2H , s), 6.60 (2H, d); 6.89 (2H, d), 7.11 (1H, t),

7.25-7.27 (1H, m), 7.33-7.38 (1H, m), 7.58-7.63 (3H, m),

7.97-8.02 (1H, m).

IR (K8r) ^_1 cm: 2975, 1750, 1730, 1480, 1450, 1410, 1280, 1260,

1150, 1100, 1010, 950, 760, 750.

Following the procedure of Example 36, the following compounds were prepared:

Example 37 [1- (Cyclohexyloxycarbonyl-yloxy) -ethyl] -2-butyl-1 '- [2' - (1H-tetrazol-5-yl) -biphenyl-4-yl] -7-methyl-7-benzimidazole-7 carboxylate

Yield: 74%.

Physical constants: Mp : 102-105 ° C. Elemental Analysis a ^H 38 ^N 6 ° 5 . 1 / J-5CHC1 calcd 0 (¾) H (%) N (%) calculated: 65.39 5.95 13.00 Found: 65.18 5.99 12.86

¹ H-NMR (200MHz, COCl 3) δ: 0.87 (3H, t), 1.17-1.87 (18H, m),

2.53 (2H, t), 4.45-4.58 (1H, m), 5.52-5.75 (2H, m),

6.60 (2H, d), 6.73 (1H, q), 6.89 (2H, d), 7.12 (1H, t),

7.27-7.35 (2 H, m), 7.57-7.66 (3 H, m), 7.98-8.03 (1H, m).

IR (KBr) cm ^_1: 2950, 2875, 1760, 1740, 1450, 1420, 1280, 1250,

1080, 1000, 910, 760.

Example 38 [1- (Ethoxycarbonyloxy) ethyl] -2-butyl-1 H -2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] -7-benzimidazole-7-carboxylate

Yield: 75%. Mp 92-95 ° C. ANALYSIS: C (%) H (%) N (%) calculated: 64.46 5.76 14.55 Found: 64.56 5.69 14.52 ¹ H NMR (200MHz, CDCl-j) 5 0.86 (3H, t), 1.21 (3H, t), 1.21 (3H, t),

1.27-1.43 (2H, m), 1.42 (3H, d), 1.46-1.69 (2H, m),

2.50 (2H, t), 4.13 (2H, dq), 5.48-5.73 (2H, m), 6.56 (2H, d), 6.72 (1H, q), 6 , 86 (2H, d), 7.09 (1H, t), 7.19-

7.23 (1H, m), 7.29-7.34 (1H, m), 7.55-7.64 (3H, m),

7.97-8.01 (1H, m).

IR (KBr) cm ^-1 : 1760, 1730, 1410, 1375, 1275, 1245, 1070, 990, 760.

Example 39 β-Methyl-2-oxo-1,3-dioxolen-4-ylmethyl-2-butyl-1 H - 2 '- (1H-tetrazol-5-yl) -biphenyl-4 il_7-metiI_7 benzimidazol7-carboxylate

Yield: 71%. M.p .: 123-125 ° C.

114

Analysis

calculated:

C (2H, m),

1.68

5.54

Found:

1 H NMR (200MHz,

31 ^H 28 ^N 6 ⁰ 5 ' l / 2H ₂ O calcd c (%) H (%) N (%) 64.91 5.10 14.65 64.79 4.82 14.34 CDCl ₃ ) S: 0.84 (3H , t), 1.22-1.40 (2H, m), 1.53- H, m), 2.16 (3H, s), 2.46 (2H, t), 4.81 (2H, s), H, s), 6.53 (2H, d); 6.86 (2H, d), 7.08-7.22 7.43-7.38 (LH, m); 7.58-7.65 (3 H, m), 7.95-8.00

(LH, m).

IR (KBr) cm ^-1 : 1820, 1720, 1400, 1300, 1275, 1250, 1220, 1185,

1105, 1000, 745.

Example 40 [2-Hydroxy-ethyl-2-butyl-1H-2 '- (1H-tetrazol-5-yl) -biphenyl-4-yl] -7-methyl-7-benzimidazole-7-carboxylate

0.72 g of 2-butyl-l - (lH-tetrazol-5-yl) biphenyl-4il_7-metil_7-benzimidazole-7-carboxylic acid ethyl ester dissolved in 15 ml of ethylene glycol was added at room temperature under stirring at 0 - _ / 2 ¹ // 25 g of 60% sodium hydride in oil and the reaction mixture is stirred at room temperature for 15 hours. The reaction mixture was then treated with ice-water (100 ml) and acidified with formic acid. The resulting precipitate was dissolved in ethyl acetate (100 mL), washed with water, dried and evaporated to dryness. The resulting crystalline product is recrystallized from acetone. 0.49 g of colorless crystals are obtained. Yield: 66%.

Mp 145-147 ° C.

Elemental Analysis a ^ g ^ g ^ Oj. For l / 2C ^ H ^ 0:

112 ιί

C (%) H (%) N (%) calculated: 67.41 5.94 15.99 Found: 67.19 5.84 15.79 ¹ H-NMR (200MHz, COCl-j) Section: 0.93 (3H , t), 1.23-1.97 (4H, m), 2.13 (3H, s), 2.87 (2H, t), 3.77 (2H, t), 4.23 (2H, t), 5.73

(2H, s), 6.77 (2H, d), 7.00 (2H, d), 7.20 (1H, t), 7.43-

7.93 (6 H, m).

IR (Nujol) cm ^_1: 3340, 1715, 1410, 1290, 1265, 1035, 755th

Example 41 [2- (Morpholinone) ethyl [-2-butyl-1 H - [2 '- (1H-tetrazol-5-yl) biphenyl] -1,7-methyl-7-benzimidazole - 7 -carb ο x i1á t

0.4 g of 2-butyl-1 H - 2 '- (N-triphenylmethyl-tetrazole)

To a solution of 5-yl) -biphenyl-4-yl-7-methyl-benzimidazole-7-carboxylic acid, 0.15 g of 4- (2-hydroxyethyl) -morpholine and 0.1 g of crylethyl cyanoloylacetate in ml of dimethylformamide under cooling A solution of triethylamine (0.06 g) in dimethylformamide (1 ml) was added and the reaction mixture was stirred at room temperature for 30 hours. The reaction mixture was evaporated to dryness and the resulting residue was purified by column chromatography over silica gel. 0.3 g of a colorless powder are obtained. Yield: 65%.

This product was dissolved in methanol (7 mL) and treated with 1N hydrochloric acid (1.2 mL). The reaction mixture was stirred at room temperature for 2 hours and then evaporated to dryness. The residue is dissolved in methylene chloride / water and the aqueous phase is made alkaline with aqueous sodium bicarbonate.

The aqueous phase is extracted with methylene chloride and the methylene chloride phases are combined, washed with water, dried and

- Evaporate to dryness. The residue thus obtained was purified by column chromatography over silica gel. 0.19 g of colorless fine crystals are obtained. Yield: 87%. Mp 98-110 ° C.

Analysis a C ₃₂ H ₃₅ N ₇ 0 ₃ .3 / 5 H ₂ 0 calcd 0 (¾) Η { ^β Ό n (? - i) calculated: 66.67 6.33 17.01 Found: 66.41 6.15 16.89 ¹ H NMR (200MHz, CDCl 3) δ: 0.93 (3H, t), 1.34-1.52 (2H, m), 1.71-. 1.88 (2H, m), 2.58 (4H, br t), 2.85 (2H, t), 2.94 (2H, br t), 3.39 (2H, br t), 4.10 (2H , br t), 5.65 (2H, s), 6.63 (2H, d), 6.96 (2H, d), 7.25 (1H, t), 7.40-7.61 (4H, m),

7.77 (1H dd), 7.83 (1H, d).

42-43. Example 41 is followed as in Example 41.

Example 42 [2- (Piperidino) ethyl] -2-butyl-1 H - [1,2 '- (1H-tetrazol-5-yl) biphenyl 4-yl] -7-methyl-7-benzimidazole-7-carboxylate

Colorless powder, yield: 55 ¾. Mp: 210-213 ° C. Elemental Analysis a ^C 33 ^H 37 ^N 7 ° 2 .3 / 5 H ₂ 0 calcd 0 (¾) H ( '^) WOMAN calculated: 68.99 6.70 17,07 Found: 68.93 6.59 16.94

1 H-NMR (200MHz, CDCl 3) 0.96 (3H, t), 1.27-1.58 (8H, m), 1.79-1.94 (2H, m), 2.72-2.85 (4H, m), 2.93 (2H, t), 3.20-

3.31 (2H, m), 4.10-4.27 (2H, m), 5.63 (2H, br s), 6.596.70 (2H, m), 7.04 (2H, d), 7.26 (1H, t), 7.36-7.50 (4H, m),

- W • *

Example 43 N- (2-Methylamino) ethyl [-2-butyl] -1 - [. 2 '- (1H-Tetrazol-5-yl) -biphenyl4-yl-7-methyl-7-benzimidazole-7-carboxylate

7.72-7.77 (1H, m), 7.98 (1H, dd).

Colorless powder, 91% yield. Mp: 206-208 ° C Elemental analysis for C-jqH-j ^ Ν ^ 0 ₂ . 2.1 H ₂ 0 calcd C (%) H (%) N (%) Calculated: 64.18 6.68 17.46 Found: 64.31 6.40 17.16

¹ H-NMR (200MHz, CDCl 3) δ: 0.96 (3H, t), 1.39-1.57 (2H, m), 1.79-.

1.94 (2H, m), 2.34 (6H, s), 2.94 (2H, t), 3.10 (2H, br t),

4.19 (2H, br t), 5.66 (2H, s), 6.63 (2H, d), 7.03 (2H, d),

7.27 (1H, t), 7.397.54 (4H, m), 7.73-7.78 (1H, m), 7.97 (1H, dd).

Example 44

2-Methoxymethyl 1-12 '- (1H-tetrazol-5-yl) -biphenyl-4-yl-7-methyl-7-benzimidazole-7-carboxylic acid methyl ester

A mixture of 0.4 g of 1 - [(2'-cyano-biphenyl-4-yl) methyl] -2-methoxymethylbenzimidazole-7-carboxylic acid methyl ester and 1.0 g of trimethylone azide in 10 ml of toluene was added for 49 hours. heat to reflux. The reaction mixture was evaporated to dryness and the resulting residue was dissolved in methanol (6 mL) and 1N hydrochloric acid (6 mL). The solution was stirred for 3 hours and then evaporated to dryness. The residue thus obtained was dissolved in methylene chloride / water and neutralized with 1N sodium hydroxide. The organic phase is washed with water, dried and evaporated to dryness. The residue was purified by column chromatography over silica gel. The crystals were recrystallized from ethyl acetate / isopropyl ether,

0.3 g of colorless needle-like crystals are obtained. Evade- yield: 68%. M.p .: 191-194 ° C. Analysis a C ₂₅ H ₂₂ N ₆ 0 ₃ . 3 / 5H ₂ 0 calcd C (%) H (%) N (%) calculated: 64.53 5.03 18.06 Found: 64.57 4.94 17.97

1 H-NMR (200MHz, CDCl 3) δ: 3.27 (3H, s), 3.66 (3H, s), 4.21 (2H, s), 5.62 (2H, s), δ, 59 (2H, d), 6.87 (2H, d),

7.16 (1H, t), 7.30-7.36 (2H, m), 7.55-7.63 (3H, m), 7.93-7.99 (1H, m).

45-47. Example 44 is followed as in Example 44.

Example 45

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

Colorless powder.

1 H-NMR (200MHz, CDCl 3) δ: 1.14 (3H, t), 1.21 (3H, t), 3.45 (2H, q), 4.20 (2H, q), 4.85 ( 2H, s), 5.89 (2H, s),

6.95 (2H, d), 7.10-7.40 (3H, m), 7.56-7.70 (3H, m),

7.96 (1H, dd).

Example 46

Ethyl-2-thiomethyl-l - // _ / 2 '- (lH-tetrazol-5-yl) ^biphenyl-4-m il_7 etil_7-benzimidazole-7-carboxylate

- woman Colorless powder. Yield: 75%.

1 H-NMR (200MHz, CDCl 3) δ: 1.12 (3H, t), 1.23 (3H, t), 2.46 (2H, q), (4.11 (2H, q), 3, 36 (2H, s), 5.63 (2H, s), 6.58 (2H, d),

6.87 (2H, d), 7.10-7.36 (3H, m), 7.56-7.64 (3H, m),

7.97-8.04 (1H, m).

Example 47

2- (Methyl 1-thiomethyl-1) -1H-2 '- (1H-tetrazol-5-yl) -biphenyl-4-yl-7-methyl-7-benzimidazole-7-carboxylic acid ethyl ester

Colorless powder. Yield: 56%.

1 H-NMR (200MHz, COCl 3): 1.21 (3H, t), 2.03 (3H, s), 4.11 (2H, q)

5.63 (2H, s), 6.60 (2H, d), 6.91 (2H, d), 7.15-7.40 (3H, m), 7.55-7.68 (3H, m), 8.00-8.10 (1H, m).

Example 48

2 Hidroximeti1-1 - /// 2 '- (ΙΗ-tetrazol-5-yl) biphenyl-4-il_7 metil_7benzimidazol-7-carboxylic acid ethyl ester

The compound was prepared as described in Example 44 starting from ethyl 2-acetoxymethyl-1 ', 2' - 1 ', 4'-biphenyl-4-yl-7-methyl-7-benzimidazole-7-carboxylic acid.

Pale yellow powder. Yield: 60 H NMR (200MHz, CDCl3? 1.20 (3H, t), 4.17 (2H, q), 4.82 (2H, br s), 5.56 (2H, br s), 6.65 (2H, d), 6.86 (2H, d), 6.82-6.95 (1H, m), 7.21-7.54 (4H, m), 7.62 (1H, d), 7.75-

7.82 (1H, m).

- 1-17 -

Example 49

2-Methoxy-metÍ1-1 - /// 2 '- (lH-tetrazol-5-yl) biphenyl-4-il_7 metil_7benzimidazol-7-carboxylic acid

To a solution of 0.2 g of methyl 2-methoxymethyl-1- [2 '- (1H-tetrazol-5-yl) -biphenyl-4-yl] -7-methyl-7-benzimidazole-7-carboxylic acid in 10 ml of methanol 1 5 ml of 1 N sodium hydroxide are added and the mixture is heated at 80 ° C for 20 hours. The reaction mixture was evaporated to dryness and the resulting residue was dissolved in water and acidified. The resulting crystals were recrystallized from dimethylformamide / methyl alcohol / water to give 0.16 g of a colorless prism crystal. Yield: 80%. M.p .: 272-274 ° C.

Elemental Analysis a (Molecular weight: 440.46) 0 (¾) H (%) WOMAN calculated: 65.45 4.58 19.08 Found: 65.32 4.47 18.95 ¹ H NMR (200MHz, OMSO-dg) $ : 3.28 (3H, s), 4.68 (2H, s), 5.87 (2H, s);

6.80 (2H, d), 6.98 (2H, d), 7.29 (1H, t), 7.45-7.70 (5H, m),

7.91 (1H, dd).

50-54. Example 49 is followed as in Example 49.

Example 50

2-ethoxymethyl-l- / / 2 ¹ - (lH-tetrazol-5-yl) biphenyl-4-il_7 metil_7benzimidazol-7-carboxylic acid

Colorless powder. Yield: 80 p. 243-245 ° C. Elemental Analysis a ^C 25 ^H 22 ^N 6 ° 3 ^{1 // 2 H} 2 °:

(Molecular Weight: 463.50)

C (%) H (%) N (%) calculated: 64.78 5.00 18.13 Found: 64.99 4.97 18.26

1 H-NMR (200MHz, DMSO-d 6): 1.01 (3H, t), 3.48 (2H, q), 4.72 (2H, s), 5.89 (2H, s), 6.81. (2H, d), 6.99 (2H, d), 7.29 (1H, t), 7.44-7.70 (5H, m), 7.91 (1H, dd).

Example 51

2-methylthiomethyl-l- /. 2 '- (1H-tetrazol-5-yl) -biphenyl-4-yl-7-methyl-7-benzimidazole-7-carboxylic acid

Colorless powder. Yield: 82%. M.p .: 270-272 ° C.

Elemental Analysis for α (24 → 20 → 6 °) ₂ S.1 / 2H ₂ For 0: (Molecular weight: 465.54) C (%) H (%) N (%) Calculated: 61.92 4.55 18.05 Found: 61.94 4.44 18,20 ¹ H-NMR (200MHz, DMSO-d ₆ ) <sep> 2.09 (3H, s), 3.98 (2H, s), 5. 89 (2H, s) 6.80 (2 H, d), 7.00 (2H, d); 7.27 (1H, t), 7.45-7.69 (5H , M);

7.87 (1H, dd).

Example 52

- H i d r o x i m e t i 1 -1 - / _ /.2 '- (1H -1 e t r a z ο 1- 5 - i 1) - b i f e n i 1-4 - i 1_7 - m e t i 1_7 - Benzimidazole-7-carboxylic acid

Colorless powder. Yield: 65%. Mp: 292-294 ° C.

Elemental Analysis a

3/10

calcd

(Molecular weight: 431.84.)

Η9 -

C (%) H (%) N (%) calculated: 63.97 4.34 19.46 Found: 64.01 4.29 19.49 ¹ H NMR (200MHz, DMSO-dg) ): 4.72 (2H, s), 5.92 (2H, s), 6.83 (2H, d),

6.98 (2H, d), 7.27 (1H, t), 7.45-7.68 (5H, m), 7.88 (1H, dd).

Example 53

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

Yield: 76%.

Physical constants: colorless crystals. Mp: 157-160 ° C.

Elemental analysis for ^ 25 ^ 22 ^ 6 ^ 2 · 9/10 H ₂ 0: CC%) H (%) N (%) calculated: 61.69 4.93 17.26 Found: 61.75 4.91 17.26 ¹ H-NMR (200MHz, DMSO-d 6) $: 1.18 (3H, t), 2.54 (2H, q), 4.01 (2H, s), 5.89 (2H, s), 6.80 (2H, d); 7.00 (2H, d), 7.27 (1H, t), 7.45 7.68 (5H, m), 7.87 (1H, dd).

Example 54

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

Yield: 48%.

Physical constants: colorless powder.

¹ H-NMR (200MHz, DMSO-d 6) δ: 2.66 (3H, s), 4.42 (2H, s), 5.84 (2H, s),

6.79 (2H, d), 7.00 (2H, d), 7.27-7.68 (6H, m), 7.87 (1H, d).

«·«

12U

55-58. Example 31 is followed as in Example 31.

Example 55

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

Yield: 54%. Physical constants: colorless powder, m.p. 186-188 ° C. Elemental Analysis a ^C 25 ^H 22 ^N 6 For O2S.I / 2 H2O: C (%) H (%) N (%) calculated: 62.61 4.83 17.52 Found: 62.82 4.63 17.69

1 H-NMR (200MHz, CDCl 3): 2.03 (3H, s), 3.70 (3H, s), 3.36 (2H, s),

5.63 (2H, s), 6.64 (2H, d), 6.94 (2H, d), 7.18 (1H, t), 7.30-7.40 (2H, m), 7 , 57-7.66 (3H, m), 8.02-8.07 (1H, m).

Example 56

2-Ethylthiomethyl-1 H ”/ 2 '- (1H-tetrazol-5-yl) -biphenyl-4-yl-7-methyl-7-benzimidazole-7-carboxylic acid methyl ester

Yield: 49%. Physical constants: pale yellow powder Elanalysis a ^C 26 ^H 24 ^N 6 ° 2 Sl / 2 H ₂ 0 calcd C (%) H (%) N (%) calculated: 63.27 5.11 17.03 Found: 63.42 4.87 16.92 1 H NMR (200MHz, , CDCl ₃ ) J 3.64 (3H, s), 5.57 (2H, s),

6.84 (2H, d), 7.13 (2H, d), 7.31-7.38 (1H, m), 7.56-7.65 (3H, m), 7.89-7, 98 (1H, m).

121

Example 57

2-Hydroxymethyl-1 H - 2 '- (1H-tetrazol-5-yl) -biphenyl-4-yl-7-methyl-7-benzimidazole-7-carboxylic acid ethyl ester

Yield: 30%. Physical constants: colorless powder.

¹ H-NMR (200MHz, CDCl 3) δ: 3.63 (3H, s), 4.77 (2H, s), 5.75 (2H, s),

6.76 (2H, d), 6.99 (2H, d), 7.23 (1H, t), 7.39-7.62 (5H, m),

7.90 (1H, dd).

Example 58

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

Yield: 61 Mp: 214-217 ° C. Physical constants: colorless needle-like crystals Elemental analysis for C ₂ H 4 ^H 24 ^N 6 ° 3 · 1/5 H ₂ 0 calcd C (%) H (%) N (%) calculated: 66.08 5.18 17.87 Found: 66.15 5.21 17.80 ¹ H-NMR (200MHz, CDCl 3) δ: 1.14 (3H, t), 3.44 (2H , q), 3.68 (3H, s), 4.13 (2H, s), 5.63 (2H, s); 6.61 (2H, d), 6.89 (2H, d),

7.16 (1H, t), 7.19-7.39 (2H, m), 7.57-7.64 (3H, m), 7.978.02 (1H, m).

Example 59

2-Chloromethyl-1 H - [2 '- (1H-tetrazol-5-yl) -phenyl] -4-yl-7-methyl-7-benzimidazole-7-carboxylic acid ethyl ester

0.2 g of ethyl 2-hydroxymethyl-1H-2 '- (1H-tetrazol-5-yl) -biphenyl-4-yl-7'-methyl-7-benzimidazel-7-carboxylic acid

- 12Ζ! To a solution of methylene chloride (0.3 ml) was added dropwise 0.3 ml of thionyl chloride and the reaction mixture was refluxed for 3 hours. The reaction mixture is then poured into ice water, the organic phase is washed with water, dried and evaporated to dryness. 0.2 g of a pale yellow amorphous powder are obtained. Yield: 96%.

² H-NMR (200MHz, CDCl 3): 1.29 (3H, t), 4.19 (2H, q), 4.63 (2H, s),

5.77 (2H, s), 6.75 (2H, d), 7.03 (2H, d), 7.28 (1H, t),

7.35-7.39 (1H, m), 7.56-7.72 (4H, m), 8.06-8.11 (1H, m).

Example 60

Ethyl 2-methylaminomethyl-1- [2 '- (ΙΗ-tetrazol-5-yl) biphenyl] -4-yl-7-methyl-7-benzimidazole-7-carboxylic acid

To a solution of 0.2 g of 2-chloromethyl-1 H - 2 '- (1H-tetrazol-5-yl) -biphenyl4-yl-7-methyl-7-benzimidazole-7-carboxylic acid ethyl ester in 5 ml of acetonitrile was added 0.33 g of ethyl acetate. mass methanolic methanol solution and the reaction mixture was heated at 60 ° C for 77 hours. The reaction mixture was then cooled to give 0.12 g of a pale yellow prism-like crystal. Yield: 61%. Mp: 248-250 ° C.

¹ H-NMR (200MHz, 0MSO-d ₆ ) δ: 1.14 (3H, t), 2.62 (3H, s), 4.16 (2H, q), 4.39 (2H, s), 5.71 (2H, s), 6.73 (2H, d), 7.03 (2H, d),

7.27-7.46 (4H, m), 7.54-7.63 (2H, m), 7.94 (1H, dd).

61-62. Example 1 is followed as in Example 1.

Example 61

2-Isobutyl-1- [2 '- (1H-tetrazol-5-yl) -biphenyl-4-yl] -7-methyl-7-benzimidazole-7-carboxylic acid ethyl ester.

Yield: 71%. Physical constants: colorless prism.

1 H-NMR (90MHz, CDCl 3) δ: 0.87 (6H, d), 1.13 (3H, t), 1.23 (1H, t),

1.83-2.40 (1H, m), 2.00 (1H, s), 2.27 (2H, d), 4.03 (2H, q),

4.13 (1H, q), 5.47 (2H, s), 6.43 (2H, d), 6.73 (2H, d),

6.87-7.70 (6H, m), 7.90-8.00 (1H, m).

Example 62

2-Chair. butyl-l- /. ^- /.2 '- (tetrazol-5-i1) -bitenil-4-il_7 metil_7benzimidazol-7-carboxylic acid ethyl ester

Yield: 43%. Physical constants: colorless prism, mp 128-130 ° C.

1 H-NMR (90MHz, CDCl 3) 0.87 (3H, t), 1.00-1.17 (6H, m), 1.23 (1H, t), 1.50-1.90 (2H, m) ), 2.03 (1H, s), 2.63-3.03 (1H, m), 4.00 (2H, q), 4.13 (1H, q, 5.57 (1H, d), 5.77 (1H, d),

6.50 (2H, d), 6.77 (2H, d).

IR (Nujol) cm ^_1: 2720, 1730, 1450, 1280, 1265, 1200, 760, 765th

63-64. Example 49 is followed as in Example 49.

Example 63

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

Yield: 62%. Physical constants: Colorless powder 205-207 ° C (dec.). Elemental Analysis for C ^ H ^ N ^ O ^ .2 / 5 H ₂ 0 calcd C (%) H (%) N (%) Calculated: 67.93 5.44 18.23 Found: 67.98 5.63 18.43

. Mp .:

¹ H NMR (90MHz, CDCl 3) 1.57 (6H, d), 3.40-3.83 (1H, m), 6.00 (2H, s), 6.90 (2H, d) ), 7.13 (2H, d), 7.43-7.83 (5H, m),

7.97-8.12 (2 H, m).

IRNujoDcm ¹ : 1260, 1690, 1410, 1290, 1245, 1200, 1120, 760.

Example 64

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

Yield: 79 %. Physical constants: colorless prism. Mp 185-186 ° C. Anal the ^C 26 ^H 24 ^N 6 ° 2 · 1/2 EtOH calcd C (%) H (%) N (%) calculated: 68.20 5.72 17.67 Found: 67.96 5.71 17.46 1 H NMR (90MHz, DMSI-dg) 5: 0.83 (3H , t), 1.17 (1H, t), 1.30 (3H, d); 1,53- 2.13 (2 H, m), 2 , 77-3.13 (1H, m), 3.63 (1H, q), 5, 90

(2H, s), 6, (0 (2H, d), 7.03 (2H, d), 7.23 (1H, t), 7.33-

7.97 (7 H, m).

IR (NujoDcm ¹ : 2600, 1700, 1450, 1410, 1275, 1230, 1200,

1140, 750.

65-66. Example 19 is followed as in Example 19.

Example 65

2- (2-methoxyethyl) -1 / ^- / 2 '- (1H-tetrazol-5-yl) biphenyl-4-il_7 metil_7benzimidazol-7-carboxylic acid methyl ester

Yield: 35%. Physical constants: Pale yellow powder.

12.5 II ¹ H-NMR (200MHz, CDCl-j) δ: 2.60 (2H, t), 3.61 (2H, t), 3.19 (3H, t);

3.63 (3H, t), 5.60 (2H, s), 6.56 (2H, d), 6.85 (2H, d),

7.07-7.12 (2H, m), 7.30-7.35 (1H, m), 7.51-7.65 (3H, m),

7.96 (1H, dd).

Example 66

2- (2-methylthioethyl) -l- / ^- / 2 ¹ - (lH-tetrazol-5-yl) biphenyl-4-il_7metil_7-benzimidazole-7-carboxylic acid methyl ester

Yield: 16%. Physical constants: pale yellow powder.

¹ H-NMR (200MHz, CDCl 3) δ: 2.09 (3H, t), 3.63 (3H, s), 2.72-2.96 (4H, m), 5.65 (2H, s) , 6.60 (2H, d), 6.87 (2H, d), 7.06-7.20 (2H, m), 7.29-7.34 (1H, m), 7.54-7 , 63 (3H, m), 7.99-8.05 (1H, m).

Example 67

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

2.0 g of 2-butyl-1 * / 2 '- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl-benzimidazole-7-carboxylic acid, 1.1 g of sodium bicarbonate and 1.5 g of methyl- iodide in 10 ml of diemylformamide was stirred at room temperature for 15 hours. The reaction mixture was then diluted with water and extracted with ethyl acetate. The organic phase is washed with water, dried and evaporated to dryness. The residue was purified by column chromatography over silica gel.

0.95 g (45 h) of the 1-methyl derivative and 0.36 g (17%) of the 2-methyl derivative are obtained.

not .1

The physical constants of the 1-methyl derivative (compound 67a) are as follows:

Mp : 200-201 ° C.

Elemental analysis a ^ 28 ^Η 28 ^Ν 6θ2 calcd C (%) H (%) N (%) Calculated. 69.98 5.87 17.49 Found: 69.67 5.8 0 17.36 ^ -NMR (200MHz, CDCl-j) $: 0.97 (3H, t), 1.39

1.97 (2H, m), 2.91 (2H, t), 3.16 (3H, s), 3.74 (3H, s),

5.72 (2H, s), 6.77 (2H, d), 7.00 (2H, d), 7.25 (1H, t),

7.48-7.69 (5H, m), 7.95 (1H, dd).

The physical constants of the 2-methyl derivative (compound 67 / b) are as follows: pale yellow syrup.

¹ H NMR (200MHz, CDCl 3) 0.96 (3H, t), 1.38-1.57 (2H, m), 1.80-

1.96 (2H, m), 2.92 (2H, t), 3.71 (3H, s), 4.18 (3H, s),

5.73 (2H, s), 6.77 (2H, d), 7.06 (2H, d), 7.24 (1H, t), 7.35-7.55 (3H, m), 7 , 59 (1H, dd), 7.80 (1H, dd), 7.94 (1H, dd).

IR (Neat) cm ^_1: 1725, 1520, 1460, 1435, 1400, 1360, 1280, 1265,

1220, 1200, 1125, 760.

Example 68

2-Butyl-l-Γ / 2 '- (tetrazol-5-yl) -biphenyl-4-methyl-i1_7 1_7- 7 (formylamino) -benzimidazole and 2-butyl-l- / ^- / j2 '- (1H-tetrazol-5-yl) biphenyl-4-yl-7-methyl-7- (7-ethoxycarbonylamino) -benzimidazole

0.94 g of 2-butyl-1 H - 2 '- (1H-tetrazol-5-yl) biphenyl-4-yl-7-methyl-7-benzimidazole-7-carboxylic acid, 0.61 g of diphenylphosphoryl azide and 0.61 g of of triethylamine (6 g) in dimethylformamide (6 ml) was stirred at room temperature for 7 hours.

The reaction mixture was evaporated to dryness. The resulting crystalline residue was purified by silica gel column chromatography. Two colorless crystals were obtained, 68a and 68b. THE

Compound 68 / a is a Harmnium amino derivative, 0.26 g, 29%, colorless crystals. Mp: 290-292 ° C (dec.).

calcd

Elemental Analysis for ^C 26 ^H 25 ^N 7 °

c (%) H (%) N (%) Calculated: 69.16 5.58 21.71 Found: 69.29 5.51 21, 94 ^ -NMR (200MHz, CDCl-j) §: 0.84 (3H, t) , 1.22 1.56-1.71 (2 H, m), 2.70 (2H, t) , 5.55 6.89 (2H, d), 6.98 -7.07 (3H, m) , 7.43 (3H, m), 8.27 (1H, s). IR (KBr) cm ^-1 : 3340, 1630, 1530, 1510, 1420

-1.40 (2H, m), (2H, d), 7.51-7.70 (2H, s), 6.79 (1H, d),

1400, 750, 730.

Ethoxycarbonylamino derivative 68 / b: 0.31 g colorless

crystal, yield: 31 %, m.p. : 190-194 ° C (dec.). Elemental Analysis of £ 28 ^ 9 ^ 7 ^ 2 ^- 0.1 H ₂ 0 calcd 0 (¾) H (%) N (%) Calculated: 67.62 5.92 19.71 Found: 67.43 5.81 19.70 1 H-NMR (200MHz, CDCl 3) δ: 0.87 (3H , t), 1.18 (3H, t), 1.25- (3H, m), 1.56-1.71 (2H, m); 2.50 (2H, t), 3.99 (2H, 5.37 (2H, s), 6.07 (LH, s); 6.66 (2H, d), 6.90-7.05

8.00 (1H, dd).

1.39

q), (5H, m),

7.34 (1H, dd), 7.55-7.64 (2H, m),

IR (KBr) cm ^-1 : 1700, 1520, 1250, 750.

Example 69

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

The compound was prepared as described in Example 44.

Yield: 56 Physical data: Colorless crystals, m.p. 178-180 ° C (dec.).

Elemental Analysis a. 2HC1.2H ₂ 0. For l / 2Ac0Et:

C (%) H (%) N (%) calculated: 58.25 6.68 15.85 Found: 58.42 6.42 15.61

¹ H NMR (200MHz, DMSO-d ₆ ) δ: 0.91 (3H, t), 1.33-1.51 (2H, m),

1.71-1.86 (2H, m), 2.50 (6H, s), 3.17 (2H, t), 4.32 (2H, s),

5.92 (2H, s), 7.07 (2H, d), 7.14 (2H, d), 7.49-7.72 (5H, m),

7.80 (1H, d), 7.92 (1H, d).

IR (KBr) cm ^_1: 3400, 1500, 1470, 1435, 1420, 750th

70-71. Example 67 is followed as in Example 67.

Example 70

----------- methyl

2-Butyl 1-1 - N/- 2 '- (1''-tetrazol-5-yl) -biphenyl-4-yl-7-methyl-7-benzimidazole-7-carboxylic acid

Yield: 78%. Physical constants: colorless prism-like crystals, m.p. 213-214 ° C.

Analysis

calculated:

Found:

a ^c ₂ 7 ^H 26 ^N 6 ° 2 · l / 2H ₂ O calcd C (%) H (%) N (%) 68.19 5.72 17.67 68.52 5.55 17.62

0.95 (3H, t), ^X H-NMR (200MHz, COCl ^) 5:

2.99

1.38-1.57 (2H, m), 1.801.95 (2H, m), (2H, t), 3.18 (3H, s), 5.82 (2H, s),

6.80 (2 H, d),

6.97 (2H, d), 7.27 (1H, t), 7.48-7.68 (4H, m),

7.80 (1H, d),

7.98 (1H, d).

i

- 12.9 IR (KBr) cm ^-1 : 1700, 1520, 1470, 1445, 1435, 1410, 1290, 1280,

1230, 1185, 1145, 1120, 1100, 820, 770, 760,

745, 730.

IL ^ heaven _for _

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

mining; 71%. Physical constants: colorless needle-shaped crystals

Lyoko. 0.p .: 226-228 ° C (dec.). Analysis ^{a C} 27 ^H 26 ^N 6 ⁰ 2 ' For the formula 0.7 H ₂ 0: C (%) H (%) N (%) calculated: 67.68 5.76 17.54 Found:. 67.48 5.51 17.26 ¹ H-NMR (200MHz, CDCl 3) δ: 0.94 (3H, t) , 1.38 -1.56 (2H, m) 1.79 -1.94 (2 H, m), 3.07 (2H, t), 4.22 (3H, s), 5.84 (2H, s); 6.81 (2H, d), 7.06 (2H, d), 7.25 -7.55 (4H.m), 7.74 (LH, d); 7.81 (1H, dd), 8.00 (LH, d). IR (KBr) cm ^- ^: 1700, 1510, 1450, 1430, 1410, 1360, 1290.1240, 1190, 1150, 1120, 1100, 1060 1035, 1000 820,

760, 750, 740, 720.

Example 12

2-Butyl 1-1 - N / 2 '- (N-pivaloyloxymethyl-tetrazol-5-yl) -biphenyl-

-1,7-methyl-7,7-benzimidazole-7-carboxylic acid

0.71 g of 2-butyl-1 H - 2 '- (1H-tetrazol-5-yl) biphenyl-4-yl-7-methyl-7-benzimidazole-7-carboxylic acid, 0.21 g of potassium carbonate and 0.36 g of iodine methyl pivalate was prepared with 2 ml of dimethylformate

the mixture was stirred at room temperature for 17 hours. The reaction mixture was then stirred with water and acidified to pH 3-4 with 1N hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic phase was washed with water, dried and dried to dryness.

- 130 t • β * j · · * i ·· ·· ♦ ·· steam. The residue was purified by column chromatography on silica gel. Yield: 23%.

gel. 0.2 g colorless

Mp .: 188-191 ° C (dec.). Analysis a ^ 32 ^Η 34 ^Ν 6θ4 '° ^Η 2θ ¹ isszegké 0 (¾) H (%) N (%) calculated: 66.56 6.14 14.55 Found: 66.82 6.28 14,13

¹ H-NMR (200MHz, CDCl ³ ) δ

1.36-1.55 (2 H, m),

0.94 (3H, t), 0.96 and 1.18 (9H, s),

1.77-1.93 (2H, m), 2.90-2.97 (2H, m),

5.39 (1.5H, s), 5.01 (2H, s), 6.36 (0.5H, s), 6.76-6.83 (2H, m), 6.96-6, 83 (2H, m), 6.96-7.03 (2H, m), 7.20-7.29 (1H, m), 7.38-7.97 (86H, m).

IR (K8r) cm ^-1 : 1760, 1600, 1460, 1410, 1275, 1240, 1125, 1100, 760.

73-76. Example 36 is followed as in Example 36.

Example 73

2-Ethyl pivaloyloxymethyl 1 -1H-2 '- (1H-tetrazol-5-yl) bi-phenyl-4-yl-7-methyl-7-benzimidazole-7-carboxylic acid

Example 74

2-Propyl-1- [2 '- (1H-tetrazol-5-yl) bi-phenyl] -4-yl-7-methyl-7-benzimidazole-7-carboxylic acid pivaloyloxymethyl ester

131

Example 75 [1- (Cyclohexyloxycarbonyloxy) ethyl] -2-propyl-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7- carboxylate

Example 76 [1- (Cyclohexyloxycarbonyloxy) ethyl] -2-ethyl-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7- carboxylate

Example 77

2-Butyl-l - ([(2'-methoxycarbonyl-biphenyl-4-yl) methyl] benzimidazole-7-carboxylic acid methyl ester

To a solution of 1.2 g of methyl 2- [N- (2'-methoxycarbonyl-biphenyl-4-yl) -methyl-N-valeryl] -amino-3-nitrobenzoic acid in 1.3 ml of concentrated hydrochloric acid in several portions 0.42 g of iron powder are added and the resulting mixture is stirred at reflux for 10 hours. Insoluble matters were removed by filtration, the filtrate was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo and the residue was recrystallized from isopropyl ether. 0.53 g of the title compound is obtained in the form of colorless prisms. Yield: 48%. Mp: 78-79 ° C.

Elemental analysis based on the formula C28 ^H 28 ^N 2 ° 4:

C (%) H (%) N%) date: 73.66; 6.18; 6.14; found: 73.56; 6.21; 6.15. 1 H-NMR (200 MHz, CDCl ₃ ) δ: 0.96 (3H, t), 1.39-1.56 (2H, m), 1.82-1.97 (2 H, m) , 2.94 (2H, t), 3.57 (3H, S), 3.73 (3H, s), 5.78

132 (2H, s), 6.86 (2H, d), 7.18 (2H, d), 7.24-7.32 (2H, m), 7.39 (1H, dt), 7.51 (1H, dt), 7.62 (1H, dd), 7.80 (1H, dd), 7.95 (1H, dd).

IR (KBr) 1735, 1725, 1530, 1450, 1440, 1425, 1400, 1310, 1290, 1255, 1200, 1150, 1125, 1115, 775, 765, 755 cm ^-1 .

Example 78

2-Butyl-l - ([(2'-carboxybiphenyl-4-yl) methyl] benzimidazole-7-carboxylic acid

0.53 g of methyl 2-butyl 1 - ([(2'-methoxycarbonyl-biphenyl-4-yl) methyl] -benzimidazole-7-carboxylic acid) and 6 ml of 1N sodium hydroxide solution The solution in methanol was heated under reflux for 5 hours, then the reaction mixture was concentrated in vacuo, diluted with water and washed with diethyl ether, the pH of the aqueous solution was adjusted to 3-4 with concentrated hydrochloric acid and the precipitate was collected by filtration. Recrystallization from methanol / chloroform gave 0.47 g (90%) of the title compound as colorless prism crystals, mp 253-254 ° C.

Elemental analysis based on the formula C26 ^H 24 ^N 2 ° 4 * ⁰ ' ^{2 H} 2 °:

C (%) H (%) N%) date: 72.27; 5.69; 6.48; found: 72.30; 5.53; 6.48. 1 H-NMR (200 MHz, DMSO-dg) 5: 0, 89 (3H, t), 1.29-1.48

(2H, m), 1.68-1.84 (2H, m), 2.88 (2H, t), 5.90 (2H, s), 6.88 (2H, d), 7.21-. 7.38 (4H, m), 7.42 (1H, dt), 7.54 (1H, dt), 7.63 (1H, dd), 7.70 (1H, dd), 7.85 (1H) dd).

IR (KBr) 1710, 1520, 1415, 1260, 1120, 1005, 820, 760 cm ^-1 .

133

Claims (5)

PATENT CLAIMS A compound of formula XVI wherein: R ² and R ³ represent a group capable of forming or converting to an anion, A is a benzene ring which may optionally carry substituents other than R ² , X is a direct bond between a phenylene and a phenyl group or a linking chain of up to two members, Q ¹ is hydrogen or -COO-t-butyl, and Q ² is -NO ² or -NH ² - when Q ¹ is and Q ² is -NO ² when Q ¹ is -COO-t-butyl and their salts. 2. The compound according to claim 1, which is methyl 3-amino-2 - [[(2'-cyanobiphenyl-4-yl) methyl] amino] benzoate. A process for the preparation of a compound of formula (XII) wherein R ² , R ³ and X are as defined in claim 1, characterized in that a compound of formula (XI) wherein R ² is as defined in claim 1 A compound of formula (III) wherein R ³ and X are as defined in claim 1, W is halogen. A process for the preparation of compounds of formula (XIII) wherein R ² , R ³ and X are as defined in claim 1, characterized in that a compound of formula (XII) wherein R ² , R ³ and X are The protecting group of claim 1 is deprotected. A process for the preparation of a compound of formula (V) wherein R ² , R ³ and X are as defined in claim 1, wherein a compound of formula (XIII) wherein R ² , R ³ and X are as defined in claim 1, reduced.