LT3246B - Benzimidazole derivatives, their production and use in pharmaceutical compositions - Google Patents

Abstract

This invention is for benzimidazole, which has a formula (I), derivatives:<IMAGE>in which ring A is benzene ring, which, supplementing R1 group, can be substituted without choice. R1 is a hydrogen or hydrocarbon residual changed for choice; R2 is a group, which can compound anion, or a group, which can become anion; X is a linkage or a linking group, its length is two atoms or less, between phenylene and phenyl groups R? is carboxyl or its ester, or amide, or a group, which can form anion, or a group, which can become anion; Y is -O-, -S(O)m- or -N(R4)-, where m is a whole number 0, 1 or 2, and R4 is hydrogen or any changed alkyl group; n is a whole number equal of 1 or 2; and its pharmaceutically proper saline; Also, the abovementioned compound has a strong angiotensin II inhibiting activity and can be used as a remedy for curing blood circulation diseases, such as hypertensis, heart blood vessel diseases, for example cardiomegalia, heart deficiency, infarcts and so on, shocks, strokes, nephritis and so on.

Description

i

The invention relates to novel benzimidazole derivatives, 5 as well as intermediates used for the preparation of these derivatives. The present invention is also directed to compounds which exhibit potent hypotensive activity and are potent angiotensin II antagonists and may be 10th used as medicines for the treatment of disorders of the bloodstream, such as hypertonic diseases, heart diseases (e.g., cardiomegaly, heart failure, infarctions, etc.), shocks, bleeding into the brain, nephrites, etc. 15th The renin-angiotensin system in the body performs a homeostatic function by regulating systemic blood pressure, fluid volume, ionic balance, and more. * - important body states associated with aldesterone 20th secretion. Studies on the production of inhibitors of the enzymes that stimulate the formation of angiotensin II (ACE-inhibitors), the enzymes that catalyze the formation of angiotensin II with potent vasoconstrictor effects, have clearly shown a relationship between the renin-angiotensin system and hypertension. Because angiotensin II, through its receptors on the cell membranes, stimulates blood vessels 25th while increasing blood pressure, it is advisable to treat angiotensin-induced hypertension * · use compounds that are angiotensin II antagonists such as the ACE inhibitor. 30th Various analogues of angiotensin II, such as saralazine [Sar ¹ Ile ⁸ ] A II, etc., are known to have potent antagonistic activity against angiotensin II. 35 However, it is also known that parenteral administration of peptide antagonists has a short-term effect and that oral administration of

are ineffective. (M.A. Ondetti and D.W. Cushman, Annual Reports in Medical Chemistry, 13, 82-91, (1978)).

It is therefore appropriate to use non-peptide angiotensin II antagonists in order to avoid the above disadvantages. - Earlier works for studies in this field have described imidazole derivatives having antagonistic activity against angiotensin II, e.g. 71073/1981; No. 71074/1981; No. 92270/1982; No. 157768/1983; US # 4355040; No. 4340598 and so on. Later in European Patent Nos. 0253310, no. Japanese Patent Application Serial No. 0291969; No. 23868/1988 and no. 117876/1989, improved imidazole derivatives have been disclosed. In addition, the European patent no. No. 0323841 and Japanese Applied Application Nos. 287071/1989 are described as pyrrole, pyrazole and triazole derivatives as angiotensin II antagonists.

U.S. Pat. No. 4,380,804 discloses benzimidazole derivatives which antagonize the angiotensin II receptor and are active in vivo by intravenous administration to rats with hepatic hypertension. The following benzimidazole derivatives are exemplified by compounds of formula (A):

(A),

At the 5- and / or 6- position, formyl, chloro or substituted, for example, by hydroxymethyl, methoxy, carboxy. In general, most of the compounds mentioned are inactive with oral administration and only 6-hydroxymethyl and 6-chloro compounds are effective with oral administration (at least 100 mg / kg). However, this activity is not sufficient for the clinical use of these compounds.

The present invention relates to benzimidazole derivatives having potent hypotensive activity and high angiotensin II inhibitory activity, which makes them useful as medicaments.

The present inventors believe that the regulation and treatment of the renin-angiotensin system is associated with disorders of the circulatory system related to this system, such as hypertension, heart disease (e.g., cardiomegaly, heart failure, infarction, etc.), stroke, and the like. ., compounds with high antagonistic activity against the angiotensin II receptor and compounds and potent and long acting inhibitors of angiotensin II by oral administration are required. The above statement was based on intensive research carried out by the authors of the present invention. These studies have led to the successful synthesis of novel 2-substituted benzimidazole (I) derivatives having high antagonistic activity against the angiotensin II receptor and having a potent and long lasting effect by oral administration.

The present invention relates to benzimidazole derivatives of the formula (I):

(I) wherein ring A is a benzene ring which may optionally be substituted on R '; R ¹ is hydrogen or optionally substituted hydrocarbon. Residue 2; R is a group capable of forming an anion or becoming an anion; X is a bond or linking group between phenylene and phenyl groups having 2 or less atoms in length; R 'is a carboxyl, an ester, an amide thereof, or a group which may form or become an anion; Y is -O-, -S- (O) _m - or -N (R ⁴ ) -, wherein m is an integer equal to 1 or 2 and R ⁴ is hydrogen or an optionally substituted alkyl group; and n is an integer equal to 1 or 2, or a pharmaceutically acceptable salt thereof.

The compounds described are unexpectedly potent angiotensin antagonists and can therefore be successfully used in the treatment of diseases associated with circulatory disorders such as hypertension, cardiovascular disease, shock, renal failure, nephrites and the like.

Another object of the present invention are pharmaceutical compositions comprising an effective amount of a benzimidazole derivative (Formula (I) and a pharmaceutically acceptable carrier) that can be used as medicaments for the treatment of diseases associated with circulatory disorders such as hypertension, cardiovascular disease, shock, renal failure, nephrites, etc. The present invention is also directed to a process for the preparation of said compounds and compositions.

In addition, the present invention is directed to the treatment of the aforementioned circulatory system by administering to the body an effective amount of a benzimidazole of the formula (I) derivatives or a pharmaceutical composition containing the compounds.

FIG. Figure 1 is an X-ray scattering diagram obtained in Experiment 1.

FIG. Figure 2 is a graph of the IR spectrum obtained in Experiment 1.

FIG. Figure 3 is a diagram obtained in Experimental Example 1 using differential emission calorimetry.

The present invention relates to benzimidazole (I) derivatives and pharmaceutically acceptable salts thereof which have a high angiotensin II inhibitory activity and can be used in the treatment of diseases related to circulatory disorders such as hypertonic diseases, cardiovascular diseases, shock, nephrites, etc., also, for use in the preparation of pharmaceutical compositions containing an effective amount of benzimidazole (Formula I) derivatives in combination with a pharmaceutically acceptable carrier for the treatment of the aforementioned diseases, as well as a process for the preparation of said compounds and compositions.

An important group of compounds of the present invention includes compounds of formula (I ''):

wherein A is a benzene ring optionally substituted with R '; R ¹ is hydrogen or an optionally substituted hydrocarbon residue; R is a group capable of forming an anion or a group capable of becoming an anion; X is a bond or linking group having two or less atoms in length between the phenylene and phenyl groups; R 'is carboxyl or an ester or amide thereof; Y is -O-, -S (O) _m - or -N (R ⁴ ) -, wherein m is an integer equal to 0, 1, 2, and R is hydrogen or an optionally substituted alkyl group; and n is an integer equal to 1 or 2; and pharmaceutically acceptable salts thereof.

In the above formula (I), the hydrocarbon radicals represented by R ¹ may be, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl and aralkyl. Of these, alkyl, alkenyl and cycloalkyl are most suitable.

In addition, the alkyls represented by R ¹ are lower alkyl groups having 1 to 2 carbon atoms and may have both straight and branched chain, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl , t-butyl, pentyl, i-pentyl, hexyl, heptyl, octyl and so on

The alkenyls represented by R ¹ are lower alkenyl groups having straight or branched chain containing from 2 to 8 carbon atoms, such as vinyl, propenyl, 2-butenyl, 3-butenyl, isobutenyl, octenyl, etc.

The alkynyls represented by R ¹ are lower alkynyl groups having 2 to 8 carbon atoms in the straight or branched chain, such as, for example, ethynyl, 2-propynyl, 2-butynyl, 2-pentynyl, 2-octinyl and the like.

Cycloalkyls substituted with R ¹ are lower cycloalkyl groups having from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, etc.

The above-mentioned alkyl, alkenyl, alkynyl, cycloalkyl may be substituted with hydroxyl, optionally substituted amino (such as amino, methylamino, etc.)., Halogen, lower (C ₄ _ ₄₎ alkoxy group and so on.

The aralkyls represented by R ¹ may for example be phenyl-lower (C _1-4 ) alkyl such as benzyl, phenethyl and the like; along said aralkyl may be substituted with, for example, halogen (F, Cl, Br and 1.1.), nitro, lower (Ο _{fourth 4)} alkoxy (methoxy, ethoxy, etc.). group; a lower (C _{x 4} ) alkyl (methyl, ethyl, etc.) group; or analogous groups at various positions on the benzene ring.

The aryl group represented by R ¹ may include phenyl, or substituted, for example, halogen (F, Cl, Br and the like.), Nitro, lower (C _{1. 4)} alkoxy group such as methoxy, ethoxy and the like. ), a lower C _{( 1-4)} alkyl group (such as methyl, ethyl, etc.) or analogous groups at various positions on the benzene ring.

Of the above groups represented by R ^1, preferred are optionally substituted alkyl or alkenyl group (for example, lower (Cx_ ₅₎ alkyl and lower (C ₂ _ ₅₎ alkenyl group optionally substituted by a hydroxyl group, amino, halogen or lower ( Cx- ₄ ) alkoxy).

Groups which may form an anion or a thiolate anion, and which are illustrated in the formula R is carboxyl examples, tetrazolyl, trifluoromethanesulfonamide (NHS ₂ CF _3), phosphoric acid, sulfonic acid, cyano, lower (C ₁ _ ₄₎ alkoskikarbonilas and so on. Said groups may be substituted, for example, by an optionally lower alkyl group (such as lower (C ₄ -C ₄ ) alkoxymethyl, optionally substituted arylmethyl, etc.) or an acyl group (such as lower (C ₂ -C ₅ ) alkanoyl, optionally substituted benzoyl, etc.). .). Said groups may be groups capable of forming anions or, under appropriate chemical, biological and / or physiological conditions, themselves become anions (for example, by an in vivo reaction such as an oxidation-reduction reaction or enzyme-catalyzed hydrolysis).

Compounds in which R ² is a group capable of forming or becoming an anion by chemical reactions (such as oxidation, reduction or hydrolysis) [For example, not necessarily substituted with a tetrazolyl group (for example, a group of the formula:

where R is methyl, triphenylmethyl, 2-tetrahydropyranyl, tert-butyl, methoxymethyl, ethoxymethyl, or optionally substituted with benzyl such as pmethoxybenzyl, p-nitrobenzyl), cyano, etc.] can be used as synthetic intermediates.

Of the above groups represented by R ² , the most preferred are tetrazolyl groups optionally substituted by lower alkyl or alcyl; carboxyl groups optionally substituted with alkyl; and trifluoromethanesulfonic acid amide.

Carboxyl, esters thereof and amides shown in R 'are examples of groups having the formula: -CO-D' wherein D 'is hydroxyl, optionally substituted amino group (for example, amino, N - the lower (C _x _ ₄₎ alkylamino, N, Ndi lower (C _x _ ₄₎ alkylamino and 1.1., and optionally substituted alkoxy group [for example, lower (C ^ g) alkoski alkyloxy optionally substituted with hydroxy, optionally substituted amino group (for example, amino, dimethylamino, diethylamino, piperidino, , morpholino, etc.), halogen, lower (Ο ₇ _ ₆₎ alkoxy, lower (Οχ, β) alkylthio or optionally substituted dioxolenyl (for example, 3-methyl-2-oxo-l, 3-dioxolen-4-yl and the like) in the alkyl moiety and a group of formula: -OCH (R ⁷ ) OCOR ⁸ where R ⁷ is hydrogen, straight or branched lower alkyl having 1 or 6 carbon atoms (e.g., methyl, ethyl, n-propyl). , isopropyl, isopentyl, neopentyl, etc.) or cycloalkyl having 5 or 7 carbon atoms (e.g., cyclopentyl, c cyclohexyl, cycloheptyl, etc.) and R is straight or branched lower alkyl having 1 or 6 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, t-butyl, n- heptyl, isopentyl, neopentyl, etc.), straight or branched lower alkenyl containing from 2 to 8 carbon atoms (e.g., vinyl, propenyl, 2-butenyl, 3-butenyl, isobutenyl, octenyl, etc.), cycloalkyl with 5- 7 carbon atoms (for example, cyclopentyl, cyclohexyl, cycloheptyl and the like.), lower (C? ₃₎ alkyl (such as methyl, ethyl, n-propyl, isopropyl and the like.), which is substituted by an optionally substituted aryl or cycloalkyl with 5 7 carbon atoms (e.g., cinnamyl, etc.), optionally substituted aryl (e.g., phenyl, n-toluene, naphthyl, etc.), straight or branched lower alkoxy with 1 or 6 carbon atoms (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, secondary-butoxy, t-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy and the like), straight or branched lower alkenyl containing from 2 to 8 carbon atoms (e.g., allyloxy, isobutenyloxy, etc.), cycloalkyloxy 5-7 carbon atoms (e.g., cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, etc.), lower (C _{x 3} ) alkoxy (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, etc.) substituted with optionally substituted aryl, or cycloalkyl with 5-7 carbon atoms (for example, benzyloxy, phenethyloxy ciklopentilmetiloksi, cikloheksimetiloksi and the like.), lower (C _{2nd 3} ) alkenyloxy (e.g., vinyloxy, propenyloxy, allyloxy, isopropenyloxy, etc.) which is substituted with optionally substituted aryl or cycloalkyl with 5 to 7 carbon atoms (e.g., cinnyloxy, etc.) optionally substituted with aryloxy (e.g., phenoxy, n) -nitrophenoxy, naphthoxy, etc.). Group capable of forming anion or groups which can be the anion of the examples shown in R 'is, for example, tetrazolyl groups optionally protected by optionally substituted lower alkyl, such as lower (C _x _ ₄₎ alkyl and lower (C _x _ ₄₎ alkoksižemesnis (C _x _ ₄₎ alkyl or acyl, such as lower (C _2-5) alkanoyl; and optionally substituted benzoyl, trifluoromethanesulfonamyl, phosphoric acid, sulfuric acid and the like. Examples of R ¹ substituents include -COOH and their salts -COOMe, -COOEt, -COOtBu, -COOPr, mustyloxymethoxycarbonyl, 1- (cyclohexyloxycarbonyloxy) ethoxycarbonyl, 1- (cyclohexyloxycarbonyloxy) ethoxycarbonyl, 5-methyl-2-oxy-1,3- -4-ylmethyloxycarbonyl, acetoxymethyloxycarbonyl, propionyloxymethoxycarbonyl, n-butyryloxymethoxycarbonyl, isobutyryloxymethoxycarbonyl, 1- (ethoxycarbonyloxy) ethoxycarbonyl, 1- (acetyloxy) ethoxycarbonyl, benzoxymethoxycarbonyl, cyclohexyloxycarbonyl, cyclohexyloxycarbonyl, cyclohexylmethylcarboxylic Said groups may also contain groups which may form anions (e.g., -COO-, their derivatives, etc.) or groups which may become anions under appropriate chemical or biological and / or physiological conditions (e.g., in vivo reactions). such as oxidation-reduction reaction or enzyme-catalyzed hydrolysis in vivo).

A benzene ring A which may be substituted on the R 'group with halogen (e.g. F, Cl, Br, etc.); nitro; cyano; optionally substituted amino group (e.g., amino, lower (C _{x -4} ) alkylamino such as methylamine and ethylamino, N, N-di-lower (C _{x -4} ) alkylamino such as dimethylamino and diethylamino, N-arylamino such as phenylamino and naphthylamino, N-aralkylamino such as benzylamino and naphthylmethylamino, an alicyclic amino group such as morpholine, piperidine piperazine and N-phenylpiperazine] having the formula: -W-R ¹³ where W is a chemical bond, -0-, -S-, or -C-,

And R ¹³ is hydrogen or optionally lower alkyl (e.g. lower (C _{x 4} ) alkyl optionally substituted with hydroxyl, optionally substituted with amine (e.g., amine, dimethylamine, diethylamine, piperidine, morpholine, etc.), halogen or lower (C _x _ ₄₎ alkoxy and etc.). a group of the formula: - (CH _{2) p} -CO-D wherein D is hydrogen, hydroxy, optionally substituted amino group (for example, amino, N-lower (C _x _ ₄₎ alkylamino, N, N-di-lower (C _x _ ₄₎ alkylamino, etc.)., or optionally substituted alkoxy (for example, lower (C _x _ ₄₎ alkoxy optionally substituted with hydroxy, optionally substituted amino group (for example, amino, dimethylamino, diethylamino, piperidino, morpholino, and etc.)., halogen, lower (C _x _ ₆₎ alkoxy, lower (C _x _ ₆₎ alkilitio or optionally dioksolinilu (such as 5-methyl-2-oxo-l, 3dioksolen-4-yl, etc.). and groups having the formula: -OCH (R) OCOR, wherein R is hydrogen with straight or branched lower alkyl having from 1 to 6 carbon atoms (e.g., methyl, ethyl, nLT 3246B butenyl, cycloalkyl propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, etc.) or cycloalkyl with 5-7 carbon atoms s (e.g., cyclopentyl, cyclohexyl, cycloheptyl, etc.), and R ¹⁰ is straight or branched lower alkyl of 1 to 6 carbon atoms (e.g., methyl, ethyl, npropyl, isopropyl, n-butyl, isobutyl, secondary butyl, t -butyl, n-pentyl, isopentyl, isopentyl, neopentyl, etc.), straight or branched lower alkenyl containing from 2 to 8 carbon atoms (e.g. vinyl, propenyl, 2-butenyl, 3-isobutenyl, octenyl, etc.), with 5-7 carbon atoms (for example, cyclopentyl, cyclohexyl, cycloheptyl and the like.), lower _(τ 0 _ ₃₎ alkyl (such as methyl, ethyl, npropilas, isopropyl and the like.), which is substituted by an optionally substituted aryl or cycloalkyl with 5 -7 carbon atoms (e.g. benzyl, p-chlorobenzyl, phenethyl, cyclopentylmethyl, cyclohexylmethyl, etc.), lower (C ₂ . ₃ ) alkenyl (e.g., vinyl, propenyl, allyl, isopropenyl, etc.) which is substituted with optionally substituted aryl or cycloalkyl with 5-7 carbon atoms (e.g., cinnamyl, etc.), optionally substituted with aryl (e.g., phenyl, ptoluene) , naphthyl, etc.), straight or branched alkoxy having from 1 to 6 carbon atoms (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, di-butoxy, t-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy and the like), straight or branched lower alkenyloxy having from 2 to 8 carbon atoms (e.g., allyloxy, isobutenyloxy, etc.), cycloalkyloxy with 5 to 7 carbon atoms (e.g., cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and the like). lower alkoxy (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, etc.) which is substituted with optionally substituted aryl or cycloalkyl with 5-7 carbon atoms (e.g. benzyloxy, phenethyloxy, cyclopentylethyloxy, cyclohex). silyloxy and the like), lower (C ₂ - ₃ ) alkenyloxy (e.g., vinyloxy, propenyloxy, allyloxy, isopropenyloxy, etc.) which is substituted with optionally substituted aryl or cycloalkyl with 5-7 carbon atoms (e.g., cinnamoyloxy and the like). ) optionally substituted with aryloxy (e.g., phenyloxy, pnitrophenoxy, naphthoxy, etc.), op equal to 0 or 1; tetrazolyl optionally protected, for example, optionally substituted lower alkyl (for example, a lower (C _x _ ^) alkoxymethyl, optionally substituted arylmethyl and the like.), or acyl (eg lower (C ₂ _ ₅₎ alkanoyl, optionally substituted benzoyl and the like. ); trifluoromethanesulfonic acid amide, phosphoric acid; sulfuric acid and the like.

One or two of the above substituents may be present at various positions on the benzene ring. When two substituents at the 4- and -5 or -5 and -6 positions are present in the ring, they may together form a ring (e.g., benzene, etc.). Said rings may be replaced by groups analogous to ring A substituents.

X means that the mixed phenylene and phenyl groups are bonded either directly to each other or via a linking group to a chain of 2 or less atoms. The spacer group may be any divalent bond in which the number of atoms forming a straight chain is equal to 1 or 2; this group may also have a side chain. Examples of said intermediate groups may be lower (C 1 -C 3 alkylene, 'C 1 - O -, - S - N - C - N - O - C -, - S - C -, - C - C -,

I | I II I | III ^and P ^an · o

Preferably, X is a chemical bond between phenylene and phenyl groups.

Y means that R ¹ is attached via the ¹ heteroatom to the 2 positions of the benzimidazole. Examples of Y are -0-, -S · ra, where m is 0, 1 or 2; -N (R ⁴ ) - wherein R ⁴ is hydrogen or optionally substituted with a lower (·. 4) alkyl group, etc., preferably -O-, -S- and -NH-, more preferably -O- and - S-, and particularly well -O- R ¹ and R ⁴ taken together with the N atoms to which they are attached form a heterocyclic ring (e.g., piperidine, morpholine, etc.).

When R ¹ is equal to H, the compounds of formula (I) [Compounds (I)] may exist in two tautomeric forms.

If the compounds of the present invention have multiple asymmetric carbon atoms, they may exist in several stereochemical forms. The present invention also includes mixtures of isomers and stereoisomers. The invention includes geometric isomers, rotational isomers, enantiomers, racemates and diastereomers.

The compounds of the present invention may exist in the form of prodrugs wherein R 'is a carboxyl or an anion derived therefrom.

Among the compounds represented by formula (I), the most preferred compounds are those of formula (I ')

R

wherein R 'is lower (Cy_ ₅₎ alkyl optionally substituted by hydroxy, amino, halogen or lower (C _X - ₄₎ alkoxy group (inter alia, a lower (C _2-3) alkyl; R' is -CO-D ' wherein D 'is hydroxy, amino, N-lower (C _{x- 4} ) alkylamine, N, N-di-lower (C _{x- 4} ) alkylamine or lower (C _x - ₄ ) alkoxy optionally substituted with hydroxy; halogen, lower (C _x _ ₄₎ alkoxy, lower _{(C2. 6)} alkanoyloxy (eg acetyloxy, pivaloyloxy and the like.), or 1-lower C _{(first 6)} alkoxycarbonyloxy (eg Methoxycarbonyloxy, ethoxycarbonyloxy, cyclohexyloxycarbonyloxy and , etc.) in the alkyl portion, or tetrazolyl optionally protected by an optionally substituted lower (C _x _ ₄₎ alkyl, or an acyl group (e.g. a lower (C ₂ _ ₅₎ alkanoyl, benzoyl, etc.). R ² is tetrazolyl optionally protected by an optionally substituted lower (C 1-4) alkyl (e.g. methyl, triphenylmethyl, trityl, methoxymethyl, ethoxymethyl, p -metoksibenzilu, p-nitrobenzyl and the like.), or acyl (eg lower (C ₂ _ ₅₎ alkanoyl, benzoyl and the like.), or carboxyl optionally protected by an optionally substituted lower (Ci- ₄₎ alkyl (for example, methyl, triphenylmethyl , trityl, methoxymethyl, ethoxymethyl, pmethoxybenzyl, p-nitrobenzyl and the like); R is hydrogen, halogen, lower (C _x _ ₄₎ alkyl, lower (C _x _ ₄₎ alkoxy, nitro or -CO-D, wherein D is hydroxyl or a lower (C ₂ _ _x) alkoxy optionally substituted by hydroxy, lower ( C _x _ ₄₎ alkoxy, lower _{(C2. 6)} alkanoyloxy (eg acetyloxy, pivaloyloxy and the like.), or 1-lower (C _x _ ₆₎ alkoxycarbonyloxy (eg Methoxycarbonyloxy, ethoxycarbonyloxy, cyclohexyloxycarbonyloxy, etc.). the alkyl portion ; or amino optionally substituted with lower (C _x _ ₄₎ alkyl (for example, hydrogen, a lower (C _V4) alkyl or halogen, and more preferably hydrogen); Y is -O-, -S-, or -N (R ⁴ ) - wherein R ⁴ is hydrogen or lower (C _{x 4} ) alkyl; or a pharmaceutically acceptable salt thereof.

Compounds (I) can be prepared using the reactions shown in the schemes below.

Scheme A

R ¹

II wherein R ¹ , R ² , R ', X, Y and n have the meanings given above and Z is halogen.

Scheme B

(CH

N.

'N

N, NH

Ib where each group has the above meanings

Scheme C

·>

COOH

.®I> -y · 'N

-R *

Id

where R ¹ , R ', A, X, Y and n have values, and R ⁵ is optionally (Cg. ^) Alkyl.

the above replaced by the lower one

Scheme D

where each group has the above meanings

Scheme E

If where each group has the above values

where each group has the above meanings

LTS 6 B

IV

Scheme G

-> i® £ /> “SH

R ²

Ih where each group has the above meanings

Scheme H

where each group has the above meanings

Scheme I

where each group has the above meanings

where each group has the above meanings

Scheme I

where each group has the above meanings

Scheme J

Ij

Wherever each group has the above meanings

Scheme K

where each group has the above meanings

Scheme L

Ip wherein A, R, R ^1, X, Y and n are as defined above and R ⁶ is lower (C _x _ ₆₎ alkyl, optionally substituted lower (C _{2nd 6)} alkanoyloxy, 1žemesne (C ^ J alkoksikarboniloksi- group or group R '.

The reaction depicted in Scheme A is alkylation using an alkylating agent in the presence of a base. 1-3 M base and 1-3 M alkylating agent are used per mol of Compound (II). The reaction is usually carried out in solvents such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, acetone, ethylmethylketone and the like. examples include sodium hydride, potassium t-butoxide, sodium carbonate and examples of agents include tetrahydrofuran, examples of bases carbonate, potassium, etc. Alkylating halides (for example, chlorides, bromides, iodides, etc.), substituted sulfuric acid esters (for example, toluene sulfuric acid esters, etc.). The reaction conditions may be varied depending on the combination of base and alkylating agent. Preferably, the reaction is carried out for 1 to 10 hours, from ice-cooling to room temperature.

In said alkylation reaction, a mixture of two isomers (I) and (I ') may be obtained in a ratio depending on the N position of the alkylating atom. Because the ratio of the resulting compounds (I) to (1 ') varies depending on the reaction conditions and substituents on the benzimidazole ring, these two compounds can be readily obtained as pure products using standard separation and / or purification techniques (e.g. crystallization, chromatography). column, etc.).

As shown in Scheme B, the nitrile compound (la) reacts with various azides to form tetrazole compounds (Id). 1-5 M azide is used in 1 M compound (Ia). The reaction is usually carried out in solvents such as dimethylformamide, dimethylacetamide, toluene, benzene and the like. Examples of azides are trialkyl azide (e.g. trimethyl azide, tributyl azide, triphenyl azide, etc.), hydrogen azide and its ammonium salts, and the like. When tin organic compound azide is used, compound (Ia) is present in 1-4 M azide and the reaction is carried out for 1 to 4 days in toluene or benzene under reflux.

When hydrogen azide or its ammonium salts are used, 1-5M sodium azide and ammonium chloride and triamine (e.g. triethylamine, tributylamine, etc.) are present in compound (Ia) and the reaction is carried out in dimethylformamide at 100 ° C to 120 ° C. days. To facilitate the reaction, it is best to add an appropriate amount of sodium azide and ammonium chloride during the reaction. In this case, an increase in the yield is sometimes observed when appropriate fractions of the azide compound are added.

As depicted in Scheme C, the ester (Ic) is hydrolyzed in the presence of alkali to give the carboxylic acid (Id). The aforesaid reaction is usually carried out in a solvent such as aqueous alcohol (e.g. ethanol, methanol, ethylene glycol monomethyl ether, etc.) using 1-3 M alkali in 1M of compound (Ic). Examples of alkali include sodium hydroxide, potassium hydroxide and the like. Said reaction is carried out for 1 to 10 hours at 100 ° C and preferably for 2 to 5 hours at the reflux temperature of the solvent.

As depicted in Scheme D, the 2-alkoxy derivative (Ie) is obtained by reaction of phenylenediamine (IV) and alkyl orthocarbonate. The reaction is carried out in the presence of acid and using 1-3 M alkylotocarbonate of 1M compound (IV). Examples of said alkyl carbonates include methyl, ethyl, propyl, isopropyl, butyl and the like. orthocarbonates. And, for example, the use of acetic acid or ptoluene sulfuric acid accelerates the reaction and increases the yield of the resulting ring-closed compounds. Solvents may include halogenated hydrocarbons and ethers, but the reaction is usually carried out in a solvent-free manner, as a rule, for 1 to 5 hours at 70 to 100 ° C. The dialkoximine compounds obtained in the above reaction are intermediates which are used immediately in the presence of an acid in the ring closure reaction to give the 2-alkoxy compounds (Ie).

It is also possible to isolate the intermediates of the reaction, which are then used in the ring closure reaction in the presence of an acid to form the 2-alkoxy (Ie).

Scheme E illustrates the reaction of phenylenediamine compounds (IV) with various reagents to give 2-keto (or 2-hydroxy) compounds (1f). The reaction is carried out using 1 to 5 M carbonylating agent (e.g. urea) in 1M compound (IV). , diethyl carbonate, bis (1-imidazollyl) ketone, etc.) and using, for example, halogenated hydrocarbons (such as methylene chloride, chloroform, etc.), alcohols (such as methanol, ethanol, etc.) or amides (such as dimethylformamide, dimethylacetamide, etc.).

Scheme F shows the selective O-alkylation of the 2-hydroxy compound (1f) using Meerwein's reagent to give the 2-alkoxy compound (Ig). The aforesaid reaction is carried out using 1 to 3 M Meerwein's reagent 1M compound (lf) as well as the use of halogenated hydrocarbons (e.g., methylene chloride, chloroform, etc.) and ethers (e.g., methyl ether, ethyl ether, etc.). ). Examples of Meerwein's reagent include trimethyloxonium fluoroborate (Me ₃ O ⁺ BF 4 '), tretyloxonium fluoroborate (Et 3 ⁺ BF 4 ~) and the like. For in situ production, it is best to use the method described in the literature (H. Meerwein, Org.Syn. 46,113 and 120 (1966). The reaction is preferably carried out for 2 to 20 hours, from room temperature to the boiling point of the solvent.

Scheme G depicts the reaction of phenylenediamine compound (IV) with various reagents in an organic solvent to give 2-mercapto compound (Ih). The 1 M phenylenediamine compound (IV) utilizes 1-3 M thiocarboLT 3246 B diluent (e.g., carbon disulfide, thiourea, potassium xanthate, etc.) or isothiocyanate (e.g., methyl isothiocyanate, ethyl isothiocyanate, etc.). Reaction solvents may include alcohols (e.g., methanol, ethanol, etc.), amides (e.g., dimethylformamide, dimethylacetamide, etc.) or the like. The preferred reaction is from room temperature to the boiling point of the solvent, from 5 to 20 hours.

Scheme H depicts the alkylation of 2-mercapto compound (Ih) in the presence of an organic, base-based solvent to give the alkylthio compound (II). The reaction is carried out using 1M of compound (Ih) in a 1-3 M alkylating agent in a solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, acetone, ethylmethylketone, ethanol, methanol and water. The base may include sodium hydroxide, potassium carbonate, sodium carbonate, sodium hydride, potassium t-butoxide, potassium hydroxide and the like. The alkylating agent may be, for example, a halide (such as methyl iodide, ethyl iodide, propyl iodide, butyl iodide or their bromide and chloride). The aforesaid reaction is usually carried out from ice-cooling to the boiling point of the solvent, and the reaction conditions are varied depending on the bases, alkylating agents and solvents used.

Scheme I depicts the reaction of phenylenediamine (IV) with isothiocyanate to form thiourea (V), which is then subjected to desulfurization-cyclization to afford the 2-substituted amino compound (Ij). The aforesaid reaction is carried out using 1-3 M isothiocyanate of 1 M compound (IV) in a solvent such as halogenated hydrocarbons (e.g. chloroform, methylene chloride, etc.), ethers (e.g. tetrahydrofuran, hydrocarbons other), alcohols other), acetonitrile, The reaction may be carried out with dioxane and others) (e.g. benzene, (e.g. methanol, aromatic toluene and ethanol and dimethylformamide, etc., and solvent-free. Examples of said isothiocyanates are methyl, ethyl, propyl, isopropyl, butyl isothiocyanates, etc.). when the reaction is carried out for 10-60 hours, from room temperature to 50 [deg.] C. The desulfurization-cyclization can be carried out as described below.

The reaction is carried out on halogenated hydrocarbons (e.g. HgCl ₂ ) using 1-3 M metal halide (e.g. HgCl ₂ ) 1 M urea (V) obtained as described above. Preferably, the reaction is carried out for 3 to 10 hours, from room temperature to the reflux temperature of the solvent. The reaction can also be carried out using 1-3 M methyl iodide in 1 M urea (V) alcohol (e.g. methanol or ethanol), preferably for 3-15 hours, starting at room temperature to the reflux temperature of the solvent.

As shown in Scheme I ', the 2-halogenated compound can be readily obtained from compound (If) by reaction of this compound with various nucleophilic reagents to form compound (I). The above reaction can be carried out in a standard manner (e.g., D. Harrison, T.I. Ralph, J. Chem. Soc. 1965, 236. The compound (If) is reacted with a halogenating agent (e.g., phosphorus oxychloride, phosphorus trichloride, etc.) to form 2 -halo compound (V ') which reacts with various nucleophilic reagents (e.g., alcohols, mercaptans, amines, etc.) in the appropriate organic solvent to form compound (I) The reaction conditions may be varied depending upon the use of the nucleophilic reagent. when the reaction utilizes alcohols, alcoholates (e.g., sodium methoxide, sodium ethoxide, sodium propoxide, etc.) consisting of alcohol and metallic sodium Alcohols can be used as a solvent for nucleophilic reagents. The reaction is preferably carried out at the reflux temperature of the solvent for about 1-3 hours, and 3-10 M of amine is used in the reaction with the 1 M compound (V). Alcohols may be used as the solvent, but then there must be an excess of amine. The reaction is preferably carried out for 1 to 10 hours at a temperature ranging from the boiling point of the solvent to 150 ° C. In the reaction with mercaptans, 2-5 M mercaptan is used in 1 M compound (V). Preferably, the reaction is carried out in the presence of 1 M compound (IV) of 1-3 M base (e.g., sodium carbonate, potassium carbonate, etc.). Examples of solvents include acetonitrile, alcohols, halogenated hydrocarbons (e.g., chloroform, dichloroethane, etc.), ethers (e.g., tetrahydrofuran, dioxane, etc.) or amides (e.g., dimethylformamide, dimethylacetamide, etc.). The reaction is preferably carried out for 1 to 5 hours, at a temperature between 50 ° C and the boiling point of the solvent.

In Scheme I, compound (Ih) is reacted with an oxidizing agent (e.g., m-chlorperbenzoic acid, etc.) to form a sulfoxide or sulfonium compound (Ih ') which reacts with various nucleophilic reagents (e.g., alcohols, amines, mercaptans, etc.). thanks to which compound (I) is obtained. The oxidation of compound (Ih) to the sulfoxide or sulfonic compound (Ih ') is preferably carried out in solvents such as halogenated hydrocarbons (e.g., dichloromethane, chloroform, chloroethane, etc.), ethers (e.g., tetrahydrofuran, dioxane, etc.) and the like. Examples of said oxidizing reagents include organic acids such as m-chloroperbenzoic acid, N-halo-succinimides such as NLT 3246 B bromo-succinimide and a slight excess of the oxidizing reagent, and the like. Usually, the amount used is equal to or relative to the amount of compound (Ih). The sulfoxide can be prepared using 1 M oxidizing agent and the sulfonic compound (Ih ') using 2 M oxidizing agent. The reaction is preferably run for 3 to 10 hours, from ice-cooling to room temperature.

The reaction of compound (Ih ') to give compound (I) is carried out in a manner analogous to Scheme 1'.

Scheme J depicts the preparation of carboxylic acid (Ik) by hydrolysis of the base compound (Ij) and the carboxylic acid ester. The reaction is carried out using 1-3 M alkaline 1 M compound (Ij), typically in a solvent such as aqueous alcohol (methanol, ethanol, ethylene glycol monomethyl ether, etc.). Examples of said alkali include sodium hydroxide, potassium hydroxide and the like. The reaction is preferably carried out for ΙΙΟ hours, from room temperature to 100 ° C, and preferably for 3-5 hours at the boiling point of the solvent.

Scheme K shows deprotection of a protected tetrazole derivative (II) to give compound (Im). The above conditions for deprotection depend on the subsequent use of the blocked group (R). If R is triphenylmethyl, 2-tetrahydropyranyl, methoxymethyl, ethoxymethyl or the like, the reaction is carried out in aqueous alcohol (e.g. methanol, ethanol, etc.) containing 0.5 N-2 N hydrochloric acid or acetic acid at room temperature for 1-10 hours. .

Scheme L illustrates the preparation of compound (Ig) by protection of a tetrazole group in the presence of a base followed by the carboxyl group to afford the ester compound (lp) followed by removal of the protecting group in acidic medium. In the reaction to give compound (lo) from compound (ln), 1 to 1.5 alkylating agent of compound (ln) is used. Examples of solvents used in the reaction include halogenated hydrocarbons such as chloroform, methylene chloride and ethylene chloride; ethers such as dioxane, tetrahydrofuran, acetonitrile, pyridine and the like. Examples of bases include potassium carbonate, sodium carbonate, triethylamine, pyridine and the like. Examples of alkylating agents include halides such as triphenylmethyl chloride and methoxymethyl chloride and the like. Because the reaction conditions vary with the combination of base and alkylating agent, the reaction is preferably carried out using triphenylmethyl chloride for 1-3 hours, from ice-cooling to room temperature in methylene chloride in the presence of triethylamine. In the reaction whereby compound (1p) is obtained from compound (lo) thus obtained, 1-3 M of alkylating agent is used in 1M of compound (lg). Examples of reaction solvents include amides such as dimethylformamide and dimethylacetamide, acetonitrile, dimethylsulfoxide, acetone, ethylmethylketone, and 1.1. Examples of bases include potassium carbonate, sodium carbonate, sodium hydride, potassium t-butoxide and the like. Examples of said alkylating agents include halides such as cyclohexyl 1-iodoethyl carbonate, ethyl 1-iodoethyl carbonate, pivyloxymethyl iodide and the like. Since the reaction conditions vary with the combination of base and alkylating agent, it is preferable that the reaction of compound (lo) be carried out in dimethylformamide (DMF) with the addition of an alkylating agent in the presence of potassium carbonate for 30 minutes to 1 hour at room temperature.

The deprotection reaction of the compound (lp) thus obtained is preferably carried out in a manner analogous to the reaction (K). If a trityl group is used as the protecting group for the tetrazole group, the reaction is preferably carried out in methanol or ethanol by addition of 1N-HCl for 30 minutes to 1 hour at room temperature.

By the reactions described above (A) - (L), the resulting products can be readily isolated and / or purified by standard techniques such as evaporation of solvent, extraction with water or organic solvents, concentration, neutralization, crystallization, distillation, column chromatography and 1.1. . Compound (I) obtained by the reactions described in Schemes (A) (L) may be isolated and / or purified from the reaction mixture by standard techniques such as crystallization or column chromatography to give crystalline products.

The compounds obtained by the reactions described in Schemes (A) to (L) may be solvates or salts derived from pharmaceutically or physiologically acceptable acids or bases. Examples of such salts include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid as well as organic acids such as acetic acid, oxalic acid, succinic acid. , citric acid, ascorbic acid, lactic acid, ptoluenoic acid, methanesulfonic acid, fumaric acid, tartaric acid and maleic acid. Other examples of salts may also include salts of ammonium, alkali metals or alkaline earth metals such as sodium, potassium, calcium or magnesium, or salts with organic bases such as trialkylamine, dibenzylamine, ethanolamine, triethanolamine, methylmorpholine and the like.

Compounds (I) can be obtained by using standard methods as salts with non-toxic, physiologically or pharmaceutically acceptable acids and bases, for example salts with inorganic acids such as hydrochloride, sulfate or nitrate, and depending on the compound as salts with organic acids such as acetate, oxalate, succinate or maleate; alkali metal salts such as sodium and potassium salts; or alkaline earth salts such as calcium salts.

The starting compounds (II) and (IV), which may be obtained by the methods described in the literature below, or analogous to those depicted in Schemes (M), (N), (O) and (P) below, are used for the synthesis of said compounds (I).

(1) P.N. Preston, The Chemistry of Heterocyclic Compounds, vol. 40, P.N. Preston, John Wiley & Sons Ine., New York (1981), p. 1-286, (2) E.S. Schipper and A.R. Day, Heterocyclic Compounds, vol. 5, R.C. Elderfield, John Wiley & Sons Ine., New York (1965), p. 194-297, (3) N.J. Leonard, D.Y. Curtin, & K.M. Beck, J. Am. Chem.Soc. 69,2459 (1947), (4) S. Weiss, H. Michaud, H. Prietzel, & H. Kromer, Angew. Chem. 85, 866 (1973), (5) W.B. Wright, J. Heterocycl. Chem., 2.41 (1965), (6) A.M.E. Omar, Synthesis, 41, (7) d.J., 1974. Brown & R.K. Lynn, J. Chem.Soc. (Perkin I), 349, 1974, (8) J.A. Van Allan & B.D. Deacon, Org.Syn., 30.56 (1950), (9) S.P. Singh, S.S. Parmar & B.R. Pandey, J.

Heterocycl. Chem., 14, 1093 (1977), (10) S. Nakajima, I. Tanaka, T. Seki & T. Anmo, Yakugaku Zashi, 78, 1378 (1959), (11) K. Seno, S. Hagishita, T. Shato & K. Kuriyama, J. Chem.Soc., Perkin Trans. (1984), 2013, (12) D.R. Buckle et al., J. Med. Chem., 30, 2216 (1987), (13) R.P. Gupta, C.A. Larroąuette & K.C. Agrawal, J. Med. Chem., 25, 1342 (1982), et al.

Scheme M

VI \ VII

CON,

IV wherein R ² , R ', A, X and n have the meanings given above and R ³ is a lower (C 1-4) alkyl group.

Scheme M '

R

H, N- (CH,) .- ^^> - X - ^> n · ((JH,). Illb

N0 _;

R '

ί®Ί

H

NCOOR ^; • NO:

NH NO, XII

OHC— ©> "

R ²

IV

NH,

NO:

X

IIIc l Z'C- (CH,) .. ₁ Hy> -X - ^>

9, ^HId ^ νη-ο '- ^ ηω., Τ - ^ - χ-Ο j

'NH,

IV

3 wherein R, R, R ', A, Z, X and n have the meanings given above.

Schemes M and M 'illustrate a route for the preparation of important intermediates used in the synthesis of compound (I).

These compounds can be obtained by the methods described above. The Curtius reaction of compound (VI) yields the carbamic acid (X), followed by alkylation followed by reduction of the nitro compounds to give the diamine compound (IV). The rearrangement of compound (VI) to compound (X) yields a high yield compound (X) following the standard Curtius regrouping: Chloro Anhydride (VII) -> Acid Azide (VIII) -> Isocyanate (IX) - »Compound (X) ). Compound (VI) is usually heated with diphenylphosphoryl azide (DPPA) in the presence of triethylamine dimethylformamide (DMF), which results in the formation of isocyanate (IX) by azoic acid (VIII), which is subsequently reacted with alcohol to form the compound (X). ) with a high yield. The compound (X) thus obtained is alkylated in a manner analogous to that depicted in Scheme A to give compound (XI). In the aforesaid reaction, the reaction mixture is heated to reflux for 4 to 6 hours in the presence of a base, namely potassium carbonate in acetonitrile. Reflux Compound (XI) in a refluxing vessel, in an alcohol containing mineral acid (e.g., hydrochloric acid, sulfuric acid, etc.) or organic acid (trifluoroacetic acid, etc.) for about 1-2 hours, resulting in the compound (XI). XII). Various reducing agents (e.g., nickel skeleton catalyst, ferric chloride, etc.) can be used to reduce the nitro compound (XII) to the diamine compound (IV). Therefore, it is best to use ferric chloride and hydrazine hydrate in alcohol. In addition, compound (IV) may be obtained by other routes than those mentioned above.

Compound (X ') can be purchased or readily obtained by methods known in the art, preferably by reaction with an amine (Illb) in the presence of a base (e.g. potassium carbonate, sodium carbonate, amine, etc.) in an organic solvent (e.g., alcohols, ethers). , halogenated hydrocarbons, amides, etc.) at temperatures ranging from solvent to 100 ° C for 5-20 hours.

Compound (X), which may be obtained by treating compound (X) with an acid, is condensed under dehydration conditions including azeotropic removal of water (or in the presence of a dehydrating agent) in an organic solvent (e.g., ethers, halogenated hydrocarbons, etc.). a subsequent reaction with reducing agents (e.g. NaC NBH ₃ , etc.) to give compound (XII). Said condensation under dehydration conditions can be accelerated using appropriate acid or base catalysts.

Compound (X) is reacted with chloro anhydrides (IIld), preferably in the presence of a base (e.g., pyridine, triethylamine, dimethylaminopyridine, etc.), in an organic solvent (e.g., halogenated hydrocarbons, pyridine, etc.) at a temperature of 2 to 20 hours. from room temperature to about the reflux temperature of the solvent, resulting in the formation of an amide (XI). The amide (XI) thus obtained is reacted with a reducing agent (e.g., sodium aluminum hydride, bis (2-methoxyethoxy) sodium aluminum hydride, etc.) to give the diamine compound (IV).

Scheme N

R '

NH:

->

NH ₂

XIV where each group

* L®ly / -s — r ¹

Ha

XIII has the above meanings

Scheme O

XIV [®I 7-or ^k S

Ilb where each group has above

The values given in Scheme P

R '

XIV

IIc.

where each group has above

From the starting compounds (III), the compound wherein n = 1, that is, the compound (IIIa), can be purchased or can be readily obtained by the halomethylation of compound (XV) as described in the literature, for example:

1) J.R. Hoover, A.W. Chow, R.J. Stedman, N.M. Hali, H.S. Greenberg, M.M. Dolan, R.J. Feriauto, J. Med. Chem., 7,245 (1964),

2) R.J. Stedman, J.R.E. Hoover, A.W. Chow, M.M. Dolan, N.M. Hali, R.J. Feriauto, J. Med. Chem., 7,251 (1964),

3) H. Gilman, R.D. Gorsich, J. Am.Chem.Soc., 78, 2217 (1956),

4) M. Orchin, E. Oscar Woolfolk, J..

122 (1945) et seq.

Am. Chem. Soc.,

XV

Scheme Q

Illa where each group has the above meanings.

The compound (IIla ') can also be readily obtained by the method described by L.N. Bridgen, L. Snyoler, J. Prol, Jr., J. Org.Chem., 54,1523, (1989), in works as shown

In Scheme R with subsequent halogenation (R ¹² = Me) or halomethylation (R ¹² = H)

Scheme R

wherein R is hydrogen or methyl.

From the starting compounds (III), the compound wherein n = 2, that is the compound (IIIb), can be obtained according to the reaction shown in Scheme S.

Scheme S

VTb where each group can have the values above.

The compounds and groups thus obtained are less toxic and are potent inhibitors of the vasoconstrictor and hypertensive angiotensin II which can be used as drugs in animals, mostly mammals (e.g. humans, dogs, rabbits, pigs, rats, etc.), not only hypertension. , but also for the treatment of diseases associated with circulatory disorders such as heart failure (cardiac hypertrophy, heart attack, etc.), shock, stroke, nephropathy and nephritis. Compounds (I) and salts thereof according to the present invention are potent inhibitors of vasoconstrictor and hypertensive angiotensin II and therefore exhibit hypotensive activity when administered to animals, particularly mammals (e.g., humans, dogs, pigs, rabbits, rats, and etc.). In addition, Compounds (I) and their salts are extremely low toxic and therefore are of particular clinical value as drugs not only for hypertension but also for cardiovascular diseases such as cardiovascular disorders, shock, renal failure, nephritis and 1.1. , treat.

For therapeutic purposes, the compounds (I) and their salts may be administered orally, parenterally, rectally, by inhalation or topically, as pharmaceutical compositions or preparations (e.g., powders, granules, tablets, peas, capsules, solutions, syrups, emulsions, elixirs). suspensions, injection solutions, etc.) containing at least one compound taken alone or in admixture with a pharmaceutically acceptable carrier, adjuvant, excipient and / or diluent. Said pharmaceutical compositions may be formulated according to the relevant standards of pharmaceutical technology. The term parenteral administration as used in the specification refers to subcutaneous, intravenous, intramuscular, intraperitoneal or infusion administration. Injectable preparations, for example, sterile aqueous or oleaginous suspensions may be formulated in a standard manner using appropriate dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be formulated as sterile injectable solutions or suspensions for injection in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in water. Suitable fillers and diluents may be water, Ringer's solution, isotonic sodium chloride solution. Additionally, suspending media may be sterile fatty oils. Any fatty oils or fatty acids may be used for these purposes, including natural, synthetic and equilibrium fatty oils or acids, and natural, synthetic or equilibrium mono-, di-, or triglycerides.

Suppositories for rectal drug delivery can be obtained by mixing the active ingredient with a suitable non-irritating excipient such as cocoa oil and polyethylene glycol, which are solid at room temperature and melted to the rectum upon administration into the rectum while releasing the drug. . Solid unit dosage forms suitable for oral administration may take the form of powders, granules, tablets, pellets, and capsules. In said solid dosage forms, the active component may be present as a mixture with at least one additive such as sucrose, lactose, cellulose, mannitol, maltitol, dextran, starch, agar, alginates, chitin, chitosan, pectin, tragacanth, gelatine, gum arabic. , collagens, casein, albumin and synthetic or equilibrium polymers or glycerides. Said dosage forms may contain, in addition to inert diluents and other additives, such as lubricating agents such as magnesium stearate; preservatives such as parabans and sorbic acid; antioxidants such as ascorbic acid, α-tocopherol and cisterns; disintegrating agents, binding buffers, sweetening agents, flavoring agents and ventilators. In addition, tablets and peas can be coated. Liquid dosage forms for oral administration may be formulated as pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and solutions containing solvents commonly used in pharmaceuticals such as water.

The specific dose for each patient will depend on a number of factors such as activity, age, body weight, health, gender and diet of the compound, route and timing of administration, drug combination and severity of the disease. The dose may vary depending on the particular disease, the symptoms, the route of administration and the individual patient, but basically the best daily dose is 1-50 mg for oral administration or 1-30 mg for intravenous injection and can be administered immediately or in 2-3 times for an adult. For example, in the treatment of hypertension in an adult, it is best to administer the active ingredient 10-100 mg per day orally, and about 5-50 mg per day by intravenous administration. The active ingredient is preferably administered in equal doses 2 or 3 times daily. The following examples illustrate the present invention, but do not limit the scope thereof.

Examples

The following formulation examples, working examples, experimental examples, and comparative examples illustrate the present invention in more detail, but at the same time, variations and modifications are within the scope of the present invention.

The following abbreviations are used in the description of the present invention:

Me: methyl; Et: ethyl; Tet: tetrazolyl; cycl:

cyclo; Pr: propyl; Bu: butyl; Pen: pentyl; Hex: hexyl; Hep: heptyl; Ph: phenyl; DMF:

dimethylformamide; THF: tetrahydrofuran;

Examples of compositions

If compound (I) is used as a medicament for circulatory disorders such as cardiovascular disease, shock, kidney disease and the like. treatment, it can be administered in the form of the following preparations:

1. Capsules:

(1) (2-Ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl4-yl] methyl] benzimidazole-7-carboxylic acid 10 mg (2) Lactose 90 mg (3) Finely ground crystalline cellulose 70 mg (4) Magnesium stearate 10 mg

One capsule 180 mg

Components (1), (2), (3) and half (4) are mixed and granulated. 1 obtains the remaining half of component (4) from the resulting granules and encapsulates the entire mixture in a gelatin capsule.

2. Tablets (1) (2-Ethoxy-1 - [[2- (1H-tetrazol-5-yl) biphenyl4-yl] methyl] benzimidazole-7-carboxylic acid 10 mg (2) Lactose 35 mg (3) Corn starch 150 mg (4) finely divided crystalline cellulose 30 mg (5) magnesium stearate 5 mg

One tablet 230 mg

Components (1), (2), (3), two-thirds of component (4), and half of component (5) are mixed and granulated. Add the remaining parts (4) and (5) to the resulting granules and compress the granules.

3. Injection (1) Disodium salt of 2-methyl-1 - [[2'- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid 10 mg (2) Inositol 100 mg (3) ) Benzyl alcohol 20 mg

One ampoule of 130 mg

Components (1), (2), (3) are dissolved in distilled water for injection resulting in 2 ml of solution for filling in ampoules. The solution is prepared under sterile conditions.

4. Capsules:

(1) (1- (Cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) -biphenyl-4-yl] methyl] benzimidazole-7-) carboxylate 10 mg (2) Lactose 90 mg (3 ) Finely ground crystalline cellulose 70 mg (4) Magnesium stearate 10 mg

One capsule 180 mg

Components (1), (2), (3) and half (4) are mixed and granulated. Add the remaining half of component (4) to the resulting granules and place the gelatin capsule in the entire mixture.

5. Tablets (1) 1- (Cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1 - [[2- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate 10 mg (2) Lactose 35 mg (3) Maize starch 150 mg (4) Finely ground crystalline cellulose 30 mg (5) Magnesium stearate 5 mg

One tablet 230 mg

Components (1), (2), (3), two-thirds of component (4), and half of component (5) are mixed and granulated. Add the remaining parts (4) and (5) to the resulting granules and compress the granules.

3. Disodium salt of injection (1) 2-ethoxy-1 - [[2- '(1H-tetrazol-5) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid (2) Inositol (3) Benzyl alcohol 100 mg mg 130 mg

One ampoule

Components (1), (2), (3) are dissolved in distilled water for injection resulting in 2 ml of solution for filling in ampoules. The solution is prepared under sterile conditions.

a comparative example

2- Propoxybenzimidazole.

To a solution of o-phenylenediamine (2 g) in propyl orthocarbonate (5 mL) was added acetic acid (1.1 mL) and the resulting solution was stirred for 3 h at 80 ° C. Ethyl acetate was added to the reaction mixture and the solution was washed with aqueous sodium bicarbonate solution, then dried over sodium sulfate and concentrated to dryness. The concentrate was purified using silica gel column chromatography and crystals were obtained. Recrystallization of the product from ethyl acetate-benzene gave colorless crystals (1.54 g, 47%): mp 163164 ° C.

a comparative example

Ethyl 2-carboxy-3-nitrobenzoate.

A mixture of 3-nitrophthalic acid (35 g) in ethanol (300 ml) containing concentrated sulfuric acid (20 ml) was heated under reflux for 24 hours. The solvent was evaporated in vacuo and the residue was poured into cold water (700 mL). The mixture was extracted with ethyl acetate. The organic layer was washed with water and washed with aqueous potassium carbonate solution. The aqueous layer was acidified with hydrochloric acid and the resulting mixture was extracted with methylene chloride. The organic layer was washed with water, dried and the solvent evaporated. The resulting solid product (29 g, 74%) was used in the next reaction without purification.

¹ H-NMR (90MHz, CDCl ₃ ) δ; 1.43 (3H, t), 4.47 (2H, q), 7.70 (1H, t), 8.40 (2H, d), 9.87 (1H, ds).

R (Nuj ol) cm ^-1 : 1725, 1535, 1350, 1300, 1270.

comparative example

Ethyl -2-t-butoxycarbonylamino-3-nitrobenzoate (26 g Mixture High Quality) was added dropwise to

A mixture of 2-carboxyl-3-nitroenzoate (23.9 g) and thionyl chloride (12 mL) in jenzole (150 mL) was heated in a flask under reflux for 3 hours. The reaction mixture was then concentrated to dryness. The resulting chloroanhydride was dissolved in methylene chloride (20 mL). sodium azide (9.75 g) in dimethylformamide (20 mL) with vigorous stirring. The reaction mixture was poured into a mixture of ether in hexane (3: 1, 200 mL) and water (250 mL) to separate the two layers. The organic layer was washed with water and the solvent evaporated. The residue was dissolved in t-butanol (200 mL) and the mixture was heated gradually with stirring and then heated to reflux for 2 hours. The reaction mixture was concentrated in vacuo to give an oily product (30 g).

¹ H-NMR (90MHz, CDCl ₃ ) δ: 1.40 (3H, t), 1.53 (9H, s), 4.43 (2H, sq), 7.23 (1H, t), δ , 03-8.27 (2 H, m), 9.70 (1H, br s).

IR (neat) cm ^-1 : 3320, 2980, 1740, 1585, 135, 1500, 1440, 1375, 1265, 1155.

1. Work Example

Ethyl 2 - [[2'-cyanobiphenyl] amino] -3-nitrobenzoate

Sodium hydride (60% dispersion in mineral oil, 2.8 g) was added to a solution of ethyl 3-t-butoxycarbonylamino-3-nitrobenzoate (20 g) in tetrahydrofuran (50 mL) with stirring and ice-cooling. Stir the mixture for 20 min. After stirring at room temperature, 4- (2-cyanodiphenyl) benzyl bromide (18 g) and potassium iodide (360 mg) were added and the resulting mixture was refluxed for 10 hours. The solvent was then evaporated to dryness and the residue partitioned between water (250 mL) and ether (200 mL). The organic layer was washed with water, dried and concentrated, and a yellow syrup formed. This syrup was dissolved in a mixture of trifluoroacetic acid (60 mL) and methylene chloride (40 mL) and the resulting solution was stirred for 1 hour at room temperature. The reaction mixture was concentrated to dryness and ether (200 mL) was added to the residue to give crystals. These crystals were filtered off, washed with ether to give pale yellow crystals (2.21 g, 85%), mp 118-119 ° C.

¹ H-NMR (90MHz, CDCl ₃ ) δ: 1.37 (3H, t), 4.23 (2H, s), 4.37 (2H, sq), 6.37 (1H, t), 7, 33-7.83 (9H, m), 7.97-8.20 (2H, m)

IR (Nujol) cm ^-1 : 3280, 1690, 1575, 1530, 1480, 1450,

1255, 1105, 755.

Work example

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

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

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.33 (3H, t), 4.23 (2H, s), 4.27 (2H, q), 6, 83-6, 93 (2H, m), 7.35-7.55 (7H, m), 7.64 (1H, dt),

7.76 (dd).

IR (KBr) cm ^-1 : 3445, 3350, 2220, 1680, 1470, 1280, 1240,

1185, 1160, 1070, 1050, 1020, 805, 750.

Work example

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

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

¹ H-NMR (200MHz, CDCl ₃ ) δ: 1.23 (3H, t), 4.23 (2H, kv),

4.2 δ (3H, s), 5.72 (2H, s), 7.09 (2H, d), 7.20 (1H, t), 7.3878.48 (4H, m) 7.58-7 , 66 (2H, m), 7.73-7.79 (2Hm).

IR (KBr) cm ^-1 : 3000.2220, 1725, 1560, 1465, 1440, 1415,

1285, 1250, 1220, 1040, 760, 750, 740.

Work example

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

Acetic acid (0.2 g) was added to a solution of ethyl 3-amino-2-N - [[2 'cyanobiphenyl-4-yl) methyl] amino] benzoate (1.0 g) in ethyl orthocarbonate (5 mL). The mixture was stirred at 80 ° C for 1 hour. The reaction mixture was concentrated and the concentrate was extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate and water. The solvent was evaporated to give crystals and then recrystallized from atyl acetate-benzene to give colorless crystals (0.79 g, vol .: 131-132 ° C).

^C 26 ^H 23 ^N 3 ° 3 elemental analysis:

C

Calculated,%: 73.39

Found,%: 73.36

69%), melting temperaH N

5, 45 9, 88

5.42 9, 83 ¹ H-NMR (200MHz, CDCl ₃ ) δ: 24 (3H, t), 1.49 (3Ht), 4.24 (2H, q), 4.68 (2H, q ), 5, 72 (2H, s), 7.10 (2H, d), 7.19 (1H, t), 7, 3

8-7.4 δ (4H, m), 7.56-7, 66 (2H, m), 7.73-7, 77 (2Hm).

IR (KBr) cm ^-1 : 2220, 1720, 1550, 1480, 1430, 1280, 1245,

1215, 1040, 760, 740.

Work example

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

To a solution of ethyl 3-amino-2-N - [[(2'-cyanobiphenyl-4-yl) methyl] amino] benzoate (0.9 g in propyl orthocarbonate (5 mL)) was added acetic acid (0.2 g). After stirring for 1 hour at 80 [deg.] C., the solution was washed with aqueous sodium bicarbonate solution, evaporated to give crystals, and recrystallized from ethyl acetate and (0.72 g,

N

9.55

9.54 benzene mixture, 68% colorless crystals), melting point 90-92 ° C.

Analysis of C ₂₇ H ₂₅ N ₃ O ₃ (%):

C H

Calculated,%: 73.79 5.73

Found,%: 73.84 5.79 ¹ H-NMR (200 MHz, CDC1 ₃₎ δ: 1.01 (3H, t), 1.25 (3Ht), 1,801,97 (2H, m);

4.24 (2H, sq), 4.57 (2H, sq), 5.72 (2H, s), 7.11 (2H, d), 7.19 (1H, t), 7.38-7 , 4 6 (4H, m), 7.56-7, 66 (2H, m), 7, 73-7, 77 (2H, m).

IR (KBr) cm ^-1 : 2220, 1725, 1550, 1480, 1460, 1370, 1280,

1245, 1210, 1115, 1040, 760, 750, 740.

Work example

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

A mixture of ethyl 3-amino-2-N - [[(2'-cyanobiphenyl-4-yl) methyl] amino] benzoate (5.6 g) and O-sodium ethyl dithiocarbonate (7.3 g) in ethanol (50 mL) 8 heated in a reflux dish for hours. The reaction mixture was concentrated and the residue was dissolved in water. With hydrochloric acid the solution reached a pH of 3-4. Collected the precipitated crystals by filtration to give yellow crystals (5.0 g, 80%), melting point: 225227 ° C.

¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 08.08 (3H, t), 4.12 (2H, q), 5.90 (2H, p s), 7.08 (2H, d) ), 7.27 (1H, t), 7.38-7.59 (6H, m), 7.76 (1H, dt), 7.92 (1H, dd).

IR (KBr) cm ^-1 : 2210, 1720, 1460, 1440, 1420, 1375, 1335,

1265, 1180, 1135, 1115, 1100, 985, 760, 740.

a comparative example

Methyl 2 - [(2'-cyanobiphenyl) methyl] amino] -3-nitrobenzoate

A mixture of ethyl 2 - [[2'-cyanobiphenyl) methyl] amino] -3-nitrobenzoate (5 g) and sodium hydride (60% dispersion in mineral oil, 1.62 g) in methanol (50 mL) was stirred at room temperature for 1 day. The reaction mixture was concentrated and the residue was poured into a saturated aqueous solution of sodium bicarbonate (100 mL), followed by extraction with chloroform. The organic layer was washed with water, dried, and concentrated to dryness to give crystals which, after recrystallization from a mixture of ethyl acetate and hexane, afforded pale yellow crystals (3.98 g, 83%), mp 106-108 ° C.

¹ H-NMR (200MHz, CDCl ₃ ) δ: 3.81 (3H, s) 3.97 (2H, pi s), 4.23 (2H, s), 6.40 (ΙΗ, ρΙ s), δ , 88-6, 91 (2H, m), 7, 34-7, 55 (7H, t),

7.65 (1H, dt, J = 1.2, 7.7 Hz), 7.77 (1H, dd, J = 1.4, 8.0 Hz)).

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

1200, 780, 760.

Work example

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

To a solution of methyl 3-amino-2 - [[(2 '-cyanobiphenyl-4-yl) methyl] amino] benzoate (2.03 g) in orthocarbonate (5 mL) was added acetic acid (0.37 g). The mixture was stirred at 80 ° C for 1 hour. The reaction mixture was concentrated to dryness and the residue was dissolved in ethyl acetate. The solution was washed with aqueous sodium bicarbonate.

H N

5.14 10.21

5.19 9.97

The solvent was evaporated in vacuo to give crystals. They were recrystallized from ethyl acetate as colorless crystals (2.01 temperature: 168.5-169.5 ° C).

• Element Analysis:

C

Calculated,%: 72.98

Found,%: 72.71 ^X H-NMR (200 MHz, CDC1 ₃₎ 5: 1.2 (3H, t, J = 7, lHz), 3.71 (3H s), 4, 63 (2H, g J = 7.1 Hz), 5.51 (2H, s), 7.09 (2H, d J = 8.4 Hz), 7.20 (1H, t, J = 7.9 Hz), 7, 45-7.59 (5H, m), 7.69-7.80 (2H, m), 7.92 (1H, dd, J = 1.4, 7.8Hz).

IR (KBr) cm ^-1 : 2225, 1725, 1550, 1480, 1430, 1350, 1280,

1250, 1040, 760, 750.

a comparative example

Ethyl 2 - [[(2 '-cyanobiphenyl-4-yl) methyl] amino] -3- (3-ethylthioureido) benzoate and benzene mixture, gave g, 86%), m.p.

A mixture of ethyl 3-amino-2 - [[(2'-cyanobiphenyl-4-yl) methyl] amino] benzoate (1.6 g), ethyl isothiocyanate (1.5 mL) and ethanol (1 mL) was stirred at room temperature for 3 days. at temperature. The reaction mixture was dissolved in acetate and the solution was washed to dryness and concentrated to dryness to give crystals. Recrystallization from ethyl acetate with water yielded crystals (1.92 g, 91%), 110 ° C.

pale yellow melting point 108 ¹ H-NMR (200MHz, CDCl ₃ ) δ: 1.15 (3H, t), 1.40 (3H, t), 3.50-3.70 (2H, pl s), 4.37 (2H, kv), 4.56 (2H, D), 6.07 (1H, t), 6.78 (1H, t),

7.19-7.24 (1H, m), 7.38-7.53 (6H, t), 7.63 (1H, dt), 7.727.76 (1H, m), 7.99 (1H, dd), 8.29 (ΙΗ, ρΙ s).

IR (KBr) cm ^-1 : 2225, 1725, 1550, 1480, 1430, 1350, 1280,

1250, 1040, 760, 750.

a comparative example

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

Using a procedure analogous to that described in Comparative Example 5, a pale yellow syrup (2.0 g, 98%) was obtained from ethyl 3-amino-2 - [[(2'-cyanobiphenyl-4-yl) methyl] amino] benzoate. (1.6 g), propyl isothiocyanate (1.5) ml) and ethanol (1 ml).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.88 (3H, t), 1.40 (3H t), 1.481.67 (2H, m);

3.42-3, 68 (2H pi s), 4.37 (2H, kv), 4.56 (2H, d), 6.13 (1H, t), 6.78 (1H, t), 7 , 21-7.25 (1H, m), 7.36-7.53 (6H, m), 7.36-7.53 (6H, m), 7.64 (1H, dt), 7.73 -7.77 (1H, m), 7.99 (1H, dd), 8.208.40 (1H, p s).

IR (pure) cm ^-1 : 3325, 3175, 2960, 2930, 2875, 2220, 1710, 1690, 1590, 1475, 1360, 1175, 1140, 1090, 1020, 760.

Work example

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

A solution of ethyl 2 - [[(2'-cyanobiphenyl-4-yl) methyl] amino] -3- (ethylthioureido) benzoate (1.8 g) in ethanol (50 mL) was heated under reflux for 12 hours. The resulting reaction mixture was added with IN HCl (60 mL) and added for 20 min. the mixture was stirred at room temperature. The reaction mixture was concentrated to dryness and the concentrate was dissolved in ethyl acetate. The mixture was washed with aqueous sodium bicarbonate solution and water and dried. The solvent was evaporated to dryness and the residue was purified by silica gel column chromatography to give yellow syrup (0.96 g, 58%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.23 (6H, t), 3.48-3, 62 (2H, m), 4.09 (1H, t), 4.23 (2H, kv), 5.57 (2H, s), 7.15 (1H, t), 7.25 (2H, d), 7.4-0-7.77 (8H, m).

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

1100, 1060, 770, 750.

Work example

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

Using a procedure analogous to that described in Working Example 8, yellow syrup (1.2 g, 65%) was obtained from ethyl 2 - [[(2'-cyanobiphenyl-4-yl) methyl] amino] -3- (3-propylthioureido) benzoate. (2.0 g), and a solution of methyl iodide (4.8 g) in ethanol (50 mL) ¹ H-NMR (200MHz, CDCl ₃ ) δ: 0.87 (3H, t), 1.25 (6H) 1.52-1.70 (2 H, m);

3, 42-3, 52 (2H t), 4.12 (1H, t), 4.25 (2H, sq), 5.58 (2H, s), 7.16 (1H, m), 7, Δ 9 (2H, d), 7.41-7.78 (8H, m).

IR (pure) cm ^-1 : 3400, 3250, 2975, 2950, 2890, 2225,

1715, 1620, 1590, 1570, 1480, 1430, 1370, 1285, 1220,

1135, 1070, 760.

Work example

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

To a solution of ethyl 1 - [(2'-cyanobiphenyl-4-yl) methyl] -2-methoxybenzimidazole-7-carboxylate (1.3 g) in methanol (50 mL) was added a solution of 5.2 M sodium methoxide in methanol (0.5 mL). ml). The mixture was heated to reflux for 4 hours. The reaction mixture was then concentrated and the precipitated crystals were filtered off. Recrystallization from methanol gave prismless colorless crystals (1.1 g, 85%), melting point: 149150 ° C.

C ₂₄ H ₁₉ N ₃ O ₃ elemental analysis:

Calculated,% Found:

C

72.53

72.38

H

4.82 4, 93

N

10.57

10.44 ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 3.75 (3H s),

4.26 (3H, s), 5.69 (2H, s), 7.09 (2H, d), 7.23 (1H, t), 7.37-7.46 (3H, m), 7,557 , 65 (2H, m), 7.72-7.78 (2H, m).

a comparative example

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

The title compound was synthesized (86% yield) using a procedure analogous to that described in Reference Example 5, mp 152155 ° C.

¹ H-NMR (200MHz, CDCl ₃ ) δ: 3.05-3.07 (3H, p s), 3.92 (3H s)

4.58 (2H, d), 6.04-6.08 (1H, pi s), 6.77 (1H, t), 7.22-7.26 (1H, m), 7.39-. 7.52 (6H, m), 7.63 (1H, dt), 7.75 (1H, dd), 7.97 (1H, dd), 8.28 (ΙΗ, ρΙ s).

IR (KBr) cm ^-1 : 3375, 3325, 3175, 2220, 1680, 1590, 1540,

1500, 1480, 1450, 1435, 1265, 1230, 1190, 1145, 1050,

830, 760, 740.

Work example

Methyl 2 - [(2'-cyanobiphenyl-4-yl) methyl] -2-methylaminobenzimidazole-7-carboxylate.

The above syrup-like compound was synthesized (yield 42%) using a procedure analogous to that described in Working Example 8.

¹ H-NMR (200MHz, CDCl ₃ ) δ: 3.11 (3H, d), 3.73 (3H s), 4.22 (1H, kv), 5.54 (2H, s), 7.17 (1H, t), 7.27 (2H, d), 7.417.79 (8H, m).

IR (pure) cm ^-1 : 3400, 3250, 3025, 2950, 2220, 1720,

1625, 1610, 1580, 1480, 1410, 1340, 1280, 1240, 1210,

1130, 1060, 750.

a comparative example

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

Under ice-cooling, sodium hydride (60% dispersion in mineral oil, 0.24 g) was added to a stirred solution of 2-propoxybenzimidazole (0.71 g) in dimethylformamide (10 mL). After stirring the mixture for 20 minutes, N-triphenylmethyl-5- [2- (4-bromoethylbiphenyl)] tetrazole (2.3 g) was added and the resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was then quenched with ice water and extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated to dryness. The concentrate was dissolved in methanol (50 mL), treated with IN HCl (15 mL) and stirred at 60 ° C for 2 h. The reaction mixture was concentrated, then added to water (15 mL) and ethyl acetate (15 mL). The mixture was basified with IN NaOH and shaken. With the help of IN HC1 the pH of the aqueous layer was 3-4 and then it was extracted with chloroform. The organic layer was washed with water, dried and concentrated to dryness. The concentrate was purified by silica gel column chromatography to give crystals. Them

after recrystallization from ethyl acetate; of methanol mixture, obtained colorless crystals (0.58 g, 35%) melting temperature: 177-179 ° C (decomposition) • Analysis of C ₂₄ H ₂₂ N ₆ O elements: C H N Calculated,%: 70.23 5.40 20.47 Found,%: 69.93 5.43 20.22

¹ H-NMR (200MHz, DMSO-d ₆ ) δ: 95, 95 (3H, t), 1.70-1.88 (2H, m), 4.46 (2H, t), 5.23 (2H) , s), 7.04-7, 10 (4H, m), 7.20 (2H, d), 7.3873.43 (2H, m), 7.48-7.70 (4H, m).

IR (KBr) cm ^-1 : 1540, 1535, 1488, 1475, 1450, 1425, 1285,

1271, 1040, 980, 755, 745.

Work example

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

The title compound was obtained from methyl [[(2 * - cyanobiphenyl-4-yl) methyl] amino] -3- (butylureide) benzoate using a procedure analogous to that described in Example 8.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.89 (3H, t), 1.21-1.39 (2H, m), 1.45-1.60 (2H, m), 3, 50-3.65 (3H, pl s), 3.92 (3H, s), 4.56 (2H, d), 6.08 (1H, t), 6.78 (1H, t), 7, 21-7.30 (1H, m), 7.397.54 (6H, m), 7.64 (1H, dt), 7.75 (1H, dd), 8.26 (ΙΗ, ρΙ s)

Work example

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

A mixture of sodium hydride (60% dispersion in mineral oil 0.13 g) was stirred in dimethylformamide (6 ml) for 5 minutes under ice-cooling, followed by the addition of methyl 2-ethylamino-1 - [(2'-cyanobiphenyl-4-yl) methyl] benzimidazole. -carboxylate (0.95 g) was stirred for a further 10 minutes. Methyl iodide (0.2 mL) was then added and the mixture was stirred for 20 minutes. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was diluted with water, dried and evaporated to dryness. The residue was purified by silica gel column chromatography to give crude crystals, which were recrystallized from ethyl acetate-hexane to give colorless needle-like crystals (0.88 g, 82%), mp 66-69 ° C.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.25 (3H, t), 3.03 (3H s), 3.36 (2H, q), 3.73 (3H, s), δ 60 (2H, s), 6.88 (2H, d), 7.16 (1H, t), 7.34-7.49 (5H, m), 7.59 (1H, dt), 7.73 (1H, dd), 7.78 (1H, dd).

IR (KBr) cm ^-1 : 2210, 1710, 1540, 1530, 1435, 1420, 1385,

1300, 1275, 1250, 1005, 760.

a comparative example

Methyl 1 - [(2'-cyanobiphenyl-4-yl) methyl] -2-oxo-2,3-dihydrobenzimidazole-7-carboxylate methyl [[2'-cyanobiphenyl-4-yl) methylamino] -3-methoxycarbonylaminobenzoate (10, A solution of 5 g) in methanol (100 mL) was added to NaOMe (10 g) and the mixture was heated under reflux for 20 hours. The reaction mixture was neutralized with IN HCl and concentrated to dryness. The residue was extracted with a mixture of chloroform and water to give colorless crystals (8.67 g, 89%) as a needle, m.p. 250-253 ° C.

¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 3.65 (3H, s), 5.35 (2H, s), 7.047.16 (3H, m), 7.48-7, 59 ( 4H, m), 7.76 (1H, dt), 7.92 (1H, dd).

IR (KBr) cm ^-1 : 2210, 1720, 1690, 1635, 1430, 1390, 1270,

1255, 760, 750, 730, 690.

a comparative example

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

A mixture of methyl [(2'-cyanobiphenyl-4-yl) methyl] -2-oxo-2,3-dihydrobenzimidazole-7-carboxylate (8.02 g) in phosphorus oxychloride (30 mL) was heated under reflux for 8 hours. The reaction mixture was concentrated and the resulting residue was poured into ice water. The residue was extracted with chloroform. The extract was washed with water, dried and evaporated. The residue was purified by silica gel column chromatography to give crystals, which were then recrystallized from a mixture of chloroform and methanol to give colorless needle-like crystals (2.2 g, 28%), melting point: 154157 ° C.

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

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

1350, 1290, 1270, 1200, 1150, 1120, 1000, 775, '60,

750.

a comparative example

Methyl 2 - [(2'-cyanobiphenyl-4-yl) methylamino] -3-methoxycarbonylaminobenzoate

To a stirred solution of methyl 3-amino-2 - [(2'-cyanobiphenyl-4-yl) methylamino] benzoate (10 g) in pyridine (50 mL) was added dropwise methyl chloroformate (9.0 mL) under ice-cooling. The mixture was stirred at room temperature for 3 hours. The residue was extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The residue was then recrystallized from a mixture of ethyl acetate and hexane to give needle-like pale yellow crystals (10.5 g, 90%), m.p. 113115 ° C.

¹ H-NMR (200MHz, CDCl ₃ ) δ: 3.80 (3H, s), 3.83 (3H, s), 4.11 (2H, d), 6.29 (1H, pi s), δ , 09 (1H, t), 7.40-7.70 (10H, m),

8.11 (1H, d).

Work example

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

Methyl 2-chloro-1 - [(2'-cyanobiphenyl-4-yl) methyl] benzimidazole-7-carboxylate (0.8 g) was stirred in morpholine (15 ml) for 2 hours at 100 ° C and the reaction mixture was concentrated to dryness. The residue was extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The resulting crystals were recrystallized from a mixture of ethyl acetate and hexane to give colorless prism crystals (0.69 g, 77%).

¹ H-NMR (200MHz, CDCl ₃ ) δ: 3.38 (4H, t), 3.72 (3H, s), 3.90 (4H, t), 5.63 (2H, s), 6, 89 (2H, d), 7.20 (1H, t), 7.377, 65 (6H, m), 7.74 (1H, dd), 7.82 (1H, dd).

IR (KBr) cm ^-1 : 2225, 1715, 1520, 1440, 1415, 1280, 1260,

1220, 1130, 1120, 1010, 860, 770, 760, 750.

Work example

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

The title compound was obtained using a procedure analogous to that described in Working Example 14. Yield: 81%, m.p. 119-121 ° C.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.62-1.77 (6H, m), 3, 31-3, 36 (4H, m), 3.73 (3H, s), δ, 58 (2H, s), 6.88 (2H, d), 7.15 (1H, t), 7.357.4 (9H, m), 7.56-7, 64 (1H, m), 7, 73 (1H, dd), 7.79 (1H, dd).

IR (KBr) cm ^-1 : 2225, 1720, 1530, 1445, 1410, 1385, 1305,

1285, 1265, 1250, 1130, 1110, 770, 750.

a comparative example

Methyl 2 - [(2'-methoxycarbonylphenyl-4-yl) methylamino] -3-nitrobenzoate

To a solution of methyl 2-tert-butoxycarbonylamino-3-nitrobenzoate (1.84 g) in acetonitrile (10 mL) was added a solution of 4- (2 * -methoxycarbonylbiphenyl-4-yl) methyl bromide (1.9 g) in acetonitrile (5 mL) and Potassium carbonate (0.86 g) was added and the reaction mixture was refluxed to dryness with ethyl acetate and water, water, dried, and chromatographed to give a pale yellow solution of ethanol washed with bicarbonate and water, yielded a yellow spa mixture and heated in a vessel for 20 hours. The reaction mixture was concentrated and the organic layer was evaporated. The residue was purified on a silica gel column and colored syrup (ml) and added to a solution of . Reactions at room temperature and the residue was dissolved in ethyl acetate with water-saturated sodium and evaporated to give syrup (1.39 g, 53%).

¹ H NMR (200MHz, CDCl ₃ ) δ: 3.61 (3H, s), 3.89 (3H, s), 4.21 (2H, d), 6.72 (1H, t), 7 , 30 (4H, d), 7.36 (1H, dd), 7.42 (1H, dd), 7.35 (1H, dd), 7.82 (1H, dd), 8.00 (1H, dd), 8.10 (1H, dd).

a comparative example

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

The title compound was obtained as a pale yellow syrup from methyl 2 - [(2'-methoxycarbonylbiphenyl-4-yl) methylamino] -3-nitrobenzoate using a procedure analogous to that described in Working Example 2. Yield: 79%.

¹ H-NMR (200MHz, CDCl ₃ ) δ: 3.63 (3H, s), 3.80 (3H, s), 3.7 δ (3H, p s), 4.22 (2H, d), 6.40 (1H, p s), 6.82-6, 92 (2H, m), 7.277.44 (7H, m), 7.53 (1H, dt), 7.79-7.83 (1H , t).

IR (pure) cm ^-1 : 3450, 3360, 2970, 1730, 1700, 1470,

1460, 1450, 1440, 1290, 1250, 1200, 770, 750.

Work example

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

The title compound was obtained as colorless plaque crystals from methyl 3-amino-2 - [(2'-methoxycarbonylbiphenyl-4-yl) methylamino] benzoate using a procedure analogous to that described in Working Example 4. Yield: 72%, melting point: 112-113 ° C.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.50 (3H, t), 3.55 (3H, s), 3.77 (3H, s), 4.68 (2H, sq), δ , 65 (2H, s), 6.99 (2H, d), 7.17 (2H, d), 7.17 (1H, t), 7.31-7.55 (4H, m), 7, 73 (1H, dd), 7.77 (1H, dd).

IR (pure) cm ^-1 : 1730, 1710, 1545, 1470, 1430, 1380, 1340, 1320, 1270, 1250, 1235, 1210, 1120, 1080, 1030, 750, 740, 710.

Work example

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

The title compound was obtained as colorless needle-like crystals using a procedure analogous to that described in Working Example 7. Yield: 75%, melting point: 74-75 ° C.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.95 (3H, t), 1.35-1.54 (2H, m), 1.77, 90 (2H, m), 3.7 (3H, s), 4.60 (2H, t), 5.69 (2H, s), 7.10 (2H, d), 7.17 (1H, t), 7.43 (4H, d) , 7.54-7, 65 (2H, m), 7.74 (2H, dd).

IR (KBr) cm ^-1 : 2220, 1725, 1560, 1490, 1470, 1440, 1395,

1320, 1295, 1265, 1245, 1120, 1050, 1020, 770.

Work example

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

-The name of the plates indicated in the form analogous to the described melting point:

The compound was obtained as colorless crystals using the method of Working Example 7. Yield: 73%, 118-119 ° C.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 3.76 (3H, s), 5.12 (2H, m), 5.33 (1H, m), 5.43 (1H, m), δ , 72 (2H, s), 6.02-6.21 (1H, m), 7.11 (2H, d), 7.19 (1H, t), 7.44 (4H, d), 7, 56-7, 66 (2H, m), 7.75 (2H, dd).

IR (KBr) cm ^-1 : 2220, 1705, 1540, 1470, 1460, 1425, 1410, 1400, 1330, 1300, 1275, 1250, 1225, 1205, 1100, 1015,

995, 760, 750, 740, 730.

Work example

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

The title compound was obtained as colorless crystals (3.2 g, 32%) from methyl 3 - [[(2'-cyanobiphenyl-4-yl) methyl] amino] -3- (3-ethyloureido) benzoate (10.5 g), obtained in a manner analogous to Comparative Example 5 from methyl 3-amino-2 - [[[(2'-cyanobiphenyl-4-yl) methyl] amino] benzoate.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.24 (3H, t), 3.49-3, 63 (2H, m), 4.06 (1H, t), 5.55 (2H) , s), 7.16 (1H, t), 7.27 (2H, d), 7.417.79 (8H, m).

IR (KBr) cm ^-1 : 3275, 2225, 1720, 1620, 1610, 1580, 1570,

1480, 1350, 1275, 1240, 1215, 1100, 1070, 770, 760.

Work example

2-Cyano-4'-methylbiphenyl

a) N- (2-Methoxyphenyl) methyldicyclohexylamine

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

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.21-1, 87 (10H, m), 3.14-3.28 (1H, m), 3.86 (3H, s), δ, 88-7.00 (2H, m), 7.36 (1H, m), 7.95 (2H, dd),

8.75 (1H, s).

b) 4'-Methyl-2-biphenylcarbaldehyde

A solution of 4-bromotoluene (7.5 g) in tetrahydrofuran (10 ml) was added dropwise to a suspension of metallic magnesium (1.1 g) in tetrahydrofuran (3 ml) with slight wetting. The resulting Grignard reagent solution was added dropwise to an ice-cooled hexylamine reaction solution of N (-2-methoxyphenyl) methylenedicyclic (4.3 g) in tetrahydrofuran (30 mL). the mixture was stirred at room temperature for 1.5 hours and then heated under reflux for 7 hours. After the addition of ice water, the reaction mixture was acidified using concentrated hydrochloric acid. The reaction mixture was then extracted with ethyl acetate and the extract was washed with IN HCl and water, dried and evaporated to dryness. The residue was purified by silica gel column chromatography to give pale yellow syrup (2.0 g, 51%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.43 (3H, s), 7.28 (4H, s), 7.427.51 (2H, m), 7.63 (1H, t), δ , 02 (1H, d), 10.00 (1H, s).

c) 2-Cyano-4-methylbiphenyl

A mixture of 4-methyl-2-biphenylcarbaldehyde (2.0 g) and hydroxyamine hydrochloride (1.0 g) in pyridine (10 mL) was stirred at room temperature for 15 minutes, followed by the addition of acetic anhydride (4.1 g). The reaction mixture was stirred at 90-100 ° C for 1 hour and concentrated to dryness. Water was added to the residue and the precipitated crystals were filtered off. Recrystallization from hexane gave colorless needle crystals (1.5 g, 79%).

¹ H-NMR (90 MHz, CDCl ₃ ) δ: 2.40 (3H, s), 7.720-7.80 (8H, m).

The title compound can easily be converted to the compound (IIa ') by the above references.

Work example

Methyl 2-carboxy-3-nitrobenzoate

To a suspension of 3-nitrophthalic acid (211 g) and methyl orthoformate (127 g) in methanol (420 ml) was added dropwise concentrated sulfuric acid (20 ml) with stirring. The reaction mixture was refluxed for 18 hours and then concentrated to dryness. After adding water (30 mL) to the residue, the mixture was stirred at 3-10 ° C for 1 hour. The precipitated crystals were recrystallized from a mixture of ethyl acetate and hexane to give a pale yellow prism crystal (185 g, 82%), m.p. 166-168 ° C.

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

8.39 (1H, dd), 8.42 (1H, dd).

Work example

Methyl 2-tert-butoxycarbonylamino-3-nitrobenzoate

To a solution of methyl 2-carboxy-3-nitrobenzoate (7.23 g) in dimethylformamide (50 ml) was added diphenylphosphorylazide (11.3 g) at room temperature and triethylamine (6.7 ml) was added dropwise to the stirred reaction mixture. It was then stirred at room temperature for 3 hours. Tert-butanol (54 mL) was added to the stirred reaction mixture. After stirring for 50 minutes at room temperature, the reaction mixture was refluxed for 1 hour and evaporated to dryness. The resulting residue was dissolved in ethyl acetate, washed with dilute hydrochloric acid, aqueous sodium bicarbonate and water, and then dried. After evaporation of the solvent, methanol was added to the resulting residue and the mixture was cooled to give colorless crystals (g, 70%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.50 (9H, s), 3.96 (3H, s), 7.23 (1H, t), 8.10 (1H, dd), δ , 17 (1H, dd).

IR (KBr) ' ¹ : 3360, 1730, 1705, 1580, 1520, 1490, 1440,

1365, 1355, 1310, 1270, 1240, 1150, 870, 770, 725, 705.

Work example

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

Methyl 2-tert-butoxycarbonylamino-3-nitrobenzoate (0.6 g), 2- (4-bromomethylphenyl) benzonitrile (0.54 g) and K ₂ CO ₃ (0.28 g) in acetonitrile (10 mL) for 4 hours reflux and concentrate to dryness, add the resulting residue to water and extract with ethyl acetate. The extract was washed with water, dried and evaporated to dryness. The residue was purified by silica gel column chromatography to give crystals. Recrystallization from a mixture of ethyl acetate and hexane gave colorless prism crystals (0.83 g, 85%), m.p. 153154 ° C.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.35 (9H, s), 3.70 (3H, s), 4.63 (1H, d), 4.80 (1H, d), δ 23-7.29 1 H-NMR (200 MHz, CDCl ₃ ) δ: 1.35 (9H, s), 3.70 (3H, s), 4.63 (1H, d), 4.80 (1H) , d), 7.23-7.29 (3H, m), 7.39-7.53 (6H, m), 7,597.67 (1H, m), 7.75 (1H, dd), 7, 93 (1H, dd) 7.99 (1H, dd) 8.05 (1H, dd), 8.11 (1H, dd).

IR (KBr) ' ¹ : 2220, 1700, 1530, 1390, 1360, 1315, 1290,

1160, 765.

Work example

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

A mixture of methyl 2 - [[N-tert-butoxycarbonyl-N- (2'-cyanobiphenyl-4-yl) methyl] amino] -3-nitrobenzoate (0.49 g), 20% HClethanol (3 mL) and ethyl acetate (3 mL) Stir at room temperature for 1 hour. After evaporation of the solvent, methanol and saturated sodium bicarbonate were added to the residue and crystals were obtained. Filtration of the crystals and recrystallization from a mixture of chloroform and methanol gave pale yellow crystals (0.3 g, 77%), m.p. 140-141 ° C.

1 H-NMR (200 MHz, DMSO-d ₆ ) δ: 3.84 (3H, s), 4.26 (2H, m),

6.8 δ (1H, t), 7.4 δ (2H, d), 7.54 (4H, m), 7.7 δ (1H, d), 7.95 (dd), δ 8.11 (2H, m), 8.67 (1H, t).

Work example

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

A mixture of methyl 2 - [[2'-cyanobiphenyl-4-yl] methyl] amino-3-nitrobenzoate (10 g), FeCl ₃ .6H ₂ O (0.1 g), activated carbon (1.0 g) in methanol ( 100 ml) and tetrahydrofuran (50 ml) were heated under reflux for 30 minutes. Hydrazine hydrate (7.2 mL) was added dropwise to the reaction mixture, followed by heating under reflux for 14 hours. Filtration removed the insoluble product from the reaction mixture and concentrated the resulting filtrate to dryness. Aqueous sodium bicarbonate was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and evaporated to dryness. The residue was purified by silica gel column chromatography to give crystals. Recrystallization from isopropyl ether gave pale yellow needle crystals (6.0 g, 64%), m.p. 110-111 ° C.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 3.81 (3H, s), 3.97 (2H, p s), 4.23 (2H, d), 6.39 (1H, t), 6, 84-6, 93 (2H, m), 7.2 6-7, 55 (8H, m),

7.64 (1H, dt), 7.77 (1H, dd).

Work example

Methyl 1 - [(2'-cyanobiphenyl-4-yl) -2- (2,2,2-trifluoroethoxy) benzimidazole-7-carboxylate

The title crystalline compound was obtained from methyl 3-amino-2 - [[2'-cyanobiphenyl-1-yl] methyl] amino benzoate and 2,2,2-trifluoroethylorthocarbonate according to the procedure described in Working Example 3. Yield 25%, m.p. 143-145 ° C.

^c 25Hi8F3N ₃ O ₃ elemental analysis

Estimated%:

C

64.52

H

3.90

N

9.03

Found,%: 64.35 3.95 8.98 ^X H-NMR (200 MHz, CDC1 ₃₎ δ: 3.80 (3H, s), 5, 01 (2H, q)

5.74 (2H, s), 7.13 (2H, d), 7.23 (1H, t), 7.38-7.47 (4H, m), 7.587, 66 (2H, s), 7 , 72-7.78 (2 H, m).

IRiKBrjcm ¹ : 2225, 1735, 1550, 1465, 1430, 1305, 1280,

1270, 1250, 1170, 1060, 770, 745.

Work example

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

To a solution of ethyl 2-chloro-1 - [(2'-cyanobiphenyl-4-yl) methyl] benzimidazole-7-carboxylate (1.0 g) in ethanol (30 ml) was added NaOEt (0.17 g) and the mixture 1 Refluxed for one hour. The reaction mixture was concentrated to dryness. The residue was dissolved in ethyl acetate and the solution was washed with water and then dried. After evaporation of the solvent, the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.37 g, 70%).

^{The 1} H-NMR and IR spectra confirm that the product obtained according to the procedure described is identical to the product obtained in Working Example 4.

a comparative example

2- (4-formylphenyl) benzonitrile

A mixture of 2- (4-bromomethylphenyl) benzonitrile (12 g) and sodium bicarbonate (26 g) in dimethyl sulfoxide (150 mL) was heated at 120 ° C for 5 hours with stirring. After the addition of water, the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated to dryness. The residue was purified by silica gel column chromatography to give crystals. Recrystallization from a mixture of chloroform and isopropyl gave colorless needles (5.77 g, 63%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.4 9-7.58 (2H, m), 7.677.84 (4H, m), 8.00-8.05 (2H, m) , 10.10 (1H, s).

a comparative example

2- (4-Aminomethylphenyl) benzonitrile

A mixture of 2- (4-bromomethylphenyl) benzonitrile (12 g) and potassium phthalamide (15 g) in dimethylformamide (200 mL) was stirred for 5 h at 70 ° C. After the addition of water, the mixture was extracted with methylene chloride. The extract was washed with water, dried and concentrated to dryness, resulting in crystals. Recrystallization from ethyl acetate / isopropyl ether gave colorless crystals. To the crystal suspension in methanol (500 mL) was added hydrazine hydrate (10 mL) and the mixture was heated to reflux for 12 hours. The solvent was evaporated, the residue was dissolved in ethyl acetate and the solution was washed with IN NaOH and water. The organic layer was dried and concentrated to dryness to give crystals (14.2 g, 93%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.56 (2H, pi s), 3.88 (2H, s), 7.277.78 (8H, m)

Work example

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

A mixture of ethyl 1- (2'-cyanobiphenyl-4-yl) methyl] -2-ethoxybenzimidazole-7-carboxylate (0.7 g) and trimethyltin azide (0.7 g) in toluene (15 mL) was heated under reflux for 4 days. refrigerator. The reaction mixture was concentrated to dryness and methanol (20 mL) and IN HCl (10 mL) were added to the residue. The mixture was stirred at room temperature for 30 minutes and reached pH 3-4 using NaOH. After removal of the solvent, the residue was partitioned between chloroform and water. The organic layer was washed with water and dried, the solvent was evaporated to dryness and syrup was obtained. The syrup was purified by silica gel column chromatography to give crystals. Recrystallization from ethyl acetate / benzene gave colorless crystals (0.35 g, 45%), m.p. 158-159 ° C.

^C 26 ^H 24 ^N 6 ° 3 elemental analysis:

Calculated,%: Found,%:

66.56 66, 61

H

5.16-5.05

17, 94 17, 84 H-NMR (200 MHz, CDCl ₃ ) δ: 1.09 (3H, t), 1.43 (3H, t), 4, 02

8.04-8.09 (4 H, m)

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

750.

Work example

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

Ethyl 2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate (0.24 g) and 1N NaOH (1.5 mL) a solution of ethanol (4 mL) was stirred at 80 ° C for 1 h. The reaction mixture was concentrated for a while

the concentrate was extracted water and ethyl acetate. Using IN HCl, achieved that of the aqueous layer pH would be 3-4 and got crystals. After recrystallization crystals of ethyl acetate and methanol mixture, obtained colorless crystals temperature (183-185 ° C). (0.15 g, 67%), melting C ₂₄ H ₂₀ N ₆ O ₃ elemental analysis C H N Estimated%: 64, 91 4.63 18.93 % Found: 65, 04 4.51 18.77

¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.38 (3H, t), 4.58 (2H, kv),

5.63 (2H, s), 6.67 (4H, sq), 7.17 (1H, t), 7.47-7, 68 (6H, m).

IR (KBr) cm ^-1 : 1710, 1550, 1480, 1280, 1240, 1040, 760.

Work example

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

A mixture of ethyl 1 - [(2'-cyanobiphenyl-4-yl) methyl] -2-propoxybenzimidazole-7-carboxylate (0.69 g) and trimethyltin azide (0.7 g) in toluene (15 mL) was heated in a vessel with Refrigerator. The reaction mixture was concentrated to dryness, then methanol (20 mL) and IN HCl (10 mL) were added. Stir at room temperature for 30 minutes using IN NaOH to bring the mixture to pH 3-4. After removal of the solvent, the residue was extracted with a mixture of chloroform and water. The organic layer was washed with water and dried, and the solvent was evaporated to dryness to give syrup. This syrup was purified by silica gel column chromatography to give crystals. Recrystallization from ethyl acetate / benzene gave colorless crystals (0.31 g, 43%), m.p. 157-159 ° C.

C ₂₇ H ₂₆ N ₆ O ₃ elemental analysis:

Calculated,% Found,%:

C H N

67.21 5.43 17.42

67.26 5.45 17.28

1 H-NMR (200 MHz, CDCl ₃ ) δ: 1.03 (3H, t), 1.13 (3H, t), 1.751, 92 (2H, m), 4.05 (2H, kv), 4, 23 (2H, sq), 5.57 (2H, s), 6.75 (2H, d), 6.90 (2H, d), 6.96 (2H, d), 7.28-7, 33 (1H, m), 7.397.44 (2H, m), 7.57-7, 62 (2H, m), 8.07-8.11 (1H, m).

IRiKBrJcm ¹ : 1720, 1540, 1470, 1430, 1280, 1250, 1130,

1020, 750.

Work example

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

Ethyl 2-propoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate (0.23 g) in ethanol (4 mL) containing 1N NaOH (1.5 mL) was heated at 80 ° C for 2 h. The reaction mixture was concentrated to dryness and the residue was extracted with water and ethyl acetate. Using IN HCl, the pH of the aqueous layer was 3-4 and crystals were obtained. Recrystallization from a mixture of ethyl acetate and methanol gave colorless crystals (0.15 g, 69%), m.p. 174-175 ° C.

Analysis of C ₂₅ H ₂₂ N ₆ 0 ₃ o, 3H ₂ O elements:

C H N

65.29 4.95 18.27

65.41 4.92 18.20

Calculated,% Found,%:

¹ H-NMR (200 MHz, DMSO-d 6 δ: 0, 92 (3H, t), 1.70-1, 87 (2H, m), 4.47 (2H, kv), 5.63 (2H, s), 6.96 (4H, dd), 7.16 (1H, t), 7.427, 67 (6H, m).

IR (KBr) cm ^-1 : 1700, 1550, 1430, 1290, 1240, 765.

Work example

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

A mixture of ethyl [1- (2'-biphenyl-4-yl) methyl] -2-mercaptobenzimidazole-7-carboxylate (4.1 g) and trimethyltin azide (8.0 g) in toluene (100 mL) was heated under reflux for 4 days. . The solvent was evaporated to dryness and the residue was stirred at room temperature for 20 minutes in a mixture of concentrated hydrochloric acid (2 ml) and methanol (20 ml). Then, 1N NaOH was added to the reaction mixture to bring the pH to 4 and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried, concentrated to dryness and obtained crystals. Recrystallization gave colorless crystals (5.0 g, 89%), m.p. 262-264 ° C (dec).

C ₂₄ H ₂₀ N ₆ O ₂ S. Analysis of 1 / 2H ₂ O elements:

Calculated,%: Found,%:

C

61.92 61.99

H

4.55

4.30

N

18.05

17.86 ^X H-NMR (200 MHz, DMSO-D _e ^: 1.10 (3H, t), 4, 09 (2H, q)

5.82 (2H, br, s), 6.87 (2H, d), 7.00 (2H, d), 7.26 (1H, t), 7.377, 69 (6H, m).

IR (KBr) <. j.720, 1460, 1440, 1365, 1340, 1260, 1180,

114 ^c .150, 1110, 990, 745.

'J Example of work

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

To ethyl 2-mercapto-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] benzimidazole-7-carboxylate (0.68 g) and ethanol (10 mL) containing 1N NaOH (3, 0 mL), methyl iodide (0.24 g) was added and the resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was then neutralized with dilute hydrochloric acid to give crystals. These crystals were purified using silica gel column chromatography. Recrystallization from ethyl acetate gave colorless prism crystals (0.3 g, 44%), m.p. 207-208 ° C (decomposition).

Analysis of C ₂ 5H ₂₂ N ₆ O ₂ S elements:

Calculated,% Found,%:

C H N

63.81 4.71 17.86

63.55 4.81 17.50 ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.13 (3H, t), 2.77 (3H, s), 4.14 (2H, s) , 5.62 (2H, s), 6.84 (2H, d), 7.26 (1H, t), 7.467.50 (5H, m).

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

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

Work example

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

To ethyl 2-mercapto-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-methyl] benzimidazole-7-carboxylate (0.91 g) and ethanol (13 mL) containing 1N NaOH (4, 0 ml), ethyl iodide (0.34 g) was added and the resulting mixture was stirred at room temperature for 4 hours. Using dilute hydrochloric acid, the reaction mixture was brought to pH 4 and crystals were obtained. They were collected by filtration, and the crystals were purified by silica gel column chromatography. Recrystallization from ethyl acetate gave colorless prism crystals (0.55 g, 57%), m.p. 153-154 ° C (decomposition).

Analysis of C ₂₆ H ₂₄ N ₆ O ₂ S elements:

Calculated,%: Found,%:

C H N

64.44 4.99 17.34

64.37 5.05 17.20 ¹ H-NMR (200 MHz, CDC1 ₃₎ δ: 1.19 (3H, t), 1.37 (3H, t), 3, 20 (2H, q) 4 , 12 (2H, sq), 5, 67 (2H, s), 6, 75 (2H, d), 6, 92 (2H, d), 7.05 (1H, t), 7.26-7, 34 (2H, m), 7.50 (1H, dd), 7, 53-7, 63 (2H, m),

8.05-8.11 (1H, m).

IR (KBr) cm ^-1 : 1715, 1540, 1420, 1365, 1345, 1280, 1195,

1145, 1110, 1035, 1015, 990, 760, 745.

Work example

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

To ethyl 2-mercapto-1 - [[2 '(1H-tetrazol-5-yl) biphenyl-4-yl) methyl] benzimidazole-7-carboxylate (0.91 g) and ethanol (13 mL) containing 1N NaOH Ethyl iodide (0.34 g) was added (4.0 mL) and the resulting mixture was stirred at room temperature for 5 hours. Using dilute hydrochloric acid, the reaction mixture was brought to pH 4 and crystals were obtained. The crystals were collected by filtration and purified by column chromatography on silica gel. Recrystallization from ethyl acetate / ether gave colorless prism crystals (0.40 g, 40%), m.p. 177-178 ° C (decomposition).

Analysis of C ₂₇ H ₂₆ N ₆ O ₂ S elements:

Calculated,% Found,%:

C H N

65.04 5.26 16.85

64.88 5.25 16 78 ¹ H-NMR (200 MHz, CDC1 ₃₎ δ: 1.04 (3H, t), 1. 19 (3H, t), 1.76 (2H, m), 3 , 18 (2H, t), 4, 12 (2H, sq), 5, 69 (2H, s), 6, 75 (2H, d), 6, 9 3 (2H, d), 7.05 (1H , t), 7.27-7.34 (2H, m), 7.50 (1H, dd), 7.547.63 (2H, m), 8.07-8.12 (1H, m).

IR (KBr) cm ^-1 : 1715, 1450, 1420, 1380, 1365, 1350, 1280,

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

Work example

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

A solution of ethyl 2-methylthio-1 - [(2'-tetrazol-5-yl) biphenyl-4-yl) methyl] benzimidazole-7-carboxylate (0.2 g) in methanol (5 mL) containing IN NaOH (1, 3 ml), heated in reflux for 2 hours. Using dilute hydrochloric acid, the reaction mixture was brought to pH 4 and crystals were obtained. The crystals were collected by filtration and purified by column chromatography on silica gel. Recrystallization from a mixture of ethyl acetate and ethane gave colorless prism crystals (0.17 g, 81%), m.p. 223-225 ° C (decomposition).

C ₂₃ H ₁₈ N ₆ O ₂ S. 1 / 2C ₄ H ₈ O ₂

C

Calculated,%: Found,%:

element analysis:

H

61.72

61.59

N

4.56 17.27

4.54 17.54 ¹ H-NMR (200 MHz, DMSO-d ₆₎ δ: 2.75 (3H, s), 5, 76 (2H, s), 6, 88 (2H, d), 7, 01 (2H, d), 7.25 (1H, t), 7.47-7, 66 (5H, m),

7.82 (1H, d).

IRiKBrJcm ' ¹ : 1710, 1485, 1450, 1420, 1370, 1345, 1320,

1280, 1245, 1195, 1150, 990, 780, 760.

Work example

2-Ethylthio-1-t [2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid

Ethyl 2-ethylthio-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] benzimidazole-7-carboxylate (0.35 g) in methanol (7 mL) containing 1N NaOH (2.2 ml) was heated in a refluxing vessel for 2 hours. After evaporation of the solvent, the HCl was brought to pH 3-4 by filtration of the aqueous layer and crystals were obtained. Recrystallization from a mixture of ethyl acetate and methanol gave colorless crystals (0.21 g, 84%), m.p. 209-210 ° C (decomposition).

Analysis of C ₂₄ H ₂₀ N ₆ O ₂ S elements:

Calculated,%: Found,%:

C

63, 14 62.89

H

4.42 4.35

N

18, 41 18.15 ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.39 (3H, t), 3.36 (2H, q), 5.76 (2H, s), 6 87 (2H, d), 7.01 (2H, d), 7.25 (1H, t), 7.47-7, 69 (5H, m), 7.82 (1H, dd).

IRiKBricm ' ¹ : 1695, 1450, 1415, 1350, 1275, 1225, 1190,

1180, 1145, 755, 740.

Work example

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

Ethyl 2-propylthio-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] benzimidazole-7-carboxylate (0.25 g) in methanol (5 mL) containing 1N NaOH (5 mL), heated in reflux for 2 hours. After removal of the solvent, 1N HCl achieved a water residue pH of 3-4 and obtained crystals which were filtered off. Recrystallization from a mixture of ethyl acetate and hexane gave colorless crystals (0.21 g, 91%), m.p. 222-223 ° C (dec.).

Analysis of C ₂₅ H ₂₁ N ₆ O ₂ S elements:

Calculated,% Found,%:

C H N

63, 95 4.51 17.90

63.78 4.85 17.59 ¹ H-NMR (200 MHz, DMSO-d ₆₎ δ: 0, 99 (3H, t), 1, 67 to 1.85 (2H m), 3.35 (2H , t), 5.77 (2H, s), 6.87 (2H, d), 7.01 (2H, d), 7.25 (1H, t), 7.46-7.70 (5H, m), 7.82 (1H, dd).

IRiKBrJcm ' ¹ : 1700, 1450, 1280, 1240, 1195, 1140, 755,

740.

Work example

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

A mixture of methyl 2-ethoxy-1 - [(2'-cyanobiphenyl-4-yl) methyl] -2-ethoxy-benzimidazole-7-carboxylate (2.80 g) in toluene (15 mL) was heated under reflux for 1 day. .

The reaction mixture was then concentrated to dryness. methanol (50 mL) and IN HCl (20 mL) were added to the residue and the mixture was stirred at room temperature for 30 min. Using NaOH, the reaction mixture was brought to pH 4 of the reaction mixture. The solvent removed in the form of a syrup was purified by silica gel column chromatography to give crystals.

Recrystallization from ethyl acetate / benzene gave colorless crystals (1.16 g, 56%), m.p. 191-193 ° C (dec.).

C ₂₅ H ₂₂ N ₆ O ₃ 1 / 5H ₂ O elemental analysis:

Calculated,% Found,%:

CHN 65.58 4.75 18.53

65.55 4, 93 18.35

1 H-NMR (200 MHz, CDCl ₃ ) δ: 1.43 (3H, t, s), 4.30 (2H, kv, J = 7.0Hz), 5.54

6.72 (2H, d, J = 8.2),

J = 7.0Hz), (2H, d,

3.57 (3H, J = 8.2),

5.54 (2H, s),

7.28-7, 33 (1H, m), 7.40 (1H, dd,

7.62 (2H, m), 8.03-807 (1H, m)

6.84-6.97 (4 H, m),

J = 1.8, 7.0Hz), 7.57IR (KBr) cm ^-1 : 1720, 1550, 1475, 1430, 1280, 1250, 1040, 755, 735.

Work example

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

A mixture of ethyl 1- [2'-cyanobiphenyl-4-yl) methyl] -2-ethylaminobenzimidazole-7-carboxylate (1.23 g) and trimethyltin azide (2.80 g) in toluene (15 ml) was heated under reflux for 40 hours. refrigerator. The precipitate was collected by filtration and suspended in methanol (50 mL). 1N HCl (15 mL) was added to the suspension and the mixture was stirred at room temperature for 10 minutes. Using NaOH, the reaction mixture was brought to pH 5 and then extracted with chloroform. The organic layer was washed with water, dried and concentrated to dryness. The residue was purified by silica gel column chromatography to give colorless crystals (0.83 g, 61%) after recrystallization from ethyl acetate-methanol, m.p. 166168 ° C.

1 H-NMR (200 MHz, CDCl ₃ ) δ: 1.13 (3H, t), 1.21 (3H, t),

3.43 (2H, kv), 4.13 (2H, kv), 5.48 (2H, d), 6.99 (2H, d), 7.7 (1H, t), 7.22 (1H) , dd), 7.42-7, 49 (2H, m), 7,547.69 (3H, m).

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

Work example

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

A mixture of ethyl 1- [2'-cyanobiphenyl-4-yl) methyl] -2-propylaminobenzimidazole-7-carboxylate (1.20 g) and trimethyltin azide (2.70 g) in toluene (15 ml) was heated under reflux for 50 hours. refrigerator. The precipitate was collected by filtration and suspended in methanol (20 mL). After the addition of IN HCl (15 mL), the reaction mixture was stirred at room temperature for 10 minutes. Using NaOH, the reaction mixture was brought to pH 5 and then extracted with chloroform. The organic layer was washed with water, dried and concentrated to dryness. The concentrate was purified by silica gel column chromatography to give crystals which, after recrystallization from ethyl acetate-methanol, gave colorless crystals (10 g, 77%), mp 170-172 ° C.

¹ H-NMR (200 MHz, 1.52-1.70 (2H, m),

s), 6.77 (2H, d), dd), 7.39-7.47 (2H,

IR (KBr) cm ^-1 : 1720,

CDC1 ₃₎ 0: 0.89 (3H, t)

3.35 (2H, t), 4.14 (2H,

6.99 (2H, d), 7.05 (1H,

m), 7.50-7, 65 (3H, m).

1.14 (3H, t),

q), 5.49 (2H,

t), 7.21 (1H,

1670, 1660, 1290, 1270, 760.

Work example

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

A solution of 2-ethoxy- [(2 '- (N-tetrazol-5-yl) biphenyl-4-yl) methyl] benzimidazole-7-carboxylic acid (2.07 g) in methylene chloride (10 mL) was added with trityl chloride (1.59). g) and triethylamine (0.8 g). The mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with water, dried, and concentrated to dryness. The residue was purified by silica gel column chromatography to give crystals. Recrystallization from ethyl acetate / benzene gave colorless crystals (2.12 g, 66%), m.p. 168-170 ° C. C ₄₃ H ₃₄ N ₆ O ₃ elemental analysis:

Estimated%:

C

75, 64

H

5, 02

N

12, 31

Found,%: 75.37 4.96 11.20 1 H-NMR (200 MHz, CDCl ₃ ) δ: 1.40 (3H, t), 4.61 (2H, s),

6.76 (2H, d), 6.91-6.96 (8H, m), 7.12 (1H, t), 7.177.41 (12H, m), 7.6 (1H, dd), 7 , 73-7.83 (2 H, m)

Work example

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

To a solution of 2-ethoxy-1 - [[2 '- (N-triphenylmethyl-tetrazol-5-yl) -biphenyl-4-yl] -methyl] -benzimidazole-7-carboxylic acid (2.2 g) in dimethylformamide (10 mL) was added potassium carbonate ( 0.53 g) and pivaloyloxymethyl iodide (0.94 g) and the resulting mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried. After removal of the solvent, the residue was dissolved in methanol (30 mL) and IN HCl (6 mL). The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness and partitioned between water and ethyl acetate. The organic layer was washed with water and dried. After removal of the solvent, the residue was purified by silica gel column chromatography to give crystals, which were recrystallized from ethyl acetate-hexane to give colorless crystals (1.13 g, 63%), mp 104104 ° C.

C ₃₀ H ₃₀ N ₆ O ₅ 1 / 5C ₄ H ₈ O ₂ 1 / 5C ₆ H ₁₄ elemental analysis:

o · o ·

N

14.32

14.43

C

65.06

64.79

H

5, 90 5, 85

Calculated,% Found:

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.13 (9H, s), 144 (3H, t), 4.37 (2H, kv), 5.61 (2H, s), 5.68 (2H, d), 6.93 (2H, d),

6.99-7.11 (2H, m), 7.33-7.37 (1H, m), 7.49-7.54 (1H, m), 7.59-7.62 (2H, m) ), 8.03-8.07 (1H, m).

Work example

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

To a solution of 2-ethoxy-1 - [[2 '- (N-triphenylmethyl-tetrazol-5-yl) -biphenyl-4-yl] -methyl] -benzimidazole-7-carboxylic acid (0.5 g) was added potassium carbonate (0 , 12 g) and cyclohexyl-1-iodethyl carbonate (0.26 g). The resulting mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried. After removal of the solvent, the residue was dissolved in methanol (10 mL) and treated with IN HCl (2 mL). The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness and partitioned between water and ethyl acetate. The organic layer was washed and dried. After removal of the solvent, the residue was purified by silica gel column chromatography to give a colorless powder (0.21 g, 47%), m.p. 103-106 ° C.

C ₃₃ H ₃₄ N ₆ O ₆ elemental analysis:

Calculated,% Found,%:

C

64, 91, 64.94

H

5, 61 5.71

N

13.76 13, 66

Ethanol was added to the resulting powder (1.0 g). The mixture was stirred at room temperature for 3 hours and left to cool under ice. The mixture was then stirred for 1 hour at room temperature but not higher than 10 ° C. The resulting crystals were collected by filtration and washed with cold ethanol. The crystals were dried for 9 hours at 25 ° C under reduced pressure and then for a further 18 hours at 35 ° C

tempetarūroj e and received white splat crystals in the form of powder (0.94 (g) melting point: 158-166 ° C (decomposition). C ₃₃ H ₃₄ N ₆ O ₆ elements analysis: C H N Estimated%: 64.91 5.61 13.76 % Found: 64.73 5, 66 13, 64

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 13-14.84 (16H, m), 4,284.55 (3H, m), 5.65 (2H, d), 6.72 (1H, q), 6.81 (2H, d),

6.93 (2H, d), 7. 03 (1H, t), 7.22-7, 23 (1H, m), 7.377.36 (1H, m), 7.52-7.60 (3H, m), 8.02-8.07 (1H, m).

IR (KBr) cm ^-1 : 2942, 1754, 1717, 1549, 1476, 1431, 1076, 1034, 750.

MS (m / z: 611 [M + H] ⁺⁾ .

Work example

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

A mixture of methyl [1- [2'-cyanobiphenyl-4-yl) methyl] -2-methoxy-benzimidazole-7-carboxylate (1.60 g) and trimethyltin azide (1.50 g) in toluene (15 mL) was heated for 40 hours. in a container with reflux. The precipitated crystals were dissolved in methanol (10 mL) and IN HCl (3 mL) was added. The mixture was stirred at room temperature for 10 minutes and the methanol was evaporated. Using NaOH, the aqueous layer was brought to pH 3-4 and then extracted with ethyl acetate. The organic layer was washed with water and dried. The residue was purified by silica gel column chromatography to give crystals which were recrystallized from ethyl acetate to give colorless prism crystals (0.65 g, 65%), m.p. 165-166 ° C.

Analysis of C ₂₄ H ₂₀ N ₆ O ₃ 1/10 H ₂ O elements:

Calculated,%: Found,%:

C H N

65, 18 4, 60 19, 00

64.91 4.49 18.99 ^X H-NMR (200 5.55 (2H, s), 7.36 (1H, m), 8.03 to 8.07 (1H,

MHz, CDCl ₃ ) δ: 6.75 (2H, d) 7.49 (1H, dd), m).

3.64 (3H, s), 3.93 (3H, s), 6.90-7.01 (4H, m), 7.377.55-7.64 (7.55-7.64 (2H, m),

Work example

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

To a solution of 2-methoxy-1 - [[2 '- ¹ (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] benzimidazole-7-carboxylate (0.22 g) in methanol (10 mL) was added 1N NaOH. (1.5 mL). The mixture was heated to reflux for 6 hours. The reaction mixture was concentrated to dryness and water was added to the residue. With IN HCl, the pH of the mixture was reached

3- 4 and obtained crystals. Recrystallization from methanol-chloroform gave colorless needle-like crystals. (0.17 g, 77%), mp 208209 ° C.

C ₂₃ H ₁₈ N ₆ O ₃ Analysis of 0.7H ₂ O elements:

Calculated,% Found:

C

62, 92 62, 81

H

4.45

4.08

N

19.14 19, 19

1 H-NMR (200 MHz, DMSO-d 6) δ: 4.15 (3H, s), 5.63 (2H, s),

6.90 (2H, d), 7.00 (2H, d), 7.18 (1H, t), 7.46-7.70 (6H, m)

Work example

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

To a solution of ethyl 2-ethylamino-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl4] benzimidazole-7-carboxylate (0.52 g) in ethanol (5 ml) was added 1N NaOH (4 ml) and stirred for 2 hours at 80 ° C. The reaction mixture was concentrated to dryness, and using a water residue of pH 4-5,

IN HCl reached and obtained crystals, recrystallized from methanol

242 ° C.

and chloroform mixture, gave colorless (0.3 g, 63.4%) melting point: 240C ₂₄ H ₂₁ N ₇ O ₂ 1.1H ₂ O elemental analysis:

Calculated,%: Found,%:

C

62.76

62.65

H

5, 09, 5.15

N

21.35

21.23 ¹ H-NMR (200 MHz, DMSO-d _fi) 6: l, 20 (3H, t), 3.43 (2H, q), 5, 62 (2H, s), 6.85 (2H , d), 6.99 (2H, g), 7.34 (1H, d), 7.44-7.68 (5H, m).

Work example

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

The title compound (yield 73%, mp 244-246 ° C) was obtained using the procedure described in Working Example 47.

C ₂₅ H ₂₃ N ₇ O ₂ 1 / 2H ₂ O elemental analysis:

Calculated,% Found,%:

C

64.92

64.79

H

5.23

5.27

N

21.20

21.08

The following compounds (Working Examples 49-53) were obtained using the procedure described in Working Example 43.

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

Yield 55%, melting point 122-125 ° C (decomposition). C ₂₉ H ₂₄ N ₆ O ₆ CHC _{1 3} elemental analysis: C H N Calculated,%: 53.63 3, 75 12.51 Found,%: 53.32 3.58 12.24 ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.43 (3H, t), 2.11 (3H, s), 4.40 (2H, sq), 4.80 (2H, s), 5.58 (2H, s), 6.79 (2H, d), 6.94 (2H, d), 7. 02 (1H, t), 7.15 (1H, dd), 7.35-7.39 (1H, m), 7.49-7.63 (3H, m), 8.00-8.04 (1H, m).

Work example

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

Yield 38%, m.p. 152-154 ° C (decomposition).

C ₂₇ H ₂₄ N ₆ O ₅ elemental analysis:

C

Calculated,%: 63.27

Received,%: 63.55 ¹ H-NMR (200 MHz, CDC1 ₃₎ 6: 1.43 (3H,

4.33 (2H, sq), 5.61 (2H, s), 5.69 (2H,

6.93 (2H, d), 7.01 (1H, t), 7.13 (H, d), 7.53-7.62 (3H, m), 8.03-8.07 (1H, m).

H N 4.72 16, 40 4.70 16, 18th t), 2.01 ( 3H, s), s), 6.81 (2H, d), 7.33-7.38 (IH, m),

Work example

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

Yield 60%, m.p. 145-150 ° C (decomposition).

C ₂ gH ₂₆ N ₆ O ₅ .0.2C ₇ H ₈ elemental analysis:

Calculated,% Found,%:

C H N

64.79 5.10 15.42

64.70 5.10 15.44 ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.04 (3H, t), 1.44 (3H, t),

2.29 (2H, sq), 4.40 (2H, sq), 5.61 (2H, s), 5.71 (2H, s),

6.82 (2H, d), 6, 92-7.14 (3H, m), 7.2O (1H, m), 7.377.38 (1H, m), 7.53-7.61 (3H, m), 8.03-8.08 (1H, m).

Work example

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

Yield 36%, mp 96-100 ° C.

C ₂₉ H ₂₈ N ₆ O ₅ 0.4C ₇ H ₈ elemental analysis:

Calculated,%: Received,%:

C

66.15 66, 1

H

5.45 5, 44

N

14.55 14, 65

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.85 (3H, t), 1.44 (3H, t), 1.55 (2H, m), 2.24 (2H, sq), 4.38 (2H, sq), 5.61 (2H, s), 5.70 (2H, s), 6.81 (2H, d), 6.93 (2H, d), 7.00 (1H, t), 7.20 (1H, m), 7.33-7.38 (1H, m), 7.52-7.61 (3H, m), δ, 01- 8.10 (1H, m). 53 Working example

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

Yield 53%, m.p. 143-145 ° C.

Analysis of C ₂₉ H ₂₈ N ₆ O ₅ 0, lC ₇ H ₈ elements:

Calculated,%: Found,%:

C

64.88 65, 04

H

5.28

5.25

N

15.29 15.18

ABMR (200 MHz, CDCl ₃ ) δ: 09 (2H, s), 1.44 (3H, t),

2.50 (1H, m), 4.38 (2H, sq), 5.61 (2H, s), 5.70 (2H, s),

6.81 (2H, d), 6.91-7.00 (3H, m), 7.19 (1H, m), 7.377.37 (1H, m), 7.51-7.63 (3H, m), 8.02-8.01 (H, m).

The following compounds (54-56 Working examples) were obtained using the procedure described in Working Example 44.

Work example

1- (Ethoxycarbonyloxy) ethyl 2-ethoxy-1 - [[2'- (tetrazol5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate

Yield 44%, m.p. 85-87 ° C.

C ₂₉ H ₂₈ N ₆ O ₆ 0.3H ₂ O elemental analysis:

Calculated,% Found,%:

C H N

61.98 5, 13 14, 95

62.11 5.02 14.69

t), 1.30 (3H,

4.31-4.47 (1H,

1 H-NMR (200MHz, CDCl ₃ ) δ: 20 (3H,

1.41 (3H, t), 4.03-4.22 (3H, m),

5.61 (2H, s), 6, 62-6, 72 (3H, m), 6, 80-6, 95 (4H, m), 7.297.32 (1H, m), 7.47 (1H, dd), 7.54-7, 64 (2H, m), 7.978.01H, m).

d), m),

Work example

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

Yield 31%, mp 105-107 ° C. C _2S H ₂₆ N ₆ O ₅ 0.5 H ₂ O elements analysis: C H N Estimated%: 62, 80 5, 08 15, 69 Received, %: 62.77 4.69 15, 85

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.46 (3H, t), 1.49 (3H, d),

4.47-4.62 (2H, m), 5.59 (1H, d), 5.83 (1H, d), 6.84 (1H, kv), 6.90 (2H, d), 7 , 03 (2H, d), 7.11 (1H, t), 7.477.39 (1H, m), 7.49 (1H, d), 7.53-7.61 (3H, m), 8, O7-8.11H, m).

Work example

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

Yield 33%, m.p. 74-76 ° C.

C ₃₀ H ₃₀ N ₆ O ₅ Analysis of 1.5 H ₂ O elements:

Calculated,% Found,%:

C H N

61.95 5.72 14.45

62.02 5.43 14.20 ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.20 (3H, d), 1.21 (3H, d), 1.30 (3H, d), , 42 (3H, t), 4.08-4.24 (1H, m), 4.344.5O (1H, m), 4.79 (1H, m), 5.61 (2H, s), 6, 62-6, 75 (3H,

m), 7.27-7.32 (1H, m), 7.48 (1H, dd), 7.54-7, 64 (2H, m),

7.98-8.03 (1H, m).

Work example

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

The above compound was obtained using the method described in Working Examples 40 and 47

Yield 40%, melting point: 247-250 ° C (decomposition),

C ₂₃ H ₁₉ N ₇ O ₂ Analysis of 2.0 H ₂ O elements:

Calculated,%: Found,%:

C

59, 86 59, 88

H

5, 02 4.89

N

21.25

21.36 ^r H-NMR (200 MHz, CDC1 ₃₎ 5: 2.94 (3H, s), 5, 64 (2H, s), 6, 82 (2H, d), 6.99 (2H, d ), 7. 0 (1H, t), 7.31 (1H, d), 7.42-7, 63 (5H, m)

The following compounds (58-60) were obtained using Working Example 43

Work examples) as described.

Work example

Cyclohexylcarbonyloxymethyl 20-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate

Yield: 54%, melting point: 140-142 ° C.

C ₃₂ H ₃₂ N ₆ O ₅ elemental analysis:

Calculated,% Found,%:

C H N

66.19 5.55 14.47

65.93 5.46 14.39 ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.21-1.87 (13H, m) 2.20-2.23 (1H m), 4.47 ( 2H, kv), 5.60 (2H, s), 5.73 (2H, s), 6.86 (2H)

d), 7. 107 (1H, m), 7.27-7.40 (3H, m), 7.54-7.61 (2H, m) 8.05-8.09 (1H, m)

Work example

Benzyloxymethyl 2-ethoxy-1 - [[2'- (1H-tetrazol-5-yl) bi-phenyl-4-yl] methyl] benzimidazole-7-carboxylate

Yield 47%, m.p. 138-142 ° C.

C ₃₂ H ₂₆ N ₆ O ₅ .0.5H ₂ O. Analysis of 0, 1H ₈ O ₂ elements:

Calculated,% Found,%:

C H N

65.67 4.76 14.18

65.71 4.66 13.96 ¹ H-NMR (200 MHz, CDC1 ₃₎ 5: 1.43 (3H,

5.60 (2H, s), 5.98 (2H, s), 6.74 (4H,

7.09-7.14 (1H, m), 7.21-7.36 (3H, m),

7.90 (2H, d), 8, 02-8.06 (1H, m)

Work example

m), 4.36 (2H,

s), 6.99 (1H,

7.50-7.59 (4H,

q) r m), m), (E) -Cinnamoyloxymethyl 2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate

Yield: 56%, melting point: 146-147 ° C.

Analysis of C ₃₄ H ₂₈ N ₆ O ₅ .0,4C ₄ H ₈ O ₂ :

Calculated,% Found,%:

1 H-NMR (200 5.61 (2H, s),

7.5 (1H, t),

8.04 (1H, m).

C H N

67.16 5.07 13.20

66.97 4.86 13.28

MHz, CDCl ₃ ) δ: 1.44 (3H, m), 4.45 (2H, kv),

5.87 (2H, s), 6.33 (1H, d), 6.84 (2H, d),

7.31-7.57 (10H, m), 7.65 (1H, d), 8.00 The following compounds (61-63 in Working Examples) were obtained using the procedure described in Working Example 43.

Work example

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

Yield: 54%, m.p. 136-138 ° C.

C ₃₁ H ₃₀ N ₆ O ₅ elemental analysis:

Calculated,%: Found,%:

CHN 65.71 5.34 14.83

65.59 5.33 14.67

1 H-NMR (200 MHz, CDCl ₃ ) δ:

2.76 (1H, m), 4.43 (2H, kv),

6.84 (2H, d), 6.96 (2H, d),

1.41-1.84 (11H, 5.61 (2H, s),

7.5 (1H, t),

m), 7.35-7.39 (1H, m), 7.53-7.61 (3H, m),, m), 2,615.72 (2H, s),

7.22-7.26 (1H, 8.03-8.08 (1H,

m)

Work example

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

Yield 59%, melting point; 130-135 ° C.

C ₃₀ H ₃₁ N ₇ O ₄ .0,4CHCl ₃ .0,2H ₂ O elemental analysis:

C H N Estimated %: 60.36 5.30 16, 21st % Found: 60.20 5.20 16, 08 ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.12 (9H, s), 1.20 (3H, m), 3.43 (2H, kv), 5.52 (2H, s), 5.81 (2H, s), 6.80 (2H, d),

7.43-7.68 (5H,

6.99 (2H, d), 7.8 (1H, t), 7.24 (1H, dd), m).

Work example

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

Yield 76%, m.p. 149-152 ° C.

C ₃₃ H ₃₅ N ₇ O ₅ .0. 5H ₂ O elemental analysis:

Calculated,%: Found,%:

C H N

64.06 5.86 15.85

64.27 6, 02 15, 86 ^{X 1} H-NMR 3.47 (2H, 6.88 (5H, 7.51 (3H,

(200 MHz, CDCl ₃ ) δ: 1, 12-1.88 (16H, m), 3, 38- m), 4.48-4.59 (1H, m), 5.51 (2H, s), 6.75- m), 7.4 (1H, t), 7.29-7, 40 (2H, m), 7, 47- m), 7, 91-7.95 (1H, m).

Work example

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

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

Yield: 30%, melting point: 154-156 ° C.

C ₂₆ H ₂₂ N ₆ O ₃ .0,5H ₂ O elemental analysis:

Calculated,%: Found,%:

C

65, 67 65, 63

H

4.88 4.71

N

17, 67 17, 68 ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.75 (3H, d), 4.58-4, 61 (1H, m),

4.92-4.95 (1H, m), 5.18-5.48 (2H, m), 5.52 (2H, d), 5.836.15 (1H, m), 6.98-7, 05 (2H, m), 7.09-7.17 (2H, m), 7.357.44 (2H, m), 7.47-7.60 (3H, m), 8, 09-8.19 ( 1H, m).

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

Work example

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

The title compound was obtained as colorless needle crystals from methyl 2-butoxy-1 - [(2'-cyanobiphenyl-4-yl) methyl] benzimidazole-7-carboxylate according to the procedure described in Working Example 28.

Yield 91%, melting point 146-148 ° C.

C ₂₇ H ₂₆ N ₆ O ₃ . element analysis:

C H N

Estimated %: 67.21 5.43 17.42 % Found: 67.00 5.45 17.49 ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.99 (3H, t), 1.37-1. , 55 (2H, m), 1.74-1.88 (2H, m), 3.61 (3H, s), 4.27 (2H, t) , 5.53 (2H, s), 6.75 (2H, d), 6.90 (2H, d), 6.97 (2H, d), 7.30- 7.34 (1H, m), 7.41 (2H, dd), 7.57-7.61 (2H, m), 8.04- 8.09 (1H, m). IR (KBr) cm ^-1 : 1720, 1600, 1540, 1470, 1430, 1270, 1250, 1020, 750.

Work example

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

The title compound was obtained as colorless crystals from methyl 2-butylamino-1 - [(2'-cyanobiphenyl-4-yl) methyl] benzimidazole-7-carboxylate according to the procedure described in Working Example 41.

Yield 42%, mp 216-218 ° C.

C27H27N7O2 .H ₂ O Elemental analysis

C H N

Estimated%: 64, 91 5.85 19.63 % Found: 64.86 5.68 19.41 ¹ H-NMR (200 MHz, m), 1.52-1.67 (2H, d), 6.98-7.05 (3H, DMSO-d ₆₎ δ: 0.91 (3H, m), 3, 65 (3H, s) 5, m), 7.18 (1H, dd), t), 1.25-1.43 (2H 47 (2H, s), 6.79 (2H 7.42-7.64 (5 H, m). IR (KBr) cm ^-1 : 1720, 1665, 1660, 1650, 1430, 1260, 745. 67 Work example

f f

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

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

Yield 62%, m.p. 163-167 ° C.

Analysis of C ₂₇ H ₂₅ N ₇ O ₃ .0.6CHCl ₃ O:

C H N

Estimated %: 58.45 4.55 17.29 % Found: 58, 66 4.36 17.54 ¹ H-NMR (200 3, 90 (4H, t), 7.17 (1H, t), 7.61 (2H, m), MHz, CDCl ₃ ) δ: 3.33 (4H, 5.44 (2H, s), 6.62 (2H, 7.33-7.38 (1H, m), 7.43-8.08-8 13 (1H, m). t), 3.73 (3H, s), d), 6.97 (2H, d), 7.50 (2H, m), 7.55-

IR (KBr) cm ^-1 : 1730, 1600, 1630, 1455, 1420, 1405, 1282, 1260, 1120, 1110, 1000, 760, 750, 740.

Work example

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

The title compound was obtained as colorless crystals from methyl 1 - [(2 '-cyanobiphenyl-4-yl) methyl] pipridinobenzimidazole-7-carboxylate according to the procedure described in Working Example 41.

Yield: 47%, melting point: 146-150 ° C.

C ₂₈ H ₂₇ N ₇ O ₂ .0,8CHC _{1 3-} element analysis:

C H N Estimated %: 58.72 4.76 16, 64 % Found: 58.69 4, 66 16, 75 ¹ H-NMR (200 L MHz, CDCl ₃ ) δ: 1.72 (6H r Pi s), 3.11 (4H, m) 3.61 (3H, s), 5.38 (2H, s), 6.45 (2H, d), 6.80 (2H, d) 6, 89-6, 96 (2H, m), 7.28-7.37 (2H, m), 7.56-7.64 (2H, m) 8.01-8.06 (1H, m).

IR (KBr) cm ^-1 : 1715, 1600, 1530, 1450, 1420, 1415; 1405, 1300, 1280, 1260, 1240, 1215, 1130, 770, 760, 750.

Work example

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

The title compound was obtained as colorless crystals from methyl 2-ethylmethylamino-1 - [(2'-cyanobiphenyl-4-yl) methyl] benzimidazole-7-carboxylate according to the procedure described in Working Example 41.

Yield 54%, m.p. 130-136 ° C (dec.).

Analysis of C ₂₆ H ₂₅ N ₇ O ₂ .0, 6H ₂ O elements:

Calculated,%: Found,%:

C H N

59.26 4.79 18.19

59.04 4.95 18.05 ¹ H-NMR (200 3.22 (2H, s);

6.78-6.94 (4H, 7.63 (2H, m),

t), 2.57 (3H, s),

s), 6.43 (2H, d),

7.57 (1H, dd), 7,59MHz, CDC1 ₃₎ 5: 1.19 (3H, 3, 62 (3H, s), 5.40 (2H,

m), 7.30-7.34 (1H, m),

6.78-6.94 (1H, m)

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

Work example

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

The title compound was obtained as colorless crystals from methyl 1 - [[2 '-tetrazol-5-yl) methyl] biphenyl-4LT 3246 B

100 ii] methyl] -2-piperidinobenzimidazole-7-carboxylate according to the procedure described in Working Example 29.

Yield 91%, mp 215-218 ° C (decomposition).

C ₂₇ H ₂₅ N ₇ O ₂ .0,5CHC1 ₃ elemental analysis

Calculated,% Found,%:

C H N

61.25 4.77 18.18

60.95 4.70 17.90 ¹ H-NMR (200 MHz, DMSO-d 6 δ: 1.67 (6H, pi s), s), 5.48 (2H, s), 6.71 (2H, d), 6.92 (2H, d), 7.42-7.48 (2H, m), 7.54-7, 67 (2H, m).

3.24 (4H, pi 7.17 (1H, t),

IR (KBr) cm ^-1 : 1685, 1530, 1450, 1440, 1420, 1400, 1285, 1270, 1245, 750, 730.

Work example

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

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

Yield: 59%, m.p. 202-206 ° C (decomposition).

C ₂₆ H ₂₃ N ₇ O ₃ .0, 6CHC _{1 3} elemental analysis:

Calculated,%: Found,%:

C

57.76

57.55

H

4.30

4.25

N

17.73 17, 66

101 ¹ H-NMR (200 MHz, DMSO-d _p) 8: 3.24 (4H, br s), 3.76 (4H, br

s), 5.56 (2H, s), 6.72 (2H, d), 6.93 (2H, d), 7.16 (1H, t), 7.41-7.70 (6H, m). ).

IR (KBr) cm ^-1 : 1690, 1535, 1460, 1450, 1420, 1410, 1290, 1260, 1245, 1120, 760, 740.

Work example

2- (N-Ethylmethylamino) -1 - [[2 '- (1H-tetrazol-5-yl) biphenyl4-ii] methyl] benzimidazole-7-carboxylic acid

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

Yield 66%, mp 204-206 ° C (decomposition).

C25H23N7O2 · 0.5 H ₂ O element analysis:

Calculated,% Found,%:

C H N

64.92 5.23 21.20

65.22 5.31 21.11 ¹ H-NMR (200 3.27 (2H, m),

7.13 (1H, t),

MHz, CDCl ₃ ) δ: 1.13 (3H,

5.54 (2H, s), 6.68 (2H,

7.43-7.48 (2 H, m), 7.53-7

t), 2.93 (3H,

d), 6.92 (2H,, 67 (2H, m).

s), d),

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

102

Work example

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

The title compound was obtained as colorless crystals from methyl 2-butylamino-1 - [[2'-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate according to the procedure described in Working Example.

Yield 67%, m.p. 213-216 ° C (decomposition).

C ₂₆ H ₂₅ N ₇ O ₂ H ₂ O elemental analysis:

Calculated,% Found,%:

C H N

64,32 5, 60 20, 19

64.07 5.77 20.16 ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 0.89 (3H, t), 1.24-1.41 (2H,

m), 1.51-1.66 (2H, m), 3.34-3.43 (2H, m), 5.65 (2H, s),

6.83 (2H, d), 6.97-7.05 (3H, m), 7.29 (1H, dd), 7.407, 67 (5H, m).

IR (KBr) cm ^-1 : 1660, 1580, 1540, 1485, 1440, 1380, 1215, 850, 810, 780, 760, 750.

Work example

2-Ethoxy-1 - [(2'-carboxyphenyl-4-yl) methyl] benzimidazole-7-carboxylic acid

To a solution of methyl 2-ethoxy-1 - [(2'-methoxycarbonylbiphenyl-4-yl) methyl] benzimidazole-7-carboxylate (0.7 g) in methanol (10 mL was added 1N NaOH (5 mL)) and the mixture was stirred for 80 hours. C. After evaporation of methanol, the aqueous residue was neutralized with IN HCl to give crystals.

103

These crystals were recrystallized from a mixture of methanol and chloroform to give colorless crystals (0.54 g, 83%), m.p. 213-215 ° C.

C ₂₄ H ₂₀ N ₂ O ₅ elemental analysis:

Calculated,% Found,%:

C

69.22 68, 98

H

4, 84 4.89

N

6.73

6.71 ¹ H-NMR 9200 MHz, DMSO-d ₆₎ δ: 1.42 (3H, t), 4.61 (2H, q)

5.68 (2H, s), 7.01 (2H, d), 7, 13-7.56 (7H, m), 7.647.71 (2H, m).

IR (neat) cm ^-1 : 1725, 1545, 1460, 1420, 1380, 1280,

1260, 1230, 1205, 1120, 1030, 750.

Work example

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

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

Yield 63%, mp 256-258 ° C.

C ₂₅ H ₂₃ N ₇ O ₂ H ₂ O elemental analysis:

Calculated,%: Found,%:

C

63, 68 63, 99

H

5, 34 5, 09

N

20.79 20, 68

104 ¹ H-NMR (200 MHz, DMSO-d6 δ: 1.21 (3H, t), 3.40-3, 60 (2H,

m), 3.63 (3H, s), 5.47 (2H, s), 6.78 (2H, d), 6.987.05 (3H, m), 7.18 (1H, dd), 7, 42-7, 66 (5H, m).

IR (pure) cm ^-1 : 1710, 1660, 1650, 1645, 1430, 1340,

1300, 1280, 1250, 1050, 740.

Work example

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

The title compound was obtained as colorless needle-like crystals (0.37 g, 77%) from methyl 1 - [(2'-cyanobiphenyl-4-yl) -2- (2,2,2-trifluoroethoxy) benzimidazole-7-carboxylate ( 0.48 g) according to the procedure described in Working Example 28.

Melting point: 210-212 ° C.

C ₂₅ H ₁₉ F ₃ N ₆ O ₃ elemental analysis:

Calculated,% Found,%:

C H N

59.06 3.77 16.53

59.02 3.71 16.36

1 H-NMR (200 MHz, CDCl ₃ ) δ: 3.82 (3H,

5.64 (2H, s), 6.99 (2H, d), 7.14 (2H,

7.37-7.41 (1H, m), 7.51-7.63 (3H, m), 8.22 (1H, m).

s), 5.01 (2H, q),

d), 7.25 (1H, t),

7.71 (1H, dd), 8.17 IR (KBr) cm ^-1 : 1710, 1550, 1425, 1275, 1240, 1180, 1160, 1055, 750.

105

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

The title compound was obtained as colorless crystals (0.23 g, 88%) from methyl 1 - [[1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -2- (2,2,2-trifluoro) fluoroethoxy) benzimi10 dazole-7-carboxylate (0.27 g) according to the procedure described in Working Example 47.

Melting point: 204-206 ° C.

Analysis of C ₂₄ H ₁ 7N ₇ F ₃ N ₆ O ₃ H ₂ O Elements:

Calculated,% Found,%:

C

57.26

57.09

H

3, 60 3.59

N

16 16.72 69 ¹ H-NMR (200 MHz, DMSO-d _e) δ: 5.28 (2H, q), 5.66 (2H, s);

6.98 (2H, d), 7.23 (1H, t), 7.44-7, 68 (5H, m), 7.12 (1H, dd),

IR (KBr) cm ^-1 : 1690, 1540, 1470, 1430, 1270, 1225, 1210, 1160, 1050, 740.

106

Compounds in the Table according to the procedures described in the Comparative and Working Examples.

TABLE I

TABLE I (cont'd)

The compound No. R ^la _R 2a _R 3a R ^4a rSh R ^6a 78 OEt Me H H Tet COOH 79 OEt OMe H H Tet COOH 80 OEt NHMe H H Tet COOH 81 OEt F H H Tet COOH 82 OEt Cl H H Tet COOH 83 OEt Br H H Tet COOH 84 OEt cf ₃ H H Tet COOH 85 OEt H Me H Tet COOH 86 OEt H OMe H Tet COOH 87 OEt H NHMe H Tet COOH 88 OEt H F H Tet COOH 89 OEt H Cl H Tet COOH 90 OEt H Br H Tet COOH 91 OEt H cf ₃ H Tet COOH 92 OEt H H Me Tet COOH 93 OEt H H OMe Tet COOH 94 OEt H H NHMe Tet COOH

107

TABLE I (cont'd)

The compound No. R ^la R ^2a R ^3a R ^4a R ^5a R ^6a 95 OEt H H F Tet COOH 96 OEt H H Cl Tet COOH 97 OEt H H Br Tet COOH 98 OEt H H cf ₃ Tet COOH 99 OEt Me H H COOH COOH 100 OEt H Me H COOH COOH 101 OEt H H Me COOH COOH 102 OEt H H H COOH COOH 103 OEt Cl H H COOH COOH 104 OEt H Cl H COOH COOH 105 OEt H Cl H COOH COOH 106 SEt Me H H Tet COOH 107 NHMe H Me H Tet COOH 108 OMe H H Me Tet COOH 109 OPr H H H Tet COOH 110 SMe Me H H Tet COOH 111 OMe H H H Tet Tet 112 OEt H H H Tet Tet 113 OEt Me H H Tet Tet 114 OEt H / Tet COOH 115 OEt & H Tet COOH 116 OEt H H H Tet cooch ₂ oco- cyclo-Pr 117 OEt H H H Tet COOCH ₂ OCO- ant-Bu

108

TABLE I (cont'd)

The compound No. R ^la R ^2a R ^3a R ^4a _R 5a R ^5a 118 OEt H H H Tet COOCH ₂ OCO-n- Bu 119 OEt H H H Tet COOCH ₂ OCO- cyclo-Bu 120 OEt H H H Tet COOH ₂ OCO-n- Pen 121 OEt H H H Tet COOCH ₂ OCO-i- Pen 122 OEt H H H Tet COOCH ₂ OCO- antr-Pen 123 OEt H H H Tet COOCH ₂ OCO-n- Hex 124 OEt H H H Tet COOCH ₂ OCO- antr-Hex 125 OEt H H H Tet COOCH ₂ OCO-n- Hep 126 OEt H H H Tet COOCH ₂ COOCH ₂ Ph 127 OEt H H H Tet COOCH (Me) - OCOEt 128 OEt H H H Tet COOCH (Me) - OCO-n-Pr 129 OEt H H H Tet COOCH (Me) - OCO-i-Pr 130 OEt H H H Tet COOCH (Me) - OCO-cyclo-Pr 131 OEt H H H Tet COOCH (Me) - OCO-n-Bu 132 OEt H H H Tet COOCH (Me) - OCO-i-Bu

109

TABLE I (cont'd)

The compound No. R ^la R ^2a R ^3a R ^4a rSH R ^6a 133 OEt H H H Tet COOCH (Me) - OCO-antr-Bu 134 OEt H H H Tet COOCH (Me) - OCO-tert-Bu 135 OEt H H H Tet COOCH (Me) - OCO-cyclo-Bu 136 OEt H H H Tet COOCH (Me) - OCO-n-Pen 137 OEt H H H Tet COOCH (Me) - OCO-i-Pen 138 OEt H H H Tet COOCH (Me) - OCO-sec-Pen 139 OEt H H H Tet COOCH (Me) - OCO-cyclo-Pen 140 OEt H H H Tet COOCH (Me) - OCO-n-Hex 141 OEt H H H Tet COOCH (Me) - OCO-i-Hex 142 OEt H H H Tet COOCH (Me) - OCO-sec-Hex 143 OEt H H H Tet COOCH (Me) - OCO-cyclo-Hex 144 OEt H H H Tet COOCH (Me) - OCO-n-Hep 145 OEt H H H Tet COOCH (Et) - OCO-n-Pr 146 OEt H H H Tet COOCH (Mon) - OCO-n-Bu

110

TABLE I (cont'd)

The compound No. R ^la R ^2a R ^3a R ^4a _R 5a _R 6a 147 OEt H H H Tet COOCH (iPr) - OCO-n-Pr 148 OEt H H H Tet COOCH (Me) - OCO-OMe 149 OEt H H H Tet COOCH (Me) - OCO-O-n-Pr 150 OEt H H H Tet COOCH (Me) - OCO-O-i-Bu 151 OEt H H H TEt COOCH (Me) - OCO-O-sec-Bu 152 OEt H H H Tet COOCH (Me) - OCO-O-n-Pen 153 OEt H H H Tet COOCH (Me) - OCO-O-i-Pen 154 OEt H H H Tet COOCH (Me) - OCO-O-cyclo- Fri. 155 OEt H H H Tet COOCH (Me) - OCO-O-n-Hex 156 OEt H H H Tet COOCH (Me) - OCO-O-cyclo- Hex 157 OEt H H H Tet COOCH (Me) - OCO-O-cyclo- Hep 158 OMe H H H Tet COOCH ₂ OCO- tret-Bu 159 OPr H H H Tet COOCH ₂ OCO- tret-Bu

TABLE I (cont'd)

111

The compound No. R ^la R ^2a R ^3a R ^4a R ^5a R ^6a 160 OMe H H H Tet COOCH (Me) - OCO-O-cyclo- Hex 161 OPr H H H Tet COOCH (Me) - OCO-O-cyclo- Hex 162 NHEt H H H Tet COOCH ₂ OCO- tret-Bu 163 NHEt H H H Tet cooch ₂ oco-o- cyclo-Hex

An experimental example

Stable C-type-crystalline 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1 - [[2 '- (1H-tetrazol-6-yl) biphenyl 4-ii] methyl] -benzimidazole-7-carboxylate and its preparation.

Typically, 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl] methyl] benzimidazole-7-carboxylate is purified using silica gel column chromatography and the eluted fraction concentrated to dryness to afford amorphous This powder is unstable on heating and impractical in production To overcome the above disadvantages, the present inventors have carried out many crystallization experiments and described the crystal form of Ctype. The C-type crystal is unexpectedly stable during heating and can be successfully used in production. -Type crystals have the following crystal lattice parameters:

112

3.5 Angstremo;

3.7 Angstrem; Weak

3.8 Angstremo; Average 4.0 Angstremo; Average

4.1 Angstremo; Weak

4.3 Angstremo; Weak

4.4 Angstremo;

4.6 Angstremo;

4.8 Angstremo, average

5.1 Angstremo;

5.2 Angstremo; Weak

6.9 Angstremo; Weak

7.6 Angstremo; weak 8.8 Angstremo; medium 9.0 Angstremo; strong

15.9 Angstremo; Weak

The IR spectrum of a C-type crystal (KBr - tablet) is shown in Fig. 2. with precise absorption maxima at 2942, 1754, 1717, 1615, 1549, 1476, and 750 cm @ ^-1 and having a melting point of 158-166 ° C (decomposition).

Figures 1-3 are a radiograph (powder method), an IR spectrum (KBr tablet) and a differential calorimeter diagram, respectively.

The C-type crystal of 1- (cyclohexyloxycarbonyloxy) methyl-2-ethoxy-1 - [[2 '(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate has the following advantages:

1. It is more thermostable and more applicable in practice.

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2. The amount of solvent remaining in the crystal may be minimal.

3. These crystals are economically useful for industrial and clinical applications.

Concentrated residues, amorphous powders and / or crystals other than C-type crystals were mixed in the appropriate solvent to form the required C-type crystal to obtain the compound of interest. In the case where no C-type crystal is formed, a small amount of C-type crystal can be added to stimulate crystallization as a starting crystallization. The solvents mentioned may be any solvent, provided that they afford a C-type crystal, but lower alcohols (e.g. methanol, ethanol, isopropyl alcohol, etc.), a mixture of lower alcohol and water, and a lower alkyl ketone (e.g. acetone, etc.) are preferred. ) and water. The amount of solvent is also unlimited, but in practice is 2 to 30 times the weight of the crystal. The ratio of lower alcohol to water and lower alkyl ketone to water is not limited, but preferably the ratio is 4: 1-1: 1. The stirring temperature is also not limited, but is preferably from -5 ° C to 40 ° C, more preferably from 0 ° C to 25 ° C.

An experimental example

Inhibition of angiotensin II binding to the angiotensin receptor

Angiotensin II (A II) receptor binding II inhibition experiment was performed according to a modification of the method described by Douglas et al., Endocrinology, 102, 685-696 (1978). The membrane fraction of receptor A II was obtained from a bull's adrenal cortex. At the receptor

The membrane fraction 114 was charged with the compound of the present invention (10 ' ⁶ M or 10 ⁷ M) and ¹²⁵ I-angiotensin II ( ¹²⁵ IA II) (1.85 kVq / 50 L) and the resulting mixture was incubated for 1 hour at room temperature. Free and receptor-bound IA were separated by filtration (Whatman G / F filter) and measured the radioactivity of IA II bound to the receptor.

The obtained results of the compound of the present invention are shown in Table 2.

An experimental example

Effect of the compound of the present invention on vasoconstrictor A II activity

For the experiment used IF: SD rats (9 weeks old male). The animals were injected with a pentobarbital Na catheter into the femoral vein the day before the experiment under anesthesia. The animals were hungry but had no restrictions on drinking until the start of the experiment. On the day of the experiment, the arterial catheter was connected to a blood pressure transducer and the average blood pressure was recorded with a polygraph. Before administration, the instantaneous pressure produced by the injection of A II (100 ng / kg) was measured for control purposes. The drugs were administered orally, followed by intravenous injection of A II at each measurement step, and analogous measurement of instantaneous pressure. The resulting inhibition of drug A II was evaluated by comparing the instantaneous pressure before and after administration.

The results obtained are shown in Table 2.

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TABLE II

TABLE II (cont'd)

Work happy dys No. R ¹ Y R ² R ' Radi oreceptor analysis Instant pressure on Ali (p.o.) 3mg / kg 1x10 ⁷ M lxl05l 28th No. 0 Tet COOEt 46th 82 +++ a) 29th No. 0 Tet COOH 61 91 +++ 30th Ms. 0 Tet COOEt 16th 48 +++ ^31st Ms. 0 Tet COOH 40 79 +++ 33 Me S Tet COOEt 2 26th + 34 No. S Tet COOEt 17th 54 +++ 35 Ms. S Tet COOEt 7th 32 NT 36 Me s Tet COOH 51 82 +++ 37 No. s Tet COOH 41 80 +++ 38 Ms. s Tet COOH 6th 50 +++ 39 No. 0 Tet COOMe 58 89 +++ 40 No. NH Tet COOEt 54 83 +++ 41 Ms. NH Tet COOEt 45 57 DK b) |? 74 94 +++ 43 No. 0 Tet COOCH ₂ OCtBu 44 No. 0 Tet CH ₃ 0 i II 32 77 +++ COOCH-OCO- /) 45 Me 0 Tet COOMe 17th 67 +++ 46th Me 0 Tet COOH 66 88 +++ 47 No. NH Tet COOH 84 96 +++

116

TABLE II (cont'd)

Work happy dys No. R ¹ Y R ² R ' Radi oreceptor analysis Instant pressure 1 Ali (p.o.) 3mg / kg 1x10 ⁷ M 1x10 ^ 4 48 49 Ms. No. NH 0 Tet Tet COOH 0 X COOCH ₂ _ \ - Ρ CH, ·· 67 66 92 91 ++ +++ 50 No. 0 Tet COOCH ₂ OCOCH ₃ 63 92 +++ 51 No. 0 Tet COOCHjOCOEt 44 84 +++ 52 No. 0 Tet COOCH ₂ OCOPr 48 84 +++ 53 No. 0 Tet COOCH ₂ OCOiPr 55 85 +++ 54 No. 0 Tet CH ₃ O; n COOCH-OCOEt 42 81 +++ 55 No. 0 Tet CH ₃ O i ii cooch-occh ₃ 63 91 +++ 56 No. 0 Tet ch ₃ 0 i! i. COOCH-OCOiPr 31st 76 +++ 57 Me NH Tet COOH 41 79 NT 58 eT 0 Tet COOCH ₂ OCO —θ 55 84 +++ 59 No. 0 Tet cooch ₂ oco 37 69 +++ 60 No. 0 Tet COOCH = CH— 44 81 +++ 61 No. 0 Tet COOCHjOCO— <Q 54 89 +++ 62 No. NH Tet COOCH ₂ OCOtBu 48 87 +++ 63 No. NH Tet CH ₃ O COOCH-OCO - {^ J 19th 61 +++

a) +++> 70%> ++> 50%> +> 30%>

(b) NT, not tested

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It should be noted that modifications made to the examples described above, which do not go beyond the scope of the present invention, yield analogous results.

Therefore, various modifications are possible within the scope of the present invention.

Claims (7)

DEFINITION OF INVENTION A compound of the formula wherein ring A is a benzene ring optionally substituted with R ¹ ; R ¹ is hydrogen or an optionally substituted hydrocarbon residue; R is a group capable of forming an anion or a group capable of becoming an anion; X is a bond or linking group of two or less atoms between the phenylene and phenyl groups; R 'is a carboxyl or an ester thereof, or an amide thereof, or a group capable of forming an anion or a group capable of becoming an anion; Y is -O-, -S (O) _m -, or -N (R ⁴ ) -, wherein m is an integer of 0, 1 or 2 and R ⁴ is hydrogen or an optionally substituted alkyl group; n is 1 or 2; or a pharmaceutically acceptable salt thereof. 2. Stable crystal of 1- (cyclohexyloxycarbonyloxy) -ethyl-2-ethoxy-1 - [[2 '- (1H-tert-1-5-ii) bi-phenyl-4-yl] methyl] -benzimidazole-7-carboxylate. 3. Stable crystals on this basis are: 3.5 Angstremo; 3.7 Angstremo; 3.8 Angstremo; 4.0 Angstremo; 4.1 Angstremo; according to claim 2, the crystalline lattice has a mean lean mean lean mean 119 4.3 Angstremo; weak 4.4 Angstremo; average 4.6 Angstremo; average 4.8 Angstremo; average 5.1 Angstremo; average 5.2 Angstremo; weak 6.9 Angstremo; weak 7.6 Angstremo; weak 8.8 Angstremo; average 9.0 Angstremo; strong 15.9 Angstremo; weak A pharmaceutical composition for inhibiting angiotensin II, comprising a therapeutically effective amount of a compound as defined in any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier, excipient or diluent. 5. A process for preparing a compound of formula (I): wherein ring A is a benzene ring optionally substituted with R '; R ¹ is hydrogen or an optionally substituted hydrocarbon residue; R is a group capable of forming an anion or a group capable of becoming an anion; X is a bond or linking group of two or less atoms between the phenylene and phenyl groups; R 'is a carboxyl or an ester thereof, or an amide thereof, or a group capable of forming an anion or a group capable of becoming an anion; Y is -O-, -S (O) _m - or -N (R ⁴ ) -, wherein m is an integer 0, 1 or 2 and R is hydrogen or optionally substituted An alkyl group of 120; n is an integer equal to 1 or 2, such that: (i) Compound of Formula (II): wherein R ¹ , R ', A and Y have the meanings indicated above, reacting with a compound of formula (III): (III) wherein R ² , X and n are as defined above and Z is halogen; (ii) a compound of formula (IV) R ² wherein each group has the meanings indicated above, reacts with alkyl orthocarbonate which is a carbonylating or thiocarbonylating agent or isothiocyanate; (iii) a compound of formula (V ') wherein each group has the above 10, reacting with a nucleophilic agent and, if desired, the product of the above processes (i) to (iii) using azidification, hydrolysis, reduction, halogenation, O-, N- or alkylation, nucleophilic reaction, ring closure, Converting acylation, esterification, oxidation and / or deprotection to a compound of formula (I); and optionally converting the compound into a pharmaceutically acceptable salt.