Imidazole derivatives, pharmaceutical composition, inhibiting the activity of angiotensin ii, and a method of treating hypertension in mammals

 

(57) Abstract:

Described new compounds having the formula I, in which X, R1, R2, R3, R4and R5defined in the description. These compounds inhibit the action of angiotensin II and therefore useful, for example, as protivogipertonicheskoe funds. The formula I are given in the description. 19 C. 2 S. p. f-crystals, 2 tab.

The invention relates to new substituted imidazoles useful as protivogipertonicheskoe funds.

Described new compounds that inhibit the action of the hormone angiotensin II.

These compounds have the General formula I:

< / BR>
including their pharmaceutically acceptable salts and prodrugs, where X can be N or

if X is N, then there is always a double bond, R1represents hydrogen, halogen. NO2, halide alkyl or-CN,

R2represents a hydrogen atom, CN, alkyl with 1-10 carbon atoms, alkenyl with 3-10 carbon atoms or the same groups substituted by fluorine, phenylalkyl, in which the aliphatic portion contains 2 to 6 carbon atoms, -(CH2)m- imidazol-1-yl, -(CH2)m-1,2,3-triazolyl, optionally substituted with one or two group nOR6,(CH2)n, -(CH2)nSR8, -CH = CH(CH2)s, -CH = CH(CH2)s-CH = CH(CH2)s, -(CH2)s, -(CH2)n, -(CH2)nOTHER10, -CH2)nNR6-(CH2)nNR6CNHR10, -(CH2)nNR6SO2R10, -(CH2)n-(CH2)nF, -(CH2)mONO2,

-(CH2)mN3, -(CH2)mNO2, -(CH2) -

or R1and R2taken together with the carbon atoms of imidazole nucleus to which they are attached, may form a benzimidazole following formula:

,

where A can be hydrogen, alkyl (CxF2x+1C6F5, halogen, C1-C6-alkoxy, -(CH2)x-OC1-4-alkyl, -(CH2)x, -(CH2)x-alkyl or-COR9and B may be hydrogen, alkyl, CxR2x+1C6F5, halogen or C1-C6-alkoxy,

R3represents alkyl with 2 to 10 carbon atoms, alkenyl or alkinyl with 3-10 carbon atoms or the same groups substituted by fluorine or CO2R7cycloalkyl with 3-8 carbon atoms, cycloalkenyl 4-10 carbon atoms, cycloalkylcarbonyl odorata, C1-C6-alkyl, C3-C6-cycloalkyl, C2-C4-alkenyl or C2-C4-quinil), optionally substituted by a fluorine atom or CO2F7, benzyl or substituted benzyl on the phenyl ring by one or two halogen, alkoxy with 1-4 carbon atoms, alkyl with 1-4 carbon atoms or a nitro-group, R4and R4'independently from each other selected from among hydrogen, halogen, haloalkyl, quinil, aryl, cycloalkyl, aralkyl, ,

R5represents hydrogen, -NHSO2CF3, , -SO3H, -C(CF3)2OH, , -NHSO2CF3, -CONHOR15, CONHNHSO2CF3,

R6represents a hydrogen atom, alkyl with 1-6 carbon atoms, cycloalkyl with 3-6 carbon atoms, phenyl or benzyl,

R7represents a hydrogen atom, alkyl or pettorelli with 1-8 carbon atoms, cycloalkyl with 3-6 carbon atoms, phenyl or benzyl,

R8represents a hydrogen atom, alkyl with 1-6 carbon atoms, cycloalkyl with 3-6 carbon atoms, phenyl, benzyl, acyl, with 1-4 carbon atoms, phenacyl,

R9represents a hydrogen atom, alkyl with 1-6 carbon atoms, cycloalkyl with 3-6 carbon atoms, (CH<6 carbon atoms or pettorelli with 1-6 carbon atoms, 1-substituted, 1-naphthyl, 1-(1-naphthyl)-ethyl or (CH2)pC6H5,

R11represents a hydrogen atom, alkyl with 1-6 carbon atoms, cycloalkyl with 3-6 carbon atoms, aryl, arylalkyl, 5-7-membered carbocyclic ring which may have a different 5-7-membered carbocyclic ring fused to it.

< / BR>
R12and R13independently from each other represent a hydrogen atom, alkyl with 1-4 carbon atoms, phenyl, benzyl, - -methylbenzyl or taken together form a ring of the formula

< / BR>
< / BR>
where Q is NR14, O, or CH2,

R14and R15independently from each other represent a hydrogen atom, alkyl, aryl: aralkyl or cycloalkyl,

R16represents a C1-C6-alkyl, -NR17R18or

R17and R18independently from each other represent a hydrogen atom, alkyl with 1-6 carbon atoms, benzyl or taken together comprise 3-6 carbon atoms, form a 4-7-membered ring with the nitrogen atom to which they are attached,

R19represents an atom of hydrogen, C1-C5-alkyl, phenyl,

R20represents a-CH, -NO2-CO2R7in which R2 what volume of hydrogen, alkyl, cycloalkyl, aryl, arylalkyl or alkoxy, R21and R22together are -(CH2)2-, -(CH2)3-, -CH=CH - or

Y is an oxygen atom or a sulfur atom,

Z is an oxygen atom, NR6or sulfur atom, m is from 1 to 5, n is 1-10, p=0-3, q=2-3, r=0-2, s=0-5, t is zero or one and x is an integer from one to 6.

The present invention concerns the compounds of formula I, pharmaceutical compositions and methods of using such compounds.

The term "aryl" used in the description either as such or as part of a larger group, refers to phenyl or phenyl substituted by halogen, alkyl, alkoxy, alkylthio, hydroxy, alkanoyl, nitro, amino, dialkylamino or trifluoromethyl. Preferred phenyl and monosubstituted phenyl and the most preferred phenyl.

The term "alkyl" used in the description either as such or as part of a larger group, refers to groups having from 1 to 10 carbon atoms. Preferred alkyl groups having from 1 to 4 carbon atoms.

The term "cycloalkyl" used in the description either as such or as part of a larger group, refers to groups having from 3-7 carbon atoms.

The term "halogen" used as such, or as part of a larger group, refers to fluorine, chlorine, bromine and iodine, while the preferred fluorine and chlorine.

It should be borne in mind that the present invention includes proletarienne form, i.e., esters, acetals and/or mixed acetylene derivatives of compounds of formula I. for Example, such derivatives are described in Design of Prodrugs, published A. Bundgard (Elsevier, 1985) and Methods in Ensymology so 42, 309-396, published by K. Wrobder et. al. (Academic Press, 1985).

Because proletarienne forms of the compounds of formula I are usually represented by compounds in which one or more groups R11(where R11is not a hydrogen atom) are present at R2, R4and/or R5it becomes clear that any part of the molecule at R11that will be cleaved in vivo to obtain compounds of the formula I, where R11is hydrogen, falls in volume and corresponds to the idea of this invention.

To obtain the compounds of formula I in which R4is a hydrogen atom, R4is a hydrogen atom and a double bond is present. X is-C - and golodny-alkyl, or connection

formula II'

subjected to interaction with the compound of the formula III

< / BR>
in which L is a removable group, such as halogen, in the presence of a coupling agent, for example, hexamethyldisilazane potassium in solvents such as tetrahydrofuran and dimethylformamide to obtain the compound of formula IV or IV'

< / BR>
< / BR>
The product of formula IV' can turn into products having different values of R2using known techniques, such as acylation and alkylation.

The aldehyde of formula IV can then be treated with a reducing agent such as sodium borohydride in a solvent such as ethanol, to obtain the compound of formula Ia

< / BR>
i.e., the compound of formula I, in which R2is-CH2-OH. Using known methods, the compounds of formula I in which R2differs from-CH2-OH, can be obtained from the compounds of formula Ia. For example, the alcohols of the formula Ia can be alkylated or etilirovany to obtain the corresponding compounds of formula I. Alternative the compounds of formula I can be obtained from compounds of formula IV homologation of the aldehyde by Wittig.

Imidazole aldehyde of formula II (i.e., connection,

oxidizing agent, for example magnesium oxide in pyridine.

The compounds of formula III can be obtained by the coupling of compounds of formula VI

< / BR>
with the compound of the formula VII

< / BR>
where X is a halogen atom such as bromine in pyridine and in the presence of copper oxide to obtain a compound of formula VIII

< / BR>
Remove the group L, for example halogen, such as bromine, can be introduced by known methods to obtain the compounds of formula IIIa

< / BR>
The compounds of formula VI can be obtained by known methods, for example, described in J. Heterocyclic Chem., 25.1. (1988).

The compounds of formula I in which X is a nitrogen atom, can be obtained by the interaction of formula IX

< / BR>
received as described Mathias et al, Synthetik Communications, 5,461-469 (1975) with the compound of the formula X

< / BR>
in the presence of a base, for example potassium carbonate, in a solvent, for example dimethylformamide, to obtain the compounds of formula XI

.

The compound of formula XI can then be formed with N-bromosuccinimide and the initiator radical reactions, for example, 2,2' - azobisisobutyronitrile in a solvent, for example, carbon tetrachloride to obtain the compounds of formula XII

< / BR>
Intermediate The R>
The aldehyde of formula XIII can be treated as the aldehyde IV above to obtain compounds of formula XIV

< / BR>
Compound XIV may then be subjected to the interaction with the compound of the formula (n-Bu)3SnN3obtaining the compounds of formula I in which X is nitrogen and R5group of the formula

.

The compounds of formula I in which X is nitrogen and R3is a group other than the group of the formula

< / BR>
can be obtained using the intermediate compounds of formula VII instead of the compounds of formula X above.

The compounds of formula I in which R1and R2together form imidazolines the core to which they are attached, form a benzimidazole, can be obtained using the technology of U.S. patent N 4880804.

The compounds of formula II'

< / BR>
(i.e., compounds in which R1is halogen-alkyl) can be obtained first by treating compound of formula XV

haloalkyl - CH2-COOR7XII,

for example with sodium nitrite and acid, for example acetic acid, to obtain the intermediate compounds of formula XVI

haloalkyl .

This compound can then be treated with an aldehyde, such as aldehyde BR>
after restore, for example, titanium trichloride in the presence of a buffer such as sodium acetate, to obtain the compounds of formula II.

The compounds of formula I in which X is nitrogen, can be obtained by the combination of the compounds of formula IIIb

< / BR>
with the compound of the formula II or II', as described above, for a combination of compounds of formulas II and III.

Compounds of formula IIIb can be obtained using known methods. For example, to obtain a compound of the formula IIIb in which R4is haloalkyl first compound of the formula XIX:

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

XX,

(for example, CF3-C-O-C-CF3) in solvents such as dioxane and pyridine, to obtain the intermediate compounds of formula XXI

< / BR>
The compound of formula XXI can be treated with a reducing agent such as zinc in the presence of acid, such as sulfuric acid, in a solvent, such as water and methanol, to obtain the compounds of formula XXII

< / BR>
The compound of formula XXII can be treated as a connection IX, XI, XII, XIII and XIV above to obtain the corresponding compounds of formula I.

The compounds of formula IIIb in which uly IX azatadine group, for example, (CH3)3CH2-CH2-OCH2Cl in the presence of a base such as sodium hydride and in a solvent, for example tetrahydrofuran, to obtain, for example, the compound of formula XXIII

< / BR>
The compound of formula XXIII is treated then base, such as n-utility, with subsequent treatment of the simple ester of formula XXIV

< / BR>
(obtained as described in W. E. Barnette, J. Amer. Chem. Soc., so 106, S. 452 - 454 (1984) for the intermediate compounds in which R4is a fluorine atom, or N-bromosuccinimide, R4is a bromine atom, to obtain the corresponding intermediate compounds of formula XXVa

< / BR>
and formula XXVb

< / BR>
Using known technology, such as the processing of fluorinated n-tetrabutylammonium in tetrahydrofuran, the compounds of formula XXVa and XXVb, can be converted into compounds of formula XXVIa

< / BR>
and formula XXVIb

< / BR>
Thus obtained intermediate compound can then be subjected to the above-described processing to obtain the corresponding compounds of formula I.

The compounds of formula I can be represented in General as the compounds of formula I'

< / BR>
or the compounds of formula I"

< / BR>
where R1- R5immoraly I', where:

R1represents hydrogen, halogen or haloalkyl,

R2represents-CH2-OH,-CHO or-COORII,

R3represents a C2-10-alkyl or C/-C10alkenyl,

R4represents hydrogen or-COOH and

R5represents ortho - tetrazol, which can be substituted for R11or COOR11or compounds of the formula I, in which

R1represents a hydrogen atom, halogen or haloalkyl,

R2represents - CH2OH, -CHO or - COOR11,

R3represents a C2-C10-alkyl or C3-C10-alkyl or C3-C10alkenyl,

R4represents a hydrogen atom, a halogen atom (preferably bromine or fluorine) or halogen alkyl (preferably CF3and

R5represents ortho - tetrazol, which can be substituted for R11or - COOR11.

The present invention of the formula I inhibit the action of the hormone angiotensin II (A - II) and is therefore useful as protivogipertonicheskoe funds.

The action of the enzyme renin on angiotensinogen, pseudoglobulin plasma causes the production of angiotensin I. Angiotens substance, involved as a causative factor in various forms of hypertension in various mammalian species such as humans. Compounds according to the invention inhibit the action of angiotensin II to its receptors in target cells and thus prevents the increase in blood pressure caused by this interaction of the hormone with the receptor. Therefore, the introduction of a composition containing one (or a combination) of the compounds according to the invention, is facilitated by the position of the suffering caused by angiotensin hypertension species of mammals (e.g. humans). Single dose, or preferably two to four divided doses on the basis of 0.1 - 100 mg per 1 kg of body weight per day, preferably from 1 to 15 mg per 1 kg of body weight per day is sufficient to reduce blood pressure. The substance is preferably administered pills, but can also be used intranasal, intradermal and parenteral routes of administration, such as subcutaneous, intramuscular, intravenous or intraperitoneal. Compounds according to the invention are also useful in the treatment of congenital heart failure and hypertrophy of the heart.

Compounds according to the invention can also be prepared in dosage forms with diuretic ESWL to be introduced in an effective amount, which makes a total daily dose of from 30 to 600 mg, preferably 30 to 330 mg of the compounds according to the invention and from 15 to 300 mg, preferably from 15 to 200 mg of the diuretic species of mammal in need of it. Examples of diuretics, considered for use in combination with a peptide according to the invention include triazide diuretics, for example chlorthiazide, hydrochlorthiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichlormethiazide, polythiazide or benzthiazide, as well as ethacrynic acid, ticrynafen, chlorthalidone, furosemide, muzolimine, bumetanide, triamterene, amiloride and spironolactone and salts of such compounds.

The compounds of formula I can be prepared in dosage forms for use in the reduction of blood pressure in compositions such as tablets, capsules or elixirs for oral administration, sterile solutions or suspensions for parenteral administration or administration into the nose or transcutaneous inclusions.

From 10 to 500 mg of the compounds of formula I is mixed with a physiologically acceptable carrier, excipient, diluent, ligament, preservative, stabilizer, an aromatic substance, and so forth in a single dosage form is Ephratah is to provide a suitable dose at the specified interval.

The present invention further can be explained by the following examples.

Example 1. Dulaiova Sol-5-{/2-butyl-5-(hydroxymethyl)-1H-imidazol-1-yl/-methyl}-1- (2-carboxyphenyl)-1H-indole-2-carboxylic acid.

A. Ethyl ester 2-/(4-were)-hydrazino/-propanoic acid.

Pair-tolylhydrazine (1,2024 g, 9,84 mmole, 1.0 EQ.) mixed with the ethyl ester of pyruvic acid (1.08 ml, 9,84 mmole, 1.0 EQ) and a zeolite with a pore diameter of 3A (3.6 g, 300 wt.%) in methylene chloride (9,8 ml, 1.0 M) at room temperature. After 30 min the reaction mixture was filtered through anhydrous magnesium sulfate, concentrated and received the connection specified in the item title A (2,095 g), which was used in the next stage without purification or identification.

B. Ethyl ester 5-methyl-1H-indole-2-carboxylic acid.

The target compound obtained in stage A (2,095 g of 9.51 mmole, 1.0 EQ) was dissolved in absolute ethanol (9.8 ml, 1 M) and the reaction mixture was barbotirovany gaseous hydrochloric acid until then, until the reaction medium was left of the original material (45 min). Then the reaction solution, concentri the second phase was dried over sodium sulfate, filtered through magnesium sulfate and concentrated. The residue was chromatographically on silica gel (60 g), elwira toluene, followed by elution with a mixture of chloroform-hexane in the ratio of 1:4, then a mixture of ether-hexane in the ratio 2:3 and they received of the target compound indicated in the title of stage B (1,5187 g)

C. Ethyl ester 2-bromobenzoyl acid.

2-Bromobenzoyl acid (2,005 g, for 9.47 mmole, 1.0 EQ) was mixed with iodine and methane (1.60 ml, to 19.9 mmole, 2.0 EQ) and sodium bicarbonate (1, 68 g, 1 M) and stirred at room temperature in a total of 4 days. Then the reaction mixture was diluted with water (20 ml) and was extracted with a mixture of ether-hexane in the ratio of 1: 1, three times with 20 ml combined organic extracts washed with water, 10% sodium bisulfite (20 ml), water (20 ml), and aqueous saturated sodium chloride solution (20 ml). Then the organic extracts were dried over sodium sulfate, filtered through magnesium sulfate and concentrated. The residue was chromatographically on silica gel (50 g), elwira a mixture of ether-hexane in the ratio of 1:6 and has been indicated in the name phase C target compound (2.17 g).

D. Ethyl ester 1-/2-(etoxycarbonyl)-phenyl/5-methyl-1H-indole-2 - carboxylic acid.

The target connection, poluce EQ) and copper oxide (I) (424 mg, 2.97 mmole, 1.0 EQ) in pyridine (3.0 ml, 1 M) and heated at 130oC for 8 h and Then the reaction mixture was cooled, diluted with ethyl acetate, combined with earlier epaulettes target compound obtained at this stage D, and filtered through celite. The filtrate was washed with water (3 times 30 ml) and 0.5 N. hydrochloric acid (twice 30 ml) and saturated aqueous sodium bicarbonate (once 30 ml). Then the organic solution was dried over sodium sulfate, filtered through magnesium sulfate and concentrated. The residue was chromatographically on silica gel (45 g), elwira a mixture of ether-hexane in the ratio of 1:8, and got the connection specified in the stage name D (1,0246 g).

E. Ethyl ester 5-(methyl bromide)-1-/2-(etoxycarbonyl)-phenyl/-1H - indole-2-carboxylic acid.

The compound obtained in stage D (1,0084 g, 2,87 mmole, 1.0 EQ) was mixed with N-bromosuccinimide (531,4 mg, 2,96 mmole, 1.03 EQ) and azobisisobutyronitrile (20.2 mg, 2 wt.%) in carbon tetrachloride (47.8 ml, 0,06 M) and heated at 80oC for 2 h Then the reaction mixture was cooled to 0oC, filtered and concentrated. The residue was chromatographically on silica gel (45 g), elwira a mixture of ether-hexane in the ratio of 1:8, then in the ratio of 1:5 and received yasananlari

Gaseous hydrogen chloride was barbotirovany in tared solution valeronitrile (92.0 g, a 1.08 mol) in absolute ethanol (64 ml, of 1.08 mol) in a flask with a round bottom, with a capacity of 1 l, cooled to 0oC. the Flask was periodically weighed and gaseous hydrogen chloride was continued to barbthroat up until the increment in weight was more than 39 g (1,08 mol). The mixture is then corked and kept at 0oC for six days. Then was added ether (650 ml, cooled and the mixture was kept at -30oC for 24 h resulting solid substance was collected on a Buechner funnel, quickly transferred in large chemical glass, quickly triturated with cold ether and collected by Buchner funnel. The solid was dried and then received target compound indicated in the title of stage F, in the form of freely current solid white (95 g).

G. 2-butyl-4-(hydroxymethyl) imidazole.

The reactor high pressure Parr, capacity 300 ml stainless steel containing dimer dioxooleana (5.0 g, 55 mmol), cooled in a bath of dry ice for 1 h

In the process of cooling the lid of the reactor was closed and kept at the place of application small vacuum: metal, employees dlya the reactor was cooled enough, liquid ammonia are condensed in a three-neck flask with a capacity of 250 ml, equipped with a fridge on dry ice at -78oC. the Cooled reactor was then opened to fill the vacuum and added to the target compound obtained in stage G (9,1 g, 55 mmole), followed by immediate addition of liquid ammonia from the 250 ml flask (added approximately 55 ml of ammonia). The reactor was sealed relevant items were removed from the bath with dry ice and warmed up to room temperature. Then the reactor was immersed about halfway into the oil bath and was heated to 75oC for 3 h, during which the pressure was increased to 22.5 kg/cm2. The heating was then stopped and the reactor was cooled to room temperature. When the pressure fell below 7 kg/cm2slowly opened the drain valve high pressure and the ammonia was evaporated (cooling by evaporation helped cooled reactor). When the pressure is completely balanced, the reactor was opened and the contents transferred to a regular bulb, using acetonitrile for washing off the residue. The mixture was concentrated in vacuo and the residue was purified evaporative chromatography on silica gel (1500 g), elwira a mixture of chloroform-methanol-ammonium hydroxide in the ratio of 80:20:1. Free from acetonitrile (200 ml) and received the target connection, specified in the stage name G, in the form of a white crystalline substance (5,74 g), melting point 92-93oC.

H. 2-Butyl-1H-imidazol-5-carboxaldehyde.

The target compound obtained in stage C (3.0 g, 19.5 mmole, 1.0 EQ), was dissolved in pyridine (100 ml, 0.2 M) was heated to 100oC. was Added magnesium oxide (IV) (20 g, 230 mmol, 11,8 EQ) and the reaction mixture was stirred at 100oC 1 h Then the reaction mixture was filtered and concentrated. The residue is triturated with ether and was obtained target compound indicated in the title of stage H, (2.0 g), melting point 113,5-114,5oC.

I. Ethyl ester 5-/(2-butyl-5-formyl-1H-imidazol-1-yl)methyl/- 1-/2-oxycarbonyl)-phenyl/-1H-indole-2-carboxylic acid.

The target compound obtained in stage H (207,4 mg of 1.36 mmole, 1.1 EQ), was dissolved in tetrahydrofuran (of 1.03 ml, 1.3 M) was cooled to 0oC and treated with hexamethyldisilazane potassium (1.90 ml of 1.42 mmole, 1.15 EQ. 0.75 M in toluene). The reaction mixture was stirred 10 min at 0oC, was heated to room temperature and then was added the compound obtained in stage E (533 mg, 1,24 mmole, 1.0 EQ) in tetrahydrofuran (2.0 ml, 0.6 M). The reaction mixture was stirred 4 h, the reaction was stopped with saturated aqueous solution of chloric trevali over magnesium sulfate and concentrated. The residue was chromatographically on silica gel (20 g), elwira a mixture of toluene-acetone in the ratio of 8:1 and got the target compound indicated in the title of stage j (517 mg).

J. Ethyl ester 2-{/-butyl-5-(hydroxymethyl)-1H-imidazol-1 - ml/methyl} -1-/2-(etoxycarbonyl)-phenyl/-1H-indole-2-carboxylic acid.

The target compound obtained in stage I (517 mg, of 1.03 mmole, 1.0 EQ), was dissolved in absolute ethanol (10.3 ml, 0.1 M) was cooled to 0oC and treated with sodium borohydride (38,8 mg, dissolved in 3.9 ml of absolute ethyl alcohol, of 1.03 mmole, 1.0 EQ). The reaction mixture was stirred at 0oC for 20 min, the reaction was stopped 1 N. hydrochloric acid at pH 4.0 and concentrated. The residue was dissolved in water and three times were extracted with ethyl acetate. The organic extracts were dried over sodium sulfate, filtered through magnesium sulfate and concentrated. The residue was chromatographically on silica gel (20 g), elwira a mixture of chloroform-methanol-ammonium hydroxide in the ratio of 30:1, 2:0,05, and received the target compound indicated in the title of stage J (345 mg).

K. Delitala salt of 5-{ /2-butyl-5-(hydroxymethyl)-1H-imidazol-1 - ml/methyl}-1-/2-(carboxyphenyl)-1H-indole-2-carboxylic acid.

Target coed N. the lithium hydroxide (5.0 ml, 5.0 mmol, 7.3 EQ). The reaction mixture was stirred at room temperature for 20 h and concentrated. The residue was dissolved in water and was chromatographically on HP.20 (20 g), elwira water (100 ml), 1% acetone in water (120 ml) 3% acetone in water (120 ml) and 5% acetone in water (120 ml). The mixture was concentrated approximately to a volume of 50 ml and liofilizirovanny. After obtaining the spectra of nuclear magnetic resonance in nuclei of carbon and proton product was dissolved in water, filtered through a polycarbonate membrane, liofilizirovanny and received the target connection specified in the stage name K (277,4 mg).

Example 2. Monolithian salt of 2-/5-{/2-butyl-5-(hydroxymethyl)- 1H-imidazol-1-yl/methyl}-1H-indol-1-yl/-benzoic acid.

A. Ethyl ester of 2-(5-methyl-1H-indol-1-yl)-benzoic acid.

5-Methylindol (730,6 mg, 5,57 mmole, 1.0 EQ) was mixed with the target compound obtained in stage C of example 1 (3,186 g, 13.9 mmole, 2.5 EQ) and copper oxide (I) (797 mg, 5,57 mmole, 1.0 EQ) in pyridine (5.6 ml, 1 M). The reaction mixture was heated at 120oC 3 h, cooled to room temperature, diluted with ethyl acetate and filtered through celite. The filtrate is twice washed with water, two times with aqueous 1N. hydrochloric acid is trevali over magnesium sulfate and concentrated. The residue was chromatographically on silica gel (50 g), elwira a mixture of hexane-ether in the ratio of 40: 1, then the ratio of 20:1 and received 848 g of target compound obtained in stage A.

B. Ethyl ester 2-/3-(2,3-di-bromo-5-(methyl bromide)-1H-indol - 1-yl/benzoic acid.

The target compound obtained in stage B of example 1 (834,7 mg, 2,99 mmole, 1.0 EQ) was mixed with N-bromosuccinimide (1,074 g, 6,04 mmole, 2,02 EQ) and azobisisobutyronitrile (25.0 mg, 3 wt.%) in carbon tetrachloride (49,8 ml of 0.06 M) and heated at 80oC for 2.5 h, the Reaction mixture was cooled to room temperature and concentrated. The residue was dissolved in chloroform (5 ml) in a mixture of ether-hexane in the ratio of 1:1 (50 ml), filtered and concentrated. The product was chromatographically on silica gel (50 g), elwira a mixture of hexane-ether in the ratio of 30:1, then the ratio of 15:1 and received 747,7 mg mixture dibromopropanol and tribromopropane target connection specified by the stage name B.

C. Ethyl ester 2/-3-(2,3-di-bromo-5-/2-butyl-5-formyl-1H - imidazol-1-yl)-methyl/-1H-indol-1-yl/-benzoic acid.

The target compound obtained in stage H of example 1 (273,7 mg of 1.80 mmole, 1.15 EQ) was dissolved in tetrahydrofuran (3,90 ml, 0.46 M) and dimethylformamide (1,30 is (e). The reaction mixture was heated to room temperature for 15 min, cooled to 0oC and then added obtained in stage B of this example, the mixture of compounds (607,1 mg of 1.56 mmole, 1.0 EQ) in tetrahydrofuran (1,56 ml, 1 M). The ice in an ice bath melted and the mixture is stirred to room temperature in a total of three days. The reaction was stopped aqueous saturated solution of ammonium chloride (15 ml) and was extracted with ethyl acetate (3 x 15 ml). The organic extracts were dried over sodium sulfate, filtered through sulfate magic and concentrated. The residue was chromatographically on silica gel (35 g), elwira a mixture of toluene-acetone in the ratio of 14:19, then the ratio of 10:1 and received 469,2 kg mixture monobromobimane and dibromononane target connection specified by the stage name C.

D. Ethyl ester 2-/3- (2,3-di-bromo-5-{/2-butyl-5- (hydroxymethyl)-1H-imidazol-1-yl/methyl}-1H-indol-1-yl/benzoic acid.

The mixture of compounds obtained in stage C above (469,2 mg of 1.02 mmole, 1.0 EQ), was dissolved in absolute ethanol (10,2 ml, 0.1 M) and treated at room temperature with sodium borohydride (38,6 mg, dissolved in 3.9 ml of absolute ethyl alcohol, of 1.02 mmole, 1.0 EQ). The reaction mixture was stirred at room temperorily in the water and was extracted three times with ethyl acetate. The organic extracts were dried over sodium sulfate, filtered through magnesium sulfate and concentrated. The residue was chromatographically on silica gel (18 g), elwira mixture chloroformmethanol-ammonium hydroxide in the ratio of 30:0,8:0,05), then the ratio of 30:1: 0,05, then in respect of 30:2:0.05 and received 446,1 mg in a mixture monobromobimane and dibromononane target compound obtained in stage d

E. Ethyl ester 2-/5-{ /2-butyl-5-(hydroxymethyl)-1H-imidazol-1 - yl/methyl}-1H-indol-1-yl/benzoic acid.

The target compound obtained in stage D (420 mg, 0,823 mmole, 1.0 EQ) was mixed with triethylamine (0,34 ml, 2,47 mmole, 3.0 EQ) and palladium hydroxide on coal (84 mg, 20% wt.) in absolute ethyl alcohol (16.4 ml, 0.05 M) and placed under the tank with gaseous hydrocarbons at room temperature for 45 minutes Then the reaction mixture was diluted with ethanol, filtered through regenerated cellulose and concentrated. The residue was chromatographically on silica gel (10 g), elwira hexane-acetone-ammonium hydroxide in the ratio 20:10:0.05 and received the target connection at the stage E (321,3 mg).

F. Monolithian salt- 2-/5-{/2-butyl-5-(hydroxymethyl-)-1H - imidazol-1-yl/methyl}-1H-indol-1-yl/-benzoic acid.

Target soy is N. the lithium hydroxide (1.0 ml, 1.0 mmole, 1.7 EQ). The reaction mixture was stirred at room temperature for three days and then concentrated. The residues were dissolved in water and was chromatographically on HP-20, was suirable water (100 ml), 2% acetone in water (75 ml), 5% acetone in water (75 ml), 10% acetone in water (100 ml) and 20% acetone in water (100 ml). The mixture was concentrated to approximately 50 ml and liofilizirovanny. After obtaining the spectra of nuclear magnetic resonance in nuclei of carbon and hydrogen, the product was dissolved in water (20 ml), filtered through a polycarbonate membrane, liofilizirovanny and received 184,1 mg of target compound specified in the named stage F.

Example 3. Monolithian salt of 5-{/2-butyl-5-(hydroxymethyl)-1H - imidazol-1-yl/-methyl}-1-phenyl-1H-indole-2-carboxylic acid.

A. Ethyl ester 5-methyl-1-phenyl-1H-indole-2-carboxylic acid.

The target compound obtained in stage B of example I (1,016 g, 5.0 mmol, 1.0 EQ), and brobinson (1,32 ml, 12.5 mmole, 2.5 EQ) was dissolved in pyridine (5 ml, 1 M) was treated with copper oxide (I) (715 mg, 5.0 mmol, 1.0 EQ). The mixture was heated at 35oC total of 5.5 hours After 2.5 hours from the start of heating was added brobinson (0.4 ml) and copper oxide (I) (215 mg). After cooling stevedorage acid (twice 50 ml) and saturated sodium bicarbonate solution (50 ml), was dried over anhydrous magnesium sulfate and freed from solvent in vacuo. The brown residue was chromatographically on silica gel, elwira 10% ether in hexane, and received the target compound indicated in the title of A stage (1,107 g). Thin layer chromatography: Rf=0,48, silica gel, mixture of hexane-ether in the ratio of 3:1.

B. Ethyl ester 5-(bromophenyl)-1-phenyl-1H-indole-2-carboxylic acid.

The mixture of compounds obtained in stage A (1,105 g of 3.96 mmole, 1.0 EQ), N-bromosuccinimide (726 mg, 4,08 mmole, 1.03 EQ) and azobisisobutyronitrile (22 mg, 2 wt.%) in tetrachloride hydrogen (40 ml, 0.1 M) was heated in an oil bath at 80 - 90oC for 75 min, the Mixture was cooled to 0oC. the Solid was removed by filtration and washed with cold carbon tetrachloride. The filtrate is evaporated to dryness in a vacuum. The residue was chromatographically on silica gel, elwira 10% ether in hexane, and received the target compound indicated in the title of stage B (872 mg). Thin layer chromatography: Rf=0,42, silica gel, mixture of ether-hexane in the ratio of 1:3.

C. Ethyl ester 5-/(2-butyl-5-formyl-1H-imidazol-1-yl)methyl/1 - phenyl-1H-indole-2-carboxylic acid.

Imidazole aldehyde obtained in stage H of example 1 (105 is tmosphere argon. The solution was cooled in an ice bath and added dropwise thereto was added a solution caliphaxisindicative (0,7 N. in toluene, of 1.03 ml, 0.72 mmole, 1.2 EQ). The cooling bath was removed and the mixture was stirred 20 minutes After re-cooling in an ice bath was added a solution of compound obtained in stage B (215 mg, 0.6 mmole, 1.0 EQ) in tetrahydrofuran (1 ml) and the mixture was heated to room temperature, leaving it overnight with stirring. The reaction was stopped by adding a saturated solution of ammonium hydroxide. The product was extracted into ethyl acetate (3 times 30 ml). The combined extracts were dried over anhydrous magnesium sulfate and freed from solvent in vacuo. The residue was chromatographically on silica gel, elwira a mixture of acetone-toluene in the ratio of 1:15, then, in the ratio of 1: 12 and then 1:10, and got the target compound indicated in the title of stage C (251 mg). Thin chromatography: Rf=0,30, silica gel, a mixture of acetone-toluene in the ratio of 1:4.

D. Ethyl ester 5-{/2-butyl-5-(oxymethyl)-1H-imidazol-1-yl/methyl}- 1-phenyl-1H-indole-2-carboxylic acid.

The compound obtained in stage C (251 mg, of 0.58 mmole, 1.0 EQ), was dissolved in ethanol (5,8 mol, 0.1 M) and treated with a solution of sodium borohydride (22 mg, of 0.58 mmole, 1.0 EQ) in ethanol (2 ml is the cosmology vacuum. Added water and the solution was podslushivaet solid sodium bicarbonate. The product was extracted in ethyl acetate (three times with 20 ml), dried over anhydrous magnesium sulfate and freed from solvent in vacuo. The residue was chromatographically on silica gel, elwira a mixture of hexane-acetone in the ratio of 1: 1, then in the ratio of 1:2 containing 0.05% ammonium hydroxide, and received the connection specified in the stage name D (219 mg). Thin layer chromatography: Rf= 0.31, silica gel, mixture of hexane-acetone in the ratio of 1:2, plus ammonium hydroxide.

E. Monolithian Sol - 5-{ /2-butyl-5-(oxymethyl)-1H-imidazol - 1-yl/methyl}-1-phenyl-1H-indole-2-carboxylic acid.

The compound obtained in stage D (218 mg, 0,507 mmole, 1.0 EQ), was dissolved in methanol (2.5 ml) was added 1 n solution of lithium hydroxide (1.5 ml) causing precipitation. The cloudy mixture was stirred, leaving overnight at room temperature. The solvent was removed in vacuum. The residue was dissolved in water and introduced into a column Packed with HP-20 (20 ml). The column was suirable water (about 250 ml) up until the eluate has not been neutral, then suirable water with increasing content of acetone (100 ml of a 5% acetone, 100 ml of 10% acetone and 100 ml of 15% aqueous acetone). Products is utilizacii material used to obtain an NMR spectrum, was isolated, dissolved in water, again liofilizirovanny and received the connection specified in the title stage E (164 mg).

Example 4. Monolithian salt- 2-/4-{/2-butyl-5-(hydroxymethyl)- 1H-imidazol-1-yl/methyl}-1H-indol-1-yl/-benzoic acid.

A. 2-/2-(2-methyl-6-nitrophenyl)-ethylidene/-hydrazinecarboxamide.

3-Nitro-ortho-xylyl (1.77 ml, 13,23 mmole, 1.0 EQ) was mixed with dimethylacetal of dimethylformamide (2,11 ml, 15,88 mmole, 1.2 EQ), dimethylformamide (7,35 ml, 1.8 M) and pyrrolidine (1,352 ml, 15,88 mmole, 1.2 EQ) and heated to 110oC for 8 h, the Reaction mixture was then cooled to room temperature and concentrated. The residue was dissolved in diethylformamide (7,35 ml, 1.8 M) and treated at room temperature with a solution of the hydrochloride semicarbazide (1.55 g, 13,79 mmole, of 1.05 equiv) in concentrated hydrochloric acid (1.2 ml, 14,55 mmole, 1.1 EQ) in water (16.5 ml, 0.8 M). The mixture was stirred at room temperature for 30 min, cooled to 0oC and filtered. The residue was washed with water (30 ml), cold ethanol (15 ml) and ethyl ether (25 ml), then dried in vacuum and got the connection specified in the title of A stage (2,44 g).

B. 4-methyl-1H-indole.

The compound obtained in stage A (to 206.6 mg, 0,875 mmole, 1.0 EQ) is re hydrogen (4.2 kg/cm2) for 5 hours Then the reaction mixture was diluted with methanol, filtered through regenerated cellulose and concentrated. The residue was chromatographically on Merck silica gel (5 g), elwira a mixture of chloroform-hexane in the ratio of 4:1, then 3: 1 and got the connection specified in the title of stage B (of 101.7 mg).

C. Ethyl ester 2-(4-methyl-1H-indol-1-yl)-benzoic acid.

The compound obtained in stage B (101,5 mg, 0,774 mmole, 1.0 EQ) was mixed with ortho - brahmativartate (443 mg, of 1.93 mmole, 2.5 EQ) (as obtained in example I, the connection at the stage C) and copper oxide (I) (132,9 mg, 0,928 mmole, 1.2 EQ) in pyridine (of 0.77 ml, 1M) and was heated at 130oC for 2 h Then the reaction mixture was cooled to room temperature, diluted with ethyl acetate and filtered through celite. The filtrate is twice washed with water, two times with 1 N. hydrochloric acid and once with saturated aqueous acidic sodium carbonate. Then the solution was dried over sodium sulfate, filtered through magnesium sulfate and concentrated. The residue was chromatographically on silica gel (10 g), elwira a mixture of toluene-hexane in the ratio of 1 : 2, then a mixture of ether-hexane in the ratio of 1 : 10. The product was again chromatographically on Merck silica gel (10 g), elwira a mixture of ether-CLASS="ptx2">

D. Ethyl ester 2-/3-(2,3-di-bromo-4-(methyl bromide)-1H-indol-1-yl/benzoic acid.

The compound obtained in stage C (146,8 mg, 0,526 mmole, 1.0 EQ) was mixed with N-bromosuccinimide (188,9 mg of 1.06 mmole, 2,02 EQ) and azobisisobutyronitrile (4.4 mg), 3 wt.%, staged Chemical Dynomics Corp, in carbon tetrachloride (8,8 ml of 0.06 M) and heated at 60oC for 30 minutes a drop of the mixture at this time showed negative reaction of starch on potassium iodide. The reaction mixture was then cooled to 0oC, filtered and concentrated. The residue was chromatographically on Merck silica gel (10 g), elwira a mixture of ether-hexane in the ratio of 1 : 40, then in the ratio of 1 : 10 and got the target compound indicated in the title of stage B, (112,7 mg) in a mixture of di - and tribromide.

E. Ethyl ester 2-/3-(2,3-di-bromo-4-/(2-butyl-5-formyl-1H-imidazol-1-yl)-methyl/-1H-indol-1 - yl/benzoic acid.

The compound obtained in stage D (112,7 mg, 0,258 mmole, 1.0 EQ) was mixed with the compound obtained in stage H of example 1 (to 43.2 mg, 0,284 mmole, 1.1 EQ), was dissolved in tert-butanol (0,52 ml, 0.5 M) and tetrahydrofuran (of 0.26 ml, 1M). Then the solution was treated with tert-butyl potassium (to 36.5 mg, 0,309 mmole, 1.2 EQ) and stirred at room temperature for 4 h was Added eseau temperature, the reaction was stopped with saturated aqueous solution of ammonium chloride and water, and three times were extracted with ethyl acetate. The organic extracts were dried over sodium sulfate, filtered through magnesium sulfate and concentrated. The residue was chromatographically on Merck silica gel (5 g), elwira a mixture of toluene-acetone in the ratio of 12 : 1 and got the connection specified in the title stage E (128 mg).

F. Ethyl ester 2-/3-(2,3-di-bromo-4-{/2-butyl-5- (hydroxymethyl)-1H-imidazol-1-yl-/methyl}-1H-indol-1-yl/benzoic acid.

The compound obtained in stage E (123,3 mg, 0,242 mmole, 1.0 EQ), was dissolved in ethanol (2.4 mg, 0.1 M) and treated at room temperature with sodium borohydride (9,2 mg, 0,242 mmole, 1.0 EQ) dissolved in ethanol (0.95 ml). The reaction mixture was stirred at room temperature for 1H, the reaction was stopped 1 N. hydrochloric acid and concentrated. To the residue was added saturated aqueous sodium bicarbonate and water mixture three times were extracted with ethyl acetate. The organic extracts were filtered through magnesium sulfate and concentrated. The residue was chromatographically on Merck silica gel (5 g), elwira a mixture of chloroform-methanol-ammonium hydroxide in the ratio of 30 : 0,8 : 0,05, and received the connection specified in n the 1-Il/benzoic acid.

The compound obtained in stage F (117,4 mg, 0,230 mmol, 1.0 EQ) was mixed with palladium hydroxide on coal (23,5 mg, 20 wt.%), by triethylamine (0.10 ml, 0,690 mmol, 3.0 EQ) and ethanol (4.6 ml, 0.05 M) and placed under the tank with gaseous hydrogen for 45 minutes Then the reaction mixture was diluted with ethanol, filtered through regenerated cellulose and concentrated. The residue was chromatographically on Merck silica gel (5 g), elwira a mixture of chloroform-methanol-ammonium hydroxide in the ratio of 30 : 0,7 : 0,05, and received the connection specified in the stage name O (65,2 mg).

H. Monolithian salt of 2-/4-{/2-butyl-5-(hydroxymethyl)-1H-imidazol - 1-yl-/methyl}-1H-indol-1-yl/benzoic acid.

The compound obtained in stage G (to 65.2 mg, 0,151 mmole, 1.0 EQ), was dissolved in ethanol (1 mg) and aqueous 1 N. and lithium hydroxide (1 ml). The reaction mixture was stirred at room temperature for three days and then concentrated. The residue was chromatographically on HP-20 ionoobmennoi resin (10 g), elwira water (100 ml), 5% acetal linkages in water (80 ml), 10% acetone in water (80 ml), 20% acetone in water (80 ml) and 35% acetone in water (80 ml). Collected product, suirvey water with acetone content of 10 to 35%. Fractions were concentrated to approximately a volume of 25 ml and liofilizirovanny. After the floor is Wali and received the target connection, or 64.7 mg), specified in the stage name H.

Example 5. Delitala Sol-5-{/2-butyl-4-chloro-5-(hydroxymethyl)- 1H-imidazol-1-yl-/methyl} -1-/2-(1H-tetrazol-5-yl)-phenyl/-2H-indole - 2-carboxylic acid.

A. Ethyl ester 1-(2-cyanophenyl)-5-methyl-1H-indole-2-carboxylic acid.

The mixture of compounds obtained in stage B of example 1 (2,027 g 9,975 mmole, 1.0 EQ) obtained as described in stage B of example 1, powdered potassium carbonate (2.76 g, 19,95 mmole, 2.0 EQ), 2-perbenzoate (2,71 ml, 24,9 mmole, 2.5 EQ) and 18-crown-6 (263 mg, 0.99 mmole, 0.1 EQ) in dimethylformamide (20 ml, 0.5 M) was stirred and heated in an oil bath maintaining the temperature 150 5oC. After 3.5 h was added 2-perbenzoate (1.1 ml, 9,975 mmole, 1.0 equiv) and 18-crown (263 mg, 0.1 EQ) in 18 hours After heating for 28 h, the mixture was cooled, diluted with water and was extracted with a mixture of ether-hexane in the ratio of 1 : 1 (3 times 100 ml). The combined extracts washed once with water, once with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and the solvent was removed in vacuum. The product was purified by chromatography on silica gel (150 g), washed movable admixture with a mixture of toluene-hexane in the ratio 2 : 1, then the desired product was suirable toluene-hexane is EDINENIE (1.88 g). Thin layer chromatography : Rf= 0,41, silica gel, 5% ethyl acetate in toluene, UV.

B. Ethyl ester 5-(methyl bromide)-1-(2-cyanophenyl)-1H-indole-2 - carboxylic acid.

The compound obtained in stage A (1.88 g, 6,17 mmole, 1.0 EQ), was dissolved in carbon tetrachloride (62 ml, 0.1 M) and treated with N-bromosuccinimide (1.13 g, 6,36 mmole, 1.03 EQ) and azobisisobutyronitrile (38 mg, 2 wt. % supplied Chemical Dynamics Corp.). The mixture was heated under reflux 5 hours droplet mixture showed negative reaction in the test starch-potassium iodide by this time. After cooling in an ice bath, the solid was removed by filtration and washed with cold carbon tetrachloride. The filtrate is evaporated to dryness in a vacuum. The residue was chromatographically on silica gel (180 g). Mobile impurities were suirable 5% acetone in hexane. The desired bromide connection then suirable 10% acetone in hexane and was obtained target compound indicated in the title of stage B (1.54 g). Thin layer chromatography: Rf= 0,29, silica gel, 20% acetone in hexane, UV.

C. 2-butyl-4-chloro-5-formylamino.

A solution of the compound obtained in stage C of example 1 (6,15 g, 39,9 mmole) in a mixture of absolute ethanol (40 g, for 44.4 mmole) in small portions over 60 min the resulting mixture was stirred 30 min in an ice bath, then 30 min at 25oC, after which the reaction of potassium iodide on the starch was negative. The mixture was concentrated in vacuum and the obtained residue, which was triturated with ether (400 ml) and received a brown solid substance. The mother liquor from the trituration was concentrated and the residue is again triturated with ether (40 ml) and got some more brown solid substance. The solids were mixed, dissolved in pyridine (200 ml) and was heated to 100oC. To the warm solution was added manganese dioxide (20 g) and the resulting dark mixture was stirred at 100oC 1 tsp Hot solution was filtered and concentrated. The residue was purified by chromatography on silica gel (500 g), elwira a mixture hexanitrate in the ratio of 3:1, and got the main product, with Rf0,4. The product is triturated with petroleum ether and was obtained target compound indicated in the title of stage C, in the form of a white crystalline substance (3,9 g), melting point of 96-97oC.

D. Ethyl ester 5-/2-butyl-4-chloro-5-formyl-1H-imidazol-1 - yl)-methyl/-1-(2-cyanophenyl)-1H-indole-2-carboxylic acid.

A solution of the compound obtained not (15.1 ml, the 0.2 M) in an argon atmosphere, was treated with tert-butyl potassium (462 mg, of 3.78 mmole, 1.25 equiv) and 18-crown-6 (160 mg, 0.6 mmole, 0.2 EQ) and the mixture was stirred at room temperature for 27 h). The reaction was suppressed with a saturated solution of ammonium chloride and diluted with water. The product was extracted into ethyl acetate (3 times 50 ml), dried over anhydrous magnesium sulfate and the solvent was removed in vacuum. The residue was chromatographically on silica gel (120 g). Unreacted source imidazole material was washed 10% acetone in hexane. The desired product was suirable 20% acetone in hexane and received the connection specified in the stage name D (815 mg). Thin layer chromatography: Rf= 0,34, silica gel, 30% acetone in hexane, UV.

E. Ethyl ester 5-{/2-butyl-4-chloro-5-(hydroxymethyl)-1H - imidazol-1-yl/-methyl}-1-(2-cyanophenyl)-1H-indole-2-carboxylic acid.

The compound obtained in stage D (815 mg, 1,67 mmole, 1.0 EQ) was dissolved in ethanol (17 ml, 0.1 M) and treated with a solution of sodium borohydride (63 mg, 1,67 mmole, 1.0 EQ in ethanol (5 ml). The mixture was stirred at room temperature for 1 h, then acidified to pH 4.0 with the help of 1H. hydrochloric acid and stirred at room temperature for 30 minutes the Solvent was removed in vacuum. Dobarganes extracts were dried over anhydrous magnesium sulfate and the solvent was removed in vacuum. The residue was chromatographically on silica gel (70 g). Less polar impurities were washed with a mixture of ether-hexane in the ratio of 1:1, then 2:1. The desired alcohol was suirable ether and received the connection specified in the title stage E, (569 mg). Thin layer chromatography Rf= 0,48, silica gel, ethyl ether, UV.

F. Ethyl ester 5-{/2-butyl-4-chloro-5-(hydroxymethyl)-1H - imidazol-1-yl/-methyl}-1-/2-(2-tetrazol-5-yl)-phenyl/ 1H-indole-2-carboxylic acid.

The compound obtained in stage F (72,2 mg, 0,1429 mmole, 1.0 EQ) and azide presence of TBT (71,2 mg, 0,214 mmole, 1.5 EQ) was dissolved in xylene (1,4 ml, 0.1 M) and heated in an oil bath maintaining the temperature of 140-150oC. After 6 h was added azide presence of TBT (47,5 mg, 0,1429 mmole, 1.0 equiv) and heating was continued for a total of 12 hours After cooling, the solvent was removed in vacuo, and the residue was chromatographically on silica gel (13 g), elwira 3% methanol in dichloromethane containing 0.2% acetic acid, then 5% methanol in dichloromethane with 0.2% acetic acid and got the connection specified in the title of stage F, (55 mg). Thin layer chromatography: Rf= 0,28, silica gel, 7% methanol in dichloromethane containing acetic acid (two drops per 10 ml, UV).

The compound obtained in stage F (55 mg, is 0.102 mmole, 1.0 EQ), was dissolved in methanol (1 ml) and treated with 1 N. a solution of lithium hydroxide (1 ml). The mixture was stirred at room temperature for 20 hours the Solvent was removed in vacuum. The residue was combined with the residue obtained from a similar reaction carried out with 0,04-mmol mentioned compounds were purified on a column Packed 12 ml of ion-exchange resin HP-20. First column was suirable water, followed by 20% acetone in water. The desired product, which began to degrade after about 50 ml of water was passed through the column and elution was accelerated by the addition and acetone. The fractions containing the desired product were collected, concentrated to small volume and liofilizirovanny. The product was used to obtain NMR spectra, was isolated, dissolved in water (10 ml) was passed through a polycarbonate filter, re-liofilizirovanny and received the connection specified in the title stage (55 mg).

Example 6. Ethyl ester, monosodium salt of 5-{/2-butyl-4-chloro - 5-(hydroxymethyl)-1H-indole-imidazol-1-yl/-methyl} -1-/2-(2H-tetrazol - 5-yl)-phenyl/-1H-indole-2-carboxylic acid.

The compound obtained in stage F of example 5 (82 mg, 0,158 mmole, 1.0 EQ), was dissolved in methanol (5 ml) and obrabatyvali, then evaporated to dryness in a vacuum. The residue is taken out in a column Packed with ion-exchange resin HP-20 (10 ml). The column was suirable first with water, then increasing amounts of acetone in water with 5% increments. The reaction product was suirable 15 - and 20% acetone in water. The fractions containing the desired product were combined and liofilizirovanny. The product is used to obtain an NMR spectrum was allocated, was dissolved in water (10 ml) was passed through a polycarbonate membrane, again liofilizirovanny and received the connection specified in the name of the example (63.5 mg).

Example 7. Monolithian salt of 2-butyl-4-chloro-1-{/1-/2-(2H - tetrazol-5-yl)-phenyl)-1H-indol-4-yl}-methyl/-1H-imidazole-5 - methanol.

A. 1-(2-cyclofenil)-4-methyl-1H-indole.

The compound obtained in stage B of example 4 (1,042 g, 7,94 mmole, 1.0 EQ) was combined with phthorbenzotephum (1,29 ml, 11.9 mmole, 1.5 EQ) and potassium carbonate (2,195 g 15,88 mmole, 2.0 EQ) in dimethylformamide (7,94 ml, 1M) and was heated at 150oC 4 h the Reaction mixture was cooled to room temperature, diluted with water and three times were extracted with ethyl acetate. The organic extracts were washed with water and aqueous saturated sodium chloride, dried over magnesium sulfate and concentrated. The rest of chromatogr and connection indicated in the name phase A (1,57 g).

B. 2-/3-( 2,3-di-bromo-4-(methyl bromide)-1H-indol-1-yl/ benzonitrile.

N-bromosuccinimide (3,615 g, 20,11 mmole, 3.0 EQ) was added to a solution of compound obtained in stage A (1,557 g, 6,70 mmole, 1.0 EQ) in carbon tetrachloride (134 ml of 0.05 M) and benzene (26,8 ml, 0.25 M) and the reaction mixture was placed near a bright lamp at room temperature for 3 hours Then the mixture was diluted with chloroform (134 ml of 0.05 M was cooled to 0oC, filtered and concentrated. The residue was chromatographically on Merck silica gel (100 g), elwira a mixture hexanchiformes in the ratio of 1:1, then 2:3 in ratio 1:2 and received the connection specified in the title of stage B (2,268 g).

C. 2-/3-( 2,3-di-bromo-4-/(2-butyl-4-chloro-5-formyl - 1H-imidazol-1-yl)-methyl/-1H-indol-1-yl/-benzonitrile.

The compound obtained in stage B (2,268 g, 4,84 mmole, 1.0 EQ) was mixed with the compound obtained in stage C of example 5 (993 mg, 5,32 mmole, 1.1 EQ), was dissolved in tert-butanol (9.7 ml, 0.5 M) and dimethylformamide (9.7 ml, 0.5 M). Then the solution was treated with tert-butyl potassium (671 mg, 5,80 mmole, 1.2 EQ) and heated at 60oC for 90 minutes Then the reaction mixture was cooled to room temperature, diluted with water (40 ml) and was extracted with ethylacetate was dried over sodium sulfate, filtered through magnesium sulfate and concentrated. The residue was chromatographically on Merck silica gel (100 g), elwira a mixture of toluene-ethyl acetate in the ratio of 25:1, and received the connection specified in the title stage C (at 1,865 g).

D. 2-/3-( 2,3-di-bromo-4-{/2-butyl-4-chloro-5 - (hydroxymethyl)-1H-imidazol-1-yl/-methyl}-1H-indol-1-yl/benzonitrile.

The compound obtained in stage C (1.65 g, 3,24 mmole, 1.0 EQ), was dissolved in ethanol (32,4 ml, 0.1 M) and treated at room temperature with sodium borohydride (124 mg, 3,24 mmole, 1.0 EQ), was dissolved in ethanol (32,4 ml, 0.1 M) and treated at room temperature with sodium borohydride (124 mg, 3,24 mmole, 1.0 EQ) dissolved in ethanol (12,4 ml). The reaction mixture was stirred at room temperature for 1 h, the reaction was suppressed 1H. hydrochloric acid and concentrated. To the residue was added saturated aqueous sodium bicarbonate in water and the aqueous mixture three times were extracted with ethyl acetate. The organic extracts were dried over sodium sulfate, filtered through magnesium sulfate and concentrated. The residue was chromatographically on Merck silica gel (50 g), elwira a mixture of chloroform-ether in the ratio of 10:1, then 5:1 and got the connection specified in the stage name D (1,638 g).

E. 2-/4-{ /2-butyl-4-chloro-5-((1,638 g, 2,84 mmole, 1.0 EQ) was mixed with palladium hydroxide on coal (328 mg, 20 wt.%), by triethylamine (1,19 ml, charged 8.52 mmole, 3.0 EQ) and ethanol (56,8 ml of 0.05 M) and placed under the tank with gaseous hydrogen for 45 minutes Then the reaction mixture was diluted with methanol (60 ml), filtered through regenerated cellulose and concentrated. The residue was chromatographically on Merck silica gel (35 g), elwira a mixture of chloroform-ethyl acetate in the ratio of 4:1, and obtained target compound indicated in the title of stage E (1,188 g).

F. 2-butyl-4-chloro-1-{/2-(2H-tetrazol-5-yl)-phenyl/-1H-indol - 4-yl/-methyl} -1H-imidazole-5-methanol.

The compound obtained in stage E (1,119 g, to 2.67 mmole, 1.0 EQ) and azide anti - (2,218 g of 6.68 mmole, 2.5 EQ), was dissolved in xylene (10,7 ml, 0.25 M) and heated at 150oC for 5 h Then the reaction mixture was heated to room temperature and concentrated. The residue was chromatographically on silica gel Mercr (75 g), elwira a mixture of chloroform-methanol-acetic acid in the ratio of 30:1,5:0,05, then in respect of 30:3:0.05 and received the target connection specified in the title stage F (940 mg).

G. Monolithian salt of 2-butyl-4-chloro-1-{/1-/2-(2H-tetrazol-5-yl)-phenyl-/1H-indol-4-yl}-methyl/ -1H-imidazole-5-methanol.

Connection received on stadsnes was stirred at room temperature for 30 min and concentrated. The residue was chromatographically on ion-exchange resin HP-20(50 g), elwira water (400 ml), 5% acetone in water (400 ml), 10% acetone in water (400 ml), 20% acetone in water (400 ml) and 30% acetone in water (400 ml). Product blueraven 20-30% acetone. Fractions were concentrated to a volume of approximately 50 ml and liofilizirovanny. After obtaining NMR spectra, the product was dissolved in water (50 ml), filtered through a polycarbonate membrane, liofilizirovanny and received the target connection (708 mg).

Example 8. Monolithian salt of 2-butyl-4-chloro-1-{1-/2-(2H-tetrazol-5-yl)-phenyl/-1H-benzimidazole-4-yl}-methyl/ -1H-imidazole-5-methanol.

A. 4-Methyl-1H-benzimidazole.

2,3-diaminotoluene (675 mg, of 5.53 mmole) was dissolved in 10 ml of dry tetrahydrofuran was added triethylamine (0,77 ml of 5.53 mmole). The mixture was cooled to 0oC and was added 1,1-dichloromethyl methyl ether (0,50 ml, 5,33 mol) and the reaction mixture was heated to room temperature. After 20 h the reaction was stopped with sodium bicarbonate. The aqueous phase was extracted with ethyl acetate, dried over magnesium sulfate, filtered, the solvent was removed and got 730 mg of the target compound A as a brown solid, which was used in the next stage without purification.

B. 2-isonitrile (164 μl, is 1.51 mmole), and fine potassium carbonate (279 mg, 2,02 mmole) were mixed in 1 ml of N,N-dimethylformamide and heated to 80oC. After stirring for 20 h the dimethylformamide was removed in vacuo and the brown solid residue was distributed between sodium bicarbonate and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic extracts were dried over magnesium sulfate, filtered and the solvent was removed. The residue was purified by thin-layer chromatography (20 mg of silica gel, eluate served 50% ethyl acetate, hexane) and received 160 mg of the target compound as a white solid.

C. 2-/4-(methyl bromide)-1H-benzimidazole-1-yl/ benzonitrile.

The compound obtained in stage B (71 ml, 0.30 mmole), was dissolved in 5 ml and 50% of carbon tetrachloride and benzene. Added azobisisobutyronitrile (10 mg, 0.06 to mmole) of N-bromosuccinimide (65 mg, of 0.36 mmole) and the mixture was heated to 75oC for 4 h the Solvent was removed and the residue was purified by thin-layer chromatography (20 g silica gel, eluate - 10% acetone in Toole) and received 79 mg of target compound indicated in the title of stage C in the form of a white solid, melting point 135oC (decomposes).

D. 2-{4/(2-butyl-4-chloro-5-formyl-1H-imides is 2-butyl-4-chloro-1H-imidazol-5-carboxaldehyde (949 mg, 4,15 mmole) (obtained in stage C of example 5) was dissolved in argon atmosphere in 20 ml of dichloromethane. Added 1,8-diazabicyclo-(5,4,0)-undec-7-ene (0,621 ml, 4,15 mmole) and the reaction mixture was stirred 15 h at room temperature. Then the solvent was removed in vacuum and the remaining orange oil was purified by thin-layer chromatography (145 g of silica gel, 10% acetone in toluene) and received 1,0563 g of target compound D as a yellow solid, melting point 117-135oC.

E. 2-/4-{/2-butyl-4-chloro-5-(hydroxymethyl-1H-imidazol-1-yl/methyl}-1H-benzimidazole-1-yl/-benzonitrile.

The compound obtained in stage D (757 mg, is 1.81 mmole), suspended in 8 ml of ethanol was added sodium borohydride (69 mg, is 1.81 mmole). The reaction mixture was stirred at room temperature for 50 minutes, during this time the solid dissolved. The ethanol was removed and the residue (yellow oil) was distributed between ethyl acetate and 1N. the sodium hydroxide. The aqueous phase was extracted with ethyl acetate and the combined organic extracts were dried over magnesium sulfate, filtered and the solvent was removed. The residue was purified by thin-layer chromatography (110 g silica gel, 7% isopropanol in toluene) and received 675 g of target compound E as a white solid westmorel in 4 ml of xylene under argon and heated to 110oC for 20 hours, the Xylene was removed in vacuo and received a brown oil, which was purified by thin-layer chromatography (165 g of silica gel, 5% acetic acid, 5% methanol, 50% toluene, 40% ethyl acetate) and got the oil nerastvorim white precipitate. This residue was dissolved in methanol, filtered and received 494 mg of brown oil. The oil was dissolved in 2 ml of 1N. the lithium hydroxide and purified column chromatography (100 ml of ion-exchange resin HP-20, elyuirovaniya each time 100 ml of water followed by increments of 5% acetone to 45% acetone) and got 255 mg of the target compound in the form of friable white substance with a melting temperature of 240-270oC.

Example 9. Delitala salt of 2-butyl-4-chloro-1-{ /1-/2-(2H-tetrazol-5-yl)phenyl-/1H-indol-4-yl}-methyl/ -1H-imidazole-5-carboxylic acid

A. 2-/2,3-dibromo-4-(methyl bromide)-1H-indol-1-yl/benzonitrile.

To 2-(4-methyl-1H-indol-1-yl)-benzonitrile (2,323 g of 0.01 mol, 1.0 EQ) (obtained as the connection at the stage A of example 7) in 200 ml of carbon tetrachloride and 40 ml of benzene at room temperature was added N-bromosuccinimide (5,340 g 0,03 mol, 3.0 equiv) and placed near a bright lamp. The mixture was stirred at room temperature in a total of 5 hours On the third and on the fourth hour was added N-bromosuccinic the district and the mixture was cooled to 0oC and filtered. The filtrate was concentrated, the residue was chromatographically on silica gel, elwira a mixture of hexane-methylene chloride in the ratio of 1:1, and received the connection specified in the title of A stage (3.28 g). Thin layer chromatography : Rf= 0,65, toluene-ethyl acetate in the ratio 10:1 UV.

B. 2-{ 2,3-dibromo-4-/(2-butyl-4-chloro-5-formyl-1H-indol-1-yl)-methyl /-1H-indol-1-yl}-benzonitrile.

To a solution of 2-butyl-4-chloro-1H-imidazol-5-carboxaldehyde (679 mg, 3,636 mmole, 1.1 EQ) (obtained in stage C of example 5) in a mixture of tert-piperonyl-dimethylformamide (1: 1 to 13.2 ml, 0.25 M) was added tert-butyl potassium (445 mg, 3,966 mmole, 1.2 EQ) and the mixture was stirred at room temperature for 25 minutes and Then added to the solid obtained in stage A (1550 mg, 3,305 mmole, 1.0 EQ). After stirring at room temperature for 5 h the mixture was added 30 ml of water and was extracted with methylene chloride (30 ml three times). The extracts were washed with water (10 ml) and saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated. The residue was chromatographically on silica gel, elwira a mixture of methylene chloride-ethylacetat in the ratio 100:1, and obtained target compound indicated in the title of stage B (1335 mg). Thin-layer chromatogra-4-yl/ methyl}-1H-imidazole-5-carboxylic acid.

To the compound obtained in stage B (1455 mg, 2,532 mmole, 1.0 EQ) and sulfamic acid (860 mg, 8,862 mmole, 3.5 EQ) in tetrahydrofuran (24 ml, 0.1 M) at 0oC was added dropwise sodium chloride (801 mg, 8,862 mmole, 3.5 EQ) in water (24 ml, 0.1 M). After stirring at 0oC for 30 min in the reaction mixture were added 30 ml of methylene chloride. The aqueous layer was extracted with methylene chloride (three times 30 ml). The organic extracts were washed with water, dried over magnesium sulfate, concentrated and received 2-butyl-4-chloro-1-{ /2,3-dibromo-1-(2-cyanophenyl)-1H-indol-4-yl/-methyl} -1H-imidazole-5-carboxylic acid.

2-butyl-4-chloro-1-1{/2,3-dibromo-1-(2-cyanophenyl)-1H-indol-4-yl/-methyl} -1H-imidazole-5-carboxylic acid in ethanol (50,6 ml of 0.05 M) was added 1N. sodium hydroxide (8,86 ml, 8,86 mmole, 3.5 EQ) and palladium hydroxide on coal (299 mg, 20 wt.%). The reaction mixture was placed under a balloon with gaseous hydrogen for 1 hour 15 minutes 45 minutes was added palladium hydroxide on coal (100 mg, 6.7 wt.%). Added water 50 ml) and methylene chloride (200 ml) and the reaction mixture was filtered. To the filtrate was added 1N. hydrogen chloride to establish the pH of the filtrate of 4.0 to 5.0. The aqueous layer was extracted with methylene chloride. The organic extract is was cromatografia on silica gel, elwira a mixture of methylene chloride-methanol-acetic acid in the ratio of 100:2:0,1, and got a target connection specified in the title stage C (940 mg). Thin layer chromatography: Rf=0,3 ethyl acetate: methanol in the ratio of 5:1, UV.

D. Militia salt of 2-butyl-4-chloro-1-{/1-/2-(2H-tetrazol-5-yl)phenyl/-1H-indol-4-yl} -methyl/-1H-imidazole-5-carboxylic acid.

The mixture of compounds obtained in stage C (916 mg, 2,116 mmole, 1 EQ) azide anti - (Bu3SnN3) (2108 mg, 6,348 mmole, 3.0 EQ) and xylene (26,45 ml of 0.08 M) was heated at 120oC for 49 hours After cooling to room temperature, was added methanol (13,2 ml) and acetic acid (0,485 ml, 4.0 EQ) and the mixture was stirred at room temperature for three days. The mixture was concentrated and the residue was chromatographically on silica gel, elwira ethyl acetate, pyridine-acetic acid-water in the ratio of 40:1:1:0.5 and received 2-butyl-4-chloro-2-{ /1-/2-(2H-tetrazol-5-yl)-phenyl/-1H-indol-4-yl} -methyl/-1H-imidazole-5-carboxylic acid.

2-Butyl-4-chloro-1-{ /1-/2-(2H-tetrazol-5-yl)-phenyl/-1H - indol-4-yl}-methyl/-1H-imidazole-5-carboxylic acid was dissolved in methanol (20 ml, 0.1 M). Solution was added lithium hydroxide (1 N. of 5.29 ml of 5.29 mmole, 2.5 EQ). After stirring at room temperature for 30 min Bong water, and received the target connection, indicated in the name of the example (472 mg). Thin layer chromatography: Rf=0.31, mixture of ethyl acetate-pyridine-acetic acid-water in the ratio 10:1:0.5, the UV.

Example 10. Delitala salt-2-butyl-4-chloro-1-{/1-/2-(2H-tetrazol-5-yl)-phenyl-benzimidazole-4-yl}-1H-imidazole-5-carboxylic acid.

A. 2-butyl-4-chloro-1-{ /1-(2-cyanophenyl)-1H-benzimidazole-4-yl/ -methyl}-1H-imidazol-5-carboxaldehyde 2-/4-(methyl bromide)-1H-benzimidazole-1-yl/-benzonitrile (0.65 g, 2,08 mmole, obtained as described in stage C of example 8) and 2-butyl-4-chloro-1H-imidazol-5-carboxaldehyde (0,409 g, 2,19 mmole, obtained as described in stage C of example 5) were placed in 20.8 ml of anhydrous dimethylformamide. Then add freshly ground cesium carbonate (1,02 g of 3.12 mmole), the reaction mixture was stirred at room temperature for 16 hours Then the reaction medium was distributed between ethyl acetate and water and the organic phase was washed with brine, dried and concentrated. The crude oil was purified by thin-layer chromatography (silica, hexane-acetone in the ratio 80:20) and received the target connection, indicated in the name phase A (0.68 g), in the form of a white solid.

B. 2-Butyl-4-chloro-1-{ /1-(2-cyclofenil)-1H-benzimidazole-4-yl/ methyl}-1H-imidazol-5 the slot (0,369 g, of 3.80 mmole ) was dissolved in 10.0 ml of dry tetrahydrofuran and the solution was cooled to 0oC. Then was added a solution of sodium chloride (0,361 g, 4.0 mmole) in 4.0 ml of water and the reaction mixture was stirred at 0oC for 45 minutes and Then the reaction medium was distributed between methylene chloride and water and the organic phase was dried and concentrated. The crude oil was purified by thin-layer chromatography (silica, a mixture of acetone-hexane-methanol-acetic acid in the ratio of 60:25:10:5 and got the connection specified in the title of stage B (0,474 g)

C. 2-Butyl-4-Chloro-1-{ /1-/2-(2H-tetrazol-5-yl/-phenyl/ 1H-benzimidazole-4-yl}-methyl/-1H-imidazole-5-carboxylic acid.

The compound obtained in stage B (0,462 g of 1.06 mmole) and azide butyanova (1,41 g, 4,24 mmole) were mixed in 6.0 ml of xylene and the reaction mixture was heated to 100oC for 18 h Then the reaction mixture was concentrated to half the original volume and was heated for a further 18 hours and Then the reaction mixture was purified by thin-layer chromatography (silica, a mixture of toluene-acetone-acetic acid in the ratio of 70:23:7) and got the target connection specified in the stage name C.

D. Delitala salt of 2-butyl-4-chloro-1-{/1-/2-(2H-tetrazol-5-yl)phenyl/- benzimidazole-4-yl} -methyl/-1H-imidazol-5-carbonate in the water. Was added 7 ml of water and 0.5 methanol to accelerate dissolution. Then the solution was purified using a column with resin HP-20, elwira water with the addition of methanol in 2% to 20% methanol and 80% of water, each time with 500 ml of Product was collected, passed through militarily filter, liofilizirovanny and received the target connection, indicated in the name of example, in the form of a white solid (0,377 g), melting point above 280oC.

Example 11. Monogalia salt, butyl ester of 2-butyl-4-chloro-1-{/1-/2-(2H-tetrazol-5-yl)-phenyl-/-1H-indol-yl} - methyl/-1H-imidazol-5 carboxylic acid.

A. Butyl ester 2-butyl-4-chloro-1-{/1-(2-cyanophenyl) 1H-indol-4-yl-/methyl}-1H-imidazole-5-carboxylic acid.

2-butyl-4-chloro-1-{ /1-(2-cyanophenyl)-1H-indol-4-yl/methyl} -1H-imidazole-5-carboxylic acid (661 mg, 1,527 mmole), obtained as described in stage C of example 9, in the amount of 1.0 EQ) and eudistoma n batilo (562 mg, 3,054 mmole, 2.0 EQ) in dimethylformamide (3,05 ml 05 M) under argon was added cesium carbonate (1244 mg, 3,818 mmole, 2.5 EQ). The reaction mixture was stirred at room temperature for 2.5 hours was Added ethyl acetate and the mixture was filtered. The filtrate was washed with buffer with a pH of about 4.0 and saturated sodium chloride, dried over anhydrous magnesium sulfate and the and got the connection, specified in the title of A stage (671 mg). Thin layer chromatography: Rf-0,21, hexane-ethyl acetate you the ratio of 3:1.

B. Butyl ether, monogalia salt of 2-butyl-4-chloro-1-{/1-/2- (2H-tetrazol-5-yl)-phenyl/-1H-indol-4-yl/-methyl} -1H-imidazole-5-carboxylic acid.

The mixture of compounds obtained in stage A (693 mg, 1,417 mmole, 1.0 EQ) azide anti - (2,353 g 7,086 mmole, 5.0 EQ) and xylene (1 ml) was heated at 100oC, leaving for the night. The reaction mixture was chromatographically on silica gel, elwira a mixture of hexane-ethyl acetate-acetic acid in the ratio of 100:8 to 15:1 and then with a mixture of hexane-ethyl acetate-acetic acid in the ratio of 60: 40: 1 and got 2-butyl-4-chloro-1-{/1-/2-(2H-tetrazol-5-yl) -phenyl/1H-indol-4-yl}-methyl/-1H-imidazole-5-carboxylic acid.

2-Butyl-chloro-1-{ /1-/2-(2H-tetrazol-5-yl)-phenyl/-1H-indol-4-yl} -methyl /-1H-imidazole-5-carboxylic acid was dissolved in methanol (28 ml of 0.05 M) was added an aqueous solution of potassium bicarbonate (1H., of 1.84 ml, of 1.84 mmole, 1.3 EQ). The mixture was stirred at room temperature for 20 minutes was Added 10 ml of water and part of the solvent was evaporated in vacuum. The residue was chromatographically on a column Packed with ion-exchange resin HP-20, elwira water, then a mixture of water-acetone in the ratio 100:25-40, and got Telefoon-1-/2- (1H-tetrazol-5-yl)-phenyl/-1H-indol-4-yl}-methyl /-1H-imidazole-5-carboxylic acid.

2-Butyl-4-chloro-1-{ /2,3-dibromo-1-(2-cyanophenyl)-1H-indol-4-yl/-methyl} -1H-imidazole-5-carboxylic acid (0.3 g, of 0.51 mmole, obtained as described in example 9, step C) and the azide tributylamine (0.51 g, 1.5 mmole) of solvent in 0.3 ml of toluene and heated at 80oC for 15 h the Crude reaction mixture was chromatographically directly through Merck silica gel (80 g) using a system was dissolved with hexane-ethyl acetate-acetic acid in the ratio of 60:40:0,2. The desired fractions were collected, concentrated in vacuo and dissolved in 4 ml of a mixture methanol-1H. the lithium hydroxide in the ratio of 1:1. This material was chromatographically in 80 ml of resin HP-20 using water system containing 15% acetone. The desired fractions were collected, concentrated to 100 ml, filtered through militarily filter and liofilizirovanny. The product is lyophilized dried over pjatiokisi phosphate and received the target compound (0.24 g) as a white solid.

Example 13. 2-Methyl-1-(2-methyl-1-oxopropoxy)-propyl ester, monogalia salt of 2-butyl-4-chloro-1-{ /1-/2-(2H-tetrazol-5-yl) phenyl-/-1H-imidazol-4-yl}-methyl/-1H-imidazole-5-carboxylic acid.

A. 1-Metaliteracy ester 2-chloro-3-methylbutanoic acid.

To svezhenanesennomu zinc chloride (27.3 mg) and sobouti redistilling) (4.26 deaths ml, 46,9 mmole), keeping the temperature below 25oC. After the end of the additives, the reaction mixture was stirred at room temperature for 2.5 hours, the Reaction mixture was then washed with 20% acetylator sodium, dried over anhydrous magnesium sulfate, filtered, concentrated in vacuo and obtained target compound indicated in the title of stage A (6.0 g) in the form of a transparent liquid.

B. 2 - Methyl-1-(2-methyl-1-oxopropoxy)-propyl ester of 2-butyl-4-chloro-1-{ /1-(2-cyanophenyl)-1H-indol-4-yl/-methyl} -1H-imidazole-5-carboxylic acid.

2-Butyl-4-chloro-1-{ /1-(2-cyanophenyl)-1H-indol-4-yl/-methyl} -1H-imidazole-5-carboxylic acid (630 mg, of 1.46 mmole, obtained as described in stage C of example 9), the target compound obtained in stage A (1.04 g, of 5.84 mmole), modesty sodium (438 mg, of 2.92 mmole), cesium carbonate (2.14 g, 6,57 mmole) and dimethylformamide (3.2 ml) were mixed and stirred at 60oC for 7 h, the Reaction mixture was diluted with ethyl acetate and filtered. The organic phase was washed with buffer with a pH of 4.0 (twice 25 ml), buffer with pH 7.0 (twice 25 ml), saturated sodium chloride (once, 25 ml), dried over anhydrous magnesium sulfate, filtered, concentrated and received a clear oil. Purification by chromatography on silica gel Meskil-1-(2-methyl-1-oxopropyl)-propyl ester of 2-butyl-4-chloro-1-{ /I/2-(2H-tetrazol-5-yl)-phenyl 1H-indol-4-yl/-methyl} -1H-imidazole-5-carboxylic acid.

The target compound obtained in stage B (451 mg, 0,784 mmole), and azide anti - (1.3 g, 3.9 mmole) in xylene (0.45 ml), was stirred in a stoppered flask at 93oC for 17 h, the Reaction mixture was injected directly onto a silica gel Merck (46 g) for chromatography, elwira a mixture of ethyl acetate-hexane-acetic acid in the ratio of 40:59:1. The product containing the desired fractions were collected and again purified on silica gel Merck, elwira a mixture of ethyl acetate-acetic acid-hexane in the ratio of 35:1:64. The target compound (435 mg) was obtained in the form of butter.

D. 2-Methyl-1-(2-methyl-1-oxopropoxy)-propyl ester, monogalia salt of 2-butyl-4-chloro-1-{ /1-/2-(2H-tetrazol-5-yl) -phenyl-/1H-indol-4-yl} -methyl/1H-imidazole-5-carboxylic acid.

The target compound obtained in stage C (424 mg, 0,70 mmole) in acetone was added 1 M potassium bicarbonate (0.75 ml, 0.75 mmole) up to pH 8.0. Thin layer chromatography showed some decomposition by this time. The solution was concentrated in vacuum and purified on ion-exchange resin HP-20. Product suirvey in 25-30% acetone in water, filtered and liofilizirovanny about 30 ml of ethanol and obtained target compound indicated in the title of stage D, in the form of a white product lyophilization (280 mg).

PR is}-methyl/-1H-imidazole-5-carboxylic acid.

A. 1-chloro-2-methylpropionyl ether of 2,2-dimethylpropanoyl acid.

To svezhenanesennomu zinc chloride (27.3 mg) and trimethylacetylchloride (5,11 ml, 41.5 mmole) in methylene chloride (10 ml) at 10oC was added dropwise Isobutyraldehyde (freshly distilled) (3.77 ml, 41.5 mmole), keeping the temperature below 25oC. Upon completion of the additive, the reaction mixture was stirred at room temperature for 1 h Then the reaction mixture is washed with 20% sodium acetate, dried over anhydrous magnesium sulfate, filtered, concentrated in vacuum and got the connection specified in the title of A stage (3.25 g), in the form of a transparent liquid.

B. 2-methyl-1-(2,2-dimethyl-1-oxopropoxy)-propyl ester of 2-butyl-4-chloro-1-{ /1-(2-cyanophenyl)-1H-indole-yl/methyl} -1H-imidazole-5-carboxylic acid.

A mixture containing 2-butyl-4-chloro-1-{/1-(2-cyanophenyl)- 1H-inla-4-yl/-methyl} -1H-imidazole-5-carboxylic acid (550 mg, of 1.27 mmole, obtained as described in stage C of example 9), the target compound obtained in stage A of this example, (979 mg, 5.08 mmole) modesty sodium (381 mg, of 2.54 mmole) and cesium carbonate (1.86 g, 5.72 mmole) in 2.5 ml of dimethylformamide, was heated at 60oC for 7 h in a stoppered flask. After cooling, the reaction with the 15 ml with a pH of 4.0, 20 ml of a mixture of water-brine respect and 30 ml of brine, then dried over anhydrous magnesium sulfate, concentrated in vacuo and obtained 1.3 g of crude product. Chromatography on 75 g of silica gel, elwira a mixture of hexane-ethyl acetate in the ratio of 4:1, received 576 mg of target compound B.

C. 1-(2,2-dimethyl-1-oxopropoxy)-2-methylpropionyl ether, monogalia salt of 2-butyl-4-chloro-1-{/1-/2-(2H-tetrazol - 5-yl)-phenyl-1H-indol-4-yl}-methyl/-1H-imidazole-5-carboxylic acid.

The compound obtained in stage B of this example (553 mg, 0,939 mmole), azide anti - (1.56 g, 4,69 mmole) and xylene (1.0 ml) were mixed and heated in a sealed flask at 93oC for 18 h Then the reaction mixture was cooled and directly chromatographically on 100 g of silica gel, elwira a mixture of ethyl acetate-acetic acid-hexane in the ratio of 40:1:80. The product containing the desired fraction, accumulated with toluene and received 533 mg source of the acid form of the desired compound (0,843 mmole). The acid was converted to the corresponding potassium salt by the addition of potassium bicarbonate (101 mg, 1,01 mmole) and water to the original acid, dissolved in a minimal amount of methanol. Purification by reversed-phase chromatography on resin HP-20 using water and acetone, AluI Alieva salt of 2-butyl-4-chloro-1-{/1-/2-tetrazol-5-yl)-phenyl/-1H-indol-4-yl/ -methyl}-1H-imidazole-5-carboxylic acid.

A. 2-chloro-N,N-diethylacetamide.

To a solution of Chloroacetic acid (10 g, of 0.11 mol) in methylene chloride (530 ml) at 0oC was added the hydrochloride diethylamino of 15.3 g of 0.14 mmole) of the hydrochloride of 1-(3-dimethylaminopropyl)-3 - ethylcarbodiimide (26,4 g of 0.14 mmole) and 4-methylmorpholine (29 ml of 0.27 mol). After stirring the reaction mixture for 1 h at 0oC it was stirred at room temperature for 4 h Then the reaction mixture was washed with water, 1N. hydrochloric acid (to obtain colorless aqueous phase) and saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, concentrated and received the connection specified in the named stage A, in the form of a yellow oil (9.3 g).

B. 2-(diethylamino)-2-oksietilnye ester of 2-butyl-4-chloro- 1-{/1-(2-cyanophenyl)-1H-indol-4-yl/-methyl}-1H - imidazole-5-carboxylic acid.

2-butyl-4-chloro-I-{ /1-(2-cyanophenyl)-1H-indol-4-yl/- methyl} -1H-imidazole-5-carboxylic acid (331 mg, 0.77 mmole, obtained as described in stage C of example 9), the target compound obtained in stage A of this example (229 mg, 1,53 mmole), modesty sodium (172 mg, 1.15 mmole), cesium carbonate (622 mg, at 1.91 mmole) and dimethylformamide (1.5 ml) were mixed and stirred at room temperature for 5.5 hours Reaccionar 7,0 (3 times 30 ml) and saturated sodium chloride (once 30 ml), dried over anhydrous magnesium sulfate, filtered, concentrated and received a yellow oil. Chromatographic purification on silica gel Merck (250 g), elwira 40% ethyl acetate in hexane, got 401 mg of target compound B.

C. 2-(Diethylamino)-2-oksietilnye ester of 2-butyl-4-chloro-1 {/1-/2-/2-tetrazol-5-yl)-phenyl/-1H-indol-4-yl}-methyl/ -1H-imidazole-5-carboxylic acid.

The target compound B (401 mg, of 0.79 mmole) and azide tributyrate (0.8 g, 2.4 mmole) in xylene (0.8 ml) was stirred in a sealed flask at 100oC for 24 h, the Reaction mixture was directly placed on a silica gel (46 g) for the chromatography was carried out, elwira a mixture of ethyl acetate-hexane-acetic acid in the ratio of 70:29:1. Selected two fractions, which were separately purified on silica gel Merck, elwira every a mixture of ethyl acetate-acetic acid-hexane in the ratio 60: 1: 39. Received target connection C (484 mg) as a solid.

D. 2-(Diethylamino)-2-oksietilnye ether, monogalia salt of 2 - butyl-4-chloro-I-{ /1-/2-(2H-tetrazol-5-yl)-phenyl /-1H - indol-4-yl}-methyl/-1H-imidazole-5-carboxylic acid.

The target compound C (484 mg, of 0.82 mmole) in methanol (1 ml) was added 1 M potassium bicarbonate (0.9 ml, 1,1 mol) to pH 8.0. The solution was concentrated in vacuum and PTS who were intervali: liofilizirovanny and received the target compound D as a light yellow product lyophilization (270 mg).

Example 16. (2-Butyl-1-{/1-/2-(2H-tetrazol-5-yl)-phenyl/-1H-indol-4-yl/-methyl}-1H - imidazole-5-carboxylic acid.

A. 2-Butyl-1-{ /2,3-dibromo-1-(2-cyanophenyl)-1H-indol-4-yl/-methyl} -1H - imidazol-5-carboxaldehyde.

2-butyl-1H-imidazol-5-carboxaldehyde (161 mg, 1,058 mmole, 1.0 EQ, obtained as described in stage H of example 1) and 2-/2,3-dibromo-4-(methyl bromide)-1H-indol-1-yl/-benzonitrile (546 mg, 1,164 mmole, 1.1 equiv., obtained as described in stage C of example 9) in dimethylformamide (4.4 ml, 0.24 M) was added cesium carbonate (862 mg, 2,646 mmole, 2.5 EQ). The mixture was stirred at 50oC 2 h was Added methylene chloride and the mixture was filtered. The filtrate was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographically on silica gel, elwira a mixture of toluene-ethyl ester in the ratio of 4:1 and got the target compound A (451 mg). Thin layer chromatography: Rf= 0,4, silica gel, mixture of hexane-ethyl acetate in the ratio 2:3.

B. 2-Butyl-1-{/1-(cyanophenyl)-1H-indol-4-yl/-methyl}-1H-imidazole-5 - carboxylic acid.

The target compound A (451 mg, 0,835 mmole, 1.0 EQ) and sulfamic acid (284 mg, 2,922 mmole, 3.5 EQ) in tetrahydrofuran (8,4 ml, 0.1 M) at 0oC was added a solution of sodium chloride (264 mg, 2,922 mmole, 3,5 was ekstragirovanie 10% methanol in methylene chloride. The extract was dried over anhydrous magnesium sulfate, concentrated and received 2-butyl-1-{/2,3-bromo-1-(2-cyanophenyl)-1H - indol-4-yl/-methyl}-1H-imidazole-5-carboxylic acid.

2-butyl-1-{/2,3-dibromo-1-(2-cyanophenyl)-1H-indol-4-yl/-methyl}-1H - imidazole-5-carboxylic acid in ethanol (26 ml, to 0.032 M) was added a solution of sodium hydroxide in water (1 N., 2,923 ml, 2,923 mmole, 3.5 EQ) and palladium hydroxide on coal (186 mg). The mixture was placed under a balloon with gaseous hydrogen and stirred at room temperature. After 1.5 h was added 20 ml of water and 40 ml of methanol and the reaction mixture was filtered. The filtrate was concentrated to 20 ml and acidified 1 N. hydrochloric acid to a pH of about 2.0. The mixture was extracted with 10% methanol in methylene chloride. The extract was washed with brine and concentrated. The residue was chromatographically on silica gel, elwira a mixture of ethyl acetate-pyridine-acetic acid-water in the ratio of 40:1:0.5 and received the target compound B (200 mg).

C. 2-Butyl-1-{ /1-2-(2H-tetrazol-5-yl)-phenyl/-1H-indol-4-yl}-methyl/-1H - imidazole-5-carboxylic acid.

The mixture of target compound B (184 mg, 0,462 mmole, 1.0 EQ), azide presence of TBT (613 mg, 1,847 mmole, 4.0 EQ) and xylene (4.6 ml, 0.1 M) was stirred at 120oC within 24 hours After cooling, cm is the ratio of 100:1, and then with a mixture of ethyl acetate-pyridine-acetic acid-water in the ratio 100:10:10:5 and received solid, which was purified liquid chromatography high-pressure column UMC 5-10 ODS, elwira mixture consisting of 50% water-methanol-Cryptor-acetic acid in the ratio 90:10:0.1 and 50% water-methanol-triperoxonane acid in the ratio of 90:800:0.9 and received the target compound indicated in the title of stage C (140 mg).

Example 17. (1-(atomic charges)-ethyl ester, monogalia salt of 2-butyl-4-chloro-1-{ /1-/2H - tetrazol-5-yl/-phenyl/-1H-indol-4-yl/-methyl}-1H-imidazole-5-carboxylic acid.

A. 1-chlorotalonil ether acetic acid.

To svezhenanesennomu zinc chloride (0.25 g) and acetylchloride (11 ml, 150,0 mmol) in 10oC was added dropwise acetaldehyde (8,4 ml of 150.0 mmol), keeping the temperature below 20oC. Upon completion of the additive, the reaction mixture was stirred at room temperature for 2 hours the Reaction mixture was distributed between methylene chloride and 20% acetylator sodium before concentrating in vacuo to a brown liquid. Purification by distillation at 28 mm RT. Art. and 37-39oC gave the target compound A (4,2 g) as a clear liquid.

B. 1-(atomic charges)-ethyl ester of 2-butyl-phenyl)-1H-indol-4-yl/-methyl}-1H-imidazole-5 - carboxylic acid (910 mg, 2.1 mmole, obtained as described in stage C of example 9), the target compound B (930 mg, of 5.03 mmole), cesium carbonate (2.6 g, 7,98 mmole) and dimethylformamide (4.0 ml) were mixed and stirred at room temperature for 16 hours, the Reaction mixture was diluted with ethyl acetate and filtered. The organic phase is twice washed with buffer with a pH of 4.0, once a buffer with pH 7.0, once with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, concentrated and received a brown oil. Purification by chromatography on Merck silica gel (250 g), elwira a mixture of hexane-ethyl acetate in the ratio 8:2, gives the target compound B (1.06 g)

C. 1-(atomic charges)-ethyl ester of 2-butyl-4-chloro-1-{/1-2-(2H-tetrazol-5 - yl)-phenyl/-1H-indol-4-yl}-methyl/-1H-imidazole-5-carboxylic acid.

The target compound B (943,0 mg, equal to 1.82 mmole), azide presence of TBT (2,41 g, 7,27 mmole) and xylene (0.9 ml) was heated at 65oC for 42 h was Added azide anti - (0.7 g, 2,11 mmole) and the reaction mixture was heated for another 4 h at 70oC. the Crude reaction mixture was diluted in 1 ml of methylene chloride and was quickly chromatographically on 130 g of silica gel Merck, elwira a mixture of ethyl acetate-acetic acid-hexane in the ratio of 35:1:65, then the ratio 50:5:50 and got the target connection C.

The target compound obtained in stage C (783 mg, 1,32 mmole) in absolute ethanol (1 ml) was added 1 M potassium bicarbonate (1,45 mmole, 1.1 ml) to pH 8.0. The solution was concentrated in vacuum and twice purified by reversed-phase chromatography on resin HP-20. Fraction of the product, erwerbende at 25-40% ethanol in water, collected, filtered, liofilizirovanny and received is indicated in the name stage D compound (534 mg) as a white solid.

Example 18. 2,3-Dihydro-1H-inden-5-silt ether-2-butyl-5,5-chloro-{/1-/2-(2H-tetrazol-5-yl)-phenyl/-1H-indol-4-yl/-methyl} - -1H-imidazole-5-carboxylic acid

A. 5-indaily ester of 2-butyl-4-chloro-1-{/1-(2-cyano-phenyl)-1H-indol-4 - yl/-methyl}-1H-imidazole-5-carboxylic acid.

To a mixture containing 2-butyl-4-chloro-1-{/1-(2-cyano-phenyl)-1H-indol-4-yl/- methyl} -1H-imidazole-5-carboxylic acid (903 mg, 2,03 mmole, obtained as described in stage C of example 9), 5-indanol (307 mg, to 2.29 mmole) of 2,6-dimethylaminopyridine (50,8 mg, 0,416 mmole) and triethylamine (0,377 ml, 2,70 mmole) in 9 ml of dichloromethane, chilled in an ice bath, was added the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethyl carbamide (519 mg, 2,70 mmole). Clogged the reaction mixture was left overnight to heat to room temperature, then was diluted chlorite is hell anhydrous magnesium sulfate, concentrated in vacuo and got to 1.83 g of the crude product. Rapid chromatography on 75 g of silica gel, lirovannomu a mixture of hexane-ethyl acetate in the ratio 8:2, received of 1.03 g of target compound A.

B. 2,3-Dihydro-1H-inden-5-silt ester of 2-butyl-4-chloro-1-{/1-/2-(2H - tetrazol-5-yl/-phenyl/-1H-indol-4-yl/-methyl}-1H-imidazole-5-carboxylic acid.

The mixture of target compound obtained in stage A (1,03 g, a 1.88 mol), azide presence of TBT (1,87 g, 5,63 mmole) and xylene (2 ml), was heated in a sealed flask at 88oC 19 h, and heating was continued for 6 hours Then the reaction mixture was cooled and directly chromatographically on 200 g of silica gel, lirovannomu a mixture of ethyl acetate-acetic acid-hexane in the ratio of 35:1:65. The fractions containing the desired product were collected, concentrated in vacuum, evaporated with toluene and received 940 mg of the target compound.

Example 19.-2-Methyl-1-(1-oxopropoxy)-propyl ester, monogalia salt of 2-butyl-4-chloro-1-{ /1-/2-(2H-tetrazol-5-yl) -phenyl/-1H-indol-4-yl/-methyl}-1H-imidazole-5-carboxylic acid.

A. 1-Chloro-2-methylpropionic ester propanoic acid.

To svezhenanesennomu zinc chloride (41 mg) in methylene chloride (10 ml) was added chloride propionyl (5.0 g, 54, 0 Miva temperature at 25oC. Upon completion of the additive, the reaction mixture was stirred 1 h at room temperature. The reaction mixture is washed with 20% acetylator sodium and the organic phase was concentrated in vacuum to obtain the target compound A.

B. 2-Methyl-1-(1-oxopropoxy)-propyl ester of 2-butyl-4-chloro-1-{/1-(2-cyanophenyl)-1H-indol-4-yl/-methyl}-1H - imidazole-5-carboxylic acid.

2-Butyl-4-chloro-1-{ /1-(2-cyanophenyl)-1H-indol-4-yl/- methyl} -1H-imidazole-5-carboxylic acid (870 mg, 2.01 mmole, obtained as described in stage C of example 9), the target compound A(1,16 g, 7.03 is mmole), modesty sodium (745 mg, of 5.03 mmole, cesium carbonate (2; 3 g, 7.03 is mmole) and dimethylformamide) and 4.4 ml) were mixed and heated to 80oC for 6 hours, the Reaction mixture was diluted with ethyl acetate, filtered, washed with buffer with a pH of 4.0 with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuum to 1.50 g of crude product. Rapid chromatography on 70 g of silica gel Merck, buyowner a mixture of hexane-ethyl acetate, was obtained target compound B (0.84 g).

C. 2-Methyl-1-(1-oxopropoxy)-propyl ester of 2-butyl-4 - chloro-1-{/1-/2-(2H-tetrazol-5-yl)-phenyl /-1H-indol-4-yl) -methyl} -1H-imidazole-5-carboxylic acid.

The target compound B ( 840 mg, 1.50 mmole), azide, tributed room temperature and was directly chromatographically in 144 g of Merck silica gel, lirovannomu a mixture of ethyl acetate-acetic acid-hexane in the ratio of 35:1:65. Accumulation fractions containing product gave 682 mg of target compound.

D. 2-Methyl-1-(1-oxopropoxy)-propyl ester, monogalia salt of 2-butyl-4-chloro-1-{ /1-/2-(2H-tetrazol-5-yl/-phenyl 1H - indol-4-yl/-methyl}-1H-imidazole-5-carboxylic acid.

To the compound obtained in stage C ( 682 mg, of 1.06 mmole) in absolute ethanol (1 ml) was added 1 M potassium bicarbonate ( 1,11 ml of 1.11 mmole) up to pH 8.0. The solution was concentrated in vacuum and purified by reversed-phase chromatography on resin HP-20. Fraction of the product, erwerbende 35-40% ethanol in water, collected, filtered, liofilizirovanny and received the target compound as white solid (517 mg).

Example 20. Ethyl ester, monogalia salt of 2-butyl-4-chloro-1- {1/-/2(H-tetrazol-5-yl)-phenyl/-1H-indol-4-yl/-methyl} -1H-imidazole-5-carboxylic acid.

A. Ethyl ester of 2-butyl-4-chloro-1-{/1-(2-cyanophenyl) 1H-indol-4-yl/-methyl}-1H-imidazole-5-carboxylic acid.

Modesty ethyl (561,5 mg, 3,60 mmole) and cesium carbonate (1.5 g, 4.5 mmole) was added to a solution of 2-butyl-4-chloro-1-{/1-(2- cyanophenyl)-1H-indol-4-yl/-methyl} -1H-imidazole-5-carboxylic acid (779,2 mg of 1.80 mmole, obtained as described in camping was diluted with ethyl acetate and filtered to remove cesium carbonate. The ethyl acetate was washed with buffer with a pH of 4.0 ( twice 20 ml), buffer with pH 7.0 (2 times 25 ml), saturated sodium chloride (20 ml) and dried over anhydrous magnesium sulfate, concentrated to obtain a yellow oil (890 mg). Cleaning Express chromatography ( silica gel 83 g, eluate with hexane-ethyl acetate in the ratio 8:2) gave 662 mg of the compound indicated in the title of stage A.

B. Ethyl ester of 2-butyl-4-chloro-1-{/1-/2-(2H-tetrazol-5 - yl)-phenyl/-1H-indol-4-yl/-methyl}-1H-imidazole-5-carboxylic acid.

The compound obtained in stage A ( 598, 8 mg, 1.3 mmole) and azide anti - (1.73 g, 5.2 mmole) in xylene (6,64 ml), stirred, kept at 100oC for 30 hours was Added azide presence of TBT (0.65 g, 1,95 mmole) and heating was continued for 18 hours, the Reaction mixture was directly placed on a silica gel Merck (228 ml) for purification, elwira a mixture of ethyl acetate-hexane-acetic acid in the ratio 35:64:1. The target compound B (585,3 mg) was obtained as yellow solid

C. Ethyl ester, monogalia salt of 2-butyl-4-chloro-1-{1-/2- (2H-tetrazol-5-yl)-phenyl-/1H-indol-4-yl/-methyl} 1H-imidazole-5-carboxylic acid.

To the compound obtained in stage B (584 mg, 1,19 mmole) in absolute ethanol (1 ml) was added 1 M potassium bicarbonate (1.31 ml, 25-40% ethanol in water, was filtered, liofilizirovanny and received the target compound (510 mg) as a white solid.

Example 21. Ethyl ester of 2-butyl-1-{/1-/2-(2H-tetrazol - 5-yl)-phenyl/-1H-indol-4-yl/-methyl}-4-(trifluoromethyl)-1H - imidazole-5-carboxylic acid.

A. Ethyl ester 4,4,4-Cryptor-2 (hydroxyimino)-butane acid.

A solution of sodium nitrite (to 0.29 mmole) in 35 ml of water was added dropwise over 50 min to a stirred, cooled with ice to a solution of 22.8 g of ethyl ether, 4,4,4,-triftoratsetofenona acid (0.12 mmole) in 30 ml of acetic acid. The reaction was continued for 2 h with gradual heating up to the 15oC. was Added water and acetic acid was removed under reduced pressure (azeotrope with toluene). The crude product was distributed between ethyl acetate and saturated aqueous potassium bicarbonate. The layers were separated. An ethyl acetate layer was washed with a saturated aqueous solution of potassium bicarbonate and brine, dried over sodium sulfate, concentrated to obtain the output connection A 21,4 g as a pale yellow oil.

B. Ethyl ester of 2-butyl-1-hydroxy-4-(trifluoromethyl)-1H - imidazole-5-carboxylic acid.

The solution valeraldehyde (9,87 ml of 92.9 mmole) in 150 ml of a saturated ethanol ammonium onlinemedical in an argon atmosphere for 30 min and then left at room temperature and was stirred overnight. The solvent was removed under reduced pressure and co-evaporation with ether. The residue was dissolved in 150 ml of ether and 0.1 g of insoluble material was removed by filtration. Concentration of the filtrate under reduced pressure got to 27.7 g of a bright yellow-orange substance. Rapid chromatography on 750 g of silica gel, elution with 2 ml of methylene chloride, followed by elution with a mixture of methylene chloride-methanol-acetic acid in the ratio of 98: 1: 1 gave the target compound B ( 9,8 g in the form of a light yellow solid, the melting point in 77,5-80,5oC).

C. Ethyl ester of 2-butyl-4-(trifluoromethyl)-1H-imidazole-5 - carboxylic acid.

To a mixture of target compound obtained in stage B (4,25 g, 15.00 mmol), and sodium acetate (15 g) in methanol (50 ml) and water (50 ml) at a temperature of an ice bath was added dropwise a solution of titanium chloride (50 ml, 20% solution) for 20 min under stirring. After 1 h at 0oC the reaction mixture was heated to room temperature and stirred 1 h the reaction Product was extracted with ethyl acetate (two times 300 ml). The combined organic layer was washed with citric acid (100 ml of a 5% solution), then aqueous sodium bicarbonate solution (100 ml), dried on the 3,42 g in the form of solids, the melting point 51,0-53,0oC).

D. Methyl ester 1H-imidazole-4-carboxylic acid.

To a solution of ethyl ester of 2-butyl-1-hydroxy-4-(trifluoromethyl) -1H-imidazole-5-carboxylic acid (506 mg, 3,14 mmole), dissolved in a mixture of 5 ml of methanol and 10 ml of diethyl ether was added ethereal diazomethane until the disappearance of the original acid, determined by thin-layer chromatography. Then was added anhydrous magnesium sulfate and the solution was filtered and concentrated in vacuum. Rapid chromatography on 10 g of silica gel Merck, lirovannomu a mixture of chloroform-hexane in the ratio 2:1, then a mixture of chloroform-diethyl ether in the ratio of 10: 1, gave the target compound indicated in the title of stage D ( 540 mg).

E. Methyl ester 1-(2-cyanophenyl)-1H-indole-4-carboxylic acid.

The mixture of target compound obtained in stage D (40,6 mg, 0,232 mmole), 2-perbenzoate (38 μl, 0,348 mmole), potassium carbonate ( 64, 1 mg, 0,464 mmole) and 18-crown-6-(6,1 mg, 0,0232 mmole) of 0.23 ml of dimethylformamide, was heated at 150oC for 150 min After cooling to room temperature the reaction mixture was diluted with ethyl acetate, filtered and rinsed with buffer with a pH of 4.0. The aqueous layer was further extracted with two further portions of ethyl acetate and svodnyy magnesium sulfate and concentrated in vacuum. Rapid chromatography on 5 g of silica gel Merck, lirovannomu a mixture of chloroform-hexane in the ratio of 5:1, followed by elution with 100% chloroform, gave the target compound indicated in the title of stage E (61,6 mg).

F. the Compound obtained in stage E (8.0 g, 28,95 mmole), 1N. sodium hydroxide (43,4 ml, 43,4 mmole), methanol (43,4 ml, 43,4 mmole) and tetrahydrofuran (43,4 ml) were mixed and heated at 50oC. After 4 h 10 min the reaction mixture was cooled to room temperature and was added 10% hydrochloric acid (50 ml) to precipitate a white solid. The mixture was filtered and the product was collected as white solid 7,2,

C. 2-/4-(hydroxymethyl)-1H-indol-1-yl/-benzonitrile.

The complex of borane-tetrahydrofuran (1 M in tetrahydrofuran to 27.3 ml) was added to a solution of compound obtained in stage F (7,17 g, 27.3 mmole) in tetrahydrofuran (distilled and 27.3 ml) at - 20oC, was heated to room temperature and stirred for 21 hours, the Solution was cooled to 0oC and the reaction was suppressed 1H. the sodium hydroxide to pH of 14.0. The solution was extracted with ether (three times 100 ml), washed with sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated to a light green unity, specified in the stage name G (5.34 g).

H. 2-/4-(methyl bromide)-1H-indol-1-yl/benzonitrile.

To a solution of compound obtained in stage G (5,46 g, 22 mmole) in methylene chloride (distilled, 60 ml) at 0oC, was added chetyrehhloristy carbon (10.2 g, 30.8 mmole) and triphenylphosphine (7.5 g, 28.6 mmole). The reaction mixture was stirred at 0oC for 15 min, then was heated to room temperature. After 2.5 h the reaction mixture was diluted with methylene chloride and placed directly on a column of Merck silica gel (66 g), elwira a mixture of toluene-hexane in the ratio of 1:1 for cleaning. Fractions of product were collected, concentrated, then triturated with cold ethyl acetate and received the connection specified in the title stage H (5.8 g).

I. Ethyl ester of 2-butyl-1-{/1-(2-cyanophenyl)-1H-indol-4-yl/-methyl}-4-(trifluoromethyl)-1H - imidazole-5-carboxylic acid.

The mixture of compounds obtained in stage C (470 mg, of 1.78 mmole) and cesium carbonate (585 mg, 1.8 mmole) in dimethylformamide 4 ml) was stirred at room temperature for 15 minutes To this reaction mixture was added the compound obtained in stage H (555 mg, of 1.78 mmole). The resulting mixture was stirred at room temperature for 3 hours, the Solid was filtered and what graphy (silica, a mixture of ethyl acetate-hexane in the ratio of 1 : 2 and received the connection specified in the title of stage I (870 mg) as oil.

J. Ethyl ester of 2-butyl-1-{/1-/2-(2H-tetrazol-5-yl)-phenyl-1H-indol-4-yl/-methyl}-4- (trifluoromethyl)-1H-imidazole-5-carboxylic acid.

A solution of the compound obtained in stage I (800 mg, of 1.62 mmole), and azide anti - (1.88 g, 5,66 mmole) in xylene (5 ml) was stirred at 100 - 110oC for 24 h the Reaction mixture was concentrated in vacuo and the residue was purified by preparative chromatography. The fractions containing the desired product were combined, concentrated and received the target connection, indicated in the name of the example (675 mg), melting point 93,0 - 95,0oC.

Example 22. A mixture of ethyl ester of 2-butyl-1-{/1-/2-(2H-tetrazol-5-yl)-phenyl/-1H-indol-4-yl/-methyl} -4- (trifluoromethyl)-1H-imidazole-5-carboxylic acid (400 mg, 0,744 mmole) and aqueous sodium hydroxide (2n., 1.5 ml) in methanol (5 ml) and stirred at room temperature, leaving for the night. The reaction mixture was concentrated in vacuo and the residue was passed through a column of resin HP-20, elwira water, then 30% methanol in water. The fractions containing the desired product were concentrated under vacuum and obtained target compound (387 mg), melting point above 250 is x higher received the following additional compounds (see table. 1):

< / BR>
Name compounds that were tested (see table. 2):

Example 23. 2-Butyl-1-[[1-(2-(2H-tetrazol-5-yl)phenyl]-1H - indol-4-yl]-methyl/-4-chloro-1H-imidazole-5-carboxylic acid, delitala salt.

Example 24. 2-Butyl-1-[[1-2-(2-(2H-tetrazol-5-yl)phenyl]-1H - indol-4-4-yl] -methyl] -4-chloro-1H-imidazole-5-carboxylic acid, ethyl ester, monolithian salt.

Example 27. 2-butyl-1-[[1-(2-(2H-tetrazol-5-yl)phenyl]-1H-indol - 4-yl]-methyl]-4-trifluoromethyl-1H-imidazole-5-carboxylic acid, disodium salt.

Example 28. (2-Butyl-1-[[1-(2-(2H-tetrazol-5-yl)phenyl/1H-indol- -4-yl/-methyl/-4-trifluoromethyl-1H-imidazole-5-carboxylic acid, ethyl ester, monolithian salt.

Example 31. 2-Butyl-1-[[1-(2-(2H-tetrazol-5-yl)phenyl/1H-indol-4 - yl]-methyl]-4-perforated-1H-imidazole-5-carboxylic acid, delitala salt.

Example 32. 2-Butyl-1-[[1-(2-(2H-tetrazol-5-yl)phenyl/-1H-indol-4 - yl]-methyl]-4-perforated-1H-imidazole-5-carboxylic acid, ethyl ester.

Example 33. 2-Butyl[[1-(2-(2H-tetrazol-5-yl)phenyl]-1H-indol-4 - yl]-methyl] -4-perforated-1H-imidazole-5-carboxylic acid 2-methyl-1-(1-oxopropoxy)propyl ether.

Example 35. 2-butyl-1-[[1-(2-(2H-tetrazol-5-yl)phenyl]-2 - triptime is(Definition Kd)

Labeled angiotensin II was purchased from New England Nuclear, Boston MA, USA. Peptides: angiotensin II (human), /Sar', IIe8/ - angiotensin II were obtained in the laboratory Peninsula Labs, Belmont, CA, USA.

BMS 180, 560 and D and P 753 were synthesized in the Department of chemistry and cardiovascular diseases pharmaceutical Institute of company Bristol-Myers Squibb To. Products Dulbecco''s modified Eagle's Medium were purchased in the laboratory GibcoLabs, Grand Island, NY, USA.

RASM cells were kindly provided by Dr. M. Runge from the cardiology Department of Emory University, GA, USA. B. C. A.-protein analytical reagent was purchased from Pierce firm, Rocrford IL, USA. Bovine serum albumin, 1,10-phenanthrolin, Aprotinin (bovine lung), fetal calf serum (deactivated by heating) were obtained from the company Sigma Chemical Co, St Louis, Mo, USA.

Preparation of membranes. The adrenal cortex of rats.

Rats were killed by asphyxiation CO2the adrenal glands were removed, the cortex was separated from the core at 4oC and placed in a cooled ice in buffer A(0.2 M sucrose, 1 mmol EDTA, 10 mol Tris-HCl pH 7,4) and homogenized in 10 volumes of buffer A at 4oC using the homogenizer company Brinkmann transmitter station. Homogenized product was centrifuged at 1000 etka was suspended in 50 mmol Tris-HCl pH 7,4, 5 mmol of Mg Cl2(2.5 volume of buffer to the original raw weight) by mild homogenization using a homogenizer firms Potter-Elvehjem glass/phone. Aliquots (5 ml) of the prepared membranes were frozen at protein concentration of 0.1 mg protein per 1 ml and stored frozen at -80oC until use.

Smooth muscle cells in the aorta of rats (RASM).

RASM cells were grown at 37oC in flasks T-75 in moist air (95% humidity), with the content of CO25% in Dulbecco's (DMEM) containing Hepes buffer and 10% of fetal bovine serum, 50 U/ml penicillin and 50 µg/ml streptomycin (Gibco laboratories Labs).

RASM cells were used between transformations 5-24. Approximately 90-100% confluence (5-7 days) cells were exposed to trypsin (2 ml 0.25% trypsin in 1 mm EDTA). Then the cells were harvested in buffer (0.1 mmol, phenylmethylsulfonyl fluoride, 10 μg/ml of inhibitor on the basis of soybean trypsin, 20 mmol Hepes buffer with a pH of 7.4, diluted in DMEM) at a concentration of 3-4 105cells/ml Cell suspensions were washed with this buffer and homogenized in a mixture of 50 mmol Tris-HCl, 1 mmol EGTA, 10 mmol MgCl2, 0,24 TI units/ml Aprotinin, 0.1 mg/ml of 1,10-phenanthroline homogenizer company Brinkmann transmitter station (and 4oC. the Supernatant was discarded and the membrane presuspension buffer and washed three times. The tablet was presuspension in this buffer at a concentration of 0.2-0.8 mg protein per 1 ml solution. Cells product homogenization was stored in 1 ml aliquots at -80oC prior to use.

The binding of angiotensin II and analysis of radiometric method.

The analysis was performed in a total volume of 250 ml in a tripod for micrometrology. The incubation mixture contained 50 μl of [125|JS|-A|| (80-200 pM, 70.000-180.000 cpm); 25 l moved drugs or angiotensin II, in order to determine non-specific binding (1 Microm); and the incubation buffer. Binding to membranes from RASM cells were carried out in the following buffer for analysis: 50 mmol Tris - HCl pH 7,4, 5 mmol MgCl2, 0.1% bovine serum albumin, 1 mmol PMSF, 0,24 TI units/ml Aprotinin, 0.1 mg/ml of 1,10-phenanthroline. Linking RAC membranes was carried out in the usual manner in the following buffer for analysis: 50 mmol Tris - HCl pH 7,4, 5 mmol MgCl2, 0,22% BSA. In some cases, the concentration of BSA was changed to 0.07 or 0.01%. The binding reaction was initiated by adding 100 l of the membrane (7-12 µg protein) diluted in incubation buffer. The tubes were incubated at 37oC (metabody the radio was separated when the equilibrium of the simultaneous filtering on the collector cells in combination with the filter-substrate B, which was previously soaked for 1 h in 0.1% polyethylenimine (PEI) to reduce nonspecific binding. The filter pad was washed from excess PEI during the preliminary washing cycle, membranes were filtered and washed with 150 mmol NaCl, 5 mmol Tris-HCl pH 7,4 at 4oC. the Filter substrate was removed and treated with microwave radiation in a microwave oven with the upper side of the membrane at full power 3 x 2 minutes the Dried filter substrate was placed in the collection of the samples, the plate solid scintillation wax MultiLex was placed on the filter side of the membrane and will melt into the substrate using the device for sealing (Wallac, Pharmacia). Impregnated sheet was subjected account in a liquid scintillation counter with an efficiency of 60%.

Protein analysis was performed on the obtained membranes with the use of reagent B. C. A. and bovine serum albumin as the standard.

Test in vitro for antagonists of angiotensin II receptors (definition of KB)

Primary screening of the aorta of the rabbit.

The essence of the method.

Angiotensin II (A II) is a peptide hormone that causes narrowing of blood vessels when binding its receptors on vascular smooth muscle (Chiu et al vessels and high blood pressure. Designed peptide antagonists that prevent the binding of A II to its receptors and cause a hypotensive effect in some animal models. However, as has been shown, these peptide antagonists have little time of life and behave as partial antagonists (Wong et al 1989). To assist in the opening of the new ones antagonist of A receptor II was screened on isolated muscle of rabbit aorta with the aim of monitoring the effects of new compounds on reduction with respect to A II.

Analysis techniques. A solution of physiological salt (PSS). PSS with bicarbonate buffer contained (in mmol): 118,4 NaCl, A 4.7 KCl, 1.2 And MgSO4, 1,2 KH2PO4, 1,9 CaCl225,0 NaHCO3, 10,1 D - glucose and 0.01 mmol of Na2EDTA. Containing buffer solutions PSS are used to hold tissue and containing (in mmol): 140,0 NaCl, A 4.7 KCl, 1.2 And Na2HPO4, 2,0 MOPS, of 0.02 Na2EDTA, 1,6 CaCl2that 1.2 MgSO4and 5.6 D - glucose.

The compounds. Concentrated (10 mmol) of the original solutions of the investigated compounds are prepared daily and serially diluted to the appropriate concentrations. Aqueous solutions of the compounds used directly in the muscle cells. Solutions of water-insoluble compounds thC.

Preparation of tissues. Male new Zealand white rabbits (2-3 kg) were killed by overdosage of Brevitas (1 - 1.5 ml: 50 mg/ml solution) injection into the marginal ear vein. Thoracic aorta quickly, but carefully removed, washed off the blood, and carefully cleaned from connective tissue in MOPS buffer PSS, cooled by ice. Tissue was kept full viability within 4 days, which was ensured by keeping them chilled in a large volume of buffer solution MOPS - PSS, which is daily changed.

Peripheral strips of aorta (3,5 - 5,0 mm wide) were subjected to registration on isometric force between two gold clips in individual muscle cell, with a shirt containing PSS with bicarbonate buffer, aeronavali a gas mixture of 95% O2- 5% CO2and was maintained at 37oC. One of the terminals connected with the micrometer to control the length of the fabric, and the other with the power sensor and the polygraph. Strips were balanced for at least 1 h before the tension with a load of 4 g, and then subjected to reduction with 80 mmol of KCl (4 M initial solution) to test for viability. After the maximum development efforts strips were washed with PSS solution with bicarbonate buffer every 10 min for the Oh on A II (0.1 to 100 nm). At each concentration gave a constant force (about 5 minutes) before adding the next portion of the solution. After A portion II, which causes the maximum reduction, the strips were washed with PSS bicarbonate buffer every 15 min for at least 60 min or until complete relaxation. The only portion (10 mmol) of the investigated compounds is then added to the solution and incubated for 15 min before repeated concentration response curve for A II. Once received the maximum force when 80 mmol KCl was added with continued presence of A II and test the connection. Induced using KCl contraction was used primarily to show that the test compound does not cause non-specific attenuation in the response reductions. Any investigational compound with KB100 PM were studied again at a concentration of 0.1 μmol to confirm the initial determination of KB.

The statistics. The data were plotted on a graph as the average of 4 different animals. The values of EC50calculated for each tissue from the equation of a straight line connecting points corresponding to the maximum concentration, providing less than 50% of socii KBwas calculated by the following equation:

< / BR>
where SQ is proven concentration SQ;

value EC50given in response to A II separately (Ariens and Var Rossum 1957, Arunlakshana and Schild 1959). For compounds exhibiting significant blocking ability, schedule shilda is constructed based on the average ratio of doses at several concentrations of the antagonist. The results are presented as values pA2and KB. The value of pA2calculated as a line passing through the average ratio of doses in the graph, a simple transformation of values pA2. KBexpressed as an average of all the individual values of KBand is used as a reference value in various chemical syntheses.

qqqq

 

Same patents:

The invention relates to the field of new biologically active compounds, in particular to 1-benzyl-2-oxitriptan hydrochloride and its derivatives, possess hepatoprotective activity, which can be used as potential drugs in medical practice

The invention relates to 2-/2-imidazolin-2-yl/benzoheterocycles compounds, which have the following structure:

< / BR>
in which: R1is hydrogen, CI/C1-C4/ alkylamino,

C1-C12the alkyl may be substituted by one to three substituents: C1-C4alkoxy, C1-C4alkylthio, halogen, hydroxy, C1-C4cycloalkyl, benzoyloxy, fullam, phenyl, possibly substituted by nitro, one to three halogen, C1-C4alkyl groups or C1-C4alkoxy groups, carboxy, C1-C4alkoxycarbonyl, cyano or three/C1-C4/ alkylammonium a halide;

C3-C12alkenyl may be substituted by one to three substituents: C1-C4alkoxy, phenyl, halogen or C1-C4alkoxycarbonyl;

C3-C6cycloalkyl, can be substituted one to three C1-C4alkyl groups;

C3-C16the quinil may be substituted by one to three halogen or a cation;

R2is C1-C4by alkyl;

R3is C1-C4the alkyl or C3-C6cyclo is the best C1-C4cycloalkyl possibly replaced by stands;

B is hydrogen, COR4or SO2R5with the proviso that when B is COR4or SO2R5, R1is other than hydrogen or a cation, and R9different from hydrogen;

R4is C1-C11the alkyl, chlorochilon or phenyl, possibly substituted with halogen, nitro or C1-C4by alkyl;

R5is C1-C4the alkyl or phenyl, possibly substituted C1-C4by alkyl;

X, Y and Z each independently is CR6, CR7R8, N or NR9with the proviso that at least one of X, Y and Z must be N or NR9;

configuration is either a simple bond or double bond with the proviso that when any of X, Y or Z is CR7R8or NR9then === configuration, attached to it, is a simple connection, with one proviso that at least one of the === configuration represents a simple bond;

R6, R7and R8are independently hydrogen, halogen, C1-C4alkoxy or C1-C4the alkyl may be substituted one is;

R9is hydrogen or C1-C4the alkyl possibly substituted by hydroxy or one to three halogen, C1-C4alkoxy groups, or C1-C4alkylthio groups;

Q is hydrogen, halogen, C1-C4alkoxy or C1-C4the alkyl, possibly substituted by one to three of the following substituents: halogen, C1-C4alkoxy, C1-C4alkylthio or C2-C4alkenyl;

their optical isomers, when R2and R3not the same or when R7and R8unequal;

their tautomers and geometric isomers, and their attached salts of acids, except when R1is salabrasion cation

The invention relates to chemical-pharmaceutical industry, namely to new biologically active substances on the basis of which can be created drugs with hypotensive and analepticheskih activity

The invention relates to new imidazolidones alkoxy-imino derivative of tetrahydronaphthalene and chromane, to a method for producing them, to pharmaceutical compositions containing them and to their use as therapeutic agents

The invention relates to novel condensed heterocyclic compounds or their salts, and their intermediate compounds, method of their production and the fungicide on their basis for the processing of agricultural and horticultural crops

The invention relates to new derivatives of 1-phenylimidazole formula 1

CFN< / BR>
where R represents a hydrogen atom or methyl;

x represents a fluorine atom, a chlorine atom or a nitro-group;

y represents a fluorine atom or a chlorine atom;

z represents a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom, a process for the preparation of these compounds and insecticides containing as active components of these compounds

The invention relates to the creation of new chemical compounds with anticonvulsant, antihypoxic and antioxidant activity and belonging to a new class of anticonvulsants
The invention relates to pharmaceutical industry

The invention relates to medicine, namely to the way the pharmacological treatment of acute respiratory viral infections and influenza using an inducer of endogenous interferon-Dibazol

The invention relates to a method for the oral drugs with intersolubility coating, which contain unstable in the acidic environment of the connection, in particular to oral medication with intersolubility coating obtained in the form of a stable in the acidic environment of standard doses in the form of an inclusion complex obtained by the reaction of a benzimidazole derivative is unstable in an acidic compound with cyclodextrin in alkaline solution

The invention relates to a derivative of asola, method of production thereof and to pharmaceutical compositions based on
The invention relates to the field of Bioorganic chemistry and molecular biology and can be used to obtain oligo(poly)nucleotides and biologically active proteins that carry bootieful group
Up!