RU2092481C1 - 1-biphenylmethyl imidazole, pharmaceutically acceptable salts or ethers thereof, and method of preparation thereof - Google Patents

Abstract

FIELD: pharmaceutical industry. SUBSTANCE: present invention describes compounds of formula (I):

wherein R¹ is alkyl or alkenyl; R² and R³ are hydrogen, alkyl, alkenyl, cycloalkyl, aralkyl, aryl or aryl fused with cycloalkyl; R⁴ is hydrogen, alkyl, alkanoyl, alkenoyl, arylcarbonyl, alkoxycarbonyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothienyl, tetrohydrofuryl, group of formula: SiR^aR^bR^c in which R^a, R^b and R^c are alkyl or aryl, alkoxymethyl, alkoxyalkoxy methyl, halo-alkoxy methyl, aralkyl, aryl or alkanoyloxymethoxy carbonyl; R⁵ is carboxy group or group of formula: -CONR⁸R⁹ in which R⁸ and R⁹ together form alkylene; R⁶ is hydrogen, alkyl, alkoxy or halogen; R⁷ is carboxy group or tetrazol-5-yl; or pharmaceutically acceptable salts and esters thereof have hypertensive activity and are useful for treatment and prophylaxis of hypertension. Compounds of the present invention are prepared by inter alia by reaction of a biphenylmethyl compound with imidazole compound. EFFECT: improved properties. 32 cl, 1 tbl

Description

 The invention relates to a series of new derivatives of 1-biphenylmethylimidazole with hypotensive activity, and therefore intended for the treatment and prevention of hypertension, including heart disease and circulatory system, as well as to methods for producing these compounds, to compositions containing these compounds, and to methods for producing these compositions.

 It is known that the renin-angiotensin system provides one of the most important mechanisms aimed at maintaining blood pressure homeostasis in living organisms. With a decrease in blood pressure or a decrease in the concentration of sodium ions in body fluids, this system is activated. As a result of this, the renin enzyme and the angiotensin-converting enzyme (hereinafter referred to as “ACF”) are activated and act on the angiotensinogen, which is first decomposed by renin to form angiotensin I, hereinafter referred to as “AI”, and then converted into angiotensin II by ACF hereinafter referred to as "A II". Since A II contributes to a strong contraction of blood vessels and accelerates the secretion of aldosterone, the activation of this system leads to an increase in blood pressure. Inhibitors or suppressors of the renin-angiotensin system, for example, renin inhibitors, ACF inhibitors and AII antagonists, contribute to the expansion of blood vessels, thereby causing a decrease in blood pressure and improving blood circulation function. Therefore, the treatment of heart disease is based on the use of the above agents.

 Currently, only ACF inhibitors find clinical use, although studies are underway to use renin inhibitors and AII antagonists for this purpose. Some of them, for example, peptide type II antagonists, such as saralazine, have been known for a long time, while other non-peptide type antagonists have been discovered recently (see, for example, Europatent Publication Nos. 28833, 28834, 245637, 253310, 323841 , 324377, 380959, 399732, 399731 and 400835 and Japanese patent application Coca N 57-98270). Of these works, the closest prototype is the publication of Europatent N 253310 and N 324377.

 A well-known publication discloses a number of derivatives of 1-phenyl-, 1-phenethyl- or 1-benzylimidazole with the ability to inhibit AII. Compounds included in the scope of the specified prototype are derivatives of 1-biphenylmethylimidazole, which, however, differ from the proposed compounds by the nature of the substituent at the 4- or 5-positions of imidazole.

 Europatent publication 324377 also discloses a number of similar compounds. However, the activity of the compounds of this prototype, as well as the compounds of the above prototype N 253310 are insufficient and to obtain good clinical results it is necessary to use stronger AII antagonistic agents.

где4 R¹ представляет собой алкильную группу, имеющую 1-6 атомов углерода;
R² и R³ являются одинаковыми или различными и каждый представляет собой алкильную группу, имеющую 1-6 атомов углерода, или арильную группу, имеющую 6-10 атомов углерода;
R⁴ представляет собой атом водорода или алкильную группу, имеющую 1 6 атомов углерода;
R⁵ представляет собой карбокси-группу или группу формул -COOR^5a или -CONR⁸R⁹, где R⁸ и R⁹ являются одинаковыми или различными и каждый из них представляет собой атом водорода, незамещенную алкильную группу, имеющую 1-6 атомов углерода, замещенную алкильную группу, имеющую 1-6 атомов углерода и замещенную карбокси-группу или алкоксикарбонильной группой, в которой алкильная часть имеет 1-6 атомов углерода, или R⁸ и R⁹ вместе представляют собой замещенную алкиленовую группу, которая имеет 2-6 атомов углерода и которая является замещенной, алкоксикарбонильной группой, в которой алкильная часть имеет 1-6 атомов углерода; R^5a представляет собой алкильную группу, имеющую 1-6 атомов углерода, алканоилоксиалкильную группу, в которой каждая из алканоильной и алкильных частей имеет 1-6 атомов углерода, алкоксикарбонилоксиалкильную группу, в которой каждая из алкокси и алкильной частей имеет 1-6 атомов углерода, (5-метил-2-оксо-1,3-диоксолен-4-ил)метильную группу, или фталидильную группу,
R⁶ представляет собой атом водорода;
R⁷ представляет собой карбокси-группу или тетразол-5-ильную группу,
и его фармацевтически приемлемые соли и эфиры.The invention relates to compounds of the formula

where 4 R ¹ represents an alkyl group having 1-6 carbon atoms;
R ² and R ³ are the same or different and each represents an alkyl group having 1-6 carbon atoms, or an aryl group having 6-10 carbon atoms;
R ⁴ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms;
R ⁵ represents a carboxy group or a group of the formulas —COOR ^5a or —CONR ⁸ R ⁹ , where R ⁸ and R ⁹ are the same or different and each represents a hydrogen atom, an unsubstituted alkyl group having 1-6 carbon atoms, a substituted alkyl group having 1-6 carbon atoms and a substituted carboxy group or an alkoxycarbonyl group in which the alkyl part has 1-6 carbon atoms, or R ⁸ and R ⁹ together represent a substituted alkylene group that has 2-6 carbon atoms and which is substituted, alkoxycarbon Flax group in which the alkyl moiety has 1-6 carbon atoms; R ^5a represents an alkyl group having 1-6 carbon atoms, an alkanoyloxyalkyl group in which each of the alkanoyl and alkyl parts has 1-6 carbon atoms, an alkoxycarbonyloxyalkyl group in which each of the alkoxy and alkyl parts has 1-6 carbon atoms, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl group, or phthalidyl group,
R ⁶ represents a hydrogen atom;
R ⁷ represents a carboxy group or a tetrazol-5-yl group,
and its pharmaceutically acceptable salts and esters.

 The invention also relates to pharmaceutically acceptable salts and esters of the compounds described above.

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

 In addition, the 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 proposed compounds, where R ¹ , R ² , R ³ , R ⁴ , R ⁸ , R ⁹ are an alkyl group, said alkyl group is an alkyl group with 1-6 carbon atoms, which may be a straight or branched group, 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. R ¹ is preferably a straight or branched alkyl group containing 2-5 carbon atoms, and more preferably a direct group, and most preferably ethyl, propyl or butyl. R ² and R ³ may be the same or different, represent a straight or branched alkyl group containing 1-4 carbon atoms, preferably methyl, ethyl, propyl, isopropyl or t-butyl group, and more preferably methyl or ethyl group, if R ⁵ is a carboxy group, or an isopropyl or t-butyl group when r ⁵ is a group of formula -CONR ⁸ r ^9, r ⁴ is preferably straight or branched alkyl group having 1-4 carbon atoms, and more preferably methyl or ethyl th group. If R ⁸ and R ⁹ are alkyl groups, then they can be the same or different, and each of them is preferably an alkyl group containing 1-4 carbon atoms, more preferably a methyl, ethyl, propyl or butyl group, and most preferably methyl or ethyl group. In the case where the substituent (b) is an alkyl group, then preferably it is a group with 1-4 carbon atoms, and more preferably a methyl or ethyl group.

In the case where R ² and R ³ represent an aryl group, this group is an aromatic carbocyclic group which has 6-14 (preferably 6-10, and more preferably 6 or 10) ring atoms, R ⁵ represents a carboxyl group or group formulas -CONR ⁸ R ⁹ . If R ⁵ is a group of the formula —CONR ⁸ R ⁹ and R ⁸ and R ⁹ are an alkyl group, then this group may be an unsubstituted alkyl group having 1-6 carbon atoms, for example, such as the groups indicated above, or a substituted alkyl group which has 1-6 carbon atoms and which is a substituted carboxy group or alkoxycarbonyl group.

If R ⁸ and R ⁹ together represent a substituted alkylene group, then this group contains 2-6 carbon atoms and may be straight or branched. As a substituent, for example, an alkoxycarbonyl group is used, the alkyl part of which contains 1-6 carbon atoms.

 Examples of such substituents are methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl, of which carboxy, methoxycarbonyl and ethoxycarbonyl groups are preferred.

If R ⁵ represents a carboxyl group, then the compound is a carboxylic acid, and therefore can form esters in which the carboxyl group represented by R ⁵ is replaced by a group of the formula —COOR ^5a , where R ^5a is an ester residue (in the case of a carboxylic acid, R ^5a is a hydrogen atom). It can also form salts. The nature of the ester thus formed is not critical, except that this ester must satisfy pharmaceutical requirements, that is, its toxicity should not be higher and its activity should not be lower than the original acid. However, if this ester is used for other purposes, for example, as an intermediate to produce another, possibly more active, compound, even this limitation can be ignored, and in this case any commonly used ether residue may be acceptable, which may be selected based on its functionality and commercial advantages. However, it is well known that certain ether residues give compounds certain advantages, for example, such compounds are easier and better absorbed in vivo, and therefore, if necessary, such ether residues can be used in the invention.

Examples of these ester residues are:
alkyl groups having 1-6 carbon atoms, such as the groups given above as examples for R ¹ ;
alkanoyloxyalkyl groups in which each of the alkanoyl and alkyl parts has 1-6 carbon atoms and can be any of the above examples for R ¹ and R ⁴ , respectively, and preferably the alkanoyl part has 1-5 carbon atoms, and the alkyl part 1- 4 carbon atoms, and more preferably, if the alkanoyl portion has 2-5 carbon atoms and an alkyl portion of 1-2 carbon atoms, while examples of alkanoyloxyalkyl groups are formyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, in aryloxymethyl, isovaleryloxymethyl, hexanoyloxymethyl, 1- (formyloxy) ethyl, 1- (acetoxy) ethyl, 1- (propionyloxy) ethyl, 1- (butyryloxy) ethyl, 1- (pivaloyloxy) ethyl, 1- (butyloxy) ethyl, 1 - (pivaloyloxy) ethyl, 1- (valeryloxy) ethyl, 1- (isovaleryloxy) ethyl, 1- (hexanoyloxy) ethyl, 1- (formyloxy) ethyl, 1- (acetoxy) ethyl, 2- (propionyloxy) ethyl, 2- (butyryloxy) ethyl, 2- (pivaloyloxy) ethyl, 2- (valeryloxy) ethyl, 2- (isovaleryloxy) ethyl, 2- (hexanoyloxy) ethyl, 1- (formyloxy) propyl, 1- (acetoxy) propyl, 1- (propionyloxy) propyl, 1- (butyryloxy) propyl, 1- (pivaloyloxy) propyl, 1- (valerylox i) propyl, 1- (isovaleryloxy) propyl, 1- (hexanoyloxy) propyl, 1- (acetoxy) butyl, 1- (propynoyloxy) 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 formyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethoxy, 1- are preferred ) ethyl, 1- (acetoxy) ethyl, 1- (propionyloxy) ethyl, 1- (butyryloxy) ethyl and 1- (pivaloyloxy) ethyl, and acetoxymethyl, propynoylox are more preferred methyl, butyryloxymethyl, pivaloyloxymethyl, 1- (acetoxy) ethyl, 1- (propionyloxy) ethyl, 1- (butyryloxy) ethyl and 1- (pivaloyloxy) ethyl, and pivaloyloxymethyl and 1-pivaloyloxyethyl are most preferred;
alkoxycarbonyloxyalkyl groups in which each of the alkoxy and alkyl moieties has 1-6 carbon atoms are the same as defined above for R ¹ , respectively, moreover, preferred ones have 1-4 carbon atoms, and most preferably, alkoxy the part has 1-4 carbon atoms and the alkyl part has 1-2 carbon atoms, examples of these alkoxycarbonyloxyalkyl are methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonium oxymethyl, isobutoxycarbonyloxymethyl, pentyloxycarbonyloxymethyl, hexyloxycarbonyloxymethyl, 1- (methoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, 1- (propoxycarbonyloxy) ethyl, 1- (isopropoxycarbonyloxy) ethyl, 1- (isopropoxycarbonyloxy) ethyl, 1- (isopropoxycarbonyloxy) ethyl, 1- ( 1- (pentyloxycarbonyloxy) ethyl, 1- (hexyloxycarbonyloxy) ethyl, 2- (methoxycarbonyloxy) ethyl, 2- (ethoxycarbonyloxy) ethyl, 2- (propoxycarbonyloxy) ethyl, 2- (isopropoxycarbonyloxy) ethyl, 2- (butoxycarbonyloxy) ethyl, 2 - (isobutoxycarbonyloxy) ethyl, 2- (pentyloxycarbonyl xi) ethyl, 2- (hexyloxycarbonyloxy) ethyl, 1- (methoxycarbonyloxy) propyl, 1- (ethoxycarbonyloxy) propyl, 1- (propoxycarbonyloxy) propyl, 2- (isopropoxycarbonyloxy) propyl, 1- (butoxycarbonyloxy) propyl, 1- (isobutoxycarbonyloxy) propyl, 1- (pentyloxycarbonyloxy) propyl, 1- (hexyloxycarbonyloxy) propyl, 1- (methoxycarbonyloxy) butyl, 1- (ethoxycarbonyloxy) butyl, 1- (propoxycarbonyloxy) butyl, 1- (isopropoxybonyloxy) (butoxycarbonyloxy) butyl, 1- (isobutoxycarbonyloxy) butyl, 1- (methoxycarbonyloxy) pentyl, 1- (ethoxycarbonyloxy) pentyl, 1- (methoxycarbonyloxy) -hexyl and 1- (ethoxycarbonyloxy) hexyl, preferably methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, 1- (meth) ethoxybenoxycarbonyloxymethyloxy, 1- (meth) - (isopropoxycarbonyloxy) ethyl, 1- (butoxycarbonyloxy) ethyl, 1- (isobutoxycarbonyloxy) ethyl, 1- (methoxycarbonyloxy) propyl, 1- (ethoxycarbonyloxy) propyl, 1- (propoxycarbonyloxy) propyl, 1- (isopropoxycarbonyloxy) i) propyl, 1- (butoxycarbonyloxy) propyl, 1- (isobutoxycarbonyloxy) propyl, 1- (methoxycarbonyloxy) butyl, 1- (ethoxycarbonyloxy) butyl, 1- (propoxycarbonyloxy) butyl, 1- (isopropoxycarbonyloxy) butyl, 1- (butoxycarbonyloxy) butyl ) butyl, 1- (isobutoxycarbonyloxy) butyl, more preferably methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxy (ethoxycarbonyloxy (ethoxycarbonyloxy) ethoxycarbonyloxy (ethoxycarbonyloxy) 1 poxycarbonyloxy) ethyl, 1- (butoxycarbonyloxy) ethyl and 1- (isobutoxycarbonyloxy) ethyl, and most preferably methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, 1- (methoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl.

где R⁶ является атомом водорода;
R⁷ может быть карбоксильной группой или тетразол-5-ильной группой. Если R⁷ и является карбоксильной группой, то полученные в результате соединения могут образовывать соли или сложные эфиры. Указанные соли или сложные эфиры могут быть любой природы при условии, что они являются пригодными для терапевтического использования и фармацевтически приемлемыми. Если эти соли или сложные эфиры не предназначены для терапевтического использования, а предназначены для использования в качестве промежуточных соединений, для получения других, возможно более активных соединений, то даже указанным выше ограничением можно пренебречь. Примерами таких солей могут служить соли щелочных металлов, таких как натрий, калий или литий, соли щелочно-земельных металлов, таких как барий или кальций, соли других металлов, таких как магний или алюминий, соли органических оснований, таких как соли гванидина, триэтиламина или дихлоргексиламина, или соли с основными аминокислотами, такими как лизин или аргинин. Примерами сложноэфирных групп могут быть группы, представленные выше для R^5a. Предпочтительно, если R⁷ находится во 2- или 3-положении фенильной группы, а более предпочтительно во 2-положении фенильной группы.Preferably, if the benzene ring having substituents represented by R ⁶ and R ⁷ is in the 3- or 4-positions, and more preferably in the 4-position of the benzyl group to which it is attached, i.e., preferred compounds have the formula

where R ⁶ is a hydrogen atom;
R ⁷ may be a carboxyl group or a tetrazol-5-yl group. If R ⁷ is a carboxyl group, the resulting compounds may form salts or esters. Said salts or esters may 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, but are intended to be used as intermediates, to obtain other, possibly more active compounds, then even the above limitation can be neglected. Examples of such salts include alkali metal salts such as sodium, potassium or lithium, alkaline earth metal salts such as barium or calcium, salts of other metals such as magnesium or aluminum, salts of organic bases such as guanidine, triethylamine or dichlorohexylamine, or salts with basic amino acids such as lysine or arginine. Examples of ester groups may be those set forth above for R ^5a . Preferably, if R ⁷ is in the 2- or 3-position of the phenyl group, and more preferably in the 2-position of the phenyl group.

 The proposed compounds must necessarily contain at least one basic nitrogen atom in the imidazole ring, and therefore they can form acid addition salts. Examples of such acid addition salts are addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, and addition salts with organic acids such as maleic acid, fumaric acid, tartaric acid or citric acid.

Preferred classes of compounds of the invention are:
compounds of formula I and their salts and esters in which R ⁵ represents an alkyl group having 1-4 carbon atoms, an alkanoyloxyalkyl group in which each alkanoyl part has 1-5 carbon atoms and the alkyl parts have 1-4 carbon atoms, an alkoxycarbonyloxyalkyl group in which each alkoxy and alkyl moieties has 1-4 carbon atoms, [5-methyl-2-oxo-1,3-dioxolen-4-yl] methyl groups, a phthalidyl group;
compounds in which R ^5a represents a C ₁ -C ₄ alkyl group, an alkanoyloxyalkyl group in which the alkanoyl group has 1-5 carbon atoms, and an alkyl group has 1-4 carbon atoms, an alkoxycarbonyloxyalkyl group in which the alkoxy part has 1-4 carbon atoms and the alkyl part has 1-2 carbon atoms, [5-methyl-2-oxo-1,3-dioxolen-4-yl] methyl group or phthalidyl group;
compounds in which R ^5a is pivaloyloxymethyl, ethoxycarbonyloxymethyl, 1- (ethoxycarbonyloxy) ethyl, isopropoxycarbonyloxymethyl, 1- (isopropoxycarbonyloxy) ethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl phthyl groups
compounds in which
R ¹ represents an alkyl group having from 2 to 5 carbon atoms;
R ² and R ³ are the same or different and each of them represents an alkyl group having 1-4 carbon atoms, a benzyl, naphthyl or phenyl group;
R ⁴ represents a hydrogen atom or an alkyl group having 1-4 carbon atoms;
R ⁵ represents a group of the formula —COOR ^5a or a group of the formula —CONR ⁸ R ⁹ in which R ^5a represents an alkyl group having 1-4 carbon atoms, an alkanoyloxyalkyl group in which the alkanoyl moiety has 1-5 carbon atoms, and the alkyl the part has 1-4 carbon atoms, an alkoxycarbonyloxyalkyl group in which the alkoxy part has 1-4 carbon atoms, and the alkyl part has 1-4 carbon atoms, [5-methyl-2-oxo-1,3-dioxolen-4- an il] methyl group in which the alkyl part has 1-4 carbon atoms or a phthalidyl group;
R ⁸ and R ⁹ are the same or different and each represents a hydrogen atom, an alkyl group having 1-4 carbon atoms, and a substituted alkyl group that has 1-4 carbon atoms and which is a substituted, carboxy group or alkoxycarbonyl group, where the alkyl part has 2-5 carbon atoms; or
R ⁸ and R ⁹ together represent a substituted alkylene group which has 4 or 5 carbon atoms and which is substituted by at least one substituent selected from methoxycarbonyl groups and ethoxycarbonyl groups;
a benzene ring which has substituents represented by R ⁶ and R ⁷ is in the 3-4 position of the benzyl group to which it is attached;
compounds in which R ¹ represents an alkyl group having 2-5 carbon atoms; R ² and R ³ are the same or different and each represents an alkyl group having 1-4 carbon atoms, a benzyl or phenyl group;
R ⁴ and represents a hydrogen atom, a methyl or ethyl group;
R ⁵ represents a group of the formula —COOR ^5a or a group of the formula —COOR ⁸ R ⁹ in which R ^5a represents an alkyl group having 1-4 carbon atoms, an alkanoyloxyalkyl group in which the alkanoyl moiety has 1-5 carbon atoms, and the alkyl the part has a methyl or ethyl group, a cycloalkanoyloxyalkyl group in which the cycloalkanoyl part has 6 or 7 carbon atoms, and the alkyl part is a methyl or ethyl group, an alkoxycarbonyloxyalkyl group in which the alkoxy part has 1-4 carbon atoms, and the alkyl part is a methyl or ethyl group, [5-methyl-2-oxo-1,3-dioxolen-4-yl] methyl group or a phthalidyl group;
R ⁸ and R ⁹ are the same or different and each represents a hydrogen atom, a methyl group, an ethyl group or a substituted methyl or ethyl group, which is substituted by at least one substituent selected from carboxy groups, methoxycarbonyl groups and ethoxycarbonyl groups ; or
R ⁸ and R ⁹ together represent a substituted alkylene group which has 4 or 5 carbon atoms and which is substituted by at least one substituent selected from methoxycarbonyl groups and ethoxycarbonyl groups;
R ⁶ represents a hydrogen atom;
R ⁷ represents a carboxy group or a tetrazol-5-yl group at the 2- or 3-position of the benzene ring;
a benzene ring which has substituents represented by R ⁶ and R ⁷ is in the 4-position of the benzyl group to which it is attached;
compounds in which R ¹ represents an alkyl group having 2-5 carbon atoms;
R ² and R ³ are the same or different and each represents a hydrogen atom or an alkyl group having 1-4 carbon atoms;
R ⁴ represents a hydrogen atom, a methyl group or an ethyl group;
R ⁵ represents a group of the formula —COOR ^5a or a group of the formula —CONR ⁸ R ⁹ wherein R ^5a represents a methyl, ethyl, or benzyl group, an alkanoyloxymethyl group in which the alkanoyl moiety has 1-5 carbon atoms, 1- (alkanoyloxy) ethyl group in which the alkanoyl part has 1-5 carbon atoms, the alkoxycarbonyloxymethyl group in which the alkoxy part has 1-4 carbon atoms, the 1- (alkoxycarbonyloxy) ethyl group in which the alkoxy part has 1-4 carbon atoms, [5- methyl-3-oxo-1,3-dioxolen-4-yl] methyl group or phthalidyl a group;
R ⁸ and R ⁹ are the same or different, and each represents a hydrogen atom, a methyl group or an ethyl group, a methoxycarbonylmethyl group, an ethoxycarbonylmethyl group or a carboxymethyl group; or
R ⁸ and R ⁹ together represent a tetramethylene, pentamethylene, 1-carboxytetramethylene or 1-carboxypentamethylene group;
R ⁶ represents a hydrogen atom;
R ⁷ represents a carboxy group or a tetrazol-5-yl group at the 2-position of the benzene ring;
a benzene ring which has substituents represented by R ⁶ and R ⁷ is in the 4-position of the benzyl group to which it is attached;
compounds in which R ¹ represents an ethyl, propyl or butyl group;
R ² and R ³ are the same or different and each represents a methyl group;
R ⁴ represents a hydrogen atom or a methyl group;
R ⁵ represents a group of formula COOR ^5a in which R ^5a represents a hydrogen atom, pivaloyloxymethyl group, ethoxycarbonyloxymethyl group, 1- (ethoxycarbonyloxy) ethyl group, isopropoxycarbonyloxymethyl group, 1- (isopropoxycarbonyloxy) ethyl group, (5-methyl-2- oxo-1,3-dioxolen-4-yl) methyl group or phthalidyl group;
R ⁶ represents a hydrogen atom;
R ⁷ represents a carboxy group or a tetrazol-5-yl group at the 2-position of the benzene ring;
a benzene ring which has substituents represented by R ⁶ and R ⁷ is in the 4-position of the benzyl group to which it is attached;
compounds in which R ¹ represents an ethyl, propyl or butyl group;
R ² and R ³ represent a methyl group;
R ⁴ represents a hydrogen atom or a methyl group;
R ⁵ represents a group of the formula —COOR ^5a in which R ^5a represents a hydrogen atom, pivaloyloxymethyl group, ethoxycarbonyloxymethyl group, 1- (ethoxycarbonyloxy) ethyl group, isopropoxycarbonyloxymethyl group, 1- (isopropoxycarbonyloxy) ethyl group, (5-methyl-2- oxo-1,3-dioxolen-4-yl) methyl group or phthalidyl group;
R ⁶ represents a hydrogen atom;
R ⁷ represents a carboxy group or tetrazol-5-yl at the 2-position of the benzene ring;
the benzene ring, which has substituents represented by R ⁶ and R ⁷ , is in the 4-position of the benzyl group to which it is attached.

 The proposed compounds may contain one or more asymmetric carbon atoms in their molecules, and therefore can form optical isomers. Although they can all be represented by the same molecular formula, the invention includes individual isomers and mixtures thereof, including racemates. When using stereospecific synthesis or when using optically active compounds, individual isomers can be obtained directly as starting materials, and on the other hand, if there is a mixture of isomers, individual isomers can be obtained using standard resolution techniques.

 Specific examples of the compounds of the invention are presented at the end of the description by formulas I-1, I-2, I-3, I-4, I-5 and I-6.

The values of R ¹ R ⁷ in these formulas are indicated above.

 Of these, the following compounds are most preferred: 2-butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (1-hydroxy-1-methylethyl) imidazole-5-carboxylic acid and its pharmaceutically acceptable salts ; pivaloyloxymethyl 2-butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (1-hydroxy-1-methylethyl) imidazole-5-carboxylate and its pharmaceutically acceptable salts; (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl 2-butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (1-hydroxy-1-methylethyl ) imidazole-5-carboxylate and its pharmaceutically acceptable salts; 1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylic acid and its pharmaceutically acceptable salts; 1 - [(2'-carboxybiphenyl-4-yl) methyl] -2-ethyl-4- (1-hydroxy-1-methylethyl) imidazole-5-carboxylic acid and its pharmaceutically acceptable salts; 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylic acid and its pharmaceutically acceptable salts; 2-butyl-4- (1-hydroxy-1-methylethyl) -1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylic acid and its pharmaceutically acceptable salts; pivaloyloxymethyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate and its pharmaceutically acceptable salts; pivaloyloxymethyl 2-butyl-4- (1-hydroxy-1-methylethyl) -1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate and its pharmaceutically acceptable salts; 5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl-4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (tetrazol-5-yl ) phenyl] phenyl} methylimidazole-5-carboxylate and its pharmaceutically acceptable salts; (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl 2-butyl-4- (1-hydroxymethylethyl) -1- {4- [2- (tetrazol-5-yl) phenyl ] phenyl} methylimidazole-5-carboxylate and its pharmaceutically acceptable salts; ethoxycarbonyloxymethyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate and its pharmaceutically acceptable salts; isopropoxycarbonyloxymethyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate and its pharmaceutically acceptable salts; 1- (ethoxycarbonyloxy) ethyl 4- (1-hydroxy-1-methyl-ethyl) -2-propyl-1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate and its pharmaceutically acceptable salts; 1- (isopropoxycarbonyloxy) ethyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate and its pharmaceutically acceptable salts; pivaloyloxymethyl 2-ethyl-4- (1-hydroxy-1-methylethyl) -1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate and its pharmaceutically acceptable salts; (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl 2-ethyl-4- (1-hydroxy-1-methylethyl) -1- {4- [2- (tetrazol-5-yl ) phenyl] phenyl} methylimidazole-5-carboxylate and its pharmaceutically acceptable salts; pivaloyloxymethyl 1- [1 (2'-carboxybiphenyl-4-yl) methyl] -4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate and its pharmaceutically acceptable salts; (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl 1- [(2'-carboxybiphenyl-4-yl) methyl] -4- (1-hydroxy-1-methylethyl) -2- propyl midazole 5-carboxylate and pharmaceutically acceptable salts thereof; phthalidyl 1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate and its pharmaceutically acceptable salts.

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

где R¹ определен выше;
R^d является группой формулы

где R², R³ и R⁴ определены выше,
или R^d представляет собой группу формулы -COOR^f, где R^f является карбокси-защитной группой, группу формулы -COR² где R² определен выше, или циано-группу;
R^e представляет собой циано-группу, карбокси-группу или группу формулы -COOR^f, где R^f определен выше,
с соединением формулы

где R⁶ определен выше;
R^7a является защищенной карбоксильной группой, циано-группой, защищенной тетразол-5-ил-группой, карбамоильной группой, или алкилкарбамоильной группой;
X является атомом галогена,
в результате чего получают соединение формулы

где R^d, R^e, R¹, R⁶ и R^7a определены выше,
и в любом порядке, с последующим удалением защитных групп и при необходимости превращением указанной группы R^d в группу формулы

где R², R³ и R⁴ определены выше,
и при необходимости с превращением указанной группы R^e в группы R⁵, превращением указанной группы R^7a в группу R⁷ или алкилированием или ацилированием гидроксильной группы в R⁴ с получением соединения формулы I, и необязательно, с последующим солеобразованием или этерификацией полученного продукта.For example, in general terms, compounds can be prepared by the reaction of a compound of the formula

where R ^{1 is as} defined above;
R ^d is a group of the formula

where R ² , R ³ and R ^{4 are} defined above,
or R ^d represents a group of the formula —COOR ^f , where R ^f is a carboxy protecting group, a group of the formula —COR ² where R ^{2 is as} defined above, or a cyano group;
R ^e represents a cyano group, a carboxy group or a group of the formula —COOR ^f , where R ^{f is as} defined above,
with a compound of the formula

where R ^{6 is as} defined above;
R ^7a is a protected carboxyl group, a cyano group, a protected tetrazol-5-yl group, a carbamoyl group, or an alkylcarbamoyl group;
X is a halogen atom,
resulting in a compound of the formula

where R ^d , R ^e , R ¹ , R ⁶ and R ^{7a are} defined above,
and in any order, followed by removal of the protective groups and, if necessary, converting said R ^d group into a group of the formula

where R ² , R ³ and R ^{4 are} defined above,
and optionally converting said R ^e group to R ⁵ groups, converting said R ^7a group to R ⁷ group or alkylating or acylating a hydroxyl group to R ⁴ to give a compound of formula I, and optionally followed by salt formation or etherification of the resulting product.

Preferably, if R ^e is a protected carboxyl group when R ^7a is a protected carboxy group protected by a tetrazolyl group and R ^e is a cyano group when R ^7a is a protected carboxyl group or a protected tetrazolyl group.

 In particular, the compounds of the invention can be obtained in accordance with the reaction schemes given at the end of the description.

Reaction Scheme A. In this reaction scheme, a compound of formula I is prepared by reacting an imidazole-5-carboxylic acid or its ester of formula V with a biphenylmethyl halide of formula III, followed by, if necessary, removal of the protecting groups, conversion of the group of the formula —COOR ^5a to any another group represented by R ⁵ by converting the group represented by R ^7a to any other group represented by R ⁷ and / or by alkylating or acylating a hydroxy group in R ⁴ , as shown in reaction scheme A, where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^5a , R ⁶ , R ⁷ , R ^7a and X are defined above.

If R ^7a is a protected carboxyl group, then the protective group may be any ester residue of the above illustrated for R ^5a . Alternatively, R ^7a may be a carbamoyl group or a substituted carbamoyl group of the formula CONHR, where R represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, for example, any of the groups illustrated above for R ¹ . Examples of such carbamoyl groups which R ^7a may represent are carbamoyl, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, t-butylcarbamoyl, pentylcarbamoyl, t-pentylcarbamoyl, and hexylcarbamoyl-carbamoyl, of which If R ^7a is a protected tetrazolyl group, then the protective group can be any protective group that is commonly used to block tetrazolyl groups in standard compounds of this type. Examples of suitable protecting groups are aralkyl groups defined and illustrated above for R ² , however, a benzyl, diphenylmethyl (benzhydryl) and triphenylmethyl (trityl) group are preferred, and a trityl group is most preferred. X is a halogen atom, preferably a chlorine, bromine or iodine atom.

 In step AI of Reaction Scheme A, a compound of formula Ia is prepared by reacting an imidazole-5-carboxylate compound of formula V with a biphenylmethyl compound of formula III. Usually and preferably, the reaction proceeds in an inert solvent and preferably in the presence of a base.

 The reaction is usually and preferably carried out in the presence of a solvent. In principle, there are no particular restrictions on the nature of the solvent, provided that it does not adversely affect the reaction or reagents and is capable of dissolving the reagents, at least to a certain extent. Examples of suitable solvents are 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 acetonitriles, and sulfoxides, such as dimethyl sulfoxide. Of these solvents, amides, ketones, nitriles and sulfoxides are preferred.

 Similarly, the nature of the base used in the reaction is not critical, and any base capable of reacting with acid H-X may be used in this reaction. Examples of preferred bases that can be used in the reaction are alkali metal carbonates, such as sodium or potassium carbonate, alkali metal hydrides, such as sodium, potassium or lithium hydride, alkali metal alkoxides, such as sodium methoxide, sodium ethoxide potassium t-butoxide or lithium methoxide, and alkali metal bicarbonates, such as sodium or potassium bicarbonate. Of these, alkali metal carbonates, alkali metal hydrides or alkali metal alkoxides are preferred.

This reaction can take place over a wide range of temperatures and the specific temperature is not critical to the invention. But, basically, a suitable reaction temperature is from -10 to 100 ^° C, and more preferably a temperature of 0-80 ^° C. The time required for the reaction can also vary widely, depending on many factors, namely reaction temperatures and the nature of the reactants and solvent involved in the reaction. However, under the preferred reaction conditions, this time is from 30 minutes to 24 hours, and more preferably 1-16 hours.

 After completion of the reaction, the desired compound of formula Ia can be reduced from the reaction mixture by standard methods. One such method is to remove the solvent by distillation under reduced pressure, mix the resulting residue with water, extract the residue with a water-immiscible solvent such as ethyl acetate, dry the resulting extract, for example anhydrous sodium sulfate, and isolate the product from the solvent by distillation. If necessary, the resulting product can be purified by standard methods, for example, by recrystallization, or using chromatographic techniques, for example preparative thin layer chromatography or column chromatography.

Stage A2 may include one or (if appropriate) several of the following reactions:
I) removing carboxy-protecting groups selectively or non-selectively from a group of the formula —COOR ^5a and / or an R ^7a group to convert it (or them) to a free carboxy group represented by R ⁵ or R ⁷ ;
II) the esterification of any specified free carboxyl group to obtain a group, such as, for example, illustrated above for R ⁵ ;
III) converting said free carboxyl group represented by R ⁵ into a group of the formula —CONR ⁸ R ⁹ ;
Iv) removing the tetrazolyl protecting group;
V) the conversion of the cyano group represented by R ^7a into a tetrazolyl group;
VI) the conversion of a monoalkylcarbamoyl group or a carbamoyl group represented by R ^7a , first into a cyano group and then into a tetrazolyl group;
VII) in the case where R ⁴ represents a tri-substituted silyl group, an aralkyl group, an aliphatic acyl group, an alkoxymethyl group, an alkoxyalkoxymethyl group, a haloalkoxymethyl group, a tetrahydropyranyl group, a tetrahydrothiopyranyl tetrahydrothienidi tetrahydrothienidi tetrahydrothienidi tetrahydrothienidi tetrahydrothienidi tetrahydrino tetranidyl tetrahydrinoid, tetrahydrothirani tetrahydrinoid, tetrahydro-tyrnidiothirophenyl, tetrahydrothiopyrnyl, tetrahydrothiopyranyl, tetrahydrothiopyrnyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl and tetrahydrothiopyranyl groups. or a tetrahydrofuryl group having a halogen or alkoxy substituent, all of which may be considered ak-protected hydroxy group, the deprotection is carried out to give a compound wherein R ⁴ represents a hydrogen atom;
VIII) if R ⁴ is a hydroxyl group, then alkylation or acylation of this group is carried out.

 I. Removal of the carboxy protecting group.

 The type of reaction used to remove the carboxy protecting group depends on the nature of the group to be removed and is well known to those skilled in the art of organic synthesis.

 For example, if the carboxy-protecting group is an aralkyl group, for example, a benzyl or p-nitrobenzyl group, then this protective group can be removed by catalytic reduction in the presence of hydrogen at atmospheric pressure or at atmospheric pressure, for example up to 5 atm. Usually and preferably, the reaction proceeds in an inert solvent, preferably in an alcohol, such as methanol or ethanol, or a carboxylic acid, such as acetic acid, and in the presence of a catalyst. Any catalyst commonly used for catalytic hydrogenation or reduction, preferably palladium carbon or platinum oxide, can be used in this reaction.

 If the carboxy-protecting group is t-butyl or diphenylmethyl, then this group can be removed by reaction of the protected compound with an acid, preferably a mineral acid, such as hydrochloric or sulfuric acid, or an organic acid, such as p-toluenesulfonic 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 the carboxy-protecting group is a silyl group, then it may be a group of the formula SiR ^a R ^b R ^c in which R ^a , R ^b and R ^{c are as} defined above. In this case, the protecting group can be removed by reacting the protected compound with an acid, preferably a mineral acid, such as acetic acid, trifluoroacetic acid, methanesulfonic acid or p-toluenesulfonic acid, or a fluorine salt, such as tetrabutylammonium fluoride. Usually and preferably, the reaction proceeds in an inert solvent, preferably in an ether, such as tetrahydrofuran or dioxane, an alcohol, such as methanol or ethanol, such as N, N-dimethylforiamide, N, N-dimethylacetamide, water or a mixture of water and one or more of the solvents mentioned above.

If the carboxy protecting group is an ester residue, then the protecting group can be removed by hydrolysis using a base, preferably an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide, or an alkali metal carbonate such as sodium carbonate or carbonate potassium, in an inert solvent, preferably in an alcohol, such as methanol or ethanol, in ether, such as tetrahydrofuran or dioxane, in water or in a mixture of water and one or more organic solvents Above. If R ⁴ is an acyl group, then it can be removed during the reaction.

The reaction can be carried out over a wide range of temperatures and the exact value of the reaction temperature does not play a decisive role. A generally suitable reaction temperature is 0-100 ^° C., and more preferably 60 ^° C. The reaction time can also vary widely depending on many factors, namely the reaction temperature and the nature of the reagents and solvent. However, under the preferred reaction conditions outlined above, this period is from 30 minutes to 24 hours, and more preferably 1-16 hours.

 After completion of the reaction, the desired compound can 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, then the target product can be restored by filtering the catalyst and distilling off the solvent. If the unlocking is carried out using an acid, the target product can be isolated by collecting 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 distillation of the solvent and then neutralization of the residue with aqueous acid, followed by collection of the obtained precipitate in an aqueous solvent by filtration; alternatively, this product can be isolated by neutralizing the aqueous layer obtained by extraction of the reaction mixture a water-immiscible organic solvent (such as ethyl acetate or diethyl ether), then extracting the neutralized solution with water esmeshivayuschimsya organic solvent (such as ethyl acetate), followed by distilling off the solvent. If necessary, the reaction product can be purified by standard methods, for example, by recrystallization or using various chromatographic techniques, for example preparative thin layer chromatography or column chromatography.

Each of the protecting groups represented by R ^5a and R ^7a can be selectively eliminated with an appropriate choice of protecting groups and specific reaction conditions in order to remove it.

 II. Esterification.

If the resulting compound contains one or more free carboxyl groups, then this group or these groups can be esterified by standard methods known in organic chemistry. For example, this reaction can be carried out by reacting the corresponding carboxylic acid with a compound of the formula R ^5b —Y, where R ^5b may be any of the groups defined above for R ^5a and Y is a halogen atom, for example, a chlorine, bromine or iodine atom, a group of the formula —OSO ₃ R ^5b , wherein R ^{5b is as} defined above, or by a sulfonyloxy group such as methanesulfonyloxy or p-toluenesulfonyloxy group. The reaction is carried out in the presence of a base, for example an organic amine, such as triethylamine, pyridine or N-methylmorpholine, an alkali metal carbonate, such as sodium or potassium carbonate, or an alkali metal bicarbonate, such as sodium bicarbonate or potassium bicarbonate. Usually and preferably, the reaction is carried out in an inert solvent, preferably in an amide, such as N, N-dimethylformamide or N, N-dimethylacetamide, a halogenated hydrocarbon, preferably a halogenated aliphatic hydrocarbon, such as methylene chloride, a ketone, such as acetone or methyl ethyl ketone, or ether, such as tetrahydrofuran or dioxane. If the desired ester group is an alkyl group, the reaction is carried out by reacting the carboxylic acid with the corresponding dialkyl sulfate.

The reaction can be carried out over a wide range of temperatures and the exact value of the reaction temperature does not play a decisive role. In general, a suitable reaction temperature is from 0-120 ^° C., and more preferably 20-80 ^° C. The reaction time can also vary widely depending on many factors, in particular the reaction temperature and the nature of the reagents and solvent. However, under the preferred reaction conditions outlined above, this period is from 30 minutes to 24 hours, and more preferably 1-16 hours.

If the carboxy-protecting group is a C ₁ -C ₆ alkyl group, then the esterification reaction can be carried out by reacting a carboxylic acid with a C ₁ -C ₆ alcohol, such as methanol, ethanol, propanol or hexanol, in the presence of an acid catalyst, such as hydrogen chloride or sulfuric acid, in an inert solvent, for example in one of the C ₁ -C ₆ alcohols, which can be used as the starting material described above, a halogenated hydrocarbon such as methylene chloride or in an ether such as tetrahydrofuran or dioxane at a temperature of 0-100 ^o C for 1-24 hours or by reacting the corresponding carboxylic acid with a halogenation agent, for example phosphorus pentachloride, thionyl chloride or oxalyl chloride, in an inert solvent, for example a halogenated hydrocarbon such as methylene chloride, an ether such as tetrahydrofuran or dioxane, or an aromatic hydrocarbon such as benzene or toluene, at approximately room temperature for a period of 30 minutes to 5 hours, to obtain the corresponding acyl halide, which is then under They react with the corresponding alcohol in an inert solvent, for example benzene or methylene chloride, in the presence of a base, for example triethylamine, and in the case of t-butyl ester, it is preferable to use potassium t-butoxide, at about room temperature for a period of 30 minutes to 10 h. The target compound can be restored in a standard manner, for example, by the method described above for step A1.

 III. The formation of carbamoyl groups.

The conversion of the carboxyl group represented by R ⁵ to a group of the formula —CONR ⁸ R ⁹ where R ⁸ and R ^{9 are} defined above can be carried out by standard methods, for example, by reacting a carboxylic acid compound in which the R ⁷ group is protected with a compound formulas
R ⁸ R ⁹ NH (VI),
where R ⁸ and R ^{9 are as} defined above.

 This reaction involves the formation of a 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, an ester such as ethyl acetate, an ether such as tetrahydrofuran or dioxane, or an amide such as as N, N-dimethylacetamide or N, N-dimethylformamide, in the presence of a condensing agent.

 Examples of condensing agents that can be used in this reaction are carbodiimides, such as N, N-dicyclohexylcarbodiimide or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, phosphoryl compounds, such as diphenylphosphoryl azide or diethylphosphoryl diphenyl diphenyl carbamide - diethyl azodicarboxylate. Of these, carbodiimides and diphenylphosphoryl azide are most preferred. If a phosphoryl compound is used, the reaction is preferably carried out in the presence of a tertiary amine, such as triethylamine or N-methylmorpholine.

 Alternatively, in this step, the reaction can be carried out by reacting a carboxylic acid with a (lower) alkyl chloroformate, such as ethyl chloroformate or isobutyl chloroformate, in the presence of a tertiary amine such as triethylamine or N-methylformolin, to obtain a mixed acid anhydride or by reacting a carboxylic acid with N-hydroxysuccinimide, N-hydroxybenzotrazole or p-nitrophenol or the like in the presence of carbodiimide, such as N, N-dicyclohexylcarbodiimide, to give the corresponding active ester and followed by reaction of the mixed acid anhydride or active ester with an amine compound of formula VI.

 As another alternative, the reaction in this step can be carried out by reacting the carboxylic acid with a halogenating agent such as phosphorus pentachloride, oxalyl chloride or thionyl chloride in an inert solvent, such as a halogenated hydrocarbon such as methylene chloride, an ether such as tetrahydrofuran or dioxane, or an aromatic hydrocarbon such as benzene or toluene, to give the corresponding acyl halide, followed by reaction of the acyl halide with an amine compound of formula VI.

All these reactions can be carried out in a wide temperature range and the exact temperature does not play a decisive role. In general, a suitable reaction temperature is from −20 ^° C. to 100 ^° C., and more preferably from −5 ^° C. to 50 ^° C. The reaction time can also vary widely depending on many factors, in particular the reaction temperature and nature reagents and solvent. However, under the preferred reaction conditions outlined above, this period is from 30 minutes to 24 hours, and more preferably 1-16 hours.

 After completion of the reaction, the resulting product can be isolated from the reaction mixture by standard methods. For example, the material insoluble in the reaction system is filtered off, a water-immiscible organic solvent, such as ethyl acetate, is added to the filtrate, and water, the organic solvent layer is separated and dried in the presence of a drying agent, such as anhydrous magnesium sulfate, and then the solvent is distilled off to obtain the target product . If necessary, the reaction product can then be purified by standard methods, for example, by recrystallization or using various chromatographic techniques, for example preparative thin-layer chromatography or column chromatography.

 IV. Removal of tetrazolyl-protecting groups.

 Said reaction can be carried out by reacting the protected compound with an acid. Usually and preferably, the reaction is carried out in an inert solvent.

 The reaction is preferably carried out in the presence of a solvent. In principle, there are no particular restrictions on the nature of the solvent, provided that it does not adversely affect the reaction or reagents, and has the ability to dissolve the reagents, at least to a certain extent. Examples of suitable solvents are an organic acid, such as acetic acid, an ether, such as tetrahydrofuran or dioxane, an alcohol, such as methanol, ethanol or t-butanol, or a mixture of any of two or more of these solvents. Of these solvents, water, an organic acid, an alcohol, or a mixture thereof are most preferred.

 Basically, there are no specific restrictions on the acid used in this reaction, provided that it is able to function as Bronsted acid. Preferred examples of such acids are organic acids, such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid or trifluoroacetic acid and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid. Of these, acetic acid, formic acid, trifluoroacetic acid or hydrochloric acid are preferred.

The reaction can take place over a wide range of temperatures, and the precise temperature is not critical to the invention. A generally suitable reaction temperature is from -10 ^° C to 120 ^° C, and more preferably 0-100 ^° C. The time required for the reaction can also vary widely and depends on many factors, in particular the reaction temperature and the nature of the reagents and solvent. However, under the preferred reaction conditions outlined above, this period is 0.5-24 hours, and more preferably 1-16 hours.

 After completion of the reaction, the resulting product can be isolated from the reaction mixture by standard methods. For example, after distilling off the solvent, the residue is dissolved in water and a water-immiscible organic solvent. The organic layer containing the desired compound is separated and dried with anhydrous magnesium sulfate. After distilling off the solvent, the desired compound is obtained. If necessary, the reaction product can be purified by standard methods, for example, by recrystallization or using various chromatographic techniques, for example preparative thin layer chromatography or column chromatography.

 V. Conversion of the cyano group to a tetrazolyl group.

 In this step, the cyano group is converted to the tetrazolyl group by reaction of the cyano compound with an alkali metal azide.

 The reaction is preferably carried out in the presence of a solvent. In principle, there are no specific restrictions on the nature of the solvent, provided that it does not adversely affect the reaction or 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-dimethylforiamide or N, N-dimethylacetamide, ethers, such as dioxane or 1,2-dimethoxyethane, and sulfoxides, such as dimethyl sulfoxide.

 Examples of suitable alkali metal azides are lithium azide, sodium azide and potassium azide, of which sodium azide is preferred. There are no particular restrictions on the amount of alkali metal azide used, but it is preferable to use 1-5 equivalents. and more preferably 1-3 eq. alkali metal azide per 1 equiv. cyano compounds.

 It is also preferred that the reaction proceeds in the presence of ammonium halide, for example ammonium fluoride, ammonium chloride or ammonium bromide, of which ammonium chloride is preferred. There are no specific restrictions on the amount of ammonium halide used, however, 0.5-2 equiv. and more preferably 1-1.2 equiv. ammonium halide at 1 equiv. cyano compounds.

The reaction can take place over a wide range of temperatures, and the precise temperature is not critical to the invention. Basically, a suitable reaction temperature is 70-150 ^° C., and more preferably 80-120 ^° C. The time required for the reaction can also vary widely, depending on many factors, in particular the reaction temperature and the nature of the reagents and solvent. However, under the preferred reaction conditions outlined above, this period is from 10 hours to 7 days, and more preferably 1-5 days.

 Alternatively, the cyano group can be converted to a tetrazolyl group by reacting the cyano compound with a trialkyltin azide or triaryl tin azide, followed by treating the tin compound with an acid, base or alkali metal fluoride.

 The reaction of the cyano compound with a trialkyltin azide or triaryl tin azide is usually and preferably carried out in the presence of a solvent. In principle, there are no particular restrictions on the nature of the solvent, provided that it does not adversely affect the reaction or 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, and esters, such as ethyl acetate or butyl acetate.

Although the nature of the trialkyltin azide or triaryl tin azide is not particularly limited and any compound of this type can be used in this reaction, it is preferable that the trialkyltin azide in which each of the alkyl groups, which may be the same or different, but rather the same, has 1- 4 carbon atoms, for example, such as trimethyltin azide, triethyltin azide or tributyltin azide, or triaryl tin azide, in which each of the aryl groups, which may be the same or different, is better are not the same, are as defined above with respect to aryl groups which may be represented by R ² , preferably phenyl or substituted phenyl groups, and triphenyltin azide and tritolyltin azide are examples of this. The amount of trialkyltin azide or triaryl tin azide used is not critical, although 1-3 eq. by 1 equiv. cyano compounds, and more preferred 1-2 eq. by 1 equiv. cyano compounds.

The reaction of the cyano compound with trialkyltin or triaryl tin azide can take place over a wide range of temperatures, and the exact temperature is not critical to the invention. A generally suitable reaction temperature is 60-150 ^° C., and more preferably 80-120 ^° C. The time required for the reaction can also vary widely depending on many factors, in particular the reaction temperature and the nature of the reagents and solvent. However, under the preferred reaction conditions outlined above, this period is from 8 hours to 7 days, and more preferably 1-5 days.

 The tin-containing compound resulting from the above reaction is then treated with an acid, base or alkali metal fluoride to convert it to a tetrazolyl compound. Any acid, base or alkali metal fluoride can be used in the reaction of this type, and examples of suitable compounds are acids, in particular mineral acids, such as hydrochloric acid or sulfuric acid, bases, in particular inorganic bases, such as alkali metal carbonates and alkali metal bicarbonates, for example sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate, or alkali metal hydroxides, for example sodium or potassium hydroxide, alkali metal fluorides, e, like lithium fluoride, sodium fluoride or potassium fluoride.

The reaction is usually and preferably carried out in the presence of a solvent. In principle, there are no specific restrictions on the nature of the solvent, provided that it does not adversely affect the reaction or reagents and has the ability to dissolve these reagents at least to a certain extent. Examples of suitable solvents are those listed above for the reaction of a cyano compound with a trialkyltin or triaryl tin azide, and other solvents such as alcohols, for example methanol or ethanol, water or aqueous alcohols. The reaction can take place over a wide range of temperatures and the exact temperature does not play a significant role for the present invention. Generally suitable for carrying out the reaction, the temperature is 0-100 ^° C. and preferably room temperature. The time required to carry out the reaction can also vary widely depending on many factors, in particular the reaction temperature and the nature of the reagents and solvent used. However, under the preferred reaction conditions outlined above, this period is from 30 minutes to 3 days, and more preferably 1-24 hours.

 Another alternative method for converting a cyano group to a tetrazolyl group involves reacting the cyano compound with a trialkyltin or triaryl tin halide in the presence of an alkali metal azide, followed by treating the resulting tin compound with an acid, base or alkali metal fluoride.

 The reaction of a cyano compound with a trialkyltin or triaryltin halide in the presence of an alkali metal azide usually and preferably proceeds in the presence of a solvent. In principle, there are no particular restrictions on the nature of the solvent used, provided that it does not adversely affect the reaction or reagents and has the ability to dissolve these reagents at least to a certain extent. Examples of suitable solvents are hydrocarbons, which can be aliphatic or aromatic hydrocarbons, such as benzene, toluene, xylene or heptane, halogenated hydrocarbons, in particular halogenated aliphatic hydrocarbons, such as 1,2-dichloroethane or chloroform, ethers, such 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, and esters, such as ethyl acetate or butyl acetate.

Although there are no particular restrictions on the nature of the trialkyltin halide or triaryltin halide and any of these compounds can be used in the reaction of the indicated type, the preferred compounds are the trialkyltin halide in which each of the alkyl groups, which may be the same or different, and preferably the same, have 1 -4 carbon atoms, for example, such as trimethyltin chloride, trimethyltin bromide, triethyltin chloride or tributyltin chloride, or triaryl tin halide, in which each of the aryl groups, torye may be identical or different, preferably identical, are as previously defined in relation to the aryl groups for R ^2, but preferably phenyl or substituted phenyl group, wherein examples of the aforementioned halide trialkyltin and halide triaryltin are chloride trifenioolova or chloride tritolilolova . The amount of trialkyltin or triaryl tin halide used in the reaction is not critical, although 1-3 eq. by 1 equiv. cyano compounds, and more preferably 1-2 eq. on the cyano compound.

 There are also no particular restrictions on the alkali metal azide used in this reaction. Examples of such an azide are lithium azide, sodium azide and potassium azide, of which sodium azide is preferred. The amount of alkali metal azide used is not critical, however, it is preferable to use 1-3 eq. by 1 equiv. cyano compounds, and more preferably 1-2 eq. by 1 equiv. cyano compounds.

The reaction of a cyano compound with a trialkyltin or triaryltin halide in the presence of an alkali metal azide can proceed over a wide range of temperatures and the exact temperature does not play a significant role for the present invention. Basically, a suitable temperature for carrying out the reaction is 60-150 ^° C., and preferably 80-120 ^° C. The time required for carrying out the reaction can also vary widely depending on many factors, in particular the reaction temperature and the nature of the reagents and solvent used . However, under the preferred reaction conditions outlined above, this period is from 8 hours to 7 days, and more preferably 1-5 days.

 The tin-containing compound resulting from the above reaction is then treated with an acid, base or alkali metal fluoride in order to convert it to a tertrazolyl compound. This reaction is basically similar to the reaction of a tin-containing compound obtained by reacting a cyano compound with a trialkyltin or triaryl tin azide with an acid, base or alkali metal fluoride, and can be carried out using the same solvents and reaction conditions.

 VI. Conversion of an alkyl carbomoyl group or carbamoyl group to a cyano group.

 In order to convert the alkyl carbamoyl group to the cyano group, the alkyl carbamoyl compound is reacted with a halogen compound which is a halogenating agent, preferably a chlorinating agent, for example, oxalyl chloride, phosphorus oxychloride or sulfonyl chloride. The amount of halogen compound used is not critical, although 1-3 eq. and more preferably 1-2 eq. one equivalent carbamoyl compound.

 The reaction is usually and preferably carried out in the presence of a solvent. In principle, there are no specific restrictions on the nature of the solvent, provided that it does not adversely affect the reaction or reagents and has the ability to dissolve these reagents at least to a certain extent. Examples of suitable solvents are a hydrocarbon, which can be an aliphatic or an aromatic hydrocarbon, such as benzene, toluene, xylene or heptane, a halogenated hydrocarbon, in particular a halogenated aliphatic hydrocarbon, 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 can take place over a wide range of temperatures, and the precise temperature is not critical to the invention. In general, a suitable temperature is from -10 to 100 ^° C, and more preferably 0-50 ^° C. The time required for the reaction to be carried out can also vary widely depending on many factors, in particular the reaction temperature and the nature of the reagents used and solvent. However, under the preferred reaction conditions outlined above, this period is from 10 minutes to 16 hours, and more preferably from 30 minutes to 6 hours.

 To convert the carbamoyl group to a cyano group, the carbamoyl compound is reacted with a dehydrogenating agent, for example, acetic anhydride, trifluoroacetic anhydride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, oxalyl chloride or aminosulfonylamine, for example, trimethylamine amide, trimethyl organolamine, amyridine or amine triamine.

 The reaction is preferably carried out in the presence of a solvent. In principle, there are no specific restrictions on the nature of the solvent, provided that it does not adversely affect the reaction or reagents and has the ability to dissolve these reagents, at least to a certain extent. Examples of suitable solvents are hydrocarbons, which can be either aliphatic or aromatic hydrocarbons, such as benzene, toluene, xylene or heptane, halogenated hydrocarbons, in particular 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 can take place over a wide range of temperatures and the exact temperature does not play a significant role for the present invention. In general, a suitable temperature is from -10 to 100 ^° C, and more preferably 0-50 ^° C. The time required to carry out the reaction can also vary widely depending on many factors, in particular the reaction temperature and the nature of the reagents and solvent used . However, under the preferred reaction conditions outlined above, this period is from 10 minutes to 16 hours, and more preferably from 30 minutes to 6 hours.

 The target product of this reaction can be isolated from the reaction mixture by standard methods, for example, by neutralizing the mixture with a weak base, such as sodium bicarbonate, followed by treating the product with a method similar to that described for stage A1 of reaction mixture A.

 The cyano compound thus obtained can then be converted to the corresponding tetrazolyl compound using the reactions described above.

 VII. Removal of hydroxy protecting groups.

If R ⁴ is a tri-substituted silyl group, an aralkyl group, an acyl group, an alkoxymethyl group, a tetrahydropyranyl group, a tetrahydrothiopyranyl group, a tetrahydrothienyl group, a tetrahydrofuryl group or a substituted tetrahydropyranyl, tetrahydrothienyl or tetrahydrofuryl group, which may be considered a hydroxy protecting group the group can be removed to form a compound in which R ⁴ is a hydrogen atom. The type of reaction used to remove the protective group depends on the nature of the protective group and reactions well known to those skilled in the art can be used to unlock compounds of this type.

 If the hydroxy protecting group is a silyl group, then it can be removed by treating the protected compound with a compound capable of forming a fluorine anion, such as tetrabutylammonium fluoride. The reaction is preferably carried out in the presence of a solvent. In principle, there are no specific restrictions on the nature of the solvent, provided that it does not adversely affect the reaction or 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 can take place over a wide range of temperatures and the exact value of the temperature does not play a decisive role. A generally suitable temperature is room temperature. The time required to carry out the reaction can also vary widely depending on many factors, in particular the reaction temperature and the nature of the reagents and solvent used. However, under the preferred reaction conditions indicated above, this period is 10-18 hours.

If the hydroxy-protecting group is an aralkyl group, then the unlocking can be carried out by catalytic reduction at a temperature of 0-80 ^o C, and more preferably 10-60 ^o C, in a solvent in the presence of hydrogen and a catalyst.

 The reaction is preferably carried out in the presence of a solvent. In principle, there are no specific restrictions on the nature of the solvent, provided that it does not adversely affect the reaction or 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 acetate, fatty acids, such as acetic acid, or mixtures of water and one or more of these organic solvents.

 In the reaction under consideration, any catalyst that is commonly used in catalytic reduction can be used. Examples of preferred catalysts are palladium carbon, a skeletal nickel hydrogenation catalyst, platinum oxide, platinum black, rhodium-coated alumina, a complex of triphenylphosphine and rhodium chloride and palladium barium sulfate.

 The hydrogen pressure used in the reaction is not critical and can vary widely, although the reaction is preferably carried out at a pressure that is 1-3 times higher than atmospheric pressure.

The reaction can take place over a wide range of temperatures and the exact temperature does not play a significant role for the present invention. In general, a suitable temperature is 0-100 ^° C., and more preferably 10-50 ^° C. The time required to carry out the reaction can also vary widely depending on many factors, in particular on the reaction temperature and the nature of the reagents and solvent used. However, under the preferred reaction conditions outlined above, this period is from 5 minutes to 24 hours, and more preferably from 30 minutes to 16 hours.

 If the hydroxy protecting group is an aliphatic acyl group, an aromatic acyl group or an alkoxy carbonyl group, then it can be removed by treating the protected compound with a base.

 In this case, any base may be used, provided that it does not adversely affect other parts of the compound. Examples of preferred bases are metal alkoxides, in particular alkali metal alkoxides, such as sodium methoxide, alkali metal carbonates, such as sodium or potassium carbonate, alkali metal hydroxides, such as sodium 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 are no specific restrictions on the nature of the solvent, provided that it does not adversely affect the reaction or reagents and has the ability to dissolve these reagents, at least to a certain extent. Examples of suitable solvents are water, organic solvents such as alcohols, for example methanol, ethanol or propanol, or ethers, for example tetrahydrofuran or dioxane, or a mixture of water and one or more of the above organic solvents.

The reaction can take place over a wide range of temperatures and the exact value of the temperature does not play a decisive role. In general, a suitable temperature is 0-150 ^° C., and more preferably 0-60 ^° C. The time required to carry out the reaction can also vary widely depending on many factors, in particular the reaction temperature and the nature of the reagents and solvent used. However, under the preferred reaction conditions outlined above, this period is 1-20 hours, and preferably 1-16 hours.

 If the hydroxy-protecting group is an alkoxymethyl group, alkoksialkoksimetilnaya group galogenalkoksimetilnaya group, tetrahydropyranyl group, tetrahydrothiopyranyl group, a tetrahydrofuranyl group, a tetrahydrothienyl group or a substituted tetrahydropyranyl, tetrahydrothiopyranyl, totragidrofuranilnaya or tetragidrotienilnaya group having at least one halogen or alkoxy substituent, it can be removed by treating the protected compound with an acid.

 There are no specific restrictions on the acid used in this reaction, and any Bronsted acid can be used in this case. Examples of preferred acids are inorganic acids, in particular mineral acids, such as hydrochloric acid or sulfuric acid, and an organic acid, for example carboxylic acids and sulfonic acids, such as acetic acid or p-toluenesulfonic acid. Strong cation exchange resin acids, such as Dowex 50W (trademark), can also be used in this reaction.

 The reaction is preferably carried out in the presence of a solvent. In principle, there are no specific restrictions on the nature of the solvent, provided that it does not adversely affect the reaction or 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 can take place over a wide range of temperatures and the exact value of the temperature does not play a decisive role. In general, a suitable temperature is 0-50 ^° C. The time required to carry out the reaction can also vary widely depending on many factors, in particular the reaction temperature and the nature of the reagents and solvent used. However, under the preferred reaction conditions outlined above, this period is from 10 minutes to 18 hours.

 After completion of any of the above reactions, the target compound of the present invention can be isolated from the reaction mixture by standard methods, the choice of which depends on the nature of the reaction and the reaction medium. One such method is that the reaction mixture is neutralized, any insoluble material that may be present in the mixture, for example, by filtration, is removed, a water-immiscible organic solvent is added, washed with water and the solvent is distilled off. If necessary, the obtained product can be purified by standard methods, for example, by recrystallization or by various chromatographic techniques, such as preparative thin layer chromatography or column chromatography.

 Sometimes, incidentally, under the conditions used to remove the hydroxy-protecting group, a protected carboxy-group can be simultaneously unlocked.

 Viii. Alkylation and acylation of hydroxy groups.

 Alkylation of the hydroxy group can be carried out by reacting the hydroxy compound with an alkyl halide in which the alkyl group has 1-6 atoms, preferably methyl iodide, ethyl iodide, ethyl bromide, propyl iodide, propyl bromide or butyl iodide or dialkyl sulfate, in which the alkyl groups have 1-6 carbon atoms and may be the same or different, and preferably the same, such as dimethyl sulfate or diethyl sulfate.

 The reaction is preferably carried out in the presence of a solvent. In principle, there are no specific restrictions on the nature of the solvent, provided that it does not adversely affect the reaction or 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-methylpyrrolidinone, ketones, such as acetone or methyl ethyl ketone, or sulfoxides, such as dimethyl sulfoxide.

The reaction is carried out in the presence of a base, the nature of which is not critical, unless it adversely affects the reactants or products. Examples of preferred bases are alkali metal hydrides, such as sodium hydride, potassium hydride or lithium hydride. The reaction can take place over a wide range of temperatures and the exact temperature does not play a significant role for the present invention. The temperature generally suitable for carrying out the reaction is 0-120 ^° C., and preferably 20-80 ^° C. The time required for the reaction may also vary widely depending on many factors, in particular the reaction temperature and the nature of the reagents and solvent used . However, under the preferred reaction conditions outlined above, this period is from 30 minutes to 24 hours, and more preferably 1-16 hours. The acylation of the carboxy group can also be carried out by standard methods commonly used in organic chemistry. For example, it can be carried out by reacting a hydroxyl compound with an alkanoyl halide containing 2-6 carbon atoms, such as acetyl chloride, propynyl chloride, buturyl bromide, valeryl chloride or hexanoyl chloride, with a carboxylic acid anhydride in which the group derived from carboxylic acid contains 1- 6, and preferably 2-6, carbon atoms, for example, such as mixed formic and acetic anhydride, acetic anhydride, propionic acid anhydride, valeric anhydride or hexane anhydride acid, with an alkoxycarbonyl halide in which the alkoxy group contains 1 to 6 carbon atoms, such as methoxycarbonyl chloride, methoxycarbonyl bromide, ethoxycarbonyl chloride, propoxycarbonyl chloride, butoxycarbonyl chloride or hexyloxycarbonyl chloride, benzoyl-benzoyl halide, such as a halide containing 2-6 carbon atoms, such as chloroacetyl chloride, dichloroacetyl chloride, trichloroacetyl chloride or methoxyacetyl chloride, or with an alkenyl chloride containing 3-6 atoms carbon atoms such as acryloyl chloride, methacryloyl chloride, crotonoyl chloride, 3-methyl-2-butenoyl chloride or 2-methyl-2-butenoyl chloride.

The reaction is preferably carried out in the presence of a solvent. In principle, there are no particular restrictions on the nature of the solvent, provided that it does not adversely affect the reaction or reagents and has the ability to dissolve these reagents at least to a certain extent. Examples of suitable solvents are halogenated hydrocarbons, in particular 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 an organic tertiary amine, for example triethylamine, pyridine, diethylisopropylamine or 4-dimethylaminopyridine. The reaction can take place over a wide range of temperatures and the exact temperature does not play a significant role for the present invention. The temperature generally suitable for carrying out the reaction is from -10 ^° C to 120 ^° C, and more preferably 0-80 ^° C. The time required to carry out the reaction can also vary widely depending on many factors, in particular the reaction temperature and the nature of the reagents and solvent used. However, under the preferred reaction conditions outlined above, this period is from 30 minutes to 24 hours, and more preferably 1-16 hours.

 After completion of any of the above reactions, the target product can be isolated from the reaction mixture by standard methods. Examples of such isolation methods have already been indicated in the description of the isolation of the product in step A1.

 Reaction Scheme B.

Compounds of formula Ia in which R ⁴ is a hydrogen atom, that is, in other words, compounds of formula Ib can also be obtained in accordance with the reaction scheme B presented at the end of the description, in the formulas of which R ¹ , R ² , R ³ , R ^5a , R ⁶ , R ^7a and X are defined by the meanings indicated above.

 In step B1, an imidazole-5-carboxylate compound of formula VII is reacted with a biphenylmethyl compound of formula III to form a compound of formula VIII. This reaction is basically similar to the reaction of step A1 in reaction scheme A and can be carried out using the same reagents and the same reaction conditions.

In step B2, a compound of formula Ib is prepared by reacting a compound of formula VIII with a reducing agent or with a Grignard reagent of formula R ^3a- Mg-X, where R ^3a is any of the groups defined above for R ³ and is not a hydrogen atom, but X is defined above.

 Examples of reducing agents that can be used in this reaction are alkyl aluminum hydrides, such as diisobutylaluminum hydride, and metal borohydrides, in particular alkali metals, such as sodium borohydride or sodium cyanoborohydride. Of these, aluminum hydride and sodium borohydride are preferred.

 The reaction of the compound of formula VIII with a reducing agent usually and preferably proceeds in an inert solvent. In principle, there are no particular restrictions on the nature of the solvent, provided that it does not adversely affect the reaction or 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 above organic solvents. Preferred solvents are selected depending on the nature of the reducing agent used. For example, if the reducing agent is alkyl aluminum hydride, then the preferred solvents are hydrocarbons or ethers, and alternatively, if such an agent is alkali metal borohydride, then the preferred solvents are alcohols, water, or mixtures of water and alcohol.

The reaction can take place over a wide range of temperatures and the exact temperature does not play a significant role for the present invention. The temperature suitable for carrying out the reaction is generally from -30 to 80 ^° C, and more preferably from -20 to 20 ^° C, if the reducing agent is alkyl aluminum hydride, or from -30 to 80 ^° C, and more preferably 0-50 ^° C C, if the specified agent is an alkali metal borohydride. The time required to carry out the reaction can also vary widely depending on many factors, in particular the reaction temperature and the nature of the reagents and solvent used. However, under the preferred reaction conditions outlined above, this period is from 30 minutes to 24 hours, and more preferably 1-16 hours.

 The reaction of a compound of formula VIII with a Grignard reagent is usually and preferably carried out in the presence of a solvent. In principle, there are no particular restrictions on the nature of the solvent, provided that it does not adversely affect the reaction or reagents and has the ability to dissolve these reagents at least to a certain extent. Examples of suitable solvents are hydrocarbons, which can be aliphatic or aromatic, such as hexane or toluene, halogenated hydrocarbons, in particular halogenated aliphatic hydrocarbons, such as methylene chloride or 1,2-di-chloroethane, and ethers, such as tetrahydrofuran or diethyl ether, of which ethers and halogenated hydrocarbons are preferred.

The reaction can take place over a wide range of temperatures and the exact temperature does not play a significant role for the present invention. The temperature generally suitable for carrying out the reaction is from -50 ^° C to 100 ^° C, and more preferably from -10 ^° C to 50 ^° C. The time required to carry out the reaction can also vary widely depending on many factors, in particular on the reaction temperature and the nature of the reagents and solvent used. However, under the preferred reaction conditions outlined above, this period is from 30 minutes to 24 hours, and more preferably 1-16 hours.

 After completion of any of the above reactions, the target compounds of each reaction can be isolated from the reaction mixture by standard methods. For example, the reaction mixture is mixed with water or an aqueous solution of ammonium chloride, stirred at room temperature, and then extracted with a water-immiscible 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, after which the solvent is distilled off and, if necessary, the product obtained is purified by standard methods, for example, by recrystallization or by various chromatographic techniques, such as preparative thin layer chromatography or column chromatography chromatography.

In the reaction scheme D presented at the end of the description, a cyano compound of formula XII is first prepared and then the compound is converted to a compound of formula I. In the formulas of scheme DR ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and X are defined by the values indicated above, and R ^7b is a protected carboxy group protected by a tetrazolyl group, each of which may be as previously illustrated for R ^7a .

 In step D1 of this reaction scheme, an imidazole-5-carbonitrile compound of the formula XI is reacted with a biphenylmethyl compound of the formula IIIa to give a compound of the formula XII. This reaction is basically similar to the reaction described above in step A1 of reaction scheme A, and can be carried out using the same reagents and the same reaction conditions.

In step D2, the resulting compound of formula XII may be subjected to any one or (as appropriate) several of the following reactions:
the conversion of the cyano group at the 5-position of the imidazole ring into a carboxyl group;
removal of any carboxy protecting group;
esterification of the carboxy group at the 5-position of the imidazole ring or in the biphenyl group;
the conversion of the carboxyl group at the 5-position of the imidazole ring into a group of the formula —CONR ⁸ R ⁹ ;
removing the tetrazolyl protecting group; and performing alkylation or acylation of the group.

 The conversion of a cyano group to a carboxyl group.

 This conversion is carried out by hydrolysis of a cyano group in a compound of formula XII by means of a carbamoyl group. This reaction is well known in chemical synthesis and can be carried out using reagents commonly used for this purpose, such as, for example, alkali metal hydroxides, namely sodium, potassium or lithium hydroxide.

 The reaction is preferably carried out in the presence of a solvent. In principle, there are no specific restrictions on the nature of the solvent, provided that it does not adversely affect the reaction or 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, the preferred solvent being an aqueous solvent.

The reaction can take place over a wide range of temperatures and the exact temperature does not play a significant role for the present invention. The temperature generally suitable for carrying out the reaction is 0-120 ^° C., and more preferably 20-100 ^° C. The time required for the reaction may also vary widely depending on many factors, in particular the reaction temperature and the nature of the reagents used and solvent. However, under the preferred reaction conditions outlined above, this period is from 30 minutes to 24 hours, and more preferably 1-16 hours.

 After completion of the reaction, the target product can be isolated from the reaction mixture by standard methods. For example, one of the standard methods for isolating a 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 isolated by filtration, alternatively, after neutralizing the reaction mixture, the solvent is distilled off and the obtained residue is purified by column chromatography to obtain the desired product, alternatively, the residue is mixed with water and a water-immiscible solvent, such as ethyl acetate, and the resulting mixture was extracted with an organic solvent, after which the extract was dried in the presence of a drying agent, such as anhydrous magnesium sulfate, and isolated from the solution the speaker to obtain the target product. If necessary, the product can then be purified by standard methods, for example, by recrystallization or using various chromatographic techniques, such as preparative thin layer chromatography or column chromatography.

In this reaction, where the starting material is a compound in which R ⁴ is an acyl group and / or R ^7b is an ester group of a primary or secondary alcohol, such as methanol, ethanol or isopropanol, the acyl group R ⁴ and the ester residue are removed simultaneously.

 Removal of carboxy-protecting groups.

 This reaction is similar to reaction I in step A2 of reaction scheme A and can be carried out using the same reagents and the same reaction conditions.

 Esterification.

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

Conversion of a carboxyl group to a group of the formula —CONR ⁸ R ⁹ .

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

 Removal of tetrazolyl-protecting groups.

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

 Removal of hydroxy protecting groups.

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

 Alkylation and acylation of hydroxyl groups.

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

In addition to Scheme B, the preparation of some of the starting materials used in the above reaction schemes is shown in reaction schemes G and H presented at the end of the description. The values of R ¹ , R ² , R ³ and R ^5a in the formulas of reaction schemes G and H are defined above, R ¹⁰ is an alkyl group containing 1-6 carbon atoms, for example, one of the groups that have been illustrated above for R ¹ , and preferably an alkyl group containing 1-4 carbon atoms, and more preferably a methyl or ethyl group, R ¹¹ is a hydrogen atom or an imidazolyl protecting group, for example an aralkyl group such as a trityl group, a diphenylmethyl group, or a benzyl group, or C ₁ - A C ₄ alkoxymethyl group such as meth an oxymethyl group, an ethoxymethyl group, a propoxymethyl group or butoxymethyl group, of which a trityl, benzyl, methoxymethyl or ethoxymethyl group is preferred, and a trityl group is more preferred.

 Reaction Scheme G.

In reaction scheme G, a compound of formula V is prepared where R ⁴ is a hydrogen atom, i.e. a compound of formula Va (which are the starting material in reaction schemes A).

 In step GI, a compound of formula XVI is prepared by reacting an ortho-ether compound of formula XIX with diaminomaleonitrile of formula XX. The reaction is preferably carried out in the presence of a solvent. In principle, there are no specific restrictions on the nature of the solvent, provided that it does not adversely affect the reaction or 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 xylyl, halogenated hydrocarbons, in particular halogenated aliphatic hydrocarbons, such as 1,2-dichloroethane or carbon tetrachloride, ethers, such as tetrahydrofuran or dioxal, and nitriles, such like acetonitrile.

The reaction can take place over a wide range of temperatures and the exact temperature does not play a significant role for the present invention. The temperature generally suitable for carrying out the reaction is 50-180 ^° C., and preferably 80-150 ^° C. The time required for the reaction can also vary widely depending on many factors, in particular the reaction temperature and the nature of the reagents and solvent used. However, under the preferred reaction conditions outlined above, this period is 1-24 hours, and more preferably 2-10 hours.

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

 Step G2 involves preparing an imidazole-4,5-dicarboxylic acid compound of formula XVI obtained in Step G1. This reaction can be carried out by heating the compound of formula XVI under reflux in the presence of an aqueous mineral acid, such as an aqueous solution of hydrochloric, sulfuric or nitric acid acid, for 1-24 hours (preferably 3-16 hours). The product of formula XXI can be isolated by collecting crystals precipitated in the reaction mixture by cooling by filtration or distillation of the solvent.

Step G3 is an optional step and involves the preparation of a dibasic acid ester compound of the formula XI by blocking the carboxy group of the imidazole-4,5-dicarboxylic acid compound of the formula XXI obtained in step G2. This reaction can be carried out by reacting compound XXI with a compound of the formula R ^5b —Y, where R ^5b and Y are as defined above.

 The reaction is preferably carried out in the presence of a solvent. In principle, there are no specific restrictions on the nature of the solvent, provided that it does not adversely affect the reaction or 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, in particular 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 as acetates or methyl ethyl ketone, nitriles, such as acetonitrile and sulfoxides, such as dimethyl sulfoxide. Of these, nitriles, halogenated hydrocarbons or amides are preferred.

 It is also preferred that the reaction proceeds in the presence of a base, the nature of which is not critical, unless it adversely affects other parts of the reactants. Examples of preferred bases are organic amines, such as triethylamine, N, N-diisopropylethylamine or N-methylphospholine.

The reaction can take place over a wide range of temperatures and the exact value of the reaction temperature does not play a significant role. A temperature generally suitable for carrying out the reaction will depend on the nature of the starting materials, solvent and base. In this case, the preferred temperature is from -10 ^o C to 100 ^o C, and the more preferred 0-80 ^o C. The time required for the reaction may also vary widely depending on many factors, in particular the reaction temperature and the nature of the used reagents and solvent. However, under the preferred reaction conditions outlined above, this period is 0.5-24 hours, and more preferably 1-16 hours.

 After completion of the reaction, the target compound can be isolated from the reaction mixture by standard methods. For example, after distilling off the solvent, the residue is mixed with water, the mixture is extracted with a water-immiscible 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 various chromatographic techniques, such as preparative thin layer chromatography or column chromatography.

Alternatively, the dicarboxylic acid compound of formula XXI may be esterified to form a diester of formula IX. The choice of a specific reaction in this case will depend on the nature of the ester residue R ^5b .

For example, if the group represented by R ^5b is a C ₁ C ₆ alkyl group or an aralkyl group, such as a benzyl group, then the compound of formula IX can be obtained by reacting the corresponding dicarboxylic acid with a C ₁ C ₆ alcohol, such as methanol, ethanol, propanol or hexanol, or with an aralkyl 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 C ₁ -C ₆ alcohols, which may be used as source materials the yals described above, a halogenated hydrocarbon, such as methylene chloride, or an ether, such as tetrahydrofuran or dioxane, at a temperature of 0-100 ^o C, preferably 20-80 ^o C, for a period of time from 1 h to 3 days, and preferably 16-24 hours, or by treatment with an appropriate dicarboxylic acid with a halogenating agent, for example phosphorus pentachloride, thionyl chloride or oxalyl chloride, in an inert solvent, for example a halogenated hydrocarbon such as methyl chloride, an ether such as tetrahydrofuran or diox an aromatic hydrocarbon, such as benzene or toluene, at approximately room temperature for a period of time from 30 minutes to 5 hours, preferably 1-3 hours, to obtain the corresponding acyl halide, followed by reaction of the acyl halide with the corresponding alcohol (if obtained t-butyl ester, it is preferable to use potassium t-butoxide instead of alcohol) in an inert solvent, for example benzene or methylene chloride, in the presence of a base, for example triethylamine, at about room temperature over and time from 30 minutes to 10 hours

 The target compound can be isolated from the reaction mixture using standard techniques. For example, after distilling off the solvent, the residue is dissolved in water and a water-immiscible organic solvent, such as ethyl acetate, the resulting 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, then the solvent is distilled off and get the target product. This product can be (if necessary) purified by standard methods, for example by recrystallization, or by various chromatographic techniques, such as preparative thin layer chromatography or column chromatography.

In step G4, a compound of formula Va is prepared by reacting a diester compound of formula IX with a Grignard reagent of formula R ^2a MgX or R ^3a MgX, where R ^2a , R ^3a and X are as defined above.

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

 Reaction Scheme H.

In these reactions, compounds of formulas XIIIa, XIa and VIIa are obtained, where each of R ¹¹ is a hydrogen atom, i.e., compounds of formulas XIII, XI and VII and a compound of formula Va, which are the starting materials used in reaction scheme E, D, A and B, respectively.

In step H1, which is an optional step, a compound of formula XVIa is prepared by reacting a dinitrile compound XVI with a compound of formula R ^11a -X, wherein X is as defined above and R ^11a is any of the groups defined above for R ¹¹ and is not a hydrogen atom in the presence of a base.

 Examples of suitable compounds are alkali metal hydrides, such as lithium hydride or sodium hydride, alkali metal carbonates, such as sodium or potassium carbonate, and alkali metal alkoxides, such as sodium methoxide, sodium ethoxide or potassium t-butoxide.

The reaction is preferably carried out in the presence of a solvent. In principle, there are no particular restrictions on the nature of the solvent, provided that it does not adversely affect the reaction or 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, and ketones, such as acetone or methyl ethyl ketone. The reaction can take place over a wide range of temperatures and the exact temperature does not play a significant role for the present invention. The temperature generally suitable for carrying out the reaction is 0-120 ^° C., and more preferably 20-80 ^° C. The time required for the reaction may also vary widely depending on many factors, in particular the reaction temperature and the nature of the reagents used and solvent. However, under the preferred reaction conditions outlined above, this period is 1-24 hours, and more preferably 3-8 hours.

 After completion of the reaction, the target compound can be isolated from the reaction mixture by standard methods. For example, one of these methods is that water is added to the reaction mixture, the mixture is extracted with a water-miscible organic solvent such as ethyl acetate, the extract is washed with water and dried with an 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 using various chromatographic techniques, such as preparative thin layer chromatography or column chromatography.

In step H2, a compound of formula XIIIa is prepared by reacting a dinitrile compound of formula XVIa with a Grignard reagent of formula R ^2a MgX, in which R ^2a and X are as defined above, or with a reducing agent. This reaction is basically similar to the reaction described above in step B2 of reaction scheme B, and can be carried out using the same reaction conditions.

 The imidazolyl protecting group of the compound of formula XIIIa can be (but not necessarily) removed by treating the compound of formula XIIIa in a standard manner depending on the nature of the protecting group to give a compound of formula XIII.

 For example, if the protecting group is a trityl group or an alkoxymethyl group, then it can be removed by reacting 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, methanesulfonic acid or p-toluenesulfonic acid.

 The reaction is preferably carried out in the presence of a solvent. In principle, there are no particular restrictions on the nature of the solvent, provided that it does not adversely affect the reaction or 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, alcohols such as methanol or ethanol, acids such as acetic acid, water, or a mixture of any two or more of the above solvents.

The reaction can be carried out over a wide range of temperatures, and the precise reaction temperature is not critical to the present invention. The temperature generally suitable for carrying out the reaction is 0-120 ^° C., and more preferably 10-100 ^° C. The time required for carrying out the reaction can also vary widely depending on many factors, in particular the reaction temperature and the nature of the reagents used and solvent. However, under the preferred reaction conditions outlined above, this period is from 30 minutes to 24 hours, and more preferably 1-16 hours.

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

 If the imidazolyl protecting group is an aralkyl group, such as a benzyl or diphenylmethyl group, then it can be removed by catalytic hydrogenation. This reaction is basically similar to the reaction described above (I) of step A2 of reaction scheme A, where the carboxy protecting group is an aralkyl group and can be carried out using the same reagents and the same reaction conditions.

In step H3, the resulting carbonyl compound of formula XIIIa is then reacted with a Grignard reagent of formula R ^3a MgX, in which R ^3a and X are defined above, or with a reducing agent to give a compound of formula XIa. This reaction is basically similar to the reaction of step B2 of reaction scheme B described above, and can be carried out using the same reagents and the same reaction conditions.

 Optionally, the imidazolyl protecting group of the compound of formula XIa can be removed using substantially the same reaction that was described as optional in Step H2 of Reaction Scheme H, and can be carried out using the same reagents and the same reaction conditions.

In step H4, a carboxylic acid compound of formula XXII is prepared by hydrolysis of the remaining cyano group at the 5-position of the imidazole ring. The reaction can be carried out using an alkali metal hydroxide, such as sodium, potassium or lithium hydroxide, in an inert solvent, preferably in water, an alcohol, such as methanol or ethanol, an ether, such as methanol or ethanol, an ether, such as tetrahydrofuran or dioxane, or a mixture of any two or more of these solvents. The reaction can take place over a wide range of temperatures and accurate knowledge of the temperature does not play a significant role for the present invention. The temperature generally suitable for carrying out the reaction is 0-120 ^° C., and more preferably 20-100 ^° C. The time required for the reaction may also vary widely depending on many factors, in particular the reaction temperature and the nature of the reagents used and solvent. However, under the preferred reaction conditions outlined above, this period is 0.5-24 hours, and more preferably 1-16 hours. After completion of the reaction, the 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 precipitates in the reaction medium, it can be collected by filtration. Alternatively, the target compound can be isolated as follows: after neutralizing the reaction mixture, the solvent is distilled off and the residue is subjected to column chromatography, alternatively, the residue is mixed with water and a water-immiscible organic solvent and extracted with an organic solvent, after which the extract is dried in the presence of a drying agent, such as anhydrous sulfate magnesium, the solvent is distilled off and get the target product. If necessary, this product can then be purified by standard methods, for example, by recrystallization, or by various chromatographic techniques, such as preparative thin layer chromatography or column chromatography.

 In step H5, which is an optional step, a compound of formula Va is prepared by esterifying a carboxylic acid compound of formula XXII and (optionally) followed by unblocking the imidazolyl group. This esterification reaction is mainly similar to reaction II in step A2 of reaction scheme A described above, and the optional unlocking reaction is basically similar to the reaction described for step H2 of reaction scheme H, and both of these reactions can be carried out using the same reagents and the same reaction conditions.

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

 In step H7, a compound of formula VIIa is prepared by esterification of a compound of formula XXIII. This reaction is basically similar to the reaction described above for step H5 of reaction scheme H, and can be carried out using the same reagents and the same reaction conditions.

 If desired, the imidazolyl protecting group of the compound of formula VIIa can be removed mainly by a reaction similar to the optional reaction described above for step H2 of reaction scheme H, which can be carried out using the same reagents and the same reaction conditions.

 In step H8, a compound of formula Va is prepared by reacting a compound of formula VIIa with a Grignard reagent and / or with a reducing agent, and then optionally unlocking the imidazolyl group. This reaction is basically similar to the reaction described above for step B2 of reaction scheme B, and the optional unlocking reaction is basically similar to the reaction described above for step H2 of reaction scheme H, and both of these reactions can be carried out using the same reagents and reaction conditions.

 The proposed compounds can form salts. In principle, there is no restriction on the nature of the salts, provided that they are pharmaceutically acceptable and suitable for therapeutic use. However, even this limitation can be neglected if these salts are intended only for use as intermediates for the preparation of other, more active compounds. The proposed compounds can form salts 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 proposed compounds contain a basic group in their molecule, and therefore can form acid addition salts. Examples of such acid addition salts are salts with mineral acids, in particular hydrohalic acids such as hydrofluoric, hydrobromic, hydroiodic and hydrochloric acid, nitric acid, carboxylic acid, sulfuric acid or phosphoric acid, salts with lower alkyl sulfonic acids such as acid, trifluoromethanesulfonic acid or ethanesulfonic acid, salts with organic carboxylic acids such as acetic acid, formic acid, and Naya acid, oxalic acid, maleic acid, malic acid, succinic acid or citric acid, and salts with amino acids such as glutamic acid or aspartic acid. The compounds of the invention may be converted into pharmaceutically acceptable salts by treatment with an acid or base using standard methods well known in the art.

The proposed compounds are essentially non-toxic (for the compound of Example 78 LD ₅₀ more than 2000 mg / kg) and show good inhibitory activity against the increase in blood pressure induced by angiotensin II, and therefore can be successfully used to treat or prevent diseases of the circulatory system as hypotensive funds, or as a therapeutic drug for the treatment of heart disease.

 The biological activity of the proposed compounds was evaluated using the following experiments.

 Assessment of AII-receptor-blocking activity by inhibiting the vasopressor response to angiotensin III administration.

The biological activity of each compound was evaluated by determining the dose required to inhibit the vasopressor response to intravenous administration of angiotensin II to rats at a dose of 50% (LD ₅₀ ). Male Wister-Imamichi rats (each weighing 300-400 g) were injected with an intraperitoneal injection of 100 mg / kg thiobarbital -sodium (Inaktin (trademark)) and two cannulas: one cannula was inserted into the femoral artery to measure blood pressure, and the other into the femoral vein for injection of the drug. 50 ng / kg of angiotensin II was administered intravenously at intervals of about 10 minutes, and an increase in blood pressure (usually about 50 mmHg) was observed. After receiving a stable vasopressor response to angiotensin II, the test compound was administered intravenously. After 2 min, angiotensin II was again administered and the inhibitory activity of the test compound was evaluated. To calculate LD ₅₀ , the percent inhibition of the vasopressor response to angiotensin II was determined by increasing the concentration of the administered test compound. In this experiment, angiotensin II dissolved in 0.5% bovine serum albumin was used, and the test compound was dissolved in 100% dimethyl sulfoxide (DMSO). The ID ₅₀ values thus determined are shown in the table.

 In addition to the proposed compounds, which were identified in a number of examples illustrating their preparation and presented below, in these experiments, a prototype compound (designated as compound A in the table), which is 2- [4- (2-butyl-5- chloro-4-chloromethylimidazol-1-yl-methyl) phenyl] benzoic acid, which is described in Example 118 of Europatent Publication No. 253310.

 The compounds of the invention may be administered, for example, orally in the form of tablets, capsules, granules, powders, syrups, and the like. or parenterally in the form of injections, suppositories, etc. These pharmaceutical preparations can be obtained by standard methods using adjuvants well known in the art, such as, for example, excipients, binders, disintegrating agents, lubricants, stabilizers, modifiers and the like. Although the dose of the active ingredient may vary depending on the symptoms, the age of the patient, the nature and severity of the disease, as well as the method of administration of the drug, however, if the drug is administered orally to an adult, the total daily dose of the compound of the invention may be 1-1000 mg, and preferably 5 -300 mg and administered either as a single dose or as a divided dose, for example, two or three times a day, and in the case of intravenous administration, this dose can be 0.1-100 mg, and preferably flax 0.5-30 mg and be administered one to three times a day.

 The following examples illustrate the preparation of a number of the proposed compounds, and the preparations following these examples illustrate the preparation of the starting materials used in these examples.

 Example 1. Methyl 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl4-hydroxymethylimidazole-5-carboxylate (compound 1-94).

 1a) Dimethyl-1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butylimidazole-4,5-dinarboxylate.

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 g of dimethyl 2-butyl-imidazole-4,5-dicarboxylate, prepared as described in Preparation 4, in 40 ml methanol and the resulting mixture was concentrated by evaporation under reduced pressure. The resulting residue was mixed with benzene and the mixture was concentrated by distillation under reduced pressure. Then this operation was repeated three times and the resulting solid residue was dissolved in 72 ml of N, N - dimethylacetamide. After that, a solution of 10.41 g of t-butyl-4-bromomethylbiphenyl-2-carboxylate in 100 ml of N, N-dimethylacetamide was added dropwise to the resulting solution. Then the reaction mixture was stirred for 1 hour at room temperature and for 2 hours at 50-55 ^° C. At the end of this time, this mixture was mixed with ethyl acetate and water and the ethyl acetate layer was separated and dried with anhydrous magnesium sulfate, after which the solvent was distilled off under reduced pressure. . The residue was purified by silica gel column chromatography, eluting with a mixture of ethyl acetate and hexane (1: 1), to give 15.1 g of the target compound as a gum.

Nuclear Magnetic Resonance (NMR) (CDCl ₃ ) δ ppm: (0.90 3H, t, J 7 Hz), 1.26 (9H, t (triplet)), 1.1-2.0 (4H, m, (multiplet)), 2.70 (2H, t. J 7 Hz), 3.81 (3H, s, (singlet)), 4.90 (3H, s.) 5.47 (2H, s.) 6 95-7.85 (8H, m).

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

42 ml of diisobutylaluminum hydride in the form of a 1.5 M solution in toluene was added dropwise at a temperature of from -20 ^° C to -15 ^° C to a solution of 16.0 g of dimethyl 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butylimidazole-4,5-dicarboxylate, obtained as described above in step (a), in 200 ml of tetrahydrofuran, and the resulting mixture was left for 16 hours at -5 ^° C. After this time, the reaction mixture was mixed with aqueous a solution of ammonium chloride and ethyl acetate, and then stirred for 1 h. After this, the precipitate was removed by filtration. Then the ethyl acetate layer was separated, dried with anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. Then, the residue was purified by silica gel column chromatography, eluting with ethyl acetate, whereby 12.0 g of the target compound were obtained in the form of crystals, mp 99 ^o C.

NMR (CDCl ₃ ) d ppm: 0.90 (3H, t. J 7 Hz), 1.20 (9H, s), 1.1-2.0 (4H, m), 2.69 (2H, t .J 7 Hz), 3.55 (1H, br s), 3.78 (3H, s), 4.84 (2H, d (doublet) J 5 Hz), 5.60 (2H, s) 6.95-7.9 (8H, m).

 Example 2. Ethyl 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-4-hydroxymethylimidazole-5-carboxylate (compound 1-95).

 2a). Diethyl-1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butylimidazole-4,5-dicarboxylate.

 The procedure described in Example 1a was repeated, but using 8.0 g of diethyl 2-butyl-imidazole-4,5-dicarboxylate, prepared as described in Preparation 3, and 10.41 g of t-butyl 4-bromomethylbiphenyl-2 β-carboxylate, whereby 15.4 g of the target compound are obtained in the form of a gummy substance.

NMR (CDCl ₃ ) d ppm: 0.90 (3H, t. J 7 Hz), 1.1-2.0 (4H, m), 1.24 (9H, s), 1.26 (3H, t .J 7 Hz), 1.39 (3H, t. J 7 Hz), 4.40 (2H, q. J 7 Hz), 4.28 (2H, q. (Quartet) J 7 Hz), 4, 40 (2H, q, J 7 Hz), 5.50 (2H, s), 7.0-7.9 (8H, m).

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

 The procedure described in Example 1b was repeated, but using 1.50 g of diethyl 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butylimidazole-4,5-dicarboxylate, prepared as described in stage (a), and 3.9 ml of diisobutylaluminum hydride in the form of a 1.5 M solution in toluene, whereby 1.1 g of the target compound are obtained in the form of a resinous substance.

NMR (CDCl ₃ ) d ppm: 0.90 (3H, t. J 7 Hz), 1.24 (9H, s), 1.30 (3H, t. J 7 Hz), 1.1-2.0 (4H, m), 2.68 (2H, t. J 7 Hz), 3.60 (1H, br s), 4.24 (2H, q. J 7 Hz), 4.84 (2H, s .), 5.57 (2H, s), 6.9-7.85 (8H, m).

 Example 3. Methyl 2-butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4 hydroxymethylimidazole-5-carboxylate (compound 1-5).

A solution of 0.36 g of methyl 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-4-hydroxymethylimidazole-5-carboxylate, prepared as described in Example 1, in 4 ml of 4 n . a solution of hydrogen chloride in dioxane was left for 4 hours at room temperature. After this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was triturated with ethyl acetate to give crystals, which were collected by filtration, whereby 0.35 g of the target compound was obtained in the form of its hydrochloride, mp. 192-195 ^o C (decomposition).

 NMR (hexadeuterated dimethyl sulfoxide) d ppm: 0.81 (3H, t J 7 Hz), 1.22-1.35 (2H, m), 1.43-1.56 (2H, m), 3.00 ( 2H, t. J 7 Hz), 3.82 (3H, s), 4.81 (2H, s), 5.77 (2H, s), 7.18-7.75 (8H, m).

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

A solution of 2.01 g of lithium hydroxide monohydrate in 96 ml of water was added to a solution of 4.78 g of methyl 1 - [(2'-t-butoxycarbonylbiphenyl-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 resulting mixture was stirred at room temperature for 18 hours. At the end of this time, the reaction mixture was isolated from dioxane by distillation under reduced pressure, and 49.6 ml of 1 was added to the aqueous residue. n aqueous hydrochloric acid. The precipitated crystals were collected by filtration and washed successively with water and diethyl ether, whereby 4.26 g of the target compound was obtained, so pl. 187 ^o C (decomp.).

NMR (CDCl ₃ ) d ppm: 0.85 (3H, t. J 7 Hz), 1.24 (9H, s), 1.1-1.9 (4H, m), 2.80 (2H, t J 7 Hz), 5.05 (2H, s), 5.93 (2H, s), 7.0-7.85 (8H, m).

 Example 5. 2-butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4-hydroxymethyl-imidazole-5-carboxylic acid.

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

NMR (DMSO-d ₆ ) d ppm: 0.80 (3H, t. J 7 Hz), 1.2-1.33 (2H, m), 1.4-1.53 (2H, m), 2 98 (2H, t. J 7 Hz), 4.84 (2H, s), 5.81 (2H, s), 7.17-7.74 (8H, m).

 Example 6. Pivaloyloxymethyl 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-4-hydroxymethylimidazole-5-carboxylate (compound 1-97).

 350 mg of potassium carbonate was added to a solution of 552 g of 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-4-hydroxymethylimidazole-5-carboxylic acid, obtained as described in example 4, and 220 mg pivaloyloxymethyl chloride in 7 ml of N, N-dimethylacetamide, and the resulting mixture was stirred at room temperature for 5 hours. At the end of this time, the reaction mixture was mixed with ethyl acetate and water, the ethyl acetate layer was separated and dried with anhydrous magnesium sulfate, after which the solvent was distilled off. under reduced pressure. The obtained residue was purified by silica gel column chromatography using ethyl acetate as an eluent, and 0.62 g of the target compound was obtained in the form of a syrup.

NMR (CDCl ₃ ) d ppm: 0.91 (3H, t. J 7 Hz), 1.18 (9H, s), 1.21 (9H, s), 1.1-3.0 (4H, m ), 2.72 (2H, t, J 7 Hz), 3.35 (1H, br s), 4.85 (1H, 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).

 A solution of 0.62 g of pivaloyloxymethyl 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-4-hydroxymethylimidazole-5-carboxylate, prepared as described in Example 6, in 10 ml of 4 n . a solution of hydrogen chloride in dioxane was left for 4 hours at room temperature, after which the solution was concentrated by evaporation under reduced pressure. The syrupy residue was stirred in diethyl ether, after which the solvent was removed by draining, and the residue was dried in vacuo, whereby 0.46 g of the hydrochloride of the target compound was obtained in the form of a powder.

NMR (CDCl ₃ ) d ppm: 0.85 (3H, t. J 7 Hz), 1.19 (9H, s), 1.25- (1.45 (2H, m), 1.65-1, 80 (2H, m), 2.99 (2H, t J 7 Hz), 5.01 (2H, s), 5.70 (2H, s), 5.89 (2H, s), 7.05- 7.97 (8H, m).

 Example 8. Methyl-1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-4-methyl-2-butyl-4-methoxymethyl imidazole-5-carboxylate (compound 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-butoxycarbonylbiphenyl-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 for 30 minutes at room temperature. After that, 0.125 ml of iodomethane was added and the reaction mixture was stirred at 50 ^° C. for 3 hours. Then this mixture was mixed with ethyl acetate and water. The ethyl acetate layer was separated and dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluting with a mixture of ethyl acetate and methylene chloride (1: 1), whereby 0.30 g of the target compound was obtained as a gummy substance.

NMR (CDCl ₃ ) d ppm: 0.90 (3H, t, J 7 Hz), 1.24 (9H, s), 1.1-2.0 (4H, m), 2.71 (2H, t , J 7 Hz), 3.46 (3H, s), 3.80 (4H, s), 4.68 (2H, s), 5.60 (2H, s), 6.9-7.9 ( 8H, m).

 Example 9. Methyl 2-butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (methoxymethyl) imidazole-5-carboxylate (compound 1-121).

A solution of 0.30 g of methyl 1 - [(2'-t-butoxycarbonylphenyl-4-yl) methyl] -2-butyl-4- (methoxymethyl) imidazole-5-carboxylate, prepared as described in example 8, in 3 ml of a 4 n solution of hydrogen chloride in dioxane was left for 5 hours at room temperature, after which the solvent was distilled off under reduced pressure. The syrupy residue was triturated in diethyl ether and collected by filtration, whereby 0.26 g of the target compound was obtained in the form of its hydrochloride, mp. 106-110 ^o C (with softening).

NMR (DMSO-d ₆ ) d ppm: 0.81 (3H, t. J 7 Hz), 1.2-1.35 (2H, m), 1.45-1.6 (2H, m), 2 97 (2H, t. J 7 Hz), 3.39 (3H, s), 3.82 (3H, s), 4.72 (2H, s), 5.75 (2H, s), 7, 16-7.74 (8H, m).

 Example 10. 1-butyl-1 - [(2'-carboxyphenyl-4-yl) methyl] -4 [(1-hydroxy-1-methyl) ethyl] imidazole-5-carboxylic acid (compound 1-31).

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

 48 g of sodium hydride (in the form of a 55 wt. Dispersion in mineral oil) was added at room temperature and in an atmosphere of nitrogen, while stirring, to a solution of 207 mg of 2-butyl-4-cyano-4 - [(1-hydroxy-1- methyl) ethyl] imidazole, prepared as described in Preparation 7, in 10 ml of N, N-dimethylacetamide, and the resulting mixture was stirred for 30 minutes, after which 347 mg of t-butyl-4-bromomethylbiphenyl-2-carboxylate was added. Then the reaction mixture was stirred for 2 hours at room temperature, after which it was poured into a mixture of ice and sodium chloride and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, whereby an oily crude product was obtained. The product was purified by silica gel column chromatography, eluting with a mixture of hexane and ethyl acetate (1: 1), and 462 mg of the target compound was obtained.

NMR (CDCl ₃ ) d ppm: 0.90 (3H, t. J 7 Hz), 1.1-2.1 (4H, m), 1.21 (9H, s), 1.61 (6H, s ), 2.70 (2H, t. J 7 Hz), 3.40 (1H, s), 5.22 (2H, s), 7.0-8.0 (8H, m).

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

A solution of 462 mg of 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-5-cyano-4 - [(1-hydroxy-1-methyl) ethyl] imidazole obtained in accordance with the description in stage (a), in 10 ml of 4 N. a solution of hydrogen chloride in dioxane was left overnight at room temperature. After this, 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 the receipt of 457 mg of the hydrochloride of the target compound as a colorless powder, so pl. 209-210 ^o C.

NMR (DMSO = d ₆ ) d ppm: 0.85 (3H, t. J 7 Hz), 1.0-1.8 (4H, m), 1.58 (6H, s), 3.00 (2H , t. J 7 Hz), 5.51 (2H, s), 7.1-8.0 (8H, m).

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

A solution of 314 mg of 2-butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -5-cyano-4 - [(1-hydroxy-1-methyl) ethyl] imidazole hydrochloride, prepared as described in stage (b), in an aqueous solution of 460 mg of sodium hydroxide in 5 ml of water was stirred in an oil bath for 5 hours at 100 ^o C. After this time, the reaction mixture was cooled and its pH was adjusted to 3-4 by adding 1 N. aqueous hydrochloric acid. The resulting colorless precipitate was collected by filtration, washed with water and dried over anhydrous magnesium sulfate, whereby 244 mg, mp. 139-141 ^o C.

NMR (DMSO-d ₆ ) d ppm: 0.86 (3H, t. J 7 Hz), 1.0-1.9 (4H, m), 1.60 (6H, s), 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).

 11a) 4-acetyl-1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-5-cyanoimidazole.

 0.87 g of potassium carbonate and 2.4 g of t-butyl-4'-bromomethylbiphenyl-2-carboxylate were added to a solution of 1.2 g of 4-acetyl-2-butyl-5-cyanoimidazole, prepared as described in Preparation 5 in 12 ml of N, N-dimethylacetamide, and the resulting mixture was stirred for 3 hours at room temperature. After this, the reaction mixture was diluted with 100 ml of ethyl acetate and washed with a saturated aqueous solution of sodium chloride. The aqueous layer was extracted again with 50 ml of ethyl acetate, and the combined extracts were washed with a saturated aqueous solution of sodium chloride. The solvent was removed by distillation under reduced pressure, and the obtained residue was purified by silica gel column chromatography, eluting with a mixture of hexane and ethyl acetate (3: 1), whereby 1.31 g of the target compound was obtained.

NMR (CDCl ₃ ) d ppm: 0.93 (3H, t. J 7 Hz), 1.1-2.1 (4H, m), 1.23 (9H, s), 2.58 (3H, s ), 2.75 (2H, t, J 7 Hz), 5.32 (2H, s), 7.0-8.0 (8H, m).

 11b) 4-acetyl-2-butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -5-cyanoimidazole.

A solution of 1.3 g of 4-acetyl-1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-5-cyanoimidazole, prepared as described in step (a), in 30 ml 4 n a solution of hydrogen chloride in dioxane was left overnight at room temperature, after which the solution was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography, eluting with a mixture of methylene chloride and methanol (10: 1), and a colorless amorphous solid was obtained. This substance was triturated in hexane, collected by filtration and dried, resulting in 1.1 g of the target compound, so pl. above 55 ^o C (with softening).

NMR (CDCl ₃ ) d ppm: 0.84 (3H, t. J 7 Hz), 1.0-2.0 (4H, m), 2.54 (3H, s), 2.66 (2H, t J 7 Hz), 5.17 (2H, s), 6.8-7.0 (8H, m).

 11c) 2-butyl-1 - [(2'-carboxybiphenyl-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-cyano-imidazole, prepared as described in step (b), in mixtures of 20 ml of isopropanol and 10 ml of ethanol, and the resulting mixture was stirred for 3 hours at room temperature. After this time, the pH of the reaction mixture was adjusted to a value of 3 by adding 1 N. aqueous hydrochloric acid, after which the solvent was distilled off under reduced pressure. The resulting residue was mixed with methylene chloride and water, and the methylene chloride 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 resulting residue was dissolved in 10 ml of ethyl acetate and kept at room temperature. Then, the precipitated solid product was collected by filtration to obtain 398 mg of the target compound as a colorless powder, mp. 200-201 ^o C.

NMR (DMSO-d ₆ ) d ppm: 0688 (3H, t. J 7 Hz), 1.0-2.0 (4H, m), 1.54 (3H, d. J 7 Hz), 2.68 (2H, t. J 7 Hz), 4.91 (1H, q. J 7 Hz), 5.21 (2H, s), 7.0-8.0 (8H, m).

 11d) 2-butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (1-hydroxyethyl imidazole) -5-carboxylic acid.

A mixture of 300 could 2-butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -5-cyano-4- (1-hydroxyethyl) imidazole, prepared as described in step (c), and 3 ml 1 n an aqueous sodium hydroxide solution was stirred in an oil bath maintained for 3 hours at 80 ^° C. After this time, the reaction mixture was cooled and then slightly acidified with hydrochloric acid, after which the mixture was extracted 4 times with methylene chloride (30 ml x 4). The combined extracts were dried and concentrated to dryness by evaporation under reduced pressure, resulting in an amorphous solid. This material was purified by silica gel column chromatography, eluting with a mixture of methylene chloride and methanol (10: 1 and 3: 1). The solid product obtained from the eluate was triturated with diethyl ether. The resulting powder was collected by filtration and dried, resulting in the receipt of 72.3 mg of the target compound as a colorless powder, so pl. 168-170 ^o C (with softening above 140 ^o C).

NMR (DMSO-d ₆ ) d ppm: 0.84 (3H, t. J 7 Hz), 1.0-2.0 (4H, m), 1.52 (3H, d. J 7 Hz), 2 3-2.8 (2H, overlapping with a peak of dimethyl sulfoxide) 4.93 (1H, q J 7 Hz, 5.60 (2H, br.s), 6.8-7.8 (8H, m )

 Example 12. 2-butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (a - hydroxybenzyl) imidazole-5-carboxylic acid (compound 1-80).

 12a) 4-benzoyl-1 - [(2'-t-butoxycarbonylobiphenyl-4-yl) methyl] -2-butyl-5-cyanoimidazole.

 A procedure similar to that described in Example 11a was repeated, but using 1.27 g of 4-benzoyl-2-butyl-5-cyanoimidazole, prepared as described in Preparation 6, 1.74 g of t-butyl-4'-bromomethylbiphenyl -2-carboxylate 0.69 g of potassium carbonate and 20 ml of N, N-dimethylacetamide, after which the product was purified by silica gel column chromatography, eluting with a mixture of hexane and ethyl acetate (2: 1), and 2.1 g of the target compound was obtained.

NMR (CDCl ₃ ) δ ppm: 0.93 (3H, t. J 7 Hz), 1.0-2.1 (4H, m), 1.23 (9H, s), 2.79 (2H, t J 7 Hz), 5.38 (2H, s), 7.1-8.0 (11H, m), 7.3-7.7 (2H, m).

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

 50.5 mg of sodium borohydride was added to a solution of 691 mg of 4-benziol-1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-5-cyanoimidazole, prepared as described in step (a) ) in 10 ml of ethanol and the resulting mixture was stirred for 1 h at room temperature. Then the reaction mixture was neutralized with aqueous hydrochloric acid, after which it was mixed with ethyl acetate and a saturated aqueous solution of sodium chloride. The ethyl acetate layer was separated, dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a mixture of hexane and ethyl acetate (1: 1, v / v), and 589 mg of the target compound was obtained as a colorless amorphous solid.

NMR (CDCl ₃ ) δ ppm: 0.89 (3H, t. J 7 Hz), 1.0-2.0 (4H, m), 2.68 (2H, t, J 7 Hz), 5.18 (2H, s), 5.89 (1H, s), 7.0-8.0 (13H, m).

 12c) 2-butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -5-cyano-4- (a-hydroxybenzyl) imidazole.

A solution of 589 mg of 1 - [(2'-t-butoxycarbonylbiphenyl) -4-yl) methyl] -2-butyl-5-cyano-4- (α-hydroxybenzyl) imidazole obtained as described in step (b), in 20 ml 4 n. a solution of hydrogen chloride in dioxane was left overnight at room temperature, and then concentrated by evaporation under reduced pressure. The residue was triturated in hexane and collected by filtration, whereby 493 mg of the hydrochloride of the target compound was obtained in the form of a colorless powder, so pl. 95-97 ^o C (with softening).

NMR (DMSO-d ₆ ) δ ppm: 0.88 (3H, t. J 7 Hz), 1.0-2.0 (4H, m), 3.00- (2H, t. J 7 Hz), 5.47 (2H, s), 6.09 (1H, s), 7.0-8.0 (13H, m).

 12d) 2-butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (alpha-hydroxybenzyl) imidazole-5-carboxylic acid.

A mixture of 450 mg of 2-butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -5-cyano-4- (a-hydroxybenzyl) imidazole, prepared as described in step (c), and 20 ml 1 n an aqueous solution of sodium hydroxide was stirred in an oil bath maintained at 100 ^° C. for 7 hours. At the end of this time, the reaction mixture was cooled and its pH adjusted to 3-4 by adding hydrochloric acid. The resulting colorless precipitate was collected by filtration, washed with water and dried, resulting in the receipt of 331 mg of the target compound as a colorless powder, so pl. 192-194 ^o C.

NMR (DMSO-d ₆ ) δ ppm: 0.80 (3H, t. J 7 Hz), 1.0-2.0 (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-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-4- (1-hydroxy-1-methylethyl) imidazole-5-carboxylate (compound 1-118).

The procedure described in Example 1a was repeated, but using 0.92 g of ethyl 2-butyl-4- (1-hydroxy-1-methyl-ethyl) imidazole-5-carboxylate, prepared as described in Preparation 8, and 1 , 28 g of t-butyl-4'-bromomethylbiphenyl-2-carboxylate and 1.23 g of the target compound are obtained in the form of crystals, so pl. 92-93 ^o C.

NMR (CDCl ₃ ) d ppm: 0.90 (3H, t. J 7 Hz), 1.12 (3H, t, J 7 Hz), 1.26 (9H, s), 1.2-2.05 (4H, m), 1.65 (4H, s), 2.69 (2H, t. J 7 Hz), 4.24 (2H, q. J 7 Hz), 5.52 (2H, s), 5.73 (1H, s), 6.88-7.9 (8H, m).

 Example 14. Ethyl-2-butyl-1 - [(2'-carboxybiphenyl) -4-yl) methyl] -4- (1-hydroxy-1-methylethyl) imidazole-5-carboxylate (compound 1-32).

The procedure described in Example 7 was repeated, but using 0.50 g of ethyl-1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-4- (1-hydroxy-1-methylethyl) imidazole-5-carboxylate obtained in accordance with the description in example 13, and 4 N. a solution of hydrogen chloride in dioxane, resulting in 0.45 g of the hydrochloride of the target compound in the form of an amorphous powder, so pl. above 80 ^o C (with softening).

NMR (DMSO-d ₆ ) d ppm: 0.82 (3H, t. J 7 Hz), 1.14 (3H, t. J 7 Hz), 1.2-1.35 (2H, m), 1 41-1.55 (2H, m), 1.60 (6H, s), 3.00 (2H, t. J 7 Hz), 4.21 (2H, q. J 7 Hz), 5.63 (2H, s), 7.14-7.75 (8H, m).

 Example 15. Ethyl 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate (compound 1-119).

The procedure described in Example 1a) was repeated, but using 0.845 g of ethyl 4- (1-hydroxy-1-methylethyl-2-propylimidazole-5-carboxylate, prepared as described in Preparation 9, and 1.22 g of t- butyl 4-bromomethylbiphenyl-2-carboxylate and 1.31 g of the expected compound are obtained in the form of a resinous substance, then this compound is kept at room temperature in order to cause its crystallization. target compound, mp 90-91 ^o C.

NMR (CDCl ₃ ) d ppm: 0.97 (3H, t. J n Hz), 1.23 (3H, t. J 7 Hz), 1.25 (4H, s), 1.60 (6H, s ), 1.82 (2H, sextet, J 7 Hz), 2.67 (2H, t. J 7 Hz), 4.24 (2H, q. J 7 Hz), 5.51 5.72 (1H, s), 6.87-7.85 (8H, m).

 Example 16. Ethyl 1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (1-hydroxy-1-methyl-ethyl) -2-propylimidazole-5-carboxylate (compound 1-50).

 The procedure described in Example 7 was repeated, but using 0.80 g of ethyl 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -4- (1-hydroxy-1-methylethyl) -2-propylimidazole- 5-carboxylate obtained in accordance with the description in example 15, and 4 N. a solution of hydrogen chloride in dioxane, resulting in a gain of 0.67 g of the hydrochloride of the target compound in the form of an amorphous powder.

NMR (DMSO-d ₆ ) d ppm: 0.88 (3H, t. J 7 Hz), 1.14 (3H, t. J 7 Hz), 1.50-1.65 (2H, m), 1 60 (6H, s), 3.00 (2H, t. J 7 Hz), 4.20 (2H, q. J 7 Hz), 5.63 (2H, s), 7.13-7.75 (8H, m).

 Example 17. 1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (1-ydroxy-1-methylethyl) -2-propylimidazole-5-carboxylic acid (compound 1-49).

A solution of 0.20 g of ethyl 1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate hydrochloride, obtained as described in the example 16, in an aqueous solution of 84 mg of lithium hydroxide monohydrate in 5 ml of water was stirred for 6 hours at room temperature. After this time, 2 ml of 1 N was added dropwise to the reaction mixture. aqueous hydrochloric acid and the resulting precipitate was collected by filtration, whereby 0.17 g of the target compound was obtained, so pl. 176-179 ^o C (decomposition).

NMR (DMSO-d ₆ ) d ppm: 0.88 (3H, t. J 7 Hz), 1.5-1.65 (2H, m), 1.56 (6H, s), 2.66 (2H , t. J 7 Hz), 5.69 (2H, s), 7.03-7.72 (8H, m).

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

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

48 mg of sodium hydride (in the form of a 55 wt. Dispersion in mineral oil) was added to a solution of 0.26 g of ethyl 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate, prepared as described in preparation 9, in 5 ml of N, N-dimethylformamide, and the resulting mixture was stirred for 30 minutes at room temperature. Then a solution of 0.72 g of 4- [2- (trityltetrazol-5-yl) phenyl] benzyl bromide in 5 ml of N, N-dimethylformamide was added and the reaction mixture was stirred at room temperature for 2 hours and at 60 ^° C. for 4 hours After this time, the mixture was dissolved in ethyl acetate and the solution was washed three times with water. After that, the solution was dried with anhydrous sodium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography, eluting with a mixture of hexane and ethyl acetate (1: 1 by volume), whereby 0.62 g of the target compound was obtained as an amorphous solid. This substance was crystallized from diisopropyl ether and the target compound was obtained in the form of crystals, mp. 167-168 ^o C (decomposition).

NMR (CDCl ₃ ) d ppm: 0.88 (3H, t. J 7 Hz), 1.08 (3H, t, J 7 Hz), 1.5-1.8 (2H, m), 1.64 (6H, s), 2.52 (2H, t. J 8 Hz), 4.12 (2H, q. J 7 Hz), 5.38 (2H, s), 5.78 (1H, s), 6.7-7.6 (22H, m), 7.8-8.1 (1H, m).

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

A solution of 0.50 g of ethyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4 - [(2- (trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate obtained in as described in Example 18a, dissolved in 5 ml of a 4 N solution of hydrogen chloride in dioxane, was left overnight at room temperature, after which the reaction mixture was concentrated by evaporation under reduced pressure, and the resulting residue was triturated with diisopropyl ether and 0.34 g of hydrochloride was obtained target compound, mp 100-103 ^o C.

NMR (CDCl ₃ ) d ppm: 0.97 (3H, t. J 7 Hz), 1.24 (3H, t. J 7 Hz), 1.50-1.65 (2H, m), 1.70 (6H, s), 3.00 (2H, t. J 8 Hz), 4.30 (2H, q. J 7 Hz), 5.70 (2H, s), 6.9-7.8 (8H , m).

 Example 19. 4- (1-hydroxy-1-methylethyl) -2-1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylic acid (compound 2-1).

3.65 ml 1 N. 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} methylimidazole- 5-carboxylate hydrochloride, prepared as described in Example 18b, in 6 ml of methanol and the resulting 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 adjusted. to a value of 3 by adding dilute hydrochloric acid, after hours th mixture was extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The resulting residue was triturated with diisopropyl ethyl give 0.15 g of the title compound, mp. mp. 166-169 ^o C.

NMR (DMSO-d ₆ ) d ppm: 0.85 (3H, t. J 7.5 Hz), 1.54 (6H, s), 1.4-1.6 (2H, m), 2.58 (2H, t. J 8 Hz), 5.64 (2H, s), 6.94 (2H, d. J 8.5 Hz), 7.06 (2H, d. J 8.5 Hz), 7 5-7.7 (4H, m).

 Example 20. Pivaloyloxymethyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate (compound 2-15) .

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

5.30 ml 1 N. an aqueous solution of sodium hydroxide and then 5 ml of tetrahydrofuran was added to a solution of 0.76 g of ethyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4 - [(2- (trityltetrazol-5-yl) -phenyl] phenyl} methylimidazole-5-carboxylate, obtained as described in Example 18a, 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: Water was added to the concentrate and the mixture was adjusted to pH 4 by adding I was diluted with ice-cold diluted hydrochloric acid. The mixture was then 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 0.23 g of potassium carbonate and 0.13 ml of pivaloyloxymethyl chloride were added to the resulting solution. stirred for 4 hours at 50 ^° C., after which 0.06 ml of pivaloyloxymethyl chloride was added and the resulting mixture was stirred for another 2 hours. After that, the reaction mixture was diluted with ethyl acetate and washed three times with water. The organic layer was separated, dried with anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The concentrate was purified by silica gel column chromatography, eluting with a mixture of hexane and ethyl acetate (1: 1 by volume), and 0.23 g of the target compound was obtained as an amorphous solid.

NMR (CDCl ₃ ) d ppm: 0.86 (3H, t. J 7 Hz), 1.12 (9H s), 1.62 (6H, s), 1.4-169 (2H, m), 2 51 (2H, t, J 7 Hz), 5.37 (1H, br s), 5.40 (2H, s), 5.72 (2H, s), 6.6-8.1 (23H , m).

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

5 ml 4 n. a solution of hydrogen chloride in dioxane was added to 0.20 g of pivaloyloxymethyl-4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-5 -carboxylate obtained in accordance with the description in example 20A, and the resulting mixture was left overnight at room temperature. After this time, the reaction mixture was concentrated to dryness under reduced pressure. The resulting residue was triturated with diisopropyl ether to stimulate crystallization and 0.13 g of the hydrochloride of the target compound were obtained in the form of crystals, mp. 104-107 ^o C.

NMR (DMSO-d ₆ ) d ppm: 0.84 (3H, t. J 7.5 Hz), 1.09 9H, s), 1.35-1.50 (2H, m), 1.56 ( 6H, s), 2.88 (2H, t J 8 Hz), 5.58 (2H, s), 5.85 (2H, s), 7.05 (2H, d. J 8.5 Hz), 7.10 (2H, d. J, 8.5 Hz); 7.5-7.7 (4H, m).

 Example 21. 2-butyl-4- (1-ethyl-1-hydroxypropyl) -1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylic acid (compound 2-40) .

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

 The procedure described in Example 18a was repeated, but using 0.75 g of ethyl 2-butyl-4- (1-ethyl-1-hydroxypropyl) imidazole-5-carboxylate, prepared as described in Preparation 13, 0.12 g sodium hydride (as 55 wt. dispersion in mineral oil) and 1.51 g of 4- [2- (trityltetrazol-5-yl) phenyl] benzyl bromide, and 1.05 g of the target compound are obtained as an amorphous solid.

NMR (CDCl ₃ ) d ppm: 0.83 (6H, triplet, J 7.5 Hz), 0.85 (3H, triplet, J 6 Hz), 1.11 (3H, t. J 7 Hz), 1 23-1.32 (2H, m), 1.56-1.65 (2H, m), 1.80-1.89 (2H, m), 2.03-2.14 (2H, m) 2.55 (2H, t. J 8 Hz), 4.12 (2H, q, J 7.5 Hz), 5.37 (2H, s), 5.64 (1H, br s), 6 70 (2H, d. J 8.5 Hz), 6.9-7.0 (6H, m), 7.10 (2H, d. J 8.5 Hz), 7.2-7.4 ( 10H, m), 7.4-7.5 (2H, m), 7.85-7.90 (1H, m).

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

1.71 ml 1 N. aqueous hydrochloric acid was added to a solution of 0.65 g of ethyl 2-butyl-4- (1-ethyl-1-hydroxypropyl) -1- {4- [2-trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate obtained in accordance with the description in stage (a) in 10 ml in methanol and the resulting mixture was left overnight at room temperature. After that, the solvent was removed by distillation under reduced pressure, and the concentrate was again dissolved in 10 ml of methanol. The resulting solution was mixed with 4.28 ml of 1 N. aqueous sodium hydroxide solution and left overnight at room temperature. The reaction mixture was then concentrated by evaporation under reduced pressure to remove methanol, the pH of the concentrate was adjusted to a value of 3 by the addition of dilute aqueous hydrochloric acid, and the precipitated crystals were collected by filtration. The crystals thus obtained were suspended in diisopropyl ether, and then collected again by filtration, whereby 0.35 g of the target compound was obtained, so pl. 181-183 ^o C.

NMR (DMSO-d ₆ ) d ppm: 0.74 (6H, t. J 7.5 Hz), 0.79 (3H, t. J 7.5 Hz), 1.1-1.3 (2H, m), 1.40-1.50 (2H, m), 1.67-1.80 (2H, m), 1.90-2.05 (2H, m), 2.59 (2H, t. J 7.5) 5.67 (2H, s), 6.88 (2H, d. J 8.5 Hz), 7.5 (2H, d. J 8.5 Hz), 7.5-7, 7 (4H, m).

 Example 22. 2-butyl-4- (1-hydroxy-1-methylethyl) -1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylic acid (compound 2-2) .

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

 The procedure described in Example 18a was repeated, but using 0.26 g of ethyl 2-butyl-4- (1-hydroxy-1-methylethyl) imidazole-5-carboxylate, prepared as described in Preparation 8, 45.5 mg of sodium hydride (55 wt. dispersion in mineral oil) and 0.63 g of 4- [2- (trityltetrazol-5-yl) phenyl] benzyl bromide, and 0.28 g of the target compound was obtained as an oily product.

NMR (CDCl ₃ ) d ppm: 0.85 (3H, t. J 7 Hz), 1.09 (3H, t. J 7 Hz), 1.09 (3H, t, J 7 Hz), 1.64 (6H, s), 1.3-1.8 (4H, m), 2.56 (2H, t. J 8 Hz), 4.14 (2H, q. J 7 Hz), 5.38 (2H , s), 5.78 (1H, s), 6.6-7.6 (22H, m), 7.7-8.1 (1H, m).

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

The procedure described in Example 21 b was repeated and by processing 0.28 g of ethyl 2-butyl-4- (1-hydroxy-1-methylethyl) -1- {4- [2- (trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate obtained in accordance with the description in stage (a), 0.42 ml of 1 N. aqueous hydrochloric acid, followed by processing of the product 1.70 ml of 1 N. an aqueous solution of sodium hydroxide received 78 g of the target compound, so pl. 138-141 ^o C.

NMR (DMSO-d ₆ ) d ppm: 0.81 (3H, t. J 7.5 Hz), 1.15-1.35 (2H, m), 1.4-1.6 (2H, m) 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); 7.15-7.70 (4H, m).

 Example 23. 2-butyl-4- (1-hydroxy-1-methylpropyl) -1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylic acid (compound 2-38) .

23a). 2-butyl-5-cyano-4- (1-hydroxy-1-methylpropyl) -1- {4- [2-trityltetrazol-5-yl) phenyl] phenyl} methylimidazole
The procedure described in example 18a was repeated, but using 465 mg of 2-butyl-5-cyano-4- (1-hydroxy-1-methylpropyl) imidazole, prepared as described in Preparation 19, 92 mg of sodium hydride (as 55 wt. Dispersion in mineral oil), and 1.11 g of 4- [2- (trityltetrazol-5-yl) phenyl] benzyl bromide, and 1.00 g of the target compound are obtained as a gummy substance.

NMR (CDCl ₃ ) d ppm: 0.86 (3H, t. J 7.5 Hz), 0.87 (3H, t. J 7 Hz), 1.21-1.34 (2H, m), 1 54-1.66 (2H, m), 1.60 (3H, s), 1.82-1.97 (2H, m), 2.51 (2H, t. J 7.5 Hz), 3 22 (1H, s), 5.04 (2H, s), 6.87-7.52 (22 N, m), 7.93-7.96 (1H, m).

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

A mixture of 1.00 g of 2-butyl-5-cyano-4- (1-hydroxy-1-methylpropyl) -1- {4- [2- (trityltetrazol-5-yl) phenyl] phenyl} methylimidazole obtained in accordance with the description given in step (a) and 25 ml of 20% v / v. aqueous acetic acid was stirred for 2 hours at 60 ^° C., after which the solvent was distilled off under reduced pressure. The residual water and acetic acid were removed as a toluene azeotrope by distillation under reduced pressure, and the obtained residue was purified by column chromatography on silica gel, eluting with a mixture of methanol and methylene chloride (1: 9 and 1: 4, v / v), resulting in 0, 65 g of the target compound in the form of a glassy substance.

NMR (CDCl ₃ ) d ppm: 0.83 (3H, t. J 7 Hz), 0.88 (3H, t. J 7 Hz), 1.23-1.37 (2H, m), 1.57 (3H, s), 1.55-1.70 (2H, m), 1.82-1.89 (2H, m), 2.64 (2H, t. J 7 Hz), 5.12 (2H , c), 6.9-7.1 (4H, m), 7.29-7.60 (3H, m), 7.87 (1H, d. J 7.5 Hz).

 23c) 2-butyl-4- (1-hydroxy-1-methylpropyl) -1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylic acid.

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

NMR (DMSO-d ₆ ) d ppm: 0.79 (3H, t. J 7 Hz), 0.82 (3H, t. J 7 Hz), 1.20-1.34 (2H, m), 1 44-1.55 (2H, m), 1.55 (3H, s), 1.71-1.95 (2H, m), 2.62 (2H, t. J 7.5 Hz), 5 68 (2H, AB quartet, d 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} methylimidazole-5-carboxylic acid (compound 2-37) .

 24a) 5-cyano-4- (1-hydroxy-1-methylpropyl) -2-propyl-1- {4- [2-trityltetrazol-5-yl) phenyl] phenyl} methylimidazole.

 The procedure described in example 18a was repeated, but using 380 mg of 5-cyano-4- (1-hydroxy-1-methylpropyl) -2-propylimidazole, prepared as described in the preparation of 20, 88 mg of sodium hydride (as 55 by weight of dispersion in mineral oil) and 1.07 g of 4- [2- (trityltetrazol-5-yl) phenyl] benzyl bromide, whereby 0.97 g of the target compound are obtained in the form of an amorphous solid.

NMR (CDCl ₃ ) d ppm: 0.86 (3H, t. J 8 Hz), 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), 6.88 (2H, d J 8.5 Hz), 6.9-7.0 (4H, m), 7.14 (2H, d J 8.5 Hz), 7.2-7.4 (14H, m), 7, 45-7.55 (1H, m).

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

The procedure described in Example 23b was repeated, and by processing 0.51 g of 5-cyano-4- (1-hydroxy-1-methylpropyl) -2-propyl-19 {4- [2- (trityltetrazol-5-yl) phenyl ] phenyl} methylimidazole obtained in accordance with the description in stage (a), 75 vol./about. aqueous acetic acid received 0.32 g of the target compound in the form of crystals, so pl. 141-145 ^o C.

NMR (CDCl ₃ ) d ppm: 0.84 (3H, t. J 8 Hz), 0.90 (3H, t. J 8.5 Hz), 1.52 (3H, s), 1.5-1 7 (2H, m), 1.75-1.90 (2H, m), 2.65 (2H, t. J 8 Hz), 5.27 (2H, s), 7.03 (2H, d J 8.5 Hz), 7.14 (2H, doublet J 8.5 Hz), 7.45-7.63 (4H, m).

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

The procedure described in Example 23c was repeated and by processing 0.19 g of 5-cyano-4- (1-hydroxy-1-methylpropyl) -2-propyl-1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole obtained in accordance with the description in step (b), 0.15 g of lithium hydroxide-monohydrate received 0.14 g of the target compound in powder form, so pl. 174-177 ^o C.

NMR (CDCl ₃ ) Dd ppm: 0.88 (3H, t. J 7.5 Hz), 0.94 (3H, t. J 7.5 Hz), 1.50-1.65 (2H, m) 1.63 (3H, s), 1.85-2.05 (2H, m), 2.76 (2H, t. J 7.5 Hz), 5.80 (2H, AB quarter d 0 , 14 ppm, J 16.5 Hz), 7.01 (2H, d. J 8.5 Hz), 7.11 (2H, d. J 8.5 Hz), 7.48-7.75 (4H , m).

 Example 25. Pivaloyloxymethyl 1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate (compound 3-1).

 25a) Ethyl 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -4- (1-hydroxy -1-methylethyl) -2-propylimidazole-5-carboxylate.

3.00 g of potassium t-butoxide was added while cooling with ice to a solution of 6 g of ethyl 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate, prepared as described in Preparation 9, in 40 ml of N, N-dimethylacetamide and the resulting mixture were stirred for 10 minutes, after which a solution of 9.00 g of t-butyl-4'-bromomethylbiphenyl-2-carboxylate in 40 ml of N, N-dimethylacetamide was added. Then the reaction mixture was stirred for 1 hour at room temperature and 2 hours at 50 ^° C., after which the mixture was mixed with water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a mixture of hexane and ethyl acetate (1: 1, v / v), and 11.6 g of the target compound was obtained as a solid with a softening point of 85 ^° C.

NMR (CDCl ₃ ) d ppm: 0.97 (3H, t. J 7 Hz), 1.23 (3H, t. J 7 Hz), 1.25 (9H, s), 1.60 (6H, s ), 1.82 (2H, sextet, J 7 Hz), 2.67 (2H, t. J 7 Hz), 4.24 (2H, q. J 7 Hz), 5.51 (2H, s), 5.72 (1H, s), 6.87-7.85 (8H, m).

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

A solution of 4.8 g of lithium hydroxide monohydrate in 100 ml of water was added to a solution of 11.6 g of ethyl-1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -4- (1-hydroxy -1-methylethyl ) -2-propylimidazole-5-carboxylate, obtained as described in step (a), in 60 ml of dioxane, and the resulting mixture was stirred for 16 hours at room temperature. Dioxane was distilled off under reduced pressure, and the concentrate was mixed with ice water and ethyl acetate, after which 114 ml of 1N was added. aqueous hydrochloric acid. The ethyl acetate layer was separated, dried over anhydrous magnesium sulfate, and the solvent was distilled off by distillation under reduced pressure. The crystalline residue was triturated in diisopropyl ether and collected by filtration, whereby 9.09 g of the target compound was obtained, mp. 155-157 ^o C.

NMR (CDCl ₃ ) d ppm: 0.85 (3H, t. J 7.5 Hz), 1.23 (4H, s), 1.53-1.65 (2H, m), 1.65 (6H , s), 2.91 (3H, t. J 7.5 Hz), 5.90 (2H, s), 7.09 (2H, d. J 8 Hz), 7.21-7.48 (5H , m), 7.75 (1H, d. J, 9 Hz).

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

2.13 ml of chloromethyl pivalate and 3.99 g of potassium carbonate were added to a solution of 6 g of 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -4- (1-hydroxy -1-methylethyl) -2-propylimidazole -5-carboxylic acid obtained in accordance with the description in stage (b) in 70 ml of N, N-dimethylacetamide and the resulting mixture was stirred at room temperature for 1 h, and at 50 ^o C for 2 h. 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, after which the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a mixture of ethyl acetate and hexane (1: 1, v / v), and 6.80 g of the target compound was obtained in the form of crystals, mp. 106-107 ^o C.

NMR (CDCl ₃ ) d ppm: 1.07 (3H, t. J 7 Hz), 1.25 (9H, s), 1.32 (9H, s), 1.71 (6H, s), 1, 79-1.90 (2H, m), 2.75 (2H, t. J 8 Hz), 5.50 (1H, s), 5.59 (2H, s), 5.92 (2H, s) 7.05 (2H, d. J 8 Hz), 7.34-7.56 (4H, m), 7.85 (1H, d. J 7 Hz).

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

A mixture of 6.6 g of pivaloyloxymethyl 1 - [(2'-butoxycarbonylbiphenyl-4-yl) methyl] -4- (1-hydroxy -1-methylethyl-2-propylimidazole-5-carboxylate, prepared as described in step (c) ), and 57 ml of a 4N solution of hydrogen chloride in dioxane was stirred for 4 hours at room temperature, after which the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was triturated with ethyl acetate to crystallize it, whereby 6.52 g of the target compound was obtained in as hydrochloride, mp 170-173 ^o C.

NMR (DMSO-d ₆ ) d ppm: 0.87 (3H, t. J 7 Hz), 1.10 (9H, s), 1.45-1.60 (2H, m), 1.58 (6H , s), 2.96 (2H, t. J 7.5 Hz), 5.65 (2H, s), 5.87 (2H, s), 7.17 (2H, d. J 8 Hz), 7.33 (2H, d. J 8 Hz), 7.43-7.60 (3H, m), 7.74 (1H, d. J 8 Hz),
Example 26. Isopropoxycarbonyloxymethyl 1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate (compound 3-13).

 26a) Isopropoxycarbonyloxymethyl 1 - [(2'-t-butoxycarbonyl-biphenyl-4-yl) methyl] -4- (1-hydroxy-1-methylethyl) -2-propyl-imidazole-5-carboxylate.

The procedure described in example 25 (c) was repeated, and the target compound was obtained in the form of crystals (0.58 g, mp 85-87 ^° C) by stirring a mixture containing 0.50 g 1 - [(2'- t-butoxycarbonylbiphenyl-4-yl) methyl] -4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylic acid, obtained as described in example 25 (b), 0.19 g of isopropoxycarbonyloxymethyl chloride and 0.33 g of potassium carbonate in 6 ml of N, N-dimethylacetamide, for 3 hours at room temperature.

NMR (CDCl ₃ ) d ppm: 0.99 (3H, t. J 7 Hz), 1.23 (9H, s), 1.29 (6H, d J 6 Hz), 1.63 (6H, s) 1.70-1.85 (2H, m), 2.68 (2H, t. J 8 Hz), 4.89 (1H, quintet, J 6 Hz), 5.38 (1H, s), 5 61 (2H, s), 5.82 (2H, s), 6.97 (2H, d. J 8 Hz), 7.26-7.48 (5H, m), 7.77 (1H, d .J 8 Hz).

 26b) Isopropoxycarbonyloxymethyl 1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate.

The procedure described in Example 25b was repeated and, by treating 0.46 g of isopropoxycarbonyloxymethyl 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -4- (1-hydroxy-1-methylethyl) -2-propylimidazole- 5-carboxylate obtained in accordance with the description in stage (a), 4 N. a solution of hydrogen chloride in dioxane received 0.36 g of the hydrochloride of the target compound in the form of an amorphous powder, so pl. 153-155 ^o C.

NMR (CDCl ₃ ) d ppm: 0.98 (3H, t. J 7 Hz), 1.29 (6H, d. J 6 Hz), 1.50-1.65 (2H, m), 1.75 (6H, s), 3.13 (2H, t. J 7 Hz), 4.90 (1H, quintet J 6 Hz), 5.55 (2H, s), 5.82 (2H, s), 7 02 (2H, d. J 6.5 Hz), 7.21-7.57 (5H, m), 7.96 (1H, d. J 8 Hz).

 Example 27. Ethoxycarbonyloxymethyl 1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate (compound 3-9).

 27a) Ethoxycarbonyloxymethyl 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate.

 Following the procedure described in example 25c, 0.69 g of the target compound was obtained as an oily substance, starting from 0.55 g of 1 - [(2'-t-butoxycarbonylbephenyl-4-yl) methyl] -4- (1-hydroxy -1-methylethyl) -2-propylimidazole-5-carboxylic acid, obtained as described in Example 25b, 0.30 g of ethoxycarbonyloxymethyl chloride and 0.50 g of potassium carbonate.

NMR (CDCl ₃ ) d ppm: 0.99 (3H, t. J 7 Hz), 1.23 (9H, s), 1.29 (3H, t. J 7 Hz), 1.64 (6H, s ), 1.74-1.85 (2H, m), 2.69 (2H, t. J 7.5 Hz), 4.21 (2H, q. J 7 Hz), 5.39 (1H, s ), 5.52 (2H, s), 5.83 (2H, s), 6.97 (2H, g. J 8 Hz), 7.25-7.51 (5H, m), 7.77 ( 1H, d. J 6.5).

 27b) Ethoxycarbonyloxymethyl 1 - [(2'-carboxyphenyl-4-yl) methyl] -4- (1-hydroxy-1-methylethyl) -2-propyl-imidazole-5-carboxylate.

Following the procedure described in example 25d, 0.48 g of the hydrochloride of the target compound was obtained in the form of an amorphous powder (softening temperature> 70 ^° C.) by treating 0.69 g of ethoxycarbonyloxymethyl 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate, obtained as described in step (a), 4N. a solution of hydrogen chloride in dioxane.

NMR (DMSO-d ₆ ) d ppm: 0.88 (3H, t. J 7 Hz), 1.19 (3H, t. J 7 Hz), 1.5-1.65 (2H, m), 1 59 (6H, s), 2.96 (2H, t. J 7.5 Hz), 4.15 (2H, q. J 7 Hz), 5.64 (2H, s), 5.84 (2H , s), 7.18 (2H, d. J 8 Hz), 7.32-7.61 (5H, m), 7.74 (1H, d. J 7 Hz).

 Example 28. 1- (isopropoxycarbonyloxy) ethyl 1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carbo (compound 3-14 )

 28a) 1- (isopropoxycarbonyloxy) ethyl 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate.

Following the procedure described in example 25c, 0.60 g of the target compound was obtained as a gummy substance by stirring for 16 hours at 60 ^° C, 0.50 g of 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl ] -4- (1-hydroxy-1-methyl-ethyl) -2-propylimidazole-5-carboxylic acid, obtained as described in example 25b, and 0.12 g of 1- (isopropoxycarbonyloxy) ethyl chloride in a solution of 0.40 g potassium carbonate in 6 ml of N, N-dimethylacetamide.

NMR (CDCl ₃ ) d ppm: 0.97 (3H, t. J 7.5 Hz), 1.26 (4H, s), 1.27 (6H, dd doublet of doublets, J 4.5 d 6 Hz), 1.42 (3H, d. J 5.5 Hz), 1.64 (6H, d. J 3 Hz), 1.75-1.80 (2H, m), 2.65 (2H, d. J 7.5 Hz), 4.86 (1H, quin. J 6 Hz), 5.50 (2H, s), 6.90 (1H, q. J 5.5 Hz), 6.97 (2H, d .J 8.5 Hz), 7.26-7.50 (5H, m), 7.78 (1H, d J 8 Hz),
28b) 1- (isopropoxycarbonyloxy) ethyl 1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate.

Following the procedure described in example 25d, 0.41 g of the hydrochloride of the target compound (as an amorphous powder with a melting point of 94-96 ^° C) was obtained by treating 0.60 g of 1- (isopropoxycarbonyloxy) ethyl 1 - [(2 ' t-butoxycarbonylbiphenyl) -2-yl methyl] -4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate, obtained as described in step (a), 4 N. a solution of hydrogen chloride in dioxane.

NMR (CDCl ₃ ) d ppm: 0.94 (3H, t. J 7 Hz), 1.27 (6H, dd. J 6.5 & 11 Hz), 1.47 (3H, d. J 5.5 Hz) 1.50-1.65 (2H, m), 1.76 (6H, d. J 8.5 Hz), 3.08 (2H wide triple. J 8 Hz), 4.86 (1H, septet , J 7 Hz), 5.56 (2H, s), 6.87 (1H, q, J 5.5 Hz), 7.04 (2H, d. J 7.5 Hz), 7.27-7 65 (5H, m); 7.97 (1H, d. J, 8 Hz).

 Example 29. (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl 1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate (compound 3-25).

 29a) (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl 1 - [(2'-t-butoxy-carbonylbiphenyl-4-yl) methyl] -4- (1-hydroxy-1 -methylethyl) -2-propylimidazole-5-carboxylate.

 Following the procedure described in example 25c, 0.65 g of the target compound was obtained in the form of a gum, starting from 0.50 g of 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -4- (1-hydroxy -1-methylethyl) -2-propylmidazole-5-carboxylic acid obtained in accordance with the description of Example 25b, 0.27 g of (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl bromide and 0, 3 g of potassium carbonate in 6 ml of N, N-dimethylacetamide.

NMR (CDCl ₃ ) d ppm: 0.99 (3H, t. J 6.5 Hz), 1.28 (9H, s), 1.64 (6H, s), 1.55-1.90 (2H , m), 2.07 (4H, s), 2.70 (2H, t. J 7 Hz), 4.90 (2H, s), 5.47 (2H, s), 5.51 (1H, s), 6.91 (2H, d. J, 8.5 Hz), 7.2-7.9 (6H, m).

29b) (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate
Following the procedure described in example 25d, 0.54 g of the hydrochloride of the target compound was obtained in the form of an amorphous powder (mp 90-93 ^° C) by treating 0.65 g (5-methyl-2-oxo-1,3- dioxolen-4-yl) methyl-1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate obtained in accordance with the description in stage (a), 4 N. a solution of hydrogen chloride in dioxane.

NMR (DMSO-d ₆ ) d ppm: 0.88 (3H, t. J 7.5 Hz), 1.5-167 (2H, m), 1.59 (6H, s), 2.11 (3H , s), 3.00 (2H, t J 7.5 Hz), 5.13 (2H, s), 5.63 (2H, s), 7.13 (2H, d. J 8 Hz), 7 26-7.75 (6H, m).

 Example 30. Pivaloyloxymethyl 1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate (compound 3-1).

 30a) Pivaloyloxymethyl 1 - [(2'-t-butoxycarbonyl bephenyl-3-yl) methyl] -4- (1-hydroxy-1-methylethyl-2-propylimidazole-5-carboxylate.

 Following the procedure described in example 25a, 0.81 g of the target compound was obtained based on 500 mg of pivaloyloxymethyl 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate, prepared as described in Preparation 22 ii and 560 mg of t-butyl 5'-bromomethylbiphenyl-2-carboxylate. This product has the same melting point and the same NMR spectrum as the compound obtained in Example 25c.

 30b) Pivaloyloxymethyl 1 - [(2-carboxybiphenyl-4-yl) methyl] -4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate.

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

 Example 31. Pivaloyloxymethyl 2-butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (1-hydroxy-1-methylethyl) imidazole-5-carboxylate (compound 3-27).

 31a) Methyl 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-4- (1-hydroxy -1-methylethyl) imidazole-5-carboxylate.

 Following the procedure described in example 25a, 3.54 g of the target compound was obtained in the form of a syrup, starting from 2.00 g of methyl 2-butyl-4- (1-hydroxy-1-methylethyl) imidazole-5-carboxylate obtained in as described in Preparation 21, and 3.03 g of t-butyl 4'-bromomethylbiphenyl-2-carboxylate.

NMR (CDCl ₃ ) d ppm: 0.92 (3H, t, J 7.5 Hz), 1.25 (9H, s), 1.33-1.46 (2H, m), 1.64 (6H , s), 1.68-1.78 (2H, m), 2.70 (2H, t. J 8 Hz), 3.78 (3H, s), 5.50 (2H, s), 5, 70 (1H, s), 6.97 (2H, d.J. 8.5 Hz), 7.26-7.33 (3H, m), 7.37-7.54 (2H, m), 7, 76-7.81 (1H, m).

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

Following the procedure described in example 25b, 2.46 g of the target compound were obtained in the form of crystals (mp 158-159 ^° C.) by hydrolysis of 3.31 g of methyl 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl ) -methyl] -2-butyl-4- (1-hydroxy -1-methylethyl) imidazole-5-carboxylate obtained as described in step (a) using 1.37 g of lithium monohydrate hydroxide.

NMR (CDCl ₃ ) d ppm: 0.84 (3H, t. J 7.5 Hz), 1.23 (9H, s), 1.25-1.38 (2H m), 1.52-1, 65 (2H, m), 1.68 (6H, s), 2.83 (2H, t. J 6.5 Hz), 5.81 (2H, s), 7.07 (2H d. J 8, 0 Hz), 7.22-7.28 (3H m), 7.34-7.50 (2H, m), 7.74-7.78 (1H, m).

 31c) Pivaloyloxymethyl 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-4- (1-hydroxy -1-methylethyl) imidazole-5-carboxylate.

 Following the procedure described in example 25c, 0.48 g of the target compound was obtained in the form of a syrup by esterification of 0.40 g of 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-4- (1 -hydroxy -1-methylethyl) imidazole-5-carboxylic acid, obtained as described in step (b), using chloromethyl pivalate and potassium carbonate.

NMR (CDCl ₃ ) d ppm: 0.92 (3H, t. J 7.5 Hz), 1.17 (9H, s), 1.24 (9H, s), 1.32-1.47 (2H , m), 1.63 (6H, s), 1.66-1.79 (2H, m), 2.69 (12H, t. J 8 Hz), 5.41 (1H, s), 5, 51 (2H, s), 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).

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

Following the procedure described in example 25d, 0.45 g of the hydrochloride of the target compound was obtained as an amorphous solid (mp 139-144 ^° C, softener 127 ^° C) by treating 0.48 g of pivaloyloxymethyl 1- [ (2'-t-butoxycarbonyl-biphenyl-4-yl) methyl] -2-butyl-4- (1-hydroxy-1-methylethyl) imidazole-5-carboxylate, prepared as described in step (c), 4 n a solution of hydrogen chloride in dioxane.

NMR (DMSO-d ₆ ) d ppm: 0.80 (3H, t, J 7.5 Hz), 1.10 (9H, s), 1.21-1.35 (2H, m), 1.39 -1.50 (2H, m), 1.58 (6H, s), 2.96 (2H, t. J 7.5 Hz), 5.65 (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), 7.55-7.61 ( 1H, m), 7.73-7.75 (1H, m).

 Example 32. Isopropoxycarbonyloxymethyl 2-butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (1-hydroxy-1-methylethyl) imidazole-5-carboxylate (compound 3-39).

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

Following the procedure described in example 25c, 0.46 g of the target compound were obtained in the form of crystals (mp. 91-93 ^° C) starting from 0.40 g of 1 - [(2'-t-tuboxycarbonylbiphenyl-4-yl) ) methyl] -2-butyl-4- (1-hydroxy -1-methylethyl) -imidazole-5-carboxylic acid, prepared as described in Example 31b, 0.15 g of isopropoxycarbonyloxymethyl chloride and 0.31 g of potassium carbonate.

NMR (CDCl ₃ ) d ppm: 0.92 (3H, t. J 7.5 Hz), 1.23 (9H, s), 1.29 (6H, d. J 6 Hz), 1.35-1 45 (2H, m), 1.63 (6H, s), 1.65-1.80 (2H, m), 2.71 (2H, t. J 7.5 Hz), 4.90 (1H , septet J 6 Hz), 5.39 (1H, s), 5.51 (2.s), 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).

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

Following the procedure described in Example 25d, 0.39 g of the hydrochloride of the target compound was obtained in the form of crystals (mp 154-156 ^° C.) by treating 0.40 g of isopropoxycarbonyloxymethyl 1 - [(2'-t-butoxycarbonylbiphenyl-4- il) methyl] -2-butyl-4- (1-hydroxy-1-methylethyl) imidazole-5-carboxylate obtained in stage (a), 4 N. a solution of hydrogen chloride in dioxane.

NMR (DMSO-d ₆ ) d ppm: 0.81 (3H, t. J 7.5 Hz), 1.21 (6H, d. J 6.5 Hz), 1.23-1.36 (2H, m), 1.38-1.52 (2H, m), 1.59- (6H, s), 2.98 (2H, t. J 6.5 Hz), 4.79 (1H, septet, J 6.5 Hz), 5.65 (2H, s), 5.85 (2H, s), 7.18 (2H, d. J 8 Hz), 7.30-7.38 (3H, m), 7.42-7.62 (2H, m); 7.74 (1H, d J 7.5 Hz).

 Example 33. (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl 2-butyl-1 - [(2'carboxybiphenyl-4-yl) methyl] -4- (1-hydroxy-1 methyl ethyl imidazole-5-carboxylate (compound 3-51).

 33a) (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-4- (1-hydroxy -1-methylethyl) imidazole-5-carboxylate.

Following the procedure described in example 25c, 0.43 g of the target compound was obtained in the form of crystals (mp 156-157 ^° C), starting from 0.40 g of 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl ) methyl] -2-butyl-4- (1-hydroxy-1-methylethyl) imidazole-5-carboxylic acid, obtained as described in example 31b, 0.22 g (5-methyl 2-oxo-1,2 -dioxolen-4-yl) methyl bromide; and 0.26 g of potassium carbonate in 5 ml of N, N-dimethylacetamide.

NMR (CDCl ₃ ) d ppm: 0.92 (3H, t, J 7.5 Hz), 1.27 (9H, s), 1.30-1.45 (2H, m), 1.62 (6H , s), 1.65-1.80 (3H, m), 2.07- (3H, s), 2.70 (2H, t J 7.5 Hz), 4.89 (2H, s), 5.46 (2H, s), 5.55 (1H, s), 6.91 (2H, d.J. 8.5 Hz), 7.26-7.50 (5H, m), 7.76 ( 1H, d. J 6.5 Hz).

 33b) (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl-2-butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (1-hydroxy- 1-methyl-ethyl) imidazole-5-carboxylate.

Following the procedure described in example 25d, 0.26 g of the hydrochloride of the target compound was obtained in the form of a powder (mp. More than 70 ^° C. with softening) by treatment with 0.32 g (5-methyl-2-oxo-1,3 -dioxolen-4-yl) methyl 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -4- (1-hydroxy-1-methylethyl) imidazole-5-carboxylate, obtained as described in the step (a) 4 n. a solution of hydrogen chloride in dioxane.

NMR (DMSO-d ₆ ) Dd ppm: 0.82 (3H, t. J 7 Hz), 1.20-1.40 (2H, m), 1.40-1.60 (2H, m), 1 59 (6H, s), 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), 7.30-7.60 (5H, m), 7.74 (1H, d J 7.5 Hz),
Example 34. Phthalidyl 1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate (compound 3-26).

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

Following the procedure described in example 25c, 0.62 g of the target compound was obtained in the form of crystals (mp 144 ^° C), starting from 0.50 g of 1 - [(2'-t-butoxycarbonylbiphenyl) methyl] -4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylic acid, obtained as described in example 25b, 0.25 g of 3-bromophthalide and 0.3 g of potassium carbonate in 6 ml of N, N-dimethylacetamide .

NMR (CDCl ₃ ) d ppm: 0.97 (2H, t. J 7.5 Hz), 1.25 (9H, s), 1.62 (6H, s), 1.75 (2H, sextet, J 7.5 Hz), 2.66 (2H, t. J 6.5 Hz), 5.38 (2H, AB quartet, d0.10 ppm J 17 Hz), 5.42 (1H, s), 6 69 (2H, d. J 7.5 Hz), 7.15 (2H, d. J 7.5 Hz), 7.28-7.89 (9H, m).

 34d) Phthalidyl 1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate.

In accordance with the procedure described in example 25d, 0.37 g of the hydrochloride of the target compound was obtained in the form of an amorphous powder (mp 142-144 ^° C.) by treating 0.45 g of phthalidyl 1 - [(2'-t-butoxycarbonylbiphenyl) -4-yl) methyl] -4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate obtained in stage (a), 4 N. a solution of hydrogen chloride in dioxane.

NMR (DMSO-d ₆ ) d ppm: 0.92 (3H, t. J 7.5 Hz), 1.50-1.70 (2H, m), 1.59 (6H, s), 3.00 (2H, t, J 7.5 Hz), 5.65 (2H, s), 7.01 (2H, d. J 8 Hz), 7.27 (2H, d. J 8 Hz), 7.36 -7.98 (9H, m).

 Example 35. Ethyl 4-hydroxymethyl-2-propyl-1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methyl imidazole-5-carboxylate (compound 4-3).

 35a) Diethyl 2-propyl-1- {4- [2-trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-4,5-dicarboxylate.

 0.441 g of potassium t-butoxide was added to a solution of 1.00 g of diethyl 2-propylimidazole-4,5-dicarboxylate, prepared as described in Preparation 12, in 15 ml of N, N-dimethylacetamide, and the resulting mixture was stirred for 30 minutes at room temperature. . A solution of 2.19 g of 4- [2- (trityltetrazol-4-yl) phenyl] benzyl bromide in 15 ml of N, N-dimethylacetamide was added dropwise to the reaction mixture at room temperature, after which the reaction mixture was stirred for 3 hours at room temperature. After this time, the mixture was diluted with water and then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off by distillation. The residue was purified by silica gel column chromatography, eluting with a mixture of hexane and ethyl acetate (1: 1, v / v), and 2.24 g of the target compound was obtained as an amorphous solid.

NMR (CDCl ₃ ) d ppm: 0.88 (3H, t. J 7.5 Hz), 1.20 (3H, t. J 7.5 Hz), 1.39 (3H, t. J 7.5 Hz), 1.59 (6H, s), 1.61-1.72 (3H, m), 2.55 (2H, t. J 7.5 Hz), 4.20 (2H, q. J 7 5 Hz), 4.39 (2H, q, J 7.5 Hz), 5.30 (2H, s), 6.78 (2H, d. J 8 Hz), 6.92-7.52 ( 20H, m), 7.90 (1H, d. J 7.5 Hz).

 35b) Ethyl 4-hydroxymethyl-2-propyl-1- {4- [2- (trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate.

10 ml of a 1.5 M solution of diisobutylaluminum hydride in toluene was added dropwise at -20 ^° C and under nitrogen atmosphere to a solution of 4.27 g of diethyl 2-propyl-1- {4- [2- (trityltetrazol-5-yl) phenyl ] phenyl} methylidimidazole-4,5-dicarboxylate obtained in stage (a) in 50 ml of tetrahydrofuran. The resulting mixture was left for 16 hours at 0 ^° C., and then mixed with ethyl acetate and a saturated aqueous solution of ammonium chloride, and the resulting mixture was stirred for 1 hour at room temperature, the precipitate was filtered off, the ethyl acetate layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off. by distillation under reduced pressure. The crystalline residue was washed with diisopropyl ether and 4.03 g of the target compound were obtained, so pl. 135-138 ^o C.

NMR (CDCl ₃ ) d ppm: 0.94 (6H, t. J 7.5 Hz), 1.29 (3H, t J 7 Hz), 1.67-1.77 (2H, m), 2, 56 (2H, t. J 7.5 Hz), 3.43 (1H, br.t. J 4 Hz), 4.25 (2H, q. J 7 Hz), 4.91 (2H, d. J 4 Hz), 5.49 (2H, s), 6.82 (2H, d.J. 7.5 Hz), 6.98-7.57 (20H, m), 7.94 (1H, d.J 7 Hz).

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

A solution of 0.28 g of ethyl 4-hydroxymethyl-2-propyl- {4- [2- (trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate obtained in stage (b) in 4 ml of 75% ./about. aqueous acetic acid was stirred for 2 hours at 60 ^° C. Then the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was dissolved in toluene. The resulting solution was again concentrated by evaporation under reduced pressure to remove as much water and acetic acid as possible. After that, the residue was purified by silica gel column chromatography, eluting with a mixture of methylene chloride and methanol (9: 1 and 4: 1 by volume), and 0.20 g of the target compound was obtained as an amorphous solid.

NMR (CDCl ₃ ) d ppm: 0.80 (3H, t. J 7.5 Hz), 1.20 (3H, t. J 7.5 Hz), 1.45-1.65 (2H, m) 2.44 (2H, t. J 7.5 Hz), 4.20 (2H, q. J 7.5 Hz), 4.58 (2H, s), 5.43 (2H, s), 6 78 (2H, d. J 7.5 Hz), 6.98 (2H, d. J 7.5 Hz), 7.38-7.60 (3H, m), 7.79 (1H, d. J 7.5 Hz)
Examples 36. 4-hydroxymethyl-2-propyl-1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylic acid (compound 4-1).

A mixture of 0.20 g of ethyl 4-hydroxymethyl-2-propyl-1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate, prepared as described in example 35c, and 0 10 g of lithium hydroxide monohydrate in 3 ml of water was stirred for 3 hours at room temperature, after which the mixture was left at the same temperature for 16 hours. Then the reaction mixture was mixed with 2.38 ml of 1N aqueous hydrochloric acid, and the resulting precipitate was collected by filtration, as a result of which 150 mg of the target compound were obtained, so pl. 233 ^o C (decomp.).

NMR (DMSO-d ₆ ) d ppm: 0688 (3H, t. J 7.5 Hz), 1.59 2H, sextet, J 7.5 Hz), 2.58 (2H, t, J 7.5 Hz ), 4.64 (2H, s), 2.62 (2H, s), 6.98 (2H, d. J 8 Hz), 7.08 (2H, d. J 8 Hz), 7.39- 7.69 (3H, m).

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

 37a) 4-hydroxymethyl-2-propyl-1- {4- [2- (trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylic acid.

A solution of 0.66 g of lithium hydroxide monohydrate in 20 ml of water was added to a solution of 1.22 g of ethyl 4-hydroxymethyl-2-propyl-1- {4- [2- (trititerrazol-4-yl) phenyl] phenyl} methylimidazole-5 -carboxylate obtained as described in example 35b in 5 ml of dioxane and the resulting mixture was stirred for 5 hours at 80 ^° C. After this, the reaction mixture was isolated from dioxane by distillation under reduced pressure, and the aqueous residue was mixed with ice and ethyl acetate, then 15.7 ml of 1N was added. aqueous hydrochloric acid. The target compound precipitated and was collected by filtration and washed with water. Then the ethyl acetate layer was isolated from the filtrate and dried over anhydrous magnesium sulfate, and the solvent was distilled off by distillation under reduced pressure. The resulting residue was washed with diethyl ether, and the target compound was obtained in powder form. Two parts of the target compound were combined (together they weighed 0.98 g) and immediately, without further purification or identification, was used in the subsequent esterification reaction.

 37b) Pivaloyloxymethyl 4-hydroxymethyl-2-propyl-1- {4- [2- (trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate.

 0.30 g of potassium carbonate and 0.24 g of pivaloyloxymethyl chloride were added to a solution of 0.98 g of 4-hydroxymethyl-2-propyl-1- {4- [2- (trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-5- carboxylic acid obtained in stage (a) in 10 ml of N, N-dimethylacetamide and the resulting mixture was stirred at room temperature for 6 hours. At the end of this time, the reaction mixture was mixed with ethyl acetate and water. The ethyl acetate layer was separated and dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel chromatography, eluting with a mixture of ethyl acetate and hexane (2: 1, v / v), whereby 0.91 g of the target compound was obtained as a gummy substance.

NMR (CDCl ₃ ) d ppm: 0.89 (3H, t. J 7.5 Hz), 1.18 (9H, s), 1.70 (1H, sextet, J 7.5 Hz), 2.52 (2H, t. J 8 Hz), 3.35 (1H, br s), 4.83 (2H, s), 5.32 (2H, s), 5.80 (2H, s), 6, 76 (2H, d. J 8 Hz), 6.92-7.51 (20H, m), 7.90 (1H, d J 7.5 Hz).

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

According to the procedure described in Example 35c, 0.91 g of pivaloyloxymethyl 4-hydroxymethyl-2-propyl-1- {4- [2- (trityltetrazol-5-yl) phenyl] phenyl} methylimidazole obtained in stage (b) , were detritilated by treatment with 75 vol./about. aqueous acetic acid, resulting in a 0.42 g of the target compound was obtained in the form of a powder, so pl. above 60 ^o C (with softened.).

NMR (CDCl ₃ ) d ppm: 0.94 (3H, t. J 7.5 Hz), 1.14 (9H, s), 1.72 (2H, sextet, J 7.5 Hz), 2.61 (2H, t. J 7.5 Hz), 2.90 (2H, br s), 4.77 (2H, s), 4.49 (2H, s), 5.84 (2H, s), 6.94 (2H, d. J g Hz), 7.15 (2H, d. J 8 Hz), 7.26-7.61 (3H, m), 8.07 (1H, d. J 7, 5 Hz).

 Example 38. Methyl 2-butyl-4-hydroxymethyl-1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate (compound 4-47).

 38a) Dimethyl 2-butyl-1- {4- [2- (trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-4,5 dicarboxylate.

 The procedure described in example 35a was repeated, but using 0.50 g of dimethyl-2-butylimidazole-4,5-dicarboxylate, prepared as described in Preparation 4, and 1.17 g of 4 [2-trityltetrazole-5 -yl) phenyl] benzyl bromide, whereby 0.51 g of the target compound is obtained as an amorphous solid.

NMR (CDCl ₃ ) d ppm: 0.85 (3H, t. J 7.5 Hz), 1.20-1.80 (4H, m), 2.59 (2H, t. J 8.0 Hz) 3.73 (3H, s), 3.92 (3H, s), 5.30 (3H, s), 6.6-7.6 (22H, m), 7.8-8.0 (1H , m).

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

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

NMR (CDCl ₃ ) d ppm: 0.86 (3H, t. J 7.5 Hz), 1.23-1.36 (2H, m), 1.58-1.70 (2H, m), 1 80-1.95 (1H, m), 2.54 (2H, t. J 8.0 Hz), 3.72 (3H, s), 4.85 (2H, d. J 6.0 Hz) 5.43 (2H, s), 6.77 (2H, d. J 8.5 Hz), 6.92-6.95 (4H, m), 7.08 (2H, d, J 8.5 Hz), 7.22-7.51 (14H, m), 7.87-7.90 (1H, m),
38c) Methyl 2-butyl-4-hydroxymethyl-1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate.

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

NMR (DMSO-d ₆ ) d ppm: 0.81 (3H, t. J 7.5 Hz), 1.19-1.32 (2H, m), 1.38-1.51 (2H, m) 2.95 (2H, t. J 7.5 Hz), 4.80 (2H, s), 5.71 (2H, s), 7.20-7.75 (8H, m).

 Example 39. 2-butyl-4-hydroxymethyl-1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylic acid (compound 4-46).

The procedure described in Example 36 was repeated, but using 0.30 g of methyl 2-butyl-4-hydroxymethyl-1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate in example 38c, and 2.50 ml of 1 N. an aqueous solution of sodium hydroxide, resulting in the receipt of 95 mg of the target compound in the form of crystals, so pl. 215-217 ^o C.

NMR (DMSO-d ₆ ) d ppm: 0.82 (3H, t. J 7.5 Hz), 1.27 (2H, m), 1.52 (2H, m), 2.56 (2H, t .J 7.5 Hz), 4.60 (2H, s), 5.58 (2H, s), 6.94 (2H, d. 8.5 Hz), 7.06 (2H, d. J 8.5 Hz), 7.50-7.70 (4H, m).

 Example 40. Ethyl 4- (1-hydroxyethyl) -2-propyl-1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate (compound 4-30).

 40a) Ethyl 4-formyl-1-propyl-1- {4- [2- (trityltetrazol-4-yl) phenyl] phenyl} methylimidazole-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- (trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate obtained in example 35b, in 40 ml of methylene chloride and the resulting mixture was stirred 2.5 hours at room temperature. After that, manganese dioxide was filtered off and the filtrate was concentrated by evaporation under reduced pressure. The obtained residue was purified by silica gel column chromatography, eluting with a mixture of ethyl acetate and hexane (1: 1, v / v), whereby 1.45 g of the target compound were obtained in the form of crystals, mp 177-179 ^o C (decomposition).

NMR (CDCl ₃ ) d ppm: 0.88 (3H, t. J 7.5 Hz), 1.29 (2H, t. J 7 Hz), 1.74 (2H, sextet, J 7.5 Hz) 2.57 (2H, t. J 7.5 Hz), 4.29 (2H, q. J 7 Hz), 5.49 (2H, s), 6.76 (2H, d. J 8.5 Hz), 6.92-7.88 (20H, m), 7.90 (1H, d. J 7.5 Hz), 10.42 (1H, s).

 40b) Ethyl 4- (1-hydroxyethyl) -2-propyl-1-4- [2- (trityltetrazol-4-yl) phenyl] phenyl} methylimidazole-5-carboxylate.

4.0 g of a 1 M solution of methyl manganese bromide tetrahydrofuran was added dropwise at 10 ^° C. to a solution of ethyl 4-formyl-2-propyl-1- {4- [2- (trityltetrazol-4-yl) phenyl] phenyl} methylimidazole -5-carboxylate obtained in stage (a) in 5 ml of tetrahydrofuran and the resulting mixture was stirred for 3 hours at a temperature of from -10 ^o C to 0 ^o C. After that, the reaction mixture was mixed with ethyl acetate and an aqueous solution of ammonium chloride and the resulting mixture was stirred 20 min at room temperature. Then the 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 silica gel column chromatography, eluting with mixtures of ethyl acetate and methylene chloride (1: 4 and 1: 2, by volume), whereby 1.23 g of the target compound was obtained in the form of a viscous oil .

NMR (CDCl ₃ ) d ppm: 0.78 (3H, t, J 7.5 Hz), 1.22 (3H, t, J 7 Hz), 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, q. 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, doublet, J, 7.5 Hz).

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

 Following the procedure described in example 35c, 1.23 g of ethyl 4- (1-hydroxyethyl) -2-propyl-1- {4- [2- (trityltetrazol-4-yl) phenyl] phenyl} methylimidazole-5-carboxylate, obtained in stage (b) was treated with 75% vol./about. aqueous acetic acid, whereby 0.82 g of the target compound is obtained in the form of an amorphous solid.

NMR (CDCl ₃ ) d ppm: 0.85 (3H, t. J 7.5 Hz), 1.24 (3H, t. J 7 Hz), 1.42 (3H, d. J 6 Hz), 1 59 (2H, sextet J 7.5 Hz), 2.50 (2H, t. J 7 Hz), 4.22 92H, q. J 7 Hz), 5.13-5.20 (1H, m), 5.44 (2H, AB quartet, d 0.12 ppm, J 16.5 Hz), 6.78 (2H, d.J 8 Hz), 6.99 (2H, d. J 8 Hz), 7.38-7.59 (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} methylimidazole-5-carboxylic acid (compound 4-29).

According to the procedure described in Example 36, 0.82 ethyl 4- (1-hydroxyethyl) -2-propyl-1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate obtained in Example 40c was hydrolyzed using 0.43 g of lithium hydroxide monohydrate, whereby 0.50 g of the target compound was obtained in the form of a powder, so pl. 198-201 ^o C.

NMR (DMSO-d ₆ ) d ppm: 0.86 (3H, t. J 7.5 Hz), 1.38 (3H, d. J 6.5 Hz), 1.55 (2H, sextet J 7, 5 G3) 2.58 (2H, t. J 8 Hz), 5.21 (1H, q. J 6.5 Hz), 5.61 (2H, s), 6.95-7.08 (4H, m), 7.51-7.70 (4H, m).

 Example 42. Ethyl 4- (1-hydroxyethyl) -2-propyl-1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate (compound 4-30).

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

 The procedure described in Example 35a was repeated, but using 114 mg of ethyl 4- (1-hydroxyethyl-2-propylimidazole-5-carboxylate, prepared as described in Preparation 23 iii, 280 mg of 4- [2- (trityltetrazole -4-yl) phenyl] benzyl bromide and 60 mg of potassium t-butoxide, yielding 255 mg of the target compound as a viscous oil.The NMR spectrum of this compound is identical to the NMR spectrum of the compound obtained in Example 40b.

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

 According to the procedure described in Example 35c, 255 mg of ethyl 4- (1-hydroxyethyl) -2-propyl-1- {4- [2- (trityltetrazol-4-yl) phenyl] phenyl} methylimidazole-5-carboxylate obtained in stage (a) was subjected to detritification by processing 75% vol./about. aqueous acetic acid, whereby 170 mg of the target compound are obtained in the form of an amorphous solid. The NMR spectrum of this compound is identical to the NMR spectrum of the compound obtained in Example 40c.

 Example 43. Ethyl 2-butyl-4- (1-hydroxyethyl) -1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate (compound 4-75).

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

 The procedure described in example 35a was repeated, but using 400 mg of ethyl 2-butyl-4- (1-hydroxyethyl) imidazole-5-carboxylate, prepared as described in Preparation 24 iii, 1.00 g 4_ [2- ( trityltetrazol-4-yl) phenyl] benzyl bromide and 197 mg of potassium t-butoxide, whereby 0.94 g of the target compound are obtained in the form of a viscous oil.

NMR (CDCl ₃ ) d ppm: 0.87 (3H, t. J 7.5 Hz), 1.24 (3H, t. J 7 Hz), 1.25-1.38 (2H, m), 1 55 (3H, d. J 6.5 Hz), 1.60-1.72 (2H, m), 2.54 (2H, t. J 8 Hz), 3.84 (1H, d. J 6 5 Hz), 4.20 (4H, q, J 7 Hz), 5.25 (1H, quintet, J 6.5 Hz), 5.44 (2H, s), 6.78 (2H, d. J 8 Hz), 6.94-7.54 (20H, m), 7.90 (1H, d. J 7.5 Hz).

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

 Following the procedure described in Example 40c, 0.84 g of ethyl 2-butyl- (4-1-hydroxyethyl) -1- {4- [2- (trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate, obtained in accordance with the description in stage (a), processed 75% vol./about. aqueous acetic acid, whereby 0.54 g of the target compound was obtained as an amorphous solid.

NMR (CDCl ₃ ) d ppm: 0.78 (3H, t. J 7.5 Hz), 1.15-1.30 (2H, m), 1.19 (3H, t. J 7 Hz), 1 35 (3H, d. J 6.5 Hz), 1.44-1.60 (2H, m), 2.49 (2H, t. J 8 Hz), 4.17 (2H, q, J 7 Hz), 5.09 (1H, q, J 6.5 Hz), 5.35 and 5.45 (each 1H, AV quartet, J 16.5 Hz), 6.89 (2H, d. J 8 Hz), 6.96 (2H, d. J 8 Hz), 7.30-7.50 (3H, m), 17.65 (1H, d, J 7.5 Hz).

 Example 44. 2-butyl-4- (1-hydroxyethyl) -1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylic acid (compound 4-74).

According to the procedure described in Example 36, 0.54 g of ethyl 2-butyl-4- (1-hydroxyethyl) -1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole -5- the carboxylate obtained in example 43b was hydrolyzed using 245 mg of lithium hydroxide monohydrate, whereby 0.43 g of the target compound was obtained in powder form, mp 214-217 ^o C.

NMR (DMSO-d ₆ ) d ppm: 0.82 (3H, t. J 7.5 Hz), 1.27 (2H, sextet, J 7.5 Hz), 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, q. J 6.5 Hz), 5, 61 (2H, s), 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 5-64).

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

0.192 g of sodium hydride (as a 55 wt. Dispersion in mineral oil) was added to a solution of 0.843 g of 4-acetyl-2-butylimidazole-5-carbonitrile, prepared as described in Preparation 24 i, in 17 ml of N, N -dimethylacetamide, and the resulting mixture was stirred for 20 minutes at room temperature. Then, 1.68 g of t-butyl-4 '- (bromomethyl) biphenyl-2-carboxylate was added, and the resulting mixture was stirred for 2.5 hours at 55 ^° C. After this, an aqueous solution of sodium chloride was added to the mixture, and then extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The obtained oily residue was purified by silica gel column chromatography, eluting with mixtures (4: 1 and 2: 1, by volume) of hexane and ethyl acetate, and 1.14 g of the target compound was obtained as an oily viscous substance.

NMR (CDCl ₃ ) d ppm: 0.93 (3H, t. J 7 Hz), 1.23 (9H, s), 1.3-2.1 (4H, m), 2.58 (3H, s ), 2.75 (2H, t. J 7 Hz), 5.32 (2H, s), 7.0-8.0 (8H, m).

 45b) 1 - [(2'-t-butoxycarbonylbiphenyl-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-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-imidazole-5-carbonitrile obtained in step (a), in 30 ml of ethanol and the resulting mixture was stirred for 1 h at room temperature. Excess sodium borohydride was removed by adding acetone, after which the reaction mixture was concentrated by evaporation under reduced pressure. The residue was diluted with an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was dried and concentrated by evaporation under reduced pressure. The oily precipitate was purified by silica gel column chromatography, eluting with a mixture of ethyl acetate and hexane (3: 2, v / v), and 1.18 g of the target compound was obtained as a viscous oil.

NMR (CDCl ₃ ) d ppm: 0.92 (3H, t. J 7.5 Hz), 1.25 (9H, s), 1.3-1.5 (2H, m), 1.60 (3H d.J. 6.5 Hz), 1.6-1.8 (2H, m), 2.6-268 (2H, m), 5.00 (1H, q, J 6.5 Hz), 5 22 (2H, s), 7.1-7.9 (8H, m).

 45c) 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-4- (1-hydroxyethyl) imidazole-5-carboxamide. 12 ml 1 n. aqueous sodium hydroxide solution was added to a solution of 0.52 g of 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] 2-butyl-4- (1-hydroxyethyl) imidazole-5-carbonitrile obtained in step (b) ) in 3 ml of ethanol and the resulting mixture was heated under reflux for 3 hours. After this, the reaction mixture was neutralized by adding dilute aqueous hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. Then, the solvent was removed by distillation under reduced pressure. The resulting mixture was purified by silica gel column chromatography, eluting with a mixture of ethyl acetate and hexane (4: 1, v / v) and then with ethyl acetate alone, whereby 0.14 g of the target compound was obtained as an amorphous solid.

NMR (CDCl ₃ ) d ppm: 0.90 (3H, t. J 7.5 Hz), 1.23 (4H, s), 1.2-1.5 (1H, m), 1.6-1 8 (2H, m), 1.66 (3H, d.J. 6.5 Hz), 2.63 (2.t. J 8 Hz), 5.11 (1H, q. J 6.5 Hz) 5.59 and 5.74 (each 1H, AB quartet, J 16 Hz), 7.0-7.9 (8H, m),
45d) 2-butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (1-hydroxyethyl) imidazole-5-carboxamide.

A solution of 0.15 g of 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-4- (1-hydroxyethyl) imidazole-5-carboxamide obtained in stage (c), dissolved in 3 ml of a 4 n solution of hydrogen chloride in dioxane was left overnight at room temperature. Then, the solution was concentrated by evaporation under reduced pressure. The residue was triturated in hexane and the powder thus obtained was collected by filtration, whereby 0.105 g of the hydrochloride of the target compound was obtained as an amorphous solid, mp 212-214 ^o C (decomp.).

NMR (CDCl ₃ ) d ppm: 0.94 (3H, t. J 7.5 Hz), 1.3-1.6 (2H, m), 1.59 (3H, d. J 6.5 Hz) 1.6-2.0 (2H, m), 3.0-3.4 (2H, m), 5.16 (1H, q. J 6.5 Hz), 5.41 and 5.58 ( each 1H, AB quart. J 15 Hz), 7.1-7.9 (8H, m).

 Example 46. 2-butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (1-hydroxypropyl) imidazole-5-carboxamide (compound 5-65).

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

 The procedure described in Example 45a was repeated, but using 0.923 g of 2-butyl-4-propionylimidazole-2-carbonitrile, prepared as described in Preparation 25, 1.56 g of t-butyl 4 '- (bromomethyl) - biphenyl-2-carboxylate and 196 mg of sodium hydride (in the form of 55 wt./wt. dispersion in mineral oil) in 20 ml of N, N-dimethylacetamide, resulting in 1.84 g of the target compound as an oily viscous substance.

NMR (CDCl ₃ ) d ppm: 0.91 (3H, t. J 7 Hz), 1.0-2.1 (4H, m), 1.25 (9H, s), 2.72 (2H, t .J 7 Hz), 3.02 (2H, q, J 7 Hz), 5.30 (2H, s), 7.0-8.0 (8H, m).

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

 The procedure described in Example 45b was repeated, but using 451 mg of 1 - [(2'-t-butoxycarbonyloxybiphenyl-4-yl) methyl] -2-butyl-4-propionyl-imidazole-5-Kirbonitrile obtained in stage (a) ), and 36 mg of sodium borohydride in 10 ml of ethanol, whereby 369 mg of the target compound are obtained in the form of a viscous oil.

NMR (CDCl ₃ ) d ppm: 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), 3.16 (1H, d. J 6.5 Hz), 4.74 (1H, q. J Hz), 5.21 ( 2H, s), 7.0-8.0 (8H, m). 46c) 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-4- (1-hydroxypropyl) imidazole-5-carboxamide.

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

NMR (CDCl ₃ ) d ppm: 0.89 (6H, t. J 7 Hz), 1.0-2.3 (6H, m), 1.24 (9H, s), 2.61 (2H, t .J 7 Hz), 4.76 (1H, t. J 7 Hz), 5.52 and 5.83 (each 1H, AB quarter. J 17 Hz), 6.9-7.9 (8H, m).

 46d) 2-butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (1-hydroxyropyl) imidazole-5-carboxamide.

The procedure described in Example 45d was repeated, but using 316 mg of 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-4- (1-hydrosipropyl) imidazole-5-carboxamide obtained in stage (s), and 10 ml of 4 N. a solution of hydrogen chloride in dioxane, resulting in the receipt of 148 mg of the hydrochloride of the target compound in the form of an amorphous powder, so pl. above 120 ^o C (with softening).

NMR (DMSO-d ₆ ) d ppm: 0.80 (3H, t. J 7.5 Hz), 0.87 (3H, t. J 7.5 Hz), 1.1-2.0 (6H, m), 2.94 (2H, t, J 7.5 Hz), 4.85 (1H, t. J 7 Hz), 5.68 (2H, s), 7.0-7.8 (8H, m).

 Example 47. 2-butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (1-hydroxybutyl) imidazole-5-carboxamide (compound 5-66).

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

 The procedure described in Example 45a was repeated, but using 0.877 g of 2-butyl-4-butyrylimidazole-5-carbonitrile obtained in accordance with the description given in Preparation 26, 1.53 g of t-butyl 4 '- (bromomethyl) - biphenyl-2-carboxylate and 0.175 g of sodium hydride (as 55% w / w dispersion in mineral oil) in 18 ml of N, N-dimethylacetamide, whereby 0.99 g of the target compound is obtained in the form of a viscous oil.

NMR (CDCl ₃ ) d ppm: 0.93 (3H, t. J 7 Hz), 1.01 (3H, t. J 7 Hz), 1.28 (9H, s), 1.4-2.1 (6H, m), 2.74 (2H, t. J 7 Hz), 3.00 (2H, t. J 7 Hz), 5.30 (2H, s), 7.0-7.0 (8H , m).

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

 The procedure described in Example 45b was repeated, but using 0.99 g of 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-4-butyrylimidazole-5-carbonitrile obtained in step ( a), and 0.077 g of sodium borohydride in 20 ml of ethanol, whereby 0.88 g of the target compound is obtained in the form of a viscous oily substance.

NMR (CDCl ₃ ) d ppm: 0.7-1.2 (6H, m), 1.2-2.1 (8H, m), 1.23 (9H, s), 2.71 (2H, t .J 7 Hz), 4.28 (1H, d. J 6 Hz), 4.82 (1H, q. J 6 Hz), 5.28 (2H, s), 7.0-8.0 (8H , m).

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

 14 ml 1 n. an aqueous solution of sodium hydroxide was added to a solution of 0.86 g of 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-4- (1-hydroxybutyl) imidazole-5-carbonitrile obtained in step ( b) in 14 ml of ethanol and the resulting mixture was heated under reflux for 10 hours. At the end of this time, the reaction mixture was processed in accordance with the procedure described in Example 45c, whereby 0.58 g of the target compound was obtained as an amorphous solid .

NMR (CDCl ₃ ) d ppm: 0.90 (3H, t. J 7.5 Hz), 0.94 (3H, t. J 7.5 Hz), 1.23 (9H, s), 1.3 -2.1 (8. 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).

 47d) 2-butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (1-hydroxybutyl) imidazole-5-carboxide.

The procedure described in Example 45d was repeated, but using 0.58 g of 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-4- (1-hydroxybutyl) imidazole-5-carboxamide, obtained in stage (C), and 13 ml of 4 N. a solution of hydrogen chloride, resulting in a gain of 0.55 g of the hydrochloride of the target compound in the form of an amorphous powder, so pl. above 110 ^o C (with softening).

NMR (DMSO-d ₆ ) d ppm: 0.80 (3H, t. J 7.5 Hz), 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), 5.68 (2H, s), 7.2-7.8 ( 8H, m).

 Example 48. 2-butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (1-hydroxy) -2-methylpropyl) imidazole-5-carboxamide (compound 5-67).

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

 The procedure described in Example 45 (a) was repeated, but using 0.85 g of 2-butyl-4-isobutyrylimidazole-5-carbonitrile obtained as described in Preparation 27, 1.34 t-butyl-4'- (bromomethyl) biphenyl-2-carboxylate and 170 mg of sodium hydride (as 55% w / w dispersion in mineral oil) in 15 ml of N, N-dimethylacetamide, whereby 1.62 g of the target compound are obtained in the form of a viscous oils.

NMR (CDCl ₃ ) d ppm: 0.93 (3H, t. J 7 Hz), 1.0-2.1 (4H, m), 1.21 (6H, d. J 7 Hz), 1.22 (9H, s), 2.73 (2H, t. J 7 Hz), 3.66 (1H, septet J 7 Hz), 5.30 (2H, s), 7.0-8.0 (8H, m).

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

 The procedure described in Example 45b was repeated, but using 500 mg of 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl-2-butyl-4-isobutyrylimidazole-5-carbonitrile obtained in step (a), and 25 mg of sodium borohydride in 10 ml of ethanol, resulting in 297 mg of the target compound as an oily viscous substance.

NMR (CDCl ₃ ) d ppm: 0.7-1.2 (9H, m), 1.0-2.5 (5H, m), 1.27 (9H, s), 2.70 (2H, d .J 7 Hz), 3.01 (1H, d. J 7 Hz), 4.54 (1H, t. J 7 Hz), 5.23 (2H, s), 7.0-7.0 (8H , m).

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

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

NMR (CDCl ₃ ) d ppm: 0.66 (3H, d. J 7 Hz), 0.85 (3H, t. J 7 Hz), 1601 (3H, d. J 7 Hz), 1.0-2 4 (5H, m), 1.22 (9H, s), 2.59 (2H, t. J 7 Hz), 4.40 (1H, d. J 7 Hz), 5.53 and 5.83 (each 1H, AB quartet, J 17 Hz), 6.9-7.9 (8H, m).

 48d) 2-butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] 4- (1-hydroxy-2-methylpropyl) imidazole-5-carboxamide.

The procedure described in Example 45d was repeated, but using 151 mg of 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-4- (1-hydroxy-2-methylpropyl) -5-carloxamide obtained in stage (C), and 5 ml of 4 N. a solution of hydrogen chloride in dioxane, resulting in the receipt of 119 mg of the hydrochloride of the target compound in the form of an amorphous powder, so pl. 131 ^o C (with softening).

NMR (DMSO-d ₆ ) d ppm: 0.73 (3H, d. J 6.5 Hz), 0679 (3H, t. J 7.5 Hz), 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), 4.65 (1H, d.J 8 Hz), 5.69 (2H, s), 7.1-7.8 (8H, m).

 Example 49. 1 - [(2'-carboxyphenyl-4-yl) methyl] -4- (1-hydroxybutyl) -2-propoxyimidazole-5-carboxamide (compound 5-4).

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

 The procedure described in Example 45a was repeated, but using 1,026 g of 4-butyryl-2-propylimidazole-5-carbonitrile obtained as described in Preparation 28, 1.91 g of t-butyl-4 '- (bromomethyl) -biphenyl-2-carboxylate and 0.209 g of sodium hydride (as 55% w / w dispersion in mineral oil) in 20 ml of N, N-dimethylacetamide, 1.70 g of the target compound are obtained in the form of a viscous oily substance.

NMR (CDCl ₃ ) d ppm: 1.00 (6H, t. J 7.5 Hz), 1.25 (9H, s), 1.7-1.9 (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).

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

 The procedure described in Example 45b was repeated, but using 1.13 g of 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -4-butyryl-2-propylimidazole-5-carbonitrile obtained in step (a) ), and 0.091 g of sodium borohydride in 23 ml of ethanol, whereby 1.07 g of the target compound is obtained in the form of a viscous oily substance.

NMR (DMSO-d ₆ ) d ppm: 0.87 (3H, t. J 7.5 Hz), 0.90 (3H, t. J 7.5 Hz), 1.17 (9H, s), 1 , 2-1.4 (2H, m), 1.5-1.7 (4H, m), 2.67 (2H, t. J 7.5 Hz), 4.58 (1H, m), 5 34 (2H, s), 5.41 (1H, d.J. 4.5 Hz), 7.1-7.7 (8H, m).

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

 16 ml 1 n. an aqueous solution of sodium hydroxide was added to a solution of 1.07 g of 1 - [(2'-t-butoxy-carbonylbiphenyl-4-yl) methyl] -4- (1-hydroxybutyl) -2-propylimidazole-4-carbonitrile, obtained in stage (b) in 16 ml of ethanol and the resulting mixture was treated as described in Example 45c, whereby 0.82 g of the target compound was obtained as an amorphous solid.

NMR (CDCl ₃ ) d ppm: 0.93 (3H, t. J 7.5 Hz), 0.95 (3H, t. J 7.5 Hz), 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).

 49d) 1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (1-hydroxybutyl) -2-propylimidazole-5-carboxamide.

The procedure described in Example 45d was repeated, but using a solution of 0.82 g of 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -4- (1-hydroxybutyl) -2-propylimidazole-5-carboxamide, obtained in stage (C), in 17 ml of 4 N. a solution of hydrogen chloride in dioxane, resulting in 0.78 g of the hydrochloride of the target compound was obtained in the form of an amorphous powder, so pl. 118-121 ^o C (with softening).

NMR (CDCl ₃ ) d ppm: 0.90 (3H, t. J 7.5 Hz), 0.93 (3H, t. J 7.5 Hz), 1.1-1.5 (2H, m) , 167-2.1 (4H, m), 2.9-3.1 (2H, m), 5.00 (1H, t. J 7.5 Hz), 5.4 and 5.56 (each. 1H, AB quartet, J 1.5 Hz), 7.1-7.9 (8H, m).

 Example 50. 2-butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (1-hydroxy-1-methylethyl) imidazole-5-carboxamide (compound 5-69).

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

 10 ml 1 n. aqueous sodium hydroxide was added to a solution of 232 mg of 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-4- (1-hydroxy-1-methylethyl) imidazole-5-carbonitrile as described in example 10a, 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 similar manner to that described in example 45c, whereby 185 mg of the target compound were obtained as an amorphous solid substances.

NMR (CDCl ₃ ) d ppm: 0.89 (3H, t. J 7 Hz), 1.0-2.0 (4H, m), 1.23 (9H, s), 1.68 (6H, s ), 2.62 (2H, t, J 7 Hz), 5.63 (2H, s), 6.9-7.9 (8H, m).

 50b) 2-butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -5- (1-hydroxy-1-methylethyl) imidazole-5-carboxamide.

The procedure described in Example 45d was repeated, but using 185 mg of 1 - [(2'-t-butoxy-carbonylbiphenyl-4-yl) methyl] -2-butyl-4- (1-hydroxy -1-methylethyl) imidazole -5-carboxamide obtained in stage (a), and 10 ml of 4 N. a solution of hydrogen chloride in dioxane, resulting in 88 mg of the hydrochloride of the target compound in the form of an amorphous solid, so pl. 130-138 ^o C (with softening).

NMR (DMSO-d ₆ ) d ppm: 0.78 (3H, t. J 7.0 Hz), 1.17-1.30 (2H, m), 1.30-1.42 (2H, m) 1.61 (6H, s), 2.96 (2H, t. J 7.5 Hz), 5.55 (2H, s), 7.20-7.75 (8H, m).

 Example 51. 2-butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (1-hydroxy-2-methyl) -1- (1-methylethyl) propyl] imidazole-5-carboxamide ( compound 5-333).

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

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

 The procedure described in Example 45a was repeated, but using 282 mg of 2-butyl-4 - [(1-hydroxy-2-methyl-1- (1-methylethyl) propyl] imidazole-5-carbonitrile obtained in accordance with the procedure, described in the preparation of 30, 409 mg of t-butyl-4 '- (bromomethyl) biphenyl-2-carboxylate and 47 mg of sodium hydride (as 55% w / w dispersion in mineral oil) in 5 ml of N, N-dimethylacetamide resulting in 513 mg of the target compound as a viscous oil.

NMR (CDCl ₃ ) d ppm: 0.7-1.1 (15H, m), 1.0-2.0 (4H, m), 1.21 (9H, s), 2.15-2.60 (2H, m), 2.68 (2H, t. J 7 Hz), 3.20 (2H, s), 5.26 (2H, s), 6.9-8.0 (8H, m).

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

 10 ml 1 n. aqueous sodium hydroxide was added to a solution of 500 mg of 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-4- [1-hydroxy-2-methyl-1 - (1-methylethyl) propyl ] imidazole-5-carbonitrile obtained 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 processed as described in example 45c, resulting in received 220 mg of the target compound as an amorphous substance.

NMR (CDCl ₃ ) d ppm: 0.7-1.1 (15H, m), 1.0-2.1 (4H, m), 1.20 (9H, s), 2.2-2.9 (4H, m), 5.59 (2H, s), 6.8-7.9 (8H, m).

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

The procedure described in Example 45d was repeated, but using 220 mg of 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-4- [1-hydroxy-2-methyl-1- (1 -methylethyl) propyl] imidazole-5-carboxamide obtained in stage (b), and 4.5 ml of 4 N. a solution of hydrogen chloride in dioxane, as a result of which 201 mg of the hydrochloride of the target compound were obtained in the form of an amorphous solid, mp 178-181 ^o C.

NMR (DMSO-d ₆ ) d ppm: 0.76 (3H, t. J 7.5 Hz), 0.8-0.9 (12H, m), 1.1-1.4 (4H, m) 2.2-2.4 (2H, m), 2.8-3.1 (2H, m), 5.51 (2H, s), 7.2-7.8 (8H, m).

 Example 52. 2-butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4-hydroxymethylimidazole-5-carboxamide (compound 5-63).

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

206 mg of N, N-dicyclohexylcarbodiimide was added to a suspension of 464 mg of 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-4-hydroxymethylimidazole-5-carboxylic acid, obtained as described in the example 4 and 140 mg of N-hydroxysuccinimide in 10 ml of tetrahydrofuran and the resulting mixture was stirred for 16 hours at room temperature. After that, the precipitated material was filtered off, and the filtrate was concentrated by evaporation under reduced pressure. The concentrate was purified by silica gel column chromatography, eluting with a mixture of methanol and methylene chloride (1:15, v / v), and 0.52 g of the target compound was obtained in the form of crystals, mp 107-109 ^o C.

NMR (CDCl ₃ ) d ppm: 0.89 (3H, t. J 7 Hz), 1.0-2.0 (4H, m), 1.23 (9H, s), 2.70 (2H, t J 7.5 Hz), 2.69 (4H, s), 4.10 (1H, br s), 4.96 (2H, s), 5.56 (2H, s), 7.00- 7.90 (8H, m).

 52b) 1 - [(2'-t-butoxycarbonylbiphenyl-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 of succinimido 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-4-hydroxymethyl-imidazole-5-carboxylate, obtained in stage (a) in 6 ml of tetrahydrofuran and after that the target compound was immediately separated. The solvent was removed by distillation under reduced pressure, and the obtained residue was washed with diethyl ether and water, resulting in 0.38 g of the target compound in the form of a powder, so pl. 222-224 ^o C.

NMR (DMSO-d ₆ ) d ppm: 0.85 (3H, t. J 7 Hz), 1.19 (9H, s), 1.0-1.9 (4H, m), 2.57 (2H , t. J 7.5 Hz), 4.52 (2H, d.J. 4.5 Hz), 5.63 (2H, s), 5.83 (1H, t. J 4.5 Hz (6, 95-7.8 (8H, m).

 52c) 2-butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4-hydroxymethylimidazole-5-carboxamide.

A solution of 0.28 g of 1 - [(2-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-4-hydroxymethylimidazole-5-carboxamide obtained in stage (b) in 3 ml of 4 N. a solution of hydrogen chloride in dioxane was stirred at room temperature for 5 hours, and then concentrated by evaporation under reduced pressure. The concentrate was triturated with a mixture of ethyl acetate and diethyl ether and the cured material was collected by filtration, whereby 0.26 g of the hydrochloride of the target compound was obtained, which softens at more than 150 ^° C. and decomposes at 235 ^° C.

NMR (DMSO-d ₆ ) d ppm: y 0.80 (3H, t. J 7.5 Hz), 1.20-1.31 (2H, m), 1.43-1.54 (2H, m) 2.96 (3H, t. J 7.5 Hz), 4.68 (2H, s), 5.71 (2H, s), 7.21-7.75 (8H, m).

 Example 53. N-methyl-2-butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4-hydroxymethylimidazole-5-carboxamide (compound 5-71).

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

 0.4 ml of 40% vol. a solution of methylamine in water was added at room temperature to a solution of 0.287 g of succinimido 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-4-hydroxymethylimidazole-5-carboxylate, prepared as described in example 52 (a), in a mixture of 3 ml of methylene chloride and 2 ml of methanol, and the resulting mixture was left for 16 hours at room temperature. After that, the solution was concentrated 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 (sequentially), after which the solution was dried with anhydrous magnesium sulfate. Then, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with ethyl acetate, to obtain 176 mg of the target compound as a glassy product.

NMR (CDCl ₃ ) d ppm: 0.85 (3H, t. J 7 Hz), 1.23 (9H, s), 1.0-2.0 (4H, m), 2.54 (2H, t J 7.5 Hz), 2.91 (3H, d.J 5 Hz), 4.70 (2H, s), 5.62 (2H, s), 6.9-7.85 (8H, m ), 8.38 (1H, q J, 5 Hz).

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

A solution of N-methyl-1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-4-hydroxymethylimidazole-5-carboxamide obtained in stage (a) in 2 ml of 4 N. a solution of hydrogen chloride in dioxane was left for 16 hours at room temperature, and then concentrated under reduced pressure. The obtained crystalline precipitate was washed with a mixture of ethyl acetate and diethyl ether and 0.15 g of the hydrochloride of the target compound was obtained, so pl. 205-208 ^o C (decomp.)
NMR (DMSO-d ₆ ) d ppm: 0.81 (3H, t. J 7.5 Hz), 1.25 (2H, sextet, J 7.5 Hz), 1.49 (2H, quintet, J 7 5 Hz), 2.75 (3H, d. J 4.5 Hz), 2.96 (2H, t. J 8 Hz), 5.64 (2H, s), 7.21-7.75 ( 8H, m), 8.91 (1H, q, J 4.5 Hz).

 Example 54. N-ethoxycarbonylmethyl-2-butyl-1 - [(2'-carboxyphenyl-4-yl) methyl] -4-hydroxymethylimidazole-5-carboxamide (compound 5-126).

The procedure described in Example 53 was repeated, but using 0.307 g of succinimido 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-4-hydroxymethylimidazole-5-carboxylate, prepared as described in Example 52a, 89 mg of ethyl glycinate hydrochloride and 0.089 ml of triethylamine, resulting in 0.202 g of the hydrochloride of the target compound in the form of an amorphous powder, so pl. above 80 ^o C (with softening).

NMR (DMSO-d ₆ ) Dd ppm: 0.80 (3H, t. J 7.5 Hz), 1.18 (3H, t. J 7 Hz), 1.20-1.33 (2H, m) 1.47 (2H, quintet, J 7.5 Hz), 2.94 (2H, t. J 8 Hz), 4.05 (2H, d. J 6 Hz), 4.12 (2H, q. J 7 Hz), 4.72 (2H, s), 5.63 (2H, s), 7.24-7.75 (8H, m), 9.37 (1H, t. J 6 Hz).

 Example 55. N-carboxymethyl-2-butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4-hydroxymethylimidazole-5-carboxamide (compound 5-125).

The procedure described in example 53 was repeated, but using 0.32 g of succinimido 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-4-hydroxymethylimidazole-5-carboxylate obtained in example 52a , 0.11 g of t-butyl glycinate hydrochloride and 80 mg of 4-dimethylaminopyridine, resulting in 0.21 g of the hydrochloride of the target compound in the form of an amorphous powder, so pl. > 110 ^o C (with softening).

NMR (DMSO-d ₆ ) d ppm: 0.81 (3H, t. J 7.5 Hz), 1.25 (2H, sextet J 7.5 Hz), 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), 7.26-7.75 (8H, m); 9.22 (1H, t. J 6 Hz).

 Example 56. N - [(S) -1-ethoxycarbonylethyl-2-butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4-hydroxymethylimidazole-5-carboxamide (compound 5-128).

 The procedure described in example 53 was repeated, but using 0.39 g of succinimide 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-4-hydroxymethylimidazole-5-carboxylate obtained in example 52a, 0.13 g of ethyl (S) -alanate hydrochloride and 0.21 ml of triethylamine, resulting in 0.27 g of the hydrochloride of the target compound as an amorphous solid.

NMR (DMSO-d ₆ ) d ppm: 0682 (3H, t. J 7.5 Hz), 1.17 (3H, t. J 7 Hz), 1.20-1.35 (2H, m), 1 34 (3H, d. J 7 Hz), 1.43-1.58 (2H, m), 2.98 (2H, t. J 7.5 Hz), 4.10 (2H, q. J 7 Hz), 4.44 (1H, quintet, J 7 Hz), 4.70 (2H, s), 5.63 (2H, ABR d 0.10 ppm, J 16 Hz), 7.24- 7.76 (8H, m), 9.39 (1H, d, J 7.5 Hz).

 Example 57. N- (2-ethoxycarbonylethyl-2-butyl-1 - [(2'-carboxybiphenylmethyl] -4-hydroxymethylimidazole-5-carboxamide (compound 5-130).

 The procedure described in Example 53 was repeated, but using 305 mg of succinimido 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-4-hydroxymethylmidazole-5-carboxylate, prepared as described in Example 52 (a), 96 mg of ethyl alpha-alanate hydrochloride and 0.088 ml of triethylamine, resulting in 0.20 g of the hydrochloride of the target compound as an amorphous solid.

NMR (DMSO-d ₆ ) d ppm: 0682 (3H, t. J 7.5 Hz), 1.16 (3H, t. J 7 Hz), 1.20-1.38 (2H, m), 1 42-1.58 (2H, m), 2.97 (2H, t. J 7.5 Hz), 3.3-3.6 (4H, m), 4.04 (2H, q, J 7 Hz), 4.60 (2H, s), 5.63 (2H, s), 7.21-7.76 (8H, m), 9.01 (1H, br t).

 Example 58. Methyl (S) -N- {2-butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4-hydroxymethylimidazole-5-carbonyl} propinate (compound 5-335).

The procedure described in Example 53 was repeated, but using 529 mg of succinimido 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-4-hydroxymethylimidazole-5-carboxylate, prepared as described in Example 52a, 180 mg of methyl (S) -proline hydrochloride and 0.2 ml of triethylamine, resulting in 0.39 g of the hydrochloride of the target compound in the form of an amorphous powder, so pl. more than 120 ^o C (with softening).

NMR (DMSO-d ₆ ) d ppm: 0.88 (3H, t. J 7.5 Hz), 1.34 (2H, sextet, J 7.5 Hz), 1.4-2.25 (6H, m), 2.9-3.7 (2H, m), 3.64 (3H, s), 4.34 (1H, t. J 7.5 Hz), 4.55 (2H, s), 5 25 and 5.56 (each 1H, AB quartet, J 15.5 Hz); 7.26-7.77 (8H, m).

 Example 59. 2-butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (1-hydroxy-2,2-dimethylpropyl) imidazole-5-carboxamide (compound 5-68).

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

5.07 ml of triethylamine and 6.0 g of a complex of sulfur trioxide / pyridine were added in turn at a temperature of 10-15 ^o C to a solution of 3.0 g of methyl 1 - [(2'-t-butoxycarbonylbiphenyl-3-yl) methyl] -2-butyl-4-hydroxymethylimidazole-4-carboxylate, prepared as described in Example 1b, in 18 ml of dimethyl sulfoxide and the resulting mixture was stirred at the same temperature for 45 minutes. After that, the reaction mixture was mixed with water and extracted with ethyl acetate. The extract was washed with water and then with an aqueous solution of sodium bicarbonate, after which the extract was dried with anhydrous magnesium sulfate, and the solvent was distilled off by distillation under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a mixture of hexane and ethyl acetate (1: 1, v / v), whereby 2.88 g of the target compound was obtained as an amorphous solid.

NMR (CDCl ₃ ) Dd ppm: 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), 5.65 (2H, s), 6.9-7.9 (8H, m), 106 48 (1H, s).

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

2.77 ml of a 2 M solution of t-butyl magnesium bromide in tetrahydrofuran was added at -55 ^° C and under nitrogen atmosphere to a solution of 1.32 g of methyl 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2- butyl 4-formyl imidazole-5-carboxylate obtained in stage (a) in 26 ml of tetrahydrofuran and the resulting mixture was stirred at a temperature of -55 ^o C (-50 ^o C) for 30 minutes After that, the reaction mixture was diluted with 50 ml of ethyl acetate and a saturated aqueous solution of ammonium chloride. The organic layer was separated and dried with anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a mixture of hexane and ethyl acetate (2: 1, v / v), whereby 0.87 g of the target compound was obtained as an amorphous solid.

NMR (CDCl ₃ ) d ppm: 0.90 (3H, t. J 7.5 Hz), 0.93 (9H, s), 1.0-2.0 (4H, m), 1.19 (9H , s), 2.68 (2H, t. J 7.5 Hz), 3.41 (1H, d. J 10 Hz), 3.74 (3H, s), 4.92 (1H, d. J 10 Hz), 5.59 (2H, s), 6.9-7.9 (8H, m).

59c) 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-4- (1-hydroxy-2,2-dimethylpropyl) imidazole-5-carboxylic acid
According to the procedure described in Example 4, 0.87 g of methyl-1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] 2-butyl-4- (1-hydroxy-2,2-dimethylpropyl) imidazole -5-carboxylate obtained in stage (b) was hydrolyzed using 342 mg of lithium hydroxide monohydrate, whereby 0.73 g of the target compound was obtained in the form of crystals, mp 199-201 ^o C (decomp.).

NMR (DMSO-d ₆ ) d ppm: 0.84 (3H, t. J 7.5 Hz), 0689 (9H, s), 1.16 (9H, s), 1.22-1.4 (2H , m), 1.58 (2H, quintet, J 7.5 Hz), 2.64 (2H, t. J 7.5 Hz), 4.78 (1H, s), 5.68 (2H, AB quartet, d 0.14 ppm, J 17 Hz), 7.02 (2H, d.J 8 Hz), 7.22-7.58 (5H, m), 7.65 (1H, d. J 7 5 Hz).

 59d) Succinimido 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-4- (1-hydroxy -2,2-dimethylpropyl) imidazole-5-carboxylate.

 The procedure described in Example 52a was repeated, but using 600 mg of 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-4- (1-hydroxy-2,2-dimethylpropyl) imidazole- 5-carboxylic acid obtained in stage (C), 172 mg of N-hydroxysuccinimide and 250 mg of N, N-dicyclohexylcarbodiimide, resulting in the receipt of 663 mg of the target compound as an amorphous solid.

NMR (CDCl ₃ ) d ppm: 0.92 (3H, t. J 7.5 Hz), 1.01 (9H, s), 1.21 (9H, s), 1.38 (2H, sextet, J 7.5 Hz), 1.73 (2H, quintet J 7.5 Hz), 2.71 (2H, t. J 7.5 Hz), 2.84 (4H, s), 4.99 (1H, d.J. 7.5 Hz), 5.53 (2H, s), 7.03 (2H, d.J. 8.5 Hz), 7.26-7.50 (5H, m), 7.77 ( 1H, d. J 8 Hz).

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

 The procedure described in Example 52b was repeated, but using 0.66 g of succinimido 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-4- (1-hydroxy -2,2-dimethyl -propyl) imidazole-5-carboxylate obtained as described in step (d), whereby 0.33 g of the target compound is obtained as an amorphous solid.

NMR (CDCl ₃ ) d ppm: 0.89 3H, t. J 7.5 Hz 0.96 (9H, s), 1.22 (9H, s), 1.34 (2H, sextet, J 7.5 Hz), 1.64 (2H, quintet, J 7.5 Hz), 2.62 (2H, t. J 7.5 Hz), 4.67 (1H, d. J 5.5 Hz, 5.48 and 5.82 (each 1H, AB quartet, J 16 Hz), 7.02 (2H, d.J 8.5 Hz), 7.23-7.50 (5H, m), 7.76 ( 1H, d. J 6.5 Hz).

 59f) 2-butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (1-hydroxy-2,2-dimethylpropyl) imidazole-5-carboxamide.

The procedure described in Example 52c was repeated, but using 326 mg of 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-butyl-4- (1-hydroxy-2,2-dimethylpropyl) imidazole- 5-carboxamide, obtained as described in step (e), whereby 228 mg of the hydrochloride of the target compound are obtained in the form of a powdery solid, mp 150-154 ^o C (with softening).

NMR (DMSO-d ₆ ) d ppm: 0.80 (3H, t. J 7.5 Hz), 0.91 (9H, s), 1.24 (2H, sextet, J 7.5 Hz), 1 45 (2H, quintet, J 7.5 Hz), 2.99 (2H, t. J 7.5 Hz), 4.78 (1H, s), 5669 (2H, s), 7.12 (2H d, J 8 Hz), 7.33-7.61 (5H, m), 7.75 (1H, d, J 8 Hz).

 Example 60. 1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (1-hydroxy-2,2-dimethyl-propyl) -2-propylimidazole-5-carboxamide (compound 5-6).

 60a) Diethyl 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -2-propylimidazole-4,5-dicarboxylate.

 The procedure described in Example 1a was repeated, but using 9.0 g of diethyl-2-propyl-imidazole-4,5-dicarboxylate, prepared as described in Preparation 12, 12.3 g of t-butyl 4-bromomethylbiphenyl -2-carboxylate and 4.1 g of potassium t-butoxide as the base, whereby 16.47 g of the target compound are obtained in the form of a viscous oil.

NMR (CDCl ₃ ) d ppm: 0.95 (3H, t. J 7.5 Hz), 1.5-2.0 (2H, m), 1.23 (9H, s), 1.25 (3H , t. J 7 Hz), 1.37 (3H, t. J 7 Hz), 2.69 (2H, t. J 7 Hz), 4.26 (2H, q. J 7 Hz), 4638 (2H sq. J 7 Hz), 5.48 (2H, s), 7.0-7.9 (8H, m).

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

In accordance with the procedure described in example 1b, 16.47 g of diethyl 1 - [(2'-t-butoxycarbonyloxybiphenyl-4-yl) methyl] -2-propylimidazole-4,5-dicarboxylite obtained in stage (a), restored using 44.4 ml of a 1.5 M solution of diisobutylaluminum hydride in tetrahydrofuran, resulting in 10.83 g of the target compound in the form of crystals, so pl. 108-110 ^o C.

NMR (CDCl ₃ ) d ppm: 0.98 (3H, t. J 7.5 Hz), 1.23 (9H, s), 1.31 (3H, t. J 7 Hz), 1.79 (2H sextet J 7.5 Hz), 2.67 (2H, t. J 7.5 Hz), 4.27 (2H, q. J 7 Hz), 4.87 (2H, s), 5.59 ( 2H, s), 7.00 (2H, d. J, 8.5 Hz), 7.24-7.75 (5H, m), 7.78 (1H, d. J, 7 Hz).

60c) Ethyl-1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -4-formyl-2-propylimidazole-5-carboxylate
In accordance with the procedure described in example 59a, 2.71 g of ethyl 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -4-hydroxymethyl-1-propylimidazole-5-carboxylate obtained in stage (b ), was subjected to oxidation using 4.6 ml of triethylamine and 5.5 g of a complex of sulfur trioxide and pyridine in 17 ml of dimethyl sulfoxide, resulting in 2.57 g of the target compound in the form of crystals, so pl. 117-199 ^o C.

NMR (CDCl ₃ ) d ppm: 0.99 (3H, t. J 7.5 Hz), 1.26 (9H, s), 1.84 (1H, sex. J 7.5 Hz), 2.73 (2H, t. J 7.5 Hz), 4.40 (2H, q, J 7 Hz), 5.67 (2H, s), 7.02 (2H, d. J, 8.5 Hz), 7 29-7.54 (5H, m), 7.80 (1H, d. J = 8 Hz), 10.48 (1H, s).

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

 According to the procedure described in example 59b, 1.14 g of ethyl 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -4-formyl-2-propylimidazole-5-carboxylate obtained in step (c ) was reacted with 2.4 ml of a 2 M solution of t-butyl magnesium bromide in tetrahydrofuran to give 0.78 g of the target compound as a viscous oily substance.

NMR (CDCl ₃ ) d ppm: 0.97 (3H, t. J 7.5 Hz), 1.00 (9H, s), 1.25 (9H, s), 1.35 (3H, t. J 7 Hz), 1.77 (2H, sext. J 7.5 Hz), 2.68 (2H, t. J 7.5 Hz), 3.46 (1H, d. J 9 Hz), 4.29 (2H, q. J 7 Hz), 4.99 (1H, d. 9 Hz), 5.62 (2H, s), 7.00 (2H, d. J 8 Hz) 7.29-7.54 (5H, m), 7.80 (1H, d. J, 7.5 Hz).

 60f) 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -4- (1-hydroxy-2,2-dimethylpropyl) -2-propylimidazole-5-carboxylic acid.

According to the procedure described in Example 4, 0.78 g of ethyl 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -4- (1-hydroxy-2,2-dimethylpropyl) -2-propylimidazole -5-carboxylate obtained in stage (d) was hydrolyzed using 209 mg of lithium hydroxide monohydrate, whereby 0.62 g of the target compound was obtained in the form of crystals, mp 207 ^o C.

NMR (DMSO-d ₆ ) d ppm: 0.88 (3H, t. J 7.5 Hz), 0.89 (9H, s), 1.15 (4H, s), 1.63 (2H, sextet , J 7.5 Hz), 2.63 (2H, t. J 7.5 Hz), 4.79 (1H, s), 5.63 and 5.76 (each 1H, AB quartet J 18, 5 Hz), 7.02 (2H, d. J 8 Hz), 7.22-7.67 (6H, m).

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

 The procedure described in Example 52a was repeated, but using 300 mg of 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -4- (1-hydroxy-2,2-dimethylpropyl) -2-propylimidazole-5 of the β-carboxylic acid obtained in step (e), 110 mg of N-hydroxysuccinimide and 130 mg of N, N-dicyclohexylcarbodiimide, whereby 321 mg of the target compound are obtained as an amorphous solid.

NMR (CDCl ₃ ) d ppm: 0.94 (3H, t. J 7.5) 0698 (9H, s), 1.18 (9H, s), 1.75 (2H, sextet, J 7.5 Hz ), 2.64 (2H, t. J 7.5 Hz), 3.12 (1H, d. J 9.5 Hz), 4.98 91H, d. J 9.5 Hz), 5.52 ( 2H, s), 7.0-7.9 (8H, m).

60g) 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -4-yl methyl 4- (1-hydroxy-2,2-dimethylpropyl) -2-propylimidazole-5-carboxamide
The procedure described in Example 52b was repeated, but using 0.13 g of succinimido 1 - [(2'-t-butoxycarbonyl-biphenyl-4-yl) methyl] -4- (1-hydroxy-2,2-dimethylpropyl) - 2-propylimidazole-5-carboxylate obtained in stage (f), resulting in 0.12 g of the target compound was obtained in the form of a glassy substance.

NMR (CDCl ₃ ) d ppm: 0.88 (3H, t. J 7.5 Hz), 0.90 (9H, s), 1.24 (9H, s), 1.60 (2H, sextet, J 7.5 Hz), 2.58 (2H, t. J 7.5 Hz), 4.65 (1H, d. J 6 Hz), 5.53 and 5.87 (each 1H, AV quartet, J 16 Hz), 7.02 (2H, d. J 8 Hz), 7.23-7.48 (5H, m), 7.78 (1H d. J 6.5 Hz).

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

The procedure described in Example 52c was repeated, but using 149 mg of 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -4- (1-hydroxy-2,2-dimethylpropyl) -2-propylimidazole-5 -carboxamide obtained in stage (g), with the result that received 96 mg of the hydrochloride of the target compound in the form of a powder, so pl. 160 ^o C (with softened.).

NMR (DMSO-d ₆ ) d ppm: 0.82 (3H, t. J 7.5 Hz), 0.90 (9H, s), 1.53 (2H, sextet J 7.5 Hz), 2, 97 (2H, t. J 7.5 Hz), 4.79 (1H, s), 5.69 (2H, s), 7.19-7.75 (8H, m).

 Example 61. (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (tetrazole - 5-yl) phenyl] phenyl} methylimidazole-5-carboxylate (compound 2-17).

 61a) (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (trityltetrazol-5 -yl) phenyl] phenyl} methylimidazole-5-carboxylate.

A suspension of 0.97 g of potassium carbonate in 100 ml of N, N-dimethylacetamide was heated at 60 ^° C., and then a solution of 1.14 g (5-methyl-2-oxo-1,3-) was added dropwise to the heated suspension. dioxolen-4-yl) methyl 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate, prepared as described in Preparation 31, and 2.35 g of 4- [2- (trityltetrazole -5-yl) phenyl] benzyl bromide in 50 ml of N, N-dimethylacetamide. the reaction mixture was stirred for 3.5 hours at 60 ^° C. and then diluted with ethyl acetate. The ethyl acetate layer was separated, washed with water and dried with anhydrous magnesium sulfate, and the solvent was distilled off by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluting with a mixture of hexane and ethyl acetate (1: 1, v / v), whereby 1.4 g of the target compound was obtained as an amorphous solid. This product was crystallized from diisopropyl ether to give the pure target compound, mp. 98-99 ^o C (decomposition).

NMR (CDCl ₃ ) d ppm: 0.89 (3H, t. J 7.5 Hz), 1.62 (6H, s), 1.6-1.75 (2H, m), 1.97 (3H , s), 2.54 (2H, t. J 8 Hz), 4.70 (2H, s), 5.30 (2H, s), 5.61 (1H, s), 6.68 (2H, d. J 7.5 Hz), 6.90-7.52 (20H, m), 7.87 (1H, d. J 7.5 Hz).

 61b) (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl-4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (tetrazole 5 -yl) phenyl] phenyl} methylimidazole-5-carboxylate.

A mixture of 1.4 g (5-methyl-2-oxo-1,3-dioxolen-4-yl methyl 4- (1-hydroxy-1methylethyl) -2-propyl-1- {4- [2- (trityltetrazole -4 -yl) phenyl] phenyl} methylimidazole-5-carboxylate obtained in step (a) and 48 ml of 75 v / v aqueous acetic acid were stirred for 1 h at 60 ^° C, after which the mixture was concentrated by evaporation under reduced The residue was dissolved in toluene, and the resulting solution was concentrated by distillation under reduced pressure, after which this operation was repeated once more to remove residual water and acetic acid. and by column chromatography on silica gel eluting with mixtures of methanol and methylene chloride (1: 9 to 1: 4, by volume) to give 0.73 g of the title compound, mp 170-172 ^o C...

NMR (CDCl ₃ ) d ppm: 0.93 (3H, t. J 7.5 Hz), 1.63 (6H, s), 1.6-1.8 (2H, m), 2.19 (3H , s), 2.70 (2H, t. J 7.5 Hz), 5.00 (2H, s), 5.45 (2H, s), 6.83 (2H, d. J 8 Hz), 7.10 (2H, d. J 8 Hz), 7.42-7.63 (3.m), 7.83 (1H, dd. J 1 and 7.5 Hz),
Example 62. Pivaloyloxymethyl-4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2 (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate (compound 2-15) .

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

 The procedure described in Example 61a was repeated, but using 0.85 g of pivaloyloxymethyl 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate, prepared as described in Preparation 22 ii, 1.52 g 4_ [2- (trityltetrazol-5-yl) phenyl] benzyl bromide and 0.72 g of potassium carbonate, resulting in 1.02 g of the target compound as an amorphous solid.

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

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

Pivaloyloxymethyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2-trityltetrazol-4-yl) phenyl] phenyl} methylimidazole-5-carboxylate, prepared as described in step (a) ) were subjected to detritylation according to the procedure described in example 29b, whereby the hydrochloride of the target compound was obtained in 80% yield
The melting point and NMR spectrum of this compound were identical, so pl. And the NMR spectrum of the compound obtained as described in example 20b.

 Example 63. Phthalidyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1 - {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate (compound 2-65) .

 63a) Phthalidyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate.

The procedure described in Example 61a was repeated, but using 0.456 g of phthalidyl 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate, prepared as described in Preparation 32, 0.736 g of 4- [2- (trityl tetrazole -4-yl) phenyl] benzyl bromide and 0.366 g of potassium carbonate, resulting in 0.196 g of the target compound, so pl. 118-120 ^o C.

NMR (CDCl ₃ ) d ppm: 0.95 (3H, t. J 7.5 Hz), 1.66 (6H, s), 1.65-1.80 (2H, m), 2.60 (2H , t. J 7.5 Hz), 5.09 (2H, s), 6.92-7.56 (2H, m), 7.93 (1H, dd. J 1 and 8 Hz).

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

According to the procedure described in Example 61b, 0.196 g of phthalidyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (trityltetrazol-5-yl) phenyl] phenyl} methylimidazole- 5-carboxylate obtained in stage (a), and was subjected to dithritylation by heating with 75% vol./about. aqueous acetic acid, whereby 0.110 g of the target compound was obtained, mp 168-170 ^o C.

NMR (CDCl ₃ ) d ppm: 0.92 (3H, t. J 7.5 Hz), 1.57 (6H, s), 1.60-1677 (6H, s), 2.65 (2H, t J 7.5 Hz), 5.13 (2H, s), 6.91-7.57 (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} methylimidazole-5-carboxylate (compound 2-21) .

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

 The procedure described in Example 61a was repeated, but using 656 mg of isopropoxycarbonyloxymethyl 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate, prepared as described in Preparation 33, 1.20 g 4- [2 - (trityltetrazol-5-yl) phenyl] benzyl bromide and 0.51 g of potassium carbonate, whereby 0.78 g of the target compound is obtained in the form of a viscous oily product.

NMR (CDCl ₃ ) d ppm: 0.87 (3H, t. J 7.5 Hz), 1.24 (6H, d. J 6 Hz), 1.63 (6H, s), 1.65-1 80 (2H, m), 2.52 (2H, t. J 7.5 Hz), 4.87 (1H, quintet, J 6 Hz), 5.35 (2H, s), 5.42 (1H , s), 5.66 (2H, s), 6.74-7.87 (22H, m), 7.87-7.96 (1H, m).

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

 According to the procedure described in Example 61b, 0.78 g of isopropoxycarbonylosimethyl 4- (1-hydroxy-1-methyl-ethyl) -2-propyl-1- {4- [2- (trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate obtained in stage (a) was subjected to detritylation by heating with 75% vol./about. aqueous acetic acid, whereby 0.48 g of the expected preparation is obtained in the form of an amorphous solid.

NMR (CDCl ₃ ) d ppm: 0.96 (3H, t. J 7.5 Hz), 1.21 (6H, d. J 6 Hz), 1.63 (6H, s), 1.72 (2H , sextet J 7.5 Hz), 2.60 (2H, t. J 7.5 Hz), 4.72 (1H, quintet J 6.5 Hz), 5.33 (2H, s), 5.76 (2H, s), 6.77 (2H, d.J. 7.5 Hz), 6.92 (2H, d. J 7.5 Hz), 7.37-7.60 (3H, m.) 7 87 (1H, d. J 7.5 Hz).

 Example 65. Ethyl 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] 2-ethyl-4-1-hydroxy-1-methylethyl imidazole-5-carboxylate (compound 1-130).

 0.337 g of potassium t-butoxide was added to a solution of 0.68 g of ethyl 2-ethyl-4- (1-hydroxy-1-methylethyl) imidazole-5-carboxylite, prepared as described in Preparation 37, in 7 ml of N, N -dimethylacetamide, and the resulting mixture was stirred for 10 minutes at room temperature. Then, 1.04 g of t-butyl 4'-bromomethylbiphenyl-2-carboxylate was added to the resulting solution, and the reaction mixture was stirred for 4 hours at room temperature. At the end of this time, this mixture was mixed with ethyl acetate and water. The ethyl acetate layer was separated, dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a mixture of ethyl acetate and hexane (1: 1, v / v), whereby 1.32 g of the target compound was obtained in the form of a gum.

NMR (CDCl ₃ ) d ppm: 1.23 (9H, s), 1.23 (3H, t. J 7.5 Hz), 1.29 (3H, t. J 7.5 Hz), 1.63 (6H, s), 2.73 92H, q. J 7.5 Hz), 4.26 (2H, q, J 7.5 Hz), 5.54 (2H, s), 6.73 (1H, s), 6.98 (2H, d. J 8 5 Hz), 7.5-7.9 (6H, m).

 Example 66. Ethyl 1 - [(2'-carboxybiphenyl-4-yl) methyl] -2-ethyl-4- (1-hydroxy-1-methylethyl) imidazole-5-carboxylate (compound 1-131).

 The procedure described in Example 7 was repeated, but using 1.32 g of ethyl 1 - [(2'-t-butoxycarbonylphenyl-4-yl) methyl] -2-ethyl-4- (1-hydroxy -1-methylethyl) imidazole -5-carboxylate obtained as described in example 65, and 4 N. a solution of hydrogen chloride in dioxane, whereby 0.94 g of the hydrochloride salt of the target compound are obtained in the form of an amorphous powder.

NMR (DMSO-d ₆ ) d ppm: 1.09 (3H, t. J 7.5 Hz), 1.15 (3H, t. J 7.5 Hz), 1.61 (6H, s), 3 03 (2H, q, J 7.5 Hz), 4.22 (2H, q, J 7.5 Hz), 5.64 (2H, s), 7.16 (2H, d, J 8.5 Hz), 7.32-7.75 (6H, m).

 Example 67. 1 - [(2'-Carboxybiphenyl-4-yl) methyl] -2-ethyl-4- (1-hydroxy-1-methylethyl) imidazole-5-carboxylic acid (compound 1-132).

 The procedure described in Example 17 was repeated, but using 0.40 g of ethyl 1 - [(2'-carboxyphenyl-4-yl) methyl] -2-ethyl-4- (1-hydroxy-1-methylethyl) imidazole hydrochloride 5-carboxylate obtained in Example 66 and 0.18 g of lithium hydroxide monohydrate, whereby 0.25 g of the target compound is obtained in the form of an amorphous powder.

NMR (DMSO-d ₆ ) d ppm: 1.17 (3H, t, J 7.5 Hz), 1.64 (6H, s), 2.85 (2H, q, 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} methylimidazole-5-carboxylate (compound 1-72) .

 65a) Ethyl 2-ethyl-4- (1-hydroxy-1-methylethyl) -1- {4- [2- (trityltetrazol-4-yl) phenyl] phenyl} methylimidazole-5-carboxylate.

0.52 g of potassium t-butoxide was added to a solution of 1.00 g of ethyl 2-ethyl-4- (1-hydroxy-1-methylethyl) imidazole-5-carboxylate, prepared as described in Preparation 37, in 26 ml of N, N -dimethylacetamide, and the resulting mixture was stirred for 10 minutes at room temperature. A solution of 2.71 g of 4- [2- (trityltetrazol-5-yl) phenyl] benzyl bromide in 35 ml of N, N-dimethylacetamide was added dropwise to the resulting solution, after which the reaction mixture was stirred for 4 hours at 50 ^° C. After that, the reaction the mixture was treated in a manner similar to that described in example 18a, resulting in 2.01 g of the target compound in the form of crystals, so pl. 150-152 ^o C.

NMR (CDCl ₃ ) d ppm: 1.10 (3H, t, J 7.5 Hz), 1.18 (3H, t. J 7.5 Hz), 1.65 (6H, s), 2.52 (2H, sq. J 7.5 Hz), 4.14 (2H, sq. J 7.5 Hz), 5.35 (2H, s), 5.80 (1H, s), 6.73 (2H d, J 8.5 Hz), 6.93-7.52 (20H, m), 7.87 (1H, d J 7.5 Hz).

 68b) Ethyl 2-Ethyl-4- (1-hydroxy-1-methylethyl) -1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate.

A solution of 1.9 g of ethyl 2-ethyl-4- (1-hydroxy-1-methylethyl) -1- {4- [2 '- (trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate obtained in stage (a), in 28 ml of 75% vol./about. aqueous acetic acid was stirred for 2 hours at 60 ^° C. After this, the reaction mixture was diluted with 7 ml of water and cooled at room temperature. Precipitated triethyl alcohol was removed by filtration, and the filtrate was concentrated by evaporation under reduced pressure. A syrupy residue was crystallized in diisopropyl ether, whereby 1.21 g of the target compound was obtained, so pl. 166-167 ^o .

NMR (CDCl ₃ ) d ppm: 1.14 (3H, t, J 7.5 Hz), 1.20 (3H, t, J 7.5 Hz), 1.48 (6H, s), 2.52 (2H, sq. J 7.5 Hz), 4.19 (2H, sq. J 7.5 Hz), 5.41 (2H, s), 6.79 (2H, d, J 8.5 Hz) 7.09 (2H, d, J 8.5 Hz), 7.41-7.62 (3H, m), 7.85 (1H, d, J 7.5 Hz).

 Example 69. 2-Ethyl-4- (1-hydroxy-1-methylethyl) -1- {4 - [(tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylic acid.

A solution of 0.54 g of lithium hydroxide monohydrate in 10 ml of water was added to a solution of ethyl 2-ethyl-4- (1-hydroxy-1-methyl-ethyl-1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate obtained as described in Example 68b in 10 ml of dioxane and the resulting mixture was stirred for 4 hours at room temperature, after which the dioxane was removed by evaporation under reduced pressure and 12.6 ml of 1 n was added to the resulting aqueous residue. aqueous hydrochloric acid Precipitated crystals were collected by filtration to give 0.93 g of the target compound, mp 179-18 1 ^o C.

NMR (DMSO-d ₆ ) d ppm: 1.09 (3H, t, J 7.5 Hz), 1.55 (6H, s), 2.63 (2H, q, J 7.5 Hz), 5 65 (2H, s), 6.96 (2H, d, J 8.5 Hz), 7.03 (2H, d, J 8.5 Hz), 7.08-7.64 (4H, m) .

 Example 70. Ethyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate (compound 2-7) .

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

The procedure described in Example 68a was repeated, but using 4.01 g of ethyl 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate, prepared as described in Preparation 9, 5.0 g of 4'- bromomethylbiphenyl-2-carbonitrile and 1.97 g of potassium t-butoxide, whereby 6.86 g of the target compound are obtained in the form of crystals, mp 92-93 ^o C.

NMR (CDCl ₃ ) d ppm: 0.97 (3H, t, J 7.5 Hz), 1.16 (3H, t, J 7 Hz), 1.65 (6H, s), 1.74 (2H , sextet, J 7.5 Hz), 2.67 (2H, t, J 7.5 Hz), 4.24 (2H, q. J 7 Hz), 5.52 (2H, s), 5.77 (1H, s), 7.05 (2H, d, J 8.5 Hz), 7.42-7.67 (5H, m), 7.76 (1H, d, J 8 Hz).

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

A solution of 2.00 g of ethyl 1- (2'-cyanobiphenyl-4-yl) methyl 4-1-hydroxy-1-methylethyl-2-propylimidazole-5-carboxylate obtained in stage (a), and 2.00 g tributyltin azide in 15 ml of toluene was stirred for 5 days at 100 ^o C. After this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was dissolved in 30 ml of 4 N. a solution of hydrogen chloride in dioxane. The solution was left for 16 hours at room temperature, after which it was concentrated by evaporation under reduced pressure. The residue was triturated with diisopropyl ether to give 2.00 g of the hydrochloride of the target compound.

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

 Example 71. Ethyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (tetrazol-4-yl) phenyl] phenyl} methylimidazole-5-carboxylate (compound 2-7) .

 72a) Ethyl 1- {4- [2- (t-butylaminocarbonyl) phenyl] phenyl} methyl-4-1-hydroxy-1-methylethyl-2-propylimidazole-5-carboxylate.

The procedure described in Example 68a was repeated, but using 4.16 g of ethyl 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate, prepared as described in Preparation 9, 6.00 g N-t -butyl-4'-bromomethylbiphenyl-2-carboxamide obtained as described in Preparation 38 and 2.14 g of potassium t-butoxide, whereby 5.87 g of the target compound are obtained in the form of crystals, mp 145-146 ^o C.

NMR (CDCl ₃ ) d ppm: 0.97 (3H, t, J 7.5 Hz), 1.12 (9H, s), 1.24 (3H, t, J 7 Hz), 1.64 (6H , s), 1.75 (2H, sex. J 7.5 Hz), 2.66 (2H, t, J 7.5 Hz), 4.25 (2H, q. J 7 Hz), 5.03 (1H, s), 5.52 (2H, s), 5.69 (1H, s), 6.98 (2H, d, J 8.5 Hz), 7.28-7.47 (5H, m ), 7.65 (1H, d, J Hz).

 71b) Ethyl 1- (2'-cyanobiphenyl-4-yl) methyl 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate.

 0.345 ml of oxalyl chloride was added dropwise while cooling with ice to a solution of 1.00 g of ethyl 1- {4- [2- (t-butylaminocarbonyl) phenyl] phenyl} methyl-4- (1-hydroxy-1-methylethyl) - 2-propylimidazole-5-carboxylate obtained in stage (a) in 10 ml of methylene chloride, and the resulting mixture was stirred for 2 hours at the same temperature. After this, the reaction mixture was diluted with an aqueous solution of sodium bicarbonate and ethyl acetate, then the ethyl acetate layer was separated, dried with anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a mixture of ethyl acetate and hexane (1: 1, v / v), whereby 0.69 g of the target compound was obtained in the form of crystals.

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

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

The procedure described in Example 70b was repeated, but using ethyl 1- (2'-cyanobiphenyl-4-yl) methyl 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate, obtained in step ( b), resulting in the obtained target compound with a yield of 91%
The NMR spectrum of this compound is identical to the spectrum of the compound obtained in example 18b.

 Example 72. Ethyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate (compound 2-7) .

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

The procedure described in Example 68a was repeated, but using 4.80 g of ethyl 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate, prepared as described in Preparation 9, 6.94 g of t-butyl 4'-bromomethylbiphenyl-2-carboxylate and 2.28 g of potassium t-butoxide, resulting in the receipt of 7.50 g of the target compound in the form of crystals, so pl. 90-91 ^o C.

NMR (CDCl ₃ ) d ppm: 0.97 (3H, t, J 7 Hz), 1.23 (3H, t. J 7 Hz), 1.25 (9H, s), 1.60 (6H, s ), 1.82 (1H, sextet, J 7 Hz), 2.67 (2H, t, J 7 Hz), 4.24 (2H, q. J 7 Hz), 5.51 (2H, s), 5.72 (1H, s), 6.87-7.85 (8H, m).

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

 The procedure described in Example 18b was repeated, but using 0.80 g of ethyl 1 - [(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -4- (1-hydroxy-1-methylethyl) -2-propylimidazole- 5-carboxylic obtained in stage (a), and 4 N. a solution of hydrogen chloride in dioxane, resulting in the obtained hydrochloride of the target compound in the form of an amorphous powder.

NMR (DMSO-d ₆ ) d ppm: 0.88 (3H, t, J 7 Hz), 1.14 (3H, t, J 7 Hz), 1.50-1.65 (2H, m), 1 60 (6H, s), 3.00 (2H, t, J 7 Hz), 4.20 (2H, q. J 7 Hz), 5.63 (2H, s), 7.13-7.75 (8H, m),
72 (c) Ethyl 1 - [(2'-carbamoylbiphenyl-4-yl) methyl] -4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate.

3 ml of oxalyl chloride was added dropwise while cooling with ice to a solution of 4.00 g of ethyl 1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (1-hydroxy-1-methylethyl) -2- hydrochloride propylimidazole-5-carboxylate obtained in stage (b), see above] in 40 ml of methylene chloride, and the resulting mixture was stirred for 2 hours at room temperature. Then the reaction mixture was concentrated by evaporation under reduced pressure. After this, benzene was added to the residue, and the mixture was again concentrated by evaporation under reduced pressure to remove the remaining oxalyl chloride. The crystalline residue was suspended in 100 ml of ethyl acetate and mixed with 15 ml of concentrated ammonia, while cooling with ice, after which the mixture was stirred for 10 minutes at room temperature. Then, the ethyl acetate layer was separated, washed with water, dried with anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The crystalline residue was washed with diisopropyl ether and 2.97 g of the target compound were obtained with mp. 148-151 ^o C.

NMR (CDCl ₃ ) d ppm: 0.96 (3H, t, J 7.5 Hz), 1.19 (3H, t, J 7 Hz), 1.64 (6H, s), 1.73 (2H , sextet, J 7.5 Hz), 2.65 (2H, t J 7.5 Hz), 4.24 (1H, q, J 7 Hz), 5.36 (1H, br s), 5, 49 (2H, s), 5.66 (1H, br s), 5.76 (1H, s), 6.99 (2H, d, J 8 Hz), 7.32-7.53 (5H, m), 7.71 (1H, d, J = 6 Hz).

 72d) Ethyl 1- (2'-cyanobephenyl-4-yl) methyl 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate.

 264 μl of trifluoroacetic anhydride was added while cooling in a bath containing a mixture of ice and sodium chloride to a solution of 0.70 g of ethyl 1 - [(2'-carbamolybiphenyl-4-yl) methyl] -4- (1-hydroxy -1-methylethyl) -2-propylimidazole-5-carboxylate obtained in step (c) and 0.43 ml of triethylamine in 7 ml of methylene chloride and the resulting mixture was stirred for 30 minutes at the same temperature. After this, the reaction mixture was diluted with an aqueous solution of sodium bicarbonate and ethyl acetate, the ethyl acetate layer was separated, dried with anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a mixture of ethyl acetate and hexane (1: 1, v / v), whereby 0.60 g of the target compound was obtained in the form of crystals.

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

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

The procedure described in Example 70b was repeated, but using ethyl 1- (2'-cyanobiphenyl-4-yl) methyl 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate obtained in step ( d), resulting in the obtained target compound with a yield of 90%
The NMR spectrum of this compound is identical to the spectrum of the compound obtained in example 18b.

 Example 73. Pivaloyloxy 4- (1-hydroxyethyl) -2-propyl-1- {4- [2-tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate (compound 4-31).

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

A solution of 196 mg of sodium hydroxide monohydrate in 15 ml of water was added to a solution of 2.87 g of ethyl 4- (1-hydroxyethyl 0-2-propyl-1- {4- [2- (trityltetrazol-4-yl) phenyl] phenyl} methylimidazole- The 5-carboxylate obtained as described in Example 42a was stirred in 30 ml of dioxane and the resulting mixture was stirred for 16 hours at room temperature, after which a small piece of dry ice was added to the mixture, and then the mixture was concentrated by evaporation under reduced pressure to dryness. ml of N, N-dimethylacetamide, and 0.45 g of potassium carbonate was added to the solution, followed by 1.1 ml ivaloiloksihlorida. The resulting mixture was stirred for 3 hours at 50 ^o C. Thereafter, the reaction mixture was added water and ethyl acetate, the ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate and hexane (1: 1, v / v), and 2.41 g of the target compound are obtained in the form of an amorphous powder.

NMR (CDCl ₃ ) d ppm: 0.88 (3H, t, J 7.5 Hz), 1.17 (9H, s), 1.50 (3H, d, J 6 Hz), 1.69 (2H sex. J 7.5 Hz), 2.51 (2H, t, J 7.5 Hz), 3.62 (1H, d, J 8 Hz), 5.17-5.291 N, m), 5, 37 (1H, d, J 16.5 Hz), 5.46 (1H, d, J 16.5 Hz), 5.77 (1H, d, J 5.5 Hz), 5.82 (1H, d , J 5.5 Hz), 6.75 (2H, d, J 8.5 Hz), 6.92-7.89 (20P, m), 7.90 (1H, d, J 7.5 Hz) .

 73b) Pivaloyloxymethyl 9- (1-hydroxyethyl) -2-propyl-1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate.

 The procedure described in Example 35c was repeated, but using 2.87 g of pivaloyloxymethyl 4- (1-hydroxyethyl) -2-propyl-1- {4- [2- (trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-5 -carboxylate obtained in stage (a), and 75% vol. /about. aqueous acetic acid, whereby 1.21 g of the target compound are obtained in powder form.

NMR (CDCl ₃ ) d ppm: 0.90 (3H, t, J 7.5 Hz), 1.13 (9H, s), 1.43 (3H, d, J 6.5 Hz), 1.67 (2H, sext. J 7.5 Hz), 2.55 93H, t, J 7.5 Hz), 5.16 (1H, q. J 6.5 Hz), 5.40 (1H, d, J 16.5 Hz), 5.51 (1H, d, J 16.5 Hz), 5.80 (1H, d, J 6 Hz), 5.85 (1H, d, J 6 Hz), 6.86 (2H, d, J 8 Hz), 7.08 (2H, d, J 8 Hz), 7.40-7.61 (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} methylimidazole-5-carboxamide (compound 5-37 )

 74a) 2-Propyl-4-pivaloyl-1- {4- [2- (trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carbonitrile.

1.08 g of potassium t-butoxide was added while cooling with ice to a solution of 2.00 g of 2-propyl-4-pivaloylimidazole-5-carbonitrile obtained in accordance with the description in Preparation 41 in 20 ml of N, N -dimethylacetamide and the resulting mixture was stirred for 10 minutes at the same temperature. Then, 6.10 g of 4- [2- (trityltetrazol-5-yl) phenyl] benzyl bromide was added to the solution, and the resulting mixture was stirred for 4 hours at 50 ^° C. After this, ethyl acetate and water were added to the mixture, and the ethyl acetate layer was separated and dried. anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The syrupy residue was purified by silica gel column chromatography, eluting with mixtures of ethyl acetate and hexane (1: 3 and 1: 2, v / v), whereby the target compound was obtained in the form of crystals, mp 107-100 ^o C.

NMR (CDCl ₃ ) d ppm: 0.92 (3H, t, J 7.5 Hz), 1.42 (9H, s), 1.72 (2H, sext. 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).

 74b) 4- (1-hydroxy-2,2-dimethylpropyl) -2-propyl-1- {4- [2- (trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-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- (trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carbonitrile obtained in step (a), in 40 ml of tetrahydrofuran and the resulting mixture was stirred for 2.5 hours at room temperature. After this, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was dissolved in a mixture of ethyl acetate and water. The ethyl acetate layer was separated, washed with water, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. A syrupy residue was crystallized in a mixture of ethyl acetate and hexane (1: 4, v / v) to obtain 1.93 g of the target compound in the form of crystals, mp 115-117 ^o C.

NMR (CDCl ₃ ) d ppm: 0.87 (3H, t, J 7.5 Hz), 0.99 (9H, s), 1.64 (2H, sext. J 7.5 Hz), 2.49 (2H, t, J 7.5 Hz), 2.76 (1. 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).

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

Suspension 1.65 g of 4- (1-hydroxy-2,2-dimethylpropyl) -2-propyl-1- {4- [2- (trityltetrazol-5-yl)] phenyl} phenyl methylimidazole-5-carbonitrile obtained in as described in step (b), in 24 ml of 75% v / v. aqueous acetic acid was stirred for 2 hours at 60 ^° C. After this, 6 ml of water was added to the reaction mixture and cooled with ice. Precipitated trityl alcohol was removed by filtration, and the filtrate was concentrated by evaporation under reduced pressure, whereby 1.07 g of the target compound was obtained in the form of a glassy substance.

NMR (CDCl ₃ ) d ppm: 0.87 (3H, t, J 7.5 Hz), 0.92 (9H, s), 1.63 (2H, sex. J 7.5 Hz), 2.58 (2H, t, J 7.5 Hz), 4.36 (1H, s), 5.15 (2H, s), 7.00 (2H, d, J 8 Hz), 7.07 (2H, d , J 8 Hz), 7.30-7.61 (3H, m), 7.80 (1H, d, J 7.5 Hz).

74d) 4- (1-Hydroxy-2,2-dimethylpropyl) -2-propyl-1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxamide
A mixture of 0.70 g of 4- (1-hydroxy-2,2-idmethylpropyl) -2-propyl-1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carbonitrile obtained according to the description in stage (c), in 14 ml of 1 N. aqueous sodium hydroxide and 7 ml of ethanol were heated under reflux for 2 hours. After this, ethanol was removed from the reaction mixture by evaporation under reduced pressure, and ethyl acetate and 14 ml of 1N were added to the residue. aqueous hydrochloric acid. The ethyl acetate layer was separated, dried with anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure, whereby 0.45 g of the target compound was obtained in the form of a powder, mp 174-175 ^o C.

NMR (DMSO-d ₆ ) d ppm: 0.83 (3H, t, J 7.5 Hz), 0.88 (9H, s), 1.44-1.63 (2H, m), 2.46 (2H, t, J 7.5 Hz), 4.45 (1H, s), 5.39 (1H, d, J 16 Hz), 5.77 (1H, d, J 16 Hz), 6.20 (1H, d, J 4.5 Hz), 6.91 (2H, d, J 8.5 Hz), 7.04 (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} methylimidazole-5-carboxamide (compound 5-99 )

 75a) 2-Butyl-4-pivaloyl-1- {4- [2- (trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carbonitrile.

The procedure described in Example 74a was repeated, but using 2.04 g of 2-butyl-4-pivaloylimidazole-5-carbonitrile, prepared as described in Preparation 40, 5.6 g of 4_ [2- (trityltetrazol-5-yl ) phenyl] benzyl bromide and 1.06 g of potassium t-butoxide, whereby 5.43 g of the target compound are obtained in the form of crystals, so pl. 103-103 ^o C.

NMR (CDCl ₃ ) d ppm: 0.88 (3H, t, J 7.5 Hz), 1.32 (2H, sext. J 7.5 Hz), 1.41 (9H, s), 1.66 (2H, quin. J 7.5 Hz), 2.53 (2H, t, J 7.5 Hz), 5.09 (2H, s), 6.91-7.50 (22H, m), 7 96 (1H, d, J 7.5 Hz).

 75b) 2-Butyl-4- (1-hydroxy-2,2-dimethylpropyl) -1- {4- [2- (trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carbonyryl.

The procedure described in Example 74b was repeated, but using 4.03 g of 2-butyl-4-pivaloyl-1- {4- [2- (trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carbonitrile prepared according to the description in step (a) and 0.22 g of sodium borohydride, whereby 3.79 g of the target compound are obtained in the form of crystals, so pl. 134-135 ^o C.

NMR (CDCl ₃ ) d ppm: 0.85 (3H, t, J 7.5 Hz), 0.99 (9H, s), 1.27 (2H, sext. J 7.5 Hz), 2.52 -1.67 (2H, m), 2.51 (2H, t, J 7.5 Hz), 2.74 (1H, d, J 7.5 Hz), 4.45 (1H, d, J 7 5 Hz), 5.04 (2H, s), 6.85-7.53 (22H, m), 7.95 (1H, d, J 7.5 Hz).

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

 The procedure described in Example 74c was repeated, but using 1.00 g of 2-butyl-4- (1-hydroxy-2,2-dimethylpropyl) -1- {4- [2- (trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carbonitrile obtained as described in step (b) in 75% v / v aqueous acetic acid, whereby 0.65 g of the target compound are obtained in the form of a glassy substance.

NMR (CDCl ₃ ) d ppm: 0.91 (3H, t, J 7.5 Hz), 0.96 (9H, s), 1.28-1.42 (2H, m), 1.58-1 74 (2H, m), 2.69 (2H, t, J 7.5 Hz), 4.40 (1H, s), 5.21 (2H, s), 7.10-7.32 (4H , m), 7.43-7.65 (3H, m), 8.06 (1H, d, J = 8 Hz).

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

The procedure described in Example 74d was repeated, but using 0.34 g of 2-butyl-4- (1-hydroxy-2,2-dimethylpropyl) -1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carbonitrile, obtained as described in step (c), in 1N. an aqueous solution of sodium hydroxide, resulting in a received 0.30 g of the target compound in powder form, so pl. 157-160 ^o C.

NMR (DMSO-d ₆ ) d ppm: 0.79 (3H, t, J 7.5 Hz), 0.88 (9H, s), 1.16-1.30 (2H, m), 1.39 -1.54 (2H, m), 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), 7.51-7.70 (4H, m).

 Example 76. 4- (1-Hydroxy-2-methylpropyl) -2-propyl-1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxamide (compound 5-36) .

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

The procedure described in Example 74a was repeated, but using 0.97 g of 4-isobutyryl-2-propylimidazole-5-carbonitrile, prepared as described in Preparation 39, 2.90 g of 4- [2- (trityltetrazol-5-yl) phenyl] benzyl bromide and 0.56 g of potassium t-butoxide, whereby 1.90 g of the target compound are obtained in the form of crystals, mp. 133-134 ^o C.

NMR (CDCl ₃ ) d ppm: 0.91 (3H, t, J 7.5 Hz), 1.22 (6H, d, J 6.5 Hz), 1.69 (2H, sextet, J 7.5 Hz), 2.54 (2H, t, J 7.5 Hz), 3.64 (1H, quin. J 6.5 Hz), 5.12 (2H, s), 6.7-8.0 ( 23H, m).

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

The procedure described in Example 75b was repeated, but using 1.60 g of 4-isobutyryl-2-propyl-1- {4- [2- (trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carbonitrile prepared according to the description in stage (a), and 0.13 g of sodium borohydrin, resulting in the receipt of 1.50 g of the target compound in the form of crystals, so pl. 154-155 ^o C.

NMR (CDCl ₃ ) d ppm: 0.87 (3H, t. J 7.5 Hz), 0.94 (3H, d, J 6.5 Hz), 1.00 (3H, d, J 6.5 Hz), 1.66 (2H, sext. J 7.5 Hz), 2.12 (1H, sext. J 6.5 Hz), 2.50 (2H, t, J 7.5 Hz), 4, 54 (1H, d, J 6 Hz), 5.04 (2H, s), 6.85-6.95 (6H, m), 7.14 (2H, d, J 8.5); 7.23-7.53 (14H, m), 7.94 (1H, d, J 7.5 Hz).

 76c) 9- (1-Hydroxy-2-methylpropyl) -2-propyl-1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carbonitrile.

 The procedure described in Example 74c was repeated, but using 1.36 g of 4- (1-hydroxy-2-methylpropyl) -2-propyl-1- {4- [2- (trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carbonitrile obtained in stage (b), in 75% vol./about. aqueous acetic acid, whereby 0.87 g of the target compound are obtained in the form of a glassy substance.

NMR (CDCl ₃ ) d ppm: 0.77 (3H, d, J 6.5 Hz), 0.81 (3H, d, J 7.5 Hz), 0.93 (3H, d, J 6.5 Hz), 1.54 (2H, sextet, J 7.5 Hz), 1.92-2.07 (1H, m), 2.55 (2H, t, J 7.5 Hz), 4.33 ( 1H, d, J 7.5 Hz), 5.12 (2H, s), 6.96-6.99 (4H, m), 7.35-7.69 (3H, m), 7.71 ( 1H, d, J 7.5 Hz).

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

The procedure described in Example 74d was repeated, but using 0.90 g of 4- (1-hydroxy-2-methylpropyl) -2-propyl-1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carbonitrile obtained in stage (C), in 1 N. an aqueous solution of sodium hydroxide, resulting in a gain of 0.64 g of the target compound in powder form, so pl. 153-157 ^o C.

NMR (DMSO-d ₆ ) delta, ppm: 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, sext. J 7.5 Hz), 2.05 (1H, quin. J 6.5 Hz), 2.68 (2H, t, J 7.5 Hz) 4.45 (1H, d, J 7.5 Hz), 5.55 (1H, d, J 16.5 Hz), 5.70 (1H, d, J 16.5 Hz), 7.02 ( 2H, d, J 8.5 Hz), 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} methylimidazole-5-carboxamide (compound 5-98) .

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

The procedure described in Example 74a was repeated, but using 1.42 g of 2-butyl-4-isobutyrylimidazole-5-carbonitrile obtained as described in Preparation 27, 4.49 g of 4- [2- (trityltetrazol-5-yl) phenyl] benzyl bromide and 0.76 g of potassium t-butoxide, whereby 3.04 g of the target compound are obtained in the form of crystals, mp. 115-116 ^o C.

ppm: 0,87 (3Н, т, J 7,5 Гц), 1,22 (6Н, д, J 6,г Гц), 1,31 (2Н, секстет, J 7,5 Гц), 1,63 (2Н, квин. J 7,5 Гц), 2,57 (2Н, т, J 7,5 Гц), 3,64 (1Н, септ. J 7,5 Гц), 5,11 (2Н, с), 6,90-7,52 (22Н, м), 7,96 (1Н, д, J 9 Гц).NMR (CDCl ₃ )

ppm: 0.87 (3H, t, J 7.5 Hz), 1.22 (6H, d, J 6, g Hz), 1.31 (2H, sextet, J 7.5 Hz), 1.63 (2H, quin. J 7.5 Hz), 2.57 (2H, t, J 7.5 Hz), 3.64 (1H, sept. J 7.5 Hz), 5.11 (2H, s) 6.90-7.52 (22H, m); 7.96 (1H, d, J = 9 Hz).

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

The procedure described in Example 74b was repeated, but using 2.00 g of 2-butyl-4-isobutyryl-1- {4- [2- (trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carbonitrile obtained in stage (a), and 0.22 g of sodium borohydride, resulting in 1.68 g of the target compound were obtained in the form of crystals, so pl. 127-128 ^o C.

NMR (CDCl ₃ ) delta, ppm: 0.85 (3H, t, J 7.5 Hz), 0.93 (3H, d, J 6.5 Hz), 1.00 (3H, d, J 6, 5 Hz), 1.26 (2H, sextet, J 7.5 Hz), 1.59 (2H, quin. J 7.5 Hz), 2.13 (1H, sext. J 6.5 Hz), 2 52 (2H, t, J 7.5 Hz), 4.53 (1H, d, J 6 Hz), 5.04 (2H, s), 6.85-7.52 (22H, m), 7 95 (1H, d, J = 9 Hz).

 77c) 2-Butyl-4- (1-Hydroxy-2-methylpropyl) -1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carbonitrile.

 The procedure described in Example 74c was repeated, but using 1.29 g of 2-butyl-4- (1-hydroxy-2-methylpropyl) -1- {4- [2- (trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carbonitrile obtained in stage (b), in 75% vol./about. aqueous acetic acid, whereby 0.83 g of the target compound is obtained in the form of a glassy substance.

NMR (CDCl ₃ ) delta, ppm: 0.81 (3H, d, J 6.5 Hz), 0.83 (3H, t, J 7.5 Hz), 0.95 (3H, d, J 6, 5 Hz), 1.26 (2H, sextet, J 7.5 Hz), 1.54 (2H, quin. J 7.5 Hz), 1.97-2.09 (1H, m), 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); 7.32-7.60 (3H, m); 7.77 (1H, d, J 7.5 Hz).

 77d) 2-Butyl-4- (1-hydroxy-2-methylpropyl) -1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxamide.

The procedure described in Example 74d was repeated, but using 0.34 g of 2-butyl-4- (1-hydroxy-2-methylpropyl) -1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carbonitrile obtained in stage (C), in 1 N. an aqueous solution of sodium hydroxide, resulting in a 0.24 g of the target compound was obtained in the form of a powder, so pl. 155-157 ^o C.

NMR (DMSO-d ₆ ) delta, ppm: 0.69 (3H, d, J 6.5 Hz), 0.79 (3H, t, J 7.5 Hz), 0.93 (3H, d, J 6.5 Hz), 1.22 (2H, sex. J 7.5 Hz), 1.45 (2H, quin. J 7.5 Hz), 2.00-2.12 (1H, m), 2 65 (2H, t, J 7.5 Hz), 4.41 (1H, d, J 8 Hz), 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-2oxo-1,3-dioxolen-4-yl) methyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (tetrazol-5- il) phenyl] phenyl} methylimidazole-5-carboxylate (compound 2-17).

 78a) (5-Methyl-2oxo-1,3-dioxolen-4-yl) methyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (trityltetrazol-5-yl ) phenyl] phenyl} methylimidazole.

A solution of 2.65 g of lithium hydroxide monohydrate in 158 ml of water was added while cooling with ice to a solution of 30 g of ethyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (trityltetrazole -5-yl) phenyl] phenyl} methylimidazole-5-carboxylate, prepared as described in Example 18a, in 344 ml of dioxane, and the resulting mixture was stirred for 20 hours at 5 ^° -10 ^° C. After this time, a small piece of dry ice was added to the mixture. after which the mixture was concentrated by evaporation under reduced pressure to obtain a volume of about 100 ml, then ethyl acetate and chlorine were added to the concentrate sodium chloride, and the resulting mixture was stirred. The ethyl acetate layer was separated, dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure, whereby 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (trityltetrazol-5-yl) was obtained phenyl] phenyl} lithium methylimidazole-5-carboxylate in the form of a glassy material. Then, to a solution of all the obtained lithium carboxylate in 160 ml of N, N-dimethylacetamide, 6.08 g of potassium carbonate was added while cooling with ice, after which a solution of 11.2 g of 4-chloromethyl was added dropwise to the mixture while cooling with ice. -5-methyl-2-oxo-1,3-dioxolene (74 purities) in 26 ml of N, N-dimethylacetamide. The resulting mixture was stirred for 3 hours at 50 ^° C. At the end of this time, water and ethyl acetate were added to the reaction mixture, and the ethyl acetate layer was separated, dried with anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was crystallized in diisopropyl ether, whereby 29.3 g of the target compound were obtained, mp. 98-100 ^o C (decomp.).

 The NMR spectrum of this compound is identical to the spectrum of the compound obtained in example 61a.

 78b) (5-Methyl-2-oxo-1,3-dioxolen-4-yl) methyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (tetrazole -5 -yl) phenyl] phenyl} methylimidazole-5-carboxylate.

75 ml of water was added to a suspension of 29.3 g of (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1 {4- [2- (trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate obtained in step (a) in 225 ml of acetic acid, and the resulting mixture was stirred for 1.5 hours at 60 ^o C. After this time 75 ml of water was added to the mixture, and the mixture was cooled. Precipitated trityl alcohol was removed by filtration, and the filtrate was concentrated by evaporation under reduced pressure. Toluene was added to the residue, and the resulting mixture was again concentrated by evaporation under reduced pressure to remove residual water and acetic acid. The residue was crystallized in ethyl acetate, whereby 16.6 g of the target compound were obtained in the form of crystals, mp. 177-180 ^o C (decomp.).

 The NMR spectrum of this compound is identical to the spectrum of the compound obtained in example 61 (b).

 Example 79. (5-Methyl-2-oxo-1,3-dioxolen-4-yl) methyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (tetrazole - 5-yl) phenyl] phenyl} methylmidazole-5-carboxylate (compound 2-17).

 79a) Ethyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate.

A solution of 1.00 g of ethyl 1- (2'-cyanobiphenyl-4-yl) methyl 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate, obtained as described in example 71b, and 1, 00 g of tributyltin azide in 7.5 g of toluene was stirred for 5 days at 100 ^° C. Then, 2.5 g of sodium bicarbonate and 20 ml of water were added to the mixture, and the resulting 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 adding 3 N. aqueous hydrochloric acid. The ethyl acetate layer was separated, dried with anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure, whereby ethyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (tetrazole-5- il) phenyl] phenyl} methylimidazole-5-carboxylate in the form of a syrup. 0.80 g of trityl chloride was added to a solution of this syrup obtained in 15 ml of pyridine, and the mixture was stirred for 4 hours at 60 ^° C. After this, the reaction mixture was concentrated by evaporation under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and hexane (1: 1, v / v), and then crystallized from diisopropyl ether to give 1.15 g of the target compound as crystals.

 The NMR spectrum of this compound is identical to the spectrum of the compound obtained in example 18a.

 79b) (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (tetrazole -5 -yl) phenyl] phenyl} methylimidazole-5-carboxylate.

The procedure described in examples 78a and 78b was repeated, but using ethyl 4- (1-hydroxy-1-methylethyl) -2-propi- {4- [2- (trityltetrazol-5-yl) phenyl] phenyl} methylimidazol-5 -carboxylate obtained in stage (a), resulting in the obtained target compound with a yield of 71%
The NMR spectrum of this compound is identical to the spectrum of the compound obtained as described in example 61b.

 Example 80. Pivaloyloxymethyl 2-ethyl-4- (1-hydroxy-1-methylethyl) -1- {4- [2- (tetrazole-5-phenyl] phenyl} methylimidazole-5-carboxylate (compound 2-69).

 80a) Pivaloyloxymethyl 2-ethyl-4- (1-hydroxy-1-methylethyl) -1- {4- [2- (trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate.

 The procedure described in Example 78a was repeated, but using 2.25 g of ethyl 2-ethyl-4- (1-hydroxy-1-methylethyl) -1- {4- [2- (trityltetrazol-5-yl) phenyl] phenyl } methylimidazole-5-carboxylate obtained as described in example 68a, as well as 203 mg of lithium hydroxide monohydrate for hydrolysis and 0.90 g of pivaloyloxymethyl chloride for esterification, resulting in 2.53 g of the target compound as a glassy product, purified using silica gel column chromatography using ethyl acetate and hexane (1: 1, v / v) as eluent lifting).

NMR (CDCl ₃ ) delta, ppm: 1.14 (4H, s), 1.19 (3H, t, J 7.5 Hz), 1.64 (6H, s), 2.50 (2H, q, J 7.5 Hz), 5.34 (2H, s), 5.43 (1H, s), 5.72 (2H, s), 6.73 (2H, d, J 8 Hz), 6.92 -7.49 (20H, m), 7.90 (1H, d, J 8.5 Hz).

 80b) Pivaloyloxymethyl 2-ethyl-4- (1-hydroxy-1-methylethyl) -1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate.

 The procedure described in Example 78b was repeated, but using 2.53 g of pivaloyloxymethyl 2-ethyl-4- (1-hydroxy-1-methylethyl) -1- {4- [2- (trityltetrazol-5-yl) phenyl] phenyl } methylimidazole-5-carboxylate obtained in stage (a), and 28 ml of 75% vol./about. aqueous acetic acid, whereby 1.70 g of the target compound are obtained in the form of a glassy product.

NMR (CDCl ₃ ) delta, ppm: 1.09 (9H, s), 1.24 (3H, t, J 7.5 Hz), 1.59 (6H, s), 2.64 (2H, q, 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), 7.42-7.62 (4H, m).

 Example 81. (5-Methyl-2oxo-1,3-dioxolen-4-yl) methyl 2-ethyl-4- (1-hydroxy-1-methylethyl) -1- {4- [2- (tetrazole -5- il) phenyl] phenyl} methylimidazole-5-carboxylate (compound 2-73).

 81a) (5-Methyl-2-oxo-1,3-dioxolen-4-yl) methyl 2-ethyl-4- (1-hydroxy-1-methylethyl) -1- {4- [2- (trityltetrazole -5 -yl) phenyl] phenyl} methylimidazole-5-carboxylate.

The procedure described in Example 78a was repeated, but using 2.25 g of ethyl 2-ethyl-4- (1-hydroxy-1-methylethyl) -2- {4- [2- (trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate obtained as described in Example 68a, as well as 203 mg of lithium hydroxide monohydrate for hydrolysis and 0.95 g of 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene (74% pure ) for esterification, as a result of which 1.23 g of the target compound were obtained in the form of crystals, mp. 145 ^o C.

NMR (CDCl ₃ ) delta, ppm: 1.21 (3H, t, J 7.5 Hz), 1.63 (6H, s), 1.98 (3H, s), 2.55 (2H, q. J 7.5 Hz), 4.783 (2H, s), 5.30 (2H, s), 5.59 (1H, s), 6.69 (2H, d, J 8 Hz), 6.90-7 53 (20H, m); 7.87 (1H, d, J = 8 Hz).

 81b) (5-Methyl-2-oxo-1,3-dioxolen-4-yl) methyl 2-ethyl-4- (1-hydroxy-1-methylethyl) -1- {4- [2- (tetrazole -5 -yl) phenyl] phenyl} methylimidazole-5-carboxylate.

 The procedure described in Example 78b was repeated, but using 1.90 g (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl 2-ethyl-4- (1-hydroxy-1-methylethyl) -1- {4- [2- (trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate obtained as described in step (a) and 20 ml of 75% v / v. aqueous acetic acid, whereby 1.23 g of the target compound are obtained in the form of a crystalline powder.

NMR (DMSO-d ₆ ) delta, ppm: 1.24 (3H, t, J 7.5 Hz), 1.54 (6H, s), 2.10 (3H, s), 2.69 (2H, quin. J 7.5 Hz), 4.99 (2H, s), 5.44 (2H, s), 6.86 (2H, d, J 8.5 Hz), 7.08 (2H, d, J 8.5 Hz), 7.50-7.65 (3H, m),
Preparation 1. 2-Butylimidazole-4,5-dicarbonitrile.

A suspension of 51.4 g of diaminomaleonitrile and 85.6 g of trimethylorthovalerate in 300 ml of acetonitrile in an oil bath maintained at 85 ^° C was stirred for 6 hours. After this, the reaction mixture was concentrated by evaporation under reduced pressure and the concentrate was purified by silica gel column chromatography, eluting with a mixture of ethyl acetate and hexane (1: 1, v / v), whereby 99 g of 1-amino-2-N- (1-methoxypentylidene) amino-succitrile were obtained. This compound was completely dissolved in 300 ml of xylene and the resulting solution was stirred in an oil bath maintained at 150 ^° C for 8 hours, after which the reaction mixture was concentrated to obtain half of the initial volume and left at room temperature. Precipitated crystals were collected by filtration and washed with a small amount of xylene, as a result of which 55.2 g of the target compound were obtained, mp 109-111 ^o C.

 Getting 2. 2-Butylimidazole-4,5-dicarboxylic acid.

A solution of 100 g of 2-butylimidazole-4,5-dicarbonitrile, obtained as described in Preparation 1, in 1 liter of 6 N. 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, as a result of which 84 g of the target compound were obtained, so pl. 261-263 ^o C.

 Getting 3. Diethyl 2-butylimidazole-4,5-dicarboxylate.

Dry hydrogen chloride was bubbled through a suspension of 40 g of 2-butylimidazole-4,5-dicarboxylic acid, obtained as described in Preparation 2, in 600 ml of ethanol at room temperature, while stirring for 2 hours, and a solution was obtained. This solution was left at room temperature for 18 hours, after which the reaction mixture was concentrated by evaporation under reduced pressure. The concentrate was mixed with ethyl acetate and aqueous sodium bicarbonate and neutralized by adding sodium bicarbonate in powder form. The ethyl acetate layer was separated and dried with anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The obtained crystalline residue was triturated with a mixture of diisopropyl ether and hexane and collected by filtration, whereby 43 g of the target compound were obtained, mp. 82-84 ^o C.

 Getting 4. Dimethyl 2-butylimidazole-4,5-dicarboxylate.

The procedure described in Preparation 3 was repeated using 40 g of 2-butylimidazole-4,5-dicarboxylic acid, and methanol was used instead of ethanol, whereby 41.6 g of the target compound were obtained in the form of crystals, mp 88 ^o C.

 Preparation 5. 4-Acetyl-2-butyl-5-cyanoimidazole.

 5 (i). 2-Butyl-1-tritylimidazole-4,5-dicarbonitrile.

1.25 g of sodium hydride (in the form of 55 wt./wt. Dispersion in mineral oil) was added, while cooling with ice, to a solution of 5 g of 2-butylimidazole-4,5-dicarbonitrile obtained in accordance with the description in obtaining 1, in 50 ml of N, N-dimethylformamide, and the resulting mixture was stirred for 15 minutes. Then, 10 g of trityl chloride was added and the reaction mixture was stirred for 6 hours at 50 ^° C. After that, the mixture was mixed with ethyl acetate and water and the resulting product was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluting with a mixture of ethyl acetate and hexane (1: 5, v / v), whereby 9.83 g of the target compound were obtained in the form of a syrup, which was left to solidify. The solid product has a mp of 144-147 ^o C (decomposed. And stained. At 94-98 ^o C).

NMR (CDCl ₃ ) delta, ppm: 0.60 (3H, t, J 7 Hz), 0.5-1.4 (4H, m), 2.03 (2H, t, J 7 Hz), 7, 0-7.6 (15H, m).

 5 (ii). 4-Acetyl-2-butyl-cyano-1-tritylimidazole.

11.1 ml of a 2 M solution of methylmagnesium iodide in diethyl ether was slowly added dropwise 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, in 45 ml of tetrahydrofuran and the resulting mixture was stirred for 3 hours at room temperature. After this time, a saturated aqueous solution of ammonium chloride was added dropwise to the mixture, cooling with ice. The tetrahydrofuran layer was separated, washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. The aqueous layer was again extracted with 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 extract obtained was combined with the concentrate obtained above, and this product was purified by silica gel column chromatography, eluting with a mixture of hexane and ethyl acetate (3: 1, by volume). The resulting product was crystallized from a mixture of ethyl acetate and hexane, as a result of which 1.46 g of the target compound were obtained, so pl. 159-160 ^o C (decomp.).

NMR (CDCl ₃ ) delta, ppm: 0.60 (3H, t, J 7 Hz), 0.5-1.5 (4H, m), 2.08 (2H, t, J 7 Hz), 2, 58 (3H, s), 7.1-7.6 (15H, m).

 5δ. 4-Acetyl-2-butyl-5-cyanoimidazole.

A suspension of 1.78 g of 4-acetyl-2-butyl-5-cyano-1-tritylimidazole, obtained as described in step (ii) in 80% v / v. aqueous acetic acid was stirred for 1 hour at 60 ^° C. The solution thus obtained was concentrated to dryness by evaporation under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluting with a mixture of hexane and ethyl acetate (3: 1, v / v), whereby 0.66 g of the target compound was obtained as a colorless solid, mp 77-78 ^o C.

ppm: 0,93 (3Н, т, J 7 Гц), 1,0-2!6 (4Н, м), 2,72 (3Н, с), 2,89 (2Н, т, J 7 Гц).NMR (CDCl ₃ )

ppm: 0.93 (3H, t, J 7 Hz), 1.0-2! 6 (4H, m), 2.72 (3H, s), 2.89 (2H, t, J 7 Hz).

 Preparation 6. 4-Benzoyl-2-butyl-5-cyanoimidazole.

 6 (i). 4-benzoyl-2-butyl-5-cyano-1-tritylimidazole.

 According to the procedure described in Preparation 5 (ii), 10.3 g of the target compound was obtained as an amorphous solid by reaction of a solution of 10 g of 2-butyl-1-trityl-imidazole-4,5-dinitrile, prepared as described in obtaining 5δ in 100 ml of tetrahydrofuran with 25 ml of a 2 M solution of phenylmagnesium iodide in diethyl ether.

ppm: 0,67 93Н, т, J 7 Гц), 0,5-1,5 (4Н, м), 2,11 (2Н, т, J 7 Гц), 7,1-8,0 (20Н, м).NMR (CDCl ₃ )

ppm: 0.67 93H, t, J 7 Hz), 0.5-1.5 (4H, m), 2.11 (2H, t, J 7 Hz), 7.1-8.0 (20H, m).

). 4-Бензоил-2-бутил-5-цианоимидазол.6 (

) 4-benzoyl-2-butyl-5-cyanoimidazole.

A suspension of 10.3 g of 4-benzoyl-2-butyl-5-cyano-1-tritylimidazole obtained in step δ in 80% v / v aqueous acetic acid was stirred for 5 hours at 60 ^° C. At the end of this time, the solution thus obtained was concentrated by evaporation under reduced pressure, and the concentrate was purified by column chromatography on silica gel, eluting with a mixture of hexane and ethyl acetate (2: 1, by volume). The resulting 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 4.46 g of the target compound, so pl. 121-122 ^o C.

ppm: 0,90 (3Н, т, J 7 Гц), 1,0-2,3 (4Н, м), 2,85 (2Н, т, J 7 Гц), 7,2-8,0 (5Н, м), 11,0-12,1 (1Н, шир. с).NMR (CDCl ₃ )

ppm: 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) 11.0-12.1 (1H, broad s).

 Preparation 7. 2-Butyl-5-cyano-4- (1-hydroxy-1-methylethyl) imidazole.

 7 (i). 2-Butyl-5-cyano-4- (1-hydroxy-1-methylethyl) -1-tritylimidazole.

1 ml of a 2 M solution of methylmagnesium iodide in tetrahydrofuran, stirring at room temperature, was added dropwise to a solution of 840 g of 4-acetyl-2-butyl-5-cyano-1-tritylimidazole, obtained as described in the preparation of 5δ, in 15 ml tetrahydrofuran and the resulting mixture were stirred for 1 h at 40 ^° C. The resulting mixture was cooled, and then a saturated aqueous solution of ammonium chloride was added dropwise to this mixture. The tetrahydrofuran layer was separated and concentrated by evaporation under reduced pressure. The concentrate was purified by silica gel column chromatography, eluting with a mixture of hexane and ethyl acetate (2: 1, v / v), whereby 539 mg of the target compound was obtained as a colorless solid, mp 151-152 ^o C.

NMR (CDCl ₃ ) d ppm: 0.60 (3H, t, J 7 Hz), 0.6-1.5 (4H, m), 1.59 (6H, s), 2.01 (2H, t , 7 Hz), 3.78 (1H, s), 7.0-7.6 (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% vol./about. aqueous acetic acid was stirred for 3 hours at 50 ^° C., after which the solvent was removed by distillation under reduced pressure. The resulting residue was washed with carbon tetrachloride and purified by silica gel column chromatography, eluting with a mixture of methylene chloride and methanol (10: 1, v / v), after which the product was crystallized in carbon tetrachloride to give 0.6 g of the target compound as colorless crystals, i.e. pl. 171-172 ^o C.

NMR (CDCl ₃ + CD ₃ OD) d ppm: 0.90 (3H, t. J 7 Hz), 1.0-2.0 (4H, m), 1.62 (6H, s), 2.68 (2H, t, J = 7 Hz).

 Preparation 8. Ethyl 2-butyl-4- (1-hydroxy-2-methylethyl) imidazole-5-carboxylate.

A solution of 5.36 g of diethyl 2-butylimidazole-4,5-dicarboxylate, prepared as described in Preparation 3) in 100 ml of tetrahydrofuran, was cooled to -30 ^° C under nitrogen atmosphere and to this cooled solution at -30 - (-20) ^o C and dropwise were added 32 and ml of a solution of methyl magnesium bromide (2.5 M in tetrahydrofuran). Then the reaction mixture was stirred at 0 ^° C. for 1.5 hours and then mixed with ethyl acetate and an aqueous solution of ammonium chloride. The ethyl acetate layer was separated and dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a mixture of methanol and methylene chloride (1:20, v / v), whereby 5.01 g of the target compound was obtained as an oily product.

NMR (CDCl ₃ ) d ppm: 0.90 (3H, t, J 7 Hz), 1.32 (3H, t, J 7 Hz), 1.2-2.0 (4H, m), 1.64 (6H, s), 2.70 (2H, t, J 7 Hz), 4.33 (2H, q, J 7 Hz), 5.97 (1H, br s), 10.2 (1 H, br . from).

 Preparation 9. Ethyl 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate.

In accordance with the procedure described in preparation 8, 2.34 g of the target compound was obtained as an oily product by the reaction of 3.01 g of diethyl 2-propylimidazole-4,5-dicarboxylate obtained as described in preparation 12, with 16 ml 2, 5 M solution of methylmagnesium bromide in tetrahydrofuran. The resulting compound was crystallized, leaving it at room temperature, and the product was obtained, so pl. 69-71 ^o C. After recrystallization of this product from diisopropyl ether received the product, so pl. 101-102 ^o C.

NMR (CDCl ₃ ) d ppm: 0.96 (3H, t, J 7 Hz), 1.35 (3H, t, J 7 Hz), 1.64 (6H, s), 1.81 (2H, sextet , J 7 Hz), 2.68 (2H, t, J 7 Hz), 4.35 (2H, q. J 7 Hz), 5.81 (1H, s), 9.9 (1H, br s )

 Getting 10. 5-Propylimidazole-4,5-dicarbonitrile.

The procedure described in Preparation 1 was repeated, but using 16.0 g of diaminomaleonitrile and 24 g of trimethylorthobutyrate, whereby 18.7 g of the target compound were obtained in the form of crystals, mp 141-144 ^o C.

 Getting 11. 2-Propylimidazole-4,5-dicarboxylic acid.

The procedure described in Preparation 2 was repeated, but using 18.2 g of 2-propylimidazole-4,5-dicarbonitrile, prepared as described in Preparation 10, to give 9.95 g of the target compound as crystals, i.e. pl. 261-263 ^o C.

 Getting 12. Diethyl 2-propylimidazole-4,5-dicarboxylate.

The procedure described in Preparation 3 was repeated, but using 10.0 g of 2-propylimidazole-4,5-dicarboxylic acid, obtained as described in Preparation 11, to give 9.55 g of the target compound as crystals, t pl. 81-83 ^o C.

 Preparation 13. Ethyl 2-butyl-4- (1-ethyl-1-hydroxypropyl) imidazole-5-carboxylate.

In accordance with the procedure described in obtaining 8, received 2.68 g of the target compound with so pl. 63-64 ^° C in the form of crystals, by reaction of 2.68 g of diethyl 2-butylimidazole-4,5-dicarboxylate, prepared as described in Preparation 3, with a 3.0 M solution of ethyl magnesium bromide in diethyl ether.

NMR (CDCl ₃ ) d ppm: 0.82 (6H, t, J 7 Hz), 0.93 (3H, t, J 7 Hz), 1.38 (3H, t, J 7 Hz), 1.31 -1.45 (2H, m), 1.65-1.76 (2H, m), 1.79-1.89 (2H, m), 1.97-2.11 (2H, m), 2 76 (2H, t, J 7.5 Hz), 4.36 (2H, q. J 7 Hz), 5.70 (1H, br s),
Preparation 14. 2-Propyl-1-tritylimidazole-4,5-dicarbonitrile.

The procedure described in Preparation 5 (i) was repeated, but using 7.8 g of 2-propylimidazole-4,5-dicarbonitrile prepared as described in Preparation 10), 2.14 g of sodium hydride (as 55% w / w) wt. dispersion in mineral oil) and 17.1 g of trityl chloride, whereby 14.6 g of the target compound are obtained in the form of crystals, mp. 107 ^o C (decomposed and stained yellow at 103 ^o C).

NMR (CDCl ₃ ) d ppm: 0.52 (3H, t, J 7 Hz), 1.07-1.21 (2H, m), 2.03 (2H, t, J 8 Hz), 7.19 -7.48 (15H, m).

 Preparation 15. 2-Butyl-5-cyano-3-propionyl-1-tritylimidazole.

14 ml of a 3 M solution of ethyl magnesium bromide in diethyl ether at 10 ^° C. and under nitrogen atmosphere were added dropwise to a solution of 8.33 g of 2-butyl-1-tritylimidazole-4,5-dicarbonitrile, prepared as described in preparation 5 (i) in 83 ml of tetrahydrofuran and the resulting mixture was stirred for 3 hours at room temperature. Thereafter, a mixture of a saturated aqueous solution of ammonium chloride and ethyl acetate was added to the reaction mixture, while cooling with ice. The ethyl acetate layer was separated, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The crystalline product thus obtained was washed with diisopropyl ether and 4.56 g of the target compound was obtained, so pl. 140-143 ^o C (with softening at 83 ^o C).

NMR (CDCl ₃ ) d ppm: 0.61 (3H, t. J 7 Hz), 0.84-1.14 (4H, m), 1.18 (3H, t. J 8 Hz), 2.08 (2H, t, J 7 Hz), 3.03 (2H, q, J 7 Hz), 7.22-7.42 (15H, m).

 Preparation 16. 5-Cyano-4-propionyl-2-propyl-1-tritylimidazole.

The procedure described in Preparation 15 was repeated, but using 8.05 g of 2-propyl-1-tritylimidazole-4,5-dicarbonitrile obtained as described in Preparation 14 and 14 ml of a 3 M solution of ethyl magnesium bromide in diethyl ether, resulting which received 7.03 g of the target compound in the form of crystals, so pl. 96 ^o C (soft. At 87 ^o C).

NMR (CDCl ₃ ) d ppm: 0.52 (2H, t, J 7 Hz), 1.05-1.3 (2H, m), 1.18 (3H, t, J 7 Hz), 2.05 (2H, t, J 7 Hz), 3.03 (2H, q, J 7 Hz), 7.20-7.49 (15H, m).

 Preparation 17. 2-Butyl-5-cyano-4- (1-hydroxy-1-methylpropyl) -1-tritylimidazole.

5 ml of a 1 M solution of methylmagnesium bromide in tetrahydrofuran at 10 ^° C and under nitrogen atmosphere were added dropwise to a solution of 2 g of 2-butyl-5-cyano-3-propionyl-1-trityl imidazole, obtained as described in preparation 15, in 36 ml tetrahydrofuran and the resulting mixture were stirred for 1 hour at 20 ^° C. and another 1 hour at 30 ^° C. At the end of this time, a mixture of a saturated aqueous solution of ammonium chloride and ethyl acetate was added to the reaction mixture and the resulting mixture was well shaken. The ethyl acetate layer was separated and dried with anhydrous magnesium sulfate. After that, the drying agent was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a 1: 2 by volume mixture of ethyl acetate and hexane, and 1.29 g of the target compound were obtained in the form of crystals, mp. 90-93 ^o C.

NMR (CDCl ₃ ) d ppm: 0.60 (3H, t, J 7 Hz), 0.80 (3H, t, J 7 Hz), 0.80-1.00 (2H, m), 1.00 -1.13 (2H, m), 1.58 (3H, s), 1.75-2.05 (4H, m), 3.98 (1H, br s), 7.23-7.43 (15H, m).

 Preparation 18. 5-Cyano-4- (1-hydroxy-1-methylpropyl) -2-propyl-1-tritylimidazole.

The procedure described in Preparation 17 was repeated, but using 5.00 g of 5-cyano-4-propionyl-2-propyl-1-tritylimidazole, prepared as described in Preparation 16, and 12.5 ml of a 1 M solution of methylmagnesium bromide in tetrahydrofuran, resulting in 3.32 g of the target compound was obtained in the form of a crystalline powder, so pl. above 120 ^o C (softening at 110 ^o C).

NMR (CDCl ₃ ) d ppm: 0.50 (3H, t, J 7 Hz), 0.80 (3H, t, J 7 Hz), 1.07-1.12 (2H, m), 1.58 (3H, s), 1.74-2.00 (4H, m), 3.90 (1H, br s), 7.24-7.37 (15H, m).

 Preparation 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 Preparation 17, and 20 ml of 75 vol / vol. aqueous acetic acid was stirred for 1 h at 50 ^o C, after which the mixture was cooled, and the precipitated crystals of trityl alcohol were removed by filtration. The filtrate was concentrated by evaporation under reduced pressure, the remaining water and acetic acid were distilled off as toluene azeotrope under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a mixture of methylene chloride and methanol (5: 1, v / v), and 0.47 g of the target compound was obtained in the form of a crystalline powder, mp 139-142 ^o C.

NMR (DMSO-d ₆ ) d ppm: 0.74 (3H, t, J 7 Hz), 0.87 (3H, t, J 7 Hz), 1.21-1.34 (2H, m), 1 49 (3H, s), 1.53-1.64 (2H, m), 1.72 (2H, q, J 7.5 Hz), 2.56 (2H, t, J 7 Hz), 5 45 (1H, s).

 Preparation 20. 5-Cyano-4- (1-hydroxy-1-methylpropyl) -2-propylimidazole.

The procedure described in Preparation 19 was repeated, but using 1.20 g of 5-cyano-4- (1-hydroxy-1-methylpropyl) -2-propyl-1-tritylimidazole, prepared as described in Preparation 18, whereby 0.48 g of the target compound in the form of a crystalline powder, so pl. 157-159 ^o C.

NMR (CDCl ₃ ) d ppm: 0.89 (3H, t, J 7.5 Hz), 0.98 (3H, t, J 7.5 Hz), 1.57 (3H, s), 1.76 (2H, q, J, 7.5 Hz), 1.83-2.08 (2H, m), 2.00 (1H, s), 2.67 (2H, t, J, 7.5 Hz).

 Getting 21. Methyl 2-butyl-4- (1-hydroxy-1-methylethyl) imidazole-5-carboxylate.

A solution of 9.73 g of dimethyl 2-butylimidazole-4,5-dicarboxylate, prepared as described in Preparation 4, in 100 ml of tetrahydrofuran was cooled to -30 ^° C under a nitrogen atmosphere and to this solution at a temperature of -30 ^° C - (-20 ^o C) 162 ml of a 1 M solution of methylmagnesium bromide in tetrahydrofuran were added dropwise. The resulting mixture was stirred for 2.5 hours at 0 ^° C., and then ethyl acetate and an aqueous solution of ammonium chloride were added to this mixture. The ethyl acetate layer was separated and dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluting with a mixture of methanol and methylene chloride (1:20, v / v), whereby 7.15 g of the target compound was obtained as an oily product. This product crystallized, keeping it at room temperature, after which the product was obtained, so pl. 60-65 ^o C.

ppm: 0,88 (3Н, т, J 7 Гц), 1,0-2,0 (4Н, м), 1,64 (6Н, с), 2,69 (2Н, т, J 7,5 Гц), 3,84 (3Н, с), 7,35 (2Н, шир.с).NMR (CDCl ₃ )

ppm: 0.88 (3H, t, J 7 Hz), 1.0-2.0 (4H, m), 1.64 (6H, s), 2.69 (2H, t, J 7.5 Hz ), 3.84 (3H, s), 7.35 (2H, br s).

 Preparation 22. Pivaloyloxymethyl 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate.

 22 (i). 4- (1-Hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylic acid.

A solution of 0.28 g of lithium hydroxide monohydrate in 5 ml of water was added to a solution of 0.48 g of ethyl 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate, prepared as described in Preparation 9, in 5 ml methanol and the resulting mixture was stirred for 18 hours at room temperature. After this time, the pH of the reaction mixture was adjusted to a value of 2.3 by adding 6.67 ml of 1 N. aqueous hydrochloric acid and the resulting mixture was concentrated by filtration, as a result of which 0.20 g of the target compound was obtained, so pl. 232 ^o C (decomposed).

NMR (DMSO-d ₆ ) delta, ppm: 0.87 93H, t, J 7.5 Hz), 1.48 (6. s), 1.65 (2H, sextet, J 7.5 Hz), 2 62 (2H, t, J 7.5 Hz).

 22δ. Pivaloyloxymethyl 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate.

1.76 ml of N, N-diisopropylethylamine was added to a suspension of 1.14 g of 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylic acid obtained in step (i) in 12 ml of N, N- dimethylacetamide and the resulting mixture was stirred at room temperature for 10 minutes, after which 1.36 ml of pivaloyloxymethyl chloride was added to the mixture. The reaction mixture was stirred for 4 hours at 60 ^° C. and then it was mixed with ethyl acetate and water. The ethyl acetate layer was separated and concentrated by evaporation under reduced pressure. The precipitated crystals were triturated with diisopropyl ether and collected by filtration, whereby 1.53 g of the target compound was obtained, mp. 177 ^o C.

ppm: 0,99 (3Н, т, J 7,5 Гц), 1,22 (9Н, с), 1,62 (6Н, с), 1,76 (2Н, секст. J 7,5 Гц), 2,70 (2Н, т, J 7,5 Гц), 5,15 (1Н, шир.с), 5,95 (2Н, с).NMR (CDCl ₃ )

ppm: 0.99 (3H, t, J 7.5 Hz), 1.22 (9H, s), 1.62 (6H, s), 1.76 (2H, sext. J 7.5 Hz), 2.70 (2H, t, J 7.5 Hz), 5.15 (1H, br s), 5.95 (2H, s).

 Preparation 23. Ethyl 4- (1-hydroxyethyl) -2-propylimidazole-5-carboxylate.

 23δ. 4-acetyl-2-propylimidazole-5-carbonitrile.

194 ml of a 1 M solution of methylmagnesium bromide in tetrahydrofuran was added dropwise at a temperature of 10-15 ^o C and in a nitrogen atmosphere to a solution of 10 g of 2-propylimidazole-4,5-dicarbonitrile, obtained as described in preparation 10, in 100 ml of tetrahydrofuran and obtained the mixture was stirred for 30 minutes at a temperature of 10-15 ^° C. Then the reaction mixture was cooled and 200 ml of ethyl acetate and 100 ml of a saturated aqueous solution of ammonium chloride were added. This mixture was acidified by adding an aqueous solution of potassium bisulfate. The organic layer was separated and dried with anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was subjected to silica gel column chromatography, eluting with a mixture of ethyl acetate and hexane (1: 1, v / v), whereby 9.18 g of the target compound were obtained in the form of crystals, mp 93-95 ^o C.

NMR (CDCl ₃ ) d ppm: 0.99 (3H, t, J 7.5 Hz), 1.83 (2H, sex. J 7.5 Hz), 2.71 (3H, s), 2.82 (2H, t, J = 8 Hz).

 23ii. Ethyl 4-acetyl-2-propylimidazole-4-carboxylate.

A mixture of 4.0 g of 4-acetyl-2-propylimidazole-5-carbonitrile obtained in stage (i) and 60 ml of 6 N. 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 manner. The residue was dissolved in ethanol, and the solvent was again distilled off. This sequence of dilutions and concentrations was carried out a total of five times, and then the residue was dissolved in 60 ml of ethanol. A stream of hydrogen chloride was bubbled through the resulting solution at room temperature for 20 minutes, after which this solution was left for 16 hours at room temperature. After this time, the solution was concentrated by evaporation under reduced pressure. The concentrate was dissolved in a mixture of ethyl acetate and aqueous sodium bicarbonate, and the resulting solution was neutralized by adding sodium bicarbonate. The 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 silica gel column chromatography, eluting with a mixture of ethyl acetate and hexane (1: 1, v / v), whereby 3.07 g of the target compound was obtained in the form of crystals at 76 78 ^° C .

ppm: 0,96 (3Н, т, J 7,5 Гц), 1,39 (3Н, т, J 7,0 Гц), 1,82 (2Н, секстет, J 7,5 Гц), 2,75 (3Н, с), 2,80 (2Н, т, J 7,5 Гц), 4,44 (2Н, кв. J 7 Гц).NMR (CDCl ₃ )

ppm: 0.96 (3H, t, J 7.5 Hz), 1.39 (3H, t, J 7.0 Hz), 1.82 (2H, sextet, J 7.5 Hz), 2.75 (3H, s), 2.80 (2H, t, J 7.5 Hz), 4.44 (2H, q, J 7 Hz).

 23δ. Ethyl 4- (1-hydroxyethyl) -2-propylimidazole-5-carboxylate.

125 ml of sodium borohydride was added to a solution of 1.50 g of ethyl 4-acetyl-2-propylimidazole-5-carboxylate obtained in step (ii) in 15 ml of ethanol, and the resulting mixture was stirred for 30 minutes at room temperature. Then 2 L of acetone was added and the mixture was 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 silica gel column chromatography, eluting with mixtures of methylene chloride and methanol (1:20 and 1: 10, by volume), whereby 1.32 of the target compound was obtained in the form of crystals, t. pl. 151-153 ^o C.

NMR (CDCl ₃ + DMSO d ₆ ) d ppm: 0.95 (3H, t, 7.5 Hz), 1.38 (3H, t, J 7 Hz), 1.48 (3H, d, J 6, 5 Hz), 1.74 (2H, sextet, J 7.5 Hz), 2.67 (2H, t, J 8 Hz), 4.34 (2H, q. J 7 Hz), 5.28 (1H sq. J 6.5 Hz).

 Getting 24. Ethyl 2-butyl-4- (1-hydroxyethyl) imidazole-5-carboxylate.

 24 (i). 4-Acetyl-2-butylimidazole-5-carbonitrile.

The procedure described in Preparation 23 (i) was repeated, but using 10 g of 2-butylimidazole-4,5-dicarbonitrile, prepared as described in Preparation 1, to give 9.15 g of the target compound as crystals, mp . 77-78 ^o C.

ppm: 0,93 (3Н, т, J 7 Гц), 1,0-2,1 (4Н, м), 2,72 (3Н, с), 2,89 (2Н, т, J 7 Гц).NMR (CDCl ₃ )

ppm: 0.93 (3H, t, J 7 Hz), 1.0-2.1 (4H, m), 2.72 (3H, s), 2.89 (2H, t, J 7 Hz).

. Этил 4-ацетил-2-бутилимидазол-5-карбоксилат.24

. Ethyl 4-acetyl-2-butylimidazole-5-carboxylate.

 The procedure described in Preparation 23 (ii) was repeated, but using 1.00 g of 4-acetyl-2-butylimidazole-5-carbonitrile obtained in Step δ, to give 0.92 g of the target compound as a viscous oil.

ppm: 0,88 (3Н, т, J 7 Гц), 1,1-2,1 (4Н, м), 1,33 (3Н, т, J 7 Гц), 2,74 (3Н, с), 2,82 (2Н, т, J 7,5 Гц), 4,38 (2Н, кв. J 7 Гц).NMR (CDCl ₃ )

ppm: 0.88 (3H, t, J 7 Hz), 1.1-2.1 (4H, m), 1.33 (3H, t, J 7 Hz), 2.74 (3H, s), 2.82 (2H, t, J 7.5 Hz); 4.38 (2H, q, J 7 Hz).

. Этил 2-бутил-4-(1-гидроксиэтил)имидазол-5-карбоксила.24

. Ethyl 2-butyl-4- (1-hydroxyethyl) imidazole-5-carboxyl.

, в результате чего получали 0,55 г целевого соединения в виде кристаллов, т. пл. 149^oC.The procedure described in Preparation 23ii was repeated, but using 0.64 g of ethyl 4-acetyl-2-butylimidazole-5-carboxylate, prepared as described in step

, resulting in a gain of 0.55 g of the target compound in the form of crystals, so pl. 149 ^o C.

NMR (CDCl ₃ + DMSO-d ₆ ) δ ppm: 0.91 (3H, t, 7.5 Hz), 1.37 (3H, t, J 7 Hz), 1.3-1.42 (2H, m), 1.50 (3H, d, J 6.8 Hz), 1.69 (2H, quin. J 7.5 Hz), 2.69 (2H, t, J 8 Hz), 4.34 ( 2H, q J 7 Hz), 5.26 (1 H, q J 6.5 Hz).

 Preparation 25. 2-Butyl-4-propionylimidazole-5-carbonitrile.

, но с использованием бромида этилмагния вместо бромида метилмагния, и получали в результате целевое соединение, т. пл. 84-85^oC и выходом 51,9%
ЯМР (CDCl₃) δ ppm: 0,95 (3Н, т, J 7 Гц), 1,0-2,2 (4Н, м), 1,28 (3Н, т, J 7,0 Гц), 2,88 (2Н, т, J 7 Гц), 3,15 (2Н, кв. J 7 Гц).The procedure described in Preparation 24 was repeated.

but using ethyl magnesium bromide instead of methyl magnesium bromide, and the target compound was obtained, mp 84-85 ^o C in 51.9% yield
NMR (CDCl ₃ ) δ ppm: 0.95 (3H, t, J 7 Hz), 1.0-2.2 (4H, m), 1.28 (3H, t, J 7.0 Hz), 2 88 (2H, t, J 7 Hz); 3.15 (2H, q, J 7 Hz).

 Preparation 26. 2-Butyl-4-butyrylimidazole-5-carbonitrile.

, но с использованием бромида пропилмагния вместо бромида метилмагния, в результате чего получали целевое соединение, т. пл. 91-92^oC и выходом 57,2%
ЯМР (CDCl₃) δ ppm: 1,02 (3Н, т, J 7,5 Гц), 1,11 (3Н, т, J 7,5 Гц), 1,3-1,6 (2Н, м), 1,7-2,0 (4Н, м), 2,88 (2Н, т, J 8 Гц), 3,13 (2Н, т, J 7,5 Гц).The procedure described in Preparation 24 was repeated.

but using propylmagnesium bromide instead of methylmagnesium bromide, whereby the target compound is obtained, mp 91-92 ^o C with a yield of 57.2%
NMR (CDCl ₃ ) δ ppm: 1.02 (3H, t, J 7.5 Hz), 1.11 (3H, t, J 7.5 Hz), 1.3-1.6 (2H, m) 1.7-2.0 (4H, m), 2.88 (2H, t, J 8 Hz), 3.13 (2H, t, J 7.5 Hz).

 Preparation 27. 2-butyl-4-isobutyrylimidazole-5-carbonitrile.

, но с использованием бромида изопропилмагния вместо бромида метилмагния, в результате чего получали целевое соединение, т. пл. 88-89^oC и выходом 36,2%
ЯМР (CDCl₃) δ ppm: 0,94 (3Н, т, J 7 Гц), 1,0-2,1 (4Н, м), 1,30 (6Н, д, J 7 Гц), 2,91 (2Н, т, J 7 Гц), 3,71 (1Н, септет, J 7 Гц).The procedure described in Preparation 24 was repeated.

, but using isopropyl magnesium bromide instead of methyl magnesium bromide, as a result of which the target compound was obtained, so pl. 88-89 ^o C in a yield of 36.2%
NMR (CDCl ₃ ) δ ppm: 0.94 (3H, t, J 7 Hz), 1.0-2.1 (4H, m), 1.30 (6H, d, J 7 Hz), 2.91 (2H, t, J 7 Hz), 3.71 (1H, septet, J 7 Hz).

 Preparation 28. 4-Butyryl-2-propylimidazole-5-carbonitrile.

, но с использованием 2-пропилимидазол-4,5-дикарбонитрила, полученного согласно описанию в получении 10, и бромида пропилмагния, в результате чего получали целевое соединение, т. пл 94-95^oC и выходом 49,8%
ЯМР (CDCl₃) δ ppm: 1,00 (3Н, т, J 7,5 Гц), 1,04 (3Н, т, J 7,5 Гц), 1,7-1,9 (4Н, м), 2,79 (2Н, т, J 7,5 Гц), 3,06 (2Н, т, J 7,5 Гц).The procedure described in Preparation 24 was repeated.

but using 2-propylimidazole-4,5-dicarbonitrile, prepared as described in Preparation 10, and propyl magnesium bromide, whereby the title compound is obtained, mp 94-95 ^° C. in 49.8% yield
NMR (CDCl ₃ ) δ ppm: 1.00 (3H, t, J 7.5 Hz), 1.04 (3H, t, J 7.5 Hz), 1.7-1.9 (4H, m) 2.79 (2H, t, J 7.5 Hz); 3.06 (2H, t, J 7.5 Hz).

 Preparation 29. 2-Butyl-4- (1-hydroxy-1-methylethyl) imidazole-5-carbonitrile.

, но с использованием 4-ацетил-2-бутилимидазол-5-карбонитрила, полученного согласно описанию в получении 24 (i), и раствора бромида метилмагния в тетрагидрофуране, в результате чего получали целевое соединение, т. пл. 171-172^oC и с выходом 66,3%
ЯМР (CDCl₃ + CD₃OD) δ ppm: 0,91 (3Н, т, 7 Гц), 1,0-2,1 (4Н, м), 1,62 (6Н, с), 2,69 (2Н, т, J 7 Гц).The procedure described in Preparation 23 was repeated.

but using 4-acetyl-2-butylimidazole-5-carbonitrile obtained as described in Preparation 24 (i) and a solution of methyl magnesium bromide in tetrahydrofuran, whereby the title compound is obtained, mp 171-172 ^o C and with a yield of 66.3%
NMR (CDCl ₃ + CD ₃ OD) δ ppm: 0.91 (3H, t, 7 Hz), 1.0-2.1 (4H, m), 1.62 (6H, s), 2.69 ( 2H, t, J 7 Hz).

 Preparation 30. 2-Butyl-4- [1-hydroxy-2-methyl-1- (1-methylethyl) propyl] imidazole-5-carbonitrile.

, но с использованием 2-бутил-4-изобутирилимидазол-5-карбонитрила, полученного согласно описанию в получении 27, и раствор бромида изопропилмагния в тетрагидрофуране, в результате чего получали целевое соединение, т. пл. 63-65^oC и выходом 87%
ЯМР (CDCl₃) δ ppm: 0,7-1,0 (3Н, м), 0,87 (6Н, д, J 7 Гц), 0,91 (6Н, д, J 7 Гц), 1,0-2,1 (4Н, м), 2,0-2,9 (2Н, м), 2,71 (2Н, т, J 7 Гц).The procedure described in Preparation 23 was repeated.

but using 2-butyl-4-isobutyrylimidazole-5-carbonitrile obtained as described in Preparation 27 and a solution of isopropyl magnesium bromide in tetrahydrofuran, whereby the title compound is obtained, mp 63-65 ^o C in 87% yield
NMR (CDCl ₃ ) δ ppm: 0.7-1.0 (3H, m), 0.87 (6H, d, J 7 Hz), 0.91 (6H, d, J 7 Hz), 1.0 -2.1 (4H, m), 2.0-2.9 (2H, m), 2.71 (2H, t, J = 7 Hz).

 Preparation 31. (5-Methyl-2-oxo-1,3-dioxolen-4-yl) methyl 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate.

, в 10 мл N,N-диметилацетамида, и полученную смесь размешивали 10 мин при комнатной температуре, после чего к смеси добавляли 1,12 г (5-метил-2-оксо-1,3-диоксолен-4-ил)метилхлорида, и смесь размешивали 4 ч при 60^oC. После этого реакционную смесь смешивали с этилацетатом и водой. Этилацетатный слой отделяли и концентрировали путем выпаривания при пониженном давлении и концентрат очищали с помощью колоночной хроматографии на силикагеле, элюируя смесью метанола и метиленхлорида (1:15, по объему), в результате чего получали 1,14 г целевого соединения в виде вязкого маслянистого продукта.1.76 ml of N, N-diisopropylethylamine was added to a suspension of 1.06 g of 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylic acid, obtained as described in Preparation 22

in 10 ml of N, N-dimethylacetamide, and the resulting mixture was stirred for 10 min at room temperature, after which 1.12 g of (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl chloride was added to the mixture, and the mixture was stirred for 4 hours at 60 ^° C. After this, the reaction mixture was mixed with ethyl acetate and water. The ethyl acetate layer was separated and concentrated by evaporation under reduced pressure, and the concentrate was purified by silica gel column chromatography, eluting with a mixture of methanol and methylene chloride (1:15, v / v), whereby 1.14 g of the target compound was obtained as a viscous oily product.

NMR (CDCl ₃ ) δ, ppm: 0.94 (3H, t, J 7.5 Hz), 1.62 (6H, s), 1.6-1.8 (2H, m), 2.19 ( 3H, s), 2.67 (2H, t, J = 8 Hz), 5.03 (2H, s).

 Preparation 32. Phthalidyl 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate.

 The procedure described in Preparation 31 was repeated, but using 1.06 g of 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylic acid obtained as described in Preparation 22 and 1.15 g of 3- bromophthalide, whereby 1.63 g of the target compound are obtained in the form of an amorphous solid.

NMR (CDCl ₃ ) d ppm: 0.92 (2H, t, J 7.5 Hz), 1.64 (6H, s), 1.6-1.75 (2H, m), 2.63 (2H , t, J 7.5 Hz), 7.63-7.79 (4H, m), 7.91 (1H, d, J 8.5 Hz).

 Preparation 33. Isopropoxycarbonyloxymethyl 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate.

, но с использованием 1,06 г 4-(1-гидрокси-1-метилэтил)-2-пропилимидазол-5-карбоновой кислоты, полученной в соответствии с описанием в получении 22

, и 0,83 г изопропоксикарбонилоксиметилхлорида, в результате чего получали 1,22 г целевого соединения, т. пл. 144-146^oC.The procedure described in Preparation 22 was repeated.

but using 1.06 g of 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylic acid, obtained as described in Preparation 22

, and 0.83 g of isopropoxycarbonyloxymethyl chloride, whereby 1.22 g of the target compound are obtained, so pl. 144-146 ^o C.

NMR (CDCl ₃ ) δ ppm: 0.98 (3H, t, J 7.5 Hz), 1.32 (6H, d, J 6.5 Hz), 1.62 (6H, s), 1.76 (2H, sextet, J 7.5 Hz), 2.69 (2H, t, J 7.5 Hz), 4.93 (1. quin. J 6.5 Hz), 5.95 (2H, s) .

 Preparation 34. 2-Ethylimidazole-4,5-dicarbonitrile.

The procedure described in Preparation 1 was repeated, but using 53.3 g of diaminolaleonitrile and 91.3 g of triethyl orthopropionate, resulting in 59.5 g of the target compound in the form of crystals, mp 179-181 ^o C.

 Getting 35. 2-Ethylimidazole-4,5-dicarboxylic acid.

The procedure described in Preparation 2 was repeated, but using 45.0 g of 2-ethylimidazole-4,5-dicarbonitrile prepared as described in Preparation 34, whereby 31.2 g of the target compound were obtained in the form of crystals, mp . 265-268 ^o C.

 Getting 36. Diethyl 2-ethylimidazole-4,5-dicarboxylate.

The procedure described in Preparation 3 was repeated, but using 35.0 g of 2-ethylimidazole-4,5-dicarboxylic acid obtained in accordance with Preparation 35, whereby 38.7 g of the target compound were obtained in the form of crystals, mp . 83-84 ^o C.

 Getting 37. Ethyl 2-ethyl-4- (1-hydroxy-1-methylethyl) imidazole-5-carboxylate.

The procedure described in Preparation 8 was repeated, but using 3.60 g of diethyl 2-ethylimidazole-4,5-dicarboxylate, prepared as described in Preparation 36, 60 ml of a 1 M solution of methyl magnesium bromide in tetrahydrofuran, whereby 2 , 05 g of the target compound in the form of crystals, so pl. 181-184 ^o C.

NMR (DMSO-d ₆ ) d ppm: 1.22 (3H, t, J 7 Hz), 1.33 (3H, t, J 7.5 Hz), 1.50 (6. s), 2.65 (2H, q, J 7.5 Hz), 3.30 (1 H, br s), 4.31 (2 H, q, 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 of oxalyl chloride was added dropwise while cooling with ice to a solution of 6.91 g of 4'-methylbiphenyl-2-carboxylic acid in 70 ml of methylene chloride, and the resulting mixture was stirred for 2 hours at room temperature. The mixture was then concentrated by evaporation under reduced pressure, and the residue was dissolved in 70 ml of tetrahydrofuran. After this, a solution of 7.5 ml of t-butylamine 4 50 ml of tetrahydrofuran was added dropwise to the solution, cooling with ice, and the resulting mixture was stirred for 10 min at room temperature. After this time, the reaction mixture was diluted with water and ethyl acetate. The ethyl acetate layer was separated, washed with an aqueous solution of sodium bicarbonate, and then with an aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and concentrated by evaporation under reduced pressure, whereby 7.48 g of the target compound were obtained in the form of crystals, mp 105-106 ^o C (after recrystallization from ethyl acetate and hexane).

NMR (CDCl ₃ ) d, ppm: 1.12 (9H, s), 2.41 (3H, s), 5.04 (1H, br s), 7.2-7.5 (7H, m) 7.71 (1H, d, J = 8 Hz).

. N-т-Бутил-4'-бромометилбифенил-2-карбоксамид.38

. N-t-Butyl-4'-bromomethylbiphenyl-2-carboxamide.

4.39 g of N-bromosuccinimide and 50 mg of benzoyl peroxide were added to a solution of 6600 g of N-t-butyl-4'-methylbiphenyl-2-carboxamide, prepared as described in Preparation 38i, in 90 ml of carbon tetrachloride, and the resulting mixture was heated under reflux for 4 hours. After this, 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 silica gel column chromatography, eluting with a mixture of ethyl acetate and hexane (1: 4, v / v), whereby 7.04 g of the target compound were obtained in the form of crystals, mp 124-126 ^o C.

NMR (CDCl ₃ ) δ ppm: 1.14 (9H, s), 4.55 (2H, s), 4.99 (1H, br s), 7.30-7.32 (8H, m).

 Preparation 39. 4-Isobutyl-2-propylimidazole-5-carbonitrile.

The procedure described in Preparation 23 (i) was repeated, but using 8.24 g of 2-propylimidazole-4,5-dicarbonitrile obtained as described in Preparation 10 and 103 ml of a 2 M solution of isopropyl magnesium iodide in diethyl ether, resulting in received 45.0 g of the target compound in the form of crystals, so pl. 90.5-91 ^o C.

NMR (CDCl ₃ ) d ppm: 1.01 (3H, t, J 7.5 Hz), 1.29 (6H, d, J 6.5 Hz), 1.82 (2H, sext. J 7.5 Hz), 2.81 (2H, t, J 7.5 Hz), 3.66 (1H, septet, J 6.5 Hz).

 Preparation 40. 2-Butyl-4-pivaloylimidazole-5-carbonitrile.

A solution of 10.4 g of 2-butylimidazole-4,5-dicarbonitrile, prepared as described in Preparation 1, in 150 ml of methylene chloride was added dropwise, at 10-15 ^° C. and under nitrogen, to 100 ml of a 2 M solution of t- butyl magnesium in diethyl ether and the resulting mixture was stirred for 1 h at the same temperature. Then, 200 ml of ethyl acetate and 100 ml of an aqueous solution of potassium bisulfate were added dropwise to the reaction mixture, and the resulting mixture was stirred for 20 minutes at room temperature. After this time, insoluble material was removed by filtration, and the organic layer was separated, dried with anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a mixture of ethyl acetate and hexane (1.3, v / v), whereby 7.95 g of the target compound were obtained in the form of crystals, mp 135-137 ^o C.

NMR (CDCl ₃ ) d ppm: 0.95 (3H, t, J 7.5 Hz), 1.42 (2H, septet, J 7.5 Hz), 1.46 (9H, s), 1.75 (2H, quin. J 7.5 Hz), 2.79 (2H, t, J 7.5 Hz).

 Preparation 41. 2-Propyl-2-pivaloylimidazool-5-carbonitrile.

The procedure described in Preparation 40 was repeated, but using 3.2 g of 2-propylimidazole-4,5-dicarbonitrile prepared as described in Preparation 10 and 33 ml of a 2 M solution of t-butyl magnesium chloride in diethyl ether, whereby 2.35 g of the target compound in the form of crystals, so pl. 176-178 ^o C.

NMR (CDCl ₃ ) d ppm: 0.93 (3H, t, J 7.5 Hz), 1.36 (9H, s), 1.75 (2H, sextet, J 7.5 Hz), 2.68 (2H, t, J 7.5 Hz).

Claims (31)

1. Derivatives of 1-biphenylmethylimidazole of the general formula I

where R ^{1 is an} alkyl group having 1 to 6 carbon atoms;
R ² and R ³ , the same or different, each alkyl group having 1 6 carbon atoms, or an aryl group having 6 10 carbon atoms;
R ^{4 is} hydrogen or an alkyl group having 1 to 6 carbon atoms;
R ^{5 is a} carboxy group or a group of the general formula COOR ^5a or —CONR ⁸ R ⁹ where R ⁸ and R ⁹ are the same or different, each hydrogen, an unsubstituted alkyl group having 1 6 carbon atoms, a substituted alkyl group having 1 6 carbon atoms and a substituted carboxy group or an alkoxycarbonyl group in which the alkyl part has 1 6 carbon atoms, or R ⁸ and R ⁹ together represent a substituted alkylene group which has 2 6 carbon atoms and is a substituted alkoxycarbonyl group in which the alkyl part has 1 6 carbon atoms ; R ^{5a is an} alkyl group having 1 to 6 carbon atoms, an alkanoyloxyalkyl group in which each of the alkanoyl and alkyl parts has 1 to 6 carbon atoms; an alkoxycarbonyloxyalkyl group in which each of the alkoxy and alkyl moieties has 1 to 6 carbon atoms, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl group or phthalidyl group;
R ^{6 is} hydrogen;
R ⁷ carboxy group or tetrazol-5-yl group
their pharmaceutically acceptable salts or esters. 2. The compound according to claim 1, characterized in that it is an ester in which R ^{5 is an} alkyl group having 1 4 carbon atoms; an alkanoyloxyalkyl group in which each alkanoyl part has 1 to 5 carbon atoms and an alkyl part has 1 to 4 carbon atoms, an alkoxycarbonyloxyalkyl group in which each alkoxy and alkyl part has 1 to 4 carbon atoms, (5-methyl-2-oxo-1, 3-Dioxolen-4-yl) methyl group, or phthalidyl group. 3. The compound according to claim 2, characterized in that in it R ^5a C ₁ C _{4 is an} alkyl group, an alkanoyloxyalkyl group in which the alkanoyl group has 1 5 carbon atoms and the alkyl group is 1 4 carbon atoms; alkoxycarbonyloxyalkyl group in which the alkoxy part has 1 4 carbon atoms and the alkyl part of 1 2 carbon atoms; (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl group or phthalidyl group. 4. The compound according to claim 2, characterized in that in it R ^5a is pivaloyloxymethyl, ethoxycarbonyloxymethyl, 1- (ethoxycarbonyloxy) ethyl, isopropoxycarbonyloxymethyl, 1- (isopropoxycarbonyloxy) ethyl, (5-methyl-2-oxo-1,3- dioxolen-4-yl)) methyl or phthalidyl group. 5. The compound according to claim 1, characterized in that R ^{1 is an} alkyl group having 2 5 carbon atoms; R ² and R ³ , the same or different, each of them is an alkyl group having 1 4 carbon atoms; benzyl, naphthyl or phenyl group; R ^{4 is} hydrogen or an alkyl group having 1 to 4 carbon atoms; R ^{5 a} group of the formula is COOR ^5a or a group of the formula CONR ⁸ R ⁹ in which R ^{5a is an} alkyl group having 1 to 4 carbon atoms, an alkanoyloxyalkyl group in which the alkanoyl part has 1 to 5 carbon atoms and the alkyl part to 1 to 4 carbon atoms; alkoxycarbonyloxyalkyl group in which the alkoxy part has 1 4 carbon atoms and the alkyl part is 1 4 carbon atoms; (5-methyl-2-oxo-1,3-dioxolan-4-yl) methyl group or phthalidyl group; R ⁸ and R ⁹ , the same or different, each hydrogen, an alkyl group having 1 4 carbon atoms, and a substituted alkyl group that has 1 4 carbon atoms and which is a substituted carboxy group or alkoxycarbon group, where the alkyl part has 2 to 5 atoms carbon, or R ⁸ and R ⁹ together represent a substituted alkylene group which has 4 or 5 carbon atoms and is substituted by at least one substituent selected from methoxycarbonyl and ethoxycarbonyl groups; the benzene ring, which has the substituents R ⁶ and R ⁷ , is in the 3-4 position of the benzyl group to which it is associated. 6. The compound according to claim 1, characterized in that R ^{1 is an} alkyl group having 2 5 carbon atoms; R ² and R ³ , the same or different, each alkyl group having 1 to 4 carbon atoms, a benzyl or phenyl group, R ⁴ hydrogen, a methyl or ethyl group, R ^{5 a} group of the formula —COOR ^5a or a group of the formula —CONR ⁸ R ⁹ , in which R ^{5a is an} alkyl group having 1 to 4 carbon atoms, an alkanoyloxyalkyl group in which the alkanoyl part has 1 to 5 carbon atoms, and the alkyl part means a methyl or ethyl group, an alkoxycarbonyloxyalkyl group in which the alkoxy part has 1 to 4 carbon atoms, and the alkyl part is methyl or ethyl th group, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl group or a phthalidyl group; R ⁸ and R ⁹ , the same or different, each hydrogen, methyl group, ethyl group or substituted methyl group, which is substituted by at least one substituent selected from carboxy groups, methoxycarbonyl groups and ethoxycarbonyl groups, or R ⁸ and R ⁹ together substituted an alkylene group which has 4 or 5 carbon atoms and is substituted with at least one substituent selected from methoxycarbonyl and ethoxycarbonyl groups; R ^{6 is} hydrogen; R ^{7 is a} carboxy group or tetrazol-5-yl group at the 2- or 3-position of the benzene ring; the benzene ring, which has substituents represented by R ⁶ and R ⁷ , is in the 4th position of the benzyl group to which it is attached. 7. The compound according to claim 1, characterized in that R ^{1 is an} alkyl group having 2 5 carbon atoms, R ² and R ³ are the same or different, each is an alkyl group having 1 4 carbon atoms, R ⁴ hydrogen, methyl group or an ethyl group, R ^{5 a} group of the formula —COOR ^5a or a group of the formula —CONR ⁸ R ⁹ in which R ^{5a is a} methyl, ethyl or benzyl group, an alkanoyloxymethyl group in which the alkanoyl moiety has 1 5 carbon atoms, 1- (alkanoyloxy) ethyl group in which the alkanoyl moiety has 1,5 carbon atoms, an alkoxycarbonyloxymethyl group in which the alkoxy part has 1 4 carbon atoms, a 1- (alkoxycarbonyloxy) ethyl group in which the alkoxy part has 1 4 carbon atoms, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl group or phthalidyl group, R ⁸ and R ⁹ , the same or different, each hydrogen, methyl or ethyl group, methoxycarbonylmethyl group, ethoxycarbonylmethyl group or carboxymethyl group, or R ⁸ and R ⁹ together - tetramethylene, pentamethylene, 1-carboxytetramethylene or 1-carboxypentamethylene group, R ⁶ hydrogen, R ⁷ is a carboxy group or tetrazole-5 the -yl group in the 2-position of the benzene ring, and the benzene ring, which has substituents represented by R ⁶ and R ⁷ , is in the 4th position of the benzyl group to which it is attached. 8. The compound according to claim 1, wherein R ^{1 is an} ethyl, propyl or butyl group, R ² and R ³ are the same or different, each is a methyl group; R ^{4 is} hydrogen or a methyl group; R ^{5 is a} group of the formula —COOR ^5a in which R ^{5a is} hydrogen, pivaloyloxymethyl, ethoxycarbonyloxymethyl groups, 1- (ethoxycarbonyloxy) ethyl group, isopropoxycarbonyloxymethyl group, 1- (isopropoxycarbonyloxy) ethyl group, (5-methyl-2-oxo-1,3 -dioxolen-4-yl) methyl group or phthalidyl group; R ^{6 is} hydrogen; R ^{7 is a} carboxy group or a tetrazol-5-yl group in the 2nd position of the benzene ring, and the benzene ring, which has the substituents R ⁶ and R ⁷ , is in the 4th position of the benzyl group to which it is attached. 9. The compound according to any one of claims 1 to 4, characterized in that R ¹ is an ethyl, propyl or butyl group; R ² and R ^{3 are} methyl groups; R ^{4 is} hydrogen or a methyl group; R ^{5 a} group of the formula is COOR ^5a in which R ^{5a is} hydrogen, pivaloyloxymethyl group, ethoxycarbonyloxymethyl group, 1- (ethoxycarbonyloxy) ethyl group, isopropoxycarbonyloxymethyl group, 1- (isopropoxycarbonyloxy) ethyl group, (5-methyl-2-oxo-1 , 3-dioxolen-4-yl) methyl group or phthalidyl group; R ^{6 is} hydrogen; R ^{7 is a} carboxy group or tetrazol-5-yl in the 2nd position of the benzene ring, the benzene ring, which has the substituents R ⁶ and R ⁷ , is in the 4th position of the benzyl group to which it is associated.  10. The compound according to claim 1: 2-butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (1-hydroxy-1-methylethyl) imidazole-5-carboxylic acid and its pharmaceutically acceptable salts . 11. The compound according to claim 1: pivaloyloxymethyl-2-butyl-1 - [(2 ^' -carboxybiphenyl-4-yl) methyl] -4- (1-hydroxy-1-methylethyl) imidazole-5-carboxylate and its pharmaceutically acceptable salt. 12. The compound according to claim 1: (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl-2-butyl-1- [(2 ^' -carboxybiphenyl-4-yl) methyl] -4 - (1-hydroxy-1-methylethyl) imidazole-5-carboxylate and its pharmaceutically acceptable salts.  13. The compound according to claim 1: 1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylic acid and its pharmaceutically acceptable salts.  14. The compound according to claim 1: 1 - [(2'-carboxybiphenyl-4-yl) methyl] -2-ethyl-4- (1-hydroxy-1-methylethyl) imidazole-5-carboxylic acid and its pharmaceutically acceptable salts .  15. The compound according to claim 1: 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylic acid and its pharmaceutically acceptable salts.  16. The compound of claim 1: 2-butyl-4- (1-hydroxy-1-methyl-ethyl) -1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylic acid and its pharmaceutically acceptable salts.  17. The compound according to claim 1: pivaloyloxymethyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate and its pharmaceutically acceptable salts.  18. The compound according to claim 1: pivaloyloxymethyl 2-butyl-4- (1-hydroxy-1-methylethyl) -1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate and its pharmaceutically acceptable salts.  19. The compound according to claim 1, which is (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4 - [2- (tetrazol-5-yl) phenyl] phenyl} methylmidazole-5-carboxylate and its pharmaceutically acceptable salts.  20. The compound according to claim 1, which is (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl 2-butyl-4- (1-hydroxy-1-methyl-ethyl) 1- { 4- [2- (tetrazol-5-yl) phenyl] phenyl} methylmidisal-5-carboxylate and its pharmaceutically acceptable salts.  21. The compound according to claim 1: ethoxycarbonyloxymethyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (trtrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate and its pharmaceutically acceptable salts.  22. The compound according to claim 1: isopropoxycarbonyloxymethyl 4- (1-hydroxy1-methylethyl) -2-propyl-1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate and its pharmaceutically acceptable salts.  23. The compound according to claim 1: 1- (ethoxycarbonyloxy) ethyl 4- (1-hydroxy-1-methyl-ethyl) -2-propyl -1- {4- [2- (tetrazol-5-yl) phenyl] phenyl } methylimidazole-5-carboxylate and its pharmaceutically acceptable salts.  24. The compound according to claim 1: 1- (isopropoxycarbonyloxy) ethyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole 5-carboxylate and pharmaceutically acceptable salts thereof.  25. The compound according to claim 1: pivaloyloxymethyl 2-ethyl-4- (1-hydroxy-1-methylethyl) -1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate and its pharmaceutically acceptable salts.  26. The compound according to claim 1: (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl 2-ethyl-4- (1-hydroxy-1-methylethyl) -1- {4- [ 2- (tetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate and its pharmaceutically acceptable salts.  27. The compound according to claim 1: pivaloyloxymethyl 1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate and its pharmaceutically acceptable salts . 28. The compound of claim 1:. (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl 1- [(2 ^{'-karboksibifenil-4-yl)} methyl] -4- (1-hydroxy -1-methylethyl) -2-propylimidazole-5-carboxylate and its pharmaceutically acceptable salts.  29. The compound according to claim 1: phthalidyl-1 - [(2'-carboxybiphenyl4-yl) methyl] -4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate and its pharmaceutically acceptable salts. 30. A method of producing compounds according to any one of claims 1 to 29, characterized in that the following stages are carried out: reaction of a compound of general formula II

where R ¹ has the indicated meanings;
R ^d is a group of the general formula

where R ² R ^{4 are} defined in claim 1,
R ^{d a} group of the formula —COOR ^f , where R ^f is a carboxy-protecting group, or R ^{d a} group of the formula —COR ² , where R ^{2 is} defined above, is a cyano group;
R ^{l is a} cyano, carboxy group or a group of the formula —COR ^f , wherein R ^{f is as} defined above,
with a compound of general formula III

where R ^{6 is as} defined above;
R ^{7a is a} protected carboxyl group, a cyano group, a protected tetrazol-5-yl group, a carbamoyl or alkylcarbamoyl group;
X is halogen;
to obtain the compounds of General formula IV

where R ^d , R ^l , R ¹ , R ⁶ and R ^{7a are} defined above,
and in any order, removing the protective groups and, if necessary, converting said R ^d group to a group of the general formula

where R ² , R ³ and R ^{4 are} defined above,
and, if necessary, converting the group R ^l to the group R ⁵ , converting the group R ^7a to the group R ^7, or alkylating or acylating the hydroxyl group to the group R ⁴ to obtain a compound of formula I,
and optionally converted to a salt or ester of the obtained product. Priority by signs:
02/21/91 at R ¹ C ₁ C ₆ -alkyl; R ² and R ^{3 are the} same or different, each alkyl group having 1 6 carbon atoms, or an aryl group having 6 10 carbon atoms, R ⁴ hydrogen or an alkyl group having 1 6 carbon atoms; R ^{5 is a} carboxy group or a group of the formula —COOR ^5a , where R ^5a is an alkyl group having 1 to 6 carbon atoms, an alkanoyloxyalkyl group in which each alkanoyl and alkyl moieties has 1 to 6 carbon atoms, an alkoxycarbonyloxyalkyl group in which each alkoxy and the alkyl part has 1 6 carbon atoms (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl group, R ⁶ hydrogen, R ⁷ carboxy group. 04/26/91 at R ^5a phthalidyl group, R ⁷ tetrazol-5-yl. 07.24.91 at R ^5a CONR ⁸ R ⁹ where R ⁸ and R ^{9 are the} same or different, each hydrogen, an unsubstituted alkyl group having 1 6 carbon atoms, a substituted alkyl group having 1 6 carbon atoms and a substituted carboxy group or alkoxycarbonyl group, in which the alkyl part has 1 6 carbon atoms, or R ⁸ and R ^{9 are} together a substituted alkylene group which has 2 6 carbon atoms and is a substituted alkoxycarbonyl group in which the alkyl part has 1 6 carbon atoms.

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