Heterocyclic compounds, pharmaceutical composition active antagonist of angiotensin ii and the way anthonyjasony of angiotensin ii in mammals

 

(57) Abstract:

Scope: new benzimidazole derivatives are clinically useful for treatment of diseases of the circulatory system, such as hypertension, heart disease, disorders of cerebral circulation. Product: 1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl] methyl] -2-propyl-benzimidazole-7-carboxylic acid, yield 90 %, so pl. 169-171oC, Brutto-formula C26H22N4O4. 4 C. and 25 C.p. f-crystals, 1 table.

The invention relates to heterocyclic compounds having excellent pharmacological properties, and to intermediate compounds used for the synthesis of these compounds.

In particular, the invention relates to compounds of General formula

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where R1may be substituted hydrocarbon residue may be linked via a heteroatom; R2may be a residue substituted 5-7-membered heterocycle containing, as a substituent carbonyl group, thiocarbonyl group, possible oxidized sulfur atom or a group which can in turn; X is a direct bond "spacer", containing two or fewer atoms between cycles Y and W; W and Y nezavisim substituted heterocycle; n = 1-2; a and b are included in the heterocyclic structure, represent different one or two possibly substituted carbon atoms or heteroatoms; c can be substituted carbon atom or a heteroatom; and in the group of the formula

< / BR>
the substituents at adjacent atoms, together with the two atoms of the cycle form a 5-6-membered cycle, or their salt.

System chymosin-angiotensin is involved in the homeostatic functioning of the body, controlling blood pressure, the volume of m fluid balance electrolytes, etc. that are associated with aldosterone system. The relationship between system chymosin-angiotensin and high pressure was established in the production of angiotensin II (A II), transforming inhibitors enzyme (ACE inhibitor), which leads to the production of angiotensin II, with a strong sosudosuzhayushcheye action. Because angiotensin II constricts blood vessels, which increases blood pressure through the receptors of angiotensin II, acting on the cell membrane, the substance of the opposite action, such as ACE inhibitors, can be used to treat hypertension, which is caused by angiotensin. It is known that a number of analogues of angiotensin II, such as claratin, (Sar1

On the other hand, to solve the problems associated with these peptide antagonists of angiotensin II research was conducted ones antagonists of angiotensin II. Previously imidazole derivatives having activity as an antagonist antiotensin II, have been described in the claims of Japan S56 N 71073, 1981, S56 N 71074, 1981, S57 N 98270, 1982, S58 N 157768, 1983, U.S. patents 4355040 and 4340598 etc. Later improved imidazole derivatives have been described in EP 0253310, EP 0291969, EP 0324377, EP 403158, WO 9100277, application Japan S63 N 23868, 1988, and the application of Japan HI N 117876, 1989; derivatives of pyrrole, pyrazole and triazole described in EP 0323841, EP 0409332 and the application of Japan HI N 287071, 1989; benzimidazole derivatives described in U.S. patent 4880804, EP 0392317, EP 0399732, EP 0400835 and the application of Japan NC N 632264, 1991, derivatives of ashenden - EP 0399731; derivative pyrimidone - EP 0407342; derivatives of hintlian - EP 0441766, as antagonists of angiotensin II.

However, in order to become useful for the treatment of drug antagonists of angiotensin II should have a strong long is the sources, strong antagonists have the acido group, for example tetrazolyl or carboxyl side chain biphenyl, especially preferred tetryzoline group, and the clinical test compounds having tetrazolyl group, as antihyperuricemic agents known (Y. Christen, B. Waeber, J. Nussberger, R. J. Lee, P. B. M. W. M. Timmermans, H. R. Brunner, Am.J. Hypertens, 4, 350 S, 1991). However, it is known that compounds containing a cycle of tetrazole and azide compounds, easily explode, which is a major problem for their production on a large scale.

The invention aims at obtaining new compounds containing heterocyclic residue, which you can override on tetrazolyl or carboxyl group, and having a strong effect, the opposite action of angiotensin II and protivogipertonicheskoe action when administered orally and which can be used as a useful therapeutic agent.

The inventors believe that compounds that block the action of the system chymosin-angiotensin, which are clinically useful for treatment of diseases of the circulatory system, such as hypertension, heart disease (tachycardia, heart failure, inflow activity the opposite effect of angiotensin II receptor and have a strong long-term effect of angiotensin II antagonistic and protivogipertonicheskoe the effect of oral application. They conducted intensive studies of these compounds having antagonistic action to the action of angiotensin II in a long time.

In the result it was found that the new heterocyclic compounds I have potential activity in the opposite effect of angiotensin II receptor, and have a strong long-term effect, the opposite action of angiotensin II and protivoparkinsonicheskimi action oral application.

More specifically the invention relates to a compound of the formula

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where R1may be a residue substituted hydrocarbon may be linked via a heteroatom; R2may be a residue substituted 5-7-membered heterocycle containing, as a substituent carbonyl group, thiocarbonyl group, possible oxidized sulfur atom or a group which can in turn; X is a direct bond or a spacer containing two or fewer atoms between cycles I and W; W and Y independently can be the remnants of a substituted Aromasin part heterocyclic residue, represent different one or two possibly substituted carbon atoms or heteroatoms; c can be substituted carbon atom or a heteroatom; and in the group of the formula

< / BR>
the substituents at adjacent atoms of the cycle may relate to each other and to two other atoms of the loop to form a ring, or its salt, more predominantly connection (2) formula

< / BR>
where R1may be a residue substituted hydrocarbon may be linked via a heteroatom; R2may be a residue substituted 5-7-membered heterocycle containing, as a substituent carbonyl group, thiocarbonyl group, possible oxidized sulfur atom or a group that they can turn; X is a direct bond or a spacer containing two or fewer atoms between cycles Y and W; W and Y independently can be the remnants of a substituted aromatic hydrocarbon may contain heteroatom or residue substituted heterocycle; n = 1-2; a and b are included in the heterocyclic residue are different, one or two possibly substituted carbon atoms or heteroatoms; c can be substituted carbon atom or a heteroatom; and when a can be substituted carbon atom, R1and a possible can be the s

< / BR>
where R1may be a residue substituted hydrocarbon may be linked via a heteroatom; R2may be a residue substituted 5-7-membered heterocycle containing, as a substituent carbonyl group, thiocarbonyl group, possible oxidized sulfur atom or a group that they can turn; X is the first bond or a spacer containing two or fewer atoms between cycles Y and W; W and Y independently can be the remnants of a substituted aromatic hydrocarbon may contain heteroatom or residue substituted heterocycle; a and e, forming the heterocyclic residue are independently one or two possibly substituted carbon or heteroatoms; d and f, forming a heterocyclic residue, independently of one possibly substituted carbon or a heteroatom; b and c independently of one possibly substituted carbon or nitrogen atom; n = 1-2; when a possibly substituted carbon atom, R1and a may be connected to each other, forming a group of the formula

< / BR>
forming a cycle, or its salt.

In the General formula I, examples of the hydrocarbon residue denoted by R1can be alkyl, alkenyl, quinil, cycloalkyl, aryl and aralkyl. Preferred among them are OU turn be substituted hydrocarbon residue, linked via a heteroatom.

The alkyl group represented as R1may be straight or branched lower alkyl group containing 1-8 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, out-of pentyl, hexyl, heptyl or octyl.

Alchemilla group, depicted as R1may be straight or branched lower alkenylphenol group containing 2-8 carbon atoms, for example vinyl, protanilla, 2-bucinellina, 3-bucinellina, isobutylene or 2-octenidine.

Alchemilla group, depicted as R1may be straight or branched lower alkenylphenol group containing 2-8 carbon atoms, for example etinilnoy, 2-through 2-bucilina, 2-pencilina or 2-aktiline.

Cycloalkyl group, depicted as R1may be lower cycloalkyl group containing 3-6 atoms of a hydrocarbon, for example cyclopropyl, cyclobutyl, cyclopentene or tsiklogeksilnogo.

The above-mentioned alkyl, Alchemilla, alkyl or cycloalkyl group can be substituted, for example, hydroxyl group, amino group, for example amino, N-lower (1-4C) alkyl

Kalkilya group, depicted as R1may be, for example, phenyl-lower (1-4C) alkyl, such as benzyl or phenethyl, and the aryl group represented as R1may be, for example, phenyl.

The above kalkilya or alkyl group may possibly have in its benzene ring, for example, halogen, such as F, CI or Br), nitro, possibly substituted by an amino group such as amino, N-lower (1-4C) alkyl amino, or N, N-di-lower (1-4C) alkyl-amino; lower (1-4C) alkoxy, for example methoxy, or ethoxy; lower (1-4C) alkylthio, for example methylthio or ethylthio, or lower (1-4C) alkyl, for example methyl or ethyl.

Among the above-mentioned groups represented by R1possible substituted alkyl or alkeneamine groups, for example lower (1-5C) alkyl or lower (2-5C) Alchemilla group, possibly substituted by hydroxyl, amino, halogen or lower (1-4C) alkoxygroup preferred.

The group R1may be linked through a heteroatom, such as nitrogen (N(R9)(R9) denotes hydrogen or lower (1-4C)alkyl), oxygen or sulfur (-S(O)m(m = 0-2), and so on), among them possible substituted alkyl or alkenyl connected via a heteroatom, such as methylamino, ethylamino, po, methoxy, ethoxy, propoxy, isopropoxy, propenyloxy, allyloxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, 2-butenyloxy, 3 butenyloxy, isobutyryloxy, pentox, isopentane, hexyloxy, methyl -, thio, ethylthio, propylthio, isopropylthio, allylthio, butylthio, isobutyric, sec-butylthio, tert.-butylthio, 2-butylthio, 3 butylthio, Isobutanol, pentylthio, isopentyl, hexylthio, etc. preferred.

Examples of possibly substituted aromatic hydrocarbon or heterocyclic residue may contain heteroatom, which are represented by Y and W, are remnants of aromatic hydrocarbons, such as phenyl, 4 - and 7-membered monocyclic and condensed heterocyclic residues containing one or more atoms of N, S and O, for example pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolin, isooxazolyl, benzofuranyl, isobenzofuranyl, indolizinyl, sandoli, 3H-indolyl, indolyl, 1H-indazole, pyrenyl, 4H-hemolysins, ethanolic, hinely, phthalazines, naphthyridine, honokalani, hintline, cinnoline and pteridinyl, preferably phenyl.

The above-mentioned aromatic hydrocarbon or heterocyclic residue,examples of which are possibly substituted 5 - and 7-membered, preferably 5 - and 6-membered, monocyclic heterocyclic residue containing one or more atoms of N, S and O, preferably N-containing heterocyclic residue having a hydrogen atom that can protonemata, or group, which could be developing. Groups represented by R2:

< / BR>
In addition to carbon-carbon, as shown above, the group represented by R2may be associated with a possibly substituted aromatic hydrocarbon or geterotsiklicheskikh residue may contain heteroatom, which is represented as Y g = -NH - in the formula above, via one of the many existing nitrogen atoms.

For example, when

,

this group is represented

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Examples of groups R2bonded via the nitrogen atom, are

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In the above formula, g = CH2-, -NR9- the atom O or >=Z; >=Z' >= Z", respectively, denote a carbonyl, thiocarbonyl group or perhaps oxidized sulfur atom, such as S, S(O), and S(O2), mainly carbonyl or thiocarbonyl group, more preferably a carbonyl group, m = 0,1 or 2, and R9denotes a hydrogen atom or a possibly substituted lower alkyl.

2may form a condensed cycle through links deputies cycle, preferably 5 - and 6-membered heterocyclic residues, more preferably 5-membered cycles. Additional area as R2a preferred group of the formula

< / BR>
where i = -O - or-S-, j >= O >S or >S (O)mand m has the same meaning as in the formula above. In the case when Y, for example, phenyl, R2may have substituents in the ortho-, meta - or para-position, ortho-position is preferable.

When the above-mentioned heterocyclic residue R2can exist in tautomeric forms as shown below, for example in the form of three tautomers, a', b' and c' in

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When Z = 0, g = 0,

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the heterocyclic residue represented by the formula

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includes all of the above a', b' and c'.

And the above-mentioned heterocyclic residue R2may be substituted by a group R10< / BR>
< / BR>
Examples of the group R10mentioned above are the group represented by the formula CH(R4)-OCOR5where R4- Voditel, tert-butyl, n-pentyl, isopentyl or neopentyl, C2-6straight or branched lower Alchemilla group or C3-8cycloalkenyl group, such as cyclopentyl, cyclohexyl or cycloheptyl; R5- C1-6straight or branched lower alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl or neopentyl, C2-6straight or branched lower Alchemilla group, C3-8cycloalkyl group, such as cyclopentyl, cyclohexyl or cycloheptyl, C1-3lower alkyl group, a substituted cycloalkyl group C3-8for example cyclopentyl, cyclohexyl or cycloheptyl, or possible a substituted aryl group such as phenyl, such as benzyl, para-chlorobenzene, phenethyl, cyclopentylmethyl or cyclohexylmethyl, C2-3lower Alchemilla group, substituted cycloalkyl C3-8or maybe substituted aryl group such as phenyl, for example the group that has alkanniny residue, such as vinyl, for example cinnamyl, propenyl, allyl or Isopropenyl, possible substituted aryl group such as phenyl, for example phenyl, para-tolyl, or naphthyl, C1-6straight or branched lower alkoxysilane, isopentane or neopentylene, C2-8straight or branched lower alkenylacyl, for example, allyloxy or isobutyryloxy, C3-8cycloalkane group, for example, cyclopentyloxy, cyclohexyloxy or cyclopentyloxy, C1-3lowest alkoxygroup, replaced by cycloalkyl C3-8for example cyclopentyl, cyclohexyl or cycloheptyl, or possible a substituted aryl group such as phenyl, for example the group with alkoxy residue, such as methoxy, ethoxy, n-propoxy or isopropoxy, for example benzyloxy, penetrate, cyclopentyloxy or cyclohexylmethoxy, C2-3lowest alkenylacyl, replaced by cycloalkyl C3-8for example cyclopentyl, cyclohexyl or cycloheptyl, or possible substituted aryl, such as phenyl, for example the group with alkenylacyl residue, such as vinyloxy, for example, cinnamoyloxy, propenyloxy, allyloxy or isopropanolate, aryloxy group, including possibly substituted fenoxaprop, for example, phenoxy, pair-nitrophenoxy or naphthyloxy, and possible substituted alkyl, for example lower (C1-4) alkyl or acyl, for example lower (C2-5) alkanoyl or that may be substituted benzoyl. Examples R10are methyl, ethyl, elextronics)ethyl, 5-methyl-2-oxo-1,3-dioxolan-4-ylmethyl, acetoxymethyl, propionyl oxymethyl, H-butyrylacetate, isobutyrylacetate, 1-(ethoxycarbonyl)ethyl, 1-atomic charges)ethyl, 1-(isobutyryloxy)ethyl, cyclohexylcarbodiimide, benzoyloxymethyl, cinnamyl and cyclopentanecarboxylate. Such groups can have substituents that are capable of easily turning into the initial heterocyclic residue represented by the formula

< / BR>
or chemical or biological means, i.e., under physiological conditions, for example by reaction in vivo, such as oxidation, restore or hydrolysis catalyzed by enzymes in vivo, what is called a prodrug.

As mentioned above, the tautomers heterocyclic residue (a', b' and c') and a heterocyclic residue (a", b" and c") is replaced with R10included in the heterocyclic residues represented as substituent R2in the invention, tautomers and their substituted compounds of various heterocyclic residue, described below, are in reality included in the substituent R2of the invention. And the substituent R2may also have substituents other than the substituents represented by R10as described previously, for example the possibility of the C1-4alkoxy and possible substituted amino group, for example amino, methylamino and dimethylamino, and others.

Aromatic hydrocarbon residue and heterocyclic residue may contain one or more N, O or S atom, may have such substituents as halogen, for example F, Cl and Br, nitro, cyano, lower C1-4alkoxy, possibly substituted by an amino group, for example amino, methylamino and dimethylamino.

X indicates that the adjacent ring W, for example fenelonov group, associated with the ring Y, for example, phenyl group, directly or via a spacer containing two or fewer atoms, preferred is a direct link. As a "spacer" can be any divalently a circuit in which a straight chain are one or two atoms and may have a side chain, for example the lower C1-4alkylene, -CO-, -O-, -S-, -NH, -CO-, -NH-, -O-CH2-, -S-CH2-, and-CH = CH-.

n denotes an integer equal to 1 or 2, preferably 1.

Among the compounds denoted R2, W, X, Y and n are described above, preferred are those which are listed on the following formula:

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preferred compounds represented by the following formulas, for example

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Typical examples of the heterocyclic compounds is higher and R is used instead of the formula

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Examples of compounds of formula II, as compounds shown by the formula

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are all of the following, but not limited to all their possible options

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< / BR>
< / BR>
< / BR>
< / BR>
where h >CH2, >=O >=S >-(O)m, -NR9- and-O -, and m and R9the same meaning as in the formula above or the compounds of formula

< / BR>
< / BR>
where A denotes the residue possibly substituted aromatic hydrocarbon may contain heteroatom or heterocyclic residue, mainly such aromatic hydrocarbon residue as phenyl; h and h1every means CH2, >=O >=S >S(O)m, -NR9- and-O-, and m and R9have the same meaning as in the formula above. Examples of these compounds are the following compounds:

formula

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can mean heterocyclic cycle and tricyclic heterocyclic compounds

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where R and h are the same values as in the formulas given above, and R1aindicates a possibly substituted hydrocarbon residue, or a bicyclic heterocyclic compounds

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where R, b, and c have the same meaning as in formulas, etc the ptx2">

Heterocyclic compound of the formula II may be substituted in addition to groups designated as R, R1and R1agroup R3that can form an anion or a group that could be developing. Deputy R3is in a loop, which is located near the loop, associated with R, predominantly in position adjacent to R (position f of the atom).

Examples of the group R3, capable of forming anion or a group which can in his turn, are possible heterophilically or aminirovanie carboxyl, tetrazolyl, amid triftoratsetata (-NHSO2CF3), phosphoric acid and sulfuric acid. These groups may be protected, possibly substituted lower alkyl group or acyl group and may be any group which can form an anion in biological or physiological conditions, for example in the reaction in vivo, such as oxidation, repair, or hydrolysis by enzymes in vivo, or by chemical means.

Examples may esterified or emitirovannykh carboxyl groups R3are groups represented by the formula-CO-D, where D denotes the carboxyl group, possibly substituted by an amino group, on the lower (1-6C) alkoxy group, in which the alkyl residue is possibly substituted by a hydroxyl group, possibly substituted amino, such as amino, dimethylamino, diethylamino, piperidino, morpholino, halogen, lower (1-6C)alkoxy, lower (1-6C) alkylthio or possibly substituted DIOXOLANYL, for example 5-methyl-2-oxo-1,3-dioxolan-4-yl, or a group represented by formula-O-CH(R4)-OCOR5where R4denotes hydrogen, C1-6straight or branched alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl and neopentyl, C2-6straight or branched lower alkenylphenol group or a C3-8cycloalkyl group, such as cyclopentyl, cyclohexyl and cycloheptyl, R5denotes a straight or branched lower C1-6alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl and neopentyl, C2-6straight or branched lower Alchemilla group, C3-8cycloalkene group, such as cyclopentyl, cyclohexyl and cycloheptyl, C1-3lower alkyl group substituted by cycloalkyl C3-8for example cyclopentyl, cyclohexyl and cycloheptyl, or possibly substituted aryl group such as phenyl, for example Sogno replaced by cycloalkyl C3-8or maybe substituted aryl group such as phenyl, for example cinnamyl, etc. having such alkanniny balance as vinyl, propenyl, allyl and Isopropenyl, aryl group, such as a possibly substituted phenyl, for example phenyl, para-tolyl and naphthyl, C1-6straight or branched lower alkoxygroup, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isopropoxy, sec-butoxy, n-pentyloxy, isopentylamine, neopentane, C2-8straight or branched lower alkenylamine group, for example, allyloxy, isobutyryloxy, C3-8cycloaliphatic group, for example, cyclopentyloxy, cyclohexyloxy, cycloheptylamine, C1-3the lower alkoxy group substituted by cycloalkyl C3-8for example cyclopentyl, cyclohexyl and cycloheptyl, or aryl group, such as a possibly substituted phenyl, for example benzyloxy, penetrate, cyclopentylmethyl, cyclohexylmethoxy having alkoxy residue, such as methoxy, ethoxy, n-propoxy, isopropoxy, C2-3lowest alkenylacyl, replaced by cycloalkyl C3-8for example cyclopentyl, cyclohexyl and cycloheptyl, or aryl group, such as a possibly substituted phenyl, for example cinnamoyloxy, with the remainder alce is substituted on fenoxaprop, for example, phenoxy, pair-nitrophenoxy, naphthoxy. Examples of the group R3can also be a group which can form an anion or a group which could be developing, such as tetrazole, amid triftoratsetata, phosphoric acid or sulfuric acid may protected by alkyl, for example lower C1-4alkyl or acyl, for example lower C2-5alkanoyl and possibly benzoyl protected.

Examples R3are-COOH and its salt, -COOMe, -COOEt, -COO-tert-Bu-COOPr, pivaloyloxymethyl, 1-(cyclohexyloxycarbonyloxy) etoxycarbonyl, 5-methyl-2-oxo-1,3-dioxolan-4-ylmethoxycarbonyl, ecotoxicologically, propionatetestosterone, n-butylmethacrylate, isobutyltrimethoxysilane, 1-(ethoxycarbonyl)etoxycarbonyl, 1-(acetoxy)etoxycarbonyl, 1-(isobutyryloxy)etoxycarbonyl, cyclohexyloxycarbonyl, benzyloxycarbonyl, cinnamoylcocaine and cyclopentanecarbonyl. As such groups can be any group which can form an anion, such as COO-and its derivatives, or a group which can be converted in biological or physiological conditions, for example in the reactions is3can be carboxyla or its prodrug. R3can also be a group, turn in anion in vivo, for example, biological or chemical means.

Compounds in which R3is a group which can form an anion or a group which can be transformed into it, for example a protected carboxyl group, tetrataenia group, carboxaldehyde group, hydroxymethylene group, cyano, chemically, for example by oxidation, repair or hydrolysis, useful as intermediates for the synthesis.

Among the groups R3preferred carboxyl, esterified carboxyl, such as methyl ester, ethyl ester or ether formed by the linking group represented by the aforementioned formula-O-CH(R4)-OCOR5to the carbonyl, and possibly protected tetrazolyl, carbaldehyde and hydroxymethyl.

Heterocyclic compound of the formula II can have, in addition to the groups R, R1, R1aand R3yet substituents, such as halogen, for example F, Cl and Br, nitro, cyano, possibly substituted by an amino group such as amino, N-lower (1-4C)alkylamino, such as methylamino, N,N-di-lower(1-4C)alkylamino, for example dimethylamino, N-Azino, group represented by the formula U-R6where U denotes the link-O-, -S - or-CO - and R6denotes hydrogen, possibly substituted lower alkyl group, for example lower(1-4C)alkyl group, substituted by hydroxyl, possibly substituted by an amino group such as amino, halogen, nitro, cyano or lower (1-4C) alkoxygroup, group, set by the formula -(CH2)1-CO-D1where D denotes hydrogen, a hydroxyl group, possibly substituted amino group such as amino, N-lower (1-4C) alkylamino and N,N-di-lower (1-4C) alkylamino) or possibly substituted alkoxygroup, for example, lower (1-6C) alkoxy group, the alkyl residue which may be substituted by a hydroxyl group, possibly substituted amino, such as amino, dimethylamino, diethylamino, piperidino and morpholino, halogen, lower (1-6C) alkoxy, lower (1-6C)alkylthio or possibly substituted DIOXOLANYL, for example 5-methyl-2-oxo-1,3-dioxolan-4-yl, or a group represented by the formula OCH(R7)OCOR8where R7denotes hydrogen, 1-6C straight or branched lower alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl and neopentyl, or 5-7C cycloalkyl (cyclopentyl, cyclohexyl and cycloheptyl), R8putting the p-butyl, tert-butyl, n-pentyl, isopentyl and neopentyl, 2-8C lower Alchemilla group, vinyl, protanilla, allyl, Isopropenyl, 5-7C cycloalkyl group, such as cyclopentyl, cyclohexyl and cycloheptyl, 1-3C lower alkyl group substituted with 5-7C cycloalkyl group, such as cyclopentyl, cyclohexyl and cycloheptyl, or aryl group such as phenyl, such as benzyl, para-chlorobenzene, phenethyl, cyclopentylmethyl and cyclohexylmethyl, 2-3C lower Alchemilla group, substituted cycloalkyl 5-7C, for example, cyclopentyl, cyclohexyl and cycloheptyl, or aryl group such as phenyl, for example cinnamyl with such alkanniny balance as vinyl, propenyl, allyl or Isopropenyl, possible substituted aryl group such as phenyl, for example phenyl, para-tolyl and naphthyl, 1-6C straight or branched lower alkoxygroup, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentox, isopentylamine, neopentylene, 2-8C straight or branched lower alkenylamine group, for example, allyloxy, isobutyryloxy, 5-7C, cycloalkane group, for example, cyclopentyloxy, cyclohexyloxy, cycloheptylamine, 1-3C lower alkoxy group substituted with 5-7C, cycloalkyl is, for example benzyloxy, penetrate, cyclopentyloxy, cyclohexylmethoxy with such alkoxy residue as methoxy, ethoxy, n-propoxy, isopropoxy, 2-3C, alkenylamine group substituted with 5-7C by cycloalkyl, such as cyclopentyl, cyclohexyl and cycloheptyl possible or substituted aryl group such as phenyl, for example cinnamic with alkenylacyl residue, such as vinyloxy, propenyloxy, allyloxy, isopropanolate, and alloctype, such as possibly substituted, phenyloxy, for example, phenoxy, pair-nitrifiers, naphthoxy, and l = 0 or 1, or tetrazolyl, triftoratsetata amide, phosphoric acid or sulfuric acid, each possibly protected by alkyl, for example lower (1-4C) alkyl, or acyl, for example lower (2-5C) alkanoyl and possibly substituted benzoyl.

One or two of these substituents may be substituted at the same time in the ring. When two or more of these substituents exist, the priority is the case when two deputies are the atoms forming the ring, next to each other in a, b and C groups, forming a loop, they can be connected to each other so that they form a 5 - and 6-membered ring, possibly substituted aromatic hydrocarbon residue or heterocyclic together with the two atoms, forming a ring. These cycles can be further substituted by any of the above substituents.

Among the compounds of the formula

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as a condensed heterocyclic cycles indicated by the formula

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preferred

< / BR>
where R1R and R3and h have the same meaning as in the formula above, as well as heterocyclic loop formulas

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preferred

< / BR>
where R, R1, R3and R9have the same meanings as in the formula above.

Among the compounds Ia preferred compounds of formula

< / BR>
where R1indicates a possibly substituted lower (1-5C) alkyl, which may be linked through a heteroatom, such as O, N (H) and S, preferably lower (2-4C) alkyl; R2denotes oxadiazole or thiadiazole may possibly protected substituted lower (1-4C) alkyl, such as alkyl, triphenylmethyl, methoxymethyl, acetoxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, cyclohexyloxycarbonyloxy and pivaloyloxymethyl, or acyl, for example lower (2-5C)alkanoyl or benzoyl; R3denotes a group of formula-CO-D", where D" stands for hydroxyl group, amino group, N-lower (1-is substituted by hydroxyl, amino group, halogen, lower (2-6C) alkanoyloxy, such as atomic charges, pivaloyloxy, 1-lower (1-6C) alkoxycarbonyl, for example, methoxycarbonylamino, ethoxycarbonyl, cyclohexyloxycarbonyloxy, or lower (1-4C) alkoxy group, or tetrazolyl may secure the lower (1-4C) alkyl or acyl group, e.g. lower (2-5C) alkanoyl or benzoyl, and represents a heterocyclic ring of the formula

< / BR>
Among the compounds Ib preferred compounds of formula

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where R1indicates a possibly substituted lower (1-5C) alkyl, which may be linked through a heteroatom, such as O, N (H) and S, preferably lower (2-4C) alkyl; R2denotes oxadiazole or thiadiazole may possibly protected substituted lower (1-4C) alkyl, for example methyl, triphenylmethyl, methoxymethyl, acetoxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, cyclohexyloxycarbonyloxy and pivaloyloxymethyl, or acyl, for example lower (2-5C) alkanoyl and benzoyl; R3denotes hydrogen, a group of the formula-CO - D", where D" stands for hydroxyl group, amino group, N-lower (1-4C) alkylamino, N, N-di-lower (1-4C) alkylamino or lower (1-4C) alkoxygroup, the alkyl residue which may be substituted of hydroxy (1-6C) alkoxycarbonyl, for example, methoxycarbonylamino, ethoxycarbonyl, cyclohexyloxycarbonyloxy, or lower (1-4C) alkoxy or tetrazolyl may secure the lower (1-4C) alkyl or acyl, for example lower (2-5C) alkanoyl or benzoyl, and condensed heterocyclic ring represented by the formula

< / BR>
shows

< / BR>
which may be further substituted by the above substituents in addition to the groups R, R1and R3. As the compounds of formula (IB) are preferred compounds having benzamidine, teenmodeling or imidazopyridine structure, the preferred benzimidazole or teenymodel. And the compounds of formula (Ia) or (IB), where R2- hydroxykynurenine (-C(NH2)= N-OH), can be used as intermediates for the synthesis of compounds of formulas (Ia) and (IB), where R2- oxadiazol or thiadiazole.

The method of obtaining.

Compounds of the above formula (I), (Ia) or (IB) can be obtained, for example, by the methods below.

Reaction (a)

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where R1, R2, W, X, Y, a, b, c, and n have the same meaning as in the formula given earlier; L denotes a halogen atom.

Reaction (a), above, is the unlocking is carried out using about 1-3 mol of each of the grounds and an alkylating agent per mole of compound (III), when used as a solvent of dimethylformamide, dimethylacetamide, dimethyl sulfoxide, acetonitrile, acetone or methyl ethyl ketone.

Examples of bases are sodium hydride, tert-piperonyl potassium, potassium carbonate and sodium carbonate.

As the alkylating agent can be used, for example, substituted halides, for example chlorides, bromides and iodides, and esters of substituted sulfonic acids, such as ether paratoluenesulfonyl.

Although the conditions of the reaction depend on a combination of base and alkylating agent, it is preferable to conduct the reaction at a temperature of from 0oC to room within 1-10 hours

When the alkylation is obtained a mixture of regioisomers, depending on the position of the atom N. Although the ratio of the components in the reaction products depends on the conditions of the reaction and the heterocyclic substituents at cycle, these compounds can be easily obtained as pure products by conventional methods of separation and purification such as recrystallization and columnar chromatography.

Reaction (b)

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where R1, W, X, Y, a, b, c, and n have the same meaning as before.

The above reaction (b) the state shall provide for the closure of the ring.

The reaction of obtaining compound (Ib) is carried out using approximately 2-10 mol of hydroxylamine per 1 mol of compound (Ia) is usually in an organic solvent.

Examples of such solvents are amines, such as dimethylformamide and dimethylacetamide, sulfoxidov, for example dimethyl sulfoxide, alcohols, such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, and halogenated hydrocarbons such as methylene chloride and chloroform.

When using hydroxylamine reaction is carried out in the presence of a suitable base, for example potassium carbonate, sodium carbonate, sodium hydroxide, triethylamine, methanolate sodium, ethanolate sodium and sodium hydride, in an almost equimolar ratio, when using salts of inorganic acids such as hydrochloride hydroxyl amine or sulfate hydroxyl amine, or salts of organic acids, such as oxalic hydroxyl amine. Although the conditions of the reaction depend on the nature of the reagent and solvent, the reaction is mainly carried out at 50-100oC for 2-10 h after hydroxylamine hydrochloride treated with sodium methoxide in dimethyl sulfoxide.

Thus obtained amidoxime (Ib), then the e, for example chloroform, methylene chloride, dioxane, tetrahydrofuran, acetonitrile and pyridine, in the presence of a base, such as triethylamine, pyridine, sodium carbonate and potassium carbonate, with the formation of o-acyl compounds.

Mostly the reaction is carried out at a ratio of ethylformate and amidoxime (Ib) 2-5 mol : 1 mol in the presence of 2-5 mol of triethylamine in tetrahydrofuran at a temperature from 0oC to room within 1-5 hours

When heated derived o-acyl amidoxime in a conventional organic solvent is formed cyklinowanie compound (Ic).

Examples of solvents are aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane and tetrahydrofuran, and halogenated hydrocarbons such as dichloroethane and chloroform. Preferably oxidiazol get when heated o-acyl amidoxime under reflux for 1-3 hours in boiling xylene.

Response (s)

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Reaction (C) is in receipt of oxadiazoline (Id) by the hydrolysis of compounds (V), which is the product of alkylation of the compound (III) alkylating agent obtained by the reaction (m).

Examples of organic solvents are agut to be used sodium hydroxide, the potassium hydroxide and lithium hydroxide.

Preferably the compound (V) is reacted at a temperature of from 0oC to room within 0.5-2 h 2-10 mol 0.5 to 1 N. sodium hydroxide.

Reaction (d)

< / BR>
Reaction (d) is the connection of alcohol (Ie) in the reduction of aldehyde (If).

The reaction is carried out at a ratio of 2-5 moles of reducing agent per 1 mol of compound (Ie) is usually in the ether, for example tetrahydrofuran and dioxane, alcohol, for example methanol and ethanol.

As a reducing agent can be used complexes of metals, such as sodium borohydride.

Preferably the reaction is carried out by adding a reducing agent to a solution of compound (Ie) in methanol at a temperature of from 0oC to room, followed by stirring for 0.5-2 hours

Reaction (e)

< / BR>
where R1, R2, W, X, Y, a, b, c, d, e, f, n have the same meaning as above; L represents a halogen atom.

Reaction (e) is the alkylation using an alkylating agent in the presence of a base.

The reaction is carried out using 1-3 mol of the base and 1-3 mol of alkylating agent per 1 mol of compound (III) is usually in a solvent such as demetia bases are sodium hydride, tert-piperonyl potassium, potassium carbonate and sodium carbonate.

As the alkylating agent used substituted halides, for example chloride, bromide and iodide, and esters of substituted sulfonic acids, such as ether, para-toluenesulfonic acid.

Although the reaction conditions depend on a combination of base and alkylating agent, it is preferable to conduct the reaction at a temperature of from 0oC to room within 1-10 hours

By alkylation receive a mixture of regioisomers, which depends on the position of atom N, which is subjected to alkylation. Although the ratio of the components in the reaction mixture depends on the reaction conditions and on the nature of substituent at the heterocycle, the compound (Ib) can be easily obtained in pure form by conventional methods of separation and purification such as recrystallization and column chromatography.

Reaction (f)

< / BR>
< / BR>
where R1, W, X, Y, a, b, c, d, e, f, n have the same meaning as before.

Reaction (f) is in receipt of oxadiazole (Ibc) by transformation of cyanocobalamine (Iba) amidoxime (Ibb) with subsequent crystallization.

The reaction of obtaining compound (Ibb) is carried out using what reamers solvents are amides, for example, dimethylformamide and dimethylacetamide, sulfoxidov, for example dimethyl sulfoxide, alcohols, such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, and halogenated hydrocarbons such as methylene chloride and chloroform.

When using hydroxylamine reaction is carried out in the presence of a suitable base, for example potassium carbonate, sodium carbonate, sodium hydroxide, triethylamine, methanolate sodium, ethanolate sodium and sodium hydride, in an almost equimolar ratio, when using salts of inorganic acids, such as hydroxylamine hydrochloride or hydroxylamine sulfate, or salts of organic acids such as oxalate, hydroxylamine.

Although the conditions of the reaction depend on the nature of the reagent and solvent, the reaction is preferably carried out at a temperature of 50-100oC for 2 to 10 h, and then hydroxylamine hydrochloride is treated with sodium methoxide in dimethyl sulfoxide.

Thus obtained amidoxime (Ibb) is treated with ether Harborview acid, such as methyl ester and ethyl ester, in a conventional organic solvent, for example chloroform, methylene chloride, dioxane, tetrahydrofuran, AC sodium, with the formation of o-acyl compounds.

Preferably the reaction is carried out using 2-5 mol of salts of ethylchloride 1 mol amidoxime (Ibb) in the presence of 2-5 mol of triethylamine in tetrahydrofuran at a temperature from 0oC to room within 1-5 hours

When heated thus obtained amidoxime in a conventional organic solvent easily get cyklinowanie compound (Ic).

Examples of the solvent are aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane and tetrahydrofuran, and halogenated hydrocarbons such as dichloroethane and chloroform. Preferably the heating of the o-acyl amidoxime within 1-3 h in boiling xylene.

Reaction (g)

< / BR>
where R1, R2, R9, W, Y, a, b, c, d, e, X and n have the same meanings as in the formula above.

Reaction (g) is to obtain the carboxylic acid (Ibe) by alkaline hydrolysis of the ester (Ibd).

This reaction is carried out at a ratio of alkali : compound (Ibd) = (1-3):1 (mol) usually in a solvent such as aqueous alcohol, for example methanol, ethanol and methyl cellulose.

Examples of alkali hydroxide are the 100oC for 1-10 hours, preferably at the boiling temperature of the solvent within 3-5 hours

Reaction (h)

< / BR>
where R1, R2, W, X, Y, a, b, c, d, e and n have the same meaning as in the formula above; R11indicates a possibly substituted alkyl group, similar to the above.

Reaction (h) is the reaction of alkylation with an alkylating agent in the presence of a base.

The alkylation is carried out using 1-3 mol of the base and 1-3 mol of alkylating agent per 1 mol of compound (Ibe) usually in a solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, acetone and ethylmethylketone.

Examples of the base are sodium hydride, tert-piperonyl potassium, potassium carbonate and sodium carbonate.

Examples of the alkylating agent are substituted halides, for example chloride, bromide and iodide, and esters of substituted sulfonic acids, such as ether, para-toluenesulfonic acid.

Although the conditions of the reaction depend on the nature of the base and the alkylating agent, it is preferable to conduct the reaction at a temperature of from 0oC to room within 1-10 hours

When using as the bits sodium to increase the reaction rate.

Reaction (i)

< / BR>
where R1, W, X, Y, a, b, c, d, e, f and n have the same meaning as in the formula above.

Reaction (i) is in receipt of oxadiazole (Ibg) by cyclization aldoxime (Ibb) obtained by the reaction (f). The compound (Ibg) are obtained by cyclization aldoxime (Ibb) with thionyl chloride in a conventional organic solvent, for example dichloromethane, chloroform, dioxane and tetrahydrofuran, in the presence of a base, such as pyridine and triethylamine.

It is preferable to conduct the reaction in the presence of 2-10 mol of thionyl chloride while cooling to 0-30oC in the presence of 1-3 moles of pyridine per 1 mol aldoxime (Ibb) using as solvent dichloromethane for 0.5-1 h

Reaction (j)

< / BR>
The above reaction (j) is to get diamino derivative (VIII), which involves the deprotonation of nitro-derivatives (VII) obtained by the method of EP 434038 and EP 459136, the usual method followed by treatment with a reducing agent, for example by catalytic regeneration using Raney Nickel or palladium-carbon, iron-hydrochloric acid, ferric chloride-hydrazine, chloride of tin, borohydride rubbed ether, anhydride or halogenerator, ortho-ether, aminoethanol or imino-tieferen with the formation of a condensed cycle, thereby making the diamino derivative (VIII) to the compound (IX).

Thus obtained compound (IX) is reacted with 1-2-fold excess tetrafluoroborate triethyloxonium in a halogenated hydrocarbon, such as methylene chloride or chloroform, at a temperature of from 0oC to room within 30 min to 2 h with the formation of the imino ester (X) with a good yield.

Then carry out the reaction of the imino-ester (X) with 1-2-fold excess of the ether Harborview acid, such as chlorothioformate or characiformes, in a conventional organic solvent, for example benzene, toluene, methylene chloride, chloroform, dioxane or pyridine, in the presence of 1-2-fold excess of base, for example 2,4,6-trimethylpyridine, triethylamine, trimethylpyridine, methylpyridine, diethylaniline, etc., In particular, the reaction is performed in toluene at 80-100oC for 1-3 hours to obtain N-alkoxycarbonyl (XI) with a good yield.

Thus obtained acylaminoacyl (XI) is reacted with a twofold excess of hydroxylamine hydrochloride and a base such as sodium methoxide, ethoxide sodium, carbon at a temperature of from about 50oC to the boiling temperature of the solvent within 3-10 hours

Reaction (k)

< / BR>
.

Reaction (k) includes the transformation of a nitrile derivative (XII), synthesized in accordance with methods of the EP 434038 and EP 459136 in aldoxime (XIII) obtained by a reaction similar to the above reaction (b), followed by reaction aldoxime (XIII) with a 1-2-fold excess of the ether Harborview acid, such as chlorothioformate or characiformes, in the presence of 1-2 mol of base, such as triethylamine or pyridine, in a normal aprotonin organic solvent, for example benzene, toluene, methylene chloride, chloroform, dioxane or pyridine, in the same way, as in the above reaction (b). When carrying out the reaction in tetrahydrofuran the reaction is carried out at a temperature of from 0oC to room to get On-alkoxycarbonyl (XV) with a good yield.

The obtained compound (XV) is reacted in a conventional organic solvent, for example methanol, ethanol, ethyl acetate, benzene, acetonitrile, acetone or N, N-dimethylformamide, in the presence of a base, for example potassium carbonate, sodium carbonate, sodium hydride, tert-butoxide potassium or 1,8-diazabicyclo[5, 4, 0]undecene-7 (DBU). This reaction p is Yes, the reaction is carried out in ethyl acetate using DBU at 50-80oC for 1-2 h, can be obtained with a good yield of the product ring closure (Ibc).

Reaction (l)

< / BR>
For reaction (l) receive thiadiazoline derivative (Ibc) carrying out ring closure aldoxime (Ibb).

This reaction is carried out in a conventional organic solvent, using 1 to 2 mol of 1,1'-thiocarbonyl of diimidazole on 1 mol of the compound (Ibb).

As the solvent used, for example, ethers, for example dioxane or tetrahydrofuran, or a halogenated hydrocarbon, for example methylene chloride or chloroform.

This reaction is preferably carried out by dissolving the compound (Ibb) in the above solvent, followed by adding a solution of 1,1'-thiocarbonyldiimidazole under stirring at a temperature of from 0oC to room temperature.

The products of reaction obtained by reacting (a)-(l), as shown above, can be easily separated by conventional means of separation and purification, such as column chromatography and recrystallization.

In this case, these compounds (I) can be converted by conventional means into salts with physiologically acceptable acids or bases. For example, these salts include the STI from compounds salts with organic acids such as acetic acid, nitric acid, succinic acid and maleic acid, salts with alkaline metals such as sodium and potassium, salts with alkaline earth metal such as calcium.

Starting compound can be obtained in the following ways:

Reaction (m)

< / BR>
where L has the same value as before.

The compound (IVd) are obtained by the reaction of (m) the conversion of compounds (IVa) containing a cyano group, aldoxime (IVb) in the same conditions as in the reaction (b), followed by cyclization aldoxime (IVb) with the formation of oxadiazole (IVc), accompanied by halogenoalkanes of oxadiazole (IVc).

The following example is a preferred embodiment of the reaction.

Aldoxime (IVb) obtained from the compound (IVa) by the method similar to that described in the reaction (f), which consists in the interaction of 1-10 mol of anhydride trichloroacetic acid or hexachloroacetone with 1 mol aldoxime (IVb) in accordance with the known method (F. Eloy, et. al., Helv. Chim. Acta, 49, 1430, 1966), with the formation of oxadiazole (IVc), then (IVc) halogenous such agent, as N-bromosuccinimide or N-bromoacetamide (molar ratio of from 1/1 to 1/1,5) story boiling solvent for 1-3 h in the presence of catalytic amounts of initiator, for example benzoyl peroxide and azobisisobutyronitrile. This reaction can be conducted by irradiation with light.

Reaction (n)

< / BR>
,

where R13- arbitrarily substituted alkyl group, similar to the above-mentioned R10for example triphenylmethyl, methoxymethyl and cyanoethyl, or tert-butyldimethylsilyl group and has the same value as before.

Reaction (n) obtain oxadiazole (IVh) includes adding a carboxylic acid to arylisocyanate acceptable way interaction of the latter with alcohol with the formation of carbonylcyanide (IVf), methylation of the compound (IVf) with the formation of carbonate (IVg), the interaction of the compound (IVg) with hydroxylamine followed by cyclization when heated.

When carrying out the reaction of obtaining carbonylcyanide (IVf) of carboxylic acid (IVe), the compound (IVe) is injected into the reaction with a halogenation agent, such as chloride tiomila, (molar ratio 1 : approximately 2-5) in a halogenated hydrocarbon, for example chloroform or methylene chloride, for 1-5 hours at a temperature of from 50oC to the boiling point of the employed solvent. The obtained acid chloride acid is introduced into reaction with 2-5 mol of tioti the 50oC to the boiling point of the employed solvent, for 1-3 hours, with isocyanates. It is preferable to subject the thus obtained isothiocyanate heat together with 2-10 mol of alcohol, such as methanol and ethanol, at 50oC to the boiling point of the employed solvent for 15 min to 1 h

In the reaction of obtaining iminodicarboxylate (IVg) from compound (IVf) is preferably the compound (IVf) in the reaction with methyliodide (molar ratio 1 : (1-2)) in an organic solvent, for example methanol, ethanol, dimethylformamide (DMF) and acetonitrile, in the presence of 1-2 mol, relative to 1 mol (IVf) base, such as NaOMe, Na2CO3and K2CO3at a temperature of from room temperature up to 50oC for 10-24 hours

If the reaction of obtaining oxadiazole (IVh) from compound (IVg) preferably (IVg) in the reaction with hydroxylamine (molar ratio 1 : approximately 1-2) in alcohol, for example methanol or ethanol, at temperatures from room temperature up to 50oC for approximately 10-20 hours followed by heating the reaction mixture in an organic solvent, for example toluene and benzene, in the presence of approximately catalytic amounts of the solvent for 1-3 h

If the reaction of obtaining demetilirovannogo connection (IVi) from compound (IVh) is preferably subjected to an excessive amount of pyridinylamino and (IVh) melting in a nitrogen atmosphere at a temperature of about 150-160oC for approximately 30 min to 1 h

If the reaction of obtaining compound (IVj) from compound (Vj) is preferably interact compounds (IVi) with an alkylating agent, such as triphenylmethylchloride, methoxymethanol and cyanoethylation, (molar ratio of 1 : 1-2) in an organic solvent, for example chloroform, methylene chloride, dioxane, tetrahydrofuran and pyridine, in the presence of 1-2 mol of base, for example potassium carbonate, sodium carbonate, triethylamine and pyridine, at temperatures from 0oC to room temperature for 1-3 h

The reaction of obtaining compound (IVk) halogenoalkanes connection (IVj) can be performed in the same manner as the reaction of obtaining compound (IVd) from the compound (IVc) according to reaction (m).

Reaction (o)

< / BR>
where R13and L have the same values as before.

Reaction (o) includes the transformation of carboxylic acid (IVe) in the formation (IVm) via hydrazide (the m transformation (IVn) leads to galogensoderjasimi connection (IVp).

If the reaction obtain the hydrazide (IVl) of carboxylic acid (IVe), (IVe) reacts with approximately 2-5 mol halogenation agent, such as oxalicacid and thionyl chloride, in an organic solvent, for example tetrahydrofuran, chloroform and methylene chloride, at a temperature from room temperature up to the boiling point of the employed solvent for 1-20 hours In this case, it is preferable to add a catalytic amount of dimethylformamide to accelerate the reaction. The resulting gelegenheid acid is introduced into reaction with approximately 2-5 mol of hydrazine hydrate is added in an organic solvent, such as tetrahydrofuran and dioxane, at temperatures from room temperature up to 50oC for 1-10 h with the formation of compound (IVl). If the reaction of obtaining semicarbazide (IVm) of the hydrazide (IVl) is preferably introduced into the reaction (IVe) with approximately 2-5 mol of isocyanate, for example, sodium or potassium salt, in aqueous solution in the presence of acid, such as hydrochloric or sulfuric, in an amount equivalent to the number of isocyanate at a temperature of from 0oC to room within 1-5 hours

If the reaction of obtaining oxadiazole (IVn) from semicarbazide (IVm) is preferably n is for 5-20 hours

If the reaction of obtaining galogensoderjasimi connection (IVp) of oxadiazole (IVn), it is preferably in a manner analogous to that described for reaction (n).

Reaction (p)

< / BR>
Reaction (p) to obtain the amide (IVq) is carried out in essentially the same way as if the reaction (o).

Carboxylic acid (IVe) is injected into the reaction with approximately 2-5 mol halogenation agent, such as oxalicacid or thionyl chloride, in an organic solvent, such as tetrahydrofuran, chloroform or methylene chloride, at a temperature from room temperature up to the boiling point of the employed solvent for about 1-20 hours, Preferably to accelerate this reaction by addition of catalytic amounts of dimethylformamide. The resulting gelegenheid acid is preferably introduced into the reaction with excess of aqueous ammonium hydroxide in an organic solvent, for example tetrahydrofuran or dioxane, at a temperature of from 0oC to room temperature for about 1-10 hours with a good yield of amide derivative (IVq).

The reaction of obtaining halogenated (IVr) of the resulting amide derivative (IVq) preferably essentially those who e effective inhibitors against asdourian and hypertensive actions of angiotensin II, contribute to the hypotensive effect in animals, especially in warm-blooded animals, e.g. humans, dogs, rabbits and rats and, therefore, they are useful as therapeutic agents not only in the case of hypertension, but also in the case of diseases of the circulatory system such as heart disorder, cardiac hypertrophy, heart failure, heart attack or similar disorders, hemorrhage of the brain and nephropathy. The compound (I) also has CNS activity for the treatment of Alzheimer's disease and senile dementia and has the properties of a tranquilizer and anti-depressant.

In the case of use as a therapeutic agent, especially in the case noted above, the compound (I) and its salt can be administered orally, nearline, by inhalation, rectally or topically as pharmaceutical compositions or forms, such as powders, granules, tablets, pills, capsules, injections, syrups, emulsions, elixirs, suspensions or solutions, including at least one kind of the compounds of this invention in pure form or in a mixture with pharmaceutically acceptable carriers, adjuvantly, fillers and/or diluents.

Farmatsevticheskaia" includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection or instillation. Injectable preparations, such as sterile suitable for injection, aqueous or oil suspensions can be obtained well-known in this field by means of a suitable dispersant chemical, wetting or dispersing agent. The injection can be in the form of, for example, solution or suspension, which can be obtained with a non-toxic diluent used nearline, for example in aqueous solution or solvent, suitable for sterile injection. The example used fillers or acceptable solvents include water, ringer's solution and isotonic aqueous saline solution. Next, a sterile non-volatile oil can be generally used as a solvent or suspending agent. Any non-volatile oil or fatty acid may be used for this purpose, including natural, synthetic, or synthetic fatty oil or fatty acid or synthetic, or synthetic mono-, di - or triglycerides.

Rectal suppositories can be prepared by mixing the drug with acceptable non-irritating carrier, for example to the anii at a temperature of bowel and melt in the rectum to release the drug.

As solid forms for oral administration can be used powders, granules, tablets, pills and capsules, as noted above. In such forms, examples of which are outlined above, the active ingredient compound may be mixed with at least one additive, for example sucrose, lactose, cellulose sugar, mannitol, malt sugar, dextrin, starch, agar, alginate, chitin, chitosan, pectin, resin tragakant, gum Arabic, gelatin, collagen, casein, albumin, synthetic or artificial polymers or glycerides. These forms can contain further additives, for example an inactive diluent, lubricating substance, such as magnesium stearate, relief disintegrator, binder, thickening agent, a buffer, a sweetener, flavor and fragrance additive. Tablets and pills can be used with the floor. Examples of liquid preparations for oral administration include pharmaceutical acceptable emulsions, syrups, elixirs, suspensions and the solution, which may contain inactive diluent, for example water, which is usually used in this field.

The dose for each patient is assigned depending on its vozrastali drugs and the occurrence of diseases, treated, and other factors that need to be taken into account.

The dose may vary depending on the nature of the diseases, their conditions of flow, condition of the patients and method, while it is preferable that a daily dose of 1-50 mg for oral administration or 1-30 mg for intravenous injection, which may be taken once or may be divided into 2-3 doses, when used as a therapeutic agent of hypertension in the adult.

Working examples.

The following formula examples, working examples, experimental examples and comparative examples, the invention is illustrated more specifically and there is no need to say that they can not be considered as limitations of this invention.

When the compound (I) of the invention is used as a therapeutic agent for the treatment of circulatory disorders such as hypertension, heart disease, cerebral palsy and jade, it can be used, for example, in accordance with the following formulations.

1. Capsules mg:

(1) 2-Ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-] methyl]benzimidazole-7-carb
One capsule - 180

(1), (2), (3) and half of (4) are mixed and granularit. To the granules is added the remainder of (4) and all of this puts in gelatin capsules.

2. Tablets mg

(1) 2-Ethoxy-1[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid - 10

(2) Lactose - 35

(3) Wheat starch - 150

(4) Microcrystalline cellulose 30

(5) magnesium Stearate - 5

One tablet - 230

(1), (2), (3), two-thirds (4) and half of (5) are mixed and granularit. To the granules is added the remainder of (4) and (5), followed by casting the mixture under pressure.

3. Injection, mg:

(1) 2-Ethoxyl-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)-biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid disodium salt - 10

(2) Inositol - 100

(3) Benzyl alcohol 20

One ampoule 130

(1), (2) and (3) dissolved in distilled water for injection to get a complete volume of 2 ml, which is filled ampoule. All operations are performed in sterile conditions.

4. Capsules mg:

(1) 2-Butyl-4-chloro-5-hydroxymethyl-1-[[2'(2,5-dihydro-5-oxo - 1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]imidazole - 10

(2) Lactose - 90

(3) Microcrystalline cellulose 70

(4) magnesium Stearate - 10

5. Tablets mg

(1) 2-Butyl-4-chloro-5-hydroxymethyl-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]imidazole - 10

(2) Lactose - 35

(3) Wheat starch - 150

(4) Microcrystalline cellulose 30

(5) magnesium Stearate - 5

One tablet - 230

(1), (2), (3), two-thirds (4) and half of (5) are mixed and granularit. To the granules is added the remainder of (4) and (5) with the subsequent casting of the mixture under pressure.

6. Injection, mg:

(1) 2-Butyl-4-chloro-5-hydroxymethyl-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]imidazole sodium salt - 10

(2) Inositol - 100

(3) Benzyl alcohol 20

One ampoule 130

(1), (2) and (3) dissolved in distilled water for injection to obtain total volume of 2 ml, which is poured a vial. All operations are performed in sterile conditions.

7. Capsules mg:

(1) 2-Ethoxy-1-[[2'-2,5-dihydro-5-1,2,4-thiadiazole-3-yl) biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid - 10

(2) Lactose - 90

(3) Microcrystalline cellulose 70

(4) magnesium Stearate - 10

One capsule - 180

(1), (2), (3) and half of (4) are mixed and granularit. To the granules is added the remainder of (4) and all of these fill gelatin capsules.

8. Tablets mg
<>/BR>(2) Lactose - 35

(3) Wheat starch - 50

(4) Microcrystalline cellulose 30

(5) magnesium Stearate - 5

One tablet - 230

(1), (2), (3), two-thirds (4) and half of (5) are mixed and granularit. To the granules is added the remainder of (4) and (5) with the subsequent casting of the mixture under pressure.

9. Injection, mg:

(1) 2-Ethoxy-1-[[2'-dihydro-5-oxo-1,2.4-thiadiazole-3-yl)- biphenyl-4-]methyl]benzimidazole-7 carboxylic acid disodium salt - 10

(2) Inositol

100

Benzyl alcohol - 20

One ampoule 130

(1), (2) and (3) dissolved in distilled water for injection to obtain a total volume of 2 ml, which is filled ampoule. All operations are performed in sterile conditions.

Working example 1. 2 Ethoxy-1[[2'-(2,5-dihydro-5-oxo-1, 2, 4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid.

1A) Methyl-3-amino-2-[[2'-cyanobiphenyl-4-yl)methylamino]benzoate.

A mixture of methyl 2-[[2'-cyanobiphenyl-4-yl)methyl]methyl]amino]-3-nitrobenzoate (10 g) synthesized in accordance with the method described in the official Gazette EP-0425921, FeCl36H2O (0.1 g) and activated charcoal (1 g) in a mixture of methanol (100 ml) and THF (50 ml) was boiled under reflux for 30 minutes To the reaction mixture substance was filtered to dryness. To the residue was added an aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with water and dried, the solvent was removed to dryness, the residue was purified column chromatography on silica gel. Thus obtained crystals are recrystallized from isopropyl ether with the formation of pale yellow needles (6.0 g, 64 %).

So pl. 110-111oC.

1H-NMR (200 MHz, CDCl3) : 3,81 (3H, s), of 3.97 (2H, Shir. C) to 4.23 (2H, d), to 6.39 (1H, t), 6,84-6,93 (2H, m), 7,26-of 7.55 (8H, m), of 7.64 (1H, dt), to 7.77 (1H, DD).

1b) Methyl-1-[[2'-cyanophenyl-4-yl)methyl]-2-ethoxybenzonitrile.

To a solution of methyl 3-amino-2-[(2'-cyanobiphenyl-4-yl)methyl]amino-benzoate (2,03 g) atractocerinae (5 ml) was added acetic acid (0,37 g) and the mixture was stirred for 1 h at 80oC. the Reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The solution was washed with an aqueous solution of sodium bicarbonate and water. The solvent was removed by drying with formation of crystals. Recrystallization of the crystals from a mixture of ethyl acetate-hexane resulted in the receipt of colorless crystals (2,01 g, 86 %).

So pl. 168,5-169, 5mmoC.

Elemental analysis of C25H21N3O3:

Calculated, %: C ), 4,63 (2H, K, J = 7.1 Hz), 5.59 (2H, s), 7.09 (2H, d, J = 8,4 Hz), 7.20 (1H, t, J = 7.9 Hz), 7.45-7.59 (5H, m), 7.69-7.80 (2H, m), 7.92 (IH, DD, J = 1.4, 7.8 Hz).

IR (KBR), cm-1: 2225, 1725, 1550, 1480, 1430, 1350, 1280, 1250, 1040, 760, 750.

1c) of Methyl 2-ethoxy-1[[2'-hydroxycarbonylmethyl)biphenyl)-4-yl]- methyl-1H-benzimidazole-7-carboxylate.

To a mixture of hydroxylaminopurine (of 6.95 g) in dimethyl sulfoxide (DMSO) (80 ml) solution was added 28 % NaOMe in methanol (5,2 g) under stirring at room temperature. The mixture was stirred at room temperature for 10 min, then was added the compound obtained in working example (1b) (8,2 g) and the mixture was stirred for 4 h at 90oC. To the stirred reaction mixture was added water (50 ml) at room temperature. The resulting crystalline precipitate was collected by filtration, washed with water and dried with formation of a white powder (8.0 g, 90 %).

1H-NMR (90 MHz, CDCl3): 1.43 (3H, t), of 3.73 (3H, t), of 3.73 (3H, s), 4.67 (2H, K), 5.63 (2H, s), 6.97-7.80 (IIH, m).

IR (Nujol), cm-1: 3430, 3320, 1720, 1545, 1430, 1280, 1040, 750.

1d) Methyl-2-ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate.

To a stirred suspension of the compound obtained in working example (1c) and triethylamine (0.2 g) in tetrahydro ice. The mixture was stirred 2 h at room temperature, and then the insoluble products were filtered off and the filtrate was concentrated to dryness. A mixture of the residue in xylene (10 ml) was heated for 1.5 h at boiling. To the reaction mixture was added ethyl acetate, washed with water, dried and was concentrated by drying. The residue was purified column chromatography on silica gel, with the formation of crude crystals. By recrystallization from ethyl acetate with isopropyl ether obtained colorless prisms (0.22 g, 23 %).

So pl. 195-197oC.

Elemental analysis of C26H22N4O5:

Calculated, %: C, 66.38; H, 4.71; N, 11.91.

Found, %: C, 66.17; H, 4.66; N, 11.84.

1H-NMR (90 MHz, CDCl3) : 1.43 (3H, t), 3.77 (3H, s), 4.60 (2H, K), 5,63 (2H, s), 7.00-7.73 (11H, m)

IR (Nujol), cm-1: 2740, 2670, 1775, 1720, 1545, 1450, 1435, 1275, 1040, 750.

1e) 2-Ethoxy-I[[2'-2,5-dihydro-5-oxo-1, 2, 4-oxadiazol-3-yl] biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid.

The compound obtained in working example (1d) (0,165 g), was dissolved in methanol (122 ml), to the solution was added 2 N. an aqueous solution of LiOH (1 ml), then it was heated to boiling and kept at this temperature under reflux for 3 hours and Then the pH of the reaction mixture is brought up to 3), then the organic layer was washed with water and dried. The solvent was evaporated to dryness, the crystalline product was led from ethyl acetate with the formation of colorless prisms (is 0.135 g, 84 %).

So pl. 156-157oC.

Elemental analysis for C25H20N4O51/2C4H8O21/5H2O:

Calculated, %: C, 64.33; H, 4.88; N, 11.11.

Found, %: C, 64.37; H, 4.89; N, 11.04.

1H-NMR (90 MHz, CDCl3) : 1.47 (3H, t), 4.60 (2H, K), 5.65 (2H, s), 6.97-7-77 (11H, m).

IR (Nujol), cm-1: 1775, 1730, 1685, 1540, 1425, 1270, 1030, 750.

Working example 2. Methyl 2-butyl-1[[2'-(2-oxo-3H-1, 2, 3, 5-oxadiazol-4-yl) biphenyl]methyl]benzimidazole-7-carboxylate.

In DMSO (3 ml) was dissolved methyl 2-butyl-1[(2'- cyanobiphenyl-4-yl) methyl] benzimidazole-7-carboxylate (1.27 g) synthesized in accordance with the method, published in the official Gazette EP-0425921, and gidroxinimesoulid (0.35 g). To the solution was added a 28 % solution of sodium methoxide in methanol (0,965 g) and the mixture was stirred 3 h at 90-100oC. To the reaction mixture were added water (20 ml) and the resulting precipitate was filtered. The filtrate was concentrated to dryness and the residue was purified column chromatography on silica gel with the formation of a light brown powder which was added upon cooling from -20oC to -25oC thionyl chloride (1.19 g). The mixture is stirred for some time, and then thereto was added water (3 ml) at a temperature of from -5oWith -10oC. To the reaction mixture was then added water (15 ml), the mixture was extracted with methylene chloride (20 ml). The organic layer was washed with water, dried and concentrated to dryness. The residue was purified column chromatography on silica gel. The resulting crude crystals are recrystallized from isopropyl ether with the formation of prisms (0.12 g, 7 %).

So pl. 124-125oC.

Elementary analysis for C27H26N4ABOUT4S 1/5C6H14O 1/5H2O:

Calculated, %: C, 64.02; H, 5.56; N, 10.59.

Found, %: C, 64.11; H, 5.52; N, 10.51.

1H-NMR (90 MHz, CDCl3: of 0.90 (3H, t), 1.20-2.00 (4H, m), 2.63 (2H, t), 3.70 (3H, c) 5.63 (2H, c), 6.73 (2H, d), 7.00-7.70 (8H, m), 7.83-7.93 (1H, m).

IR (Nujol), cm-1: 1725, 1520, 1435, 1410, 1290, 1180.

MS m / z: 502 (M+), 438, 423, 381, 192, 64.

Working example 3. Methyl-2-ethoxy-1-[(2'-(2-oxo-3H-1,2,3,5-oximation-4-yl)-biphenyl-methyl[benzimidazole-7-carboxylate.

To a solution of the compound (2.0 g) obtained in working example (1c), in THF (100 ml) was added pyridine (with 0.711 g). The mixture was added dropwise over 45 min with ice cooling to a solution of actuarial evaporated to dryness. To the residue was added water (50 ml) and the mixture was extracted with chloroform (100 ml). The extract was concentrated to dryness and the residue was purified by column chromatography. The obtained crystals are recrystallized from ethyl acetate with the formation of colorless prisms (0.35 g, 16 %).

So pl. 109-111oC.

Elemental analysis of C25H22N4O5S 1/5H2O:

Calculated, %: C, 60.77; H, 4.53; N, 11.34; S 6.49.

Found, %: C, 60.76; H, 4.49; N, 11.11; S 6.49.

1H-NMR (90 MHz, CDCl3) : 1.47 (3H, t), 3.73 (2 H,s), 4.53 (2 H, K) the ceiling of 5.60 (2H, s), 6.90 to-7,93 (11 H, m).

IR (Nujol), cm-1: 1720, 1545, 1430, 1280, 1040, 750.

Working example 4. 1-(Cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl] methyl] benzimidazole-7-carboxylate.

The compound obtained in working example (1E), was dissolved in dimethylformamide (8) ml). To the solution was added 1-(cyclohexyloxycarbonyloxy)ethylchloride (0.3 g), potassium carbonate (0,4) and potassium iodide (0,04). The mixture was stirred for 15 h at 80oC. the Solvent is evaporated to dryness. To the residue was added chloroform (100 ml), water (5 ml), ethanol (5 ml) and the mixture was shaken. The bottom layer was concentrated to dryness under reduced pressure and the residue was purified by using the Association in the form of colorless prisms (0.2 g, 36 %).

So pl. 108-109oC.

Elemental analysis of C34H34N4O85H2O:

Calculated, %: C, 64.24; H, 5.55; N, 8.81.

Found, %: C At 64.34; H, 5.50; N, 8.79.

1H-NMR (90 MHz, CDCl3) : 1.07-2.00 (16H, m), 4.03-4.67 (3H, m), 5.67 (2H, c), 6.57.90 (12H, m), 10.57 (1H, broad.).

IR (Nujol), cm-1: 1780, 1750, 1545, 1275, 1235, 1070, 1030.

Working example 5. 2 Ethylthio-4-methyl-1-[[2'-(2,dihydro-3-oxo-1,2,4-oxadiazol-5-yl) biphenyl-4-yl]methyl]-1H-thieno[3,4-d]imidazole-6-carboxylic acid.

5A) 0-methyl(4'-methylbiphenyl-2-yl)carbonylcyanide.

In chloroform (40 ml) was dissolved (4'-methylbiphenyl-2-yl)carboxylic acid (10 g). To the solution was added thionyl chloride (7 ml) and the mixture was stirred at the boil under reflux for 3 hours, the Reaction mixture was poured into ice water, then the organic layer was separated, washed with water and concentrated to dryness to form a syrup, which was dissolved in dioxane (80 ml). To the solution was added powdered potassium thiocyanate (9.16) and the mixture was heated 1 h at boiling under reflux. The reaction mixture was cooled and the insoluble part was filtered. After addition of methanol (15 ml) to the filtrate solution was heated for 15 min to boil with obratnyi from isopropyl ether with the formation of the specified product as white plates (7,4 g, 55 %).

So pl. 149-150oC.

1H-NMR (200 MHz, CDCl3) : 2.50 (3H, s), 4.01 (3H, c), 7.23-7.34 (4H, m), 7.38-7.60 (3H, m), 7.47 (1H, DD), 8.37 (1H, broad. C).

5b) of Dimethyl (4'-methylbiphenyl-2-yl)carboalumination.

To a solution of compound (7.4 g) obtained in working example (5A), in methanol (35 ml) was added methyliodide (4.0 g) and 28 % solution of sodium methoxide in methanol (5.5 g) and then the mixture was stirred for 24 h at room temperature. The reaction mixture was concentrated to dryness, then the residue was extracted with a mixture of ethyl acetate-water. The organic layer was washed with water and concentrated to dryness. The residue was purified by column chromatography on silica gel to obtain a colorless syrup (4.4 g, 57 %).

1H-NMR (200 MHz, CDCl3) : 2.29 (3H,C), 3.36 (3 H, s), is 2.37 (3H, c), 7.13-7.27(4H, m), 7.32-7.53 (3H, m), 7.93 (1H, m).

5c) of 3-methoxy-5-(4'-methylbiphenyl-2-yl)-1,2,4-oxadiazole.

To a solution of potassium hydroxide (1.1 g) in methanol (20 ml) was added powdered gidroxinimesoulid (1.2 g) and the mixture was well shaken. The mixture was added to a solution of compound (4.4 g) obtained in working example (5b), in 95 % ethanol (10 ml) and the resulting mixture was stirred for 18 h at room temperature. The reaction smack was dissolved in toluene (50 %). The solution was heated to boiling under reflux for 2 h with a catalytic amount of n-toluenesulfonic acid, followed by concentration to dryness. The residue was purified by column chromatography on silica gel to obtain a colorless syrup (2.5 g, 64 %).

1H-NMR (200 MHz, CDCl3) : 2.38 (3H, c), 4.08 (3H, s), 7.11-7.21 (4H, m), 7.41-7.62 (3H, m), 7.96(1H, DD).

5d) 5-(4'-methylbiphenyl-2-yl)-1,2,4-oxadiazole-3(2H)-he.

A mixture of compound (0.5 g) obtained in working example (5C), and pyridinylamino (5 g) was heated to 155oC for 30 min in nitrogen atmosphere. The reaction mixture was extracted with a mixture of ethyl acetate-water. The organic layer was washed with water and concentrated to dryness with the formation of pale yellow prisms (0.5 g, 100 %).

So pl. 145-150oC.

1H-NMR (200 MHz, CDCl3) : 2.36 (3H, c), 7.09-7.20 (4H, m), 7.44-7.53 (2H, m), 7.58-7.67 (1H, m), 7.88 (1H, DD).

IR (Nujol), cm-1: 1605, 1590, 1480, 1340, 815, 750.

5e) 5-(4'-Methylbiphenyl-2-yl)-2-trityl-1,2,4-oxadiazol-3(2H)-he.

To a solution of compound (1 g) obtained in working example (5d), and Fritillaria in dichloromethane (20 ml) was added dropwise with stirring. Then the mixture was stirred for 1 h at room temperature. The reaction mixture is Vatan prisms (0.9 g, 45 %).

So pl. 181-184oC.

1H-NMR (200 MHz, CDCl3) : 2.37 (3H, c), 7.06 (4H, c), 7.16-7.43 (17H, m), 7.52-7.60 (1H, m), 7.79 (1H, DD).

IR (Nujol), cm-1: 1745, 1595, 1580, 1440, 1335, 1160.

5f) 5-(4-Bromomethylbiphenyl-2-yl)-2-trityl-1,2,4-oxadiazol-3(2H)-he.

A mixture of compound (0.9 g) obtained in working example (5e), N-bromosuccinimide (0.3 g) and a catalytic amount of benzoyl peroxide was heated to boiling for 1 h in carbon tetrachloride (20 ml) when exposed to light. The reaction mixture was cooled, and then the precipitate was filtered. The filtrate was dried to dryness with the formation of the compounds in the form of a pale yellow amorphous powder (1.0 g, 99 %).

1H-NMR (200 MHz, CDCl3) : 4.47 (2H,c), 7.06-7.63 (22H, m), 7.85 (1H, DD).

5g) Methyl-2-ethylthio-4-Methyl-1-[[2'-(2,3-dihydro-3-oxo-2-trityl-1,2,4 - oxadiazol-5-yl)-4-yl]methyl]-1H-thieno [3,4-d]]imidazole-6-carboxylate.

To a stirred solution of methyl 2-ethylthio-4-methyl-1H-thieno [3,4-d]imidazole-6-carboxylate (0.4 g) in dimethylformamide (10 ml) was added in portions sodium hydride (60 % dispersion in mineral oil, 70 mg) under ice cooling. The mixture was still stirred for 30 min at room temperature. To the reaction mixture were added the compound (1 g), poluchennom was extracted with a mixture of ethyl acetate-water. The organic layer was washed with water, then concentrated to dryness. The residue was purified by column chromatography on silica gel with obtaining the specified compound as a yellow amorphous powder (0.6 g, 50 %).

1H-NMR (200 MHz, CDCl3) : 1.32 (3H, t), 2.66 (3H, c), 3.61 (3H, c), 3.25 (3H, K), 5.75 (2H, c), 7.10 (H, c), 7.19 (15H, c), 7.26-7.43 (2H, m), 7.53-7.60 (1H, m), 7.70 (1H, DD).

IR (Nujol), cm-1: 1740, 1685, 1595, 1330, 1315, 1160, 1080.

5h) Methyl-2-ethylthio-1] ] 2'-(2,3-dihydro-3-oxo-1,2,4-oxadiazol-5-yl)- biphenyl-4-yl]methyl]-4-methyl-1H-thieno[3,4-d] imidazole-6-carboxylate.

Compound (0.6 g) obtained in working example (5g) was dissolved in methanol (15 ml) and chloroform (10 ml). To the solution was added 1 N. HCl (0.9 ml) and the mixture was stirred for 1 h at room temperature. The reaction mixture was concentrated to dryness, the residue was distributed between a mixture of chloroform-water. The organic layer was washed with water and concentrated to dryness. The obtained residue was purified by column chromatography on silica gel with obtaining the specified connection in the form of a pale yellow amorphous powder (0.4 g, 95 %).

Elemental analysis of C25H22N4O4S22/5 CH2Cl2.

Calculated, %: C, 56.64; H, 4.25; N, 10.36.

Found.12 (2H, d), 7.12 (2H, d), 7.41-7.68 (3H, m), 7.80 (1H, d).

IR (Nujol), cm-1: 1685, 1590, 1530, 1355, 1315, 1230, 1160, 1085.

5i) 2 Ethylthio-1-[[2'-(2,3-dihydro-3-oxo-1,2,4-oxadiazol-5-yl)-biphenyl - 4-yl]methyl]-4-methyl-1H-thieno[3,4-d]imidazole-6-carboxylic acid.

The compound (0.1 g) obtained in working example (5h), was dissolved in tetrahydrofuran (2 ml) and water (1 ml). To the solution was added monohydrate hydroxadrine (25 mg) and the mixture was stirred for 17 h at boiling under reflux. The reaction mixture was concentrated to dryness, there was added water and then was filtered insoluble products. The filtrate was acidified using 1 N. HCl and the resulting precipitate was collected by filtration to obtain the specified connection powder (60 mg, 62 %).

So pl. 144-147oC.

Elemental analysis of C24H20N4O4S2:

Calculated, %: C, 58.52; H, 4.09; N, 11.37.

Found, %: C, 58.47; H, 4.25; N, 11.33.

1H-NMR (200 MHz, d6-DMCO) : 1.34 (3H, t), of 2.54 (3H, s) of 3.25 (2H, K) 5,70 (2H, s), 7,16 (2H, d), 7,20 (2H, d), 7,45-7.73 (3H, m), 7,88 (1H, d).

IR (Nujol), cm-1: 1650, 1590, 1525, 1310, 1160, 1085.

Working example 6. 2-Butyl-1[[2'-(2,3-dihydro-2-oxo-1,3,4-oxadiazol-5-yl)-biphenyl - yl]methyl]benzimidazole-7-carboxylic acid.

6a) 4'-methylbiphenyl-2-carb is N,N-dimethylformamide (two drops) and oxacillin (4.4 g). The mixture was stirred at room temperature for 16 hours the Solvent was evaporated to dryness under reduced pressure with the formation of oil, which was added dropwise to a solution of hydrazine monohydrate (7.5 g) in tetrahydrofuran (50 g) with stirring, followed by stirring for 6 hours the Reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel with the formation of crude crystals. By recrystallization from a mixture of chloroform-isopropyl ether received the specified compound as colourless needles (4.3 g, 63 %).

So pl. 98-99oC.

Elemental analysis of C14H14N2O:

Calculated, %: C 74,31; H 6,24; N 12,38.

Found, %: C 74,17; H 6,17; N 12,46.

1H-NMR (200 MHz, CDCl3) : (3H c) to 2.65 (2H, broad), 7,20-7,31 (4H, m), 7,35-of 7.55 (3H, m), to 7.67 (1H, DD).

IR (KBR), cm-1: 3280, 3220, 1670, 1610, 1520, 1320, 1185, 1100, 820, 755.

6b) 1-[2-(4'-Were)benzoyl]the formation.

To a solution of compound (4.3 g) obtained in working example (6a), in 1H. HCl (20 ml) was added dropwise an aqueous solution (20 ml) of sodium isocyanate (1.7 g) and the mixture paramashiva"ptx2">

So pl. 183-184oC (Razlog.).

Elemental analysis of C15H15N3O22H2O:

Calculated, %: C 65,79; H 5,61; N 15,38.

Found, %: C 65,79; H 5,61; N 15,38.

1H-NMR (200 MHz, DMCO-d6) : of 2.33 (3H, c), 5,71 (2H, broad), 7,18 (2H, d), 7,33-7,56 (6H, m) to 7.84 (1H, s), 9,84 (1H, broad).

IR (KBR), cm-1: 3260, 3230, 1700, 1650, 1520, 1305, 820, 765.

6c) of 2,3-Dihydro-5-(4'-methylbiphenyl-2-yl)-1,3,4-oxadiazol-2 (3H)-he.

The compound (4.0 g) obtained in working example (6b), suspended in acid (100 ml) and the mixture is boiled under reflux for 18 hours the Solvent drove to dryness under reduced pressure and the residue was purified by column chromatography on silica gel with the formation of crude crystals. By recrystallization from a mixture of ethyl acetate-hexane received the specified compound as colourless needles (2.0 g, 53 %).

So pl. 130-131oC.

Elemental analysis of C15H12N2O2:

Calculated, %: C 71,42; H 4,79; N 11,10.

Found, %: C 71,45; H 4,79; N 11,05.

1H-NMR (200 MHz, CDCl3) : 2,39 (3H, s), 7,19 (4H, s), 7,37-of 7.60 (3H, s), to 7.77 (1H, DD), 8,89 (1H, broad).

IR (KBR), cm-1: 1765, 1600, 1490, 1330, 1240, 1035, 960, 925, 815, 770, 750, 715, 700.

6b) of 2,3-Dihydro-5-(4'-methylbiphenyl-2-yl)-3-Trife what Rista the methylene (25 ml) was added triethylamine (0,89 g) and triphenylmethylchloride (2.5 g) and the mixture was stirred. The reaction mixture was washed with water, then dried. The solvent was evaporated to dryness under reduced pressure and the residue was purified column chromatography on silica gel with obtaining the specified connection in the form of a colorless amorphous powder (4.0 g, 100 %).

So pl. 60-63oC.

Elemental analysis of C34H26N2O:

Calculated, %: C 82,57; H And 5.30; N 5,66.

Found, %: C 82,67; H Lower Than The 5.37; N 5,20.

1H-NMR (200 MHz, CDCl3) : 2,31 (3H, s) to 7.00 (2H, d), 7,05-7,54 (20H, m), 7,68 (1H, DD).

IR (KBR), cm-1: 1780, 1490, 1445, 1335, 1280, 1005, 875, 820, 770, 755, 740, 700.

6e) 5-(4'-Bromomethylphenyl-2-yl)-2,3-dihydro-3-triphenylmethyl-1,3,4-oxadiazol-2 (3H)he.

To a solution of the compound (4.0 g) obtained in working example (6d) in carbon tetrachloride (50 ml) was added N-bromosuccinimide (1.4 g) and benzoyl peroxide (19 mg) and the reaction mixture is boiled under reflux for 1 h under irradiation with light. Insoluble products were filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel with the formation of the compounds in the form of a colorless amorphous powder (4.3 g, 93 %).

1H-NMR (200 MHz, CDCl3) : was 4.42 (2H, s), [2'-(2,3-dihydro-2-oxo-1,3,4-oxadiazol-5-yl) biphenyl-4-yl]-methyl-N-valeryl]amino-3-nitrobenzoate.

To a solution of compound (0,86 g) obtained in working example (6e), in acetonitrile (10 ml) was added methyl-3-nitro-2-valerianovna (0,42 g) and potassium carbonate (0.26 g) and the mixture is boiled under reflux for 36 h, the Reaction mixture was diluted with water, extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated to dryness under reduced pressure, the residue was purified by column chromatography on silica gel. Thus obtained oily product was dissolved in triperoxonane acid (5 ml), the solution was stirred for 30 min at 60oC. Triperoxonane acid was evaporated to dryness under reduced pressure. The residue was dissolved in ethyl acetate, washed with aqueous sodium hydrogen carbonate solution and dried. The solvent was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica gel with obtaining the specified oily product (0.50 g, 63 %).

1H-NMR (200 MHz, CDCl3) : of 0.85 (3H, t), 1.18 to about 1.36 (2H, m), 1,58-1,71 (2H, m), 2.05-of 2.15 (2H, m), of 3.69 (3H, s), 4,58 (1H, d), of 4.95 (1H, d), 7,06-7,16 (4H, m), 7,34 (1H, DD), 7,41-rate of 7.54 (2H, m), a 7.62 (1H, t), to 7.77 (1H, DD), 8,02 (1H, DD), 8,17 (1H, DD), 8,97 (1H, Shir.).

IR (neat), cm-1: 1815, 1780, 1730, 1660, 1530, 1445, 1390, 1370, 1340, 1285, 1260, 1230, 750.

To a solution of the compound (0.50 g) obtained in working example (6f), in methanol (10 ml) was added conc. HCl (1 ml) and iron powder (0.34 g). The mixture was boiled under reflux for 24 hours of Insoluble products were filtered off, the filtrate was concentrated to dryness. The residue was diluted with water and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated to dryness under reduced pressure, the residue was purified column chromatography on silica gel. The crude crystals thus obtained, recrystallized from a mixture of ethyl acetate-chloroform to obtain the specified connection in the form of colorless crystals (73 mg, 16 %).

So pl. 204-205oC.

Elemental analysis of C28H26N4O4:

Calculated, %: C 69,70; H 5,43; N Of 11.61.

Found, %: C 69,43; H 5,49; N 11,59.

1H-NMR (200 MHz, CDCl3) : of 0.94 (3H, t, 1,36-of 1.55 (2H, m), 1,79-of 1.94 (2H, m) to 2.94 (2H, t), of 3.73 (3H, s), 5,78 (2H, s), at 6.84 (2H, d) 7,16 (2H, d) 7,21 was 7.36 (2H, m), 7,41-EUR 7.57 (2H, m), of 7.64 (1h, DD), of 7.96 (1H, DD), a 9.35 (1H, broad.).

IR (KBR), cm-1: 1760, 1710, 1600, 1430, 1405, 1335, 1270, 750.

6h) 2-Butyl-1-[[2'-(2, 3-dihydro-2-oxo-1, 3, 4-oxadiazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid.

To a solution of compound (30 g) obtained in working the 1,5 hours After evaporation of the solvent the residue was washed with water, the pH was brought up to 3-4 with 1 N. HCl, the precipitate precipitated crystals. The crystals were collected by filtration, recrystallized from a mixture of ethyl acetate: methanol with the formation of the compounds in the form of colorless needles (16 mg, 54 %).

So pl. 247-248oC.

Elemental analysis of C27H24N4O40.5 H2O:

Calculated, %: C 67,91; H 5,28; N 11,73.

Found, %: C 68,19; H To 5.21; N 11,89.

1H-NMR (200 MHz, CDCl3) : and 0.98 (3H, t), 1,40-1,60 (2H, m), 1,81-of 1.97 (2H, m), 3,05 (2H, t), by 5.87 (2H, s) 6,86 (2H, d), 7,17 (2H, d), 7,28 (1H, t), of 7.36 to 7.62 (3H, m), to 7.67 (1H, DD), 7,83 (1H, DD), to 7.99 (1H, DD).

IR (KBR), cm-1: 1770, 1700, 1600, 1410, 1230, 740.

Working example 7. 2 Ethylthio-1-[[2' -(2, 3-dihydro-2-oxo-1, 3, 4-oxadiazol-5-yl)biphenyl-4-yl] methyl] -4-methylthieno[3, 4-d] imidazole-6-carboxylic acid.

7a) Methyl-2-ethylthio-1-[[2'-(2, 3-dihydro-2-oxo-1,3,4-oxadiazol-5-yl)biphenyl-4-yl]methyl]-4-methylthieno[3,4-d]imidazole-6-carboxylate.

It chilled with ice to a solution of methyl 2-ethylthio-methylthieno [3, 4-d]imidazole-6-carboxylate (0.26 g) in N,N-dimethylformamide (2 ml) was added sodium hydride (60 % dispersion in mineral oil, 44 mg) and the mixture was stirred for 15 minutes, then there was added 5-(4'-bromomethyl room temperature, then was diluted with water and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated to dryness under reduced pressure and the residue was dissolved in triperoxonane acid (5 ml). The solution was stirred for 30 min at 60oC and then concentrated to dryness under reduced pressure, the residue was dissolved in ethyl acetate. The solution was washed with an aqueous solution of sodium bicarbonate and dried. The solvent was evaporated to dryness under reduced pressure, the residue was purified by column chromatography on silica gel with the formation of crude crystals. By recrystallization from ethyl acetate has received the connection specified in the form of yellow prisms (0.17 g, 33%).

So pl. 220-221oC.

Elemental analysis of C25H22N4O4S2:

Calculated, %: C 59,27; H To 4.38; N 11,06.

Found, %: C 59,18; H 4,50; N 10,91.

1H-NMR (200 MHz, CDCl3) : of 1.42 (3H, t), 2,62 (3H, s), 3,30 (2H, in), 3.75 (3H, s) 5,70 (2H, s), 7,13-of 7.23 (4H, m), 7,34-7,58 (3H, m), to 7.77 (1H, DD), 8,82 (1H, broad).

IR (neat), cm-1: 1770, 1695, 1600, 1530, 1445, 1340 1320, 1240, 1195, 1165, 1085, 1000, 750.

7b) 2-Ethylthio-1-[[2'-(2,3-dihydro-2-1,3,4-oxadiazol-5-yl)biphenyl - 4-yl] methyl]-4-methylthieno[3,4-d]imidazole-6-carboxylic acid.

To a solution of compound (0 is s (60 mg) in water (3 ml). The mixture was stirred for 60 min at 50-60oC. the Solvent was evaporated to dryness under reduced pressure. The residue was diluted with water, the pH of the solution brought up to 3-4 using 1 N. HCl until precipitation of crystals. The crystals were collected by filtration by recrystallization from a mixture of ethyl acetate: methanol, received the connection specified in the form of yellow prisms (72 mg, 60 %).

So pl. 195-196oC (decomp.).

Elemental analysis of C24H20N4O4S2H2O:

Calculated, %: C 58,10; H 4,14; N 11,29.

Found, %: C 58,13; H 4,22; N 11,22.

1H-NMR (200 MHz, DMCO-d6) : of 1.34 (3H, t), to 2.55 (3H, s), 3.25 (2H, s), 7.19 (2H, d), 7.28 (2H, d), 7. 42 (1H, DD), 7.49-7.62 (2H, m), 7.76(1H, DD), 12.40 (1H, broad.).

IR (KBr), cm-1: 1760, 1685, 1600, 1440, 1330, 1185, 1160, 1080, 960, 925, 760, 750.

Working example 8. 2 Ethylthio-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl] methyl]-4-methylthieno[3,4-d]imidazole-6-carboxylic acid.

8a) of Methyl 2-utilty-4-methyl-1-[2'-(5-trichloromethyl-1,2,4-oxadiazol-3-yl)biphenyl - 4-yl]methylthieno[3,4-d]imidazole-6-carboxylate.

It chilled with ice to a solution of methyl-2-ethylthio-4-methylthieno [3.4-d]imidazole-6-carboxylate (3 g) in DMF (20 ml) solution was added sodium hydride (60 %, oil) (0.56 g) and the mixture was stirred for 10 minutes To klemeshev at room temperature for 2 hours To the reaction mixture were added water and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of salt. The solvent is kept at reduced pressure, the residue was purified by column chromatography on silica gel, with the formation of the compounds in the form of a pale yellow syrupy product (4.15 g, 58 %).

IH-NMR (200 MHz, CDCl3) : 1.42 (3H, t), 2.62 (3H, s), 3.29 (2H, K), 3.77 (2H, K), 3.77(3H, s), 5.71 (2H, s), 7.16 (4H, s), 7.42-7.62 (3H, m), 7.83-7.88 (1H, m).

IR (neat), cm-1: 1690, 1600, 1450, 1430, 1345, 1330, 1315, 1230, 1190, 1160, 1090, 850, 820, 800, 755, 730.

8b) Methyl-2-ethylthio-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl]-4-methylthieno[3,4-d]imidazole-6-carboxylate.

To a solution of compound (4.15 g) obtained in working example (8a), in MeOH (50 ml) - CHCl3(10 ml) was added 1 N. NaOH (10 ml) and the mixture was stirred for 30 min at room temperature. The reaction mixture was acidified to pH 4 using 1 N. HCl, and then thereto was added water, followed by extraction with CHCl3. The extract was washed with water, dried and the solvent is kept at reduced pressure to dryness with the formation of crude crystals. By recrystallization from a mixture of ethyl acetate-methanol-hexane received the specified connected 25H22N4O4S2:

Calculated, %: C 59,27; H, 4.38; N, 11.06

Found, %: C, 59.07; H, 4.26; N, 11.00

IH-NMR (200 MHz, CDCl3) : 1.42 (3H, t), 2.61 (3H, s) 3.29 (2H, K), 3.75 (2H, K), 3.75 (3H, s), 5.74 (2H, s) 7.26 (4H, s), 7.42 (1H, dt), 7.51(1H, DD), 7.61(1H, dt), 7.85 (1H, DD), 7.90 (1H, broad. C).

IR (KBr), cm-1: 1760, 1680, 1595, 1455, 1450, 1430, 1315, 1230, 11,60, 1085, 755.

8c) 2-Ethylthio-1[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl - 4-yl]methyl]-4-methylthieno[3,4-d]imidazole-6-carboxylic acid.

To a solution of the compound (0.5 g) obtained in working example (8b), in tetrahydrofuran (THF) (5 ml) and H2O (2.5 ml) was added monohydrate monoxide sodium (0.12 g) and the mixture is boiled under reflux for 7 hours To the reaction mixture were added water and the mixture acidified to pH 3 using 1 N. HCl. The resulting crystals were collected by filtration and recrystallized from a mixture of chloroform-methanol with the formation of the compounds in the form of colorless needles (0.36 g, 73 %).

So pl. 217-219oC (Razlog.).

Elemental analysis of C24H20N4O4S 3H2O:

Calculated, %: C At 57.89; H, 4.17; N, 11.25.

Found, %: C At 57.89; H, 4.02; N, 11.08.

1H-NMR (200 MHz, DMCO-d6): 1.34 (3H, t), 2.55 (3H, s), 3,24 (3H, K), 5.71 (2H, s), 7.19 (2H, d), 7,28(2H, d), 7.28 (2H, d), 7.4, ethoxy-1[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4 - yl]methyl]-4-methylthieno[3,4-d]imidazole-6-carboxylic acid.

9a) of Methyl 2-ethylsulfinyl-1-[[2'-(2,5-dihydro-5-oxo-1,2.4 - oxadiazol-3-yl)biphenyl-4-yl]methyl]-4-methylthieno[3,4-d]imidazole-6 - carboxylate.

To a solution of compound (3.15 g) obtained in working example (8b), in methylene chloride (100 ml) was added m-chloroperbenzoic (13 g) and the mixture was stirred for 20 h at room temperature. To the reaction mixture were added saturated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated to dryness and the residue was purified on silica gel using column chromatography with the formation of crude crystals. By recrystallization from a mixture of ethyl acetate-methanol-hexane received the specified compound as colourless needles (2,60 g, 80 %).

So pl. 206-208oC (Razlog.).

Elemental analysis of C25H22N4O5S2:

Calculated, %: C, 57.46; H, 4.24; N, 10.72.

Found, %: C, 57.28; H, 4.27; N, 10.45.

IH-NMR (200 MHz, CDCl3) : of 1.27 (3H, t), a 2.71 (3H, s), 3.38 (2H, K), 3.82 (3H, s), 5,98(1H, d), 6,40(1H, d), 7.26(3H, m), 7.41-7.64 (3H, m), 7.81 (1H, DD), 8.75 (1H, broad. C)

IR (KBr), cm-1: 1770, 1685, 1450, 1420, 1315, 1235, 1090, 1050, 1040, 1020, 780, 750.

9b) Methyl-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl]-2-metiloksi-4-matiltan is zero (20 ml) was added sodium methoxide (28 %, a methanol solution) (0.88 g) and the mixture was stirred for 30 min at room temperature. To the reaction mixture were added water and the pH of the mixture was brought to 4 with 1 N. HCl, then was extracted with ethyl acetate, then washed with a saturated aqueous saline solution and dried. The solution drove to dryness under reduced pressure with the formation of crude crystals. By recrystallization from a mixture of ethyl acetate-hexane received the specified compound as colourless needles (0.71 g, 98 %).

So pl. 207-209oC (Razlog.).

Elemental analysis of C24H20N4O5S:

Calculated, %: C, 60.49; H, 4.23; N, 11.76.

Found, %: C, 60.23; H, 4.29; N, 11.49.

IH-NMR (200 MHz, CLCl3) : 2.37 (3H, s) 3.73(3H, s), 3.99(3H, s) 5,59 (2H, s), 7.25(4H, s), 7.38(1H, DD), 7.59 (1H, dt), 7.61 (1H, dt), 7.83 (1H, DD), 8.79 (1H, broad. C).

IR (KBr), cm-1: 1750-1685, 1610, 1570, 1525, 1450, 1440, 1430, 1375, 1330, 1230, 1055, 750.

9c) 1-[[2'-(2,5-Dihydro-5-oxo-1,2,4-oxadiazol-3-yl)- biphenyl-4-yl]-methyl]2-methoxy-4-methylthieno[3,4-d]imidazole-6-carboxylic acid.

To a mixture of compound (0.6 g) obtained in working example (9b), in a mixture of THF (10 ml) and water (5 ml) was added monohydrate of lithium hydroxide (0.16 g). The mixture was boiled under reflux for 8 hours To the reaction mixture were added water Oh and dried. The solvent was evaporated to dryness under reduced pressure with the formation of crude crystals. By recrystallization from a mixture of ethyl acetate: methanol received the specified compound as colourless needles (0.35 g, 54 %).

So pl. 183-186oC (Razlog.).

Elemental analysis of C23H18N4O5S 0/5AcOEt:

Calculated, %: C 59,28; H, 4.38; N, 11.06.

Found, %: C, 58.94; H, 4.15; N, 11.18.

IH-NMR (200 MHz, DMCO-d6) : 2.48 (3H, s), 4.06(3H, c), 5/56 (2H, s), 7.21-7.31 (4H, m), 7.49-7.72 (4H, m).

IR (KBr), cm-1: 1800, 1660, 1650, 1570, 1450, 1380, 1370, 1330, 1240, 760, 730.

Working example 10. 2 Ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl]-4-methylthieno[3,4-d]imidazole-6-carboxylic acid.

10a) Methyl-2-ethoxy-1[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl]-4-methylthieno[3,4-d]imidazole-6-carboxylate.

To a solution of sodium (0.1 g) in ethanol (20 ml) was added compound (0.7 g) obtained in working example (9a), and the mixture was stirred for 30 min at room temperature. To the reaction mixture were added water and the mixture was acidified with 1 N. HCl to pH 4, then it was extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated to dryness under reduced pressure with the formation of the foi %) and the mixture is boiled under reflux for 7 hours After addition of water the mixture was acidified to pH 4 using 1 N. HCl, then was extracted with ethyl acetate. The extract was washed with water and dried, the solvent was evaporated to dryness under reduced pressure to obtain crude crystals. By recrystallization from a mixture of ethyl acetate-methanol-hexane received the connection specified in the form of pale yellow prisms (0.5 g, 76 %).

So pl. 215-217oC (Razlog.).

Elemental analysis of C25H22N4O5:

Calculated, %: C, 61.21; H, 4.52; N, 11.42.

Found, %: C, 61.02; H, 4.32; N, 11.28.

IH-NMR (200 MHz, CDCl3) : 1.42 (3H, t), 2.45 (3H, s), 3.75 (3H, s), of 4.45 (2H, K), 5.59 (2H, s), 7.23-7.33 (4H, m), 7.38 (1H, DD), 7.49 (1H, dt), 7.60 (1H, dt), 7.84 (1H, DD), 8.27 (1H, broad., C).

IR (KBr), cm-1: 1760, 1685, 1610, 1570, 1460, 1445, 1435, 1410, 1380, 1330, 1230, 1100, 1060, 760.

10b) 2 Ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)- biphenyl-4-yl]methyl]-4-methylthieno[3,4-d]imidazole-6-carboxylic acid.

To a suspension of compound (0.4 g) obtained in working example (10a), in a mixture of THF (10 ml) and water (5 ml) was added monohydrate of lithium hydroxide (0.1 g), the mixture is then boiled under reflux for 12 hours To the reaction mixture was added water, then the mixture was acidified to pH 4 using 1 N. HCl. By recrystallization of the obtained crystal is PL ... 206-208oC (Razlog.).

Elemental analysis of C24H20N4O5S:

Calculated, %: C 60,49; H, 4.23; N, 11.76.

Found, %: C, 60.27; H, 4.15; N, 11.70.

1H-NMR (200 MHz, DMCO-d6) : 1.32 (3H, t), 2.46 (3H, s), 4.47 (2H, K), 5.56 (2H, s), 7.27 (4H, s), 7.49-7.72 (4H, m).

IR (KBr), cm-1: 1760, 1650, 1600, 1570, 1525, 1460, 1445, 1330, 1240, 760.

Working example 11. 1-[2'-(2,5-Dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl] methyl-4-methyl-2-p-proposition[3,4-d]imidazole-6-carboxylic acid.

11a) Methyl-12-[[2'-(2,5-dihydro-5-oxo-1,2,4, oxadiazol-3-yl] biphenyl-4-yl]methyl-4-methyl-2-p-proposition[3,4-d]imidazole-5-carboxylate.

To a solution of sodium (0.1 g) in isopropanol (20 ml) was added compound (0.7 g) obtained in working example (9a), and the mixture was stirred for 30 min at room temperature. To the reaction mixture was added water, acidified her to pH 4 using 1 N. HCl, then the mixture was extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated to dryness under reduced pressure with the formation of crystals. Crystals suspended in methanol and the suspension was added sodium methoxide (28% solution in methanol) (0.65 g). The mixture was boiled under reflux for 7 hours To the reaction mixture were added water and left the house taking. The solvent was evaporated to dryness under reduced pressure with the formation of crude crystals. By recrystallization from a mixture of ethyl acetate-methanol-hexane received the connection specified in the form of pale yellow prisms (0.5 g, 74 %).

So pl. 213-215oC (Razlog.).

Elemental analysis of C26H24N4O5S:

Calculated, %: C, 61.89; H, 4.79; N, 11.10.

Found, %: C, 61.73; H, 4.63; N, 10.93.

1H-NMR (200 MHz, CDCl3): 0.98 (3H, t), 1.71-1.91 (2H, m), 2.47 (3H, s), 4.37 (2H, s), 7.23-7.34 (4H, m), 7.37 (1H, DD), 7.49 (1H, dt), 7.60 (1H, dt), 7.83 (1H, DD), 8.22 (1H, broad. C)

IR (KBr), cm-1: 1760, 1690, 1615, 1570, 1530, 1460, 1445, 1430, 1410, 1360, 1330, 1230, 1100, 1060, 755.

11b) 1-[2'-(2,5-Dihydro-5-oxo-1,2,4 oxidiazol-3-yl)biphenyl-4 - yl] methyl-4-methyl-2-p-proposition[3,4-d]imidazole-6-carboxylic acid.

To a suspension of compound (0.4 g) obtained in working example (11a), in a mixture of THF (10 ml) and water (5 ml) was added monohydrate of lithium hydroxide (0.1 g), the mixture is then boiled under reflux for 12 hours To the reaction mixture was added water, the mixture was acidified to pH 4 using 1 N. HCl. The resulting crystals were collected by filtration and recrystallized from a mixture of chloroform-methanol-ether with the formation of the compounds in the form of colorless needles (0.28 g, 72 %).

Designed, %: C, 60.55; H, 4.59; N, 11.30.

Found, %: C, 60.58; H, 4.43; N, 11.39.

1H-NMR (200 MHz, DMCO-d6) : 0.89 (3H, t), 1.65-1.82 (2H, m), 2.48 (3H, s), 4.38 (2H, t), 5.59 (2H, s), 7.28 (4H, s), 7.49-7.74 (4H, m).

IR (KBr), cm-1: 1760, 1650, 1645, 1605, 1570, 1530, 1460, 1445, 1325, 1240, 760.

Working example 12. 2 Ethylamino-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-yl] methyl] -4-methylthieno[3,4-d] imidazole-6-carboxylic acid.

12b) Methyl-2-ethylamino-1[[2'-(2,5-dihydro-5-oxo-1,2,4 - oxadiazol-3- -yl)biphenyl-4-yl]methyl]-4-methylthieno[3,4-d]imidazole-6-carboxylate.

A mixture of compound (0.60 g) obtained in working example (9a), and 70 % aqueous solution of ethylamine (10 ml) was heated at 80oC in an autoclave for 2 hours the Reaction mixture was concentrated to dryness and acidified to pH 4 using 1 N. HCl. The mixture was extracted with chloroform, the extract was washed with water and dried. The solvent was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica gel with the formation of crude crystals. By recrystallization from a mixture of ethyl acetate-methanol-hexane, received the specified compound as pale orange needles (0.28 g, 45 %).

So pl. 219-221oC (Razlog.).

Elemental analysis of C25H23N5O4S 0.5 Acoet (533.60. .40 (3H, s), 3.31 (2H, K), 3.67 (3H, s), 5.61 (2H, s), 7.16 (2H, d), 7.23 (2H, d), 7.38 (2H, dt), 7.47 (1H, DD) 7.58 (1H, dt), 7.72 (1H, DD).

IR (KBr), cm-1: 3325, 1740, 1690, 1610, 1590, 1540, 1460, 1435, 1335, 1230, 1090, 765.

12b) 2 Ethylamino-1[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)-biphenyl-4-yl]- methyl]-4-methylthieno[3,4-d]imidazole-6-carboxylic acid.

To a suspension of compound (0.2 g) obtained in working example (12b), in a mixture of THF (5 ml) and water (2.5 ml) was added monohydrate of lithium hydroxide (51 mg), the mixture was boiled under reflux for 24 hours the reaction mixture was added water, then the mixture was acidified to pH 4 using 1 N. HCl. The crystals which precipitated were collected by filtration and recrystallized from a mixture of chloroform-methanol with the formation of the specified compound in the form of pale yellow crystals. (0.12 g, 67 %).

So pl. 189-192oC (Razlog.).

Elemental analysis of C24H21n5O4S 1.0 MeOH (507.56):

Calculated, %: C, 59.16; H, 4.96; N, 13.80.

Found, %: C, 59.34; H, 4.76; N 14.00.

1H-NMR (200 MHz, DMCO-d6) : 1.13 (3H, t), 2.34 (3H, s), 3.28 (2H, K), 5.84 (2H, s), 7.06 (2H, s), 7.22 (2H, d), 7.28 (1H, DD), 7.34-7.43 (2H, m), 7.47 (1H, DD).

IR (KBr), cm-1: 1700, 1680, 1670, 1650, 1635, 1560, 1540, 1510.

Working example 13. Acetoxymethyl-1[[2'-(4-acetoxymethyl-4,5-dihydr the organisations (1.02 g), obtained in working example (1), in DMF (4 ml) was added triethylamine (413 mg). To stir the mixture was added azoxymethane (444 mg) at room temperature, then the mixture was stirred for another 20 h in the same conditions. To the reaction mixture was added dichloromethane (40 ml), water (25 ml) and 2 N. HCl (3 ml) and the mixture was shaken. The organic layer was separated and concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel with the formation of crude crystals. Precrystallization from a mixture of ether-isopropyl ether got the connection specified in the form of colorless prisms (350 mg, 30 %).

So pl. 132-133oC.

Elemental analysis of C31H28N4O9:

Calculated, %: C, 62.00; H, 4.70; N, 9.33.

Found, %: C, 62.08; H, 4.60; N, 9.29.

1H-NMR (90 MHz, CDCl3) : 1.47 (3H, t), 1.77 (3H,s), 2.10 (3H, s). 4.67 (2H, K), 4.87 (2H, s), 5.70 (2H, s), 5.87 (2H, s), 7.00-7.83 (11H, m).

IR (Nujol), cm-1: 1790, 1760, 1730, 1200, 1035, 980.

Working example 14. Acetoxymethyl 2-ethoxyl-1[[2'-(2,5-dihydro-5-oxo-1,2,4 - oxadiazol-3-yl)butenyl-4-yl]methyl]benzimidazole-7-carboxylate.

Was carried out the same reaction as in working example 13, and the reaction mixture was purified using a column of chromatography who received the specified connection in the form of colorless prisms (250 mg, 29 %).

So pl. 111-112oC.

Elemental analysis of C28H24N4O71/30C6H14O 1/5H2O:

Calculated, %: C, 63.24; H, 4.68; N, 10.46.

Found, %: C, 63.31; H, 4.64; N, 10.20.

1H-NMR (90 MHz, CDCl3) : 1.40 (3H, t), 2.00 (3H, s), 4.40 (2H, K), 5.67 (2H, s), 5.70 (2H, s), 6.87-7.90 (11H, m).

IR (Nujol), cm-1: 1780, 1730, 1545.

Working example 15. 1-[[2'-(4-Acetoxymethyl-4,5-dihydro-5-oxo-4H-1,2,4 - oxadiazol-3-yl-biphenyl-4-yl]methyl]-2-ethoxybenzylidene-7-carboxylate.

Was carried out the same reaction as in working example 13, and the reaction mixture was purified by column chromatography on silica gel with the formation crude crystals, followed by recrystallization from ethyl acetate with the formation of the compounds in the form of colorless prisms (50 mg, 5 %).

So pl. 177-179oC.

Elemental analysis of C28H24N4O71/3 H2O:

Calculated, %: C, 62.92; H, 4.65; N, 10.48.

Found, %: C, 62.86; H, 4.44; N, 10.35.

1H-NMR (90 MHz, CDCl3) : 1.47 (3H, t), 1.77 (3H, s), 4.70 (2H, K), 4.80 (2H, s), 5.70 (2H, s), 6.97-7.83 (11H, m).

IR (Nujol), cm-1: 1785, 1760, 1690, 1550, 1205, 1035.

Working example 16. 1-[[2'-(2,5-Dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl] methyl]-2-p)biphenyl - 4-yl] methyl]-2-propylpyrazole[1,5-b][1,2,4]triazole-7-carboxylate.

To a solution of ethyl 2-propyl-1H-pyrazolo [1,5-b][1,2,4]triazole-7-carboxylate (0.4 g), cooled with ice, N,N-dimethylformamide (7 ml) was added sodium hydride (60 %, oil; 72 mg) in a nitrogen atmosphere and the mixture was stirred for 30 min at the same temperature. To the reaction mixture was added a solution of compound (1.15 g) obtained in working example (22c) in N,N-dimethylformamide (7 ml). The mixture was stirred for 1 h under ice cooling, and then 3 h at room temperature. The reaction mixture was concentrated to dryness under reduced pressure. To the residue was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried, then the solvent is evaporated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel with the formation of the compounds in the form of a white amorphous powder (0.92 g, 89 %).

1H-NMR (200 MHz, CDCl3) : 1.01 (3H, t), 1.30 (3H, t), 1.70-1.88 (2H, m), 2.67 (2H, t), 4.27 (2H, K), 5.72 (2H, s), 7.14 (2H, d), 7.24 (2H, d), 7.40-7.60 (3H, m), 7.90-7.94 (1H, m), 8.00 (1H, s).

IR (KBr), cm-1: 2970, 1692, 1600, 1538, 1470.

16b) Ethyl 1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl]-2-propylpyrazole[1,5-b][1,2,4]-triazole-7 - carboxylate.

To the solution was cooled with ice, connections (0.9 ivali for 15 minutes under ice cooling. To the reaction mixture were added 1 N. HCl (2.5 ml) and water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried, then the solvent is evaporated to dryness under reduced pressure. The residue was led from a mixture of ethyl acetate-ether with the formation of the compounds in the form of colorless crystals (0.666 g, 88 %).

So pl. 227-228oC.

Elemental analysis of C25H24N6O4:

Calculated, %: C, 63.55; H, 5.12; N, 17.79.

Found, %: C, 63.53; H, 5.20; N 17.67.

1H-NMR (200 MHz, DMCO - d6) : 0.91 (3H, t), 1.16 (3H, t), 1.54-1.73 (2H, m), 2.73 (2H, t), 4.16 (2H, K), 5.75 (2H, s), 7.26 (2H, d), 7.32 (2H, d), 7.48-7.73 (4H, m), 7.96 (1H, s).

IR (KBr), cm-1: 3100, 2980, 1795, 1702, 1602, 1540, 1468.

16c) 1-[[2'-(2,5-Dihydro-5-oxo-1,2,4-oxadiazol-3-yl)- biphenyl-4-yl]methyl]-2-propylpyrazole[1,5-b][1,2,4]-triazole-7 - carboxylic acid.

To a mixture of compound (0.2 g) obtained in working example (16b), in a mixture of methanol (5 ml), tetrahydrofuran (5 ml) and water (5 ml) was added 2 N. NaOH (2.1 ml) and the mixture is boiled under reflux for 3 hours, the Reaction mixture was cooled, and thereto was added 2 N. HCl (3.0 ml) and water, then the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and the solvent evaporated to dryness at below the x crystals (0.17 g, 90 %).

So pl. 223-225oC.

Elemental analysis of C23H20N6O40.2 Acoet:

Calculated, %: C, 61.87; H, 4.71; N 18.19.

Found, %: C, 61.81; H, 4.66; N 18.28.

1H-NMR (200 MHz, DMCO - d6) : 0.90 (3H, t), 1.52-1.70 (2H, m), 2.71 (2H, t), 5.79 (2H, s), 7.32 (4H, s), 7.50-7.73 (4H, m), 7.92 (1H, s), 12.35 (1H, broad. C.).

IR (KBr), cm-1: 3060, 2960, 2700-2200, 1783, 1668, 1590, 1540, 1483.

Working example 17. 1-[[2'-(2,5-Dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl] methyl-2-propylimidazol[1,2-b]pyrazole-7-carboxylic acid.

17a) Ethyl-2-propyl-[[2'-(5-trichloromethyl-1,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl]imidazol[1,2-b] pyrazole-7-carboxylate.

A reaction similar to that shown in working example (16a), was the compound obtained in the form of a pale yellow oil (0.16 g, 47 %) of ethyl 2-propyl-1H-imidazo[1,2-b]pyrazole-7-carboxylate (0,132 g).

1H-NMR (200 MHz, CDCl3) : 0.98 (3H, t), 1.28 (3H, t), 1.53-1.72 (2H, m), 2.46 (2H, t), 4.23 (2H, K), 5.75 (2H, s), 7.05 (2H, d), 7.14 (1H, s), 7.18 (2H, d), 7.41-7.63 (3H, m), 7.86-7.91 (1H, m), 8.01 (1H, s).

IR (neat), cm-1: 2975, 1702, 1690, 1603, 1582, 1562, 1562, 1495.

17b) Ethyl-1[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl]-2-propylimidazol[1,2-b]pyrazole-7-carboxylate.

By conducting the reaction similar to prevedeno the>
C (ethyl acetate-ether), from the compound obtained in working example (17a) (0.15 g).

Elemental analysis of C26H25N5O40.5 H2O:

Calculated, %: C, 64.99; H, 5.45; N, 14.57.

Found, %: C, 65.27; H, 5.50; N, 14.38.

1H-NMR (200 MHz, CDCl3) : 0.99 (3H, t), 1.27 (3H, t), 1.53-1.72 (2H, m), 2.48 (2H, K), 5.74 (2H, s), 7.13 (2H, d), 7.27 (2H, d), 7.38-7.65 (3H, m), 7.80-7.84 (1H, m), 7.92 (1H, s), 8.31 (1H, broad.).

IR (KBr), cm-1: 3125, 2960, 1780, 1705, 1600, 1585, 1492, 1470.

17c) 1-[[2'-(2,5-Dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4 - yl]methyl]-2-propylimidazol[1,2-b]pyrazole-7-carboxylic acid.

Reactions similar to that shown in working example (16c), was obtained the specified connection, in the form of colorless crystals (48 mg, 57 %), so pl. 191-196oC (Razlog.) (methanol-water), from the compound obtained in working example (17b) (90 mg).

Elemental analysis of C24H21N5O4:

Calculated, %: C, 65.00; H, 4.77; N, 15.79.

Found, %: C, 65.28; H, 4.68; N, 15.72.

1H-NMR (200 MHz, DMCO - d6) : 0.89 (3H, t), 1.43-1.62 (2H, m), 2.43-2.51 (2H, m), 5.80 (2H, s), 7.18 (2H, d), 7.29 (2H, d), 7.50-7.72 (5H, m), 11.87 (1H, broad. C.).

IR (KBr), cm-1: 3025, 2960, 1700-2200, 1780, 1634, 1595, 1580, 1498.

Working example 18. Ethyl-2-ethyl-4,7-dihydro-7-[[2'-(2,5-dihydro-5-oxo-1,2,4 - oxa is-1,2,4-oxadiazol-3-yl)biphenyl - 4-yl] methyl]-2-ethyl-4,7-dihydro-4-oxathiane[2,3-b]pyridine-5 - carboxylate.

It chilled with ice to a solution of ethyl-2-ethyl-4-hydroxyimino [2,3-b]pyridine-5-carboxylate (0.25 g) in N,N-dimethylformamide (DMF) (7 ml) was added under nitrogen atmosphere sodium hydride (60 % in oil; 40 mg) and the mixture was stirred for 30 minutes To the reaction mixture was added a solution of the compound obtained in working example (22c) (0.6 g) in N,N-dimethylformamide (4 ml) and the mixture was stirred for 2 h at room temperature. The reaction mixture was concentrated to dryness under reduced pressure. To the residue was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried, the solvent is evaporated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel with the formation of the compounds in the form of a white powder (0.5 g, 83 %).

1H-NMR (200 MHz, CDCl3) : 1.32 (3H, t), 1.41 (3H, t), 2.82 (2H, d), 4.40 (2H, K), 5.22 (2H, s), 7.23-7.33 (5H, m), 7.43-7.65 (3H, m), 7.93-7.98 (1H, m), 8.39 (1H, s).

IR (KBr), cm-1: 2975, 1672, 1580, 1493.

Ethyl-2-ethyl-4,7-dihydro-7-[[2'-(2,5-dihydro-5-oxo-1,2,4 - oxadiazol-3-yl)biphenyl-4-yl]methyl]-4-oxathiane[2,3-b]pyridine-5 - carboxylate.

It chilled with ice to a solution of compound (0.49 g) obtained in working example (18a), in a mixture of dioxane (8 ml), tetrahydrofuran (THF) Thlayli 1 N. NaOH (0.4 ml) and the mixture was stirred for 20 minutes under ice cooling. To the reaction mixture were added 1 N. NaCl (2.0 ml) and water and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried, then the solvent is evaporated to dryness under reduced pressure. The residue was led from methanol to obtain the specified connection in the form of colorless crystals (0.278 g, 68 %).

So pl. 243-235oC.

Elemental analysis of C27H23N3O5S:

Calculated, %: C, 64.66; H, 4.62; N, 8.33.

Found, %: C, 64.70; H, 4.70; N, 8.33.

1H-NMR (200 MHz, DMCO - d6) : 1.22 (3H, t), 1.29 (3H, t), 2.79 (2H, d), 4.23 (2H, K), 5.50 (2H, s), 7.10 (1H, t), 7.31-7.40 (4H, m), 8.77 (1H, s), 12.37 (1H, broad. C.).

IR (KBr), cm-1: 3430, 2980, 1782, 1727, 1602, 1542, 1500.

Working example 19. 3-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl] methyl]-2-propyl-4-(3H)-hintline.

19a) 3-[[2-(5-trichloromethyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl] methyl]-2-propyl-4-(3H)-hintline.

It chilled with ice to a solution of 2-propyl-4(3H)-hintline (0,283 g) in N, N-dimethylformamide (8 ml) was added under nitrogen atmosphere sodium hydride (60 % in oil, 60 mg) and at the same temperature and the mixture was stirred for 30 minutes To the reaction mixture solution was added soedinenii temperature. The reaction mixture was concentrated to dryness under reduced pressure and to the mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and dried, and the solvent was evaporated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel and received the specified compound as a colourless oil (0.50 g, 62 %).

1H-NMR (200 MHz, CDCl3) : of 1.02 (3H, t), a 1.75-of 1.94 (2H, m) of 2.75 (2h, t), 5,44 (2H, C0, 7,16 (2H, d), 7.41-7.79 (6H, m), 7.87-7.92 (1H, m), 8.28-8.32 (1H, m).

IR (neat), cm-1: 2960, 1668, 1595, 1567.

19b) 3-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl] methyl]- 2-propyl-4(3H)-hintline.

To a mixture of compound (0,42 g) obtained in working example (19a), with a mixture of dioxane (6 ml) and water (1.5 ml) under ice cooling was added 1 N. NaOH (1.0 ml). The mixture with ice cooling was stirred for 30 minutes To the reaction mixture were added 1 N. HCl (2.0 ml) and water, and then the mixture was Proektirovanie with ethyl acetate.

The organic layer was washed with water and dried, and the solvent was evaporated to dryness under reduced pressure. The precipitate was perekristalizovanny from a mixture of ethyl acetate-ether and received the connection specified in the form of colorless crystals (0,311 g, 91 %).

C 81,22, H 5.06, N 12,78.

Found, %: C 70,93, H 5,04, H 12,72.

1H-NMR (200 MHz, DMCO-d6) : (3H, t), 1,63-to 1.82 (2H, m), is 2.74 (2H, t), the 5.45 (2H, d), 7.31 (2H, d), 7.49-7.74 (6H, m), 7,80-7,88 (1H, m), 8,16-to 8.20 (1H, m), 12,38 (1H, sh. C.)

IR (KBr), cm-1: 3120, 2970, 1768, 1638, 1605, 1590.

Working example 20. Methyl-2-butyl-1-[[2-(4,4-dihydro-5-oxo-6H-1,2,4-oxadiazol - 3-yl)-biphenyl-4-yl]methyl]benzimidazole-7-carboxylate.

20A) Methyl-2-butyl-1-[2-(-ethoxycarbonylmethyl (hydroxycarbonylmethyl) biphenyl-4-yl]methyl]benzimidazole-7-carboxylate.

The mixture of compounds (20,0 g) obtained in working example (1C), ethylbromoacetate (0.84 g) and potassium carbonate (0,67 g) in acetonitrile (20 ml) was stirred 15 min at room temperature. To the reaction mixture were added saturated aqueous salt solution and the mixture was Proektirovanie with ethyl acetate. The extract was washed with water and dried (Mgso4), and then the solvent is boiled away in a vacuum. The residue was purified by chromatography on a column of silica gel (80 g) and received the specified connection (1.10 g, 42 %) as oil.

1H-NMR (200 MHz, CDCl3) : to 0.96 (3H, t, J = 7.4 Hz), of 1.23 (3H, t, J = 7.2 Hz), to 1.48 (2H, m), for 1.49 (2H, m) to 2.94 (2H, t, J = 7,6 Hz), 3,74 (3H, s), 4,20 (2H, K, J = 7,2 Hz), of 4.45 (2H, sh.C) 4,56 (2H, s) 5,77 (H, s), 6.89 in (2H, d, J = 0.8 Hz), 7,19-of 7.70 (8H, m), 7.94 (1H, DD, J = 1.2 Hz, 7.8 Hz).

IR (neat), cm-1yl]benzimidazole-7-carboxylate.

A mixture of compound (1.10 g) obtained in working example (20A), and the chloride of p-toluenesulfonic acid (0.1 g) in toluene (20 ml) was boiled under reflux for 18 hours, the Reaction mixture was concentrated to dryness and the residue was extracted with chloroform. The extract was washed with water and dried (MgSO4), and then the solvent was evaporated in vacuum. The residue was purified through column chromatography with silica gel (80 g) and received the connection specified in the form of colorless crystals (0.25 g, 25 %).

So pl. 226-227 of theoC.

Elemental analysis for C29H28N4O41/2 H2O

Calculated, %: C 68,90; H 5,78; N 11,08.

Found, %: C 69,06; H 5,78; N Of 10.73.

1H-NMR (200 MHz, DMCO-d6) : of 0.90 (3H, t, J = 7.2 Hz), of 1.40 (2H, m), 1.77 in (2H, m), is 2.88 (2H, t, J = 7.4 Hz), the 3.65 (2H, s), is 4.15 (2H, s) 5,72 (H, s), 6.89 in (2H, d, J = 8,4 Hz), 7,27-to 7.64 (8H, m), 7,87 (1H, DD, J = 1.0 Hz, 8.0 Hz), 10,91 (1H, sh.S.).

Working example 21. 2-butyl-1-[[2'-(2,4,-dioxothiazolidine-5-yl)biphenyl-4-yl]methyl]benzimidazole.

21A) 2-butyl-1[[2'-hydroxymethyluracil-4-yl]methyl]-benzimidazole.

The stirred solution of 2-butyl-1-[(2'-carboxyphenyl-4-yl)methyl] benzimidazole (1.50 g) in benzene (30 ml) was dropwise added to dihydro-bis(2-methoxyethoxy)sodium aluminate (70% solution in tawanna the mixture was cooled, poured 2 N. HCl and was extracted with dichloromethane. The extract was washed with water and dried (MgSO4), and the solvent was evaporated in vacuum. The residue was purified through column chromatography with silica gel (80 g) and received the specified connection (0,67 g, 46 %) as oil, which was crystallized from a mixture of ethyl acetate-ether with the formation of pale yellow prisms.

So pl. 162-163oC.

Elemental analysis for C25H26N2O 1/3H2O:

Calculated, %: C 79,75; H 7,14; N 7,44.

Found, %: C 78,75; H 7,01; N 7,29.

1H (200 MHz, CDCl3) : to 0.92 (3H, t, J = 7.2 Hz), USD 1.43 (2H, m) and 1.83 (2H, m) to 1.86 (1H, s), 2,87 (2H, t, J = 7.4 Hz), of 4.57 (2H, s), of 5.39 (2H, s), to 7.09 (2H, d, J = 8,4 Hz), 7,19-to 7.61 (9H, m), 7,72-7,81 (1H, m).

IR (Nujol) cm-1: 3170.

21b) 2-butyl-1-[(2-formylphenyl-4-yl)methyl]benzimidazole.

The mixture of alcohol (0.65 g) obtained in working example (21A), and pyridinediamine (0,67 g) in dichloromethane (20 ml) was mixed for 15 h at room temperature. Insoluble material was filtered and the filtrate concentrated to dryness. The residue was purified through column chromatography with silica gel (60 g) and received the specified product in the form of an oil (0.52 g, 80 %), which was led from isopropyl ether with the formation of colorless crystals (0,46 is R>
Calculated, %: C 80,72; H Is 6.61; N 7,53.

Found, %: C 80,73; H 6,55; N 7,41.

1H-NMR (200 MHz, CDCl3) : of 0.94 (3H, t, J = 7.2 Hz), to 1.45 (2H, m) to 1.86 (2H, m), is 2.88 (2H, t, J = 7.4 Hz), 5,42 (2H, s), 7,14 (2H, d, J = 7.8 Hz), 7,21-to 7.68 (8H, m), 7,76-7,83 (1H, m), 8,01 (1H, DD, J = 1.6 Hz and 7.6 Hz), 9,94 (1H, s).

IR (Nujol) cm-1: 1690, 1655, 1615, 1595.

S) 2-butyl-1-[[2'-(2,4-dioxothiazolidine-5-yl)-biphenyl-4-yl] methyl]-benzimidazole.

To a stirred mixture of aldehyde obtained in working example 21(b), (0,44 g) in ethyl acetate (4 ml) and tetrahydrofuran (4 ml) was added an aqueous solution (2 ml) of sodium sulfate and an aqueous solution (1.2 ml) of potassium cyanate (0,78 g). The reaction mixture was stirred for 4 h at room temperature and then for another 1 h at 60oC. the Reaction mixture was concentrated in vacuo and to the precipitate was added water, and then Proektirovanie chloroform. The extract was washed with water and dried (MgSO4), and the solvent is boiled away in a vacuum. The precipitate was led from the ether with the formation of cyanhydrin (0,43 g, 91 %) as colorless crystals. The product used for the respective reactions without further purification.

1H-NMR (200 MHz, CDCl3) : 0,78 (3H, t, J = 7.4 Hz), 1,25 (2H, M0, of 1.61 (2H, m), 2,69 (2H, t, J = 7,6 Hz), 5,32 (2H, s), the 5.51 (1H, s), 7,03 (2H, d, J = 8.0 Hz), 7,11-of 7.60 (9H, m), 7,92 (1H, DD, J = 1,8 Hz).

4), and then evaporated in vacuum. The residue purified on a chromatographic column with silica gel (70 g) and get the crystals. After recrystallization from ethyl acetate has been specified compound (0.31 g, 66 %) as colorless prisms.

So pl. 249-250oC.

Elemental analysis for C27H25N3O2:

Calculated, %: C 71,18; H Of 5.53; N Which 9.22.

Found, %: C 70,93; H 5,51; N Is 9.09.

1H-NMR (200 MHz, DMCl-d6) : to 0.88 (3H, t, J = 7.4 Hz), to 1.38 (2H, m),1,74 (2H, m), 2,87 (2H, t, J = 7.4 Hz), 5,52 (1H, s) to 5.56 (2H, s), 7.13-to 7.64 (12H, m), 12,20 (1H, sh).

IR (Nujol) cm-1: 1690.

Working example 22. 2-butyl-4-chloro-5-formyl-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol - 3-yl)biphenyl-4-ml]methyl]imidazole.

22A) 4'-mative) was added a methanol solution of sodium methoxide, obtained from metallic sodium (of 5.92 g) and anhydrous methanol (50 ml). The mixture was mixed for 10 min at room temperature and added 2'-cyano-4-methylbiphenyl (10 g). The reaction mixture was stirred for 5 h at 100oC. the Reaction mixture was then divided between ethyl acetate and water. The aqueous solution was extracted with ethyl acetate. The organic layers were combined, washed with water and dried, and the solvent is then boiled away into the vacuum. The residue was purified through column chromatography with silica gel and received the specified connection amorphous product (11.2 g, 96 %).

1H-NMR (200 MHz, CDCl3) : 2,39 (3H, s), 4,42 (2H, sh.C), 7,22 (2H, d), 7,31-to 7.50 (5H, m), 7.56-of 7.60 (1H, m).

IR (KBr), cm-1: 3490, 3380, 1642, 1575, 1568.

22b) 5-trichloromethyl-3-(4'-methylbiphenyl-2-ID)-1,2,4-oxadiazole.

To a solution of compound (10 g) obtained in working example (22A), in benzene (100 ml) was dropwise added trichloroacetic anhydride and the reaction mixture is then boiled for 2 hours under reflux. The reaction mixture was cooled and concentrated to dryness. The residue is distributed between ether and water. The aqueous layer was Proektirovanie ether. The organic layers were combined, washed with water and dried, and the solvent is then boiled away under reduced pressure left a yellow oil (12 g, 77 %).

1H-NMR (200 MHz, CDCl3Delta: of 2.38 (3H, s), 7,16 (4H, s), 7,44-to 7.64 (3H, m), 7,88-to 7.93 (1H, m).

IR (neat), cm-1: 3025, 1600, 1580, 1561, 1508.

22 ° C) 3-(4'-bromomethylbiphenyl-2-yl)-5-trichloromethyl-1,2,4-oxadiazole.

To a solution of compound (24.8 g) obtained in working example (22b) in carbon tetrachloride (300 ml) was added N-bromosuccinimide (12.5 g) and azobisisobutyronitrile (1,15 g) and the mixture was boiled for 2 hours under reflux. The reaction mixture is cooled and the insoluble material was filtered. The filtrate was dissolved in dichloromethane. The organic layer was washed with water and dried, and the solvent is boiled away under reduced pressure. The residue was paracrystalline from ether-hexane mixture and got the connection specified in the form of colorless crystals (23,0 g, 76 %).

So pl. 77-79oC.

Elemental analysis for C16H10N2OBCl30.5 H2O:

Calculated, %: C 43,52; H Of 2.51; N 6,34.

Found, %: C: 43,76; H 2,33; N Of 6.31.

1H-NMR (200 MHz, CDCl3) : to 4.52 (2H, s), 7.23 percent (2H, d), (2H, d), 7,44-the 7.65 (3H, m), to $ 7.91-of 7.95 (1H, m).

IR (KBr), cm-1: 1600, 1560, 1475, 1428, 1332.

22d) 2-butyl-4-chloro-1-[[2-(5-trichloromethyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-5-formylindole.

To klaipedosfilialas (0.2 g) in methanol (3 ml) under nitrogen atmosphere. The mixture was mixed for 1 h at room temperature and concentrated to dryness. To a solution of the residue in N,N-dimethylformamide (2 ml) was dropwise added a solution of compound (0.56 g) obtained in working example (22 ° C), N, N-dimethylformamide (3 ml) while cooling the mixture with ice. The reaction mixture was mixed for 2.5 h at room temperature and concentrated to dryness under reduced pressure. To the residue was added water and the mixture was Proektirovanie with ethyl acetate. The organic layer was washed with water and dried, and the solvent is boiled away under reduced pressure. The residue was purified through column chromatography with silica gel and received the specified product as colourless oil (0,44 g, 76 %).

1H-NMR (200 MHz, CDCl3) : of 0.91 (3H, t), 1,28 of 1.46 (2H, m), 1,63-of 1.78 (2H, m) to 2.65 (2H, t) 5,59 (2H, s), 7,05 (2H, d), of 7.23 (2H, d), 7,41-the 7.65 (3H, m), of 7.90-of 7.95 (1H, m), made up 9.77 (1H, s).

IR (neat), cm-1: 2960, 1670, 1652, 1580, 1565, 1510.

22E) 2-butyl-4-chloro-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl]-5-formylindole.

To a solution of the compound obtained in working example (22d), in a mixture of dioxane (4 ml) and water (1 ml) was added 1 N. NaOH (0.75 ml) under cooling with ice. The mixture under cooling with ice mixed 30 minutes To the reaction mixture were added 1 N. HCl (1 ml) and water, and then proem pressure. The remainder perekristalizovanny from a mixture of ether-hexane and got the connection specified in the form of white crystals (0,255 g, 87 %).

So pl. 181-183oC.

Elemental analysis for C23H21N4O3Cl 0,2 H2O:

Calculated, %: C 62,71; H 4,90; N 12,72.

Found, %: C 62,71; H 4,79; N Br12.62.

1H-NMR (200 MHz, CDCl3) : of 0.91 (3H, t), 1,29 is 1.48 (2H, m), 1,63-to 1.79 (2H, m), 2,68 (2H, t), of 5.55 (2H, s), 7,10 (2H, d), 7,31 (2H, d), 7,38-to 7.67 (3H, m), 7,80 (1H, DD), and 8.50 (1H, sh), 9,68 (1H, s).

IR (KBr), cm-1: 2960, 1772, 1673, 1522, 1490, 1460.

Working example 23. 2-butyl-4-chloro-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)-biphenyl-4-yl] methyl]-5-hydroxymethylimidazole.

To a solution of the compound (0.15 g) obtained in working example (22E), in a mixture of methanol (3 ml) and tetrahydrofuran (2 ml) was added sodium hydroxide (16 mg) and the mixture was mixed at room temperature for 1 h To the reaction mixture was added a mixture of ice-water and the mixture was Proektirovanie with ethyl acetate. The organic layer was washed with water, dried and the solvent is boiled away in vacuum under reduced pressure. The residue was recrystallized from a mixture of ether-hexane and got the connection specified in the form of white crystals (67 mg, 45 %).

So pl. 202-205 areoC.

Elemental analysis ideno, %: C 61,81; H 5,56; N 12,07.

1H-NMR (200 MHz, DMCO-d6) : to 0.80 (3H, t), of 1.16 to 1.34 (2H, m), 1,40-of 1.55 (2H, m), 2,45-2,52 (2H, m), 4,34 is 4.36 (2H, m), 5.25-inch (1H, sh), from 5.29 (2H, s), 7,14 (2H, d), of 7.48-7,72 (4H, m).

HK (KBr), cm-1: 3470, 2960, 1755, 1501, 1463.

Working example 24. 5-butyl-3-etoxycarbonyl-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl]pyrazole.

24A) 5-butyl-3-etoxycarbonyl-1-[[2'-(5-trichloromethyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]pyrazole.

To a cooled with ice to a solution of 3-butyl-5-ethoxycarbonylpyrimidine (0.3 g) and the compound (0.95 g) obtained in working example (22 ° C), in anhydrous tetrahydrofuran (100 ml) under nitrogen atmosphere was added sodium hydride (60 %, 61 mg). The mixture was mixed for 10 min at room temperature and then boiled for 3 hours under reflux. The reaction mixture is cooled, added water and was Proektirovanie with ethyl acetate. The organic layer was washed with water and dried, and the solvent is boiled away under reduced pressure. The residue was purified through column chromatography with silica gel and got the connection specified in the form of a pale yellow oil (0.29 grams, 35 %).

1H-NMR (200 MHz, CDCl3) : to 0.89 (3H, t), 1,26-of 1.44 (2H, m) of 1.40 (3H, t), 1,50 by 1.68 (2H, m), 2.49 USD (2H, t) to 4.41 (2H, K) 5,41 (2H, s), only 6.64 (1H, s), was 7.08 (2H, d), 7,20 (2H, d), 7,40-7,63 (3H, m), 7,88-a 7.92 (1H, m).

l) biphenyl-4-yl]methyl]pyrazole.

To a solution of compound (0.27 g) obtained in working example (24A), in a mixture of dioxane (4 ml) and water (1 ml) under ice cooling was added 1 N. NaOH (0.6 ml). The mixture under cooling with ice up to 20 minutes To the reaction mixture were added 1 N. HCl (0.9 ml) and water, and then the mixture was Proektirovanie with ethyl acetate. The organic layer was washed with water, dried and concentrated to dryness under reduced pressure. The residue was recrystallized from a mixture of ether-hexane and got the connection specified in the form of colorless crystals (0,176 g, 80 %).

So pl. 166-168oC.

Elemental analysis for C25H26N4O4:

Calculated, %: C 67,25; H By 5.87; N 12,55.

Found, %: C 66,99; H 5,91; N 12,45.

1H-NMR (200 MHz, CDCl3) : (3H, t), 1,28 of 1.46 (2H, m) to 1.37 (3H, t), 1,53 by 1.68 (2H, m), of 2.56 (2H, t), 4,35 (2H, K), are 5.36 (2H, s), only 6.64 (1H, s), to 7.15 (2H, d), 7,30 (2H, d), 7,37-the 7.65 (3H, m), 7,79-7,83 (1H, m), 8,49 (1H, m), 8,49 (1H, sh).

IR (KBr), cm-1: 2960, 1725, 1600, 1485.

Working example 25. 2-butyl-4-chloro-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)-biphenyl-4-yl] methyl]imidazole-5-carboxylic acid.

To a solution of compound (0.27 g) obtained in working example (22E), in pyridine (5 ml) was added an aqueous solution (2.5 ml) of potassium permanganate (0,147 g). The mixture was stirred 3 h at room temperature and ethyl acetate and diluted hydrochloric acid. The resulting suspension was filtered through celite. The filtrate was Proektirovanie with ethyl acetate. The organic layer was washed with water, dried and concentrated to dryness under reduced pressure. The residue was purified through column chromatography with silica gel and the product was led from a mixture of ethyl acetate-isopropyl ether to obtain the specified connection in the form of colorless crystals (0.17 g, 61 %).

So pl. 188-189oC (decomposition).

Elemental analysis for C23H21N4O4Cl 0,1 AcOEt 2,9 H2O:

Calculated, %: C 54,69; H 5,41; N 10,90.

Found, %: C 54,91; H 5,17; N To 10.62.

1H-NMR (200 MHz, DMCO-d6) : to 0.80 (3H, t), of 1.16 and 1.35 (2H, m), 1,43 is 1.58 (2H, m), 2,46 of $ 2.53 (2H, m), 5,80 (2H, s), to 6.95 (2H, d), 7,25 (2H, d), 7,29-7,51 (4H, m).

IR (KBr), cm-1: 3390, 2960, 1765, 1648, 1590, 1525, 1488.

Working example 26. 2-butyl-4-chloro-1-[[2'-(2,3-dihydro-2-oxo-1,3,4-oxadiazol-5-yl) biphenyl-4-yl]methyl]imidazole-5-carbaldehyde.

To a cooled with ice to a solution of 2-butyl-4-chloroimidazo-5-carbaldehyde (0,19 g) in N, N-dimethylformamide (1 ml) was added sodium hydride (60 % in oil, 44 mg), the mixture was mixed for 10 minutes and Then was added to the mixture of 5-(4'-bromomethylbiphenyl-2-yl)2,3-dihydro-3-triphenylmethyl-1,3,4-oxadiazol-2-he (or 0.57 g). The reaction mixture was paramesh with water and dried. The solvent is boiled away under reduced pressure and the residue was purified through column chromatography with silica gel. Thus obtained crude product was dissolved in triperoxonane acid (4 ml) and the solution was mixed at 60oC for 30 minutes Triperoxonane acid boiled away under reduced pressure. The residue was dissolved in ethyl acetate, the solution washed with an aqueous solution of sodium bicarbonate, and dried. The solvent is boiled away under reduced pressure and the residue was purified through column chromatography with silica gel. Thus obtained crude crystals are recrystallized from ethyl acetate-hexane mixture and got the connection specified in the form of colorless prisms (0.12 g, 27 %).

So pl. 178-179oC.

Elemental analysis for C23H21N4ClO3:

Calculated, %: C 63,23; H 4,84; N 12,83.

Found, %: C 63,07; H To 4.87; N 12,69.

1H-NMR (200 MHz, CLCl3) : of 0.90 (3H, t), 1,28 of 1.46 (2H, m), 1,62-of 1.78 (2H, m), 2,68 (2H, t) 5,59 (2H, s), was 7.08 (2H, d), 7,26 (2H, d), 7,35 (1H, DD), 7,43 of 7.60 (2H, m), 7,79 (1H, DD), cent to 8.85 (1H, sh), 9,76 (1H, s).

IR (neat), cm-1: 1810, 1775, 1660, 1455, 1340, 1275, 900, 840, 770, 750.

Working example 27. 2-butyl-4-chloro-1-[[2'-(2,3-dihydro-2-oxo-1,3,4-oxadiazol-5-yl) biphenyl-4-yl]methyl]-5-imidazolidone.

Xmas mixed 1 h at 0oC. the Solvent is boiled away under reduced pressure and the pH of the residue is brought to values of 3-4 1 N. HCl. The crystalline precipitate was filtered and recrystallize from a mixture of ethyl acetate-hexane, resulting in the connection specified in the form of colorless prisms (47 mg, 94 %).

So pl. 163-164oC.

Elemental analysis for C23H23N4ClO3:

Calculated, %: C 62,94; H 5,28; N 12,76.

Found, %: C 62,76; H 5,16; N 12,54.

1H-NMR (200 MHz, CDCl3) : to 0.88 (3H, t), 1,25-of 1.41 (2H, m), 1,58 is 1.70 (2H, m), 2,62 (2H, t), 4,50 (2H, s), of 5.24 (2H, s), 7,06 (2H, d), 7,27 (2H, d), 7/37 (1H, DD), 7,43-to 7.59 (2H, m), 7,81 (1H, DD), to 9.93 (1H, sh).

IR (KBr), cm-1: 3400, 1800, 1775, 1455, 1410, 1340, 1260, 1000, 900, 770, 750.

Working example 28. 1,2,4,5-etoxycarbonyl-3-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol - 3-yl)biphenyl-4-yl]methyl]-4-(3H)-pyrimidinone.

28a) 2-butyl-5-etoxycarbonyl-3-[[2'-(5-trichloromethyl-1.2,3 - oxadiazol-3-yl)biphenyl-4-yl]methyl]-4(3H)-pyrimidinone

To a cooled with ice to a solution of 2-butyl-5-etoxycarbonyl-4-hydroxypyrimidine (0.36 g) in anhydrous tetrahydrofuran (8 ml) under nitrogen atmosphere was added sodium hydride (60 % in oil, 65 mg) and the mixture was stirred 15 min at room temperature. To the reaction mixture was added a solution of compound (1,02 g) obtained in working examples, the mixture is then cooled, added in the water and was Proektirovanie with ethyl acetate. The organic layer was washed with water and dried, and the solvent is boiled away under reduced pressure. The residue was purified through column chromatography with silica gel and received the specified compound as a colourless oil (0.18 g, 20 %).

1H-NMR (200 MHz, CDCl3) : to 0.92 (3H, t), 1,29 to 1.47 (2H, m) of 1.39 (3H, t), 1,64-to 1.79 (2H, m) of 2.75 (2H, t), 4,39 (2H, K) 5,38 (2H, s), 7,19 (2H, d), 7,25 (2H, d), 7,41-the 7.65 (3H, m), to 7.93 (1H, DD), 8,64 (1H, s).

IR (neat), cm-1: 2960, 1748, 1705, 1685, 1580, 1521.

28b) 2-butyl-5-etoxycarbonyl-3-[[2'-(2,5-dihydro-5-oxo-1,2,4 - oxadiazol-3-yl)biphenyl-4-yl]methyl]-4(3H)-pyrimidinone.

Compound (0.18 g) obtained in working example (28a), was dissolved in a mixture of dioxane (4 ml) and water (1 ml). To ice the solution was added 1 N. NaOH (0.4 ml) and the reaction mixture while cooling with ice, stirred for 30 minutes After adding 1 N. HCl (0.6 ml) and water, the reaction mixture was Proektirovanie with ethyl acetate. The organic layer was washed with water, dried and the solvent was evaporated under reduced pressure. The residue was purified on a column of silica gel. Thus obtained crude product was recrystallize from a mixture of ethyl acetate-isopropyl ether and received the connection specified in the form of colorless crystals (62 UB>2O:

Calculated, %: C, 65.56; H 5,54; N 11,76.

Found, %: C 65,41; H Of 5.68; N Are 11.62.

1H-NMR (200 MHz, CDCl3) : of 0.91 (3H, t), of 1.28 to 1.48 (2H, m) of 1.34 (3H, t), of 1.65 and 1.80 (2H, m), and 2.79 (2H, t), or 4.31 (2H, K), and 5.30 (2H, s), 7,22 (2H, d), 7,32 (2H, d), 7,37-the 7.65 (3H, m), 7,78 (1H, DD), 8,61 (1H, s).

IR (KBr), cm-1: 3210, 2960, 1795, 1705, 1660, 1523.

Working example 29. 1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4 - yl]methyl]-6-propoxy-3-propiconazol.

29A) 6-chloro-1-[[2-(5-trichloromethyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl] methyl]- 3-propiconazol.

It chilled with ice to a solution of 6-chloro-3-propylurea (0.2 g) in N,N-dimethylformamide (4 ml) under nitrogen atmosphere was added sodium hydride (60 % in oil; 43 mg). The mixture was stirred 30 min at room temperature. To the reaction mixture was added a solution of compound (0.64 g) obtained in working example (22c) in N,N-dimethylformamide (4 ml). The mixture was stirred 2.5 h at room temperature. The reaction mixture is concentrated to dryness under reduced pressure and to the residue was added water, and then Proektirovanie with ethyl acetate. The organic layer was washed with water, dried and concentrated to dryness under reduced pressure. The residue was purified through column chromatography with silica gel and got the connection specified in the form bn, C) of 7.24 (2H, d), 7,31 (2H, d), 7,43-to 7.64 (3H, m), 7,89-to 7.93 (1H, m).

IR (neat), cm-1: 2960, 1712, 1668, 1608, 1582, 1568, 1508.

29b) 1-[[2'-(2,4-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4 - yl] methyl]-6-propoxy-3-propiconazol.

To a solution of compound (0,42 g) obtained in working example (29A), in a mixture of dioxane (4 ml) and water (1 ml) was added ice 1 N. NaOH. The mixture was stirred for 30 minutes under ice cooling and then to the reaction mixture were added 1 N. HCl (1.5 ml) and water and were Proektirovanie with ethyl acetate. The organic layer was washed with water, dried and concentrated to dryness under reduced pressure. The residue was dissolved in a mixture of propanol (4 ml) and N,N-dimethylformamide (4 ml). To ice the solution is dropwise added a solution of sodium peroxide, prepared from metallic sodium (72 mg), and propanol (2 ml), and then the solution was heated for 1.5 h at 100-110oC. the Reaction mixture was cooled and then concentrated to dryness under reduced pressure. To the residue was added dilute hydrochloric acid and the mixture was Proektirovanie with ethyl acetate. The organic layer was washed with water, dried and boiled away to dryness under reduced pressure. The residue was purified through column chromatography with silica gel. The thus obtained crude about allow (0,223 g, 63 %).

So pl. 129 - 132oC.

Elemental analysis for C25H26N4O5:

Calculated, %: C 64,92; H 5,67; N 12,11.

Found, %: C 64,82; H 5,77; N 11,91.

1H-NMR (200 MHz, CDCl3) : to 0.92 (3H, t), and 1.00 (3H, t), and 1.56 to 1.76 (2H, m), 1,74-of 1.93 (2H, m), 3,85 (2H, t), 3,98 (2H, t), 55,11 (2H, s), 5,15 (1H, s), 7,28-to 7.67 (7H, m), 7,81-7,86 (1H, m), 8,15 (1H, sh. C.).

IR (KBr), cm-1: 3120, 2970, 1775, 1705, 1638, 1472.

Working example 30. 1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4 - yl]-methyl]-2-propylbenzamide-7-carboxylic acid.

30A) Methyl-1-[[2-cyanobiphenyl-4-yl)methyl] -2-propylbenzamide-7-carboxylate.

To a solution of methyl 3-amino-2-[2'-cyanobiphenyl-4-yl)methyl]benzoate (1,43 g) in dioxane (8 ml) was added butyric aldehyde (950 mg) and the solution was stirred 3 h at room temperature, and then a further 2 hours at 110oC. To the reaction mixture was added concentrated HCl (1 ml) and the mixture was stirred for 15 h at 80oC. the Reaction mixture was distributed between ethyl acetate (150 ml) and aqueous solution of sodium bicarbonate (70 ml). The upper layer was washed twice with water (50 ml) and concentrated under reduced pressure. The crystalline product was recrystallize from a mixture of ethyl acetate-ether and received the specified connection is(3H, t), 1,77 is 2.10 (2H, m), 2,87 (3H, t) to 3.67 (3H, s), 5,77 (2H, s), 6,93 (2H, d), 7,13-to 7.77 (8H, m), to 7.93 (1H, d).

IR (Nujol) cm-1: 2225, 1710, 1450, 1280, 1270, 1200, 1130, 760.

30b) Methyl-1-[(2'-hydroxycarbonylmethyl)biphenyl-4-yl)methyl]-2-propylbenzamide-7-carboxylate.

To a solution of hydroxylamine hydrochloride (2,78 g) in DMCO (12 ml) was added triethylamine (Android 4.04 g) and tetrahydrofuran (15 ml), and then the resulting crystals were filtered. The filtrate is concentrated to dryness under reduced pressure. To the residue was added methyl-1-[(2'-cyano-biphenyl-4-yl)methyl]-2-propylbenzamide-7-carboxylate (1.6 g) and triethylamine (1 g). The mixture was stirred 15 h at 75oC and then dissolved in ethyl acetate (200 ml). The solution was washed with water (200 ml) and 50 ml x 3), dried and boiled away under reduced pressure. Upon completion of these operations has received the connection specified in the form of a pale yellow product (1,57 g, 89 %).

1H-NMR (90 MHz, CDCl3) : of 1.10 (3H, t), 1,73 is 2.10 (2H, m), 2,90 (2H, t), 3,70 (3H, s) to 4.33 (2H, s), 5,73 (2H, s), 6.87 in (2H, d), 7,10-to 7.67 (8H, m), to 7.93 (1H, d).

IR (Nujol) cm-1: 1720, 1440, 1380, 1290, 1265.

30c) Methyl-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4 - yl]methyl]-2-propylbenzamide-7-carboxylate.

To a solution of methyl 1-[(2'-N-hydroxylaminopurine-4-yl)methyl]-2 - propylbenzamide the ri constant stirring and cooling in an ice bath. The mixture was mixed under these conditions for 0.5 h and then added methanol (3 ml) and the mixture was mixed for another 0.5 h at room temperature. The reaction mixture was dissolved in ethyl acetate (250 ml) and the solution was washed with water (200 ml) and 50 ml x 3). The ethyl acetate was boiled away under reduced pressure. The residue was dissolved in xylene (150 ml) and the solution was boiled with reverse refrigerator for 4 hours the Reaction mixture is then kept for 20 h at room temperature and has received the connection specified in the form of colorless prisms (1,03 g, 58 %).

So pl. 224 - 226oC.

Elemental analysis for C27H24N4O41/2 C8H10:

Calculated, %: C 71,46; H Ceiling Of 5.60; N A 10.74.

Found, %: C 71,41; H 5,44; N 10,53.

1H-NMR (90 MHz, CDCl3) : of 0.90 (3H, t), 1,13-of 1.73 (2H, m), 2,43 (2H, t), of 3.57 (3H, s), to 5.57 (2H, s), 6,50-7,93 (11H, m).

IR (Nujol) cm-1: 1770, 1720, 1267.

30d) 1-[[2'-(2,5-dihydro-2-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4 - yl]-methyl]-2-propylbenzamide-7-carboxylic acid.

A mixture of methyl-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)- biphenyl-4-yl] methyl] -2-propylbenzamide-7-carboxylate (703 mg) in 0.3 N. NaOH (12 ml) was mixed 1 h at 60oC and then HCl 0.1 N. brought the pH of the mixture to 3. The resulting precipitate was extracted with a mixture of chlor allocation specified connection in the form of colorless prisms (550 mg, 90 %).

So pl. 169-171oC.

Elemental analysis for C26H22N4O4:

Calculated, %: C 67,38; H 5,00; N 12,09.

Found, %: C 67,39; H Is 4.85; N 11,91.

1H-NMR (90 MHz, DMCO d6-CDCl3) : of 1.03 (3H, t), 1,67 is 2.10 (2H, m), and 2.83 (2H, t), 5,97 (2H, s) to 7.00 (2H, d), 7,20-8,03 (9H, m).

IR ( Nujol) cm-1: 1785, 1710, 1500, 1380, 760.

Working example 31. 2-ethyl-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)-biphenyl - 4-yl]methyl]benzimidazole-7-carboxylic acid.

31A) Methyl-1-[2'-cyanobiphenyl-4-yl)methyl] -2-ethylbenzamide-7-carboxylate.

Methyl 3-amino-2-[2'-cyanobiphenyl-4-yl)methyl]benzoate (1,79 g) was treated with propionic anhydride (1.04 g) analogously to the method described in working example (30A). Product recrystallize from ethyl acetate and got the connection specified in the form of colorless prisms (1.5 g, 76 %).

So pl. 153-154oC.

1H-NMR (90 MHz, CDCl3) : of 1.47 (3H, t), 2,90 (2H, K), of 3.73 (3H, s), of 5.83 (2H, s), 6,97 (2H, d), 7,30-7,83 (9H, m), of 7.97 (1H, d).

IR (Nujol) cm-1: 2225, 1725, 1710, 1480, 1440, 1285, 1250, 1205, 1120.

31b) Methyl-2-ethyl-1-[(2'-(hydroxycarbonylmethyl)-biphenyl-4 - yl)methyl] benzimidazole-7-carboxylate.

Methyl-1-[(2'-(cyanobiphenyl-4-yl)methyl]-2-ethylbenzamide-7 - carboxylate (2 g) was Paige pale yellow resinous substance (1.85 g, 85 %).

1H-NMR (90 MHz, CDCl3) : USD 1.43 (3H, t), of 2.97 (2H, K), of 3.73 (3H, s), and 4.40 (2H, s), 5,73 (2H, s), make 6.90 (2H, d), 7,17-7,80 (8H, m), of 7.97 (1H, d).

IR (Nujol) cm-1: 1720, 1380, 1290, 1265.

Working example 32. 2-cyclopropyl-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid.

32A) Methyl-1-[(2'-cyanobiphenyl-4-yl)methyl] -2-cyclopropylamino-7-carboxylate.

Methyl-3-amino-2-[(2'-cyanobiphenyl-4-yl)methyl]benzoate (1,79 g) was treated cyclopropanecarbonyl anhydride (1.3 g) by the method described in working example (30A), with the formation of the indicated compound as an orange syrup (1.85 g, 91 %).

1H-NMR (90 MHz, CDCl3) : 1,00-1,40 (4H, m), 1,87-of 2.23 (1H, m), 3,70 (3H, s), to 5.93 (2H, s), 7,00-7,93 (11H, m).

IR(Neat), cm-1: 2225, 1720, 1710, 1525, 1440, 1285.

32b) Methyl-2-cyclopropyl-1-[(2-(hydroxycarbonylmethyl)biphenyl-4-yl)methyl-benzimidazole-7-carboxylate.

Methyl-1-[(2'-cyanobiphenyl-4-yl)methyl)-2-cyclopropylamino-7-carboxylate (1.8 g) was subjected to the same reaction as described in working example (32b), with education as a result of this connection in the form of a pale yellow syrup (1.75 g, 90 %).

1H-NMR (90 MHz, CDCl3) : 0,97 was 1.43 (4H, m), 1,80-2,17 (1H, m), 3,70 (3H, s) to 4.33 (2H, s), is chlorophyl-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol - 3-yl)biphenyl-4-yl]methyl] benzimidazole-7-carboxylate.

Methyl-2-cyclopropyl-1-[(2'-N-gidroksiaminopirimidinov-4-yl)methyl] benzimidazole-7-carboxylate (1.7 g) was subjected to the same reaction as described in working example (30C). From the reaction mixture xylene was evaporated under reduced pressure. The residue was recrystallize from ethyl acetate and got the connection specified in the form of colorless prisms (780 mg, 48 %).

So pl. 188-190oC.

Elemental analysis for C27H22N4O4:

Calculated, %: C 69,52; H 4,75; N 12,01.

Found, %: C 69,52; H Of 4.77; N 11,90.

1H-NMR (90 MHz, CDCl3) : 0,87 - of 1.07 (4H, m), 1,53 and 1.80 (1H, m), of 3.73 (3H, c), by 5.87 (2H, c), 6,83-7,87 (11H, m).

IR (Nujol) cm-1: 1778, 1765, 1728, 1716, 1211.

32d) 2-cyclopropyl-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)- biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid.

Methyl-2-cyclopropyl-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol - 3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (550 mg) was subjected to the same reaction as described in working example (30d). Product recrystallize from ethyl acetate and got the connection specified in the form of colorless prisms (480 mg, 90 %).

So pl. 199-200oC.

Elemental analysis for C28H20N4O41/3 H2O:

R IS OF 1.30 (4H, m) 2,07-to 2.40 (1H, m), 6,07 (2H, s), 7,00-7,83 (11H, m), 12,27 (1H, sh).

IR(Nujol) cm-1: 1755, 1703, 1699, 1257.

Working example 33. 2-butyl-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid.

Methyl ester (of 0.53 g) obtained in working example 2, was subjected to the same reaction as described in working example (30d), followed by the formation of the compounds in the form of colorless prisms (0.36 g, 64 %).

So pl. 165-167oC.

Elemental analysis for C27H24N4O41/3 CHCl3:

Calculated, %: C 64,59; H A 4.83; N 11,02.

Found, %: C 64,76; H Of 4.95; N 10,83.

1H-NMR (90 MHz, DMCO - d6) : of 0.90 (3H, t), 1,13-2,00 (4H, m), and 2.83 (2H, t), to 5.93 (2H, s), 6,93 (2H, d), 7,13-of 7.90 (9H, m).

IR (Nujol) cm-1: 1770, 1440, 1420, 1250, 765.

Working example 34. 1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl] methyl]-2-propertieseditor-7-carboxylic acid.

34a) Methyl-2-(2'-cyanobiphenyl-4-yl)methylamino-3-methoxycarbonyl - aminobenzoate.

To a cooled with ice to a solution of the compound (10.0 g) obtained in working example (1A), in pyridine (50 ml) was dropwise added methylchloroform (9.0 ml) and the mixture was stirred 3 h at room temperature. The reaction mixture is th, dried and concentrated to dryness. The residue was led from a mixture of ethyl acetate-hexane, and the obtained pale-yellow crystals (10.5 g, 90 %).

So pl. 113-115oC.

1H-NMR (200 MHz, CDCl3) : of 3.80 (3H, c), 3,83 (3H, c), 4,11 (2H, d), of 6.29 (1H, sh.C) to 7.09 (1H, t), 7.40 - 7.80 (10H, m), 8,19 (1H, d).

34b) Methyl-1-[(2'-cyanobiphenyl-4-yl)methyl] -2,3-dihydro-2 - oxopentanoate-7-carboxylate.

To a suspension of compound (10.5 g) obtained in working example (34a), in methanol (100 ml) was added a solution of 28% sodium methoxide in methanol (10 g). The mixture was boiled for 21 h under reflux. Introduction 1 N. HCl brought the pH of the reaction mixture to 3 and then concentrated to dryness. After adding to the residue water the mixture was extracted with chloroform. The extract was dried and concentrated to dryness. The residue was led from a mixture of chloroform-methanol emitting colorless needle-like crystals (8.7 g, 90 %).

So pl. 250-253oC.

1H-NMR (200 MHz, DMCO d6) : the 3.65 (3H, s), to 5.35 (2H, s),? 7.04 baby mortality-7,76 (1H, dt), 7,92 (1H, DD).

IR (KBr), cm-1: 2210, 1720, 1690, 1635, 1430, 1390, 1270, 1255, 760, 750, 730, 690.

34C) Methyl-1-[(2'-cyanobiphenyl-4-yl)methyl] -2-propertieseditor-7-carboxylate.

A mixture of compound (11 g) obtained in Ramachandran processing received methyl-2-chloro-1-(2'-cyanobiphenyl-4-yl)methylbenzimidazole-7-carboxylate (11,37 g). To a solution of the compound in dioxane (100 ml) was added propylmercaptan (2.4 g) and 28% solution of methoxide sodium in methanol (6.4 g). The mixture was mixed for 1.5 h at room temperature. The reaction mixture is concentrated to dryness under reduced pressure. The residue was distributed between ethyl acetate (300 ml) and water (150 ml), and then the upper layer was washed with water (50 ml x 1). The ethyl acetate was boiled away under reduced pressure. After adding to the residue, methanol (50 ml) of the resulting crystalline precipitate was filtered, washed with methanol, dried and got the connection specified in the form of pale yellow prisms (10 g, 80 %).

So pl. 107-108oC.

1H-NMR (90 MHz, CDCl3) with 1.07 (3H, t), 1,63-2,03 (2H, m), 3,40 (2H, t), of 3.73 (3H, s) 5,80 (2H, s), 7,00-7,93 (11H, m).

IR (Nyjol), cm-1: 2220, 1725, 1280.

34d) Methyl-1-[(2'-(hydroxycarbonylmethyl)biphenyl-4-yl)-methyl]-2 - propertieseditor-7-carboxylate.

To a solution of hydroxylaminopurine (of 20.85 g) in DMCO (200 ml) was added triethylamine (3.9 g) and the mixture was mixed for 30 min at room temperature. To the reaction mixture was added the compound (16 g) obtained in example (34c), and the mixture was stirred for 60 h at 70oC. To the resulting mixture was added tetrahydrofuran (100 ml). After removal of cristallisation (350 ml), and then the upper layer was washed with water (70 ml x 3). The ethyl acetate was evaporated under reduced pressure and to the residue was added methanol (70 ml). The resulting crystalline precipitate was filtered. The filtrate is concentrated to dryness under reduced pressure and got the connection specified in the form of a pale yellow syrup (13,0 g, 76 %).

1H-NMR (90 MHz, CDCl3) with 1.07 (3H, t), 1,63-2,03 (2H, m), 3,40 (2H, t), of 3.73 (3H, s), 4,37 (2H, broad), 5,13 (1H, broad) 5,73 (2H, s), 6,97 (2H, d), 7,10-of 7.60 (8H, m), 7,87 (2H, d).

IR (Nujol) cm-1: 1720, 1645, 1280, 755.

E) Methyl-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-2 - propertieseditor-7-carboxylate.

To a stirred solution of compound (13,0 g) obtained in working example (3d), in DMF (20 ml) was added pyridine (2.2 g) and 2-ethylhexylcarbonate (4.83 g) successively under cooling in an ice bath. The mixture was mixed for 30 min in the same conditions, then added methanol (5 ml) and mixed for another 30 min at room temperature. The reaction mixture was distributed between ethyl acetate (250 ml) and water (250 ml). The upper layer was washed with water (150 ml × 3) and concentrated to dryness under reduced pressure. The residue was dissolved in xylene (180 ml) and the solution was stirred with heating in a bath at 160oC in those who, idemili the connection specified in the form of pale yellow prisms (7,16 g, 57 %).

So pl. 220-221oC.

Elemental analysis for C27H24N4O4S:

Calculated, %: C 64,7; H A 4.83; N 11,19.

Found, %: C 64,54; H To 4.92; N 10,89.

1H-NMR (90 MHz, CDCl3) : of 1.03 (3H,t), 1,60-2,00 (2H, m), with 3.27 (2H, t), of 3.73 (3H,c), 5,73 (2H,s), 6.90 to-7,87 (11H, m).

IR (Nujol) cm-1: 1760, 1720, 1280, 1260.

34f) 1-[[2-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4]-methyl] -2-propertieseditor-7-carboxylic acid.

To a solution of compound (0.3 g) obtained in working example (34e), in tetrahydrofuran (10 ml) were added 2 N. NaOH (2 ml) and methanol (5 ml). The mixture was mixed for 3 h at 80oC. the Reaction mixture was concentrated under reduced pressure. To the residue was added water and then an aqueous solution of 2 N. HCl brought to pH 3. Formed after this precipitate was filtered and recrystallize from ethyl acetate emitting colorless prisms (0,19 g, 65 %).

So pl. 228-229oC.

Elemental analysis for C26H22N4O4S:

Calculated, %: C 64,18; H 4,56; N To 11.52.

Found, %: C 64,15; H To 4.62; N To 11.56.

1H-NMR(90 MHz, CDCl-CD3OD) with 1.07 (3H, t), 1,63-2,03 (2H, m), 3,37 (2H, t), by 5.87 (2H, s), 6,97-of 7.90 (11, m).

IR (Nujol) cm-1: 1795, 1700, 1455, 1280, 755.

Working example 35. 1 - [Prov.) Methyl-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-propylsulfonylbenzimidazole-7-carboxylate.

To a stirred solution of compound (2.5 g) obtained in working example (34e), in dichloromethane (60 ml) was added in portions while cooling in an ice bath metallocarborane acid (1.1 g). The mixture was mixed under these conditions for 1 h, and then washed with a solution of sodium bicarbonate (500 mg) in water (50 ml). The organic layer was washed with water (30 ml x 1) and dried over anhydrous magnesium sulfate. The solvent is boiled away under reduced pressure, and got the connection specified in the form of a pale yellow syrup (2.58 g, 100 %).

1H-NMR (90 MHz, CDCl3) : of 1.03 (3H, t), 1,57 is 2.00 (2H, m), 3,13-3,63 (2H, m), of 3.77 (3H, c), 6,07 (1H, d), 6,17 (1H, d), 6,93 (2H, d) 7,17-8,03 (9H, m).

IR (Nujol) cm-1: 1780, 1720, 1285, 1260, 755.

35b) Methyl-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-2-methoxybenzimidazole-7-carboxylate.

To a solution of compound (517 g) obtained in working example (35A), in methanol (5 ml) was added a 28% solution of sodium methoxide in methanol (579 mg) and the mixture stood for 1 h at room temperature. To the mixture was added 2 N. HCl, bringing the pH of the mixture to 3, and then the mixture was concentrated under reduced pressure. The residue was distributed between water (20 ml) and dichloromethane (50 ml). The organic layer was concentrated to dryness under reduced is

So pl. 215 - 216oC.

Elemental analysis for C25H4O50,1 H2O:

Calculated, %: C 65,53; H Of 4.44; N 12,23.

Found, %: C, Compared With 65.38; H 4,56; N 12,12.

1H-NMR (90 MHz, DMCO-d6) : to 3.73 (3H, s), 4,27 (3H, c), 5,63 (2H, s), 7,03 (2H, d), 7,20 - to 7.77 (9H, m).

IR (Nujol) cm-1: 1760, 1720, 1560, 1435, 1405, 1285, 1250, 1040, 740.

35c) 1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl] methyl]-2 - methoxybenzimidazole-7-carboxylic acid.

The compound (228 mg) obtained in working example (35b), was subjected to the reaction described in working example (34f), recrystallize the product from ethyl acetate and got the connection specified in the form of colorless prisms (133 mg, 60 %).

So pl. 189 - 190oC.

Elemental analysis for C24H18N4O50,75 H2O:

Calculated, %: C 63,22; H Or 4.31; N 12,29.

Found,%: C: 63,50; H 4,28; N A 12.03.

1H-NMR (90 MHz, DMCO-d6) : 4,20 (3H, s), 5,73 (2H, s), 7.03 is - 7,73 (11H, s), 12,17 (1H, broad), 12,93 (1H, broad).

IR (Nujol) cm-1: 1780, 1705, 1560, 1415, 1250, 1040.

Working example 36. 1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-2 - propoxybenzene-7-carboxylic acid.

36A) Methyl-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]IU who was interaval to dryness under reduced pressure and the residue was dissolved in propanol (10 ml). In the solution was dissolved the compound (517 mg) obtained in working example (35A), and the solution was stirred for 2 h at room temperature. 2 N. HCl solution pH was brought to 3 and under reduced pressure, concentrated to dryness. The residue was dissolved in methanol (15 ml) and to the solution was added a 28% solution of methoxide sodium in methanol (710 mg). The mixture was stirred for 15 h at room temperature, and then the pH of the solution 2 N. HCl brought to 3 and concentrated under reduced pressure. The residue was distributed between water (25 ml) and dichloromethane (25 ml). The organic layer was concentrated to dryness under reduced pressure. The obtained dry residue was led from methanol and got the connection specified in the form of colorless prisms (310 mg, 64 %).

So pl. 172 and 174oC.

Elemental analysis for C27H24N4O50,2 H2O:

Calculated, %: C 66,44; H 5,04; N 11,48.

Found, %: C 66,57; H 5,01; N 11,55.

1H-NMR (90 MHz, CDCl3) : and 1.00 (3H, t), 1,60 - 2,00 (2H, m), 3,63 (3H, s) to 4.23 (2H, t), the ceiling of 5.60 (2H, s), 6,80 - 7,93 (11H, m).

IR (Nujol) cm-1: 1780, 1720, 1550, 1440, 1280, 755.

36b) 1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)-biphenyl-4-yl]methyl]-2 - propoxybenzene-7-carboxylic acid.

The compound (194 mg) obtained in working the, receiving the connection specified in the form of colorless prisms (132 mg, 70 %).

So pl. 170 - 172oC.

Elemental analysis for C26H22N4O5H2O:

Calculated, %: C 63,93; H Of 4.95; N 11,47.

Found, %: C 63,82; H 4,65; N 11,41.

1H-NMR (90 MHz, CDCl3CD3OD) : and 1.00 (3H, t), 1,67 - of 1.07 (2H, m), 4,50 (2H, t), 5,67 (2H, m), 7,00 - 7,80 (11H, m).

IR (Nujol) cm-1: 1765, 1725, 1550, 1430.

Working example 37. 2 ethylthio-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid.

37A) Methyl-2-ethylthio-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl]benzimidazole-7-carboxylate.

To a solution of compound (517 mg) obtained in working example (35A), in methanol (3 ml) was added triethylamine (404 mg) and ethyl mercaptan (186 mg). The mixture stood at room temperature for 60 h, and then concentrated to dryness in vacuo. After adding to the residue water, the mixture is brought 2 N. HCl to pH 3. The solution was extracted with ethyl acetate (60 ml). The upper layer was washed with water (10 ml x 3) and then concentrated to dryness in vacuo. The residue was led from ethyl acetate and got the connection specified in the form of colorless prisms (370 mg, 76 %).

So pl. 210 - 211o="ptx2">

Found, %: C 64,06; H 4,58; N 11,40.

1H-NMR (90 MHz, CDCl3) : of 1.40 (3H, t), with 3.27 (2H, K), 3,70 (3H, s) 5,70 (3H, s), 6.87 in - 7,87 (11H, m).

IR (Nujol) cm-1: 1760, 11720, 1280, 1260.

37b) 2 ethylthio-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl - 4-yl]methyl]benzimidazole-7-carboxylic acid.

The compound (260 mg) obtained in working example (37A), was subjected to the same reaction as described in example (34f), recrystallize the product from methanol-water and got the connection specified in the form of colorless needle-like crystals (160 g, 63 %).

So pl. 146 - 148oC.

Elemental analysis for C25H20N4O4S:

Calculated, %: C 63,55; H 4,27; N Up 11,86.

Found, %: C 63,28; H 4,37; N 11,59.

1H-NMR (90 MHz, CDCl3) : USD 1.43 (3H, t), 3,40 (2H, K) 5,70 (2H, K) 5,70 (2H, s), 6.90 to - 7,87 (11H, m).

IR (Nujol) cm-1: 1785, 1765, 1700, 1350, 760.

Working example 38. 1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4]methyl]-2 - methylthiopyrimidine-7-carboxylic acid.

38A) Methyl-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl] methyl]-2-methylthiopyrimidine-7-carboxylate.

The compound (690 mg) obtained in working example (35A), was subjected to the same reaction as described in the working Primm, 73 %).

So pl. 231 - 232oC.

Elemental analysis for C25H20N4O4S:

Calculated, %: C 63,55; H 4,27; N Up 11,86.

Found, %: C 63,36; H 4,33; N 11,76.

1H-NMR (90 MHz, DMCO-d6) : 2,77 (3H, s), of 3.73 (3H, s), 5,73 (2H, c), 7,00 - 7,93 (11H, m), of 12.33 (1H, broad).

IR (Nujol) cm-1: 1760, 1710, 1430, 1270, 1250, 760.

38b) 1-[[2-(2,5-(dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]- methyl]-2-methylthiopyrimidine-7-carboxylic acid.

The compound (360 mg) obtained in working example (38A), was subjected to the same reaction as in example (34f), recrystallize the product from methanol and got the connection specified in the form of colorless prisms (270 mg, 77 %).

So pl. 222 - 223oC.

Elemental analysis for C24H18N4S 0,8 H2O:

Calculated, %: C 60,95; H 4,18; N 11,85.

Found, %: C 60,83; H 4,40; N 11,58.

1H-NMR (90 MHz, DMCO-d6) : 2,77 (3H, s), of 5.83 (2H, s), 7,00 - to 7.77 (11H, m), 12,60 (2H, broad).

IR (Nujol) cm-1: 1760, 1270, 760.

Working example 39. Dohyleva salt of 2-ethoxy-1-[[2'-(oxide-1,2,4-oxadiazol-3-yl)-biphenyl - 4-yl]methyl]benzimidazole-7-carboxylic acid.

A solution of 2-ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol - 3-yl)-biphenyl-4-yl] methyl] benzimidazole-Eton (30 ml) and the mixture was mixed for three days at room temperature. The precipitated crystals were filtered and dried (120oC, 1.5 h) and received the connection specified in the form of colorless needle-like crystals (470 mg, 89 %).

So pl. 245 - 247oC.

Elemental analysis for C25H18N4O5K23/2H2O:

Calculated, %: C 53,65; H Of 3.78; N 10,01.

Found, %: C 53,77; H 3,63; N To 9.93.

1H-NMR (90 MHz, DMCO-d6) : of 1.40 (3H, t), a 4.53 (2H, K) of 5.83 (2H, s), 6.90 to-of 7.70 (11H, m).

IR (Nujol) cm-1: 3370, 1660, 1570, 1540, 1385.

Working example 40. The disodium salt of 2-ethoxy-1-[[2'-(5-oxide-1,2,4-oxadiazol-3-yl)-biphenyl-4-yl]methyl] benzimidazole-7-carboxylic acid.

A solution of sodium methoxide (28 %) in methanol (43,7 g) was dissolved in ethanol (500 ml) and then the solution was concentrated to dryness under reduced pressure. To the residue was added ethanol (500 ml) and 2-ethoxy-1-[[2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid, and the mixture was dissolved. The solution was concentrated to dryness under reduced pressure. The residue was dissolved in ethanol (250 ml) under heating, and then the solution has stood for 40 h at room temperature. Saducees crystals otpolirovala, washed with ethanol (30 ml), dried (140oC, 2 h) and received colorless prisms (35.5 g), kotoe compound as colorless prisms (42,34 g, 61 %).

So pl. 294-297oC.

Elemental analysis for C25H18N4O5Na25,5 H2O:

Calculated, %: C 50,09; H 4,88; N 9,35.

Found, %: C 50,32; H 4,71; N Of 9.21.

1H-NMR (90 MHz, DMCO-d6) : USD 1.43 (3H, t), of 4.57 (2H, K) 5,80 (2H, s), 6.87 in-7,63 (11H, m).

IR (Nujol) cm-1: 3375, 1655, 1615, 1410, 1350, 1280, 1040, 770.

Working example 41. Methyl-2-ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl]-4-methylthieno[3,4-d]imidazole-6-carboxylate.

41A) Methyl-1,3-dihydro-4-methyl-2-oxo-thieno[3,4-d] imidazole-6-carboxylate.

Methyl 3,4-diamino-5-methylthiophene-2-carboxylate (3.0 g) was dissolved in a mixture of N, N-dimethylformamide (5 ml) and dichloromethane (15 ml). To the solution in portions added triphosgene (2.4 g). The mixture was mixed for two days at room temperature, the precipitate was filtered, washed with dichloromethane and dried. The resulting white powder (2.4 g) suspended in N,N-dimethylformamide (25 ml). To the suspension was added sodium hydride (60 % in oil, 0.55 g) and the mixture was stirred for three days at room temperature. The solvent is evaporated under reduced pressure. To the precipitate was added 2 N. HCl. The resulting precipitate was filtered, washed successively with water, ether and mean-NMR (200 MHz, DMCO-d6) : 2,32 (3H, s), of 3.73 (3H, s), 10,71 (1H, sh.with. ), 11,06 (1H, sh.S.).

IR (KBr), cm-1: 3300, 1735, 1675, 1585, 1440.

41b) of Methyl 2-ethoxy-4-methylene[3,4-d] imidazole-6-carboxylate.

The compound (1.0 g) obtained in working example (41A), suspended in a mixture of dioxane (10 ml) and dichloromethane (20 ml). To the suspension was added excess triethylorthoformate at room temperature in a nitrogen atmosphere, and then the mixture was mixed for 19 hours, the Reaction mixture was poured into ice water, and then Proektirovanie four times with a mixture of chloroform and ethanol. The organic layers were combined dried and concentrated under reduced pressure. The residue was purified through column chromatography with silica gel and received the specified connection (945 mg, 75 %) as a pale-yellow powder.

So pl. 209-210oC.

Elemental analysis for C10H12N2O3S 0.02 H2O:

Calculated, %: C 49,25; H 5,12; N 11,49.

Found, %: C 49,42; H Of 4.95; N 11,29.

1H-NMR (200 MHz, CDCl3) : the 1.44 (3H, t), to 2.57 (3H, s), a 3.87 (3H, s), of 4.54 (2H, K), 9,03 (1H, CL).

IR (KBr), cm-1: 3250, 1670, 1580, 1540.

41p) Methyl-2-ethoxy-1-[[2'-5(5-trichloromethyl-1,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl]-4-methylthieno[3,4-d]imidazol-6-oxadiazol-3-yl)biphenyl (193 mg), dissolved in N, N-dimethylformamide (3.5 ml). It chilled with ice to a solution under nitrogen atmosphere was added sodium hydride (60 % in oil, 18 mg). The mixture was mixed for 15 minutes under cooling with ice, and then 1 h at room temperature. The reaction mixture was diluted with ethyl acetate, washed successively with diluted hydrochloric acid, water and aqueous salt solution, and then dried. The solvent is boiled away under reduced pressure. The residue was purified through column chromatography with silica gel and received the specified connection (121 mg, 55 %) as a pale yellow oil.

1H-NMR (200 MHz, CDCl3) : (3H, t), to 2.55 (3H, s,), with 3.79 (3H, s) to 4.52 (2H, K), to 5.57 (2H, s), to 7.15 (2H, d), of 7.23 (2H, d), 7,86 (1H, d).

IR (Neat), cm-1: 1690, 1615, 1570, 1535.

41d) of Methyl 2-ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl]-4-methylthieno[3,4-d]imidazole-6-carboxylate.

The compound (120 mg) obtained in working example (41p), was dissolved in a mixture of dioxane (4 ml) and water (1 ml). To ice the solution was added 1 N. NaOH (0,26 ml) and the mixture at the same temperature mixed for 50 minutes, the Reaction mixture was acidified using 2 N. HCl and Proektirovanie with ethyl acetate. The extract was washed with water, dried, and the solvent is then boiled away under reduced pressure is Ali from a mixture of ether and hexane and received the specified compound (81 mg, 77 %) as pale yellow crystals.

So pl. 208-210oC.

Elemental analysis for C25H22N4O5S:

Calculated, %: C 61,21; H To 4.52; N 11,42.

Found, %: C 60,98; H 4,55; N 11,27.

1H-NMR (200 MHz, CDCl3) : of 1.42 (3H, t), 2,42 (3H, s), 3,74 (3H, s), 4,42 (2H, K), to 5.58 (2H, s), of 7.2 to 7.7 (7H, m), 7,82 (1H, DD), to 7.68 (1H, CL).

IR (KBr), cm-1: 1760, 1700, 1620, 1580, 1535.

Working example 42. Disodium salt 1-[[2'-(2,5-dihydro-5-oxo-1,2.4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-methoxy-4-methylthieno[3,4-d] imidazole-6-carboxylic acid.

The compound (0.5 g) obtained in working example 9, suspended in methanol (10 ml). To the suspension was added an aqueous solution (5 ml) of sodium hydroxide (90 mg) and the mixture was mixed for 10 min at room temperature. The reaction solution was concentrated to dryness with the formation of crude crystals. After recrystallization from a mixture of ethanol-ether got the connection specified in the form of pale yellow crystals (0.28 g, 49 %).

So pl. 263-266oC (decomposition).

Elemental analysis for C23H16N4O5SNa21,0 H2O (mol. m 524,46):

Calculated, %: C 52,67; H Of 3.46; N Is 10.68.

Found, %: C 52,88; H 3,43; N 10,45.

1H-NMR (200 MHz, DMCO-d6) : Rimer 43. 2 Atila-1-[[3'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-4-methylthieno[3,4-d]imidazole-6-carboxylic acid.

43A) 4'-methyl-3-cyanobiphenyl.

This compound was synthesized in accordance with known procedure (E. Hamana, S. Furushima & t.Hiyama, Chem. Lett. 1989, 1711).

So pl. 71-73oC.

1H-NMR (200 MHz, CDCl3) : to 2.41 (3H, s), 7,28 (2H, d), 7,46 (2H, d), 7,51 (1H, t), 7,60 (1H, TD), 7,79 (1H, TD), to 7.84 (1H, t).

IR (KBr), cm-1: 2230, 1475, 825, 800.

43b) 4'-methylbiphenyl-3-carboxamide.

To a solution of hydroxylaminopurine (2,61 g) in DMCO (20 ml) was added a solution of 20 % NaOMe in methanol (7,25 g) and the mixture was mixed for 10 min at room temperature. To the reaction mixture was added a solution of compound (1.45 g) obtained in working example (43A), DMCO (10 ml). To the reaction mixture was added water and the mixture was Proektirovanie with ethyl acetate. The extract was washed with water and dried. The solvent is boiled away in vacuum, the residue was purified through column chromatography with silica gel and the obtained colorless crystals (1,30 g, 76.6 per cent).

So pl. 134-136oC.

1H-NMR (200 MHz, CDCl3) : 2,39 (3H, s), is 4.93 (2H, sh.C.), of 7.25 (2H, d), 7,41-7,66 (5H, m), a 7.85 (1H, t).

IR (KBr), cm-1: 3495, 3385, 1660, 1585. 1440, 1375, 940, 925, 900, 795.

And 43C) 5-Tr is the example (43b), in toluene (30 ml) was added trichloroacetic anhydride (2,13 g). The mixture was mixed for 30 min at 80oC. the Reaction mixture was concentrated to dryness and the residue distributed between water and ethyl acetate. The organic layer was dried over Na2SO4and concentrated to dryness. The residue was purified through column chromatography with silica gel and the obtained colorless oil (2,09, quantitatively).

1H-NMR (200 MHz, CDCl3) : to 2.41 (3H, s), 7,28 (2H, d), at 7.55 (2H, d), 7,56 (1H, t), 7,76 (1H, TD), 8,07 (1H, TD), 8,32 (1H, t).

IR (Neat), cm-1: 1570, 1515, 1460, 1355, 1335, 850, 825, 800, 745, 690.

43d) 3-(4'-bromomethylbiphenyl-3-yl)-5-trichloromethyl-1,2,4-oxadiazole.

To a solution of compound (29,09 g) obtained in working example (and 43C), CCl4(50 ml) was added NBS (1.10 g) and BPO (0.20 g). The mixture was irradiated with light. The reaction mixture was cooled to room temperature and the insoluble material was filtered. The filtrate was concentrated to dryness. The residue was purified through column chromatography with silica gel (Merk. Art. 9385 (1980), AcOEt:n-Gex. = 1:10) and received a colorless syrup (2,40 g, 60 %).

1H-NMR (200 MHz, CDCl3) : of 4.57 (2H, s), 7,49-to 7.68 (5H, m), 7,75-7,79 (1H, m), 8,09-8,17 (1H, m), with 8.33 (1H, m).

43th) Methyl-2-Atila-1-[[3'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl] methyl]-4-methyl (0,80 g) in DMF (10 ml) under ice cooling was added sodium hydride (60 % in oil, 0.14 g). The mixture was mixed for 10 minutes, and then under ice cooling was added a solution of compound (1,53 g) obtained in working example (43d) in DMF (10 ml). The mixture was mixed for 1 h at room temperature. The reaction mixture is distributed between water and ethyl acetate. The organic layer was washed with water, saturated brine and dried. The solvent is boiled away in vacuum and the residue was purified through column chromatography with silica gel, resulting in colorless crystals. To a solution of the crystals in a mixture of chloroform (10 ml) - methanol (10 ml) was added 1 N. NaOH (3 ml) and the mixture was mixed for 1 h at room temperature. The reaction mixture was concentrated and 1 N. HCl brought the pH of the mixture to a value of 3-4. The mixture was distributed between CHCl3and water. The organic layer was dried over Na2SO4and concentrated to dryness with the release of crude crystals. Recrystallization from methanol-utilized allowed to obtain colorless crystals (0.74 g, 84 %).

So pl. 248-251 (decomposition).

Elemental analysis for C25H22N4O4S20.5 H2:

Calculated, %: C 58,24; H 4,50; N 10,87.

Found, %: C 58,24; H To 4.38; N 10,77.

1H-NMR (200 MHz, CDCl3) : of 1.41 (3H, t), 2,63 (3H, s), 3,30 (2H, K), of 3.78 (3H, s), of 5.75 (2H, s), 7,27 (2H, d), 7,51-7,60 (5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) -biphenyl-4-yl]methyl]-4-methylthieno[3,4-d]imidazole-6-carboxylic acid.

Connection of 0.60 g) obtained in working example (43e), suspended in a mixture of tetrahydrofuran (20 ml) - H2O (20 ml). To the suspension was added lithium hydride (0.25 g, 5,96 mmol) and the mixture is boiled under reflux for 15 hours, the Reaction mixture was concentrated, water balance with the addition of 1 N. HCl brought to pH 3. Drawn while the crystals were filtered and dried. The crystals were recrystallize and gave colourless crystals (0.33 g, 56,7 %).

So pl. 177-179oC (decomp).

Elemental analysis for C24H20N4O4S20.5 H2O:

Calculated, %: C 57,47; H 4,22; N 11,17.

Found, %: C 57,63; H Of 4.04; N 11,17.

1H-NMR (200 MHz, DMCO-d6) : of 1.35 (3H, t), of 2.56 (3H, c), 3,26 (2H, K), 5,73 (2H, c), 7,26 (2H, d), the 7.65 (1H, t), of 7.69 (2H, d), 7,81 (1H, dt), of 7.90 (1H, TD), 8,08 (1H, t).

IR (KBr), cm-1: 1770, 1755, 1650, 1530, 1460, 1165, 765.

Working example 44. 2 ethylthio-1-[[4'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) -biphenyl-4-yl] methyl] -4-methylthieno [3,4-d]imidazole-6-carboxylic acid.

44a) 4'-Methyl-4-cyanobiphenyl.

This compound is synthesized analogously to the procedure described in working example (43A).

So pl. 108-109oC.

1H-NMR (200 MHz, CDCl3) : to 2.42 (3H, s), 7,29 (2H, d), to 7.50 (2H, d), of 7.64 to 7.75 (4H, m).

44c) 3-(4'-methylbiphenyl-4-yl)-5-trichloromethyl-1,2,4-oxadiazole.

This compound was synthesized according to the procedure similar to that described in working example (and 43C).

So pl. 126-127oC. A Yield Of 75 %.

1H-NMR (200 MHz, CDCl3) : to 2.42 (3H, s), 7,29 (2H, d), at 7.55 (2H, d), 7,72 (2H, d), 8,17 (2H, d).

IR (KBr), cm-1: 1610, 1585, 1540, 1470, 1420, 1345, 905, 855, 845, 825, 810, 755, 725.

44d) 3-(4'-bromomethylbiphenyl-4-yl)-trichloromethyl-1,2,4-oxadiazole.

The indicated compound was obtained as colorless needle crystals (71 %) of the compound obtained in working example (s), according to the method described in working example (43d).

So pl. 113-116oC.

1H-NMR (200 MHz, CDCl3) : 4,56 (2H, s), 7,51 (2H, d), to 7.64 (2H, d), 7,73 (2H, d), to 8.20 (2H, d).

IR (KBr), cm-1: 1475, 1400, 1350, 845, 830, 800, 760, 755.

44th) Methyl 2-ethylthio-1-[[4'-(2,5-dinitro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl]-4-methylthieno[3,4-d]imidazole-6-carboxylate.

The indicated compound was obtained as pale-yellow crystals (0.4 g, 25 %) from compound (1,53 g) obtained in working example (44d), in a way similar to that described in working example (43th).

So pl. 251-255oC (decomposition).

Found, %: C 58,89; H 4,35; N 10,81.

1H-NMR (200 MHz, DMCO-d6) : of 1.36 (3H, t), to 2.57 (3H, c), with 3.27 (2H, K), 3,70 (3H, c), 5,70 (2H, c), 7,22 (2H, d), 7,72 (2H, d), 7,87 (4H, c).

IR (KBr), cm-1: 1760, 1690, 1460, 1320, 1305, 1255, 1240, 1160, 1090, 760.

44f) 2 Ethylthio-1-[[4'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl]-4-methylthieno[3,4-d]imidazole-6-carboxylic acid.

The indicated compound was obtained as colorless crystals (0.29 grams, 90 %) from compound (0.33 g) obtained in working example (44th), according to the method similar to that described in working example (43f).

So pl. 202-204oC (decomposition).

Elemental analysis for C24H20N4O4S2:

Calculated, %: C 57,68; H 4,19; N 11,21.

Found, %: C 57,83; H 4,48; N Is 11.39.

1H-NMR (200 MHz, DMCO-d6) : of 1.35 (3H, t), of 2.56 (3H, s), 3,26 (2H, K) 5,72 (2H, s), from 7.24 (2H, d), 7,72 (2H, d), 7,87 (4H, s),

IR (KBr), cm-1: 1760, 1640, 1610, 1600, 1535, 1460, 1165, 770.

Working example 45. 2 Ethylthio-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) methyl-biphenyl-4-yl]methyl]-4-methylthieno[3,4-d]imidazole-6-carboxylic acid.

45A) 4'-Methyl-2-hydroxymethylbilane.

To ice the suspension lithium-aluminiumhydride (1,79 g) tetrahydrofurane (50 ml) was added dropwise a solution of 4-methylpiperazine mixture was added ethyl acetate (10 ml) and water (50 ml), and then insoluble materials were filtered through celite. The filtrate was concentrated to dryness and the residue dissolved in ethyl acetate. The solution was washed with an aqueous solution of sodium bicarbonate and dried. The solvent is evaporated under reduced pressure and the residue was purified through column chromatography with silica gel and got the connection specified in the form of a colorless syrup (3,95 g, 84 %).

1H-NMR (200 MHz, CDCl3) : to 2.41 (3H, s), to 4.62 (2H, s), 7,20-7,41 (7H, m), 7,51-7,56 (1H, m).

IR (Neat), cm-1: 3350, 3020, 2920, 1480, 1440, 1030, 1000, 820, 755.

45b) 4'-Methyl-2-chlorotoluene.

It chilled with ice to a solution of compound (3,95 g) obtained in working example (45A), in chloroform (50 ml) was dropwise added thionyl chloride (of 3.56 g). To the mixture then added one drop of dimethylformamide and the mixture was boiled under reflux for 1 h, the Reaction mixture was concentrated to dryness and the residue suspended in saturated aqueous sodium bicarbonate solution and was Proektirovanie with ethyl acetate. The extract was washed with water and dried, the solvent is boiled away under reduced pressure, and got the connection specified in the form of a pale yellow oil (4.15 g, 96 %).

1H-NMR (200 MHz, CDCl3) : to 2.41 (3H, s), a 4.53 (2H, s), 7.23 percent-7,41 (7H, m),phenyl.

To a solution of compound (4.15 g) obtained in working example (45b), in acetonitrile (50 ml) was added potassium cyanide (2.5 g) and 18-crown-6 (0.5 g). The mixture is boiled for 10 hours under reflux. Insoluble materials were filtered off and the filtrate concentrated to dryness. The residue was dissolved in ethyl acetate, washed with water and dried. The solvent is evaporated under reduced pressure and the residue was purified through column chromatography with silica gel and got the connection specified in the form of a pale yellow oil (3,71 g, 93 %).

1H-NMR (200 MHz, CDCl3) : to 2.41 (3H, c), 3,62 (2H, c), 7,14-7,39 (7H, m), 7,50-of 7.55 (1H, m).

IR (Neat), cm-1: 2240, 1480, 820, 760.

45d) 4'-Methylbiphenyl-2-acetamidoxime.

To a solution of hydroxylaminopurine (1.68 g) in dimethyl sulfoxide (10 ml) was added a solution of 28% aqueous solution of sodium methoxide in methanol (4,65 g) and the mixture was stirred 20 min at room temperature. To the mixture was added a solution of the compound obtained in working example (45C), in dimethyl sulfoxide (3 ml) and the mixture was stirred 1.5 h at 100oC. the Reaction mixture is distributed between water and ethyl acetate. The organic layer was washed with water and dried, and the solvent is then evaporated under reduced pressure. Remainder the eyes of the crystals (0,92 g, 79 %).

So pl. 127-128oC.

1H-NMR (200 MHz, CDCl3) : 2,40 (3H, c), of 3.46 (2H, c) to 4.33 (2H, s), 7.18 in-the 7.43 (8H, m).

IR (KBr), cm-1: 3450, 3350, 1670, 1590, 1480, 1380, 940, 820, 760.

E) 3-(4'-methylbiphenyl-2-yl)methyl-5-trichloromethyl-1,2,4-oxadiazole.

The compound obtained in working example (45d) (0,92 g) suspended in toluene (20 ml). To the suspension was added trichloroacetic anhydride (1.42 g) and the mixture was stirred at 80-90oC for 1 h, the Reaction mixture was concentrated to dryness, the residue dissolved in ethyl acetate, washed with water and dried. The solvent is boiled away under reduced pressure. The residue was purified through column chromatography with silica gel and received the specified compound as a colourless oil (1.25 g, 88 %).

1H-NMR (200 MHz, CDCl3), : 2,40 (3H, c), 4,11 (2H, c), 7,19-7,42 (8H, m).

IR (Neat), cm-1: 1580, 1490, 1355, 1050, 860, 800, 760, 735, 705.

45f) 3-(4'-bromethylamine-2-yl)methyl-5-trichloromethyl-1,2,4-oxadiazole.

To a solution of compound (1.25 g) obtained in working example (e) in carbon tetrachloride (20 ml) was added N-bromosuccinimide (0,67 g) and azo-visitbotanical (0.1 g) and the mixture was boiled for 1 h under reflux. Insoluble materials were filtered off and Villena-yellow syrup (0,91 g, 60 %).

1H-NMR (200 MHz, CDCl3) : 4,10 (2H, c), 4,55 (2H, c), 7.23 percent-7,41 (8H, m).

45g) Methyl-2-ethylthio-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) methylbiphenyl-4-yl]methyl]thieno[3,4-d]]imidazol-4-methyl-6-carboxylate.

It chilled with ice to a solution of methyl-2-ethylthio-4-methylthieno-[3,4-d]imidazole-6-carboxylate (0.75 g) in dimethylformamide (5 ml) was added sodium hydride (60 % in oil, of 0.13 g) and the mixture was stirred 10 minutes To ice the mixture was added dropwise a solution of compound (0,91 g) obtained in working example (45f) in dimethylformamide (5 ml) and then stirred 1 h at room temperature. To the reaction mixture was added water and the mixture was Proektirovanie with ethyl acetate. The extract was washed with saturated aqueous brine and dried. The solvent is boiled away in vacuum and the residue was purified through column chromatography with silica gel, resulting in a pale yellow syrup. The syrup was dissolved in a mixture of chloroform (5 ml) - methanol (10 ml), then to the solution was added 1 N. NaOH (2 ml) and moved 30 min at room temperature. The reaction mixture was concentrated to dryness and the residue was diluted with water. the pH of the aqueous solution of 1 N. HCl brought to 3 and Proektirovanie chloroform. The extract was washed with water, dried and the solvent is boiled away when the crude crystals were recrystallize from a mixture of ethyl acetate-methanol and got the connection specified in the form of pale-yellow needle crystals (0.31 g, 20 %).

So pl. 172-173oC (decomposition).

Elemental analysis for C26H24N4O4S2(mol. m 520, 63):

Calculated, %: C 59,98; H 4,65; N 10,76.

Found, %: C 59,78; H 4,55; N 10,41.

1H-NMR (200 MHz, CDCl3) : of 1.41 (3H, t), 2,61 (3H, s), or 3.28 (2H, K), 3.76 (3H, s), 3,83 (2H, s), 7.16-7,39 (8H, m), 8,68 (1H, sh.C).

IR (KBr), cm-1: 1765, 1695, 1685, 1600, 1540, 1460, 1430, 1320, 1240, 1170, 1090, 760.

45h) 2 Ethylthio-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) methylbiphenyl-4-yl]-methyl]thieno[3,4-d]imidazol-4-methyl-6-carboxylic acid.

To a solution of compound (0.25 g) obtained in working example (45g), in a mixture of tetrahydrofuran (10 ml) - water (5 ml) was added litigated-monohydrate (0.10 g) and the mixture was boiled for 30 h under reflux, 1 N. HCl brought the pH of the mixture to 3 and Proektirovanie chloroform. The extract was washed with water, dried and the solvent is boiled away under reduced pressure and gave crude crystals. As a result of recrystallization from a mixture of ethyl acetate-hexane received the specified compound as pale-yellow needle crystals (0.18 g, 74 %).

So pl. 184-186 (decomposition).

Elemental analysis for C25H22N4O4S2(mol. m 506, 61):

Calculated, %: C 59,27; H To 4.38; N 11,06.

IR (KBr), cm-1: 1810, 1790, 1650, 1535, 1460, 1326, 1170, 760.

Working example 46. 2 Ethylthio-1-[[2'-(1,4-dihydro-3-trifluoromethyl-5-oxo-1,2,4-triazolyl - 4-yl)biphenyl-4-yl]methyl] thieno[3,4-d]imidazol-4-methyl-6-carboxylic acid.

46a) 4-(4'-Methylbiphenyl-2-yl)semicarbazide.

To a cooled with ice to a solution of (4'-methylbiphenyl-2-yl)carboxylic acid (3.0 g) and triethylamine (2.2 ml) in N,N-dimethylformamide (10 ml) under nitrogen atmosphere was added DPPA (1,4, ml) and the mixture was mixed at the same temperature for 4 hours To the reaction mixture was added water and the mixture was Proektirovanie with ethyl acetate. The organic layer was washed with water and dried. The resulting solution was added dropwise to the heated to 80oC benzene (150 ml). The mixture was then mixed for 20 min at the same temperature. Thus obtained solution of isocyanate dropwise added to a solution of hydrazine (2.0 ml) in benzene (50 ml), heated to 70oC for 90 minutes Powdery product obtained by evaporating the solvent under reduced pressure, washed with ethyl acetate and dried, receiving the connection specified in the form of a white powder (2.9 g, 85 %).

So pl. 148-151oC.

Elemental analysis for C14H15N3O 0.5 H2O:

The caters is(2H, W.C) 6,11 (1H, sh) of 7.0 to 7.4 (7H, m), 8,21 (1H, d), 8,32 (1H, sh).

IR (KBr), cm-1: 1690, 1615, 1580, 1520.

46b) 3-Trifluoromethyl-4-(4'-methylbiphenyl-2-yl)-1,2,4-thiazole-5-he.

To a cooled with ice to a solution of the compound (700 mg) obtained in working example (46a), in dichloromethane (10 ml) under nitrogen atmosphere was added triperoxonane anhydride (0,43 ml) and pyridine (0,32 ml). The mixture under cooling with ice, stirred 1 h, and then another 20 h at room temperature. To the reaction mixture was added water and the mixture was Proektirovanie chloroform. The extract was dried and the solvent is boiled away under reduced pressure. The residue was dissolved in benzene (8 ml) and to the solution was added phosphorus oxychloride (1.5 ml). The mixture was stirred 4 h at 80oC. the Solvent is boiled away under reduced pressure and the residue was dissolved in ethyl acetate (30 ml). The solution was washed with water and aqueous salt solution and then the solution was concentrated to dryness under reduced pressure. The residue was purified through column chromatography with silica gel and got the connection specified in the form of a pale brown oil (620 mg, 66 %).

1H-NMR (200 MHz, CDCl3) : to 2.42 (3H, s), 7,1-7,5 (7H, m), 8,17 (1H, d).

IR (KBr), cm-1: 1620, 1520, 1510.

46c) 4-(4'-Methylbiphenyl-2-yl)-3-methoxyethoxy-5 example (46b), triethylamine (0,34 ml) in dichloromethane (12 ml) under nitrogen atmosphere was added CHLOROTHALONIL ether (0.17 ml). The mixture was mixed 9 h and then added triethylamine (0.15 ml) and CHLOROTHALONIL ether (0.17 ml). The mixture under cooling with ice mixed in for 13 hours, the Solvent is boiled away under reduced pressure. To the residue was added dilute hydrochloric acid and the mixture was extracted with ethyl acetate. The extract was dried and concentrated to dryness under reduced pressure. The residue was purified through column chromatography with silica gel and the obtained pale-yellow oil (395 mg, 57 %).

1H-NMR (200 MHz, CDCl3) : of 2.34 (3H, s), 3,40 (3H, s), to 9.91 (2H, s), 7,0-7,5 (8H, m).

IR (neat), cm-1: 1620, 1600, 1580, 1520.

46d) 4-(4'-bromomethylbiphenyl-2-yl)-3-methoxyethoxy-5-trifluoromethyl-1,2,4-triazole.

To a solution of compound (390 mg) obtained in working example (s) in carbon tetrachloride (15 ml) was added N-bromosuccinimide (230 mg) and azobisisobutyronitrile (20 mg). The mixture was mixed for 4.5 h at 80oC. the Reaction mixture was diluted with chloroform, the solution washed with an aqueous solution of sodium bicarbonate and dried. The solvent is boiled away under reduced pressure. The residue was purified through column chromatography with silica gel and got specified with(2H, C) to 7.2 and 7.6 (8H, m).

IR (neat), cm-1: 1615, 1600, 1575.

46e) Methoxymethyl-2-ethylthio-4-methylthieno[3,4-d]imidazole-6-carboxylate.

A mixture of methyl-2-ethylthio-4-methylthieno-[3,4-d]imidazole-6-carboxylate (2.15 g) with 1 N. LiOH (8 ml) and methanol (25 ml) was mixed for 60 h at 70oC. the Methanol was boiled away under reduced pressure. To the residue was added 1 N. HCl. The resulting precipitate was filtered, washed with chloroform and dried. Thus obtained brown powder (560 mg) suspended in dichloromethane (10 ml). To the suspension was added triethylamine (0.35 ml) and CHLOROTHALONIL ether (0,19 ml). The mixture was stirred 2 hours To the reaction mixture was added diluted hydrochloric acid and the mixture was Proektirovanie chloroform. The extract was dried and concentrated by dryness under reduced pressure. The residue was purified through column chromatography with silica gel and received the specified compound (445 mg, 19 %) as a white powder.

So pl. 128-130oC.

Elemental analysis for C11H14N2O3S2:

Calculated, %: C 46,14; H Is 4.93; N 9,78.

Found, %: C 45,90; H Is 4.93; N 9,56.

1H-NMR (200 MHz, CDCl3) : to 1.45 (2H, t) of 2.64 (3H, s), and 3.31 (2H, K), 3,53 (3H, s), 9,29 (1H, CL).

IR (KBr), cm-1: 1640, 1620, 1540.

the - 6-carboxylic acid.

The compound (280 mg) obtained in working example (46e), and the compound obtained in working example (46d), was dissolved in N,N-dimethylformamide 912 ml). To a cooled with ice to a solution under nitrogen atmosphere was added sodium hydride (60 % in oil, 47 mg).

The mixture was stirred 2 h at the same temperature. To the reaction mixture was added diluted hydrochloric acid and the mixture was Proektirovanie with ethyl acetate. The extract was washed with water and aqueous brine, and then dried. The solvent is boiled away under reduced pressure. The residue was purified through column chromatography with silica gel and the obtained yellow oil (464 g). The oil was dissolved in a mixture triperoxonane acid (4 ml) and chloroform (5 ml). The solution was mixed 5 h at 70oC. the Reaction mixture was diluted with chloroform, washed with water, dried and the solvent is boiled away under reduced pressure. The residue was purified through column chromatography with silica gel and received the specified connection (60 mg, 10 %) as pale brown powder.

So pl. 178-180oC (decomposition).

Elemental analysis for C25H20N5O3S2F30.5 H2O:

Calculated, %: C 52,81; H 3,72; N 12,32.

Found, %: C 52,83; H 3,54; N 12,30.

1H-NMR (200 MHz, CDCl3<2">

Working example 47. Methyl 2-ethylthio-1-[[2'-[1,4-dihydro-3-methyl-5-oxo-1,2,4-triazole-4-yl] - biphenyl-4-yl] methyl]thieno[3,4-d]-imidazol-4-methyl-6-carboxylate.

47a) 1-Acetyl-4-(4'-metallifer-2-yl)semicarbazide.

To a solution of the compound (300 mg) obtained in working example (31a), in dichloromethane (5 ml) was added acetic anhydride (0,12 ml) and pyridine (0.10 ml). The mixture was mixed for 15 h at room temperature. The reaction mixture was poured into a mixture of ice water and was Proektirovanie with a mixture of chloroform and ethanol. The extract was washed with water, dried and the solvent is boiled away under reduced pressure, followed by separation of the specified compound (320 mg, 90 %) as a white powder.

So pl. 203-205oC.

Elemental analysis for C16H17N3O2:

Calculated, %: C 67,83; H Equal To 6.05; N 14,83.

Found, %: C 67,53; H 5,90; N 14,84.

1H-NMR (200 MHz, DMCO-D6) : of 1.75 (3H, s), is 2.37 (3H, s), 7,0-7,4 (7H, m), 7,55 (1H, s), 7,94 (1H, d), with 8.33 (1H, s), 9,59 (1H, s).

IR (KBr) cm-1: 1660, 1595, 1540.

47b) 3-Methyl-4-(4'-methylbiphenyl-2-yl)-1,2,4-triazole-5-(4H)-he.

To a solution of compound (950 mg) obtained in working example (31a), in benzene (920 ml) was added phosphorus oxychloride (1.2 ml) and the mixture was mixed for 20 h at 90oC. Races is I. The solvent is boiled away under reduced pressure. The residue was purified through column chromatography with silica gel and received the specified connection (460 mg, 51 %) as a white powder.

So pl. 102-104oC.

Elemental analysis for C16H153O:

Calculated, %: C 72,43; H 5,70; N 15,84.

Found,%: C: 72,37; H Of 5.68; N 15,96.

1H-NMR (200 MHz, CDCl3) : is 2.40 (3H, s), 6,83 (1H, sh.C) 7,0-7,5 (7H, m), to 8.20 (1H, d).

IR (KBr) cm-1: 1640, 1575, 1530.

47c) 3-Methyl-4-(4'-methylbiphenyl-2-yl)-1-methoxymethyl-1,2,4 - triazole-5(H)-he.

To a cooled ice connection (250 ml) obtained in working example (31b), in dichloromethane (8 ml) under nitrogen atmosphere was added CHLOROTHALONIL ether (0,18 ml) and triethylamine (0,20 ml). The mixture was stirred for 23 h at room temperature. The solvent is boiled away under reduced pressure. The residue was purified through column chromatography with silica gel and received the specified connection (75 mg, 25 %) as a pale-yellow oil.

1H-NMR (200 MHz, CDCl3) : of 2.09 (3H, s), of 2.34 (3H, s), or 3.28 (3H, s), of 4.95 (2H, s), 7,0-7,4 (8H, m).

IR (Neat), cm-1: 1715, 1640, 1590, 1570, 1515.

D) Methyl-2-ethylthio-1-[[2'[1,4-dihydro-1-methoxymethyl-3-methyl-5-oxo - 1,2,4-triazole-4-yl] - biphenyl-4-yl] methyl]thieno[3,4-d]imidazo the ω carbon (5 ml) was added N-bromosuccinimide (48 mg) and azobisisobutyronitrile (95 ml). The mixture was stirred 5 h at 80oC. the Reaction mixture was poured into aqueous sodium bicarbonate solution and was Proektirovanie chloroform. The extract was dried and concentrated to dryness under reduced pressure. The residue was purified through column chromatography with silica gel and the obtained pale-yellow oil (34 mg). This oil (34 mg) and methyl-2-editio-4-methylthieno[3,4-d] imidazole-6-carboxylate (30 mg) was dissolved in N,N-dimethylformamide (4 ml). To a cooled with ice to a solution under nitrogen atmosphere was added sodium hydride (60 % in oil, 5 mg). The mixture was mixed overnight at room temperature and concentrated to dryness under reduced pressure. The residue was struck with ethyl acetate, the solution washed with water, aqueous brine, and then dried. The solvent is boiled away under reduced pressure. The residue was purified through column chromatography with silica gel and rested the specified connection (42 mg, 85 %) as a pale yellow oil.

1H-NMR (200 MHz, CDCl3) : of 1.42 (3H, t), is 2.05 (3H, d), 2,62 (3H, s) 3,18 (3H, s), 3,30 (2H, K), of 3.77 (3H, s), 4,91 (2H, d), 5,69 (2H, s), 7,0-7,4 (8H, m).

IR (Neat), cm-1: 1720, 1695, 1645, 1605, 1540.

E) Methyl-2-ethylthio-1-[[2'-(1,4-dihydro-3-methyl-5-oxo-1,2,4-triazole-4-yl]methyl]thieno[3,4-d]imidazol-4-methyl-6-carboxilic.

Connection (4 the target was stirred for 12 h at 60oC. the Reaction mixture was diluted with chloroform, washed with water, dried and concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel and the obtained pale-yellow oil. After crystallization from chloroform-ether mixture received the specified connection (34 mg, 87 %) as pale yellow crystals.

So pl. 204 - 206oC.

The elemental composition of C26H25N5O3S20,4 CHCl3:

Calculated, %: C 55,88; H 4,51; N 12,34.

Found, %: C 55,73; H 4,49; N 12,57.

1H-NMR (200 MHz, CDCl3) : the 1.44 (3H, t), is 2.41 (3H, s), 2.63 in (3H, s) to 3.33 (2H, K), of 3.80 (3H, s), 5,77 (2H, s), 6,83 (1H, CL), of 7.0 and 7.6 (7H, m), 8,18 (1H t).

IR (KBr), cm-1: 1685, 1630, 1600, 1570, 1535, 1520.

Working example 48. 1[[2'-(2,4-dihydro-4-methyl-3-oxo-1,2,4-triazole-5-yl)biphenyl-4-yl] -methyl] -2-ethylthio-4-methylthieno[3,4-d]imidazole-6-carboxylic acid.

48A) 4-Methyl-1-[24(4-phenyl)benzoyl] semicarbazide.

To a solution of 4'-methylbiphenyl-2-carbohydrazide (2.3 g) in chloroform (20 ml) was added methyl isocyanate (10 ml) and the mixture was stirred 1 h at room temperature. The resulting crystalline precipitate was filtered and purified through column chromatography with silica gel. Obtained icatia crystals (0,86 g, 31 %).

So pl. 181-182oC.

Elemental analysis for C16H17N3O2:

Calculated, %: C 67,83; H Equal To 6.05; N 14,83.

Found, %: C 67,65; H 6,90; N 14,85.

1H-NMR (200 MHz, DMCO-d6) : of 2.34 (3H, s), 3,30 (3H, d), of 5.55 (1H, sh), 7,21 (2H, d), 7,32-7,56 (6H, m), a 7.85 (1H, s), 9,79 (1H, s).

IR (KBr), cm-1: 3380, 3250, 3220, 1690, 1645, 1540, 820, 760.

48b) of 2,4-Dihydro-5-(4'-methylbiphenyl-2-yl)-4-methyl-1,2,4-triazole-3-one.

Connection (0,86 g) obtained in working example (48A), dissolved in 1 N. NaOH (8 ml) and the solution was boiled under reflux for 15 h, 1 N. HCl the pH of the solution brought to a 3-4 and Proektirovanie with ethyl acetate. The extract was washed with water and dried. The solvent is boiled away under reduced pressure. The residue was purified through column chromatography with silica gel and the obtained crude crystals. After recrystallization from ethyl acetate-hexane mixture received the connection specified in the form of colorless needle-like crystals (0,60 g, 74 %).

So pl. 181-182oC.

Elemental analysis for C16H15N3O:

Calculated, %: C 72,43; H 5,70; N 15,84.

Found, %: C 72,54; H 5,74; N 15,95.

1H-NMR (200 MHz, CDCl3) : is 2.37 (3H, s) to 2.55 (3H, s), 7,16 (2H, d), 7,22 (2H, d), 7,42-the 7.65 (4H, m), 9,72 (1H, s).

methylbiphenyl-2-yl)-4-methyl-1,2,4-triazole-3-one.

To a cooled with ice to a solution of the compound (0.40 g) obtained in working example (48b), in DMF (1 ml) was added sodium hydride (60 % in oil, 72 mg). The mixture was stirred 30 min, and then added CHLOROTHALONIL ester (0.14 g). The reaction mixture was stirred at 0ofor 1.5 h, and then diluted with water and was Proektirovanie acetic acid. The extract was washed with water and dried. The solvent was removed under reduced pressure. The residue was purified through column chromatography with silica gel and received the specified compound as a colourless oil (0.40 g, 87 %).

1H-NMR (200 MHz, CDCl3) : 2,35 (3H, s) to 2.55 (3H, s), 3.43 points (3H, s), 5,20 (2H, s), 7,14 (2H, d), 7,21 (2H, d), 7,40-to 7.64 (4H, m).

IR (Neat), cm-1: 1720, 1490, 1460, 1440, 1395, 1380, 1330, 1295, 1175, 1095, 1040, 920, 820, 785, 760.

48d) 5-(4'-bromomethylbiphenyl-2-yl)-4,5-dihydro-1-methoxymethyl-4-methyl-1,2,4-triazole-3-one.

The compound (0.40 g) obtained in working example (48S), NBS (0,23 g) and benzoyl peroxide (17 mg) was added to carbon tetrachloride (10 ml). The mixture was boiled under reflux and exposed to light for one hour. Insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified through column chromatography with silica gel and the obtained crude krivenik prisms (0,38 g, 73 %).

So Kip. 137-138oC.

Elemental analysis for C18H18N3BrO20.5 H2O:

Calculated, %: C 54,42; H 4,82; N Of 10.58.

Found, %: C 54,50; H Of 4.66; N 10,51.

1H-NMR (200 MHz, CDCl3) : 2,60 (3H, s) to 3.41 (3H, s), of 4.49 (2H, s), 5,19 (2H, s), 7,29 (2H, d), 7,38 (2H, d), 7,45-to 7.67 (4H, m).

IR (KBr), cm-1: 1710, 1490, 1470, 1455, 1440, 1375, 1380, 1295, 1235, 1180, 1090, 915, 860, 855, 790, 765, 755, 610.

48th) Methyl-1-[[2'-(2,4-dihydro-2-methoxymethyl-4-methyl-3-oxo-1,2,4 - triazole-5-yl)biphenyl-4-yl]methyl]2-ethylthio-4-methylthieno[3,4-d] imidazole-6-carboxylate.

To a cooled with ice to a solution of methyl-2-ethylthio-4-methylthieno-[3,4-d] imidazole-6-carboxylate (0.26 g) in DMF (1 ml) was added sodium hydride (60 % in oil, 48 mg). The mixture was stirred 20 minutes To the reaction mixture was added the compound (0,38 g) obtained in working example (36d), and the reaction mixture was stirred 1.5 h at room temperature. The reaction mixture was diluted with water and was Proektirovanie with ethyl acetate. The extract solution was washed with water and dried. The solvent was removed under reduced pressure. The residue was purified through column chromatography with silica gel and received the specified compound as a colourless oil (0,30 g, 55 %).

1H-NMR (200 MHz, CDCl3) : of 1.42 (3H, s) to 2.55 (3H, s),05, 1605, 1540, 1460, 1440, 1320, 1240, 1170, 1095, 755.

48f) Methyl-2-ethylthio-1-[[2'(2,4-dihydro-4-methyl-3-oxo-1,2,4 - triazole-5-yl)biphenyl-4-yl]methyl]-4-methylthieno[3,4-d] imidazole-6 - carboxylate.

Connection of 0.30 g) obtained in working example (48e), was dissolved in a mixture triperoxonane acid (2 ml) and chloroform (2 ml). The solution was stirred for 5.5 days at 60oC. the Reaction mixture was concentrated under reduced pressure. The residue was purified through column chromatography with silica gel and received the specified compound as a colourless oil (0.27 g, 96 %).

1H-NMR (200 MHz, CDCl3) : of 1.42 (3H, t), of 2.53 (3H, s), 2.63 in (3H, s), 3,30 (2H, K), of 3.77 (3H, s), 5,71 (2H, s), to 7.15 (2H, d), of 7.23 (2H, d), 7,42-the 7.65 (4H, m).

IR (Neat), cm-1: 1700, 1600, 1540, 1460, 1435, 1320, 1240, 1195, 1170, 1095, 750.

48g) 2 Ethylthio-1-[[2'-(2,4-dihydro-4-methyl-3-oxo-1,2,4-triazole-5-yl)biphenyl-4-yl]methyl]-4-methylthieno[3,4-d]imidazole-6-carboxylic acid

Connection (0,27) obtained in working example (48f), and lithium-hydrocodonehydroc (0.11 g) was dissolved in a mixture of THF (2 ml) and water (2 ml) and the solution was stirred 8 h at 60-70oC. the Reaction mixture was diluted with water, the insoluble material was filtered and 1 N. HCl brought the pH of the filtrate to a value of 3-4. The crystalline precipitate was filtered and purified on khromatograficheskoe got the connection specified in the form of pale yellow prisms (70 mg, 27 %).

So pl. 228-229oC (decomposition).

Elemental analysis for C25H23N5O3S25 H2O:

Calculated, %: C 58,35; H 4,70; N 13,61.

Found, %: C 58,64; H 4,59; N 13,71.

1H-NMR (200 MHz, CDCl3) : of 1.46 (3H, t), is 2.44 (3H, s), 2.63 in (3H, s) to 3.35 (2H, K), 5,61 (2H, s), 7,10 (2H, d), 7,20 (2H, d), 7,46-to 7.64 (4H, m).

IR (KBr), cm-1: 1690, 1605, 1540, 1490, 1460, 1415, 1315, 1240, 1200, 1170, 1100, 940, 805, 780, 760.

Working example 49. 2 Ethylthio-1-[[2'-(5-hydroxy-2-1,2,4-triazole-3-yl)biphenyl-4 - yl-methyl]-4-methylthieno[3,4-d]imidazole-6-carboxylic acid.

1-Methyl-1-(4'-methylbiphenyl-2-carbonyl)hydrazide.

To a solution of 4'-methylbiphenyl-2-carboxylic acid (3.2 g) and DMF (one drop) in THF (35 ml) was dropwise added oxalicacid (2.9 g) and the mixture was stirred 18 hours, the Reaction mixture was concentrated under reduced pressure. The residue is dropwise added to a solution of monomethylhydrazine (6,9 g) in THF (80 ml). The reaction mixture was stirred for one hour at room temperature and concentrated under reduced pressure. The residue is distributed between water and ethyl acetate. An ethyl acetate layer was separated, washed with water and dried. The solvent is evaporated under reduced pressure. The residue was purified on a chromatographic column with the UB>3
) : 2,39 (3H, s), 2,62 (3H, s), 4,39 (2H/ W), 7-, 19-7,47 (8H, m).

IR (Neat), cm-1: 3300, 3200, 1630.

49b) 1-Methyl-1-[2-(4-were)benzoyl]semicarbazide.

To a solution of compound (3.6 g) obtained in working example (49a), 1 N. HCl (37 ml) was dropwise added an aqueous solution (30 ml) of sodium isocyanate (2.6 g) and the mixture was stirred 3 h at room temperature. The crystalline precipitate was filtered and recrystallize from methanol-an ethyl acetate mixture and highlighted the connection specified in the form of colorless prisms (3.1 g, 74 %).

So pl. 217-218oC.

Elemental analysis for C16H17N3O2:

Calculated, %: C 67,83; H Equal To 6.05; N 14,83.

Found, %: C 67,99; H Of 6.02; N 15,03.

1H-NMR (200 MHz, DMCO-d6) : of 2.34 (3H, s) of 3.00 (3H, s), between 6.08 (1H, sh), 7,19 (2H, d), 7.24 to to 7.50 (6H, m), 8,15 (1H, s).

IR (KBr), cm-1: 3470, 3330, 1680, 1645, 1610, 1520, 1460, 1390, 1340, 825, 755.

49c) 1-Methyl-5-(4'-methylbiphenyl-2-yl)-3-hydroxy-1,2,4-triazole.

In accordance with the procedure described in working example (48b), the indicated compound was obtained as colorless prisms (2.7 g, 93 %) from compound (3.1 g) obtained in working example (49b).

So pl. 271-272oC.

Elemental analysis for C16H15N3O:

The calculated), 2,95 (3H, s), 7,06 (2H, d), 7,18 (2H, d), 7,51-to 7.68 (4H, m), 10,84 (1H, s).

IR (KBr), cm-1: 1580, 1510, 1490, 1440, 1325, 1275, 890, 880, 840, 820, 760, 620.

49d) 3 Ethoxycarbonyl-1-methyl-5-(4'-methylbiphenyl-2-yl)-1,2,4-triazole.

To a suspension of compound (0.65 g) obtained in working example (s), and triethylamine (0.29 grams) in methylene chloride (10 ml) was added ethylchloride (0.31 g) and the mixture was stirred 3 h at room temperature. The reaction mixture is washed with water and dried. The solvent was removed under reduced pressure and the residue was purified through column chromatography with silica gel and got the connection specified in the form of a colorless oil (0.55 g, 68 %).

1H-NMR (200 MHz, CDCl3) : of 1.40 (3H, t), of 2.34 (3H, s), to 3.02 (3H, c) 4,37 (2H, K), to 7.09 (2H, d), 7,41-to 7.64 (4H, m).

IR (Neat), cm-1: 1780, 1505, 1360, 1230.

49E) 5-(4-bromomethylphenyl-2-yl-3-ethoxycarbonyl-1-methyl-1,2,4-triazole.

In accordance with the procedure described in working example (48d), the indicated compound was obtained as a colourless oil (0,63 g, 94 %) from compound (0.55 g) obtained in working example (49d).

1H-NMR (200 MHz, CDCl3) : of 1.41 (3H, t), of 3.05 (3H, s), 4,37 (2H, K), 4,48 (2H, s), 7,19 (2H, d), 7,54-7,66 (4H, m).

IR (Neat), cm-1: 1770, 1500, 1470, 1435, 1400, 1360, 1230, 760.

49f) Methyl 1-[[2 the lat.

In accordance with the procedure described in working example (48th), the indicated compound was obtained as a colourless oil (0,22 g, 25 %) from compound (0,63 g) obtained in working example (49E).

1H-NMR (200 MHz, CDCl3) : of 1.40 (3H,t), of 1.41 (3H, t), 2,63 (2H, s), of 2.97 (3H, c), 3,29 (2H, K) 3,76 (3H, s), 4,36 (2H, K) 5,69 (2H, s), 7,14 (4H, s), 7,42-77,64 (4H, m).

IR (Neat), cm-1:1780, 1690, 1605, 1540, 1510, 1460, 1440, 1365, 1320, 1240, 1170, 1090, 760.

49g) 2 ethylthio-1-[[2'-(3-hydroxy-1-methyl-1,2,4-triazole-5-yl) biphenyl-4-yl]methyl]-4-methylthieno[3,4-d] imidazol-6-carboxylic acid.

In accordance with the procedure described in working example (48g), the indicated compound was obtained as colorless prisms from the compound (0,22 g) obtained in working example (49E).

So pl. 236-237oC.

Elemental analysis for C25H23N5O3S20,2 H2O:

Calculated, %: C 59,97; H 4,63; N Of 13.75.

Found, %: C 59,00; H Amounts To 4.76; N 13,68.

1H-NMR(200 MHz, DMCO-d6) : of 1.33 (3H, t), to 2.55 (3H, s), of 2.92 (3H, s), 3,24 (2H, K) 5,69 (2H, c), 7,12 (4H, c-like), 7,50-to 7.68 (4H, m).

IR (KBr), cm-1: 1690, 1640, 1600, 1585, 1540, 1460, 1415, 1370, 1305, 1270, 1235, 1200, 1170, 1095, 935, 775, 765.

Working example 50. 1-[[2'-(2,4-dihydro-3-oxo-1,2,4-triazole-5-yl)biphenyl-4-yl] methyl]-2 - ethylthio-4-methylthieno[3,4-ethylphenyl)benzoyl] semicarbazide (4.6 g) and phosphorus oxychloride (10.3 g) suspended in benzene (100 ml), and then, the suspension was boiled under reflux for 3 hours, the Reaction mixture was concentrated to dryness under reduced pressure. To the residue was added water and the precipitated crystals were filtered. After recrystallization from methanol has received the connection specified in the form of colorless needle-like crystals (3.4 g, 79 %).

So pl. 245-246oC (decomposition).

Elemental analysis for C15H13N3O:

Calculated, %: C 71,70; H To 5.21; N 16,72.

Found, %: C 71,37; H 5,42; N 16,72.

1H-NMR (200 MHz, CDCl3) : 2,39 (3H, s), 4,84 (2H, sh. C), 7,17 (4H, s) 7,39-7,58 (3H, m), a 7.85-7,89 (1H, m).

IR (KBr), cm-1: 3260, 3080, 1670, 1655, 1605, 1580, 1025, 820, 765, 750.

50b) 1,2-(&(2,4-dihydro-1,2-(& (2,4-bis - (methoxymethyl)-3-(4-methylbiphenyl-2-yl)1,2,4-triazole-3-one.

In accordance with the procedure described in working example (48S), mixture of isomers (1:2) of the said compound was obtained as a colourless oil (1.6 g, 73 %) from compound (1.6 g) obtained in working example (50A).

1H-NMR(200 MHz, CDCl3), : of 2.38 (3H, s) to 3.09 (3H, s), 3,30 (1H, s) 3,40 (2H, s), 4,30 (2H, s), 4,56 (2H, s) 7,20-7,30 (4H, m), 7,39-rate of 7.54 (4H, m).

IR (Neat), cm-1: 2220, 1685, 1480, 1440, 1360, 1290, 1240, 1190, 1090, 915, 820, 760.

50C) 3-(4'-Bromomethylbiphenyl-2-yl)-1,2-(& 2,4-dihydro-1,e (48d), the mixture of isomers (1:2) of the said compound was obtained as a colourless oil (2.0 g, 100 %), from the compound obtained in working example (50b).

1H-NMR (200 MHz, CDCl3) : 3,10 (3H, s), 3,23 (1H, s) to 3.41 (2H, s), or 4.31 (2H, s), of 4.54 (2H, s), 7,35-the 7.65 (8H, m).

IR (Neat), cm-1: 2210, 1680, 1440, 1360, 1285, 1240, 1230, 1190, 915, 760.

50d) Methyl-2-ethylthio-1-[[2'-(1,2-& 2,4)-dihydro-1,2-(& 2,4)-bis-methoxymethyl)-5-oxo-1,2,4-triazole-3-yl]methyl]-4-methyl-thio-[3,4-d]imidazole-6-carboxylate.

In accordance with the procedure described in working example (48th), a mixture of isomers of the compounds was obtained as pale-yellow oil (0.65 g, 43 %) from the compound (1.0 g) obtained in working example (50).

1H-NMR (200 MHz, CDCl3) : of 1.42 (3H, t), 2,62 (3H, s), 3,05 (3H, s), 3,26 (1H, s), 3,30 (2H, K), 3,36 (2/3H, s), of 3.77 (3H, s), 4,22 (2H, s), 4,22 (2H, s), 4,42 (2H, s) 5,72 (2H, s), 7,21-EUR 7.57 (8H, m).

IR, cm-1: 2220, 1690, 1600, 1540, 1460, 1430, 1360, 1320, 1285, 1240, 1195, 1165, 1090, 755.

50 ppm) Methyl-2-ethylthio-1-[[2'-(4,5-dihydro-5-oxo-1,2,4-triazole-3-yl)-biphenyl-4-yl]methyl]-4-methylthieno[3,4-d] imidazole-6-carboxylate.

In accordance with the procedure described in working example (48f), the indicated compound was obtained as yellow prisms (0.28 g, 50 %) from compound (0.65 g) obtained in working example (50d).

UB>:

Calculated, %: C 59,39; H 4,58; N 13,85.

Found, %: C 59,17; H 4,74; N 13,81.

1H-NMR (200 MHz, d6) : of 1.36 (3H, t), of 2.56 (3H, s), 3,26 (2H, K), 3,70 (3H, s), to 5.66 (2H, s), of 6.96 (2H, sh. C), 7,12 (2H, d), 7,22 (2H, d), 7,41-7,63 (3H, m), of 7.69 (1H, DD).

IR (KBr), cm-1: 3275, 3100, 1680, 1660, 1535, 1450, 1430, 1320, 1235, 1160, 1090, 755.

50f) 2 Ethylthio-1-[[2'-(4,5-dihydro-5-oxo-1,2,4-triazole-3-yl)biphenyl-4-yl]methyl]-4-methylthieno[3,4-d]imidazole-6 - carboxylic acid.

In accordance with the procedure described in working example (48g), the indicated compound was obtained as colorless needle crystals (0.17 g, 65 %) from compound (0.27 g) obtained in working example (50 ppm).

So pl. 205-207o(decomposition).

Elemental analysis for C24H21N5O3S2:

Calculated, %: C 58,64; H Or 4.31; N Of 14.25.

Found, %: C 58,30; H 4,16; N 14,12.

1H-NMR (200 MHz, DMCO-d6) : of 1.35 (3H, t), of 2.54 (3H, s), 3,24 (2H, K) 5,70 (2H, s), to 6.95 (2H, s), to 7.15 (2H, d), 7,22 (2H, d), 7,41-7,63 (3H, m), of 7.69 (1H, DD).

IR (KBr), cm-1: 1660, 1650, 1595, 1535, 1450, 1305, 1240, 1160.

Working example 51. Methyl 2-n-butyl-1-[[2'-(2,4-dioxoimidazolidin-1-yl) biphenyl-4-yl]-methyl]benzimidazole-7-carboxylate.

51A) Methyl-2-n-butyl-1-[[2'-(t-butoxycarbonylamino)-biphenyl)-4-yl] methyl]benzimidazole-7-carboxymethylamino (0.2 ml) were dissolved in N,N-dimethylformamide (3 ml). To a cooled with ice to a solution under nitrogen atmosphere dropwise added diphenylphosphoryl (DPPA) (0,32 ml). The mixture was stirred for 4.5 h at the same temperature. The reaction mixture was diluted with ethyl acetate, washed with water three times and dried. Thus obtained solution was concentrated under reduced pressure to a volume equal to 20 ml of the Concentrate with stirring at 80oC dropwise added to a toluene (25 ml). The mixture was stirred at the same temperature for 20 minutes To the reaction mixture was added t-butanol (15 ml) and the mixture was stirred for 17 hours, the Solvent is boiled away under reduced pressure, and the residue was purified through column chromatography with silica gel and received the specified compound (510 mg, 73 %) as a pale yellow oil.

51b) Methyl 2-n-butyl-1-[(2'-aminobiphenyl-4-yl) methyl]benzimidazole-7-carboxylate.

The compound (510 mg) obtained in working example (51), was dissolved in concentrated HCl (0.8 ml) and methanol (10 ml), and then the solution was stirred for 70 min at 70oC. the Solvent was removed under reduced pressure. To the precipitate was added an aqueous solution of bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with water and dried. The solvent is boiled away under reduced pressure and the obtained pale-yellow s.

So pl. 97-99oC.

Elemental analysis for C26H27N3O2:

Calculated, %: C 75,52; H To 6.58; N, 10,16.

Found, %: C 75,27; H For 6.81; N 9,99.

1H-NMR (200 MHz, CDCl3) : 0.95 (3H, t), 1,4-1,6 (2H, m), of 1.8-2.0 (2H, m), of 2.92 (2H, t), the 3.65 (2H, sh) of 3.73 (3H, s), 5,79 (2H, s), 6,7-7,5-)9H, m), of 7.64 (1H, DD), 7,95 (1H, DD).

IR (KBr), cm-1: 1720, 1630, 1600, 1575, 1520.

51c) Methyl-2-n-butyl-1-[[2'-(ethoxycarbonylmethylene)biphenyl-4-yl] -methyl]benzimidazole-7-carboxylate.

The compound (408 mg) was dissolved in N, N-dimethylformamide (12 ml) and to the solution at room temperature was added potassium carbonate (150 mg). The mixture was stirred for 63 hours at room temperature, and then the solvent was removed under reduced pressure. The residue is distributed between water and ethyl acetate. The organic layer was dried, concentrated to dryness under reduced pressure. The remainder of the purification through column chromatography with silica gel and received the specified connection (139 mg, 28 %) as a pale yellow oil.

1H-NMR (200 MHz, CDCl3) : to 0.96 (3H, t), of 1.24 (3H, t), 1,4-1,6 (2H, m), of 1.8-2.0 (2H, m), with 2.93 (2H, t), of 3.73 (3H, s), 3,85 (2H, d), 4,17 (2 H, K) 4,51 (1H, t), 5,79 (2H, s), 6,55 (IH, d), 6,7-7,5 (8H, m), of 7.64 (IH, DD), of 7.95 (1H, DD).

IR (Neat), cm-1: 1745, 1720, 1600, 1580, 1520, 1505.

51d) Methyl 2-n-butyl="ptx2">

To a cooled with ice to a solution of compound (260 mg) obtained in working example (s), in dichloromethane (10 ml) under nitrogen atmosphere was added dropwise characaterization (80 ál). The mixture was stirred 2 h at the same temperature and concentrated to dryness. The residue was purified through column chromatography with silica gel and received the specified compound (193 mg, 60 %) as a white powder.

So pl. 149-151oC.

Elemental analysis for C33H35N4O6Cl O 2H2O:

Calculated, %: C 63,65; H 5,73; N 9,00.

Found, %: C 63,46; H 5,65; N 8,72.

1H-NMR (200 MHz, CDCl3) : and 0.98 (3H, t), of 1.25 (3H, t), 1,3-1,6 (2H, m), 1,7-2,0 (2H, m), only 2.91 (2H, t), of 3.32 (1H, d), 4,58 (1H, d), 5,79 (2H, s) 6,91 (2H, d), 7,11 (2H, d), of 7.2 to 7.7 (6H, m), 7,95 (1H, d).

IR (KBr), cm-1: 1750, 1720, 1690, 1520.

51e) Methyl-2-n-butyl-1-[[2'-(2,4-dioxoimidazolidin-1-yl)biphenyl-4-yl] methyl] benzimidazole-7-carboxylate.

Compound (180 g) obtained in working example (51d), was dissolved in a mixture of methanol (10 ml) and chloroform (3 ml). To a solution under nitrogen atmosphere at room temperature was added N-methyldithiocarbamate sodium. The mixture was stirred 5 h at room temperature, and then the solvent was removed under reduced pressure. The residue was purified on chromatographically (3 ml) under nitrogen atmosphere was added sodium hydride (60 % in oil, 13 mg). The mixture was mixed for 2 hours while cooling with ice, and then another 4 h at room temperature. After evaporation of the solvent the residue was diluted with chloroform, then washed with diluted hydrochloric acid and dried. The solvent was removed under reduced pressure and the residue was purified through column chromatography with silica gel and the obtained yellow oil. This product has led from chloroform and received the specified connection (40 mg, 32 %) as a pale-yellow powder.

So pl. 175-178oC.

Elemental analysis for C29H27N4O40,3 H2O:

Calculated, %: C At 69,39; H 5,74; N 11,16.

Found, %: C 69,47; H Of 5.83; N 10,98.

1H-NMR (200 MHz, CLCl3) : of 0.95 (3H, t), 1,3-1,6 (2H, m), 2,95 (2H, t), 3,68 (2H, s), 3,71 (3H, s), 5,79 (2H, s), 6.89 in (2H, d), a 7.1 to 7.5 (7H, m), 7,63 (1H, d), of 7.97 (1H, DD), 8,14 (1H, sh. C).

IR (KBr), cm-1: 3450, 2960, 2740, 1170, 1730, 1610, 1525.

Working example 52. Methyl 2-butyl-1-[[2'-(2,4-dioxo-3H-thiazolidin-5-yl)biphenyl - 4-yl]methyl]benzimidazole-7-carboxylate.

52a) Methyl-2-[N-(2'-butoxycarbonylmethyl-4-yl)methyl-N-valeryl] amino-3-nitrobenzoate.

To a solution of methyl-3-nitro-2-valerianovna (2,79 g) in DMF (20 ml) under stirring and ice cooling was added sodium hydride (60 % in oil, 0.40 g). The reaction mixture was stirred 2 h at 70oC and Proektirovanie with ethyl acetate. The extract was washed with water and dried (MgS)4and then the solvent evaporated in vacuum. The residue was purified through column chromatography and the obtained crude crystals. After recrystallization from isopropyl ether has received the specified connection (to 4.41 g, 81 %) as colorless crystals.

So pl. 127-128oC.

Elemental analysis for C31H34N2O7:

Calculated, %: C 68,12; H 6,27; N 5,12.

Found, %: C 68,27; H 6,27; N 4,85.

1H-NMR (200 MHz, CDCl3) : to 0.80 (3H, t), of 1.20 (2H, m) of 1.23 (9H, c) of 1.53 (2H, m), is 2.05 (2H, t), 3,62 (3H, s), 4,56, and of 4.77 (2H, each d), 7,05 (2H, d), 7,13 (2H, d), 7,27-7,83 (5H, m) to 8.12 (1H, DD), 8,23 (1H, DD).

IR (Nujol) cm-1: 1740, 1710, 1675, 1600.

52b) Methyl-2-butyl-1-[2'-tert. -butoxycarbonylmethyl-4-yl]methyl - benzimidazole-7-carboxylate.

To a mixture of compound (3,20 g) obtained in working example (52a), concentrated HCl (0.5 ml) and methanol (30 ml) was added iron powder (1.35 g). The mixture was boiled under reflux for 1.5 hours, the Insoluble materials were filtered through celite. The filtrate was concentrated to dryness and to the residue was added concentrated HCl (0.5 ml) and methanol (50 ml). The mixture was boiled under reflux the cue layer was dried and concentrated to dryness. The residue was purified through column chromatography with silica gel and received the specified connection (2.38 g, 82 %) as oil.

Elemental analysis for C31H34N2O41/2H2O:

Calculated, %: C 73,35; H 6,95; N 5,52.

Found, %: C 73,42; H 6,98; N The 5.45.

1H-NMR (200 MHz, CDCl3) : to 0.97 (3H, t) to 1.19 (9H, s) to 1.48 (2H, m), with 2.93 (2H, t), 3,76 (3H, s), of 5.83 (2H, s), 6.87 in (2H, d), 7,16-7,51 (6H, m), of 7.64-to 7.77 (2H, m), 7,95 (1H, DD).

IR (Neat), cm-1: 1715, 1700, 1595.

S) Methyl-2-butyl-1-[2'-carboxymethyl-4-yl]methylbenzimidazole - 7-carboxylate.

To a solution of compound (2.35 g) obtained in working example (52b), in dichloromethane (8 ml) was added triperoxonane acid (10 ml). The mixture was heated 1 h at room temperature, diluted with water and was Proektirovanie chloroform. The extract was washed with water, dried (MgSO4), and the solvent is boiled away in a vacuum. The residue was purified on a chromatographic column with the separation of crystals. After recrystallization from diethyl ether got the connection specified in the form of colorless prisms (2,04 g, 98 %).

So pl. 192-194oC.

1H-NMR (200 MHz, DMCO-d6) : of 0.90 (3H, t), of 1.40 (2H, m), of 1.78 (2H, m) to 2.94 (2H, t), the 3.65 (3H, s), a-3.84 (1H, sh), 5,73 (2H, s), 6.87 in (2H, d), 7,22-EUR 7.57 (7H, m), of 7.70 (1H, DD), 7,88 (1H, DD).

A mixture of methyl 2-butyl-1-[2'-carboxyphenyl-4-yl] methylbenzimidazole - 7-carboxylate (0,44 g) and thionyl chloride (0.15 ml) in chloroform (4 ml) with constant stirring was boiled under reflux for 30 minutes, the Reaction mixture was concentrated and the obtained product was used in subsequent reactions without purification. Mixed mortar of the specified product in tetrahydrofuran (6 ml) under ice cooling dropwise added to a suspension of aluminiumhydride (40 mg) in tetrahydrofuran (6 ml). The reaction mixture was mixed for 1 min at the same temperature, to the mixture was added 2 N. HCl, then water and Proektirovanie chloroform. The extract was washed with water and dried (MgSO4), and then purified through column chromatography with silica gel emitting oil. Crystallization of this product from isopropyl ether allowed to obtain colorless prisms (0,13 g, 31 %).

So pl. 126-127oC.

Elemental analysis for C27H28N2O3:

Calculated, %: C 75,68; H 6,59; N 6,54.

Found, %: C 75,20; H 6,66; N 6,55.

52e) Methyl 2-butyl-1-[2'-formylphenyl-4-yl] methylbenzimidazole-7-carboxylate.

A mixture of compound (0.73 g) obtained in working example (52d), pyridinediamine (0,75) and dichloromethanol to dryness. The residue was purified through column chromatography with silica gel emitting crude crystals. After recrystallization from a mixture of ethyl acetate-diethyl ether obtained colorless prisms (0,62 g, 85 %).

So pl. 103-104oC.

Elemental analysis of C27H26N2O3:

Calculated, %: C 76,03; H 6,1; N 6,57.

Found, %: C 75,95; H 6,07; N 6,56.

1H-NMR (200 MHz, CDCl3) : to 0.96 (3H, t) to 1.48 (2H, m), with 2.93 (2H, t), 3,74 (3H, s), of 5.84 (2H, s), of 6.96 (2H, d), 7,22-7,72 (7H, m), 7,94-of 8.06 (2H, m), to 9.91 (1H, s).

IR (Nujol) cm-1: 1720, 1695, 1595.

52f) Methyl-2-butyl-1-[2'-cyanohydroxybutene-4-yl]methyl-benzimidazole-7-carboxylate.

To a solution of compound (0,61 g) obtained in working example (e) in ethyl acetate (6 ml) was added an aqueous solution (1.5 ml) of sodium hydrosulphate (0.74 g) and an aqueous solution (1.5 ml) of potassium cyanide (0,47 g). The reaction mixture was stirred 2 h at room temperature, and then 1 h at 60oC. the Mixture was diluted with water and was Proektirovanie with ethyl acetate. The extract was washed with water, dried (MgSO4) and concentrated to dryness. The residue was purified through column chromatography with silica gel and received the specified connection (0,61 g, 94 %) as syrup.

1H-NMR (200 MHz, CDCl3) : 0, 2360, 1720, 1605.

52g) Methyl-2-butyl-1-[2'-(2,4-dioxothiazolidine-5-yl)-biphenyl-4-yl)-biphenyl-4-yl]-methylbenzimidazole-7-carboxylate.

Thionyl chloride (0.15 ml, 2.1 mmol) was added to a solution of compound (0,60 g) obtained in working example (52f) in chloroform. The solution was boiled for 1 h under reflux. The reaction mixture was concentrated and the residue was used in subsequent reactions without purification.

The mixture of compounds obtained above, and thiourea (0.11 g) in methanol (10 ml) was boiled under reflux for 1 h and Then added 2 N. HCl (13 ml) and the reaction mixture is boiled under reflux for another 12 hours, the Extract was washed with water, dried (MgSO4) and then the solvent is boiled away in a vacuum. The residue was purified through column chromatography with silica gel emitting crystals. After recrystallization from dichloromethane-an ethyl acetate mixture received the specified connection (0.40 g, 59 %) as colorless prisms.

So pl. 141-142oC.

Elemental analysis for C29H27N3O4S:

Calculated, %: C 67,82; H And 5.30; N 8,18.

Found, %: C 67,71; H 5,62; N 8,14.

1H-NMR (200 MHz, DMCO-d6) : to 0.89 (3H, t), of 1.40 (2H, m), of 1.78 (2H, m), only 2.91 (2H, t), of 3.69 (3H, s), 5,46 (1H, s), USD 5.76 (2H, s), 6,93 (2H, d), 7,15-to 7.61 (8H, m), 7,87 (1H, is 5-oxo-1,2, 4-oxadiazol-3-yl) biphenyl-4-yl] methyl] thieno[3,4-d] imidazol-4-methyl-6-carboxylic acid.

53A) Methyl-4'-methylbiphenyl-3-carboxylate.

To a mixture of methyl-3-iodobenzoate (26,1 g) in 4-iodotoluene (21,9 g) at 180-190oC was gradually added to the copper powder. The mixture was then stirred for 6 hours at 200-210oC. the Reaction mixture was cooled to room temperature and thereto was added toluene. Insoluble materials were filtered and the filtrate concentrated to dryness. The residue was purified through column chromatography with silica gel and the obtained colorless oil (6,61 g, 29 %).

1H-NMR (200 MHz, CDCl3) : is 2.40 (3H, s), of 3.94 (3H, s), 7,26 (2H, d), 7,49 (1H, t), 7,52 (2H, d), to 7.77 (1H, m), to 7.99 (1H, TD), compared to 8.26 (1H, t).

53b) 4'-Methylbiphenyl-3-carboxylic acid.

To a solution of compound (2,36 g) obtained in working example (53A), in tetrahydrofuran (20 ml) and water (10 ml) mixture was added lithium-hydrocodonehydroc (1.31 g). The mixture was stirred 3 h at room temperature. The reaction mixture was concentrated, diluted with water and washed with ethyl acetate. The aqueous layer with 1 N. HCl brought to pH 3. The crystalline precipitate was filtered, dried and got the connection specified in the form of colorless needle-like crystals (1.73 g, 78 %).

So pl. 182-187CLASS="ptx2">

IR (KBr), cm-1: 1700, 1450, 1415, 1310, 1300, 1270, 1260, 810, 755, 720.

53c) 4'-Methylbiphenyl-3-carboxamide.

To a suspension of compound (1.73 g) obtained in working example (53b), in chloroform (25 ml) was added thionyl chloride (1,94 g) and dimethylformamide (two drops). The mixture was boiled under reflux 4 h, the Reaction mixture was concentrated to dryness and to the residue was added toluene. The mixture was again concentrated to dryness. This procedure was repeated four times and gave a pale yellow oil, which was dropwise added under ice cooling to 25% of the resultant aqueous ammonia (20 ml). The mixture was stirred 30 min at room temperature. The resulting crystalline precipitate was filtered, dried and got the connection specified in the form of colorless crystals (1.73 g, quantitatively).

So pl. 200-205oC.

1H-NMR (200 MHz, DMCO-d6) : a 2.36 (3H, s), 7,30 (2H, d), 7,41 (1H, sh), 7,51 (1H, t), 7,63 (2H, d), 7,76-7,86 (2H, m), 810 (1H, sh. C) to 8.14 (1H, t).

IR (KBr), cm-1: 3300, 3150, 1670, 1630, 1605, 1580, 1450, 1410, 1390, 1125, 800, 685.

53d) 4'-Methyl-3-cyanobiphenyl.

A mixture of compound (1.70 g) obtained in working example (s), and thionyl chloride (10 ml) for 4.5 h was heated under reflux. The reaction mixture is concentrated by dryness and is atok was purified through column chromatography with silica gel and got the connection specified in the form of colorless crystals (1.50 g, 96 %).

So pl. 71-73oC.

1H-NMR (200 MHz, CDCl3) : to 2.41 (3H, s), 7,28 (2H, d), 7,46 (2H, d), 7,51 (1H, t), 7,60 (1H, TD), 7,79 (1H, TD), to 7.84 (1H, t).

IR (KBr), cm-1: 2230, 1475, 825, 800.

53e) 4'-Methylbiphenyl-3-carboxylicacid.

To a solution of hydroxylaminopurine (2,61 g) diethylsulfoxide (20 ml) was added a solution of 28 % of methoxide sodium in methanol (7,25 g). The mixture then was stirred 10 min at room temperature, and then added the solution of compound (1.45 g) obtained in working example (53d), in dimethyl sulfoxide (10 ml). The mixture was stirred for one hour at 100oC, and then to the mixture was added water. The resulting mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated in vacuo to dryness, dried and concentrated in vacuum drying. The residue was purified through column chromatography with silica gel and got the connection specified in the form of colorless crystals (1,30 g, 76 %).

So pl. 134-136oC.

1H-NMR (200 MHz, CDCl3) : 2,39 (3H, s), is 4.93 (2H, sh.C) to 7.25 (2H, d), 7,41-7,66 (5H, m), a 7.85 (1H, t).

IR (KBr), cm-1: 3495, 3385, 1660, 1585, 1440, 1375, 940, 925,900, 795.

53f) 3-4'-Methylbiphenyl-3-yl)-5-trichloromethyl-1,3,4-oxadiazole.

To a suspension of compound (1,3 is ivali 30 min at 80oC. the Reaction mixture was concentrated to dryness and dissolved in ethyl acetate. The solution was washed with water, dried and concentrated to dryness in vacuum. The residue was purified through column chromatography with silica gel and got the connection specified in the form of oil (2,09 g, quantitatively).

1H-NMR (200 MHz, CDCL3) : to 2.41 (3H, s), 7,28 (2H, d), at 7.55 (2H, d), 7,56 (1H, t), 7,76 (1H, TD), 8,07 (1H, TD), 8,32 (1H, t).

53g) 3-4'-Bromomethylbiphenyl-3-yl)-5-trichloromethyl-1,2,4-oxadiazole.

To a solution of compound (2,09 g) obtained in working example (53f) in carbon tetrachloride (50 ml) was added N-bromosuccinimide (N) (1.10 g) and benzoyl peroxide (BPO) (0.20 g). The mixture was boiled under reflux and with a light irradiation 1 h, the Reaction mixture was cooled to room temperature and the insoluble material was filtered. The filter was concentrated, the material was filtered. The filter was concentrated to dryness, and the residue was purified through column chromatography with silica gel and received the specified compound as a colourless oil (2,40 g, 59 %).

1H-NMR (200 MHz, CDCl3) : of 4.57 (2H, s), 7,49-to 7.68 (5H, m), 7,75-7,79 (1H, m), 8,09-8,17 (1H, m), with 8.33 (1H, m).

53h) Methyl-2-ethylthio-1-[[3'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]thieno [imidazol-6-carboxylate (0,80 g) in dimethylformamide (10 ml) was added sodium hydride (60 % in oil, 0.14 g). After stirring for 10 min to a cooled ice mixture was added a solution of compound (1,53 g) obtained in working example (53g), in dimethylformamide (10 ml) and then stirred one hour at room temperature. To the reaction mixture was added water and was Proektirovanie with ethyl acetate. The extract was washed with saturated aqueous brine, dried and concentrated to dryness. The residue was purified through column chromatography with silica gel emitting colorless crystalline product. To a solution of the crystals in a mixture of chloroform (10 ml) - methanol (10 ml) was added 1 N. NaOH (3 ml) and the mixture was stirred one hour at room temperature. The reaction mixture was concentrated and 1 N. HCl brought the pH to 3-4. The aqueous mixture was distributed between chloroform and water. The organic layer was dried, the solvent was removed in vacuo and the obtained crude crystals. After recrystallization from methanol-an ethyl acetate mixture has allocated the specified connection in the form of colorless needle-like crystals (0.74 g, 83 %).

So pl. 248-251oC (decomposition).

Elemental analysis for C25H22N4S2H2O:

Calculated, %: C 58,24; H 4,50; N 10,87.

Found, %: C 58,24; H 4,33; N 10,77.

1H-NMR (200 MHz, CDCl3 -1
: 1780, 1755, 1690, 1460, 1320, 1170, 1090, 760.

53i) 2 Ethylthio-1[[3'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)-biphenyl-4-yl]methyl]thieno[3,4-d]imidazol-4-methyl-6-carboxylic acid.

To a suspension of compound (0,60 g) obtained in working example (53h), in a mixture of tetrahydrofuran (20 ml) - water (10 ml) was added litohydrodynamical (0.25 g). The mixture was boiled under reflux for 15 hours, the Reaction mixture was concentrated and the aqueous residue 1 N. HCl brought to pH 3.The crystalline precipitate was recrystallize and received colorless needle crystals (0.33 g, 56 %).

So pl. 177-179oC (decomposition).

Elemental analysis for C24H20N4O4S20 5H2O:

Calculated, %: C 57,47; H 4,22; N 11,17.

Found, %: C 57,63; H Of 4.04; N 11,17.

1H-NMR (200 MHz, DMCO-d6) : of 1.35 (3H, t), of 2.56 (3H, s), 3.26 (2H, K), 5,73 (2H, s), 7,26 (2H, d), the 7.65 (1H, t), of 7.69 (2H, d), 7,81 (1H, t e), 8,08 (1H, t).

KV (KBr), cm-1: 1770, 1755, 1650, 1530, 1460, 1165, 765.

Working example 54. 2 Ethoxy-1-[[2'-(2, 5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid.

54a) 4'-bromomethylbiphenyl-2-carboxamide.

A mixture of 4'-methylbiphenyl-2-carboxamide (2.1 g), N-bromo-succinimide (2.5 g) and azobisisobutyronitrile (AIBN; 82 mg) in baie and, washed with isopropyl ether and suspended in water. The suspension was stirred 30 min, insoluble products were filtered, dried and isolated crude crystals. After recrystallization from ethyl acetate-methanol mixture obtained colorless needle crystals (1.6 g), 55 %).

So pl. 220-221oC (decomposition).

Elemental analysis for C14H12B2NO:

Calculated, %: C 57,95; H 4,17; N Of 4.83.

Found, %: C 57,85; H 4,16; N 4,77.

1H-NMR (200 MHz, DMCO-d6) : of 4.75 (2H, s), 7,31-7,69 (10H, m).

IR (KBr), cm-1: 3150, 3000, 1570, 1520, 1500, 1300, 665.

54b) Methyl-2-[N-tert-butoxycarbonyl-N-(2'-carbamoylbiphenyl-4-yl)-methylamino]-3-nitrobenzoate.

A mixture of methyl 2-(N-tert-butoxycarbonylamino)-3-nitrobenzoate (1.8 g), 4'-bromomethylbiphenyl-2-carboxamide (1.8 g) and K2CO3(0,86 g) in acetonitrile (25 ml) was boiled for 6 hours under reflux. To the reaction mixture was added water and the mixture was Proektirovanie with ethyl acetate. The extract was washed with water and dried over MgSO4. The solvent was removed in vacuo and the residue was purified through column chromatography with silica gel and received a yellow syrup (2,3, 90%).

1H-NMR (200 MHz, CDCl3) : of 1.35 (9H, s), 3,83 (3H, s), 4,48 (1H, d), to 4.92 (1H, d), from 5.29 (1H, sh), 7,13 the Teal-2-(2'-carbamoylbiphenyl-4-yl)methylamino-3-nitrobenzoate.

A mixture of compound (2.8 g) obtained in example (54b), in methanol (15 ml) and 1 N. HCl (6 ml) was boiled for 2 hours under reflux. After removal of solvent the residue was podslushivaet aqueous solution of NaHCO3and the mixture was Proektirovanie with ethyl acetate. The extract was washed with water, dried over MgSO4and concentrated to dryness. The residue was purified through column chromatography with silica gel, the product has to recrystallize from ethyl acetate-hexane mixture and received a yellow needle crystals (1.6 g, 73 %).

1H-NMR (200 MHz, CDCl3) : 3,90 (3H, s), 4,25 (2H, s), 5,20 (1H, sh), 5,46 (1H, sh), was 6.73 (1H, t), 7, 32-7,54 (7H, m), 7,78 (1H, DD), of 7.97 (1H, DD), to 8.12 (1H, DD).

IR (KBr), cm-1: 3470, 3330, 1695, 1670, 1605, 1580, 1530, 1500, 1450, 1350, 1260, 1120, 1110, 765, 745.

54d) Methyl-3-amino-2-(2'-carbamoylbiphenyl-4-yl)methyl-aminobenzoic.

To a suspension of Nickel chloride (4 mg) in methanol (20 ml) was added a small amount of NaBH4the compound (1.2 g) obtained in example (C). To a cooled ice the reaction mixture in portions over 30 min was added NaBH4(0.45 g). After stirring for 30 min the reaction mixture was distributed between water and ethyl acetate. The organic layer was washed with water and dried over MgSO4. The solvent was removed in vacuo, and the mod 1H-NMR (200 MHz, CDCl3) : of 3.80 (3H, s), 4,25 (2H, s), 5,12 (1H, sh), 5,42 (1H, sh), 688-6,94 (2H, m), 7,20-7,56 (8H, m), 7,78-7,83 (1H, m).

IR (Neat), cm-1: 3450, 3350, 3180, 1700-1660, 1610, 1470 1380, 1290, 1200, 760.

54e) Methyl-1[(2'-carbamoylbiphenyl-4-yl)methyl] -2-ethoxybenzylidene-7-carboxylate.

To dioxane (2 ml) was added the compound (0.84 g) obtained in example (54d), tetraethoxysilane (0,63 g) and acetic acid (0,13 g) and the mixture was stirred 6 h at 80-90oC. the Solvent was removed in vacuo and the residue was purified through column chromatography with silica gel. After recrystallization from ethyl acetate-hexane mixture obtained colorless needle crystals (0,61 g, 64 %).

So pl. 198-199oC.

Elemental analysis for C25H23N3O4:

Calculated, %: C 69,92; H Of 5.40; N 9,78.

Found, %: C 69,96; H Of 5.68; N 9,81.

1H-NMR (200 MHz, CDCl3) : of 1.52 (3H, t), of 3.78 (3H, s), to 4.73 (2H, K), 5,14 (1H, sh), of 5.39 (1H, sh), to 5.66 (2H, s), 7,03 (2H, d), 7,20 (1H, t), 7,30-7,56 (6H, m), 7,73-7,81 (2H, m).

54f) Methyl-2-ethoxy-1[(2' -(ethoxycarbonylethyl)biphenyl-4-yl)methyl]-benzimidazole-7-carboxylate.

To methylene chloride (50 ml) was added the compound (4, 3 g) obtained in example (54e), and Triethylenetetramine (2.8 g). The mixture was stirred one hour at room temperature. The reaction in vacuum, and the residue was purified through column chromatography with silica gel. After recrystallization from isopropyl ether obtained colorless prismatic crystals (3.6 g, 78 %).

So pl. 105-106oC.

Elemental analysis for C27H27N3O4:

Calculated, %: C To $ 70.88; H 5,95; N 9,18.

Found, %: C 70,66; H 5,96; N 9,16.

1H-NMR (200 MHz, CDCl3) : to 0.92 (3H, t) of 1.50 (3H, t), with 3.79 (3H, s) to 4.01 (2H, K), of 4.67 (2H, K), to 5.66 (2H, s), 7,02 (2H, d), 7,13-7,58 (8H, m), 7,73 (1H, DD).

IR (KBr), cm-1: 3310, 1715, 1640, 1620, 1550, 1480, 1460, 1430, 1390, 1375, 1350, 1330, 1280, 1250, 1220, 1170, 1130, 1110, 1080, 1040, 1005, 870, 760, 750, 740.

54g) Methyl-2-ethoxy-1-[[2'-[(N-methoxycarbonyl)ethoxycarbonyl] biphenyl-4-yl]methyl]benzimidazole-7-carboxylate.

To toluene (10 ml) was added the compound (1.5 g) obtained in example (54f), ethylchloride (0,41 g) and 2,6-dimethylpyridine (0,46 g) and the mixture was stirred 3 h at 80-90oC. the Reaction mixture was diluted with ethyl acetate, washed with saturated aqueous solution of NaHCO3and dried over MgSO4. The solvent was removed in vacuo and the residue was recrystallize from ethyl acetate, receiving colorless prisms (1.5 g, 88 %).

So pl. 157-158oC.

Elemental analysis for C29H29N3O6:

Re: to 0.68 (3H, t) a 1.50 (3H, t), of 3.57 (3H, s), 3,81 (3H, s), a 3.87 (2H, K), of 4.67 (2H, K), 5,67 (2H, s),? 7.04 baby mortality (2H, d), to 7.15 (1H, t), 7.23 percent is 7.50 (6H, m), 7,55 (1H, DD), 7,72 (1H, DD).

IR (KBr), cm-1: 1710, 1650, 1615, 1550, 1475, 1455, 1445, 1430, 1410, 1390, 1375, 1350, 1320, 1270, 1240, 1220, 1140, 1010, 800, 765, 755.

54h) Methyl-2-ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate.

To a methanol (15 ml) was added the compound (1.0 g) obtained in example (54g), gidroxinimesoulid (0.28 g) and MeONa (0,22 g). The mixture was boiled under reflux for 6 hours To the reaction mixture were added water. The resulting crystalline precipitate was filtered and after recrystallization from ethyl acetate-hexane mixture obtained colorless prisms (0.7 g, 77 %).

So pl. 186-187oC.

1H-NMR (200 MHz, CDCl3) : USD 1.43 (3H, t), of 3.46 (3H, s), 4,39 (2H, K), 5,62 (2H, s), 6,88-7,01 (4H, m), to 7.09 (2H, d), 7,26-7,30 (1H, m), 7,45 (1H, DD), 7,54-of 7.60 (2H, m), a 7.85-7,89 (1H, m), of 10.25 (1H, sh).

IR (KBr), cm-1: 1780, 1720, 1610, 1550, 1490, 1470, 1435, 1410, 1390, 1350, 1280, 1220, 1130, 1040, 755.

54i) Methyl-2-ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate.

The mixture of compounds (0,23 g) obtained in example (54g), methylcarbamate (66 mg) and 2,4,6-trimethylpyridine (85 mg) in toluene (1 ml) was stirred 16 h at 80-90oC. Sadakane (32 mg) in methanol (2 ml). The mixture was heated for 5.5 h under reflux. The reaction mixture was concentrated to dryness, and the residue was dissolved in ethyl acetate, washed with diluted hydrochloric acid and dried over MgSO4. The solvent is boiled away in vacuum, the residue was led from ethyl acetate-methanol mixture and the obtained colorless prisms (of 0.13 g, 55 %).

54j) 2 ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid.

Estimates of connections (of 0.47 g) obtained in example (54h) and 1 N. NaOH (3 ml) in methanol (3 ml) was boiled under reflux for 30 minutes, the Reaction mixture was brought to 1 N. HCl to pH 3-4. The resulting crystals were filtered and recrystallize from ethyl acetate-hexane mixture. Crystals suspended in water (2 ml) and the suspension was stirred 2 h at 60oC. Insoluble material was filtered, dried and obtained colorless crystals (0.25 g, 54 %). This product corresponded to the product obtained in example 1.

1H-NMR (20-0 MHz, DMCO-d6) : to 1.38 (3H, t), 4,58 (2H, K) of 5.68 (2H, s),? 7.04 baby mortality (2H, d), 7,13-of 7.25 (3H, m), 7,45-of 7.69 (6H, m).

Example 55. 2-Ethyl-3-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-5,7-dimethylimidazo[4,5-d]pyridine.

To a solution of 5,7-dimethyl-2-this is the IDA (10 ml) under ice cooling was added hydride (60 % in oil, 0.18 g) and the mixture was stirred 10 minutes To a cooled with ice, the reaction mixture was added the compound (2.10 g) obtained in example (22c), and the mixture was stirred 30 min at room temperature. The reaction mixture is distributed between water and ethyl acetate. The organic layer was washed with water, dried and concentrated to dryness. The residue was purified through column chromatography with silica gel and got a brown syrup. To a solution of the product in methanol (10 ml) was added an aqueous solution of 1 N. NaOH and the solution was stirred 30 min at room temperature. The reaction mixture is 1 N. HCl brought to pH 3-4 and extracted with chloroform. The extract was dried and the solvent removed under reduced pressure. The residue was purified through column chromatography with silica gel. Thus obtained crude crystals were paracetalmol from ethyl acetate-hexane mixture and got the connection specified in the form of colorless crystals (0.35 g, 20 %).

So pl. 149-152oC.

Elemental analysis for C25H23N5O20,1 H2O (427,29).

Calculated, %: C 70,27; H Vs. 5.47; N 16,39.

Found, %: C 70,24; H 5,42; N 16,40.

1H-NMR (200 MHz, CDCl3) : of 1.24 (3H, t), 2,42 (3H, s), of 2.51 (3H, s) of 2.64 (2H, K), of 5.39 (2H, s), 6,83 (1H, s), 7,05 (2H, d), 7,17 (2H, d), 7,29-7,34 (1H, m), the p 56. 2-Ethyl-3-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-7-methylimidazo [4,5-b]pyridine-5-carboxylic acid.

56a) 4-Methyl-2-nitropyrimidin.

2-Amino-4-methylpyridin (25 g) was gradually added under ice cooling to concentrated sulfuric acid (150 ml). To the mixture dropwise added pre-cooled with ice, the mixture of concentrated nitric (26 ml) and concentrated sulfuric (19 ml) acids, while maintaining the temperature of the mixture 0oC. the Mixture was then stirred for 2.5 hours, the Reaction mixture was poured into 300 g of ice and the mixture was neutralized under cooling with ice water ammonia. Insoluble material was filtered, and the filtrate was concentrated. The resulting crystalline precipitate was filtered, dried and got the connection specified in the form of yellow needle crystals (26,3 g, 74 %).

So pl. 185-187oC.

1H-NMR (200 MHz, DMCO-d6) : is 2.40 (3H, s), 7,02 (1H, DD), 7,47 (1H, s), with 8.05 (1H, d).

IR (KBr), cm-1: 1625, 1600, 1520, 1415, 1375, 1365, 1320, 1295, 1260, 1215, 1165.

56b) 2 Amino-4-methyl-3(and 5)-nitropyridine.

4-Methyl-2-nitropyrimidin from 34.1 g) was added to concentrated sulfuric acid (170 ml), while maintaining the 0oC. the Mixture was stirred 24 h at room temp the second mixture was cooled to the selection of crystalline products. The crystals were filtered, dried and received a mixture of 3-nitro - and 5-nitro-derivatives in the form of yellow crystals (23,5 g, 3-nitro-derivatives : 5-nitro-derived 1 : 1,7).

3-Nitro-derivative:1H-NMR (200 MHz, DMCO-d6) : a 2.36 (3H,s), 6,60 (1H, d), to 7.09 (2H, sh), 8,07 (1H, d).

5-Nitro-derivative: 1H-NMR (200 MHz, DMCO-d6) : the 2.46 (3H,s), 6,32 (1H, s), 7,30 (2H, s), 8,76 (1H, s).

56c) 2-Ethyl-7-methylimidazo[4,5-b]pyridine.

A suspension of compound (23,4 g) obtained in example (56b), and 5 % Pd-C (13 g) in methanol (500 ml) were mixed under nitrogen atmosphere. Insoluble materials were filtered off, the filtrate is concentrated to dryness and got a brown syrup. The syrup was mixed with polyphosphoric acid (240 g) and propionic acid (40 g) and the mixture was stirred 20 min at room temperature. The reaction mixture is poured into ice-water mixture and neutralized aqueous ammonium hydroxide. The resulting crystalline precipitate was filtered and recrystallize from chloroform. The resulting crystalline precipitate (by-product) was filtered. The filtrate and the mother liquor were combined and concentrated, and then the resulting crystalline precipitate was filtered and washed with chloroform. The filtrates were combined and concentrated to which Li has recrystallize from ethyl acetate-hexane mixture and got the connection specified in the form of pale yellow crystals (4,55 g).

So pl. 117-119oC.

1H-NMR (200 MHz, CDCl3) : of 1.56 (3H, t), 2,70 (3H, s), 3,11 (2H, K), 7,05 (1H, d), 8,19 (1H, d).

IR (KBr), cm-1: 1630, 1540, 1445, 1375, 1365, 890, 820.

56d) 2-Ethyl-7-methylimidazo[4,5-b]pyridine-4N-oxide.

To a cooled with ice to a solution of the compound (2.0 g) obtained in example (56c), in chloroform (30 ml) was added m-chlorbenzoyl acid (2,78 g). The mixture was stirred 10 min and then boiled under reflux for one hour. The reaction mixture is concentrated to dryness under reduced pressure. The concentrate was purified through column chromatography with silica gel and the obtained crude crystals. After recrystallization from ethyl acetate-methanol mixture received the connection specified in the form of colorless needle-like crystals (1.92 g, 85 %).

So pl. 189-191oC.

Elemental analysis for C9H11N3O 0,2 H2O (180,81):

Calculated, %: C 59,79; H 6,36; N 23,24.

Found, %: C 59,94; H Is 6.61; N 23,23.

1H-NMR (200 MHz, CDCl3) : of 1.33 (3H, t), of 2.46 (3H, s), of 2.86 (2H, K) of 6.96 (1H, d), of 8.00 (1H, d).

IR (KBr), cm-1: 1480, 1420, 1280, 1250, 1230, 1170, 765.

56e) 5-Cyano-2-ethyl-7-methylimidazo [4,5-b]pyridine.

To a suspension of the compound (2.0 g) obtained in example (56d), acetonitril the Reaction mixture is concentrated to dryness under reduced pressure. The residue was purified through column chromatography with silica gel. Thus obtained crystals were recrystallize from ethyl acetate and got the connection specified in the form of pale-yellow needle crystals (1.40 g, 66 %).

So pl. 216-218oC (decomposition).

Elemental analysis for C10H10N4(186,22):

Calculated, %: C 64,50; H 5,41; N 30,09.

Found, %: C 64,26; H The 5.45; N 29,87.

1H-NMR (200 MHz, CDCl3) : and 1.54 (3H, t) of 2.75 (3H, s), up 3.22 (2H, K) to 7.50 (1H, s).

IR (KBr), cm-1: 2225, 1615, 1600, 1515, 1415, 1395, 1375, 1295, 1270, 785.

56f) Methyl-2-ethyl-7-methylimidazo [4,5-b]pyridine-5-carboxylate.

The compound (1.3 g) obtained in example (56e), suspended in a solution of 9 N. florodora in methanol. The suspension is boiled under reflux for 3 hours, the Reaction mixture was concentrated under reduced pressure and the pH was brought to 5 with a saturated aqueous solution of sodium bicarbonate, and then Proektirovanie chloroform. The extract was dried and the solvent removed under reduced pressure with the release of crude crystals. After recrystallization from ethyl acetate-methanol mixture received the connection specified in the form of colorless prisms (1,33 g, 86 %).

So pl. 208-210oC.

Element Is: C 60,14; H OF 5.99; N 19,07.

1H-NMR (200 MHz, CDCl3) : of 1.41 (3H, t), is 2.74 (3H, s), 3,14 (2H, K), a 4.03 (3H, s), 7,92 (1H, s).

IR (KBr), cm-1: 3240, 1730, 1615, 1510, 1435, 1405, 1385, 1300, 1250, 1200, 750.

56g) Methyl-2-ethyl-3-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl]-7-methylimidazo[4,5-b]pyridine-5-carboxylate.

To a solution of the compound (1.0 g) obtained in example (56f) in dimethylformamide (10 ml) was added sodium hydride (60 % in oil, 0.21 g) at room temperature. The mixture was stirred for 5 min, added the connection of 2.27 g) obtained in example (22c), and then mixed at room temperature for another 1 h, the Reaction mixture was distributed between water and ethyl acetate. The organic layer was water washed with brine and dried. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel and the obtained colorless crystals. The crystals were dissolved in chloroform (7.5 ml)-methanol (15 ml) mixture. To the solution was added an aqueous solution of 1 n sodium hydroxide and the mixture was stirred 20 min at room temperature. To the reaction mixture were added 1 N. HCl to achieve a pH of 3-4, and then Proektirovanie chloroform. The extract was dried, the solvent was removed under reduced pressure and the obtained crude crystals. After the switch is%).

So pl. 246-248oC (decomposition).

Elemental analysis for C26H23N5O4(469,50):

Calculated, %: C 66,51; H, 5.94; N 14,92.

Found, %: C 66,37; H Equal To 4.97; N 14,84.

1H-NMR (200 MHz, CDCl3) : of 1.31 (3H, t), 2,63 (3H, s), 2,80 (2H, K) 3,93(3H, s) 5,52 (2H, s), 7,14(2H, d), of 7.23(2H, d), 7,35(1H, DD), 7,43-7,63 (2H, m), 7,76(1H, DD), 7,92(1H, s) to 9.15(1H, CL),

IR (KBr), cm-1: 1780, 1705, 1485, 1465, 1435, 1275, 1220, 760.

56h) 2-Ethyl-3-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl]-7-Mei[4,5-b]pyridine-5-carboxylic acid.

To a suspension of compound (0.9 g) obtained in example (56g), in methanol (20 ml) was added 1 N. aqueous sodium hydroxide solution (4.5 ml) and the mixture was stirred 3 h at 60oC. To the reaction mixture were added 1 N. HCl and brought the pH of the mixture to the 3-4. Released the crystalline precipitate was filtered and dried. The thus obtained crystals were recrystallize from ethyl acetate-methanol mixture and got the connection specified in the form of colorless crystals (0,61 g, 69 %).

So pl. 161-164oC (decomposition).

Elemental analysis for C25H21N5O4(455,47):

Calculated, %: C 65,93; H 4,65; N 15,38.

Found, %: C 65,63; H Of 4.67; N Br15.15.

1H-NMR (200 MHz, DMCO-d6) : a 1.25 (3H, t), 2,64 (3P> Example 57. Methyl-2-ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol - 3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate.

57a) Methyl-3-amino-2-[[2'-(ethoxycarbonylmethyl-4-yl]methylamino]benzoate.

To a suspension of compound (7,1) obtained in example (1a), in methanol (120 ml) was added gidroxinimesoulid (5,56 g) and triethylamine (6,06 g). The mixture was stirred 3 days at 70oC in nitrogen atmosphere. The methanol was removed in vacuum. The residue was distributed between ethyl acetate (200 ml) and water (50 ml). The organic layer was washed with water, dried and concentrated to dryness under reduced pressure. To a solution of the residue in tetrahydrofuran (100 ml) under ice cooling was added triethylamine (2 g). To the mixture dropwise added a solution of atilglukuronida (1.4 g) in tetrahydrofuran (20 ml). The reaction mixture was stirred 1 h at the same temperature and the solvent was removed in vacuum. The residue was distributed between ethyl acetate and water. The organic layer was washed with water, dried and concentrated to dryness with the formation of a pale yellow syrup (8.6 g).

1H-NMR (200 MHz, CDCl3) : of 1.35 (3H, t), of 3.80 (3H, s), 4,20 (2H, s) 4,32 (2H, K), of 4.57 (2H, CL), 6,83-6,93 (2H, m), 7,27-rate of 7.54 (8H, m), of 7.64-of 7.70 (1H, m).

IR (CHCl3), cm-1: 3520, 3415, 3350, 1765, 1700, 1635.

Pale brown syrup (8,58 g) obtained in example (57a) was dissolved in dioxane (20 ml). To the solution was added tetraethoxysilane (8,64 g) and acetic acid (1.56 g). The mixture was stirred 2 h at 100oC. the Reaction mixture was concentrated to dryness. The residue was led from ethyl acetate (50 ml). The resulting crystalline precipitate was filtered and received the specified connection.

1H-NMR (200 MHz, CDCl3) : 1,50 (3H, t), of 3.77 (3H, s), or 4.31 (2H, K), 4,69 (2H, K), 5,64(2H, s),7,01 (2H, d), 7,17 (1H, t), 7,26-of 7.55 (6H, m), 7,72 (1H, d).

IR (CHCl3), cm-1: 3520, 3410, 1765, 1710, 1635, 1545.

57c) Methyl-2-ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl]benzimidazole-7-carboxylate.

Grey crystals (4.0 g) obtained in example (57b), dissolved in ethyl acetate (50 ml). To the solution was added 1,8-diazabicyclo[5.4.0]-Antec-7-ene (DBA, 3.2 g) and the mixture was stirred 2 h at 80oC. the Reaction mixture was distributed between ethyl acetate (50 ml) and 1 N. HCl (20 ml). The organic layer was washed with water, dried and concentrated to dryness. The residue was led from chloroform-an ethyl acetate mixture and got the connection specified in the form of colorless prisms (2.1 g, 45 %), which corresponded to the compound obtained in example (1d).

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Grey crystals (4.0 g) obtained in example (57), was dissolved in ethyl acetate (50 ml). To the solution was added potassium carbonate (3 g) (instead DBA) and the mixture was stirred 18 h at 90oC. the Resulting crystalline precipitate was filtered and suspended in water (30 ml), the pH of the suspension 2 N. HCl brought to 3-4. The resulting crystals were filtered, dried and got the connection specified in the form of colorless crystals (1,81 g, 38 %), which corresponded to the compound obtained in example (57).

Example 59. 2 Ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)-biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid.

Compound (3.2 g) obtained by the method of example (1d), suspended in 0.5 N. NaOH (50 ml). This suspension is stirred for 3 h at 60oC, the pH of the reaction mixture was adjusted to 3-4 by addition of 2 N. HCl. The resulting crystals are collected by filtration and washed with water. Thus obtained crystals are stirred in ethanol (45 ml) for 1 h, receiving colorless prismatic crystals (2.9 g, 94 %).

So pl. 212-214oC.

Elemental analysis for C25H20N4O4:

Calculated, %: C 65,78; H 4,42; N 12,27.

Found, %: C 65,72; H Of 4.67; N To 12.28.

1H-NMR (200 MHz, CDCl3) : 1,47 (3P 60. Methyl-2-ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazole-3-yl) biphenyl-4-yl]methyl]benzimidazole-7-carboxylate.

To tetrahydrofuran (15 ml) under stirring at room temperature was added first, 1,1'-thiocarbonyldiimidazole (0.36 g), and then the compound obtained in example (1c) (0,89 g). After 30 minutes of stirring, the reaction mixture was concentrated to dryness. The concentrate was dissolved in ethyl acetate, the resulting solution was washed with diluted hydrochloric acid and water, then dried. To a solution of the obtained residue in a mixture of chloroform-methanol (5:1, 150 ml) was added silica gel (7 g) and the mixture was stirred for 48 h at room temperature. Insoluble products filter and concentrate the filtrate to dryness, getting syrupy product. Its clear chromatographytandem on a column of silica gel, receiving crystals. Recrystallization from ethyl acetate gives colorless prismatic crystals (0.33 g, 34 %).

So pl. 211-212oC.

Elemental analysis for C26H22N4O4S:

Calculated, %: C 64,18; H 4,56; N To 11.52; S 6,59.

Found, %: C 64,44; H 4,56; N 11,44; S 6.42 Per.

1H-NMR (90 MHz, CDCl3) : USD 1.43 (3H, t), 3,70 (3H, c), of 4.57 (2H, K), 5,67 (2H, s) 6,93-of 7.60 (10H, m), to 7.77-of 7.90 (1H, m), 9,43 (1H, CL).

The compound obtained in example (60a) (0.68 g), suspended in 0.2 N. aqueous NaOH solution (10 ml). The suspension is stirred for 20 h at 60oC, and then its pH was adjusted to 3-4 by addition of 1 N. HCl. The resulting crystals are collected by filtration and recrystallized from methanol, receiving colorless prismatic crystals (0,29 g, 44 %).

So pl. 210-211oC.

Elemental analysis for C25H20N4O4S:

Calculated, %: C 63,55; H 4,27; N Up 11,86; S 6,79.

Found, %: C 63,26; H 4,32; N 11,84; S 6,59.

1H-NMR (90 MHz, CDCl3) : 1,49 (3H, m), with 4.64 (2H, K), USD 5.76 (2H, c), 7,06-of 7.70 (11H, m), 12,13 (1H, CL)

IR (Nujol) cm-1: 1720, 1670, 1550, 1425, 1425, 1280, 1035.

Working example 62. Methyl-2-ethoxy-1-[[2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)- biphenyl-4-yl]methyl] benzimidazole-7-carboxylate.

The mixture obtained in working example (1c) methyl-2-ethoxy-1[[2'-hydroxycarbonylmethyl)biphenyl-4-yl] methyl] benzimidazole-7-carboxylate (0.66 g), thiocarbonyldiimidazole (0.3 g) and 1,5-diazabicyclo[4.3.0]non-5-ene (0.56 g) in acetonitrile (15 ml) was stirred at room temperature for 20 h, after evaporation of the solvent the residue is dissolved in water and adjusted the pH of the resulting solution to 4-5, then extracted with ethyl acetate. Extract sushi. recristallization from a mixture of ethyl acetate-methanol gives colorless crystals (0.2 g, 20 %)

1H-NMR (200 MHz, DMCO-d) : of 1.41 (3H, t), 3,68 (3H, c), br4.61 (2H, K) 5,49 (2H, s), 6.89 in (2H, d), to 7.15(2H, d), 7,18 (1H, t), 7,25-to 7.61 (5H, m), 7,68 (1H, DD), 8,81 (1H,s).

Working example 63. Methyl-2-butyl-1-[[2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl] benzimidazole-7-carboxylate.

63a) Methyl-1-[[2'-(N-acetoxymethyl)biphenyl-4-yl] methyl] -2 - butylbenzothiazole-7-carboxylate.

To a solution of methyl 2-butyl-1-[[2'-(hydroxycarbonylmethyl)-biphenyl-4-yl]methyl] benzimidazole-7-carboxylate (1,83 g) in dichloromethane (20 ml), add triethylamine (0,46 g) and acetic anhydride (0,46 g) and stirred for 2 h the reaction mixture at room temperature. After evaporation of the solvent the residue is divided between ethyl acetate and water, the organic layer was washed with aqueous solution of NaHCO3and water. The solution is dried and concentrated to dryness, obtaining a pale yellow solid (1,99 g, quantitative yield).

1H-NMR (200 MHz, CDCl3) : to 0.96 (3H, t), 1,38-of 1.56 (2H, m), 1,80-of 1.95 (2H, m), and 2.14 (3H, s), with 2.93(2H, t), 3,74 (3H, s), 4,60 (2H, CL), USD 5.76 (2H, s), 6.87 in (2H, d), 7,20 is 7.50 (6H, m), 7,55-the 7.65 (2H, m), to 7.93 (1H, d).

IR (Nujol) cm-1: 3325, 3170, 1750, 1720, 1630, 1280.

This connection is used in the following reaction biphenyl-4-yl]]methyl]-benzimidazole-7-carboxylate.

To a mixture of methyl 2-butyl-1-[[2'-(ecotoxicological)biphenyl-4-yl]methyl] benzimidazole-7-carboxylate (2.0 g) and CS2(1.5 g) in DMF (12 ml) for 10 min add sodium hydride (60 % in oil, 0.56 g) and the reaction mixture is stirred 2 h at room temperature. The mixture is then poured into a mixture of ice and water and bring the pH of the resulting solution to 3. Extracted the mixture with ethyl acetate, the extract washed with water, dried and concentrated to dryness. The residue is crystallized from a mixture of chloroform-methanol, obtaining a pale yellow prismatic crystals (0.64 g, 32 %).

So pl. 180-181oC.

Elemental analysis for C28H26N4O3S:

Calculated, %: C 67,45; H 5,26; N 11,24.

Found, %: C 67,14; H Of 5.05; N 10,97.

1H-NMR (200 MHz, DMCO-d6) : of 0.90 (3H, t), 1,30-1,50 (2H, m), 1,69-of 1.84 (2H, m), 2,90(2H, t), the 3.65 (3H, c), 5,73 (2H, s), 6.89 in (2H, d), 7,19 (2H, d), 7,28 (1H, t), 7,44-7,72 (5H, m), 7,87 (2H, d).

IR (Nujol) cm-1: 1720, 1430, 1285, 1265, 755.

Working example 64. 2-butyl-1-[[2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)-biphenyl-4-yl] methyl]benzimidazole-7-carboxylic acid.

The solution obtained in working example 63 methyl ester (0,42 g) in an aqueous solution of 0.3 N. NaOH (8.2 ml) is stirred for 1.5 h at 50oC, the pH of the reaction solution is adjusted to 3 by adding 2 the scientists crystals are recrystallized from a mixture of ethanol-ethyl acetate, receiving a colorless prismatic crystals (0.25 g, 63 %).

So pl. 178-180oC.

Elemental analysis for C27H24N4O3S:

Calculated, %: C 66,92; H 4,99; N To 11.56.

Found, %: C 66,72; H Of 4.95; N 11,72.

1H-NMR (200 MHz, DMCO-d6) : to 0.88 (3H, t), of 1.28 to 1.47 (2H, m) of 1.65 and 1.80 (2H, m), 2,85 (2H, t), 5,90 (2H, s), make 6.90 (2H, d), 7,17 (2H, d), 7,26 (1H, t), 7,42-of 7.69 (5H, m), a 7.85 (1H, d).

IR (Nujol) cm-1: 3400, 1700, 1430, 1410, 1335, 1230.

Working example 65. Methyl-2-butyl-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazole-3-yl) biphenyl-4-yl]methyl]benzimidazole-7-carboxylate.

The target connection (0,22 g) is obtained in yield 44 % according to the method described in working example 60, from hydroxycarbonylmethyl derived ones (0.46 g) obtained in working example 2.

So pl. 178-179oC.

Elemental analysis for C28H26N4O3S:

Calculated, %: C 67,45; H 5,26; N 11,24.

Found, %: C 67,31; H 5,27; N 11,25.

1H-NMR (200 MHz, CDCl3), : to 0.92 (3H, t), 1,30-1,50 (2H, m), 1.60-to of 1.73 (2H, m), 3,62 (3H, s) 5,69 (2H, s), 6,72 (2H, d), 6,98-7,27 (5H, m), 7,53-7,80 (3H, m), 7,80 for 7.78 (1H, m), 11,35 (1H, sh.C).

IR (Nujol) cm-1: 1720, 1700, 1660, 1453, 1290, 1280, 1265, 1125, 760, 750

Working example 66. 2-butyl-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazole-3-yl) biphenyl-4-yl]methyl]benzimidazole-7-1 from compound (0.2 g), obtained in working example 65.

So pl. 238-239oC (decomp.).

Elemental analysis for C27H24N4O3S 1/3H2O:

Calculated, %: C 66,11; H 5,07; N 11,42.

Found, %: C 66,29; H To 4.98; N 11,58.

1H-NMR (200 MHz, DMCO-d6) : to 0.88 (3H, t), 1,27-to 1.45 (2H, m) of 1.65 and 1.80 (2H, m), and 2.83 (2H, t), 5,88 (2H, s), 6.87 in (2H, s), 7,14 (2H, d), from 7.24 (1H, t), 7,41-to 7.64 (5H, m), 7,83 (2H, d).

IR (Nujol) cm-1: 3255, 1675, 1450, 1420, 1240, 1230, 1205, 755.

Working example 67. Methyl-2-ethyl-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazole-3-yl) biphenyl-4-yl]methyl]benzimidazole-7-carboxylate.

The target compound (0.17 g) obtained in 38 % according to the method of the working example 60 from compound (0.4 g) obtained in working example 31.

So pl. 203-205oC.

Elemental analysis for C26H22N4O3S 0,5 H2O:

Calculated, %: C 65,12; H A 4.83; N 11,68.

Found, %: C 65,30; H Of 4.54; N 11,63.

1H-NMR (200 MHz, CDCl3) : of 1.13 (3H, t) of 2.64 (2H, K), 3,53 (3H, s), 5,62 (2H, s), 6,59 (2H, d), of 6.8 to 7.9 (7H, m)

IR (KBr), cm-1: 1715, 1690, 1600, 1520.

Working example 68. 2-ethyl-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazole-3-yl) biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid.

The target compound (0.4 g) is obtained in yield of 58 % by the method of working : of 1.30 (3H, t) of 2.86 (2H, K) of 5.89 (2H, s), make 6.90 (2H, d), to 7.15 (2H, d), 7,27 (1H, t), of 7.4 to 7.7 (5H, m), 7,86 (1H, d)

IR (KBr), cm-1: 1700, 1655, 1570.

Working example 69. Methyl-2-ethyl-1-[[2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate.

The target compound (0.12 g) obtained in yield of 22 % according to the method of the working example 62 compound (0.45 g) obtained in working example 31.

1H-NMR (200 MHz, CDCl3) : of 1.23 (3H, t), 2,78 (2H, K) 3,76 (3H, s) 5,52 (2H, s) 6,91 (2H, d), 7,10 (2H, d), and 7.1 to 7.7 (6H, m), to 7.93 (1H, d).

Working example 70. Methyl-1-[[2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl]-2-propylbenzamide-7-carboxylate.

70A) Methyl-1-[[2'-(N-acetoxymethyl)biphenyl-4-yl] methyl] -2-propylbenzamide-7-carboxylate.

The target compound (0.95 g) is obtained in yield of 86 % by the method of the working example 63 from hydrocarbonengineering derivative (1 g) obtained in working example 30.

So pl. 177-178oC.

Elemental analysis for C28H28N4O4S 0,1 H2O (486, 36):

Calculated, %: C 69,15; H Of 5.84; N To 11.52.

Found, %: C 68,93; H 5,80; N 11,54.

1H-NMR (200 MHz, CDCl3) with 1.07 (3H, t), 1,84-2,03 (2H, m), of 2.15 (3H, t), only 2.91 (2H, t), 3,74 (3H, s), of 4.57 (2H, sh), USD 5.76 (2H, s), 6.87 in (2H, d), 7,21-7,52 (6H, m), to 7.59-of 7.64 draw 5-thioxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl]-2-propylbenzamide-7-carboxylate.

The target compound (0.14 g) obtained in yield of 28 % according to the method of the working example (63b) of N-acetoxyvalerenic derivative (0.5 g) obtained in working example (70A).

So pl. 206-209oC (decomp.).

Elemental analysis for C27H24N4O3S 0,2 H2O (488,18):

Calculated, %: C 66,43; H 5,04; N 11,48.

Found, %: C 66,42; H 5,14; N 11,51.

1H-NMR (200 MHz, DMCO-d6) : and 0.98 (3H, t), 1,71-1,90 (2H, m), is 2.88 (2H, t), the 3.65 (3H, C0, 5,73 (2H, s), 6.89 in (2H, d), 7,21 (2H, d), 7,28 (1H, t), 7,44-7,72 (5, M0, 7,88 (1H, DD).

IR(KBr), cm-1: 1725, 1450. 1435, 1410, 1335, 1325, 1285, 1270, 1210, 1125, 770, 760.

Working example 71. Methyl-1- [[2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazole-3-yl) biphenyl-4-yl]methyl]-2-propylbenzamide-7-carboxylate.

The target compound (0.16 g) obtained in yield of 25 % according to the method of the working example 60 from hydroxycarbonylmethyl derivative (of 0.58 g) obtained in working example 30.

So pl. 225-227oC (decomp).

Elemental analysis for c27H24N4O3S 0,2 H2O:

Calculated, %: C 66,43; H 5,04; N 11,48.

Found, %: C 66,64; H 5,16; N Of 11.26.

1H-NMR (200 MHz, CDCl3) : a 1.01 (3H, t), 1,60-1,80 (2H, m), 2,70 (3H, t), of 3.60 (3H, s) 5,69 (3H, s) of 6.71 (2H, d), of 6.96-7,05 (4H, m), 7,22-7,26 (1H, m), 7,50-to 7.59 (3H, m), 7,83-7,87 (1H, m), 11,40 (1H, get methods described in the working examples 1-71.

Working example 72. 1[[2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazole-3-yl) biphenyl-4-yl]-methyl]-2-methoxybenzimidazole-7-carboxylic acid.

Working example 73. 1-[[2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazole-3-yl) biphenyl-4-yl]-methyl]-2-propoxybenzene-7-carboxylic acid.

Working example 74. 1-[[2'-(2,5-dihydro-5-oxo-1,24-thiadiazole-3-yl) biphenyl-4-yl]-methyl]-2-isopropoxybenzonitrile-7-carboxylic acid.

Working example 75. 2 butoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazole-3-yl)-biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid.

Working example 76. 1-[[2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazole-3-yl) biphenyl-4-yl]-methyl]-2-methylthiopyrimidine-7-carboxylic acid.

Working example 77. 1-[[2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazole-3-yl) biphenyl-4-yl]-methyl]-2-utilitiesa-7-carboxylic acid.

Working example 78. 1-[[2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazole-3-yl) biphenyl-4-yl]methyl]-2-propertieseditor-7-carboxylic acid.

Working example 79. 1-[[2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazole-3-yl) biphenyl-4-yl]-methyl]-2-isopropylimidazole-7-carboxylic acid.

Working example 80. 1-[[2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazole-3-yl) biphenyl-4-yl]-methyl]-2-methylaminomethyl]-2-ethylaminoethanol-7-carboxylic acid.

Working example 82. 1-[[2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazole-3-yl) biphenyl-4-yl]-methyl]-2-propylimidazol-7-carboxylic acid.

Working example 83. 1-[[2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazole-3-yl) biphenyl-4-yl]-methyl]-2-methylbenzimidazole-7-carboxylic acid.

Working example 84. 2-cyclopropyl-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazole-3-yl] biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid.

Working example 85. 1-[[2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazole-3-yl) biphenyl-4-yl]-methyl]-2,4-dimethylthieno[3,4-d]imidazole-6 - carboxylic acid.

Working example 86. 1-[[2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazole-3-yl)- biphenyl-4-yl] -methyl] -2-ethyl-4-methylthieno[3,4-d] imidazole-6-carboxylic acid.

Working example 87. 1-[[2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazole-3-yl) biphenyl-4-yl]-methyl]-4-methyl-2-propertiee[3,4-d]imidazole-6-carboxylic acid.

Working example 88. 2-cyclopropyl-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazole-3-yl)-biphenyl-4-yl] methyl] -4-methylthieno[3,4-d] imidazole-6-carboxylic acid.

Working example 89. 1-[[2'-(2,5-dihydro-5-oxo-1,24-thiadiazole-3-yl) biphenyl-4-yl]-methyl]-2-methoxy-4-methylthieno[3,4-d]imidazole-6-carboxylic acid.

Working example 90. 1-[[2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazole-3-yl)biphenyl-4-yl] - methyl]-2-ethoxy-4-mil)biphenyl-4-yl]-methyl]-4-ethoxy-2-propoxyimino[3,4-d]imidazole-6-carboxylic acid.

Working example 92. 1-[[2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazole-3-yl)biphenyl-4-yl]-methyl]-4-ethoxy-2-methylthieno[3,4-d]imidazole-6-carboxylic acid.

Working example 93. 1-[[2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazole-3-yl)biphenyl-4-yl] -methyl] -2-ethylthio-4-methylthieno[3,4-d]imidazole-6-carboxylic acid.

Working example 94. 1-[[2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazole-3-yl)biphenyl-4-yl] -methyl] -4-methyl-2-methylaminoethanol[3,4-d] imidazole-6-carboxylic acid.

Working example 95. 1-[[2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazole-3-yl)biphenyl-4-yl] - methyl] -2-ethylamino-4-methylthieno[3,4-d]imidazole-6-carboxylic acid.

Working example 96. 1-[[2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]-methyl]-2-methoxybenzimidazole-7-carboxylic acid.

Working example 97. 1-[[2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4 - yl]methyl]-2-propoxybenzene-7-carboxylic acid.

Working example 98. 1-[[2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-2-isopropoxybenzonitrile-7-carboxylic acid.

Working example 99. 2 butoxy-1-[[2'-2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)- biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid.

Working example 100. 1-[[2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]METI the azole-3-yl)biphenyl-4 - yl]methyl]-2-utilitiesa-7-carboxylic acid.

Working example 102. 1-[[2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4 - yl]methyl]-2-propertieseditor-7-carboxylic acid.

Working example 103. 1-[[2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4 - yl]methyl]-2-isopropylimidazole-7-carboxylic acid.

Working example 104. 1-[[2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4 - yl]methyl]-2-methylaminoethanol-7-carboxylic acid.

Working example 105. 1-[[2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl-biphenyl-4 - yl]methyl]-2-ethylaminoethanol-7-carboxylic acid.

Working example 106. 1-[[2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl-biphenyl-4 - yl]methyl]-2-propylimidazol-7-carboxylic acid.

Working example 107. 1-[[2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl-biphenyl-4 - yl]methyl]-2-methylbenzimidazole-7-carboxylic acid.

Working example 108. 2-cyclopropyl-1-[[2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol - 3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid.

Working example 109. 1-[[2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl-biphenyl-4 - yl] methyl] -2,4-dimethylthieno[3,4-d]imidazole-6-carboxylic acid.

Working example 110. 1-[[2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl-biphenyl-4 - yl] methyl] -2-ethyl-4-matiltan the phenyl-4 - yl] methyl]-4-methyl-2-propertiee[3,4-d]imidazole-6-carboxylic acid.

Working example 112. 2-cyclopropyl-1-[[2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol - 3-yl)biphenyl-4-yl] methyl] -4-methylthieno[3,4-d]imidazole-6-carboxylic acid.

Working example 113. 1-[[2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4 - yl] methyl]-2-methoxy-4-methylthieno[3,4-d]imidazole-6-carboxylic acid.

Working example 114. 1-[[2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4 - yl] methyl] -2-ethoxy-4-methylthieno[3,4-d]imidazole-6-carboxylic acid.

Working example 115. 1-[[2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4 - yl]methyl]-4-methyl-2-propoxyimino[3,4-d]imidazole-6-carboxylic acid.

Working example 116. 1-[[2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4 - yl]methyl]-4-methyl-2-methylthieno[3,4-d]imidazole-6-carboxylic acid.

Working example 117. 1-[[2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4 - yl] methyl] -2-ethylthio-4-methylthieno[3,4-d]imidazole-6-carboxylic acid.

Working example 118. 1-[[2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4 - yl] methyl] -4-methyl-2-methylaminoethanol[3,4-d]imidazole-6-carboxylic acid.

Working example 119. 1-[[2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)biphenyl-4 - yl]methyl]-2-ethylamino-4-methylthieno[3,4-d]imidazole-6-carboxylic acid.

Work.

Working example 121. 1-[[2'-2,5-dihydro-5-thioxo-1,2,4-thiadiazole-3-yl)biphenyl-4 - yl]methyl]-2-ethoxybenzylidene-7-carboxylic acid.

Working example 122. 2-butyl-1-[[2'-2,5-dihydro-5-thioxo-1,2,4-thiadiazole-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid.

Working example 123. 1-[[2'-2,5-dihydro-5-thioxo-1,2,4-thiadiazole-3-yl)biphenyl-4 - yl]methyl]-2-utilitiesa-7-carboxylic acid.

Working example 124. 1-[[2'-2,5-dihydro-5-thioxo-1,2,4-thiadiazole-3-yl)biphenyl-4 - yl] methyl]-2-methoxy-4-methylthieno[3,4-d]imidazole-6-carboxylic acid.

Working example 125. 1-[[2'-2,5-dihydro-5-thioxo-1,2,4-thiadiazole-3-yl)biphenyl-4 - yl] methyl] -2-ethoxy-4-methylthieno[3,4-d]imidazole-6-carboxylic acid.

Working example 126. 2-butyl-1-[[2'-2,5-dihydro-5-thioxo-1,2,4-thiadiazole-3-yl)biphenyl-4 - yl]methyl]-4-methylthieno[3,4-d]imidazole-6-carboxylic acid.

Working example 127. 1-[[2'-2,5-dihydro-5-thioxo-1,2,4-thiadiazole-3-yl)biphenyl-4-yl] methyl]-2-ethylthio-4-methylthieno[3,4-d]imidazole-6-carboxylic acid.

Working example 128. 2-ethyl-3-[[2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazole-3-yl)biphenyl - 4-yl]methyl]-5,7-dimethylimidazo[4,5-b]pyridine.

Working example 129. 2-propyl-3-[[2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazole-3-yl)biphenyl - 4-yl]methyl]-5,7-dimethylimidazo[4,5-is elimidate[4,5-b]pyridine.

Working example 131. 2-methoxy-3-[[2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazole-3-yl) biphenyl-4-yl]methyl]-5,7-dimethylimidazo[4,5-b]pyridine.

Working example 132. 2 ethoxy-3-[[2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazole-3-yl) biphenyl-4-yl]methyl]-5,7-dimethylimidazo[4,5-b]pyridine.

Working example 133. 2-propoxy-3-[[2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazole-3-yl) biphenyl-4-yl]methyl]-5,7-dimethylimidazo[4,5-b]pyridine.

Working example 134. 2-cyclopropyl-3-[[2'-(2,5-dihydro-5-oxo-1,2,4-thiadiazole-3-yl) biphenyl-4-yl]methyl]-5,7-dimethylimidazo[4,5-b]pyridine.

Working example 135. 2-ethyl-3-[[2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl]-5,7-dimethylimidazo[4,5-b]pyridine.

Working example 136. 2-propyl-3-[[2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)- biphenyl-4-yl]methyl]-5,7-dimethylimidazo[4,5-b]pyridine.

Working example 137. 2-butyl-3-[[2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)- biphenyl-4-yl]methyl]-5,7-dimethylimidazo[4,5-b]pyridine.

Working example 138. 2-methoxy-3-[[2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)-biphenyl-4-yl]methyl]-5,7-dimethylimidazo[4,5-b]pyridine.

Working example 139. 2 ethoxy-3-[[2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl)- biphenyl-4-yl]methyl]-5,7-dimethylimidazo[4,5-b]pyridine.

Working example 140. 2-propoxy-3-[[2'-(2,5-dihyd the-cyclopropyl-3-[[2'-(2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl) -biphenyl-4-yl]methyl]-5,7-dimethylimidazo[4,5-b]pyridine.

Working example 142. 2-methyl-3-[[2'-(2,5-dihydro-5-thioxo-1,2,4-thiadiazole-3-yl) -biphenyl-4-yl]methyl]-5,7-dimethylimidazo[4,5-b]pyridine.

Working example 143. 2-ethyl-3-[[2'-(2,5-dihydro-5-thioxo-1,2,4-thiadiazole-3-yl) -biphenyl-4-yl]methyl]-5,7-dimethylimidazo[4,5-b]pyridine.

Working example 144. 2-cyclopropyl-3-[[2'-(2,5-dihydro-5-thioxo-1,2,4-thiadiazole-3-yl) -biphenyl-4-yl]methyl]-5,7-dimethylimidazo[4,5-b]pyridine.

Working example 145. 2 ethoxy-3[[2'-(2,5-dihydro-5-thioxo-1,2,4-thiadiazole-3-yl)- biphenyl-4-yl]methyl]-5,7-dimethylimidazo[4,5-b]pyridine.

Experimental example 1. Inhibition of binding of angiotensin-II angiotensinogen receptor.

Method.

Experiment on inhibition of binding of angiotensin-II (A-II) with an appropriate receptor was performed by modifying the method described by Douglas and others (Endocrinology, 102, 685-696, 1978)). The membrane fraction containing A-II-receptor prepared from cortical bovine adrenal gland.

The connection according to the invention (10-6M or 10-7M) and125I-angiotensin II (125I-AII) (of 1.85 kBq/50 ál) was added to a faction receptorassociated membranes and the resulting mixture was incubated for 1 h at room temperature. Associated with the receptor and unbound125I-A.

The results are shown in the table.

Experimental example 2.

Inhibition of the compounds according to the invention vazopressornye actions AII.

Method.

As experimental animals used in rats (age 9 weeks, males). Before the experiment, the femoral artery and vein shot phenobarbital sodium animals were Coulibaly. Animals were not given food, but were allowed to freely drink water until the beginning of the experiment. On the day of the experiment, the arterial cannula was connected with a sensor of blood pressure and record the average blood pressure of a polygraph. Before the introduction of medications to control was determined vazopressornye action A-II, by injecting it intravenously (100 ng/kg). Drugs administered orally, then in each predefined time was intravenously injected A-II and similarly defined vazopressornye action. The percentage inhibition of medicine called A-II vazopressornye validity was evaluated by comparing its values before and after drug administration.

The results are shown in the table.

1. Heterocyclic compounds of General formula I
9)-, where R9hydrogen or lower WITH1WITH4-alkyl, -O - or-S(O)m- where m is 0 to 2, and which may be substituted by a hydroxy-group, optionally substituted amino, halogen, lower1WITH4-alkoxygroup or lower WITH1WITH4-alkylthiophene;

R2group selected from

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
where g is CH2-, -NR9where R9hydrogen or lower WITH1WITH4-alkyl, -O - or-SOmwhere m 0 2;

groups independently carbonyl, thiocarbonyl, optionally oxidized sulfur atom or a group capable of developing in them;

a and e, forming the heterocyclic residue are independently represent one or two optionally substituted carbon atom, nitrogen, sulfur or oxygen;

d, forming a heterocyclic residue, is one optionally substituted carbon atom, nitrogen, sulfur or oxygen;

b and c independently represent one optionally substituted carbon atom or nitrogen;

f, forming a heterocyclic residue, a represents a carbon atom, optionally substituted optionally esterified under item 1, in which group of the formula

< / BR>
represents a group selected from the following:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
where h is

< / BR>
< / BR>
where m 0 2, integer, -NR9where R9hydrogen or lower WITH1WITH4is an alkyl group or-O-, and the group in addition to the groups R and R1optionally substituted.

3. Connection on p. 1, in which a group of the formula

< / BR>
has a structure selected from the following

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
where h is

< / BR>
< / BR>
where m 0 2, integer, -NR9where R9hydrogen or lower WITH1WITH4is an alkyl group, or-O-;

R3optionally esterified or aminirovanie carboxyl.

4. The compound or its salt under item 1, in which a group of the formula

< / BR>
represents a benzimidazole, tanakadate or imidazopyridine.

5. The compound or its salt according to p. 3, in which R3optionally etherified carboxy.

6. The compound or its salt under item 5, in which R3a group of the formula-CO-D, atoroidal substituted amino, halogen, lower-C1WITH6-alkoxy, lower-C1- C6-alkylthiophene or optionally substituted DIOXOLANYL, or a group of the formula-O-R4-OCOR5in which R4hydrogen, lower-C1C6-alkyl, lower-C2C6alkenyl or lower WITH3WITH8-cycloalkyl and R5lower1- C6-alkyl, lower-C2WITH6-alkylene, lower-FROM3- C8-cycloalkyl, lower-C1WITH3is alkyl, substituted lower WITH3WITH8-cycloalkyl or aryl, lower-C2< / BR>
WITH3alkenyl, optionally substituted lower-C3- C8-cycloalkyl or aryl, aryl, lower-C1WITH6-alkoxy, lower-C2WITH8-alkenylamine, lower-FROM3- C8-cycloalkane, lower-FROM1WITH3-alkoxy, substituted lower WITH3WITH8-cycloalkyl or aryl, lower-C2- C3-alkenylamine, substituted lower WITH3WITH8-cycloalkyl or aryl, or aryloxy.

7. The compound or its salt under item 1, in which R1lower1WITH8-alkyl, which may be bound through a group of the formula-NR9in which R9hydrogen or lower-C1- C4-alkyl, -S-O - yl the amino, N,N-dignissim-C1WITH4-alkylamino, halogen, lower-C1- C4-alkoxy or lower-C1WITH4-alkylthio.

8. The compound or its salt under item 1, in which R1lower1WITH5-alkyl, which may be bound through a group of the formula-NR9-, in which R9hydrogen or lower-C1- C4-alkyl, -O - or-SOm- where m is 0 to 2 and which may be substituted by hydroxy, amino, halogen or lower-C1WITH4-alkoxy.

9. The compound or its salt under item 1, in which R2a group of the formula

< / BR>
in which i-O - or-S-;

j carbonyl group, thiocarbonyl group, an optionally oxidized sulfur atom or a group, turn in him.

10. The compound or its salt under item 1, in which R2- 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-ilen group.

11. The compound or its salt under item 1, in which R2- 2,5-dihydro-5-oxo-1,2,4-thiadiazole-3-ilen group.

12. The compound or its salt under item 1, in which R2- 2,5-dihydro-5-thioxo-1,2,4 - oxadiazol-3-ilen group.

13. Heterocyclic compound or its salt

< / BR>
in which R1lower1WITH5-alkyl, which may be linked via-O-, -NH - ILS4-alkylamino, halogen, lower-C1- C4-alkoxy or lower-C1WITH4-alkylthio;

R2a group of the formula

< / BR>
in which i-O - or-S-;

j carbonella group, thiocarbonyl group, an optionally oxidized sulfur atom or a group, turn in him;

R3optionally esterified or aminirovanie carboxyl and a group of the formula

< / BR>
has a structure selected from the group consisting of

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
14. The compound or its salt under item 13, in which R1the lowest-FROM2WITH4-alkyl, which may be linked via-O-, -NH - or-S-.

15. The compound or its salt under item 13, in which R3a group of the formula-CO-D, in which D hydroxy, amino, N-lower-C1- C4-alkylamino, N,N-Denizli-C1WITH4-alkylamino, lower-FROM1WITH6-alkoxy, lower-C1WITH6-alkylthio or optionally substituted DIOXOLANYL, or a group of the formula-O-CHR4-OCOR5in which R4hydrogen, lower-C1- C6-alkyl, lower-C2WITH6alkenyl or lower WITH3- C8-cycloalkyl;

R5lower1WITH6-alkyl, lower-C2- C6-alkene the-cycloalkyl or aryl, lower2WITH3alkenyl, optionally substituted lower-C3WITH8-cycloalkyl or aryl, aryl, lower-C1- C6-alkoxy, lower-C2C8-alkenylamine, lower-FROM3WITH8-cycloalkane, lower-FROM1WITH3-alkoxy, substituted lower WITH3WITH8-cycloalkyl or aryl, lower-C2- C3-alkenylamine, substituted lower WITH3WITH8-cycloalkyl or aryl, or aryloxy.

16. The compound or its salt under item 13, in which R3a group of the formula-CO-D", where D ' is hydroxy, amino, N-lower-C1- C4-alkylamino, N,N-Denizli-C1WITH4-alkylamino or lower WITH1WITH4-alkoxy, the alkyl portion of which may be substituted by hydroxy, amino, galaida, lower-FROM2WITH6-alkanoyloxy, 1-low-C1WITH6-alkoxycarbonyl or lower WITH1- C4-alkoxy.

17. The compound or its salt under item 13, in which R3optionally etherified carboxy.

18. The compound or its salt under item 13, in which a group of the formula

< / BR>
has the structure of benzimidazole, tanakadate or imidazopyridine.

19. Connection on p. 13, in which R2group selected from the co-1,2,4-oxadiazol-3-yl.

20. Connection on p. 1, which is 1-(cyclohexyloxycarbonyloxy)ethyl-2-ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)-biphenyl-4-yl]methyl]benzimidazole-7-carboxylate.

21. Connection on p. 1, which is 1-[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)-biphenyl-4-yl] methyl-4 - methyl-2-propoxyimino[3,4-d]imidazole-6-carboxylic acid.

22. Connection on p. 1, which is 2-ethyl-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)-biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid.

23. Connection on p. 1, which is a 2-ethoxy-1-[[2'- (2,5-dihydro-5-oxo-1,2,4-thiadiazole-3-yl-biphenyl-4-yl] methyl] benzimidazole-7)-carboxylic acid.

24. Connection on p. 1, which is 2-ethyl-3-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)-biphenyl-4-yl] - methyl] -5,7-dimethylimidazo[4,5-b]pyridine.

25. Connection on p. 1, which is 2-methoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)-biphenyl-4-yl] methyl] -4-methylthieno[3,4-d]imidazole-6-carboxylic acid.

26. Connection on p. 1, which is a 2-cyclopropyl-1-[[2'-(2,5-dihydro-5-oxo-1,2,4 - oxadiazol-3-yl)-biphenyl-4-yl] methyl]benzimidazole-7 - carboxylic acid.

27. The pharmaceutical is citiesi acceptable carrier, the filler or diluent, wherein the active component it contains a therapeutically effective amount of the compounds under item 1 or its pharmaceutically acceptable salt.

28. Connection on p. 1, which is a 2-ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)-biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid or its pharmaceutically acceptable salt.

29. How anthonyjasony of angiotensin II in mammals by introduction of the active substance to a mammal, characterized in that the active substance is administered to the mammal a therapeutically effective amount of the compounds under item 1 or its pharmaceutically acceptable salt.

 

Same patents:

The invention relates to a neuroprotective (anti-ischemic and excited by blocking amino acid receptor) analogues 5-(1-hydroxy-2-piperidinophenyl)-2-(1H, 3H)-indole-defined formula (I), (II) and (III) below; their pharmaceutically acceptable salts; method of using these compounds in the treatment of stroke, traumatic brain injury or degenerative diseases of the CNS (Central nervous system), such as disease Alzheimer, senile dementia Alzheimers.com type, Huntington's disease and Parkinson's disease; and some of their intermediates

The invention relates to a neuroprotective (anti-ischemic and excited by blocking amino acid receptor) analogues 5-(1-hydroxy-2-piperidinophenyl)-2-(1H, 3H)-indole-defined formula (I), (II) and (III) below; their pharmaceutically acceptable salts; method of using these compounds in the treatment of stroke, traumatic brain injury or degenerative diseases of the CNS (Central nervous system), such as disease Alzheimer, senile dementia Alzheimers.com type, Huntington's disease and Parkinson's disease; and some of their intermediates

The invention relates to a new derivative of uracil with herbicide action

Derivative oxazole // 2032677
The invention relates to heterocyclic carbon compounds that have medicinal and biosdecode properties and to their preparation and use

The invention relates to new biologically active chemical compounds, in particular to cyclic amino compounds of the formula I

BANwhere In - perederina, piperidinyl or pyrrolidinyl group, each of which may be substituted by a lower alkyl group, lower alkylcarboxylic group, carbobenzoxy, afterburner (lower) accelgroup, phenylketone (lower) alkyl group, phenylcarbamoyl (lower) alkyl group or phenyl (lower) alkyl group, each of which may be substituted by a halogen atom or a lower alkoxygroup; p is 1 or 2; And -- is a bond, or two-, or trivalent aliphatic C1-6hydrocarbon residue which may be substituted by a lower alkyl group, oxo, hydroximino or hydroxy-group;means either simple or double bond, provided that when a represents a bond, thenmeans of a simple bond; R2and R3independent means ATO condition, both R2and R3are not hydrogen atoms, or R2and R3together with the adjacent nitrogen atom form piperidino, hexamethyleneimino, morpholino, pyrolidine, pieperazinove or 1-imidazolidinyl group, each of which may be substituted by a lower alkyl group, a phenyl (lower) alkyl group, a lower alkylcarboxylic group or diphenyl (lower) alkyl group or a physiologically acceptable salt additive acid

The invention relates to heterocyclic compounds having angiotensin II antagonistic activity

The invention relates to compounds of the formula

< / BR>
and their pharmaceutically acceptable salts, in which:

R represents phenyl, substituted with 1-2 substituents, each independently from each other selected from halogen;

R1represents C1-4alkyl;

R2denotes H or C1-4alkyl; and

"Het", which are attached to adjacent carbon atom by a ring carbon atom, chosen from pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, "Het" optionally substituted C1-4the alkyl, C1-4alkoxy, halogen, CN, NH2or-NHCO2(C1-C4) alkyl

The invention relates to imidazo - annelirovaniya ISO - and heterocyclic compounds, method of their production and to the tools based on them

The invention relates to indole derivative of General formula (l):

(I)

where R and R1such that:

or R and R1the same or different hydrogen atom, a straight or branched lower alkyl, cycloalkyl to 6 carbon atoms;

or R and R1together with the nitrogen atom to which they are bound, form a piperazinil, substituted lower alkyl,

A -:

or chain /CH2/n, where n can take the values 2 or 3,

or circuit< / BR>
X and Y or each a hydrogen atom,

or one hydrogen atom and the other is a hydroxy radical or1-C4-alkyl,

or X and Y together form an oxo radical, a radical alkyltin with 1-4 carbon atoms or a radical N-OR5where R5a hydrogen atom or an alkyl radical with 1-4 carbon atoms, the substituents a, b, c, d such that:

either each hydrogen atom,

or a and b together form a function oxo and C and d are each a hydrogen atom;

Z -:

or a hydrogen atom,

or a moiety of the lower alkyl or the group aminoalkyl formula:

R2NH2,

where R2lowest alkylen;

moreover, these compounds of formula (I) can nachtergaele or organic acids

The invention relates to new biologically active chemical compounds, in particular to cyclic amino compounds of the formula I

BANwhere In - perederina, piperidinyl or pyrrolidinyl group, each of which may be substituted by a lower alkyl group, lower alkylcarboxylic group, carbobenzoxy, afterburner (lower) accelgroup, phenylketone (lower) alkyl group, phenylcarbamoyl (lower) alkyl group or phenyl (lower) alkyl group, each of which may be substituted by a halogen atom or a lower alkoxygroup; p is 1 or 2; And -- is a bond, or two-, or trivalent aliphatic C1-6hydrocarbon residue which may be substituted by a lower alkyl group, oxo, hydroximino or hydroxy-group;means either simple or double bond, provided that when a represents a bond, thenmeans of a simple bond; R2and R3independent means ATO condition, both R2and R3are not hydrogen atoms, or R2and R3together with the adjacent nitrogen atom form piperidino, hexamethyleneimino, morpholino, pyrolidine, pieperazinove or 1-imidazolidinyl group, each of which may be substituted by a lower alkyl group, a phenyl (lower) alkyl group, a lower alkylcarboxylic group or diphenyl (lower) alkyl group or a physiologically acceptable salt additive acid

The invention relates to new imidazole derivative of General formula I

where R1-COOH or the group< / BR>
R2=H-C3H7or n-C4H9;

R3-Cl, CF3C2F5C6H5or COOH;

R4-COOH, CHO, or CH2HE, provided that

a) when R4-CH2OH, R3-C2F5and R2-n-C3H7,

b) when R3-COOH, R4also is COOH,

b) when R2-n-C3H7, R3-C2F5and R4-COOH, R1is the groupwhich inhibit the action of the hormone angiotensin and can be used in medicine

The invention relates to new indolinone derived formula, method of production thereof and to pharmaceutical compositions based on
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