Derivatives of 1-biphenylmethanol, the method of production thereof and pharmaceutical composition for the treatment and prevention of hypertension

 

(57) Abstract:

Derivatives of 1-biphenylmethanol formula I, where R1- C1-C6-alkyl; R2and R3is a hydrogen atom, a C1-C6-alkyl, C6-C10-aryl; R4Is h or alkyl; R5- COOR5a, -CONR8R9; R8and R9- H, alkyl, possibly substituted by carboxy or alkoxycarbonyl group, or R8and R9together represent a2-C6-alkylen, possibly substituted by alkoxycarbonyl; R5Ais alkyl or alkanoyloxy, alkoxycarbonylmethyl, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl or phthalidyl; R6- N; R7- carboxyl or tetrazol-5-ilen group, or its pharmaceutically acceptable salts and esters possess hypotensive activity and are intended for the treatment and prevention of hypertension, including heart disease and circulatory system. 4 C. and 11 C.p. f-crystals, 7 PL.

The invention relates to a series of new derivatives of 1-biphenylether imidazole having hypotensive activity and are therefore intended for the treatment and prevention of hypertension, including heart disease and circulatory system. The present invention is also relative to the Oia these compositions.

It is known that the renin-angiotensin system provides one of the most important mechanisms aimed at maintaining homeostasis of blood pressure in living organisms. Lowering blood pressure or lowering the concentration of sodium ions in the body fluids of the system is activated. As a result of this activated enzyme renin and angiotenzinkonvertiruyuschego enzyme (hereinafter referred to as ACF) and affect angiotensinogen that first using renin decomposes with the formation of angiotensin I (denoted hereinafter "AI"), and then use the ACF is converted to angiotensin II (hereinafter referred to "AII"). Since AII to a strong contraction of the blood vessels and accelerates the secretion of aldosterone, the activation of this system leads to increased blood pressure. Inhibitors or suppressors of the renin-angiotensin system, such as renin inhibitors, ACE inhibitors and AII antagonists, promote the dilation of blood vessels, thereby reducing blood pressure and improving circulatory functions. Therefore, the treatment of heart disease based on the use of the above agents.

Currently, only the ACF inhibitors are clinically the RC. Some of them, such as AII antagonist peptide type, such as saralasin known for a long time, while other antagonists, not peptide type, opened recently (see, for example, publishing Europatent NN 28833, 28834, 245637, 253310, 323841, 324377, 380959, 399732, 399731 and 400835, and a patent application in Japan Coca N 57-98270). Of these works the closest prototype are publishing Europatent N 253310 and N324377.

In the publication of Europatent N 253310 revealed a number of derivatives of 1-phenyl, 1-phenethyl or 1-benzylimidazole, with the ability to inhibition of AII. Compounds included in the scope of the specified prototype, are derivatives of 1-biphenyl-methylimidazole, which, however, differ from the compounds of the present invention the nature of the substituent at the 4 - or 5-positions of the imidazole.

In the publication of Europatent N 324377 also reveals a number of similar compounds. However, the activity of the compounds specified prototype, as well as connections above prototype N 253310 are insufficient, and to obtain good clinical results, it is necessary to use a stronger AII-antagonist tools.

The authors of this application it was found a limited number proizvodyaschiy, and so they can be successfully used as antihypertensive drugs in the treatment and prevention of heart disease.

The aim of the present invention to provide a series of new derivatives of 1-(biphenylyl)imidazole-5-carboxylic acid.

Another objective of the present invention is to obtain compounds with AII-inhibitory activity.

Other objectives of the present invention and its advantages will be described below during the description of the invention.

Thus, the present invention relates to compounds of the formula I

< / BR>
where R1is an alkyl group with 1-6 carbon atoms or alkenylphenol group with 3-6 carbon atoms;

R2and R3independently selected from the group consisting of hydrogen atoms; alkyl groups having from 1 to 6 carbon atoms; alkenyl groups having from 3 to 6 carbon atoms; cycloalkyl group having generally 3 to 10 carbon atoms in one or more saturated carbocyclic rings; Uralkalij groups in which the alkyl part is as defined below, and systems of condensed rings, in which aryl group, as defined below, sediada; alkyl group having from 1 to 6 carbon atoms; alkanoyloxy group having from 1 to 6 carbon atoms; substituted alkanoyloxy group having from 2 to 6 carbon atoms and substituted by at least one Deputy, selected from the group consisting of halogen atoms and alkoxygroup having from 1 to 6 carbon atoms; alkanoyloxy group having from 3 to 6 carbon atoms; arylcarboxylic the group in which the aryl part is as defined below; alkoxycarbonyl group, in which the alkyl part contains from 1 to 6 carbon atoms; tetrahydropyranyloxy, tetrahydropyranyloxy, tetrahydrocannabinol or tetrahydrofuryl group; substituted tetrahydropyranyl, tetrahydropyranyl, tetrahydrocannabinol or tetrahydrofuryl group, which is substituted by at least one Deputy, selected from the group consisting of halogen atoms or alkoxygroup having from 1 to 6 carbon atoms; a group of the formula - SiRaRbRcin which 1, 2 or 3 groups represented by Ra, Rband Rcare independently selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, and 2, 1 or 0 groups represented by RaR alkoxymethyl group, in which alkoxides has from 1 to 6 carbon atoms; (alkoxyalkane)methyl group, in which each alkoxides has from 1 to 6 carbon atoms; halogenoacetyl group, in which alkoxides has from 1 to 6 carbon atoms; kalkilya group in which an alkyl group having from 1 to 6 carbon atoms is substituted by at least one aryl group, as defined below; and alcoholattributable groups in which alcoolica part has from 1 to 6 carbon atoms;

R5represents a carboxyl group, or a group of the formula-CONR8R9where R8and R9are independently selected from the group consisting of hydrogen; unsubstituted alkyl groups having from 1 to 6 carbon atoms, and substituted alkyl groups having from 1 to 6 carbon atoms and substituted by at least one Deputy, selected from the group consisting of substituents (a), defined below; or R8and R9together represent unsubstituted alkylenes group having from 2 to 6 carbon atoms; or substituted alkylenes group having from 2 to 6 carbon atoms and substituted by at least one Deputy, selected from the group of sostojashhee;

R6represents a hydrogen atom, alkyl group having from 1 to 6 carbon atoms, alkoxygroup having from 1 to 6 carbon atoms, or a halogen atom;

R7represents a carboxyl group or tetrazol-5-ilen group

moreover, these substituents (a) are selected from the group consisting of aryl groups defined below; aromatic heterocyclic groups having 5 or 6 ring atoms, of which 1-4 are heteroatoms selected from oxygen atoms, nitrogen or sulfur; halogen atoms; hydroxyl groups; alkoxygroup having from 1 to 6 carbon atoms; carboxyl groups; alkoxycarbonyl groups in which the alkyl part has from 1 to 6 carbon atoms; amino groups and acylamino, in which the acyl part is alcoolica group having from 1 to 6 carbon atoms, or arylcarbamoyl group in which the aryl part is defined below; and the above aryl groups are aromatic carbocyclic groups that contain from 6 to 14 atoms in the ring are unsubstituted or substituted by at least one Deputy, selected from substituents (b), which, in turn, is chosen from the group comprising nitro, lanague group, having from 1 to 6 carbon atoms, alkoxygroup having from 1 to 6 carbon atoms, carboxyl group, alkoxycarbonyl group, in which alkoxides contains from 1 to 6 carbon atoms, and alkylenedioxy and alcaligenaceae having from 1 to 3 carbon atoms;

thus the present invention also relates to pharmaceutically acceptable salts and esters of the above compounds.

The present invention also relates to pharmaceutical compositions intended for the treatment and prevention of hypertension and containing an effective amount of a hypotensive means in combination with a pharmaceutically acceptable carrier or diluent, where anti-hypertensive agent selected from the group consisting of compounds of the formula I and their pharmaceutically acceptable salts and esters.

In addition, the present invention relates to methods for producing compounds of formula I and their pharmaceutically acceptable salts and esters, which are described in detail below.

In the compounds of the present invention, where R1, R2, R3, R4, R6, R8, R9or Deputy (b) are alkyl group, mentioned alkyl group predstavljaet, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, t-pentyl, 2-methylbutyl, 3-methylbutyl, 1-ethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, hexyl and isohexyl, R1is preferably a straight or branched alkyl group containing from 2 to 5 carbon atoms, and more preferably a straight group, and most preferably an ethyl, propylene or bootrom, R2and R3may be the same or different, represent a straight or branched alkyl group containing from 1 to 4 carbon atoms, preferably methyl, ethyl, sawn, ISO-propyl or t-boutelou group, and more preferably a methyl or ethyl group, and if R5is carboxypropyl, or ISO-propyl or t-boutelou group if R5is a group of formula-CONR8R9, R4and R6are preferably straight or branched alkyl group having from 1 to 4 carbon atoms, and more preferably a methyl or ethyl group. If R8and R9are alkyl g is POI, containing 1 to 4 carbon atoms, more preferably methyl, ethyl, sawn, or butilkoi group, and most preferably a methyl or ethyl group. If the substituent (b) is an alkyl group, preferably, if it is a group with 1 to 4 carbon atoms, and more preferably a methyl or ethyl group.

If R1, R2and R3are alkenylamine groups, they can be straight or branched alkenylamine groups having from 3 to 6 carbon atoms. Examples of such groups are: 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 1-butenyl, 2-butenyl, 3-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, 1-pentenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl. R1is preferably a straight or branched alkenylphenol group containing 3 or 4 carbon atoms, and more preferably 1-propenyloxy or 1-bouteilles group, R2and R3can be tinakulumalitsa 3 or 4 carbon atoms, and more preferably 2-propenyloxy or 2-bouteilles group.

If R2and R3are cycloalkyl group, this group generally has from 3 to 10 carbon atoms in one or more saturated carbocyclic rings, and each ring preferably has 3 to 6 carbon atoms. If this group represents a system with multiple rings, it may be a system of rings with an internal bridge, or a system of condensed rings. Examples of such groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl and substituted. Of these preferred groups are groups having from 3 to 6 carbon atoms in a single ring, and more preferred cyclopentolate and tsiklogeksilnogo group.

Alternative, R2and R3can imagine aracelio group in which the alkyl part has from 1 to 6 (more preferably 1 to 4, and still more preferably 1 or 2 and most preferably 1) of carbon atoms and the aryl portion represents an aromatic carbocyclic group containing from 6 to 14 (preferably from 6 to 10, and more preferably 6 or 10) of atoms in the ring; and which is resumes the above. Specific examples of alkyl groups which can form the alkyl part, above and refer to the examples of the groups represented by R2and specific examples of aryl groups that may form the aryl part, below, as a group, which can be represented by R2. Examples of such Uralkalij groups are benzyl, 1 - and 2-naphthylmethyl, intermetal, phenantrolinate, anthranilates, diphenylmethyl, triphenylmethyl, 1-phenylethyl, phenethyl, 1-naphtalate, 2-naphtalate, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1-naftilamin, 2-naftilamin, 3-naftilamin, 1-phenylbutyl, 2-phenylbutyl, 3-phenylbutyl, 4-phenylbutyl, 1-naphthylmethyl, 2-naphthylmethyl, 3-naphthylmethyl, 4-naphthylmethyl, 1-fenilpentil, 2-fenilpentil, 3-fenilpentil, 4-fenilpentil, 5-fenilpentil, 1-naphthylmethyl, 2-naphthylmethyl, 3-naphthylmethyl, 4-naphthylmethyl, 5-naphthylmethyl, 1-phenylhexa, 2-phenylhexa, 3-phenylhexa, 4-phenylhexa, 5-phenylhexa, 6-phenylhexa, 1-nattinger, 2-nattinger, 3-nattinger, 4-nattinger, 5-nattinger and 6-nattinger. When kalkilya group contains naftalina group, then this group may be 1 - or 2-naftalina group. Of these Uralkalij groups, preferred are a group who think the group. These groups can be unsubstituted or substituted at least by one or more substituents (b), examples of which are given above. Examples of the substituted groups may be unsubstituted those groups listed above, except that they aryl part is replaced by one of the substituted aryl groups below.

In the case when R2and R3represent aryl group, then this group is an aromatic carbocyclic group which has from 6 to 14 (preferably from 6 to 10, and more preferably 6 or 10, ring atoms and which is unsubstituted or substituted by at least one Deputy, selected from the group consisting of substituents (b), defined above and illustrated below. These groups can be unsubstituted or substituted by at least one, and preferably from 1 to 3 substituents (b), such as the nitro-group, cyano, halogen atoms such as fluorine atoms, chlorine, bromine or iodine, of which preferred are fluorine atoms, chlorine, and bromine; unsubstituted carbocyclic aryl groups, such as groups, which are listed below for R2and R3; alkyl groups, examples of e from 1 to 6, and preferably from 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, pentyloxy, neopentylene, 2-methylbutoxy, 3 methylbutoxy, 1 ethylpropoxy, 4-methylpentylamino, 3 methylpentane, 2-methylpentane, 1 methylpentylamine, 3,3-Dimethylbutane, 2,2-Dimethylbutane, 1,1-Dimethylbutane, 1,2-Dimethylbutane, 1,3-Dimethylbutane, 2,3-Dimethylbutane, 2-ethylbutane, hexyloxy and isohexadecane, while preferred is methoxy or ethoxypropan; alkoxycarbonyl group, in which alkoxides has from 1 to 6 and preferably from 1 to 4 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, solutionline, t-butoxycarbonyl, ventilatsiooniga and hexyloxybenzoyl groups, of which the most preferred are methoxycarbonyl and ethoxycarbonyl group; carboxyl group; alkylenedioxy and alcaligenaceae having from 1 to 3 carbon atoms, such as methylenedioxy, Ethylenedioxy, Propylenediamine, trimethylenediamine, utilizandose and isopropylidenedioxy, most preppy aryl group, the preferred substituents are alkyl and alkoxy.

If the group is substituted, the number of substituents is not critical and is limited only by the number of substitutable positions and possibly by steric difficulties. In practice, however, the preferred number of substituents is 1, 2 or 3.

Examples of substituted and unsubstituted aryl groups are phenyl, naphthyl, phenanthrene, anthracene, 2-were, 3-were, 4-were 2-ethylphenyl, 3-propylphenyl, 4-ethylphenyl, 2-butylphenyl, 3-pentylphenol, 4-pentylphenol, 3, 5dimethylphenyl, 2,5-dimetilfenil, 2,6-dimetilfenil, 2,4-dimetilfenil, 3,5-dibutyltin, 2.5-dipentylester, 2,6-dipropyl-4-were, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-propoxyphenyl, 4-ethoxyphenyl, 2-butoxyphenyl, 3-pentyloxide and 4-pentyloxide, of which the most preferred are phenyl, 2-were, 3-were, 4-were, 2-methoxyphenyl, 3-methoxyphenyl and 4-methoxyphenyl.

If R2and R3represent a system of condensed rings, in which the aryl group fused with cycloalkyl group having from 3 to 10 carbon atoms, the aryl and cycloalkyl parts can blna group, and cycloalkyl part has 5 or 6 carbon atoms. Examples of such systems with condensed rings are indanyl, tetrahydronaphthyl and tetrahedronal, of which preferred are indanyl and tetrahydronaphthyl.

R4have to imagine alkanoyloxy group which may be straight or branched and have from 1 to 6 carbon atoms. Examples of such groups are formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl and isovaleryl, of which preferred are formyl and acetyl.

Alternative, R4may be substituted alkanoyloxy group where the Deputy or deputies, chosen from halogen atoms and alkoxygroup. Examples of such substituted alkanoyl groups are chloroacetyl, dichloroacetyl, trichloroacetyl, triptorelin and methoxyacetyl, of which preferred are chloroacetyl and trichoroethylene group.

If R4is alkanoyloxy group, it may contain from 3 to 6, and preferably from 3 to 5 carbon atoms. Examples of such groups are acryloyl, methacryloyl, crotonoyl, 3-methyl-2-butanol and 2-methyl-2-butanol, and particularly preferred is E-2-Mateescu can be any of the aryl groups, above for R2. However, in this case, if the group is substituted, substituents preferably selected from the group comprising halogen atoms, alkyl groups, alkoxygroup, nitro, alkoxycarbonyl groups and unsubstituted aryl groups, of which more preferred are methyl, methoxy, fluorescent-, and chorography. Examples arylcarboxylic groups are benzoyl, -naphtol-naphtol, 3-forestsoil, 2-bromobenzoyl, 4-chlorobenzoyl, 2,4,6-trimethylbenzoyl, 4-toluene, 4-anisoyl, 4-nitrobenzoyl, 2-nitrobenzoyl, 2-methoxycarbonyl benzoyl and 4-phenylbenzyl, of which the preferred groups are benzoyl, 4-toluoyl and 4-anisoyl.

If R4represents alkoxycarbonyl group, its alkoxides contains from 1 to 6 carbon atoms, i.e., the whole group generally contains from 2 to 7 carbon atoms, and examples of such groups are methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxide, t-butoxycarbonyl, pentyloxybenzoyl and hexyloxybenzoyl, of which the preferred groups are methoxycarbonyl and etoxycarbonyl.

If R4is a then it is carbonated which may be substituted or unsubstituted. If the group is substituted, the substituents can be halogen atoms or alkoxygroup having from 1 to 6 carbon atoms, which can be any of the groups and atoms, mentioned above as an example, for R4while preferred are chloro-, bromo - and methoxypiperidine. Examples of these substituted and unsubstituted groups are tetrahydrofuran-2-yl, 3-chlorotetracycline-2-yl, 3-promoterdriven-2-yl, 4-methoxyacridine-2-yl, tetrahydrothiopyran-2-yl, 4-methoxytryptamine-2-yl, tetrahydrofuran-2-yl and tetrahydrothieno-2-yl, of which the preferred groups are tetrahydrofuran-2-yl, 4-methoxyacridine-2-yl, tetrahydrothiopyran-2-yl and 4-methoxytryptamine-2-yl.

If R4are silloway group of the formula-SiRaRbRcin which 1, 2 or 3 groups represented by Ra, Rband Rcare independently selected from alkyl groups containing from 1 to 6 carbon atoms, and 2, 1 or 0 groups represented by Ra, Rband Rcare independently selected from aryl groups, as defined above, with alkyl and aryl part can be any of the groups above is the SCP. Examples of such silyl groups are trimethylsilyl, triethylsilyl, isopropylaminomethyl, t-butyldimethylsilyl, methyldiisopropanolamine, methyl-di-t-Boticelli, triisopropylsilyl, diphenylmethylsilane, diphenylbutyric, diphenylethylene and phenyldimethylsilane, of which preferred are trimethylsilyl, t-butyldimethylsilyl and diphenylmethylsilane.

If R4is alkoxymethyl group, in which alkoxides has from 1 to 6 carbon atoms, alkoxysilyl can be either alkoxygroup presented above for the substituents (b). Examples of such alkoxymethyl groups are methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxyphenyl, butoxymethyl and t-butoxymethyl, of which preferred are ethoxymethylene and ethoxymethylene group.

If R4is (alkoxyalkane) methyl group, each alkoxides has from 1 to 6 carbon atoms and may be any of alkoxygroup presented above for the substituents (b). Examples of such alkoxyalkane methyl groups are methoxyethoxymethyl, 2-methoxyethoxymethyl, 2-methoxypropionate and 2-methoxybenzonitrile, of which site is a methyl group, alkoxides has from 1 to 6 carbon atoms, and the atoms of halogen and alkoxygroup can be atoms and groups represented above for substituents (b). Examples of such halogenoacetyl groups are 2,2,2-trichloroacetyl, 2,2,2-tribromoethanol, bis(2-chloroethoxy)methyl and bis(2-bromoethoxy)methyl, of which 2,2,2-trichloroacetyl and (2 chloroethoxy)methyl are preferred.

If R4is aracelio group in which an alkyl group having from 1 to 6 and preferably from 1 to 4 carbon atoms is substituted by at least one aryl group, the alkyl and the aryl part can be any alkyl and aryl groups described above for R1and R2. Examples of such Uralkalij groups are benzyl, -naphthylmethyl-naphthylmethyl, diphenylmethyl(benzhydryl), trityl, -naphthyl-diphenylmethyl, 9-antimetal, 4-methylbenzyl, 6-phenylhexa, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenylalanine, 2-nitrobenzyl, 4-nitrobenzyl, 4-Chlorobenzyl, 4-bromobenzyl and 4-cyanobenzyl, of which the preferred groups are 4-methylbenzyl, 4-methoxybenzyl, 4-Chlorobenzyl and 4-bromobenzyl.

If R4playboy of alkanoyl groups, above for P. Examples of such alcoholcontaining groups are formyloxyethyl, acetoxymethyl, propionatetestosterone, butyrylcholinesterase and pivaloyloxymethyl, of which preferred is pivaloyloxymethyl group.

R5represents a carboxyl group or a group of the formula - CONR8R9. If R5is a group of formula - CONR8R9and R8and R9are an alkyl group, this group can be unsubstituted alkyl group having from 1 to 6 carbon atoms such as the groups mentioned above, or a substituted alkyl group which has from 1 to 6 carbon atoms and which is substituted by at least one Deputy, selected from the group of substituents (a) defined above and specifically shown below.

If R8and R9together represent alkylenes group, this group has from 2 to 6 carbon atoms and may be substituted or unsubstituted; this group may be straight or branched. Examples of the unsubstituted groups are ethylene, trimethylene, propylene, ethylethylene, teow carbon. In these cases, the group of the formula-NR8R9is a nitrogen-containing heterocyclic group having from 3 to 7 atoms in the ring (one nitrogen atom), for example, if Allenova group contains 4 or 5 carbon atoms, it is 1-pyrrolidino or piperidino. If this group is substituted, the substituents may be carboxyl group and alkoxycarbonyl group, in which alkoxides has from 1 to 6 carbon atoms. Examples of such substituents are carboxy, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxide, t-butoxycarbonyl, pentyloxybenzoyl and hexyloxybenzoyl, of which preferred are carboxy, methoxycarbonyl and ethoxycarbonyl group.

If R5represents carboxyl group, the compound is a carboxylic acid, and therefore can form esters, in which the carboxyl group represented by R5is replaced by a group of the formula COOR5awhere R5arepresents an ester residue (in the case of a carboxylic acid R5ais a hydrogen atom). It can also form a salt, examples of which are presented below for R7. Prefer must meet the pharmaceutical requirements i.e. its toxicity should not be higher, and the activity must not be lower than the original acid. However, if the ester is used for other purposes, for example as an intermediate connection to a different, perhaps more active compounds, even this limitation can not be taken into account, and in this case is acceptable any commonly used essential residue that can be selected on the basis of its functionality and commercial benefits. However, it is well known that some essential residues give the compounds certain advantages, such connections easier and better absorbed in vivo, and therefore, if necessary, these essential residues can be used in the present invention.

Examples of the above ester residues are alkyl groups having from 1 to 6 carbon atoms such as the groups described above as examples for R1; halogenoalkane group having from 1 to 6 and preferably from 1 to 4 carbon atoms in which the alkyl part may be selected from the above groups for R1such as trifluoromethyl, 2,2,2-trichloroethyl, 2,2,2-triptorelin, 2-chloroethyl, 2-toroidal, 2-iodoethyl; hydroxyalkyl group having from 1 to 6 and preferably from 1 to 4 carbon atoms, where the alkyl part may be any of the above for R1for example 2-hydroxyethyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, 3,4-dihydroxybutyl and 4-hydroxybutyl, of which the preferred group is 2-hydroxyethyl; alkoxyalkyl and alkoxylalkyl groups in which the alkoxy and alkyl parts have from 1 to 6 and preferably from 1 to 4 carbon atoms, and can be any of the above examples of substituents (b) and R1respectively, such as 2-methoxyethyl, 2-ethoxyethyl and 2-methoxyethoxymethyl, of which the preferred group is methoxymethyl group; fenceline group and fenceline groups that are substituted by one or more substituents (b), preferred is unsubstituted penicilina group; alkoxycarbonyl groups, such as methoxycarbonylmethylene group; cyanoaniline group having from 1 to 6 and preferably from 1 to 4 atoms in which the alkyl part may be any one of the above groups for R1such as 2-cyanoethylene and cyanomethylene group; alkylthiomethyl group in which the above groups for R1for example methylthiomethyl and ethylthiomethyl; aryldialkyl groups in which the alkyl part has from 1 to 6 and preferably from 1 to 4 carbon atoms and may be any of the above groups for R1and the aryl part may be as defined and illustrated above for R2; for example penultimately group; alkylsulfonyl groups in which each alkyl part has from 1 to 6 and preferably from 1 to 4 carbon atoms and may be selected from illustrated above for R1and may be unsubstituted or substituted by one or more halogen atoms; for example, such as 2-methanesulfonyl ethyl or 2-trifloromethyl ethyl group; arylsulfonyl groups in which the alkyl part has from 1 to 6 and preferably from 1 to 4 carbon atoms and may be any of the examples above for R1and the aryl part may be as above definitions for R2; for example, 2-(benzoylphenyl)-ethyl and 2-(p-toluensulfonyl) ethyl group; aryl groups defined above for R2; kalkilya groups, such as presented above for R2in particular benzyl, p-methoxybenzyl, p-nitrobenzyl is SUP>ReRf(where Rd, Reand Rfdefined above in relation to Ra, Rband Rcsuch as they were defined for R4; alkanoyloxy groups in which each of alkanols and alkyl parts has from 1 to 6 carbon atoms, and may be any of the examples above for R1and R4respectively, and preferably alcoolica part has from 1 to 5 carbon atoms and the alkyl part has from 1 to 4 carbon atoms, and more preferably, if alcoolica part has from 2 to 5 carbon atoms, and the alkyl portion is from 1 to 2 carbon atoms; examples alkanoyloxy groups are formyloxyethyl, acetoxymethyl, propionylacetate, butyraldoxime, pivaloyloxymethyl, valerolactone, isovalerylglycine, hexaniacinate, 1-(formyloxy)ethyl, 1-(acetoxy)ethyl, 1-(propionyloxy)ethyl, 1-(butyryloxy)ethyl, 1-(pivaloyloxy)ethyl, 1-(butyryloxy)ethyl, 1-(valeriote)ethyl, 1-(isovalerianic)ethyl, 1-(hexanoate)ethyl, 2-(formyloxy)ethyl, 2-(acetoxy)ethyl, 2-(propionyloxy)ethyl, 2-(butyryloxy)ethyl, 2-(pivaloyloxy)ethyl, 2-(valeriote)ethyl, 2-(isovalerianic)ethyl, 2-(hexanoate)ethyl, 1-(formyloxy)propyl, 1-(acetoxy)propyl, 1-(propionyloxy)prop and)propyl, 1-(acetoxy)butyl, 1-(propionyloxy)butyl, 1-(butyryloxy)butyl, 1-(pivaloyloxy)butyl, 1-(acetoxy)pentyl, 1-(propionyloxy)phenyl, 1-(butyryloxy)pentyl, 1-(pivaloyloxy)pentyl and 1-(pivaloyloxy)hexyl, of which preferred are formyloxyethyl, acetoxymethyl, propionylacetate, butyraldoxime, pivaloyloxymethyl, 1-(formyloxy)ethyl, 1-(acetoxy)ethyl, 1-(propionyloxy)ethyl, 1-(butyryloxy)ethyl and 1-(pivaloyloxy)ethyl, and bluee are preferred acetoxymethyl, propionylacetate, butyraldoxime, pivaloyloxymethyl, 1-(acetoxy)ethyl, 1-(propionyloxy)ethyl, 1-(butyryloxy)ethyl and 1-(pivaloyloxy)ethyl and most preferred are pivaloyloxymethyl and 1 pivaloyloxy ethyl; cycloalkylcarbonyl groups in which cycloalkyl part has 5 or 6 carbon atoms and the alkyl part has from 1 to 6 carbon atoms, and both of these parts are such as defined above for R2; preferably the alkyl part has from 1 to 4, and more preferably from 1 to 2 carbon atoms; examples of these cycloalkylcarbonyl groups are Cyclopentasiloxane, cyclohexasiloxane, 1-(cyclopentyloxy)ethyl, 1-(cyclohexyloxy)ethyl, 1-(cyclopentano the s are preferred Cyclopentasiloxane, cyclohexanoltramadol, 1-(cyclopentyloxy)ethyl and 1-(cyclohexyloxy)ethyl; alkoxycarbonylmethyl groups in which each of the alkoxy and alkyl parts has from 1 to 6 carbon atoms and are the same as defined above for substituents (b) and R1accordingly, preferably of them have from 1 to 4 carbon atoms, and most preferably, if alkoxides has from 1 to 4 carbon atoms and the alkyl part has from 1 to 2 carbon atoms; examples of these alkoxycarbonylmethyl groups are methoxycarbonylmethyl; ethoxycarbonylmethyl, propoxycarbonyl, isopropoxycarbonyloxymethyl, butoxycarbonylmethyl, msobuttoniconandcaption, ventilatsioonisusteemi, hexyloxybenzoyl, 1-(methoxycarbonylamino)ethyl, 1-(ethoxycarbonyl)ethyl, 1-(propoxycarbonyl)ethyl, 1-(isopropoxycarbonyl)ethyl, 1-(butoxycarbonylamino)ethyl, 1-(isobutoxyethene)ethyl, 1-(ventilatsioonile)ethyl, 1-(hexyloxyethoxy)ethyl, 2-(methoxycarbonylamino)ethyl, 2-(ethoxycarbonyl)ethyl, 2-(propoxycarbonyl)ethyl, 2-(isopropoxycarbonyl)ethyl, 2-(butoxycarbonylamino)ethyl, 2-(isobutoxyethene)ethyl,yloxy)propyl, 1-(propoxycarbonyl)propyl, 1-(isopropoxycarbonyl)propyl, 1-(butoxycarbonylamino)propyl, 1-(isobutoxyethene)propyl, 1-(ventilatsioonile)propyl, 1-(hexyloxyethoxy)propyl, 1-(methoxycarbonyl)butyl, 1-(ethoxycarbonyl)butyl, 1-(propoxycarbonyl)butyl, 1-(isopropoxycarbonyl)butyl, 1-(butoxycarbonylamino)butyl, 1-(isobutoxyethene)butyl, 1-(methoxycarbonylamino)pentyl, 1-(ethoxycarbonyl)pentyl, 1 -(methoxycarbonyl)hexyl and 1-(ethoxycarbonyl)hexyl, preferably methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonyl, isopropoxycarbonyloxymethyl, butoxycarbonylmethyl, msobuttoniconandcaption, 1-(methoxycarbonylamino)ethyl, 1-(ethoxycarbonyl)ethyl, 1-(propoxycarbonyl)ethyl, 1-(isopropoxycarbonyl)ethyl, 1-(butoxycarbonylamino)ethyl, 1-(isobutoxyethene)ethyl, 1-(methoxycarbonylamino)propyl, 1-(ethoxycarbonyl)propyl, 1-(propoxycarbonyl)propyl, 1-(isopropoxycarbonyl)propyl, 1-(butoxycarbonylamino)propyl, 1-(isobutoxyethene)propyl, 1-(methoxycarbonyl)butyl, 1-(ethoxycarbonyl)butyl, 1-(propoxycarbonyl)butyl, 1-(isopropoxycarbonyl)butyl, 1-(butoxycarbonyl intoximeter, propoxycarbonyl, isopropoxycarbonyloxymethyl, butoxycarbonylmethyl, msobuttoniconandcaption, 1-(methoxycarbonylamino)ethyl, 1-(ethoxycarbonyl)ethyl, 1-(propoxycarbonyl)ethyl, 1-(isopropoxycarbonyl)ethyl, 1-(butoxycarbonylamino)ethyl and 1-(isobutoxyethene)ethyl, and most preferably methoxycarbonylmethyl, ethoxycarbonylmethyl, isopropoxycarbonyloxymethyl, 1-(methoxycarbonylamino)ethyl, 1-(ethoxycarbonyl)ethyl and 1-(isopropoxycarbonyl)ethyl; cycloalkylcarbonyl groups in which cycloalkyl part has 5 or 6 carbon atoms, and the alkyl part has from 1 to 6 carbon atoms, and both of these parts are illustrated above for R2; however, preferably, if the alkyl part has from 1 to 4 carbon atoms, and more preferably 1 or 2 carbon atoms; examples of these cycloalkylcarbonyl groups are cyclopentanecarboxylate, cyclohexyloxycarbonyloxy, 1-(cyclopentanecarbonyl)ethyl, 1-(cyclohexyloxycarbonyloxy)ethyl, 1-(cyclopentanecarbonyl)propyl, 1-(cyclohexyloxycarbonyloxy)propyl, 1-(cyclopentanecarbonyl)butyl and 1-(cyclohexyloxycarbonyloxy)Buti is carbonyloxy)-ethyl and 1-(cyclohexyloxycarbonyloxy)ethyl; [5-(aryl - or alkyl-)-2-oxo-1,3 - dioxolan-4-yl] methyl groups in which the alkyl part has from 1 to 6 carbon atoms and may be the same as defined above for R1and R2and the aryl part may be as defined above for R2, and is preferably substituted or unsubstituted phenyl group; preferably, the alkyl part had from 1 to 4 carbon atoms, and more preferably 1 or 2 carbon atoms; examples of these [5-(aryl - or alkyl-)-2-oxo-1,3-dioxolan-4-yl] methyl groups are [5-phenyl-2-oxo-1,3-dioxolan-4-yl]-methyl, [5-(4-were)-2-oxo-1,3-dioxolan-4-yl] methyl, [5-(4-methoxyphenyl)-2-oxo-1,3-dioxolan-4-yl]methyl, [5-(4-chlorphenyl)-2-oxo-1,3-dioxolan-4-yl]methyl, [5-(4-forfinal)-2-oxo-1,3-dioxolan-4-yl] methyl, [5-methyl-2-oxo-1,3-dioxolan-4-yl] methyl, (5-ethyl-2-oxo-1,3-dioxolan-4-yl] methyl, (5-propyl-2-oxo-1,3-dioxolan-4-yl]methyl, (5-isopropyl-2-oxo-1,3-dioxolan-4-yl] methyl and (5-butyl-2-oxo-1,3-dioxolan-4-yl]methyl, preferably (5-phenyl-2-oxo-1,3-dioxolan-4-yl]methyl, (5-methyl-2-oxo-1,3-dioxolan-4-yl] methyl and (5-ethyl-2-oxo-1,3-dioxolan-4-yl]methyl, and more preferably (5-methyl-2-oxo-1,3-dioxolan-4-yl] methyl, and phthalidyl group.

Preferred slozhnoefirnoi group, having one or more, and preferably from 1 to 3 substituents, such as methyl, methoxy, ethyl, ethoxy, fluorescent and chloro, which in the case of 2 or 3 substituents may be the same or different; benzyl, diphenylmethylene, and - and-naphthylmethyl group, and a substituted benzyl group having one or more substituents, and preferably 1 to 3, such as methyl, ethyl, methoxy, ethoxy, fluorescent and chloro, which in the case of 2 or 3 substituents may be the same or different; group of the formula SiRdReRfin which 1, 2 or 3 groups represented by Rd, Reand Rfare independently selected from alkyl groups having from 1 to 4 carbon atoms, and 2, 1 or 0 are phenyl groups; alkanoyloxy groups in which alcoolica group has from 1 to 5 carbon atoms, and the alkyl group has from 1 to 4 carbon atoms; cycloalkylcarbonyl groups in which cycloalkyl part has 5 or 6 carbon atoms and the alkyl portion is from 1 to 4 carbon atoms; alkoxycarbonylmethyl group, in which alkoxides and the alkyl part has from 1 to 4 carbon atoms; cycloalkylcarbonyl group, in which cycloalkyl part has 5 yl]methyl group, in which the alkyl part has from 1 to 4 carbon atoms, and phthalidyl group.

Preferred essential residues are, for example, C1-C4-alkyl groups; benzyl groups; alkanoyloxy groups in which alcoolica part has from 1 to 5 carbon atoms and the alkyl part has 1 or 2 carbon atoms; cycloalkylcarbonyl groups in which cycloalkyl part has from 5 to 6 carbon atoms and the alkyl part has 1 or 2 carbon atoms; alkoxycarbonylmethyl group, in which alkoxides has from 1 to 4 carbon atoms and the alkyl part has 1 or 2 carbon atoms; cycloalkylcarbonyl groups in which cycloalkyl part has 5 or 6 carbon atoms, and the alkyl part has 1 or 2 carbon atoms; [5-(phenyl or alkyl-)-2-oxo-1,3-dioxolan-4-yl] methyl groups in which the alkyl part has 1 or 2 carbon atoms, and phthalidyl group.

The most preferred ester residues are, for example, pivaloyloxymethyl, ethoxycarbonylmethyl, 1-(ethoxycarbonyl)ethyl, isopropoxycarbonyloxymethyl, 1-(isopropoxycarbonyl)ethyl, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl and phthalidyl.

PI, defined above for R2; heterocyclic groups having 5 or 6 atoms in the ring, of which 1-4 are heteroatoms selected from nitrogen atoms, oxygen and sulfur, such as groups below; halogen atoms, alkoxygroup and alkoxycarbonyl groups, such as groups, refer to substituents (b); a hydroxyl group, carboxyl group and amino group and alluminare, in which the acyl part is alkanoyloxy group having from 1 to 6 carbon atoms, or arylcarboxylic group in which the aryl part is as defined above, this acyl portion may be the same as presented above for R4; examples of these groups are benzamidoxime, and preferably alkanolamines having from 1 to 4 carbon atoms, and more preferably acetamido - or formamidine.

If the substituent (a) is a heterocyclic group, this group has 5 or 6 atoms in the ring, of which 1-4 are heteroatoms selected from nitrogen atoms, oxygen and sulfur. If you have a 4 heteroatoms, preferably, they were all nitrogen atoms. If you have 3 heteroatoms, preferably at least about whom neither may be the same or different. If there are two heteroatom, they may be the same or different and are selected from nitrogen atoms, oxygen, and sulfur; however, more preferably, one atom of nitrogen or oxygen, and the other was a nitrogen atom, oxygen or sulfur. Examples of such heterocyclic groups are pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, triazolyl and pyridyl, preferably furyl, thienyl, imidazolyl, oxazolyl or thiazolyl, and more preferably furyl or thienyl.

Preferably, if the benzyl ring having the substituents represented by R6and R7is 3 - or 4-positions, and more preferably in the 4-position of the benzyl group with which it is associated, i.e., the preferred compounds have formula Ia

< / BR>
R6may be a hydrogen atom, alkyl group having from 1 to 6 carbon atoms, for example, such as described above, or alkoxygroup having from 1 to 6 carbon atoms, or a halogen atom, both of which may be such as described above in relation to the groups or atoms represented by the substituents (b). Preferably, if R6is a 6-position of the benzene ring.

the second group of people or if the substituent (a) is a carboxyl group, the resulting compounds can form salts or esters. These salts or esters can be of any nature, provided that they are suitable for therapeutic use and pharmaceutically acceptable. If these salts or esters are not intended for therapeutic use, and are intended for use as intermediates for other, perhaps more active compounds, even the above constraint can be neglected. Examples of such salts include: salts of alkali metals such as sodium, potassium or lithium; salts of alkaline-earth metals such as barium or calcium; salts of other metals, such as magnesium or aluminum; salts of organic bases, such as salts guanidine, triethylamine or dichlorophenylamino; and salts with basic amino acids such as lysine or arginine. Examples of ester groups may be groups presented above for R5a.

Preferably, if R7is a carboxyl group or tetrazol-5-ilen group, and if R7is a carboxyl group, salts of the above compounds are also preferred. The preferred group.

Compounds of the present invention must contain at least one basic nitrogen atom in the imidazole ring, and therefore, they can form acid additive salt. Examples of such acid additive salts are: additive salts with inorganic acids, such as chloride-hydrogen acid, Hydrobromic acid, sulfuric acid or phosphoric acid; and an additive salts with organic acids such as maleic acid, fumaric acid, tartaric acid or citric acid.

Preferred classes of compounds of the present invention are the compounds of formula I and their salts and esters in which R1is an alkyl group having from 2 to 5 carbon atoms or alkenylphenol group having 3 to 5 carbon atoms; R2and R3are independently selected from the group comprising hydrogen atoms, alkyl groups having from 1 to 4 carbon atoms; alkeneamine group having 3 to 5 carbon atoms; cycloalkyl group having 5 or 6 carbon atoms; benzyl, raftiline and phenyl groups, and substituted benzyl and phenyl groups which are substituted by at least one Deputy who fluorine and chlorine; R4represent a hydrogen atom; alkyl group having from 1 to 4 carbon atoms; alkanoyloxy group having from 1 to 5 carbon atoms, substituted alkanoyloxy group which has 2 or 3 carbon atoms and which is substituted by at least one Deputy, selected from the group consisting of fluorine atoms and chlorine, methoxy - and taksigrup; alkanoyloxy group having 3 to 5 carbon atoms, naftolin group; benzoyloxy group; substituted benzoyloxy group, which is substituted by at least one Deputy, selected from the group consisting of substituents (b'), defined below; alkoxycarbonyl group having from 2 to 5 carbon atoms; tetrahydropyranyloxy, tetrahydropyranyloxy, tetrahydrocannabinol or tetrahydrofuryl group, substituted tetrahydropyranyl, tetrahydropyranyl, tetrahydrocannabinol or tetrahydrofuryl group, which is substituted by at least one Deputy atoms selected from chlorine and bromine and metoxygroup; a group of the formula-SiRaRbRcwhere 1, 2 or 3 groups represented by Ra, Rband Rcare independently selected from alkyl groups having from 1 to 4 methoxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethylidene, bis(2-chloroethoxy)methyl, benzyl, diphenylmethyl, or naphthylmethyl group, or a substituted benzyl group, which is substituted by at least one Deputy, selected from the group of substituents (b'), defined below, or pivaloyloxymethyl group; R5represents a group of formula-COOR5aor a group of the formula-CONR8R9where R5ais a hydrogen atom; alkyl group having from 1 to 4 carbon atoms; phenyl, naftilos, benzyl; diphenylmethylene or naphthylmethyl group; substituted phenyl or benzyl group which is substituted by at least one Deputy, selected from the group of substituents (b'), defined below; a group of the formula-SiRaRbRcwhere Ra, Rband Rcdefined above; alkanolamines group, where alcoolica part has from 1 to 5 carbon atoms and the alkyl part has from 1 to 4 carbon atoms; cycloalkylcarbonyl group, where cycloalkenyl part has from 6 to 7 carbon atoms and the alkyl part has from 1 to 4 carbon atoms; alkoxycarbonylmethyl group, W is beneluxtunnel group, in which cycloalkanes has 5 or 6 carbon atoms and the alkyl part has from 1 to 4 carbon atoms; [5-(phenyl - or alkyl-)-2-oxo-1,3 - dioxolan-4-yl] -methyl group in which the alkyl part has from 1 to 4 carbon atoms, or italicising group; R8and R9are independently selected from the group comprising hydrogen atoms; alkyl groups having from 1 to 4 carbon atoms, and substituted alkyl groups which have from 1 to 4 carbon atoms and which are substituted by at least one Deputy, selected from the group of substituents (a) defined below, or R8or R9together represent unsubstituted alkylenes group which has 4 or 5 carbon atoms or substituted alkylenes group which has 4 or 5 carbon atoms and which is substituted by at least one Deputy, selected from carboxyl groups, methoxycarbonyl groups and ethoxycarbonyl groups, while the substituents (a) are selected from phenyl groups, fueling groups, thienyl groups, fluorine atoms, chlorine atoms, hitkashrut, methoxypropyl, taksigrup, carboxyl groups and alkoxycarbonyl groups having from 2 to 5 carbon atoms; R6is is gerada, fluorine atom, a chlorine atom, or bromine atom; R7is a carboxyl group or tetrazol-5-ilen group and the benzene ring has substituents represented by R6and R7is 3 - or 4-position of the benzyl group with which it is associated.

More preferred classes of compounds of the present invention are the compounds of formula I and their salts and esters in which R1represents an alkyl group having from 2 to 5 carbon atoms, or alkenylphenol group having 3 to 5 carbon atoms; R2and R3are independently selected from the group comprising hydrogen atoms, alkyl groups having from 1 to 4 carbon atoms; alkeneamine group having 3 to 5 carbon atoms; cycloalkyl group having 5 or 6 carbon atoms, and benzyl, and phenyl groups; R4represents a hydrogen atom, a methyl or ethyl group; alkanoyloxy group having from 1 to 5 carbon atoms; alkanoyloxy group having 3 to 5 carbon atoms; benzoyloxy group; or alkoxycarbonyl group having from 2 to 5 carbon atoms; R5represents a group of formula-COOR5aor a group of the formula-CONR8R9group; alkanolamine group where alcoolica part has 1-5 carbon atoms and the alkyl part is a methyl or ethyl group; cycloalkylcarbonyl group where cycloalkenyl part has 6 or 7 carbon atoms, and the alkyl group is a methyl or ethyl group; alkoxycarbonylmethyl group in which the alkyl part is a methyl or ethyl group; cyclohexanecarbonitrile group, in which cycloalkanes has 5 or 6 carbon atoms and the alkyl part is a methyl or ethyl group; [5-(phenyl-, methyl - or ethyl-)-2-oxo-1,3-dioxolan-4-yl]methyl group or italicising group; R8and R9are independently selected from the group comprising a hydrogen atom; a methyl group; an ethyl group; and a substituted methyl or ethyl group, which are substituted by at least one Deputy, selected from carboxyl groups, methoxycarbonyl groups and ethoxycarbonyl groups; or R8and R9together represent unsubstituted alkylenes group having 4 or 5 carbon atoms, or substituted alkylenes group which has 4 or 5 carbon atoms and which t the groups and ethoxycarbonyl groups; R6is a hydrogen atom, or methyl group, ethyl group, methoxy group, ethoxypropane, a fluorine atom, or chlorine atom in the 6-position of the benzene ring; R7is a carboxyl group or tetrazol-5-strong group in the 2 - or 3-position of the benzene ring; and benzene ring has substituents represented by R6and R7is in the 4-position of the benzyl group with which it is associated.

Even more preferred classes of compounds of the present invention are the compounds of formula I and their salts and esters in which R1are an alkyl group having from 2 to 5 carbon atoms; R2and R3are independently selected from hydrogen atoms and alkyl groups having from 1 to 4 carbon atoms; R4is a hydrogen atom, methyl group, ethyl group, or alkanoyloxy group having from 1 to 5 carbon atoms; R5is a group of the formula-COOR5aor a group of the formula-CONR8R9in which R5ais a hydrogen atom; a methyl, ethyl or benzyl group; alkanolamines group where alcoolica part has from 1 to 5 carbon atoms; 1-(alkanoyloxy)ethyl gruperas alkoxides has from 1 to 4 carbon atoms; 1-(alkoxycarbonyl)ethyl group in which the alkoxy part has from 1 to 4 carbon atoms; [5-(phenyl - or methyl-)-2-oxo-1,3-dioxolan-4-yl]methyl group, or italicising group; R8and R9are independently selected from the group comprising hydrogen atoms, methyl groups, ethyl groups, methoxycarbonylmethylene group, ethoxycarbonylmethyl group and carboxymethyl group; or R8and R9taken together, represent tetramethylene, pentamethylene, 1-carboxytetramethyl or 1-carboxypolymethylene group; R6is a hydrogen atom, or R6represents a methyl group, a methoxy group, a fluorine atom or a chlorine atom in the 6-position of the benzene ring; R7is a carboxyl group or tetrazol-5-ilen group in 2-position of the benzene ring and the benzene ring, which contains the substituents represented by R6and R7is in the 4-position of the benzyl group with which it is associated.

Even more preferred classes of compounds of the present invention are the compounds of formula I and their salts esters, in which either R1is ethyl, sawn or butilkoi groupauto hydrogen or methyl group; R5is a group of the formula-COOR5ain which R5arepresents a hydrogen atom, pivaloyloxymethyl group, ethoxycarbonylmethyl group, 1-(ethoxycarbonyl)ethyl group, isopropoxycarbonyloxymethyl group, 1-(isopropoxycarbonyl)ethyl group, [5-methyl-2-oxo-1,3-dioxolan-4-yl] methyl group, or phthalidyl group; R6is a hydrogen atom; R7is a carboxyl group or tetrazol-5-ilen group in 2-position of benzene ring; and benzene ring has substituents represented by R6and R7is in the 4-position of the benzyl group with which it is associated; or R1is ethyl, sawn or butilkoi group; R2is ISO-propyl group or a t-butilkoi group; R3is a hydrogen atom; R4is a hydrogen atom or methyl group; R5is a group of formula-CONR8R9in which R8and R9are independently selected from the group consisting of: hydrogen atoms, methyl groups, methoxycarbonylmethylene, ethoxycarbonylmethylene group, and carboxymethyl group; R6is a hydrogen atom; R7is the / establishment, which has substituents, presents R6and R7is in the 4-position of the benzyl group with which it is associated.

The most preferred classes of compounds of the present invention are the compounds of formula I and their salts and esters in which R1is ethyl, sawn or butilkoi group; R2and R3both are methyl groups; R4is a hydrogen atom or methyl group; R5represents a group of formula-COOR5ain which R5ais a hydrogen atom, pivaloyloxymethyl group, ethoxycarbonylmethyl group, 1-(ethoxycarbonyl)-ethyl group, isopropoxycarbonyloxymethyl group, 1-(isopropoxycarbonyl)ethyl group, [5-methyl-2-oxo-1,3-dioxolan-4-yl]methyl group, or italicising group; R6is a hydrogen atom; R7is a carboxyl group or tetrazol-5-ilen group in 2-position of benzene ring; and benzene ring has substituents represented by R6and R7is in the 4-position of the benzyl group with which it is associated.

Compounds of the present invention may contain one or more asymmetric carbon atoms the molecular formula, however, the present invention includes the individual isomers and mixtures thereof, including racemates. When using stereospecific synthesis or by using optically active compounds as starting materials, can be directly obtained from the individual isomers; and on the other hand, if there is a mixture of isomers, the individual isomers may be obtained using standard techniques permissions.

Specific examples of the compounds of the present invention is represented by the following formula I-1, I-2, I-3, I-4, I-5 and I-6:

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< / BR>
< / BR>
In these formulas, the values of various groups of substituents given in the following tables 1-6, where table 1 relates to formula I-1, table 2 - a to the formula I-2 table 3 - the formula I-3, etc. In the above tables the following symbols are used: Ac is acetyl, Boz - benzoyl, Bu is butyl, - isobutyl, t - butyl, Buc - butoxycarbonyl - isobutoxide, Bz is benzyl, Et is ethyl, Etc - etoxycarbonyl, Fo - formyl, Fu - 2-furyl, cyclohexyl, Im - 4-imidazolyl, Me is methyl, Mec - methoxycarbonyl, Mod - (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl, Ph is phenyl, Phth - phthalidyl, Piv - pivaloyl, Pn - pentyl - cyclopentyl - isopentyl, Pr is propyl, - isopropyl, - isopropoxycarbonyl is their connection N 1-1, 1-2, 1-3, 1-9, 1-11, 1-12, 1-15, 1-22, 1-23, 1-24, 1-25, 1-27, 1-28, 1-31, 1-35, 1-36, 1-37, 1-39, 1-41, 1-49, 1-54, 1-56, 1-58, 1-59, 1-60, 1-61, 1-62, 1-82, 1-84, 1-98, 1-102, 1-103, 1-132, 1-133, 1-134, 1-138, 1-139, 1-140, 2-1, 2-2, 2-3, 2-4, 2-5, 2-6, 2-15, 2-16, 2-17, 2-18, 2-19, 2-20, 2-21, 2-22, 2-23, 2-24, 2-25, 2-26, 2-27, 2-28, 2-29, 2-30, 2-31, 2-32, 2-37, 2-38, 2-39, 2-40, 2-49, 2-50, 2-64, 2-65, 2-66, 2-67, 2-68, 2-69, 2-70, 2-71, 2-73, 2-74, 2-75, 2-76, 2-77, 3-1, 3-9, 3-10, 3-13, 3-14, 3-25, 3-26, 3-27, 3-35, 3-36, 3-39, 3-40, 3-51, 3-52, 3-53, 3-61, 3-65, 3-77, 3-78, 3-79, 3-87, 3-91, 3-103, 3-104, 3-105, 3-107, 3-109, 3-111, 3-112, 3-121, 3-127, 3-128, 3-129, 3-135, 3-136, 4-1, 4-4, 4-5, 4-6, 4-7, 4-8, 4-9, 4-10, 4-11, 4-14, 4-15, 4-16, 4-17, 4-18, 4-19, 4-20, 4-21, 4-22, 4-23, 4-25, 4-26, 4-27, 4-29, 4-31, 4-32, 4-33, 4-34, 4-35, 4-36, 4-38, 4-39, 4-41, 4-43, 4-44, 4-46, 4-49, 4-50, 4-51, 4-52, 4-53, 4-54, 4-55, 4-56, 4-59, 4-60, 4-61, 4-62, 4-63, 4-64, 4-65, 4-66, 4-67, 4-68, 4-70, 4-71, 4-72, 4-74, 4-76, 4-77, 4-78, 4-79, 4-80, 4-81, 4-83, 4-84, 4-85, 4-91, 4-96, 4-98, 4-99, 4-107, 4-109, 4-110, 4-112, 4-113, 4-114, 4-115, 5-1, 5-2, 5-3, 5-5, 5-6, 5-13, 5-14, 5-18, 5-19, 5-23, 5-24, 5-32, 5-33, 5-34, 5-36, 5-37, 5-44, 5-45, 5-49, 5-50, 5-54, 5-55, 5-63, 5-64, 5-65, 5-67, 5-68, 5-75, 5-76, 5-80, 5-81, 5-85, 5-86, 5-94, 5-95, 5-96, 5-98, 5-99, 5-106, 5-107, 5-111, 5-112, 5-116, 5-117, 5-125, 5-138, 5-151, 5-164, 5-177, 5-190, 5-203, 5-216, 5-229, 5-242, 5-255, 5-268, 5-281, 5-294, 5-307, 5-320, 5-348, 5-349, 5-350 and 5-351, from which the compounds NN 1-22, 1-25, 1-27, 1-28, 1-31, 1-35, 1-36, 1-37, 1-49, 1-54, 1-56, 1-58, 1-59, 1-132, 1-133, 1-134, 2-1, 2-2, 2-3, 2-5, 2-6, 2-15, 2-16, 2-17, 2-18, 2-19, 2-20, 2-21, 2-22, 2-23, 2-24, 2-25, 2-26, 2-27, 2-28, 2-29, 2-30, 2-31, 2-32, 2-65, 2-66, 2-67, 2-68, 2-69, 2-70, 2-71, 2-73, 2-74, 2-75, 2-76, 2-77, 3-1, 3-9, 3-10, 3-13, 3-14, 3-25, 3-26, 3-35, 3-39, 3-40, 3-52, 3-53, 3-61, 3-65, 3-77, 3-78, 3-79, 3-87, 3-91, 3-103, 3-104, 3-105, 3-107, 3-109, 3-111, 3-112, 4-4, 4-5, 4-6, 4-7, 4-11, 4-14, 4-15, 4-16, 4-17, 4-20, 4-29, 4-31, 4-32, 4-33, 4-34, 4-35, 4-36, 4-38, 4-39, 4-41, 4-43, 5-32, 5-36, 5-37, 5-44, 5-45, 5-63, 5-67, 5-68, 5-75, 5-76, 5-80, 5-81, 5-94, 5-98, 5-99, 5-106, 5-107, 5-348, 5-349, 5-350 and 5-351 are more preferred, and compounds N 1-28, 1-31, 1-35, 1-36, 1-49, 1-56, 1-58, 1-59, 1-132, 1-133, 1-134, 2-1, 2-2, 2-3, 2-5, 2-6, 2-15, 2-16, 2-17, 2-18, 2-19, 2-20, 2-21, 2-22, 2-23, 2-24, 2-25, 2-26, 2-27, 2-28, 2-29, 2-30, 2-31, 2-32, 2-65, 2-66, 2-67, 2-68, 2-69, 2-70, 2-71, 2-73, 2-74, 2-75, 2-76, 2-77, 3-1, 3-9, 3-10, 3-13, 3-14, 3-25, 3-26, 3-53, 3-61, 3-65, 3-77, 3-78, 4-29, 4-31, 4-32, 5-36 and 5-37 are even more preferred.

Of these the most preferred are the following compounds:

1-31. 2-Butyl-1-[(2'-carboxyphenyl-4-yl)methyl] -4-(1 - hydroxy-1-methylethyl)imidazole-5-carboxylic acid.

1-35. Pivaloyloxymethyl 2-butyl-1-[(2'-carboxyphenyl-4 - yl)methyl]-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate.

1-36. (5-Methyl-2-oxo-1,3-dioxolan-4-yl)methyl-2 - butyl-1-[2'-carboxyphenyl-4-yl)methyl]-4-(1-hydroxy-1-methylethyl) imidazole-5-carboxylate.

1-49. 1-[2'-Carboxyphenyl-4-yl)methyl]-4-(1-hydroxy-1 - methylethyl)-2-propylimidazol-5-carboxylic acid.

1-132. 1-[2'-Carboxyphenyl-4-yl)methyl] -2-ethyl-4-(1 - hydroxy-1-methylethyl)imidazole-5-carboxylic acid.

2-1. 4-(1-Hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(tetrazol - 5-yl)phenyl] phenyl}Mei-5-carboxylic acid.

2-2. 2-Butyl-4-(1-hydroxy-1-methylethyl)-1-{ 4-[2-(tetrazol - 5-yl)phenyl�-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}Mei-5-carboxylate.

2-16. Pivaloyloxymethyl 2-butyl-4-(1-hydroxy-1-methylethyl)- 1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}Mei-5-carboxylate.

2-17. (5-Methyl-2-oxo-1,3-dioxolan-4-yl)methyl-4-(1 - hydroxy-1-methylethyl)-2-propyl-1-{ 4-[2-(tetrazol-5-yl)phenyl] phenyl} Mei-5-carboxylate.

2-18. (5-Methyl-2-oxo-1,3-dioxolan-4-yl)methyl-2-butyl-4- (1-hydroxy-1-methylethyl)-1-{ 4-[2-(tetrazol-5-yl)phenyl] phenyl} Mei-5-carboxylate.

2-19. Ethoxycarbonylmethyl 4-(1-hydroxy-1-methylethyl)- 2-propyl-1-{ 4-[2-(tetrazol-5-yl)phenyl]phenyl}Mei-5-carboxylate.

2-21. Isopropoxycarbonyloxymethyl-4-(1-hydroxy-1-methylethyl)- 2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}Mei-5-carboxylate.

2-23. 1-(Ethoxycarbonyl)ethyl 4-(1-hydroxy-1-methylethyl)- 2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}Mei-5-carboxylate.

2-25. 1-(Isopropoxycarbonyl)ethyl 4-(1-hydroxy-1 - methylethyl)-2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}Mei - 5-carboxylate.

2-69. Pivaloyloxymethyl 2-ethyl-4-(1-hydroxy-1-methylethyl)- 1-{ 4-[2-(tetrazol-5-yl)phenyl]phenyl}Mei-5-carboxylate.

2-73. (5-Methyl-2-oxo-1,3-dioxolan-4-yl)methyl 2-ethyl - 4-(1-hydroxy-1-methylethyl)-1-{ 4-[2-(tetrazol-5-yl)phenyl] phenyl} methylimidazolidine-5-carboxylate.

3-25. (5-Methyl-2-oxo-1,3-dioxolan-4-yl)-methyl 1-[2'-carboxyphenyl-4-yl)-methyl]-4-(1-hydroxy-1-methylethyl)- 2-propylimidazol-5-carboxylate.

3-26. Phthalidyl 1-[2'-carboxyphenyl-4-yl)-methyl]-4-(1 - hydroxy-1-methylethyl)-2-propylimidazol-5-carboxylate.

4-29. 4-(1-Hydroxyethyl)-2-propyl-1-{ 4-[2-(tetrazol-5-yl) phenyl]phenyl} Mei-5-carboxylic acid.

4-31. Pivaloyloxymethyl 4-(1-hydroxyethyl)-2-propyl-1-{4-[2- (tetrazol-5-yl)phenyl]phenyl}Mei-5-carboxylate.

4-32. (5-Methyl-2-oxo-1,3-dioxolan-4-yl)methyl 4-(1-hydroxyethyl)-2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl} Mei-5-carboxylate

and their pharmaceutically acceptable salts.

Compounds of the present invention can be obtained by standard methods, typically used in the preparation of compounds of this type.

For example, in General terms, the compounds can be obtained by reaction of compounds of formula II

< / BR>
where R1defined above;

Rdis a group of the formula

< / BR>
where R2, R3and R4defined above, or Rdrepresents a group of formula-COORfwhere Rfis carboxyamide group, a group of the formula-COR2where R2op the OORfwhere Rfdefined above,

with the compound of the formula III

< / BR>
where R6defined above;

R7ais a protected carboxyl group, cyano, protected tetrazol-5-yl group, carbamoyl group or alkylcarboxylic group;

X is a halogen atom,

in the result, get the connection formula IV

< / BR>
where Rd, Re, R1, R6and R7adefined above;

and in any order, followed by removal of protective groups and optionally converting the specified group Rdin the group of the formula

< / BR>
where R2, R3and R4defined above,

and, if necessary, with the conversion of the specified group Rethe group R5, the transformation of the specified group R7athe group R7or by alkylation or acylation of the hydroxyl group in the R4obtaining the compounds of formula I; and optionally followed by salt formation or esterification of the obtained product.

Preferably, if Reis a protected carboxyl group, when R7ais a protected carboxyl group, cyano, protected tetrazolyl group, carbamoyl group or the Oh group or protected tetrazolyl group.

In particular, the compounds of the present invention can be obtained in accordance with the following reaction schemes A - F.

Reaction scheme A.

In this reaction scheme, the compound of the formula I are obtained by reaction of the imidazole-5-carboxylic acid or a complex ester of the formula V with biphenylmethanol formula III, followed, if necessary, removing the protective groups, transformation groups of the formula-COOR5ain any other group, represented by R5, transformation groups represented by R7ain any other group, represented by R7and/or by alkylation or acylation of the hydroxy-group in R4as shown below.

Reaction scheme A.

< / BR>
< / BR>
In the above reaction scheme, R1, R2, R3, R4, R5, R5a, R6, R7, R7aand X is defined above, and R5apreferably not a hydrogen atom.

If R7ais a protected carboxyl group, the protective group may be any ester residue of illustrated above for R5a. Alternative, R7acan be carbamoyl group or substituted carbamoyl group of the formula-CO the th group, illustrated above for R1. Examples of such carbamoyl groups which may be represented by R7aare carbarnoyl, methylcarbamoyl, ethylcarbitol, propellerblades, butylcarbamoyl, t-butylcarbamoyl, intercalator, t-intercalator and exaltabitur, of which preferred are carbarnoyl, t-butylcarbamoyl, and t-intercalator. If R7ais protected tetrazolyl group, the protective group may be any protective group that is generally used to block tetrazolyl groups in the standard connections of this type. Examples of suitable protective groups are kalkilya groups defined and illustrated above for R2however , preferred are benzyl, diphenylmethylene (benzhydryl) or triphenylethylene (trityl) group, and most preferred is triticina group.

X is a halogen atom, preferably a chlorine atom, bromine or iodine.

In stage A1 mentioned reaction scheme, the compound of formula Ia get through the reaction of the imidazole-5-carboxylate compounds of the formula V with biphenylmethane compound of formula III. Typically and preferably, the reaction protectfile carried out in the presence of a solvent. In principle, there is no particular restriction on the nature of the solvent, provided that it does not adversely affect the reaction or the reagents and has the ability to dissolve the reagents, at least to a certain extent. Examples of suitable solvents include: hydrocarbons, preferably aromatic hydrocarbons such as toluene; ethers, such as tetrahydrofuran or dioxane; alcohols, such as methanol, ethanol or t-butanol; amides such as N,N-dimethylacetamide, N,N-dimethylformamide, or N-methyl-2-pyrrolidinone; ketones, such as acetone or methyl ethyl ketone; NITRILES, such as acetonitrile; and sulfoxidov, such as dimethylsulfoxide. Of these solvents, preferred are amides, ketones, NITRILES and sulfoxidov.

Similarly, the nature of the base used in the reaction is not critical and this reaction can be used any base capable of reacting with the acid H-X. preferred Examples of bases that can be used in the reaction, are alkali metal carbonates such as sodium carbonate or potassium; alkali metal hydrides such as sodium hydride, potassium or lithium; alkaline alkoxides m is materials, such as sodium bicarbonate or potassium. Of these compounds, preferred are carbonates of alkali metals, hydrides of alkali metals, or alkoxides of alkali metals.

This reaction may proceed in a wide temperature range, and a specific value of temperature is not critical to the present invention. But mostly suitable temperature of the reaction is from -10 to 100oC, and more preferred is a temperature from 0 to 80oC. the Time required for the reaction may also vary widely, depending on many factors, namely the reaction temperature and the nature of the reagents and solvent involved in the reaction. However, in the preferred conditions for the reaction time is from 30 minutes to 24 hours, and more preferably from 1 to 16 hours

After completion of the reaction, the desired compound of formula Ia can be recovered from the reaction mixture by standard means. One such method is that removing the solvent by distillation under reduced pressure; mixing the obtained residue with water; the residue is extracted with vodonasosnaya solvent, such as at the La by distillation. If necessary, the resulting product can be purified by standard methods, for example by recrystallization or by using chromatographic techniques, such as preparative thin-layer chromatography or column chromatography.

Stage A2 may include one or (if appropriate) more of the following reactions:

(I) removing carboxyamide groups selectively or indiscriminately from a group of the formula-COOR5agroups and/or R7ato convert it (or them) into the free carboxyl group represented by R5or R7;

(II) esterification of any specified free carboxyl group to obtain the group, such as for example illustrated above for R5;

(III) the transformation specified free carboxyl groups represented by R5in the group of the formula-CONR8R9;

(IV) removing tetrasilicate group;

(V) the transformation of ceanography represented by R7ain tetrazolyl group;

(VI) transforming monoalkylamines group or carbamoyl group represented by R7afirst in the cyano, and then in tetrazolyl group;

(VII) if R4is a Tr is alkoxyethyl group, halogenoacetyl group, tetrahydropyranyloxy group, tetrahydropyranyloxy group, tetrahydrocannibinol group, tetrahydrofuryl group or substituted tetrahydropyranyl, tetrahydropyranyl, tetrahydrocannabinol or tetrahydrofuryl group having a halogen or alkoxylation, all of which can be considered as hydroxyamine groups, then carry out the removal of the protective group to obtain compounds in which R4is a hydrogen atom; and

(VIII) if R4is a hydroxyl group, carry out the alkylation or acylation of this group.

(I). Remove carboxyamide group.

The type of reaction used to remove carboxyamide group depends on the nature of the deleted group, and is well known to specialists in the field of organic synthesis.

For example, if carboxyamide group is kalkilya group, for example benzyl or p-nitrobenzyl group, this protective group can be removed by catalytic reduction in the presence of hydrogen at atmospheric pressure or Surgutgazprom pressure, for example up to 5 ATM. Usually predpochtitelnei acid, such as acetic acid and in the presence of a catalyst. In this reaction, can be used any catalyst commonly used for catalytic hydrogenation or recovery, preferably palladium charcoal or platinum oxide.

If carboxyamide group is t-butyl or diphenylmethyl, this group can be removed by reaction of the protected compound with an acid (preferably a mineral acid, such as chloroethanol or sulfuric acid, or organic acid, such as p-toluensulfonate acid) in an inert solvent (preferably in an alcohol, such as methanol or ethanol; an ether, such as tetrahydrofuran or dioxane; water or a mixture of water and one or more of the above organic solvents).

If karbassian group is a silyl group, it can be a group of the formula-SiRaRbRcin which Ra, Rband Rcdefined above. In this case, the protective group can be removed by reaction of the protected compound with an acid (preferably a mineral acid, such as acetic acid, triperoxonane acid, methanesulfonate acid or eacce proceeds in an inert solvent (preferably in simple ether, such as tetrahydrofuran or dioxane; an alcohol such as methanol or ethanol; amide, such as N,N-dimethylformamide or N, N-dimethylacetamide; water or a mixture of water and one or more of the solvents listed above).

If carboxyamide group is an ester residue, the protective group can be removed by hydrolysis using a base (preferably a hydroxide of an alkali metal such as lithium hydroxide, sodium hydroxide or potassium hydroxide, or carbonate of an alkali metal such as sodium carbonate or potassium carbonate) in an inert solvent (preferably in an alcohol, such as methanol or ethanol; an ether such as tetrahydrofuran or dioxane; water; or a mixture of water and one or more organic solvents mentioned above). If R4is an acyl group, it may be removed during the reaction.

The reaction can be carried out in a wide temperature range, and the exact value of the reaction temperature does not play a decisive role. Mainly suitable reaction temperature is a temperature from 0oC to 100oC, and more preferred is from room temperature up to 60oC. the reaction can also Shiro is vorites. However, under the preferred conditions of the reactions mentioned above, this period is from 30 min to 24 h, and more preferably from 1 to 16 hours

After completion of the reaction, the desired compound may be isolated by standard methods, the choice of which depends on the nature of the reaction. For example, if the unlocking is carried out by catalytic reduction, the target product can be recovered by filtration of the catalyst and distillation of the solvent. If the unlocking is performed with the use of acid, the target product can be isolated by collecting the precipitate in the reaction system by filtration or by concentration of the reaction mixture. If the unlocking is carried out by alkaline hydrolysis, the target product can be isolated by removal of the solvent, and then neutralizing the remainder of the aqueous acid, followed by collection of the resulting sludge in an aqueous solvent by filtering; alternatively, this product may be isolated by neutralization of the aqueous layer obtained by extraction of the reaction mixture of water-immiscible organic solvent (such as ethyl acetate or diethyl ether), and then extracting naturalchoice solvent. If necessary, the reaction product can be purified by standard methods, for example by recrystallization or by using various chromatographic techniques, such as preparative thin-layer chromatography or column chromatography.

Each of the protective groups represented by R5aand R7acan be selectively eliminated with proper selection of protective groups and specific reaction conditions in order to remove it.

(II). Etherification.

If the compound contains one or more free carboxyl groups, this group or these groups can be tarifitsirovana standard methods known in organic chemistry. For example, this reaction can be carried out by reaction of the corresponding carboxylic acid with the compound of the formula R5b-Y [where R5bcan be any of the groups defined above for R5aaddition of a hydrogen atom and Y is a halogen atom such as chlorine atom, bromine or iodine, a group of the formula-OSO3R5b(where R5bdefined above) or sulfonyloxy, such as methanesulfonate or p-toluensulfonate] . The reaction is carried out in Pris is the alkali metal, such as sodium carbonate or potassium; or bicarbonate of an alkali metal such as sodium bicarbonate or potassium bicarbonate. Typically and preferably, the reaction is carried out in an inert solvent (preferably in amide, such as N,N-dimethylformamide or N,N-dimethylacetamide; halogenated hydrocarbon, preferably halogenated aliphatic hydrocarbon, such as methylene chloride; a ketone, such as acetone or methyl ethyl ketone; or an ether such as tetrahydrofuran or dioxane). If desired ester group is an alkyl group, the reaction is carried out by reaction of carboxylic acid with the appropriate diallylsulfide.

The reaction can be carried out in a wide temperature range, and the exact value of the reaction temperature does not play a decisive role. Mainly suitable reaction temperature is from 0oC to 120oC, and more preferably from 20oup to 80oC. the Time of reaction can vary widely depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. However, the preferred reaction conditions mentioned above, this period is 30 >is an alkyl group, the esterification reaction can be carried out through the interaction of carboxylic acids with C1-C6-alcohol, such as methanol, ethanol, propanol or hexanol, in the presence of an acid catalyst, such as chlorodrol or sulfuric acid, in an inert solvent (for example, in one of the C1-C6-alcohols, which can be used as a starting material described above; halogenated hydrocarbon, such as methylene chloride; or an ether such as tetrahydrofuran or dioxane) at 0 - 100oC for 1 to 24 h, or by reaction of the corresponding carboxylic acid with a halogenation agent (for example, pentachloride phosphorus, thionyl chloride or oxalicacid) in an inert solvent (for example, halogenated hydrocarbon such as methylene chloride, an ether such as tetrahydrofuran or dioxane; or an aromatic hydrocarbon such as benzene or toluene) at about room temperature over a period of time from 30 min to 5 h to obtain the corresponding acylhalides, which is then subjected to reaction with the corresponding alcohol in an inert solvent (e.g. benzene or methylene chloride) in the presence of a base (naprimeir at room temperature over a period of time from 30 minutes to 10 hours. The target compound can be recovered by standard means, for example by the method described above for stage A1.

(III). Education carbamoyl groups.

Conversion of carboxyl groups represented by R5in the group of the formula-CONR8R9where R8and R9defined above, can be carried out by standard methods, for example by reaction of compounds of carboxylic acids, in which R7group is protected, with a compound of formula VI

R8R9NH,

where R8and R9defined above.

This reaction involves the formation of the peptide bond and is well known in organic chemistry. It can be carried out in an inert solvent (preferably in a halogenated hydrocarbon, more preferably in a halogenated aliphatic hydrocarbon, such as methylene chloride or chloroform; complex ester such as ethyl acetate; a simple ether, such as tetrahydrofuran or dioxane; or amide, such as N,N-dimethylacetamide or N, N-dimethylformamide) in the presence of a condensing agent.

Examples of the condensing agents which can be used in this reaction are carbodiimide connection such as diphenylphosphoryl or diethylphosphoramidite; carbonyldiimidazole; and triphenylphosphine-diethylazodicarboxylate. Of these the most preferred are carbodiimide and diphenylphosphoryl. If you are using phosphorylase connection, then the reaction is preferably carried out in the presence of a tertiary amine such as triethylamine or N-methylmorpholine.

Alternatively, in this stage, the reaction can be carried out by reaction of carboxylic acid with (lower)alkylchlorosilanes, such as etelcharge.com or isobutylacetate, in the presence of a tertiary amine such as triethylamine or N-methylmorpholine, obtaining mixed andguided acid; or by reaction of carboxylic acid with N-hydroxysuccinimide, N-hydroxybenzotriazole or p-NITROPHENOL or etc., in the presence of a carbodiimide such as N,N-dicyclohexylcarbodiimide, to obtain the corresponding active complex ester, and subsequent reaction of the mixed acid anhydride or an active complex with ether aminoven compound of formula VI.

As another alternative, the reaction in this stage can be carried out by reaction of carboxylic solvent, for example, halogenated hydrocarbon such as methylene chloride; simple ether, such as tetrahydrofuran or dioxane; or an aromatic hydrocarbon such as benzene or toluene to obtain the corresponding acylhalides, with subsequent reaction of allvalid with aminoven compound of formula VI.

All these reactions may be carried out in a wide temperature range, and the exact temperature does not play a decisive role. Mainly suitable reaction temperature is from -20 to 100oC, and more preferably from -5 to 50oC. the Time of reaction can vary widely depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. However, the preferred reaction conditions mentioned above, this period is from 30 min to 24 h, and more preferably 1 to 16 hours

After completion of the reaction the resulting product can be isolated from the reaction mixture by standard means. For example, insoluble in the reaction system, the material is filtered; the filtrate add vodorazreshimye organic solvent such as ethyl acetate, and water; the organic layer of the solvent is separated and soluction the target product. If necessary, the reaction product can then be purified by standard methods, for example by recrystallization or by using various chromatographic techniques, for example, preparative thin-layer chromatography or column chromatography.

(IV). Remove tetrasilicate groups.

This reaction can be carried out by reaction of the protected compound with an acid. Typically and preferably, the above reaction is carried out in an inert solvent.

The reaction is preferably carried out in the presence of a solvent, provided that it does not adversely affect the reaction or the reagents and has the ability to dissolve the reagents, at least to a certain extent. Examples of suitable solvents are organic acid such as acetic acid; a simple ether such as tetrahydrofuran or dioxane; an alcohol such as methanol, ethanol or t-butanol; or a mixture of any two or more of these solvents. Of these solvents, preferred are water, organic acid, alcohol, or their mixture.

Basically there are no particular restrictions on the acid, the equipment examples of such acids are organic acids, such as acetic acid, formic acid, oxalic acid, methanesulfonate acid, p-toluensulfonate acid or triperoxonane acid, and inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid or phosphoric acid. Of them, preferred are acetic acid, formic acid, triperoxonane acid or hydrochloric acid.

The reaction may proceed in a wide range of temperatures and the precise temperature value does not play a decisive role for the present invention. Basically, a suitable reaction temperature is from -10 to 120oC, and more preferably 0 - 100oC. the Time required for the reaction may also vary widely and depends on many factors, particularly the reaction temperature and the nature of the reagents and solvent. However, under the preferred conditions of the reactions mentioned above, this period is 0.5 - 24,0 h, and more preferably 1 to 16 hours

After completion of the reaction the resulting product can be isolated from the reaction mixture by standard means. For example, after removal of the solvent the residue is dissolved in water and vodosmeshivayuschego organic dissolve once solvent receive the desired connection. If necessary, the reaction product can be purified by standard methods, for example by recrystallization or by using various chromatographic techniques, such as preparative thin-layer chromatography or column chromatography.

(V). Conversion ceanography in tetrazolyl group.

In this stage, a cyano turn in tetrazolyl group through reaction of cyanocobalamine with the azide of an alkali metal.

The reaction is preferably carried out in the presence of a solvent. In principle, there is no particular restriction on the nature of the solvent, provided that it does not adversely affect the reaction or the reagents and has the ability to dissolve the reagents, at least to a certain extent. Examples of suitable solvents are amides, such as N,N-dimethylformamide or N, N-dimethylacetamide; ethers, such as dioxane or 1,2-dimethoxyethane; and sulfoxidov, such as dimethylsulfoxide.

Examples of suitable alkali metal azides are lithium azide, sodium azide and potassium azide, of which preferred is sodium azide. On the number azide of an alkali metal it is up to the up to 3 equivalents of alkali metal azide to one equivalent of cyanocobalamine.

It is preferable that the reaction proceeded in the presence of ammonium halide such as ammonium fluoride, ammonium chloride or bromide of ammonium, of which preferred is ammonium chloride. The amount of ammonium halide no specific restrictions, but typically use 0.5 to 2 equivalents, and more preferably from 1 to 1.2 equivalents of ammonium halide per one equivalent of cyanocobalamine.

The reaction may proceed in a wide range of temperatures and the precise temperature value does not play a decisive role for the present invention. Mainly suitable reaction temperature is 70 - 150oC, and more preferably 80 to 120oC. the Time required for the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. However, the preferred reaction conditions mentioned above, this period is from 10 hours to 7 days, and more preferably from 1 to 5 days.

Alternatively, the cyano may be converted into tetrazolyl group through interaction cyanocobalamine with azide triamcinolone or azide triarylamine followed the connection with azide triamcinolone or azide triarylamine usually and preferably carried out in the presence of a solvent. In principle, there is no particular restriction on the nature of the solvent, provided that it does not adversely affect the reaction or the reagents and has the ability to dissolve these reagents, at least to a certain extent. Examples of suitable solvents are hydrocarbons, which may be aliphatic or aromatic hydrocarbons, such as benzene, toluene, xylene or heptane; halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as 1,2-dichloroethane or chloroform; ethers, such as dioxane or 1,2-dimethoxyethane; amides such as N, N-dimethylformamide or N,N-dimethylacetamide; esters such as ethyl acetate or butyl acetate.

Although the nature of the azide triamcinolone or azide triarylamine no specific limitation, and this reaction can be used for any connection of this type, however, is preferred azide triamcinolone in which each alkyl group (which may be the same or different, and preferably the same) has from 1 to 4 carbon atoms, such as azide trimacinolone, azide teatralova or azide anti; or azide triarylamine in which each is to they were defined above in relation to aryl groups, which can be represented by R2, preferably phenyl or substituted phenyl groups; and examples of the specified azide triarylamine is azide triphenylamine and azide traileryou. The number azide triamcinolone or azide triarylamine is not critical, although it is preferable to use from 1 to 3 equivalents per equivalent of cyanocobalamine, and more preferably from 1 to 2 equivalents to one equivalent. cyanocobalamine.

The reaction cyanocobalamine with azide triamcinolone or trialyou can be carried out in a wide temperature range, and the exact temperature does not play a decisive role for the present invention. Basically, a suitable reaction temperature is 60 - 150oC, and more preferably 80 to 120oC. the Time required for the reaction may also vary widely, depending on many factors, in particular on the reaction temperature and the nature of the reagents and solvent. However, the preferred reaction conditions mentioned above, this period is from 8 h to 7 days, and more preferably from 1 to 5 days.

Tin-containing compound obtained by the above reasonalbe connection. In the reaction of the specified type can be used any acid, base or a fluoride of an alkali metal, and examples of suitable compounds are: acids, in particular mineral acids such as hydrochloric acid or sulfuric acid; bases, including inorganic bases such as alkali metal carbonates and bicarbonates of the alkali metal (e.g. sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate) or hydroxides of alkali metals (e.g. sodium hydroxide or potassium); the fluorides of alkali metal such as lithium fluoride, sodium fluoride or potassium fluoride.

The reaction is normally and preferably carried out in the presence of a solvent. In principle, there is no particular restriction on the nature of the solvent, provided that it does not adversely affect the reaction or the reagents and has the ability to dissolve these reagents, at least to a certain extent. Examples of suitable solvents are the solvents listed above for the reaction of cyanocobalamine with azide triamcinolone or triarylamine, and other solvents, such as alcohols, for example methanol or ethanol, water or aqueous alcohols. The reaction can prohibitin. Mainly suitable for implementing the reaction temperature is 0 - 100oC, and preferably room temperature. The time required to perform the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. However, the preferred reaction conditions mentioned above, this period is from 30 minutes to 3 days, and more preferably 1 to 24 hours

Another alternative way of turning ceanography in tetrazolyl group involves the reaction of cyanocobalamine with halide triamcinolone or triarylamine in the presence of alkali metal azide, followed by treatment of compounds of tin acid, base or fluoride of an alkali metal.

The reaction cyanocobalamine with halide triamcinolone or triarylamine in the presence of alkali metal azide is usually and preferably proceeds in the presence of a solvent. In principle, there is no particular restriction on the nature of the used solvent, provided that it does not adversely affect the reaction or the reagents and has the ability to dissolve these reagents can be aliphatic or aromatic hydrocarbons, such as benzene, toluene, xylene or heptane; halogenated hydrocarbons, particularly halogenated aliphatic hydrocarbons, such as 1,2-dichloroethane or chloroform; ethers, such as dioxane or 1,2-dimethoxyethane; ketones, such as acetone or methyl ethyl ketone; amides such as N,N-dimethylformamide or N,N-dimethylacetamide; esters such as ethyl acetate or butyl acetate.

Although there is no particular restriction on the nature of the halide triamcinolone or triarylamine, and in the reaction of the specified type can be used any of these compounds, however, the preferred compounds are the halide triamcinolone in which each alkyl group (which may be the same or different, preferably identical) have from 1 to 4 carbon atoms, such as chloride trimethylamine, bromide trimacinolone, chloride teatralova or the presence of TBT chloride; or a halide triarylamine, in which each of the aryl groups (which may be the same or different, preferably identical) are such as they were defined above in relation to the aryl groups for P, and is preferably phenyl or substituted phenyl group; examples of the above which of halide triamcinolone or triarylamine, used in the reaction is not critical, although it is preferable to use from 1 to 3 equivalents to one equivalent of cyanocobalamine, and more preferably from 1 to 2 equivalents to cenocoeliinae.

There is also no particular restrictions on the azide of an alkali metal used in this reaction. Examples of such azide are lithium azide, sodium azide and potassium azide, of which preferred is sodium azide. The number of used alkali metal azide is not critical, however, it is preferable to use from 1 to 3 equivalents to one equivalent of cyanocobalamine, and more preferably from 1 to 3 equivalents to one equivalent of cyanocobalamine.

The reaction cyanocobalamine with halide triamcinolone or triarylamine in the presence of alkali metal azide may take place in a wide temperature range, and the exact temperature is not important for the present invention. Basically, a suitable temperature for the implementation of the reaction is 60 - 150oC, and preferably 80 to 120oC. the Time required to perform the reaction may also vary widely, depending on many factors, in particular the pace of the tion reaction, above, this period is from 8 h to 7 days, and more preferably from 1 to 5 days.

Tin-containing compound obtained by the above reaction is then treated with acid, base or a fluoride of an alkali metal for its transformation into tetrazolium connection. This reaction is basically a similar reaction of tin-containing compounds (obtained by reaction of cyanocobalamine with azide triamcinolone or triarylamine) with acid, base or a fluoride of an alkali metal and can be carried out using the same solvents and reaction conditions.

(VI). Conversion alkylcarboxylic group or carbamoyl group in the cyano.

To turn alkylcarboxylic group in the cyano, alkylcarboxylic compound is subjected to reaction with a halogen compound and a halogenation agent, preferably gloriouse agent, such as oxacillin, phosphorus oxychloride or sulphonylchloride. The number of halogen compounds is not critical, although it is preferable to use from 1 to 3 equivalents, and more preferably from 1 to 2 equivalents to the one equivale is orites. In principle, there is no particular restriction on the nature of the solvent, provided that it does not adversely affect the reaction or the reagents and has the ability to dissolve these reagents, at least to a certain extent. Examples of suitable solvents are hydrocarbons, which may be either aliphatic and aromatic hydrocarbons, such as benzene, toluene, xylene or heptane; halogenated hydrocarbons, particularly halogenated aliphatic hydrocarbons, such as methylene chloride or chloroform; ethers, such as dioxane, tetrahydrofuran or diethyl ether; and esters such as ethyl acetate or butyl acetate.

The reaction may proceed in a wide range of temperatures and the precise temperature value does not play a decisive role for the present invention. Basically, a suitable temperature is from -10 to 100oC, and more preferably from 0 to 50oC. the Time required to perform the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. However, the preferred reaction conditions, pointed to by the of carbamoyl group in the cyano, carbamoyl connection is subjected to interaction with a dehydrating agent such as acetic anhydride, triperoxonane anhydride, methanesulfonyl anhydride, trifluromethanesulfonate anhydride, oxalicacid, or sulphonylchloride, in the presence of an organic amine, such as triethylamine, pyridine or N-methylmorpholine.

The reaction is preferably carried out in the presence of a solvent. In principle, there is no particular restriction on the nature of the solvent, provided that it does not adversely affect the reaction or the reagents and has the ability to dissolve these reagents, at least to a certain extent. Examples of suitable solvents are hydrocarbons, which can be both aliphatic and aromatic hydrocarbons, such as benzene, toluene, xylene or heptane; halogenated hydrocarbons, particularly halogenated aliphatic hydrocarbons, such as methylene chloride or chloroform; ethers, such as dioxane, tetrahydrofuran or diethyl ether; and esters such as ethyl acetate or butyl acetate.

The reaction may proceed in a wide range of temperatures, and the precise value Talaat from -10 to 100oC, and more preferably from 0 to 50oC. the Time required to perform the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. However, the preferred reaction conditions mentioned above, this period is from 10 min to 16 h, and more preferably from 30 minutes to 6 o'clock

Target product specified reaction can be isolated from the reaction mixture by standard means, for example by neutralizing a mixture of a weak base, such as sodium bicarbonate, followed by treatment of the product in a manner analogous to that described for stage A1 of reaction scheme A.

Thus obtained cenocoeliinae can then be converted into the corresponding tetrazolium connection using the reactions described above.

(VII). Remove hydroxyamine groups.

If R4is tizamidine silyl group, aranceles group, acyl group, alkoxymethyl group, tetrahydropyranyloxy group, tetrahydropyranyloxy group, tetrahydrocannibinol group, tetrahydrofuryl group, or substituted then it is carbonated is expressed as hydroxyamine group, the protective group can be removed with the formation of compounds in which R4is a hydrogen atom. The type of reaction used for the removal of the protective group, depends on the nature of the protective group, and to unlock the connections of the specified type can be used reactions, well known to experts.

If hydroxyamino group is a silyl group, it can be removed by treating the protected compound with the compound capable of forming anion fluoride, such as tetrabutylammonium fluoride. The reaction is preferably carried out in the presence of a solvent. In principle, there is no particular restriction on the nature of the solvent, provided that it does not adversely affect the reaction or the reagents, and has the ability to dissolve these reagents, at least to a certain extent. Examples of suitable solvents are ethers, such as tetrahydrofuran or dioxane.

The reaction may proceed in a wide range of temperatures and the precise temperature value does not play a decisive role. Basically, the suitable temperature is room temperature. The time required to perform the reaction, also Molsheim reagents and solvent. However, the preferred reaction conditions mentioned above, this period is 10 - 18 o'clock

If hydroxyamino group is kalkilya group, the unlocking can be effected by catalytic reduction at 0 - 80oC, and more preferably at 10 to 60oC, in a solvent in the presence of hydrogen and catalyst.

The reaction is preferably carried out in the presence of a solvent. In principle, there is no particular restriction on the nature of the solvent, provided that it does not adversely affect the reaction or the reagents, and has the ability to dissolve these reagents, at least to a certain extent. Examples of suitable solvents are alcohols, such as methanol, ethanol, or isopropanol; ethers, such as diethyl ether, tetrahydrofuran or dioxane; aromatic hydrocarbons, such as toluene, benzene or xylene; aliphatic hydrocarbons, such as hexane or cyclohexane; esters such as ethyl acetate or propyl; fatty acids, such as acetic acid; or a mixture of water and one or more of these organic solvents.

In this Rei. Examples of preferred catalysts are palladium charcoal, skeletal Nickel catalyst for hydrogenation, platinum oxide, platinum black, alumina, rhodium plated, a complex of triphenylphosphine and rhodium chloride and palladium barium sulfate.

Used in the reaction, the hydrogen pressure is not critical and can vary within wide limits, although the reaction preferably takes place at a pressure which exceeds atmospheric pressure in 1 to 3 times.

The reaction may proceed in a wide temperature range, and the exact temperature is not important for the present invention. Basically, a suitable temperature is 0 - 100oC, and more preferably 10 - 50oC. the Time required to perform the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. However, the preferred reaction conditions mentioned above, this period ranges from 5 min to 24 h, and more preferably from 30 min to 16 h

If hydroxyamino group is an aliphatic acyl group, aromatic allisonoliviat.

In this case, can be used in any connection, unless it has an adverse impact on other parts of the connection. Examples of preferred bases are alkoxyl metals, in particular, alkoxides of alkali metals such as sodium methoxide; carbonates of alkali metals such as sodium carbonate or potassium hydroxide; hydroxides of alkaline metals such as sodium hydroxide or potassium hydroxide; and ammonia, preferably in the form of aqueous ammonia or in the form of a concentrated solution of ammonia in methanol.

The reaction is preferably carried out in a solvent. In principle, there is no particular restriction on the nature of the solvent, provided that it does not adversely affect the reaction or the reagents and has the ability to dissolve these reagents, at least to a certain extent. Examples of suitable solvents include water; organic solvents, such as alcohols (e.g. methanol, ethanol or propanol) or ethers (e.g. tetrahydrofuran or dioxane; or a mixture of water and one or more of the above organic solvents.

The reaction may proceed in a wide range of temperatures, and the precise value is doctitle 0 - 60oC. the Time required to perform the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. However, the preferred reaction conditions mentioned above, this period is 1 to 20 hours, and preferably 1 to 16 hours

If hydroxyamino group is alkoxymethyl group, alkoxycarbonyl group, halogenoacetyl methyl group, tetrahydropyranyl group, tetrahydropyranyl group, tetrahydrofuranyl group, tetrahydroquinoline group or substituted tetrahydropyranyl, tetrahydropyranyl, tetrahydrofuranyl or tetrahydroquinoline group having at least one halogen or alkoxylation, it can be removed by treating the protected compound with an acid.

Particular restrictions on the acid used in this reaction does not exist, and in this case can be used any acid Branstad. Examples of preferred acids are inorganic acids, in particular mineral acids such as hydrochloric acid or sulfuric acid; and organizationa acid. In this reaction can be also used strong cation exchange resin acids, such as Dowex 50W (trade mark).

The reaction is preferably carried out in the presence of a solvent. In principle, there is no particular restriction on the nature of the solvent, provided that it does not adversely affect the reaction or the reagents and has the ability to dissolve these reagents, at least to a certain extent. Examples of suitable solvents are alcohols, such as methanol or ethanol; ethers, such as tetrahydrofuran or dioxane; organic acids such as formic acid or acetic acid; and mixtures of water and one or more of these solvents.

The reaction may proceed in a wide range of temperatures and the precise temperature value does not play a decisive role. Basically, a suitable temperature is 0 to 50oC. the Time required to perform the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. However, the preferred reaction conditions mentioned above, this period is from retene can be isolated from the reaction mixture by standard means, the choice of which depends on the nature of the reaction the reaction medium. One such method is that the reaction mixture is neutralized, remove any insoluble material, which may be present in the mixture, for example, by filtration; add vodorazreshimye organic solvent; washed with water; and finally the solvent is distilled off. If necessary, the obtained product may be purified by standard methods, for example by recrystallization or by using various chromatographic techniques, such as preparative thin layer chromatography or column chromatography.

Sometimes along the way, in the conditions used to remove hydroxyamino group, can be unlocked protected carboxypropyl.

(VIII). Alkylation and acylation of hydroxy groups.

Alkylation of the hydroxy-group can be carried out by reaction of hydroxycodone with alkylhalides, in which the alkyl group has from 1 to 6 atoms, preferably methyliodide, ethyliodide, ethylbromide, propyliodide, propyl bromide or mutiliation, or diallylsulfide (in which the alkyl groups have from 1 to 6 carbon atoms and can be one of the

The reaction is preferably carried out in the presence of a solvent. In principle, there is no particular restriction on the nature of the solvent, provided that it does not adversely affect the reaction or the reagents and has the ability to dissolve these reagents, at least to a certain extent. Examples of suitable solvents are amides, such as N, N-dimethylformamide, N,N-dimethylacetamide, or N-methylpyrrolidone; ketones, such as acetone or methyl ethyl ketone; or sulfoxidov, such as dimethylsulfoxide.

The reaction is carried out in the presence of a base, the nature of which is not critical, providing it does not adversely affect the reactants or products. Examples of preferred bases are the hydrides of alkali metals, such as sodium hydride, potassium hydride or lithium hydride. The reaction may proceed in a wide temperature range, and the exact temperature is not important for the present invention. Mainly suitable for the implementation of the reaction temperature is 0 - 120oC, and preferably 20 - 80oC. the Time required for the implementation of the reaction, also can vary widely dependent on the However, the preferred reaction conditions, above, this period is from 30 min to 24 h, and more preferably 1 to 16 hours

The acylation of carboxypropyl can also be carried out by standard methods commonly used in organic chemistry. For example, it can be made by reaction of hydroxyl compounds with alkanolamine containing from 2 to 6 carbon atoms, such as acetylchloride, propisochlor, butylbromide, valerianic or hexanoate; with a carboxylic acid anhydride, in which the group derived from the carboxylic acid contains from 1 to 6 and preferably from 2 to 6, carbon atoms, such as a mixed anhydride of formic and acetic acids, acetic anhydride, propionic anhydride acid anhydride valerianic acid or anhydride hexanoic acid; alkoxycarbonylmethyl, where alkoxygroup contains from 1 to 6 carbon atoms, such as methoxycarbonylamino, methoxycarbonylamino, ethoxycarbonylphenyl, propoxycarbonyl, butoxycarbonyl or hexyloxybenzoic; arylcarboxamide, such as benzoyl chloride, benzylbromide or aftercare; with halogen or alkoxyalkanols containing from 2 to 6 atoms of plerotserkoida, containing from 3 to 6 carbon atoms, such as akriloilkhlorida, methacryloylamido, 3-methyl-2-butanolate or 2-methyl-2-butanolate.

The reaction is preferably carried out in the presence of a solvent. In principle, there is no particular restriction on the nature of the solvent, provided that it does not adversely affect the reaction or the reagents and has the ability to dissolve these reagents, at least to a certain extent. Examples of suitable solvents are halogenated hydrocarbons, particularly halogenated aliphatic hydrocarbons, such as methylene chloride or chloroform; esters, such as ethyl acetate; and ethers, such as tetrahydrofuran or dioxane. The reaction is carried out in the presence of a base, preferably such as organic tertiary amine, e.g. triethylamine, pyridine, diethylethanolamine or 4-dimethylaminopyridine. The reaction may proceed in a wide temperature range, and the exact temperature is not important for the present invention. Mainly suitable for the implementation of the reaction temperature is from -10 to 120oC, and more preferably 0 to 80oC. Time trausti from the reaction temperature and the nature of the reagents and solvent. However, the preferred reaction conditions mentioned above, this period is from 30 min to 24 h, and more preferably 1 to 16 hours

After completion of the reaction, the target product can be isolated from the reaction mixture by standard means. Examples of such cues were listed in the description selection product stage A1.

The reaction scheme B.

The compounds of formula Ia, in which R4is a hydrogen atom, that is, in other words, the compounds of formula Ib can be obtained in accordance with the below reaction scheme B.

The reaction scheme B.

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In the above above formulas, R1, R2, R3, R5a, R6, R7aand X is defined above, and R5apreferably not a hydrogen atom.

In stage B1 connection imidazole-5-carboxylate of formula VII interact with bivariately compound of formula III to form compounds of formula VIII. This reaction is basically a similar reaction stage A1 in reaction scheme A and can be carried out using the same reagents and the same reaction conditions.

In stage B2 connection termporary R3a-Mg-X (where R3arepresents any of the groups defined above for R3and is not a hydrogen atom, and X is defined above).

Examples of reducing agents that can be used in this reaction are the hydrides alkylamine, such as hydride diisobutylaluminum; and borohydride metals, in particular alkali metals, such as borohydride sodium or cyanoborohydride sodium. Of them, preferred are aluminum hydride and borohydride sodium.

The reaction of the compound of formula VIII with a regenerating agent is typically and preferably occurs in an inert solvent. In principle, there is no particular restriction on the nature of the solvent, provided that it does not adversely affect the reaction or the reagents and has the ability to dissolve these reagents, at least to a certain extent. Examples of suitable solvents are hydrocarbons, especially aromatic hydrocarbons, such as toluene or hexane; ethers, such as tetrahydrofuran or dioxane; alcohols, such as methanol or ethanol; water; and mixtures of water with one or more of the foregoing organic solvents. Preferred age is flowing agent is a hydride alkylamine, the preferred solvents are hydrocarbons or ethers; alternatively, if this agent is borohydride alkali metal, the preferred solvents are alcohols, water or mixtures of water with alcohol.

The reaction may proceed in a wide temperature range, and the exact temperature is not important for this invention. Mainly suitable for the implementation of the reaction temperature is from -30 to 80oC, and more preferably from -20 to 20oC, if the regenerating agent is a hydride alkylamine, or from -30 to 80oC, and more preferably 0 to 50oC, if the specified agent is borohydride alkali metal. The time required to perform the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. However, the preferred reaction conditions mentioned above, this period is from 30 min to 24 h, and more preferably 1 to 16 hours

The reaction of the compound of formula VIII with a Grignard reagent is normally and preferably carried out in the presence of a solvent. In principle, there is Oia on the reaction or the reagents and has the ability to dissolve these reagents, at least to a certain extent. Examples of suitable solvents are hydrocarbons, which may be aliphatic or aromatic, such as hexane or toluene; halogenated hydrocarbons, particularly halogenated aliphatic hydrocarbons, such as methylene chloride or 1,2-dichloroethane; and ethers, such as tetrahydrofuran or diethyl ether, of which preferred are ethers, and halogenated carbohydrates.

The reaction may proceed in a wide temperature range, and the exact temperature is not important for this invention. Mainly suitable for the implementation of the reaction temperature is from -50 to 100oC, and more preferably from -10 to 50oC. the Time required to perform the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. However, the preferred reaction conditions mentioned above, this period is from 30 min to 24 h, and more preferably 1 to 16 hours

After completion of the reaction, the target compound in each reaction can bitnum solution of ammonium chloride, stirred at room temperature, and then extracted with odonatologica solvent, such as ethyl acetate. The extract is washed with water and dried in the presence of a drying agent such as anhydrous magnesium sulfate, then the solvent is distilled off and, if necessary, the resulting product was then purified by standard methods, for example by recrystallization or by using various chromatographic techniques, such as preparative thin layer chromatography or column chromatography.

The reaction scheme C.

The compounds of formula Ia, in which R2, R3and R4all are hydrogen atoms, i.e. compounds of formula Ic, and the compounds of formula VIII, which are intermediate compounds in the reaction scheme B can be obtained in accordance with the following reaction scheme C.

The reaction scheme C.

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In the above formulas, R1, R2, R5a, R6, R7aand X are as defined above, and R5apreferably not a hydrogen atom.

In stage C1 of this reaction scheme, the compound of the imidazole-5-carboxylate of formula IX interacts with biphenylmethane with the reaction schemes A and can be carried out using the same reagents and the same reaction conditions.

In stage C2 consider the reaction scheme dicarboxylate compound of the formula X obtained as described in stage C1, interacts with approximately one equivalent of a Grignard reagent of formula R2aMgX (where X is defined above, and R2ais any of the groups defined above for R2and is not a hydrogen atom) and/or from about one equivalent of reducing agent to obtain compounds of formula VIII. These reactions are similar to the reactions described above for stage B2 reaction scheme B, and can be carried out using the same reagents and the same reaction conditions.

In stage C3 of this reaction scheme, the compound of formula X interacts with two or more molar equivalents of a reducing agent with the formation of the compounds of formula Ic. This reaction is basically a similar reaction described above for stage B2 reaction scheme B, and can be carried out using the same reagents and the same reaction conditions.

In stage C4 hydroxymethylene compound of formula Ic are oxidized to make hydroxymethylene group to a formyl group and obtain the compounds of formula VIIIa.

The oxidation reaction can is magnesium or silver oxide.

The reaction is normally and preferably carried out in the presence of a solvent. In principle, there is no particular restriction on the nature of the solvent, provided that it does not adversely affect the reaction or the reagents and has the ability to dissolve these reagents, at least to a certain extent. Examples of suitable solvents are hydrocarbons, which may be aliphatic or aromatic hydrocarbons, such as benzene, toluene, xylene or heptane; halogenated hydrocarbons, particularly halogenated aliphatic hydrocarbons, such as methylene chloride or chloroform; ethers, such as diethyl ether, tetrahydrofuran or dioxane; esters, such as ethyl acetate or butyl acetate; and ketones, such as acetone or methyl ethyl ketone.

The reaction may proceed in a wide temperature range, and the exact temperature is not important for this invention. Mainly suitable for the implementation of the reaction temperature is 0 - 100oC, and more preferably 10 - 60oC. the Time required to perform the reaction may also vary widely, depending on many factors, castleview the reaction, above, this period is from 30 min to 24 h, and more preferably 1 to 16 hours

Alternatively, the reaction stage C4 can be achieved by interaction hydroxymethylene the compounds of formula Ic with dimethylsulfoxide and dehydrating agent in the presence of an organic amine. Suitable dehydrating agents are, for example, the complex trioxides, oxalicacid and anhydride triperoxonane acid. Suitable organic amines are, for example, triethylamine and pyridine.

The reaction is preferably carried out in the presence of a solvent. In principle, there is no particular restriction on the nature of the solvent, provided that it does not adversely affect the reaction or the reagents and has the ability to dissolve these reagents, at least to a certain extent. Examples of suitable solvents are halogenated hydrocarbons, particularly halogenated aliphatic hydrocarbons, such as methylene chloride or chloroform; ethers, such as diethyl ether, tetrahydrofuran or dioxane; esters, such as ethyl acetate or butyl acetate; and sulfoxidov, such as dimethylsulfoxide.

After completion of the reaction, the target product can be isolated from the reaction mixture by standard means. For example, the reaction mixture is mixed with water and vodonasosnaya solvent, such as ethyl acetate. The organic layer was separated, washed with water and dried in the presence of a drying agent such as anhydrous magnesium sulfate; the solvent is then removed by distillation under reduced pressure. If necessary the product can be purified by standard methods, for example by recrystallization or by using various chromatographic techniques, such as preparative thin layer chromatography or column chromatography.

The resulting connection is 3aMgX (where R3aand X is defined above) in accordance with the method described above for stage B2 reaction scheme B, to obtain the corresponding compounds having a group of the formula-CR2(R3a)-OH (where R2and R3adefined above) in the 4-position imidazolidine ring (reaction not shown).

The reaction scheme D.

In this reaction scheme, first get cenocoeliinae formula XII, and then this compound is converted into a compound of formula I.

The reaction scheme D.

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In the above formulas, R1, R2, R3, R4, R5, R6, R7and X is defined above, and R7bis protected by carboxypropyl protected tetrazolyl group, each of which may be the same as they were illustrated previously for R7a.

In stage D1 of this reaction scheme imidazol-5-carbonitrile compound of formula XI interacts with biphenylmethane compound of formula IIIa with obtaining the compounds of formula XII. This reaction is basically a similar reaction described above in stage A1 of reaction scheme A, and can be carried out using the same reagents and the same reaction conditions.

is Ah) several of the following reactions:

(IX) the transformation of ceanography in the 5-position of the imidazole ring carboxyl group;

(X) the transformation of ceanography in the 5-position of the imidazole ring in karbamoilnuyu group;

(XI) removing any carboxyamide group;

(XII) esterification carboxypropyl in the 5-position of the imidazole ring or biphenylenes group;

(XIII) conversion of the carboxyl group in the 5-position of the imidazole ring group of the formula-CONR8R9;

(XIV) removal tetrasilicate group;

(XV) if R4is tizamidine silyl group, aranceles group, aracelikarsaalyna group, an aliphatic acyl group, alkoxymethyl group, alkoxycarbonyl group, halogenoacetyl group, tetrahydropyranyloxy group, tetrahydropyranyloxy group, tetrahydrocannibinol group, tetrahydropyranyloxy group or substituted tetrahydropyranyl, tetrahydropyranyl, tetrahydrocannabinol or tetrahydrofuryl group having at least one halogen or alkoxylation, each of which can be considered as hydroxyamine groups, then carry out the removal of the protective group to obtain compounds are alkylation or acylation of this group.

(IX) the Transformation of ceanography in the carboxyl group.

The specified conversion is carried out by hydrolysis of ceanography in the compound of formula XII by carbamoyl group. This reaction is well known in chemical synthesis and can be carried out using reagents commonly used for this purpose, such as hydroxides of alkali metals, such as sodium hydroxide, potassium or lithium.

The reaction is preferably carried out in the presence of a solvent. In principle, there is no particular restriction on the nature of the solvent, provided that it does not adversely affect the reaction or the reagents and has the ability to dissolve these reagents, at least to a certain extent. Examples of suitable solvents are water, alcohols, such as methanol or ethanol; ethers, such as tetrahydrofuran or dioxane; or a mixture of any two or more of these solvents; preferably the solvent is an aqueous solvent.

The reaction may proceed in a wide temperature range, and the exact temperature is not important for this invention. Mainly suitable for oswae for the implementation of the reaction, also can vary widely depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. However, the preferred reaction conditions mentioned above, this period is from 30 min to 24 h, and more preferably 1 to 16 hours

After completion of the reaction, the target product can be isolated from the reaction mixture by standard means. For example, one of the standard methods of isolation of the product includes the following procedures: neutralizing the reaction mixture by adding a mineral acid such as hydrochloric acid, if necessary, the product of formula I is precipitated, and then allocate filtering; alternatively, after neutralization of the reaction mixture, the solvent is distilled off and the resulting residue purified by column chromatography, resulting in a gain target product; alternatively, the residue is mixed with water and with vodonasosnaya solvent, such as ethyl acetate, and the resulting mixture is extracted with an organic solvent, after which the extract is dried in the presence of a drying agent, such as anhydrous magnesium sulfate, and separated from the solvent to obtain the target product. Not the use of various chromatographic techniques, such as preparative thin layer chromatography or column chromatography.

In this reaction, where the starting material is a compound in which R4is an acyl group and/or R7bis the ester group of a primary or secondary alcohol (such as methanol, ethanol or isopropanol), acyl group, R4and ester residue is removed at the same time.

(X). Conversion ceanography in karbamoilnuyu group.

In this reaction, the cyano in the compound of formula XII in turn karbamoilnuyu group.

The product of this reaction is an intermediate compound from the previous reaction IX. Therefore, the reaction is carried out in milder conditions than the reaction IX.

This reaction is carried out by treatment of compounds of formula XII alkali, such as alkali metal hydroxide such as lithium hydroxide, sodium or potassium; or a carbonate of an alkali metal such as sodium carbonate or potassium. The reaction is preferably carried out in the presence of a solvent. In principle, there is no particular restriction on the nature of the solvent, provided that it does not adversely affect the reaction, or has the ability of rastlose water; a mixture of water and alcohol, such as methanol or ethanol; or a mixture of water and simple ether such as tetrahydrofuran or dioxane.

The reaction may proceed in a wide temperature range, and the exact temperature is not important for this invention. Mainly suitable for the implementation of the reaction temperature is 0 - 100oC, and preferably 10 to 80oC. the Time required to perform the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. However, the preferred reaction conditions mentioned above, this period is 0.5 - 24,0 h, and more preferably 1 to 8 hours, the Reaction may be accelerated by adding catalytic amounts of hydrogen peroxide.

After completion of the reaction, the reaction product can be isolated from the reaction mixture by standard means. For example, one of the standard methods of isolation of the product includes the following stages: neutralizing the reaction mixture with a mineral acid, such as hydrochloric acid; the distillation of the solvent under reduced pressure; adding to the resulting stackcheck extract dewatering agent, such as anhydrous magnesium sulfate; and the distillation of the solvent. If necessary the product can then be purified by standard methods, for example by recrystallization or by using various chromatographic techniques, such as preparative thin layer chromatography or column chromatography.

(XI). Remove carboxyamide groups.

This reaction is the same reaction I in stage A2 of the reaction schemes A and can be carried out using the same reagents and the same reaction conditions.

(XII). Etherification.

This reaction is analogous reaction stage II A2 and can be carried out using the same reagents and the same reaction conditions.

(XIII). The conversion of the carboxyl group of the formula-CONR8R9.

This reaction is analogous reaction stage III A2 and can be carried out using the same reagents and the same reaction conditions.

(XIV). Remove tetrasilicate groups.

This reaction is analogous reaction stage IV A2 and can be carried out using the same reagents and the same reaction conditions.

(XV). Remove hydroxyamine groups.

(XVI). Alkylation and acylation of hydroxyl groups.

This reaction is analogous reaction stage VIII A2 and can be carried out using the same reagents and the same reaction conditions.

The reaction scheme E.

In this reaction scheme, the compound of formula XII in which R4is hydrogen, i.e. the compound of formula XV is obtained from the corresponding compounds of formula XIII, having a ketone group [-C(O)R2] in the 4-position of the imidazole ring.

The reaction scheme E.

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In the above formulas, R1, R2, R3, R4, R7band X are as defined above.

In stage E1 of this reaction scheme, the compound of the imidazole-5-carboxylate of formula XIII interacts with biphenylmethane compound of formula XIIIa with the formation of compounds of formula XIV. This reaction is basically a similar reaction described above for stage A1 of reaction scheme A, and can be carried out using the same reagents and reaction conditions.

The resulting compound of formula XIV is then subjected to interaction in stage E2 with regenerating agent or with a Grignard reagent of formula R3a-Mg-X (where R

The reaction scheme F.

Some derivatives of 5-renominate used in the above reaction schemes as intermediate compounds can be obtained in accordance with reaction scheme F below.

The reaction scheme F.

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In the above formulas, R1, R2, R6, R7band X is defined above.

In stage F1 of this reaction scheme, the compound of the imidazole-5-carboxylate of formula XVI is subjected to interaction with biphenylmethane compound of formula IIIa with obtaining the compounds of formula XVII. This reaction is basically a similar reaction described above for stage A1 of reaction scheme A, and can be carried out using the same reagents and reaction conditions.

Stage F2, F3 and F4 are similar to the stages of the C2, C3 and C4, respectively, of reaction scheme C and can be carried out using the same reagents and the same reaction conditions. Optionally, the resulting product can be isolated and purified spoh in the above reaction schemes, shown in the reaction schemes G and h

The reaction scheme G.

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The reaction scheme H.

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In the above formulas, R1, R2, R3and R5adefined above. R10is an alkyl group containing from 1 to 6 carbon atoms, for example one of the groups that have been illustrated above for R1and preferably an alkyl group containing from 1 to 4 carbon atoms, and more preferably a methyl or ethyl group. R11is a hydrogen atom or imidazolidine group, for example aranceles group, such as triticina group, diphenylmethylene group, or benzyl group; or (C1-C4-alkoxymethyl group, such as methoxymethyl group, ethoxymethylene group, propoxymethyl group or butoxymethyl group, of which preferred are triticina, benzyl, methoxymethyl or ethoxyethylene group, and more preferred is triticina group.

The reaction scheme G.

In reaction scheme G get the connection formula V, where R4is a hydrogen atom, i.e. a compound of formula Va Va can be (if necessary) and then protected, for example, by alkylation, acylation, and education tetrahydropyranyloxy, tetrahydropyranyloxy or tetrahydropyranyloxy, replaced tetrahydropyranyloxy, tetrahydrofuranate, tetrahydropyranyloxy or tetrahydropyranyloxy or a group of the formula-SiRaRbRcwhere Ra, Rband Rcdefined above. These reactions, in addition to education optionally substituted, tetrahydropyranyloxy, tetrahydropyranyloxy, tetrahydropyranyloxy or tetrahydropyranyloxy, can be carried out in a manner analogous to that described for reaction stage VIII A2 reaction scheme A, to obtain compounds in which R4is any of groups represented by R4except that R4is not a hydrogen atom.

The formation of tetrahydropyranyloxy, tetrahydropyranyloxy, tetrahydropyranyloxy or tetrahydrofuranyl or substituted, tetrahydropyranyloxy, tetrahydropyranyloxy, tetrahydropyranyloxy or tetrahydrofuranyl can be carried out by reaction of compounds of formula V in which R4is a hydrogen atom, dihydropyrano, dihydrothiophene, dihydrothiophene or dihydrofuran the re one halogen or C1-C6-CNS Deputy, in the presence of acid (such as p-toluensulfonate acid) in an inert solvent (for example, halogenated hydrocarbon such as methylene chloride) at approximately room temperature during the period from 1 to 24 hours.

In G1 phase, the compound of formula XVI is obtained by reaction artefiera the compounds of formula XIX with diaminomaleonitrile formula XX. The reaction is preferably carried out in the presence of a solvent. In principle, there is no particular restriction on the nature of the solvent, provided that it does not adversely affect the reaction or the reagents and has the ability to dissolve these reagents, at least to a certain extent. Examples of suitable solvents are aromatic hydrocarbons, such as benzene, toluene or xylene; halogenated hydrocarbons, particularly halogenated aliphatic hydrocarbons, such as 1,2-dichloroethane or carbon tetrachloride; ethers, such as tetrahydrofuran or dioxane; NITRILES, such as acetonitrile.

The reaction may proceed in a wide range of temperatures and the precise temperature value does not play a vital is 0 - 180oC, and preferably 80 to 150oC. the Time required to perform the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. However, the preferred reaction conditions mentioned above, this period is 1 to 24 hours, and more preferably 2 to 10 hours

The reaction product of formula XVI can be isolated by collecting the crystals precipitated in the reaction system, or by removal of the solvent. If necessary the product can then be purified by standard methods, for example by recrystallization or by using various chromatographic techniques, in particular preparative thin-layer chromatography or column chromatography.

Stage G2 includes receiving connection imidazole-4,5-dicarboxylic acid of the formula XVI received in G1 phase. This reaction can be carried out by heating the compounds of formula XVI at reflux distilled in the presence of aqueous mineral acid, such as aqueous solution of hydrochloric, sulfuric or nitric acid, over a period of time of 1 to 24 hours (preferably 3 to 15 hours).

The product of formula XXI whether the removal of the solvent.

Stage G3 is an optional stage, and includes the connection of ester of the dibasic acid of the formula XI by blocking carboxypropyl connection imidazole-4,5-dicarboxylic acid of the formula XXI, obtained in stage G2. This reaction can be carried out with the cooperation of compound XXI with a compound of formula R5b-Y, where R5band Y are as defined above.

The reaction is preferably carried out in the presence of a solvent. In principle, there is no particular restriction on the nature of the solvent, provided that it does not adversely affect the reaction or the reagents and has the ability to dissolve these reagents, at least to a certain extent. Examples of suitable solvents are hydrocarbons, in particular aromatic hydrocarbons, such as benzene or toluene; halogenated hydrocarbons, particularly halogenated aliphatic hydrocarbons, such as methylene chloride or chloroform; ethers, such as tetrahydrofuran or dioxane; alcohols, such as methanol, ethanol or t-butanol; amides such as N,N-dimethylformamide, N,N-dimethylacetamide or N-methyl-2-pyrrolidone; ketones such to whom they are preferred NITRILES, halogenated hydrocarbons or amides.

It is preferable that the reaction proceeded in the presence of a base, the nature of which is not critical, providing it does not adversely affect other parts of reagents. Examples of preferred bases can serve as organic amines, such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine.

The reaction may proceed in a wide range of temperatures and the precise value of the reaction temperature does not play a significant role. Mainly suitable for the implementation of the reaction temperature will depend on the nature of the starting materials, solvent and base. In this case, the preferred temperature is from -10 to 100oC, more preferred 0 - 80oC. the Time required to perform the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. However, the preferred reaction conditions mentioned above, this period is 0.5 - 24,0 h, and more preferably 1 to 16 hours

After completion of the reaction, the target compound can be isolated from Rea is extracted monodesmethyl organic solvent, such as ethyl acetate; the extract is dried using a drying agent such as anhydrous magnesium sulfate; and the solvent is distilled off. If necessary the product can then be purified by standard methods, for example, by recrystallization, or by using various chromatographic techniques, such as preparative conclusiona chromatography or column chromatography.

Alternatively, the compound of dicarboxylic acid of the formula XXI can be subjected to esterification with obtaining complex diapir formula IX. The choice of a particular reaction in this case will depend on the nature of the ester residue R5b.

For example, if the group represented by R5bis C1-C6is an alkyl group or aranceles group such as benzyl group, the compound of formula IX can be obtained by reaction of the corresponding dicarboxylic acids with C1-C6-alcohol, such as methanol, ethanol, propanol or hexanol, or aralkylated alcohol such as benzyl alcohol, in the presence of an acid catalyst such as hydrogen chloride or sulfuric acid, in an inert solvent (for example, one of the C1-C6-alcohols, which can be Lenhard; or simply ether, such as tetrahydrofuran or dioxane) at 0 - 100oC, preferably 20 - 80oC, during the period of time from 1 to 3 days, and preferably 16 to 24 hours; or by treatment of the corresponding dicarboxylic acid with a halogenation agent (for example, pentachloride phosphorus, thionyl chloride or oxalylamino) in an inert solvent (for example, halogenated hydrocarbon such as methyl chloride; simple ether, such as tetrahydrofuran or dioxane; or an aromatic hydrocarbon such as benzene or toluene) at about room temperature over a period of time from 30 min to 5 h, preferably from 1 to 3 h, to obtain the corresponding allvalid and subsequent reaction of allvalid with the corresponding alcohol (if you get the t-butyl ester, it is preferable to use t-butoxy potassium instead of alcohol) in an inert solvent (e.g. benzene or methylene chloride) in the presence of a base (for example triethylamine) at about room temperature over a period of time from 30 min to 10 h

The target compound can be isolated from the reaction mixture using standard techniques. For example, after removal of the solvent, the residue To the solution is neutralized with sodium bicarbonate; then the organic layer is separated and dried in the presence of a drying agent such as anhydrous magnesium sulfate; the solvent is then distilled off and finally get the target product. This product can be, if necessary purified by standard methods, for example by recrystallization or by using various chromatographic techniques, such as preparative thin layer chromatography or column chromatography.

In stage G4 compounds of formula Va are obtained by reaction of compound complex diapir formula IX with a Grignard reagent of formula R2aMgX and/or R3aMgX (where R2a, R3aand X are defined above).

This reaction is basically a similar reaction described above for stage B2 reaction scheme B, and can be carried out using the same reagents and the same reaction conditions.

The reaction scheme H.

In these reactions get compounds of formulae XIIIa, XIa VIIa and where each of R11is a hydrogen atom, i.e. compounds of formula XIII, XI and VII and the compound of formula Va, which are the starting materials used in the reaction schemes E, D, A and B, respectively.

In stage H1, which is an optional stage, - X (where X is defined above, and R11ais any of the groups defined above for R11and is not a hydrogen atom) in the presence of a base.

Examples of suitable compounds are the hydrides of alkali metals such as lithium hydride or sodium hydride; carbonates of alkali metals such as sodium carbonate or potassium; and alkoxyl alkali metals, such as sodium methoxide, ethoxide sodium or t-piperonyl potassium.

The reaction is preferably carried out in the presence of a solvent. In principle, there is no particular restriction on the nature of the solvent, provided that it does not adversely affect the reaction or the reagents, and has the ability to dissolve these reagents, at least to a certain extent. Examples of suitable solvents are halogenated hydrocarbons, such as methylene chloride or chloroform; ethers, such as tetrahydrofuran or dioxane; amides, such as dimethylformamide or dimethylacetamide; ketones, such as acetone or methyl ethyl ketone. The reaction may proceed in a wide temperature range, and the exact temperature is not important for this invention. Mainly suitable for the implementation of the reaction the reaction, also can vary widely depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. However, the preferred reaction conditions mentioned above, this period is 1 to 24 hours, and more preferably 3 to 8 hours

After completion of the reaction, the target compound can be isolated from the reaction mixture by standard means. For example, one such method is that to the reaction mixture, water is added; the mixture is extracted with a water-soluble organic solvent such as ethyl acetate; the extract was washed with water and dried in the drying agent such as anhydrous magnesium sulfate; and finally the solvent is distilled off. If necessary the product can then be purified by standard methods, for example by recrystallization or by using various chromatographic techniques, such as preparative thin layer chromatography or column chromatography.

In stage H2 of the compounds of formula XIIIa get through reaction dimitriadou the compounds of formula XVIa with a Grignard reagent of formula R2aMgX, in which R2aand X is defined above, or with a regenerating agent. This reaction is whether the same reagents and the same reaction conditions.

Imidazolidine group of compounds of formula XIIIa may be (but not necessarily) is removed by treating the compounds of formula XIIIa standard way depending on the nature of the protective group to obtain the compounds of formula XIII.

For example, if the protecting group is triticina group or alkoxymethyl group, it may be removed by reaction of the protected compound with an acid.

Examples of suitable acids are inorganic acids such as hydrochloric acid or sulfuric acid; and organic acids such as acetic acid, formic acid, methanesulfonate acid or p-toluensulfonate acid.

The reaction is preferably carried out in the presence of a solvent. In principle, there is no particular restriction on the nature of the solvent, provided that it does not adversely affect the reaction or the reagents and has the ability to dissolve these reagents, at least to a certain extent. Examples of suitable solvents include: ethers, such as tetrahydrofuran or dioxane; alcohols, such as methanol or ethanol; acids such as acetic acid; water; or a mixture of any two or more of in the offered value of the reaction temperature does not play a decisive role for the present invention. Mainly suitable for the implementation of the reaction temperature is 0 - 120oC, and more preferably 10 - 100oC. the Time required to perform the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. However, the preferred reaction conditions mentioned above, this period is from 30 min to 24 h, and more preferably 1 to 16 hours

After completion of the reaction, the target compound can be isolated from the reaction mixture by standard means. For example, one such method is that the solvent is evaporated and the product purified by recrystallization or chromatography; or the reaction mixture is neutralized with a weak acid (such as sodium bicarbonate), extracted with vodonasosnaya organic solvent such as ethyl acetate, and the solvent is evaporated. The resulting product, if necessary, can then be purified by recrystallization or by chromatography, for example by preparative thin-layer chromatography or column chromatography.

If imidazolidine group is kalkilya greytale. This reaction is basically a similar reaction described above I in stage A2 of the reaction scheme A, where carboxyamide group is aranceles group, and can be carried out using the same reagents and the same reaction conditions.

In stage H3 received a carbonyl compound of the formula XIIIa then subjected to reaction with a Grignard reagent of formula R3aMgX, in which R3aand X is defined above, or with a regenerating agent with obtaining the compounds of formula XIa. This reaction is basically a similar reaction stage B2 reaction scheme B described above, and can be carried out using the same reagents and the same reaction conditions.

Optionally imidazolidine group of compounds of formula XIa can be removed using mainly this reaction, which was described as optional in stage H2 reaction scheme H, and can be carried out using the same reagents and the same reaction conditions.

In stage H4 connection carboxylic acid of formula XXII is obtained by hydrolysis of the remaining ceanography in the 5-position of the imidazole ring. The reaction can be carried out using a hydroxide of an alkali metal, such as hydroxide by nacosta ether, such as tetrahydrofuran or dioxane; or a mixture of any two or more of these solvents). The reaction may proceed in a wide temperature range, and the exact temperature is not important for this invention. Mainly suitable for the implementation of the reaction temperature is 0 - 120oC, and more preferably 20 - 100oC. the Time required to perform the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. However, the preferred reaction conditions mentioned above, this period leaves of 0.5 - 24,0 h, and more preferably 1 to 16 hours After completion of the reaction, reaction product can be isolated by standard methods. For example, the reaction mixture is neutralized by adding a mineral acid such as hydrochloric acid; and if the target compound of formula XXII is deposited in the reaction medium, it may be collected by filtration. Alternatively, the target compound can be selected as follows: after neutralization of the reaction mixture, the solvent is distilled off and the residue is subjected to column chromatography; alter the m solvent, then the dry extract in the presence of a drying agent such as anhydrous magnesium sulfate, the solvent is distilled off and get the target product. If necessary the product can then be purified by standard methods, for example by recrystallization or by using various chromatographic techniques, such as preparative thin layer chromatography or column chromatography.

In stage H5, which is an optional stage, the compound of formula Va is obtained by esterification of compounds of carboxylic formula XXII, and optional, with the subsequent unlocking imidazolidine group. This esterification reaction is basically a similar reaction II in stage A2 of the reaction scheme A, above, and the reaction of the optional unlock basically similar to the reaction described for stage H2 reaction scheme H, and both of these reactions can be carried out using the same reagents and the same reaction conditions.

In stage H6 compound of formula XXIII is obtained by hydrolysis of compounds of formula XIIIa. This reaction is basically a similar reaction described above for stage H4 reaction scheme H, and can be carried out using the same reagents and surveillance of formula XXIII. This reaction is basically a similar reaction described above for stage H5 reaction scheme H, and can be carried out using the same reagents and the same reaction conditions.

Optionally imidazolidine group of compounds of formula VIIa can be removed mainly through reactions similar to the optional reaction described above for stage H2 reaction scheme H, which can be carried out using the same reagents and the same reaction conditions.

In stage H8 compound of formula Va are obtained by reaction of compounds of formula VIIa with a Grignard reagent and/or regenerating agent, and then an optional unlock imidazolidine group. This reaction is basically a similar reaction described above for stage B2 reaction scheme B, optional reaction unlock basically similar to the reaction described above for stage H2 reaction scheme H, both of these reactions can be carried out using the same reagents and reaction conditions.

Compounds of the present invention may form a salt. In principle, there are no restrictions on the nature of salts, provided that they are pharmaceutically acceptable and prigodnymi connections for other, more active compounds. Compounds of the present invention may form a salt with a base. Examples of such salts are salts with alkali metals such as sodium, potassium or lithium; salts with alkaline earth metals such as barium or calcium; salts with other metals such as magnesium or aluminum; salts of organic bases such as dicyclohexylamine, guanidine or triethylamine; and salts with basic amino acids such as lysine or arginine. In addition, the compounds of the present invention contain a basic group in its molecule, and therefore can form an acid additive salt. Examples of such acid additive salts are salts with mineral acids, in particular halogen acids (such as fluoride-hydrogen, Hydrobromic, Modesto-hydrogen chloride and hydrogen acid), nitric acid, carbonic acid, sulfuric acid or phosphoric acid; salts with lower alkylsulfonyl acids such as methanesulfonate acid, triftormetilfullerenov acid or econsultancy acid; salts with organic carboxylic acids such as acetic acid, formic acid, tartaric acid, oxalic acid, maleinos caminova acid or aspartic acid. Compounds of the present invention can be converted into pharmaceutically acceptable salts by treatment with acid or base using standard methods, well known to experts.

Compounds of the present invention show good inhibitory activity against the increase in blood pressure induced by angiotensin II, and therefore can be successfully used for treating or preventing diseases of the circulatory system as antihypertensives or as therapeutic drugs for the treatment of heart disease.

The biological activity of the compounds of the present invention was evaluated by means of the following experiments.

Assessment AII-receptorlike activity by inhibiting vazopressornah response to the introduction of angiotensin II.

The biological activity of each compound was assessed by determining the dose required for inhibition vazopressornah response to intravenous angiotensin II to rats at a dose of 50% (ID50). Male rats of Wister-Imamichi (each weighing 300 - 400 g) were injected intraperitoneal injection of 100 mg/kg thiobarbital-sodium [Inaction (trademark)] the vein for injection of a medicinal product. 50 ng/kg of angiotensin II was administered intravenously at intervals of about 10 min, and observed a rise in blood pressure (usually about 50 mm RT.cent.). After obtaining a stable vazopressornah response to angiotensin II was administered intravenously test connection. Two minutes later he again entered angiotensin II, and evaluated the inhibitory activity of the test compounds. For calculation, I determined the percentage of inhibition vazopressornah response to angiotensin II to increase the concentration of the input of the test compounds. In the present experiment used angiotensin II, dissolved in 0.5% bovine serum albumin, and the test compound was dissolved in 100% dimethyl sulfoxide (DMSO). Defined this way ID50-values are presented in table 7.

In addition to the compounds of the invention (which were identified in a number of examples illustrating the receipt and below) in these experiments was used as the connection of the prototype (shown in table as "compound A"), which is 2-[4-(2-butyl-5-chloro-4-chloromethylthiazole-1-yl-methyl)phenyl] benzoic acid, and which is described in example 118 publishing Europatent N 253310.

Connections will insist.p. or parenterally in the form of injections, suppositories, etc. These pharmaceutical preparations can be obtained by standard methods with the use of adjuvants well known in the art, such as fillers, binders, dezintegriruetsja agents, samelevel, stabilizers, modifiers, etc., Although the dose of active ingredient may vary depending on symptoms, age of the patient, nature and severity of the disease and the route of administration of the medicinal product, however, in the case of oral administration the specified means an adult, a full daily dose of the compounds of the present invention may be 1 to 1000 mg, and preferably 5 to 300 mg, and be entered either as a single dose or in divided doses, for example two or three times a day; and in the case of intravenous administration, the dose may be 0.1 - 100.0 mg, and preferably 0.5 to 30.0 mg, and be administered one to three times a day.

The following examples illustrate the production of several compounds of the present invention, and obtain the following two examples illustrate the raw materials used in these examples.

Example 1.

Methyl-1-[(2'-t-Butoh is imetal 1-[(2'-t-butoxycarbonylmethyl-4-yl)-methyl]-2 - butylimidazole-4,5, in primary forms.

A solution of sodium methoxide obtained from 0,69 g of sodium and 40 ml of methanol, was added to a solution of 7.2 dimethyl 2-butylimidazole-4,5 - in primary forms (obtained in accordance with the description given in obtaining 4) in 40 ml of methanol, and the resulting mixture was concentrated by evaporation under reduced pressure. The obtained residue was mixed with benzene, and the mixture was concentrated by distillation under reduced pressure. Then this operation is repeated three times, and the resulting solid residue was dissolved in 72 ml of N, N-dimethylacetamide. Then, to the obtained solution drop by drop solution was added 10,41 g t-butyl-4-bromomethylbiphenyl-2-carboxylate in 100 ml of N,N-dimethylacetamide. Then the reaction mixture is stirred for 1 hour at room temperature and for 2 h at 50-55oC. after this time the mixture was mixed with ethyl acetate and water, and an ethyl acetate layer was separated and dried with anhydrous magnesium sulfate, then the solvent drove away under reduced pressure. The residue was purified by column chromatography on silica gel, elwira a mixture of ethyl acetate and hexane (1:1), resulting in received of 15.1 g of target compound in the form of a resinous substance.

Nuclear magnetic resonator which are 3.90 (3H, C) vs. 5.47 (2H, s), 6,95-a 7.85 (8H, m).

1(b). Methyl 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] -2-butyl-4 - hydroxymethylimidazole-5-carboxylate.

42 ml hydride diisobutylaluminum (1.5 M solution in toluene) was added drop at a temperature of from -20 to -15oC to a solution of 16.0 g of dimethyl 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] - 2-butylimidazole-4,5-in primary forms (obtained as described above in stage (a)) in 200 ml of tetrahydrofuran, and the mixture was left for 16 h at -5oC. after this time the reaction mixture was mixed with an aqueous solution of ammonium chloride and ethyl acetate, and then was stirred for 1 hour. After that, the precipitate was removed by filtration. Then an ethyl acetate layer was separated and dried with anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. Then the residue was purified by column chromatography on silica gel, elwira with ethyl acetate, which was obtained 12.0 g of target compound in the form of crystals, so pl. 99oC.

NMR (CDCl3) ppm: of 0.90 (3H, t, J = 7 Hz), of 1.20 (9H, s), 1,1-2,0 (4H, m), 2,69 (2H, t, J = 7 Hz), 3,55 (1H, Shir. C) of 3.78 (3H, s), 4,84 (2H, d (doublet), J = 5 Hz), the ceiling of 5.60 (2H, s), 6,95-7,9 (8H, m).

Example 2.

Ethyl-1-[(2'-t-butoxycarbonylmethyl-4-yl)IU iluvenis-4-yl)methyl] -2 - butylimidazole-4,5, in primary forms.

Repeating the procedure described in example 1(a), but using 8.0 g diethyl 2-butyl-imidazole-4,5-in primary forms (obtained in accordance with the description in obtaining 3) and 10,41 g of t-butyl 4-bromomethylbiphenyl-2-carboxylate, which was obtained 15,4 target compound in the form of a resinous substance.

NMR (CDCl3) ppm: of 0.90 (3H, t, J = 7 Hz), 1,1-2,0 (4H, m) of 1.24 (9H, s) of 1.26 (3H, t, J = 7 Hz), of 1.39 (3H, t, J = 7 Hz), of 2.72 (2H, t, J = 7 Hz), 4,28 (2H, square (Quartet, J = 7 Hz), and 4.40 (2H, square, J = 7 Hz), of 5.50 (2H, s), 7,0-7,9 (8H, m).

2(b). Ethyl-1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] -2 - butyl-4-hydroxymethylimidazole-5-carboxylate.

Repeating the procedure described in example 1(b), but using 1.50 g of the diethyl 1-[(2'-t-butoxycarbonylmethyl - 4-yl)methyl]-2-butylimidazole-4,5-in primary forms (obtained as described in stage (a)) and 3.9 ml of hydride diisobutylaluminum (1.5 M solution in toluene), which was obtained 1.1 g of target compound in the form of a resinous substance.

NMR (CDCl3) ppm: of 0.90 (3H, t, J = 7 Hz), 1,24 (9H, s) of 1.30 (3H, t, J = 7 Hz), 1,1-2,0 (4H, m), 2,68 (2H, t, J = 7 Hz), 3,60 (1H, Shir. C) are 4.24 (2H, square, J = 7 Hz), 4,84 (2H, s), to 5.57 (2H, s), 6,9-a 7.85 (8H, m).

Example 3.

Methyl 2-butyl-1-[(2'-carboxyphenyl-4-yl)methyl] -4 - hydroxymethylimidazole-5-carboxylate (Conn the azole-5-carboxylate (obtained in accordance with the description in example 1 in 4 ml of 4n. solution florodora in dioxane was left for 4 h at room temperature. After this time the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was pereirae with ethyl acetate to form crystals, which were collected by filtration, which was obtained 0.35 g of target compound in the form of its hydrochloride with so pl. 192-195 (in Russian)oC (decomposition).

NMR (hexadeuterated dimethyl sulfoxide) ppm: 0,81 (3H, t, J = 7 Hz), 1,22-of 1.35 (2H, m), USD 1.43-of 1.56 (2H, m) of 3.00 (2H, t, J = 7 Hz), 3,82 (3H, s), to 4.81 (2H, s), 5,77 (2H, s), 7.18 in-of 7.55 (8H, m).

Example 4.

1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl]-2-butyl-4 - hydroxymethylimidazole-5-carboxylic acid (compound 1-96 N).

The solution 2,01 g of hydroxide monohydrate lithium in 97 ml of water was added to the solution 4,78 g of methyl 1-[(2'-t-butoxycarbonylmethyl - 4-yl)methyl]-2-butyl-4-hydroxymethylimidazole-5-carboxylate (obtained in accordance with the description in example 1) in 48 ml of dioxane, and the mixture was stirred at room temperature for 18 hours, after this time the reaction mixture was extracted from dioxane by distillation under reduced pressure and the aqueous residue was added 47,6 ml of 1N. aqueous hydrochloric acid. Besieged Krista is Ali 4.26 deaths / g of target compound with so pl. 187oC (with decomp.).

NMR (CDCl3) ppm: of 0.85 (3H, t, J = 7 Hz), 1,24 (9H, s), 1,1-1,9 (4H, m), 2,80 (2H, t, J = 7 Hz), of 5.05 (2H, s), to 5.93 (2H, s), 7,0-a 7.85 (8H, m).

Example 5.

2-Butyl-1-[(2'-carboxyphenyl-4-yl)methyl] -4 - hydroxymethylimidazole-5-carboxylic acid.

A solution of 0.12 g of 1-[(2'-butoxycarbonylmethyl-4-yl)methyl]-2 - butyl-4-hydroxymethylimidazole-5-carboxylic acid (obtained as described in example 4) in 2 ml of 4n. solution florodora in dioxane was left at room temperature for 5 hours, after which the solvent was removed by distillation under reduced pressure. The resulting residue is triturated in ethyl acetate and was obtained 0.11 g of target compound in the form of its hydrochloride, T. pl. 130-140oC (softening).

NMR (DMSO-d6) ppm: to 0.80 (3H, t, J = 7 Hz), 1,2-1,33 (2H, m), 1,4-of 1.53 (2H, m), 2,98 (2H, t, J = 7 Hz), 4,84 (2H, s), of 5.81 (2H, s), 7,17-7,74 (8H, m).

Example 6.

Pivaloyloxymethyl 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] - 2-butyl-4-hydroxymethylimidazole-5-carboxylate (compound 1-97 N).

350 mg of potassium carbonate were added to a solution of 552 g of 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] -2-butyl-4 - hydroxymethylimidazole-5-carboxylic acid (obtained as described in example 4) and 220 mg pimalai is the 5 o'clock After this time the reaction mixture was mixed with ethyl acetate and water, an ethyl acetate layer was separated and dried with anhydrous magnesium sulfate, then the solvent is kept at reduced pressure. The obtained residue was purified by column chromatography on silica gel using as eluent ethyl acetate and got to 0.62 g of target compound in the form of syrup.

NMR (CDCl3) ppm: of 0.91 (3H, t, J = 7 Hz), of 1.18 (9H, s) to 1.21 (9H, s), 1,1-2,0 (4H, m), of 2.72 (2H, t, J = 7 Hz), 3,35 (1H, Shir. C) is 4.85 (2H, d, J = 5 Hz), 5,61 (2H, s), 5,90 (2H, s), 6,95-7,9 (8H, m).

Example 7.

Pivaloyloxymethyl 2-butyl-1-[(2'-carboxyphenyl-4-yl)methyl]-4 - hydroxymethylimidazole-5-carboxylate (compound 1-98 N).

A solution of 0.62 g pivaloyloxymethyl 1-[(2'-t-butoxycarbonylmethyl - 4-yl)methyl]-2-hydroxymethylimidazole-5-carboxylate (obtained in accordance with the description in example 6) in 10 ml of 4n. solution florodora in dioxane was left for 4 h at room temperature, after which the solution was concentrated by evaporation under reduced pressure. Syrup-like residue is stirred in diethyl ether, after which the solvent was removed by draining, and the residue was dried under vacuum, resulting in received and 0.46 g of the hydrochloride of the target with the Hz), free 5.01 (2H, s) 5,70 (2H, s), of 5.89 (2H, s), 7,05-7,97 (8H, m).

Example 8.

Methyl 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl]-2-butyl-4- (methoxymethyl)imidazole-5-carboxylate (compound N 1-99).

0,057 g of sodium hydride (as a 55 wt.% dispersion in mineral oil) was added to a solution of 0,478 g of methyl 1-[(2'-t-butoxycarbonylmethyl - 4-yl)methyl] -2-butyl-4-hydroxymethylimidazole-5-carboxylate (obtained in accordance with the description in example 1) in 5 ml of N,N-dimethylacetamide, and the resulting mixture was stirred 30 min at room temperature. After this was added 0,125 ml iodomethane, and the reaction mixture is stirred at 50oC for 3 hours Then the mixture was mixed with ethyl acetate and water. An ethyl acetate layer was separated and dried with anhydrous magnesium sulfate, and the solvent is kept at reduced pressure. The obtained residue was purified by column chromatography on silica gel, elwira a mixture of ethyl acetate and methylene chloride (1:1), resulting in received of 0.30 g of target compound in the form of a resinous substance.

NMR (CDCl3) ppm: of 0.90 (3H, t, J = 7 Hz), 1,24 (9H, s), 1,1-2,0 (4H, m), a 2.71 (2H, t, J = 7 Hz), of 3.46 (3H, s), of 3.80 (3H, s), and 4.68 (2H, s), ceiling of 5.60 (2H, s), 6,9-7,9 (8H, m).

Example 9.

Methyl 2-butyl-1-[(2'-carboxyphenyl-4-yl)methyl]-4- (methoxime the yl]- 2-butyl-4-(methoxymethyl)imidazole-5-carboxylate (obtained in accordance with the description in example 8) in 3 ml of 4n. solution florodora in dioxane was left for 5 hours at room temperature, after which the solvent is kept at reduced pressure. Syrupy residue was pereirae in diethyl ether and collected by filtration, which was obtained 0.26 g of target compound in the form of its hydrochloride, T. pl. 106-110oC (softening).

NMR (DMSO-d6) ppm: 0,81 (3H, t, J = 7 Hz), 1.2 to about 1.35 (2H, m), 1,45-1,6 (2H, m), of 2.97 (2H, t, J = 7 Hz), 3,39 (3H, s), 3,82 (3H, s), 4.72 in (2H, s), of 5.75 (2H, s), 7,16-7,74 (8H, m).

Example 10.

2-Butyl-1-[(2'-carboxyphenyl-4-yl)methyl] -4-[(1-hydroxy-1 - methyl)ethyl] imidazole-5-carboxylic acid (compound 1-31 N).

10(a). 1-[(2'-t-Butoxycarbonylmethyl-4-yl)methyl]-2 - butyl-5-cyano-4-[(1-hydroxy-1-methyl)ethyl]imidazole.

48 mg of sodium hydride (as a 55 wt.% dispersion in mineral oil) was added at room temperature and under nitrogen atmosphere, while stirring, to a solution of 207 mg of 2-butyl-5-cyano-4-[(1-hydroxy - 1-methyl)ethyl]imidazole (obtained in accordance with the description in obtaining 7) in 10 ml of N,N-dimethylacetamide, and the resulting mixture was stirred 30 min, then was added 347 mg of t-butyl 4-bromomethylbiphenyl-2-carboxylate. Then the reaction mixture is stirred 2 hours at room temperature, then e is magnesium and concentrated under reduced pressure, as a result, we received an oily crude product. The product was purified by column chromatography on silica gel, elwira with a mixture of hexane and ethyl acetate (1:1), and received 462 mg of the target compound.

NMR (CDCl3) ppm: of 0.90 (3H, t, J = 7 Hz); 1,1-2,1 (4H, m) to 1.21 (9H, s) to 1.61 (6H, s), 2,70 (2H, t, J = 7 Hz), 3,40 (1H, s), with 5.22 (2H, s), 7,0-8,0 (8H, m).

10(b). 2-Butyl-1-[(2'-carboxyphenyl-4-yl)methyl] -5-cyano-4- [(1-hydroxy-1-methyl)ethyl]imidazole.

A solution of 462 mg (1-[(2'-t-butoxycarbonylmethyl-4-yl)- methyl]-2-butyl-5-cyano-4-[(1-hydroxy-1-methyl)ethyl] imidazole (obtained as described in stage (a)) in 10 ml of 4n. solution florodora in dioxane was left overnight at room temperature. Then the reaction mixture was concentrated by evaporation under reduced pressure, and the concentrate was dissolved in methylene chloride. The precipitate was collected by filtration and dried, resulting in a received 457 mg of the hydrochloride of the target compound as a colorless powder, so pl. 209-210oC.

NMR (DMSO-d6) ppm: of 0.85 (3H, t, J = 7 Hz), 1,0-1,8 (4H, m), was 1.58 (6H, s) of 3.00 (2H, t, J = 7 Hz), the 5.51 (2H, s); 7,1-8,0 (8H, m).

10(c). 2-Butyl-1-[(2'-carboxyphenyl-4-yl)methyl]-4-[(1-hydroxy - 1-methyl)ethyl]imidazole-5-carboxylic acid.

A solution of 314 mg of 2-butyl-1-[(2'-carbox is observed in stage (b)] in an aqueous solution of 460 mg of sodium hydroxide in 5 ml water is stirred in an oil bath for 5 h at 100oC. after this time the reaction mixture was cooled and its pH was brought to values of 3-4 by adding 1N. aqueous hydrochloric acid. The obtained colorless precipitate was collected by filtration, washed with water and dried with anhydrous magnesium sulfate, resulting in a received 244 mg, so pl. 139-141oC.

NMR (DMSO-d6) ppm: 0,86 (3H, T., J = 7 Hz), 1,0-1,9 (4H, m) to 1.60 (6H, s) to 2.66 (2H, t, J = 7 Hz), 5,70 (2H, s), 6,9-7,9 (8H, m).

Example 11.

2-Butyl-1-[(2'-carboxyphenyl-4-yl)methyl] -4-(1 - hydroxyethyl)-imidazole-5-carboxylic acid (compound 1-25 N).

11(a). 4-Acetyl-1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] - 2-butyl-5-cyanomelana.

0.87 g of potassium carbonate and 2.4 g of t-butyl 4'-bromomethylbiphenyl - 2-carboxylate was added to solution of 1.2 g of 4-acetyl-2-butyl-5-renominate (obtained in accordance with the description in obtaining 5) in 12 ml of N,N-dimethylacetamide, and the mixture was stirred 3 hours at room temperature. Then the reaction mixture was diluted with 100 ml ethyl acetate and washed with saturated aqueous sodium chloride. The aqueous layer was once again extracted with 50 ml of ethyl acetate, and the combined extracts were washed with saturated aqueous solution of sodium chloride. The solvent was removed by distillation under ponie the hexane and ethyl acetate (3:1), resulting received 1,31 g of target compound.

NMR (CDCl3) ppm: of 0.93 (3H, t, J = 7 Hz), 1,1-2,1 (4H, m) of 1.23 (9H, s), 2,58 (3H, s) of 2.75 (2H, t, J = 7 Hz), 5,32 (2H, s), 7,0-8,0 (8H, m).

11 (b). 4-Acetyl-2-butyl-1-[(2'-carboxyphenyl-4-yl)methyl]- 5-cyanomelana.

A solution of 1.3 g of 4-acetyl-1-[(2-'-t-butoxycarbonylmethyl - 4-yl)methyl]-2-butyl-5-renominate (obtained as described in stage (a)) in 30 ml of 4n. solution florodora in dioxane was left overnight at room temperature, after which the solution was concentrated under reduced pressure. The concentrate was purified by column chromatography on silica gel, elwira mixture of methylene chloride and methanol (10:1), and received a colorless amorphous solid. This substance is triturated in hexane, collected by filtration and dried off, the result was obtained 1.1 g of the target compound, so pl. above 55oC (softening).

NMR (CDCl3) ppm: 0,84 (3H, t, J = 7 Hz), 1.0 to 2.0 (4H, m), of 2.54 (3H, s) to 2.66 (2H, t, J = 7,0 Hz) to 5.17 (2H, s), 6,8-7,0 (8H, m).

11(c). 2-Butyl-1-[(2'-carboxyphenyl-4-yl)methyl] -5-cyano - 4-(1-hydroxyethyl)imidazole.

68 mg of sodium borohydride was added to a solution of 718 g of 4-acetyl-2-butyl-1-[(2'-carboxyphenyl-4-yl)methyl] -5-renominate (obtained in accordance with the OPI is mperature. After this time the pH of the reaction mixture is brought to 3 by adding 1N. aqueous hydrochloric acid, after which the solvent is kept at reduced pressure. The obtained residue was mixed with methylene chloride and water, and methylenechloride layer was separated. The aqueous layer was extracted three times with methylene chloride, and the combined extracts were dried and concentrated by evaporation under reduced pressure. The obtained residue was dissolved in 10 ml of ethyl acetate and kept at room temperature. Then the precipitated solid product was collected by filtration and was received as a result of 398 mg of the target compound as a colorless powder, so pl. 200-201oC.

NMR (DMCO-d6) ppm: to 0.88 (3H, t, J = 7 Hz), 1.0 to 2.0 (4H, m), and 1.54 (3H, d, J = 7 Hz), 2,68 (2H, t, J = 7 Hz), 4,91 (1H, square, J = 7 Hz), to 5.21 (2H, s), 7,0-8,0 (8H, m).

11(d). 2-Butyl-1-[(2'-carboxyphenyl-4-yl)methyl] -4-(1 - hydroxymethylimidazole)-5-carboxylic acid.

A mixture of 300 mg of 2-butyl-1-[(2'-carboxyphenyl-4-yl)methyl]-5-cyano - 4-(1-hydroxyethyl)imidazole [obtained as described in stage (c)] and 3 ml of 1N. aqueous sodium hydroxide solution is stirred in an oil bath supported 3 h at 80oC. after this time the reaction mixture was cooled, and then the extracts were dried and concentrated to dryness by evaporation under reduced pressure, getting in the amorphous solid. This substance was purified by column chromatography on silica gel, elwira mixture of methylene chloride and methanol (10: 1 and 3:1). Obtained from the eluate of the solid product is triturated in diethyl ether. The resulting powder was collected by filtration and dried, resulting in a received 72,3 mg of target compound as a colorless powder, so pl. 168-170oC (softening above 140oC).

NMR (DMCO-d6) ppm: 0,84 (3H, t, J = 7 Hz), 1.0 to 2.0 (4H, m), of 1.52 (3H, d, J = 7 Hz), 2,3-2,8 (2H, blocking. with the peak of DMSO), is 4.93 (1H, square, J = 7 Hz), ceiling of 5.60 (2H, Shir. C) of 6.8 to 7.8 (8H, m).

Example 12.

2-Butyl-1-[(2'-carboxyphenyl-4-yl)methyl]-4-(-hydroxybenzyl)imidazole-5-carboxylic acid (compound 1-80 N).

12(a). 4-Benzoyl-1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl]-2 - butyl-5-cyanomelana.

Repeated the procedure similar to that described in example 11(a), but used of 1.27 g of 4-benzoyl-2-butyl-5-renominate (obtained in accordance with the description in obtaining 6), 1,74 g of t-butyl 4'-bromomethylbiphenyl-2-carboxylate, to 0.69 g of potassium carbonate and 20 ml of N,N-dimethylacetamide, and then the product was purified by column chromatography on silica gel, elwira with a mixture of hexane and mean), and 2.79 (2H, t, J = 7 Hz), 5,38 (2H, s), and 7.1 to 8.0 (11H, m), 8,3-8,7 (2H, m).

12(b). 1-[(2'-t-Butoxycarbonylmethyl-4-yl)methyl]-2-butyl - 5-cyano-4-(-hydroxybenzyl)imidazole.

50.5 mg of sodium borohydride was added to a solution of 691 mg of 4-benzoyl-1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] -2-butyl - 5-renominate [obtained in accordance with the description of stage (a)] in 10 ml of ethanol, and the mixture was stirred 1 h at room temperature. Then the reaction mixture was neutralized aqueous hydrochloric acid, after which it was mixed with ethyl acetate and saturated aqueous sodium chloride. An ethyl acetate layer was separated, dried with anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography on silica gel, elwira with a mixture of hexane and ethyl acetate (1:1, by volume) and received 589 mg of the target compound as colorless amorphous solid.

NMR (CDCl3) ppm: to 0.89 (3H, t, J = 7 Hz), 1.0 to 2.0 (4H, m), 2,68 (2H, t, J = 7 Hz), is 5.18 (2H, s), of 5.89 (1H, s), 7,0-8,0 (13H, m).

12(c). 2-Butyl-1-[(2'-carboxyphenyl-4-yl)methyl]-5-cyano - 4-(-hydroxybenzyl)imidazole.

The solution 589 mg of 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl]-2 - butyl-5-cyano-4-(-hydroxybenzyl)imidazole [obtained in the temperature, and then concentrated by evaporation under reduced pressure. The residue was pereirae in hexane and collected by filtration, resulting in a received 493 mg of the hydrochloride of the target compound as a colorless powder, so pl. 95-97oC (softening).

NMR (DMSO-d6) ppm: to 0.88 (3H, t, J = 7 Hz), 1.0 to 2.0 (4H, m) of 3.00 (2H, t, J = 7 Hz), vs. 5.47 (2H, s) 6,09 (1H, s), 7,0-8,0 (13H, m).

12(d). 2-Butyl-1-[(2'-carboxyphenyl-4-yl)methyl-4-(-hydroxybenzyl)imidazole-5-carboxylic acid.

A mixture of 450 mg of 2-butyl-1-[(2'-carboxyphenyl-4-yl)methyl] - 5-cyano-4-(alpha-hydroxybenzyl)imidazole [obtained as described in stage (c)] and 20 ml of 1N. an aqueous solution of sodium hydroxide, stirred in an oil bath maintained during the 100oC for 7 hours, after this time the reaction mixture was cooled and its pH was brought to values of 3-4 by adding hydrochloric acid. The obtained colorless precipitate was collected by filtration, washed with water and dried, resulting in a received 331 mg of the target compound as a colorless powder, so pl. 192-194oC.

NMR (DMSO-d6) ppm: to 0.80 (3H, t, J = 7 Hz), 1.0 to 2.0 (4H, m), 2,69 (2H, t, J = 7 Hz), 5,69 (2H, s), 6,32 (1H, s), 6,9-7,9 (13H, m).

Example 13.

Ethyl 1-([(2'-t-butoxycarbonylmethyl-4-yl)m is, is written in example 1(a), but using 0,92 g ethyl-2-butyl-4-(1-hydroxy-1-methylethyl)imidazole - 5-carboxylate [obtained in accordance with the description in obtaining 8] and 1.28 g of t-butyl 4'-bromomethylbiphenyl-2-carboxylate, was obtained as the result of 1.23 g of target compound in the form of crystals with so pl. 92-93oC.

NMR (CDCl3) ppm: of 0.90 (3H, t, J = 7 Hz), of 1.23 (3H, t, J = 7 Hz), 1.26 in (9H, s), 1,2-2,05 (4H, m), of 1.65 (6H, s), 2,69 (2H, t, J = 7 Hz), 4,24 (2H, square, J = 7 Hz), 5,52 (2H, s), 5,73 (1H, s), 6,88-7,9 (8H, m).

Example 14.

Ethyl-2-butyl-1-[(2'-carboxyphenyl)-4-yl)methyl] -4-(1-hydroxy - 1-methylethyl)imidazole-5-carboxylate (compound N 1-32).

Repeating the procedure described in example 7, but using 0.50 g of ethyl 1-[(2'-t-butoxycarbonylmethyl-4-yl)-methyl] -2-butyl - 4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate (obtained as described in example 13) and 4h. the solution florodora in dioxane, which was obtained 0.45 g of the hydrochloride of target compound in the form of amorphous powder, so pl. above 80oC (softening).

NMR (DMSO-d6) ppm: of 0.82 (3H, t, J = 7 Hz), to 1.14 (3H, t, J = 7 Hz), 1.2 to about 1.35 (2H, m), 1.41 to 1.55V (2H, m) to 1.60 (6H, s) of 3.00 (2H, t, J = 7 Hz), is 4.21 (2H, square, J = 7 Hz), 5,63 (2H, s), 7,14-of 7.75 (8H, m).

Example 15.

Ethyl-1-[(2'-t-butoxycarbonylmethyl-4-yl)metopiinae in example 1(a), but using 0,845 g of ethyl 4-(1-hydroxy-1-methylethyl)-2 - propylimidazol-5-carboxylate (obtained in accordance with the description in obtaining 9) and 1.22 g of t-butyl 4-bromomethylbiphenyl-2-carboxylate, and received 1,31 g of target compound in the form of a resinous substance. Then, the connection is kept at room temperature in order to cause crystallization. Then the compound was recrystallized from a mixture of diisopropyl ether and hexane, resulting in a net target connection so pl. 90-91oC.

NMR (CDCl3) ppm: to 0.97 (3H, t, J = 7 Hz), of 1.23 (3H, t, J = 7 Hz), 1,25 (9H, s) to 1.60 (6H, s), equal to 1.82 (2H, sextet, J = 7 Hz), to 2.67 (2H, t, J = 7 Hz), 4,24 (2H, square, J = 7 Hz), 5,51-5,72 (1H, s), 6.87 in-a 7.85 (8H, m).

Example 16.

Ethyl-1-[(2'-carboxyphenyl-4-yl)methyl] -4-(1-hydroxy-1 - methylethyl)-2-propylimidazol-5-carboxylate (compound N 1-50).

Repeating the procedure described in example 7, but using 0,80 g of ethyl 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] -4-(1 - hydroxy-1-methylethyl)-2-propylimidazol-5-carboxylate (obtained as described in example 15) and 4h. chloride solution in dioxane, resulting in received of 0.67 g of the hydrochloride of target compound as amorphous powder.

NMR (DMSO-d6) ppm: to 0.88 (3H, t, J =7.

1-[(2'-Carboxyphenyl-4-yl)methyl] -4-(1-hydroxy-1-methylethyl)-2 - propylimidazol-5-carboxylic acid (compound N 1-49).

A solution of 0.20 g of ethyl 1-[(2'-carboxyphenyl-4-yl)methyl]-4-(1 - hydroxy-1-methylethyl)-2-propylimidazol-5-carboxylate hydrochloride (obtained as described in example 16) in an aqueous solution of 84 mg hydroxide monohydrate lithium in 5 ml of water is stirred 6 h at room temperature. After this time the reaction mixture was added drop by drop to 2 ml of 1N. aqueous hydrochloric acid, and the precipitate was collected by filtration, which was obtained 0.17 g of target compound with so pl. 176-179oC (decomposition).

NMR (DMSO-d6) ppm: to 0.88 (3H, t, J = 7 Hz), 1,5-of 1.65 (2H, m), and 1.56 (6H, s) to 2.66 (2H, t, J = 7 Hz), 5,69 (2H, s), 7.03 is-7,72 (8H, m).

Example 18.

Ethyl-4-(1-hydroxy-1-methylethyl)-2-propyl-1-{ 4-[2-(tetrazol - 5-yl)phenyl] phenyl}Mei-5-carboxylate (compound N 2-7).

18(a). Ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2- (triliteral-5-yl)phenyl]phenyl}Mei-5-carboxylate.

48 mg of sodium hydride (as a 55 wt.% dispersion in mineral oil) was added to a solution of 0.26 g of ethyl 4-(1-hydroxy-1-methylethyl)- 2-propylimidazol-5-carboxylate (obtained in accordance with the description of the em solution was added to 0.72 g of 4-[2-(triliteral-5-yl)phenyl] benzylbromide in 5 ml of N,N-dimethylformamide, and the reaction mixture stirred at room temperature for 2 h and at 60oC for 4 h after which time the mixture was dissolved in ethyl acetate and the solution washed three times with water. After that, the solution was dried with anhydrous sodium sulfate, and the solvent is then drove away. The residue was purified by column chromatography on silica gel, elwira with a mixture of hexane and ethyl acetate (1:1, by volume), resulting in received of 0.62 g of the target compound as amorphous solid. This substance was led from diisopropyl ether, and received in the target connection in the form of crystals, so pl. 167-168oC (decomposition).

NMR (CDCl3) ppm: to 0.88 (3H, t, J = 7 Hz), a 1.08 (3H, t, J = 7 Hz), 1,5-1,8 (2H, m) of 1.64 (6H, s), 2,62 (2H, t, J = 8 Hz), of 4.12 (2H, square, J = 7 Hz), 5,38 (2H, s), 5,78 (1H, s), 6,7-7,6 (22H, m), 7,8 and 8.1 (1H, m).

18 (b). Ethyl-4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2 - tetrazol-5-yl)phenyl]phenyl}Mei-5-carboxylate.

A solution of 0.50 g of ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl- 1-{ 4-[2-(triliteral-5-yl)phenyl]phenyl}Mei-5-carboxylate (obtained as described in example 18(a)), dissolved in 5 ml of 4n. solution florodora in dioxane, was left overnight at room temperature, after which re is Isopropylamine ether and obtained 0.34 g of the hydrochloride of the target compounds, so pl. 100-103oC.

NMR (CD3OD) ppm: to 0.97 (3H, t, J = 7 Hz), 1,24 (3H, t, J = 7 Hz), 1,50-of 1.65 (2H, m) to 1.70 (6H, s) of 3.00 (2H, t, J = 8 Hz), 4,30 (2H, square, J = 7 Hz), 5,70 (2H, s), the 6.9 to 7.8 (8H, m).

Example 19.

4-(1-Hydroxy-1-methylethyl)-2-1-{ 4-[2-(tetrazol-5-yl)phenyl] phenyl} Mei-5-carboxylic acid (compound N 2-1).

the 3.65 ml of 1N. an aqueous solution of sodium hydroxide was added to a solution of 0.31 g of ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2- (tetrazol-5-yl)phenyl]phenyl} Mei-5-carboxylate hydrochloride [obtained as described in example 18(b)] in 6 ml of methanol, and the mixture was left overnight at room temperature. After this time the reaction mixture was concentrated by evaporation under reduced pressure to remove methanol. The concentrate was diluted with water and the pH brought up to a value of 3 by adding diluted hydrochloric acid, after which the mixture was extracted with ethyl acetate. The organic extract was dried with anhydrous sodium sulfate, and then concentrated by evaporation under reduced pressure. The obtained residue was washed with diisopropyl-ethyl and obtained 0.15 g of target compound, so pl. 166-169oC.

NMR (DMSO-d6) ppm: of 0.85 (3H, t, J = 7.5 Hz), and 1.54 (6H, s), 1,4-1,6 (2H, m), 2,5 methyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2- (tetrazol-5-yl)phenyl]phenyl}Mei-5-carboxylate (compound N 2-15).

20 (a). Pivaloyloxymethyl 4-(1-hydroxy-1-methylethyl)-2-propyl- 1-{4-[2-(tritiltimidilil-5-yl)phenyl]phenyl}Mei-5-carboxylate.

and 5.30 ml of 1N. an aqueous solution of sodium hydroxide, and then 5 ml of tetrahydrofuran was added to a solution 0,76 g of ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{ 4-[2-(triliteral-5 - yl)phenyl]phenyl}Mei-5-carboxylate (obtained as described in example 18(a)) in 30 ml of methanol, after which the resulting mixture was stirred at room temperature for 8 hours. Then the reaction mixture was concentrated by evaporation under reduced pressure to remove methanol and tetrahydrofuran. To the concentrate was added water, and the pH of the mixture was brought to a value of 4 by the addition of dilute hydrochloric acid cooled with ice. Then the mixture was extracted with ethyl acetate. The extract was dried with anhydrous magnesium sulfate and concentrated by evaporation to dryness. The residue was dissolved in 10 ml of dimethylacetamide, and the resulting solution was added to 0.23 g of potassium carbonate and 0.13 ml of pivaloyloxymethyl. The mixture is then stirred 4 h at 50oC, after which it was added 0.06 ml of pivaloyloxymethyl, and the resulting mixture was stirred for another 2 times. After the reaction mixture was diluted centriole by evaporation under reduced pressure. The concentrate was purified by column chromatography on silica gel, elwira with a mixture of hexane and ethyl acetate (1:1 by volume), and got to 0.23 g of target compound in the form of an amorphous solid product.

NMR (CDCl3) ppm: 0,86 (3H, t, J = 7 Hz); of 1.12 (9H, s) of 1.62 (6H, s), 1,4-1,9 (2H, m), of 2.51 (2H, t, J = 7 Hz), lower than the 5.37 (1H, Shir. C) of 5.40 (2H, s) 5,72 (2H, s), 6,6-8,1 (23H, m).

20(b). Pivaloyloxymethyl 4-(1-hydroxy-1-methylethyl)-2-propyl- 1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}Mei-5-carboxylate.

5 ml of 4n. solution florodora in dioxane was added to 0.20 g of pivaloyloxymethyl-4-(1-hydroxy-1-methylethyl)-2-propyl- 1-{ 4-[2-(triliteral-5-yl)phenyl] phenyl} Mei-5-carboxylate (obtained as described in example 20a), and the mixture was left overnight at room temperature. After this time the reaction mixture was concentrated to dryness under reduced pressure. The obtained residue was washed with diisopropyl ether to stimulate crystallization and received with 0.13 g of the hydrochloride of target compound in the form of crystals with so pl. 104-107oC.

NMR (DMSO-d6) ppm: 0,84 (3H, t, J = 7.5 Hz), of 1.09 (9H, s), 1,35 of 1.50 (2H, m), and 1.56 (6H, s), is 2.88 (2H, t, J = 8 Hz), to 5.58 (2H, s), to 5.85 (2H, s), 7,05 (2H, d, J = 8.5 Hz), 7,10 (2H, d, J = 8.5 Hz), of 7.5 to 7.7 (4H, m).

Example 21.

21(a). Ethyl-2-butyl-4-(1-ethyl-1-hydroxypropyl)-1-{4-[2- (triliteral-5-yl)phenyl]phenyl}Mei-5-carboxylate.

Repeating the procedure described in example 18a, but using 0.75 g of ethyl 2-butyl-4-(1-ethyl-1-hydroxypropyl)imidazole - 5-carboxylate (obtained in accordance with the description in obtaining 13), 0.12 g of sodium hydride (as a 55 wt. % dispersion in mineral oil), and 1.51 g of 4-[2-(triliteral-5-yl)phenyl] benzylbromide, and received in the result of 1.05 g of the target compound as an amorphous solid product.

NMR (CDCl3) ppm: or 0.83 (6H, triplet, J = 7.5 Hz), of 0.85 (3H, triplet, J = 6 Hz), is 1.11 (3H, t, J = 7 Hz), 1,23-1,32 (2H, m), 1.56 to of 1.65 (2H, m), 1,80-1,89 (2H, m), 2,03 with 2.14 (2H, m) to 2.55 (2H, t, J = 8 Hz), of 4.12 (2H, square, J = 7.5 Hz), lower than the 5.37 (2H, s), 5,64 (1H, Shir. C) 6,70 (2H, d, J = 8.5 Hz), the 6.9 to 7.0 (6H, m), 7,10 (2H, d, J = 8.5 Hz), 7,2-7,4 (10H, m), between 7.4 to 7.5 (2H, m), a 7.85-of 7.90 (1H, m).

21(b). 2-Butyl-4-(1-ethyl-1-hydroxypropyl)-1-{ 4-[2-(tetrazol - 5-yl)phenyl]phenyl}Mei-6-carboxylic acid.

1,71 ml of 1N. aqueous hydrochloric acid was added to a solution of 0.65 g of ethyl 2-butyl-4-(1-ethyl-1-hydroxypropyl)-1-{ 4-[2-trailersa - 5-yl)phenyl]phenyl} Mei-5-carboxylate [obtained as described in stage (a)] in 10 ml of methanol, and the mixture was left overnight at room temperature. After that, the and. The resulting solution was mixed with 4,28 ml of 1N. aqueous sodium hydroxide solution and left overnight at room temperature. Then the reaction mixture was concentrated by evaporation under reduced pressure to remove methanol. the pH of the concentrate is brought to a value of 3 by adding a diluted aqueous hydrochloric acid, and precipitated crystals were collected by filtration. Thus obtained crystals suspended in diisopropyl ether and then collected by filtration, which was obtained 0.35 g of target compound with so pl. 181-183oC.

NMR (DMSO-d6) ppm: 0,74 (6H, t, J = 7.5 Hz), of 0.79 (3H, t, J = 7.5 Hz), 1,1-1,3 (2H, m), 1,40-of 1.55 (2H, m), 1,67 and 1.80 (2H, m), 1,90-of 2.05 (2H, m) at 2.59 (2H, t, J = 7,5), 5,67 (2H, s), to 6.88 (2H, d, J = 8.5 Hz), 7,05 (2H, d, J = 8.5 Hz), of 7.5 to 7.7 (4H, m).

Example 22.

2-Butyl-4-(1-hydroxy-1-methylethyl)-1-{ 4-[2-(tetrazol-5 - yl)phenyl]phenyl} Mei-5-carboxylic acid (compound N 2-2).

22(a). Ethyl-2-butyl-4-(1-hydroxy-1-methylethyl)-1-{4-[2- (triliteral-5-yl)phenyl]phenyl}Mei-5-carboxylate.

Repeating the procedure described in example 18a, but with 0.26 g of ethyl 2-butyl-4-(1-hydroxy-1-methylethyl)imidazole - 5-carboxylate (obtained in accordance with the description in obtaining 8), and 45.5 mg is the beginning of 0.28 g of target compound in the form of an oily product.

NMR (CDCl3) / ppm: of 0.85 (3H, t, J = 7 Hz), of 1.09 (3H, t, J = 7 Hz), of 1.09 (3H, t, J = 7 Hz), of 1.64 (6H, s), 1,3-1,8 (4H, m), of 2.56 (2H, t, J = 8 Hz), 4,14 (2H, square, J = 7 Hz), 5,38 (2H, s), 5,78 (1H, s), 6,6-7,6 (22H, m), and 7.7 and 8.1 (1H, m).

22(b). 2-Butyl-4-(1-hydroxy-1-methylethyl)-1-{4-[2-(tetrazol-5 - yl)phenyl] phenyl}Mei-5-carboxylic acid.

Repeating the procedure described in example 21(b), and by processing 0.28 g of ethyl 2-butyl-4-(1-hydroxy-1-methylethyl)-1-{4-[2-(triliteral - 5-yl)phenyl] phenyl}Mei-5-carboxylate [obtained as described in stage (a)] 0,42 milliliters of 1N. aqueous hydrochloric acid, followed by treatment of the product of 1.70 ml of 1N. an aqueous solution of nitroxide sodium received 78 g of target compound with so pl. 138-141oC.

NMR (DMSO-d6) ppm: 0,81 (3H, t, J = 7.5 Hz), 1,15-1,35 (2H, m), 1,4-1,6 (2H, m) of 1.53 (6H, s), 2,58 (2H, t, J = 8.5 Hz), 5,64 (2H, s) 6,94 (2H, d, J = 8.5 Hz), 7,06 (2H, d, J = 8.5 Hz), 7,15-of 7.70 (4H, m).

Example 23.

2-Butyl-4-(1-hydroxy-1-methylpropyl)-1-{ 4-[2-(tetrazol-5 - yl)phenyl]phenyl}Mei-5-carboxylic acid (compound N 2-38).

23(a). 2-Butyl-5-cyano-4-(1-hydroxy-1-methylpropyl)-1-{ 4-[2- trailersa-5-yl)phenyl]phenyl}Mei.

Repeating the procedure described in example 18(a), but with 465 mg of 2-butyl-5-cyano-4-(1-hydroxy-1-methylpropyl in mineral oil), and of 1.11 g of 4-[2-(triliteral-5-yl)phenyl] benzylbromide, and received in the result of 1.00 g of target compound in the form of a resinous substance.

NMR (CDCl3) ppm: 0,86 (3H, t, J = 7.5 Hz), of 0.87 (3H, t, J = 7 Hz), to 1.21 to 1.34 (2H, m), 1,54-of 1.66 (2H, m) to 1.60 (3H, s), 1,82-of 1.97 (2H, m), of 2.51 (2H, t, J = 7.5 Hz), up 3.22 (1H, s), 5,04 (2H, s), 6.87 in-7,52 (22H, m), 7,93-of 7.96 (1H, m).

23(b). 2-Butyl-5-cyano-4-(1-hydroxy-1-methylpropyl)-1-{4-[2- (tetrazol-5-yl)phenyl]phenyl}Mei.

A mixture of 1.00 g of 2-butyl-5-cyano-4-(1-hydroxy-1-methylpropyl)- 1-{4-[2-(triliteral-5-yl)phenyl] phenyl}methylimidazole (obtained in accordance with the description given in stage (a) and 25 ml of 20%.about. aqueous acetic acid is stirred 2 hours at 60oC, after which the solvent is kept at reduced pressure. Residual water and acetic acid was removed as the toluene azeotrope by distillation under reduced pressure, and the obtained residue was purified by column chromatography on silica gel, elwira mixture of methanol and methylene chloride (1:9 and 1:4 by volume), which was obtained 0.65 g of target compound in the form of a glassy substance.

NMR (CDCl3) ppm: or 0.83 (3H, t, J = 7 Hz), to 0.88 (3H, t, J = 7 Hz), of 1.23 to 1.37 (2H, m), of 1.57 (3H, s), 1,55-1,70 (2H, m), 1,82-1,89 (2H, m) of 2.64 (2H, t, J = 7 Hz), 5,12 (2H, s), 6,9-7,1 (4H, m), 7,29-of 7.60 (3H, m), 7,87 (1H, t, J = 7.5 Hz).

A mixture of 360 mg of 2-butyl-5-cyano-4-(1-hydroxy-1-methylpropyl)- 1-{4-[2-(tetrazol-5-yl)phenyl] phenyl} methylimidazole [obtained as described in stage (b)], 266 mg hydroxide monohydrate lithium and 3.6 ml of water stirred in an oil bath maintained during 115oC, for 16 hours, after this time the reaction mixture was cooled and to the mixture was added 6.4 ml of 1N. aqueous hydrochloric acid, cooling the thus ice. Precipitated crystals were collected by filtration and received 302 mg of the target compound with so pl. 152-154oC.

NMR (DMSO-d6) ppm: of 0.79 (3H, t, J = 7 Hz), of 0.82 (3H, t, J = 7 Hz), of 1.20 to 1.34 (2H, m), 1,44-of 1.55 (2H, m) of 1.55 (3H, s), 1,71-of 1.95 (2H, m), 2,62 (2H, t, J = 7.5 Hz), of 5.68 (2H, AB-Quartet, = 0,10 ppm, J = 17 Hz), 6,86-7,10 (4H, m), 7,53-7,72 (4H, m).

Example 24.

4-(1-Hydroxy-1-methylpropyl)-2-propyl-1-{ 4-[2-(tetrazol-5 - yl)phenyl] phenyl}Mei-5-carboxylic acid (compound N 2-37).

24(a). 5-Cyano-4-(1-hydroxy-1-methylpropyl)-2-propyl-1-{ 4-[2 - trailersa-5-yl)phenyl]phenyl}Mei.

Repeating the procedure described in example 18a, but with 380 mg of 5-cyano-4-(1-hydroxy-1-methylpropyl)-2-propylimidazol (obtained in accordance with the description in obtaining 20), 88 mg of sodium hydride (as a 55 wt. % dispersion in mineral oil) and 1.07 g of 4-[2-th solid.

NMR (CDCl3) ppm: 0,86 (3H, t, J = 8 Hz), of 0.87 (3H, t, J = 7.5 Hz), 1,60 (3H, s), 1,60-1,75 (2H, m), 1,80-2,00 (2H, m), 2,48 (2H, t, J = 8 Hz), 5,04 (2H, s), to 6.88 (2H, d, J = 8.5 Hz), the 6.9 to 7.0 (4H, m), 7,14 (2H, d, J = 8.5 Hz), 7,2-7,4 (14H, m), 7,45-of 7.55 (1H, m).

24(b). 5-Cyano-4-(1-hydroxy-1-methylpropyl)-2-propyl-1-{4-[2- (tetrazol-5-yl)phenyl]phenyl}Mei.

Repeating the procedure described in example 23, and by processing 0.51 g of 5-cyano-4-(1-hydroxy-1-methylpropyl)-2-propyl-1-{ 4-[2- (triliteral-5-yl)phenyl] phenyl} methylimidazole (obtained as described in stage (a)) 75% vol./about. aqueous acetic acid was obtained 0.32 g of target compound in the form of crystals with so pl. 141-145oC.

NMR (CD3OD) ppm: 0,84 (3H, t, J = 8 Hz), of 0.90 (3H, t, J = 8.5 Hz), of 1.52 (3H, s), 1,5-1,7 (2H , m), 1,75-1,90 (2H, m) to 2.65 (2H, t, J = 8 Hz), at 5.27 (2H, s), 7,03 (2H, d, J = 8.5 Hz), 7,14 (2H, d, J = 8.5 Hz), 7,45-7,63 (4H, m).

24(c). 4-(1-Hydroxy-1-methylpropyl)-2-propyl-1-{ 4-[2-(tetrazol - 5-yl)phenyl]phenyl}Mei-5-carboxylic acid.

Repeating the procedure described in example 23(C), and by processing to 0.19 g of 5-cyano-4-(1-hydroxy-1-methylpropyl)-2-propyl-1- {4-[2-(tetrazol-5-yl)phenyl] phenyl} methylimidazole (obtained as described in stage (b) 0.15 g of hydroxide monohydrate lithium was obtained 0.14 g of target compound in powder form with so pl. 174-177oC. 80 (2H, AB-quart., = 0,14 ppm, J = 16.5 Hz), 7,01 (2H, d, J = 8.5 Hz), 7,11 (2H, d, J = 8.5 Hz), of 7.48 to 7.75 (4H, m).

Example 25.

Pivaloyloxymethyl 1-[(2'-carboxyphenyl-4-yl)methyl]-4-(1 - hydroxy-1-methylethyl)-2-propylimidazol-5-carboxylate (compound N 3-1).

25(a). Ethyl 1-[(2'-butoxycarbonylmethyl-4-yl)methyl]-4-(1 - hydroxy-1-methylethyl)-2-propylimidazol-5-carboxylate.

3.00 g t butoxide potassium was added, the cooling in this ice, to a solution of 6 g of ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazol-5-carboxylate (obtained in accordance with the description in obtaining (9) in 40 ml of N,N-dimethylacetamide, and the mixture was stirred 10 min, then was added a solution of 9.00 g of t-butyl 4'-bromomethylbiphenyl-2-carboxylate in 40 ml of N,N-dimethylacetamide. Then the reaction mixture was stirred 1 h at room temperature and 2 h at 50oC, after which the mixture was mixed with water and was extracted with ethyl acetate. The extract was dried with anhydrous magnesium sulfate, and the solvent is kept at reduced pressure. The residue was purified by column chromatography on silica gel, elwira with a mixture of hexane and ethyl acetate (1:1 by volume), and obtained 11.6 g of target compound in the form of a solid with a softening temperature of 85oC.

NMR (CDCl3) ppm: 0,97) 6,87-a 7.85 (8H, m).

25(b). 1-[2'-t-Butoxycarbonylmethyl-4-yl)methyl] -4-(1-hydroxy - 1-methylethyl)-2-propylimidazol-5-carboxylic acid.

A solution of 4.8 g of the hydroxyl-monohydrate of lithium in 100 ml of water was added to a solution of 11.6 g of ethyl 1-[(2'-t-butoxycarbonylmethyl - 4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propylimidazol-5-carboxylate [obtained as described in stage (a)] in 60 ml of dioxane, and the resulting mixture was stirred 16 hours at room temperature. Dioxane drove away under reduced pressure, and the concentrate was mixed with ice water and ethyl acetate, after which was added 114 ml of 1N. aqueous hydrochloric acid. The ethyl acetate layer was separated, dried with anhydrous magnesium sulfate, and the solvent drove by distillation under reduced pressure. The crystalline residue is triturated in diisopropyl ether and collected by filtration, resulting received a 9.09 g of target compound, so pl. 155-157oC.

NMR (CDCl3) ppm: of 0.85 (3H, t, J = 7.5 Hz), of 1.23 (9H, s), 1,53-of 1.65 (2H, m), of 1.65 (6H, s), 2.91 in (3H, t, J = 7.5 Hz), 5,90 (2H, s), to 7.09 (2H, d, J = 8 Hz), 7,21-of 7.48 (5H, m), of 7.75 (1H, d, J = 9 Hz).

25(c). Pivaloyloxymethyl 1-[(2'-t-butoxycarbonylmethyl - 4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propylimidazol-5-carboxylate.

2,13 ml chloromethylmethylether)-2-propylimidazol-5-carboxylic acid (obtained as described in stage (b)) in 70 ml of N,N-dimethylacetamide, and the resulting mixture was stirred at room temperature for 1 h and at 50oC for 2 hours, after this time the reaction mixture was mixed with ethyl acetate and water. The ethyl acetate layer was separated and dried with anhydrous magnesium sulfate, then the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography on silica gel, elwira a mixture of ethyl acetate and hexane (1:1 by volume), and got to 6.80 g of target compound in the form of crystals with so pl. 106-107oC.

NMR (CDCl3) ppm with 1.07 (3H, t, J = 7 Hz), 1,25 (9H, s) of 1.32 (9H, s), 1,71 (6H, s), 1,79-1,90 (2H, m) of 2.75 (2H, t, J = 8 Hz), of 5.50 (1H, s) 5,59 (2H, s), of 5.92 (2H, s), 7,05 (2H, d, J = 8 Hz), 7,34-7,56 (5H, m), the 7.85 (1H, d, J = 7 Hz).

25(d). Pivaloyloxymethyl 1-[(2'-carboxyphenyl-4-yl)methyl]- 4-(1-hydroxy-1-methylethyl)-2-propylimidazol-5-carboxylate.

A mixture of 6.6 g pivaloyloxymethyl 1-[(2'-t-butoxycarbonylmethyl - 4-yl)methyl] -4-(1-hydroxy-1-methylethyl)-2-propylimidazol-5-carboxylate (obtained as described in stage (c) and 57 ml of 4n. solution florodora in dioxane is stirred 4 h at room temperature. Then the reaction mixture was concentrated by evaporation under reduced pressure, and the residue triturated with ethyl acetate in aiming is UP>C.

NMR (DMSO-d6) ppm: of 0.87 (3H, t, J = 7 Hz), 1,10 (9H, s), 1,45-to 1.60 (2H, m), was 1.58 (6H, s), 2,96 (2H, t, J = 7.5 Hz), the 5.65 (2H, s), by 5.87 (2H, s), 7,17 (2H, d, J = 8 Hz), 7,33 (2H, d, J = 8 Hz), 7,43-of 7.60 (3H, m), 7,74 (1H, d, J = 8 Hz).

Example 26.

Isopropoxycarbonyloxymethyl 1-[(2'-carboxyphenyl-4-yl)methyl]- 4-(1-hydroxy-1-methylethyl)-2-propylimidazol-5-carboxylate (compound N 3-13).

26(a). Isopropoxycarbonyloxymethyl 1-[(2'-t-butoxycarbonylmethyl - 4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propylimidazol-5-carboxylate.

Repeating the procedure described in example 25(c), and the target compound was obtained as crystals (0,58 g, so pl. 85-87oC) by mixing a mixture containing 0.50 g of 1-[(2'-t-butoxycarbonylmethyl - 4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propylimidazol-5-carboxylic acid [obtained as described in example 25(b)] 0,19 g isopropoxycarbonyloxymethyl and 0.33 g of potassium carbonate in 6 ml N,N-dimethylacetamide, for 3 h at room temperature.

NMR (CDCl3) ppm: 0,99 (3H, t, J = 7 Hz), of 1.23 (9H, s) of 1.29 (6H, d, J = 6 Hz), and 1.63 (6H, s), 1.70 to of 1.85 (2H, m), 2,68 (2H, t, J = 8 Hz), 4,89 (1H, quintet, J = 6 Hz), 5,38 (1H, s), the 5.51 (2H, s), of 5.82 (2H, s), 6,97 (2H, d, J = 8 Hz), 7,26-of 7.48 (5H, s), to 7.77 (1H, d, J = 8 Hz).

26(b). Isopropoxycarbonyloxymethyl 1-[(2'-carboxyphenyl - 4-yl)methyl] -5, and by processing 0,46 g isopropoxycarbonyloxymethyl 1-[(2'-t-butoxycarbonylmethyl - 4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propylimidazol-5-carboxylate [obtained as described in stage (a)] 4h. restoom of florodora in dioxane was obtained 0.36 g of the hydrochloride of target compound in the form of amorphous powder with so pl. 153 to 155oC.

NMR (CDCl3) ppm: 0,98 (3H, t, J = 7 Hz), 1,29, (6H, d, J = 6 Hz), 1,50-of 1.65 (2H, m) of 1.76 (6H, s), of 3.13 (2H, t, J = 7 Hz), of 4.90 (1H, quintet, J = 6 Hz), of 5.55 (2H, s), of 5.82 (2H, s), 7,02 (2H, d, J = 6.5 Hz), 7,21-EUR 7.57 (5H, m) of 7.96 (1H, d, J = 8 Hz).

Example 27.

Ethoxycarbonylmethyl 1-[(2'-carbonylmethyl-4-yl)methyl] - 4-(1-hydroxy-1-methylethyl)-2-propylimidazol-5-carboxylate (compound N 3-9).

27(a). Ethoxycarbonylmethyl 1-[(2'-t-butoxycarbonylmethyl - 4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propylimidazol-5-carboxylate.

Following the procedure described in example 25(c), received 0,69 g of target compound in the form of oily substance on the basis of 0.55 g of 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] -4-(1-hydroxy-1 - methylethyl)-2-propylimidazol-5-carboxylic acid [obtained as described in example 25b], 0,30 g ethoxycarbonylmethylene and 0.50 g of potassium carbonate.

NMR (CDCl3) ppm: 0,99 (3H, t, J = 7 Hz), 1,23 ), 7,26-7,51 (5H, m), to 7.77 (1H, d, J = 6.5 Hz).

27(b). Ethoxycarbonylmethyl 1-[(2'-carboxyphenyl-4-yl)methyl]- 4-(1-hydroxy-1-methyl)-2-propylimidazol-5-carboxylate.

Following the procedure described in example 25(d), got to 0.48 g of the hydrochloride of target compound in the form of amorphous powder (softening temperature of >70oC) by processing 0,69 g ethoxycarbonylmethyl 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] - 4-(1-hydroxy-1-methylethyl)-2-propylimidazol-5-carboxylate (obtained as described in stage (a)) 4h. solution florodora in dioxane.

NMR (DMSO-d6) ppm: to 0.88 (3H, t, J = 7 Hz), 1,19 (3H, t, J = 7 Hz), 1,5-of 1.65 (2H, m) to 1.59 (6H, s), 2,96 (2H, t, J = 7.5 Hz), is 4.15 (2H, square, J = 7 Hz), 5,64 (2H, s), of 5.84 (2H, s), 7,18 (2H, d, J = 8 Hz), 7,32-to 7.61 (5H, m), 7,74 (1H, d, J = 7 Hz).

Example 28.

1-(Isopropoxycarbonyl)ethyl 1-[(2'-carboxyphenyl - 4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propylimidazol-5-carboxylate (compound N 3-14).

28(a). 1-(Isopropoxycarbonyl)ethyl 1-[(2'-t-butoxycarbonylmethyl - 4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propylimidazol-5-carboxylate.

Following the procedure described in example 25(c), received 0,60 g of target compound in the form of a resinous substance by stirring for 16 hours at 60oC 0.5 scientists in accordance with the description in example 25(b)] and 0.21 g of 1-(isopropoxycarbonyl)ethylchloride a solution of 0.40 g of potassium carbonate in 6 ml N,N-dimethylacetamide.

NMR (CDCl3) ppm: to 0.97 (3H, t, J = 7.5 Hz), of 1.26 (9H, s) of 1.27 (6H, DD, doublet of doublets, J = 4,5 & 6 Hz), of 1.42 (3H, d, J = 5.5 Hz), of 1.64 (6H, d, J = 3 Hz), 1,75-1,80 (2H, m), 2,65 (2H, d, J = 7.5 Hz), a 4.86 (1H, Queen., J = 6 Hz), of 5.50 (2H, s), make 6.90 (1H, square, J = 5.5 Hz), 6,97 (2H, d, J = 8.5 Hz), 7,26-to 7.50 (5H, m), 7,78 (1H, d, J = 8 Hz).

28(b). 1-(Isopropoxycarbonyl)ethyl 1-[(2'-carbonylmethyl - 4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propylimidazol-5-carboxylate.

Following the procedure described in example 25(d), received 0,41 g of the hydrochloride of the target compounds (in the form of amorphous powder with so pl. 94-96oC) by treatment of 0.60 g of 1-(isopropoxycarbonyl)ethyl 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] -4-(1-hydroxy-methylethyl)- 2-propylimidazol-5-carboxylate [obtained as described in stage (a)] 4h. solution florodora in dioxane.

NMR (CDCl3) ppm: to 0.94 (3H, t, J = 7 Hz), 1.27mm (6H, DD, J = 6.5 and 11 Hz), of 1.47 (3H, d, J = 5.5 Hz), 1,50-of 1.65 (2H, m) of 1.76 (6H, d, J = 8.5 Hz), is 3.08 (2H, Shir. the triple., J = 8 Hz), a 4.86 (1H, septet, J = 7 Hz), to 5.56 (2H, s), 6.87 in (1H, square , J = 5.5 Hz),? 7.04 baby mortality (2H, d, J = 7.5 Hz), 7,27-the 7.65 (5H, m), of 7.97 (1H, d, J = 8 Hz).

Example 29.

(5-Methyl-2-oxo-1,3-dioxolan-4-yl)methyl 1-[(2'-carboxyphenyl - 4-yl)methyl] -4-(1-hydroxy-1-methylethyl)-2-propylimidazol-5-carboxylate (compound N 3-25).

29(a). (5-Methyl-2-oxo-1,3-dioxolan-4-yl)methyl 1-[(2'-t - bootiedude, described in example 25(c), was obtained 0.65 g of target compound in the form of a resinous substance, on the basis of 0.50 g of 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] -4-(1-hydroxy-1 - methylethyl)-2-propylimidazol-5-carboxylic acid [obtained according to example 25(b)] 0.27 g (5-methyl-2-oxo-1,3 - dioxolan-4-yl)methyl, and 0.3 g of potassium carbonate in 6 ml N,N-dimethylacetamide.

NMR (CDCl3) ppm: 0,99 (3H, t, J = 6.5 Hz), of 1.28 (9H, s) of 1.64 (6H, s), 1,55-1,90 (2H, m) 2,07 (3H, s), 2,70 (2H, t, J = 7 Hz), of 4.90 (2H, s), vs. 5.47 (2H, s), the 5.51 (1H, s) 6,91 (2H, d, J = 8.5 Hz), 7,2-7,9 (6H, m).

29(b). (5-Methyl-2-oxo-1,3-dioxolan-4-yl)methyl 1-[(2'-carboxyphenyl-4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2 - propylimidazol-5-carboxylate.

Following the procedure described in example 25(d), received of 0.54 g of the hydrochloride of target compound in the form of amorphous powder (so pl. 90-93oC) by treating 0.65 g (5-methyl-2-oxo-1,3-dioxolan - 4-yl)methyl 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] -4-(1-hydroxy - 1-methylethyl)-2-propylimidazol-5-carboxylate (obtained as described in stage (a)) 4h. solution florodora in dioxane.

NMR (DMSO-d6) ppm: to 0.88 (3H, t, J = 7.5 Hz), 1,5-1,7 (2H, m) to 1.59 (6H, s), 2,11 (3H, s) of 3.00 (2H, t, J = 7.5 Hz), 5,13 (2H, s), 5,63 (2H, s), 7,13 (2H, d, J = 8 Hz), 7,26 to 7.75 (6H, m).

Example 30.

Pimalai the N 3-1)

30(a). Pivaloyloxymethyl 1-[(2'-t-butoxycarbonylmethyl - 4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propylimidazol-5-carboxylate.

Following the procedure described in example 25(a), received 0,81 g of target compound based on 500 mg pivaloyloxymethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazol-5 - carboxylate [obtained in accordance with the description in obtaining 22(ii)] and 560 mg of t-butyl 4'-bromomethylbiphenyl-2-carboxylate. This product has the same melting point and the same NMR spectrum as the compound obtained in example 25(c).

30(b). Pivaloyloxymethyl 1-[(2'-carboxyphenyl-4-yl)methyl]-4- (1-hydroxy-1-methylethyl)-2-propylimidazol-5-carboxylate.

Following the procedure described in example 25(d), was obtained 0.45 g of the hydrochloride of target compound in the form of crystals based on 0.5 g pivaloyloxymethyl 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] -4- (1-hydroxy-1-methylethyl)-2-propylimidazol-5-carboxylate [obtained as described in stage (a)]. This product has the same melting point and the same NMR spectrum as the compound obtained in example 25(d).

Example 31.

Pivaloyloxymethyl-2-butyl-1-[(2'-carboxyphenyl-4-yl)methyl]- 4-(1-hydroxy-1-methylethyl)-2-propylimidazol-5-carboxylate (soudaseal-5-carboxylate.

Following the procedure described in example 25(a), received of 3.54 g of target compound in the form of syrup, based on a 2.00 g of methyl 2-butyl-4- (1-hydroxy-1-methylethyl)imidazole-5-carboxylate [obtained in accordance with the description in obtaining 21), and 3.03 g of t-butyl 4'-bromomethylbiphenyl-2-carboxylate.

NMR (CDCl3) ppm: to 0.92 (3H, t, J = 7.5 Hz), 1,25 (9H, s), 1,33 of 1.46 (2H, m) of 1.64 (6H, s), 1,68-of 1.78 (2H, m), 2,70 (2H, t, J = 8 Hz), of 3.78 (3H, s), of 5.50 (2H, s) 5,70 (1H, s), 6,97 (2H, d, J = 8.5 Hz), 7,26-7,33 (3H, m), 7,37-rate of 7.54 (2H, m), 7,76-7,81 (1H, m).

31(b). 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] -2-butyl - 4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylic acid.

Following the procedure described in example 25(b), received 2,46 g of target compound in the form of crystals (so pl. 158-159oC) by hydrolysis of 3.31 g of methyl 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] - 2-butyl-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate (obtained as described in stage (a)) with the use of 1.37 g of hydroxide monohydrate lithium.

NMR (CDCl3) ppm: 0,84 (3H, t, J = 7.5 Hz), of 1.23 (9H, s), 1,25-to 1.38 (2H, m), 1,52-of 1.65 (2H, m), by 1.68 (6H, s), and 2.83 (2H, t, J = 6.5 Hz), of 5.81 (2H, s), 7,07 (2H, d, J = 8.0 Hz), 7,22-7,28 (3H, m), 7,34-to 7.50 (2H, m), 7,74 for 7.78 (1H, m).

31(c). Pivaloyloxymethyl 1-[(2'-t-butoxycarbonylmethyl - 4-yl)methyl]-2-butyl-4-(1-hydroxy-1-methylethyl)imidazol-5-carboxyla the esterification of 0.40 g of 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] -2-butyl-4-(1-hydroxy - 1-methylethyl)imidazole-5-carboxylic acid [obtained as described in stage (b)) using climaterealists and potassium carbonate.

NMR (CDCl3) ppm: to 0.92 (3H, t, J = 7.5 Hz), 1,17 (9H, s) of 1.24 (9H, s), 1.32 to about 1.47 (2H, m), and 1.63 (6H, s), 1,66-to 1.79 (2H, m), 2,69 (2H, t, J = 8 Hz), 5,41 (1H, s), the 5.51 (2H, s), of 5.83 (2H, s), 6,97 (2H, d, J = 8 Hz), 7,25-7,28 (3H, m), 7,38-7,51 (2H, m), 7,75-7,79 (1H, m).

31(d). Pivaloyloxymethyl 2-butyl-1-[(2'-carboxyphenyl-4-yl)methyl]- 4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate.

Following the procedure described in example 25(d), was obtained 0.45 g of the hydrochloride of target compound in the form of amorphous solids (I. pl. 139-144oC, so RASMAG. 127oC) by treatment of 0.48 g pivaloyloxymethyl 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] -2 - butyl-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate (obtained as described in stage (c)) 4h. solution florodora in dioxane.

NMR (DMSO-d6) ppm: to 0.80 (3H, t, J = 7.5 Hz), 1,10 (9H, s), to 1.21 and 1.35 (2H, m), 1,39 of 1.50 (2H, m), was 1.58 (6H, s), 2,96 (2H, t, J = 7.5 Hz), 5,64 (2H, s), 5,88 (2H, s), 7,17 (2H, d, J = 8.5 Hz), 7,32-7,34 (3H, m), 7,43-7,49 (1H, m), 7,55-to 7.61 (1H, m), 7,73 to 7.75 (1H, m).

Example 32.

Isopropoxycarbonyloxymethyl 2-butyl-1-[(2'-carboxyphenyl - 4-yl)methyl] -4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate (compound N 3-39).

32(a). Isopropoxycarbonyloxymethyl 1-[(2'-t-butoxycarbonylmethyl - 4-yl)methyl]-2-butyl-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate.

Following paragraph which I am from 0.40 g of 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl]-2-butyl-4-(1 - hydroxy-1-methylethyl)imidazole-5-carboxylic acid [obtained as described in example 31(b)], 0.15 g of isopropoxycarbonyloxymethyl and 0.31 g of potassium carbonate.

NMR (CDCl3) ppm: to 0.92 (3H, t, J = 7.5 Hz), of 1.23 (9H, s) of 1.29 (6H, d, J = 6 Hz), 1,35-1,45 (2H, m), and 1.63 (6H, s) of 1.65 and 1.80 (2H, m), a 2.71 (2H, t, J = 7.5 Hz), the 4.90 (1H, septet, J = 6 Hz), of 5.39 (1H, s), the 5.51 (2H, s), of 5.82 (2H, s), 6,98 (2H, d, J = 8 Hz), 7,25-7,30 (3H, m), 7,35-7,52 (2H, m), 7,75-7,80 (1H, m).

32(b). Isopropoxycarbonyloxymethyl 2-butyl-1-[(2'-carboxyphenyl - 4-yl)methyl]-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate.

Following the procedure described in example 25(d) were 0.39 g of target compound in the form of crystals (so pl. 154-156oC) by treatment of 0.40 g isopropoxycarbonyloxymethyl 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] -2-butyl-4-(1-hydroxy-1 - methylethyl)imidazole-5-carboxylate (obtained in stage (a)) 4h. solution florodora in dioxane.

NMR (DMSO-d6) ppm: 0,81 (3H, t, J = 7.5 Hz), to 1.21 (6H, d, J = 6.5 Hz), 1,23-of 1.36 (2H, m), 1,38-of 1.52 (2H, m) to 1.59 (6H, s); 2,98 (2H, t, J = 6.5 Hz), 4,79 (1H, septet, J = 6.5 Hz), the 5.65 (2H, s), to 5.85 (2H, s), 7,18 (2H, d, J = 8 Hz), 7,30-7,38 (3H, m), 7,42 to 7.62 (2H, m), 7,74 (1H, d, J = 7.5 Hz).

Example 33.

(5-Methyl-2-oxo-1,3-dioxolan-4-yl)methyl-2-butyl-1-[(2'- carboxyphenyl-4-yl)methyl]-4-(1-hydroxy-1-methylethyl)imidazole - 5-carboxylate (compound N 3-51).

33(a). (5-Methyl-2-oxo-1,3-dioxolan-4-yl)methyl-1-[(2'-t - butoxycarbonylmethyl-4-yl)25 IU(c), received of 0.43 g of target compound in the form of crystals (so pl. 156-157oC) on the basis of 0.40 g of 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl]-2-butyl-4-(1 - hydroxy-1-methylethyl)imidazole-5-carboxylic acid (obtained as described in example 31(b)) and 0.22 g of (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl bromide, and 0.26 g of potassium carbonate in 5 ml of N,N-dimethylacetamide.

NMR (CDCl3) ppm: to 0.92 (3H, t, J = 7.5 Hz), of 1.27 (9H, s), 1,30-1,45 (2H, m) of 1.62 (6H, s) of 1.65 and 1.80 (2H, m) 2,07 (3H, s), 2,70 (2H, t, J = 7.5 Hz), 4,89 (2H, s), 5,46 (2H, s), of 5.55 (1H, s) 6,91 (2H, d, J = 8.5 Hz), 7,26 is 7.50 (5H, m), 7,76 (1H, d, J = 6.5 Hz).

33(b). (5-Methyl-2-oxo-1,3-dioxolan-4-yl)methyl-2-butyl - 1-[(2'-carboxyphenyl-4-yl)methyl]-4-(1-hydroxy-1-methylethyl)imidazole - 5-carboxylate.

Following the procedure described in example 25(d), was obtained 0.26 g of the hydrochloride of the target compounds in powder form (i.e pl. more than 70oC softened.) by processing 0.32 g (5-methyl-2-oxo-1,3 - dioxolan-4-yl)methyl-1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] - 4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate (obtained as described in stage (a)) 4h. solution florodora in dioxane.

NMR (DMSO-d6) ppm: of 0.82 (3H, t, J = 7 Hz), 1,20-1,40 (2H, m), 1,40-1,60 (2H, m) to 1.59 (6H, s) a 2.12 (3H, s), 2,98 (2H, t, J = 7.5 Hz), 5,14 (2H, s), 5,63 (2H, s), 7,13 (2H, d, J = 7.5 Hz), 7,30-of 7.60 (5H, m), 7,74 (1H, d, J = 7.5 Hz).

34(a). Phthalidyl 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl]- 4-(1-hydroxy-1-methylethyl)-2-propylimidazol-5-carboxylate.

Following the procedure described in example 25(c), received and 0.62 g of target compound in the form of crystals (so pl. 144oC) on the basis of 0.50 g of 1-[(2'-t-butoxycarbonylmethyl)methyl] -4-(1-hydroxy-1 - methylethyl)-2-propylimidazol-5-carboxylic acid [obtained as described in example 25(b)] , 0.25 g of 3-bromophthalide and 0.3 g of potassium carbonate in 6 ml N,N-dimethylacetamide.

NMR (CDCl3) ppm: to 0.97 (3H, t, J = 7.5 Hz), 1,25 (9H, s) of 1.62 (6H, s) of 1.75 (2H, sextet, J = 7.5 Hz), to 2.66 (2H, t, J = 6.5 Hz), 5,38 (2H, AB-Quartet, = 0,10 ppm, J = 17 Hz), 5,42 (1H, s), 6,69 (2H, d, J = 7.5 Hz), to 7.15 (2H, d, J = 7.5 Hz), 7,28-7,89 (9H, m).

34 (b). Phthalidyl 1-[(2'-carboxyphenyl-4-yl)methyl]-4-(1 - hydroxy-1-methylethyl)-2-propylimidazol-5-carboxylate.

In accordance with the procedure described in example 25(d), received and 0.37 g of the hydrochloride of target compound in the form of amorphous powder (so pl. 142-144oC) by treatment of 0.45 g phthalidyl 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] -4-(1-hydroxy-1 - methylethyl)-2-propylimidazol-5-carboxylate [obtained in stage (a)] 4h. solution florodora in dioxane.

NMR (DMSO-d6) ppm: to 0.92 (3H, t, J = 7.5 Hz), 1,50-1,70 (2H, m) to 1.59 (6H, s) of 3.00 (2H, t, J = 7.5 Hz), the 5.65 (2H,[2-tetrazol-5-yl)phenyl] phenyl} Mei-5-carboxylate (compound N 4-3).

35(a). Diethyl-2-propyl-1-{ 4-[2-trailersa-5-yl)phenyl]phenyl} Mei-4,5, in primary forms.

0,441 g t-piperonyl potassium was added to a solution of 1.00 g of diethyl 2-propylimidazol-4,5-in primary forms (obtained in accordance with the description in obtaining 12) in 15 ml of N,N-dimethylacetamide, and the mixture was stirred for 30 minutes at room temperature. The solution 2,19 g of 4-[2-(triliteral-5-yl)phenyl] benzylbromide in 15 ml of N,N-dimethylacetamide one drop was added to the reaction mixture at room temperature, after which the reaction mixture is stirred 3 h at room temperature. After this time the mixture was diluted with water, and then extracted with ethyl acetate. The extract was dried with anhydrous magnesium sulfate, and the solvent drove by distillation. The residue was purified by column chromatography silica gel, elwira with a mixture of hexane and ethyl acetate (1:1 by volume), and received 2.24 g of target compound as amorphous solid.

NMR (CDCl3) ppm: to 0.88 (3H, t, J = 7.5 Hz), of 1.20 (3H, t, J = 7.5 Hz), of 1.39 (3H, t, J = 7.5 Hz), to 1.59 (6H, s), 1,61-1,72 (2H, s) to 2.55 (2H, t, J = 7.5 Hz), 4,20 (2H, square, J = 7.5 Hz), 4,39 (2H, square, J = 7.5 Hz), and 5.30 (2H, s), is 6.78 (2H, d, J = 8 Hz), 6,92-7,52 (20H, m), of 7.90 (1H, d, J = 7.5 Hz).

35(b). Ethyl-4-hydroxymethyl-2-propyl-1-{ 4-[2-(triliteral - 5-yl)phenyl]f is added at -20oC and under nitrogen atmosphere to a solution 4,27 g of diethyl 2-propyl-1-{ 4-[2-(triliteral-5-yl)phenyl] phenyl} Mei - 4,5-in primary forms [obtained in stage (a)] in 50 ml of tetrahydrofuran. The resulting mixture was left for 16 hours at 0oC, and then mixed with ethyl acetate and saturated aqueous ammonium chloride and the resulting mixture was stirred for 1 h at room temperature. The precipitate was filtered off, the ethyl acetate layer was separated and dried with anhydrous magnesium sulfate, and the solvent drove by distillation under reduced pressure. The crystalline residue is washed with diisopropyl ether and was obtained by a 4.03 g of target compound with so pl. 135-138oC.

NMR (CDCl3) ppm: to 0.94 (6H, t, J = 7.5 Hz), of 1.29 (3H, t, J = 7 Hz), 1,67-to 1.77 (2H, m), of 2.56 (2H, t, J = 7.5 Hz), 3,43 (1H, Shir. so, J = 4 Hz), 4,25 (2H, square, J = 7 Hz), 4,91 (2H, d, J = 4 Hz), 5,49 (2H, s), PC 6.82 (2H, d, J = 7.5 Hz), 6,98-EUR 7.57 (20H, d, J = 7 Hz).

35 (c). Ethyl 4-hydroxymethyl-2-propyl-1-{4-[2-(tetrazol - 5-yl)phenyl]phenyl}Mei-5-carboxylate.

A solution of 0.28 g of ethyl 4-hydroxymethyl-2-propyl-{4-[2- (triliteral-5-yl)phenyl] phenyl} Mei-5-carboxylate [obtained in stage (b)] in 4 ml of 75%.about. aqueous acetic acid is stirred 2 h at 60oC. Then the reaction mixture concentrate by evaporation under reduced pressure to remove the maximum amount of water and acetic acid. After that, the residue was purified by column chromatography on silica gel, elwira mixture of methylene chloride and methanol (9:1 and 4:1 by volume), and was obtained 0.20 g of target compound as amorphous solid.

NMR (CDCl3) ppm: to 0.80 (3H, t, J = 7.5 Hz), of 1.30 (3H, t, J = 7.5 Hz), 1,45-of 1.65 (2H, m) 2,44 (2H, t, J = 7.5 Hz), 4,20 (2H, square, J = 7.5 Hz), 4,58 (2H, s), 5,43 (2H, s), is 6.78 (2H, d, J = 7.5 Hz), 6,98 (2H, d, J = 7.5 Hz), 7,38-of 7.60 (3H, m), 7,79 (1H, d, J = 7.5 Hz).

Example 36.

4-Hydroxymethyl-2-propyl-1-{ 4-[2-(terazol-5-yl)phenyl] phenyl} Mei-5-carboxylic acid (compound N 4-1).

A mixture of 0.20 g of ethyl 4-hydroxymethyl-2-propyl-1-{ 4-[2-(tetrazol - 5-ml)phenyl] phenyl} Mei-5-carboxylate (obtained as described in example 35(c)) and 0.10 g hydroxide monohydrate lithium in 3 ml of water is stirred 3 h at room temperature, after which the mixture was left at this temperature for 16 hours Then the reaction mixture was mixed with 2.38 ml 1N. aqueous hydrochloric acid, and the precipitate was collected by filtration, resulting in a received 150 mg of target compound with so pl. 233oC (Razlog.).

NMR (DMSO-d6) ppm: to 0.88 (3H, t, J = 7.5 Hz), 1,59 (2H, sextet, J = 7.5 Hz), 2,58 (2H, t, J = 7.5 Hz), with 4.64 (2H, s), 2,62 (2H, s), 6,98 (2H, d, J = 8 Hz), was 7.08 (2H, d, J = 8 Hz), 7,39-of 7.69 (4H, m).

Example 37 the Silat (compound N 4-4).

37(a). 4-Hydroxymethyl-2-propyl-1-{ 4-[2-(triliteral - 5-yl)phenyl] phenyl}Mei-5-carboxylic acid.

A solution of 0.66 g of the monohydrate of lithium hydroxide in 20 ml of water was added to a solution of 1.22 g of ethyl 4-hydroxymethyl-2-propyl-1-{4-[2- (triliteral-5-yl)phenyl] phenyl} Mei-5-carboxylate (obtained as described in example 35(b)) in 5 ml of dioxane, and the mixture was stirred 5 h at 80oC. After the reaction mixture was extracted from dioxane by distillation under reduced pressure and the aqueous residue was mixed with ice and ethyl acetate; then added to 15.7 ml of 1N. aqueous hydrochloric acid. The target compound was precipitated and was collected by filtration and washed with water. Then an ethyl acetate layer was isolated from the filtrate was dried with anhydrous magnesium sulfate, and the solvent drove by distillation under reduced pressure. The obtained residue was washed with diethyl ether, and was received as a result of the target compound in the form of powder. Two parts of the target compound were combined together they weighed 0,98 g) and immediately, without additional purification or identification used in the subsequent esterification reaction.

37(b). Pivaloyloxymethyl 4-hydroxymethyl-2-propyl-1-{4-[2- (triliteral-5-obvsly to a solution of 0.98 g of 4-hydroxymethyl-2-propyl-1-{4-[2 - trailersa-5-yl)phenyl] phenyl} Mei-5-carboxylic acid (obtained in stage (a)) in 10 ml of N, N-dimethylacetamide, and the mixture was stirred at room temperature for 6 hours, after this time the reaction mixture was mixed with ethyl acetate and water. An ethyl acetate layer was separated and dried with anhydrous magnesium sulfate, and the solvent is kept at reduced pressure. The obtained residue was purified by chromatography on silica gel, elwira a mixture of ethyl acetate and hexane (2:1 by volume), resulting in received of 0.91 g of target compound in the form of a resinous substance.

NMR (CDCl3) ppm: to 0.89 (3H, t, J = 7.5 Hz), of 1.18 (9H, s) to 1.70 (1H, sextet, J = 7.5 Hz), 2,52 (2H, t, J = 8 Hz), 3,35 (1H, Shir. C) a 4.83 (2H, s), 5,42 (2H, s) 5,80 (2H, s) 6,76 (2H, d, J = 8 Hz), 6,92-7,51 (20H, m), of 7.90 (1H, d, J = 7.5 Hz).

37(c). Pivaloyloxymethyl 4-hydroxymethyl-2-propyl-1-{4-[2- (tetrazol-5-yl)phenyl]phenyl}Mei-5-carboxylate.

In accordance with the procedure described in example 35(c) of 0.91 g pivaloyloxymethyl 4-hydroxymethyl-2-propyl-1-{ 4-[2-trailersa - 5-yl)phenyl] phenyl} Mei (obtained in stage (b)) detritivorous by processing 75%.about. water, acetic acid, resulting in a received 0,42 g of target compound in powder form with so pl. above 60oC (softened.).

NMR (CDCl3) ppm: to 0.94 (3H, t, J = 7.5 Hz), 1.14 in (9H, s), 1,72 (2H, sexte, J = 7.5 Hz).

Example 38.

Methyl-2-butyl-4-hydroxymethyl-1-{ 4-[2-(tetrazol-5 - yl)phenyl]phenyl}Mei-5-carboxylate (compound N about 4-47).

38(a). Dimethyl-2-butyl-1-{4-[2-(trimethylacetyl-5 - yl)phenyl]phenyl}Mei-4,5, in primary forms.

Repeating the procedure described in example 35(a), but using 0.50 g of dimethyl 2-butylimidazole-4,5-in primary forms (obtained in accordance with the description given in obtaining 4) and of 1.17 g of 4-[2-trailersa-5-yl)phenyl]benzylbromide, which was obtained 0.51 g of the target compound as amorphous solid.

NMR (CDCl3) ppm: of 0.85 (3H, t, J = 7.5 Hz), 1,20-1,80 (4H, m) at 2.59 (2H, t, J = 8.0 Hz), to 3.73 (3H, s) to 3.92 (3H, s), and 5.30 (2H, s), 6,6-7,6 (22H, m), 7,8-8,0 (1H, m).

38(b). Methyl 2-butyl-4-hydroxymethyl-1-{4-[2-trailersa - 5-yl)phenyl] phenyl}Mei-5-carboxylate.

In accordance with the procedure described in example 35 (b), 0.51 g of dimethyl 2-butyl-1-{4-[2-(triliteral-5-yl)phenyl]phenyl}Mei - 4,5-in primary forms (obtained in stage (a)) was restored with the use of 0.99 ml of a 1.5 M solution of hydride diisobutylaluminum in toluene, resulting in received of 0.44 g of the target compound as an oily substance.

NMR (CDCl3) ppm: 0,86 (3H, t, J = 7, is), was 7.08 (2H, d, J = 8.5 Hz), 7,22-7,51 (14H, m), 7,87-of 7.90 (1H, m).

38(c). Methyl 2-butyl-4-hydroxymethyl-1-{4-[2-tetrazol-5 - yl)phenyl]phenyl} Mei-5-carboxylate.

A solution of 0.44 g of methyl 2-butyl-4-hydroxymethyl-1-{4-[2- (triliteral-5-yl)phenyl] phenyl} Mei-5-carboxylate [obtained in stage (b)] in 10 ml of methanol and 0.70 ml of 1N. aqueous hydrochloric acid was left overnight at room temperature. Then the reaction mixture was concentrated to dryness by distillation under reduced pressure, and the residue is triturated with diethyl ether, resulting in received of 0.30 g of the hydrochloride of target compound in the form of a solid substance.

NMR (DMSO-d6) ppm: 0,81 (3H, t, J = 7.5 Hz), 1,19-1,32 (2H, m), 1,38-is 1.51 (2H, m), 2,95 (2H, t, J = 7.5 Hz), 4,80 (2H, s), 5,71 (2H, s), 7,20 to 7.75 (8H, m).

Example 39.

2-Butyl-4-hydroxymethyl-1-{ 4-[2-(tetrazol-5-yl)phenyl]phenyl} Mei-5-carboxylic acid (compound N 4-46).

Repeating the procedure described in example 36, but using a 0.30 g of methyl 2-butyl-4-hydroxymethyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl} Mei-5-carboxylate (obtained in example 38(c)] and of 2.50 ml of 1N. an aqueous solution of sodium hydroxide, resulting in a received 95 mg of target compound in the form of crystals with so pl. 215 - 217o8.5 Hz), 7,06 (2H, d, J = 8.5 Hz), 7,50-of 7.70 (4H, m).

Example 40.

Ethyl-4-(1-hydroxyethyl)-2-propyl-1-{ 4-[2-(tetrazol-5-yl) phenyl] phenyl} Mei-5-carboxylate (compound N 4-30).

40(a). Ethyl-4-formyl-1-propyl-1-{4-[2-(triliteral-5 - yl)phenyl]phenyl} Mei-5-carboxylate.

6 g of activated manganese dioxide was added to a solution of 2 g of ethyl 4-hydroxymethyl-2-propyl-1-{ 4-[2-(triliteral-5-yl)phenyl] phenyl} Mei-5-carboxylate (obtained in example 35(b)) in 40 ml of methylene chloride, and the mixture was stirred 2.5 h at room temperature. After the manganese dioxide was filtered, and the filtrate was concentrated by evaporation under reduced pressure. The obtained residue was purified by column chromatography on silica gel, elwira a mixture of ethyl acetate and hexane (1:1 volume), resulting in a received 1.45 g of target compound in the form of crystals with so pl. 177-179oC (decomposition).

NMR (CDCl3) ppm: to 0.88 (3H, t, J = 7.5 Hz), of 1.29 (3H, t, J = 7 Hz), 1,74 (2H, sextet, J = 7.5 Hz), to 2.57 (2H, t, J = 7.5 Hz), the 4.29 (2H, square, J = 7 Hz), 5,49 (2H, s) 6,76 (2H, d, J = 8.5 Hz), 6,92-7,88 (20H, m), of 7.90 (1H, d, J = 7.5 Hz), 10,42 (1H, s).

40(b). Ethyl 4-(1-hydroxyethyl)-2-propyl-1-{ 4-[2-(triliteral - 5-yl)phenyl]phenyl}Mei-5-carboxylate.

oC. After the reaction mixture was mixed with ethyl acetate and an aqueous solution of ammonium chloride, and the mixture was stirred 20 min at room temperature. Then an ethyl acetate layer was separated and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography on silica gel, elwira mixtures of ethyl acetate and methylene chloride (1:4 and 1:2 by volume), resulting in received of 1.23 g of target compound in the form of a viscous oil.

NMR (CDCl3) ppm: of 0.87 (3H, t, J = 7.5 Hz), to 1.22 (3H, t, J = 7 Hz), and 1.54 (3H, d, J = 7 Hz), 1,68 (2H, sextet, J = 7.5 Hz), 2,50 (2H, t, J = 7.5 Hz), 3,82 (1H, d, J = 8 Hz), 4,18 (2H, square, J = 7 Hz), 5,23 (1H, quintet, J = 7 Hz), 5,42 (2H, s) 6,76 (2H, d, J = 8 Hz), 6,93-7,52 (20H, m), 7,88 (1H, d, J = 7.5 Hz).

40(c). Ethyl-4-(1-hydroxyethyl)-2-propyl-1-{ 4-[2-(tetrazol - 5-yl)phenyl] phenyl}Mei-5-carboxylate.

Following the procedure described in example 35 (c) of 1.23 g of ethyl 4-(1-hydroxyethyl)-2-propyl-1-{ 4-[2-trailersa-5-yl)phenyl]phenyl} Mei-5-carboxylate (obtained in stage (b)) was treated with 75% vol./about. water, acetic acid, resulting in received of 0.82 g of the target compound as an amorphous solid(2H, t, J = 7 Hz), 4,22 (2H, square, J = 7 Hz), 5,13-5,20 (1H, m), 5,4 (2H, AB-Quartet, = 0,12 ppm, J = 16.5 Hz), 6,78 (2H, d, J = 8 Hz), of 6.99 (2H, d, J = 8 Hz), 7,38-to 7.59 (3H, m), 7,76 (1H, d, J = 7.5 Hz).

Example 41.

4-(1-Hydroxyethyl)-2-propyl-1-{ 4-[2-(tetrazol-5-yl)phenyl]phenyl} Mei-5-carboxylic acid (compound N 4-29).

In accordance with the procedure described in example 36, 0.82 ethyl 4-(1-hydroxyethyl)-2-propyl-1-{ 4-[2-tetrazol-5-yl)phenyl] phenyl} Mei-5-carboxylate [obtained in example 40(c)] hydrolyzed with the use of 0.43 g of the monohydrate of lithium hydroxide, resulting in a received 0.50 g of target compound in powder form with so pl. 198-201oC.

NMR (DMSO-d6) ppm: 0,86 (3H, t, J = 7.5 Hz), to 1.38 (3H, d, J = 6.5 Hz), of 1.55 (2H, sextet, J = 7.5 Hz), 2,58 (2H, t, J = 8 Hz), to 5.21 (1H, square, J = 6.5 Hz), 5,61 (2H, s), 6,95-was 7.08 (4H, m), 7,51-of 7.70 (4H, m).

Example 42.

Ethyl-4-(1-hydroxyethyl)-2-propyl-1-{ 4-[2-(tetrazol-5-yl)phenyl] phenyl} Mei-5-carboxylate (compound N 4-30).

42(a). Ethyl-4-(1-hydroxyethyl-2-propyl-1-{ 4-[2-(triliteral - 5-yl)phenyl]phenyl}Mei-5-carboxylate.

Repeating the procedure described in example 35(a), but with ispolzovaniem 113 mg of ethyl 4-(1-hydroxyethyl-2-propylimidazol-5-carboxylate [obtained in accordance with the description given in the recip and 255 mg of the target compound in the form of a viscous oil, The NMR spectrum of this compound is identical to the NMR spectrum of the compound obtained in example 40( ).

42(b). Ethyl-4-(1-hydroxyethyl-2-propyl-1-{4-[2-(tetrazol - 5-yl)phenyl]phenyl}Mei-5-carboxylate.

In accordance with the procedure described in example 35(c), 255 mg of ethyl 4-(1-hydroxyethyl)-2-propyl-1-{4-[2-(triliteral-5-yl)phenyl]phenyl} Mei-5-carboxylate [obtained in stage (a) above] were subjected to detritivorous by processing 75%.about. aqueous acetic acid, which was obtained 170 mg of the target compound as amorphous solid. The NMR spectrum of this compound is identical to the NMR spectrum of the compound obtained in example 40(c).

Example 43.

Ethyl 2-butyl-4-(1-hydroxyethyl)-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl} Mei-5-carboxylate (compound N 4-75).

43 (a). Ethyl 2-butyl-4-(1-hydroxyethyl-1-{ 4-[2-trailersa - 5-yl)phenyl]phenyl}Mei-5-carboxylate.

Repeating the procedure described in example 35 (a), but using 400 mg of ethyl 2-butyl-4-(1-hydroxyethyl)imidazole - 5-carboxylate [obtained in accordance with the description in obtaining 24(iii)], and 1.00 g of 4-[2-(triliteral-5-yl)phenyl] benzylbromide and 197 mg of the t-butoxide potassium, resulting in received 0,94 g C is m), of 1.55 (3H, d, J = 6.5 Hz), 1.60-to 1,72 (2H, m), of 2.54 (2H, t, J = 8 Hz), a-3.84 (1H, d, J = 6.5 Hz), 4,20 (4H, square, J = 7 Hz), 5.25-inch (1H, quintet, J = 6.5 Hz), 5,44 (2H, s), is 6.78 (2H, d, J = 8 Hz), 6,94-7,54 (20H, m), of 7.90 (1H , d, J = 7.5 Hz).

43(b). Ethyl-2-butyl-4-(1-hydroxyethyl)-1-[4-[2-(tetrazol - 5-yl)phenyl]phenyl}Mei-5-carboxylate.

Following the procedure described in example 40(c), 0.84 g of ethyl 2-butyl-4-(1-hydroxyethyl)-1-{ 4-[2-(triliteral-5-yl)phenyl] phenyl} Mei-5-carboxylate [obtained as described in stage (a)] was treated with 75% V/V aqueous acetic acid, resulting in received of 0.54 g of the target compound as amorphous solid.

NMR (CDCl3) ppm: 0,78 (3H, t, J = 7.5 Hz), 1,15-1,30 (2H, m) to 1.19 (3H, t, J = 7 Hz), of 1.35 (3H, d, J = 6.5 Hz), 1,44 is 1.60 (2H, m), 2.49 USD (2H, t, J = 8 Hz), 4,17 (2H, square, J = 7 Hz), 5,09 (1H, square, J = 6.5 Hz), to 5.35 and 5.45 (each 1H, AB-Quartet, J = 16.5 Hz), 6.89 in (2H, d, J = 8 Hz), of 6.96 (2H, d, J = 8 Hz), 7,30 is 7.50 (3H, m), the 7.65 (1H, d, J = 7.5 Hz).

Example 44.

2-Butyl-4-(1-hydroxyethyl)-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl} Mei-5-carboxylic acid (compound N 4-74).

In accordance with the procedure described in example 36, of 0.54 g of ethyl 2-butyl-4-(1-hydroxyethyl)-1-{ 4-[2-(tetrazol - 5-yl)phenyl]phenyl}Mei-5-carboxylate [obtained in example 43(b)] hydrolyzed using 245 mg of the monohydrate is"ptx2">

NMR (DMSO-d6) ppm: of 0.82 (3H, t, J = 7.5 Hz), 1.27mm (2H, sextet, J = 7.5 Hz), of 1.37 (3H, d, J = 6.5 Hz), 1,50 (2H, quintet, J = 7.5 Hz), 2,58 (2H, t, J = 8 Hz), 5,20 (1H, square, J = 6.5 Hz), 5,61 (2H, s), of 6.96 (2H, d, J = 8 Hz), 7,06 (2H, d, J = 8 Hz), 7,50-7,66 (4H, m).

Example 45.

2-Butyl-1-[(2'-carboxyphenyl-4-yl)methyl] -4-(1-hydroxyethyl)imidazole - 5-carboxamide (compound N 5-64).

45(a). 4-Acetyl-1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] -2 - butylimidazole-5-carbonitrile.

0,192 g of sodium hydride (as a 55% by weight. dispersion in mineral oil) was added to a solution of 0,843 g of 4-acetyl-2-butylimidazole-5-carbonitrile [obtained in accordance with the description given in the completion of 24(i)] in 17 ml of N,N-dimethylacetamide, and the mixture was stirred 20 min at room temperature. Then was added 1.68 g of t-butyl-4'-(bromomethyl)biphenyl-2-carboxylate, and the mixture was stirred for 2.5 h at 55oC. thereafter, to the mixture was added an aqueous solution of sodium chloride, and then extracted with ethyl acetate. The extract was washed with water and dried with anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The obtained oily residue was purified by column chromatography on silica gel, elwira mixtures (4:1 and 2:1 by volume) hexane and ethylacetate, t, J = 7 Hz), of 1.23 (9H, s), 1,3-2,1 (4H, m), 2,58 (3H, s) of 2.75 (2H, t, J = 7 Hz), 5,32 (2H, s), 7,0-8,0 (8H, m).

45(b). 1-[(2'-t-Butoxycarbonylmethyl-4-yl)methyl] -2-butyl - 4-(1-hydroxyethyl)imidazole-5-carbonitrile.

0,098 g of sodium borohydride was added to a solution of 1.18 g of 4-acetyl-1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] -2-butylimidazole - 5-carbonitrile [obtained in stage (a)] in 30 ml of ethanol, and the mixture was stirred 1 h at room temperature. Excess sodium borohydride was removed by the addition of acetone, after which the reaction mixture was concentrated by evaporation under reduced pressure. The residue was diluted aqueous solution of sodium chloride and was extracted with ethyl acetate. The extract was dried and concentrated by evaporation under reduced pressure. Oily residue was purified by column chromatography on silica gel, elwira a mixture of ethyl acetate and hexane (3:2, by volume), and obtained 1.18 g of target compound in the form of a viscous oil.

NMR (CDCl3) ppm: to 0.92 (3H, t, J = 7.5 Hz), 1,25 (9H, s), 1,3-1,5 (2H, m) to 1.60 (3H, d, J = 6.5 Hz), 1,6-1,8 (2H, m), 2,6-2,8 (2H, m) 5,00 (1H, square, J = 6.5 Hz), with 5.22 (2H, s), 7,1-7,9 (8H, m).

45(c). 1-[(2'-t-Butoxycarbonylmethyl-4-yl)methyl] -2-butyl - 4-(1-hydroxyethyl)imidazole-5-carboxamide.

12 ml of 1N. aqueous solution of Girasol-5-carbonitrile [obtained in stage (b)] in 3 ml of ethanol, and the resulting mixture was heated under reflux for 3 h then the reaction mixture was neutralized by adding dilute aqueous hydrochloric acid and was extracted with ethyl acetate. The extract was washed with water and dried with anhydrous magnesium sulfate. Then the solvent was removed by distillation under reduced pressure. The resulting mixture was purified by column chromatography on silica gel, elwira a mixture of ethyl acetate and hexane (4:1 by volume), and then one by ethyl acetate, which was obtained 0.14 g of target compound as amorphous solid.

NMR (CDCl3) ppm: of 0.90 (3H, t, J = 7.5 Hz), of 1.23 (9H, s), 1.2 to 1.5 (2H, m), 1,6-1,8 (2H, m) of 1.66 (3H, d, J = 6.5 Hz), 2,63 (2H, t, J = 8 Hz), 5,11 (1H, square , J = 6.5 Hz), 5,59 and 5,74 (each 1H, AB-Quartet, J = 16 Hz), 7,0-7,9 (8H, m).

45(d). 2-Butyl-1-[(2'-carboxyphenyl-4-yl)methyl] -4-(1 - hydroxyethyl)imidazole-5-carboxamide.

A solution of 0.15 g of 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl]-2 - butyl-4-(1-hydroxyethyl)imidazole-5-carboxamide (obtained in stage (c)), dissolved in 3 ml 4n. solution florodora in dioxane was left overnight at room temperature. Then the solution was concentrated by evaporation under reduced pressure. The residue is triturated in hexane, and the obtained takiya in the form of amorphous solids with so pl. 212-214oC (with decomp.).

NMR (CDCl3) ppm: to 0.94 (3H, t, J = 7,5), 1,3-1,6 (2H, m) to 1.59 (3H, d, J = 6.5 Hz), 1,6-2,0 (2H, m), of 3.0-3.4 (2H, m), 5,16 (1H, square, J = 6.5 Hz), 5,41, and 5.58 (each 1H, AB-kvar., J = 15 Hz), 7,1-7,9 (8H, m).

Example 46.

2-Butyl-1-[(2'-carboxyphenyl-4-yl)methyl] -4-(1-hydroxypropyl) imidazole-5-carboxamide (compound N 5-65).

46(a). 1-[(2'-t-Butoxycarbonylmethyl-4-yl)methyl] -2-butyl-4 - propylimidazol-5-carbonitrile.

Repeating the procedure in example 45(a), but using 0,923 g of 2-butyl-4-propylimidazol-5-carbonitrile [obtained in accordance with the description provided in the receiving 25], 1.56 g of t-butyl 4'-(bromomethyl)-butenyl-2-carboxylate and 196 mg of sodium hydride (as a 55% by weight. /Mac. dispersion in mineral oil) in 20 ml of N,N-dimethylacetamide, which was obtained 1.84 g of target compound in the form of a viscous oily substance.

NMR (CDCl3) ppm: of 0.91 (3H, t, J = 7 Hz), 1,0-2,1 (4H, m), 1,25 (9H, s), of 2.72 (2H, t, J = 7 Hz), to 3.02 (2H, square, J = 7 Hz), and 5.30 (2H, s), 7,0-8,0 (8H, m).

46(b). 1-[(2'-t-Butoxycarbonyloxyimino-4-yl)methyl]-2-butyl - 4-(1-hydroxypropyl)imidazole-5-carbonitrile.

Repeating the procedure in example 45(b), but using 451 mg of 1-[(2'-t-butoxycarbonyloxyimino-4-yl)methyl] - 2-butyl-4-propionyloxy 369 mg of the target compound in the form of a viscous oil.

NMR (CDCl3) ppm: of 0.91 (3H, t, J = 7 Hz), 0,99 (3H, t, J = 7 Hz), 1,0-2,3 (6H, m), 1,25 (9H, s), 2,70 (2H, t, J = 7 Hz), and 3.16 (1H, d, J = 6.5 Hz), 4,74 (1H, square, J = 7 Hz), to 5.21 (2H, s), 7,0-8,0 (8H, m).

46(c). 1-[(2'-t-Butoxycarbonylmethyl-4-yl)methyl]-2-butyl - 4-(1-hydroxypropyl)imidazole-5-carboxamide.

20 ml of 1N. an aqueous solution of sodium hydroxide was added to a solution of 368 mg of 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] -2-butyl - 4-(1-hydroxypropyl)imidazole-5-carbonitrile [obtained in stage (b)] dissolved in 20 ml of ethanol, and the resulting mixture was heated under reflux for 6 hours. After this time the reaction mixture was treated in accordance with the procedure described in example 45(c), and received 316 mg of the target compound as amorphous solid.

NMR (CDCl3) / ppm: to 0.89 (6H, t, J = 7 Hz), 1,0-2,3 (6H, m) of 1.24 (9H, s), 2,61 (2H, t, J = 7 Hz), was 4.76 (1H, t, J = 7 Hz), 5,52 and of 5.83 (each 1H, AB-kvar., J = 17 Hz), 6,9-7,9 (8H, m).

46(d). 2-Butyl-1-[(2'-carboxyphenyl-4-yl)methyl] -4-(1 - hydroxypropyl)imidazole-5-carboxamide.

Repeating the procedure in example 45(d), but using 316 mg of 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] - 2-butyl-4-(1-hydroxypropyl)imidazole-5-carboxamide [obtained in stage (c)] (see above) and 10 ml of 4n. solution florodora in dio the 120oC (softening).

NMR (DMSO-d6) ppm: to 0.80 (3H, t, J = 7.5 Hz), of 0.87 (3H, t, J = 7.5 Hz), 1,1-2,0 (6H, m) to 2.94 (2H, t, J = 7.5 Hz), is 4.85 (1H, t, J = 7 Hz), of 5.68 (2H, s), 7,0-7,8 (8H, m).

Example 47.

2-Butyl-1-[(2'-carboxyphenyl-4-yl)methyl]-4-(1 - hydroxybutyl)imidazol-5-carboxamide (compound N 5-66).

47(a). 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl]-2-butyl - 4-butylimidazole-5-carbonitrile.

Repeating the procedure in example 45(a), but using 0,877 g of 2-butyl-4-butylimidazole-5-carbonitrile (obtained in accordance with the description provided in the receiving 26), 1,53 g of t-butyl 4'-(bromomethyl)-biphenyl-2-carboxylate and 0,175 g of sodium hydride (as a 55% wt./wt. dispersion in mineral oil) in 18 ml of N,N-dimethylacetamide, resulting received 0,99 g of target compound in the form of a viscous oil.

NMR (CDCl3) ppm: of 0.93 (3H, t, J = 7 Hz), a 1.01 (3H, t, J = 7 Hz), of 1.28 (9H, s), 1,4-2,1 (6H, m), is 2.74 (2H, t, J = 7 Hz), of 3.00 (2H, t, J = 7 Hz), and 5.30 (2H, s), 7,0-8,0 (8H, m).

47(b). 1-[(2'-t-Butoxycarbonylmethyl-4-yl)methyl]-2-butyl - 4-(1-hydroxybutyl)imidazol-5-carbonitrile.

Repeating the procedure in example 45(b), but using 0,99 g of 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] - 2-butyl-4-butylimidazole-5-carbonitrile [obtained in stage (a)] islamicthe substances.

NMR (CDCl3) ppm: 0,7-1,2 (6H, m), 1,2-2,1 (8H, m) of 1.23 (9H, s), a 2.71 (2H, t, J = 7 Hz), 4,28 (1H, d, J = 6 Hz), 4,82 (1H, square, J = 6 Hz), 5,28 (2H, s), 7,0-8,0 (8H, m).

47(c). 1-[(2'-t-Butoxycarbonylmethyl-4-yl)methyl]-2-butyl - 4-(1-hydroxybutyl)imidazol-5-carboxamide.

14 ml of 1N. an aqueous solution of sodium hydroxide was added to the solution 0,86 g of 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] -2-butyl - 4-(1-hydroxybutyl)imidazol-5-carbonitrile [obtained in stage (b)] in 14 ml of ethanol, and the resulting mixture was heated under reflux for 10 hours, after this time the reaction mixture was treated in accordance with the procedure described above in example 45(c), resulting received of 0.58 g of the target compound as amorphous solid.

NMR (CDCl3) ppm: of 0.90 (3H, t, J = 7.5 Hz), were 0.94 (3H, t, J = 7.5 Hz), of 1.23 (9H, s), 1,3-2,1 (8H, t, J = 8 Hz), 2,63 (2H, t, J = 8 Hz), 4,91 (1H, t, J = 7 Hz), 5.56, and 5,77 (each 1H, AB-Quartet, J = 16 Hz), 7,0-7,8 (8H, m).

47(d). 2-Butyl-1-[(2'-carboxyphenyl-4-yl)methyl] -4-(1 - hydroxybutyl)imidazol-5-carboxamide.

Repeating the procedure in example 45(d), but with the use of 0.58 g of 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] - 2-butyl-4-(1-hydroxybutyl)imidazole-5-carboxamide [obtained in stage (c)] and 13 ml of 4n. solution florodora, the resulting increase).

NMR (DMSO-d6) ppm: to 0.80 (3H, t, J = 7.5 Hz), to 0.89 (3H, t, J = 7.5 Hz), 1,1-1,9 (8H, m), 2,96 (2H, t, J = 7.5 Hz), 4,96 (1H, t, J = 7.5 Hz), of 5.68 (2H, s), 7,2-7,8 (8H, m).

Example 48.

2-Butyl-1-[(2'-carboxyphenyl-4-yl)methyl] -4-(1-hydroxy-2 - methylpropyl " imidazole-5-carboxamide (compound N 5-67).

48(a). 1-[(2'-t-Butoxycarbonylmethyl-4-yl)methyl]-2-butyl-4 - isobutylamino-5-carbonitrile.

Repeating the procedure in example 45(a), but with the use of 0.85 g of 2-butyl-4-isobutylamino-5-carbonitrile (obtained in accordance with the description given in obtaining 27), of 1.34 g of t-butyl-4'-(bromomethyl)-biphenyl-2-carboxylate and 170 mg of sodium hydride (as a 55% wt/wt dispersion in mineral oil) in 15 ml of N,N-dimethylacetamide, resulting in received of 1.62 g of target compound in the form of a viscous oil.

NMR (CDCl3) ppm: of 0.93 (3H, t, J = 7 Hz), 1,0-2,1 (4H, m) to 1.21 (6H, d, J = 7 Hz), 1,22 (9H, s), by 2.73 (2H, t, J = 7 Hz), 3,66 (1H, septet, J = 7 Hz), and 5.30 (2H, s), 7,0-8,0 (8H, m).

48(b). 1-[(2'-t-Butoxycarbonylmethyl-4-yl)methyl] -2-butyl-4- (1-hydroxy-2-methylpropyl " imidazole-5-carbonitrile.

Repeating the procedure in example 45(b), but using 500 mg of 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] - 2-butyl-4-isobutylamino-5-carbonitrile [obtained in stage (a)] viscous oily substance.

NMR (CDCl3) ppm: 0,7-1,2 (9H, m), 1,0-2,5 (5H, m) of 1.27 (9H, s), 2,70 (2H, d, J = 7 Hz), 3,01 (1H, d, J = 7 Hz), of 4.54 (1H, t, J = 7 Hz), 5,23 (2H, s), 7,0-8,0 (8H, m).

48(c). 1-[(2'-t-Butoxycarbonylmethyl-4-yl)methyl] -2-butyl-4- (1-hydroxy)-2-methylpropyl]imidazol-5-carboxamide.

20 ml of 1N. an aqueous solution of sodium hydroxide was added to a solution of 297 mg of 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] -2-butyl - 4-(1-hydroxy-2-methylpropyl " imidazole-5-carbonitrile [obtained in stage (b)] in 20 ml of ethanol, and the resulting mixture was heated under reflux for 8 hours. After this time the reaction mixture was treated in accordance with the procedure described in example 45(c), and received 151 g of target compound as amorphous solid.

NMR (CDCl3) ' ppm: 0,66 (3H, d, J = 7 Hz), of 0.85 (3H, t, J = 7 Hz), a 1.01 (3H, d, J = 7 Hz), 1,0-2,4 (5H, m) to 1.22 (9H, s) at 2.59 (2H, t, J = 7 Hz), and 4.40 (1H, d, J = 7 Hz), of 5.53 and of 5.83 (acwc. 1H, AB-Quartet, J = 17 Hz), 6,9-7,9 (8H, m).

48(d). 2-Butyl-1-[(2'-carboxyphenyl-4-yl)methyl]-4-(1-hydroxy - 2-methylpropyl)-5-carboxamid.

Repeating the procedure in example 45(d), but using 151 mg of 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] -2 - butyl-4-(1-hydroxy-2-methylpropyl " imidazole-5-carboxamide [obtained in stage (c)] and 5 ml of 4n. solution florodora in eoC (softening).

NMR (DMSO-d6) ppm: to 0.73 (3H, d, J = 6.5 Hz), of 0.79 (3H, t, J = 7.5 Hz), and 0.98 (3H, d, J = 6.5 Hz), 1,1-1,6 (4H, m), 1,9-2,1 (1H, m), 2,98 (2H, t, J = 7.5 Hz) and 4.65 (1H, d, J = 8 Hz), 5,69 (2H, s), a 7.1 to 7.8 (8H, m).

Example 49.

1-[(2'-Carboxyphenyl-4-yl)methyl]-4-(1-hydroxybutyl)-2 - propoxyimino-5-carboxamide (compound N 5-4).

49(a). 1-[(2'-t-Butoxycarbonylmethyl-4-yl)methyl] -4 - butyryl-2-propylimidazol-5-carbonitrile.

Repeating the procedure in example 45(a), but using 1,026 g of 4-butyryl-2-propylimidazol-5-carbonitrile (obtained in accordance with the description provided in the receiving 28), 1,91 g of t-butyl 4'-(bromomethyl)-biphenyl-2-carboxylate and 0,209 g of sodium hydride (as a 55% wt/wt dispersion in mineral oil) in 20 ml of N,N-dimethylacetamide, got 1.70 g of target compound in the form of a viscous oily substance.

NMR (CDCl3) ppm: 1.00 m (6H, t, J = 7.5 Hz), 1,25 (9H, s), 1.7 to 1.9 (4H, m), 2,70 (2H, t, J = 7.5 Hz), 2,99 (2H, t, J = 7.5 Hz), 5,31 (2H, s), 7,1-7,9 (8H, m).

49(b). 1-[(2'-t-Butoxycarbonylmethyl-4-yl)methyl] -4-(1 - hydroxybutyl)-2-propylimidazol-5-carbonitrile.

Repeating the procedure in example 45(b), but using 1.13 g of 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl]-4 - butyryl-2-propylimidazol-5-carbonitrile [policea in the form of a viscous oily substance.

NMR (DMSO-d6) ppm: of 0.87 (3H, t, J = 7.5 Hz), of 0.90 (3H, t, J = 7.5 Hz), 1,17 (9H, s), 1,2-1,4 (2H, m). of 1.5-1.7 (4H, m) to 2.67 (2H, t, J = 7.5 Hz), 4,58 (1H, m), of 5.34 (2H, s) 5,41 (1H, d, J = 4.5 Hz), and 7.1 to 7.7 (8H, m).

49(c). 1-[(2'-t-Butoxycarbonylmethyl-4-yl)methyl] -4- (1-hydroxybutyl)-2-propylimidazol-5-carboxamide.

16 ml of 1N. an aqueous solution of sodium hydroxide was added to a solution of 1.07 g of 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] -4- (1-hydroxybutyl)-2-propylimidazol-5-carbonitrile [obtained in stage (b)] in 16 ml of ethanol, and the resulting mixture was treated in accordance with the description given in example 45(c), resulting in received of 0.82 g of the target compound as amorphous solid.

NMR (CDCl3) ppm: of 0.93 (3H, t, J = 7.5 Hz), of 0.95 (3H, t, J = 7.5 Hz), of 1.23 (9H, s), 1,2-2,1 (6H, m) 2,60 (2H, t, J = 8 Hz), 4,89 (1H, t, J = 7.5 Hz), 5.56, and 5,77 (each 1H, AB-Quartet, J = 16 Hz), 7,0-7,8 (8H, m).

49(d). 1-[(2'-t-Carboxyphenyl-4-yl)methyl]-4-(1-hydroxybutyl)- 2-propylimidazol-5-carboxamide.

Repeating the procedure in example 45(d), but using a solution of 0.82 g of 1-[(2'-t-butoxycarbonylmethyl - 4-yl)methyl]-4-(1-hydroxybutyl)-2-propylimidazol-5-carboxamide [obtained in stage (c)] in 17 ml of 4n. solution florodora target compound as amorphous powder with so pl. 118-121oC (RASMAG is,5 Hz), 5,4 and 5.56 (acwc. 1H, AB-Quartet, J = 15,5 Hz), 7,1-7,9 (8H, m).

Example 50.

2-Butyl-1-[(2'-carboxyphenyl-4-yl)methyl] -4-(1-hydroxy-1 - methylethyl)imidazol-5-carboxamide (compound N 5-69).

50(a). 1-[(2'-t-Butoxycarbonylmethyl-4-yl)methyl] -2-butyl - 4-(1-hydroxy-1-methylethyl)imidazol-5-carboxamide.

10 ml of 1N. an aqueous solution of sodium hydroxide was added to a solution of 232 mg of 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] -2-butyl - 4-(1-hydroxy-1-methylethyl)imidazol-5-carbonitrile [obtained as described in example 10(a)] in 10 ml of ethanol, and the resulting mixture was heated under reflux for 3 hours, after this time the reaction mixture was treated in a manner similar to that described in example 45(c), as a result, we received 185 mg of the target compound as amorphous solid.

NMR (CDCl3) ppm: to 0.89 (3H, t, J = 7 Hz), 1.0 to 2.0 (4H, m) of 1.23 (9H, s), by 1.68 (6H, s), 2,62 (2H, t, J = 7 Hz), 5,63 (2H, s), 6,9-7,9 (8H, m).

50(b). 2-Butyl-1-[(2'-carboxyphenyl-4-yl)methyl]-4-(1-hydroxy - 1-methylethyl)imidazol-5-carboxamide.

Repeating the procedure in example 45(d), but using 185 mg of 1-[(2'-t-butoxy-carbonylmethyl-4-yl)methyl] - 2-butyl-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxamide [obtained in the unity in the form of amorphous solids with so pl. 130-138oC (softening).

NMR (DMSO-d6) ppm: to 0.73 (3H, t, J = 7.0 Hz), 1,17-of 1.30 (2H, m), 1.30 and of 1.42 (2H, m) to 1.61 (6H, s), 2,96 (2H, t, J = 7.5 Hz), of 5.55 (2H, s), 7,20 to 7.75 (8H, m).

Example 51.

2-Butyl-1-[(2'-carboxyphenyl-4-yl)methyl] -4-(1-hydroxy - 2-methyl)-1-(1-methylethyl)propyl]imidazole-5-carboxamide (compound N 5-333).

51(a). 1-[(2'-t-Butoxycarbonylmethyl-4-yl)methyl] -2-butyl - 4-(1-hydroxy-2-methyl-1-(1-methylethyl)propyl]imidazole-5-carbonitrile.

Repeating the procedure in example 45(a), but using 282 mg of 2-butyl-4-[1-hydroxy-2-methyl-1-(1 - methylethyl)propyl] imidazole-5-carbonitrile [obtained according to the procedure described in obtaining 30], 409 mg of t-butyl 4'-(bromomethyl)biphenyl-2-carboxylate and 47 mg of sodium hydride (as a 55% wt./wt. dispersion in mineral oil) in 5 ml of N,N-dimethylacetamide, resulting received 513 mg of the target compound in the form of a viscous oil.

NMR (CDCl3) ppm: 0,7-1,1 (15H, m), 1.0 to 2.0 (4H, m) to 1.21 (9H, s), 2,15-2,60 (2H, m), 2,68 (2H, t, J = 7 Hz), 3,20 (2H, s), of 5.26 (2H, s), of 6.9 to 8.0 (8H, m).

51(b). 1-[(2'-t-Butoxycarbonylmethyl-4-yl)methyl]-2-butyl - 4-[1-hydroxy-2-methyl-1-(1-methylethyl)propyl]imidazole-5-carboxamide.

10 ml of 1N. an aqueous solution of sodium hydroxide was added to a solution of 500 mg of 1-[(2'-t-butoxide in stage (a)] in 10 ml of ethanol, and the resulting mixture was heated under reflux for 20 hours, after this time the reaction mixture was treated in accordance with the description given in example 45(c), which was obtained 220 mg of the target compound as an amorphous substance.

NMR (CDCl3) ppm: 0,7-1,1 (15H, m), 1,0-2,1 (4H, m) of 1.20 (9H, s), 2,2-2,9 (4H, m), 5,59 (2H, s), 6,8-7,9 (8H, m).

51(c). 2-Butyl-1-[(2'-carboxyphenyl-4-yl)methyl]-4-[1-hydroxy - 2-methyl-1-(1-methylethyl)propyl]imidazole-5-carboxamide.

Repeating the procedure in example 45(d), but using 220 mg of 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] - 2-butyl-4-[1-hydroxy-2-methyl-(1-methylethyl)propyl]imidazole-5-carboxamide [obtained in stage (b)] and 4.5 ml of 4n. solution florodora in dioxane, resulting in received 201 mg of the hydrochloride of target compound in the form of amorphous solids with so pl. 178-181oC.

NMR (DMSO-d6) ppm: 0,76 (3H, t, J = 7.5 Hz), to 0.8-0.9 (12H, m), 1.1 to 1.4 (4H, m), 2,2-2,4 (2H, m), 2,8-3,1 (2H, m), the 5.51 (2H, s), 7,2-7,8 (8H, m).

Example 52.

2-Butyl-1-[(2'-carboxyphenyl-4-yl)methyl] -4-hydroxymethylimidazole - 5-carboxamide (compound N 5-63).

52(a). Succinimido 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] - 2-butyl-4-hydroxymethylimidazole-5-carboxylate.

oC.

NMR (CDCl3) ppm: to 0.89 (3H, t, J = 7 Hz), 1.0 to 2.0 (4H, m) of 1.23 (9H, s), 2,70 (2H, t, J = 7.5 Hz), 2,69 (4H, s), 4,10 (1H, Shir. C) 4,96 (2H, s) to 5.56 (2H, s), 7,00-of 7.90 (8H, m).

52(b). 1-[(2'-t-Butoxycarbonylmethyl-4-yl)methyl]-2-butyl-4 - hydroxymethylimidazole-5-carboxamide.

0.5 ml of concentrated aqueous ammonia was added to a solution of 0.60 g succinimido 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl]-2 - butyl-4-hydroxymethyl-imidazol-5-carboxylate [obtained in stage (a)] in 6 ml of tetrahydrofuran, and then immediately separated the target connection. The solvent was removed by distillation under reduced pressure, and the obtained residue was washed with diethyl ether and water, resulting in a received 0,38 g of target compound in powder form with so pl. 222-224oC.

NMR (DMSO-d6) ppm: of 0.85 (3H, t, J = 7 Hz), 1,19 (9H, s), of 1.0 to 1.9 (4H, m), to 2.57 (2H, t, J = 7.5 Hz), to 4.52 (2H, d, J = 4.5 Hz), 5 the evil-5-carboxamide.

A solution of 0.28 g of 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl]-2 - butyl-4-getcommadelimited-5-carboxamide [obtained in stage (b)] in 3 ml of 4n. solution of hydrogen chloride in dioxane is stirred at room temperature for 5 hours and then concentrated by evaporation under reduced pressure. The concentrate is triturated with a mixture of ethyl acetate and diethyl ether, and the cured material was collected by filtration, which was obtained 0.26 g of the hydrochloride of the target compound that softens when more than 150oC and decomposes at 235oC.

NMR (DMSO-d6) ppm: to 0.80 (3H, t, J = 7.5 Hz), of 1.20 to 1.31 (2H, m), 1,43-and 1.54 (2H, m), 2,96 (3H, t, J = 7.5 Hz), and 4.68 (2H, s), 5,71 (2H, s), 7,21 to 7.75 (8H, m).

Example 53.

N-Methyl-2-butyl-1-[(2'-carboxyphenyl-4-yl)methyl] -4 - hydroxymethylimidazole-5-carboxamide (compound N 5-71).

53(a). N-Methyl-1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl]-2 - butyl-4-hydroxymethylimidazole-5-carboxamide.

0.4 ml of 40% vol. solution of methylamine in water was added at room temperature to a solution of 0,278 g succinimido 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] -2-butyl-4 - hydroxymethylimidazole-5-carboxylate [obtained as described in example 52(a)] in a mixture of 3 ml of methylene chloride and 2 is believed by evaporation under reduced pressure, and the concentrate was dissolved in ethyl acetate. The resulting solution was washed with an aqueous solution of potassium bisulfate and an aqueous solution of sodium bicarbonate (consistently), then the solution was dried with anhydrous magnesium sulfate. Then the solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, elwira with ethyl acetate, resulting in a received 176 mg of the target compound as a glassy product.

NMR (CDCl3) ppm: of 0.85 (3H, t, J = 7 Hz), of 1.23 (9H, s), 1.0 to 2.0 (4H, m), of 2.54 (2H, t, J = 7.5 Hz), 2.91 in (3H, d, J = 5 Hz), 4,70 (2H, s), 5,62 (2H, s), 6,9-a 7.85 (8H, m), scored 8.38 (1H, q, J = 5 Hz).

53(b). N-Methyl-2-butyl-1-[(2-carbonylmethyl-4-yl)methyl]-4 - hydroxymethylimidazole-5-carboxamide.

A solution of N-methyl-1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] -2 - butyl-4-hydroxymethylimidazole-5-carboxamide [obtained in stage (a)] in 2 ml of 4n. solution of hydrogen chloride in dioxane was left for 16 hours at room temperature, and then concentrated under reduced pressure. The resulting crystalline residue was washed with a mixture of ethyl acetate and diethyl and obtained 0.15 g of the hydrochloride of the target connection so pl. 205-208oC (Razlog.).

NMR (DMSO-d6) ppm: 0,81 (3H, t, J = 7.5 Hz), 1,25 (2H, sextet, J = 7.5 Hz), 1,49 (2H, ="ptx2">

N-Ethoxycarbonylmethyl-2-butyl-1-[(2'-carboxyphenyl-4-yl)methyl] - 4-hydroxymethylimidazole-5-carboxamide (compound N 5-126).

Repeating the procedure described in example 53, but using 0,307 g succinimido 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl]-2 - butyl-4-getcommadelimited-5-carboxylate [obtained as described in example 52(a)] , 89 mg ethylglycine-hydrochloride and 0,089 ml of triethylamine, the resulting received 0,202 g of the hydrochloride of target compound in the form of amorphous powder with so pl. above 80oC (softening).

NMR (DMSO-d6) ppm: to 0.80 (3H, t, J = 7.5 Hz), of 1.18 (3H, t, J = 7 Hz), of 1.20 and 1.33 (2H, m), 1,47 (2H, quintet, J = 7.5 Hz), to 2.94 (2H, t, J = 8 Hz), of 4.05 (2H, d, J = 6 Hz), of 4.12 (2H, square, J = 7 Hz), 4.72 in (2H, s), 5,63 (2H, s), 7,24 to 7.75 (8H, m), 9,37 (1H, t, J = 6 Hz).

Example 55.

N-Carboxymethyl-2-butyl-1-[(2'-carboxyphenyl-4-yl)methyl] -4 - hydroxymethylimidazole-5-carboxamide (compound N 5-125).

Repeating the procedure described in example 53, but using 0.32 g of succinimido 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl]-2 - butyl-4-getcommadelimited-5-carboxylate [obtained in example 52(a)], 0.11 g t-butyllithium-hydrochloride and 80 mg of 4-dimethylaminopyridine, which was obtained 0.21 g of the hydrochloride of the target connection is (3H, t, J = 7.5 Hz), 1,25 (2H, sextet, J = 7.5 Hz), to 1.48 (2H, quintet, J = 7.5 Hz), 2,95 (2H, t, J = 8.0 Hz), 3,98 (2H, d, J = 6 Hz), 4,71 (2H, s), 5,64 (2H, s), 7,26 to 7.75 (8H, m), which 9.22 (1H, t, J = 6 Hz).

Example 56.

N-[(S)-1-Ethoxycarbonylethyl]-2-butyl-1-[(2'-carboxyphenyl - 4-yl)methyl] -4-hydroxymethylimidazole-5-carboxamide (compound N 5-128).

Repeating the procedure described in example 53, but using 0.39 g of succinimido 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] -2 - butyl-4-hydroxymethylimidazole-5-carboxylate [obtained in example 52(a)], of 0.13 g of ethyl-elanthianlove and 0.21 ml of triethylamine, which was obtained 0.27 g of the hydrochloride of target compound as amorphous solid.

NMR (DMSO-d6) ppm: of 0.82 (3H, t, J = 7.5 Hz), of 1.17 (3H, t, J = 7 Hz), 1,20-of 1.35 (2H, m) of 1.34 (3H, d, J = 7 Hz), 1,43 is 1.58 (2H, m), 2,98 (2H, t, J = 7.5 Hz), 4,10 (2H, square, J = 7 Hz), of 4.44 (1H, quintet, J = 7 Hz), 4,70 (2H, s), 5,63 (2H, AB-sq , = 0,10 ppm, J = 16 Hz), 7.24 to 7,76 (8H, m), 9,39 (1H, d, J = 7.5 Hz).

Example 57.

N-(2-Ethoxycarbonylethyl-2-butyl-1-[(2'-carboxymefenamic] -4 - hydroxymethylimidazole-5-carboxamide (compound N 5-130).

Repeating the procedure described in example 53, but using 305 mg succinimido 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] -2 - butyl-4-getcommadelimited-5-carboxylate [obtained in the received 0.20 g of the hydrochloride of target compound as amorphous solid.

NMR (DMSO-d6) ppm: of 0.82 (3H, t, J = 7.5 Hz), of 1.16 (3H, t, J = 7 Hz), 1,20-to 1.38 (2H, m), 1,42 is 1.58 (2H, m), of 2.97 (2H, t, J = 7.5 Hz), 3,3-3,6 (4H, m), Android 4.04 (2H, square, J = 7 Hz), 4,60 (2H, s), 5,63 (2H, s), 7,21-7,76 (8H, m), 9,01 (1H, Shir. etc).

Example 58.

Methyl (S)-N-{2-butyl-1-[(2-carboxyphenyl-4-yl)methyl]-4 - hydroxymethylimidazole-5-carbonyl}-prolinate have been obtained (compound N 5-335).

Repeating the procedure described in example 53, but using 529 mg succinimido 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] -2 - butyl-4-hydroxymethylimidazole-5-carboxylate [obtained as described in example 52(a)] , 180 mg of methyl (S)-prolinate have been obtained-hydrochloride and 0.2 ml of triethylamine, the resulting received 0.39 g of the hydrochloride of target compound in the form of amorphous powder with so pl. more than 120oC (softening).

NMR (DMSO-d6) ppm: to 0.88 (3H, t, J = 7.5 Hz), of 1.34 (2H, sextet, J = 7,5), 1,4-of 2.25 (6H, m), 2,9-3,7 (2H, m) to 3.64 (3H, s), 4,34 (1H, t, J = 7.5 Hz), 4,55 (2H, s), 5.25-inch and 5.56 (acwc. 1H, AB-Quartet, J = 15,5 Hz), 7,26-to 7.77 (8H, m).

Example 59.

2-Butyl-1-[(2'-carboxyphenyl-4-yl)methyl] -4-(1-hydroxy-2,2 - dimethylpropyl)imidazol-5-carboxamide (compound N 5-68).

59(a). Methyl-1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl]-2 - butyl-4-formylindole-5-carboxylate.

5,07 ml of triethylamine and 6.0 g of a complex of sulfur trioxide/pearl-4 - hydroxymethylimidazole-4-carboxylate [obtained as described in example 1(b)] in 18 ml of dimethyl sulfoxide, and the resulting mixture was stirred at the same temperature for 45 minutes then the reaction mixture was mixed with water and was extracted with ethyl acetate. The extract was washed with water and then aqueous sodium bicarbonate solution, after which the extract was dried with anhydrous magnesium sulfate, and the solvent drove by distillation under reduced pressure. The residue was purified by column chromatography on silica gel, elwira with a mixture of hexane and ethyl acetate (1: 1 by volume), resulting in a received 2,88 g of target compound as amorphous solid.

NMR (CDCl3) ppm: of 0.90 (3H, t, J = 7 Hz), 1,25 (9H, s), 1,1-2,1 (4H, m), 2,77 (2H, t, J = 8 Hz), 3,91 (3H, s), the 5.65 (2H, s), 6,9-7,9 (8H, m), 10,48 (1H, s).

59(b). Methyl-1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] -2 - butyl-4-(1-hydroxy-2,2-dimethylpropyl)imidazole-5-carboxylate.

2,77 ml of 2 M solution of bromide t-butylamine in tetrahydrofuran was added at -55oC and under nitrogen atmosphere to a solution of 1.32 g of methyl 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl]-2-butyl-4-formylindole - 5-carboxylate [obtained in stage (a) above] in 26 ml of tetrahydrofuran, and the resulting mixture is stirred at a temperature of -55 ° C - (-50)oC for 30 minutes then the reaction mixture was diluted with 50 milliliters of ethyl acetate is fester, and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography on silica gel, elwira with a mixture of hexane and ethyl acetate (2:1, by volume), which was obtained 0.87 g of the target compound as amorphous solid.

NMR (CDCl3) ppm: of 0.90 (3H, t, J = 7.5 Hz), of 0.93 (9H, s), 1.0 to 2.0 (4H, m) to 1.19 (9H, s), 2,68 (2H, t, J = 7.5 Hz), to 3.41 (1H, d, J = 10 Hz), 3,74 (3H, c) to 4.92 (1H, d, J = 10 Hz), 5,59 (2H, s), 6,9-7,9 (8H, m).

59(c). 1-[(2'-t-Butoxycarbonylmethyl-4-yl)methyl]-2-butyl-4- (1-hydroxy-2,2-dimethylpropyl)imidazole-5-carboxylic acid.

In accordance with the procedure described in example 4, 0.87 g of methyl 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] -2-butyl-4-(1-hydroxy - 2,2-dimethylpropyl)imidazole-5-carboxylate [obtained in stage (b), see above] were subjected to hydrolysis using 342 mg of the monohydrate of lithium hydroxide, resulting in the obtained 0.73 g of target compound in the form of crystals with so pl. 199-201oC (Razlog.).

NMR (DMSO-d6) ppm: 0,84 (3H, t, J = 7.5 Hz), to 0.89 (9H, s) of 1.16 (9H, s), 1,22-1,4 (2H, m), was 1.58 (2H, quintet, J = 7.5 Hz), of 2.64 (2H, t, J = 7,5), 4,78 (1H, s), of 5.68 (2H, AB-Quartet, = 0,14 ppm, J = 17 Hz), 7,02 (2H, d, J = 8 Hz), 7,22-7,58 (5H, m), the 7.65 (1H, d, J = 7.5 Hz).

59(d). Succinimido 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl]- 2-butyl-4-(1-gidrolizuemye 600 mg of 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl]-2-butyl-4- (1-hydroxy-2,2-dimethylpropyl)imidazole-5-carboxylic acid [obtained in stage (c), see above] , 172 mg of N-hydroxysuccinimide and 250 mg N,N-dicyclohexylcarbodiimide, resulting received 663 mg of target compound as amorphous solid.

NMR (CDCl3) ppm: to 0.92 (3H, t, J = 7.5 Hz), a 1.01 (9H, s) to 1.21 (9H, s) to 1.38 (2H, sextet, J = 7.5 Hz), at 1.73 (2H, quintet, J = 7.5 Hz), a 2.71 (2H, t, J = 7.5 Hz), 2,84 (4H, s), 4,99 (1H, d, J = 7.5 Hz), of 5.53 (2H, s), 7,03 (2H, d, J = 8.5 Hz), 7,26-to 7.50 (5H, m), to 7.77 (1H, d, J = 8 Hz).

59(e). 1-[(2'-t-Butoxycarbonylmethyl-4-yl)methyl]-2-butyl-4- (1-hydroxy-2,2-dimethylpropyl)imidazol-5-carboxamide.

Repeating the procedure described in example 52b, but using 0.66 g of succinimido 1-[(2'-t-butoxycarbonylmethyl - 4-yl)methyl]-2-butyl-4-(1-hydroxy-2,2-dimethylpropyl)imidazole - 5-carboxylate [obtained as described in stage (d)], which was obtained 0.33 g of target compound as amorphous solid.

NMR (CDCl3) ppm: to 0.89 (3H, t, J = 7.5 Hz), is 0.96 (9H, s) to 1.22 (9H, s) of 1.34 (2H, sextet, J = 7.5 Hz), of 1.64 (2H, quintet, J = 7.5 Hz), 2,62 (2H, t, J = 7.5 Hz), of 4.67 (1H, d, J = 5.5 Hz), 5,48 and 5.82 (acwc. 1H, AB-Quartet, J = 16 Hz), 7,02 (2H, d, J = 8.5 Hz), 7.23 percent is 7.50 (6H, m), 7,76 (1H, d, J = 6.5 Hz).

59(f). 2-Butyl-1-[(2'-carboxyphenyl-4-yl)methyl] -4-(1 - hydroxy-2,2-dimethylpropyl)imidazol-5-carboxamide.

Repeating the procedure described in example 52(c), but with ispolzovanie [obtained as described in stage (e)] , as a result, we received 228 mg of the hydrochloride of target compound in the form of powdered solids with so pl. 150-154oC (softening).

NMR (DMSO-d6) ppm: to 0.80 (3H, t, J = 7.5 Hz), of 0.91 (9H, s), 1,24 (2H, sextet, J = 7.5 Hz), to 1.45 (2H, quintet, J = 7.5 Hz), 2,99 (2H, t, J = 7.5 Hz), 4,78 (1H, s) 5,69 (2H, s), 7,21 (2H, d, J = 8 Hz), 7,33-to 7.61 (5H, m), of 7.75 (1H, d, J = 8 Hz).

Example 60.

1-[(2'-Carboxyphenyl-4-yl)methyl] -4-(1-hydroxy-2,2-dimethylpropyl)- 2-propylimidazol-5-carboxamide (compound N 5-6).

60(a). Diethyl 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] -2 - propylimidazol-4,5, in primary forms.

Repeating the procedure described in example 1(a), but using 9.0 g diethyl 2-propylimidazol-4,5-in primary forms [obtained in accordance with the description given in obtaining 12], 12.3 g of t-butyl 4-bromomethylbiphenyl-2-carboxylate and 4.1 g of t-butoxide potassium as the basis, resulting in a received 16,47 g of target compound in the form of a viscous oil.

NMR (CDCl3) ppm: of 0.95 (3H, t, J = 7.5 Hz), of 1.5-2.0 (2H, m) of 1.23 (9H, s), 1,25 (3H, t, J = 7 Hz), of 1.37 (3H, t, J = 7 Hz), 2,69 (2H, t, J = 7 Hz), 4.26 deaths (2H, square , J = 7 Hz), to 4.38 (2H, square, J = 7 Hz), of 5.48 (2H, s), 7,0-7,9 (8H, m).

60(b). Ethyl-1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl]-4 - hydroxymethyl-2-propylimidazol-5-carboxylate.

In propylimidazol-4,5-in primary forms [obtained in stage (a) see above] was restored using 44,4 ml of 1.5 M solution of hydride diisobutylaluminum in tetrahydrofuran, resulting in received 10,83 g of target compound in the form of crystals with so pl. 108-110oC.

NMR (CDCl3) ppm: 0,98 (3H, t, J = 7.5 Hz), of 1.23 (9H, s) is 1.31 (3H, t, J = 7 Hz), to 1.79 (2H, sextet, J = 7.5 Hz), to 2.67 (2H, t, J = 7.5 Hz), 4,27 (2H, square , J = 7 Hz), to 4.87 (2H, s) 5,59 (2H, s) to 7.00 (2H, d, J = 8.5 Hz), 7,24 to 7.75 (5H, m), 7,78 (1H, d, J = 7 Hz).

60(c). Ethyl-1-[(2'-t-botcontroller-4-yl)methyl]-4 - formyl-2-propylimidazol-5-carboxylate.

In accordance with the procedure described in example 59(a), 2,71 g of ethyl 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] -4-hydroxymethyl-1 - propylimidazol-5-carboxylate [obtained in stage (b), see above] were subjected to oxidation with the use of 4.6 ml of triethylamine and 5.5 g of a complex of sulfur trioxide and pyridine in 17 ml of dimethyl sulfoxide, which was given to 2.57 g of target compound in the form of crystals with so pl. 117-119oC.

NMR (CDCl3) ppm: 0,99 (3H, t, J = 7.5 Hz), of 1.26 (9H, s) of 1.84 (2H, sex., J = 7.5 Hz), 2,73 (2H, t, J = 7.5 Hz), and 4.40 (2H, square, J = 7 Hz), 5,67 (2H, s), 7,02 (2H, d, J = 8.5 Hz), 7.29 trend-rate of 7.54 (5H, m), 7,80 (1H, d, J = 8.0 Hz), 10,48 (1H, s).

60(d). Ethyl 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] -4- (1-hydroxy-2,2-dimethylpropyl)-2-propylimidazol-5-carboxylate.

In sootvetstvocat-5-carboxylate [obtained in stage (c), see above] were subjected to interaction with 2.4 ml of a 2 M solution of t-butylacrylamide in tetrahydrofuran, resulting in received 0,78 g of target compound in the form of a viscous oily substance.

NMR (CDCl3) ppm: to 0.97 (3H, t, J = 7.5 Hz), and 1.0 (9H, s), 1,25 (9H, s) of 1.35 (3H, t, J = 7 Hz), 1.77 in (2H, Sextus, J = 7.5 Hz), 2,68 (2H, t, J = 7.5 Hz), of 3.46 (1H, d, J = 9 Hz), the 4.29 (2H, square, J = 7 Hz), 4,99 (1H, d, J = 9 Hz), 5,62 (2H, s) to 7.00 (2H, d, J = 8 Hz), 7.29 trend-rate of 7.54 (5H, m), 7,80 (1H, d, J = 7.5 Hz).

60(e). 1-[(2'-t-Botcontroller-4-yl)methyl]-4- (1-hydroxy-2,2-dimethylpropyl)-2-propylimidazol-5-carboxylic acid.

In accordance with the procedure described in example 4 0,78 g of ethyl 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] -4-(1-hydroxy - 2,2-dimethylpropyl)-2-propylimidazol-5-carboxylate [obtained in stage (d) above] were subjected to hydrolysis using 209 mg of the monohydrate of lithium hydroxide, resulting in received of 0.62 g of target compound in the form of crystals with so pl. 207oC.

NMR (DMSO-d6) ppm: to 0.88 (3H, t, J = 7.5 Hz), to 0.89 (9H, s) and 1.15 (9H, s), and 1.63 (2H, sextet, J = 7.5 Hz), 2.63 in (2H, t, J = 7.5 Hz), 4,79 (1H, s), 5,63 and 5,76 (acwc. 1H, AB-Quartet, J = 18.5 Hz), 7,02 (2H, d, J = 8 Hz), 7,22-to 7.67 (6H, m).

60(f). Succinimido 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl]- 4-(1-hydroxy-2,2-dimethylpropyl)-2-propylimidazol-5-carboxylate.

Stand-(1-hydroxy-2,2-dimethylpropyl)-2-propylimidazol-5-carboxylic acid [obtained in stage (e), see above] , 110 mg of N-hydroxysuccinimide and 130 mg of N,N-dicyclohexylcarbodiimide, resulting received 321 mg of the target compound as amorphous solid.

NMR (CDCl3) ppm: to 0.94 (3H, t, J = 7,5), AND 0.98 (9H, s) of 1.18 (9H, s) of 1.75 (2H, sextet, J = 7.5 Hz), of 2.64 (2H, t, J = 7.5 Hz), 3,12 (1H, d, J = 9.5 Hz), to 4.98 (1H, d, J = 9.5 Hz), 5,52 (2H, s), 7,0-7,9 (8H, m).

60(g). 1-[(2'-Butoxycarbonylmethyl-4-yl)methyl]-4-(1 - hydroxy-2,2-dimethylpropyl)-2-propylimidazol-5-carboxamide.

Repeating the procedure described in example 52(b), but using 0,13 g succinimido 1-[(2'-t-butoxycarbonylmethyl - 4-yl)methyl]-4-(1-hydroxy-2,2-dimethylpropyl)-2-propylimidazol - 5-carboxylate (obtained in stage (f), see above), which was obtained 0.12 g of target compound in the form of a glassy substance.

NMR (CDCl3) ppm: to 0.88 (3H, t, J = 7.5 Hz), of 0.90 (9H, s) of 1.24 (9H, s) to 1.60 (2H, sextet, J = 7.5 Hz), 2,58 (2H, t, J = 7.5 Hz) and 4.65 (1H, d, J = 6 Hz), of 5.53 and by 5.87 (acwc. 1H, AB-Quartet, J = 16 Hz), 7,02 (2H, d, J = 8 Hz), 7.23 percent-of 7.48 (5H, m), 7,78 (1H, d, J = 6.5 Hz).

60(h). 1-[(2'-Carboxyphenyl-4-yl)methyl]-4-(1-hydroxy-2,2 - dimethylpropyl)-2-propylimidazol-5-carboxamide.

Repeating the procedure described in example 52 (c), but using 139 mg of 1-[(2'-t-butoxycarbonylmethyl-4-yl)- methyl] -4-(1-hydroxy-2,2-dimethylpropyl)-2-probeware compounds in powder form with so pl. 160oC (RASMAG.).

NMR (DMSO-d6) ppm: of 0.82 (3H, t, J = 7.5 Hz), of 0.90 (9H, s) of 1.53 (2H, sextet, J = 7.5 Hz), of 2.97 (2H, t, J = 7.5 Hz), 4,79 (1H, s) 5,69 (2H, s), 7,19 to 7.75 (8H, m).

Example 61.

(5-Methyl-2-oxo-1,3-dioxolan-4-yl)methyl-4-(1-hydroxy-1 - methylethyl)-2-propyl-1-{ 4-[2-(tetrazol-5-yl)phenyl] phenyl} Mei - 5-carboxylate (compound N 2-17).

61(a). (5-Methyl-2-oxo-1,3-dioxolan-1-yl)methyl-4-(1-hydroxy - 1-methylethyl)-2-propyl-1-{ 4-[2-(triliteral-5-yl)phenyl]phenyl} Mei-5-carboxylate.

Suspension 0.97 g of potassium carbonate in 100 ml of N,N-dimethylacetamide was heated at 60oC, and then to the heated suspension, stirring, one drop was added a solution of 1.14 g (5-methyl-2-oxo-1,3-dioxolan - 4-yl)methyl-4-(1-hydroxy-1-methylethyl)-2-propylimidazol-5-carboxylate [obtained in accordance with the description presented in receiving 31] , and of 2.35 g of 4-[2-(triliteral-5-yl)phenyl] benzylbromide in 50 ml of N, N-dimethylacetamide. The reaction mixture was stirred for 3.5 h at 60oC, and then was diluted with ethyl acetate. An ethyl acetate layer was separated, washed with water and dried with anhydrous magnesium sulfate, and the solvent drove by distillation under reduced pressure. The obtained residue was purified by column chromatography on silica gel the e amorphous solids. This product has led from diisopropyl ether, and was given a clean target connection so pl. 98-99oC (decomposition).

NMR (CDCl3) ppm: to 0.89 (3H, t, J = 7.5 Hz), of 1.62 (6H, s), 1,6-of 1.75 (2H, m) of 1.97 (3H, s) to 2.54 (2H, t, J = 8 Hz), 4,70 (2H, s), and 5.30 (2H, s), 5,61 (1H, s), of 6.68 (2H, d, J = 7.5 Hz), 6.90 to-7,52 (20H, m), 7,87 (1H, d, J = 7.5 Hz).

61(b). (5-Methyl-2-oxo-1,3-dioxolan-4-yl)methyl-4-(1-hydroxy - 1-methylethyl)-2-propyl-1-{ 4-[2-(tetrazol-5-yl)phenyl] phenyl} Mei-5-carboxylate.

A mixture of 1.4 g (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl-4-(1 - hydroxy-1-methylethyl)-2-propyl-1-{ 4-[2-(triliteral-5-yl)-phenyl] phenyl} Mei-5-carboxylate [obtained in stage (a), see above] and 48 ml of 75%. /about. aqueous acetic acid is stirred for 1 h at 60oCo, after which the mixture was concentrated by evaporation under reduced pressure. The residue was dissolved in toluene and the resulting solution was concentrated by distillation under reduced pressure, after which this operation was repeated again to remove residual water and acetic acid. The obtained residue was purified by column chromatography on silica gel, elwira mixtures of methanol and methylene chloride (1:9 and 1:4 by volume), which was obtained 0.73 g of target compound with so pl. 170-172oC.

Example 62.

Pivaloyloxymethyl-4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2- (tetrazol-5-yl)phenyl]phenyl}Mei-5-carboxylate (compound N 2-15).

62(a). Pivaloyloxymethyl-4-(1-hydroxy-1-methylethyl)-2-propyl- 1-{4-[2-(triliteral-5-yl)phenyl]phenyl}Mei-5-carboxylate.

Repeating the procedure described in example 61(a), but using 0,85 g pivaloyloxymethyl 4-(1-hydroxy-1-methylethyl)-2 - propylimidazol-5-carboxylate [obtained in accordance with the description in obtaining 22(ii)], 1.52 g of 4-[2-(triliteral-5-yl)phenyl] benzylbromide and 0.72 g of potassium carbonate, resulting in a received 1,02 g of target compound as amorphous solid.

The NMR spectrum of this compound was identical to the spectrum of the compound obtained in example 20(a).

62(b). Pivaloyloxymethyl 4-(1-hydroxy-1-methylethyl)-2-propyl- 1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}Mei-5-carboxylate.

Pivaloyloxymethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{ 4-[2 - trailersa-5-yl)phenyl] phenyl}Mei-5-carboxylate, obtained in accordance with the description in stage (a) (see above) were subjected to detritivorous according to the procedure described in example 2P spectrum of this compound were identical so pl. and the NMR spectrum of the compound obtained as described in example 20(b).

Example 63.

Phthalidyl 4-(hydroxy-1-methylethyl)-2-propyl-1-{ 4-[2-(tetrazol - 5-yl)phenyl]phenyl}Mei-5-carboxylate (compound N 2-65).

63(a). Palidin 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2- (triliteral-5-yl)phenyl]phenyl}Mei-5-carboxylate.

Repeating the procedure described in example 61(a), but using 0,456 g phthalidyl 4-(1-hydroxy-1-methylethyl)-2 - propylimidazol-5-carboxylate [obtained as described in obtaining 32], 0,763 g of 4-[2-(triliteral-5-yl)phenyl] benzylbromide and 0,366 g of potassium carbonate, resulting in a received 0,196 g of target compound with so pl. 118-120oC.

NMR (CDCl3) ppm: of 0.95 (3H, t, J = 7.5 Hz), of 1.66 (6H, s) of 1.65 and 1.80 (2H, m) 2,60 (2H, t, J = 7.5 Hz), 5,09 (2H, s), 6,92-7,56 (27H, m), to 7.93 (1H, DD, J = 1 and 8 Hz).

63(b). Phthalidyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2 - tetrazol-5-yl)phenyl]phenyl}Mei-5-carboxylate.

In accordance with the procedure described in example 61(b), 0,196 g phthalidyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2- (triliteral-5-yl)phenyl]phenyl} Mei-5-carboxylate [obtained in stage (a), see above] and was subjected to detritivorous by heating to 75%.about. water UKS 3) ppm: to 0.92 (3H, t, J = 7.5 Hz), of 1.57 (6H, s), 1.60-to or 1.77 (6H, s) to 2.65 (2H, t, J = 7.5 Hz), 5,13 (2H, s), 6,91-EUR 7.57 (12H, m), 7,80 (1H, d, J = 7.5 Hz).

Example 64.

Isopropoxycarbonyloxymethyl 4-(1-hydroxy-1-methylethyl)-2-propyl- 1-{ 4-[2-(tetrazol-5-yl)phenyl] phenyl} Mei-5-carboxylate (compound N 2-21).

64(a). Isopropoxycarbonyloxymethyl 4-(1-hydroxy-1-methylethyl)- 2-propyl-1-{4-[2-(triliteral-5-yl)phenyl]phenyl}Mei-5 - carboxylate.

Repeating the procedure described in example 61(a), but using 656 mg isopropoxycarbonyloxymethyl 4-(1-hydroxy-1-methylethyl)-2 - propylimidazol-5-carboxylate [obtained as described in obtaining 33], 1.20 g of 4-[2-(triliteral-5-yl)phenyl]benzylbromide and 0.51 g of potassium carbonate, resulting in a received 0,78 g of target compound in the form of a viscous oily product.

NMR (CDCl3) ppm: of 0.87 (3H, t, J = 7.5 Hz), 1,24 (6H, d, J = 6 Hz), and 1.63 (6H, s) of 1.65 and 1.80 (2H, m), 2,52 (2H, m, J = 7.5 Hz), to 4.87 (1H, quintet, J = 6 Hz), to 5.35 (2H, s), 5,42 (1H, s), to 5.66 (2H, s), 6,74-7,87 (22H, m), 7,87-of 7.96 (1H, m).

64(b). Isopropoxycarbonyloxymethyl 4-(1-hydroxy-1-methylethyl)-2 - propyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}Mei-5-carboxylate.

In accordance with the procedure described in example 61(b) 0,78 g isopropoxycarbonyloxymethyl 4-(1-hydrox is (a), see above] were subjected to detritivorous by heating to 75% on. /about. water, acetic acid, resulting in received of 0.48 g of the target receive in the form of an amorphous solid.

NMR (CDCl3) ppm as 0.96 (3H, t, J = 7.5 Hz), to 1.21 (6H, d, J = 6 Hz), and 1.63 (6H, s), 1,72 (2H, sextet, J = 7.5 Hz), 2,60 (2H, t, J = 7.5 Hz), 4.72 in (1H, quintet, J = 6.5 Hz), 5,33 (2H, s), USD 5.76 (2H, s), 6,77 (2H, d, J = 7.5 Hz), 6,92 (2H, d, J = 7.5 Hz), 7,37-of 7.60 (3H, m), 7,87 (1H, d, J = 7.5 Hz).

Example 65.

Ethyl 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] -2-ethyl-4-(1 - hydroxy-1-methylethyl)imidazole-5-carboxylate (compound 1-130 N).

of 0.337 g t butoxide potassium was added to a solution of 0.68 g of ethyl 2-ethyl-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate [obtained in accordance with the description in obtaining 37] in 7 ml of N,N-dimethylacetamide, and the mixture was stirred 10 minutes at room temperature. Then to the resulting solution was added 1.04 g of t-butyl 4'-bromomethylbiphenyl-2-carboxylate, and the reaction mixture is stirred 4 h at room temperature. After this time the mixture was mixed with ethyl acetate and water. An ethyl acetate layer was separated, dried with anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography on with the program in the form of resin.

NMR (CDCl3) ppm: of 1.23 (9H, s) of 1.23 (3H, t, J = 7.5 Hz), of 1.29 (3H, t, J = 7.5 Hz), and 1.63 (6H, s), 2,73 (2H, square, J = 7.5 Hz), 4.26 deaths (2H, square, J = 7.5 Hz), 5,54 (2H, s), of 6.73 (1H, s), 6,98 (2H, d, J = 8.5 Hz), 7,5-7,9 (6H, m).

Example 66.

Ethyl 1-[(2'-carboxyphenyl-4-yl)methyl] -2-ethyl-4-(1-hydroxy-1 - methylethyl)imidazole-5-carboxylate (compound 1-131 N).

Repeating the procedure described in example 7, but using 1,32 g of ethyl 1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] -2-ethyl-4- (1-hydroxy-1-methylethyl)imidazole-5-carboxylate [obtained as described in example 65] and 4h. solution florodora in dioxane, resulting in received 0,94 g of the hydrochloride of target compound as amorphous powder.

NMR (DMSO-d6) ppm: 1,09 (3H, t, J = 7.5 Hz) and 1.15 (3H, t, J = 7.5 Hz), to 1.61 (6H, s), 3,03 (2H, square, J = 7.5 Hz), 4,22 (2H, square, J = 7.5 Hz), 5,64 (2H, s), 7,16 (2H, d, J = 8.5 Hz), 7,32 to 7.75 (6H, m).

Example 67.

1-[(2'-Carboxyphenyl-4-yl)methyl] -2-ethyl-4-(1-hydroxy-1 - methylethyl)imidazole-5-carboxylic acid (compound 1-132 N).

Repeating the procedure described in example 17, but using 0.40 g of the hydrochloride of ethyl 1-[(2'-carboxyphenyl-4-yl)methyl]-2-ethyl - 4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate [obtained in example 66] and 0.18 g of the monohydrate of lithium hydroxide, resulting in a received 0.25 g n., J = 7.5 Hz), 5,74 (2H, s), 7,10 (2H, d, J = 8 Hz), 7,30-7,76 (6H, m).

Example 68.

Ethyl 2-ethyl-4-(1-hydroxy-1-methylethyl)-1-{ 4-[2-(tetrazol-5 - yl)phenyl] phenyl}Mei-5-carboxylate (compound N 1-72).

68(a). Ethyl 2-ethyl-4-(1-hydroxy-1-methylethyl)-1-{4-[2- (triliteral-5-yl)phenyl]phenyl}Mei-5-carboxylate.

0.52 g of t-piperonyl potassium was added to a solution of 1.00 g of ethyl 2-ethyl-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate [obtained as described in obtaining 37] in 26 ml of N,N-dimethylacetamide, and the mixture was stirred 10 min at room temperature. To the resulting solution drop by drop solution was added a 2.71 g of 4-[2-(terecitersa-5-yl)phenyl]benzylbromide in 35 ml of N,N-dimethylacetamide, after which the reaction mixture is stirred 4 hours at 50oC. After the reaction mixture was treated in a manner similar to that described in example 18(a), resulting received a 2.01 g of target compound in the form of crystals with so pl. 150-152oC.

NMR (CDCl3) ppm: 1,10 (3H, t, J = 7.5 Hz), of 1.18 (3H, t, J = 7.5 Hz), of 1.65 (6H, s), 2,52 (2H, square, J = 7.5 Hz), 4,14 (2H, square, J = 7.5 Hz), to 5.35 (2H, s) 5,80 (1H, s), 6.73 x (2H, d, J = 8.5 Hz), 6,93-7,52 (20H, m), 7,87 (1H, d, J = 7.5 Hz).

68(b). Ethyl-2-ethyl-4-(1-hydroxy-1-methylethyl)-1-{ 4-[2- tetrazol-5-yl)phenyl]phenyl}Mei-5-carboxyl is azole-5-carboxylate [obtained in stage (a), see above] in 28 ml of 75%.about. aqueous acetic acid is stirred 2 h at 60oC. then the reaction mixture was diluted with 7 ml of water and cooled at room temperature. Besieged trailovic alcohol was removed by filtration, and the filtrate was concentrated by evaporation under reduced pressure. Syrupy residue was led in diisopropyl ether, resulting in the received 1,21 g of target compound with so pl. 166-167oC.

NMR (CDCl3) / ppm: 1.14 in (3H, t, J = 7,5), of 1.20 (3H, t, J = 7.5 Hz), to 1.48 (6H, s), 2,52 (2H, square, J = 7.5 Hz), 4,19 (2H, square, J = 7.5 Hz), 5,41 (2H, s), 6,79 (2H, d, J = 8.5 Hz), to 7.09 (2H, d, J = 8.5 Hz), 7,41 to 7.62 (3H, m), the 7.85 (1H, d, J = 7.5 Hz).

Example 69.

2-Ethyl-4-(1-hydroxy-1-methylethyl)-1-{ 4-[2-tetrazol-5-yl)phenyl] phenyl} Mei-5-carboxylic acid.

A solution of 0.54 g of the monohydrate of lithium hydroxide in 10 ml of water was added to a solution of ethyl 2-ethyl-4-(1-hydroxy-1-methylethyl-1-{ 4-[2- (tetrazol-5-yl)phenyl]phenyl}Mei-5-carboxylate [obtained as described in example 68 (b)] in 10 ml of dioxane, and the mixture was stirred 4 h at room temperature. Then the dioxane was removed by evaporation under reduced pressure, and the resulting aqueous residue was added of 12.6 ml of 1N. aqueous hydrochloric acid. Besieged Chris is">

NMR (DMSO-d6) ppm: 1,09 (3H, t, J = 7.5 Hz), of 1.55 (6H, s), 2.63 in (2H, square , J = 7.5 Hz), the 5.65 (2H, s), of 6.96 (2H, d, J = 8.5 Hz), 7,03 (2H, d, J = 8.5 Hz), 7,08-to 7.64 (4H, m).

Example 70.

Ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(tetrazol - 5-yl)]phenyl} methylimidazole-5-carboxylate (compound N 2-7).

70(a). Ethyl-1-(2'-cyanobiphenyl-4-yl)methyl-4-(1-hydroxy-1 - methylethyl)-2-propylimidazol-5-carboxylate.

Repeating the procedure described in example 68 (a), but using 4,01 g of ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazol - 5-carboxylate (obtained as described in 9), 5.0 g of 4'-bromomethylbiphenyl-2-carbonitrile and of 1.97 g t butoxide potassium, resulting in received 6,86 g of target compound in the form of crystals with so pl. 92-93oC.

NMR (CDCl3) ppm: to 0.97 (3H, t, J = 7.5 Hz), of 1.16 (3H, t, J = 7 Hz), of 1.65 (6H, s), 1,74 (2H, sextet, J = 7.5 Hz), to 2.67 (2H, t, J = 7.5 Hz), 4,24 (2H, square , J = 7 Hz), 5,52 (2H, s), 5,77 (1H, s), 7,05 (2H, d, J = 8.5 Hz), 7,42-to 7.67 (5H, m), 7,76 (1H, d, J = 8 Hz).

70(b). Ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2- (tetrazol-5-yl)phenyl]phenyl}Mei-5-carboxylate.

A solution of 2.00 g of ethyl 1-(2'-cyanobiphenyl-4-yl)methyl-4-(1-hydroxy - 1-methylethyl)-2-propylimidazol-5-carboxylate [obtained in stage (a)] (see above) and 2.0 g of azide presence of TBT in 15 ml of toluene, stirred 5 denom pressure, and the residue was dissolved in 30 ml of 4n. solution florodora in dioxane. The solution was left for 16 h at room temperature, after which it was concentrated by evaporation under reduced pressure. The residue is triturated in diisopropyl ether, which was obtained from 2.00 g of the hydrochloride of the target compounds.

The NMR spectrum of this compound was identical to the spectrum of the compound obtained in example 18(b).

Example 71.

Ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(tetrazol - 5-yl)phenyl] phenyl}Mei-5-carboxylate (compound N 2-7).

71(a). Ethyl 1-{4-[2-(t-butylaminoethyl)phenyl]phenyl}methyl - 4-(1-hydroxy-1-methylethyl)-2-propylimidazol-5-carboxylate.

Repeating the procedure described in example 68(a), but with the use of 4.16 g of ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazol - 5-carboxylate (obtained as described to obtain 9), 6,00 g N-t-butyl-4'-bromomethylbiphenyl-2-carboxamide (obtained as described in obtaining 38) and 2.14 g t butoxide potassium, resulting received by 5.87 g of target compound in the form of crystals with so pl. 145-146oC.

NMR (CDCl3) ppm: to 0.97 (3H, t, J = 7.5 Hz), of 1.12 (9H, s) of 1.24 (3H, t, J = 7 Hz), of 1.64 (6H, s) of 1.75 (2H, sex., J = 7.5 Hz), to 2.66 (2H, t, J = 7.5 Hz), 4,25 (2H, square , J = 7 Hz), 5,03 the l-4-(1-hydroxy-1 - methylethyl)-2-propylimidazol-5-carboxylate.

0,345 ml oxalicacid drop was added, the cooling in this ice, to a solution of 1.00 g of ethyl-1-{4-[2-(t-butylaminoethyl)phenyl]phenyl} methyl-4-(1-hydroxy-1-methylethyl)-2-propylimidazol-5-carboxylate [obtained in stage (a) above] in 10 ml of methylene chloride, and the mixture was stirred 2 h at the same temperature. Then the reaction mixture was diluted with aqueous sodium bicarbonate solution and ethyl acetate, then ethyl acetate layer was separated, dried with anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography on silica gel, elwira a mixture of ethyl acetate and hexane (1:1 by volume), resulting in a received 0,69 g of target compound in the form of crystals.

The melting point and NMR spectrum of this compound are identical to those of the compound obtained in example 70(a).

71(c). Ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{ 4-[2 - tetrazol-5-yl)phenyl]phenyl}Mei-5-carboxylate.

Repeating the procedure described in example 70(b), but using ethyl 1-(2'-cyanobiphenyl-4-yl)methyl-4-(1-hydroxy-1-methylethyl)-2 - propylimidazol-5-carboxylate [obtained in stage (b), see above], resulting in a received target somere 18(b).

Example 72.

Ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{ 4-[2-tetrazol - 5-yl)phenyl] phenyl}Mei-5-carboxylate (compound N 2-7).

72(a). Ethyl-1-[(2'-t-butoxycarbonylmethyl-4-yl)methyl] -4-(1 - hydroxy-1-methylethyl)-2-propylimidazol-5-carboxylate.

Repeating the procedure described in example 68 (a), but using 4,80 g of ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazol - 5-carboxylate [obtained as described in 9], 6,94 g of t-butyl 4'-bromomethylbiphenyl-2-carboxylate and 2.28 g t butoxide potassium, resulting in received 7.50 g of target compound in the form of crystals with so pl. 90-91oC.

NMR (CDCl3) ppm: to 0.97 (3H, t, J = 7 Hz), of 1.23 (3H, t, J = 7 Hz), 1,25 (9H, s) to 1.60 (6H, s), equal to 1.82 (2H, sextet, J = 7,0 Hz) to 2.67 (2H, t, J = 7 Hz), 4,24 (2H, square, J = 7 Hz), the 5.51 (2H, s) 5,72 (1H, s), 6.87 in-a 7.85 (8H, m).

72(b). Ethyl 1-[(2'-carboxyphenyl-4-yl)methyl]-4-(1-hydroxy-1 - methylethyl)-2-propylimidazol-5-carboxylate.

Repeating the procedure described in example 18(b), but using 0,80 g of ethyl 1-[(2'-t-butoxycarbonylmethyl-4-yl] methyl]- 4-(1-hydroxy-1-methylethyl)-2-propylimidazol-5-carboxylate [obtained in stage (a), see above] and 4h. solution florodora in dioxane, resulting in received hydrochloride of target compound in the form of amorino (2H, square, J= 7 Hz), 5,63 (2H, s), 7,13 to 7.75 (8H, m).

72(c). Ethyl-1-[(2'-carbamoylbiphenyl-4-yl)methyl]-4-(1-hydroxy - 1-methylethyl)-2-propylimidazol-5-carboxylate.

3 ml of oxalicacid drop was added, the cooling in this ice, to a solution of 4.00 g of the hydrochloride of ethyl 1-[(2'-carboxyphenyl-4-yl)methyl]- 4-(1-hydroxy-1-methylethyl)-2-propylimidazol-5-carboxylate [obtained in stage (b), see above] in 40 ml of methylene chloride, and the mixture was stirred 2 h at room temperature. Then the reaction mixture was concentrated by evaporation under reduced pressure. Then to the residue was added benzene, and the mixture is again concentrated by evaporation under reduced pressure to remove the remaining oxalicacid. The crystalline residue is suspended in 100 ml of ethyl acetate and mixed with 15 ml of concentrated ammonia, cooling the thus ice, after which the mixture is stirred 10 min at room temperature. Then an ethyl acetate layer was separated, washed with water, dried with anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The crystalline residue is washed with diisopropyl ether and received 2,97 g of target compound with so pl. 148-151oC.

NMR (CDCl3) ppm as 0.96 (3H, so J = 7,5 Gr. with), USD 5.76 (1H, s), of 6.99 (2H, d, J = 8 Hz), 7,32-7,53 (5H, m), 7,71 (1H, d, J = 6 Hz).

72(d). Ethyl-1-[(2'-cyanobiphenyl-4-yl)methyl] -4-(1-hydroxy-1 - methylethyl)-2-propylimidazol-5-carboxylate.

264 μl anhydride triperoxonane acid was added, the cooling in a bath containing a mixture of ice and sodium chloride, to the solution 0,70 g of ethyl 1-[(2'-carbamoylbiphenyl-4-yl)methyl] -4-(1-hydroxy-1 - methylethyl)-2-propylimidazol-5-carboxylate [obtained in stage (c), see above] and 0.43 ml of triethylamine in 7 ml of methylene chloride, and the mixture was stirred 30 min at the same temperature. Then the reaction mixture was diluted with aqueous sodium bicarbonate solution and ethyl acetate, an ethyl acetate layer was separated, dried with anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography on silica gel, elwira a mixture of ethyl acetate and hexane (1:1 by volume), resulting in received of 0.60 g of target compound in the form of crystals.

T. pl. and NMR spectrum of the compound are identical to those of the compound obtained in example 70(a).

72(e). Ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2- (tetrazol-5-yl)phenyl]phenyl}Mei-5-carboxylate.

Repeated proceduresa-5-carboxylate [obtained in stage (d), see above], resulting in a received target connection with the release of 90%.

The NMR spectrum of this compound is identical to the spectrum of the compound obtained in example 18(b).

Example 73.

Pivaloyloxy 4-(1-hydroxyethyl)-2-propyl-1-{ 4-[2-tetrazol - 5-yl)phenyl] phenyl}Mei-5-carboxylate (compound N 4-31).

73(a). Pivaloyloxymethyl 4-(1-hydroxyethyl)-2-propyl-1-{4-[2- (triliteral-5-yl)phenyl]phenyl}Mei-5-carboxylate.

A solution of 196 mg of the monohydrate of sodium hydroxide in 15 ml of water was added to the solution 2,87 g ethyl-4-(1-hydroxyethyl)-2-propyl-1-{4-[2- (triliteral-5-yl)phenyl]phenyl}Mei-5-carboxylate [obtained as described in example 42(a)] in 30 ml of dioxane, and the resulting mixture was stirred 16 h at room temperature. Then to the mixture was added a small piece of dry ice, and then the mixture was concentrated by evaporation under reduced pressure to dryness. The residue was dissolved in 40 ml of N,N-dimethylacetamide, and the solution was added 0.45 g of potassium carbonate, and then 1.1 ml of pivaloyloxymethyl. The resulting mixture was stirred 3 h at 50oC. thereafter, to the reaction mixture were added water and ethyl acetate, an ethyl acetate layer was separated, dried, anhydrous magnesium sulfate and the end of the silica gel, elwira a mixture of ethyl acetate and hexane (1: 1 by volume) and got to 2.41 g of the target compound as amorphous powder.

NMR (CDCl3) ppm: to 0.88 (3H, t, J = 7.5 Hz), 1,17 (9H, s) of 1.50 (3H, d, J = 6 Hz), 1.69 in (2H, sex., J = 7.5 Hz), of 2.51 (2H, t, J = 7.5 Hz), 3,62 (1H, d, J = 8 Hz), 5,17-of 5.29 (1H, m), lower than the 5.37 (1H, d, J = 16.5 Hz), 5,46 (1H, d, J = 16.5 Hz), 5,77 (1H, d, J = 5.5 Hz), of 5.82 (1H, d, J = 5.5 Hz), to 6.75 (2H, d, J = 8.5 Hz), 6,92-7,89 (20H, m), of 7.90 (1H, d, J = 7.5 Hz).

73(b). Pivaloyloxymethyl-4-(1-hydroxyethyl)-2-propyl-1-{4-[2- (tetrazol-5-yl)phenyl]phenyl}Mei-5-carboxylate.

Repeating the procedure described in example 35(c), but using 2,87 g pivaloyloxymethyl 4-(1-hydroxyethyl)-2-propyl- 1-{4-[2-(triliteral-5-yl)phenyl]phenyl}Mei-5-carboxylate [obtained in stage (a), see above] and 75%.about. aqueous acetic acid, resulting in a received 1,21 g of target compound in powder form.

NMR (CDCl3) ppm: of 0.90 (3H, t, J = 7.5 Hz), of 1.13 (9H, s) of 1.43 (3H, d, J = 6.5 Hz), 1,67 (2H, sex., J = 7.5 Hz), to 2.55 (3H, t, J = 7.5 Hz), 5,16 (1H, q, J = 6.5 Hz), of 5.40 (1H, d, J = 16.5 Hz), the 5.51 (1H, d, J = 16.5 Hz), 5,80 (1H, d, J = 6 Hz), to 5.85 (1H, d, J = 6 Hz), 6,86 (2H, d, J = 8 Hz), was 7.08 (2H, d, J = 8 Hz), 7,40-to 7.61 (3H, m), 7,92 (1H, d, J = 7.5 Hz).

Example 74.

4-(1-Hydroxy-2,2-dimethylpropyl)-2-propyl-1-{4-[2-(tetrazol - 5-yl)phenyl] phenyl}Mei-5-carboxamide (compound N 5-37).

74(IDA potassium was added, cooling in this ice, to a solution of 2.00 g of 2-propyl-4-Pihlajamaa-5-carbonitrile [obtained in accordance with the description given in obtaining 41] in 20 ml of N,N-dimethylacetamide, and the mixture was stirred 10 minutes at the same temperature. Then to the solution was added 6,10 g of 4-[2-(triliteral-5-yl)phenyl]benzylbromide, and the resulting mixture is stirred 4 hours at 50oC. thereafter, to the mixture was added ethyl acetate and water, and an ethyl acetate layer was separated, dried with anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. Syrupy residue was purified by column chromatography on silica gel, elwira mixtures of ethyl acetate and hexane (1:3 and 1:2, by volume), resulting in a received target compound in the form of crystals with so pl. 107-110oC.

NMR (CDCl3) ppm: to 0.92 (3H, t, J = 7.5 Hz), of 1.42 (9H, s), 1,72 (2H, Sextus. , J = 7.5 Hz), 2,50 (2H, t, J = 7.5 Hz), 5,09 (2H, s), 6,92 (2H, d, J = 8 Hz), 7,13-7,53 (20H, m), 7,95 (1H, d, J = 7 Hz).

74(b). 4-(1-hydroxy-2,2-dimethylpropyl)-2-propyl-1-{4-[2- (triliteral-5-yl)phenyl]phenyl}Mei-5-carbonitrile.

A solution of 108 mg of sodium borohydride in 20 ml of ethanol was added to a solution of 2.00 g of 2-propyl-4-pivaloyl-1-{4-[2-(triliteral-5 - yl)phenyl]phenyl}Mei-5-carbonitrile [temperature. Then the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was dissolved in a mixture of ethyl acetate and water. An ethyl acetate layer was separated, washed with water, dried with anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. Syrupy residue was led in a mixture of ethyl acetate and hexane (1:4 by volume), and received of 1.93 g of target compound in the form of crystals with so pl. 115-117oC.

NMR (CDCl3) ppm: of 0.87 (3H, t, J = 7.5 Hz), 0,99 (9H, s) of 1.64 (2H, Sextus. , J = 7.5 Hz), 2.49 USD (2H, t, J = 7.5 Hz), was 2.76 (1H, d, J = 7.5 Hz), 4,46 (1H, d, J = 7.5 Hz), 5,04 (2H, s), 6,85-7,53 (22H, m), 7,95 (1H, d, J = 7.5 Hz).

74(c). 4-(1-Hydroxy-2,2-dimethylpropyl)-2-propyl-1-{4-[2- (tetrazol-5-yl)phenyl]phenyl}Mei-5-carbonitrile.

A suspension of 1.65 g of 4-(1-hydroxy-2,2-dimethylpropyl)-2-propyl- 1-{4-[2-(triliteral-5-yl)phenyl]phenyl}Mei-5-carbonitrile [obtained as described in stage (b), supra] in 24 ml of 75%.about. aqueous acetic acid is stirred 2 hours at 60oC. thereafter, 6 ml of water was added to the reaction mixture and cooled with ice. Besieged trailovic alcohol was removed by filtration, and the filtrate was concentrated by evaporation under reduced pressure, resulting in polochon, C), and 1.63 (2H, sex. , J = 7.5 Hz), 2,58 (2H, s, J = 7.5 Hz), 4,36 (1H, s), of 5.15 (2H, s) to 7.00 (2H, d, J = 8 Hz), 7,07 (2H, d, J = 8 Hz), 7,30-to 7.61 (3H, m), 7,80 (1H, d, J = 7.5 Hz).

74(d). 4-(1-Hydroxy-2,2-dimethylpropyl)-2-propyl-1-{4-[2- (tetrazol-5-yl)phenyl]phenyl}Mei-5-carboxamide.

The mixture is 0.70 g of 4-(1-hydroxy-2,2-dimethylpropyl)-2-propyl-1-{ 4-[2- (tetrazol-5-yl)phenyl]phenyl}Mei-5-carbonitrile /obtained as described in stage (c), see above/ in 14 ml of 1N. aqueous sodium hydroxide and 7 ml of ethanol was heated under reflux for 2 hours then the ethanol was removed from the reaction mixture by evaporation under reduced pressure and to the residue was added ethyl acetate and 14 ml of 1N. aqueous hydrochloric acid. An ethyl acetate layer was separated, dried with anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure, which was obtained 0.45 g of target compound in powder form with so pl. 174-175oC.

NMR (DMSO-d6) ppm: or 0.83 (3H, t, J = 7.5 Hz), to 0.88 (9H, s), 1,44-to 1.63 (2H, m), 2,46 (2H, t, J = 7.5 Hz), of 4.45 (1H, s), of 5.39 (1H, d, J = 16 Hz), 5,77 (1H, d, J = 16 Hz), of 6.20 (1H, d, J = 4.5 Hz), 6,91 (2H, d, J = 8.5 Hz), ? 7.04 baby mortality (2H, d, J = 8.5 Hz), 7,47-7,63 (4H, m).

Example 75.

2-Butyl-4-(1-hydroxy-2,2-dimethylpropyl)-1-{ 4-[2- (tetrazol-5-yl)phenyl] phenyl}Mei-5-carboxamide (compound N 5-99).

oC.

NMR (CDCl3) ppm: to 0.88 (3H, t, J = 7.5 Hz), 1,32 (2H, Sextus., J = 7.5 Hz), of 1.41 (9H, s) of 1.66 (2H, Queen., J = 7.5 Hz), 2,53 (2H, t, J = 7.5 Hz), 5,09 (2H, s), 6,91-7,50 (22H, m), of 7.96 (1H, d, J = 7.5 Hz).

75(b). 2-Butyl-4-(1-hydroxy-2,2-dimethylpropyl)-1-{4-[2- (triliteral-5-yl)phenyl]phenyl}Mei-5-carbonitrile.

Repeating the procedure described in example 74(b), but using a 4.03 g of 2-butyl-4-pivaloyl-1-{4-[2-(triliteral-5 - yl)phenyl]phenyl}Mei-5-carbonitrile [obtained as described in stage (a), see above] and 0.22 g of sodium borohydride, which was received with 3.79 g of target compound in the form of crystals with so pl. 134-135oC.

NMR (CDCl3) ppm: of 0.85 (3H, t, J = 7.5 Hz), 0,99 (9H, s), 1.27mm (2H, Sextus. , J = 7.5 Hz), 2,52-to 1.67 (2H, m), of 2.51 (2H, t, J = 7.5 Hz), is 2.74 (1H, d, J = 7.5 Hz), of 4.45 (1H, d, J = 7.5 Hz), of 8.04 (2H, s), 6,85-7,53 (22H, m), 7,95 (1H, d, J = 7.5 Hz).

75(c). 2-Butyl-4-(1-hydroxy-2,2-dimethylpropyl)-1-{ 4-[2- (tetrazol-5-yl)phenyl]phenyl}Mei-5-carbonitrile.

P[2-(triliteral-5-yl)phenyl]phenyl}Mei-5-carbonitrile [obtained as described in stage (b) see above] 75% vol./about. aqueous acetic acid, which was obtained 0.65 g of target compound in the form of a glassy substance.

NMR (CDCl3) ppm: of 0.91 (3H, t, J = 7.5 Hz), is 0.96 (9H, s), 1,28-of 1.42 (2H, m), 1,58-of 1.74 (2H, m), 2,69 (2H, t, J = 7.5 Hz), and 4.40 (1H, s), a total of 5.21 (2H, s), 7,10-to 7.32 (4H, m), 7,43-the 7.65 (3H, m), of 8.06 (1H, d, J = 8 Hz).

75(d). 2-Butyl-4-(1-hydroxy-2,2-dimethylpropyl)-1-{4-[2- (tetrazol-5-yl)phenyl]phenyl}Mei-5-carboxamide.

Repeating the procedure described in example 74(d), but using 0.34 g of 2-butyl-4-(1-hydroxy-2,2-dimethylpropyl)-1-{ 4- [2-(tetrazol-5-yl)phenyl] phenyl} Mei-5-carbonitrile [obtained as described in stage (c), see above] in 1H. aqueous sodium hydroxide solution, resulting in received of 0.30 g of target compound in powder form with so pl. 157-160oC.

NMR (DMSO-d6) ppm: of 0.79 (3H, t, J = 7.5 Hz), to 0.88 (9H, s), 1,16-of 1.30 (2H, m), 1,39-and 1.54 (2H, m) at 2.59 (2H, t, J = 7.5 Hz), 4,51 (1H, s), 5,46 (1H, d, J = 16 Hz), 5,73 (1H, d, J = 16 Hz), 6,21 (1H, d, J = 4.5 Hz), 6,97 (2H, d, J = 8.5 Hz), 7,06 (2H, d, J = 8.5 Hz), 7,51-of 7.70 (4H, m).

Example 76.

4-(1-Hydroxy-2-methylpropyl)-2-propyl-1-{ 4-[2-(tetrazol - 5-yl)phenyl] phenyl}Mei-5-carboxamide (compound N 5-36).

76(a). 4-Isobutyryl-2-propyl-1-{4-[2-(triliteral - 5-yl)phenyl]phenyl} Mei-5-carbonitrile.

Posterolateral according to the description in obtaining 39], 2,90 g of 4-[2-(triliteral-5-yl)phenyl]benzylbromide and 0.56 g t butoxide potassium, resulting in received 1,90 g of target compound in the form of crystals with so pl. 133-134oC.

NMR (CDCl3) ppm: of 0.91 (3H, t, J = 7.5 Hz), to 1.22 (6H, d, J = 6.5 Hz), 1.69 in (2H, sextet, J = 7.5 Hz), of 2.54 (2H, t, J = 7.5 Hz), to 3.64 (1H, Queen., J = 6.5 Hz), 5,12 (2H, s), 6,7-8,0 (23H, m).

76(b). 4-(1-Hydroxy-2-methylpropyl)-2-propyl-1-{4-[2- (triliteral-5-yl)phenyl]phenyl}Mei-5-carbonitrile.

Repeating the procedure described in example 74b, but with the use of 1.60 g of 4-isobutyryl-2-propyl-1-{ 4-[2-(triliteral - 5-yl)phenyl]phenyl}Mei-5-carbonitrile [obtained as described in stage (a)] and 0.13 sodium borohydride resulting in received 1.50 g of target compound in the form of crystals with so pl. 154-155oC.

NMR (CDCl3) ppm: of 0.87 (3H, t, J = 7.5 Hz), were 0.94 (3H, d, J = 6.5 Hz), and 1.00 (3H, d, J = 6.5 Hz), of 1.66 (2H, Sextus., J = 7.5 Hz), 2,12 (1H, Sextus., J = 6.5 Hz), 2,50 (2H, t, J = 7.5 Hz), of 4.54 (1H, d, J = 6 Hz), 5,04 (2H, s), 6,85-to 6.95 (6H, m), 7,14 (2H, d, J = 8.5 Hz), 7.23 percent-7,53 (14H, m), 7,94 (1H, d, J = 7.5 Hz).

76(c). 4-(1-Hydroxy-2-methylpropyl)-2-propyl-1-{ 4-[2- (tetrazol-5-yl)phenyl]phenyl}Mei-5-carbonitrile.

Repeating the procedure described in example 74(c), but with the use of 1.36 g of 4-(1-hydroxy-2-methylpropyl)-2-propyl-1-{4-[2- (titillate the acid, the result that was obtained 0.87 g of target compound in the form of a glassy substance.

NMR (CDCl3) ppm: of 0.77 (3H, d, J = 6.5 Hz), 0,81 (3H, d, J = 7.5 Hz), of 0.93 (3H, d, J = 6.5 Hz), and 1.54 (2H, sextet, J = 7.5 Hz), 1,92-2,07 (1H, m) to 2.55 (2H, t, J = 7.5 Hz), 4,33 (1H, d, J = 7.5 Hz), 5,12 (2H, s), of 6.96-6,99 (4H, m), 7,35-of 7.69 (3H, m), 7,71 (1H, d, J = 7.5 Hz).

76(d). 4-(1-Hydroxy-2-methylpropyl)-2-propyl-1-{ 4-[2- (tetrazol-5-yl)phenyl]phenyl}Mei-5-carboxamide.

Repeating the procedure described in example 74(d), but with the use of 0.90 g of 4-(1-hydroxy-2-methylpropyl)-2-propyl-1-{4-[2- (tetrazol-5-yl)phenyl]phenyl} Mei-5-carbonitrile [obtained in stage (c)] in 1H. aqueous sodium hydroxide solution, which was obtained 0.64 g of target compound in powder form with so pl. 153-157oC.

NMR (DMSO-d6) ppm: is 0.69 (3H, d, J = 6.5 Hz), 0,81 (3H, t, J = 6.5 Hz), 0,99 (3H, t, J = 6.5 Hz), 1,49 (2H, Sextus. J = 7.5 Hz), was 2.05 (1H Queen., J = 6,5), 2,68 (2H, t, J = 7.5 Hz), of 4.45 (1H, d, J = 7.5 Hz), of 5.55 (1H, d, J = 16.5 Hz), 5,70 (1H, d, J = 16.5 Hz), 7,02 (2H, d, J = 8.5 Hz), was 7.08 (2H, d, J = 8.5 Hz), 7,51-7,71 (4H, s).

Example 77.

2-Butyl-4-(1-hydroxy-2-methylpropyl)-1-{ 4-[2-(tetrazol-5 - yl)phenyl]phenyl}Mei-5-carboxamide (compound N 5-98).

77(a). 2-Butyl-4-isobutyryl-1-{ 4-[2-(triliteral-5-yl)phenyl] phenyl} Mei-5-carbonitrile.

Outpouching as described in the getting 27], of 4.49 g of 4-[2-(triliteral-5-yl)phenyl]benzylbromide and 0,76 g t butoxide potassium, resulting in received totaling 3.04 g of target compound in the form of crystals with so pl. 115-116oC.

NMR (CDCl3) ppm: of 0.87 (3H, t, J = 7.5 Hz), to 1.22 (6H, d, J = 6.5 Hz), 1,31 (2H, sextet, J = 7.5 Hz), and 1.63 (2H, Queen., J = 7.5 Hz), to 2.57 (2H, t, J = 7.5 Hz), to 3.64 (1H, Sept., J = 7.5 Hz), 5,11 (2H, s), 6.90 to-7,52 (22H, m), of 7.96 (1H, d, J = 9 Hz).

77(b). 2-Butyl-4-(1-hydroxy-2-methylpropyl)-1-{4-[2- trailersa-5-yl)phenyl]phenyl}Mei-5-carbonitrile.

Repeating the procedure described in example 74(b), but using 2.00 g of 2-butyl-4-isobutyryl-1-{ 4-[2-(triliteral-5-yl)phenyl]phenyl} Mei-5-carbonitrile [obtained in stage (a), see above] and 0.22 g of sodium borohydride resulting in received 1.68 g of target compound in the form of crystals with so pl. 127-128oC.

NMR (CDCl3) ppm: of 0.85 (3H, t, J = 7.5 Hz), of 0.93 (3H, d, J = 6.5 Hz), and 1.00 (3H, d, J = 6.5 Hz), 1.26 in (2H, sextet. J = 7.5 Hz), 1,59 (2H, Queen., J = 7.5 Hz), 2,13 (1H, Sextus., J = 6.5 Hz), 2,52 (2H, t, J = 7.5 Hz), a 4.53 (1H, d, J = 6 Hz), 5,04 (2H, s), 6,85-7,52 (22H, m), 7,95 (1H, d, J = 9 Hz).

77(c). 2-Butyl-4-(1-Hydroxy-2-methylpropyl)-1-{ 4-[2-(tetrazol - 5-yl)phenyl]phenyl}Mei-5-carbonitrile.

Repeating the procedure described in example 74(c), but using 1.29 g of 2-butyl-4-(1-hydroxy-2-methylpropyl)-1-the. aqueous acetic acid, resulting in a received 0,83 g of target compound in the form of a glassy substance.

NMR (CDCl3) ppm: 0,81 (3H, d, J = 6.5 Hz), or 0.83 (3H, t, J = 7.5 Hz), of 0.95 (3H, d, J = 6.5 Hz), 1.26 in (2H, sextet. J = 7.5 Hz), and 1.54 (2H, Queen., J = 7.5 Hz), 1,97-of 2.09 (1H, m) at 2.59 (2H, t, J = 7.5 Hz), 4,37 (1H, d, J = 6.5 Hz), 5,14 (2H, s), 6,98 (2H, d, J = 8.5 Hz), 7,05 (2H, d, J = 8.5 Hz), 7,32-of 7.60 (3H, m), to 7.77 (1H, d, J = 7.5 Hz).

77(d). 2-Butyl-4-(1-hydroxy-2-methylpropyl)-1-{ 4-[2-(tetrazol - 5-yl)phenyl]phenyl}Mei-5-carboxamide.

Repeating the procedure described in example 74(d), but using 0.34 g of 2-butyl-4-(1-hydroxy-2-methylpropyl)-1 [obtained in stage (c), see above] in 1H. aqueous sodium hydroxide solution, which was obtained 0.24 g of target compound in powder form with so pl. 155-157oC.

NMR (DMSO-d6) ppm: is 0.69 (3H, d, J = 6.5 Hz), of 0.79 (3H, t, J = 7.5 Hz), of 0.93 (3H, d, J = 6.5 Hz), 1,22 (2H, sex., J = 7.5 Hz), to 1.45 (2H, Queen., J = 7.5 Hz), 2,0-2,12 (1H, m) to 2.65 (2H, t, J = 7.5 Hz), to 4.41 (1H, d, J = 8 Hz), of 5.53 (1H, d, J = 16 Hz), 5,71 (1H, d, J = 16 Hz), 7,00 (2H, d, J = 8.5 Hz), 7,07 (2H, d, J = 8.5 Hz), 7,50-7,71 (4H, m).

Example 78.

(5-Methyl-2-oxo-1,3-dioxolan-4-yl)methyl-4-(1-hydroxy-1 - methylethyl)-2-propyl-1-{ 4-[2-(tetrazol-5-yl)phenyl] phenyl} Mei - 5-carboxylate (compound N 2-17).

78(a). (5-Methyl-2-oxo-1,3-dioxolan-4-yl)methyl-4-(1-hydroc is the hydroxide of lithium in 158 ml of water was added, cooling in this ice, to a solution of 30 g of ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{ 4-[2-(triliteral - 5-yl)phenyl]phenyl}Mei-5-carboxylate [obtained according to the description in example 18(a)] 344 ml of dioxane, and the mixture was stirred for 20 hours at 5-10oC. after this time the mixture was added a small piece of dry ice, after which the mixture was concentrated by evaporation under reduced pressure to a final volume of about 100 ml. and Then to the concentrate was added ethyl acetate and sodium chloride, the resulting mixture was stirred. An ethyl acetate layer was separated and dried with anhydrous sodium sulfate and concentrated by evaporation under reduced pressure, resulting in a received 4-(1-hydroxy-1-methylethyl)-2-propyl- 1-{ 4-[2-(triliteral-5-yl)phenyl] phenyl} Mei-5-carboxylat lithium in the form of a glassy material. Then the only solution of the obtained lithium carboxylate in 160 ml of N,N-dimethylacetamide was added, the cooling while the ice between 6.08 g of potassium carbonate, and then to the mixture drop by drop) was added, the cooling in this ice, a solution of 11.2 g of 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene (74% purity) in 26 ml of N,N-dimethylacetamide. The resulting mixture was stirred 3 h at 50oC. after this time to react and concentrated by evaporation under reduced pressure. The residue was led in diisopropyl ether, resulting in received of 29.3 g of target compound with so pl. 98-100oC (with decomp.).

The NMR spectrum of this compound is identical to the spectrum of the compound obtained in example 61(a).

78(b). (5-Methyl-2-oxo-1,3-dioxolan-4-yl)methyl-4-(1-hydroxy - 1-methylethyl)-2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}Mei - 5-carboxylate.

75 ml of water was added to a suspension of 29.3 g (5-methyl-2-oxo-1,3 - dioxolan-4-yl)methyl-4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2- (triliteral-5-yl)phenyl] phenyl} Mei-5-carboxylate (obtained in stage (a)) in 225 ml of acetic acid, and the mixture was stirred 1.5 h at 60oC. after this time the mixture was added 75 ml of water, and the mixture was cooled. Besieged trailovic alcohol was removed by filtration, and the filtrate was concentrated by evaporation under reduced pressure. To the residue was added toluene, and the mixture was again concentrated by evaporation under reduced pressure to remove residual water and acetic acid. The residue was led in ethyl acetate, resulting in a received 16.6 g of target compound in the form of crystals with so pl. 177-180oC (Razlog.).

The NMR spectrum of this joint is oxolan-4-yl)methyl-4-(1-hydroxy-1-methylethyl)- 2-propyl-1-{ 4-[2-(tetrazol-5-yl)phenyl] phenyl} Mei-5-carboxylate (compound N 2-17).

79(a). Ethyl-4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2- (triliteral-5-yl)phenyl]phenyl}Mei-5-carboxylate.

A solution of 1.00 g of ethyl 1-(2'-cyanobiphenyl-4-yl)methyl-4-(1-hydroxy - 1-methylethyl)-2-propylimidazol-5-carboxylate [obtained as described in example 71(b)] and 1.00 g of azide anti 7.5 g of toluene stirred 5 days at 100oC. Then, to the mixture was added 2.5 g of sodium bicarbonate and 20 ml of water, and the mixture was stirred for 8 hours at room temperature. After this time the mixture was diluted with ethyl acetate and acidified to pH 3 by addition of 3h. aqueous hydrochloric acid. An ethyl acetate layer was separated, dried with anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure, resulting in a received ethyl-4-(1-hydroxy-1-methylethyl)-2-propyl-1-{ 4-[2-(tetrazol - 5-yl)phenyl]phenyl}Mei-5-carboxylate in the form of syrup. To a solution of the syrup in 15 ml of pyridine was added to 0.80 g Fritillaria, and the mixture is stirred 4 h at 60oC. then the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography on silica gel, elwira a mixture of ethyl acetate and hexane (1 : 1 by volume), and then crystallized">

The NMR spectrum of this compound is identical to the spectrum of the compound obtained in example 18(a).

79(b). (5-Methyl-2-oxo-1,3-dioxolan-4-yl)methyl-4-(1-hydroxy - 1-methylethyl)-2-propyl-1-{ 4-[2-(tetrazol-5-yl)phenyl] phenyl} Mei - 5-carboxylate.

Repeating the procedure described in example 78(a) 78(b), but using ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-{4-[2- (triliteral-5-yl)phenyl] phenyl} Mei-5-carboxylate, obtained in stage (a), (see above), resulting in a received target connection with 71% yield.

The NMR spectrum of this compound is identical to the spectrum of the compound obtained as described in example 61(b).

Example 80.

Pivaloyloxymethyl 2-ethyl-4-(1-hydroxy-1-methylethyl)-1-{4-[2- (tetrazol-5-yl)phenyl]phenyl}Mei-5-carboxylate (compound N 2-69).

80(a). Pivaloyloxymethyl 2-ethyl-4-(1-hydroxy-1-methylethyl)- 1-{4-[2-(triliteral-5-yl)phenyl]phenyl}Mei-5-carboxylate.

Repeating the procedure described in example 78(a), but using 2.25 g of ethyl-2-ethyl-4-(1-hydroxy-1-methylethyl)- 1-{ 4-[2-(triliteral-5-yl)phenyl]phenyl}Mei-5-carboxylate [obtained as described in example 60(a)], and 203 mg of the monohydrate of lithium hydroxide for hydro is the form of glass-like product, purified by column chromatography on silica gel using as eluent a mixture of ethyl acetate and hexane (1:1 by volume).

NMR (CDCl3) ppm: 1.14 in (9H, s) to 1.19 (3H, t, J = 7.5 Hz), of 1.64 (6H, s) of 2.50 (2H, square, J = 7.5 Hz), of 5.34 (2H, s), 5,43 (1H, s) 5,72 (2H, s), 6.73 x (2H, d, J = 8 Hz), 6,92-7,49 (20H, m), of 7.90 (1H, d, J = 8,5 Hz).

80(b). Pivaloyloxymethyl 2-ethyl-4-(1-hydroxy-1-methylethyl)- 1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}Mei-5-carboxylate.

Repeating the procedure described in example 78(b), but using 2,53 g pivaloyloxymethyl 2-ethyl-4-(1-hydroxy-1 - methylethyl)-1-{4-[2-(triliteral-5-yl)phenyl] phenyl}Mei - 5-carboxylate [obtained in stage (a), see above] and 28 ml of 75%.about. aqueous acetic acid, resulting in a received 1.70 g of the target compound as a glassy product.

NMR (CDCl3) ppm: 1,09 (9H, s) of 1.24 (3H, t, J = 7.5 Hz), to 1.59 (6H, s) of 2.64 (2H, square, J = 7.5 Hz), 5,41 (2H, s), 5,79 (2H, s) 6,86 (2H, d, J = 8.6 Hz), 7,11 (2H, d, J = 8.5 Hz), 7,42 to 7.62 (4H, m).

Example 81.

(5-Methyl-2-oxo-1,3-dioxolan-4-yl)methyl-2-ethyl-4-(1-hydroxy - 1-methylethyl)-1-{ 4-[2-(tetrazol-5-yl)phenyl] phenyl} Mei - 5-carboxylate (compound N 2-73).

81(a). (5-Methyl-2-oxo-1,3-dioxolan-4-yl)methyl-2-ethyl-4- (1-hydroxy-1-methylethyl)-1-{ 4-[2-(triliteral-5-yl)phenyl] FEM of 2.25 g of ethyl 2-ethyl-4-(1-hydroxy-1-methylethyl)- 1-{ 4-[2-(triliteral-5-yl)phenyl]phenyl}Mei-5-carboxylate [obtained as described in example 68(a)], and 203 mg of the monohydrate of lithium hydroxide to hydrolyze and 0.95 g of 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene (74% purity) for esterification, resulting in received of 1.23 g of target compound in the form of crystals with so pl. 145oC.

NMR (CDCl3) ppm: to 1.21 (3H, t, J = 7.5 Hz), and 1.63 (6H, s) to 1.98 (3H, s) to 2.55 (2H, square, J = 7.5 Hz), to 4.73 (2H, s), and 5.30 (2H, s) 5,59 (1H, s), 6,69 (2H, d, J = 8 Hz), 6.90 to be-7,53 (20H, m), 7,87 (1H, d, J = 8 Hz).

81(b). (5-Methyl-2-oxo-1,3-dioxolan-4-yl)methyl-2-ethyl-4-(1 - hydroxy-1-methylethyl)-1-{ 4-[2-(tetrazol-5-yl)phenyl] phenyl}Mei - 5-carboxylate.

Repeating the procedure described in example 78(b), but using 1,90 g (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl - 2-ethyl-4-(1-hydroxy-1-methylethyl)-1-{4-[2-(triliteral-5 - yl)phenyl]phenyl}Mei-5-carboxylate, obtained as described in stage (a) above and 20 ml of 75%.about. aqueous acetic acid, resulting in received of 1.23 g of target compound in the form of crystalline powder.

NMR (CDCl3and DMSO-d6) ppm: 1,24 (3H, t, J = 7.5 Hz), and 1.54 (6H, s) of 2.10 (3H, s), 2,69 (2H, Queen., J = 7.5 Hz), 4,99 (2H, s), 5,44 (2H, s) 6,86 (2H, d, J = 8.5 Hz), was 7.08 (2H, d, J = 8.5 Hz), 7.50 for-the 7.65 (4H, m).

Obtaining 1. 2-Butylimidazole-4,5-dicarbonitrile.

Suspension 51,4 g diaminomaleonitrile and 85.6 g of triethylorthoformate 300 ml ACET who has demonstrated by evaporation under reduced pressure, and the concentrate was purified by column chromatography on silica gel, elwira a mixture of ethyl acetate and hexane (1:1 by volume), resulting in a received 99 g of 1-amino-2-N-(1-methoxybenzylidene) aminobenzonitrile. This compound was completely dissolved in 300 ml of xylene, and the resulting solution was stirred in an oil bath maintained during 150oC for 8 h, after which the reaction mixture was concentrated to obtain half the original volume and left at room temperature. Precipitated crystals were collected by filtration and washed with a small amount of xylene, which was given to 55.2 g of target compound with so pl. 109-111oC.

Getting 2. 2-Butylimidazole-4,5-dicarboxylic acid.

A solution of 100 g of 2-butylimidazole-4,5-dicarbonitrile (obtained as described in obtaining 1) in 1 l of 6N. aqueous hydrochloric acid was heated for 7 hours under reflux, after which the reaction mixture was left overnight at room temperature. Then the precipitated crystals were collected by filtration and washed with water and a small amount of acetone, resulting in a received 84 g of target compound with so pl. 261-263oC.

Getting 3. Diethyl-2-butylimidazole-4,5, in primary forms.

according to the description in obtaining 2) in 600 ml of ethanol at room temperature, stirring at the same time, within 2 h, and received the solution. This solution was left for 18 h at room temperature, after which the reaction mixture was concentrated by evaporation under reduced pressure. The concentrate was mixed with ethyl acetate and aqueous sodium bicarbonate solution and neutralized by adding sodium bicarbonate in powder form. An ethyl acetate layer was separated and dried with anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting crystalline residue is triturated with a mixture of diisopropyl ether and hexane and collected by filtration, resulting in a received 43 g of target compound with so pl. 82-84oC.

Getting 4. Dimethyl 2-butylimidazole-4,5, in primary forms.

Repeated the procedure 3, using 40 g of 2-butylimidazole-4,5-dicarboxylic acid, and instead of ethanol used methanol, resulting in received of 41.6 g of target compound in the form of crystals with so pl. 88oC.

Getting 5. 4-Acetyl-2-butyl-5-cyanomelana.

5(i). 2-Butyl-1-tritylimidazole-4,5-dicarbonitrile.

of 1.25 g of sodium hydride (as a 55% wt./wt. dispersion in mineral oil) was added, the cooling in this LML N,N-dimethylformamide, and the resulting mixture was stirred 15 minutes and Then was added 10 g of Fritillaria, and the reaction mixture was stirred 6 h at 50oC. After this mixture was mixed with ethyl acetate. The extract was dried with anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The obtained residue was purified by column chromatography on silica gel, elwira a mixture of ethyl acetate and hexane (1:5 by volume), resulting in a received 9,83 g of target compound in the form of a syrup, which was left for curing. The solid product was so pl. 144-147oC (Razlog. and Abrasiv. when 94-98oC).

NMR (CDCl3) ppm: 0,60 (3H, t, J = 7 Hz), 0,5-1,4 (4H, m), 2,03 (2H, t, J = 7 Hz), of 7.0 and 7.6 (15H, m).

5(ii). 4-Acetyl-2-butyl-5-cyano-1-tritylimidazole.

11,1 ml of 2 M solution of iodide Metalmania in diethyl ether slowly drop by drop) was added at room temperature and under nitrogen atmosphere to a solution of 4.5 g of 2-butyl-1-tritylimidazole-4,5-dicarbonitrile (obtained in stage i, see above) in 45 ml of tetrahydrofuran, and the mixture was stirred 3 h at room temperature. After this time the mixture while cooling with ice, drop by drop) was added a saturated aqueous solution of ammonium chloride. Tertrahydrofuran ring layer was separated, was promelektroservis a small amount of ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried and concentrated by evaporation under reduced pressure. The obtained extract was combined with the concentrate obtained above, and the product was purified by column chromatography on silica gel, elwira with a mixture of hexane and ethyl acetate (3:1 by volume). The product was led from a mixture of ethyl acetate and hexane, resulting in received of 1.46 g of target compound with so pl. 159-160oC (Razlog.).

NMR (CDCl3) ppm: 0,60 (3H, t, J = 7 Hz), 0.5 to 1.5 (4H, m), of 2.08 (2H, t, J = 7 Hz), 2,58 (3H, s), a 7.1 to 7.6 (15H, m).

5(iii). 4-Acetyl-2-butyl-5-cyanomelana.

A suspension of 1.78 g of 4-acetyl-2-butyl-5-cyano-1-tritylimidazole [obtained as described in stage (ii)] in 80% vol./about. aqueous acetic acid is stirred for 1 hour at 60oC. the thus Obtained solution was concentrated to dryness by evaporation under reduced pressure. The obtained residue was purified by column chromatography on silica gel, elwira with a mixture of hexane and ethyl acetate (3:1 by volume), resulting in a received 0.66 g of the target compound as colorless solids with so pl. 77-78oC.

NMR (CDCl3) ppm: of 0.93 (3H, t, J = 7 Hz), 1,0-2,1 (4H, m), of 2.72 (3H, s), is-1-tritylimidazole.

In accordance with the procedure described in obtaining 5 (ii), obtained 10.3 g of target compound in the form of amorphous solids by reaction of a solution of 10 g of 2-butyl-1-tritylimidazole - 4,5-dinitrile [obtained as described in the getting 5(i)] in 100 ml of tetrahydrofuran, 25 ml of 2 M solution of iodide vinylmania in diethyl ether.

NMR (CDCl3) ppm: to 0.67 (3H, t, J = 7 Hz), 0.5 to 1.5 (4H, m), 2,11 (2H, t, J = 7 Hz), 7,1-8,0 (20H, m).

6(ii). 4-Benzoyl-2-butyl-5-cyanomelana.

A suspension of 10.3 g of 4-benzoyl-2-butyl-5-cyano-1-tritylimidazole (obtained in stage (i) above) in 80% vol./about. aqueous acetic acid is stirred for 5 hours at 60oC. after this time the resulting solution was concentrated by evaporation under reduced pressure, and the concentrate was purified by column chromatography on silica gel, elwira with a mixture of hexane and ethyl acetate (2:1 by volume). The obtained oily product was dissolved in carbon tetrachloride, and the solution was left at room temperature to precipitate crystals, which were collected by filtration, resulting in a received 4,46 g of target compound, so pl. 121-122oC.

NMR (CDCl3) ppm: of 0.90 (3H, t, J = 7 Hz), 1,0-2,3 (4H, m), 2,85 (2H, t, J = 7 Hz), 7,2-8,0 (5H, m), 11,0 compared to 12.1 (1H,4-(1-hydroxy-1-methylethyl)-1-tritylimidazole.

1 ml of 2 M solution of iodide Metalmania in tetrahydrofuran, stirring at room temperature, one drop was added to a solution of 840 g of 4-acetyl-2-butyl-5-cyano-1-tritylimidazole [obtained in accordance with the description in obtaining 5(ii)] in 15 ml of tetrahydrofuran, and the mixture was stirred 1 h at 40oC. the resulting mixture was cooled, and then to this mixture, one drop was added a saturated aqueous solution of ammonium chloride. The layer of tetrahydrofuran was separated and concentrated by evaporation under reduced pressure. The concentrate was purified by column chromatography on silica gel elwira with a mixture of hexane and ethyl acetate (2:1 by volume), resulting in a received 539 mg of the target compound as colorless solids with so pl. 151-152oC.

NMR (CDCl3) ppm: 0,60 (3H, t, J = 7 Hz), 0.6 to 1.5 (4H, m) to 1.59 (6H, s), a 2.01 (2H, t, J = 7 Hz), of 3.78 (1H, s), of 7.0 and 7.6 (15H, m).

7(ii). 2-Butyl-5-cyano-4-(1-hydroxy-1-methylethyl)imidazole.

A mixture of 1.3 g of 2-butyl-5-cyano-4-(1-hydroxy-1-methylethyl)- 1-tritylimidazole [obtained in stage (i)] and 26 ml of 75 rpm./about. aqueous acetic acid is stirred 3 h at 50oC, after which the solvent was removed by distillation under reduced pressure. The obtained residue was washed with carbon tetrachloride and cleaned the, the donkey which the product has led to the tetrachloride, and was obtained 0.6 g of target compound in the form of colorless crystals with so pl. 171-172oC.

NMR (CDCl3+ CD3OD), ppm: of 0.90 (3H, t, J = 7 Hz), 1.0 to 2.0 (4H, m) of 1.62 (6H, s), 2,68 (2H, t, J = 7 Hz).

Getting 8. Ethyl 2-butyl-4-(1-hydroxy-1-methylethyl)imidazole-5 - carboxylate.

The solution are 5.36 g of diethyl 2-butylimidazole-4,5-in primary forms (obtained as described in 3) in 100 ml of tetrahydrofuran was cooled to -30oC in nitrogen atmosphere, and to this cooled solution at-30 - (-20oC) one drop was added 32 ml of a solution of bromide Metalmania (2.5 M in tetrahydrofuran). Then the reaction mixture was stirred at 0oC for 1.5 h, and then was mixed with ethyl acetate and an aqueous solution of ammonium chloride. An ethyl acetate layer was separated and dried with anhydrous magnesium sulfate, and the solvent is kept at reduced pressure. The residue was purified by column chromatography on silica gel, elwira mixture of methanol and methylene chloride (1:20 by volume), resulting in a received 5,01 g of target compound in the form of an oily product.

NMR (CDCl3) ppm: of 0.90 (3H, t, J = 7 Hz), 1,32 (3H, t, J = 7 Hz), 1,2-2,0 (4H, m) of 1.64 (6H, s), 2,70 (2H, t, J = 7 Hz), 4,33 (2H, square, J = 7 G is at.

In accordance with the procedure described in the getting 8 received of 2.34 g of target compound in the form of an oily product by reaction 3,01 g of diethyl 2-propylimidazol-4,5-in primary forms (obtained as described in obtaining 12) with 16 ml of 2.5 M solution of bromide Metalmania in tetrahydrofuran. The compound obtained was led, by leaving it at room temperature, and received the product so pl. 69-71oC. After recrystallization of this product from diisopropyl ether was obtained a product with so pl. 101-102oC.

NMR (CDCl3) ppm as 0.96 (3H, t, J = 7 Hz), of 1.35 (3H, t, J = 7 Hz), of 1.64 (6H, s), is 1.81 (2H, sextet, J = 7 Hz), 2,68 (2H, t, J = 7 Hz), 4,35 (2H, square , J = 7 Hz), of 5.81 (1H, s), 9,9 (1H, Shir. C.).

10. 2-Propylimidazol-4,5-dicarbonitrile.

Repeating the procedure in obtaining 1, but with the use of 16.0 g of diaminomaleonitrile and 24 g of triethylorthoformate, resulting received to 18.7 g of target compound in the form of crystals with so pl. 141-144oC.

Receipt 11. 2-Propylimidazol-4,5-dicarboxylic acid.

Repeating the procedure in getting 2, but with the use of 18.2 g of 2-propylimidazol-4,5-dicarbonitrile (obtained in accordance with the description in obtaining 10), resulting in the floor is idazole-4,5, in primary forms.

Repeating the procedure in getting 3, but using 10.0 g of 2-propylimidazol-4,5-dicarboxylic acid (obtained in accordance with the description in obtaining 11), resulting in received of 9.55 g of target compound in the form of crystals with so pl. 81-83oC.

13. Ethyl-2-butyl-4-(1-ethyl-1-hydroxypropyl)imidazole - 5-carboxylate.

In accordance with the procedure described in the getting 8 received of 2.68 g of target compound with so pl. 63-64oC in the form of crystals by the reaction of 2.68 g of diethyl-2-butylimidazole-4,5-in primary forms (obtained in accordance with the description in obtaining 3) with 3.0 M solution of bromide of etermine in diethyl ether.

NMR (CDCl3) ppm: of 0.82 (6H, t, J = 7 Hz), of 0.93 (3H, t, J = 7 Hz), to 1.38 (3H, t, J = 7 Hz), 1,31-to 1.45 (2H, m) of 1.65 to 1.76 (2H, m), 1,79-1,89 (2H, m), 1,97-2,11 (2H, m), was 2.76 (2H, t, J = 7.5 Hz), 4,36 (2H, square, J = 7 Hz), 5,70 (1H, Shir. C.).

Getting 14. 2-Propyl-1-tritylimidazole-4,5-dicarbonitrile.

Repeating the procedure in obtaining 5(i), but using 7,8 g 2-propylimidazol-4,5-dicarbonitrile (obtained as described in 10), 2.14 g of sodium hydride (as a 55% wt./wt. dispersion in mineral oil) and 17.1 g of Fritillaria, resulting received 14.6 g of target compound in the form of a Cree/SUB>) ppm: 0,52 (3H, t, J = 7 Hz), 1,07-to 1.21 (2H, m), 2,03 (2H, t, J = 8 Hz), 7,19-of 7.48 (15H, m).

Get 15. 2-Butyl-5-cyano-4-propionyl-1 tritylimidazole.

14 ml of 3 M solution of bromide of etermine in diethyl ether at 10oC in nitrogen atmosphere for one drop was added to a solution of 8.33 g of 2-butyl-1-trityl-imidazole-4,5-dicarbonitrile [obtained as described in (a) obtain 5(i)] in 83 ml of tetrahydrofuran, and the mixture was stirred 3 h at room temperature. Then to the reaction mixture, cooling the thus ice, was added a mixture of saturated aqueous solution of ammonium chloride and ethyl acetate. The ethyl acetate layer was separated, washed with water and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. Thus obtained crystalline product washed with diisopropyl ether and received 4,56 g of target compound with so pl. 140-143oC (softening at 83oC).

NMR (CDCl3) ppm: 0,61 (3H, t, J = 7 Hz), 0,84-to 1.14 (4H, m) of 1.18 (3H, t, J = 8 Hz), 2,08 (2H, t, J = 7 Hz), 3,03 (2H, square, J = 7 Hz), 7,22-7,42 (15H, m).

Getting 16. 5-Cyano-4-propionyl 2-propyl-1-tritylimidazole.

Repeating the procedure in obtaining 15, but using 8,05 g of 2-propyl-1-tritylimidazole-4,5-dicarbonitrile (polocies received 7,03 g of target compound in the form of crystals with so pl. 96oC (RASMAG. when 87oC).

NMR (CDCl3) ppm: 0,52 (2H, t, J = 7 Hz), 1,05-1,3 (2H, m) of 1.18 (3H, t, J = 7 Hz), was 2.05 (2H, t, J = 7 Hz), 3,03 (2H, square, J = 7 Hz), 7,20-7,40 (15H, m).

Getting 17. 2-Butyl-5-cyano-4-(1-hydroxy-1-methylpropyl)- 1-tritylimidazole.

5 ml of 1 M solution of bromide Metalmania in tetrahydrofuran at 10oC in nitrogen atmosphere for one drop was added to a solution of 2 g of 2-butyl-5-cyano-4-propionyl-1-tritylimidazole (obtained as described in the getting 15) in 36 ml of tetrahydrofuran, and the mixture was stirred 1 h at 20oC and 1 h at 30oC. after this time the reaction mixture was added a mixture of saturated aqueous solution of ammonium chloride and ethyl acetate, and the resulting mixture was well which. An ethyl acetate layer was separated and dried with anhydrous magnesium sulfate. After the drying agent was removed by filtration, and the solvent is kept at reduced pressure. The residue was purified by column chromatography on silica gel, elwira a mixture of ethyl acetate and hexane 1:2 by volume, and received 1.29 g of target compound in the form of crystals with so pl. 90-93oC.

NMR (CDCl3) ppm: 0,60 (3H, t, J = 7 Hz), to 0.80 (3H, t, J = 7 Hz), 0,80-1,00 (2H, m), 1.00 and is 1.13 (2H, m), 1,58 (3H, s), 1,75-of 2.05 (4H, m), 3,90 (1H, Shir. C.), 7.23 percent-the 7.43 (15H, m).

oC (softening at 110oC).

NMR (CDCl3) ppm: 0,50 (3H, t, J = 7 Hz), to 0.80 (3H, t, J = 7 Hz), 1,07 by 1.12 (2H, m), 1,58 (3H, s), 1,74 is 2.00 (4H, m), 3,90 (1H, Shir. C), 7,24-7,37 (15H, m).

Getting 19. 2-Butyl-5-cyano-4-(1-butoxy-1-methylpropyl " imidazole.

A mixture of 1.21 g of 2-butyl-5-cyano-4-(1-hydroxy-1-methylpropyl)-1 - tritylimidazole [obtained as described in the getting 17] and 20 ml of 75%.about. aqueous acetic acid is stirred for 1 h at 50oC, after which the mixture was cooled, and precipitated crystals tretilova alcohol was removed by filtration. The filtrate was concentrated by evaporation under reduced pressure and the remaining water and acetic acid were released as a toluene azeotrope under reduced pressure. The residue was purified by column chromatography on silica gel, elwira mixture of methylene chloride and methanol (9:1, by volume), and got to 0.47 g of target compound in the form of a crystalline powder with so pl. 139-square, J = 7.5 Hz), of 2.56 (2H, t, J = 7 Hz), of 5.45 (1H, s).

20. 5-Cyano-4-(1-hydroxy-1-methylpropyl)-2-propylimidazol.

Repeating the procedure in obtaining 19, but using 1.20 g of 5-cyano-4-(1-hydroxy-1-methylpropyl)-2-propyl - 1-tritylimidazole (obtained as described in the getting 18), resulting in received of 0.48 g of target compound in the form of a crystalline powder with so pl. 157-159oC.

NMR (CDCl3) ppm: to 0.89 (3H, t, J = 7.5 Hz), and 0.98 (3H, t, J = 7.5 Hz), of 1.57 (3H, s) of 1.76 (2H, square, J = 7.5 Hz), 1,83-of 2.08 (2H, m) 2,00 (1H, s) to 2.67 (2H, t, J = 7.5 Hz).

Getting 21. Methyl 2-butyl-4-(1-hydroxy-1-methylethyl)imidazole - 5-carboxylate.

The solution 9,73 g of dimethyl 2-butylimidazole-4,5-in primary forms (obtained as described in obtaining 4) in 100 ml of tetrahydrofuran was cooled to -30oC in nitrogen atmosphere, and to this solution at a temperature of -30 (-20oC) one drop was added 162 ml of 1 M solution of bromide Metalmania in tetrahydrofuran. The resulting mixture was stirred 2.5 h at 0oC, and then to this mixture was added ethyl acetate and an aqueous solution of ammonium chloride. An ethyl acetate layer was separated and dried with anhydrous magnesium sulfate, and the solvent is kept at reduced pressure. The obtained residue was purified using column is made to 7.15 g of target compound in the form of an oily product. This product has led, keeping it at room temperature, and then received a product with so pl. 60-65oC.

NMR (CDCl3) ppm: to 0.88 (3H, t, J = 7 Hz), 1.0 to 2.0 (4H, m) of 1.64 (6H, s), 2,69 (2H, t, J = 7.5 Hz), of 3.84 (3H, s), 7,35 (2H, Shir. C).

Getting 22. Pivaloyloxymethyl 4-(1-hydroxy-1-methylethyl)-2 - propylimidazol-5-carboxylate.

22(i). 4-(1-Hydroxy-1-methylethyl)-2-propylimidazol-5-carboxylic acid.

A solution of 0.28 g of the monohydrate of lithium hydroxide in 5 ml of water was added to a solution of 0.48 g of ethyl 4-(1-hydroxy-1-methylethyl)-2 - propylimidazol-5-carboxylate (obtained as described in 9) in 5 ml of methanol, and the resulting mixture stirred 18 hours at room temperature. After this time the pH of the reaction mixture is brought to a value of 2.3 by adding to 6.67 ml of 1N. aqueous hydrochloric acid, and the resulting mixture was concentrated by filtration, which was obtained 0.20 g of target compound with so pl. 232oC (decomposition).

NMR (DMSO-d6) ppm: of 0.87 (3H, t, J = 7.5 Hz), to 1.48 (6H, s) of 1.65 (2H, sextet, J = 7.5 Hz), 2,62 (2H, t, J = 7.5 Hz).

22(ii). Pivaloyloxymethyl 4-(1-hydroxy-1-methylethyl)-2 - propylimidazol-5-carboxylate.

1,76 ml of N,N-diisopropylethylamine was added to a suspension of 1.14 g of 4-(1-hydride, and the resulting mixture was stirred at room temperature for 10 minutes, after which the mixture was added to 1.36 ml pivaloyloxymethyl. The reaction mixture is stirred 4 h at 60oC, and then it was mixed with ethyl acetate and water. An ethyl acetate layer was separated and concentrated by evaporation under reduced pressure. Precipitated crystals were washed with diisopropyl ether and collected by filtration, resulting in a received 1,53 g of target compound with so pl. 177oC.

NMR (CDCl3) ppm: 0,99 (3H, t, J = 7.5 Hz), 1,22 (9H, s) of 1.62 (6H, s) of 1.76 (2H, Sextus., J = 7.5 Hz), 2,70 (2H, t, J = 7.5 Hz), 5,15 (1H, Shir. C) 5,95 (2H, s).

23. Ethyl 4-(1-hydroxyethyl)-2-propylimidazol-5-carboxylate.

23(i) 4-Acetyl-2-propylimidazol-5-carbonitrile.

194 ml of 1 M solution of bromide Metalmania in tetrahydrofuran drop was added at a temperature of 10-15oC and under nitrogen atmosphere to a solution of 10 g 2-propylimidazol-4,5-dicarbonitrile (obtained as described in 10) in 100 ml of tetrahydrofuran, and the mixture was stirred 30 min at a temperature of 10-15oC. Then the reaction mixture was cooled and added to 200 ml of ethyl acetate and 100 ml of a saturated aqueous solution of ammonium chloride. This mixture was acidified by EXT and the solvent was removed by distillation under reduced pressure. The residue was subjected to column chromatography on silica gel, elwira a mixture of ethyl acetate and hexane (1:1 by volume), resulting in a received 9,18 g of target compound in the form of crystals with so pl. 93-95oC.

NMR (CDCl3) ppm: 0,99 (3H, t, J = 7.5 Hz) and 1.83 (2H, Sextus., J = 7.5 Hz), 2,71 (3H, s), 2,82 (2H, t, J = 8 Hz).

23(ii). Ethyl 4-acetyl-2-propylimidazol-4-carboxylate.

A mixture of 4.0 g of 4-acetyl-2-propylimidazol-5-carbonitrile (obtained in stage (i), see above) and 60 ml of 6N. aqueous hydrochloric acid was heated, while stirring, under reflux for 8 hours. Then the reaction mixture was concentrated by evaporation under reduced pressure, and the concentrate was dissolved in ethanol, after which the resulting solution was again concentrated in the same way. The residue was dissolved in ethanol and the solvent is again drove away. This sequence digestions and concentration was carried out in the whole five times, and then the residue was dissolved in 60 ml of ethanol. Through the resulting solution at room temperature for 20 minutes was barbotirovany stream of hydrogen chloride, after which the solution was left for 16 h at room temperature. After this time the solution was concentrated by evaporation under reduced pressure. was alitwala by adding sodium bicarbonate. An ethyl acetate layer was separated and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography on silica gel, elwira a mixture of ethyl acetate and hexane (1:1 by volume), resulting in received of 3.07 g of target compound in the form of crystals at 76-78oC.

NMR (CDCl3) ppm as 0.96 (3H, t, J = 7.5 Hz), of 1.39 (3H, t, J = 7.0 Hz), equal to 1.82 (2H, sextet, J = 7.5 Hz), a 2.75 (3H, s), 2,80 (2H, t, J = 7,50 Hz), of 4.44 (2H, square, J = 7 Hz).

23(iii). Ethyl 4-(1-hydroxyethyl)-2-propylimidazol-5-carboxylate.

125 ml of sodium borohydride was added to a solution of 1.50 g of ethyl 4-acetyl-2-propylimidazol-5-carboxylate [obtained in stage (ii), see above] in 15 ml of ethanol, and the mixture was stirred for 30 minutes at room temperature. Then added 2 ml of acetone, and the mixture is stirred for another 10 minutes After that, the mixture was concentrated by evaporation under reduced pressure, and the concentrate was dissolved in methanol. The resulting solution was again concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography on silica gel, elwira mixtures of methylene chloride and methanol (1:20 and 1:10 by volume), resulting in a received 1,32 g of target compound in VI is to 1.48 (3H, d, J = 6.5 Hz), 1,74 (2H, sextet, J = 7.5 Hz), to 2.67 (2H, t, J = 8 Hz), 4,34 (2H, square, J = 7 Hz), 5,28 (1H, square, J = 6.5 Hz).

Getting 24. Ethyl 2-butyl-4-(1-hydroxyethyl)imidazole-5-carboxylate.

24(i). 4-Acetyl-2-butylimidazole-5-carbonitrile.

Repeated the procedure described in 23(i), but using 10 g of 2-butylimidazole-4,5-dicarbonitrile (obtained as described in obtaining 1), resulting in received to 9.15 g of target compound in the form of crystals with so pl. 77-78oC.

NMR (CDCl3) ppm: of 0.93 (3H, t, J = 7 Hz), 1,0-2,1 (4H, m), of 2.72 (3H, s), 2,89 (2H, t, J = 7 Hz).

24 (ii). Ethyl 4-acetyl-2-butylimidazole-5-carboxylate.

Repeated the procedure described in 23 (ii), but using of 1.00 g of 4-acetyl-2-butylimidazole-5-carbonitrile (obtained in stage (i), see above), resulting in a received 0,92 g of target compound in the form of a viscous oil,

NMR (CDCl3) ppm: to 0.88 (3H, t, J = 7 Hz), 1,1-2,1 (4H, m) of 1.33 (3H, t, J = 7 Hz), is 2.74 (3H, s), 2,82 (2H, t, J = 7.5 Hz), to 4.38 (2H, square, J = 7 Hz).

24 (iii). Ethyl 2-butyl-4-(1-hydroxyethyl)imidazole-5-carboxylate.

Repeated the procedure described in 23(iii), but using 0.64 g of ethyl 4-acetyl-2-butylimidazole-5-carboxylate [obtained in accordance with the description in the phase ii]. In the CV>6) ppm: of 0.91 (3H, t, J = 7.5 Hz), of 1.37 (3H, t, J = 7 Hz), 1,3-is 1.42 (2H, m) of 1.50 (3H, d, J = 6.5 Hz), 1.69 in (2H, Queen., J = 7.5 Hz), 2,69 (2H, t, J = 8 Hz), 4,34 (2H, square, J = 7 Hz), 5,26 (1H, square, J = 6.5 Hz).

Getting 25. 2-Butyl-4-propylimidazol-5-carbonitrile.

Repeating the procedure in obtaining 24(i), but using bromide ethylamine instead bromide Metalmania, and received in the target connection so pl. 84-85oC and output 51,9%.

NMR (CDCl3) ppm: of 0.95 (3H, t, J = 7 Hz), 1.0 to about 2.2 (4H, m) of 1.28 (3H, t, J = 7.0 Hz), is 2.88 (2H, t, J = 7 Hz) and 3.15 (2H, q, J = 7 Hz).

Getting 26. 2-Butyl-4-butylimidazole-5-carbonitrile.

Repeating the procedure in obtaining 24(i), but using bromide Propylamine instead bromide Metalmania, resulting in a received target connection so pl. 91-92oC and output 57,2%.

NMR (CDCl3) ppm: of 1.02 (3H, t, J = 7.5 Hz), is 1.11 (3H, t, J = 7.5 Hz), 1,3-1,6 (2H, m), 1,7-2,0 (4H, m), is 2.88 (2H, t, J = 8 Hz), of 3.13 (2H, t, J = 7.5 Hz).

Getting 27. 2-Butyl-4-isobutylamino-5-carbonitrile.

Repeating the procedure in obtaining 24(i), but using bromide Isopropylamine instead bromide Metalmania, resulting in a received target connection so pl. 88-89oC and the output of 36.2%.

NMR (CDCl3) / ppm: 0 is propylimidazol-5-carbonitrile.

Repeating the procedure in obtaining 24(i), but using 2-propylimidazol-4,5-dicarbonitrile (obtained as described in 10) and bromide Propylamine, resulting in a received target connection so pl. 94-95oC with the release of 49.8%.

NMR (CDCl3) ppm: 1,00 (3H, t, J = 7.5 Hz), was 1.04 (3H, t, J = 7.5 Hz), 1.7 to 1.9 (4H, m), and 2.79 (2H, t, J = 7.5 Hz), 3,06 (2H, t, J = 7.5 Hz).

Receiving 29. 2-Butyl-4-(1-hydroxy-1-methylethyl)imidazol-5-carbonitrile.

Repeated the procedure described in 23(i), but using 4-acetyl-2-butylimidazole-5-carbonitrile [obtained as described in obtaining 24(i)] and solution of bromide Metalmania in tetrahydrofuran, resulting in a received target connection so pl. 171-172oC and with access to 66.3%.

NMR (CDCl3+ CD3OD) ppm: of 0.91 (3H, t, J = 7 Hz), 1,0-2,1 (4H, m) of 1.62 (6H, s), 2,69 (2H, t, J = 7 Hz).

30. 2-Butyl-4-[1-hydroxy-2-methyl-1-(1 - methylethyl)propyl] imidazole-5-carbonitrile.

Repeated the procedure described in 23(i), but using 2-butyl-4-isobutylamino-5-carbonitrile (obtained as described in the getting 27) and a solution of bromide Isopropylamine in tetrahydrofuran, resulting in a received target connection so pl. 63-6), a 2.71 (2H, t, J = 7 Hz).

Getting 31. (5-Methyl-2-oxo-1,3-dioxolan-4-yl)methyl - 4-(1-hydroxy-1-methylethyl)-2-propylimidazol-5-carboxylate.

1,76 ml of N, N-diisopropylethylamine was added to a suspension of 1.06 g of 4-(1-hydroxy-1-methylethyl)-2-propylimidazol-5-carboxylic acid [obtained as described in obtaining 22(i)] in 10 ml of N,N-dimethylacetamide, and the resulting mixture was placed for 10 minutes at room temperature, and then to the mixture was added 1.12 g (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl chloride, and the mixture is stirred 4 h at 60oC. After the reaction mixture was mixed with ethyl acetate and water. An ethyl acetate layer was separated and concentrated by evaporation under reduced pressure, and the concentrate was purified by column chromatography on silica gel, elwira mixture of methanol and methylene chloride (1:15 by volume), resulting in a received 1,14 g of target compound in the form of a viscous oily product.

NMR (CDCl3) ppm: to 0.94 (3H, t, J = 7.5 Hz), of 1.62 (6H, s), 1,6-1,8 (2H, m), are 2.19 (3H, s) to 2.67 (2H, t, J = 8 Hz), to 5.03 (2H, s).

Getting 32. Phthalidyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazol - 5-carboxylate.

Repeating the procedure in obtaining 31, but using 1.06 g of 4-(1-hydroxy-1-methylethyl)-2-propylimidazol - 5-ka is g target compound as amorphous solid.

NMR (CDCl3) ppm: to 0.92 (3H, t, J = 7.5 Hz), of 1.64 (6H, s), 1,6-of 1.75 (2H, m), 2.63 in (2H, t, J = 7.5 Hz), 7,63-7,79 (4H, m), to $ 7.91 (1H, d, J = 8,5 Hz).

Receiving 33. Isopropoxycarbonyloxymethyl-4-(1-hydroxy-1 - methylethyl)-2-propylimidazol-5-carboxylate.

Repeating the procedure in obtaining 22(ii), but using 1.06 g of 4-(1-hydroxy-1-methylethyl)-2-propylimidazol - 5-carboxylic acid [obtained in accordance with the description in obtaining 22(i)] and 0,83 g isopropoxycarbonyloxymethyl, which was obtained 1.22 g of target compound with so pl. 144-146oC.

NMR (CDCl3) ppm: 0,98 (3H, t, J = 7.5 Hz), of 1.32 (6H, d, J = 6.5 Hz), of 1.62 (6H, s) of 1.76 (2H, sextet, J = 7.5 Hz), 2,69 (2H, t, J = 7.5 Hz), is 4.93 (1H, Queen., J = 6.5 Hz), 5,95 (2H, s).

Getting 34. 2-Ethylimidazole-4,5-dicarbonitrile.

Repeating the procedure in obtaining 1, but using 53,3 g diaminomaleonitrile and 91.3 g of triethylenediamine, resulting in received of 59.5 g of target compound in the form of crystals with so pl. 179-181oC.

Receive 35. 2-Ethylimidazole-4,5-dicarboxylic acid.

Repeating the procedure in getting 2, but with the use of 45.0 g of 2-ethylimidazole-4,5-dicarbonitrile (obtained in accordance with the description in obtaining 34), resulting floor is dasol-4,5, in primary forms.

Repeating the procedure in getting 3, but with the use of 35.0 g of 2-ethylimidazole-4,5-dicarboxylic acid (obtained in accordance with the receiving 35), resulting in received of 38.7 g of target compound in the form of crystals with so pl. 83-84oC.

Getting 37. Ethyl-2-ethyl-4-(1-hydroxy-1-methylethyl)imidazole - 5-carboxylate.

Repeating the procedure in obtaining 8, but with the use of 3.60 g of diethyl 2-ethylimidazole-4,5-in primary forms (obtained in accordance with the description in obtaining 36), 60 ml of 1 M solution of bromide Metalmania in tetrahydrofuran, resulting in received 2,05 g of target compound in the form of crystals with so pl. 181-184oC.

NMR (DMSO-d6) ppm: 1,22 (3H, t, J = 7 Hz), of 1.33 (3H, t, J = 7.5 Hz), 1,50 (6H, s) to 2.65 (2H, square, J = 7.5 Hz), 3,30 (1H, Shir. C), or 4.31 (2H, square, J = 7.5 Hz).

Getting 38. N-t-Butyl-4'-bromomethylbiphenyl-2-carboxamide.

38(i). N-t-Butyl-4'-methylbiphenyl-2-carboxamide.

5,7 ml oxalicacid drop was added, the cooling in this ice, to a solution of 6,91 g of 4'-methylbiphenyl-2-carboxylic acid in 70 ml of methylene chloride, and the mixture was stirred 2 hours at room temperature. The mixture is then concentrated by evaporation under reduced pressure, and the residue restorana in 50 ml of tetrahydrofuran, and the resulting mixture stirred 10 minutes at room temperature. After this time the reaction mixture was diluted with water and ethyl acetate. An ethyl acetate layer was separated, washed with aqueous sodium bicarbonate solution and then with an aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and concentrated by evaporation under reduced pressure, resulting in received of 7.48 g of target compound in the form of crystals with so pl. 105-106,5oC (after recrystallization from ethyl acetate and hexane).

NMR (CDCl3) ppm: 1,12 (9H, s) to 2.41 (3H, s), of 5.05 (1H, Shir. C) a 7.2 to 7.5 (7H, m), 7,71 (1H, d, J = 8 Hz).

38(ii). N-t-Butyl-4'-bromomethylbiphenyl-2-carboxamide.

4,39 g N bromosuccinimide and 50 mg of benzoyl peroxide was added to a solution of 6.00 g of N-t-butyl-4'-methylbiphenyl-2-carboxamide [obtained as described in obtaining 38(i)] in 90 ml of carbon tetrachloride, and the resulting mixture was heated under reflux for 4 hours then the reaction mixture was cooled to room temperature, washed with water, dried with anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography on silica gel, elwira a mixture of ethyl acetate and hexane (tx2">

NMR (CDCl3) ppm: 1.14 in (9H, s) 4,55 (2H, s), 4,99 (1H, Shir. C), 7,30-to 7.32 (8H, m).

Getting 39. 4-Isobutyl-2-propylimidazol-5-carbonitrile.

Repeated the procedure described in 23 (i), but using 8,24 g 2-propylimidazol-4,5-dicarbonitrile (obtained as described in 10) and 103 ml of 2 M solution of iodide Isopropylamine in diethyl ether, resulting in the received 45,0 g of target compound in the form of crystals with so pl. 90,5-91oC.

NMR (CDCl3) ppm: a 1.01 (3H, t, J = 7.5 Hz), of 1.29 (6H, d, J = 6.5 Hz), equal to 1.82 (2H, Sextus., J = 7.5 Hz), of 2.81 (2H, t, J = 7.5 Hz), 3,66 (1H, septet, J = 6.5 Hz).

Getting 40. 2-Butyl-4-Pihlajamaa-5-carbonitrile.

A solution of 10.4 g of 2-butylimidazole-4.5-dicarbonitrile (obtained as described in obtaining 1) in 150 ml of methylene chloride drop by drop) was added at 10-15oC and under nitrogen atmosphere, 100 ml of 2 M solution of chloride t-butylamine in diethyl ether, and the resulting mixture was stirred 1 h at the same temperature. Then the reaction mixture drop by drop was added 200 ml of ethyl acetate and 100 ml of an aqueous solution of potassium bisulfate, and the resulting mixture was stirred 20 min at room temperature. After this time, nerastvorim material was removed by filtration, and the organic layer finishes and colors was purified by column chromatography on silica gel, elwira a mixture of ethyl acetate and hexane (1:3 by volume), resulting in received of 7.95 g of target compound in the form of crystals with so pl. 135-137oC.

NMR (CDCl3) Delta ppm: of 0.95 (3H, t, J = 7.5 Hz), of 1.42 (2H, septet, J = 7.5 Hz), of 1.46 (9H, s) of 1.75 (2H, Queen., J = 7.5 Hz), and 2.79 (2H, t, J = 7.5 Hz).

Getting 41. 2-Propyl-4-Pihlajamaa-5-carbonitrile.

Repeating the procedure in obtaining 40, but using 3.2 g of 2-propylimidazol-4,5-dicarbonitrile (obtained as described in 10) and 33 ml of 2 M solution of chloride t-butylamine in diethyl ether, resulting in the received 2,35 g of target compound in the form of crystals with so pl. 176-178oC.

NMR (CDCl3) Delta ppm: of 0.93 (3H, t, J = 7.5 Hz), of 1.36 (9H, s) of 1.75 (2H, sextet, J = 7.5 Hz), 2,68 (2H, t, J = 7.5 Hz).

An example of the preparative form.

The tablets. 50,0 mg pivaloyloxymethyl-4-hydroxymethyl-2-propyl- 1-[4-[2-(tetrazol-5-yl)phenyl] phenyl] Mei-5-carboxylate, 124,0 mg of lactose, 25.0 mg of corn starch and 1 mg of magnesium stearate are mixed and make a tablet weight of 200 mg on the equipment for manufacture of tablets. If necessary, the tablet is covered by the sugar-coated.

1. Derivatives of 1-biphenylmethanol General formula I

< / BR>
giacobini or different and each represents a hydrogen atom or one of R2and R3represents hydrogen and the other alkyl group having 1 to 6 carbon atoms; C6- C10-aryl group;

R4is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms;

R5represents carboxyl group, a group of the formula-COOR5aor a group of the formula-CONR8R9where R8and R9are the same or different and each represents a hydrogen atom, an unsubstituted alkyl group having 1 to 6 carbon atoms, or a substituted alkyl group having 1 to 6 carbon atoms and substituted by carboxypropyl or alkoxycarbonyl group in which the alkyl part has 1 to 6 carbon atoms, or R8and R9together represent a substituted alkylenes group which has 2 to 6 carbon atoms and is substituted alkoxycarbonyl group in which the alkyl part has 1 to 6 carbon atoms; and R5Arepresents an alkyl group having 1 to 6 carbon atoms, alkanoyloxy group, in which each of alkanoyloxy and alkyl parts has 1 to 6 carbon atoms, alkoxycarbonylmethyl group, in which each of the alkoxy and alkyl parts has 1 to 6 carbon atoms, (5-methyl-2-oxo-1,3-SUP>7represents a carboxyl group or tetrazol-5-ilen group

and its pharmaceutically acceptable salts and esters, excluding compounds and their pharmaceutically acceptable salts, in which R1represents an alkyl group having 2 to 6 carbon atoms; R2represents a hydrogen atom; R3is hydrogen, an alkyl group having 1 to 6 carbon atoms or phenyl group; R4represents a hydrogen atom or alkyl group having 1 to 6 carbon atoms; R5represents carboxyl group, a group of the formula-CODR5aor a group of the formula-CONR8R9where R8and R9each represents a hydrogen atom or an unsubstituted alkyl group having 1 to 4 carbon atoms; R5Arepresents an alkyl group having 1 to 6 carbon atoms; R6is a hydrogen atom; R7- carboxyl group, or tetrazol-5-ilen group.

2. Connection on p. 1, characterized in that it R5Arepresents a C1- C4is an alkyl group, alkanoyloxy group, in which alcoolica group has 1 to 5 carbon atoms, and an alkyl group of 1 to 4 carbon atoms, alkoxycarbonylmethyl group, in which each alkoxides iruppu.

3. Connection on p. 2, characterized in that it R5Arepresents a C1- C4is an alkyl group, alkanoyloxy group, in which alcoolica part has 1 to 5 carbon atoms and the alkyl part is of 1 to 2 carbon atoms, alkoxycarbonylmethyl group, in which alkoxides has 1 to 4 carbon atoms and the alkyl portion is of 1 or 2 carbon atoms, 5-methyl-2-oxo-1,3-dioxolan-4-yl methyl group, or phthalidyl group.

4. Connection on p. 2, characterized in that it R5Arepresents pivaloyloxymethyl ethoxycarbonylmethyl, 1-(ethoxycarbonyl)ethyl, isopropoxycarbonyloxymethyl, 1-(isopropoxycarbonyl)ethyl, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl or phthalidyl group.

5. The compound according to any one of paragraphs.1 to 4, wherein R4represents a hydrogen atom or alkyl group having 1 to 4 carbon atoms.

6. The compound according to any one of paragraphs.1 to 5, wherein R5is carboxypropyl, a group of the formula-COOR5aor a group of the formula-CONR8R9in which R5Arepresents an alkyl group having 1 to 4 carbon atoms, alkanoyloxy carboncillo group, in which alkoxides has 1 to 4 carbon atoms and the alkyl part is of 1 to 4 carbon atoms, [5-methyl-2-oxo-1,3-dioxolan-4-yl] -methyl group, or phthalidyl group; R8and R9are the same or different and each represents a hydrogen atom, unsubstituted C1- C4is alkyl or substituted C1- C4is an alkyl group which is substituted by carboxypropyl, alkoxycarbonyl group having 2 to 5 carbon atoms, or R8and R9together represent a substituted alkylenes group which has 4 or 5 carbon atoms and is substituted by at least one Deputy, selected from methoxycarbonyl and ethoxycarbonyl groups.

7. The compound according to any one of paragraphs.1 - 6, characterized in that the benzene ring has substituents represented by R6and R7is 3 - or 4-position of the benzyl group with which it is associated.

8. Connection on p. 1, wherein R1represents an alkyl group having 2 to 5 carbon atoms; R2and R3each represents a hydrogen atom, or one represents hydrogen and the other alkyl group having 1 to 4 carbon atoms; R45Aor a group of the formula-CONR8R9in which R5Arepresents a methyl or ethyl group, alkanoyloxy group, in which alcoolica part has 1 to 5 carbon atoms, 1-(alkanoyloxy)ethyl group, in which alcoolica part has 1 to 5 carbon atoms, alkoxycarbonylmethyl group, in which alkoxides has 1 to 4 carbon atoms, 1-(alkoxycarbonyl)ethyl group, in which alkoxides has 1 to 4 carbon atoms, [5-methyl-2-oxo-1,3-dioxolan-4-yl] methyl group, or phthalidyl group; R8and R9are the same or different and each represents a hydrogen atom, methyl group, ethyl group, methoxycarbonylmethyl group, ethoxycarbonylmethyl group or carboxymethyl group; R6represents a hydrogen atom; R7is carboxypropyl or tetrazol-5-strong group in the 2-position of the benzene ring and the benzene ring has substituents represented by R6and R7is in the 4th position of the benzyl group with which it is associated.

9. Connection on p. 1, wherein R1represents ethyl, sawn or boutelou group; R24represents a hydrogen atom or methyl group; R5represents a group of formula-COOR5Ain which R5Arepresents pivaloyloxymethyl group, ethoxycarbonylmethyl group, 1-(ethoxycarbonyl)ethyl group, isopropoxycarbonyloxymethyl group, 1-(isopropoxycarbonyl)ethyl group, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl group or phthalidyl group; R6is a hydrogen atom; R7is carboxypropyl or tetrazol-5-strong group in the 2-position of the benzene ring and the benzene ring has substituents represented by R6and R7is in the 4th position of the benzyl group with which it is associated.

10. Connection on p. 1, wherein R1represents ethyl, sawn or boutelou group; R2represents an isopropyl group or a t-boutelou group; R3is a hydrogen atom; R4is a hydrogen atom or a methyl group; R5represents a group of formula-CONR8R9in which R8and R9are the same or different and each represents a hydrogen atom, methyl group, methoxycarbonylmethyl group, asobi carboxypropyl or tetrazol-5-ilen group at the 2nd position of the benzene ring, and the benzene ring has substituents represented by R6and R7is in the 4th position of the benzyl group with which it is associated.

11. The compound of General formula I

< / BR>
where R1is ethyl, propyl or butyl;

R2is hydrogen or a methyl group;

R3is a hydrogen atom;

R4is a hydrogen atom or a methyl group;

R5group of the formula-COOR5awhere R5Arepresents a hydrogen atom, pivaloyloxymethyl, ethoxycarbonylmethyl, 1-(ethoxycarbonyl)ethyl, isopropoxycarbonyloxymethyl, 1-(isopropoxycarbonyl)ethyl, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl or phthalidyl;

R6is a hydrogen atom;

R7represents carboxyl group or tetrazol-5-ilen group in position 2 of the benzene ring and the benzene ring has substituents represented by R6and R7is in the 4th position of the benzyl group to which it is attached,

or its pharmaceutically acceptable salt.

12. Connection on p. 11, which represents a 4-(1-hydroxyethyl)-2-propyl-1-{ 4-/2-(tetrazol-5-yl)phenyl] phenyl}Mei-5-carboxylic acid, pivaloyloxymethyl 4-(1-hydroxyethyl)-2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl-(tetrazol-5-yl)phenyl] phenyl}Mei-5-carboxylate, 4-(1-hydroxyethyl)-2-butyl-1-{4-/2-(tetrazol-5-yl)phenyl] phenyl}Mei-5-carboxylic acid, pivaloyloxymethyl 4-(1-hydroxyethyl)-2-butyl-1-{ 4-[2-(tetrazol-5-yl)phenyl] phenyl}Mei-5-carboxylate, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl-4-(1-hydroxyethyl)-2-butyl-1-{ 4-[2-(tetrazol-5-yl)phenyl]phenyl}Mei-5-carboxylate, 4-hydroxymethyl-2-propyl-1-{ 4-[2-(tetrazol-5-yl)phenyl]phenyl}Mei-5-carboxylic acid, pivaloyloxymethyl 4-hydroxymethyl-2-propyl-1-{ 4-[2-(tetrazol-5-yl)phenyl] phenyl} Mei-5-carboxylate, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl 4-hydroxymethyl-2-propyl-1-{ 4-[2-(tetrazol-5-yl)phenyl] phenyl} Mei-5-carboxylate, 4-hydroxymethyl-2-butyl-1-{4-[2-(tetrazol-5-yl)phenyl] phenyl}methylimidazole-5-carboxylic acid, pivaloyloxymethyl 4-hydroxymethyl-2-butyl-1-{4-(2-(tetrazol-5-yl)phenyl]phenyl}Mei-5-carboxylate, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl 4-(1-hydroxymethyl)-2-butyl-1-{ 4-[2-(tetrazol-5-yl)phenyl] phenyl} Mei-5-carboxylate, or their pharmaceutically acceptable salts.

13. Pharmaceutical composition for the treatment and prevention of hypertension, including a connection with a blocking angiotensin II receptor activity, in a mixture with a pharmaceutically acceptable carrier or what aktivnosti, it contains at least one compound of formula I under item 1 in an effective amount.

14. The compound according to any one of paragraphs.1 - 12 with anti-hypertensive activity.

15. A method of obtaining a compound according to any one of paragraphs.1 - 12, characterized in that carry out the following stages: the interaction of compounds of formula II

< / BR>
in which R1the same as that defined in paragraph 1;

Rdis a group of the formula

< / BR>
where R2, R3and R4such, as defined in paragraph 1, or Rdis a group of the formula-COORfwhere Rfrepresents carboxyamide group, or Rdrepresents a group of the formula-COR2where R2the same as defined above;

Reis cyano or a group of the formula-COORfwhere Rfsuch as defined above,

with the compound of the formula III

< / BR>
in which R6the same as defined above;

R7arepresents a protected carboxyl group or a protected tetrazol-5-ilen group;

X is a halogen atom,

obtaining the compounds of formula IV

< / BR>
where Rd, Re, R1, R6and R7asuch as defined above,

with the subsequent removal in any order of the group Rdrepresents a group of formula-COORfmake this group by reaction with Grignard reagents of formula R2a- MgX and R3a- MgX, where R2arepresents any of the groups defined for R2other than hydrogen, and R3Arepresents any of the groups defined for R3other than hydrogen, and X is as defined above, to obtain the group of the formula

< / BR>
where R2Aand R3Asuch as defined above;

if Rdrepresents a group of formula-COORfmake this group by reaction with two or more molar equivalents of a reducing agent with obtaining hydroxymethylene group;

if Rdrepresents a group of the formula-COR2make this group by reaction with a regenerating agent with obtaining a group of the formula-CH(R2)(OH); and

if Rdrepresents a group of the formula-COR2make this group by reaction with a Grignard reagent of formula R3a- MgX, where R3aand X are such as defined above, to obtain the group of the formula-C(R2)(R3A)(OH), where R2and R3Asuch as defined above;

and then, if necessary,

if Repredstavili I, where R5represents a carboxyl group, and further optionally interact thus obtained compound with a compound of formula R8R9NH, where R8and R9such as defined above, to obtain compounds of formula I, where R5represents a group of formula-CONR8R9;

if R5represents a cyano, this group is subjected to hydrolysis to obtain the compounds of formula I, where R5represents a carboxyl group, and further, optionally, conducting interaction thus obtained compound with a compound of formula R8R9NH, where R8and R9such as defined above, to obtain compounds of formula I, where R5group of the formula-CONR8R9;

if R5represents a cyano, conducting hydrolysis of the specified group under mild conditions to obtain compounds of formula I, where R5- carnemolla group;

if R7arepresents a protected carboxyl or tetrazol-5-ilen group, remove protection from the specified group, and

if the group-OR4represents a hydroxyl group, carry out the interaction specified Gruppo, having 1 to 6 carbon atoms, to obtain the compounds of formula I, where R4represents an alkyl group having 1 to 6 carbon atoms, and, optionally, turn the product into salt or ester.

Priority signs and items:

21.02.91 when R1- alkyl, C1- C6; R2and R3are the same or different and each represents a hydrogen atom or one of R2and R3represents hydrogen and the other alkyl group having 1 to 6 carbon atoms, C6- C10-aryl group; R4is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; R5represents carboxyl group, a group of the formula-COOR5Aand R5Arepresents an alkyl group having 1 to 6 carbon atoms, alkanoyloxy group, in which each of the alkoxy and alkyl parts has 1 to 6 carbon atoms, (5-methyl-2-oxo-1,3-dioxolane-4-yl)methyl group, a hydrogen atom, pivaloyloxymethyl, ethoxycarbonylmethyl, 1-(ethoxycarbonyl)ethyl, isopropoxycarbonyloxymethyl, 1-(isopropoxycarbonyl)ethyl; R7- carboxyl group and the benzene ring has substituents represented by R6and R7is in the 4th position of the benzo is>and R9are the same or different and each represents a hydrogen atom, an unsubstituted alkyl group having 1 to 6 carbon atoms;

26.04.91 - R8and R9together represent phthalidyl group;

08.07.91 - p. 11.

 

Same patents:

The invention relates to new 2-(2,4,5-phenylselenenyl) compounds as their synthesis and intermediate products, as well as to the use of these compounds for weed control

The invention relates to pyrazole derivative of the General formula I

< / BR>
in which R1is phenyl, substituted cyclo(lower)alkyl, hydroxy(lower)alkyl, cyano, lower alkylenedioxy, carboxy, (lower alkoxy)carbonyl group, a lower alkanoyl, lower alkanoyloxy, lower alkoxy, phenoxy or carbamoyl, optionally substituted lower alkyl;

R2is halogen, halo(lower)alkyl, cyano, carboxy, (lower alkoxy)carbonyl group, carbamoyl, optionally substituted by alkyl;

R3is phenyl, substituted lower alkylthio, lower alkylsulfonyl, or lower alkylsulfonyl, provided that when R1is phenyl, substituted lower alkoxy, then R2represents halogen or halo(lower)alkyl,

or their pharmaceutically acceptable salts

The invention relates to medicine and can be used in the treatment of stress lesions of the nervous system in combustionengines, traumatic, neurological and surgical hospitals

The invention relates to new chemical substances possessing valuable properties, in particular nitrogen-containing cyclic derivative of General formula

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where X is carbinieri, unsubstituted or substituted at the nitrogen atom by alkyl, aryl, heteroaryl or cyano, carbonyl, thiocarbonyl, sulfonyl, 1-nitroethene-2,2-diyl or 1,1-dicyano-Eten-2,2-diyl,

Y is unsubstituted or substituted Rcor Rdor Rcand Rdnonbranched alkylen or albaniles with 2 to 4 carbon atoms, which may optionally be substituted by one or two alkyl groups and in which one or two methylene groups can be replaced by a carbonyl, 1,2-cycloalkyl with 5 to 7 carbon atoms, unsubstituted or substituted Rcor Rdor Rcand Rd, 1,2 - cycloalkenyl with 5 to 7 carbon atoms, unsubstituted or substituted Rcor Rdor Rcand Rd, 1,2-Allen, 1,2-phenylene, in which one or two methine groups are replaced by nitrogen atom or one or two groups-CH=CH - replaced by a group-CO-NH - or a methine group substituted by nitrogen atom and one group-CH= CH - replaced by a group-CO-NH-, and above heterocycles or substituted Rcor Rd,

the first of the residues Ra- Rdmeans A group-B-, in which A group of the formula

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or

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where pentostatin can be monogamist the remainder R25mono - or Disaese the remainder R26or monogamist the remainder R25and additionally monogamist the remainder R26and the substituents R25and R26that may be the same or different and have the meanings stated below, in one bancoestado 1 - 3 methine group may be replaced by a nitrogen atom or a group-CH= CH - may be replaced by a group-CO-NR1or one methine group may be replaced by nitrogen atom and one group-CH=CH - may be replaced by a group-CO-NR1-, where R1means a hydrogen atom or alkyl,

G1and G4- bond or methylene which may be mono - or Disaese the alkyl, aryl or heteroaryl, and the substituents may be the same or different,

G2- bond or methylene, substituted residues R7and R8,

G3communication, methyl nitrogen atom or Metin, unsubstituted or substituted by alkyl, aryl or heteroaryl,

R2is a hydrogen atom, alkyl, aryl or heteroaryl or hydroxyl or alkoxyl if at least one of the groups G2and G3doesn't mean the relationship,

R3is a hydrogen atom, alkyl, aryl or heteroaryl or R3together with R2form an oxygen atom, if at least one of the groups G2and G3doesn't mean the relationship,

R4and R14is a hydrogen atom, cycloalkyl with 3 to 7 carbon atoms, cycloalkyl with 3 to 7 carbon atoms in cycloalkyl parts, alkyl with 1 to 8 carbon atoms, alkenyl with 3 to 8 carbon atoms, which may not be linked to the nitrogen atom through the vinyl group, hydroxyalkyl, alkoxyalkyl, aminoalkyl, acylaminoalkyl, dialkylaminoalkyl, cianelli, carboxyethyl, alkoxycarbonylmethyl, aminocarbonylmethyl, N-alkylaminocarbonyl, N,N-dialkylaminoalkyl, arylalkyl, heteroallyl, alkoxycarbonyl, allmediascotland, formyl, acetyl, TRIFLUOROACETYL, allyloxycarbonyl, amidino or R11CO-0-(R12CR13)-O-CO-, where R11is alkyl with 1 to 8 carbon atoms, cycloalkyl with 5 to 7 carbon atoms, aryl or arylalkyl, R12is a hydrogen atom, alkyl, cycloalkyl with sweetlenny alkylen 2 - 4 carbon atoms or methylene, if G2doesn't mean the relationship,

R5is a hydrogen atom, alkyl, aryl or heteroaryl or hydroxyl or alkoxyl, if G1no means of communication, or R4together with R5mean an additional bond, if G1means of communication,

R6is a hydrogen atom, alkyl, aryl or heteroaryl or a chlorine atom, a hydroxyl, methoxyl, amino, alkylamino or dialkylamino, if G1means linking and R4together with R5mean an additional bond, or R6together with R5mean oxygen atom, if G1doesn't mean the relationship,

R7is a hydrogen atom, alkyl, aryl or heteroaryl,

R8is a hydrogen atom, alkyl, aryl or heteroaryl or R8together with R4mean the unbranched alkylene with 2 to 5 carbon atoms,

R9is a hydrogen atom, alkyl, aryl or heteroaryl or hydroxyl or alkoxyl, if G2doesn't mean the relationship,

R10is a hydrogen atom, alkyl, aryl or heteroaryl or R10together with R4mean the unbranched alkylene with 2 to 4 carbon atoms,

R15is a hydrogen atom or chlorine, alkyl, aryl, heteroaryl, hydroxyl, methoxyl, amino, alkylamino or dialkylamino,

R16- foelkel 1 8 carbon atoms, alkenyl with 3 to 8 carbon atoms, which may not be linked to the nitrogen atom through the vinyl group, hydroxyalkyl, alkoxyalkyl, aminoalkyl, acylaminoalkyl, dialkylaminoalkyl, cianelli, carboxyethyl, alkoxycarbonylmethyl, aminocarbonylmethyl, N-alkylaminocarbonyl, N,N-dialkylaminoalkyl or arylalkyl,

R17is a hydrogen atom or alkyl, or R16together with R17mean an additional bond, if G4means of communication,

R18is a hydrogen atom, alkyl or fluorine atom, chlorine or bromine, hydroxyl, methoxyl, amino, alkylamino or dialkylamino, if G4means linking and R16and R17together denote an additional bond,

n is the number 1 or 2,

In - line, alkylen, albaniles, Allen, peridinin, pyrimidinyl, personalen or pyridazinyl, in which one or two groups-CH=N - can be replaced by a group-CO-NH - and one of the nitrogen atoms may be associated with the remainder of A connection instead of a hydrogen atom, and these heterocyclic groups may be optionally substituted by one or two alkyl groups, cycloalkyl with 4 to 7 carbon atoms, unsubstituted or substituted by one or two alkyl groups, unsubstituted or RC="http://www.fips.ru/fullimg2/rupat3/19993/003.dwl/2126002-6t.gif" ALIGN="ABSMIDDLE">replaced by a nitrogen atom, and, in addition, in the above mentioned 5 - to 7-membered rings, one adjacent to the nitrogen atom of the methylene group may be replaced by carbonyl, the second of the residues Ra- Rdmeans a group of the formula

F - E - D-,

where D is alkylene with 1 to 6 carbon atoms in which one methylene group may be replaced by oxygen atom or sulfur, sulfinil, sulfonium or the group-NR19-, where R19means a hydrogen atom, alkyl, alkylaryl, alkylsulfonyl, arylcarbamoyl or arylsulfonyl, or in which one ethylene group may be replaced by a group-CO-NR20- or-NR20-CO-, where R20means a hydrogen atom or alkyl, albaniles with 2 to 6 carbon atoms, Allen, peridinin, pyrimidinyl, personalen or pyridazinyl, in which one or two groups-CH=N - can be replaced by a group-CO-NH - and one of the nitrogen atoms, together with the hydrogen atom may also be linked with the rest of E, if the latter does not mean the connection or not connected via a heteroatom or a carbonyl with the rest of D, and these heterocyclic groups may be optionally substituted by one or two alkyl groups, indaniel, naftilan, 1,2,3,4-tetrahydronaphthalen or benzoguanamine, in which one of the be substituted by one or two alkyl groups, and the aromatic ring may be substituted by fluorine atom, chlorine, bromine or iodine, alkyl, trifluoromethyl, hydroxyl, alkoxyl, alkylsulfanyl, alkylsulfonyl, alkylsulfonyl or cyano, cycloalkyl with 4 to 7 carbon atoms, unsubstituted or substituted by one or two alkyl groups, unsubstituted or substituted by one or two alkyl groups cycloalkyl with 5 to 7 carbon atoms, in which one groupreplaced by a nitrogen atom, and, in addition, in the above mentioned 5 - to 7-membered rings, one adjacent to the nitrogen atom of the methylene group may be replaced by carbonyl, unsubstituted or substituted by one or two alkyl groups piperazinyl in which one adjacent to the nitrogen atom of the methylene group may be replaced by a carbonyl, or alkilenkarbonatov with the total number of carbon atoms 2-6, if E is a cyclic aminogroup, and a carbonyl linked to a nitrogen atom of a cyclic aminogroup group E, or a link, if E does not mean the relationship,

E - communication, alkylene with 1 to 6 carbon atoms which may be substituted by one or two alkyl groups with 1 to 8 carbon atoms, alkenyl or quinil with 2 to 4 carbon atoms, hydroxyl, is POI with the total number of carbon atoms of 2 10, the group HNR21- or N-alkyl-NR21-, where R21means alkylsulphonyl or alkylsulfonyl with 1 to 8 carbon atoms in the alkyl part, allyloxycarbonyl with the total number of carbon atoms 2 and 5 cycloalkylcarbonyl or cycloalkylcarbonyl with 5 to 7 carbon atoms in cycloalkyl part, arylalkylamines, arylalkylamines, arylethoxysilanes, arylcarbamoyl or arylsulfonyl, albaniles with 2 to 6 carbon atoms, Allen, peridinin, pyrimidinyl, personalen or pyridazinyl, unsubstituted or substituted by one or two alkyl groups, unsubstituted or substituted by one or two alkyl groups cycloalkyl with 5 to 7 carbon atoms, in which one groupreplaced by a nitrogen atom linked to the carbon atom of the residue D, cycloalkyl with 4 to 7 carbon atoms in cycloalkanones part, unsubstituted or substituted by one or two alkyl groups with 1 to 8 carbon atoms, alkenyl or quinil with 2 to 4 carbon atoms, hydroxyl, amino, aryl, heteroaryl, alkoxyl or alkylamino with 1 to 8 carbon atoms, dialkylamino with the total number of carbon atoms of 2 to 10, a group HNR21- or N-alkyl-NR21-, where R2119-, -NR20-CO - or-CO-NR20-, where R19and R20have the above meanings, with alkylene may be optionally substituted by one or two alkyl groups with 1 to 8 carbon atoms, alkenyl or quinil with 2 to 4 carbon atoms, hydroxyl, amino, aryl, heteroaryl, alkoxyl or alkylamino with 1 to 8 carbon atoms, dialkylamino with the total number of carbon atoms of 2 to 10, group-HNR21- or N-alkyl-NR21where R21have the above significance, with an additional heteroatom substituent heteroatom is separated from the remainder of W by at least two carbon atoms, if D does not mean the relationship,

F - carbonyl, substituted by hydroxyl, alkoxyl with 1 to 8 carbon atoms, arialcategory or group R22O-, where R22means cycloalkyl with 4 to 8 carbon atoms and cycloalkyl with 3 to 8 carbon atoms in cycloalkyl part, in which cycloalkyl part may be substituted by alkyl, alkoxyl or dialkylamino, or alkyl and 1 to 3 methyl groups, with one methylene group in the 4 - to 8-membered cycloalkyl part may be replaced by oxygen atom or alkylaminocarbonyl, benzocyclobutene the PA R23CO-O-CHR24-O-CO-, where R23means alkyl or alkoxy with 1 to 8 carbon atoms, cycloalkyl with 5 to 7 carbon atoms, cycloalkyl with 5 to 7 carbon atoms in cycloalkyl parts, aryl, aryloxy, arylalkyl or Allakaket and R24is a hydrogen atom or alkyl,

the shortest distance between the residue of F and located at a maximum distance from the rest F the nitrogen atom of the group A-B - is at least 11 links,

the third of the residues Ra- Rdmeans a hydrogen atom, alkyl, perfluoroalkyl, alkoxy, alkylsulfanyl, alkylsulfonyl, alkylsulfonyl, amino, alkylamino, dialkylamino, aryl, heteroaryl or arylalkyl,

the fourth of the residue Ra- Rdmeans a hydrogen atom, alkyl or aryl, and if nothing else is mentioned,

under the above term "aryl" is to be understood phenyl, which can be monogamist the remainder R25mono-, di - or triamese the remainder R26or monogamist the remainder R25and additionally mono - or Disaese the remainder R26and the substituents may be the same or different, R25means cyano, carboxyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, alkoxycarbonyl, alkylboron, the Mino, alkylamino, dialkylamino, alkylcarboxylic, phenylalkylamine, phenylcarbonylamino, alkylsulfonyl, phenylalkylamine, phenylcarbonylamino, N-alkyl-alkylcarboxylic, N-alkyl-phenylalaninamide, N-alkyl-phenylcarbonylamino, N-alkyl-alkylsulfonyl, N-alkyl-phenylalaninamide, N-alkyl-phenylcarbonylamino, aminosulfonyl, alkylaminocarbonyl or dialkylaminoalkyl, R26- alkyl, hydroxyl or alkoxy, fluorine atom, chlorine, bromine or iodine, and two residue R26if they are linked to adjacent carbon atoms, may also be alkylene with 3 to 6 carbon atoms, 1,3-butadiene-1,4-deelen or methylendioxy group

under the above term "Allen" should be understood phenylene, which can be monogamist the remainder R25mono - or Disaese the remainder R26or monogamist the remainder R25and additionally monogamist the remainder R26and the substituents may be the same or different and have the above values,

under the above term "heteroaryl" should read 5-membered heteroaromatic ring containing one atom of oxygen, sulfur or nitrogen, one atom of nitrogen and one atom of oxygen, sulfur is certain heteroaromatic ring, in which one or two of the groups-CH= N - can be replaced by a group-CO-NR20where R20has the above value, the heteroaromatic ring can be substituted by one or two alkyl groups or by a fluorine atom, chlorine, bromine or iodine, hydroxyl or alkoxyl in the carbon skeleton,

and, if nothing else is mentioned, the above alkyl, alkylene or CNS groups can contain 1 to 4 carbon atoms and each of the carbon atoms in the above alkilinity and cycloalkenes groups associated at least one heteroatom,

mixtures of their isomers, or individual isomers or salts

The invention relates to pharmacology and describes a new tool for the treatment of irritable bowel syndrome

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with treating patients with uterine cervix cancer with relapses in parametral fiber and in case of no possibility for radical operative interference and effect of previous radiation therapy. During the 1st d of therapy one should intravenously inject 30 mg platidiam incubated for 1 h at 37 C with 150 ml autoblood, during the next 3 d comes external irradiation per 2.6 G-r. During the 5th d of therapy one should introduce the following composition into presacral space: 60 ml 0.5%-novocaine solution, 1 ml hydrocortisone suspension, 2 ml 50%-analgin solution, 1 ml 0.01%-vitamin B12 solution, 1.6 g gentamycine, 800 mg cyclophosphan, 10 mg metothrexate. These curative impacts should be repeated at mentioned sequence four times. The method enables to decrease radiation loading and toxic manifestations of anti-tumor therapy at achieving increased percent of tumor regression.

EFFECT: higher efficiency of therapy.

1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of new derivatives of 4,5-dihydro-1H-pyrazole of the general formula (I):

wherein R means phenyl, thienyl or pyridyl and these indicated groups can be substituted with (C1-C3)-alkoxy-group or halogen atom; R1 means phenyl that can be substituted with (C1-C3)-alkoxy-group or pyridyl group; R2 means hydrogen atom or hydroxy-group; Aa means one group among the following groups: (i) , (ii) , (iii) , (iv) or (v) ; R4 and R5 mean independently from one another hydrogen atom or (C1-C8)-branched or unbranched alkyl; or R4 means acetamido- or dimethylamino-group or 2,2,2-trifluoroethyl, or phenyl, or pyridyl under condition that R5 means hydrogen atom; R6 means hydrogen atom at (C1-C3)-unbranched alkyl; Bb means sulfonyl or carbonyl; R3 means benzyl, phenyl or pyridyl that can be substituted with 1, 2 or 3 substitutes Y that can be similar or different and taken among the group including (C1-C3)-alkyl or (C1-C3)-alkoxy-group, halogen atom, trifluoromethyl; or R3 means naphthyl, and its racemates, mixtures of diastereomers and individual stereoisomers and as well as E-isomers, Z-isomers and mixture of E/Z-compounds of the formula (I) wherein A has values (i) or (ii), and its salt. These compounds are power antagonists of Cannbis-1 (CB1) receptor and can be used for treatment of psychiatric and neurological diseases. Except for, invention relates to a pharmaceutical composition used for treatment of some diseases mediated by CB1-receptor, to a method for preparing this composition, a method for preparing representatives of compounds of the formula (I) wherein Aa means group of the formulae (i) or (ii), intermediate compounds used for preparing compounds of the formula (I) and to a method for treatment of some diseases mediated by CB1-receptor.

EFFECT: valuable medicinal properties of compounds.

16 cl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new 1-(p-thienylbenzyl)-imidazoles of the formula (I): , wherein indicated residues represent the following values: R(1) means halogen atom, (C1-C4)-alkoxyl, (C1-C8)-alkoxyl wherein one carbon atom can be replaced with heteroatom oxygen atom (O); R(2) means CHO; R(3) means aryl; R(4) means hydrogen halogen atom; X means oxygen atom; Y means oxygen atom or -NH-; R(5) means (C1-C6)-alkyl; R(6) means (C1-C5)-alkyl in their any stereoisomeric forms and their mixtures taken in any ratios, and their physiologically acceptable salts. Compounds are strong agonists of angiotensin-(1-7) receptors and therefore they can be used as a drug for treatment and prophylaxis of arterial hypertension, heart hypertrophy, cardiac insufficiency, coronary diseases such as stenocardia, heart infarction, vascular restenosis after angioplasty, cardiomyopathy, endothelial dysfunction or endothelial injures, for example, as result of atherosclerosis processes, or in diabetes mellitus, and arterial and venous thrombosis also. Invention describes a pharmaceutical composition based on above said compounds and a method for their applying also.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 19 ex

FIELD: organic chemistry and pharmaceutical compositions.

SUBSTANCE: invention relates to new 3-(5)-heteroaryl-substituted pyrazoles of formula I , tautomers or pharmaceutically acceptable salt of compounds and tautomers. In formula R1 is hydride, piperidinyl substituted with methyl, lower alkyl optionally substituted with halogen, hydroxyl, lower alkylanimo or morpholino; R2 is hydride, lower alkyl, amino, aminocarbonylamino, lower alkylaminocarbonylamino, lower alkylsulfonylamino, aminosulfonylamino, lower alkylaminosulfonylamino; Ar1 is phenyl optionally substituted with one or more independently selected halogen; HetAr2 is pyridinyl with the proviso that R2 is not amino or n-propyl when HetAr2 is pyridinyl; and HetAr2 is not 2-pyriridinyl when R2 is hydrogen or lower alkyl. Compounds of formula I have kinase p38 inhibitor activity and are useful in pharmaceutical compositions for treatment of various diseases.

EFFECT: new effective kinase p38 inhibitors.

23 cl, 6 dwg, 1 tbl, 1 ex

FIELD: veterinary science.

SUBSTANCE: a dog should be introduced with 4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazole-1-il]benzene sulfonamide or its pharmaceutically acceptable salt at daily dosage ranged about 0.1-10 mg/kg body weight.

EFFECT: higher efficiency of therapy.

4 cl,262 ex, 12 tbl

FIELD: medicine, gynecology, anesthesiology.

SUBSTANCE: invention concerns to a method for carrying out the anesthesiology assistance for woman in childbirth with accompanying bronchial asthma. Method involves administration of atropine, dimedrol, analgin and clophelin. Method involves additional intravenous administration of transamine for 5-7 min. Transamine is administrated in doses 12-14 and 15-17 mg/kg in woman in childbirth with body mass 75 kg and above and 74 kg and less, respectively. Method provides enhancing quality and safety of anesthesia in this class of woman in childbirth.

EFFECT: improved assistance method.

7 tbl, 4 ex

FIELD: medicine, dermatology, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to an antifungal gel pharmaceutical composition based on ketoconazole and clotrimazole that are derivatives of imidazole. The composition comprises ketoconazole or clotrimazole as an active component, polyethylene glycol-400 (PEG-400) as a solvent, carboxyvinyl polymer as a gel-forming agent, polyethylene glycol as a gel stabilizing agent, organic amine or inorganic bas as a regulator of pH and water taken in the definite ratio of components. The composition is prepared by dissolving active component in PEG-400, dispersing carboxyvinyl polymer in water, successive addition to dispersion propylene glycol as a stabilizing agent and regulator of pH and combination of prepared solution and gel followed by stirring the mixture up to preparing the gel composition with pH 5-7. Invention provides preparing antifungal composition with reduced adverse effect.

EFFECT: improved preparing method, valuable medicinal properties of composition.

2 cl, 1 tbl, 11 ex

FIELD: veterinary science.

SUBSTANCE: the present innovation deals with applying selector as a selenium-containing organic preparation to be introduced for cows and calves monthly intramuscularly at the dosage of 10 mcg/kg body weight. The method provides decreased fodder expenses for the synthesis of the production obtained.

EFFECT: higher productivity in cattle.

2 ex, 7 tbl

FIELD: organic chemistry, medicine, allergology, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a method for treatment of patient suffering with allergic disease. Method involves administration to patient the therapeutically effective dose of pharmaceutical composition comprising compound of the formula (I)

. The compound elicits high effectiveness in treatment of allergy and shows low toxicity also.

EFFECT: improved method for treatment.

9 cl, 2 tbl, 2 dwg, 40 ex

FIELD: veterinary science.

SUBSTANCE: one should apply a selenium-containing preparation named selecor: it should be introduced on the 80-90th d of swine gestation twice at 10-15-d-long interval parenterally at the dosage of 20 mg/kg animal body weight. Application of low-toxic antioxidant as selecor enables to improve functional properties of cell membranes of placental system and endometrium and increase inspecific immune resistance in sows. It, also, enables to increase fertility in sows, values of uncomplicated deliveries and puerperal period.

EFFECT: higher viability of off-spring.

2 ex, 3 tbl

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