Chetyrehskatnye imidazole derivatives, processes for their preparation, intermediate compounds and pharmaceutical composition

 

(57) Abstract:

New chetyrehskatnye imidazole derivatives of the formula I, in which R1- alkyl or alkylthio, R2- C1- C8alkylthio, possibly substituted by one or more halogen atoms, or the radical-CO-Z, where Z is a carboxyl radical, free, converted into a salt or ester; R3radical , where X denotes an oxygen atom or a radical of formula (a) (radicals D1D2and R5accept multiple values, as described in paragraph 1 of the claims), as well as their salts joining with acids possess antagonistic properties towards angiotensin II receptor, in particular inhibit vasoconstrictor effect, as well as trophic effect on the level of the myocytes. Describes 3 ways to obtain compounds of formula I, pharmaceutical composition and intermediate compounds. 6 and 5 C.p. f-crystals. 1 PL.

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The present invention relates to new chetyrehjadernym derivative of imidazole, to the way they are received, to new intermediate compounds and to pharmaceutical compositions containing chetyrehskatnye imidazole derivatives.

More specifically, the present invention relates to compounds of the holding not more than 4 carbon atoms,

R2= C1-C8alkylthio, possibly substituted by one or more halogen atoms, or the radical-CO-Z, in which Z denotes a carboxyl radical, free, converted into a salt or ester, R3choose from:

a) radical , in which X represents an oxygen atom or a radical:

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in which D1and D2identical or different, denote a halogen atom or microradian, and R5means:

i) a radical-CHY1Y2where:

Y1is a hydrogen atom or halogen,

and Y2- carboxy, free, turned into salt, aminirovanie or esterified, alkylthio, alkylsulfonyl and alkylsulfate, linear or branched, containing not more than 6 carbon atoms, or phenylthio, phenylsulfonyl or phenylsulfonyl,

ii) radical , in which Y3the hydroxy radical, if necessary, converted into a salt, alkoxy or alkylthio, linear or branched, containing not more than 6 carbon atoms,

iii) if X represents an oxygen atom, R5means an amino radical, possibly substituted by tetrazolyl or one or two alkilani, linear or branched, containing not more than 6 carbon atoms which may be substituted/BR>< / BR>
where A1is an oxygen atom or a radical NR6, R6- C1is alkyl or cycloalkyl, A2means the moiety C(R8)-R7where R7and R8both signify hydrogen or together form an oxo radical, R9- C1-C6alkyl or CF3;

R4means-SO2-NH2,

-SO2-N=CH-N(CH3)2,

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-SO2-NH-CO2Et, -SO2-NH-CO2H, SO2-NH-CO2Pr,

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when the sulfur atoms in the compounds of formula (I) can be oxidized to sulfone or sulfoxide; and the possible isomeric forms, enantiomers and diastereoisomers of these compounds and their salts accession mineral and organic acids or mineral and organic bases.

Among the compounds of formula (I) according to the invention include, in particular, the following connections:

- 2-butyl-1-((2'-(((((cyclohexylmethyl)amino)carbonyl) amino)sulfonyl) (1,1'-biphenyl)4-yl)methyl)4-(methylthio) - alpha - oxo-1H-imidazole-5-acetic acid;

- 2-butyl-4-(methylthio)beta-oxo-1-((2'-((((propylamino) carbonyl)amino)sulfonyl) (1,1'-biphenyl)4-yl)methyl)-1H - imidazol-5-ethylpropane;

- 2-butyl-4-(methylthio) 1-((2'-((((propylamino)carbonyl) amino)sulfone the(phenylmethyl)amino) carbonyl)amino)sulfonyl)(1,1'-biphenyl) 4-yl)methyl) 1H-imidazole-5-acetic acid;

- 4'-((2-butyl-5-(2-(methylsulfinyl)acetyl) 4-(methylthio) 1H-imidazol-1-yl)methyl)-N-(((phenylmethyl)amino)carbonyl) (1,1'-biphenyl)-2-sulfonamide;

- 4-(methylthio)-1-((2'-(((((phenylmethyl)amino)carbonyl)amino) sulfonyl)(1,1'-biphenyl) 4-yl)methyl) 2-propyl-N-(2H-tetrazol-5-yl) 1H-imidazole - 5-carboxamide,

- 2-butyl-4-(methylthio) - alpha-oxo-N-(phenylmethyl) 1-((2'- (((((phenylmethyl)amino)carbonyl)amino)sulfonyl) (1,1'- biphenyl)4-yl)methyl) 1H-imidazole-5-ndimethylacetamide;

- 4'-((4-(methylthio) 5-(2-(phenylsulfonyl)acetyl) 2-propyl-1H - imidazol-1-yl)methyl-N-(((phenylmethyl)amino)carbonyl)(1,1'-biphenyl) 2-sulfonamide;

- 2-butyl-4-(methylthio)beta-oxo-1-((2'-(((((phenylmethyl)amino) carbonyl)amino)sulfonyl)(1,1'-biphenyl)4-yl)methyl)-1H-imidazol-5 - ethylpropane;

- 4'-((2-butyl-5-(2-((4-forfinal)sulfanyl)acetyl) 4-(methylthio) 1H-imidazole 1-yl)methyl)-N-(((phenylmethyl)amino) carbonyl)(1,1'-biphenyl) 2-sulfonamide;

- 2-butyl-4'-((4-methylthio) 5-((1H-tetrazol 5-yl)carbonyl) 1H-imidazol-1-yl)methyl)-N-(((phenylmethyl)amino)carbonyl) (1,1'-biphenyl) 2-sulfonamide;

- 4'-((2-butyl-4-(methylthio) 5-((1H-tetrazol-5-yl)acetyl) 1H-imidazol-1-yl)methyl)-N-(((phenylmethyl)amino)carbonyl) (1,1'-biphenyl) 2-sulfonamide;

- 4'-((4-(methylthio) 5-((phenylsulfonyl)acetyl) 2-propyl - 1H-imidazol-1-yl)methyl)-N-(((2-thienylmethyl)amino)carbonyl) - Rev. yl) 2-propyl-1H-imidazol-1-yl)methyl)(1,1'-biphenyl) 2-sulfonamide;

- () N-(4'-((4-(methylthio) 5-((phenylsulfonyl)acetyl) 2-propyl-1H-imidazol-1-yl)methyl-(1,1'-biphenyl-2-yl)sulfonyl) cyclopentanepropionate;

- 4'-((2-butyl-5-(2,4-dioxo-5-methyl-3-propyl-5 - oxazolidinyl)-4-(methylthio) 1H-imizol-1-yl)methyl)-N-((propylamino)carbonyl)(1,1'-biphenyl) 2-sulfonamide;

- 4-(methylthio)-1-((2'-((((propylamino)carbanionic)amino) sulfonyl)(1,1'-biphenyl) 4-yl)methyl) 2-(propylthio)-1H-imidazol-5-ethylcarboxylate;

- 2-butyl-1-((2'-(((((cyclohexylmethyl)amino) carbonyl)amino)sulfonyl)(1,1'-biphenyl)4-yl)methyl) 4-(methylthio) - alpha - oxo-1H-imidazol-5-ndimethylacetamide;

- 4-(methylthio) 1-((2'-((((propylamino)carbonyl)amino) sulfonyl)(1,1'-biphenyl)4-yl)methyl) 2-(propylthio) 1H - imidazole-5-carboxylic acid;

- 4'-((2-butyl-4-(methylthio)-5-(3-phenyl-1,3 - disopropyl) 1H-imidazol-1-yl)methyl)-N-(((phenylmethyl) amino)carbonyl)(1,1'-biphenyl) 2-sulfonamide;

- 4'-((5-(cyanoacetyl) 4-(methylthio) 2-propyl-1H-imidazol - 1-yl)methyl)-N-(((phenylmethyl)amino)carbonyl)(1,1'-biphenyl) 2 - sulfonamide;

- 4'-((2-butyl-5-((1-((4-methoxyphenyl)methyl) 1H - tetrazol-5-yl)acetyl) 4-(methylthio) 1H-imidazol-1-yl)methyl) -N-(((phenylmethyl)amino)carbonyl)(1,1'-biphenyl) 2-sulfonamide.

- 4'-((2-butyl-5-((4-methoxyphenyl)(5-methyl) 2H-tetrazol-2 - yl)acetyl) 4-(methylthio) 1H-imidazol-1-yl)methyl)-N-(((phenylmethyl)amine)methyl)(1,1'-biphenyl-2-yl)sulfonyl) cyclopentanepropionate;

- 4'-((5-acetyl-2-butyl-4-(methylthio) 1H-imidazol-1-yl) methyl)-N-(((cyclohexylmethyl)amino)carbonyl)(1,1'-biphenyl) 2-sulfonamide;

2-butyl-4'-((4-methylthio)-5-((1H-tetrazol-5-yl)carbonyl) 1H-imidazol-1-yl)methyl)-N-(((phenylmethyl)amino)carbonyl) (1,1'-biphenyl) 2-sulfonamide;

4'-((2-butyl-4-(methylthio)-5-(1-oxo-2-(phenylsulfonyl) pentyl-1H-imidazol-1-yl)methyl)-N-(((phenylmethyl)amino) carbonyl)(1,1'-biphenyl) 2-sulfonamide;

4'-((2-butyl-4-(methylthio)-5-((1,1-dioxy-to-tetrahydro-2 - thienyl)carbonyl) 1H-imidazol-1-yl)methyl)-N-(((phenylmethyl) amino)carbonyl)(1,1'-biphenyl) 2-sulfonamide;

4'-((2-butyl-5-(C-cyclohexylmethyl-2,4-dioxo-5-(trifluoromethyl) 5-oxazolidinyl) 4-(methylthio) 1H-imidazol-1-yl)methyl-N- (((cyclohexylmethyl)amino)carbonyl)(1,1'-biphenyl) 2-sulfonamide;

4'-((2-butyl-5-(2-(1,1-dimethylethyl) 4-methyl-5-oxo-1,3 - dioxolane-4-yl) 4-(methylthio) 1H-imidazol-1-yl)methyl-N- (((cyclohexylmethyl)amino)carbonyl)(1,1'-biphenyl) 2-sulfonamide;

4'-((4-methylthio) 5-(phenylacetyl) 2-propyl-1H-imidazol-1-yl) methyl)-N-(((phenylmethyl)amino)carbonyl)(1,1'-biphenyl) 2-sulfonamide;

4'-((2-butyl-4-(methylthio)-5-((1H-tetrazol-5-yl) acetyl) 1H-imidazol-1-yl)methyl)-N-(((phenylmethyl)amino) carbonyl) (1,1'-biphenyl) 2-sulfonamide;

4'-((5-amatil-4-(methylthio) 2-propyl-1H-imidazol-1-yl) methyl)-N-(((phenylmethyl)amino)CT the uly (I), namely, the compound of formula (II):

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in which R1' matter referred to in paragraph 1 for R1in which the possible reactive functions can be protected by a protective group, and P is a protective group for the nitrogen atom, is subjected to a halogenation reaction for obtaining the compounds of formula (III):

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in which R1' and P have the above meanings and Hal represents a halogen atom, which is subjected to the reaction of the exchange of the halogen-metal with one of the halogen atoms, then the reaction with the compound of the formula (IVa), (IVb), (IVwith), (IVdor (IVe): (-S-R')2(IVaor MeSO2SR' (IVbor

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in which R' has the values specified in paragraph 1 for R, in which the possible reactive functions can be protected by a protective group, and "ALK" means alkyl containing not more than 4 carbon atoms. to obtain the compounds of formula (V):

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in which R1', P and Hal have the above meanings and R3"is S-R' or-O-ALK, where R' and ALK have the above specified values, and By means radical , which is subjected to the reaction of the exchange of the halogen-metal with a halogen atom, and then reacting with compound of formula (IVa'), (IVb'), (IVcranks or different from R', have the meanings indicated above for R, in which the possible reactive functions can be protected by a protective group, and ALK' are identical or different from "Ala" means alkyl containing not more than 4 carbon atoms, to obtain the compounds of formula (VII):

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in which R1' and P have the above significance, and R2and R3", identical or different, mean-S-R', -S,-R, -K-Oalk or-To-Oalk', as defined above, in which R', R', ALK, ALK' and To have the above values, from which the free amine function, the blocked group R defined above, and then carry out the reaction with the compound of the formula (VIII):

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in which R4' has the meaning specified in paragraph 1 for R4in which the possible reactive functions can be protected by a protective group, and Hal represents a halogen atom, to obtain the compounds of formula (I1):

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in which R1', R2", R3and R4' have the meanings specified in paragraph 1; the resulting product of the formula I1that is a product of the formula I, allocate or subjected, if necessary, one or more reactions of transformation to other products of the formula I, in any order:

a) etherification of ester function acyl,

d) transforming Sinopoli in an acid function,

e) conversion of the acid function into an amide function, then, if necessary, in function thioamide,

f) restoring carboxyphenyl to an alcohol function,

g) transforming functions alkoxy function hydroxyl or hydroxyl function in the function alkoxy,

h) oxidation of the alcohol function to the aldehyde, acid or keto-function

i) the conversion of the formyl radical in the radical carbarnoyl,

j) turning radical carbarnoyl in the nitrile radical,

K) converting the nitrile radical in tetrazolyl,

l) oxidation of ancilliary or aristocraty to the corresponding sulfoxide or sulfone,

m) the transformation function sulfide, sulfoxide or sulfone function corresponding sulfoximine,

n) the transformation function oxo function of thioxo,

a) the conversion of the radical in the radical

p) conversion of the acid function into a function:

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q) is the transformation function of beta-keto-sulfoxide in the function of alpha-ketotioefir,

r) the conversion of carbamate into urea and, in particular, sulfonylamino in the sulfonylurea,

s) removal of protective groups, which can protect the reaction functions,

t) colabrative the forms of compounds of formula (I)

obtaining isomers, enantiomers and diastereoisomers.

The invention relates to a method for producing compounds of formula (I) consists in the fact that the compound of formula (IX):

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in which R1' has the abovementioned meaning and M represents a hydrogen atom or the radical R2' which has the values specified above for R2in which the possible reactive functions can be protected by a protective group, is subjected to reaction with the compound of the formula (VIII) defined above, to obtain a product of formula (X):

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in which R1' M and R4' have the above values, the obtained compound of formula (X), if M implies R2' defined above, is subjected to a halogenation reaction, to obtain the product of formula (XI):

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in which R1', R2', R4' and Hal have the above values, which is subjected to the reaction of the exchange of the halogen-metal, then the reaction with the compound of the formula (XII):

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in which R9' matter referred to in paragraph 1 for R9in which the possible reactive functions can be protected by a protective group, and receive the product of formula (I2):

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in which R1', R2', R4' and R (I2) with the compound of the formula (XV):

O=C=N-R6' (XV)

in which R6' matter referred to in paragraph 1 for R6in which the possible reactive functions can be protected by a protective group, to obtain a product of formula (I3):

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in which R1', R2', R4', R6' and R9' have the above meanings, or the product of formula (I2) is subjected to a saponification reaction with the product of formula (I4):

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in which R1', R2', R4' and R9' have the above meanings, is subjected to reaction with COCl2to obtain a product of formula (I5):

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in which R1', R2', R4' and R9' have the above meanings, or the product of formula (X), provided that M denotes a hydrogen atom, is subjected to a halogenation reaction to obtain a product of formula (XIV):

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in which R1', R4' and Hal have the above values, which is subjected to the reaction of the exchange of the halogen-metal, then the processing of the compound of formula (IVa), (IVb), (IVc), (IVdor (IVe) defined above to obtain a product of formula (I6):

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in which R1', R4'Hal and R3" have an Association of the formula (IVa') (IVb'), (IVc'), (IVd') or (IVe') defined above, to obtain a product of formula (I7):

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in which R1', R4', R2and R3" have the above meanings; then the above products of formula I2, I3, I4, I5, I6, I7that are a product of the formula I, allocate or subjected, if necessary, one or more reactions of transformation to other products of the formula I, in any order:

a) esterification of the acid function,

(b) saponification functions of ester to acid functions,

C) transforming functions of ester function acyl,

d) transforming Sinopoli in an acid function,

e) conversion of the acid function into an amide function, then, if necessary, in function thioamide,

f) restoring carboxyphenyl to an alcohol function,

g) transforming functions alkoxy function hydroxyl or hydroxyl function in the function alkoxy,

h) oxidation of the alcohol function to the aldehyde, acid or keto-function

i) the conversion of the formyl radical in the radical carbarnoyl,

j) turning radical carbarnoyl in the nitrile radical,

k) the transformation is xida or sulfone,

m) the transformation function sulfide, sulfoxide or sulfone function corresponding sulfoximine,

n) the transformation function oxo function of thioxo,

a) transforming radical

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in radical

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p) conversion of the acid function in function

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q) is the transformation function of beta-keto-sulfoxide in the function of alpha-ketotioefir,

r) the conversion of carbamate into urea and, in particular, sulfonylamino in the sulfonylurea,

s) removal of protective groups, which can protect the reaction functions,

t) salt formation using mineral or organic acids or with bases,

u) the splitting of the racemic forms of the compounds of formula (I)

obtaining isomers, enantiomers and diastereoisomers.

The invention relates to a method for producing compounds of formula (I) consists in the fact that the compound of formula (XX):

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in which R1' and R2' have the above meanings and R3' matter referred to in paragraph 1 for R3in which the possible reactive functions can be protected by a protective group, is subjected to the interaction with the compound of the formula (VIII) defined above, to obtain a product of formula (I'):


a) esterification of the acid function,

(b) saponification functions of ester to acid functions,

C) transforming functions of ester function acyl,

d) transforming Sinopoli in an acid function,

e) conversion of the acid function into an amide function, then, if necessary, in function thioamide,

f) restoring carboxyphenyl to an alcohol function,

g) transforming functions alkoxy function hydroxyl or hydroxyl function in the function alkoxy,

h) oxidation of the alcohol function to the aldehyde, acid or keto-function

i) the conversion of the formyl radical in the radical carbarnoyl,

j) turning radical carbarnoyl in the nitrile radical,

k) converting the nitrile radical in tetrazolyl,

l) oxidation of ancilliary or aristocraty to the corresponding sulfoxide or sulfone,

m) the transformation function sulfide, sulfoxide or sulfone function corresponding sulfoximine,

n) the transformation function oxo function of thioxo,

on preframe is asenio function of beta-keto-sulfoxide in the function of alpha-ketotioefir,

r) the conversion of carbamate into urea and, in particular, sulfonylamino in the sulfonylurea,

s) removal of protective groups, which can protect the reaction functions,

t) salt formation using mineral or organic acids or with bases,

u) the splitting of the racemic forms of the compounds of formula (I)

obtaining isomers, enantiomers and diastereoisomers.

In the preferred conditions, the reaction of halogenation of compounds of formula (II) and (X) defined above, respectively, to the compound of formula (III) and (XI) or (XIV) as defined above can be carried out under conditions conventional for professionals, in particular, bromirovanii using N-bromosuccinimide in dichloromethane or using bromine in acetic acid.

Obtaining the corresponding compounds of formula (V) may be carried out by reaction of the compound of formula (III), defined above, with such an ORGANOMETALLIC compound as n-utility, in a solvent such as tetrahydrofuran, at a temperature of approximately -78oC, with the subsequent action of the compounds of formula (IVa), (IVb), (IVc), (IVdor (IVe).

The reaction of the compound of formula (V) above, the obtaining compounds of formula (VII) can be carried out in the same way, using n-utility as agent metallization.

The function of the amine in the compound of formula (VII) defined above, protected by P above, may be released in the usual conditions known to the expert, in particular, if P is the radical-CH2-O-(CH2)2-Si(CH3)3apply triperoxonane acid or in the presence of fluoride ion.

In the product of formula (VIII) Hal preferably denotes a bromine atom, but can also be a chlorine atom or iodine.

The reaction of the compound of formula (VIII) with the compound of the formula (VII) or (IX), or (XX) can be done in such a solvent, such as dimethylformamide or dimethylacetamide, tetrahydrofuran, dimethoxyethane or dimethylsulfoxide, in the phlegm of the solvent or at room temperature, preferably with stirring; the reaction is carried out preferably in the presence of such a base, such as sodium hydride or potassium or sodium carbonate or potassium, methylate or ethylate or tert.-the butyl sodium or potassium.

Obtaining the compounds of formula (I2), defined above, is carried out by interaction magnirostris the compounds of formula (XI) with the compound of the formula (XII), Agnes of compounds of formula (XI) is obtained by reaction of compounds of formula (XI), defined above, in which Hal may, for example, to represent a bromine atom, with a compound of magnesium, such as chloride isopropyl-magnesium in a solvent such as, for example, toluene.

The reaction of the compound of formula (I2) defined above, with a compound of formula (XV), defined above, to obtain compounds of formula (I3), defined above, can be realized, for example, acetone or tetrahydrofuran in the presence of sodium bicarbonate or potassium or sodium carbonate or potassium.

The reaction of saponification of compounds of formula (I2) to the compounds of formula (I4can be performed by conventional methods known to the expert, for example, in the presence of sodium hydroxide or potassium or cesium carbonate in a solvent such as methanol or ethanol, dioxane or dimethoxyethane.

The compound of formula (I4can be cyklinowanie to the compounds of formula (I5) defined above, in particular by reaction of compounds of formula (I4) with phosgene in dichloromethane.

The reaction conversion of the compounds of formula (I4in the compound of formula (I6can be performed, for example, by reaction of compounds of formula (I4) with an aldehyde in the presence of such acid, e, in the product of formula (I7) defined above, then the product of the formula (I8can be performed under the same conditions, which are defined to obtain products of formula (V) and (VII) as defined above, on the basis of the product of formula (III), defined above.

Depending on the values of R1', R2', R2", R3', R3and R4'the products of formula (I1), (I2), (I3), (I4), (I5), (I6), (I7) could form part of the products of formula (I) or of them you can obtain the products of formula (I), or they can be converted into other functional derivatives of products of formula (I), subjecting them to one or more reactions (a) - u) above.

Therefore, different reaction functions, which may have some connections involved in the above reactions may be protected: we are talking about, for example, the functions of hydroxyl, acyl, free carboxy or amino, monoalkylamines that can be protected by protective groups.

We can give the following non-limiting list of examples of protection of reactive functions:

the hydroxyl groups can be protected, for example, alkyl radicals, for example tert-Buti amino can be protected, for example, the acetyl radicals, trityl, benzyl, tert-butoxycarbonyl, phthalimido or other radicals known in the chemistry of peptides,

- acyl groups such as formyl, can be protected, for example, in the form of cyclic or acyclic ketals or tionately, for example dimethyl - or diethylketone, or Atlanticists, or dietetically, or atlanticocean,

acid functions of the above-described compounds can be optionally lidirovali primary or secondary amine, for example in methylene chloride in the presence of, for example, the hydrochloride of 1-ethyl-3- (dimethylaminopropyl)carbodiimide at room temperature;

acid functions can be protected, for example, in the form of esters formed with easily fissionable esters, such as complex benzyl or tert-butyl esters or esters known in the chemistry of peptides.

The reaction, which can be subjected, if desired, the products of formula (I1), (I2), (I3), (I4), (I4), (I5), (I6), (I7), can be realized, for example, as described below.

as Described above products with the carboxy functions can be entered in the esterification reaction, which implement the function can be carried out under normal conditions, well-known specialist, in particular, by hydrolysis or alkali, such as sodium hydroxide or potassium hydroxide in alcoholic medium, such as, for example, in methanol, or by acid hydrolysis using hydrochloric or sulfuric acid.

C) Reaction of attaching a function of ester , in which E1may mean a radical alkyl or aryl, possibly substituted and, if necessary, protected, making it acyl , can be carried out, in particular, by the action of a carbanion: where E2E3and E4the same or different, is chosen among hydrogen atom, alkyl radicals, alkylaryl, alkylsulfonate, arylsulfonate, alkylsulfonate, arylsulfonate, acyl, free, turned into salt, esterified or liderando carboxy, alkyl radicals, alkylthio and aryl, in case of need replaced and if necessary secured, as indicated above.

This reaction is carried out, in particular, as described in the experimental part, or by conventional methods known to the expert.

d) Functions cyano described above products can be converted into the acid function in the usual conditions known to the expert, for example, double hydrolytical these three compounds taken preferably in equal proportions, or in a mixture of sodium hydroxide, ethanol and water at a temperature of reflux.

e) a Reaction for the transformation of the function of the acid to the amide function can be realized, for example, by formation of a first acid chloride in the usual conditions known to the expert, for example, by the action of SOCl2then amidation as described above, or by direct amidation of the above acids.

In particular, it is possible to get radical:

the transformation function of the acid into the acid chloride by the action of SOCl2in this solvent, such as toluene or benzene, then the action of amine:

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Thus obtained amide may be, if desired, converted into thioamide effect of reagent LAWESSON in toluene.

f) Function is free or esterified carboxypropyl the above products, if desired, can be restored to an alcohol function well-known specialist methods: function esterified carboxypropyl can be restored to function alcohol known specialist methods, for example, using lithium hydride and aluminum in such a solvent, such as tetrahydrofuran or dioxane, or a simple ethyl ester.

Function free carboxypropyl videopix is alkoxyphenyl, such as methoxy, the above products can be converted into a hydroxyl function in the usual conditions known to the expert, for example, using trichromate boron in such a solvent, such as methylene chloride, or by using bromhidrosis or pyridine hydrochloride or by using Hydrobromic or hydrochloric acid in water or triperoxonane acid at reflux.

h) Possible alcohol functions of the above products, if desired, can be converted into a function of aldehyde or acid oxidation in conventional conditions known to the specialist, as, for example, by the action of manganese oxide to obtain aldehydes or Jones reagent to obtain acids.

i) j) Reaction conversion of the formyl radical in the radical of carbamoyl and the radical of carbamoyl in radical nitrile is carried out, in particular, in respect of the radicals R3and R8in the usual conditions known to a specialist, such as transmission of ketonitriles and substitution with amino (Chem. Comm 1971, page 733).

k) the Functions of the above nitrile products can be turned into tetrazolyl in the usual conditions known to a specialist, such as cyclopentadiene metal azide, for example azide is e: J. Organometallic Chemistry., 33, 337 (1971) COSIMA S. & coll.

l) Group alkylthio or aaltio the above products can be converted into the corresponding functions of the sulfoxide or sulfone in the usual conditions known to the specialist, as, for example, using nagkalat, for example peracetic acid or metacompetencies acid, or ozone, axonom, periodates sodium, in such a solvent, such as methylene chloride or dioxane at room temperature.

To obtain sulfoxide group it is advisable to use equimolar mixture of compounds containing the group alkylthio or aaltio, with this reagent, as nagkalat. To obtain a sulfonic group, it is advisable to use a mixture of compounds containing the group alkylthio or aaltio, with an excess of this reagent, as nagkalat.

m) Function sulfide, sulfoxide or sulfone of the above products can be converted into the corresponding functions sulfoximine in the usual conditions known to a specialist: non-limiting examples of making compounds containing function sulfoximine described below.

For example, for the preparation of compounds such as N-(arylsulfonyl) sulfoximine, and, for example, in case rasoloarivony to the corresponding sulfoxide, i.e., - S(O)CH3, preferably in the presence of copper, as indicated, for example, in the following link:

J A. C. S., 95, page 4287 (1973) Johnson, C. R.& coll.

Another used method is to process the N-tosylchloramide obtained from the sulphide by the action of, for example, chloramine T, oxidizing agent, such as sodium hypochlorite, in terms of a phase transition, as indicated, for example, in the following reference: J. Org.Chem., 19, page 2282 (1984) AKUTAGAWA K.& coll.

n) Reaction conversion functions oxo function of thioxo can be realized, in particular, using a reagent of LAWESSON under the conditions specified above.

a) Reaction of transformation of the acyl radical in the radical may be carried out by condensation with hydroxylamine derivative such as NH2-O-R6in which R6have the above significance, in an alcohol solvent, such as methanol or ethanol.

The reaction conversion of the acyl radical in the radical can be done, for example, by the condensation of a derivative of hydrazine, such as connection: in which R7and R8have the above significance, in an alcohol solvent (e.g. methanol or ethanol).

p) Reaction conversion of the acid function in tetrazolyl me what to above, then the action of copper cyanide in the usual conditions known to the specialist, the obtained acid chloride, getting a radical that can be converted into the radical:

for example, the action of compounds Sn(Bu)3in toluene.

f) a Reaction for the transformation of the function of beta-ketosulfone in function alfabeto-tiefer can bromirovanii on the alpha position of ketosulfone, for example, by the action of N-bromosuccinimide, for example, methylene chloride, followed by reaction of PUMMERER carried out in a mixture triperoxonane acid and methylene chloride or mixtures of sulfuric acid and dioxane.

In particular, as defined above in (C) and q), it is possible to carry out the reaction scheme 1 (see end of description) compounds by conventional methods known to the expert.

Illustrations of such reactions, defined above, are in receipt of the following examples.

The compounds of formula (I) and their salts joining with acids have interesting pharmacological properties.

The products of formula (I) described above, possess antagonistic properties towards angiotensin II receptor, and are inhibitors of the action of angiotensin II, in particular, inhibit vasoconstrictor effect, litvania in therapy. Thus, the compounds of formula 1 can be used as medicaments, the compounds of formula (I) can be in various racemic isomer forms or in the form of optically active isomers, as well as in the form of their salts connection with pharmaceutically acceptable mineral or organic acids.

Thus, the invention relates to the use of products of formula (I) defined above, which may be in the form of a possible isomer racemic form or in the form of optically active isomers and their salts connection with pharmaceutically acceptable mineral or organic acids as drugs.

In particular, as medicaments can be used for the products described below in the examples, and, in particular, the following products of formula (1):

- 2-butyl-1-((2'-(((((cyclohexylmethyl)amino)carbonyl) amino)sulfonyl)(1,1'-biphenyl) 4-yl)methyl) 4-methyl-thio-alpha - oxo-1H-imidazole-5-acetic acid;

- 2-butyl-4-(methylthio)beta-oxo-1-((2'-((((propylamino) carbonyl)amino)sulfonyl)(1,1'- biphenyl) 4-yl)methyl) 1H-imidazole-5-ethylpropane;

- 2-butyl-4-(methylthio) 1-((2'-((((propylamino)carbonyl)amino) sulfonyl) (1,1'-biphenyl) 4-yl)methyl)-N-(1H-tetrazol-5-yl) yl)(1,1'-biphenyl) 4-yl)methyl) 1H-imidazole 5-acetic acid;

- 4'-((2-butyl-5-(2-(methylsulfinyl)acetyl) 4-(methylthio) 1H-imidazol-1-yl)methyl)-N-(((phenylmethyl)amino)carbonyl) (1,1'-biphenyl) 2-sulfonamide;

- 4-(methylthio) 1-((2'-(((((phenylmethyl)amino)carbonyl)amino) sulfonyl)(1,1'-biphenyl) 4-yl)methyl) 2-propyl-N-(2H-tetrazol-5-yl) 1H-imidazole 5-carboxamide;

- 2-butyl-4-(methylthio) - alpha-oxo-N-(phenylmethyl) 1-((2'- ((((((phenylmethyl)amino)carbonyl)amino)sulfonyl)(1,1'-biphenyl)4-yl) 1H-imidazole-5-ndimethylacetamide;

- 4'-((4-methylthio) 5-(2-phenylsulfonyl)acetyl)-2-propyl-1H - imidazol-1-yl)methyl-N-(((phenylmethyl)amino)carbonyl)(1,1'-biphenyl)- 2-sulfonamide;

- 2-butyl-4-(methylthio)beta-oxo-1-((2'-(((((phenylmethyl)amino) carbonyl)amino)sulfonyl)(1,1'-biphenyl)4-yl) methyl) 1H-imidazole-5-ethylpropane;

-4'-((2-butyl-5-(2-((4-forfinal)sulfanyl)acetyl) 4-(methylthio) 1H-imidazol-1-yl)methyl)-N-(((phenylmethyl)amino) carbonyl)(1,1'-biphenyl) 2-sulfonamide;

- 2-butyl-4'-((4-(methylthio)-5-((1H-tetrazol-5-yl) carbonyl 1H-imidazol-1-yl)methyl)-N-(((phenylmethyl)amino)carbonyl) (1,1'-biphenyl)-2-sulfonamide;

- 4'-((2-butyl-4-(methylthio)-5-((1H-tetrazol-5-yl)acetyl) 1H-imidazol-1-yl)methyl)-N-(((phenylmethyl)amino)carbonyl) (1,1'-biphenyl) 2-sulfonamide;

-4'-((4-(methylthio)-5-((phenylsulfonyl)acetyl)-2-propyl-1H - imidazol-1-yl)methyl)-N-(((2-thienylmethyl)amino)carbonyl) (1,1'-Bipper-1H-imidazol - 1-yl)methyl)(1,1'-biphenyl)-2-sulfonamide;

-() N-(4'-((4-(methylthio)-5-(phenylsulfonyl)acetyl) 2-propyl) 1H-imidazol-1-yl)methyl)(1,1'-biphenyl-2-yl)sulfonyl) cyclopentanepropionate;

and also their salts connection with pharmaceutically acceptable mineral or organic acids.

Medication, the subject invention can be used in the treatment of cardiovascular diseases, which represent vasomotor disturbances and abnormalities of circulating blood volume: myocardial infarction and its consequences, heart failure, renal failure, angina, giperaldosteronizm, arterial hypertension and its consequences. These medicines, the subject invention can be used also for the treatment of glaucoma, atherosclerosis, and various types of visceral spasm, as well as neuronal protective substances or in the prevention of restenosis post-angioplasty.

In particular, in connection with their antihypertrophic and antifibrotic activity medicaments according to the invention can be used in cardiac and vascular levels. In particular, they can be used for the treatment and prevention of cardiovascular disorders, in particular microvascular disorders associated with diabetes.

And the others to the relaxing effects at the level of the uterus.

The medicaments according to the invention can be used also in the treatment of disorders of memory and cognitive functions, as well as anxiety.

The invention relates also to pharmaceutical compositions containing as active substance at least one of the compounds defined above.

These pharmaceutical compositions can be entered orally, rectally, parenterally or locally, by applying to the skin and mucous membranes, or by intravenous or intramuscular injection.

These compositions can be solid or liquid and can have all the pharmaceutical forms commonly used in medicine, such as conventional tablets or coated tablets, gelatin capsules, granules, suppositories, injectable preparations, ointments, creams, gels and preparations, in the form of aerosols; they are prepared by conventional methods. The active substance may be incorporated in excipients which are usually used in these pharmaceutical compositions, such as talc, gum Arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous inert basis of a medicinal product, fatty substances of animal or vegetable origin, derived paraffin, glycols, various wetting means is althemore substances, from the patient being treated, the disease may be, for example, from 1 to 100 mg per day in adult oral assignment.

Some of the source materials of formula (II), (IX) and (XX) are known and can be obtained, for example as described in European patent EP 168 950.

Other educt of formula (II), (IX) and (XX) can be, in particular, obtained as described in European patent EP ON 465368 or receive 1 to 6 described below.

Some of the source materials of formula (II), (IX) and (XX) are commercially available, for example:

the following products of formula (II):

- 2-phenylimidazole,

- 2-methoxyethylamine,

- 2-propylimidazol,

- 2-isopropylimidazole,

- 2-ethylimidazole,

- 2-Mei;

the following products of formula (IX):

- 4-methyl-2-phenylimidazol,

- 2,4-dimethylimidazole,

- 2-ethyl-4-Mei.

Examples of commercial products of the formula (XX) are given in European patent EP 0465368 or EP 0503162.

You can also get some compounds of formula (II), (IX) and (XX), on the basis of other compounds of formula (II) or (IX), for example, subjecting them to one or more of the reactions described above in paragraphs a) - u), implemented as described above.

Some O obtain the compounds of formula (P1):

< / BR>
in which R1' and P have the values specified above for the compounds of formula (II), the compound obtained after the exchange according to the reaction of the halogen-metal, well-known specialist, is subjected to reaction with an appropriate electrophilic agent in accordance with the method known to the expert, in particular, as described above, the transition from the compounds of formula (III) to the compound of formula (V). In the same way you can get some compounds of formulas (IX) and (XX), on the basis of the compounds of formula (III) described above.

It may also be noted that the compound of the formula:

< / BR>
in which R1' and M have the abovementioned meanings, are described in EP 0465368, can be subjected to thermal reaction of saponification, then the decarboxylation reaction to obtain a product of formula (IX) described above.

An illustration of this method is given in the experimental part below.

The compounds of formula (III) in which R1' means a radical of alkylthio, can be obtained or from compounds of formula (II), as described above, or such commercial compounds, as, for example, 2,4,5-tribromoimidazole, 4,5-dibromo-2-phenylimidazol as described above, for making connections to formulalocal conventional methods, well-known specialist.

The initial products of formula (IVa), (IVb), (VIa, (VIb), (VIc), (XII) and (XV) are commercially available, especially the products of formula (VIa), for example sec-butyl disulfide, ethyl disulfide, isopropyl-disulfide, methyl disulfide, benzyl disulfide, phenoldisulfonic, propyl-disulfide,

the products of formula (IVb), for example methylmethanesulfonate,

the products of formula (VIa), for example methylchloroform, benzyl chloroformate, isobutylparaben, ethylchloride, N-propyl-chloroformate, the products of formula (VIb), for example dimethylcarbonate, diethylcarbamyl; products of the formula (VIc), for example di-tert-butylacetate, diethyl-oxalate, dimethyloxalate, the products of formula (XII), for example ethylthiophen-2-glyoxylate, being, ethyl-3-methyl-2-oxybutyrate, ethyleneglycol, methylpiruvate, methylbenzofuran;

the products of formula (XV), for example, methyl isocyanate, 2-carbamidomethylation, basilidians, cyclohexylidene, N-propositional, arylisocyanate, phenylisocyanate.

The way to obtain some of the products of formula (VIII) are described in European patent EP 0465368.

Examples of preparing compounds of the formula (VIII) are also described in the literature and examples of making Yes

Finally, the present invention relates to a new industrial products, in particular intermediate products necessary to obtain products of formula (I). We are talking about the compounds of formula (II), (III), (V), (VII), when P is-CH2-O-CH2-OMe, -CH2-O-(CH2)2-Si(CH3)3, -CH2-O-CH3,

< / BR>
It was recently discovered that there are actually two subtypes of receptors of angiotensin 11 receptor AT1and the receptor AT2. Some of the products of formula (I) of the present invention have an affinity not only to the receptor AT1but also to the receptor AT2.

The invention also concerns the use of compounds of formula (1) defined above, to obtain pharmaceutical compositions intended for the treatment of diseases resulting from abnormal stimulation of receptors AT1and AT2angiotensin 11.

In particular, the invention concerns the use of compounds of formula (1) defined above, to obtain pharmaceutical compositions intended for the treatment of hypertension, postinfarction, heart failure and restenosis postangioplasty.

Primarily the invention concerns a use for the treatment of renal failure.

The invention also concerns the use of compounds of formula (I) to obtain pharmaceutical compositions intended for the treatment and prevention of cardiovascular disorders and especially microvascular circulation system associated with diabetes.

The following examples illustrate the invention without limiting it.

Preparation 1: 2-butyl-alpha-hydroxy-alpha-methyl-1-[(2'-((((dimethylamino)methylene) amino)sulfonyl)(1,1'-biphenyl) 4-yl)methyl] 4-(methylthio)-1H-imidazole-5-ethyl-acetate.

Stage A: 4'-[(2-butyl-4-(methylthio)-1H-imidazol-1-yl)methyl] - N-[(dimethylamino)methylene] (1,1'-biphenyl)-2-sulfonamide.

a). 2-butyl-4-(methylthio) 1H-imidazole.

Enter 760 mg of 2-n-butyl-4-methylthiazole-5-ethyl-carboxylate, obtained as described in European patent application EP 0465368, 15 cm3NaOH(2 n). Bring to phlegmy and stirred for 24 hours. After cooling, diluted with 50 cm3H2O, extracted 3 times with 20 cm3CH2Cl2, washed with 20 cm3H2O and dried. Get 535 mg of the expected product.

(Melting point) = 64oC.

Infrared spectrum (CHCl3)

The absence of C=0

=C-NH 3452 cm-1< / BR>
The coupled system is enyl) 2-sulfonamide.

Dissolve 5 g of 2-butyl-4-(methylthio) 1H-imidazole 120 cm3THF. Then slowly add in the resulting orange solution of 1.55 g of 50% sodium hydride in oil dispersion. The temperature rises to 25oC. Stirred for 30 minutes at this temperature, then give 14 g of 4'-bromomethyl-N-[(dimethylamino) methylene] (1,1'-biphenyl) 2-sulfonamida. Stirred at room temperature until completion of the reaction, i.e., within about 3 hours. Absorb water, extracted with ethyl acetate, separated by chromatography on silica with elution by ethyl acetate, then is infilled by a simple itapira, filtered and dried. Get a 9.35 g of the expected product (colourless crystals). So pl. = 148oC.

Range IR: CHCl3< / BR>
No =C-NH-

1627 cm-1< / BR>
aromatic and

heteroaromatic 1593-1564-1516-1500 cm-1.

Stage B: 4'-[(5-bromo-2-butyl-4-(methylthio)-1H-imidazol-1 - yl)methyl]-N-[(dimethylamino)methylene]-(1,1'-biphenyl) 2-sulfonamide.

Dissolve 10.4 g obtained above in stage And product 450 cm3CH2Cl2and type of 3.9 g of N-bromo-succinimide.

Stirred for approximately 15 minutes at room temperature, washed with water and brine, decadron, filtered and dried. Get to 11.8 g of the expected product (colourless crystals). So pl. = 158oC.

Range IR: CHCl3< / BR>
1628 cm-1< / BR>
aromatics

heteroaromatic 1592-1568 cm-1< / BR>
Microanalysis Br

calculated % 14,54

found % 14,4-14,7

Stage C: 2-butyl-alpha-hydroxy-alpha-methyl-1-[(2'-((((dimethylamino)methylene)amino)sulfonyl) (1,1'-biphenyl)4-yl)methyl] 4-(methylamino) 1H-imidazole-5-acetate.

Dissolve to 11.8 g obtained above at a stage In product 160 cm3THF. Then add, not exceeding 25oC, 17.5 cm31-molar solution of a chloride Isopropylamine dissolved in ordinary air. After approximately 30 minutes of stirring at room temperature, slowly add 4 cm3atilirovanie. Stirred for about 1 hour at room temperature, add 1 cm3atilirovanie and continue stirring for approximately 1 hour.

Absorb 200 cm310%-aqueous solution of NH4Cl and extracted with ethyl acetate. Dried, concentrated to a volume of 200 cm3filter and dry the resulting crystals.

Get 6 g of the expected product (colourless crystals). So pl. = 208 - 210oC.

Range IR: CBR> aromatics 1565, 1518 cm-1.

Ultraviolet spectrum:

1) Eton,

bend 274 nm = 3100

bend 231 nm = 23000

2) in Eton - HCl n/10

bend 228 nm = 30000

bend 273 nm = 3400

Preparation 2: 2-methyl-4-(methylthio) 1-[(2'-((((dimethylamino) methylene)amino)sulfonyl) (1,1'-biphenyl) 4-yl)methyl] - alpha-oxo-1H-imidazol-5-ethyl acetate.

Stage A: 4,5-dibromo-2-methyl-1-[(2-(trimethylsilyl)ethoxy)methyl] 1H-imidazole.

The product obtained by two consecutive reactions.

1) stage protection 2-methyl-imidazole

Dissolve 6.8 g of 2-methylimidazole 250 cm3THF and add in small pieces 4 g of 50% sodium hydride in oil. The reaction is exothermic, maintain the temperature of the medium at room temperature for about 30 minutes.

Then in the reaction medium was added dropwise 17.5 cm3chloride SEM. After about 20 minutes of mixing at 20oC hydrolyzing excess sodium hydride addition of THF with 20% H2O.

The resulting solution was adjusted to a dry condition, absorb in ethyl acetate and washed with water. The organic phase is collected and dried. Receives a yellow oil which is purified by chromatography on silica with allanton: CH23CH2Cl2. Then add to this solution 25 g of N-bromo-succinimide small parts.

Mixing support approximately 30 minutes at room temperature. The organic phase is washed with sodium bicarbonate solution, then abundant water. After drying and evaporation gain of 13.4 g of the expected product (homogeneous yellow oil).

Range IR: CHCl3< / BR>
No =C-NH-

Conjugated system

- 1520 cm-1- 1253 cm-1- 862 cm-1- 840 cm-1.

Stage B: 2-methyl-1-[(2-(trimethylsilyl)ethoxy)methyl]-5- (methylthio) - alpha-oxo-1H-imidazole-4-acetic acid ethyl ester.

Dissolved in anhydrous atmosphere, 3 g obtained above at a stage of A product in 20 cm3anhydrous THF. Then the solution is cooled to -78oC and add to it, keeping the temperature at -78oC, 5.6 cm3of 1.5 molar n-utility in hexane. Mixing support at -78oC for about 10 minutes.

Then enter 0,76 cm3dimethyl disulfide, then increase the temperature slowly until the 20oC and stirred for approximately 30 minutes.

The reaction medium is again cooled to -78oC and add, kaC enter at one time 3.5 cm3diethyloxalate. The support mixing at room temperature for about 30 minutes. Then the reaction medium is poured on ice water. Extracted with ethyl acetate, the organic phase is washed with sodium bicarbonate solution, then with water and dried. Get a brown oil which is purified by chromatography on silica with allanton: ethyl acetate-cyclohexane (50-50). Obtain 1.63 g of the expected product (oil).

Range IR: CHCl3< / BR>
C=0 - 1738-1673 cm-1< / BR>
Conjugated system - 1538 cm-1< / BR>
- 1502 cm-1< / BR>
Stage C: 2-methyl-5-(methylthio) - alpha-oxo-1H-imidazol-4 - ethyl-acetate.

Dissolve 1.6 g obtained above at a stage In product 30 cm3CH2Cl2and add 10 cm3triperoxonane acid. The reaction medium is brought to reflux temperature for about 10 hours. Then the solution is dried to dryness and the residue absorb water. The aqueous phase is alkalinized by the addition of sodium bicarbonate, extracted with ethyl acetate, washed with water, then dried and obtain 920 mg of the expected product (yellow oil), which is used in the same form in subsequent synthesis.

Range IR; CHCl3< / BR>
=C-NH - ity)-1-[(2'-((((dimethylamino) methylene)amino)sulfonyl)(1,1'-biphenyl) 4-yl)methyl] - alpha-oxo-1H - imidazol-5-ethyl acetate.

Dissolve 880 mg obtained at the stage of product in 10 cm3anhydrous dimethylformamide and add sequentially 800 mg of potassium carbonate, and then 2.2 g of 4'-bromomethyl - N-[(dimethylamino)methylene](1,1'-biphenyl)-2-sulfonamida. Stirring is maintained for approximately 3 hours at room temperature. The obtained yellow suspension was poured on the water. Extracted with ethyl acetate, washed with water, then dried, yielding a yellow resin, which is purified on silica with ethyl acetate solvent by.

Get 1,17 g of the expected product.

Range IR; CHCl3.

No =C-NH

C=0 ester - 1735 cm-1< / BR>
the other With a=0 - 1629 cm-1(F)

WITH = N

aromatics - 1570 cm-1< / BR>
heteroatoms - 1516 cm-1< / BR>
Preparation 3: 1- [(2'-(aminosulfonyl) (1,1'-biphenyl)4-yl) methyl] 4-(methylthio) - alpha-oxo-2-propyl-1H-imidazole-5-acetate.

Stage A: 4,5-dibromo-2-n-propyl-1-[(2-(trimethylsilyl)ethoxy) methyl] 1H-imidazole.

Working as A stage of preparation 2, replacing 2-methyl - 1H-imidazole 2-propyl-1H-imidazole.

The product is obtained as a result of two consecutive reactions.

1) stage protection 2-propylimidazol.

Dissolve the.

Then add in the reaction medium 53 cm3chloride EAT, hydrolyzing the tetrahydrofuran with 20% H2O.

Get of 57.3 g of the protected product.

2). Bromination

The result of the above protected product was dissolved in 500 cm3CH2Cl2. Add to 93.5 g of N-bromosuccinimide and get 93,7 g of the expected product.

Range IR: CHCl3< / BR>
No =C-NH-

Conjugated system - 1520 cm-1< / BR>
- 1253 cm-1- 862 cm-1- 840 cm-1< / BR>
Stage b: 2-n-propyl-1-[(2-(trimethylsilyl)ethoxy)methyl] 5-(methylthio) - alpha-oxo-1H-imidazol-5-ethyl acetate.

Introducing anhydrous atmosphere 36,7 g obtained at the stage of A product 200 cm3THF, added at -78oC 63.7 cm3of 1.5 molar n-utility in hexane, then to 8.62 cm3dimethyl disulfide, again increase to room temperature. Then add, as stated above, at -78oC 63.7 cm3of 1.5 molar n-utility in hexane, then 55 cm3atelocerata. Get of 11.75 g of the expected product.

Range IR: CHCl3< / BR>
C=0 - 1737-1672 cm-1< / BR>
Conjugated system - 1527 cm-1< / BR>
- 1501 cm-1< / BR>
Stage C: 2-n-propyl-5- (methylthio) - alpha-oxo-1H-imidazol-4 - etelaat the cm3CH2Cl2and 40 cm3triperoxonane acid. Get to 7.15 g of the expected product.

Range IR: CHCl3< / BR>
=- NH - 3413 cm-1< / BR>
C=0 - 1714-1633 cm-1< / BR>
Conjugated system - 1524-1492 cm-1< / BR>
Stage D: 2-n-propyl-4-(methylthio)-1-[(2'-((((dimethylamino) methylene)amino)sulfonyl)-(1,1'-biphenyl) 4-yl)methyl] - alpha-oxo-1H-imidazol-5-ethyl acetate.

Work, both at the stage D of preparation 2, based on 7 g obtained in stage C of the product in 100 cm3of dimethylformamide and 7.5 g of potassium carbonate and 15.6 g of 4'-(bromomethyl)-N-[(dimethylamino) methylene](1,1'-biphenyl)-2-sulfonamida. Get 7,83 g of the expected product.

Range IR: CHCl3< / BR>
No = C-NH

C=0 ester - 1735 cm-1< / BR>
another C=0 - 1630 cm-1(G)

WITH=N

Stage E: 1-[(2'-(aminosulfonyl)(1,1'-biphenyl) 4-yl) methyl]-2-n-propyl-4-(methylthio) - alpha-oxo-1H-imidazol-5-ethyl acetate.

Working as A stage of preparation 2 of 7.8 g obtained in stage D product, 100 cm3ethanol and 30 cm of concentrated HCl and obtain 3.6 g of the expected product.

Range IR: CHCl3< / BR>
- NH2- 3443-3343 cm-1< / BR>
C=0 - 1734-1627 cm-1< / BR>
aromatics - 1593 cm-1< / BR>
heteroatoms - 1565 cm-1 is-4-(methylthio) - alpha-oxo-1H-imidazol-5-atantic-S-methyl.

Stage A: 4'-[(2-butyl-5-((methylsulfinyl)acetyl) 4-(methylthio) 1H-imidazol-1-yl methyl](1,1'-biphenyl)-2-sulfonamide.

First get the anion of dimethyl sulfoxide introduction to 3.36 g of 50% sodium hydride in oil. NH freed from oil by three consecutive washes with Petrom. Then dry and add 70 cm3anhydrous dimethyl sulfoxide, and the mixture is brought to 75oC for about 1 hour. Lower the temperature to 0oC and add to the resulting anion of dimethyl sulfoxide 70 cm3anhydrous tetrahydrofuran (THF) and 9.6 g of 2-butyl-1-[(2'- ((((dimethylamino)methylene)amino)sulfonyl) (1,1'-biphenyl) 4-yl) methyl] 4-(methylthio) 1H-imidazole-5-ethylcarboxylate, obtained as described in European patent application EP 0503162 dissolved in 70 cm3anhydrous tetrahydrofuran. Then again increase to room temperature and stirred for approximately 1/2 hour. The reaction mixture is poured into 400 cm3H2O.

The solution is acidified to pH 2 with 2 n HCl. Extracted 4 times with 200 cm3chloride methylene and the organic phase is washed 4 times in 100 cm3with distilled water. The organic phase is dried, filtered and evaporated.

Purify on silica>BR>
No

NH2- 3440-3340 cm-1< / BR>
C=0 - 1628 cm-1< / BR>
aromatics + heterocycle - 1545-1525-1495 cm-1< / BR>
SO2- 1345-1165 cm-1< / BR>
SO - 1050 cm-1< / BR>
Stage b: 4'-[[5-[bromo(methylsulfinyl)acetyl]2-butyl-4- (methylthio) 1H-imidazol-1-yl]methyl](1,1'-biphenyl) 2-sulfonamide.

Enter 1 g obtained at the stage of A product and 530 mg K2CO3. Then add 10 cm3anhydrous CH2Cl2and bring the temperature up to 0oC and added dropwise 342 mg of N-bromosuccinimide, dissolved in a minimum amount of anhydrous CH2Cl2. Add 100 cm3CH2Cl2and the organic phase is washed 3 times in 200 cm3distilled water and 1 time 100 cm3saturated NaCl. Dry, filter and concentrate to dryness.

Get 1,09 g of the expected product.

Range of IR in CHCl3< / BR>
NH2- 3440-3344 cm-1< / BR>
> = 0 - 1634 cm-1< / BR>
Conjugated system - 1542-1520 cm-1< / BR>
+ aromatics

+ NH2< / BR>
Stage C: 1-[(2'-(aminosulfonyl) (1,1'-biphenyl) 4-yl) methyl] 2-butyl-4-(methylthio) - alpha-oxo-2-propyl-1H-imidazole-5 - atantic-S-methyl.

Dissolve 6.8 g obtained at the stage In the product in 60 cm3a mixture of 25 cm33
to pH 5-6, extracted with 2 times 200 cm3with ethyl acetate, washed 1 time 100 cm3saturated NaCl, dried, filtered and concentrated to dryness. Purify on silica with allanton ethyl acetate: cyclohexane (5 - 5). Obtain 2.7 g of the expected product.

Range of IR in CHCl3< / BR>
NH2- 3445-3350 cm-1< / BR>
>= 0 - 1670-1614 cm-1< / BR>
aromatics - 1542 cm-1- 1518 cm-1< / BR>
+ heteroaromatic

+ NH2Def.

Preparation 5: 1-[(2'-(aminosulfonyl) (1,1'-biphenyl)-4-yl) methyl] 4-(methylthio) 2-propyl-1H-imidazole-5-ethylcarboxylate.

Stage A: Cyano-[(1-oxobutyl)aminoacylated.

Mix 5 g of ethyl(hydroxyimino)cyanoacetate, 40 cm3tetrahydrofuran (THF), 1165 cm3of butyric acid anhydride and 2.5 g of platinum and stirred in hydrogen atmosphere before saturation. Filtered, washed 5 times with 15 cm3simple ethyl ether is evaporated simple ether, add a little 200 cm3gasoline fraction G, dried, washed 3 times in 10 cm3gasoline fraction G and dried at approximately the 75oC. Concentrated to a volume of 10 cm3add 50 cm3gasoline fraction G, cristalli blithedale at the 75oC. Get 5.73 g of product. So pl. = 110oC. Recrystallization for analysis:

Dissolve 540 mg of the obtained product in 50 cm3simple isopropyl ether at the temperature of reflux, filtered, concentrated, leave approximately 1 hour at rest at room temperature, dry, simple washed with isopropyl ether and dried. Obtain 440 mg of the expected product. So pl. = 110oC.

Microanalysis of C9H14N2O3= 198,22

calculated% C 54,53; H 7,12; N 14,13; O 24.22 TO

found % C 54,5; H 7,2; N 14,0

Range IR CHCl3< / BR>
=C-NH - 3430 cm-1< / BR>
- 2245 cm-1< / BR>
C=0 - 1758 cm-1ether - 1692 cm-1amide

amide 11 - 1492 cm-1< / BR>
Stage b: 3-amino-2-[(1-oxobutyl)amino] 3-(methyltin) 2 - ethyl-propenoate.

In a solution of 20 g obtained at the stage of A nitrile in 400 ml of ethanol is added to 1.4 ml of triethylamine, cooled to approximately -10oC and enter the bubbling approximately 22 g of methylmercaptan. Stirred for approximately 72 hours at 0oC. Remove excess methanethiol, distilled ethanol, is infilled gasoline fraction G, filtered and dried. Get 24,3 g of the expected product (colorless crystals).

So pl. to 115 = 120-124oC.

; 7,5; 11,4 N; S 12,6

Range IR CHCl3< / BR>
=C-NH2- 3500, 3412 cm-1< / BR>
=C-NH - 3365, 3275 cm-1< / BR>
C=0, the complex - 1665 cm-1< / BR>
C=C and NH2Def. - 1592 cm-1< / BR>
amide 11 - 1488 cm-1< / BR>
Range of UV in Eton

max 220 nm - = 5500

Max. 291-292 - = 19400

Stage C: 4-(methylthio) 2-propyl-1H-imidazole-5-ethylcarboxylate

To 20,1 g petaluridae phosphorus 300 cm3chloride methylene cooled to approximately -70oC, add a solution of 12.9 g of 4-dimethylaminopyridine 90 cm3chloride methylene.

Support for 15 minutes at a temperature of about -70oC, then injected a solution of 12 g obtained in stage B of the product in 120 cm3chloride methylene. Bring to room temperature and kept under stirring for about 22 hours.

Pour the reaction mixture into 2.5 liters of ice water and neutralized by adding approximately 60 g of sodium bicarbonate. Stirred for another 30 minutes, decanted and extracted with 500 cm3CH2Cl2. Washed with salt water, dried and the solvent is distilled off at approximately the 50oC. Purify by chromatography on silica with allanton CH2Cl2ethyl acetate (90-10), ZAT is th fraction G, filtered and dried. Gain of 7.4 g of the expected product (colourless crystals). So pl. K95= 85oC.

Microanalysis: C10H16N2O2S = 228,32

calc. % C 52,61; H 7,06; N 12,27; S 14,04; O 14,02

found % C 52,7; H 7,3; N 12,2; S 14,0

Range IR CHCl3< / BR>
=C-NH - 3440-3260 cm-1< / BR>
C=0 complex Max. about 1672 cm-1< / BR>
a heterocycle - 1542 - 1498 cm-1< / BR>
Range of UV in Eton

Max. 213-214 nm - = 14500

bend 229 nm - = 7200

Max. 286 nm - = 12200

Range of UV in Eton/HCl n/10

Max. 238 nm - = 6800

Max. 277 nm - = 9600

the main return ---> max 296 nm.

Stage D: 1-[(2'-((((dimethylamino)methylene)amino)sulfonyl) (1,1'-biphenyl) 4-yl)methyl] 4-(methylthio)-2-propyl-1H-imidazole-5-ethylcarboxylate.

Dissolve 8,1 g obtained in stage C of the product in 80 cm3of dimethylformamide and added to 16.1 g of 4'-(methyl bromide)N- [(dimethylamino)methylene](1,1'-biphenyl)-2-sulfonamida and 4.9 g of potassium carbonate. Stirred at room temperature for about 24 hours. Distilled dimethylformamide at 50oC, is infilled with water, filtered, washed with water and dried at approximately the 60oC.

Is infilled 240 cm3ethyl acetate under stirring for about 30 minutes and PR is a (colourless crystals). So pl.K163:182oC.

Range IR CHCl3< / BR>
No =C-NH

C=0 - 1690 cm-1< / BR>
C=N - 1628 cm-1< / BR>
a heterocycle - 1504-1565 cm-1< / BR>
Range of UV in Eton

the inflection. 230 nm - = 32000

Max. 287 nm - = 15500

Stage E: 1-[(2'-(aminosulfonyl)(1,1'-biphenyl) 4-yl)methyl] 4-(methylthio) 2-propyl-1H-imidazole-5-ethylcarboxylate;

Mix 11.2 g obtained in stage D product with 200 cm3ethanol and 100 cm3concentrated hydrochloric acid. Heated under reflux for about 2 hours. Evaporate the ethanol, diluted by adding 400 cm3water, alkalinized with stirring using alkali sodium and extracted with ethyl acetate. Washed with water and brine, dried, filtered and the solvent is distilled off at approximately the 50oC.

Purify by chromatography on silica with allanton: ethyl acetate 60-hexane 40. Obtain 9.3 g of the expected product (colourless crystals). So pl.K135= 130-132oC.

Range IR CHCl3< / BR>
The absence of the original product.

C=0 - 1689 cm-1< / BR>
NH2- 3444 - 3340 cm-1< / BR>
Conjugated system + aromatics - 1618-1590-1560-1540 - 1508 cm-1< / BR>
NH2Def.

Range of UV in Eton

VT-1-[(2-(trimethylsilyl)ethoxy)methyl] 1H-imidazole.

Dissolve 3.04 from g tribromoimidazole 20 cm3anhydrous tetrahydrofuran. Add small portions 550 mg of NaOH 50% in oil. After incubation for 20 minutes at room temperature add 1,95 ml chloride 2-(trimethylsilyl) ethoxymethyl. After keeping for 30 minutes at room temperature hydrolyzing a saturated solution of NH4Cl. Extracted with ethyl acetate, dried, and evaporated to dryness. Chromatographic with allanton: cyclohexane/ethyl acetate (9-1) and gain of 4.2 g of the expected product (oil).

Stage b: 2n-propylthio-4,5-dibromo-1-[1(2-(trimethylsilyl) ethoxy)methyl] 1H-imidazole.

Dissolve 3,48 g obtained at the stage And product in 25 cm3simple ether. Add 3 ml of a 3 molar solution Tmdg simple ether. After incubation for 15 minutes at room temperature add 2.5 cm3n-dipropyl-disulfide, then 40 cm3anhydrous tetrahydrofuran. Distilled a simple ether and left for 20 hours at reflux temperature of tetrahydrofuran. Hydrolyzing saturated NH4Cl, extracted with ethyl acetate, dried and evaporated to dryness.

After chromatography with allanton: (cyclohexane-ethyl acetate (9-1)) to obtain 2.7 g of the expected product (oil).3anhydrous tetrahydrofuran. Add 3 ml of a 3 molar solution of ETM In simple ether. After 1 hour at room temperature add 1,08 cm3dimethyl disulfide and leave for 1 hour at room temperature, and then hydrolyzing with saturated NH4Cl, extracted with ethyl acetate, dried and evaporated to dryness.

After chromatography with allanton: cyclohexane-ethyl acetate (9-1) receive 1.83 g of the expected product (oil).

Stage D: 2n-propylthio-5-methylthio-1-[(2-trimethylsilyl)ethoxy) methyl] 1H-imidazole.

Injected at room temperature 7,94 g obtained in stage C product, 80 cm3anhydrous tetrahydrofuran, cooled to -78oC and type of 13.75 cm3the 1.6-molar solution of n-utility in hexane. After 10 minutes add 15 cm3ethylchloride, stirred for further 15 minutes at -78oC. Add 60 cm3water, bring to room temperature, the tetrahydrofuran is evaporated, add 10 cm332% of alkali sodium to destroy excess ethylchloride, extracted with 3 times 200 cm3ethyl acetate, washed 2 times by 80 cm3water, dried, filtered and evaporated.

After chromatography on silica with allanton: ethyl acetate-
C=C - 1504 cm-1< / BR>
C=N

Stage E: 2n-propylthio-5-methylthiomethyl-4-ethylcarboxylate.

Injected at room temperature 4,34 g obtained in stage D of product, 40 cm3Eton, 28 cm3water, 28 cm3fuming HCl.

Heat up by using a bath to 70oC for two hours. Evaporated Eton, alkalinized with approximately 20 cm332% of alkali sodium, adjusted to pH 6 with 1-2 cm3acetic acid, extracted with 3 times 300 cm3ethyl acetate, washed 2 times with 70 cm3water, dried, filtered and evaporated. After chromatography on silica with allanton: ethyl acetate - cyclohexane (3-7) and thickening of the gasoline fraction G dried and receive and 3.72 g of the product, of which 200 mg of recrystallized from MeOH-water (50-50). Obtain 149 mg of the expected product.

Range IR: in CHCl3< / BR>
= C-NH - 3430-3225 cm-1< / BR>
=0 - 1682 cm-1< / BR>
a heterocycle - 1522 cm-1< / BR>
Stage F: 1- [(2'-((((dimethylamino)methylene)amino)sulfonyl) (1,1'-biphenyl) 4-yl) methyl] 4-(methylthio)-2H-propyl-thio-1H-imidazole - 5-ethylcarboxylate.

Injected at room temperature 1.04 g obtained in stage E of the product, 10 cm3of dimethylformamide, and 0.55 g K2CO3, 2.1 g of 4'-(bromo is m dimethylformamide is evaporated, absorb 3 times 150 cm3CH2Cl2, washed with 2 times 50 cm3water, once with 50 cm3a saturated solution of NaCl, dried, filtered and evaporated. Chromatographic on silica with allanton: ethyl acetate-cyclohexane (6-4), then crystallized from simple broadcast and receive of 1.93 g of the product, of which 100 mg of recrystallized from simple isopropyl ether. Obtain 66 mg of the expected product. So pl.= 160oC.

Range IR; in CHCl3,

=0 - 1685 cm-1< / BR>
- 1624 cm-1.

EXAMPLE 1: 4"-((2-butyl-5-(2,4-dioxo-5-methyl-3-propyl-5 - oxazolidinyl)-4-(methylthio) 1H-imidazol-1-yl)methyl) - N-((propylamino)carbonyl)(1,1'-biphenyl) 2-sulfonamide.

Stage A: 1-[(2'-(aminosulfonyl)(1,1'-biphenyl) 4-yl)methyl] 2-butyl-alphahydroxy-alpha-methyl-4-(methylthio) 1H-imidazole-5 - acetate.

Mix 1.24 g obtained in Preparation 1 product with 30 cm3ethanol and 10 cm3concentrated HCl.

Heated at reflux temperature the resulting solution for about 2 hours before the end of the reaction.

Cooled, diluted with water, alkalinized by addition of concentrated NaOH, saturated aqueous phase K2CO3, extracted ethylacetamide product (light yellow resin).

Range IR CHCl3.

No

OH - about 3520 cm-1complex

NH2about 3442 cm-1, -3355 cm-1< / BR>
C=0 - 1721 cm-1< / BR>
aromatics - 1614-1592-1565-1543-1517 cm-1< / BR>
heteroaromatic

NH2< / BR>
Stage b: 4'-((2-butyl-5-(2,4-dioxo-5-methyl-3-propyl-5 - oxazol)idini)-4-(methylthio)-1H-imidazol-1-yl)methyl)-N-((propylamino) carbonyl)-(1,1'-biphenyl)-2-sulfonamide.

Dissolve 300 mg obtained at the stage of A product in 10 cm3acetone and add 157 mg K2CO3. Heated at reflux temperature, then injected 0,13 cm3propositionthe. Continue the reaction at the reflux temperature for about 1 hour, add 0.5 cm3propositionthe and heated at reflux temperature for about 1 hour. Filtered K2CO3the solvent is distilled off and the reagent at 60oC. Receive 626 mg of product, which is subjected to two ochistka.

1). Purification by chromatography on silica with a solvent CH2Cl2(60), ethyl acetate (40) and CHCl/MeOH 95/05.

Get 356 mg of the product (colorless crystals). So pl.= 178-180oC.

2). Purification by recrystallization.

Dissolve 356 mg of the product obtained above haurache condition, concentrate approximately 40 cm3, crystallized, cooled, filtered and dried at 50oC.

Obtain 260 mg of the expected product (colourless crystals). So pl. = 170-172oC.

Range IR CHCl3< / BR>
No, HE

= C-NH- - -3416 and 3294 cm-1< / BR>
C=0 - 1812, 1737, 1713 cm-1< / BR>
aromatics - 1604, 1592, 1538, 1520 cm-1< / BR>
heteroaromatic

amide 11.

EXAMPLE 2: 2-methyl-4-(methylthio) 1-[(2'-(((((phenylmethyl)amino) carbonyl)amino)sulfonyl)(1,1'-biphenyl)4-yl)methyl] -alpha-oxo-1H-imidazol-5 - ethyl acetate.

Stage A: 1-[(2'-(aminosulfonyl)(1,1'-biphenyl) 4-yl) methyl]-2-methyl-4-(methylthio) - alpha-oxo-1H-imidazol-5-ethyl acetate.

Dissolve 4.8 g obtained in Preparation 2 product in a mixture of 50 cm3ethanol and 30 cm3concentrated HCl. The reaction medium is brought to reflux temperature for about 5 hours. Then the solution was concentrated in vacuo, then absorb the icy water. Alkalinized by the introduction of NH4OH to pH about 8, then extracted with ethyl acetate, washed with water, dried, then purified by chromatography on silica with ethyl acetate as eluant.

Obtain 2.4 g of the expected product.

Range IR CHCl3<565 cm-1< / BR>
NH2Def. - 1542 cm-1< / BR>
Stage B: 2-methyl-4-(methylthio)-1-[(2'-(((((phenylmethyl)amino) carbonyl)amino)sulfonyl)-(1,1'-biphenyl) 4-yl)methyl] - alpha-oxo-1H-imidazol-5-ethyl acetate.

Dissolve 0.8 g obtained at the stage of A product in 25 cm3acetone and added 465 mg of potassium carbonate. The reaction medium is brought to reflux temperature and added dropwise 0.2 cm3benzylisothiocyanate, mixing support under these conditions for about 1 hour. Evaporated until dry, absorb the residue in water, then acidified by addition of acid phosphate, and the precipitate centrifuged, washed abundantly with water, then dried. Purification is carried out by thickening in a mixture of 10 cm3isopropanol and 20 cm3simple isopropyl ether, dried, washed with 2 times 25 cm3simple isopropyl ether and obtain 480 mg of the expected product (yellow solid). So pl. = 130oC.

Range IR: CHCl3< / BR>
The absence of SO2NH2< / BR>
-NH-C= complex - 3395-3375 cm-1< / BR>
C=0 - 1732-1714-1624 cm-1< / BR>
aromatics - 1539-1497 cm-1< / BR>
heteroatoms

amide 11

EXAMPLE 3: 2-methyl-4-(methylthio)-alpha-oxo-1-((2'-(((((phenylmethyl) amino)carbonyl)amino)sulfonyl)(1,1'-bifen cm3ethanol and 0.1 cm3CON. Stirring is maintained for 1 night at room temperature. Then, the suspension is poured into water, acidified to pH 2 by adding 1 n hydrochloric acid, the obtained white solid is centrifuged, rinsed with water, then dried.

Clean

The crude product is infilled 20 cm3ethyl acetate, then 10 cm3boiling ethanol. Centrifuged, washed with 10 cm3ethanol and obtain 85 mg of the expected product (white solid).

Range IR: vaseline oil.

Integrated absorbance area HE/NH.

C=0 - 1720 - 1644-1630 cm-1er

aromatics - 1560 cm-1< / BR>
heteroatoms - 1546 cm-1< / BR>
amide 11 - 1520 - 1497 cm-1< / BR>
microanalysis

calculated % C 58,11; H to 4.52; N 9,68; S 11,08

found % C to 57.9; H 4.5; N 9,5; S 10,9

EXAMPLE 4: 4-(methylthio) - alpha-oxo-1-[(2'-(((((phenylmethyl) amino)carbonyl)amino)sulfonyl)(1,1'-biphenyl)-4-yl)methyl] - 2-propyl-1H-imidazole-5-acetate.

Injected 3.6 g obtained in Preparation 3 product 50 cm3acetone, then at once 2 g of potassium carbonate.

The reaction medium is brought to reflux and add dropwise 1 cm3benzylisothiocyanate, and maintained at reflux the odes, then acidifying the reaction medium by adding 1 n hydrochloric acid. Centrifuged, rinsed with water, then dried at 50oC. the resulting crude product was then purified by thickening of 50 cm3simple isopropyl ether.

Gain of 4.2 g of the product (I.e. square: 170oC), of which 500 mg of recrystallized from 25 cm3of ethanol. Centrifuged, dried, yielding 300 mg of the expected product. So pl.: 188oC.

Range IR CHCl3< / BR>
= C-NH - 3375 cm-1< / BR>
C=0 - 1714 (F), 1621 cm-1< / BR>
Conjugated system - 1537-1495 cm-1< / BR>
+ aromatics

+ amide 11

Microanalysis

calculated % C they accounted for 60,54; H 5,39; N 8,82; S 10,1

found % C of 60.5; H 5,3; N 8,7; S 10,0

EXAMPLE 5: 4-(methylthio)-1-((2'-(((((phenylmethyl)amino) carbonyl)amino)sulfonyl)(1,1'-biphenyl)-4-yl)methyl)-2-propyl - alpha-oxo-1H-imidazol-wxusa acid.

Enter 300 mg obtained in example 4, the product, suspended in 5 cm3ethanol, then add 5 cm32 n caustic sodium.

Mixing support approximately 1 hour at room temperature. The reaction medium is acidified by addition of 2 n hydrochloric acid. Is the precipitation of a yellow solid, which was centrifuged, rinsed ve solid is dried in a hot state, then washed with 2 times 10 cm3the ethanol. After drying at 50oC obtain 170 g of the expected product. So pl. = 215oC.

Range IR: vaseline oil.

Full absorption OH/OH

+ maximum absorbance is 3360-3350-3190 cm-1< / BR>
C=0 - 1720-1640-1610 cm-1< / BR>
Conjugated system - 1558-1538 - 1510-1498 cm-1< / BR>
+ amide 11

+ F

Microanalysis

calculated % C 59,39; H to 4.98; N 9,25; S 10,56

found % C 59,2; H is 4.9; N 9,4; S 10,4.

EXAMPLE 6: 2-butyl-1-[(2'-(((((cyclohexylmethyl)amino)carbonyl amino)sulfonyl)(1,1'-biphenyl)-4-yl)methyl] -4-(methylthio) - alpha - oxo-1H-imidazol-5-atantic-S-methyl.

Enter 3,20 mg obtained in Preparation 4 product in 100 ml of anhydrous acetone and 1.78 g of potassium carbonate. The mixture is brought to reflux temperature and injected 1.1 cm1cyclohexylethylamine. After approximately 1 hour of stirring the solution is cooled to room temperature, hydrolyzing with saturated aqueous NH4Cl (150 ml), brought to pH 4 using 1 n HCl solution, then extracted 3 times with CH2Cl2, dried, evaporated, and then filtered on silica (solvent 50 CH2Cl2the ethyl acetate). Obtain 3.5 g of the expected product (yellow solid). So pl. =opaganda system - 1598-1542-1492 cm-1< / BR>
+ aromatics

+ amide 11.

EXAMPLE 7: 2-butyl 1-((2'-(((((cyclohexylmethyl)amino)carbonyl) amino)sulfonyl)(1,1'-biphenyl)-4-yl)methyl)-4-methylthio-alpha-oxo - 1H-imidazole-5-acetic acid.

Injected 2.8 g obtained in example 6 product in 100 ml of ethanol. Then added at room temperature, 15 ml of 2 n NaOH. The ethanol is evaporated and add 50 ml of water. The aqueous phase is extracted three times with simple ether, and then at a temperature of 0oC is acidified using 1 n HCl. Filtered, dried, and recrystallized from anhydrous ethanol in the hot condition and receive 2 g of the expected product.

Microanalysis of C31H38N4O6S21H2O

calculated C of 57.8; H equal to 6.05; N 8,7; S 9,9

with 1 molecule of H2O

found C 58,0; H 5,9; N 8,6; S 9,9

calculated without molecules H2O C 59,42; H 6,07; N 8,95; S 10,22

EXAMPLE 8: 4'-((2-butyl-5-((methylsulfinyl)acetyl)-4-(methylthio) 1H-imidazol-1-yl)methyl)-N-((propylamino)carbonyl)(1,1'-biphenyl) 2-sulfonamide).

Enter to 3.52 g of 50% NaH in oil, cleaned NaH its oil 3 consecutive washings with pentane. Then dried. Add 42 cm3anhydrous dimethyl sulfoxide, bring the mixture up to 75oC for about 1 hour, then the OHL is rufuran and added dropwise 12 g of 2-butyl-H-(methylthio)-1-[[2'-((((propylamino)carbonyl)amino) sulfonyl)(1,1'-biphenyl)-4-yl] methyl] -1H-imidazole-5-ethylcarboxylate, dissolved in 80 cm3anhydrous tetrahydrofuran. Bring to room temperature and left under stirring for about 1 hour. Then the reaction mixture is poured into 400 cm3distilled water and acidified to pH 2 with 2 n hydrochloric acid. Extracted with 3 times 200 cm3chloride methylene and the organic phase is washed 1 time 200 cm3a saturated solution of NH4Cl and 2 times 200 cm3with distilled water.

The organic phase is dried, filtered and concentrated to dryness. Is infilled simple isopropyl ether, and then purified on silica with eluent: CH2Cl2-methanol (95-5), is infilled in simple Seafire and get 8,93 g of expected product (white powder).

Microanalysis

calculated % C 55,61; H of 5.99; N 9,27; S 15,9; O 13,23

found % C of 55.5; H 5,9; 9,2 N; S 16,0; O -

Range IR: CHCl3< / BR>
NH - -3370 cm-1affiliate

> = 0 - 1710-1635 cm-1< / BR>
EXAMPLE 9: 4'-((2-butyl-5-(2-methylsulfinyl)acetyl)-4- (methylthio)-1H-imidazol-1-yl)methyl)-N-(((phenylmethyl)amino) carbonyl)(1,1'-biphenyl)-2-sulfonamide.

Administered 400 mg of the product obtained in Preparation 4, step A, 162 mg K2CO3and 10 cm3anhydrous acetone. This mixture is roughly 1 hour, evaporate the acetone and absorb the remainder of NH4Cl to pH 6-7. Extracted with 3 times 50 cm3CH2Cl2and washed with 2 times 50 cm3water, then dried, filtered and concentrated to dryness. Absorb in CH2Cl2and purified on silica with allanton: CH2Cl2-methanol (93-7). Obtain 240 mg of the expected product.

Range IR: CHCl3< / BR>
= C-NH- - 3375 cm-1< / BR>
> = 0 - 1710-1637 cm-1< / BR>
aromatics - 1541-1498 cm-1< / BR>
+ amide 11

> S ---> 0 - 1044 cm-1< / BR>
EXAMPLE 10: 2-butyl-4-(methylthio) - alpha-oxo-1-((2'- (((((phenylmethyl)amino)carbonyl)amino)sulfonyl)(1,1'-biphenyl) 4-yl)methyl)-1H-imidazole-5-acetic acid.

Stage A: 2-butyl-4-(methylthio) - alpha-oxo-1-[(2'- (((((phenylmethyl)amino)carbonyl)amino)sulfonyl)(1,1'- biphenyl)-4-yl)methyl] -1H-imidazole-5-atantic-5-methyl.

Enter 1.4 g obtained in Preparation 4 product 560 mg K2CO3, is dissolved in 35 cm3acetone, the mixture is brought to reflux temperature of acetone and add 500 ál benzylisothiocyanate. Left under stirring for approximately 1/2 hour to evaporate the acetone, absorb balance at 30 cm3water, adjusted to pH 6-7 using a saturated solution of ammonium chloride. Extracted water the new water then dried, filtered and concentrated to dryness. After thickening in simple ethyl ether get 1,67 g of yellow powder, which was recrystallized from 50 cm3ethyl acetate warm, filtered, concentrated to a minimum of ethyl acetate and crystallized at room temperature. Centrifuged crystals and dried. Get 1,02 g of the expected product (yellow crystals) So pl. = 145oC.

Stage b: 2-butyl-4-(methylthio) - alpha-oxo-1-((2'-(((((phenylmethyl) amino)carbonyl)amino sulfonyl)(1,1'-biphenyl)-4-yl)methyl) 1H-imidazole-5-acetic acid.

Enter 990 mg obtained at the stage And the product dissolved in 20 cm3ethanol and 20 cm32 n NaOH. Left under stirring at room temperature for about 1/4 hour, then evaporated ethanol and absorb the residue in 50 cm3distilled water, the solution acidified to pH 6-7 using 2n HCl. Drain the formed precipitate, washed with distilled water, then dried at 80oC. For purification is dissolved in a hot condition in a minimum amount of ethanol, filtered and recrystallized at room temperature. The crystals are centrifuged, dried and receive 473 mg of the expected product. So pl. = 208oC.

Spec is ka

amide 11.

EXAMPLE 11: 2-butyl-4-(methylthio) - alpha-oxo-N-(phenylmethyl)-1- ((2'-(((((phenylmethyl)amino)carbonyl)amino)sulfonyl)(1,1'- biphenyl)-4-yl)methyl)-1-h-imidazole 5-ndimethylacetamide.

Stage A: 1-[(2'-(aminosulfonyl)(1,1'-biphenyl)-4-yl) methyl]-2-butyl-4-(methylthio) - alpha-oxo-N-(phenylmethyl) 1H-imidazole-5-ndimethylacetamide.

Mix 503 mg) obtained in Preparation 4 product, 530 μl of benzylamine (> 99%) and 6 cm3of toluene. The mixture is brought to reflux temperature of toluene under stirring for about 15 minutes, then evaporated toluene. The residue is absorbed in 50 cm3ethyl acetate and washed with this organic phase is 2 times 50 cm3distilled water, 1 in every 50 cm3saturated NaCl. Dry, filter and concentrate to dryness. Purify on silica with allanton: ethyl acetate-cyclohexane (1-1) and obtain 410 mg of the expected product (yellow foam).

Range IR: CHCl3< / BR>
NH/NH2- 3425 cm-1complex - 3345 cm-1< / BR>
> = 0 - 1682-1614 cm-1< / BR>
Conjugated system.

+ aromatics - 1526-1498 cm-1< / BR>
+ amide 11

+ NH2< / BR>
Stage B: 2-butyl-4-(methylthio) - alpha-oxo-N-(phenylmethyl) 1-((2'-(((((phenylmethyl)amino)carbonyl)amino)sulfonyl) (1,1'-biphenyl)-4-yl)methyl)-1H-it is oraut 10 cm3of acetone. Brought to the reflux temperature of acetone and add 88 μl benzylisothiocyanate (99%). Left under stirring for approximately 1 hour. Evaporate the acetone and absorb the residue in 50 cm3chloride methylene and washed 1 time 20 cm3a saturated solution of NH4Cl, 1 times 20 cm3of distilled water. The organic phase is dried, filtered and concentrated to dryness.

Is infilled in cyclohexane, centrifuged and dried. For cleaning dissolved in hot condition in a minimum amount of methanol, filtered and concentrated, then left for crystallization at room temperature and receive 75 mg of the expected product. So pl. = 194oC.

Range IR: CHCl3< / BR>
= C-NH- - - 3390 cm-1< / BR>
> = 0 - 1713-1665-1623 cm-1< / BR>
amide 11 - 1535-1497 cm-1< / BR>
aromatics

heteroaromatic

EXAMPLE 12: 2-butyl-4-(methylthio)beta-oxo-1-((2'-(((((propylamino) carbonyl)amino)sulfonyl)(1,1'-biphenyl)-4-yl)methyl)-1H-imidazol-5 - ethylpropane.

Stage A: obtain the potassium salt of ethylmalonate

< / BR>
According to the method of R. E. Strube (Organic Syntheses Coll, volume IV, 1963, 417), the modified g Bran. et M. Vieas (Bull.Soc.Chim, 1964, 945), dissolve 80 g of ethylmalonate in 50 ml of ethanol 100 and cooled. Then added dropwise who="ptx2">

Then centrifuged precipitate and rinse simple ether. Dried and obtain 61 g of the expected salt of potassium (white crystals).

Stage B: getting carboxylic acid

To a suspension 1,088 g of 2-butyl-4-(methylthio)-1-[[2'- ((((propylamino)carbonyl)amino)sulfonyl)(1,1'-biphenyl)-4 - yl]-methyl]-1H-imidazole-5-carboxylic acid, obtained as described in EP 0503162, in 44 ml of anhydrous toluene added to 2.2 ml of re-distilled chloride tiomila.

Stirred for about 1 hour at room temperature, then overnight at 55oC. to Evaporate the toluene and excess chloride tonila, absorb with 30 ml of toluene and evaporated again (3 times), then dried for approximately 2 hours at 50oC.

Stage C: condensation.

Enter 714 mg obtained at the stage of A product, dissolved in 12 ml of ethyl acetate. Cool until about 4 or 5oC and gain of 1.062 g of triethylamine, then 656 mg of anhydrous magnesium chloride.

The mixture is brought gradually to the 35oC ( 1oC) and maintain at this temperature for about 6 hours under stirring.

Again cooled to about 2oC, then add obtained at the stage In Haran is one tetrahydrofuran, then bring to room temperature, then incubated with stirring over night.

Cooled to a temperature below the 5oC, and then added dropwise 14 ml of 1 n HCl. Decanted, extracted 3 times with ethyl acetate, washed with water and brine, dried and evaporated solvents.

Purify on silica with allanton: CH2CL2-ethyl acetate (8-2) + 0.5% methanol and receive 757 mg of the expected product. So pl. = 193-195oC.

Range IR: CHCl3< / BR>
=C-NH- - 3375 cm-1complex

> = 0 - 1730-1706 cm-1- 1632 cm-1(conjugated ketone)

amide 11 - 1540 cm-1< / BR>
EXAMPLE 13: 2-butyl-4-(methylthio)-1-((2'-(((((propylamino) carbonyl)amino)sulfonyl)(1,1'-biphenyl)-4-yl)methyl)-N-(1H - tetrazol-5-yl)-1H-imidazol-5-carboxamide.

Enter 900 mg of 2-butyl-4-(methylthio)-1-[[2'-(((((propylamino) carbonyl)amino)sulfonyl)(1,1'-biphenyl)-4-yl]methyl] 1H-imidazole-5-carboxylic acid, described in EP 0503162, recrystallized from isopropanol, then suspended in 10 ml of toluene. Add 1 ml of chloride tiomila SOCl2and stirred for 1 hour at room temperature, and then 15 hours at 55oC. the Solvent is evaporated. Absorb toluene for several techniques to remove all SOCl2.

Filtered and dried, yielding 180 mg of expected product (white solid). So pl. = 130oC.

Range IR: CHCl3< / BR>
The region of OH-NH, fast absorption with NH

> = 0 - 1697-1640 cm-1< / BR>
amide 11 - 1570 cm-1< / BR>
C = N

NH2< / BR>
EXAMPLE 14: 4-(methylthio)-1-((2'-((((propylamino)carbonyl)amino) sulfonyl)(1,1'-biphenyl)-4-yl)methyl)-2-(propylthio) -1H-imidazol-5-ethylcarboxylate.

Stage A: 4-(methylthio)-1-((2'-sulfonamide-(1,1'-biphenyl)-4-yl) methyl)-3-(propylthio)-1H-imidazol-5-ethylcarboxylate.

Injected at room temperature 5.49 g obtained in Preparation 6 product, 100 cm3ethanol and 50 cm337% fuming HCl. Heated under reflux for 1 hour, alkalinized environment 32% alkaline sodium, ethanol is evaporated, extracted with 3 times 300 cm3CH2Cl2, washed with 2 times 30 cm, the ATEM crystallization of simple ether product is centrifuged, washed with simple ether and receive 2,32 g of the expected product. So pl. = 113oC.

Range IR: CHCl3.

SO2NH2- 3440-3340 cm-1< / BR>
>= 0 - 1686 cm-1< / BR>
Stage B: 4-(methylthio)-1-((2'-((((propylamino)carbonyl) amino)sulfonyl) (1,1'-biphenyl) 4-yl)methyl)-2-(propylthio) 1H-imidazole-5-ethylcarboxylate.

Injected at room temperature, 200 mg, obtained in stage A product, 4 cm3acetone and 109 mg K2CO3. Heated to reflux temperature and type of 0.06 cm3propresident, stirred at reflux temperature for approximately 15 minutes.

TECH eluant: ACOEt-CH2Cl2(3-7). Ultraviolet spectrum.

Add approximately 5 cm3solution saturated with ions NH4+Cl-and 10 cm3water, extracted with 2 times 50 cm3CH2Cl2washed 2 times with 20 cm3water, dried, filtered and evaporated. Dissolve approximately 20 cm3simple ether, filtered while hot, concentrated to approximately 3 cm3leave for crystallization at room temperature, drain the simple ether and dried at kom o
C.

Range IR: CHCl3< / BR>
= C-NH - 3404-3365 cm-1< / BR>
> = 0 - 1710-1685 cm-1< / BR>
conjugated system + - 1614-1592-1538-1500 cm-1< / BR>
aromatics +

amide 11 +

EXAMPLE 15: 4-(methylthio)-1-((2'-(((((phenylmethyl)amino)carbonyl) amino)sulfonyl)(1,1'-biphenyl)-4-yl)methyl)- 2-propyl-N-(2H-tetrazol-5-yl)-1H-imidazol-5-carboxamide.

Stage A: 4-(methylthio)-2-[(2'-(((((phenylmethyl)amino) carbonyl)amino)sulfonyl)(1,1'-biphenyl)-4-yl)methyl] -2 - propyl-1H-imidazole-5-ethylcarboxylate.

Enter 2 r obtained in Preparation 5 product dissolved in 25 ml of anhydrous acetone and 1.2 g of potassium carbonate, is Brought to reflux temperature and add 740 μl benzylisothiocyanate. After approximately 2 hours of stirring is cooled to room temperature, subjected to hydrolysis using a saturated aqueous solution of NH4Cl, then extracted with methylene chloride. Dried, recrystallized from simple ether, filtered and gain of 1.9 g of the expected product.

Stage B: 4-(methylthio)-1-[(2'-(((((phenylmethyl)amino) carbonyl)amino)sulfonyl)(1,1'-biphenyl)-4-yl)methyl] - 2-propyl-1H-imidazole-5-carboxylic acid.

Enter 1.8 g obtained at the stage of A product in 10 ml ethanol and 10 ml of 2 n caustic sodium, then ostavlyala supplements 25 ml water, the aqueous phase is extracted with simple ether, then filtered, adjusted to a temperature of 0oC and slowly acidified to pH 15 using 1 n HCl. Filtered and dried, yielding 1.4 g of the expected product.

Range IR: CHCl3< / BR>
Sour after the field OH

= C-NH - 3480 cm-1< / BR>
> = 0 - 1706 - 1690 cm-1complex

aromatics - 1539-1521-1500 cm-1< / BR>
heteroaromatic

amide 11

Stage C: 4-(methylthio)-1-((2'-(((((phenylmethyl) amino)carbonyl)amino)sulfonyl)(1,1'-biphenyl)-4-yl)methyl) 2-propyl-N-(2H-tetrazol-5-yl)-1H-imidazol-5-carboxamide.

Enter 270 mg) obtained in stage B of the product in 5 ml of toluene and 300 ál SOCl2(chloride taanila), then stirred for approximately 1 hour at room temperature, then about 15 hours at 55oC. the Solvent is evaporated, SOCl2removed in vacuum. The obtained acid chloride are suspended in 3 ml of anhydrous tetrahydrofuran, and then it is introduced into 10 ml of anhydrous tetrahydrofuran containing 150 mg of aminotetrazole and 150 μl of pyridine. Stirred for approximately 20 hours at room temperature. Then the solution is subjected to hydrolysis using a saturated aqueous solution of NH4Cl and extracted 3 times with CH2Cl2. After drying and evaporation of rastafaray high pressure reverse phase with allanton: MeOH-H2O (60-40) with NH4+AcO-0,05 M Product is recrystallized from MeOH receive 70 mg of the expected product.

So pl. = 228oC.

NMR (dimethylsulfoxide)

0,98 (t) CH3< / BR>
1,69 (m) CH2< / BR>
2,75 (m) CH2-

2,46 (C) SMe

4,0 (d,s after exchange)

of 5.53 (C) NCH2ph

PC 6.82 (2H)

? 7.04 BABY MORTALITY (2H)

7,17 (7-8H)

7,56 (m) 2H

of 8.04 (DD) 1H

< / BR>
MH+= 646.

EXAMPLE 16: 2-butyl-1-((2'-(((((cyclohexylmethyl)amino)carbonyl) amino)sulfonyl)(1,1'-biphenyl)-4-yl)methyl)-4-(methylthio) - alpha-oxo - 1H-imidazol-5-ndimethylacetamide.

Give 250 mg of the product of example 6 in 5 ml of anhydrous ethanol and 90 mg of ammonium acetate NH4The OAc. Maintained at the reflux during the night, hydrolyzing with aqueous solution of NH4Cl and extracted with ethyl acetate. After drying and evaporation of purified on silica with allanton: ACOEt-CH2Cl2(50-50), then recrystallized from CH2Cl2and minimum number of simple itapira and obtain 65 mg of the expected product.

Range IR: CHCl3< / BR>
NH/NH2- 3510-3400 cm-1< / BR>
>= 0 - 1708-1690 -/ 1622 cm-1< / BR>
conjugated system - 1560-1552-1490 cm-1< / BR>
aromatics

NH, NH2< / BR>
EXAMPLE 17: 2-butyl-1-((2'-(((((collagen-imidazole-5-acetic acid.

Act as in example 16, by introducing 250 mg of the product of example 7, in 10 ml of absolute ethanol and 150 mg of 2,4-dinitrophenylhydrazine. Support with phlegm for about 5 hours under stirring and obtain 160 mg of the expected product.

So pl. = 254oC.

Range IR: vaseline oil.

The total absorption OH/NH.

>=0 - 1706-1668-1652 cm-1< / BR>
C=N

Conjugated system - +1618-1590-1518-1501 cm-1< / BR>
aromatics +

amide 11 +

NO2< / BR>
EXAMPLE 18: 2-butyl-alpha-((2,4-dinitrophenyl)hydrazono)-4- (methylthio)-1-((2'-(((((phenylmethyl)amino)carbonyl)amino) sulfonyl)(1,1'-biphenyl)-4-yl)methyl)-1H-imidazole-5-acetic acid.

Administered 100 mg of the product of example 10 in 5 ml of ethanol and 48 mg of 2,4-dinitrophenylhydrazine. Support when the phlegm is approximately 6 hours with stirring, then cooled, filtered and receive 50 mg of the expected product. So pl. = 252oC.

Microanalysis: C37H36N8O9S2M=543

calculated % C of 55.5; H 4.5; N 14,0; S 8,0

found % C 55,3; H 4,3; N 13,7; S 8,3

EXAMPLE 19: 4-(methylthio)-1-((2'-((((propylamino)carbonyl) amino)sulfonyl)(1,1'-biphenyl)-4-yl)methyl)-2-(propylthio)-1H - imidazole-5-carboxylic acid.

Enter at room temperatur at room temperature for 24 hours.

Tetrahydrofuran is evaporated, add 10 cm3water, acidified to pH 5-6 using acetic acid, extracted with 3 times 80 cm3CH2Cl2, dried, filtered and evaporated. Crystallized from 20 cm3the ethyl acetate, 5 cm3MeOH (warm 40oC), filtered, concentrated to approximately 10 cm3leaving to crystallize, dried, washed with ethyl acetate, then a simple ether and dried at room temperature. Obtain 183 mg of the expected product. So pl. = 195oC.

Range IR: vaseline oil.

The area HE/NH max - 3340 cm-1+ full absorption

>= 0 - 1664 cm-1complex

aromatics - 1592-1552-1504-1483 cm-1< / BR>
heteroaromatic

amide 11 +

EXAMPLE 20: 4'-((4-(methylthio)-5-(2-(phenylsulfonyl) acetyl)-2-propyl-1H-imidazol-1-yl)methyl)-N-(((phenylmethyl)amino) carbonyl)(1,1'-biphenyl)-2-sulfonamide.

Cooled to 0oC 203 mg phenylmethylsulfonyl and 440 mg of ester obtained as in example 15, stage A. Add 3.6 cm3lithium bis(trimethylsilyl)amide in 1 minute. Stirred for 15 minutes at 0oC, bring to room temperature, soak 15 minutes, add 10 cm3saturated water rusty organic extracts, dried and the solvent evaporated. After chromatography of the residue on silica (eluant: CH2-MeOH 90-10) are 356 mg of crude product which is dissolved in methylene chloride, then add a simple isopropyl ether, cooled to -78oC, dissolve the residue in warm acetonitrile and receive 250 mg of the expected crystallized product.

Range IR: CHCl3< / BR>
NH - 3300 cm-1< / BR>
C=0 - 1708-1636 cm-1< / BR>
Conjugated system

aromatics - 1587-1540-1497 cm-1< / BR>
amide 11

S ---> 0 - 1038 cm-1.

Working as in example 15, step B, and C, based on the product obtained in example 15A (or similar products obtained by the same method), and the corresponding reagents, receive the following products:

EXAMPLE 21: 2-butyl-4-(methylthio)beta-oxo-1-((2'- (((((phenylmethyl)amino)carbonyl)amino)sulfonyl)(1,1'-biphenyl) 4-yl)methyl)-1H-imidazol-5-ethylpropane.

So pl. = 173-175oC.

Rf= 0,35 (CH2Cl2- ACOEt).

EXAMPLE 22: 2-butyl-4-(methylthio)beta-oxo-1-((2'- (((((phenylmethyl)amino)carbonyl)amino)sulfonyl)(1,1'- biphenyl)-4-yl)methyl)-1H-imidazol-5-methylpropanoate.

So pl. = 170oC

Rf=0,85 (CH2Cl2- MeOH 90-10).

So pl. 110oC.

Rf0,67 (CH2Cl2-MeOH 90-10).

EXAMPLE 24: 4'-((2-butyl-4-(methylthio)-5-(3-phenyl-1,3 - disopropyl)-1H-imidazol-1-yl)methyl)-N-(((phenylmethyl)amino) carbonyl)(1,1'-biphenyl)-2-sulfonamide.

So pl. 180oC.

Rf= 0,4 (CH2Cl2-MeOH 97-3)

EXAMPLE 25: 4'-((4-((deformity)thio)-5-((phenylsulfonyl) acetyl)-2-propyl-1H-imidazol-1-yl)methyl)-N-(((phenylmethyl)amino) carbonyl)(1,1'-biphenyl)-2-sulfonamide.

So pl. 103oC.

Rf=0,25 (ACOEt-cyclohexane 8-2).

EXAMPLE 26: 4-(methylthio)-1-((2'-(((((phenylmethyl)amino) carbonyl)amino)sulfonyl)(1,1'-biphenyl)-4-yl)methyl)-2-propyl - 1H-imidazol-5-carboxamide.

So pl. = 112oC.

EXAMPLE 27: 2-butyl-4-(methylthio)-1-((2'-((((propylamino) carbonyl)amino)sulfonyl)(1,1'-biphenyl)-4-yl)methyl)-1H - imidazole-6-carboxamide.

So pl. 90oC.

Rf= 0,45 (ACOEt).

EXAMPLE 28: 4'-((5-2-(methylsulfinyl)acetyl)-4-(methylthio) 2-propyl-1H-imidazole 1-yl)methyl)-N-(((phenyl-methyl)amino) carbonyl) (1,1'-biphenyl)-2-sulfonamide.

So pl. = 100oC.

Rf= 0,5 (CH2Cl2-MeOH 95-5).

EXAMPLE 29: 4'-((2-butyl-4-(methylthio)-5-((phenylsulfonyl) acetyl)-1H-imidazol-1-yl)methyl)-N-(((phenylmethyl) is Il)sulfanyl)acetyl) -4-(methylthio)-2-propyl-1H-imidazol-1-yl)methyl)-N-(((phenylmethyl) amino)carbonyl)(1,1'-biphenyl)-2-sulfonamide.

So pl. = 158oC.

EXAMPLE 31: 4'-((5-(((4-were)sulfinil)acetyl)-4- (methylthio)-2-propyl-1H-imidazol-1-yl)methyl)-N-(((phenylmethyl) amino)carbonyl)(1,1'-biphenyl)-2-sulfonamide.

So pl. 115oC.

EXAMPLE 32: (S) 4'-((5-(((4-were)sulfinil)acetyl)-4- (methylthio)-2-propyl-1H-imidazol-1-yl)methyl)-N-(((phenylmethyl) amino)carbonyl)(1,1'-biphenyl)-2-sulfonamide.

So pl. = 109oC (C = 0,5 CHCl3).

Rf= 0,40 (ACOEt-hexane 80-20).

EXAMPLE 33: 4'-((5-(cyanoacetyl)-4-(methylthio)-2-propyl-1H - imidazol-1-yl)methyl)-N-(((phenylmethyl)amino)carbonyl)(1,1'- biphenyl)-2-sulfonamide.

So pl. = 190-193oC.

Rf= 0,20 (ACOEt-hexane 60-40).

EXAMPLE 34: 4'-((4-(methylthio)-5-((phenylsulfonyl)acetyl) 2-propyl-1H-imidazol-1-yl)methyl)-N-(((2-thienylmethyl)amino) carbonyl)(1,1'-biphenyl)-2-sulfonamide.

So pl. = 200oC.

Rf= 0,37 (CH2Cl2-ACOEt 60-40).

EXAMPLE 35: 4'-((2-butyl-5-(2-methylsulphonyl)acetyl) 4-(methylthio)-1H-imidazol-1-yl)methyl)-N-((propylamino)carbonyl) (1,1'-biphenyl)-2-sulfonamide.

So pl. = 159oC.

Rf= 0,17 (CH2Cl2-ACOEt 80-20).

EXAMPLE 36: 4'-((2-butyl-4-(methylthio)-5-(2-(phenylsulfonyl) acetyl)-1H-imidazol-1-yl)methyl)-N-(((phenyl is 2-(methylsulphonyl)acetyl) 4-(methylthio)-1H-imidazol-1-yl)methyl)-N-(((phenylmethyl)amino) carbonyl)(1,1'-biphenyl)-2-sulfonamide.

So pl. = 116oC.

Rf= 0,43 (CH2Cl2-MeOH 96-4).

EXAMPLE 38: 4'-((2-butyl-5-((1-((4-methoxyphenyl)methyl)-1H tetrazol-5-yl)acetyl)-4-(methylthio)-1H-imidazol-1-yl)methyl)-N- (((phenylmethyl)amino)carbonyl)(1,1'-biphenyl)-2-sulfonamide.

So pl. = 185oC.

Rf= 0,25(CH2Cl2-MeOH 97-3).

EXAMPLE 39: 4'-((2-butyl-5-((4-methoxyphenyl)(5-methyl)-2H - tetrazol-2-yl)acetyl)-4-(methylthio)-1H-imidazol-1-yl)methyl)-N- (((phenylmethyl)amino))carbonyl-(1,1'-biphenyl)

2-sulfonamide.

So pl. = 215oC.

Rf= 0,38 (CH2Cl2-ACOEt-70-30).

EXAMPLE 40: 4'-((2-butyl-4-(methylthio)-5-(2-phenylsulfonyl) acetyl)-1H-imidazol-1-yl)methyl)-N-(((phenylmethyl)amino)carbonyl) (1,1'-biphenyl)-2-sulfonamide.

So pl. = 191oC.

Rf= 0,16 (ACOEt - cyclohexane 5-5).

EXAMPLE 41: 4'-((2-butyl-5-((4-forfinal)sulfanyl)acetyl)-4- (methylthio)-1H-imidazol-1-yl)methyl)-N-(((phenylmethyl)amino) carbonyl)(1,1'-biphenyl)-2-sulfonamide.

So pl. = 129oC.

Rf= 0,3 (ACOEt-cyclohexane 5-5).

EXAMPLE 42: 4'-((2-butyl-4-((deformity)thio)-5-((phenylsulfonyl) acetyl)-1H-imidazol-1-yl)methyl)-N-(((phenylmethyl)amino)carbonyl) (1,1'-biphenyl)-2-sulfonamide.

So pl. 95-100oC.

So pl. 190oC.

EXAMPLE 44: 4'-((2-ethyl-5-((methylsulphonyl)acetyl)-4-methylthio) 1H-imidazol-1-yl)methyl)-N-(((phenylmethyl)amino)carbonyl) (1,1'-biphenyl)-2-sulfonamide.

So pl. = 180oC.

Rf0,37 (CH2Cl2-ACOEt-MeOH 6-4-0,05).

EXAMPLE 45: 4'-((2-ethyl-4-(methylthio)-5-((phenylsulfonyl)acetyl) -1H-imidazol-1-yl)methyl)-N-(((phenylmethyl)amino)carbonyl) (1,1'-biphenyl)-2-sulfonamide.

So pl. = 228oC.

Rf= 0,3 (ACOEt-hexane 80-20).

EXAMPLE 46: () N-(((cyclopentylmethyl)amino)carbonyl)- 4'-((4-methylthio)-5-((phenylsulfonyl)acetyl)-2-propyl-1H-imidazol - 1-yl)methyl)(1,1'-biphenyl)-2-sulfonamide.

So pl. 106oC

Rf= 0,5 (CH2Cl2-ACOEt 6-4).

EXAMPLE 47: () N-(4'-((4-methylthio)-5-((phenylsulfonyl) acetyl)-2-propyl-1H-imidazol-1-yl)methyl)(1,1'-biphenyl-2-yl) sulfonyl)cyclopentanepropionate.

So pl. 95oC.

Rf=0,7 (CH2Cl2-ACOEt 6-4).

EXAMPLE 48: () N-(((cyclohexylmethyl)amino)carbonyl) 4'-((4-(methylthio)-5-((phenylsulfonyl)acetyl)-2-propyl-1H - imidazol-1-yl)methyl)(1,1'-biphenyl)-2-sulfonamide.

So pl. 90/95oC.

Rf= 0,4 (CH2Cl2-ACOEt 8-2).

EXAMPLE 49: 4'-((5-acetyl-2-butyl-4-(methylthio) -1H-imidazol-1-ifira.

Working as in example 20, but on the basis of 1-((2'-(amino - sulfonyl-1,1'-biphenyl)-4-yl)methyl)-4-(methylthio)-2-butyl - 1H-imidazol-5-ethylcarboxylate obtained in Preparation 5, but using the analogue 2-propyl lithium bis-(tri-methylsilyl)amide and dimethyl sulfoxide, get sulfoxide derivative with a yield of 70%.

b) Desulfuricans.

To 300 mg obtained at the previous stage of the product added 220 mg of zinc and a solution of 7 cm3ammonium chloride in 10 cm3of ethanol. Stirred for 48 hours at room temperature, filtered, washed with ethyl acetate, extracted with methylene chloride, the solvent is evaporated under reduced pressure and get acylated derivative with a yield of 80%.

(C) Condensation.

Heated 1 hour at a temperature of phlegmy obtained in the previous phase of the product with 2 equivalents of potassium carbonate and 1.2 equivalents cyclohexylethylamine in acetone. Leave to return to room temperature, the solvent is evaporated, absorb the residue in dichloromethane, washed with aqueous solution of 1 n hydrochloric acid, dried and concentrated under reduced pressure. After recrystallization from ethanol obtain the target product with a yield of 60%.


EXAMPLE 50: 2-butyl-4'-((4-methylthio)-5-((1H-tetrazol-5-yl) carbonyl)-1H-imidazol-1-yl)methyl)-(((phenylmethyl) amino)carbody)(1,1'-biphenyl)-2-sulfonamide.

Rf= 0,3 (CH2Cl2-MeOH 80-20).

EXAMPLE 51: N-(((cyclohexylmethyl)amino)carbonyl)-4'- ((2-ethylthio)-5-(2-(methylsulfinyl)acetyl)-4-(methylthio)-1H - imidazol-1-yl)methyl)(1,1'-biphenyl)-2-sulfonamide.

So pl. 180oC.

EXAMPLE 52: 2-butyl-4-(methylthio)-N-pentyl-1-((2'- ((((((phenylmethyl)amino)carbonyl)amino)sulfonyl) (1,1'- biphenyl)-4-yl)methyl)-1H-imidazol-5-carboxamide.

So pl. = 138oC.

Rf= 0,25 (ACOEt-cyclohexane 5-5).

EXAMPLE 53: 4'-((2-butyl-4-(methylthio)-5-(1-oxo-2- (phenylsulfonyl)pentyl-1H-imidazol-1-yl)methyl)-N-(((phenylmethyl) amino)carbonyl)(1,1'-biphenyl)-2-sulfonamide.

So pl. = 162oC.

Rf=0,34 (t-cyclohexane 5-5).

EXAMPLE 54: 4'-((2-butyl-4-(methylthio)-5-((1,1-dioxido - tetrahydro-2-thienyl)carbonyl)-1H-imidazol-1-yl)methyl)-N- (((phenylmethyl)amino)carbonyl)(1,1'-biphenyl)-2-sulfonamide.

Rf= 0,23 (CH2Cl2-AcOEt 85-15).

EXAMPLE 55: 2-ethyl-4-(methylthio)-1-((2'-(((((fenilmetilketil) amino)carbonyl)amino)sulfonyl)(1,1'-biphenyl)-4-yl) methyl)-1H-imidazol-5-Carbo is 6: 2-butyl-4-(methylthio)beta-oxo-1-((2'- ((((phenylmethoxy)carbonyl)amino)sulfonyl)(1,1'-biphenyl)-4 - yl)methyl)-1H-imidazole-5-ethyl-propanoate (potassium salt).

So pl. = 130oC

Rf0,5 (CH2Cl2-AcOEt 60-40).

EXAMPLE 57: 2-butyl-4-(methylthio)beta-oxo-1-((2'- ((((phenylmethyl)carbonyl)amino)sulfonyl)(1,1'-biphenyl)-4-yl) methyl)-1H-imidazol-5-ethylpropane.

So pl. = 110oC.

Rf0,38 (CH2Cl2-MeOH 98-2).

EXAMPLE 58: 4'-((2-butyl-5-(3-cyclohexylmethyl-2,4-dioxo - 5-(trifluoromethyl)-5-oxazolidinyl)-4-(methylthio)-1H-imidazol - 1-yl)methyl-N-(((cyclohexylmethyl)amino)carbonyl)(1,1'- biphenyl)-2-sulfonamide.

Rf= 0,50 (CH2Cl2-MeOH 99-1).

EXAMPLE 59: 4'-((2-butyl-5-(2-(1,1-dimethylethyl)-4-methyl - 5-oxo-1,3-dioxolane-4-yl)-4-(methylthio)-1H-imidazol-1-yl)methyl-N- (((cyclohexylmethyl)amino)carbonyl)(1,1'-biphenyl)-2-sulfonamide.

Rf=0,40 (AcOEt-hexane 60-40).

Working as in example 15, step B from the corresponding complex ester receive the following products:

EXAMPLE 60: 4-(butylthio)alpha-oxo-/1-((2'-(((((phenylmethyl) amino)carbonyl)amino)sulfonyl) (1,1'-biphenyl)-4-yl) methyl)-2-propyl-1H-imidazole-5-acetic acid.

So pl. = 192oC.

Rf=0.36 AND (CH2Cl2-MeOH 80-20).

EXAMPLE 61: 1-((2'-(((((cyclohexylmethyl)amino)carbonyl) amino)sulfonyl)(1,1'-biphenyl)-4-yl)methyl)-2-ethyl-4-(methylthio - Meon 90-10).

Working as described in example 49 stage b), obtain the following connection:

EXAMPLE 62: 4'-((4-methylthio)-5-(phenylacetyl)-2-propyl-1H - imidazol-1-yl)methyl)-N-(((phenylmethyl)amino)carbonyl)(1,1'- biphenyl)-2-sulfonamide.

So pl. = 140oC.

RfOR = 0.6 (CH2Cl2-AcOEt 60-40).

Heating when the phlegm obtained in example 38 compound in triperoxonane acid get the following connection:

EXAMPLE 63: 4'-((2-butyl-4-(methylthio)-5-((1H-tetrazol-5 - yl)acetyl)-1H-imidazol-1-yl)methyl)-N-(((phenylmethyl)amino) carbonyl)(1,1'-biphenyl)-2-sulfonamide.

So pl. = 170oC.

Rf= 0,15 (CH2Cl2-MeOH 90-10).

The following products were obtained according to the above operating conditions.

EXAMPLE 64: 4'-((4-(methylthio)-5-(2-(phenylthio)acetyl)-2 - propyl-1H-imidazol-1-yl)methyl)-N-(((phenylmethyl)amino)carbonyl) (1,1'-biphenyl)-2-sulfonamide.

So pl. = 178oC.

Rf= 0,55 (CHCl3-MeOH 95-5).

EXAMPLE 65: 4'-((5-acetyl-4-(methylthio)-2-propyl-1H-imidazol-1-yl)methyl) -N-(((phenylmethyl)amino)carbonyl)(1,1'-biphenyl)-2-sulfonamide

So pl. = 200-202oC.

Rf= 0,4 (CHCl3-MeOH 98-2).

EXAMPLE 66: pharmaceutical composition.


(excipient: lactose, talc, starch, magnesium stearate).

PHARMACOLOGICAL TESTS

1) Test with the receptor AT1angiotensin 11.

Using freshly preparation of membranes derived from rat liver. The fabric is crushed into Polytron in a buffer solution of Tris 50 mmol, pH of 7.4, and then perform 3 centrifugation at 30 000 g for 15 minutes with intermediate extraction precipitation buffer solution Tris pH 7,4.

Recent sediments suspended in incubation buffer solution (Tris 20 mmol NaCl 135 mmol, KCl 10 mmol, glucose 5 mmol, MgCl2135 mmol, PMSF 0.3 mmol, bacitracin 0.1 mmol, secrete lysozyme 0.1 percent). Distribute aliquot part 1 ml in glass vials and injected125I angiotensin 11 (25 000 DPM per tube) and the investigational product. (The product is first tested with 3 x 10-5M, three times). If the investigational product displaces more than 50% of the radioactivity specifically bound to the receptor, it is again tested in the range of 7 concentrations to determine the concentration that inhibits 50% of the radioactivity specifically bound to the receptor. In this way determine the 50% inhibitory concentration.

Nonspecific relationship is determined by the introduction of p is t, placed in a water bath at 0oC for 5 minutes, filtered under vacuum, rinsed with buffer solution Tris pH 7.4 and calculate the radioactivity in the presence of solid scintillation agent.

The result is expressed directly in terms of inhibitory concentration 50% (Cl50), i.e., the concentration of the investigated product, expressed in nm, necessary to offset 50% of the specific radioactivity fixed on the investigated receptor.

Results: the Receptor AT1< / BR>
The product of example - Cl50in nanomolar

7 - 0,7

9 - 0,3

10 - 0,18

The product of example - Cl50in nanomolar

11 - 0,6

12 - 0,2

13 - 0,24

15 - 0,2

20 - 0,08

21 - 0,08

34 - 0,05

46 - 0,4

47 - 0,09

2) Test with the receptor AT2angiotensin II.

Using freshly preparation of membranes derived from the uterus of rabbits pre-treated for 4 days before testing using 50 µg of estradiol, introduced through the skin. The fabric is crushed on Polytron in a buffer solution of Tris 50 mm, pH of 7.4, and then performed 3 centrifugation at 30 000g for 15 minutes with intermediate extraction precipitation buffer solution Tris pH 7,4.

Last sieges is B>O 10 mm, 0.3 mm PMSF, 0.1 mm bacitracin, secrete lysozyme of 0.01%, pH 7,4).

The resulting product homogenization pre-incubated for 20 minutes at 25oC in the presence of dithiothreitol 10 mm, and then brought up to 0-4oC.

Distribute aliquot part 1 ml glass test tube and add125I angiotensin II (25 000 DPM/tube) and the investigational product. The product is first tested with 3 x 10-5M three times. If the tested product displaces more than 50% of the radioactivity specifically bound to the receptor, it is again tested in the range of 7 concentrations to determine the concentration that inhibits 50% of the radioactivity specifically bound to the receptor. In this way determine the 50% inhibitory concentration of 50%.

The specific relationship is determined by the product introduction EXP 655 (=PD 123-177 Warners-Lambert) at 10-5M three times. Incubated at 25oC for 150 minutes, placed in a water bath at 0oC for 5 minutes, filtered under vacuum, rinsed with buffer solution Tris pH 7.4 and count the radioactivity in the presence of solid scintillation agent.

The result is expressed directly in terms of inhibitory concentration 50% (Cl50), i.e. concentrated on the study receptor.

Results: the Receptor AT2< / BR>
The product of example - Cl50in nanomolar

7 - 6,8

9 - 15,0 - Receptor AT2< / BR>
The product of example - Cl50in nanomolar

10 - 38,0

11 - 53,0

12 - 83,0

13 - 24,0

15 - 2,0

20 - 0,8

21 - 1,0

34 - 2,2

46 - 2,5

47 - 2,09

3) Test for antagonistic activity to angiotensin II in the rat, which seized the bone marrow.

Rats male breed Sprague-Dawley (weighing 250 - 350 g) were shot by intraperitoneal injection of pentobarbital sodium (60 mg/kg). Diastolic blood pressure is recorded by a catheter (RE) with heparin, is introduced into the left carotid artery of the animal and connected to a device for determining the pressure (Gould, Pressure Processor) using a pressure sensor Gould.

The catheter being in the right jugular vein of the animal for the introduction of the investigated compounds.

The animal is connected to the apparatus for artificial respiration. Produce bilateral incision vagi.

The rats then bone marrow.

After a period of stabilization proceed as follows to study antagonism of the compounds to angiotensin II (hypertensin, CIBA):

1. Three after toukou response in the form of a pressure.

2. Observing the frequency of 15 minutes for the introduction of angiotensin II, compounds (0.01 to 10 mg/kg) injected 5 minutes before the injection of angiotensin II.

The effects of angiotensin II on pressure in the presence of antagonist expressed in terms of percentage impact on one pressure angiotensin II. Thus determine the inhibitory dose 50% (DI50) investigated the connection.

Each animal was considered as its own control (inspection results, see table. at the end of the description).

1. Chetyrehskatnye imidazole derivatives of the formula I

< / BR>
in which R1means alkyl or alkylthio radical, linear or branched, containing not more than 4 carbon atoms;

R2means C1- C8alkylthio, possibly substituted by one or more halogen atoms, or the radical-CO-Z, in which Z denotes a carboxyl radical, free, converted into a salt or ester,

R3choose from:

a) radical , in which X represents an oxygen atom or a radical

< / BR>
in which D1and D2identical or different, denote a halogen atom or microradian, and R5means:

(i) the radical-CHY1Y2in Kotor and esterified, alkylthio, alkylsulfonyl and alkylsulfate, linear or branched, containing not more than 6 carbon atoms, or phenylthio, phenylsulfonyl or phenylsulfonyl,

(ii) the radical

in which Y3the hydroxy radical, if necessary, converted into a salt, alkoxy or alkylthio, linear or branched, containing not more than 6 carbon atoms,

(iii) if X represents an oxygen atom, R5means an amino radical, possibly substituted by tetrazolyl or one or two alkilani linear or branched, containing not more than 6 carbon atoms which may be substituted by one or more radicals phenyl or cyclohexyl; radical tetrazolyl, thienyl;

b) radical:

< / BR>
where A1is an oxygen atom or a radical NR6, R6- C1- C6alkyl or cycloalkyl, A2means the moiety C(R8)-R7where R7and R8both signify hydrogen or together form an oxo radical, R9- C1- C6alkyl or CF3;

R4means-SO2-NH2,

-SO2-N=CH-N(CH3)2,

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< / BR>
< / BR>
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< / BR>
-SO2-NH-CO2Et, -SO2-NH-CO2H, SO2-NH-CO2Pr,

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if this a many forms of enantiomers and diastereoisomers of these compounds and their salts accession mineral and organic acids or mineral and organic bases.

2. The compounds of formula I on p. 1, representing the following products:

2-butyl-1-((2'-(((((cyclohexylmethyl)amino)carbonyl)amino)sulfonyl)(1,1'-biphenyl) 4-yl)methyl) 4-(methylthio) - alpha-oxo-1H-imidazole-5-acetic acid;

2-butyl-4-(methylthio)beta-oxo-1-((2'-((((propylamino)carbonyl)amino)sulfonyl)(1,1'-biphenyl) 4-yl)methyl) 1H-imidazole-5-ethylpropane;

2-butyl-4-(methylthio) 1-((2'-(((propylamino)carbonyl)amino)sulfonyl)(1,1'-biphenyl) 4-yl)methyl) - N-(1H-tetrazol-5-yl) 1H-imidazole-5-carboxamide;

2-butyl-4-(methylthio) - alpha-oxo-1-((2'-(((((phenylmethyl)amino)carbonyl)amino)sulfonyl)(1,1'-biphenyl) 4-yl)methyl) 1H-imidazole-5-acetic acid;

4'-((2-butyl-5-(2-(methylsulfinyl)acetyl) 4-(methylthio) 1H-imidazol-1-yl)methyl) - N-(((phenylmethyl)amino)carbonyl)(1,1'-biphenyl)-2-sulfonamide;

4-(methylthio)-1-((2'-(((((phenylmethyl)amino)carbonyl)amino)sulfonyl)(1,1'-biphenyl) 4-yl)methyl) 2-propyl-N-(2H-tetrazol-5-yl) 1H-imidazole-5-carboxamide;

2-butyl-4-(methylthio) - alpha-oxo-N-(phenylmethyl) 1-((2'-(((((phenylmethyl)amino)carbonyl)amino)sulfonyl)(1,1'-biphenyl) 4-yl)methyl) 1H-imidazole-5-ndimethylacetamide;

4'-((4-(methylthio) 5-(2-(phenylsulfonyl)acetyl) 2-propyl-1H-imidazol-1-yl)methyl-N-(((phenylmethyl)amino)carbonyl)(1,1'-biphenyl) 2-sulfonamide;

2-butyl-4-(methylthio)beta-oxo-1-((2'-((((f is-((4-forfinal)sulfanyl)acetyl) 4-(methylthio) 1H-imidazol-1-yl)methyl) - N-(((phenylmethyl)amino)carbonyl)(1,1'-biphenyl)-2-sulfonamide;

2-butyl-4'-((4-methylthio) 5-((1H-tetrazol 5-yl)carbonyl) 1H-imidazol-1-yl)methyl) - N-(((phenylmethyl)amino)carbonyl)(1,1'-biphenyl)-2-sulfonamide;

4'-((2-butyl-4-(methylthio) 5-((1H-tetrazol 5-yl)acetyl) 1H-imidazol-1-yl)methyl) - N-(((phenylmethyl)amino)carbonyl)(1,1'-biphenyl)-2-sulfonamide;

4'-((4-(methylthio) 5-((phenylsulfonyl)acetyl) 2-propyl-1H-imidazol-1-yl)methyl) - N-(((2-thienylmethyl)amino)carbonyl)(1,1'-biphenyl)-2-sulfonamide;

() N-(((cyclopentylmethyl)amino)carbonyl) 4'-((4-(methylthio) 5-((phenylsulfonyl)acetyl) 2-propyl-1H-imidazol-1-yl)methyl)(1,1'-biphenyl)-2-sulfonamide

() N-(4'-((4-(methylthio) 5-((phenylsulfonyl)acetyl) 2-propyl-1H-imidazol-1-yl)methyl(1,1'-biphenyl-2-yl)sulfonyl)cyclopentanepropionate;

4'-((2-butyl-5-(2,4-dioxo-5-methyl-3-propyl-5-oxazolidinyl)-4-(methylthio) 1H-imidazol-1-yl)methyl) - N-((propylamino)carbonyl)(1,1'-biphenyl) 2-sulfonamide;

4-(methylthio)-1-((2'-((((propylamino)carbonyl)amino)sulfonyl)(1,1'-biphenyl) 4-yl)methyl) 2-(propylthio) 1H-imidazole-5-ethylcarboxylate;

2-butyl-1-((2'-((((cyclohexylmethyl)amino)carbonyl)amino)sulfonyl)(1,1'-biphenyl) 4-yl)methyl) 4-(methylthio) - alpha-oxo-1H-imidazol-5-ndimethylacetamide;

4-(methylthio)-1-((2'-((((propylamino)carbonyl)amino)sulfonyl)(1,1'-biphenyl) 4-yl)methyl) 2-(propylthio) 1H-imidazole-5-carboxylic acid;

4'-((2-butanamide;

4'-((5-(cyanoacetyl) 4-(methylthio) 2-propyl-1H-imidazol-1-yl)methyl) - N-(((phenylmethyl)amino)carbonyl) (1,1'-biphenyl) 2-sulfonamide;

4'-((2-butyl-5-((1-((4-methoxyphenyl)methyl) 1H tetrazol-5-yl)acetyl) 4-(methylthio) 1H-imidazol-1-yl)methyl) - N-(((phenylmethyl)amino)carbonyl)(1,1'-biphenyl) 2-sulfonamide;

4'-((2-butyl-5-((4-methoxyphenyl)(5-methyl) 2H-tetrazol-2-yl)acetyl) 4-(methylthio) 1H-imidazol-1-yl)methyl) - N-(((phenylmethyl)amino)carbonyl)(1,1'-biphenyl) 2-sulfonamide;

() N-(4'-((4-(methylthio) 5-((phenylsulfonyl)acetyl) 2-propyl-1H-imidazol-1-yl)methyl(1,1'-biphenyl-2-yl)sulfonyl)cyclopentanepropionate,

4'-((5-acetyl-2-butyl-4-(methylthio) 1H-imidazol-1-yl)methyl) - N-(((cyclohexylmethyl)amino)carbonyl)(1,1'-biphenyl) 2-sulfonamide,

2-butyl-4'-((4-methylthio)-5-((1H-tetrazol-5-yl)carbonyl) 1H-imidazol-1-yl)methyl) - N-(((phenylmethyl)amino)carbonyl)(1,1'-biphenyl) 2-sulfonamide;

4'-((2-butyl-4-(methylthio)-5-(1-oxo-2-(phenylsulfonyl) pentyl-1H-imidazol-1-yl)methyl) - N-(((phenylmethyl)amino)carbonyl)(1,1'-biphenyl) 2-sulfonamide;

4'-((2-butyl 4-(methylthio)-5-((1,1-dioxido-tetrahydro-2-thienyl)carbonyl) 1H-imidazol-1-yl)methyl) - N-(((phenylmethyl)amino)carbonyl)(1,1'-biphenyl) 2-sulfonamide;

4'-((2-butyl-5-(3-cyclohexylmethyl-2,4-dioxo-5-(trifluoromethyl) 5-oxazolidinyl) 4-(methylthio) 1H-imidazol-1-yl)methyl N-(((cyclamen-4-yl) 4-(methylthio) 1H-imidazol-1-yl)methyl-N-(((cyclohexylmethyl)amino)carbonyl)(1,1'-biphenyl) 2-sulfonamide;

4'-((4-methylthio) 5-(phenylacetyl) 2-propyl-1H-imidazol-1-yl)methyl) - N-(((phenylmethyl)amino)carbonyl)(1,1'-biphenyl) 2-sulfonamide;

4'-((2-butyl-4-(methylthio)-5-((1H-tetrazol-5-yl)acetyl) 1H-imidazol-1-yl)methyl) - N-(((phenylmethyl)amino)carbonyl)(1,1'-biphenyl) 2-sulfonamide;

4'-((5-acetyl-4-(methylthio)-2-propyl-1H-imidazol-1-yl)methyl)-N-(((phenylmethyl)amino)carbonyl)(1,1'-biphenyl) 2-sulfonamide.

3. The compounds of formula I on p. 1 as a receptor antagonist AT1and AT2angiotensin II pharmaceutical compositions for treatment of diseases caused by abnormal stimulation of these receptors.

4. Connection on p. 1 as a receptor antagonist AT1and AT2angiotensin II pharmaceutical compositions for the treatment of hypertension, post-heart attack, heart failure and restenosis post-angioplasty.

5. Connection on p. 1 as a receptor antagonist AT1and AT2angiotensin II pharmaceutical compositions in the treatment of renal failure.

6. Connection on p. 1 as a receptor antagonist AT1and AT2angiotensin II pharmaceutical compositions for the treatment and prevention of cardiovascular disorders, in particular microchimica fact, the compound of formula II

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in which R'1matter specified in paragraph 1 for R1in which the possible reactive functions can be protected by a protective group, and P is a protective group of a nitrogen atom,

subjected to a halogenation reaction for obtaining the compounds of formula III

< / BR>
in which R'1and P have the above meanings and Hal represents a halogen atom,

which is subjected to the reaction of the exchange of the halogen-metal with one of the halogen atoms, then the reaction with the compound of the formula IVaIVbIVcIVdor IVe:

(-S-R')2(IVa), or MeSO2SR' (IVb)

< / BR>
< / BR>
< / BR>
in which R' has the values specified in paragraph (1 to R, in which the possible reactive functions can be protected by a protective group, and "ALK" means alkyl containing not more than 4 carbon atoms,

to obtain the compounds of formula V

< / BR>
in which R'1, P and Hal have the abovementioned meanings and R3is S-R' or K-O-ALK, where R' and ALK have the above specified values, and K is the radical or

which is subjected to the reaction of the exchange of the halogen-metal with a halogen atom, and then reacting with compound of formula IV'aIV'bIV'cIV'deliteone or different from R' have the meanings specified for R, in which the possible reactive functions can be protected by a protective group, and ALK' are identical or different from "Ala" means alkyl containing not more than 4 carbon atoms,

to obtain the compounds of formula VII

< / BR>
in which R'1and P have the above meanings and R2and R3identical or different, mean-S-R', -S,-R, -K-Oalk or-K-Oalk', as defined above, in which R', R', ALK, ALK' and K have the above values,

from which the free amine functions, blocked by P, defined above, and then carry out the reaction with the compound of the formula VIII

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in which R'4has the meaning specified in paragraph 1 for R4in which the possible reactive functions can be protected by a protective group, and Hal represents a halogen atom,

obtaining the compounds of formula I1< / BR>
< / BR>
in which R'1, R'2, R'3and R'4have the values listed in paragraph 1,

the resulting product of the formula I1that is a product of the formula I, allocate or subjected, if necessary, one or more reactions of transformation to other products of the formula I, in any order:

a) esterification of the acid function,
the Ktsia acyl,

d) transformation of the cyano function into an acid function,

e) conversion of the acid function into an amide function, then if necessary, the function thioamide,

f) the restoration of the carboxy function to an alcohol function,

g) transforming functions alkoxy function hydroxyl, or hydroxyl function in the function alkoxy,

h) oxidation of the alcohol function to the aldehyde, acid or keto-function

i) the conversion of the formyl radical in the radical carbarnoyl,

j) turning radical carbarnoyl in the nitrile radical,

k) converting the nitrile radical in tetrazolyl,

l) oxidation of ancilliary or aristocraty to the corresponding sulfoxide or sulfone,

m) the transformation function sulfide, sulfoxide or sulfone function corresponding sulfoximine,

n) the transformation function oxo function of thioxo,

o) the transformation of radical

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in radical

< / BR>
p) conversion of the acid function into a function:

< / BR>
q) is the transformation function of beta-keto-sulfoxide in the function of alpha-ketotioefir,

r) the conversion of carbamate into urea and, in particular, sulfonylamino in the sulfonylurea,

s) removal of protective groups, which can protect the reaction functions,

obtaining isomers, enantiomers and diastereoisomers.

8. The method of obtaining compounds of formula I, as defined in paragraph 1, characterized in that compounds of the formula IX

< / BR>
in which R'1has a specified value, and M represents a hydrogen atom or a radical R'2that has the values specified above for R2in which the possible reactive functions can be protected by a protective group,

subjected to reaction with the compound of the formula VIII defined above, to obtain a product of formula X

< / BR>
in which R'1, M and R'4have the above values,

the resulting compound of formula X, if M denotes R'2defined above, is subjected to a halogenation reaction, to obtain the product of formula XI

< / BR>
in which R'1, R'2, R'4and Hal have the above values,

which is subjected to the reaction of the exchange of the halogen-metal, then the reaction with the compound of the formula XII

< / BR>
in which R'9matter specified in paragraph 1 for R9in which the possible reactive functions can be protected by a protective group,

and get the product of formula I2< / BR>
< / BR>
in which R'1, R'2, R'4and R'9 with the compound of the formula XV

O=C=N-R'6XV,

in which R'6matter specified in paragraph 1 for R6in which the possible reactive functions can be protected by a protective group,

to obtain a product of formula I3< / BR>
< / BR>
in which R'1, R'2, R'4, R'6and R'9have the specified values,

or the product of formula I2subjected to a saponification reaction with the product of formula I4< / BR>
< / BR>
in which R'1, R'2, R'4and R'9have the specified values,

which is subjected to reaction with COCl2to obtain a product of formula I5< / BR>
< / BR>
in which R'1, R'2, R'4and R'9have the specified values,

or the product of formula X, provided that M denotes a hydrogen atom, is subjected to a halogenation reaction for producing the product of formula XIV

< / BR>
in which R'1, R'4and Hal have the above values,

which is subjected to the reaction of the exchange of the halogen-metal, then the processing of the compound of the formula IVaIVbIVcIVdor IVedefined above to obtain a product of formula I6< / BR>
< / BR>
in which R'1, R'4Hal and R3have these snakehole IV'aIV'bIV'cIV'dor IV'edefined above, to obtain a product I7< / BR>
< / BR>
in which R'1, R'4, R2and R3have the specified values,

then the above products of formula I2, I3, I4, I5, I6, I7that are a product of the formula I, allocate or subjected, if necessary, one or more reactions of transformation to other products of the formula I, in any order:

a) esterification of the acid function,

(b) saponification functions of ester to acid functions,

c) transforming functions of ester function acyl,

d) transformation of the cyano function into an acid function,

e) conversion of the acid function into an amide function, then, if necessary, in function thioamide,

f) the restoration of the carboxy function to an alcohol function,

g) transforming functions alkoxy function hydroxyl or hydroxyl function in the function alkoxy,

h) oxidation of the alcohol function to the aldehyde, acid or keto-function

i) the conversion of the formyl radical in the radical carbarnoyl,

j) turning radical carbarnoyl in the nitrile radical,

k) the radical transformation of nitrofen,

m) the transformation function sulfide, sulfoxide or sulfone function corresponding sulfoximine,

n) the transformation function oxo function of thioxo,

o) the transformation of radical

< / BR>
in radical

< / BR>
p) conversion of the acid function into a function:

< / BR>
q) is the transformation function of beta-keto-sulfoxide in the function of alpha-ketotioefir,

r) the conversion of carbamate into urea and, in particular, sulfonylamino in the sulfonylurea,

s) removal of protective groups, which can protect the reaction functions,

t) salt formation using mineral or organic acids or with bases,

u) the splitting of the racemic forms of the compounds of formula I with obtaining isomers, enantiomers and diastereoisomers.

9. The method of obtaining compounds of formula I, as defined in paragraph 1, characterized in that the compound of formula XX

< / BR>
in which R'1and R'2have the above meanings and R'3matter specified in paragraph 1 for R3in which the possible reactive functions can be protected by a protective group,

subjected to interaction with the compound of the formula VIII defined above, to obtain a product of formula I'

< / BR>
in which R'1yet a product of formula I, allocate or subjected, if necessary, one or more reactions of transformation to other products of the formula I, in any order:

a) esterification of the acid function,

(b) saponification functions of ester to acid functions,

c) transforming functions of ester function acyl,

d) transformation of the cyano function into an acid function,

e) conversion of the acid function into an amide function, then, if necessary, in function thioamide,

f) the restoration of the carboxy function to an alcohol function,

g) transforming functions alkoxy function hydroxyl or hydroxyl function in the function alkoxy,

h) oxidation of the alcohol function to the aldehyde, acid or keto-function

i) the conversion of the formyl radical in the radical carbarnoyl,

j) turning radical carbarnoyl in the nitrile radical,

k) converting the nitrile radical in tetrazolyl,

l) oxidation of ancilliary or aristocraty to the corresponding sulfoxide or sulfone,

m) the transformation function sulfide, sulfoxide or sulfone function corresponding sulfoximine,

n) the transformation function oxo function of thioxo,

o) the transformation of radical

< / BR>
in radical

< / BR>
alpha ketotioefir,

r) the conversion of carbamate into urea and, in particular, sulfonylamino in the sulfonylurea,

s) removal of protective groups, which can protect the reaction functions,

t) salt formation using mineral or organic acids or with bases,

u) the splitting of the racemic forms of the compounds of formula I with obtaining isomers, enantiomers and diastereoisomers.

10. Pharmaceutical composition having antagonistic properties towards angiotensin II receptor containing as an active ingredient, at least one connection on p. 1 or 2.

11. Intermediate compounds of formulas II, III, V, VII, when P represents-CH2-O-CH2-Me, -CH2-O-(CH2)2-Si-(CH3)3, -CH2-O-CH3b

 

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