RU2144022C1 - N-(biphenylmethyl)aminobenzoic acid esters and method of their synthesis - Google Patents

Abstract

FIELD: organic chemistry and technology. SUBSTANCE: invention proposes N-(biphenylmethyl)aminobenzoic acid esters of the general formula:

where R² means lower (C₁-C₄)-alkoxy-carbonyl group; R³ means lower (C₁-C₄)-alkoxycarbonyl group or -CN; Q² means -NO₂ or -NH₂ when Q¹ means H or Q² means -NO₂ when Q¹ means -COOR where R means lower (C₁-C₄)-alkyl, or salt of this compound. For synthesis of indicated compounds the corresponding carbamic acid ester is subjected for alkylation with an alkylating agent containing halogen atom followed by if necessary the protective group removal and the following optional reduction of the group -NQ¹ to NH-group. Indicated compounds can be used as intermediate substances for synthesis of benzimidazole derivatives that are used for drug synthesis. EFFECT: improved method of synthesis. 3 cl, 1 tbl, 16 ex

Description

 The subject of the present invention are novel intermediates for benzimidazole derivatives having excellent pharmaceutical properties.

где R² представляет низшую (C₁-C₄)алкоксикарбонильную группу,
R³ представляет низшую (C₁-C₄)алкоксикарбонильную группу или -CN,
Q² представляет -NO₂ или -NH₂,
когда Q¹ представляет H, или
Q² означает -NO₂, когда Q¹ означает - COOR, где R означает низший (C₁-C₄)алкил, или соль этого соединения.In particular, the subject of the present invention is esters of N- (biphenylmethyl) aminobenzoic acid of the general formula (V):

where R ² represents a lower (C ₁ -C ₄ ) alkoxycarbonyl group,
R ³ represents a lower (C ₁ -C ₄ ) alkoxycarbonyl group or —CN,
Q ² represents —NO ₂ or —NH ₂ ,
when Q ¹ represents H, or
Q ² means —NO ₂ when Q ¹ means —COOR, where R is lower (C ₁ -C ₄ ) alkyl, or a salt of this compound.

в котором R¹ представляет необязательно замещенную алкильную группу, каждый из элементов R² и R³ имеет значения, указанные выше, или их солей, которые обладают сильным антагонизмом в отношении ангиотензина II и гипотензивным действием, и является полезными в качестве терапевтических средств для лечения болезней, связанных с расстройством кровообращения, таких как гипертонические болезни, сердечно-сосудистые заболевания, кровоизлияние в мозг и т. д. В качестве одного из ранних исследований в этой области можно отметить производные имидазола, обладающие антагонизмом в отношении ангиотензина II, которые описывались в нерассмотренной публикации патентов Японии NN 71073/1981, 71074/1981, 92270/1982 и 157768/1983, в патенте США N 4355040 и в патенте США N 4340598. Далее улучшенные производные имидазола рассматриваются в Европейском патенте 0253310, Европейском патенте 0291969, Европейском патенте 0324377, в нерассмотренной публикации патентов Японии NN 23863/1988 и 117876/1989. А в Европейском патенте 0323841 и в не прошедшей экспертизу публикации патента Японии N 287071/1989 в качестве антагонистов ангиотензина II описываются производные пиррола, пиразола и триазола.Compounds of the above formula are valuable intermediates in the synthesis of benzimidazole derivatives of the general formula (I):

in which R ¹ represents an optionally substituted alkyl group, each of the elements R ² and R ³ has the meanings indicated above, or their salts, which have strong antagonism with respect to angiotensin II and hypotensive effect, and is useful as therapeutic agents for the treatment of diseases related to circulatory disorders, such as hypertension, cardiovascular disease, cerebral hemorrhage, etc. Imidazo derivatives can be mentioned as one of the earliest studies in this area. a, possessing antagonism with respect to angiotensin II, which are described in the unexamined publication of Japanese patents NN 71073/1981, 71074/1981, 92270/1982 and 157768/1983, in US patent N 4355040 and in US patent N 4340598. Further improved imidazole derivatives are considered in European patent 0253310, European patent 0291969, European patent 0324377, in unexamined publication of Japanese patents NN 23863/1988 and 117876/1989. And in European patent 0323841 and in the unexamined publication of Japanese patent N 287071/1989, derivatives of pyrrole, pyrazole and triazole are described as antagonists of angiotensin II.

 In addition, US Pat. No. 4,880,804 discloses benzimidazole derivatives that are antagonistic to angiotensin II receptors and are effective in treating rats suffering from renal hypertension when given intravenously, for example, compounds (A) represented by the following formula (A) having hydroxymethyl, methoxy , formyl, chlorine or carboxyl group at positions 5 and / or 6. However, it is indicated that most of the compounds (A) are not active when administered orally, with only 6 being hydroxymethy nye compound and 6 - chlorine compounds are effective when administered orally (100 mg / kg or less). However, compounds having the above activity are unsatisfactory for practical use as medicines.

В указанном патенте США специально отмеченные соединения, включающие вышеуказанные соединения (A), ограничены бензимидазолом, имеющим заместители в положениях 5 и/или 6 бензольного кольца, при этом в нем не рассматриваются производные бензимидазола, имеющие заместители в положении 4 или 7.

In said U.S. patent, specially marked compounds including the aforementioned compounds (A) are limited to benzimidazole having substituents at positions 5 and / or 6 of the benzene ring, and it does not include benzimidazole derivatives having substituents at position 4 or 7.

 The inventors of the present invention have found that certain compounds, that is, 7-substituted benzimidazole derivatives, which were not specifically mentioned in US Pat. No. 4,880,804, have strong antagonism towards angiotensin II receptors, and also show unexpectedly strong antagonism against angiotensin II when administered orally. and hypertensive effects that were not observed in derivatives substituted in positions 5 and / or 6. The authors of the present invention carried out research work to achieve the goals of the present th invention.

 In the above general formula (I) and V, the definition of “alkyl group” includes straight or branched chain lower alkyl groups having from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl tert-butyl.

Production method
The compounds of the present invention of general formula (V) can be prepared according to Reaction Scheme 1 below.
/ in which R ² and R ³ have the above meanings, and W denotes a halogen atom /.

 The above reaction of compound XI with compound XII is an alkylation using an alkylating agent in an organic solvent and in the presence of a base.

 This reaction is usually carried out in a solvent such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide, acetonitrile, acetone or ethyl methyl ketone, using from 1 to 3 moles of base and from 1 to 3 moles of alkylating agent.

 As the base used, for example, sodium hydride, potassium tert-butoxide, potassium carbonate or sodium carbonate.

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

 Although the reaction conditions vary depending on the combination of the base and the alkylating agent, this reaction is usually carried out at temperatures from ice cooling to room temperature for a period of 1 to 10 hours, after which deprotection and reaction with a reducing agent (for example, skeletal nickel hydrogenation catalyst, tin tetrachloride, a mixture of iron and hydrochloric acid, a mixture of hydrazine and iron chloride (3), etc.).

и трет-бутанола.Carbamic acid ester (XI) is obtained in high yield by heating isocyanate (X):

and tert-butanol.

The compounds of formula (V) according to the invention are used as intermediates in the preparation of benzimidazole derivatives of formula I, in accordance with Reaction Scheme II below,
(in which R ¹ , R ² and R ³ have the above meanings, and Y represents an iminoether, iminothioether, carboxide, amidine, cyano group, etc.).

 The reaction Scheme (II) shows the cyclization of the diamine compound (V) with various compounds in an organic solvent to form the benzimidazole compound (1).

 The above various compounds include carboxylic acid, aldehyde, orthoester, iminoether and iminothioether.

 These reagents are usually used in an amount of 1-10 moles based on 1 mol of compound (V), and this reaction usually proceeds in an organic solvent, but the reagent can be used in a double amount compared to the solvent.

 Organic solvents that vary depending on the reagent used include alcohols (methanol, ethanol, etc.), cellosolves (methyl cellosolve, ethyl cellosolve, etc.), halogenated hydrocarbons (chloroform, methylene chloride, etc.), ethers (dioxane, tetrahydrofuran, etc.), aromatic hydrocarbons (benzene, toluene), acetonitrile and dimethylformamide, along with other substances.

 To accelerate the reaction, an acid (hydrochloric acid, sulfuric acid, paratoluene sulfonic acid, etc.) or a base (triethylamine, pyridine, sodium methylate, sodium ethylate, potassium carbonate, etc.) can be added to the reaction system.

 Although the reaction conditions vary depending on the reagents used, this reaction is preferably carried out at temperatures from room temperature to the boiling point of the solvent used for a period of time from 1 to 10 hours.

 Compounds (1) thus obtained and their salts are less toxic, well inhibit the vasoconstrictor and hypertensive effects of angiotensin II, cause a hypotensive effect in animals, in particular mammals (for example, humans, dogs, rabbits, rats, etc.) therefore, they are useful as therapeutic agents not only for the treatment of hypertension, but also for the treatment of cardiovascular diseases such as heart failure and cerebral hemorrhage. Compounds (I) and their salts, when used as the medicines mentioned above, can be used orally or non-orally, in pure form or in dosage forms such as powders, granules, tablets, capsules, injectable solutions, etc., resulting from mixing with appropriate pharmaceutically acceptable carriers, excipients or diluents.

 The invention is further illustrated by experimental examples, which should not be construed as limiting the present invention.

The following are examples of abbreviations used in this description of the invention:
Me: methyl; Et: ethyl; Pr: propyl; Bu: butyl. Pen: pentyl, Tet: tetrazolyl, THF: tetrahydrofuran, DMF: dimethylformamide, Ph: phenyl, Ac: acetyl.

Example 1
3-amino-2 - [(2'-cyanobiphenyl-4-yl) methyl] aminobenzoic acid methyl ester
A mixture of 3-amino-2 - [(2'-cyanobiphenyl-4-yl) methyl] aminobenzoic acid ethyl ester (5 g) and NaH (60% oil, 1.62 g) in methanol (50 ml) was stirred at room temperature in 24 hours. The reaction mixture was concentrated to dryness to form a syrup, which was poured into a saturated aqueous solution of NaHCO ₃ (100 ml). This mixture was extracted with chloroform, and the organic layer was washed with H ₂ O, dried and evaporated to dryness, resulting in a crystalline product.

Recrystallization from a mixture of ethyl acetate and hexane led to the formation of colorless crystals (3.9 g, 82%), melting point 106-108 ^o C.

Spectrum ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 3.81 (3H, s), 3.97 (2H, broad singlet), 4.23 (2H, s), 6.40 (1H, wide singlet ), 6.88-6.91 (2H, m), 7.34-7.55 (7H, m), 7.64 (1H, double triplet), 7.77 (1H, doublet of doublets).

Infrared spectrum (KBr) cm ^-1 : 3410, 3350, 2225, 1695, 1485, 1470, 1290, 1200, 780, 760.

Example 2
2- (2-Chloroethyl) -1 - [(2'-cyanobiphenyl-4-yl) methyl] benzimidazole-7-carboxylic acid methyl ester
To a cold solution of 3-amino-2 - [(2'-cyanobiphenyl-4-yl) methyl] aminobenzoic acid methyl ester (0.5 g) in CH ₂ Cl ₂ (5 ml) was added dropwise 3-chloropropionyl chloride (0, 15 ml). The reaction mixture was stirred at room temperature for 30 minutes, and then concentrated to dryness to form a residue. This residue was dissolved in methanol (5 ml) containing concentrated HCl (0.5 ml), after which this solution was stirred at room temperature for 16 hours. The reaction solution was concentrated to dryness to form a residue, which was dissolved in CH ₂ Cl ₂ —H ₂ O. The aqueous layer was made basic and then extracted. The organic layer was washed with H ₂ O, dried and evaporated to dryness to form a pale brown syrup (0.7 g, 100%).

¹ H-NMR spectrum (200 MHz, CDCl ₃ ) δ: 3.37 (2H, t), 3.74 (3H, s), 4.09 (2H, t), 5.87 (2H, s), 7.00 (2H, d), 7.29 (1H, t), 7.39-7.81 (7H, m), 7.97 (1H, doublet of doublets).

Example 3
Ethyl 2 - [[(2'-cyanobiphenyl) methyl] amino] -3-nitrobenzoate
To a solution of ethyl 2-tert-butoxycarbonylamino-3-nitrobenzoate (20 g) in tetrahydrofuran (50 ml) was added, with stirring and cooling with ice, sodium hydride (60% dispersion in mineral oil, 2.8 g).

The mixture was stirred at room temperature for 20 minutes, and then 4- (2-cyanophenyl) benzyl bromide (18 g) and potassium iodide (360 mg) were added to the mixture, after which it was refluxed for 10 hours. The solvent was evaporated to dryness and the residue was partitioned between water (250 ml) and ether (200 ml). The organic layer was washed with water, dried and concentrated to give a yellow syrup. The syrup is dissolved in a mixture of trifluoroacetic acid (60 ml) with methylene chloride (40 ml) and the solution is stirred for 1 hour at room temperature. The reaction mixture was concentrated to dryness and diethyl ether (200 ml) was added to the residue to give crystals. The crystals are collected by filtration, washed with ether, obtaining crystals of a pale yellow color (22.1 g; 85%); so pl. = 118-119 ^o C.

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

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

Example 4
Ethyl 3-amino-2 - [[(2'-cyanobiphenyl-4-yl) methyl] amino] benzoate
To a solution of ethyl 2 - [[(2'-cyanobiphenyl-4-yl) methyl] amino] -3-nitrobenzoate (10.4 g) in ethanol (50 ml) was added tin- (II) dichloride dihydrate (28.1 g) and the mixture is stirred at 80 ^o C for two hours. The solvent was evaporated to dryness. To an ice-cooled mixture of the residue in ethyl acetate (300 ml) was added dropwise 2 N. NaOH solution (500 ml) with stirring. The aqueous layer was extracted with ethyl acetate (2 times 200 ml). The organic layers are combined, washed with water and dried. The solvent was evaporated to dryness and the residue was purified by silica gel column chromatography to give crystals. Recrystallization from ethyl acetate-hexane gave colorless crystals (7.3 g, 79%); so pl. = 104-105 ^o C.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.33 (t, 3H), 4.23 (s, 2H), 4.27 (q, 2H), 6.83-6.93 (2H, m), 7.35-7.55 (m, 7H), 7.64 (dt, 1H), 7.76 (dd).

IR Spectrum (KBr) cm ^-1 : 3445, 3350, 2220, 1680, 1470, 1280, 1240, 1185, 1160, 1070, 1050, 1020, 805, 750.

Example 5
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] - aminobenzoate (1.0 g) in ortho-carbonic acid ethyl ester (5 ml) . The mixture was stirred at 80 ^° C. for 1 hour. The reaction mixture was concentrated and the concentrate was dissolved in ethyl acetate. The solution was washed with an aqueous solution of sodium bicarbonate and water. The solvent was evaporated to give crystals. Recrystallization from ethyl acetate - benzene gave colorless crystals (0.79 g, 69%). Mp = 131-132 ^o C.

Elemental analysis for C ₂₆ H ₂₃ N ₃ O ₃
calculated,%: C 73.39 H 5.45 N 9.88
Found,%: C 73.36 H 5.42 N 9.83
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.24 (t, 3H), 1.49 (t, 3H), 4.24 (q, 2H), 4.68 (q, 2H), 5 72 (s, 2H), 7.10 (d, 2H), 7.19 (t, 1H), 7.38-7.46 (m, 4H), 7.56-7.66 (m, 2H) ), 7.73-7.77 (m, 2H).

IR Spectrum (KBr) cm ^-1 : 2220, 1720, 1550, 1480, 1280, 1245, 1215, 1040, 760, 740.

Example 6
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 one day. The reaction mixture was concentrated and the residue was poured into a saturated aqueous sodium hydrogen carbonate solution (100 ml), after which it was extracted with chloroform. The organic layer was washed with water, dried and concentrated to dryness to give crystals. Recrystallization from a mixture of ethyl acetate and hexane gave pale yellow crystals (3.98 g, 83%), mp. = 106-108 ^o C.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 3.81 (s, 3H), 3.97 (s s, 3H), 4.23 (s, 2H), 6.40 (b s, 1H), 6.88-6.91 (m, 2H), 7.34-7.55 (m, 7H), 7.65 (dt, 1H, J = 1.2; 7.7 Hz), 7 77 (dd, 1H, J = 1.4; 8.0 Hz).

IR Spectrum (KBr) cm ^-1 : 3410, 3350, 2225, 1695, 1485, 1470, 1290, 1200, 780, 760.

Example 7
Methyl [2- (2'-methoxycarbonylbiphenyl-4-yl) methylamino] -3- nitrobenzoate
To a solution of methyl 2-tert-butoxycarbonylamino-3-nitrobenzoate (1.84 g) in acetonitrile (10 ml) was added a solution of 4- (2'-methoxycarbonylbiphenyl-4-yl) methyl bromide (1.9 g) in acetonitrile (5 ml ) and potassium carbonate (0.86 g) and the reaction mixture are refluxed for 20 hours. The reaction mixture was concentrated to dryness and the resulting residue was extracted with ethyl acetate and water. The organic layer was washed with water, dried and evaporated. The residue was purified by silica gel column chromatography to give a pale yellow syrup. The syrup is dissolved in ethanol (10 ml) and a 20% solution of hydrogen chloride in ethanol (4 ml) is added to the solution. The reaction mixture was stirred at room temperature for 22 hours and concentrated to dryness. The residue was dissolved in ethyl acetate, and the solution was washed with saturated aqueous sodium hydrogen carbonate and water, dried and evaporated to give a yellow syrup (1.39 g, 53%).

¹ H-NMR (200 MHz, CHCl ₃ ) δ: 3.61 (s, 3H), 3.89 (s, 3H), 4.21 (d, 2H), 6.72 (t, 1H), 7 30 (d, 4H), 7.36 (dd, 1H), 7.42 (dd, 1H), 7.53 (dd, 1H), 7.82 (dd, 1H), 8.00 (dd, 1H), 8.10 (dd, 1H).

Example 8
Methyl 3-amino-2 - [(2'-methoxycarbonylbiphenyl-4-yl) methylamino] benzoate
The target compound is obtained in the form of a pale yellow syrup from methyl 2 - [(2'-methoxycarbonylbiphenyl-4-yl) methylamino] -3-nitrobenzoate in essentially the same manner as described in Working Example 4.

 Yield = 79%.

¹ H-NMR (200 MHz, CHCl ₃ ) δ: 3.63 (s, 3H), 3.80 (s, 3H), 3.97 (br s, 2H), 4.22 (d, 2H) 6.40 (br s, 1H), 6.82-6.92 (m, 2H), 7.23-7.44 (m, 7H), 7.53 (dt, 1H), 7.79 -7.83 (m, 1H).

IR spectrum (pure substance) cm ^-1 : 3450, 3360, 2970, 1730, 1700, 1470, 1460, 1450, 1440, 1290, 1250, 1200, 770, 750.

Example 9
Methyl 2-ethoxy-1 - [(2'-methoxycarbonylbiphenyl-4-yl) methyl] - benzimidazole-7-carboxylate
The title compound is obtained as colorless leaves from methyl 3-amino-2 - [(2'-methoxycarbonylbiphenyl-4-yl) methylamino] benzoate in essentially the same manner as described in Example 5.

Yield = 72%, mp. = 112-113 ^o C.

¹ H-NMR (200 MHz, CHCl ₃ ) δ: 1.50 (t, 3H), 3.55 (s, 3H), 3.77 (s, 3H), 4.68 (q, 2H), 5 65 (s, 2H), 6.99 (d, 2H), 7.17 (d, 2H), 7.17 (t, 1H), 7.31-7.55 (m, 4H), 7, 73 (dd, 1H); 7.77 (dd, 1H).

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

Example 10
Methyl 2 - [[N-tert-butoxycarbonylamino-N- (2'-cyanobiphenyl-4-yl) methyl] amino] -3-nitrobenzoate
A solution of methyl 2-tert-butoxycarbonylamino-3-nitrobenzoate (0.6 g), 2- (4-bromomethylphenyl) benzonitrile (0.54 g) and K ₂ CO ₃ (0.28 g) in acetonitrile (10 ml) is boiled under reflux for 4 hours and concentrated to dryness. Water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and evaporated to dryness. The residue was purified by silica gel column chromatography to obtain crystals. Recrystallization from a mixture of ethyl acetate and hexane gives colorless prisms (0.83 g, 85%). Mp 153-154 ^o C.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.35 (s, 9H), 3.70 (s, 3H), 4.63 (d, 1H), 4.80 (1H, d), 7 , 23-7.29 (m, 3H), 7.39-7.53 (m, 6H), 7.59-7.67 (m, 1H), 7.75 (dd, 1H), 7.93 (dd, 1H), 7.99 (dd, 1H), 8.05 (dd, 1H), 8.11 (dd, 1H).

IR Spectrum (KBr) cm ^-1 : 2220, 1700, 1530, 1390, 1360, 1315, 1290, 1160, 765.

Example 11
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) in a 20% solution of hydrogen chloride in ethanol (3 ml ) and ethyl acetate (3 ml) was stirred at room temperature for 1 hour. After evaporation of the solvent, methanol and a saturated aqueous sodium hydrogen carbonate solution were added to the residue, to give crystals. The crystals are collected by filtration and recrystallized from a mixture of chloroform with methanol, obtaining crystals of a pale yellow color (0.3 g, 77%). Mp = 140-141 ^o C.

¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 3.84 (s, 3H), 4.26 (m, 2H), 6.86 (t, 1H), 7.46 (d, 2H) 7.54-7.65 (m, 4H), 7.79 (d, 1H), 7.95 (dd), 8.05-8.11 (m, 2H), 8.67 (t, 1H) )

Example 12
Methyl 3-amino-2 - [[(2'-cyanobiphenyl-4-yl) methyl] amino] benzoate
A mixture of methyl 2 - [[(2'-cyanobiphenyl-4-yl) methyl] amino] -3-nitrobenzoate (10 g), FeCl ₃ • 6H ₂ O (0.1 g), activated charcoal (1 g) in mixtures of methanol (100 ml) with THF (50 ml) are refluxed for 30 minutes. Hydrazine hydrate (7.2 ml) was added dropwise to the reaction mixture, and the mixture was then refluxed for 14 hours. Insoluble material was removed from the reaction mixture by filtration, and the filtrate was concentrated to dryness. An aqueous sodium bicarbonate solution was added to the resulting residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and evaporated to dryness. The residue was purified by silica gel column chromatography to give crystals. Recrystallization from diisopropyl ether gave pale yellow needle-like crystals (6.0 g, 64%), mp. = 110-111 ^o C.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 3.81 (s, 3H), 3.97 (br s, 2H), 4.23 (d, 2H), 6.39 (t. 1H) 6.84-6.93 (m, 2H); 7.26-7.55 (m, 8H); 7.64 (dt, 1H); 7.77 (dd, 1H).

Example 13
Ethyl 1 - [(2'-cyanobiphenyl-4-yl) methyl] -2-ethoxybenzimidazole-7-carboxyl
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 sodium ethylate (0.17 g) and the mixture refluxed for 1 hour. The reaction mixture was concentrated to dryness. The resulting residue was dissolved in ethyl acetate, and the resulting solution was washed with water and then dried. After removing the solvent, the residue was purified by silica gel column chromatography to obtain the target compound as colorless crystals (0.37 g, 70%).

¹ H-NMR spectrum and IR spectrum show that the product obtained according to this example is completely identical to that obtained in example 5.

Example 14
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) with tin trimethylazide (0.7 g) in toluene (15 ml) is refluxed within 4 days. The reaction mixture was concentrated to dryness and methanol (20 ml) and 1N were added to the residue. HCl solution (10 ml). The mixture was stirred at room temperature for 30 minutes and adjusted to pH 3-4 with 1N. NaOH solution. After removing the solvent, the residue was partitioned between chloroform and water. The organic layer was washed with water and dried, and the solvent was evaporated to dryness to give a syrup. The syrup is purified by silica gel column chromatography to give crystals. Recrystallization from a mixture of ethyl acetate - benzene leads to colorless crystals (0.35 g, 45%), so pl. = 158-159 ^o C.

Elemental analysis for C ₂₆ H ₂₄ N ₆ O ₃ :
calculated,%: C 66.65 H 5.16 N 17.94
Found,%: C 66.61 H 5.05 N 17.84
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.09 (t, 3H), 1.43 (t, 3H), 4.02 (q, 2H), 4.30 (q, 2H), 5 57 (s, 2H), 6.71 (d, 2H), 6.83-6.96 (m, 4H), 7.27-7.31 (m, 1H), 7.40 (dd. , 1H), 7.55-7.66 (2H, m), 8.04-8.09 (m, 1H).

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

Example 15
2 - [(2'-cyanobiphenyl-4-yl) methyl] amino-3-nitrobenzoic acid ethyl ester
To a solution of ethyl 2-tert-butoxycarbonylamino-3-nitrobenzoic acid (20 g) in tetrahydrofuran (50 ml) was added sodium hydride (60% oil, 2.8 g), stirring under ice-cooling. To this mixture was then added 4- (2-cyanobiphenyl) methyl bromide (18 g) and potassium iodide (0.36 g), followed by stirring for 15 hours at room temperature. The reaction mixture was heated under reflux for 4 hours. The solvent was distilled off, and the residue was extracted with water (250 ml) and ether (200 ml). The organic layer was concentrated to give a yellow oil, which was dissolved in a mixture of trifluoroacetic acid (60 ml) and methylene chloride (40 ml), and this solution was stirred for one hour at room temperature. The reaction mixture was concentrated to dryness and ethyl ether (200 ml) was added to the concentrate, whereupon crystals formed. These crystals were collected by filtration, washed with ether and dried, which allowed to obtain pale yellow crystals (22.1 g, 85%), melting point 119-120 ^o C.

Spectrum ¹ H-NMR (90 MHz, CDCl ₃ ) δ: 1.37 (3H, t), 4.23 (2H, s), 4.37 (2H, q), 6.37 (1H, t .), 7.33-7.83 (9H, m.), 7.97-8.20 (2H, m.).

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

Example 16
3-amino-2 - [(2'-cyanobiphenyl-4-yl) methyl] amino-benzoic acid ethyl ester
To a solution of 2 - [(2'-cyanobiphenyl-4-yl) methyl] amino-3-nitrobenzoic acid ethyl ester (5.5 g) in tetrahydrofuran (50 ml) was added a skeletal nickel hydrogenation catalyst (5 g). Catalytic reduction is carried out at room temperature and atmospheric pressure. The catalyst was filtered off and the filtrate was concentrated to give a yellow oil (5 g, quantification).

Spectrum ¹ H-NMR (90 MHz, CDCl ₃ • D ₂ O): 1.30 (3H, t), 4.23 (2H, s), 4.27 (2H, q), 6.87 -7.03 (2H, m), 7.33-7.87 (9H, m).

Infrared spectrum (pure) cm ^-1 : 3435, 3350, 2980, 1690, 1615, 1465, 1365, 1280, 1240, 1215, 1190, 1065, 755.

Experimental Example 1 (final product: compound of formula I)
Inhibition of Angiotensin-II Binding to Angiotensin Receptor (Method)
In an experiment on the inhibition of the binding of angiotensin-II (A-II) to the A-II receptor, they are guided by a modification of the method of Douglas et al. (Endocrinology, 102, 685-696 (1978)). The membrane fraction of the A-II receptor is prepared from bovine adrenal cortex.

A benzimidazole derivative of formula I (10 ^-6 M or 10 ^-7 M) and ¹²⁵ I-angiotensin ( ¹²⁵ IA-II) (1.85 kBq / 50 μl) are added to the membrane fraction of the receptor and the mixture is incubated at room temperature for 1 hour . Associated with the receptor and free ¹²⁵ IA-II are separated by means of a filter (Whatman GF / B filter) and the radioactivity associated with the receptor ¹²⁵ IA-II is measured.

 The results are presented in the table.

Experimental Example 2 (final product: compound of formula I)
The inhibitory effect of the compounds of the present invention on the vasoconstrictor effects of A-II
(Method)
Use Jcl: SD rats (9 weeks old, males). On the day preceding the experiment, these animals were inserted cannulas into the femoral artery and vein under anesthesia using sodium pentobarbital. Animals are not fed, except that they give free access to drinking water, before the experiment. On the exact day of the experiment, the arterial cannula is connected to a blood pressure sensor, and the average blood pressure is recorded using a combined meteorograph. Prior to drug administration, a vasoconstrictor effect is measured by intravenous administration of A-II (100 ng / kg) as a control. Medicines are administered orally, then, at each measurement moment, A-II is administered intravenously, and the vasoconstrictor effect is measured in the same way. By comparing the vasoconstrictor effects before and after the administration of the drug, the inhibition is evaluated, in percent, due to the drug induced A-II vasoconstrictor effect.

 The results are presented in the table.

Claims (3)

1. Esters of N- (biphenylmethyl) aminobenzoic acid of the general formula

where R ² represents a lower (C ₁ -C ₄ ) alkoxycarbonyl group;
R ³ represents a lower (C ₁ -C ₄ ) alkoxycarbonyl group or —CN;
Q ² represents —NO ₂ or —NH ₂ when Q ¹ represents H, or Q ² means —NO ₂ when Q ¹ means —COOR, where R is lower (C ₁ -C ₄ ) alkyl,
or a salt of this compound.  2. The compound according to claim 1, which is methyl-3-amino - 2 - [[(2'-cyanobiphenyl-4-yl) methyl] amino] benzoate. 3. The method of obtaining esters of N - (biphenylmethyl) aminobenzoic acid of the General formula

where the values of R ² , R ³ , Q ¹ , Q ² are given in claim 1,
or their salts, characterized in that the ester of carbamic acid of the General formula

where R and R ² have the meanings indicated in claim 1, are subjected to alkylation reaction with an alkylating agent of the formula

where W is a halogen atom;
R ³ has the meanings indicated in claim 1,
after which the resulting compound of the formula

where the values of R, R ² and R ³ are indicated above,
optionally subjecting a deprotection reaction to obtain a compound of the formula

where the values of R ² and R ³ are indicated above,
followed by optionally reducing the resulting compound to a compound of the formula

where the values of R ² and R ³ are indicated above.

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