Derivatives of benzimidazole, their tautomers or their salts and the drug with the antagonist against angiotensin ii action

 

(57) Abstract:

Derivatives of benzimidazole of the formula I, where R1- C1-3- alkyl, R2- 5-, 6 - or 7-membered alkalinising in which one methylene group is replaced sulfonyloxy group, unsubstituted or substituted in position 1 by alkyl benzimidazole - 2-yl or 4, 5, 6, 7-tetrahydroimidazo - 2-yl, imidazo [1,2-a] pyridine-2-yl, 3-chloro-5, 6, 7, 8 tetrahydroimidazo [1,2-a] piridin-2-yl; R3- alkyl, C3-5- cycloalkyl or alkoxy; R4- substituted in position 1 and 2 Ra-CO-O-CH2group tetrazolyl, Rin-CO-O-(RcCH)-O-CO-RaO-CO - and RinO-CO-O(RcCH)-O-CO-, Raand Rin- C1-6- alkyl, C5-7- cycloalkyl; Rwithis hydrogen or methyl, their tautomers or their salts. The compounds I extend the range of benzimidazole derivatives having antagonistic against angiotensin II action. 2 S. p. f-crystals, 1 PL.

The invention relates to new nitrogen-containing heterocyclic substances with biological activity, in particular derivatives of benzimidazole.

Known benzimidazole derivatives having biological activity, in particular antagonistic in related. is avko WO 91/11999 A1, published 22.08.91 year, A 61 K 31/395).

Object of the invention is the expansion of the range of benzimidazole derivatives having antagonistic in relation to angiotensin II action.

The problem is solved, we offer benzimidazole derivatives of General formula I

< / BR>
where R1is an alkyl group with 1 to 3 carbon atoms;

R2is unsubstituted or substituted by 1 or 2 alkyl groups with 1 to 3 carbon atoms, 5-, 6 - or 7-membered, alkylamino-group in which one methylene group is replaced sulfonyloxy group, unsubstituted or substituted in position 1 alkyl group with 1 to 6 carbon atoms, a benzimidazole-2-yl or 4,5,6,7-tetrahydroimidazo-2-yl group, and the phenyl nucleus of one of these benzimidazole groups may additionally be substituted by a fluorine atom, imidazo[1,2-a]pyridine-2-yl, 5,6,7,8-tetrahydroimidazo[1,2-a] pyridine-2-yl or 3-chloro-5,6,7,8-tetrahydroimidazo[1,2-a] pyridine-2-yl;

R3is an alkyl group with 1 to 5 carbon atoms, cycloalkyl group with 3 to 5 carbon atoms or alkoxygroup with 1 to 3 carbon atoms,

R4- substituted in position 1 or 2 Ra-CO-O-CH2group tetrazolyl, Rb-COO-, -(R< alkyl group with 1 to 6 carbon atoms, cycloalkyl group with 5 to 7 carbon atoms, Rbis unbranched or branched alkyl group with 1 to 6 carbon atoms, cycloalkyl group with 5 to 7 carbon atoms, Rcis a hydrogen atom or a methyl group, or, if (a) R1and R2have a specified value, and R3is alkoxygroup, R4- carboxy, 1H-tetrazolyl or 2N-tetrazolyl, or (b) R1has the specified values, R2has the specified values, with the exception of 1-methyl-benzimidazole-2-yl group, and R3represents cyclopropyl group, R4- carboxyl, or (C) R1and R3have the specified values, and R2represents butanesultone-1-yl group, R4- carboxyl, or (g) R1has the specified values, R2represents 1-methyl-5-fluoro-benzimidazole-2-yl group, and R3- ethyl group, R4- carboxy, 1H-tetrazolyl or 2N-tetrazolyl,

their tautomers or their salts.

The task is also solved, we offer drug with antagonist against angiotensin II action, containing at least one benzimidazole derivative of the formula I under item 1 or physiologically and/or diluents.

To obtain new derivatives of benzimidazole is used, for example, the following ways:

a) Cyclization of the resulting if necessary in the reaction mixture of the compounds of General formula II

< / BR>
where R1and R2have the specified values,

one of the radicals X1or Y1means a group of the General formula

< / BR>
and the other of the radicals X1or Y1a group of General formula

< / BR>
and R3and R4have the specified values,

R3means a hydrogen atom, or R3CO-group, and R3has the specified values;

Z1and Z2that may be the same or different, signify unsubstituted or substituted alkyl groups with 1 to 6 carbon atoms, amino, hydroxy - or mercaptopropyl or Z1and Z2together mean an oxygen atom or sulfur, unsubstituted or substituted alkyl group with 1 to 3 carbon atoms aminogroup, alkylenedioxy or alkylenedioxy, each with 2 or 3 carbon atoms.

The cyclization is advisable to be implemented in the environment of the solvent or mixture of solvents, such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, simple monomial is Lin, or in excess to be used to obtain compounds of General formula II Alliluyeva agent, for example, in the corresponding nitrile, anhydride, halogenide, complex ether or amide, for example, at temperatures between 0 and 250oC, preferably, however, at the boiling temperature of the reaction mixture, if necessary, in the presence of a condensing agent, such as chlorosis phosphorus, thionyl chloride, sulfurylchloride, sulfuric acid, p-toluensulfonate, methanesulfonate acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic anhydride, or if necessary in the presence of a base such as ethylate or tert-butyl potassium. The cyclization can, however, be implemented in the absence of solvent and/or condensing agent.

Especially advantageous to carry out the reaction, however, so that the compound of General formula II in the reaction mixture obtained by recovery of the corresponding o-nitro-amino compound, if necessary in the presence of a carboxylic acid of General formula R3COOH or by acylation of the corresponding o-diamino-compounds. Upon termination of the nitrogroup reduction at the stage of hydroxylamine receive subsequent cyclization of the General compound of General formula I.

Subsequent recovery of the N-oxide of the formula I preferably takes place in an environment of a solvent, such as water, a mixture of water and ethanol, methanol, glacial acetic acid, ethyl ester acetic acid or dimethylformamide, with hydrogen in the presence of a hydrogenation catalyst such as Raney Nickel, platinum or palladium on coal, metals such as iron, tin or zinc in the presence of acid, such as acetic, hydrochloric or sulfuric acid, with salts such as iron sulfate (II) chloride tin (II) or dithionite sodium, or with hydrazine in the presence of Raney Nickel at temperatures between 0 and 50oC, preferably at room temperature.

b) Interaction of benzimidazole of General formula III

< / BR>
where R1, R2and R3have the specified values,

with biphenylene compound of General formula IV

< / BR>
where R4has the specified values;

Z3- nucleophilic tsepliaeva group such as halogen atom, e.g. chlorine atom, bromine or iodine, or substituted sulfonyloxy, for example, methanesulfonate, vinylsulfonate - or p-toluensulfonate.

Reaction it is advisable to carry out in the environment of the solvent and sulfoxid, dimethylformamide or benzene, if necessary, in the presence of an acid acceptor such as sodium carbonate, potassium carbonate, sodium hydroxide, tert-butyl potassium, sodium hydride, triethylamine or pyridine, and triethylamine and pyridine can be used as solvent, preferably at temperatures between 0 and 100oC, for example, between room temperature and 50oC.

The result of this reaction preferably receive a mixture of 1 - and 3-isomers, which can then be separated by crystallization or chromatography when using media, such as silica gel or aluminum oxide, to the corresponding 1 - and 3-isomer.

To obtain compounds of General formula I, in which R4means carboxypropyl:

Hydrolysis, thermolysis or hydrogenolysis of the compounds of General formula V

< / BR>
where R1, R2and R3have the specified values;

R4means the group, translated by hydrolysis, thermolysis or hydrogenolysis in carboxypropyl.

For example, functional derivatives of carboxypropyl as the unsubstituted or substituted amides, esters, tilapia, orthoepy, simple aminoether, amidine or anhydrides, Nutrilite, for example, tert-butyl methyl ether, by thermolysis can be converted to carboxypropyl by thermolysis, and esters with arachnology, for example, a complex benzyl ester, can be converted to carboxypropyl by hydrogenolysis.

The hydrolysis is advisable to carry out in the presence of acid, such as hydrochloric, sulphuric, phosphoric, trichloroacetic or triperoxonane acid, in the presence of a base such as sodium hydroxide or potassium hydroxide, in a suitable solvent, such as water, a mixture of water and methanol, ethanol, a mixture of water and ethanol, a mixture of water and isopropanol, a mixture of water and dioxane, methylene chloride or chloroform, at temperatures between 10oC and 120oC, for example, between room temperature and the boiling temperature of the reaction mixture. In the case of hydrolysis in the presence of organic acids, such as trichloroacetic acid or triperoxonane acid, possible alcoholic hydroxyl group at the same time can be translated to the appropriate acyloxy group, such as, for example, triptoreline group.

If R'4in the compound of General formula V has the value cyano - or aminocarbonyl groups, then these groups can be converted to carboxypropyl and treatment with nitrite, the but to use as a solvent at temperatures between 0 and 50oC.

If R'4in the compound of General formula V has the value of tert-butyloxycarbonyl group, tert-boutelou group can be split also heat through, if necessary in an inert solvent, such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane and preferably in the presence of catalytic amount of acid such as p-toluensulfonate, sulfuric, phosphoric or polyphosphoric acid, preferably at the boiling point of the used solvent, for example, at temperatures between 40oC and 100oC.

If R'4in the compound of General formula V is set to, for example, benzyloxycarbonyl group, the benzyl group can be also split by hydrogenolysis in the presence of a hydrogenation catalyst such as palladium on charcoal, in a suitable solvent, such as methanol, ethanol, a mixture of ethanol and water, glacial acetic acid, ethyl ester acetic acid, dioxane or dimethylformamide, preferably at temperatures between 0 and 50oC, for example, at room temperature and a hydrogen pressure of 1 to 5 bar. When hydrogenolysis at the same time, you can restore and other radicals, for example nitrogroup the group or the group of cinnamic acid to the corresponding group phenyl-propionic acid, or replace hydrogen atoms, for example a halogen atom by a hydrogen atom.

g) To obtain compounds of General formula I, in which R4means 1H-tetrazolyl group:

The removal of the protective radical from compounds of General formula VI

< / BR>
where R1, R2and R3have the specified values;

R4means having in position 1 or 3 of the protective radical 1H-tetrazolyl group.

As a protective radical is suitable, for example, triphenylmethyl, tributive or triphenylamine.

The removal of the used radical is preferably carried out in the presence of kaleidotrope, preferably in the presence of hydrogen chloride, in the presence of a base such as sodium hydroxide or alcoholic ammonia, printnum a solvent such as methylene chloride, a mixture of methanol and ammonia, ethanol or isopropanol, at temperatures between 0 and 100oC, preferably, however, at room temperature or at elevated temperatures, for example between 100 and 150oC, preferably between 120 and 140oC if the reaction to take place in the presence of an alcoholic ammonia,

d) To obtain compounds of General formula I, in which R4means 1N-t is have the specified values,

with attestations acid or its salts.

The interaction is preferably carried out in a solvent such as benzene, toluene or dimethylformamide, at temperatures between 80 and 150oC, preferably at 125oC. it is reasonable to allocate attestation acid during the reaction of the alkali metal azide, e.g. sodium azide, in the presence of a weak acid such as ammonium chloride, or tetrazoles salt produced in the reaction mixture during the reaction with the salt attestations acid, preferably with aluminum azide or azide presence of TBT, which is advisable to get in the reaction mixture by reacting aluminum chloride or with anti-alkali metal azide such as sodium azide, to allocate acidification with dilute acid such as 2n. hydrochloric acid or 2n. sulphuric acid.

e) To obtain compounds of General formula I, in which R4means substituted in position 1 or 2 group Rand-CO-O-CH2-tetrazol, the group RandO-CO-, Rb-CO-O-(RcCH)-O-CO - or RbO-CO-O-(RcCH)-O-CO-:

The interaction of compounds of General formula VIII

< / BR>
where R1, R2and R3have the specified values;R>Z4- Y2< / BR>
where Y2means the group Rand-CO-O-CH2-, Rb-CO-O-(RcCH)-, RbO-CO-O-(RcCH) -, or Rand-, and Rand, Rband Rchave the specified values;

Z4means nucleophilic tsepliaeva group such as halogen atom, e.g. a chlorine atom or bromine, or hydroxy-group, if Y represents the group Rand.

The response shall be made through the esterification of the corresponding alcohol or an appropriate reactive derivative such as a halide, expediently in a solvent or mixture of solvents such as water, methylene chloride, chloroform, simple ether, tetrahydrofuran, dioxane or dimethylformamide, or in excess of the acylation agent as a solvent, if necessary, in the presence of activating the acid or drying means, such as thionyl chloride, anhydrides, esters or halides, if necessary in the presence of an inorganic or tertiary organic base, such as sodium hydroxide, potassium carbonate, triethylamine or pyridine, the triethylamine and pyridine can also be used as solvents, when the temperature is possible reactive group, such as hydroxyl or aminogroup, you can protect conventional protective groups during the above reaction, these protective groups can be split after completion of the reaction.

As a protective radical for a hydroxyl group are suitable, for example, trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl, and as a protective radical for aminogroup - acetyl, benzoyl, etoxycarbonyl or benzyl.

Further, if necessary, the removal of used protective radical preferably carried out by hydrolysis in an aqueous solvent, e.g. water, mixtures of isopropanol and water, mixture of tetrahydrofuran and water or a mixture of dioxane and water, in the presence of acid, such as hydrochloric or sulphuric acid or in the presence of an alkaline base such as sodium hydroxide or potassium hydroxide, at temperatures between 0 and 100oC, preferably at the boiling temperature of the reaction mixture. Cleavage as benzyl radical is preferably carried out by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium on charcoal, in the environment of a solvent such as methanol, ethanol, ethyl ester acetic acid, Imperatore between 0 and 50oC, preferably, however, at room temperature, and hydrogen pressure of 1 to 7 bar, preferably 3 to 5 bar.

Resulting from the above reaction mixture of isomers of compounds of General formula I can be divided preferably by chromatography using a carrier such as silica gel or alumina.

In addition, the compounds of General formula I can be converted to their kislotoupornye salts, in particular physiologically tolerated salts with inorganic or organic acids, suitable for pharmaceutical purposes. As suitable acids for this purpose, for example, hydrochloric, Hydrobromic, sulfuric, phosphoric, fumaric, succinic, lactic, citric, tartaric or maleic acid.

In addition, the compounds of General formula I having a carboxy or 1H-tetrazolyl group, can be converted to salts with inorganic or organic bases, in particular physiologically tolerated salts suitable for pharmaceutical purposes. As grounds for this suitable, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

Used is Holocene by known literature methods.

For example, the compound of General formula II are obtained by alkylation of the corresponding o-amino-acylamino connection connection of General formula IV. Required for this about-amino-acylamino connection is obtained by recovery of the corresponding o-nitro-acylamino connection, which, in turn, is obtained by nitration of the appropriate acylamino-acetophenone, further converting the received corresponding o-nitro-acylamino-acetophenone to the corresponding bromo-acetophenone, followed by cyclization - bromo-acetophenone appropriate amidon acid and subsequent recovery of the nitro group. Before restoring the nitro group thus obtained oxazol-4-yl-connection can be translated by an appropriate amine, preferably ammonia, under pressure in the corresponding imidazol-4-yl-connection or thus obtained unsubstituted in position 1 imidazol-4-yl-connection can be translated by alkylation in alkilirovanie in position 1 imidazol-4-yl connection.

The original compound of General formula III is obtained by reduction and cyclization of the above o-nitro-acylamino connection.

The original connection of General formulas V - VIII polh">

As mentioned above, the new compounds of formula I and their physiologically tolerated salts have valuable pharmacological properties. They are an antagonist against angiotensin, in particular antagonist against angiotensin II.

For example, connection A = 4'[(2-ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazole-2-yl)-benzimidazole-1-yl)-methyl] -biphenyl-2-carboxylic acid (the product of example 1)

B = 4'-[(2-n-propyl-4-methyl-6-(butanesultone-1-yl)-benzimidazole-2-yl)-methyl]-biphenyl-2-carboxylic acid (the product of example 2)

In = 4'-[(2-cyclopropyl-4-methyl-6-(imidazo[1,2-a]pyridine-2-yl)-benzimidazole-1-yl)-methyl]-biphenyl-2-carboxylic acid (the product of example 3)

G = 4'-[(2-cyclopropyl-4-methyl-6-(5,6,7,8-5-tetrahydro-imidazo[1,2-a]pyridine-2-yl) benzimidazole-1-yl)-methyl]-biphenyl-2-carboxylic acid (the product of example 4)

L = 4'-[(2-ethoxy-4-methyl-6-(1-methyl-benzimidazole-2-yl)-benzimidazole-1-yl)-methyl] -2-(1H-tetrazol-5-yl)-biphenyl (target product of example 6) were tested for their biological activity as follows:

Description of methods for detection of binding of the receptor by angiotensin II.

Tissue (lungs of rats) is subjected to homogenization in Tris-buffer (50 MMU twice to centrifugation at 20000 g, each time 20 minutes Received centrifugal resuspended in incubation buffer (50 mmol Tris, 5 mm magnesium chloride, 0.2% albumin bovine serum, pH 7,40) in the ratio 1:75, in terms of wet weight tissue. 0.1 ml of homogenate incubated in a total volume of 0.25 ml for 60 min at 37oC in the presence of 50 pmol [125I]-angiotensin II (a product of the company NEN, Dreieich, FRG) and increasing concentrations of the analyte. The incubation terminated by rapid filtration through glass fiber filter mats. Each filter was washed with 4 ml cold as ice buffer (25 mmol Tris, 2.5 mmol magnesium chloride, 0.1% albumin bovine serum, pH 7,40). Associated radioactivity determined in a gamma counter. The curve dose/actions determine the appropriate value CT50, i.e. the concentration of the analyte, which provides 50% inhibition of binding of the receptor by angiotensin II.

The results of the experiment are summarized in the following table.

On the basis of their pharmacological properties the new compounds and their fiziologicheskii tolerated salts suitable for the treatment of hypertension and heart failure, in addition, to ensure the IKI progression of heart failure after myocardial infarction, for the treatment of diabetic nephropathy, glaucoma, gastrointestinal diseases and diseases of the bladder.

Furthermore, the new compounds and their physiologically tolerated salts are suitable for the treatment of lung diseases such as lung edema and chronic bronchitis, for the prevention of restenosis after angioplasty, thickening of the vascular wall after operations on the vessels, arteriosclerosis and diabetic angiopathy. Due to the influence on the release of acetylcholine and dopamine by angiotensin in the brain new drugs with antagonistic towards angiotensin action is also suitable to correct disorders of the Central nervous system such as depression, Alzheimer's disease, Parkinson's disease, bulimia, and impaired cognitive functions.

Required to achieve the appropriate activity for adults the dosage is suitable for intravenous giving 0.5 to 100 mg, preferably 1 to 70 mg, while giving oral 0.1 to 200 mg, preferably 1 to 100 mg, in both cases 1 to 3 times a day. Obtained according to the invention compounds of General formula I, optionally in combination with other active substances, such as lowering blood is several conventional inert carriers and/or diluents, for example, corn starch, lactose, sucrose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, mixture of water and ethanol, a mixture of water and glycerol with a mixture of water and sorbitol, a mixture of water and glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as utverzhdennym fat or suitable mixtures in a known halogen drugs, e.g., the tablets, pills, capsules, powders, suspensions or suppositories.

Therefore, for the above combinations as further active substances are suitable, for example, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, spironolactone, benzthiazide, cyclothiazide, ethacrynic acid, furosemide, metoprolol, prazosin, atenolol, propanolol, (di) hydralazine hydrochloride, diltiazem, felodipine, nicardipine, nifedipine, nisoldipine, nitrendipin, captopril, enalapril, lisinopril, cilazapril, quinapril, fosinopril and ramipril. At this dose for these active substances is thus advisable 1/5 usually featured the lowest dosage of up to 1/1 of the normally recommended dosage, therefore, for example, 15 to 200 mg hydrochlo ipina, 5 - 60 mg of nifedipine or 5 - 60 mg of nitrendipine.

The following examples illustrate how to obtain derivatives of benzimidazole of formula I.

Example 1. 4'-[(2-Ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazole-2-yl)-benzimidazole-1-yl)-methyl] -biphenyl-2-carboxylic acid. a) 2-Ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazole-2-yl)-benzimidazole.

A mixture of 4.5 g (21 mmol dihydrochloride 1-methylamino-2-amino-4-fluoro-benzene and 4.3 g (21 mmol) of 3-ethyl-4-methyl-benzimidazole-6-yl-carboxylic acid in 100 g of polyphosphoric acid is stirred for four hours at 140oC, then vmeshivat approximately 300 g of ice water, alkalinized with concentrated ammonia solution. Precipitated crude product is sucked off, dried, and then purified by column chromatography (300 g silica gel; eluent: a mixture of methylene chloride and ethanol in the ratio 95:5).

Yield: 3.1 g (48% of theory).

The value of Rf: to 0.24 (silica gel; a mixture of methylene chloride and ethanol in the ratio 19:1).

b) tert-Butyl ether 4'-[(2-ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazole-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid.

To a solution of 1.55 g (5 mmol) 2-ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazole-2-yl)-benzimidazole in 30 ml dime is the temperature value. Then add to 1.9 g (5.5 mmol) of a compound tert-butyl ether 4'-methyl bromide-biphenyl-2-carboxylic acid and stirred for further 20 hours at room temperature. After that, the mixture while stirring serves approximately 80 ml of a saturated solution of sodium chloride, the precipitated crude product is sucked off and purified by chromatography (150 g silica gel; solvent: a mixture of methylene chloride and ethanol in the ratio 98:2).

Yield: 1.4 g (50% of theory).

The value of Rf: to 0.47 (silica gel; a mixture of methylene chloride and ethanol in the ratio 19:1).

C) 4'-[(2-Ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazole-2-yl)-benzimidazole-1-yl)-methyl]-biphenyl-2-carboxylic acid.

A solution of 1.4 g (2.4 mmol) of a compound tert-butyl ether 4'-[(2-ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazole-2-yl)-benzimidazole-1-yl)-methyl] -biphenyl-2-carboxylic acid and 15 ml triperoxonane acid in 30 ml of methylene chloride is stirred for 14 hours at room temperature, then evaporated, to the residue was added 30 ml of water, alkalinized by addition of 2n. sodium lye. After double extraction each time with 30 ml of a simple diethyl ether, the aqueous phase is acidified with 25% citric acid. Bypass the b: a mixture of methylene chloride and ethanol in the ratio 96:4).

Yield: 850 mg (69% of theory).

Melting point: 246 - 248oC.

C32H27FN4O2(518, 60)

Calculated: 74,11 N A 5.25 N 10,80

Found: 73,95 5,34 10,80

Mass spectrum: m/e = 518

Example 2. 4'-[(2-n-Propyl-4-methyl-6-(butanesultone-1-yl)-benzimidazole-1-yl)-methyl]-biphenyl-2-carboxylic acid.

Get analogously to example 1 from complex tert-butyl ether 4'-[(2-n-propyl-4-methyl-6-(butanesultone-1-yl)-benzimidazole-1-yl)-methyl] -biphenyl-2-carboxylic acid and triperoxonane acid.

Yield: 87% of theory.

Melting point: 269 - 271oC.

C29H31N3O4S (517, 65)

Calculated: 67,29 N 6,04 N 8,12

Found: 67,56 6,12 8,28

The value of Rf: to 0.39 (silica gel; a mixture of methylene chloride and ethanol in the ratio 19:1).

Mass spectrum: m/e = 517.

Example 3. 4'-[(2-Cyclopropyl-4-methyl-6-(imidazo[1,2-a]pyridine-2-yl)-benzimidazole-1-yl)-methyl]-biphenyl-2-carboxylic acid.

Get analogously to example 1 from complex tert-butyl ether 4'-[(2-cyclopropyl-4-methyl-6-(imidazo[1,2-a] pyridine-2-yl)-benzimidazole-1-yl)-methyl]-biphenyl-2-carboxylic acid and triperoxonane acid.

Yield: 50% theory.

Point plavleniem: a 76.88 lower than the 5.37 11,30

The value of Rf: to 0.63 (silica gel; a mixture of methylene chloride and ethanol in the ratio 9 : 1).

Mass spectrum: m/e = 498

Example 4. 4'-[(2-Cyclopropyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo-[1,2-a]pyridine-2-yl)-benzimidazole-1-yl)-methyl]-biphenyl-2-carboxylic acid.

Get analogously to example 1 from complex tert-butyl ether 4'-[(2-Cyclopropyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo-[1,2-a] pyridine-2-yl)-benzimidazole-1-yl)-methyl] -biphenyl-2-carboxylic acid, trifter-acetic acid.

Yield: 53% of theory.

Melting point: 310 - 312oC.

C32H30N4O2(502,62)

Calculated: 76,47 N 6,02 N OF 11.15

Found: 76,23 5,97 10,85

The value of Rf: to 0.17 (silica gel; a mixture of methylene chloride and ethanol in the ratio 9 : 1).

Mass spectrum: m/e = 502.

Example 5. 4'-[(2-Ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazole-2-yl)-benzimidazole-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl.

a) 4'-[(2-Ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazole-2-yl)-benzimidazole-1-yl)-methyl]-biphenyl.

To a solution of 1.55 g (5 mmol) 2-ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazole-2-yl)-benzimidazole in 30 ml of dimethyl sulfoxide add 616 mg (5.5 mmol) of potassium tert-butylate and stirred for 15 mi is giving further 20 hours at room temperature. After that, the mixture while stirring serves approximately 80 ml of a saturated solution of sodium chloride, the precipitated crude product is sucked off and acidat by column chromatography on 150 g of silica gel (solvent: a mixture of methylene chloride and ethanol in the ratio 97 : 3).

Yield: 1.9 g (76% of theory).

The value of Rf: of 0.43 (silica gel; a mixture of methylene chloride and ethanol in the ratio 19 : 1).

b) 4'-[2-Ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazole-2-yl)-benzimidazole-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl.

A solution of 1.9 g (3.8 mmol) of 4'-[2-ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazole-2-yl)-benzimidazole-1-yl)-methyl] -2-cyanobiphenyl, 4.1 g (76 mmol) of aluminium chloride and 4.9 g (76 mmol) of sodium azide in 30 ml of dimethylformamide is heated for 15 hours to 140oC, then add 2.0 g of aluminium chloride and 2.4 g of sodium azide and heated for a further 4 hours to 140oC. thereafter, the mixture was added with stirring to about 80 ml of a saturated solution of sodium chloride, the precipitated crude product is sucked off and purified by column chromatography (100 g of silicates; solvent: a mixture of methylene chloride and ethanol in the ratio 19:1).

Yield: 1.25 g (61% of theory).

Melting point: 24 20,82

The value of Rf: of 0.60 (silica gel; a mixture of methylene chloride and ethanol in the ratio 9 : 1).

Mass spectrum: m/e = 542.

Example 6. 4'-[(2-ethoxy-4-methyl-6-(1-methyl-benzimidazole-2-yl)-benzimidazole-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl.

4'-[(2-Ethoxy-4-methyl-6-(1-methyl-benzimidazole-2-yl)-benzimidazole-1-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl -

To a solution of 570 mg (1,86 mmol) 2-ethoxy-4-methyl-6-(1-methyl-benzimidazole-2-yl)-benzimidazole in 20 ml of dimethyl sulfoxide was added 224 mg (2.0 mmol) of potassium tert-butylate and stirred for 15 minutes at room temperature. Then add 1,11 g (2.0 mmol) of 4'-bromo-methyl-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl and stirred for further 3 hours at room temperature. After that, the mixture while stirring serves approximately 50 ml of a saturated solution of sodium chloride, the precipitated crude product is sucked off and purified by column chromatography on 100 g of silica gel; solvent: a complex mixture of ethyl ester of acetic acid and petroleum ether in the ratio 4:1).

Output: 860 mg (59% of theory).

The value of Rf: of 0.56 (silica gel; a complex mixture of ethyl ester of acetic acid and petroleum ether in the ratio 4 : 1).

A mixture of 830 mg (1.06 mmol) of 4'-[(2-ethoxy-4-methyl-6-(1-methyl-benzimidazole-2-yl)-benzimidazole-1-yl)-methyl] -2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl, 2.5 ml 1N. sodium liquor and 20 ml of ethanol is stirred for 2 hours at 80oC. the Solution is then evaporated, to the residue was added 30 ml of water and weakly acidified with glacial acetic acid. After this, the solution extracted three times, each time about 20 ml of methylene chloride, the combined organic extracts washed with 20 ml of water and thicken. Thus obtained crude product is purified by column chromatography on 50 g of silica gel; a mixture of methylene chloride and ethanol in the ratio 9:1).

Yield: 430 mg (75% of theory).

Melting point: 194 - 197oC.

C32H28N8O (540,60)

Calculated: 71,40 N 5,22 N 20,73

Found: 69,99 are 5.36 20,54

Mass spectrum: m/e = 540.

Example 7. Hydrate 4'-[(2-ethoxy-4-methyl-6-(imidazo[1,2-a]pyridine-2-yl)-benzimidazole-1-yl)-methyl]-biphenyl-2-carboxylic acid.

Get analogously to example 1 from complex tert-butyl ether 4'-[(2-ethoxy-4-methyl-6-(imidazo[1,2-a]pyridine-2-yl)-benzimidazole-1-yl-)-methyl] -biphenyl-2-carboxylic acid and triperoxonane acid in methylene chloride.


Calculated: 71,52 N 5,42 N 10,76

Found: 71,22 lower than the 5.37 10,76

The value of Rf: of 0.36 (silica gel; a mixture of methylene chloride and ethanol in the ratio 19:1).

Example 8. A mixture of 4'-[(2-n-propyl-4-methyl-6-(butanesultone-1-yl)-benzimidazole-1-yl)-methyl] -2-[1-pivaloyloxymethyl)-tetrazol-5-yl] -biphenyl and 4'-[(2-n-propyl-4-methyl-6-(butanesultone-1-yl)-benzimidazole-1-yl)-methyl] -2-[2-pivaloyloxymethyl)-tetrazol-5-yl]-biphenyl.

A solution of 400 mg (0,74 mmol) 4'-[(2-n-propyl-4-methyl-6-(butane-sultam-1-yl)-benzimidazole-1-yl)-methyl] -2-[1H-tetrazol-5-yl]-biphenyl, 0.16 ml (1.1 mmol) of complex chlormethiazole ether pavlinovoi acid and 194 mg (1.1 mmol) dihydrate potassium carbonate in 10 ml of dimethylformamide is stirred for 14 hours at room temperature, then added with stirring to approximately 50 ml of sodium chloride solution and extracted three times, each time with 20 ml methylene chloride. The combined organic extracts washed with water and thicken. Thus obtained crude product is purified by column chromatography on 50 g of silica gel (solvent: a mixture of methylene chloride and ethanol in the ratio 98:2).

400 mg (82% of theory).

Melting point: amorphous.

C35H41N7Ois l; a mixture of methylene chloride and ethanol in the ratio 19:1).

Example 9. A mixture of 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridine-2-yl]-benzimidazole-1-yl)-methyl]-2-[1-(pivaloyloxymethyl)-tetrazol-5-yl] -biphenyl and 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a] -pyridin-2-yl] -benzimidazole-1-yl)-methyl] -2-[2-(pivaloyloxymethyl)-tetrazol-5-yl]-biphenyl.

Get analogously to example 8 from 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridine-2-yl]-benzimidazole-1-yl)-methyl]-2-[1H-tetrazol-5-yl]-biphenyl and complex chlormethiazole ether pavlinovoi acid.

Yield 75% of theory.

Melting point: 203-205oC.

C38H42N8O2(642,80)

Calculated: 71,00 N 6,59 N 17,43

Found: 70,85 6,63 17,43

The value of Rf: of 0.43 (silica gel; a mixture of methylene chloride and ethanol in the ratio 19:1).

Mass spectrum: m/e = 642

Example 10. 4'-[(2-n-Propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a] -pyridine-2-yl]-benzimidazole-1-yl)-methyl]-2-[1-(cyclohexyloxycarbonyloxy)-ethoxycarbonyl]-biphenyl -

A solution of 504 mg (1.0 mmol) 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a] -pyridine-2-yl] -benzimidazole-1-yl)-methyl]-biphenyl-2-carboxylic acid, 600 mg of 1-(cyclohexyloxycarbonyl is based temperature then added with stirring to approximately 70 ml of saturated sodium chloride solution and extracted three times, each time with 30 ml of a complex ethyl ester of acetic acid. The combined organic extracts washed with water and thicken. Thus obtained crude product is purified by column chromatography on 100 g of silica gel (solvent: a mixture of methylene chloride and ethanol in the ratio 19:1).

Output: 325 mg (48% of theory).

Melting point: 162-164oC.

C41H46N4O4(674,85)

Calculated: 72,97 N 6,87 N 8,30

Found: 72,63 6,77 8,17

The value of Rf: of 0.52 (silica gel; a mixture of methylene chloride and ethanol in the ratio 19:1).

Mass spectrum: m/e = 674.

Example 11. 4'-[(2-n-Propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a] -pyridine-2-yl]-benzimidazole-1-yl)-methyl]-2-(pivaloyloxymethyl)-biphenyl -

Get analogously to example 8 from 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a] -pyridine-2-yl]-benzimidazole-1-yl)-methyl]-biphenyl-2-carboxylic acid and complex chlormethiazole ether pavlinovoi acid in dimethylformamide.

Yield: 76% of theory.

Melting point: 142-144oC.

C38H42N4is mesh methylene chloride and ethanol in the ratio 19:1).

Mass spectrum: m/e = 618.

Example 12. 4'-[(2-n-Propyl-4-methyl-6-(butanesultone-yl)-benzimidazole-1-yl)-methyl]-2-(pivaloyloxymethyl)-biphenyl.

Get analogously to example 8 from 4'-[(2-n-propyl-4-methyl-6-(butanesultone-yl)-benzimidazole-1-yl)-methyl] -biphenyl-2-carboxylic acid and complex chlormethiazole ether pavlinovoi acid in dimethylformamide.

Yield: 70% of theory.

Melting point: oil.

C35H41N3O6S (631,80)

Calculated: 66,54 N 6,54 N 6,65 S 5,08

Found: 66,21 6,67 6,54 5,34

The value of Rf: of 0.49 (silica gel; a mixture of methylene chloride and ethanol in the ratio 19:1).

Mass spectrum: m/e = 631.

Example 13. 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a] -pyridine-2-yl)-benzimidazole-1-yl)-methyl]-2-(1-(ethoxycarbonylmethoxy)-carbonyl]-biphenyl.

Get analogously to example 8 from 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a] -pyridine-2-yl)-benzimidazole-1-yl)-methyl]-biphenyl-2-carboxylic acid and 1-(ethoxycarbonyl)-methyl chloride in dimethylformamide.

Yield: 38.5 % of theory.

Melting point: 123 - 125oC.

C37H40N4O5(620,76)

Calculated: 71,59 N 6,50 N 9,03

Mass spectrum: m/e = 620.

Example 14. 4'-[(2-Ethoxy-4-methyl-6-(imidazo[1,2-a]pyridine-2-yl)-benzimidazole-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl.

Get analogously to example 6 from 4'-[(2-ethoxy-4-methyl-6-(imidazo[1,2-a] pyridine-2-yl)-benzimidazole-1-yl)-methyl] -2-triphenylmethanol-5-yl)-biphenyl and sodium liquor in ethanol.

Example 15. 4'-[(2-Ethoxy-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridine-2-yl)-benzimidazole-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl.

Get analogously to example 6 from 4'-[(2-ethoxy-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a] pyridine-2-yl)-benzimidazole-1-yl)-methyl] -2-triphenylmethyl-tetrazol-5-yl)-biphenyl and sodium liquor in ethanol.

Example 16. 4'-[(2-Ethoxy-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a] pyridine-2-yl)-benzimidazole-1-yl)-methyl]-biphenyl-2-carboxylic acid.

Get analogously to example 1 from complex tert-butyl ether 4'-[(2-ethoxy-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a] pyridine-2-yl)-Benzema-Gasol-1-yl)-methyl]-biphenyl-2-carboxylic acid and triperoxonane acid in methylene chloride.

Yield: 63% of theory.

Melting point: 238 - 240oC.

The value of Rf: of 0.62 (silica gel; a mixture of methylene chloride and ethanol in the ratio 19:1).

Get analogously to example 1 from complex tert-butyl ether 4'-[(2-ethyl-4-methyl-6-(butanesultone-1-yl)-benzimidazole-1-yl)-methyl] -biphenyl-2-carboxylic acid and triperoxonane acid in methylene chloride.

Yield: 68% of theory.

Melting point: > 240oC.

C28H29N3O4S (503,60)

Calculated: 66,77 N 5,80 N A 8.34

Found: 66,57 5,69 8,30

The value of Rf: of 0.36 (silica gel; a mixture of methylene chloride and ethanol in the ratio 9:1).

Example 18. 4'-[(2-Ethyl-4-methyl-(3-chloro-5,6,7,8-tetrahydro-imidazo[1,2-a] -pyridine-2-yl)-benzimidazole-1-yl)-methyl]-biphenyl-2-carboxylic acid.

Get analogously to example 1 from complex tert-butyl ether 4'-[(2-ethyl-4-methyl-6-(3-chloro-5,6,7,8-tetrahydro-imidazo[1,2-a] -pyridine-2-yl)-benzo-imidazol-1-yl)-methyl] -biphenyl-2-carboxylic acid and triperoxonane acid in methylene chloride.

Yield: 43% of theory.

Melting point: 295 - 297oC.

C31H29ClN4O2(525,06)

Calculated: 70,91 N 5,57 N 10,67 Cl 6,75

Found: 70,81 5,54 10,55 6,83

The drug according to the present invention can be in the form of any of the standard pharmaceutical composition. In the following, when the first substance of example 1, mg - 50

KH2PO4mg - 2

Na2HPO42H2O, mg - 50

NaCl, mg - 12

Water for injection purposes, ml - Up to 5

Preparation.

In parts of water dissolve buffering agents and isotonic substance, then add the active substance. After complete dissolution of the active substance is supplemented with water up to a nominal amount.

Composition II. Ampoules containing 100 mg of active substance per 5 ml

The active substance of example 1, mg - 100

Methylglucamine, mg - 35

Glycoluril, mg - 1000

Block copolymers of ethylene glycol and propylene glycol, mg - 250

Water for injection purposes, ml - Up to 5

Preparation.

In parts of water dissolve methylglucamine. The active ingredient in the mixture and cook until heated dissolution. After adding solvents complement water up to a nominal amount.

Composition III. Tablets containing 50 mg of active substance

The active substance of example 6, mg - 50,0

Calcium phosphate, mg - 70,0

Lactose, mg - 40,0

Corn starch, mg - 35,0

Polyvinylpyrrolidone, mg - 3,5

Magnesium stearate, mg - 1,5 - 200,0

Preparation.

The mixture of active substances, calcium phosphate, lactose and cook is through a sieve size of holes 2 mm, dried in the dryer with air circulation at 50oC and again passed through a sieve. After adulteration with lubricants obtained granulate is pressed into tablets.

Composition IV. Tablets containing 50 mg of active substance

The active substance of example 1, mg - 50,0

Lysine, mg - 25,0

Lactose, mg - 60,0

Corn starch, mg - 34,0

Gelatin, mg - 10,5

Magnesium stearate, mg - 1,0 - 180,0

Preparation.

The active substance is mixed with auxiliary substances and hydrate aqueous solution of gelatin. After passing through a sieve and drying the resulting gramplet mixed with magnesium stearate and pressed into the kernel.

Thus obtained core provided with a coating of standard composition. Used this suspension or solution may also contain a dye.

Composition V Tablets containing 100 mg of active substance.

The active substance of example 2, mg - 100,0

Lysine, mg - 50,0

Dakota, mg - 86,0

Corn starch, mg - 50,0

Polyvinylpyrrolidone, mg - 2,8

Microcrystalline cellulose, mg - 60,0

Magnesium stearate, mg - 1,2 - 350,0

Preparation.

The active substance is mixed with auxiliary substances the th hole of 1.5 mm and dried at 45oC. After drying are repeated passing through a sieve and mix of magnesium stearate. The resulting mixture is pressed into the kernel.

Thus obtained core provided with a coating of standard composition. Used this suspension or solution may also contain a dye.

Composition VI. Capsules containing 250 mg of active substance of example 3.

The active substance according to the invention, mg - 250,0

Corn starch, mg - 68,5

Magnesium stearate, mg - 1,5 - 320,0

The cooking. The active ingredient and the corn starch are mixed and moistened with water. The wet mass is passed through a sieve and dried. The dried granulate is passed through a sieve and mixed with magnesium stearate. The mixture is served in capsules of hard gelatin size 1.

Composition VII. Suspension for oral villas, containing 50 mg of active substance of example 4 in 5 ml

The active substance according to the invention, mg - 50

Hydroxyethylcellulose, mg - 50

Sorbic acid, mg - 5

Sorbitol 70%, mg - 600

Glycerol, mg - 200

Aroma, mg - 15

Water, mg - 5

Preparation.

Distilled water is heated to 70oC. In a hot water when mixing races is anatoy temperature, in which add sorbic acid, fragrance or active ingredient. Then the suspension was stirred for air removal. 5.0 ml contains one dose of 50 mg.

Composition VIII. Suppositories containing 100 mg of active substance of example 1

The active substance according to the invention, mg - 100

The cured fat, mg - 1600

Preparation.

Cured fat is melted. When 40oWith milled active ingredient in the melt is homogeneous distributed. The finished mass is then cooled to 38oC and poured into pre-cooled forms.

1. Derivatives of benzimidazole of General formula I

< / BR>
where R1is an alkyl group with 1 to 3 carbon atoms;

R2is unsubstituted or substituted by 1 or 2 alkyl groups with 1 to 3 carbon atoms, 5-, 6 - or 7-membered alkalinising in which one methylene group is replaced sulfonyloxy group, unsubstituted or substituted in position 1 alkyl group with 1 to 6 carbon atoms of the benzimidazole-2-yl or 4,5,6,7-tetrahydroimidazo-2-yl group, and the phenyl nucleus of one of these benzimidazole groups may additionally be substituted by a fluorine atom, imidazo[1,2-a] pyridine-2-yl, 5,6,7,8-tetrahydroimidazo[1,2-a] pyridine-2-yl alcalina group 3 - 5 carbon atoms or alkoxygroup with 1 to 3 carbon atoms;

R4- substituted in position 1 and 2 Ra-CO-O-CH2group tetrazolyl, Rb-CO-O-(RcCH)-O-CO-, Ra-O-CO - and RbO-CO-O-(RcCH)-O-CO-, where Radenotes unbranched or branched alkyl group with 1 to 6 carbon atoms, cycloalkyl group with 5 to 7 carbon atoms, Rbis unbranched or branched alkyl group with 1 to 6 carbon atoms, cycloalkyl group with 5 to 7 carbon atoms, Rcis a hydrogen atom or a methyl group, or, if (a) R1and R2have a specified value, and R3is alkoxygroup, R4- carboxy, 1H-tetrazolyl or 2H-tetrazolyl, or (b) R1has the specified value, R2has the specified values, with the exception of 1-methyl-benzimidazole-2-yl group, and R3represents cyclopropyl group, R4- carboxyl, or (C) R1and R3have the specified values, and R2represents butanesultone-1-yl group, R4- carboxyl, or (g) R1has the specified value, R2represents 1-methyl-5-fluoro-benzimidazole-2-yl group, and R3- ethyl group, R4- carboxy, 1H-tetrazol in respect of angiotensin II action, characterized in that it contains at least one benzimidazole derivative of the formula I under item 1 or its physiologically tolerable salt in a therapeutically effective amount of one or more conventional inert carriers and/or diluents.

 

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