Derivatives of benzimidazole and their salts and pharmaceutical composition antagonist against angiotensin activity based on them

 

(57) Abstract:

Derivatives of benzimidazole of General formula I, where R1is methyl, R2-benzimidazole-2-yl, possibly substituted in position 1 by the stands, imidazol-4-yl substituted in position 1 WITH1-3by alkyl, substituted in position 2 morpholino group, 5,6,7,8-tetrahydro-imidazo[1,2-a] pyridine-2-yl or propanesultone-1-yl, R3WITH2-4alkyl; R4- amino, sulfonyl, replaced dimethylaminocarbonylmethyl, cycloalkylcarbonyl, benzylaminocarbonyl, or their salts possess antagonist against angiotensin activity. 2 S. and 3 C.p. f-crystals, 1 table.

The invention relates to new derivatives of benzimidazole with valuable properties, in particular a derivative of benzimidazole of General formula (I)

< / BR>
where R1is methyl,

R2- benzimidazole-2-yl, unsubstituted or substituted in position 1 by the stands, imidazol-4-yl substituted in position 1 by alkyl with 1 to 3 carbon atoms, substituted in position 2 by morpholinopropan, 5,6,7,8-tetrahydro-imidazo[1,2 - a]pyridine-2-yl or propanesultone-1-Il,

R3- nonbranched alkyl with 2 to 4 carbon atoms,

R4- amino group, sulfonyl substituted by a residue from the group comprising Dima is the part contains 5 or 6 carbon atoms and the phenyl portion may be substituted methoxy group, triptoreline, tert. butoxycarbonylamino, 1,3-thiazolidin-2,4-Dion-5-methylidene or 2,5-dihydro-5-oxo-1,2,4 - oxadiazol-3-Il,

or their salts.

Preferred are compounds of the above General formula (I),

where R1- methyl in position 4,

R2- 6 position of the benzimidazole-2-yl, unsubstituted or substituted in position 1 by the stands, imidazol-4-yl substituted in position 1 by alkyl with 1-3 carbon atoms, substituted in position 2 by morpholinopropan, 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine-2-yl or propanesultone-1-Il,

R3- nonbranched alkyl with 2 to 4 carbon atoms,

R4- sulfonyl substituted by a residue from the group consisting of dimethylaminopropylamine, cycloalkylcarbonyl, benzylaminocarbonyl in which cycloalkyl part contains 5 or 6 carbon atoms and the phenyl portion may be substituted by a methoxy group, triptorelin, 1,3-thiazolidin-2,4-Dion-5 - methylidene or 2,5-dihydro-5-oxo-1,2,4-oxadiazol-5-on-3-yl, or their salts.

Particularly preferred are compounds of the above General formula (I),

where R1- methyl in position 4,

R2- 6 position 1-methyl-benzimidazole-2-yl, 1-(2 - morpholinoethyl)-imidazol-4-yl, 5,6,7 the sludge, substituted by a residue from the group consisting of dimethylaminopropylamine, cycloalkylcarbonyl, benzylaminocarbonyl in which cycloalkyl part contains 5 or 6 carbon atoms and the phenyl portion may be substituted by a methoxy group, triptorelin, 1,3-thiazolidin-2,4-Dion - 5-methylidene or 2,5-dihydro-5-oxo-1,2,4-oxadiazol-5-on-3-yl

or their salts.

New benzimidazole derivatives can be obtained in the following ways:

a) a Benzimidazole of General formula (II)

< / BR>
where R1- R3have the above meaning, is subjected to the interaction with biphenylene compound of General formula (III)

< / BR>
where Rahave the above for R4values, however, the available reactive hydrogen atom protected by conventional protective residue, such as, for example, alkoxycarbonyl with the total number of carbon atoms of 2 to 6 or benzyloxycarbonyl and

Z1- nucleophilic remove the group as a halogen atom, e.g. chlorine atom, bromine or iodine, or is replaced by sulfonyloxy, for example, methanesulfonate, benzosulfimide or p-toluensulfonate,

followed, if necessary, removing the applied protective residue.

the R, methylene chloride, diethyl ether, tetrahydrofuran, dioxane, dimethylsulfoxide, dimethylformamide, dimethylacetamide or benzene, if necessary in the presence of an acid acceptor, such as, for example, sodium carbonate, potassium carbonate, sodium hydroxide, tert.butyl potassium, sodium hydride, triethylamine or pyridine, while the latter two may simultaneously also be used as solvent, preferably at temperatures between 0 and 100oC, for example at temperatures between room temperature and 50oC.

Further, if necessary, the withdrawal may apply a protective residue is preferably carried out by hydrolysis in the presence of acid, such as, for example, hydrochloric acid, sulfuric acid, phosphoric acid, trichloroacetic acid or triperoxonane acid or in the presence of a base such as sodium hydroxide or potassium hydroxide, in an environment suitable solvent, such as, for example, water, mixtures of water and matinale, ethanol, a mixture of ethanol and water, a mixture of water and isopropanol or a mixture of water and dioxane, or in the presence of a primary amine, such as, for example, methylamine, ethylamine or Propylamine, at temperatures between -10 and 120oC, the reaction preferably receive a mixture of 1 - and 3 - isomers, then by crystallization or chromatography using a carrier such as silica gel or alumina, remove the corresponding 1-isomer.

b) To obtain compounds of General formula (I), where R4means 1,3-thiazolidin-2,4-Dion-5-methylidene:

The compound of General formula (IV)

< / BR>
where R1- R3have the above meaning,

subjected to interaction with 1,3-thiazolidin-2,4-dione.

To obtain compounds of General formula (I), where R4means an amino group:

Formed, if necessary, in the reaction mixture a compound of General formula (V)

< / BR>
where R1- R3have the above meaning,

subjected to sequential interaction with sodium azide and water or an aliphatic alcohol with 1 to 5 carbon atoms.

The reaction is preferably carried out in an environment of a solvent, such as, for example, a mixture of chloroform and water, with sodium azide in the presence of tetraalkylammonium chloride as, for example, tetrabutylammonium chloride, at a temperature between -5 and 20oC, preferably at 0oC.

Interaction with water or alcohol is preferably carried out in aqueous solvent, such kisatchie alcohol, such as, for example, methanol, ethanol, propanol, isopropanol, tert. butanol or pentanol at temperatures between 0 and 100oC, preferably at the boiling temperature of the reaction mixture.

g) To obtain compounds of General formula (I), where R4means sulfonil:

The compound of General formula (VI)

< / BR>
where R1- R3have the above meaning,

subjected to interaction with nitrite and then with sulfur dioxide.

The diazonium salt is advisable get in the environment of a solvent, such as, for example, a mixture of water and hydrochloric acid, a mixture of water and sulfuric acid, a mixture of methanol and hydrochloric acid, a mixture of ethanol and hydrochloric acid or a mixture of dioxane and hydrochloric acid by diazotization of the compounds of General formula (VIII) with a nitrite, e.g. sodium nitrite or a complex ester of nitrous acid at low temperatures, for example at temperatures between -10 and 5oC. Subsequent interaction with sulfur dioxide expediently carried out in the presence of copper chloride (II) in a solvent such as, for example, water, a mixture of methanol and water or a mixture of water and hydrochloric acid at low temperatures, for example at temperatures between -10 and 5oC.

d) For PAL)

< / BR>
where R1- R3have the above meaning,

subjected to interaction with the compound of General formula

Z2-X-Rc(VIII)

where Rc- alkoxy with 1-5 carbon atoms or trifluoromethyl,

X is carbonyl or sulfonyl and

Z2- removable group such as halogen atom, e.g. a chlorine atom or bromine, asiagraph or acyloxy, for example, acetoxy, methoxycarbonyl, ethoxycarbonyl or isobutoxyethene or hydroxyl, if Rbmeans trifluoromethyl.

The reaction is expediently carried out in an environment of a solvent, such as, for example, methanol, methylene chloride, chloroform, carbon tetrachloride, simple ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile, sulpholane or dimethylformamide, if necessary in the presence of inorganic or organic bases, if necessary in the presence of activator acid, if necessary in the presence of a dehydrating agent or, if necessary, in the presence of an activator of amino groups at temperatures between -20 and 200oC, preferably -10 and 160oC.

If Z2means hydroxyl, acylation, it is advisable osushestvlyaetsya in the presence of activator acid or a dehydrating agent, for example in the presence of ethyl ether of Harborview acid, thionyl chloride, trichloride phosphorus, phosphoric anhydride, N,N'-dicyclohexylcarbodiimide, a mixture of N,N'-dicyclohexylcarbodiimide and N-hydroxysuccinimide or 1 - hydroxy-benzotriazole, N,N'-carbonyldiimidazole or N,N'-conidiomata or a mixture of triphenylphosphine and carbon tetrachloride, or activator of amino groups, such as trichloride phosphorus, and, if necessary, in the presence of a base, such as, for example, sodium carbonate, potassium carbonate, tert.butyl potassium or a mixture of 1-hydroxy - benzotriazole triethylamine or in the presence of tertiary organic bases, such as, for example, 4-dimethylamino - pyridine, triethylamine, N-ethyl-disodio-pelamin, M-methyl-morpholine or pyridine, which may simultaneously also serve as solvent, at temperatures between -10 and 100oC, preferably 0 and 50oC.

The acylation or sulfonylurea preferably carried out using the appropriate galodamadruga acid or anhydride of the acid, if necessary in the presence of one of these acid acceptors.

e) To obtain compounds of General formula (I), where R4means SNO, benzylaminocarbonyl, in which each cycloalkyl portion contains 5 to 7 carbon atoms and the phenyl portion may be substituted by a methoxy group:

The compound of General formula (IX)

< / BR>
subjected to interaction with the compound of General formula

Z4-Re< / BR>
where R1- R3have the above meaning,

Z3- alkoxycarbonyl with the total number of carbon atoms of 2 to 6,

Z4- the hydrogen atom and

Re- dimethylamino, cyclooctylamine, or benzoylamino, or

Z3is a hydrogen atom,

Z4group Z5-CO-, where Z5means delete the group, such as halogen atom, e.g. a chlorine atom or bromine, allograph or alloctype, such as, for example, acetoxy, methoxycarbonyl, ethoxycarbonyl or isobutoxyethene or Z5together with the hydrogen atom adjacent to the carbonyl of aminogroup mean additional carbon-nitrogen bond,

Re- sulfonyl substituted by a residue from the group consisting of dimethylamine, cyclooctylamine, and benzylacrylamide, which cycloalkyl portion contains 5 to 7 carbon atoms and the phenyl portion may be substituted by a methoxy group.

The reaction is expediently carried out in an environment dissolve hydrofuran, dioxane, benzene, toluene, acetonitrile, sulpholane or dimethylformamide, if necessary, in the presence of inorganic or organic bases, if necessary in the presence of activator acid, if necessary in the presence of a dehydrating agent or, if necessary, in the presence of an activator of amino groups at temperatures between -20 and 200oC, preferably at temperatures between -10 and 160oC.

g) To obtain compounds of General formula (I), where R4means 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl:

Formed, if necessary, in the reaction mixture a compound of General formula (X)

< / BR>
where R1- R3have the above meaning, is subjected to the interaction with the compound of General formula (XI)

Z6-CO-ORf, (XI)

where Z6- nucleophilic remove the group as a halogen atom, e.g. chlorine atom, bromine or iodine, and

Rfis alkyl, aryl or aralkyl, preferably lower alkyl as, for example, methyl, ethyl, n-propyl or isopropyl,

followed by cyclization of the resultant acylated amidoxime.

The reaction is expediently carried out in an environment of a solvent, such as, for example, chloris the CSOs bases as sodium or potassium carbonate or in the presence of an organic base like triethylamine or pyridine, while tertiary organic base can also be used as a solvent at temperatures between 0 and 20oC.

Subsequent cyclization of the resultant acylated amidoxime expediently carried out in a medium of an organic solvent, such as, for example, benzene, toluene, xylene, tetrahydrofuran or dioxane at elevated temperatures, for example at temperatures between 50 and 100oC, preferably at the boiling point of the employed solvent.

Necessary amidoxime expediently produced by interaction of the corresponding nitrile with hydroxylamine in the presence of a solvent, such as, for example, methanol, ethanol, methylene chloride, chloroform, dimethylformamide, tetrahydrofuran or dioxane in the presence of a suitable base, such as, for example, sodium carbonate, potassium carbonate, sodium hydroxide, triethylamine, sodium methylate, sodium ethylate or sodium hydride at temperatures between 50 and 100oC.

During the above reactions may available reactive group such as, for example, amino groups can be protected customary protective groups are removed after implemented arbonyl or benzyl.

Further, if necessary, removing the applied protective residue is preferably carried out by hydrolysis in an aqueous solvent, such as, for example, water, a mixture of isopropanol and water, a mixture of tetrahydrofuran and water, or a mixture of dioxane and water in the presence of an acid as hydrochloric acid 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. Removal of the benzyl, however, preferably carried out by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst like palladium on coal in the environment of a solvent, such as, for example, methanol, ethanol, complex ethyl ester of acetic acid or glacial acetic acid, if necessary with the addition of acid as hydrochloric acid at temperatures between 0 and 50oC, preferably at room temperature, and hydrogen pressure of 1 to 7 bar, preferably 3 to 5 bar.

The resulting compounds of General formula (I) can be converted to their acid additive salts, particularly for pharmaceutical use into their physiologically tolerated salts with inorganic or DNA acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

In addition, the thus obtained new compounds of General formula (I), if desired, can then be translated into their salts with inorganic or organic bases, particularly for pharmaceutical use into their physiologically tolerated salts. As the bases can be used, for example, sodium hydroxide, potassium hydroxide, lysine, methylglucamine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

Compounds of General formulas (II) - (XI) used as starting compounds, partly known from the literature (see application EP-A-0 502 314) or you can get them well-known techniques.

For example, the compound of General formula (II) are obtained by acylation of the corresponding o-phenylene-diamine and subsequent cyclization or acylation of the corresponding o-amino-nitro-compounds, the subsequent recovery of the nitro group and cyclization, while thus obtained NH-benzimidazole by alkylation with the corresponding derivative of biphenyl can be transferred in connection, respectively Saia General formula (I) and their physiologically tolerated salts have valuable pharmacological properties. They are antagonists of angiotensin, in particular antagonists of angiotensin II.

A further object of the invention is therefore a pharmaceutical composition comprising in addition at least one pharmaceutically acceptable carrier at least one benzimidazole derivative of the above formula (I) or a mixture of isomers, or an individual isomer or its physiologically tolerable salt as the active agent in an effective amount.

For example, the biological activity was investigated following connections:

A = 4'-[(2-n-propyl-4-methyl-6-(1-methylbenzimidazole-2-yl)- benzimidazole-1-yl)-methyl]-2-(1,3-thiazolidin-2,4-Dion-5 - methylidene)-biphenyl,

B = 4'-[(2-n-propyl-4-methyl-6-(1-methylbenzimidazole-2-yl)- benzimidazole-1-yl)-methyl]-2-sulfo-biphenyl,

In = 4'-[(2-ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2 - a]-pyridine - 2-yl)-benzimidazole-1-yl)-methyl]-2-sulfone-phenyl,

G = 4'-[(2-n-propyl-4-methyl-6-(1-methylbenzimidazole-2-yl)- benzimidazole-1-yl)-methyl]-2-triptorelin-biphenyl,

L = 4'-[(2-ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2 - a]-pyridine-2-yl)-benzimidazole-1-yl)-methyl]-2-triptorelin - biphenyl,

E = 4'-[(2-n-propyl-4-methyl-6-(1-methylbenzimidazole-2-yl)- benzimidazole-1-imidazol-2-yl)- benzimidazole-1-yl)-methyl]-2-(cyclohexyloxycarbonyloxy)- biphenyl,

C = 4'-[(2-n-propyl-4-methyl-6-(1-methylbenzimidazole-2-yl)- benzimidazole-1-yl)-methyl]-2-(benzylaminocarbonyl)-biphenyl,

Th = 4'-[(2-ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2 - a]-pyridine-2-yl)-benzimidazole-1-yl)-methyl]-2- (benzylaminocarbonyl)-biphenyl,

And = 4'-[(2-n-butyl-4-methyl-6-(propanesultone-1-yl)- benzimidazole-1-yl)-methyl]-2-(benzylaminocarbonyl)-biphenyl and

K = 4'-[(2-ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2 - a]-pyridine-2-yl)-benzimidazole-1-yl)-methyl] -2-(cyclohexanecarbonyl - aminosulfonyl)-biphenyl.

Description of the method for determining binding of the receptor by angiotensin

Fabric (light rats) homogenized in Tris buffer (50 mmol Tris, 150 mmol NaCl, 5 mmol ethylendiaminetetraacetic acid, pH 7,40) and centrifuged twice, each time at 20 000 x g for 20 minutes. Get centrifugal resuspended in incubation buffer (50 mmol Tris, 5 mmol magnesium chloride, 0.3% albumin bovine serum, pH 7,40) in the ratio 1:75, in terms of wet weight tissue. 0.1 ml of homogenate and 5 pmol of [125I]- angiotensin II (product of company GIRL, Dreieich, DE) incubated with increasing concentrations of the investigated substances in a total volume of 0.25 ml at a temperature of 37oC during the th ice buffer (25 mmol Tris, 2.5 mmol magnesium chloride, 0.1% albumin bovine serum, pH 7,40). Associated radioactivity determined using a gamma counter. Along the curve of action dose concentration braking KT50the investigated compounds A-K.

Connection And in the above experiences have the following concentration braking KT50:

Connection - KT50[nm]

A - 94,0

B - 8,0

IN - 3,4

MR. 40,0

DR. 28,0

E - 110,0

W - 310,0

C - 78,0

AND - 36,0

TH - 13,9

K - 73,0

In addition, during the application of the above compounds to a dose of 30 mg/kg by intravenous giving not observed toxic side effects, the negative inotropic action and cardiac arrhythmias. Thus, the proposed compounds are well-tolerated.

Because of their pharmacological properties the new compounds and their physiologically tolerated salts are suitable for the treatment of hypertension and heart failure, as well as for the treatment of ischemic disorders of blood flow in peripheral vessels, myocardial ischemia, to prevent progression of cardiac insufficiency after myocardial infarction, for the treatment of diabetic nephropathy, glaucoma, gelado the cally tolerated salts are suitable for the treatment of lung diseases, for example, emphysema and chronic bronchitis, for the prevention of arterial restenosis after angioplasty, thickening of the walls of blood vessels after surgery last, arteriosclerosis and diabetic angiopathy. Due to the influence of angiotensin on the release of acetylcholine and dopamine in the brain new antagonists of angiotensin is also suitable for the treatment of Central nervous system disorders, such as depression, Alzheimer's disease, Parkinson's disease, bulimia and impairment of cognitive functions.

The dose necessary to achieve the proper steps to adults, it is through the giving of 0.5 - 100 mg, preferably 1 to 70 mg, while the country through the mouth - 0.1 to 200 mg, preferably 1 to 100 mg, 1 to 3 doses per day. For this we offer compounds of General formula (I) can be converted to conventional medications, for example, tablets, pills, capsules, powders, suspensions or suppositories, if necessary, in combination with other active substances, for example, substances that reduce blood pressure, acetylcholinesterase inhibitors, diuretics and/or calcium antagonists, and, if necessary, use one or more inert carriers and/ignia, polyvinylpyrrolidone, citric acid, tartaric acid, water, a mixture of water and ethanol, a mixture of water and glycerine, a mixture of water and sorbitol, a mixture of water and glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fat-containing substances, such as cured fat, or their suitable mixtures.

Thus, in combination with the proposed active substances can be applied, for example, benzofluoranthene, chlorothiazide, hydrochlorothiazide, spironolactone, benzthiazide, cyclothiazide, etakrinova acid, furosemide, metoprolol, prazosin, atenolol, propranolol, (di)hydralazine hydrochloride, diltiazem, felodipine, nicardipine, nifedipine, nisoldipine, nitrendipin, captopril, enalapril, lisinopril, cilazapril, inapril, fosinopril and ramipril. At this dose data of the active substances suitable is usually 1/5 of the recommended minimum dose, up to 1/1 of the normally recommended dose, that is, for example, 15 to 200 mg of hydrochlorothiazide, 125 - 2000 mg chlorthiazide, 15 - 200 mg etakrinova acid, 5 - 80 mg furosemide, 20 - 480 mg propranolol, 5-60 mg felodipina, 5-60 mg of nifedipine or 5-60 mg of nitrendipine.

The following examples explain the formation of compounds of formula (I).

Example 1

4'-[(2-n-propyl-4-the 8 g of 4-[(2-n-propyl-4-methyl-6-(1-methylbenzimidazole-2-yl)- benzimida-Zol-1-yl)-methyl] -2-formyl-biphenyl, dissolved in 15 ml of glacial acetic acid are heated together with 0.62 g thiazolidin - 2,4-dione 120oC and stirred at this temperature for 12 hours. After evaporation, the mixture is purified by chromatography on silica gel using as eluent a mixture of dichloromethane and ethanol in a ratio of 17: 1. Then 1.4 g lirovannomu product is dissolved in 50 ml of ethanol and mixed with 10 ml of 2 N. sodium lye. After one-hour stirring at room temperature is mixed with 40 ml of water and the alcohol evaporated in vacuum. The product is extracted with ethyl acetate, dried over sodium sulfate and evaporated.

Output: 1,1,

Melting point: 252 - 254oC.

Example 2

4'-[(2-n-propyl-4-methyl-6-(1-methylbenzimidazole-2 - yl)-benzimidazole-1-yl)-methyl]-2-tert.butoxycarbonylamino - biphenyl -

12.4 g of 4'-[(2-n-propyl-4-methyl-6-(1-methylbenzimidazole-2-yl)- Benzema-Gasol-1-yl)-methyl] -2-carboxy-biphenyl dissolved in 150 ml of chloroform, mixed with 3.5 ml of triethylamine, and then at a temperature of 0oC add 3 ml of complex ethyl ether of Harborview acid. After one-hour stirring at 0oC was added dropwise 0.2 g of tetrabutylammonium bromide and then 2.4 g of sodium azide in 8.5 ml of water. Chayut. The product is mixed with tert.butanol and heated under reflux for 3 hours. After evaporation obtain 4.8 g of crude product which is purified by chromatography on silica gel using as eluent a mixture of dichloromethane and ethanol in a ratio of 19: 1.

Output: 3,1 g

Melting point: 182 - 184oC.

Example 3

4'-[(2-n-propyl-4-methyl-6-(1-methylbenzimidazole-2 - yl)-benzimidazole-1-yl)-methyl]-2-amino-biphenyl -

10.3 g of 4'-[(2-n-propyl-4-methyl-6-(1-methylbenzimidazole-2-yl)- Benzema-Gasol-1-yl)-methyl]-2-tert.butoxycarbonylamino-biphenyl is heated under reflux in 50 ml of dichloromethane and 10 ml triperoxonane acid for one hour. After cooling, neutralized with saturated sodium bicarbonate solution, the dichloromethane phase is dried over sodium sulfate and evaporated.

Output: 8,2 g

Melting point: 208 - 210oC (acetone).

Example 4

4'-[(2-n-propyl-4-methyl-6-(1-methylbenzimidazole-2 - yl)-benzimidazole-1-yl)-methyl]-2-sulfo-biphenyl -

9.0 g of 4'-[(2-n-propyl-4-methyl-6-(1-methylbenzimidazole-2-yl)- benzimidazole-1-yl)-methyl]-2-amino-biphenyl suspended in 170 ml of 6 N. hydrochloric acid and at a temperature of 0 to 5oC for one hour pricap the military solution at 0 - 5oC was added dropwise to a mixture of 40 ml of a saturated solution of sulfur dioxide in glacial acetic acid and 2.25 g of monohydrate chloride copper (II) in 3.3 ml of water. Stirred for further 2 hours at room temperature, when cooling is alkalinized with concentrated ammonia and the precipitated product is sucked off. The filtrate is shaken with ethyl acetate and an ethyl acetate phase is condensed together with the fallen product. After chromatography on silica gel using as eluent a mixture of dichloromethane and ethanol in the ratio 19:1 gain of 4.2 g with a melting point 307 - 310oC.

Example 5

4'-[(2-ethyl-4-methyl-6-(5,6,7,8-tetrahydro - imidazo[1.2-a] pyridine-2-yl)-benzimidazole-1-yl)-methyl]-2-sulfo-biphenyl -

The target product is obtained analogously to examples 2 to 4 of 4'- [(2-ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a] pyridine-2 - yl)-benzimidazole-1-yl)-methyl]-2-carboxy-biphenyl. Melting point: >330oC.

Example 6

4'-[(2-n-propyl-4-methyl-6-(1-methylbenzimidazole-2 - yl)-benzimidazole-1-yl)-methyl]-2-triptorelin-biphenyl -

To 0.5 g of 4'-[(2-n-propyl-4-methyl-6-(1-methylbenzimidazole-2 - yl)-Benzema-Gasol-1-yl)-methyl]-2-amino-biphenyl in 25 ml of dichloromethane and 0.5 ml of triethylamine at -50oC was added dropwise 0.5 ml triperoxonane and the owls. The mixture is then washed with water, dried over sodium sulfate and evaporated. After chromatography on silica gel using as eluent a mixture of dichloromethane and ethanol in the ratio of 50:1 are 0.4 g with a melting point of 115 - 120oC.

Example 7

4'-[(2-ethyl-4-methyl-6-(5,6,7,8-tetrahydro - imidazo[1.2-a] pyridine-2-yl)-benzimidazole-1-yl)-methyl]-2 - triptorelin-biphenyl -

The target product is obtained analogously to example 8 from 4'-[(2 - ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine-2-yl)- benzimidazole-1-yl)-methyl] -2-amino-biphenyl.

Melting point: 246 - 248oC.

Example 8

4'-[(2-n-propyl-4-methyl-6-(1-methylbenzimidazole-2 - yl)-benzimidazole-1-yl)-methyl]-2-(4-methoxy - benzylaminocarbonyl-biphenyl -

of 0.37 g of 4'-[(2-n-propyl-4-methyl-6-(1-methylbenzimidazole-2-yl)- benzimidazole-1-yl)-methyl]-2-ethoxycarbonylmethyl-biphenyl in 5 ml of toluene with 0.1 ml of 4-methoxybenzylamine heated to 90oC for 18 hours. Then evaporated and purified by chromatography on silica gel using as eluent a mixture of dichloromethane and ethanol in a ratio of 100: 2.

Output: 0,15 g

Melting point: 150 - 154oC.

Example 9

4'-[(2-n-proper

0,275 g of 4'-[(2-n-propyl-4-methyl-6-(1-methylbenzimidazole-2 - yl)-Benzema-Gasol-1-yl)-methyl] -2-sulfamoyl-biphenyl in 2 ml of pyridine together with 0.5 ml cyclohexylsulfamate heated under reflux for 20 hours. Then evaporated, the residue is suspended in acetone and the insoluble solid is filtered. After evaporation of the filtrate thus obtained crude product is purified by column chromatography on silica gel using as eluent a mixture of dichloromethane and ethanol in the ratio of 50: 1.

Output: 0,14,

Melting point: 174 - 176oC.

Example 10

4'-[(2-n-propyl-4-methyl-6-(1-methylbenzimidazole-2 - yl)-benzimidazole-1-yl)-methyl]-2-(N,N - dimethylaminocarbonylmethyl-biphenyl -

1,82 g 2-n-propyl-4-methyl-6-(1-methylbenzimidazole-2-yl)- benzimidazole dissolved in 100 ml of dimethyl sulfoxide, mixed with 0.74 g of tert.the butyl potassium and stirred for 0.5 hours at room temperature. Then added to the mixture of 3.05 g of 4'-methyl bromide-2-(N,N-dimethylaminocarbonylmethyl)-biphenyl (obtained similarly to application EP 0 503 162) and stirred at 50oC for 16 hours. After adding another 1.5 g of compound of methyl bromide is stirred for further 8 hours at 50oC. Before the action phase is washed with sodium chloride solution and dried over sodium sulfate. After evaporation the product was then purified by chromatography on silica gel using as eluent a mixture of dichloromethane and ethanol in the ratio of 9: 1.

Output: 1,9,

The value of Rf: of 0.55 (silica gel; a mixture of methylene chloride and ethanol in the ratio of 50:1).

Example 11

4'-[(2-n-propyl-4-methyl-6-(1-methylbenzimidazole-2 - yl)-benzimidazole-1-yl)-methyl]-2-(benzylaminocarbonyl)-biphenyl -

145 mg of benzoic acid and 192 mg of carbonyldiimidazole stirred in 1 ml of tetrahydrofuran for 2 hours at 50oC. To this mixture a solution of 163 mg of 4'-[(2-n-propyl-4-methyl-6-(1 - methylbenzimidazole-2-yl)-benzimidazole-1-yl)-methyl]-2-sulfamoyl)- biphenyl, of 0.133 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene and 1 ml of tetrahydrofuran and support when 55oC for 2.5 hours. Then mixed with 50 ml of ethyl acetate and 20 ml of 5% citric acid. The organic phase is dried over sodium sulfate and evaporated. The resulting residue is purified by chromatography on silica gel using as eluent a mixture of dichloromethane and ethanol in the ratio 95: 5.

Output: 157 mg of amorphous product.

Mass spectrum: M+= 653.

Similar to examples 10, 11 receive the following connections:

(1) 4'-[(2-ethyl-4-Mei is obtained from 2-ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]- pyridine-2-yl)-benzimidazole.

Mass spectrum: M+= 629.

(2) 4'-[(2-n-butyl-4-methyl-6-(propanesultone-1-yl)- benzimidazole-1-yl)-methyl]-2-(benzylaminocarbonyl)-biphenyl,

obtained from 2-n-butyl-4-methyl-6-(propanesultone-1-yl)-benzimidazole.

Mass spectrum: (M+N)+= 657.

(3) 4'-[[2-n-propyl-4-methyl-6-[1-(2-morpholinoethyl)-imidazol - 4-yl)-benzimidazole-1-yl] -methyl] -2-(benzylaminocarbonyl)- biphenyl, obtained from 2-n-propyl-4-methyl-6-[1-2-morpholinoethyl)- imidazol-4-yl]-benzimidazole.

Mass spectrum: M+= 702.

Example 12

4'-[(2-ethyl-4-methyl-6-(5,6,7,8-tetrahydro - imidazo[1.2-a] pyridine-2-yl)-benzimidazole-1-yl)-methyl] -2- (cyclohexyloxycarbonyloxy)-biphenyl -

0.25 g of 4'-[(2-ethyl-4-methyl-6-(5,6,7,8-tetrahydro - imidazo[1,2-a]pyridine-2-yl)-benzimidazole-1-yl)-methyl] -2 - sulfamoyl-biphenyl in 2 ml of pyridine together with 0.5 ml cyclohexylsulfamate heated under reflux for 6 hours. After evaporation purified by chromatography on silica gel using as eluent a mixture of dichloromethane and ethanol in the ratio 95:5.

Yield: 85 mg

Mass spectrum: M+= 651.

Example 13

4'-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazole-2 - yl)-1H-benzimidazole-1-yl]-methyl]-2-(2.5-dihydro-5-imidazol-1-yl] -methyl]-2- (hydroxycarbamoyl)-biphenyl and 200 mg of triethylamine in 40 ml of tetrahydrofuran at 0oC pin 220 mg complex of ethyl ether of Harborview acid. Then the reaction mixture is heated under reflux for 6 hours. After cooling, the reaction mixture was mixed with methylene chloride, washed with water and dried. The resulting crude product is purified by chromatography on silica gel using as eluent first methylene chloride and then a mixture of methylene chloride and ethanol in the ratio of 50:1, 25:1 and 19:1. The uniform fractions are combined evaporated, triturated with simple ether and dried.

Yield: 0.27 g (27% of theory).

Melting point: 266 - 268oC.

Mass spectrum: M+= 555.

Example 14

4'-[[2-n-propyl-4-methyl-6-(1-methyl-4,5,6,7 - tetrahydro-benzimidazole-2-yl)-1H-benzimidazole-1-yl] -methyl]-2- (2,5-dihydro-5-oxo-1,2,4 - oxadiazol-3-yl)-biphenyl -

The target connection receive analogously to example 13 from 4'-[[2 - n-propyl-4-methyl-6-(1-methyl-4,5,6,7-tetrahydro-benzimidazole-2 - yl)-1H-benzimidazole-1-yl] -methyl] -2-(hydroxycarbamoyl)-biphenyl and complex mixture of ethyl ether of Harborview acid and triethylamine.

Yield: 55 % of theory.

Melting point: since 199oC (decomp.).

Mass spectrum: M+= 558.

Example 15

Tablets containing 50 mg of active substance

Active substance 50.0 mg

Calcium phosphate 70.0 mg

Milk sugar - 40,0 mg

Corn starch - 35,0 mg

Polyvinylpyrrolidone - 3.5 mg

Magnesium stearate 1.5 mg

Total: - 200.0 mg

Preparation:

The active ingredient, calcium phosphate, lactose and corn starch is uniformly moistened with an aqueous solution of polyvinylpyrrolidone. The mass is passed through a sieve of the size of cells 2 mm, dried in a drying Cabinet at a temperature of 50oC and sift again.

After adding lubricant granulate is processed into tablets on a tablet press machine.

Example 16

Tablets containing 50 mg of active substance

Active substance 50.0 mg

Lysine - 25.0 mg

Milk sugar - 60,0 mg

Corn starch is 34.0 mg

Gelatin - 10.0 mg

Magnesium stearate 1.0 mg

Total - 180,0 mg

Preparation:

Active substance stir with auxiliary substances and hydrate aqueous solution of gelatin. After sieving and drying the obtained granules are mixed with magnesium stearate and pressed into the kernel.

what you can add dye.

Example 17

Tablets containing 100 mg of active substance

Active substance 100.0 mg

Lysine - 580,0 mg

Milk sugar - 86,0 mg

Corn starch 50.0 mg

Polyvinylpyrrolidone - 2.8 mg

Microcrystalline cellulose - 60,0 mg

Magnesium stearate 1.2 mg

Total: - 350,0 mg

Preparation:

Active substance stir with auxiliary substances and hydrate aqueous solution of polyvinylpyrrolidone. The wet mass is passed through a sieve of the size of cells of 1.5 mm and dried at a temperature of 45oC. After drying, re-sift and add magnesium stearate. The resulting mixture is pressed into the kernel.

Thus obtained core-known method of supplying the shell. In the appropriate suspension or solution, you can add dye.

Example 18

Capsules containing 250 mg of active substance

Active substance - 250.0 mg

Corn starch and 68.5 mg

Magnesium stearate 1.5 mg

Total: - 320,0 mg

Preparation:

The active substance is mixed with corn starch and moisten with water. The wet mass is screened and dried. The dry granulate is sieved and blended with magnesium stearate. The resulting mixture is pressed into capsules made from solid yellow
Active substance 50.0 mg

Acetylcellulose - 50.0 mg

Sorbic acid - 5,0 mg

70% sorbitol - of 600.0 mg

Glycerin - 200.0 mg

Aroma - 15,0 mg

Water - to 5.0 mg.

Preparation:

Distilled water is heated to a temperature of 70oC. With stirring in dilute it acetylcellulose. By adding a solution of sorbitol and glycerine cooled to room temperature. At this temperature add sorbic acid, fragrance or active substance, after which the air is removed by stirring. One dose of the active substance (50 mg) contained 5.0 ml of suspension.

Example 20

Suppositories containing 100 mg of active substance

Active substance 100.0 mg

Frozen fat - 1600,0 kilowatt mg

Total - 1700,0 mg

Preparation:

Cured fat is melted. At a temperature of 40oC powdered active substance is homogeneous dispersed in the melt. Cooled to a temperature of 38oC and the mixture is poured into pre-cooled forms to obtain suppositories.

1. Derivatives of benzimidazole of General formula I

< / BR>
where R1is methyl; R2- benzimidazole-2-yl, unsubstituted or substituted in position 1 MEO-group, 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine-2-yl or propanesultone-1-yl;

R3- nonbranched alkyl with 2 to 4 carbon atoms;

R4- amino group, sulfonyl substituted by a residue from the group consisting of dimethylaminopropylamine, cycloalkylcarbonyl, benzylaminocarbonyl in which cycloalkyl part contains 5 or 6 carbon atoms and the phenyl portion may be substituted methoxy group, triptorelin, tert. butoxycarbonylamino, 1,3-thiazolidin-2,4-Dion-5-methylidene or 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-Il,

or their salts.

2. Derivatives of benzimidazole of General formula I on p. 1, where R1- methyl in position 4; R2- 6 position of the benzimidazole-2-yl, unsubstituted or substituted in position 1 by the stands, imidazol-4-yl substituted in position 1 by alkyl with 1 to 3 carbon atoms, substituted in position 2 morpholino group, 5,6,7,8-tetrahydro-imidazo[1,2-a] pyridine-2-yl or propanesultone-1-yl; R3- nonbranched alkyl with 2 to 4 carbon atoms; R4- sulfonyl substituted by a residue from the group consisting of dimethylaminopropylamine, cycloalkylcarbonyl, benzylaminocarbonyl in which cycloalkyl part contains 5 or 6 carbon atoms and phenyl h is-oxo-1,2,4-oxadiazol-5-on-3-yl, or their salts.

3. Derivatives of benzimidazole of General formula I on p. 1, where R1- methyl in position 4; R2- 6 position 1-methyl-benzimidazole-2-yl, 1-(2-morpholinoethyl)-imidazol-4-yl, 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine-2-yl or butanesultone-1-yl; R3- ethyl or n-propyl; R4- sulfonyl substituted by a residue from the group consisting of dimethylaminopropylamine, cycloalkylcarbonyl, benzylaminocarbonyl in which cycloalkyl part contains 5 or 6 carbon atoms and the phenyl portion may be substituted methoxy group, triptorelin, 1,3-thiazolidin-2,4-Dion-5-methylidene or 2,5-dihydro-5-oxo-1,2,4,-oxadiazol-5-on-3-yl, or their salts.

4. Derivatives of benzimidazole of General formula I on p. 1, representing a compound from the group including:

4'-[(2-n-propyl-4-methyl-6-(1-methylbenzimidazole-2-yl)-benzimidazole-1-yl)-methyl]-2-(1,3-thiazolidin-2,4-Dion-5-methylidene)-biphenyl,

4'-[(2-n-propyl-4-methyl-6-(1-methylbenzimidazole-2-yl)-benzimidazole-1-yl)-methyl]-2-sulfo-biphenyl,

4'-[(2-ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a] -pyridine-2-yl)-benzimidazole-1-yl)-methyl]-2-sulfo-biphenyl,

4'-[(2-n-propyl-4-methyl-6-(1-methylbenzimidazole-2-yl)-benzimidazole-1-yl)-methyl]-2-triptorelin-biphenyl, the o-biphenyl,

4'-[(2-n-propyl-4-methyl-6-(1-methylbenzimidazole-2-yl)-benzimidazole-1-yl)-methyl]-2-(4-methoxy-benzylamino-carbonyl-aminosulfonyl)-biphenyl,

4'-[(2-n-propyl-4-methyl-6-(1-methylbenzimidazole-2-yl)-benzimidazole-1-yl)-methyl]-2-(cyclohexyloxycarbonyloxy)-biphenyl,

4'-[(2-n-propyl-4-methyl-6-(1-methylbenzimidazole-2-yl)-benzimidazole-1-yl)-methyl]-2-(benzylaminocarbonyl)-biphenyl,

4'-[(2-ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a] -pyridine-2-yl)-benzimidazole-1-yl)-methyl]-2-(benzylaminocarbonyl)-biphenyl,

4'-[(2-n-butyl-4-methyl-6-(propanesultone-1-yl)-benzimidazole-1-yl)-methyl] -2-(benzylaminocarbonyl)-biphenyl and

4'-[(2-ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a] -pyridine-2-yl)-benzimidazole-1-yl)-methyl] -2-(cyclohexyloxycarbonyloxy)-biphenyl or their salts.

5. Pharmaceutical composition with antagonist against angiotensin activity, containing the active substance and at least one pharmaceutically acceptable carrier, wherein the active substance contains at least one derivative of a benzimidazole of General formula I

< / BR>
where R1is methyl;

R2- benzimidazole-2-yl, unsubstituted or substituted in position 1 by the stands, imidazol-etrahydro-imidazo[1,2-a]pyridine-2-yl or propanesultone-1-yl;

R3- nonbranched alkyl with 2 to 4 carbon atoms,

R4- amino group, sulfonyl substituted by a residue from the group consisting of dimethylaminopropylamine, cycloalkylcarbonyl, benzylaminocarbonyl in which cycloalkyl part contains 5 or 6 carbon atoms and the phenyl portion may be substituted methoxy group, triptorelin, tert. butoxycarbonylamino, 1,3-thiazolidin-2,4-Dion-5-methylidene or 2,5-dihydro-5-oxo-1,2,4-oxadiazol-5-on-3-yl,

or its physiologically tolerable salt in an effective amount.

 

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< / BR>
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