Derivatives of biphenyl and method of production thereof

 

(57) Abstract:

The inventive derivatives of biphenyl, the way they are received. The compounds of formula I

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in which a group IIa, IIb or IIc

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< / BR>
< / BR>
where R1- alkyl, alkenyl, cycloalkyl or a group of the formula R4-Y-R5where R4is hydrogen, alkyl or cycloalkyl; R5simple link or alkylene, and Y is oxygen, sulfur or aminogroups; R2is hydrogen, halogen, optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted cycloalkyl, formyl, alkylsulphonyl, hydroxy-, amino-, alkylamino, dialkylamino-, alkoxy-, alkylthio-, cyano - or nitro-group; R3is hydrogen, alkyl, carboxy or substituted carboxypropyl, carbarnoyl or tetrazol-5-yl; X is a group of formula-CH=, -N= or-C(COOR6)=, where R6is hydrogen or a protective radical for carboxypropyl; Z is a simple bond, alkylene or vinile and B - carboxy-, or substituted carboxypropyl, or tetrazol-5-yl, and pharmaceutically acceptable salts and esters have the ability to inhibit the action of angiotensin II and can be used for the treatment and prevention of hypertension and heart disease. 3 S. and 46 C.p. f-crystals, 4 tab., 6 Il.

The invention relative to asenna AP) and which can be used for the treatment and prevention of hypertension and heart disease. The invention also provides methods and products that use these new compounds and methods for their preparation.

It is known that the system of the renin-angiotensin provides one of the important mechanisms of homeostasis of blood pressure in living animals. This system is activated when blood pressure decreases or decreases the concentration of sodium ions in the body fluids. As a result, the enzyme renin and angiotensin - converting enzyme (abbreviated ACE) inhibitors are activated and act on angiotensinogen, which is first decomposed by renin to form angiotensin (abbreviated as AI). AI then becomes the ACE in the AP. As the AP causes a strong contraction of the blood vessels and accelerates the secretion of aldosterone (a hormone that facilitates the accumulation of body fluids and sodium ions), the system activation leads to increased blood pressure. Inhibitors or suppressors of the system renin-angiotensin, such as renin inhibitors, ACE inhibitors and antagonists AP, expand blood vessels, causing a decrease in blood pressure and improve the function of blood circulation, which is the basis for the use of these drugs in the treatment of heart disease.

Currently clinically used of tols them some antagonists AP peptide type, such as Saralasin known for many years, while some antagonists ones type opened recently (for example, proposed in the European patent N 28833, 28834, 245637, 253310 and 323841 and Japanese applications N Sho 57-98270 and Hei 3-63264). Most of the identified antagonist AP with relatively strong activity, have groups in the molecule (21-carboxyphenyl-4-yl)methyl or (21(tetrazol-5-yl)-biphenyl-4-yl)methyl, for example, as proposed in the European patent N 253310 and 324377 and Japanese patents N Hei 3-58942, Hei 3-63264 and Hei 3-95181.

The closest predecessor is a European patent N 545912, which describes a number of derivatives of 1-biphenyl-methylimidazole, which has an excellent activity antagonists AP, but which differ from the compounds of the invention in some respects, mainly in the nature of the substituents on the benzene ring, biphenyl, not associated with the Mei.

However, the activity of these predecessors are still insufficient and, thus, for therapeutic use antagonists AP with stronger activity.

The detected number of derivatives of biphenylmethane with excellent activity receptor antagonist AP, which is useful as antihypertene - to ensure a series of new derivatives of biphenylmethane.

An additional object of the invention is to provide such compounds having the activity of inhibitors of AP.

Other objectives and advantages of the invention will become clear in the process of presentation of the description.

Thus, the invention provides compounds of formula I

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where A is a group of formula IIa, IIb or IIc

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R1is alkyl having 1 to 6 carbon atoms, alkenyl having 2 to 6 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, or a group of the formula R4- Y - R5- where R4is hydrogen, alkyl having 1 to 6 carbon atoms or cycloalkyl having 3 to 8 carbon atoms;

R5simple link or alkylene having 1 to 4 carbon atoms, and

Y is an oxygen atom, a sulfur atom or aminogroups ;

R2is hydrogen, halogen, unsubstituted alkyl having 1 to 6 carbon atoms, unsubstituted of alkenyl having 2 to 6 carbon atoms an unsubstituted cycloalkyl having 3 to 8 carbon atoms, a hydroxy-group, amino group, alkylamino having 1 to 6 carbon atoms, dialkylamino in which each alkyl has 1 to 6 carbon atoms, formyl, alkylsulphonyl having 2 to 7 carbon atoms, alkoxygroup having 1 to 6 carbon atoms, al is in carbon and which is substituted by at least one Deputy, selected from the group consisting of the substituents defined below, replaced alkenyl, which has 2 to 6 carbon atoms and which is substituted by at least one Deputy, selected from the group consisting of the substituents defined below, or substituted cycloalkyl, which has 3 to 8 carbon atoms and which is substituted by at least one Deputy, selected from the group consisting of the substituents defined below;

R3is hydrogen, alkyl having 1 to 6 carbon atoms, carboxypropyl, protected carboxypropyl, carbarnoyl or tetrazol-5-yl;

X is a group of formula-CH=, -N=, or C(COOR6)=, where R6is hydrogen or a protective radical for carboxypropyl;

Z is a simple bond, alkylene having 1 to 4 carbon atoms, or vinile;

B - carboxypropyl or tetrazol-5-yl, substituents selected from the group consisting of halogen, hydroxy-group, amino group, alkylamino having 1 to 6 carbon atoms, dialkylamino in which each alkyl has 1 to 6 carbon atoms, formyl, alkylcarboxylic with 2 to 7 carbon atoms, alkoxygroup with 1 to 6 carbon atoms, ancilliary with 1 to 6 carbon atoms, ceanography and nitro

and their pharmaceutically acceptable salts and esters.

techno-vascular diseases, which contains an effective amount of an antihypertensive in a mixture with a pharmaceutically acceptable carrier or diluent, in which antihypertensive agent selected from the group consisting of compounds of the formula I and their pharmaceutically acceptable salts and esters.

Further, the invention provides a method of treatment or prophylaxis of hypertension or cardiovascular diseases in mammals, such as man, which consists in introducing an effective amount of an antihypertensive to a mammal, in which antihypertensive agent selected from the group consisting of compounds of the formula I and their pharmaceutically acceptable salts and esters.

The invention also provides methods of making compounds of formula I and their pharmaceutically acceptable salts and esters, which are described below.

If R1, R2, R3or R4is alkyl, it may be normal or branched, having 1-6 carbon atoms, and examples include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, pentyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, the butyl; R2and R3is methyl, ethyl, isopropyl, tert-butyl, isobutyl or 3.3-dimethylbutyl; R4is alkyl with 1-4 carbon atoms, especially methyl or ethyl.

If R2or Deputy - alkylamino, valueliner, alkylsulphonyl, alkoxygroup, allylthiourea or substituted alkyl, the alkyl may be any of those Akilov with 1-6 carbon atoms, which are given above for R1and are preferably groups with 1-4 carbon atoms. Methyl and ethyl are particularly preferred.

Specific examples of such mono - and dialkylamino include methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino-, second -, butylamino-, tert-butylamino, pentylamine, hexylamine-, dimethylamino-, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamine-, di-tert-butylamino-, N-ethyl-N-methylamino-, N-methyl-N-propylamino-, N-ethyl-N-propylamino-, N-methyl-N-isopropylamino-, N-methyl-N-butylamino and N-methyl-N-tert-butylamino.

Specific examples of such alkylcarboxylic group with 2-7 carbon atoms include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl and heptanoyl, of which the acetyl and propionyl before the oxy, propoxy, isopropoxy, butoxy-, second -, butoxy-, tert-butoxy, isobutoxy-, pentyloxy-, 2-methylbutoxy-, 3-methylbutoxy-, 2,2-DIMETHYLPROPANE, hexyloxy-, 2-methylphenoxy-, 3-methylpentane-, 4-methyleneindoline-, 3,3-dimethylbutene - and 2-ethylbutane, of which methoxy and ethoxypropan preferred.

Specific examples of such alkylthio with 1-6 carbon atoms include methylthio, ethylthio, propylthio, isopropylthio, butylthio-, second -, butylthio-, tert-butylthio, isobutyric, pentylthio-, 2-methylbutyl-, 3-methylbutyl-, 2,2-dimethylpropyl-, hexylthio-2-methylphenylthio-, 3-methylphenylthio-, 4-methylphenylthio-, 3,3-dimethylbutyl - and 2-ethylbutyrate.

If R2- substituted alkyl, the alkyl has 1-6 carbon atoms and substituted by at least one Deputy, selected from the group consisting of the substituents defined above. There are no particular restrictions on the number of such substituents except the imposed number can replace carbon atoms and possibly by steric constraints; preferably the number of substituents depends on the nature of a substitute. If the Deputy halogen, they are preferably 1-5 (1-3 in the event methyl), more preferably 2-5 (2 and the or more substituents, they may be the same or different. Examples of such substituents include halogen, such as fluorine, chlorine, bromine and iodine, of which fluorine and chlorine are preferred, the most preferred fluorine; hydroxy-group; amino group; alkylamino and dialkylamino, such as shown for R2; formyl; alkylsulphonyl, alkoxy and ancilliary, such as shown for R2; ceanography and nitro. Examples of such substituted Akilov include trifluoromethyl, pentafluoroethyl, heptafluoropropyl, forproper, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-1-methylethyl, 1-hydroxypropyl, 1-hydroxy-1-methylpropyl, 1-hydroxy-2-methylpropyl, 1-ethyl-1-hydroxypropyl, 1-hydroxy-2,2-dimethylpropyl, 2-ethyl-1-hydroxybutyl, 2-ethyl-1-hydroxyphenyl, aminomethyl, 1-amino-ethyl, 2-amino-ethyl, 1-amino-1-methylethyl, 1-aminopropyl, 1-amino-1-methylpropyl, 1-amino-2-methylpropyl, 1-amino-1-ethylpropyl, N-methylaminomethyl, N-ethylaminomethyl, N, N-dimethylaminomethyl, N, N-diethylaminomethyl, formylmethyl, formulates, acetylethyl, acetylethyl, propicillin, butylmethyl, isobutylether, methoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 1-methoxy-1-methylethyl, 1-methoxypropyl, 1-methoxy-1-methylpropyl, 1-methoxy-2-methylpropyl, 1-ethyl-1-methoxypropyl, noetic, 2-cyanoethyl, nitro methyl, 1-nitroethyl and 2-nitroethyl, of which preferred trifluoromethyl, pentafluoroethyl, hydroxymethyl, 1-hydroxyethyl, 1-hydroxy-1-methylethyl, 1-hydroxypropyl, 1-hydroxy-2-methylpropyl, 1-hydroxy-2,2-dimethylpropyl, aminomethyl, N-methylaminomethyl, N,N - dimethylaminomethyl, N, N-diethylaminomethyl, acetylethyl, propicillin, methoxymethyl and 1-methoxy-1-methylethyl.

If R1or R2is unsubstituted of alkenyl or R2- substituted alkenyl, it can be any of alkenyl with 2-6 carbon atoms and may be normal or branched. Examples of such groups include vinyl, allyl, 1-propenyl, Isopropenyl, 1-butenyl, 2-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-methyl-2-butenyl and 1-hexenyl, of which preferred group with 2-4 carbon atoms and the most preferred group with 3-4 carbon atoms. In the case of R1preferred alkenyl with 3 or 4 carbon atoms, especially 1-propenyl and 1-butenyl. In the case of R2preferably alkenyl c 3-4 carbon atoms, especially Isopropenyl and 2-methyl-1-propenyl.

If R2- substituted alkenyl, Deputy or deputies can be selected from the group consisting of the substituents defined above. the data to be substituted carbon atoms and possibly by steric constraints, and preferably the number of substituents depends on the nature of a substitute. If the Deputy is halogen, the preferred number is 1-3. In the case of other deputies only Deputy preferred. If there are two or more substituents, they may be the same or different. Examples of such substituted groups include 2,2-defermined, 2,2-dichlorovinyl, 3-hydroxy-1-propenyl, 3-hydroxy-2-methyl-1-propenyl, 3-amino-1-propanol, 3-amino-2-methyl-1-propenyl, 3-methylamino-1-propenyl, 3-methylamino-2-methyl-1-propenyl, 3-(N,N-dimethylamino)-1-propenyl, 3-(N,N-dimethylamino)-2-methyl-1-propenyl, 3-formyl-1-propenyl, 3-formyl-2-methyl-1-propenyl, 2-acetylphenyl, 2-propylaniline, 3-methoxy-1-propenyl, 3-methoxy-2-methyl-1-propenyl, 3-methylthio-1-propenyl, 3-methylthio-2-methyl-1-propenyl, 3-cyano-1-propenyl, 3-cyano-2-methyl-1-propenyl, 3-nitro-1-propenyl and 2-methyl-3-nitro-1-propenyl, of which we prefer 2,2-defermined, 2,2-dichlorovinyl, 3-hydroxy-1-propenyl, 3-hydroxy-2-methyl-1-propenyl, 3-methoxy-1-propenyl and 3-methoxy-2-methyl-1-propenyl.

If R1, R2or R4- cycloalkyl or R2- substituted cycloalkyl, then he may have 3-8 carbon atoms, preferably 3-6 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and recloak the>preferred cyclopropyl. In the case of R2cyclopentyl and cyclohexyl are preferred.

If R2- substituted cycloalkyl, it can be any cycloalkyl above, preferably having 3 to 6 carbon atoms in the ring, possibly substituted by at least one Deputy, selected from the group consisting of the substituents defined above. As previously, there are no special restrictions on the number of such substituents except the overlay number can replace carbon atoms and possibly spatial constraints, the preferred number of substituents depends on the nature of a substitute. If the Deputy is halogen, the preferred number is 1 to 3. Other preferred substituents are the only Deputy. If there are two or more substituents, they may be the same or different. Examples of such substituted groups include 1-chlorocyclopentane, 1-chlorocyclohexane, 1-hydroxyisopropyl, 1-hydroxycinnamates, 1-hydroxycyclopent, 3-hydroxycyclopent, 1-hydroxycyclohexyl, 4-hydroxycyclohexyl, 1-hydroxycyclohexyl, 1-aminocyclopent, 1-aminocyclohexane, 1-methylaminophenol, 1-methylenedicyclohexyl, 1-(N,iopentol, 1-acetylcytosine, 1-methoxycyclohexyl, 1-methoxyisobutyl, 1-methoxycyclohexyl, 1-methoxycyclohexyl, 1-methylthiomethyl, 1-methylthiouracil, 1-cyanocyclohexyl, 1-cyanocyclohexyl, 1-nitrocyclohexane and 1-nitrocyclohexane, of which the preferred 1-hydroxycyclopent, 1-hydroxycyclohexyl, 1-methoxycyclohexyl and 1-methoxycyclohexyl.

If R9or Deputy - halogen, it may be, for example, fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, most preferably fluorine or chlorine.

If R5or Z - alkylene, it can be normal or branched group of from 1 to 4, preferably 1 to 2 carbon atoms. If "free" valencies are on the same carbon atom, then these groups are sometimes called "alkylidene", although the groups, where "free" valencies are present on the same carbon atom and groups, where "free" valencies are on different carbon atoms, generally referred to as "aliran" as a more accepted. Examples of such groups include methylene, ethylene, trimethylene, tetramethylene, ethylidene, propylidene, butylidene and isobutylidene, preferably methylene and ethylene, most preferably methylene.

If decal to carboxypropyl can be any of those radical, which are widely known in the field of synthetic organic chemistry, or they may be the residue of ester, can turn into carboxypropyl in a living organism. Examples of such protective groups include:

alkali with 1 to 6 carbon atoms, such as given above for R1especially methyl, ethyl and tert-butyl;

halogenoalkane with 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as trifluoromethyl, 2,2,2-triptorelin, 2,2,2-trichloroethyl, 2-foretel, 2-chloroethyl, 2-Iodate, 3-chloropropyl, 4-terbutyl and 6-iohexol, preferably 2,2,2-trichloroethyl and 2-chloroethyl;

hydroxyalkyl from 1 to 6, preferably 2 to 4 carbon atoms, having one or more, preferably 1 or 2, hydroxy-group, such as hydroxymethyl, 2-hydroxyethyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, 3,4-dihydroxybutyl, 4-hydroxybutyl, 5-hydroxyphenyl and 6-hydroxyhexyl, preferably 2-hydroxyethyl;

alkoxyalkyl and alkoxylalkyl, in which each alkoxygroup and each alkyl contains 1 to 6, preferably 1 to 4, most preferably 1 or 2 carbon atoms, such as methoxymethyl, 2-methoxyethyl, 2-ethoxyethyl and 2-methoxyethoxymethyl, preferably methoxymethyl;

pencil;

alkoxycarbonyl, such as methoxycarbonylmethyl;

cianelli, in which alkyl has 1 to 6, preferably 1 to 4, most preferably 1 to 2 carbon atoms, such as cyanomethyl and 2-cyanoethyl;

alkylthiomethyl, in which alkyl has 1 to 6, preferably 1 to 4, more preferably 1 or 2 carbon atoms, such as methylthiomethyl and ethylthiomethyl;

arithimetic, in which aryl has 6 to 10, preferably 6 or 10 carbon atoms, such as phenylthiomethyl and Aftertime;

alkylsulfonyl, in which each alkyl has 1 to 6, preferably 1 to 4, more preferably 1 or 2 carbon atoms and in which the alkyl alkylsulfonyl may be unsubstituted or substituted by one or more, preferably 1 to 3 halogen atoms, such as 2-methanesulfonate and 2-triftormetilfullerenov;

arylsulfonyl, in which aryl has 6 to 10, preferably 6 or 10 carbon atoms in the ring and the alkyl contains 1 to 6, preferably 1 to 4, more preferably 1 or 2 carbon atoms such as 2-benzosulfimide and 2-toluensulfonate;

aralkyl, in which alkyl is substituted by one or more, preferably 1 to 3, more preferably 1 or 2 Allami from 6 to 10, preferably 6 or 10 carbon atoms and can be substituted one 4, more preferably 1 or 2 carbon atoms, and aralkyl has 7 to 13 carbon atoms as a whole in the aryl and alkyl portions, such as benzyl, phenetyl, 3-phenylpropyl, 4-phenylbutyl, diphenylmethyl and naphthylmethyl;

aryl with 6 to 10 carbon atoms, such as phenyl and naphthyl;

alkanoyloxy in which alkanoyl has 1 to 6, preferably 2 to 5 carbon atoms and the alkyl has 1 to 6, preferably 1 to 4, more preferably 1 or 2 carbon atoms, such as formyloxyethyl, acetoxymethyl, propionylacetate, butyraldoxime, pivaloyloxymethyl, valerolactone, isovalerylglycine, hexaniacinate, 1-formyloxyethyl, 1-acetoxyethyl, 1-propionylacetate, 1-butyrylacetate, 1-pivaloyloxymethyl, 1-valeriansee, 1-isovalerianic, 1-hexaniacinate, 2-formyloxyethyl, 2-acetoxyethyl, 2-propionylacetate, 2-butyrylacetate, 2-pivaloyloxymethyl, 2-valeriansee, 2-isovaleramide, 2-hexaniacinate, 1-formylacetate, 1-acetoxymethyl, 1-propionyloxy, 1-butyryloxy, 1-pivaloyloxymethyl, 1-alariaceae, 1-isovalerylglycine, 1-hexanolactone, 1-acetoxyethyl, 1-propionylacetate, 1-butyrylacetate, 1-pivaloyloxymethyl, 1-acetoxyethyl, 1-propionylacetate, 1-Buti is ethoxymethyl, propionylacetate, butyraldoxime, pivaloyloxymethyl, 1-formyloxyethyl, 1-acetoxyethyl, 1-propionylacetate, 1-butyrylacetate and 1-pivaloyloxymethyl, more preferably acetoxymethyl, propionylacetate, butyraldoxime, pivaloyloxymethyl, 1-acetoxyethyl, 1-propionylacetate, 1-butyrylacetate and 1-pivaloyloxymethyl, and most preferably pivaloyloxymethyl and 1-pivaloyloxymethyl;

cycloalkylcarbonyl in which cycloalkyl has 5 to 6 carbon atoms and the alkyl has 1 to 6, preferably 1 to 4, more preferably 1 or 2 carbon atoms, such as cyclopentanecarboxylate, cyclohexanecarboxylate, 1-cyclopentanecarboxylate, 1-cyclohexanecarbonitrile, 1-cyclopentanecarboxylate, 1-cyclohexanecarbonitrile, 1-cyclopentanecarboxylate and 1-cyclohexanecarboxylate, of which the preferred cyclopentanecarboxylate, cyclohexanecarboxylate, 1-cyclopentanecarboxylate and 1-cyclohexanecarbonitrile;

alkoxycarbonylmethyl in which alkoxygroup and alkyl have 1 to 6, preferably 1-5, more preferably 1 or 2 carbon atoms for alkyl and preferably 1-4 carbon atoms to alkoxygroup, such as isopropoxycarbonyloxymethyl, msobuttoniconandcaption, ventilatsioonisusteemi, hexyloxybenzoyl, 1-methoxycarbonylethyl, 1-ethoxycarbonylethyl, 1-propoxycarbonyl, 1-isopropoxycarbonyloxymethyl, 1-butoxycarbonylmethyl, 1-isobutoxyethanol, 1-ventilatsioonisusteemi, 1-hexyloxyethoxy, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 2-propoxycarbonyl, 2-isopropoxycarbonyloxymethyl, 2-butoxycarbonylmethyl, 2-isobutoxyethanol, 2-ventilatsioonisusteemi, 2-hexyloxyethoxy, 1-methoxycarbonylethyl, 1-ethoxycarbonylethyl, 1-propoxycarbonyl, 1-isopropoxycarbonyloxymethyl, 1-butoxycarbonylmethyl, 1-msobuttoniconandcaption, 1-pentyloxyphenylacetylene, 1-hexyloxybenzoyl, 1-methoxycarbonylethyl, 1-ethoxycarbonylethyl, 1-propoxycarbonyl, 1-isopropoxycarbonyloxymethyl, 1-butoxycarbonylmethyl, 1-msobuttoniconandcaption, 1-methoxycarbonylethyl, 1-ethoxycarbonylethyl, 1-ethoxycarbonylmethoxy and 1-ethoxycarbonylmethoxy, of which the preferred methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbazone, 1-ethoxycarbonylethyl, 1-propoxycarbonyl, 1-isopropoxycarbonyloxymethyl, 1-butoxycarbonylmethyl, 1-isobutoxyethanol, 1-methoxycarbonylethyl, 1-ethoxycarbonylethyl, 1-propoxycarbonyl, 1-isopropoxycarbonyloxymethyl, 1-butoxycarbonylmethyl, 1-msobuttoniconandcaption, 1-methoxycarbonylethyl, 1-ethoxycarbonylethyl, 1-propoxycarbonyl, 1-isopropoxycarbonyloxymethyl, 1-butoxycarbonylmethyl and 1-msobuttoniconandcaption, more preferably methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonyl, isopropoxycarbonyloxymethyl, butoxycarbonylmethyl, msobuttoniconandcaption, 1-methoxycarbonylethyl, 1-ethoxycarbonylethyl, 1-propoxycarbonyl, 1-isopropoxycarbonyloxymethyl, 1-butoxycarbonyloxyimino and 1-isobutoxyethanol and most preferably methoxycarbonylmethyl, ethoxycarbonylmethyl, isopropoxycarbonyloxymethyl, 1-methoxycarbonylethyl, 1-ethoxycarbonylethyl and 1-isopropoxycarbonyloxymethyl; cycloalkylcarbonyl in which cycloalkyl has 5 or 6 carbon atoms and alkyl is 1-6, preferably 1-4, more pre is Imlil, 1-cyclopentanecarboxylate, 1-cyclohexyloxycarbonyloxy, 1-cyclopentanecarboxylate, 1-cyclohexyloxycarbonyloxy, 1-cyclopentanecarboxylate and 1-cyclohexyloxycarbonyloxy, of which the preferred cyclopentanecarboxylate, cyclohexyloxycarbonyloxy, 1-cyclopentanecarboxylate and 1-cyclohexyloxycarbonyloxy;

(5-aryl or 5-alkyl-2-oxo-1,3-dioxolan-4-yl)methyl, in which aryl is 6-10, preferably 6 or 10 carbon atoms and is possibly substituted by one or more alkyl, alkoxygroup or halogen and alkyl is 1-6, preferably 1-4, more preferably 1 or 2 carbon atoms, such as (5-phenyl-2-oxo-1, 3-dioxolan-4-yl)methyl, [5-(4-were)2-oxo-1,3-dioxolan-4-yl] methyl, [5-(4-methoxyphenyl)-oxo-1,3-dioxolan-4-yl]methyl, [5-(4-forfinal)-2-oxo-1,3-dioxolan-4-yl] methyl, [5-(4-chlorophenyl)-2-oxo-1,3-dioxolan-4-yl] methyl, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl, (5-ethyl-2-oxo-1,3-dioxolan-4-yl)methyl, (5-propyl-2-oxo-1,3-dioxolan-4-yl)methyl), (5-isopropyl-2-oxo-1,3-dioxolan-4-yl)methyl and (5-butyl-2-oxo-1,3-dioxolan-4-yl)methyl, are preferred (5-phenyl-2-oxo-1,3-dioxolan-4-yl)methyl, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl and (5-ethyl-2-oxo-1,3-diode of the protective groups, which contain aryl ring can be substituted or unsubstituted and, if substituted, may contain one or more Akilov with 1-6 carbon atoms, alkoxygroup with 1-6 carbon atoms or halogen, above.

Preferred protective groups are: alkali with 1-4 carbon atoms; phenyl; naphthyl; benzyl; benzyl having at least one Deputy, selected from the group consisting of methyl, ethyl, metoxygroup, ethoxypropan, fluorine and chlorine; diphenylmethyl; naphthylmethyl; alkanoyloxy in which alkanoyl has 1-5 carbon atoms and the alkyl has 1-4 carbon atoms; cycloalkylcarbonyl in which cycloalkyl has 5-6 carbon atoms and the alkyl has 1-4 carbon atoms; alkoxycarbonylmethyl in which alkoxygroup and are alkyl of 1-4 carbon atoms; cycloalkylcarbonyl, where cycloalkane has 5 or 6 carbon atoms and the alkyl has 1-4 carbon atoms; (5-phenyl - or 5-alkyl-2-oxo-1,3-dioxolan-4-yl)-methyl, in which the alkyl has 1-4 carbon atoms, phthalidyl.

Preferred protective groups are: alkali with 1-4 carbon atoms; benzyl; alkanoyloxy in which alkanoyl has 1-5 carbon atoms and the alkyl has 1 or 2 atom peroglide; alkoxycarbonylmethyl in which alkoxygroup has 1-4 carbon atoms and the alkyl has 1 or 2 carbon atoms; cycloalkylcarbonyl in which cycloalkyl has 5 or 6 carbon atoms and the alkyl has 1 or 2 carbon atoms; (5-phenyl - or 5-alkyl-2-oxo-1,3-dioxolan-4-yl)methyl, in which alkyl has 1 or 2 carbon; phthalidyl.

Even more preferred protective groups are: alkanoyloxy in which alkanoyl has 2-5 carbon atoms and the alkyl has 1 or 2 carbon atoms; alkoxycarbonylmethyl in which alkoxygroup has 1-4 carbon atoms and the alkyl has 1 or 2 carbon atoms; cycloalkylcarbonyl in which cycloalkyl has 5 or 6 carbon atoms and the alkyl has 1 or 2 carbon atoms; (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl.

The most preferred protective groups are: acetoxymethyl, pivaloyloxymethyl, ethoxycarbonylmethyl, 1-(ethoxycarbonyl)ethyl, isopropoxycarbonyloxymethyl, 1-(isopropoxycarbonyl)ethyl, cyclohexyloxycarbonyloxy, 1-(cyclohexyloxycarbonyloxy)and ethyl (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl.

Compounds according to the invention can form salts. There is no special limitations on the nature of farmacevtichesky acceptable which, as is well known, means that they are not less active (or is less active) or not more toxic (or unacceptably more toxic than the original compounds. Thus, since the compounds according to the invention contain at least one basic group in its molecule, they can form acid additionai salt. Examples of such acid additiony salts include: salts with inorganic acids, especially halogen acids such as hydrofluoric acid, Hydrobromic acid, itestosterone acid and hydrochloric acid), nitric acid, carbonic acid, sulfuric acid or phosphoric acid; salts with lower alkylsulfonate, such as methanesulfonate, econsultation, triftoratsetata or econsultation; salt arylsulfonate, such as benzosulfimide, or p-toluensulfonate; and salts of organic carboxylic acids such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid, benzoic acid, mandelic acid, ascorbic acid, lactic acid, gluconic acid or basic conditions.

Also, if the connection according to the invention is a compound in which R3and/or B - carboxypropyl or tetrazol and/or X is a group of formula C(COOR6)=, where R6is hydrogen, the reaction of such compounds with a base to give a salt. Examples of such compounds include salts with alkali metals such as sodium, potassium or lithium; salts with alkaline earth metals such as barium or calcium; salts with another metal, such as magnesium or aluminum; ammonium salt; and salts with organic bases, such as salts with triethylamine, Diisopropylamine, cyclohexylamine, guanidine or dicyclohexylamine.

Compounds according to the invention can contain one or more asymmetric carbon atoms in their molecules, and can thus form optical isomers. Although all isomers presented here are only the molecular formula, the invention includes as an individual, isolated isomers and mixtures thereof, including racemates. If used methods stereospecific synthesis or use of optically active compounds as starting materials, the individual isomers can be obtained directly; on the other hand, if you get a mixture of Windows, the individual isomers can be obtained by conventional methods of splitting.

Preferred classes of compounds of this invention are those compounds of formula I and their pharmaceutically acceptable salts and esters, in which:

1(I). A group of the formula IIa, and R1is alkyl with 2 to 4 carbon atoms, alkenyl with 3-5 carbon atoms, alkoxyalkyl in which alkoxygroup has 1-3 carbon atoms and the alkyl has 1 or 2 carbon atoms, alkylthiomethyl in which allylthiourea has 1-3 carbon atoms and the alkyl has 1 or 2 carbon atoms, or allylthiourea with 1-3 carbon atoms;

1(II). A group of the formula IIa, and R2is hydrogen, halogen, alkyl with 1-6 carbon atoms, alkenyl with 3-6 carbon atoms or substituted alkyl with 1-6 carbon atoms, substituted with halogen or hydroxy-group;

1(III). A group of the formula IIa, and R3- carboxypropyl, protected carboxypropyl, carbarnoyl or tetrazol-5-yl;

1(IV). A group of the formula IIa, Z is a bond, methylene or vinile; and in particular those compounds in which A is a group of formula IIa, and R1as defined in 1(I), R2as defined in 1(II), R3as defined in 1(III) and Z is as defined in 1(IV).

2(I). A group of the formula IIb, R1is alkyl with 2 to 4 atoms coal is of erode, alkylthiomethyl in which allylthiourea has 1-3 carbon atoms and the alkyl has 1 or 2 carbon atoms, alkoxygroup with 1-3 carbon atoms or allylthiourea with 1-3 carbon atoms;

2(II). A group of the formula IIb, R2is hydrogen, halogen or alkyl with 1-4 carbon atoms;

2(III). A group of the formula IIb, R3is hydrogen, alkyl with 1-4 carbon atoms, carboxypropyl, protected carboxypropyl or tetrazol-5-yl;

2(IV). A group of the formula IIb and X is a group of formula-CH= group of formula II= or a group of the formula-C(COOR6) = in which R6is hydrogen or a protective radical for carboxypropyl;

2(V). A group of the formula IIb, and Z is a simple bond, methyl or vinile;

and especially those in which A is a group of the formula IIb and R1as defined in 2(I), R2as defined in 2(II), R3as defined in 2(III), X is as defined in 2(IV) and Z, as defined in 2(V).

3(I). A group of the formula IIc, and R1is alkyl with 2 to 4 carbon atoms, alkoxyethyl in which alkoxygroup has 1-3 carbon atoms, or alkylthiomethyl in which allylthiourea has 1-3 carbon atoms;

3(II). A group of the formula IIc, and R3is hydrogen, halogen or alkyl with 1-4 carbon atoms;

3(III). A group of the formula IIc, and R3is hydrogen, alkyl with 1-4 carbon atoms, to the H= or a group of formula-N=;

3(V). A group of the formula IIc, and Z is a simple bond, methylene or vinile;

and especially those in which A is a group of formula IIc, and R1as definitely 3(I), R2as definitely 3(II), R3as definitely 3(III), X is as defined in 3(IV) and Z, as defined in 3(V).

4. If R3or B protected carboxypropyl, or R6- protective radical for carboxypropyl, the protective radical - alkanoyloxy in which alkanoyl has 2-5 carbon atoms and the alkyl has 1 or 2 carbon atoms, alkoxycarbonylmethyl in which alkoxygroup has 1-4 carbon atoms and the alkyl has 1 or 2 carbon atoms, cycloalkylcarbonyl in which cycloalkyl has 5 or 6 carbon atoms and the alkyl has 1 or 2 carbon atoms or (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl.

5. B - carboxypropyl or tetrazol-5-yl.

More preferred classes of compounds according to the invention is the compounds of formula I and their pharmaceutically acceptable salts and esters, in which:

6(I). A group of the formula IIa and R1is ethyl, propyl, butyl, 1-propenyl, 1-butenyl, 2-butenyl, methoxymethyl, ethoxymethyl, methylthiomethyl, ethylthiomethyl, methylthiourea or ethylthiourea;

6(II). A group of the formula IIa and R2- yl or 1-hydroxy-2,2-dimethylpropyl;

6(III). A group of the formula IIa and R3- carboxypropyl, protected carboxypropyl, carbarnoyl or tetrazol-5-yl;

6(IV). A group of the formula IIa and Z is a simple bond or methylene;

and especially those compounds in which A is a group of formula IIa and R1as defined in 6(I), R2as defined in 6(II), R3as defined in 6(III) and Z is as defined in 6(IV).

7(I). A group of the formula IIb and R1is ethyl, propyl, cyclopropyl, methoxy, ethoxy-, propoxy-, methylthio -, or ethylthiourea.

7(II). A group of the formula IIb and R2is hydrogen, fluorine, chlorine, methyl, ethyl or isopropyl;

7(III). A group of the formula IIb and R3is hydrogen, methyl, ethyl, carboxypropyl, protected carboxypropyl or tetrazol-5-yl;

7(IV). A group of the formula IIb and X is a group of formula-CH=, -N= or-C(COOR6)=, where R6is hydrogen or a protective radical for carboxypropyl;

7(V). A group of the formula IIb, and Z is a simple bond or methylene;

and especially those in which A is a group of formula (IIb) and R1as defined in 7(I), R2as defined in 7(II), R3as defined in 7(III), X, as defined in 7(IV) and Z, as defined in 7(V).

8(I). A group of the formula IIc, and R1is ethyl, propyl, butyl, 2-methoxyethyl or 2-methylthioethyl;

8(II). A group of the formula, ethyl, ethyl, carboxypropyl, protected carboxypropyl or tetrazol-5-yl;

8(IV). A group of the formula IIc, and X is a group of formula-CH= or-N=;

8(V). A group of the formula IIc, and Z is a simple bond or methylene;

and especially those in which A is a group of formula IIc, and R1as defined in 8(I), R2as defined in 8(II), R3as defined in 8(III), Z, as defined in 8(IV) and Z, as defined in 8(V).

9. If R3or B protected carboxypropyl or R6- protective radical for carboxypropyl, the protective radical is acetoxymethyl, pivaloyloxymethyl, ethoxycarbonylmethyl, isopropoxycarbonyloxymethyl, 1-ethoxycarbonylethyl, 1-isopropoxycarbonyloxymethyl, cyclohexyloxycarbonyloxy, 1-cyclohexyloxycarbonyloxy or (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl.

The most preferred classes of compounds according to the invention are those compounds of formula I and their pharmaceutically acceptable salts and esters, in which:

10(I). A group of the formula IIa and R1is ethyl, propyl or butyl;

10(II). A group of the formula IIa and R2- chlorine, isopropyl, Isopropenyl, trifluoromethyl, pentafluoroethyl, 1-hydroxyethyl or 1-hydroxy-1-methylethyl and R3- carboxypropyl protected carboxytherapy, and R3- carbarnoyl;

10(IV). A group of the formula IIa and Z is a simple bond;

and especially those in which A is a group of formula IIa and R1as defined in 10(I), R2and R3as defined in 10(II) or 10(III) and Z, as defined in 10(IV).

11(I). A group of the formula IIb and R1is ethyl, propyl, cyclopropyl, ethoxy-, methylthio -, or ethylthiourea;

11(II). A group of the formula IIb and R2is hydrogen or methyl;

11(III). A group of the formula IIb and R3is hydrogen, methyl, carboxypropyl, protected carboxypropyl or tetrazol-5-yl;

11(IV). A group of the formula IIb and X is a group of formula-CH= , -N= or-C(COOR6)=, where R6is hydrogen or a protective radical for carboxypropyl;

11(V). A group of the formula IIb, and Z is a simple bond;

and especially those in which A is a group of formula IIb, and R1as defined in 11(I), R2as defined in 11(II), R3as defined in 11(III), X, as defined in 11(IV) and Z, as defined in 11(V).

12(I). A group of the formula IIc, and R1is ethyl, propyl, butyl, 2 - methoxyethyl or 2 - methylthioethyl;

12(II). A group of the formula IIc, and R2is hydrogen or methyl;

12 (III). A group of the formula IIc, and R3- carboxypropyl, protected carboxypropyl or tetrazol-5-yl;

12 (IV). A group of the formula IIc, and X - group form>as defined in 12(I), R2as defined in 12(II), R3as defined in 12 (III), X, as defined in 12(IV) and Z, as defined in 12(V).

13. If R3or B protected carboxypropyl or R6- protective radical for carboxypropyl, the protective radical is acetoxymethyl, pivaloyloxymethyl, ethoxycarbonylmethyl, isopropoxycarbonyloxymethyl, 1-ethoxycarbonylethyl, 1-isopropoxycarbonyloxymethyl, cyclohexyloxycarbonyloxy, 1-cyclohexyloxycarbonyloxy or (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl.

Typical examples of individual compounds of the invention are given by formulas I-1 to I-3, is shown in scheme I (Fig.1), in which different characters are given in table. 1-3, i.e. table. 1 relates to formula I-1, PL. 2 relates to formula I-2 and table. 3 refers to the formula I-3. For the avoidance of doubt shows peripheral numbering system used to identify the position of substituents in the heterocyclic rings of formula I-2 and I-3. It should be noted that the numbering system used to indicate the positions of the substituents in the heterocyclic ring of formula I-2, if X is a group of formula-N=, shown in partial formula (I-2A, while the system operationally-CH= or-C(COOR6)=, shown in partial formulas I-2b I-2c, respectively. The same numbering system, which is in accordance with the recommendations of IUPAC used below for the names of the compounds. In the tables for some groups use the following abbreviations: Bu-butyl, tBu is tert-butyl, Et is ethyl, cHx-cyclohexyl, Me is methyl, Mod -(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl, Pom - pivaloyloxymethyl, Pr is propyl, EAP - cyclopropyl, iPr is isopropyl, Tz - tetrazol-5-yl.

From the above table. 1-3, the preferred compounds are compounds having the following numbers: 1-1, 1-2, 1-3, 1-4, 1-6, 1-7, 1-8, 1-9, 1-10, 1-11, 1-16, 1-17, 1-18, 1-19, 1-20, 1-21, 1-22, 1-23, 1-24, 1-25, 1-27, 1-28, 1-29, 1-30, 1-31, 1-32, 1-36, 1-37, 1-38, 1-39, 1-40, 2-1, 2-2, 2-3, 2-4, 2-8, 2-9, 2-10, 2-12, 2-13, 2-14, 2-15, 2-26, 2-27, 2-28, 2-29, 2-30, 2-31, 2-32, 2-33, 2-34, 2-35, 2-36, 2-37, 2-38, 2-39, 2-40, 2-44, 2-45, 2-46, 2-47, 2-48, 2-49, 2-50, 3-1, 3-2, 3-3, 3-4, 3-5, 3-6, 3-8, 3-11, 3-12, 3-13, 3-14, 3-16, 3-23 and 3-24.

More preferred are compounds N 1-2, 1-3, 1-6, 1-7, 1-8, 1-9, 1-22, 1-24, 1-25, 1-27, 1-28, 1-29, 1-30, 1-31, 1-40, 2-1, 2-2, 2-3, 2-4, 2-26, 2-27, 2-28, 2-29, 2-30, 2-31, 2-32, 2-33, 2-34, 2-35, 2-40, 2-44, 2-45, 2-46, 2-47, 2-48, 3-1, 3-2, 3-3, 3-4, 3-5, and 3-6.

Most preferred are the following compounds:

1-2. 4-[1-Hydroxy-1-methylethyl)-1-[(21-oxalobacter-4-yl) methyl]-2-propylimidazol-5-carboxylic acid.

1-6. 4-(1-Hydroxyethyl)-1-[(21-oxalobacter-4-yl)loperamidesee-5-carboxylic acid.

1-22. 4-(1-Hydroxy-2-methylpropyl)-1-[(21-oxalobacter-4-yl)-methyl] -2-propylimidazol-5-carboxamide.

1-24. 4-(1-Hydroxy-2,2-dimethylpropyl)-1-[(21-oxalobacter-4-yl)-methyl] -2-propylimidazol-5-carboxamide.

1-27. Pivaloyloxymethyl-4-(1-hydroxy-1-methylethyl)-1-[(21- oxalobacter-4-yl)methyl]-2-propylimidazol-5-carboxylate.

1-28. (5-Methyl-2-oxo-1,3-dioxolan-4-yl)methyl-4-(1-hydroxy-1 - methylethyl)-1-[(21-oxalobacter-4-yl)methyl]-2 - propylimidazol-5-carboxylate.

1-40. 41-[4-(1-Hydroxy-1-methylethyl)-2-propyl-5-(tetrazol-5-yl) imidazol-1-ylmethyl]biphenyl-2-yl Glyoxylic acid.

2-1. 2-Ethyl-5,7-dimethyl-3-[(21-oxalobacter-4-yl)methyl] -3H-imidazo[4,5-b] pyridine.

2-2. 5,7-Dimethyl-3-[(21-oxalobacter-4-yl)methyl] -2-propyl-3H - imidazo[4,5-b]pyridine.

2-26. 2-Ethyl-[(21-oxalobacter-4-yl)methyl] benzimidazole-7-carboxylic acid.

2-28. Pivaloyloxymethyl-2-ethyl-1-[(21-oxalobacter-4-yl)methyl] benzimidazole-7-carboxylate.

2-30. (5-Methyl-2-oxo-1,3-dioxolan-4-yl)methyl-2-ethyl-1-[(21- oxalobacter-4-yl)methyl]benzimidazole-7-carboxylate.

2-44. 2 Ethoxy-1-[(21-oxalobacter-4-yl)methyl] benzimidazole-7-carboxylic sour the

2-46. (5-Methyl-2-oxo-1,3-dioxolan-4-yl)methyl-2-ethoxy-1-[(21- oxalobacter-4-yl)methyl]benzimidazole-7-carboxylate.

3-2. 2-N[(21-Oxalobacter-4-yl)methyl]-N-propylamino nicotinic acid.

3-5. N-Propyl - N-[41-(3/tetrazol-5-yl/pyrid-2-yl)aminomethyl]biphenyl-2-yl Glyoxylic acid.

and their pharmaceutically acceptable salts and esters.

Compounds according to the invention it is possible to get different well-known methods used to prepare compounds of this type. For example, in General they can be obtained by reaction of compounds of formula III: Ax-H, in which Ax- any group or such a group in which any reactive group or atom is protected, or a precursor group with compounds of formula IV

< / BR>
where B1protected carboxypropyl or protected tetrazol-5-yl and

V - halogen, preferably chlorine, bromine or iodine and, if necessary, removing the protective groups and/or conversion of the precursor ANDxin group a, as mentioned above, and possibly turning into salt, esterification or diesterification product.

In more detail, the compounds according to the invention can be obtained, as shown in the reaction CX is injected into the reaction with compounds of the formula IIIa: A1-H, where A1that more fully define the next is a group in which the respective group may be protected, and then, if necessary, removing the protective group.

In shown in Fig.2 formulas: A, B, V, and B1defined above,

A1group of the formula XIa, XIb or XIc

< / BR>
where R1a, R2a, R3aand X1defined above as R1, R2, R3and X respectively, but in which any primary or secondary amino group, any carboxypropyl or any tetrazol-5-yl protected and defined above.

There is no special limitations on the nature of the protective group used to protect the primary amino group and secondary amino group represented by R1aor R2aand any protective groups commonly used in chemistry for this purpose, can also be used here. Examples of such protective groups include: aralkyl, such as benzyl, diphenylmethyl, trityl; aliphatic acyl such as formyl or TRIFLUOROACETYL; urakelectromed, such as benzyloxycarbonyl and p-bromobenzyloxycarbonyl; alkoxycarbonyl, such as tert-butoxy-carbonyl. Of them preferred benzyl, trityl, TRIFLUOROACETYL, benzyloxycarbonyl and tert-butoxy is there restrictions on the nature of the protective group, used to protect tetrazol-5-yl, presents R3aand B1and again, any group that is used for this purpose, can be applied. Examples include aralkyl, such as benzyl, diphenylmethyl, trityl (=triphenylmethyl), preferably trityl.

Protective radical for carboxypropyl, which may be represented by or included in R3aX1and B1can be any of those defined and described in the examples above in connection with R3and B.

Stage A1.

In stage A1 of the compounds of formula V is obtained by reaction of compounds of formula IIIa with compounds of the formula IV.

The reaction is normally and preferably carried out in the presence of a solvent. There is no special limitation on the nature of the used solvent, provided that it has no adverse effect on the reaction and the reagents and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: hydrocarbons, especially aromatic hydrocarbons, such as benzene or toluene; ethers, such as tetrahydrofuran or dioxane; alcohols such methanol, ethanol or tert-butanol; amides, such as dimethylacetamide, dimethylformamide, N-methyl-2-pyrrolidinyloxy, such as dimethyl sulfoxide. You can apply one solvent of the above or a mixture of two or more of them, preferred ethers, amides, ketones, NITRILES and sulfoxidov.

The reaction is carried out in the presence of a base, the nature of which is not particularly significant to the present invention, provided that it has no harmful effect on the reagents. Examples of suitable bases include carbonates of alkali metals such as sodium carbonate or potassium hydrides of alkali metals, such as sodium hydride, potassium or lithium; alkoxides of alkali metals, such as methoxide or ethoxide sodium tert-piperonyl potassium or lithium methoxide; alkyllithium reagents, such as motility or utility; lithium amides such as diethylamid, diisopropylamide or bis(trimethylsilyl) amide and lithium; and bicarbonates of alkali metals such as sodium bicarbonate or potassium. Of these we prefer carbonates of alkali metals, hydrides of alkali metals, lithium amides and alkoxides of alkali metals.

The reaction may proceed in a wide range of temperatures and the precise reaction temperature is not essential to the invention. In General, we find it convenient to conduct the reaction at (-10) -(+100)oC, more pane. The reaction time can also vary widely depending on many factors, especially the reaction temperature, the nature of the reagents and solvent used. However, provided that the reaction is performed in the preferred conditions outlined above, a period of from 30 minutes to 24 hours, more preferably 1 to 16 hours, will usually be sufficient.

After completion of the reaction, the target compound of formula V can be isolated from the reaction mixture by conventional means. For example, the compound can be obtained by the following procedure: removal of solvent by evaporation under reduced pressure; adding water to the residue; the extraction of the residue with an organic solvent not miscible with water such as ethyl acetate; drying the extract, such as anhydrous magnesium sulfate; and removing the solvent, e.g. by evaporation. If necessary, the resulting product may be further purified by conventional methods such as recrystallization or chromatography, especially column chromatography.

Stage A2.

If necessary, you can run stage A2, which includes one or more of the following reactions:

Reaction (a): in which the protective radicals for carboxypropyl that contain the Ute protective radicals tetrazolyl, included in R3aand B1.

Reaction (c): in which removing the protective radicals for the primary and secondary amino groups, included in R1aand R2a.

These reactions can be performed in any suitable order.

Reaction (a).

The reaction used for the removal of the protective radical for carboxypropyl will vary depending on the type of protective radical can be carried out by methods well known in synthetic organic chemistry.

For example, if the protective group aralkyl, such as benzyl, the protective group can be removed by catalytic regeneration in a suitable solvent in the presence of a catalyst (preferably palladium on coal or platinum oxide) in the presence of hydrogen at a pressure of from atmospheric to 5 atmospheres. The reaction is normally and preferably carried out in the presence of a solvent. There is no special limitation on the nature of the used solvent, provided that it has no harmful effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: alcohols, such as methanol or ethanol; and carboxylic acid is ethyl, it can be removed by reaction with an acid (preferably an inorganic acid, such as hydrogen chloride or sulfuric acid, or organic acid, such as triperoxonane acid, methanesulfonate or p-toluensulfonate) in a suitable solvent, the nature of which is not crucial, provided that it has no harmful effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of solvents include: alcohols, such as methanol or ethanol; ethers, such as tetrahydrofuran or dioxane; water; or a mixture of water with one or more of the above organic solvent.

Also, if the protective radical for carboxypropyl - the remainder of ester, it can be removed by reaction with a base (preferably an alkali metal hydroxide such as lithium hydroxide, sodium or potassium hydroxide, or carbonate of an alkali metal such as sodium carbonate or potassium hydroxide) in a suitable for hydrolysis of the solvent. The reaction is normally and preferably carried out in the presence of a solvent. There is no special limitation on the nature of the used solvent, provided that it has no harmful effects of solvents include: alcohols, such as methanol or ethanol; ethers, such as tetrahydrofuran or dioxane; water; or a mixture of water with one or more of the above organic solvent.

The reaction can take place in a wide range of temperatures and the precise reaction temperature is not essential for the invention, although the preferred reaction temperature and reaction time will vary depending on the method of removal, solvent, and other factors. In General it is found that it is convenient to conduct the reaction at 0-100oC, more preferably at a temperature from room temperature up to 80oC. the reaction Time can also vary widely depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. However, provided that the reaction is performed in the preferred conditions outlined above, a period of from 30 minutes to 24 hours, more preferably 1 to 20 hours, will usually be sufficient.

If removing the protective group is carried out by the catalytic reaction, the catalyst preferably is filtered off after completion of the reaction and the solvent evaporated to obtain the product. On the other hand, if the removal of the protective group is carried out by reaction with acid, then the product can be obtained, soy protective group is carried out by alkaline hydrolysis, the product can be obtained by evaporation of an organic solvent, or by neutralization of the resulting acid system and collection released in an aqueous solvent crystals by filtration, or by acidification of the reaction mixture, extraction of the product with an organic solvent not miscible with water, and evaporation of the solvent. If necessary, the resulting product may be further purified by conventional means, such as recrystallization or chromatography, especially column chromatography.

The appropriate choice of reaction conditions and the type of reaction removal enables you to remove the protective radicals for carboxypropyl included in R3aX1and B1selectively or selectivity.

Reaction (b).

Although the nature of the reaction used to remove tetrazolyl protective group in R3aand B1will vary depending on the type of protective group removal can be performed using known methods in synthetic organic chemistry.

For example, if the protective group trail, the removal of the protective group reaches the processing of acid in the solvent. There is no special limitation on the nature of the used solvent in walenty at least partially. Examples of suitable solvents include: water, organic acids such as formic or acetic acid; ethers, such as tetrahydrofuran or dioxane; alcohols such as methanol or ethanol; or a mixture of two or more of them. Examples of acids include organic carboxylic or sulfonic acids, such as formic, acetic, oxalic, methanesulfonate, p-toluensulfonate and triperoxonane acid; and inorganic acids such as hydrochloric, Hydrobromic, sulfuric and phosphoric acid. Of them predpochtitelney acetic, triperoxonane or hydrochloric acid.

The reaction can take place in a wide range of temperatures and the precise reaction temperature is not essential to the invention. In General it is found that the reaction is conveniently carried out at 0-120oC, more preferably at 10-100oC. the reaction Time can also vary widely depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. However, provided that the reaction is performed in the preferred conditions outlined above, a period of from 30 minutes to 24 hours, more preferably 1-16 hours, will usually suffice.

If protective Ia, oxide of platinum or similar catalyst, as described for removal of the protective groups in the reaction (a) in stage A2 of the reaction scheme And, when carboxypropyl protected aralkyl.

After completion of the reaction, the removal of the protective groups of the target compound can be isolated from the reaction mixture by conventional means, for example, as in reaction (a) in stage A2 reaction scheme A.

Reaction (c).

Although the reaction used for the removal of the protective radicals for the primary and secondary amino groups included in R1aand R2awill vary depending on the nature of the protective radical, they can be carried out using methods well known in synthetic organic chemistry.

For example, if the protective group aralkyl, such as benzyl, or Uralelectromed, such as benzyloxycarbonyl, they can be removed by catalytic regeneration in a suitable solvent in the presence of a catalyst (preferably palladium on coal or platinum oxide) in the presence of hydrogen, preferably at a pressure from atmospheric to 5 atmospheres. There is no special limitation on the nature of the used solvent, provided that it has no adverse effect on rimary of suitable solvents include: alcohols, such as methanol or ethanol, and carboxylic acids such as acetic acid. This reaction can sometimes be accelerated by the addition of hydrochloric acid, for example, in the amount of 1-5 equivalents per mole secure connection.

If the protective radical tert-butoxycarbonyl, then it can be removed by reaction with an acid (preferably an inorganic acid, such as hydrogen chloride or sulfuric acid; or organic acid, such as triperoxonane, methanesulfonate, p-toluensulfonate, formic or acetic acid) in a suitable solvent. There is no special limitation on the nature of the used solvent, provided that it has no adverse effect on the reaction or on the reagents involved and that it dissolves the reagents, at least to some extent. Examples of suitable solvents include: alcohols, such as methanol or ethanol; ethers, such as tetrahydrofuran or dioxane; halogenated hydrocarbons such as methylene chloride or chloroform; water and mixtures of water and one or more of the above organic solvent.

If the protective radical of aliphatic acyl such as formyl or TRIFLUOROACETYL, it can pytilia, or carbonate of an alkali metal such as sodium carbonate or potassium hydroxide) in a solvent that promotes hydrolysis. The reaction is normally and preferably carried out in the presence of a solvent. There is no special limitation on the nature of the used solvent, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: alcohols, such as methanol or ethanol; ethers, such as tetrahydrofuran or dioxane; water; and mixtures of water and one or more of the above organic solvent.

The reaction can take place in a wide range of temperatures and the precise reaction temperature is not essential to the invention. In General it is found that it is convenient to conduct the reaction at 0-100oC, more preferably at a temperature from room temperature up to 80oC. the reaction Time can also vary widely depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. However, provided that the reaction is performed in the preferred conditions outlined above, a period of from 30 minutes to 24 hours, more preferably 1-16 h, is usually the measures if removing the protective group is carried out by catalytic regeneration, the catalyst preferably is filtered off after completion of the reaction and the solvent evaporated to obtain the product; whereas if the removal of the protection is performed by treatment with an acid, the target product in the form of salts can be obtained by collecting the salt is separated from the reaction system, or by concentrating the reaction mixture. Further, if the removal of the protection is held by the alkaline hydrolysis, the product is obtained by collecting its released in the reaction system, or extragere it with an organic solvent not miscible with water, and pariva solvent. If necessary, the resulting product may be further purified by conventional means, such as recrystallization or chromatography, especially column chromatography.

Reaction scheme B (Fig. 3).

Reaction scheme B illustrates the formation of compounds of formula Ia, corresponding to compounds of formula I, where R3- carbarnoyl.

In the formulas shown in Fig.3, V and B1defined above; A2group of the formula XIIa, XIIb, or XIIc

< / BR>
where R1a, R2aX1and Z are defined above; and A3group of the formula XIIIa, XIIIb or XIIIc

< / BR>
is of the formula IV. This stage is identical to stage A1 of reaction scheme A and can be carried out using the same reagents and reaction conditions.

Stage B2.

Stage B2 is optional and can include the following reactions.

Reaction (a): in which a cyano, a member of the A2turn in carbarnoyl.

Reaction (b): in which remove the protective radical for carboxypropyl, a member of the B1and X1.

Reaction (C): in which remove the protective radical for tetrazolyl, part of the B1.

Reaction (d): in which removing the protective radicals for the primary and secondary amino groups included in R1aand R2a.

These reactions are carried out in any suitable order.

Reaction (a).

Turning ceanography in carbarnoyl according to reaction (a) may be carried out by reaction of compounds of formula Va with the base.

There is no special limitation on the nature of the used grounds, provided that it has no adverse effects on the reagents, and any base commonly used in reactions of this type can be used here. Examples of suitable bases include hydroxides of alkali metals such as lithium hydroxide, Accreditatie carried out in the presence of a solvent. There is no special limitation on the nature of the solvent, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: alcohols, such as methanol or ethanol; ethers, such as tetrahydrofuran or dioxane; water; and mixtures of water with any one or more of these solvents.

The reaction can take place in a wide range of temperatures and the precise reaction temperature is not critical to the invention. In General it is found that it is convenient to conduct the reaction at 0-100oC, more preferably at a temperature from room temperature up to 80oC. the reaction Time can also vary widely depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. However, provided that the reaction is performed in the preferred conditions described above, the period from 30 min to 24 h, more preferably 1-6 hours, will usually suffice.

After completion of the reaction, the target product can be isolated from the reaction mixture by conventional means. For example, in one technique, the reaction mixture is neutralized, the product precipitates and grind, not miscible with water (e.g. ethyl acetate), and the solvent evaporated to obtain the product. If you want the resulting product may be further purified by conventional means, such as recrystallization or chromatography, especially column chromatography.

Reaction (b), (c) and (d).

Reaction (b), (c) and (d) at this stage correspond to reactions (a), (b) and (c) stage A2 of the reaction schemes A and can be performed using the same reagents and reaction conditions.

Reaction scheme C (Fig. 4).

Reaction scheme C illustrates obtain the compounds of formula Ib, the corresponding compounds of formula I, where A is group of formula IIb.

In the formulas shown in Fig.4, R1, R2, R3, R1a, R2a, R3aX, X1, Z, B, B1and V defined above; R7- protective radical to an amino group.

Protective radical for the amino group, R7can be any of those defined above for R1aand R2a.

Stage C1.

In stage C1 of the compounds of formula VII is obtained by reaction of compounds of formula VI with compounds of formula IV. This reaction is identical to the reactions described in stage A1 of reaction scheme A, and can be performed, Lis R7to obtain the compounds of formula VIII. This stage is performed as described in reaction (C) stage A2 reaction scheme A. If necessary, a protective radical R7can be distinguished from other protective radicals for the primary and secondary amino groups included in R2aand you can selectively delete, select the appropriate response or reaction conditions.

Stage C3.

In stage C3 are connected in formula IX is obtained by restoring the nitro group of compounds of formula VIII. This stage is carried out using methods well known in synthetic organic chemistry.

For example, the goal can be achieved by catalytic regeneration. The reaction is conducted in the presence of a catalyst, such as platinum, coal or Raney Nickel in the presence of hydrogen, preferably under a pressure from atmospheric to 5 atmospheres. The reaction is normally and preferably carried out in a solvent. There is no special limitation on the nature of the used solvent, provided that it has no adverse effect on the reaction or on the reagents involved and that it dissolves the reagents, at least to some extent. Examples of suitable solvents include: alcohols, such as methanol or ethanol is Ira, such as ethyl acetate or butyl acetate; and carboxylic acids such as acetic acid, the most preferred alcohol.

The reaction can take place in a wide range of temperatures and the precise reaction temperature is not essential for the invention. In General it is found that it is convenient to conduct the reaction at 0-60oC, more preferably at 10-40oC. the reaction Time can also vary widely depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. However, provided that the reaction is performed in the preferred conditions outlined above, a period of from 30 minutes to 24 hours, preferably 1-8 hours, will usually suffice.

After completion of the reaction the catalyst can be removed by filtration, the solvent was evaporated under reduced pressure to obtain a product. If necessary, the product may be further purified by conventional methods such as recrystallization or chromatography, especially column chromatography.

If the reductant is used chloride tin (II), the method can be performed by reaction of nitro compounds of formula VIII with a reducing agent in an inert solvent, preferably alcohol, the reaction is not essential for the invention. In General it is found that it is convenient to conduct the reaction at temperatures up to 150oC, more preferably at 50-100oC. the reaction Time can also vary widely depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. However, provided that the reaction is performed in the preferred conditions outlined above, a period of 1-24 hours, more preferably 2-8 hours, will usually be sufficient.

After completion of the reaction product can be isolated from the reaction mixture by conventional methods. For example, one suitable method: the reaction mixture was concentrated, to the residue add organic solvent not miscible with water such as ethyl acetate, and an aqueous solution of alkali such as sodium hydroxide, and the resulting mixture is stirred; the resulting insoluble tin oxide is removed by filtration; the organic solution is separated; the solvent is evaporated under reduced pressure and get the product. If necessary, the product may be further purified by conventional methods such as recrystallization or chromatography, especially column chromatography.

You can test the recovery stage C3 after stage C1 followed in which rmula X is obtained by reaction of compounds of the formula IX with the compound of the formula XIV

R1aC(OR8)3,

in which R1adefined above; R8is alkyl with 1-6 carbon atoms, preferably methyl or ethyl.

The reaction is normally and preferably carried out in the presence of a solvent. There is no special limitation on the nature of the used solvent, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: hydrocarbons, such as hexane, benzene, toluene and xylene; halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as methylene chloride and 1,2-dichloroethane; ethers such as tetrahydrofuran and dioxane; and esters such as ethyl acetate and butyl acetate. Of them preferred hydrocarbons and halogenated hydrocarbons.

The reaction can take place in a wide range of temperatures, and the precise reaction temperature is not essential to the invention. In General it is found that it is convenient to conduct the reaction at 0-120oC, more preferably at 20 to 100oC, although the preferred reaction temperature will vary depending on the nature of the source connection of the many factors especially the reaction temperature and the nature of the reagents and solvent. However, provided that the reaction is performed in the preferred conditions outlined above, a period of from 30 minutes to 24 hours, preferably 1-8 hours, will usually suffice. The reaction can sometimes be accelerated by adding a catalytic amount of acid such as hydrogen chloride, p-toluensulfonate or acetic acid.

After completion of the reaction, the target compound of formula X can be isolated by conventional methods. For example, one suitable technique: spin-off product is collected by filtration or solvent evaporated under reduced pressure, to the residue water is added and the resulting mixture is extracted with an organic solvent not miscible with water such as ethyl acetate, the extract dried, for example, anhydrous magnesium sulfate, and the solvent evaporated to obtain the product. If necessary, the resulting product may be further purified by conventional means, such as recrystallization or chromatography, especially column chromatography.

If the compounds of formula XIV to make in the reaction system stage C3, the reaction stage C4 can sometimes run concurrently with PE

Reaction (a): in which selectivity or selectivity remove the protective radical for carboxypropyl included in R3aX1and B1.

Reaction (b): in which remove the protective radical for tetrazolyl included in R3aand B1.

Reaction (c): in which removing the protective radicals for the primary and secondary amino groups included in R1aand R2a.

These reactions can be carried out by the same methods as the corresponding reaction stage A2.

The initial compounds of formulas III, IIIa and VI used in the reaction schemes A-C (Fig.2-4), is known from the patent or can be obtained by known methods (for example, as shown in EP N 503785 and N 459136, J. Med. Chem., 34, 2525 (1991), ibid., 34, 2919 (1991), ibid 35, 3714 (1992). The initial compounds of the formula (IV) can be obtained, for example, as shown in the following reaction schemes D (Fig.5) or E (Fig.6).

In the formulas shown in Fig.5, 6, V defined above; R9- protective radical for carboxypropyl, and R10- protective radical for tetrazolyl. Protective radical R9for carboxypropyl includes the radicals given for R3aand B1and protective radical R10for tetrazolyl includes the radicals given for R3aand of the formula IVa, the corresponding compounds of formula IV, where B1protected carboxypropyl.

Stage D1.

In stage D1 of the compounds of formula XVI is obtained by reaction of compounds of formula XV with an appropriate amount, preferably 1 to 3 equivalents, more preferably 1.5 to 2 equivalents, of a reducing agent (for example, metal hydride, such as diisobutylaluminium or laetrilelamygdalin; Raney-Nickel - formic acid, or chloride tin (II), preferably diisobutylaluminium) in an inert solvent (preferably an aromatic hydrocarbon, such as benzene, toluene or xylene or a simple ether, such as tetrahydrofuran and dioxane).

The reaction can take place in a wide range of temperatures and the precise reaction temperature is not critical to the invention. In General it is found that it is convenient to conduct the reaction at (-80) - (+60)oC, more preferably from -30oC to room temperature. The reaction time also can vary widely depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. However, provided that the reaction is performed in the preferred conditions outlined above, a period of from 10 min to 8 h, more predpolozhim, is decomposed by the addition of alcohol to the reaction mixture and add diluted hydrochloric acid and an organic solvent not miscible with water such as ethyl acetate), the mixture is stirred, the organic solution is separated and the solvent is removed by evaporation to obtain the product. If necessary, the resulting product can be further cleaned by conventional means, such as recrystallization or chromatography, especially column chromatography.

Stage D2.

In stage D2 of the compounds of formula XVII is obtained by reaction of compounds of formula XVI with cyanide compounds (preferably an alkali metal cyanide such as sodium cyanide or potassium, or trialkylsilanes, in which the alkyl has 1-6 carbon atoms, such as trimethylsilylacetamide) in an inert solvent. If used trialkylsilanes, the resulting O-trialkylsilyl derivative is then treated with acid.

If you use a cyanide of an alkali metal, it is used in the amount of 1-3 equivalents, more preferably 1.2 to 2 equivalents, per mole of the compounds of formula XVI. The reaction is normally and preferably carried out in the presence of a solvent. There is no special limitation on Pritula reagents and that he dissolve the reagents, at least to some extent. Examples of suitable solvents include: ethers, such as diethyl ether, tetrahydrofuran or dioxane; halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as methylene chloride or chloroform; alcohols, such as methanol or ethanol; water; or a mixture of water and one or more of the organic solvents. The reaction can take place in a wide range of temperatures, and the precise reaction temperature is not essential to the invention.

In General it is found that it is convenient to conduct the reaction at (-10) - (+80)oC, more preferably at 0-30oC. the reaction Time can also vary widely depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. However, provided that the reaction is performed in the preferred conditions outlined above, a period of 1-24 hours, more preferably 2-16 h, is usually sufficient. This reaction, if necessary, can be accelerated by the addition of sodium hydrosulphate. After completion of the reaction product can be isolated by conventional means, for example by extraction of the reaction mixture with an organic solvent not miscible with water (e.g. ethyl acetate), and privae ways, such as recrystallization or chromatography, especially column chromatography.

If used trialkylsilyl, it is usually taken in the amount of 1-2 equivalents, more preferably of 1.05 to 1.2 equivalent per mol of compound of formula XVI and the reaction is preferably carried out in the presence of catalytic amount of zinc iodide. The reaction is normally and preferably carried out in the presence of a solvent. There is no special limitation on the nature of the used solvent, provided that it has no adverse effect on the reaction or on the reagents involved and that it dissolves the reagents, at least to some extent. Examples of suitable solvents include: pratie ethers, such as diethyl ether, tetrahydrofuran or dioxane; and halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as methylene chloride and chloroform. The reaction can be places in a wide range of temperatures, and the precise reaction temperature is not essential to the invention. In General it is found that it is convenient to conduct the reaction at (-10) - (+80)oC, more preferably at 10-40oC. the reaction Time can also vary widely depending on the temperature REAKTsII conditions, as described above, the period from 30 min to 24 h, more preferably 1 to 6 hours, will usually suffice. After completion of the reaction, the target product of the formula XVII in the form of O-trimethylsilyl derivative can be obtained by concentrating the reaction mixture, extraction of the concentrate with an organic solvent not miscible with water, washing the extract of the aqueous alkaline solution such as aqueous solution of hydrocarbon sodium, and evaporation of the solvent. If necessary, the resulting product may be further purified by conventional means, such as recrystallization or chromatography, especially column chromatography.

Then remove the O-trialkylsilyl group. This reaction is carried out with the processing of a catalytic amount of acid (e.g. p-toluenesulfonic acid, methanesulfonate or hydrochloric acid) in a suitable solvent, the nature of which is not essential provided that it has no adverse effect on the reaction or on the reagents involved and that it dissolves the reagents, at least to some extent. Examples of suitable solvents include: alcohols, such as methanol or ethanol. The reaction can also take place in a wide interval of amreally at (-20) - (+60)oC, more preferably near room temperature. The reaction time also can vary widely depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. However, provided that the reaction is performed in the preferred conditions outlined above, a period of from 10 min to 5 h, more preferably from 30 minutes to 2 hours, will usually suffice.

After completion of the reaction product can be isolated from the reaction mixture by conventional means, for example by concentrating the reaction mixture, extraction of the concentrate with an organic solvent not miscible with water such as ethyl acetate, washing of the extract weakly alkaline aqueous solution such as aqueous sodium hydrogen carbonate solution, and evaporation of the solvent. If necessary, the resulting product may be further purified by conventional means, such as recrystallization or chromatography, especially column chromatography.

However, O-trialkylsilyl derivatives can also be used as a starting material in stage D3.

Stage D3.

In stage D3 compounds of formula XVIII is obtained by treatment of compounds of formula XVII or iravani hydrochloric acid) in a suitable solvent, the nature of which is not essential provided that it has no adverse effect on the reaction or on the reagents involved and that it dissolves the reagents, at least to some extent. Examples of suitable solvents include fatty acids, such as acetic or propionic acid; ethers such as dioxane; water.

The reaction can take place in a wide range of temperatures, and the precise reaction temperature is not essential to the invention. In General it is found that it is convenient to conduct the reaction at 50-120oC, more preferably at 80-100oC. the reaction Time can vary widely depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. However, provided that the reaction is performed in the preferred conditions described above, the period from 8 hours to 3 days, more preferably 16 to 40 hours, will usually suffice.

The reaction product can be isolated from the reaction mixture by conventional methods, for example by concentrating the reaction mixture, extraction of the concentrate with an aqueous solution of alkali, such as aqueous sodium hydroxide solution, acidification of an aqueous extract of acid, such as hydrochloric acid, solvent. If necessary, the resulting product may be further purified by conventional means, such as recrystallization or chromatography, especially column chromatography.

Stage D4.

In stage D4 of the compounds of formula XIX is obtained by esterification of compounds of formula XVIII. This reaction can be performed by methods well known in synthetic organic chemistry. For example, the esterification can be carried out by reaction of carboxylic acids of formula XVIII to compounds of formula XXIV

R9- W

where R9defined above;

W is halogen, such as chlorine, bromine or iodine, or a group OSO3R9(in which R9defined above).

The reaction is normally and preferably carried out in a solvent. There is no special limitation on the nature of the used solvent, provided that it has no adverse effect on the reaction or on the reagents involved at least to some extent. Examples of suitable solvents include amides, such as dimethylformamide or dimethylacetamide; halogenated hydrocarbons such as methylene chloride; ketones, such as acetone or methyl ethyl ketone; and NITRILES, such as acetonitrile, of which the preferred amides of the NAT sodium or potassium; bicarbonate of an alkali metal such as sodium bicarbonate or potassium; alkali metal hydride such as lithium hydride, sodium or potassium; or a tertiary amine, such as triethylamine, N-methylmorpholine or diisopropylethylamine. Of them preferred metal carbonates or tertiary amines. You can use the same reaction conditions, including reaction temperature and reaction time, as in stage A1 of reaction scheme A.

If the ester residue is alkyl with 1-6 carbon atoms, the carboxylic acid can be introduced into the reaction in an alcohol having 1-6 carbon atoms, such as methanol, ethanol, propanol or hexanol, in the presence of an acid catalyst such as hydrogen chloride or sulfuric acid, at a suitable temperature, for example 0-100oC, for a sufficient time, for example 1-24 hours Target compound may, for example, be selected in the same way as in stage A1 of reaction scheme A.

Stage D5.

In stage D5 compound of formula XX is obtained by reaction of compounds of formula XIX with an oxidizing agent (preferably a metal oxide such as manganese dioxide or silver oxide; a mixture of a complex of pyridine-sulfur trioxide and dimethyl sulfoxide; anhydride clfuchsia) in a suitable solvent, the nature of which is not essential provided that it has no adverse effect on the reaction or on the reagents and that it can dissolve the reagents, at least to some extent.

If using a metal oxide, the used solvent is preferably a halogenated hydrocarbon such as methylene chloride or chloroform; hydrocarbons such as hexane, benzene, toluene or xylene; a simple ether, such as diethyl ether, tetrahydrofuran or dioxane; an ester such as ethyl acetate or butyl acetate; or a ketone such as acetone or methyl ethyl ketone. The reaction temperature is preferably 0-100oC, more preferably 10-60oC, and the reaction time is preferably 30 minutes to 24 hours, more preferably 1-20 hours After completion of the reaction, the insoluble material is filtered off and the solvent evaporated to obtain the product. If necessary, the resulting product may be further purified by conventional means, such as recrystallization or chromatography, especially column chromatography.

If using a mixture of a complex of pyridine-sulfur trioxide and dimethyl sulfoxide, the acid anhydride - dimethylsulfoxide or acylchlorides-dimethylsulfone as triethylamine or N-methylmorpholine). The reaction is normally and preferably carried out in the presence of a solvent. There is no special limitation on the nature of the solvent, provided that it has no adverse effect on the reaction or on the reagents involved at least to some extent. Examples of suitable solvents include halogenated hydrocarbons such as methylene chloride or chloroform; hydrocarbons such as hexane, benzene, toluene or xylene, ethers such as diethyl ether, tetrahydrofuran or dioxane; esters, such as ethyl acetate or butyl acetate; and ketones, such as acetone or methyl ethyl ketone. The reaction can take place in a wide range of temperatures, and the precise reaction temperature is not essential to the invention. In General it is found that it is convenient to conduct the reaction at (-70) - (+60)oC, more preferably (-50) - (+30)oC. the reaction Time can also vary widely depending on the nature of the reagents and solvent. However, provided that the reaction is performed in the preferred conditions outlined above, a period of from 30 minutes to 16 hours, more preferably 1 to 8 hours, will usually be sufficient. After completion of the reaction product can be isolated by concentrating the reaction mixture, the extras is xtracta water and evaporation of the solvent. If necessary, the resulting product may be further purified by conventional means, such as recrystallization or chromatography, especially column chromatography.

If the protective radical R9for the carboxylic acid to be substituted, the protective radical of the compounds of formula XX can be removed according to the method of reaction (a) in stage A2 of the reaction schemes A and then the compounds of formula XX can be re-protected according to the method of stage D4 of the reaction schemes D or in the following way.

Carboxylic acid obtained by the reaction of (a) stage A2 of the reaction scheme A, process of halogenation reagent (for example, pentachloride phosphorus, thionyl chloride or oxalylamino) in an inert solvent (preferably a halogenated hydrocarbon, such as methylene chloride or chloroform, simple ether, such as tetrahydrofuran or dioxane, or an aromatic hydrocarbon such as benzene or toluene) at a suitable temperature, for example (-10) - (+100)oC, more preferably at 0 to 80oC, for a suitable time, for example from 30 minutes to 5 hours, to obtain the corresponding acylhomoserine. Allalone then injected into the reaction with the corresponding alcohol (e.g relating amine, such as triethylamine) in a suitable temperature such as room temperature, for a suitable period, for example from 30 minutes to 10 hours, the Target compound can then be isolated by conventional means, for example in the same way, and that way stage A1 of reaction scheme A.

Stage D 6.

In stage 6 the compounds of formula IVa is obtained by reaction of compounds of formula XX with a halogenation reagent, preferably N-chlorosuccinimide, N-bromosuccinimide or 1,3-dibromopyridine) in an inert solvent (preferably a halogenated hydrocarbon, such as methylene chloride, 1,2-dichloroethane or carbon tetrachloride) in the presence of a catalyst (preferably benzoyl peroxide or azobisisobutyronitrile).

The reaction can take place in a wide range of temperatures, and the precise reaction temperature is not essential to the invention. In General it is found that it is convenient to conduct the reaction at 0-100oC, more preferably at 20-80oC. the reaction Time can also vary widely depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. However, provided that the reaction is performed in the preferred conditions, about the Ktsia can be accelerated by irradiation, for example, a tungsten lamp.

After completion of the reaction, the reaction mixture is preferably washed with water and dried, for example over anhydrous magnesium sulfate, the solvent is removed by evaporation and obtain the target product. If necessary, the resulting product may be further purified by conventional means, such as recrystallization or chromatography, especially column chromatography.

Reaction scheme E (Fig. 6).

Reaction scheme E shows the formation of compounds of formula IVb, which correspond to the compounds of formula IV, where B1- protected tetrazolyl.

Stage E1.

In stage E1 of the compounds of formula XXI are turning ceanography compounds of formula XVII in tetrazolyl. This stage is done using the following three reactions.

Reaction (a): reaction with alkali metal azide.

Appropriate cyanocobalamine formula (XVII) enter into reaction with a suitable number, for example 1 to 5 equivalents, more preferably 1 to 3 equivalents, azide of an alkali metal such as lithium azide, sodium or potassium, in the presence of ammonium halide. The reaction is normally and preferably carried out in a solvent. There is not a comment on the reaction or on the reagents involved and that it can dissolve the reagents. Examples of suitable solvents include: ethers, such as dioxane or 1,2-dimethoxyethane; alcohols, such as methanol or ethanol; amides, such as dimethylformamide or dimethylacetamide; and sulfoxidov, such as dimethylsulfoxide. Apply ammonium halide in the amount of 0.5-2 equivalents, preferably 1-1,2 equivalent per mol of the compounds of formula XVII. Examples of suitable halides include ammonium fluoride, chloride and bromide of ammonium, preferably ammonium chloride.

The reaction can take place in a wide range of temperatures, and the precise reaction temperature is not essential to the invention. In General it is found that it is convenient to conduct the reaction at 70 - 150oC, more preferably at 90 - 120oC. the reaction Time can also vary widely depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. However, provided that the reaction is performed in the preferred conditions outlined above, a period from 10 to 7 days, more preferably 1 to 5 days is usually sufficient.

After completion of the reaction product can be isolated from the reaction mixture by conventional means. For example, to the reaction mixture, water is added and organic evaporated to obtain the product. If necessary, the resulting product may be further purified by known methods such as recrystallization or chromatography, especially column chromatography.

Reaction (b): reaction with trialkyl or triarylsulfonium.

Cyanocobalamine formula XVIII is introduced into reaction with a suitable number, for example 1 to 3 equivalents, preferably 1-2 equivalents, trialkylated or triarylamine. Examples of trialkylaluminium include compounds in which the alkyl has 1-6 carbon atoms, such as trimethylolpropane, triethylborane or tributylamine. Examples of triarylsulfonium include triphenylborane and tricholoroacetic. The reaction is normally and preferably carried out in the presence of a solvent. There is no special limitation on the nature of the used solvent, provided that it has no harmful effect on the reaction or on the reagents involved and that it dissolves the reagents, at least to some extent. Examples of suitable solvents include: hydrocarbons, such as benzene, toluene, xylene or heptane; halogenated hydrocarbons such as dichloroethane or chloroform; ethers, such as dioxane or 1,2-dimethoxyethane; sulfoxide, such as dimethylsulfoxide. The resulting adduct tin is then treated with acid (preferably hydrochloric or sulfuric acid), a base (preferably an alkali metal hydroxide, such as sodium carbonate or potassium hydrogen carbonate of an alkali metal such as sodium bicarbonate or potassium) or a fluoride of an alkali metal such as sodium fluoride or potassium. The reaction is normally and preferably carried out in a solvent. There is no special limitation on the nature of the used solvent, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include the solvents described above; alcohols, such as methanol or ethanol; water; alcohols and water.

The reaction can take place in a wide range of temperatures, and the precise reaction temperature is not essential to the invention. In General it is found that it is convenient to conduct the reaction with the compound of the tin at 60 - 150oC, more preferably at 80 - 120oC, treatment with an acid, a base or fluoride at room temperature. The reaction time can also vary widely in sale. However, provided that the reaction is performed in the preferred conditions described above, the period from 8 hours to 7 days, more preferably 1 to 5 days is usually sufficient for the reaction with the compound of the tin, while the treatment with acid, base or fluoride will typically take anywhere from 30 minutes to 24 hours, more preferably 1 to 6 hours

After completion of the reaction product can be isolated by conventional means from the reaction mixture. For example, to the reaction mixture are added water and an organic solvent not miscible with water, such as ethyl acetate, the organic layer is separated and the solvent evaporated to obtain the product. If necessary, the resulting product may be further purified by known methods such as recrystallization or chromatography, especially column chromatography.

Reaction (c): reaction with trialkyl or triarylsulfonium azide of an alkali metal.

This reaction occurs as the reaction (b), except that a suitable number, for example 1-3 equivalents, preferably 1-2 equivalents, trialkyl or trihalomethanes (such as trimethylolpropane, triethylenemelamine, tributyltinchloride or triphenylamine metal (preferably sodium azide or potassium), used instead of trialkyl or triarylamine.

Stage E2.

In stage E2 of the compounds of formula XXII receive, protecting tetrazolyl group of compounds of formula XXI. Stage carried out by reaction of compounds of formula XXI with compounds of the formula XXV

R10- W

where R10and W are defined above.

The reaction is normally and preferably carried out in the presence of a solvent. There is no special limitation on the nature of the used solvent, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: amides, such as dimethylformamide or dimethylacetamide; halogenated hydrocarbons such as methylene chloride or 1,2-dichloroethane; ketones, such as acetone or methyl ethyl ketone; and NITRILES, such as acetonitrile, of which the preferred amides and ketones. The reaction is carried out in the presence of a base such as a carbonate of an alkali metal such as sodium carbonate or potassium, bicarbonate of an alkali metal such as lithium bicarbonate, sodium or potassium; pyridine and its derivatives, such as pyridine or 1,6-lutidine; or threeseat carbonate of an alkali metal, pyridine or its derivative (which, if taken in large excess, can also serve as a solvent), or tertiary amine.

At this stage you can use the same reaction conditions, including reaction temperature and reaction time, and method of selection of the reaction product, as those used in stage A1 of reaction scheme A.

Stage E3.

In stage E3 compounds of formula XXIII is obtained by oxidation of compounds of formula XXII. This stage consists in performing the same reaction as in stage D5 reaction scheme D, and can be carried out using the same reagents and conditions. The reaction product can then be identified, as described in stage D5.

Stage E4.

In stage E4 of the compounds of formula IVb are halogenoalkanes compounds XXIII. This stage consists in performing the same reaction as in stage D6 reaction scheme D, and can be carried out using the same reagents and reaction conditions. The reaction product can then be determined as described in stage D6.

Biological activity.

The biological activity of each compound evaluated by determining the dose required for the inhibition of the Pressor response to intravenous angit irout vnutribruchinnah injection of 100 mg/kg of thiobutabarbital /Inaction (trade name)/ and enter two tips: one in the femoral artery for blood pressure measurement, and another in the femoral vein for injection of a medicinal product. Fifty ng/kg of angiotensin P injected at intervals of about 10 minutes and see a rise in blood pressure (usually about 50 mm RT.cent.). After reaching constant Pressor responses to angiotensin P intravenously injecting the test compound. After 2 min again enter angiotensin II and evaluate the inhibiting effect of the test compounds. To calculate the values of EID50use the percent inhibition of Pressor response to angiotensin P with a gradual increase of the test compounds. Angiotensin P used in this test, dissolved in 0.5% serum albumin bull, and the test compounds dissolved in 100% dimethyl sulfoxide. In table. 4 shows the so determined values of EID50.

Compounds of the invention recognize in the table.4 the number of one of the following examples, describing their receipt.

Compounds according to the invention can be introduced as such or in the form of conventional pharmaceutical preparations, the shape of which depends on the chosen route of administration. For example, for oral administration they can be entered into the composition of tablets, capsules, granules, powders, syrups, etc., and the practical preparations can be produced by conventional methods using known auxiliary substances, such as fillers, binders, tools, contributing to the collapse, lubricants, stabilizers, and so on, Although the dosage may vary depending on the symptoms and age of the patient, nature and severity of the disease or disorders and ways and a way of introduction, in the case of oral administration to an adult patient connection according to the invention can typically enter at the full daily dose of 1-1000 mg, preferably 5 are 300 mg or a single dose or divided dose, for example 1-3 times a day; in the case of internal dose of 0.1-100 mg, preferably 0.5 to 30 mg, can be entered from one to three times a day.

The invention is further illustrated by the following examples which show the various compounds of the invention. Getting some of the original materials used in these examples are shown in the following preparations. In the formulas accompanying these examples and preparations, use some abbreviations that are defined in connection with table. 1-3.

Example 1. 4-(1-Hydroxy-1-methylethyl)-1-[(21- oxalobacter-4-yl)methyl] -2-propylimidazol-5-carboxylic acid (compound No. 1-2).

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1(a). Ethyl-4-(1-hydroxy-1-methylethyl)-1-[(21-methoxycarbonyl-4-yl)methyl]-2-propylimidazol-5-carboxylatomethyl)-2-propylimidazol-5-carboxylate in 3 ml of dimethylacetamide, and the resulting mixture is stirred for 5 minutes Then to the mixture add a solution of 433 mg of methyl-(41-bromomethylbiphenyl-2-yl)glyoxylate (obtained as described in preparation 8) in 5 ml of dimethylacetamide and stirred at room temperature for 4 h Then the reaction mixture are added ethyl acetate and water, the organic layer separated and dried with anhydrous sodium sulfate. The solvent is distilled off under reduced pressure. The remainder chromatographic on a column of silica gel using a mixture of 1:1 by volume of ethyl acetate and hexane as eluent, and receive 447 mg of target compound in the form of syrup.

Spectrum of nuclear magnetic resonance (CDCl3, 270 MHz, million-1): and 0.98 (3H, triplet, J = 7.5 Hz); of 1.26 (3H, triplet, J = 7 Hz); of 1.64 (6H, singlet); about 1.75 (2H, sextet, J = 7.5 Hz); to 2.65 (2H, triplet, J = 7.5 Hz); and 3.31 (3H, singlet); 4,27 (2H, Quartet, J=7 Hz); the 5.51 (2H, singlet); of 5.68 (1H, singlet); 6,99 (2H, doublet, J=8,5 Hz) 7,27 (2H, doublet, J=8.5 Hz); 7,42 (1H, doublet, J= 7 Hz); 7,51 (1H, triplet, J=7 Hz); the 7.65 (1H, triplet, J=7 Hz); 7,81 (1H, doublet, J=7 Hz).

1(b). 4-(1-Hydroxy-1-methylethyl-1-[(21-oxalobacter-4-yl)methyl] -2-propylimidazol-5-carboxylic acid.

A solution of 247 mg of lithium hydroxide monohydrate in 3 ml of water are added to a solution of 447 mg of ethyl-4-(1-hydroxy-1-methylethyl)-1- -[(21-methoxynicotinic-4-yl)methyl] -2-propylimidazol-5-carboxilate 5 o'clock Then the dioxane is removed by evaporation under reduced pressure and add to 5.9 ml of 1N. aqueous hydrochloric acid. The precipitated crystals are collected by filtration, air-dried and obtain 310 mg of the target compound, razmyagchayuschiesya at 163oC and melting at 183-185oC.

An NMR spectrum (hexadeuterated dimethyl sulfoxide, 270 MHz), million-1: to 0.88 (3H, triplet, J=7.5 Hz); and 1.56 (6H, singlet); to 1.59 (2H, sextet, J=7.5 Hz); 2,61 (2H, triplet, J=7.5 Hz); 5,71 (2H, singlet); 7,07 (2H, doublet, J=8 Hz); of 7.25 (2H, doublet, J=8 Hz); 7,46 (1H, doublet, J=7 Hz); rate of 7.54 (1H, triplet, J=7 Hz); 7,66 - 7,72 (2H, multiplet).

Primer.2-Butyl-4-(1-hydroxy-1-methylethyl)-1-[(21-oxalobacter-4-yl)methyl]imidazole-5-carboxylic acid.

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2(a). Ethyl-2-butyl-4-(1-hydroxy-1-methylethyl)-1-[(21-methoxynicotinic-4-yl)methyl]imidazole-5-carboxylate.

The experience is conducted according to the procedure described in example 1(a), but applied 509 mg ethyl-2-butyl-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate, 247 mg of tert-butoxide potassium and 733 mg of methyl-(41-bromomethylbiphenyl-2-yl)glyoxylate (obtained as described in preparation 8). Receive 878 mg of target compound in the form of syrup.

An NMR spectrum (CDCl3, 270 MHz), million-1: of 0.91 (3H, triplet, J=7.5 Hz); of 1.27 (3H, triplet, J=7 Hz); 1.39 in ( 5,51 (2H, singlet); 5,69 (1H, singlet); 6,99 (2H, doublet, J=8 Hz); 7,27 (2H, doublet, J=8 Hz); 7,42 (1H, doublet, J= 7 Hz); 7,51 (1H, triplet, J=7 Hz); the 7.65 (1H, triplet, J=7 Hz); 7,81 (1H, doublet, J=7 Hz).

2(b). 2-Butyl-4-(1-hydroxy-1-methylethyl)-1-[(21-oxalobacter-4-yl)methyl]imidazole-5-carboxylic acid.

The experience is conducted according to the procedure described in example 1 (b), but use 878 mg of ethyl-2-butyl-4-(1-hydroxy-1-methylethyl)-1-[(21-methoxynicotinic-4-yl)methyl] imidazole-5-carboxylate (obtained as described above in stage (a) and 364 mg of the monohydrate of lithium hydroxide and receive 571 mg of target compound in the form of a powder, razmyagchayuschiesya at 140oC and melting at 165-170oC.

An NMR spectrum (encodation dimethyl sulfoxide, 270 MHz) / million-1: of 0.82 (3H, triplet, J=7.5 Hz); 1.28 (in 2H, sextet, J=7.5 Hz); 1,47 is 1.60 (2H, multiplet); of 1.55 (6H, singlet); 2.63 in (2H, triplet, J=7.5 Hz); of 6.71 (2H, singlet); was 7.08 (2H, doublet, J=8 Hz); 7,26 (2H, doublet, J=8 Hz); 7,46 (1H, doublet, J=7 Hz); at 7.55 (1H, triplet, J=7 Hz); to 7.67-7,72 (2H, multiplet).

Example 3. Hydrochloride ethyl-4-(1-hydroxy-1-methylethyl)-1-[(21-oxalobacter-4-yl) methyl]-2-propylimidazol-5-carboxylate (hydrochloride of the compound N 1-26).

< / BR>
3(a). Ethyl-1-[(21-tert-butoxysilane-4-yl)methyl]-4- (1-hydroxy-1-methylethyl)-2-propylimidazol-5-Ki-1-methylethyl)-2-propylimidazol-5 - carboxylate, 1.12 g of tert-butoxide potassium and 3.75 g of tert-butyl(41-bromomethylbiphenyl-2-yl)glyoxylate (obtained as described in preparation 9) and get to 3.73 g of target compound in the form of resin.

An NMR spectrum (CDCl3, 270 MHz), million-1: to 0.98 (3H, triplet, J = 7.5 Hz); of 1.16 (9H, singlet); of 1.23 (2H, triplet, J = 7 Hz), of 1.64 (6H, singlet); to 1.76 (2H, sextet, J = 7.5 Hz); 2.63 in (2H, triplet, J = 7.5 Hz); 4.25 in (2H, Quartet, J = 7 Hz); of 5.50 (2H, singlet); 5,73 (1H, singlet); 7,00 (2H, doublet, J = 8 Hz); 7,30 (2H, doublet, J = 8 Hz); 7,30 (2H, doublet, J = 8 Hz); 7,40 (1H, doublet, J = 7 Hz); of 7.48 (1H, triplet, J = 7 Hz); 7,60 (1H, triplet, J = 7 Hz); 7,71 (1H, doublet, J = 7 Hz).

3(b). Hydrochloride ethyl-4-(1-hydroxy-1-methylethyl)-1- [(21-oxalobacter-4-yl)methyl]-2-propylimidazol-5-carboxylate.

570 mg of ethyl-1-[(21-tert-butoxycarbonyl-4-yl) methyl]-4-(1-hydroxy-1-methylethyl)-2-propylimidazol-5-carboxylate (obtained as described in stage (a) above) was dissolved in 6 ml of 4n. solution of hydrogen chloride in dioxane and the resulting solution stirred at room temperature for 4 h Then the reaction mixture is concentrated by evaporation under reduced pressure and the resulting residue triturated in diethyl ether, receiving 448 mg of the target compound in the form of a crystalline powder, melting at 156 - 158oC.

The J = 7 Hz); 1,50 - of 1.65 (2H, multiplet); to 1.61 (6H, singlet); 2,96 (2H, triplet, J = 7.5 Hz); 4,24 (2H, Quartet, J = 7 Hz); the 5.65 (2H, singlet); 7,17 (1H, doublet, J = 8 Hz); 7.29 trend (2H, doublet, J = 8 Hz); 7,46 (1H, doublet, J = 7 Hz); EUR 7.57 (1H, triplet, J = 7 Hz); 7,68 - 7,74 (2H, multiplet).

Example 4. Hydrochloride pivaloyloxymethyl-4-(1-hydroxy-1-methylethyl)-1-[(21-oxalobacter-4-yl)methyl] -2-propylimidazol-5 - carboxylate (hydrochloride of the compound N 1-27).

< / BR>
4(a). Pivaloyloxymethyl-1-[(21-tert-butoxycarbonyl-4-yl)methyl] -4-(1-hydroxy-1-methylethyl)-2-propylimidazol-5 - carboxylate.

The experience is conducted according to the procedure described in example 1 (a), but use of 1.64 g pivaloyloxymethyl-4-(1-hydroxy-1-methylethyl)-2 - propylimidazol-5-carboxylate, 617 mg of tert-butoxide potassium and 2.25 g tributyl- (41-bromomethylbiphenyl-2-yl)glyoxylate (obtained as described in preparation 9) and receive 936 mg of the target compound in the form of resin.

An NMR spectrum (CDCl3, 270 MHz), million-1: of 1.00 (3H, triplet, J = 7.5 Hz); to 1.15 (9H, singlet); 1,17 (3H, singlet); of 1.62 (6H, singlet) to 1.82 (2H, sextet, J = 7.5 Hz), of 2.64 (2H, triplet, J = 7.5 Hz); lower than the 5.37 (1H, singlet); 5,48 (2H, singlet); of 5.84 (2H, singlet); 7,03 (2H, doublet, J = 8 Hz); 7,30 (2H, doublet, J = 8 Hz); 7,39 (1H, doublet, J = 7 Hz); of 7.48 (1H, triplet, J = 7 Hz); 7,60 (1H, triplet, J = 7 Hz); 7,71 (1H, doublet, J = 7 Hz).

4(b). PI is roximate.

936 mg pivaloyloxymethyl-1-[(21-tert-butoxysilane - 4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propylimidazol-5 - carboxylate (obtained as described in stage (a) above) is treated with 10 ml of 4 n solution of hydrogen chloride in dioxane as described in example 3 (b), and receive 655 mg of target compound in the form of amorphous powder, razmyagchayuschiesya at 85oC.

An NMR spectrum (hexadeuterated dimethyl sulfoxide, 270 MHz), million-1: to 0.88 (3H, triplet, J = 7.5 Hz); 1,10 (9H, singlet); 1,48 - of 1.62 (2H, multiplet); was 1.58 (6H, singlet); 2,90 (2H, triplet, J = 7.5 Hz); 5,64 (2H, singlet); 5,88 (2H, singlet); 7,17 (2H, doublet, J = 8 Hz); 7,28 (2H, doublet, J = 8 Hz); 7,46 (1H, doublet, J = 7 Hz); EUR 7.57 (1H, triplet, J = 7 Hz); 7.68 per - 7,74 (2H, multiplet).

Example 5. Hydrochloride (5-methyl-2-oxo-1,3-dioxolan-4-yl)-methyl-4- (1-hydroxy-1-methylethyl)-1-[(21-oxalobacter-4-yl)methyl] -2-propylimidazol-5-carboxylate (hydrochloride of the compound N 1-28).

< / BR>
5(a). (5-Methyl-2-oxo-1,3-dioxolan-4-yl)methyl-1-[(21- tert-butoxycarbonyl-4-yl)methyl] -4-(1-hydroxy-1-methylethyl)- 2-propylimidazol-5-carboxylate.

A solution of 315 mg (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl-4- (1-hydroxy-1-methylethyl)-2-propylimidazol-5-carboxylate and 364 mg of tert-butyl(41-bromomethylbiphenyl-2-yl)glyoxylate (p is tolazamide, containing 268 mg of powdered potassium carbonate, at 60oC. After completion of addition, the resultant mixture was stirred at 60oC for 1.5 hours Then the reaction mixture are added ethyl acetate and water, the organic layer separated, washed with water and dried with anhydrous magnesium sulfate. The solvent is removed by evaporation under reduced pressure. The remainder chromatographic on column through silica gel, using as eluent a mixture of 1 : 1 by volume of ethyl acetate and hexane. The resulting crystalline product was washed with diisopropyl ether and obtain 195 mg of the target compound, melting at 154 - 156oC.

An NMR spectrum (CDCl3, 270 MHz), million-1: of 1.00 (3H, triplet, J = 7.5 Hz); of 1.18 (9H, singlet); 1,652 (6H, singlet); of 1.78 (2H, sextet, J = 7.5 Hz); of 2.08 (3H, singlet); to 2.66 (2H, triplet, J = 7.5 Hz); 4.92 in (2H, singlet); 5,43 (2H, singlet); of 5.55 (1H, singlet); of 6.96 (2H, doublet, J=8 Hz); 7,30 (2H, doublet, J= 8 Hz); 7,44 (1H, doublet, J=7 Hz); 7,49 (1H, triplet, J=7 Hz); 7,63 (1H, triplet, J=7 Hz); 7,71 (1H, doublet, J=7 Hz).

5(b). Hydrochloride (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl-4-(1-hydroxy - 1-methylethyl)-1-[(21-oxalobacter-4-yl)methyl] -2-propylimidazol-5 - carboxylate.

360 mg (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl-1-[(21- tertbutoxycarbonyl-4-yl)methyl] -4-(1-hydroxy-1-meta hydrogen chloride in dioxane, as described in example 3(b) and obtain 308 mg of target compound in the form of amorphous powder, razmyagchayuschiesya at 80oC and above.

An NMR spectrum (hexadeuterated dimethyl sulfoxide, 270 MHz), million-1: to 0.89 (3H, triplet, J=7.5 Hz); 1,50-of 1.62 (2H, multiplet); to 1.59 (9H, singlet); 2,12 (6H, singlet); 2,95 (2H, triplet, J=7.5 Hz); further 5.15 (2H, singlet); 5,63 (2H, singlet); to 7.15 (2H, doublet, J=8 Hz); 7,27 (2H, doublet, J=8 Hz); of 7.48 (1H, doublet, J=7 Hz); EUR 7.57 (1H, triplet, J=7 Hz); 7.68 per-7,76 (2H, multiplet).

Example 6. 4-Hydroxymethyl-1-[(21-oxalobacter-4-yl)methyl]-2 - propylimidazol-5-carboxylic acid (compound 1-4 N).

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6(a). Ethyl-4-acetoxymethyl-1-[(21-methoxynicotinic-4-yl)methyl] -2 - propylimidazol-5-carboxylate.

210 mg of potassium carbonate and 583 mg of methyl(41-bromomethylbiphenyl-4-yl)glyoxylate (obtained as described in preparation 8) add, in the order to 5 ml of a solution of 387 mg of ethyl-4-acetoxymethyl-2-propylimidazol-5-carboxylate in dimethylacetamide, and the resulting mixture was stirred at room temperature for 16 hours Then the reaction mixture are added ethyl acetate and water, the organic layer separated, washed with water and saturated water solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent is removed COI is I as eluent a mixture of 2:1 by volume of ethyl acetate and hexane, and receive 696 mg of target compound in the form of resin from the faction, suiryudan first.

An NMR spectrum (CDCl3, 270 MHz), million-1: to 0.98 (3H, triplet, J=7.5 Hz); of 1.31 (3H, triplet, J=7 Hz); 1.77 in (2H, sextet, J=7.5 Hz); 2,12 (3H, singlet); to 2.65 (2H, triplet, J=7.5 Hz); 3,30 (3H, singlet); 4.26 deaths (2H, Quartet, J=7 Hz); 5,33 (2H, singlet); 5,61 (2H, singlet);? 7.04 baby mortality (2H, doublet, J=8 Hz); 7,27 (2H, doublet, J=8 Hz); 7,42 (1H, doublet, J=7 Hz); 7,51 (1H, triplet, J=7 Hz); to 7.64 (1H, triplet, J=7 Hz); of 7.82 (1H, doublet, J=7 Hz).

The following suiryudan faction obtain 156 mg of ethyl-5-acetoxymethyl-1- [(21-methoxynicotinic-4-yl)methyl] -2-propylimidazol-4-carboxylate, which is the isomer of the target compound.

An NMR spectrum (CDCl3, 270 MHz), million-1as 0.96 (3H, triplet, J=7.5 Hz); of 1.41 (3H, triplet, J=7 Hz); of 1.75 (2H, sextet, J=7.5 Hz); of 1.92 (3H, singlet); 2.63 in (2H, triplet, J=7.5 Hz); to 3.41 (3H, singlet); was 4.42 (2H, Quartet, J=7 Hz); 5.25-inch (2H, singlet); 5,43 (2H, singlet); 6,99 (2H, doublet, J=8 Hz); 7,29 (2H, doublet, J=8 Hz); 7,40 (1H, doublet, J=7 Hz); 7,52 (1H, triplet, J=7 Hz); to 7.64 (1H, triplet, J=7 Hz); 7,80 (1H, doublet, J=7 Hz).

6(b). 4-Hydroxymethyl-1-[(21-oxalobacter-4-yl)methyl]-2 - propylimidazol-5-carboxylic acid.

of 8.2 ml of 1N. an aqueous solution of sodium hydroxide are added to a solution 696 mg of ethyl-4-acetoxymethyl-1-[(21-methoxynicotinic-4 - yl)methyl]-2-stirred at room temperature for 16 hours Then the dioxane is distilled off under reduced pressure and the remaining aqueous solution was added 8.2 ml of 1N. an aqueous solution of hydrochloric acid. The precipitated crystals are collected by filtration and receive 428 mg of the target compound, melting at 223-225oC (decomposition).

An NMR spectrum (hexadeuterated dimethyl sulfoxide, 270 MHz), million-1: to 0.88 (3H, triplet, J=7.5 Hz); of 1.61 (2H, sextet, J=7.5 Hz); of 4.66 (2H, singlet); of 5.68 (2H, singlet); to 7.09 (2H, doublet, J=8 Hz); 7,27 (2H, doublet, J=8 Hz); was 7.45 (1H, doublet, J=7 Hz); rate of 7.54 (1H, triplet, J=7 Hz); the 7.65 7,73 (2H, multiplet).

Example 7. [41-/4-(1-Hydroxy-1-methylethyl)-2-propyl-5-(tetrazol-5 - yl)imidazol-1-ylmethyl/biphenyl-2-yl]Glyoxylic acid (compound 1-40 N).

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7(a). Methyl 41-[4-(1-hydroxy-1-methylethyl)-2-propyl-5-(2 - trailersa-5-yl)imidazol-1-ylmethyl]biphenyl-2-yl glyoxylate, being.

The experience carried out by the method of example 1(a), but applied 479 mg of 4-(1-hydroxy-1-methylethyl)-2-propyl-5-(2-trailersa-5-yl)imidazole, 123 mg of tert-butoxide potassium and 336 mg of methyl-(41-bromomethylbiphenyl-2-yl)glyoxylate (obtained as described in preparation 8) and receive 527 mg of target compound in the form of resin.

An NMR spectrum (CDCl3, 270 MHz), million-1: to 0.97 (3H, triplet, J=7.5 Hz); of 1.57 (9H, single (2H, doublet, J=8 Hz); 7,26-7,37 (10H, multiplet); 7,51 (1H, triplet, J= 7 Hz); to 7.64 (1H, triplet, J=7 Hz); 7,81 (1H, doublet, J=7 Hz).

7(b). Methyl[41-/4-(1-hydroxy-1-methylethyl)-2-propyl-5-(tetrazol-5 - yl)imidazol-1-ylmethyl/biphenyl-2-yl]glyoxylate, being.

1.5 ml of water are added to a solution of 527 mg of methyl-[41-/4-(1-hydroxy - 1-methylethyl)-2-propyl-5-(2-trailersa-5-yl)imidazol-1-ylmethyl/biphenyl-2 - yl] glyoxylate (obtained as described in stage (a) above) in 3.5 ml of acetic acid and the resulting mixture was stirred at 70oC for 1.5 hours Then add 2 ml of water, the resulting mixture is cooled with ice and the precipitate removed by filtration. The filtrate is concentrated by evaporation azeotropic distillation with toluene. Obtain 206 mg of target compound in the form of crystals with so pl. 131-132oC (after crystallization from a mixture of diethyl ether and ethyl acetate).

An NMR spectrum (hexadeuterated dimethyl sulfoxide, 270 MHz), million-1: of 0.90 (3H, triplet, J=7.5 Hz); of 1.47 (6H, singlet); 1:59 (2H, sextet, J=7.5 Hz); 2,80 (2H, triplet, J=7.5 Hz); and 3.16 (3H, singlet); 5,67 (2H, singlet); was 7.08 (2H, doublet, J=8 Hz); 7,21 (2H, doublet, J=8 Hz); 7,47 (1H, doublet, J=7 Hz); 7,58 (1H, triplet, J=7 Hz); 7,70-to 7.77 (2H, multiplet).

7(c). [41-/4-(1-Hydroxy-1-methylethyl)-2-propyl-5-(tetrazol-5 - yl)imidazol-1-ylmethyl/biphenyl-2-yl]Glyoxylic later)-2-propyl-5-(tetrazol-5 - yl)imidazol-1-ylmethyl/biphenyl-2-yl] glyoxylate (obtained as described in stage (b) above) and 77 mg of the monohydrate of lithium hydroxide and obtain 95 mg of the target compound with so pl. 169-170oC.

An NMR spectrum (hexadeuterated dimethyl sulfoxide, 270 MHz), million-1: of 0.87 (3H, triplet, J=7.5 Hz); USD 1.43 (6H, singlet); 1,53 (2H, sextet, J=7.5 Hz); of 2.81 (2H, triplet, J=7.5 Hz); of 5.55 (2H, singlet); for 7.12 (2H, doublet, J=8 Hz); 7,22 (2H, doublet, J=8 Hz); 7,42 (1H, doublet, J=7 Hz); 7,56 (1H, triplet, J=7 Hz); 7,66 to 7.75 (2H, multiplet).

Example 8. 4-Isopropenyl-1-[21-oxalobacter-4-yl)methyl] -2 - propylimidazol-5-carboxylic acid (compound N 1-10).

< / BR>
8(a). Ethyl-4-Isopropenyl-1-[(21-methoxynicotinic-4-yl)methyl] -2 - propylimidazol-5-carboxylate.

The experience is conducted according to the procedure described in example 1 (a), but applied 445 mg of ethyl-4-Isopropenyl-2-propylimidazol-5-carboxylate, 247 mg of tert-butoxide potassium and 733 mg of methyl(41-bromomethylbiphenyl-2-yl)glyoxylate (obtained as described in preparation 8) and obtain 570 mg of target compound in the form of syrup.

An NMR spectrum (CDCl3, 270 MHz), million-1: of 1.00 (3H, triplet, J=7.5 Hz); of 1.29 (3H, triplet, J=7 Hz); of 1.78 (2H, sextet, J=7.5 Hz); of 2.16 (3H, singlet); to 2.66 (2H, triplet, J=7.5 Hz); of 3.32 (3H, singlet); to 4.23 (2H, Quartet, J= 7 Hz); from 5.29 (2H, singlet); to 5.57 (2H, singlet); 7,07 (2H, doublet, J=8 Hz); 7,29 (2H, doublet, J=8 Hz); 7,44 (1H, doublet, J=7 Hz); 7,52 (1H, triplet, J=7 Hz); 7,66 (1H, triplet, J=7 Hz); to 7.84 (1H, doublet, J=7 Hz).

8(b). 4-Isopropenyl-1-[(2Neil-1-[(21-oxalobacter-4 - yl)methyl]-2-propylimidazol-5-carboxylate (obtained as described above in stage (a)) in 3 ml of dioxane is mixed with a solution of the monohydrate of lithium hydroxide in 3 ml of water and the resulting mixture was stirred at 80oC 5 o'clock Then the dioxane is distilled off under reduced pressure and the remaining aqueous solution was added to 2.94 ml of 1N. aqueous hydrochloric acid. The precipitated crystals are collected by filtration and obtain 214 mg of the target compound, melting at 150-151oC.

An NMR spectrum (hexadeuterated dimethyl sulfoxide, 270 MHz), million-1: of 0.90 (3H, triplet, J=7.5 Hz); and 1.63 (2H, sextet, J=7.5 Hz); 2,07 (6H, singlet); 2,60 (2H, triplet, J=7.5 Hz); a total of 5.21 (1H, singlet); and 5.30 (1H, singlet); to 5.58 (2H, singlet); 7,10 (2H, doublet, J=8 Hz); 7,26 (2H, doublet, J=8 Hz); 7,46 (1H, doublet, J=7 Hz); rate of 7.54 (1H, triplet, J=7 Hz); 7,66-7,72 (2H, multiplet).

Example 9. 4-Isopropyl-1-(21-oxalobacter-4-yl)methyl-2 - propylimidazol-5-carboxylic acid.

< / BR>
9(a). Ethyl-4-isopropyl-1-[(21-methoxycarbonyl-4-yl)methyl] -2 - propylimidazol-5-carboxylate.

The experience is conducted according to the procedure described in example 1(a), but applied 448 mg of ethyl-4-isopropyl-2-propylimidazol-5-carboxylate, 247 mg of tert-butoxide potassium and 733 mg of methyl(41-bromomethylbiphenyl-2-yl)glio the Tr NMR (CDCl3, 270 MHz), million-1as 0.96 (3H, triplet, J=7.5 Hz); of 1.29 (6H, doublet, J=7 Hz); of 1.31 (3H, triplet, J= 7 Hz); 1,67 (2H, sextet, J= 7.5 Hz); to 2.65 (2H, triplet, J=6.5 Hz); 3,29 (3H, singlet); 3,61 (1H, septet, J= 7.5 Hz); 4,24 (2H, Quartet, J=7 Hz); to 5.56 (2H, singlet); 7,01 (2H, doublet, J=8 Hz); of 7.25 (2H, doublet, J=8 Hz); 7,42 (1H, doublet, J=7 Hz); 7,50 (1H, triplet, J= 7 Hz); 7,63 (1H, triplet, J=7 Hz); 7,81 (1H, doublet, J=7 Hz).

9(b). 4-Isopropyl-1-[(21-oxalobacter-4-yl)methyl] -2 - propylimidazol-5-carboxylic acid.

The experience is conducted according to the procedure described in example 8(b), but use 760 mg of ethyl-4-isopropyl-1-[(21-methoxynicotinic-4 - yl)methyl]-2-propylimidazol-5-carboxylate (obtained as described above in stage (a)) and 335 mg of the monohydrate of lithium hydroxide and receive 527 mg of the target compound in the form of a powder, melting at 177-178oC.

An NMR spectrum (hexadeuterated dimethyl sulfoxide, 270 MHz), million-1: to 0.88 (3H, triplet, J=7.5 Hz); to 1.21 (6H, doublet, J= 7.5 Hz) and 1.60 (2H, sextet, J= 7.5 Hz); 2,60 (2H, triplet, J=7.5 Hz); of 3.64 (1H, septet, J=7.5 Hz); 5,62 (2H, singlet); 7,06 (2H, doublet, J= 8 Hz); 7,26 (2H, doublet, J=8 Hz); was 7.45 (1H, doublet, J=7 Hz); 7,53 (1H, triplet, J=7 Hz); the 7.65 7,72 (2H, multiplet).

Example 10. 4-(1-Hydroxy-2-methylpropyl)-1-[(21-oxalobacter-4 - yl)methyl]-2-propylimidazol-5-carboxamide (compound 1-22 N).

< / BR>

107 mg of potassium carbonate and 309 mg of methyl(41-bromomethylbiphenyl-2-yl)glyoxylate (obtained as described in preparation 8) are added to a solution of 160 mg of 4-(1-hydroxy-2-methylpropyl)-2-propylimidazol-5-carbonitrile in 3.5 ml of dimethylacetamide, and the resulting mixture was stirred at room temperature for 3 h Then the reaction mixture are added ethyl acetate and water, the ethyl acetate layer is separated and dried with anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The resulting residue chromatographic on a column of silica gel, using as eluent a mixture of 2:1 by volume of ethyl acetate and hexane, and obtain 180 mg of the target compound in the form of crystals with so pl. 113oC.

An NMR spectrum (CDCl3, 270 MHz), million-1: to 0.94 (3H, doublet, J=6.5 Hz); of 0.97 (3H, triplet, J=7.5 Hz); and 1.00 (3H, doublet, J= 6.5 Hz); of 1.75 (2H, sextet, J= 7.5 Hz); 2,07-of 2.20 (1H, multiplet); of 2.64 (2H, triplet, J=7.5 Hz); to 3.36 (3H, singlet); 4,55 (1H, doublet, J=6 Hz); 5,24 (2H, singlet); 7,13 (2H, doublet, J= 8 Hz); 7,33 (2H, doublet, J=8 Hz); 7,42 (1H, doublet, J=7 Hz); 7,52 (1H, triplet, J=7 Hz); the 7.65 (1H, doublet, J=7 Hz); of 7.82 (1H, doublet, J=7 Hz).

10(b). 4-(1-Hydroxy-2-methylpropyl)-1-[(21-oxalobacter-4-yl)- methyl] -2-propylimidazol-5-carboxamide.

4 ml of 1N. an aqueous solution of sodium hydroxide are added to a solution of 170 mg of 4 - (is described above in stage (a)) in 3 ml of hot ethanol and the resulting mixture was stirred at the boil under reflux for 2.5 hours The ethanol is then distilled off under reduced pressure and the remaining aqueous solution was added ethyl acetate. To the mixture add 4 ml of 1N. aqueous hydrochloric acid and the ethyl acetate layer is separated and dried with anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and obtain 140 mg of the target compound as crystals, melting at 165-170oC (decomposition).

An NMR spectrum (hexadeuterated dimethyl sulfoxide, 270 MHz), million-1: is 0.69 (3H, doublet, J=6.5 Hz); of 0.85 (3H, triplet, J= 7.5 Hz); a 1.01 (3H, doublet, J= 6.5 Hz); was 1.58 (2H, sextet, J=7.5 Hz); 2,01-of 2.16 (2H, multiplet); to 2.54 (2H, triplet, J=7.5 Hz); 4,32 (1H, doublet, J=8.5 Hz); 5,54 (1H, doublet, J= 16.5 Hz); 5,79 (1H, doublet, J= 16.5 Hz); 6,21 (1H, broad singlet); 7,06 (2H, doublet, J=8 Hz); of 7.25 (2H, doublet, J=8 Hz); 7,41 (1H, broad singlet); was 7.45 (1H, doublet, J=7 Hz); 7,53 (1H, triplet, J=7 Hz): to 7.64-7,71 (2H, multiplet); 8,49 (1H, broad singlet).

Example 11. 4-(1-Hydroxy-2,2-dimethylpropyl)-1-[(21- oxalobacter-4-yl)methyl]-2-propylimidazol-5-carboxamide (compound 1-24 N).

< / BR>
11(a). 4-(1-Hydroxy-2,2-dimethylpropyl)-1-[(21- methoxynicotinic-4-yl)methyl]-2-propylimidazol-5-carbonitrile.

The experience is conducted according to the procedure described in example 10(a), but they are using 170 mg of 4-(1-hydroxy-2,2-dimethylpropyl)-2-propylimidazol-5g of potassium carbonate and obtain 257 mg of the target compound in the form of crystals, melting at 128-130oC.

An NMR spectrum (CDCl3, 270 MHz), million-1: to 0.97 (3H, triplet, J=7.5 Hz); 0,99 (9H, singlet); about 1.75 (2H, sextet, J=7.5 Hz); of 2.64 (2H, triplet, J=7.5 Hz); was 2.76 (1H, doublet, J=7 Hz); at 3.35 (3H, singlet); of 4.45 (1H, doublet, J=7 Hz); 5,23 (2H, singlet); 7,13 (2H, doublet, J=8 Hz); 7,33 (2H, doublet, J=8 Hz); 7,42 (1H, doublet, J=7 Hz); 7,53 (1H, triplet, J=7 Hz); 7,66 (1H, triplet, J=7 Hz); of 7.82 (1H, doublet, J= 7 Hz).

11(b). 4-(1-Hydroxy-2,2-dimethylpropyl)-1-[(21-oxalobacter-4 - yl)methyl]-2-propylimidazol-5-carboxamide.

246 mg of 4-(1-hydroxy-2,2-dimethylpropyl)-1-[(21- methoxynicotinic-4-yl)methyl]-2-propylimidazol-5-carbonitrile (obtained as described above in stage (a)) is subjected to hydrolysis using 6 ml of 1N. an aqueous solution of sodium hydroxide, according to the method described in example 10(b), and obtain 182 mg of the target compound as crystals, melting at 198-200oC.

An NMR spectrum (hexadeuterated dimethyl sulfoxide, 270 MHz), million-1: of 0.85 (3H, triplet, J=7.5 Hz); to 0.89 (9H, singlet); was 1.58 (2H, sextet, J=7.5 Hz); of 2.56 (2H, triplet, J=7.5 Hz); 4,51 (1H, singlet); of 5.48 (1H, doublet, J= 16.5 Hz); of 5.81 (1H, doublet, J=16.5 Hz); from 6.22 (1H, broad singlet); 7,05 (2H, doublet, J=8 Hz); 7,26 (2H, doublet, J=8 Hz); 7,39 (1H, broad singlet); 7,44 (1H, doublet, J=7 Hz); 7,52 (1H, doublet, J=7 Hz); of 7.64-7,71 (2H, multiplet); 8,68 (1H, broad singlet).

< / BR>
12(a). 2-Butyl-4-(1-hydroxy-2-methylpropyl)-1-[(21-ethoxalyl - biphenyl-4-yl)methyl]imidazole-5-carbonitrile.

The experience is conducted according to the procedure described in example 10(a), but use 178 mg of 2-butyl-4-(1-hydroxy-2-methylpropyl " imidazole-5-carbonitrile, 322 mg of methyl(41-bromomethylbiphenyl-2-yl)glyoxylate (obtained as described in preparation 8) and 11 mg of potassium carbonate and obtain 245 mg of target compound in the form of syrup.

An NMR spectrum (CDCl3, 270 MHz) / million-1: of 0.91 (3H, triplet, J=7.5 Hz); of 0.94 (3H, doublet, J=6.5 Hz); and 1.00 (3H, doublet, J= 6.5 Hz); of 1.37 (2H, sextet, J=7.5 Hz); to 1.70 (2H, quintet, J=8 Hz); 2,07-2,19 (1H, multiplet); to 2.66 (2H, triplet, J=8 Hz); to 3.36 (3H, singlet); of 4.54 (1H, doublet, J=6 Hz); 5,23 (2H, singlet); 7,13 (2H, doublet, J=8 Hz); 7,33 (2H, doublet, J=8 Hz); 7,42 (1H, doublet, J= 7 Hz); 7,52 (1H, triplet, J=7 Hz); 7,66 (1H, triplet, J=7 Hz); of 7.82 (1H, doublet, J=7 Hz).

12(b). 2-Butyl-4-(1-hydroxy-2-methylpropyl)-1-[(21-oxalobacter - 4-yl)methyl]imidazole-5-carboxamide.

245 mg of 2-butyl-4-(1-hydroxy-2-methylpropyl)-1-[(21- methoxyresorufin-4-yl)methyl] imidazole-5-carbonitrile (obtained as described above in stage (a)) is subjected to hydrolysis using 6 ml of 1N. an aqueous solution of sodium hydroxide, according to the method described in example 10(b) and obtain 187 mg of the target compound in the form of powder is MHz), million-1: is 0.69 (3H, doublet, J=6.5 Hz); 0,81 (3H, triplet, J= 7.5 Hz); a 1.01 (3H, doublet, J=6.5 Hz); 1.26 in (2H, sextet, J=7.5 Hz); of 1.52 (2H, quintet, J=7.5 Hz); 1,99-of 2.16 (1H, multiplet); 2.57 m (2H, triplet, J=7.5 Hz); 4,33 (1H, doublet, J= 8.5 Hz); of 5.55 (1H, doublet, J=16.5 Hz); 5,78 (1H, doublet, J=16.5 Hz); from 6.22 (1H, broad singlet); 7,07 (2H, doublet, J=8 Hz); of 7.25 (2H, doublet, J=8 Hz); was 7.45 (1H, doublet, J= 7 Hz); rate of 7.54 (1H, triplet, J=7 Hz); 7,50 (1H, broad singlet); to 7.64-7,72 (2H, multiplet); and 8.50 (1H, broad singlet).

Example 13. 2-Butyl-4-(1-hydroxy-2,2-dimethylpropyl)-1-[(21- oxalobacter-4-yl)methyl]imidazole-5-carboxamide (compound 1-25 N).

< / BR>
13(a). 2-Butyl-4-(1-hydroxy-2,2-dimethylpropyl)-1-[(21- metaxalone-4-yl)methyl]imidazole-5-carbonitrile.

The experience is conducted according to the procedure described in example 10(a), but they are using 340 mg of 2-butyl-4-(1-hydroxy-2,2-dimethylpropyl)imidazol-5-carbonitrile, 340 mg of methyl(41-bromomethylbiphenyl-2-yl)glyoxylate (obtained as described in preparation 8) and 117 mg of potassium carbonate and get 335 mg of the target compound in the form of syrup.

An NMR spectrum (CDCl3, 270 MHz), million-1: of 0.91 (3H, triplet, J=7.5 Hz); 0,99 (9H, singlet); of 1.36 (2H, sextet, J=7.5 Hz); 1.69 in (2H, quintet, J=7.5 Hz); of 2.66 (2H, triplet, J=7.5 Hz); to 3.36 (3H, singlet); to 4.46 (1H, singlet); 5,23 (2H, singlet); 7,13 (2H, doublet, J=8 Hz); 7,33 (2H, doublet, J=8 Hz); 7,42 (1H, doublet, J=7 ropyl)-1- [(21-oxalobacter-4-yl)methyl]imidazole-5-carboxamide.

335 mg of 2-butyl-4-(1-hydroxy-2,2-dimethylpropyl)-1- [(21-methoxynicotinic-4-yl)methyl] imidazole-5-carbonitrile (obtained as described above in stage (a) hydrolyzing, using 7 ml of 1N. aqueous solution of NaOH, according to the method described in example 10(b), and obtain 256 mg of target compound in the form of a crystalline powder, melting at 192-194oC (decomposition).

An NMR spectrum (hexadeuterated dimethyl sulfoxide, 270 MHz), million-1: 0,81 (3H, triplet, J = 7.5 Hz); 1.26 in (2H, sextet, J = 7.5 Hz); 1,51 (2H, quintet, J = 7.5 Hz); at 2.59 (2H, triplet, J = 7.5 Hz); 4,51(1H, singlet); of 5.48 (1H, doublet, J = 16.5 Hz); 5,8 (1H, doublet, J = 16.5 Hz); from 6.22 (1H, broad singlet); 7,06 (2H, doublet, J = 8 Hz); 7,26 (2H, doublet, J = 8 Hz); 7,42 (1H, broad singlet); 7,44 (1H, doublet, J = 7 Hz); 7,53 (1H, triplet, J = 7 Hz); of 7.64-7,72 (2H, multiplet); 8,69 (1H, broad singlet).

Example 14. 2-Ethoxymethyl-4-(1-hydroxy-1-methylethyl)-1-[(21- oxalobacter-4-yl)methyl]imidazole-5-carboxylic acid (compound N 1-37).

< / BR>
14(a). Ethyl-2-ethoxymethyl-4-(1-hydroxy-1-methylethyl)-1- [(21- methoxynicotinic-4-yl)methyl]imidazole-5-carboxylate.

The experience is conducted according to the procedure described in example 1(a), but use 400 mg of ethyl-2-ethoxymethyl-4-(1-hydroxy-1-mew preparation 8) and 184 mg of tert-butoxide potassium and obtain 680 mg of the target compound in the form of syrup.

An NMR spectrum (CDCl3, 270 MHz), million-1: to 1.16 (3H, triplet, J = 7 Hz); of 1.28 (3H, triplet, J = 7 Hz); of 1.64 (6H, singlet); and 3.31 (3H, singlet); of 3.54 (2H, Quartet, J = 7 Hz); the 4.29 (3H, Quartet, J = 7 Hz); of 4.57 (2H, singlet); of 5.55 (1H, singlet); to 5.66 (2H, singlet); 7,02 (2H, doublet, J = 8.0 Hz); 7,26 (2H, doublet, J = 8.0 Hz) 7,41 (1H, doublet, J = 7.5 Hz); 7,51 (1H, triplet, J = 7.5 Hz); to 7.64 (1H, triplet, J = 7.5 Hz); 7,81 (1H, doublet, J = 7.5 Hz).

14(b). 2-Ethoxymethyl-4-(1-hydroxy-1-methylethyl)-1-[(21- oxalobacter-4-yl)methyl]imidazole-5-carboxylic acid.

680 mg of ethyl-2-ethoxymethyl-4-(1-hydroxy-1-methylethyl)-1- [(21-methoxynicotinic-4-yl)methyl] imidazole-5-carboxylate (obtained as described above in stage (a) hydrolyzing, using 224 mg of the monohydrate of lithium, according to the method described in example 1 (b), and receive 423 mg of the target compound in the form of a powder, melting at 138-140oC.

An NMR spectrum (hexadeuterated dimethyl sulfoxide, 270 MHz), million-1: 1,04 (triplet, J = 7.0 Hz); and 1.56 (6H, singlet); to 3.45(2H, Quartet, J = 7.0 Hz); 4,47 (2H, singlet); 5,71 (2H, singlet); to 7.09 (2H, doublet, J = 8.0 Hz), from 7.24 (2H, doublet, J = 8.0 Hz 7,47 (1H, doublet, J = 7.5 Hz); at 7.55 (1H, triplet, J = 8.0 Hz); 7,66 - 7,73 (2H, multiplet).

Example 15. The hydrochloride of 4-(1-hydroxy-1-methylethyl)-2- (methylaminomethyl)-1-[(21-oxalobacter-4-yl)methyl] imidazole-5-carboxylic, colotox-1-methylethyl)-1-[(21-methoxynicotinic-4-yl)methyl/imidazole-5-carboxylate.

The experience is conducted according to the procedure described in example 1 (a), but applied 265 mg of ethyl-2-(N-tert-butoxycarbonyl-N-methylaminomethyl)-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate, 310 mg of methyl(41-bromomethylbiphenyl-2-yl)glyoxylate (obtained as described in preparation 8) and 92 mg of tert-butoxide potassium and obtain 380 mg of the target compound in the form of syrup.

An NMR spectrum (CDCl3, 270 MHz), million-1: of 1.28 (3H, triplet, J = 7.5 Hz) of 1.34 (9H, singlet); and 1.63 (6H, singlet); to 2.85 (3H, singlet); of 3.32 (3H, singlet); 4,27 (2H, Quartet, J = 7.5 Hz); 4,56 (2H, broad singlet); 5,6 (1H, broad singlet); 5,63 (2H, broad singlet), 6,93 (2H, doublet, J = 8.0 Hz); of 7.25(2H, doublet, J = 8.0 Hz); 7,39 (1H, doublet, J = 8.0 Hz); 7,5 (1H, triplet, J = 8.0 Hz); to 7.64 (1H, triplet, J = 8.0 Hz); 7,80 (1H, doublet, J = 8.0 Hz).

15(b). 2-(N-tert-Butoxycarbonyl-N-methylaminomethyl)-4- (1-hydroxy - 1-methylethyl)-1-[(21- oxalobacter-4-yl)methyl]imidazole-5-carboxylic acid.

A solution of 81 mg of the monohydrate of lithium hydroxide in 5 ml of water are added to a solution of 380 mg of methyl 2-(N-tert-butoxycarbonyl-N-methylaminomethyl) -4-(1-hydroxy-1-methylethyl)-1-[(21- methoxynicotinic-4-yl)methyl] imidazole-5-carboxylate (obtained as described above in stage (a)) in 5 ml of dioxane and obrazuyutsa type of 1.93 ml of 1N. aqueous hydrochloric acid. The precipitate is filtered off and obtain 339 mg of the target compound as amorphous powder.

An NMR spectrum (hexadeuterated dimethyl sulfoxide, 270 MHz), million-1: to 1.31 (9H, broad singlet); of 1.55 (6H, singlet); 2,77 (3H, broad singlet); 4,43 (2H, broad singlet); 5,69 (2H, broad singlet); 7,03 (2H, doublet, J = 8.0 Hz); of 7.25 (2H, doublet, J = 8.0 Hz), 7,44 (1H, doublet, J = 8.0 Hz); at 7.55 (1H, triplet, J = 7.0 Hz); 7,66-7,72 (2H, multiplet).

15(c). The hydrochloride of 4-(1-hydroxy-1-methylethyl)-2-(methylaminomethyl) -1-[(21-oxalobacter-4-yl)methyl]imidazole-5-carboxylic acid.

339 mg of 2-(N-tert-butoxycarbonyl-N-methylaminomethyl)-4- (1-hydroxy-1-methylethyl)-1-[(21-oxalobacter-4-yl)methyl] imidazole-5-carboxylic acid (obtained as described above in stage (b)) is treated with 3 ml of 4n. solution of hydrogen chloride in dioxane as described in example 3 (b) and obtain 260 mg of the target compound, melting at 172-175oC (decomposition).

An NMR spectrum (hexadeuterated dimethyl sulfoxide, 270 MHz), million-1: to 1.60 (6H, singlet); to 2.66 (3H, broad singlet), 4,27 (2H, broad singlet); of 5.75 (2H, singlet); for 7.12 (2H, doublet, J = 8.0 Hz); 7,28 (2H, doublet, J = 8.0 Hz); of 7.48 (1H, doublet, J = 7.5 Hz), EUR 7.57 (1H, triplet, J - 7.5 Hz); 7.68 per - 7,74 (2H, multiplet).

Example 16. 2-Ethyl-5 is Tyl-3-[(21-methoxycarbonyl-4-yl)methyl] - 5,7-dimethyl-3H-imidazo[4,5-b]pyridine.

The experience is conducted according to the procedure described in example 1(a), but use 350 mg 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b]pyridine, 828 mg of methyl(41-bromomethylbiphenyl-2-yl)glyoxylate (obtained as described in preparation 8) and 247 mg of tert-butoxide potassium and receive 684 mg of target compound in the form of syrup.

An NMR spectrum (CDCl3, 270 MHz), million-1: to 1.37 (3H, triplet, J = 7.5 Hz); to 2.57 (3H, singlet); of 2.64 (3H, singlet); 2,84 (2H, Quartet, J = 7.5 Hz); 3.24 in (3H, singlet); of 5.50 (2H, singlet); 6.90 to (1H, singlet); to 7.18 (2H, doublet, J = 8 Hz); from 7.24 (2H, doublet, J = 8 Hz); 7,41 (1H, doublet, J = 7 Hz); 7,50 (1H, triplet, J = 7 Hz); 7,63 (1H, triplet, J = 7 Hz); 7,80 (1H, doublet, J = 7 Hz).

16(b). 2-Ethyl-5,7-dimethyl-3-[(21-oxalobacter-4 - yl)methyl] -3H-imidazo/4,5-b/pyridine.

684 mg of 2-stil-3-[(21-methoxycarbonyl-4-yl)methyl] - 5,7-dimethyl-3H-imidazo[4,5-b] pyridine (obtained as described above in stage (a) hydrolyzing, using 201 mg of the monohydrate of lithium hydroxide according to the method described in example 1(b), and get 460 mg of the target compound in the form of a powder, melting at 209 - 210oC.

An NMR spectrum (hexadeuterated dimethyl sulfoxide, 270 MHz), million-1: 1,28 3H, triplet, J = 7.5 Hz); to 2.55 (6H, singlet); and 2.83 (2H, Quartet, J = 7.5 Hz); of 5.53 the t).

Example 17. 2 {N-[(21-Oxalobacter-4-yl)methyl]-N-propylamino}nicotinic acid.

< / BR>
17(a). Ethyl-2-{ N-[(21-methoxynicotinic-4-yl)methyl]- N-propylamino}nicotinate.

In nitrogen atmosphere with 4.65 ml of a 1 M solution of bis(trimethylsilyl)amide lithium add (-5) - 0oC to a solution of 0.80 g of ethyl-2-Propylenediamine in 6 ml of tetrahydrofuran and 2 ml of hexamethylphosphorotriamide and the resulting mixture is stirred at the same temperature for 10 minutes Then add a solution of 1.28 g of methyl(41-bromomethylbiphenyl-2-yl)glyoxylate (obtained as described in preparation 8) in 8 ml of tetrahydrofuran and the mixture is stirred at 10 to 15oC 4 h To the reaction mixture are added ethyl acetate and water, an ethyl acetate layer is separated, washed with water and dried over anhydrous MgSO4. The solvent is distilled off under reduced pressure, the residue chromatographic on a column of silica gel, using as eluent a mixture of ethyl acetate/hexane (1:4 by volume) and get 0,70 g of target compound in the form of resin.

An NMR spectrum (CDCl3, 270 MHz), million-1: to 0.80 (3H, triplet, J = 7.5 Hz); of 1.39 (3H, triplet, J = 7.5 Hz) and 1.60 (2H, sextet, J = 7.5 Hz); 3.24 in (3H, singlet); 3,26 (2H, triplet, J = 7.5 Hz); of 4.35 (2H, Quartet, J = 7.5 Hz); was 4.76 (2H, singlet); 6,70 (1H, doublet, J = 5 and 7.5 Hz); from 7.24 (2H, dumbleton, J = 1.5 and 7.5 Hz); 8,23 (1H, doublet of doublets, J = 1.5 and 5 Hz).

17(b). 2-{ N-{(21-Oxalobacter-4-yl)methyl]-N-propylamino}-nicotinic acid.

A solution of 350 mg of the monohydrate of lithium hydroxide in 10 ml of water are added to a solution 0,70 g ethyl-2-{N-[(21-methoxycarbonyl - 4-yl)methyl]-N-propylamino} nicotinate (obtained as described above in stage (a)) in 5 ml of dioxane and the resulting mixture is stirred for 4 h at 70oC. Then the dioxane is distilled off under reduced pressure and the remaining aqueous solution was added with 8.33 ml of 1N. aqueous hydrochloric acid, the precipitated crystals are collected by filtration and receive 0,57 g of target compound, melting at 179 - 180oC.

An NMR spectrum (hexadeuterated dimethyl sulfoxide, 270 MHz) / million-1: 0,76 (3H, triplet, J = 7.5 Hz); 1,53 (2H, sextet, J = 7.5 Hz); 3,26 (2H, triplet, J = 7.5 Hz); to 4.73 (2H, singlet); for 6.81 (1H, doublet of doublets, J = 4.5 and 8 Hz); 7,21 (2H, doublet, J = 8 Hz); 7,34 (2H, doublet, J = 8 Hz); of 7.48 (1H, doublet, J = 7 Hz); rate of 7.54 (1H, triplet, J = 7 Hz); 7,66 - 7,72 (2H, multiplet); of 7.90 (1H, doublet of doublets, J = 2 and 8 Hz); of 8.25 (1H, doublet of doublets, J = 2 and 4.5 Hz).

Example 18. 2-{N-(2-Methoxyethyl)-N-[(21-oxalobacter-4"- yl)methyl]amino} nicotinic acid (compound No. 3 - 19).

< / BR>
18 (a). Ethyl-2-{ N-[(21-methoxydiphenyl-4-yl)methyl] -750 mg ethyl-2-[(2-methoxyethyl)amino]nicotinate, of 1.17 g of methyl (41-bromomethylbiphenyl-4-yl)glyoxylate (obtained as described in preparation 8) and 4,00 ml of 1 M solution of bis(trimethylsilyl)amide lithium in tetrahydrofuran and get 535 mg of target compound in the form of syrup.

An NMR spectrum (CDCl3, 270 MHz), million-1: to 1.38 (3H, triplet, J = 7.5 Hz); of 3.25 (3H, singlet); with 3.27 (3H, singlet); 3,52 - 3,61 (4H, multiplet); to 4.33 (2H, Quartet, J = 7.5 Hz); to 4.81 (2H, singlet); 6.73 x (1H, doublet of doublets, J = 4.5 and 8 Hz), from 7.24 (2H, doublet, J = 8 Hz); 7,38 (2H, doublet, J = 8 Hz), 7,44 (1H, doublet, J = 7 Hz); of 7.48 (1H, triplet, J = 7 Hz); a 7.62 (1H, triplet, J = 7 Hz); 7,81 (1H, doublet, J = 7 Hz); a 7.92 (1H, doublet of doublets, J = 2 and 8 Hz); 8,24 (1H, doublet of doublets, J=2 and 4.5 Hz).

18(b). 2-{N-(2-Methoxyethyl)-N - [(21-oxalobacter-4-yl) methyl]amino}nicotinic acid.

To a solution of 535 mg of ethyl-2-{N-[(21-methoxynicotinic-4-yl) methyl]-N-(2-methoxyethylamine} nicotinate (obtained as described above in stage (a)) in 4.5 ml of dioxane is added 1N. an aqueous solution of NaOH and the resulting mixture is stirred for 19 h at 50oC. Then the dioxane is distilled off under reduced pressure and the remaining aqueous solution was added to 4.5 ml of 1N. of hydrochloric acid. The precipitated crystals are collected by filtration and obtain 306 mg of the target compound, melting at 173oC (decomposition).

An NMR spectrum (g is); 6,83 (1H, doublet of doublets, J=4.5 and 7.5 Hz); 7,21 (2H, doublet, J=8 Hz); 7,34 (2H, doublet, J= 8 Hz); of 7.48 (1H, doublet, J=7 Hz); rate of 7.54 (1H, triplet, J=7 Hz); 7,66-7,72 (2H, multiplet); of 7.90 (1H, doublet of doublets, J=1.5 and 7.5 Hz); 8,24 (1H, doublet of doublets, J=1.5 and 4.5 Hz).

Example 19. Ethyl-4-(1-hydroxy-1-methylethyl)-1-{ [21(tetrazol-5-yl)carbonyl) - biphenyl-4-yl] methyl}-2-propylimidazol-5 - carboxylate (compound N 1-50).

< / BR>
19(a). Ethyl-4-(1-hydroxy-1-methylethyl)-1-{ [21- (2-trailersa-5-ylcarbonyl)biphenyl-4-yl]methyl}-2-propylimidazol - 5-carboxylate.

The experience is conducted according to the procedure described in example 1(a), but use 190 mg of ethyl-4-(1-hydroxy-1-methylethyl)-2-propylimidazol-5 - carboxylate, 93 mg of tert-butoxide potassium and 470 mg of 41the methyl bromide - 2-(2-trailersa-5-ylcarbonyl)biphenyl (obtained as described in example 13) and obtain 218 mg of the target compound as amorphous powder.

An NMR spectrum (CDCl3, 270 MHz), million-1: to 0.89 (3H, triplet, J=7.5 Hz); of 1.12 (3H, triplet, J=7.0 Hz); and 1.63 (6H, singlet); 1,60-1,70 (2H, multiplet); 2,52 (2H, triplet, J=8.0 Hz); to 4.14 (2H, Quartet, J=7.0 Hz); to 5.35 (2H, singlet); 5,74 (1H, singlet); 6,76 (2H, doublet, J=8.5 Hz); 6,92 (5H, doublet, J= 7.5 Hz); 7,07 (2H, doublet, J=8.5 Hz); 7,25-7,38 (1H, multiplet); 7,45 (1H, triplet, J=7.0 Hz); to 7.59 (1H, triplet, J=7.5 Hz); of 7.70 (1H, doublet, J= 8.5 Hz).

19(b). Ethyl-4-(1-HYDR>/P>216 mg of ethyl-4-(1-hydroxy-1-methylethyl)-1-{[21-(2 - trailersa-5-ylcarbonyl)biphenyl-4-yl] methyl}-2-propylimidazol-5 - carboxylate (obtained as described in stage (a) above) will detritivorous according to the method described in example 7(b), and obtain 151 mg of the target compound as amorphous powder.

An NMR spectrum (CDCl3, 270 MHz), million-1: 0,86 (3H, triplet, J=7.5 Hz); of 1.20 (3H, triplet, J=7.5 Hz); 1,53-of 1.65 (2H, multiplet); of 1.65 (6H, singlet); in 2.68 (2H, triplet, J=8.0 Hz); 4.26 deaths (2H, Quartet, J=7.5 Hz); 5,41 (2H, singlet); to 6.80 (2H, doublet, J=8.0 Hz); from 7.24 (2H, doublet, J=8.0 Hz); 7,41-7,49 (2H, multiplet); 7,58 (1H, triplet, J=7.0 Hz); to 7.77 (1H, doublet, J=6.5 Hz).

Example 20. 4-(1-Hydroxy-1-methylethyl)-1-{ [21(tetrazol-5 - yl-carbonyl) - biphenyl-4-yl] methyl}-2-propylimidazol-5-carboxylic acid (compound 1-42 N).

< / BR>
The experience is conducted according to the procedure described in example 1(b), but use 151 mg of ethyl-4-(1-hydroxy-1-methylethyl)-1-{[21(tetrazol-5-ylcarbonyl)biphenyl-4-yl] methyl}-2-propylimidazol-5 - carboxylate and 36 mg of the monohydrate of lithium hydroxide and obtain 97 mg of the target compound in the form of a crystalline powder, melting at 166-169oC (decomposition).

An NMR spectrum (hexadeuterated dimethyl sulfoxide, 270 MHz), million-1: of 0.87 (3H, triplet, J=7.5 Hz); 1,45-of 1.56 (2H, multiple); to 7.67 to 7.75 (2H, multiplet).

Example 21. 2-Ethyl-5,7-dimethyl-3-{[21(tetrazol-5 - ylcarbonyl)biphenyl-4-yl]methyl}-3H-imidazo[4,5-b]pyridine (compound N 2-51).

< / BR>
21(a). 2-Ethyl-5,7-dimethyl-3-{ [21-(2-trailersa-5-ylcarbonyl) biphenyl-4-yl]methyl}-3H-imidazo[4,5-b]pyridine.

The experience is conducted according to the procedure described in example 1(a), but using 130 mg of 2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine, 522 mg 41the methyl bromide-2-(2-trailersa-5-ylcarbonyl)biphenyl and 87 ml of tert-butoxide potassium and obtain 144 mg of the target compound as amorphous powder.

An NMR spectrum (CDCl3, 270 MHz), million-1: of 1.23 (3H, triplet, J=7.5 Hz); of 2.56 (3H, singlet); 2.63 in (3H, singlet); to 2.66 (2H, Quartet, J=7.5 Hz); of 5.34 (2H, singlet); 6.87 in-6,95 (7H, multiplet); of 6.96 (2H, doublet, J=8 Hz); 7.23 percent-7,40 (10H, multiplet); 7,37 (1H, doublet, J=7 Hz); 7,46 (1H, triplet, J=7 Hz); 7,58 (1H, triplet, J=7 Hz); 7,71 (1H, doublet, J=7 Hz).

21(b). 2-Ethyl-5,7-dimethyl-3-{ (21(tetrazol-5-ylcarbonyl) biphenyl-4-yl] methyl}-3H-imidazo[4,5-b]pyridine.

137 mg of 2-Ethyl-5,7-dimethyl-3-{ [21-(2-trailersa-5-yl - carbonyl) - biphenyl-4-yl] methyl} -3H-imidazo[4,5-b] pyridine (obtained as described in stage (a) above) will detritivorous according to the method described in example 7(b), and obtain 68 mg of the target compound in the form of a powder, melting the 3H, triplet, J=7.5 Hz); 2,52 (6H, singlet); 2,73 (2H, Quartet, J= 7.5 Hz); 5,44 (2H, singlet); 7,03 (1H, singlet);? 7.04 baby mortality (2H, doublet, J=8 Hz); 7,17 (2H, doublet, J=8 Hz); 7,49-7,58 (2H, multiplet); to 7.67-of 7.55 (2H, multiplet); 8,31 (1H, singlet).

Example 22. 2-Butyl-1-[(21-oxalobacter-4-yl)methyl] benzimidazole-5 - carboxylic acid (compound N 2-53) and 2-butyl-1-[(2-1- oxalobacter-4-yl)methyl]benzimidazole-6-carboxylic acid (compound N 2-54).

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22(a). Methyl-2-butyl-1-[(21-methoxynicotinic-4-yl)methyl]benzimidazole-5 - and-6-carboxylate.

The experience is conducted according to the procedure described in example 1 (a), but use 404 mg of methyl 2-butylbenzothiazole-5-carboxylate, 637 mg of methyl(41-bromomethylbiphenyl-2-yl)glyoxylate (obtained as described in preparation 8) and 1200 mg of tert-butoxide potassium and obtain 620 mg of target compound in the form of a resin. From the NMR spectra established that the product is a mixture of 1:1 compounds containing the group methoxycarbonyl in positions 5 and 6.

An NMR spectrum (CDCl3, 270 MHz), million-1as 0.96 (3H, triplet, J = 7.5 Hz); 1,47 (2H, sextet, J = 7.5 Hz); of 1.88 (2H, quintet, J = 7.5 Hz); 2,89 (2H, triplet, J = 7.5 Hz); 3.24 in and 3.76 (total 3H, each singlet); 3.90 and 3,93 (total 3H, each singlet); 5,41 and 5.45 (total 2H, each singlet); 7,08 - 7,49 (10,5 H, multiplet); 8,48 (0.5 H, singlet).

methyl-2-butyl-1-[(21-oxalobacter-4-yl)-methyl]benzimidazole-5 - and-6-carboxylates (obtained as described in stage (a) above) hydrolyzing using 269 mg, hydrate, lithium hydroxide according to the method described in example 1(b), and receive a 511 mg of the target compound in the form of a powder, melting at 160 - 180oC. From an NMR spectrum established that the product is a mixture of 1:1 compounds containing carboxypropyl in positions 5 and 6.

An NMR spectrum (hexadeuterated dimethyl sulfoxide, 270 MHz), million-1: to 0.89 (3H, triplet, J = 7.5 Hz); of 1.39 (2H, sextet, J = 7.5 Hz); of 1.75 (2H, quintet, J = 7.5 Hz); 2.91 in (2H, triplet, J = 7.5 Hz); 5,62 and 5,67 (total 2H, each singlet); 7,14 - 7,87 (10H, multiplet); 8,16 - to 8.20 (1H, multiplet).

Example 23. 2-Ethyl-1-[(21-oxalobacter-4-yl)methyl]benzimidazole-7-carboxylic acid (compound No. 2 - 26).

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23(a). Ethyl-2-{ N-tert-butoxycarbonyl-N-[(21- methoxycarbonyl-4-yl)methyl]amino}-3-nitrobenzoate.

The experience is conducted according to the procedure described in example 1(a), but using 1.01 g ethyl-2-tert-butoxycarbonylamino-3-nitrobenzoate, 1.2 g of methyl(41-bromomethylbiphenyl-2-yl)glyoxylate (obtained as described in preparation 8) and 155 mg of 55% (by weight) dispersion of sodium hydride in mineral oil and get 1,43 g of target compound in the form of a resin.2H, Quartet, J = 7 Hz); of 4.45 (1H, Quartet, J = 14,5 HZ); is 4.93 (1H, doublet, J = 14,5 Hz); 7,15 - 7,27 (4H, multiplet); 7,41 - 7,51 (3H multiplet) 7,63 (1H, triplet, J = 7 Hz); 7,79 (1H, doublet, J = 7 Hz); 7,88 (1H, doublet, J = 8 Hz); 8,07 (1H, doublet, J = 7 Hz).

23(b). Ethyl-2-ethyl-1-[(21-methoxynicotinic-4-yl)methyl]benzimidazole-7 - carboxylate.

In 10 ml of 4n. solution of hydrogen chloride in ethyl acetate is dissolved 1.06 g of ethyl-N-tert-butoxycarbonyl-N[(21- methoxynicotinic-4-yl)methyl]amino-3-nitrobenzoate (obtained as described above in stage (a)) and the resulting solution allowed to stand at room temperature for 4 h Then the reaction mixture is concentrated by evaporation under reduced pressure and the retinoid residue is dissolved in 20 ml of ethanol and 10 ml of triethylamine. Add 150 mg of 5% platinum on coal and the resulting mixture is stirred for 2 h in an atmosphere of hydrogen at atmospheric pressure and left overnight at room temperature. Then the catalyst is separated by filtration, the reaction mixture is concentrated by evaporation under reduced pressure, the residue is dissolved in ethyl acetate, the solution is shaken out with saturated aqueous NaHCO3, an ethyl acetate layer is separated and dried over anhydrous MgSO4. The solvent is removed by evaporation under reduced yeah what up 343 mg of target compound in the form of crystals with so pl. 118 - 119oC.

An NMR spectrum (CDCl3, 270 MHz), million-1: of 1.28 (3H, triplet, J = 7.5 Hz); to 1.48 (3H, triplet, J = 7 Hz); 2.91 in (2H, Quartet, J = 7.5 Hz); 3,17 (3H, singlet); 4.26 deaths (2H, Quartet, J = 7 Hz); of 5.84 (2H, singlet); 6,93 (2H, doublet, J = 8.5 Hz); to 7.18 (2H, doublet, J = 8.5 Hz); 7,22 - 7,98 (7H, multiplet).

23(c). 2-Ethyl-1-[(21-oxalobacter-4-yl)methyl]benzimidazole-7-carboxylic acid.

300 mg of ethyl-2-ethyl-1-(21-methoxynicotinic-4-yl)benzimidazole-7-carboxylate (obtained as described above in stage (b) hydrolyzing using 134 mg of the monohydrate of lithium hydroxide according to the method described in example 17(b), and obtain 264 mg of the target compound in powder form with so pl. 278 - 281oC.

An NMR spectrum (hexadeuterated dimethyl sulfoxide, 270 MHz), million-1equivalent : 1.33 (3H, triplet, J = 7.5 Hz); 2,87 (2H, Quartet, J = 7.5 Hz); 5,90 (2H, singlet); 6,92 (2H, doublet, J = 8 Hz); 7,19 (2H, doublet, J = 8 Hz); 7,27 (1H, triplet, J = 7 Hz); 7,42 (1H, doublet, J = 7 Hz); 7,53 (1H, triplet, J = 7 Hz); of 7.64 - of 7.70 (3H, multiplet); 7,86 (1H, doublet, J = 8 Hz).

Example 24. 2 Ethoxy-1-[(21-oxalobacter-4-yl)methyl] benzimidazole-7-carboxylic acid (compound No. 2 - 44).

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24(a). Ethyl-2-ethoxy-1-[(21-methoxynicotinic-4-yl)methyl]benzimidazole-7 - carboxylate.

Experience conducted according to the technique described by nitrobenzoate (obtained as described in example 23 (a)) and replace triethylenediamine 7 ml tetraethylorthosilicate. Obtain 252 mg of target compound in the form of resin.

An NMR spectrum (CDCl3, 270 MHz), million-1: to 1.32 (3H, triplet, J = 7.5 Hz); 1,50 (3H, triplet, J = 7 Hz); a 3.06 (3H, singlet); or 4.31 (2H, Quartet, J = 7 Hz); of 4.67 (2H, Quartet, J = 7.5 Hz); 5,71 (2H, singlet); was 7.08 (2H, doublet, J = 8 Hz); to 7.18 (2H, doublet, J = 8 Hz) 7,29 - 8,19 (7H, multiplet).

24(b). 2 Ethoxy-1-[(21-oxalobacter-4-yl)methyl] benzimidazole-7-carboxylic acid.

252 mg of ethyl-2-ethoxy-1-[(21-methoxynicotinic-4-yl) methyl] benzimidazole-7-carboxylate (obtained as described in stage (a) above) hydrolyzing, using 136 mg of the monohydrate of lithium hydroxide, according to the method described in example 17(b), and obtain 186 mg of the target compound in the form of a powder, melting at 158 - 161oC.

An NMR spectrum (hexadeuterated dimethyl sulfoxide, 270 MHz), million-1: to 1.42 (3H, triplet, J = 7.5 Hz); br4.61 (2H, Quartet, J = 7.5 Hz); 5,67 (2H, singlet);? 7.04 baby mortality (2H, doublet, J = 8 Hz); 7,10 - 7,97 (9H, multiplet).

Example 25. Ethyl-2-(N-{[21-tetrazol-5-ylcarbonyl)biphenyl - 4-yl]methyl}-N-propylamino)nicotinate (compound N 3-25).

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25(a). Ethyl-2-(N-{ [21-trailersa-5-ylcarbonyl) biphenyl-4-yl]methyl} -N-propylaminoethyl.

The experience is conducted according to the procedure described in example 18(a), but applied 640 mg of ethyl-2-impregnated the rata 13) and 3,69 ml of bis(trimethylsilyl)amide lithium in tetrahydrofuran. Get 483 mg of the target compound as a foam solid.

An NMR spectrum (CDCl3, 270 MHz), million-1: to 0.73 (3H, triplet, J = 7 Hz); of 1.33 (3H, triplet, J = 7 Hz); to 1.48 (2H, sextet, J = 7 Hz), 3,13 (2H, triplet, J = 7 Hz); 4,30 (2H, Quartet, J = 7 Hz); 4,63 (2H, singlet); of 6.68 (1H, doublet of doublets, J = 4.5 and 7.5 Hz); 6,83 - 6,92 (5H, multiplet); of 6.96 (2H, doublet, J = 8.5 Hz); 7,05 (2H, doublet, J = 8.5 Hz); 7.23 percent - 7,44 (12H, multiplet); 7,58 (1H, doublet, J = 7.5 Hz); 7,71 (1H, doublet, J = 6.5 Hz); to $ 7.91 (1H, doublet of doublets, J = 2 and 8 Hz); to 8.20 (1H, doublet of doublets, J = 2 and 4.5 Hz).

25(b). Ethyl-1-(N-[21-tetrazol-5-ylcarbonyl)biphenyl-4-yl] -methyl-N-propylamino)nicotinate.

483 mg of ethyl-2-(N - {[21(tetrazol-5-ylcarbonyl)biphenyl-4-yl]methyl}-N-propylamino)nicotinate (obtained as described above in stage (a) detritivorous according to the method described in example 7(b), and obtain 320 mg of the target compound in the form of resin.

An NMR spectrum (CDCl3, 270 MHz) / million-1: of 0.79 (3H, triplet, J = 7 Hz); of 1.39 (3H, triplet, J = 7 Hz); and 1.54 (2H, sextet, J = 7 Hz); 3.15 in (2H, triplet, J = 7 Hz); 4,37 (2H, Quartet, J = 7 Hz); 4,58 (2H, singlet); to 6.80 (1H, doublet of doublets, J = 5.5 and 7.5 Hz); 7,06 (2H, doublet, J = 8.5 Hz); 7,16 (2H, doublet, J = 8.5 Hz); 7,44 - 7,52 (2H, multiplet); to 7.61 (1H, triplet, J = 7 Hz); a 7.85 (1H, doublet, J = 7 Hz); 8,03 (1H, doublet of doublets, J = 2 and 7 Hz); of 8.25 (1H, doublet of doublets, J = 2 and 5 Hz).

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310 mg of ethyl-2-(N-{ /21(tetrazol-5-ylcarbonyl)biphenyl-4 - yl/methyl}-N-propylaminoethyl (obtained as described in example 25 (b)) hydrolyzing using 6 ml of 1N. aqueous NaOH solution, and obtain 128 mg of the target compound in the form of amorphous powder, razmyagchayuschiesya at 107 - 109oC.

An NMR spectrum (hexadeuterated dimethyl sulfoxide, 270 MHz), million-1: 0,74 (3H, triplet, J = 7 Hz); the 1.44 (2H, sextet, J = 7 Hz); 3,12 (3,12 (2H, triplet, J = 7 Hz); 4,59 (2H, singlet); for 6.81 (1H, doublet of doublets, J = 4.5 and 8 Hz); 7,13 (2H, doublet, J = 8.5 Hz); 7,19 (2H, doublet, J = 8.5 Hz); 7,54 - to 7.61 (2H, multiplet); 7,74 (1H, triplet, J = 7.5 Hz); 7,80 (1H, doublet, J = 8 Hz); 7,89 (1H, doublet of doublets, J = 2 and 8 Hz); by 8.22 (1H, doublet of doublets, J = 2 and 5 Hz).

Preparation 1. 41-Methylbiphenyl-2-carbaldehyde.

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In nitrogen atmosphere 118 ml of a 1.5 M solution of diisobutylaluminium in toluene is added dropwise at a temperature of (-30) - (-20)oC to a solution of 22.8 g of 41-methylbiphenyl-2-carbonitrile in 200 ml of toluene and the mixture is stirred at room temperature for 2 h Then the reaction mixture is cooled with ice and add 200 ml of ethyl acetate and 60 ml of 6N. hydrochloric acid in this order. An ethyl acetate layer is separated, washed with saturated aqueous NaCl and dried with anhydrous MgSO4. ASS="ptx2">

An NMR spectrum (CDCl3, 60 MHz), million-1: 2,39 (3H, singlet); about 7.2 to 7.7 (7H, multiplet); 10,07 (1H, singlet).

The drug 2. -Hydroxy-(41-methylbiphenyl-2-yl)acetonitrile.

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To a solution of 23.1 g of 41-methylbiphenyl-2-carbaldehyde (obtained as described in preparation 1) in 250 ml of methylene chloride is added dropwise 18 ml trimethylsilylacetamide, then 0.2 g of zinc iodide. The resulting mixture was stirred at 30oC 3 h at 50oC 2 h and the solvent is removed by distillation under reduced pressure. The residue is dissolved in ethyl acetate, washed with aqueous solution of NaHCO3and saturated aqueous NaCl and dried with anhydrous Na2SO4. The solvent is distilled off under reduced pressure and get 35,0 g O-trimethylsilylpropyne target compound in the form of butter.

An NMR spectrum (CDCl3, 270 MHz), million-1: 0,09 (9H, singlet); 2,43 (3H, singlet); vs. 5.47 (1H, singlet); then 7.20 (2H, doublet, J=7.5 Hz); 7,26 (2H, doublet, J=7.5 Hz); 7,11-7,50 (3H, multiplet); 7,79-of 7.82 (1H, multiplet).

To solution just About-trimethylsilyl derived in 300 ml of methanol is added 1.5 g of the monohydrate of p-toluenesulfonic acid and the mixture is stirred at room temperature for 30 minutes and Then the reaction mixture is concentrated by evaporation under reduced pressure is in this order and dried over anhydrous Na2SO4. The solvent is distilled off under reduced pressure and gain of 26.1 g of target compound in the form of butter.

An NMR spectrum (CDCl3, 270 MHz), million-1: to 2.41 (3H, singlet); 2,89 (1H, doublet, J=6 Hz); 5,49 (1H, doublet, J=6 Hz); of 7.25 (4H, singlet); 7,26-7,33 (1H, multiplet); 7,42-7,49 (2H, multiplet); 7,78-7,81 (1H, multiplet).

Preparation 3. -Hydroxy-(41-methylbiphenyl-2-yl)acetonitrile.

A solution of 6.0 g KCN in 6 ml of water and a solution of 14 G. of NaHSO3in 35 ml of water is added dropwise at 0-5oC to a solution of 8.00 g of 41-methylbiphenyl-2-carbaldehyde (obtained as described in preparation 1) in 10 ml diethyl ether and the resulting mixture was stirred at 5-10oC 3 h and then at 20oC 30 minutes the Product is extracted with ethyl acetate. The extract was washed with water, dried with anhydrous MgSO4and the solvent evaporated under reduced pressure. The remainder chromatographic on a column of silica gel, using as eluent a mixture of ethyl acetate/hexane (1:4 by volume), and gain of 7.7 g of target compound in the form of oil. An NMR spectrum of this compound is identical to the spectrum of the compound obtained in preparation 2.

Preparation 4. Methyl--hydroxy-(41-methylbiphenyl-2-yl)acetate.

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Under stirring 26,1-hydroxy-(41-methylbiphenyl-vannoy hydrochloric acid and the mixture is stirred at 120oC 16 h Then the reaction mixture of concentrical by evaporation under reduced pressure. The remainder of the acetic acid removed by azeotropic distillation with toluene. The product is extracted with a solution of 12 g of NaOH in 200 ml of water. The resulting aqueous solution was washed with diethyl ether and add concentrated hydrochloric acid until an acid reaction. Released-hydroxy (41-methylbiphenyl-2-yl)acetic acid, extracted with ethyl acetate and the solution is dried over anhydrous MgSO4. The solvent is removed by evaporation under reduced pressure, the residue is dissolved in 300 ml of methanol and cooled with ice add 13 ml of concentrated aqueous sulfuric acid. The solution is left to stand at room temperature for 16 hours Then the reaction mixture is concentrated by evaporation under reduced pressure and the residue is mixed with ethyl acetate and water. The organic layer is separated and washed with aqueous solution of NaHCO3and water in that order and dried over anhydrous Na2SO4. The solvent is distilled off under reduced pressure, the residue chromatographic on a column of silica gel, using as eluent a mixture of ethyl acetate/hexane (1:4 by volume) and obtain 19.5 g of target compound in the form of crystals with so pl. 74-76oC.

The drug 5. Methyl (41-methylbiphenyl-2-yl)glyoxylate, being.

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To a solution of 10.6 g of methyl--hydroxy-(41-methylbiphenyl-2-yl)acetate (obtained as described in preparation 4) in 200 ml of methylene chloride add 40 g of manganese dioxide and the resulting mixture was stirred at room temperature for 16 hours, the Insoluble matter is filtered off and the filtrate is concentrated by evaporation under reduced pressure and get 9,16 g of target compound in the form of crystals with so pl. 81-84oC.

An NMR spectrum (CDCl3, 270 MHz), million-1: to 2.46 (3H, singlet); 3,39 (3H, singlet); 7.24 to to 7.32 (4H, multiplet); 7,50-7,58 (2H, multiplet); of 7.70 (1H, triplet, J=8 Hz); 7,89 (1H, doublet, J=8 Hz).

Preparation 6. (41-Methylbiphenyl-2-yl)Glyoxylic acid.

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A solution of 1.73 g of NaOH in 90 ml of water are added to a solution 9,16 g of methyl-(41-methylbiphenyl-2-yl)glyoxylate (obtained as described in preparation 5) in 90 ml of methanol and the resulting mixture was stirred at room temperature for 2 hours and Then the methanol is distilled off under reduced pressure and distilled water solution was added 14.4 ml 3h. hydrochloric acid to achieve a pH of 2. Spin-off of the target compound is extracted with ethyl acetate and extru the form of crystals with so pl. 111-112oC.

An NMR spectrum (CDCl3, 270 MHz) / million-1: a 2.36 (3H, singlet); 7,13-7,22 (4H, multiplet); 7,46-7,52 (2H, multiplet); the 7.65 (1H, triplet, J=7 Hz); 7,80 (1H, doublet, J=7 Hz).

Preparation 7. Tert-butyl(41-methylbiphenyl-2-yl)glyoxylate, being.

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To a solution of 6.35 g (41-methylbiphenyl-2-yl)Glyoxylic acid (obtained as described in preparation 6) in 40 ml of methylene chloride is added 2 drops of dimethylformamide, are then added dropwise 15 ml of oxalicacid at room temperature. The resulting mixture was stirred at room temperature for 1 h and 3 h at 35oC. the Solution is evaporated under reduced pressure, the residue is mixed with benzene and the mixture is evaporated under reduced pressure. This procedure was repeated once more and the crystalline residue is dissolved in 30 ml of tetrahydrofuran. To the solution is added dropwise at (-40)-(-30)oC a solution of 4.0 g of tert-butoxide potassium in 60 ml of tetrahydrofuran and the mixture is stirred at room temperature for 2 h Then the reaction mixture are added water and diethyl ether and hexane (2: 1 by volume). The organic layer was separated, washed with water and dried over anhydrous MgSO4. The solvent is distilled off under reduced pressure, the residue chromatographic on a column of silica gel, use the and. The resulting product crystallized upon standing at room temperature, yielding crystals with so pl. 50-51oC.

An NMR spectrum (CDCl3, 270 MHz), million-1: to 1.16 (9H, singlet); of 2.38 (3H, singlet); 7,20-7,26 (4H, multiplet); 7,39 was 7.45 (2H, multiplet); 7,47-to 7.61 (1H, multiplet); 7,73-to 7.68 (1H, multiplet).

Preparation 8. Methyl (41-bromomethylbiphenyl-2-yl)glyoxylate, being.

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Suspension 3,66 g of methyl (41-methylbiphenyl-2-yl)glyoxylate (obtained as described in preparation 5), of 2.56 g of N-bromosuccinimide and 0.1 g of benzoyl peroxide in 100 ml of carbon tetrachloride is stirred while boiling under reflux and 3 h at training tungsten lamp 200 watts. Then the reaction mixture was washed with aqueous solution of NaHCO3and saturated aqueous NaCl solution in this order and dried over anhydrous MgSO4. The solvent is distilled off under reduced pressure, the crystalline residue was washed with diisopropyl ether and receive 3,68 g of target compound with so pl. 93-96oC.

An NMR spectrum (CDCl3, 270 MHz), million-1: to 3.36 (3H, singlet); a 4.53 (2H, singlet); 7,29 (2H, doublet, J=7 Hz); 7,44-of 7.55 (4H, multiplet); a 7.62 to 7.68 (1H, multiplet); to 7.84 (1H, doublet, J=6.5 Hz).

Preparation 9. Tert-Butyl (41-bromomethylbiphenyl-2-yl)glyoxylate, being.

An NMR spectrum (CDCl3, 270 MHz), million-1: of 1.18 (3H, singlet); to 4.52 (2H, singlet); 7,27 (1H, doublet, J=7 Hz); to 7.32 (1H, doublet, J=7 Hz); 7,41-7,52 (4H, multiplet); a 7.62 (1H, triplet, J=7 Hz); 7,73 (1H, doublet, J=7 Hz).

The drug 10. 41-Methyl-2-[hydroxy(tetrazol-5-yl)methyl]biphenyl.

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The solution to 4.73 g-hydroxy-(41-methylbiphenyl-2-yl) acetonitrile (obtained as described in preparation 2) and 20.8 g tributylamine in 60 ml of toluene is stirred for 20 h at 100oC. At the end of this time the reaction mixture is added a solution of 4.05 g of NaOH in 200 ml water and the resulting mixture was stirred at room temperature for 1 h, the Reaction mixture was washed with hexane three times and added to 8.5 ml of concentrated hydrochloric acid to acid reaction. The isolated compound is extracted with ethyl acetate and dried over anhydrous Na2SO4. The solvent is distilled off under reduced pressure and obtain 3.57 g of target compound in the form of an amorphous solid wesr> The drug 11. 41-Methyl-2-[hydroxy-(2-trailersa-5 - yl)methyl]biphenyl.

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The solution 5,62 g 41-methyl-2-[hydroxy(tetrazol-5-yl)methyl] biphenyl (obtained as in preparation 10) and to 3.92 g Fritillaria in 100 ml of pyridine is stirred for 4.5 hours at 100oC. Then the reaction mixture is concentrated by evaporation under reduced pressure and the residue is dissolved in ethyl acetate. The solution is washed with water, 0.5% solution of K2CO3and a saturated NaCl solution in this order and dried over anhydrous Na2SO4. The solvent is distilled off under reduced pressure, the residue chromatographic through a column of silica gel, using as eluent a mixture of hexane and ethyl acetate (2:1 by volume), and gain of 2.68 g of the target compound as an amorphous substance.

An NMR spectrum (CDCl3, 270 MHz), million-1: is 2.37 (3H, singlet); of 6.20 (1H, singlet); 7,05-7,38 (22H, multiplet); 7,55-to 7.59 (1H, multiplet).

Preparation 12. 41-Methyl-2-(2-trailersa-5 - ylcarbonyl)biphenyl.

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To a solution 2,48 g 41-methyl-2 - [hydroxy(2 - trailersa-5-yl)methyl] biphenyl (obtained as described in preparation 11) in 50 ml of methylene chloride add 8 g of manganese dioxide and the resulting mixture was stirred at room temperatue. The remainder chromatographic on a column of silica gel, using as eluent a mixture of hexane and ethyl acetate (3: 1 by volume), and 1.20 g of target compound in the form of crystals with so pl. 145-147oC (decomposition).

An NMR spectrum (CDCl3, 270 MHz) / million-1: of 2.25 (3H, singlet); 6,82-6,92 (9H, multiplet); 7,24-7,40 (11H, multiplet); 7,46 (1H, triplet, J=7.5 Hz); to 7.59 (1H, triplet, J=7.5 Hz); 7,74 (1H, doublet, J=8.5 Hz).

Preparation 13. 41The methyl bromide-2-(2-trailersa-5 - ylcarbonyl)biphenyl.

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A suspension of 400 mg 41-methyl-2-(2-trailersa-5 - ylcarbonyl)biphenyl (obtained as described in preparation 12), 150 mg of N-bromosuccinimide and 20 mg of benzoyl peroxide is treated by the procedure described in preparation 8 and obtain the target compound in the form of crystalline powder with so pl. 161-163oC (decomposition).

An NMR spectrum (CDCl3, 270 MHz), million-1: 4,34 (2H, singlet); at 6.84-6.87 in (5H, multiplet); 6,98 (2H, doublet, J=8.0 Hz); 7,10 (2H, doublet, J=8.0 Hz); 7.24 to 7,39 (11H, multiplet); of 7.48 (1H, triplet, J=7.5 Hz); to 7.61 (1H, triplet, J=7.5 Hz); 7,74 (1H, doublet, J=6.0 Hz).

1. Derivatives of biphenyl General formula I

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where A is group of formula IIa, IIb or IIc

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R1- C1- C6-alkyl, C2- C6alkenyl,3- C8qi is or3- C8-cycloalkyl;

R5simple link or1- C4-alkylen;

Y is oxygen, sulfur or aminogroups (=NH);

R2is hydrogen, halogen, unsubstituted WITH1- C6-alkyl, unsubstituted WITH2- C6alkenyl, unsubstituted WITH3- C8-cycloalkyl, the hydroxy-group, amino group, WITH1- C6-alkylamino, dialkylamino, in which each alkyl part has 1 to 6 carbon atoms, formyl, C2- C7-alkylsulphonyl,1- C6-alkoxygroup,1- C6-allylthiourea, cyano, a nitro-group, substituted C1- C6-alkyl, which is substituted by at least one Deputy, selected from the substituents defined below substituted WITH2- C6alkenyl, which is substituted by at least one Deputy, selected from the substituents defined below, or substituted C3- C8-cycloalkyl, which is substituted by at least one Deputy, selected from the substituents defined below;

R3is hydrogen, C1- C6-alkyl, carboxypropyl, protected carboxypropyl, carbarnoyl or tetrazol-5-yl;

X is a group of formula-CH=, -N= or-C(COOR6)=, where R6is hydrogen or CA, protected carboxypropyl or tetrazol-5-yl;

substituents selected from halogen atoms, hydroxy groups, amino groups, WITH1- C6-alkylamino, dialkylamino in which each alkyl has 1 to 6 carbon atoms, formyl, C2- C7-alkylsulphonyl,1- C6-alkoxygroup,1- C6-alkylthio, cyano groups or nitro groups,

or their pharmaceutically acceptable salts and/or esters.

2. Connection on p. 1, characterized in that the a group of the formula IIa and R1- C2- C4-alkyl, C3- C5alkenyl, alkoxyalkyl in which alkoxygroup has 1 to 3 carbon atoms and the alkyl part has 1 to 2 carbon atoms, alkylthiomethyl in which allylthiourea has 1 to 3 carbon atoms and the alkyl part has 1 to 2 carbon atoms, or allylthiourea with 1 to 3 carbon atoms.

3. Connection on p. 1, characterized in that the a group of the formula IIa and R2is hydrogen, halogen, C1- C6-alkyl, C3- C6alkenyl or substituted C1- C6-alkyl substituted by halogen or hydroxy-group.

4. The compound according to any one of paragraphs.1 to 3, characterized in that the a group of the formula IIa and R3- carboxypropyl, substituted Karbala IIa and Z - simple bond, methylene or vinile.

6. Connection at one PM.1 to 5, characterized in that the a group of the formula IIa and R1is ethyl, propyl, butyl, 1-propenyl, 1-butenyl, 2-butenyl, methoxymethyl, ethoxymethyl, methylthiomethyl, ethylthiomethyl, methylthio or ethylthiourea.

7. Connection on p. 6, characterized in that the a group of the formula IIa and R1is ethyl, propyl or butyl.

8. The compound according to any one of paragraphs.1 to 7, characterized in that the a group of the formula IIa and R2- chlorine, bromine, methyl, ethyl, isopropyl, Isopropenyl, trifluoromethyl, pentafluoroethyl, hydroxymethyl, 1-hydroxyethyl, 1-hydroxy-1-methylethyl, 1-hydroxypropyl, 1-hydroxy-1-methylpropyl, 1-hydroxy-2-methylpropyl or 1-hydroxy-2,2-dimethylpropyl.

9. The compound according to any one of paragraphs.1 to 8, characterized in that the a group of the formula IIa and R2- chlorine, isopropyl, Isopropenyl, trifluoromethyl, pentafluoroethyl, 1-hydroxyethyl or 1-hydroxy-1-methylethyl, R3- carboxypropyl, protected carboxypropyl or tetrazol-5-yl.

10. The compound according to any one of paragraphs.1 to 9, characterized in that the a group of the formula IIa, R2- 1-hydroxy-2-methylpropyl or 1-hydroxy-2,2-dimethylpropyl and R3- carbarnoyl.

11. The compound according to any one of paragraphs.1 - 10, otlichayushchayasya fact, a group of the formula IIa and Z is a simple bond.

13. The compound according to any one of paragraphs.1 - 12, characterized in that the a group of the formula IIa, R1is ethyl, propyl, butyl, 1-propenyl, 1-butenyl, 2-butenyl, methoxymethyl, ethoxymethyl, methylthiomethyl, ethylthiomethyl, methylthio or ethylthiourea, R2- chlorine, bromine, methyl, ethyl, isopropyl, Isopropenyl, trifluoromethyl, pentafluoroethyl, hydroxymethyl, 1-hydroxymethyl, 1-hydroxy-1-methylethyl, 1-hydroxypropyl, 1-hydroxy-1-methylpropyl, 1-hydroxy-2-methylpropyl or 1-hydroxy-2,2-dimethylpropyl, R3- carboxypropyl, protected carboxypropyl, carbarnoyl or tetrazol-5-yl, Z is a simple bond or methylene.

14. The compound according to any one of paragraphs.1 - 13, characterized in that the a group of the formula IIa and R1is ethyl, propyl or butyl, R2- chlorine, isopropyl, Isopropenyl, trifluoromethyl, pentafluoroethyl, 1-hydroxyethyl or 1-hydroxy-1-methylethyl, R3- carboxypropyl, protected carboxypropyl or tetrazol-5-yl and Z is a simple bond.

15. The compound according to any one of paragraphs.1 to 14, characterized in that the a group of the formula IIa, R1is ethyl, propyl or butyl, R2- 1-hydroxy-2-methylpropyl or 1-hydroxy-2,2-dimethylpropyl, R3- carbarnoyl, and Z is a simple bond.

16. Connection on p. 1 which alkoxygroup has 1 - 3 carbon atoms and the alkyl has 1 to 2 carbon atoms, alkylthiomethyl in which allylthiourea has 1 to 3 carbon atoms and the alkyl has 1 to 2 carbon atoms, alkoxygroup with 1 to 3 carbon atoms or allylthiourea 1 to 3 carbon atoms.

17. Connection on p. 1 or 16, characterized in that the a group of the formula IIb and R2is hydrogen, halogen or1- C4-alkyl.

18. Connection PP. 1, 16 or 17, characterized in that the a group of the formula IIb and R3is hydrogen, C1- C4-alkyl, carboxypropyl, protected carboxypropyl or tetrazol-4-yl.

19. Connection PP.1, 16, 17 or 18, characterized in that the a group of the formula IIb, and Z is a simple bond, methylene or vinile.

20. The compound according to any one of paragraphs.1 or 16 to 19, characterized in that the a group of the formula IIb and X is a group of formula-CH=, -N= or-C(COOR6)=, where R6is hydrogen or a protective radical for carboxypropyl.

21. The compound according to any one of paragraphs.1 or 16 to 20, characterized in that the a group of the formula IIb and R1- ethyl, drank, cyclopropyl, methoxy, ethoxy-, propoxy-, methylthio -, or ethylthiourea.

22. The compound according to any one of paragraphs.1 or 16 to 21, characterized in that the a group of the formula IIb and R1is ethyl, propyl, cyclopropyl, ethoxy the formulas IIb and R2is hydrogen, fluorine, chlorine, methyl, ethyl or isopropyl.

24. The compound according to any one of paragraphs.1 or 16 to 23, characterized in that the a group of the formula IIb and R2is hydrogen or methyl.

25. The compound according to any one of paragraphs.1 or 16 to 24, characterized in that the a group of the formula IIb and R3is hydrogen, methyl, ethyl, carboxypropyl, protected carboxypropyl or tetrazol-5-yl.

26. The compound according to any one of paragraphs.1 or 16 to 25, characterized in that the group of the formula IIb and R3is hydrogen, methyl, carboxypropyl, protected carboxypropyl or tetrazol-5-yl.

27. The compound according to any one of paragraphs.1 or 16 to 26, characterized in that the a group of the formula IIb, and Z is a simple bond.

28. The compound according to any one of paragraphs.1 or 16 to 27, characterized in that the a group of the formula IIb and R1is ethyl, propyl, cyclopropyl, methoxy, ethoxy-, propoxy-, methylthio-, or ethylthiourea, R2is hydrogen, fluorine, chlorine, methyl, ethyl or isopropyl, R3is hydrogen, methyl, ethyl, carboxypropyl, protected carboxypropyl or tetrazol-5-yl, X is a group of formula-CH=, -N= or-C(COOR6)=, where R6is hydrogen or a protective radical for carboxypropyl, and Z is a simple bond or methylene.

29. The compound according to any one of paragraphs.1 or 16 to 28, characterized in that the A - group is Teal, R3is hydrogen, methyl, carboxypropyl, protected carboxypropyl or tetrazol-5-yl, X is a group of formula-CH=, -N=, or C(COOR6)=, where R6is hydrogen or a protective radical for carboxypropyl, and Z is a simple bond.

30. Connection on p. 1, characterized in that the a group of the formula IIc, and R1- C2- C4-alkyl, alkoxyaryl in which alkoxygroup has 1 to 3 carbon atoms, or alkylthiomethyl in which allylthiourea has 1 to 3 carbon atoms.

31. Connection on p. 1 or 30, characterized in that the a group of the formula IIc, and R2is hydrogen, halogen or1- C4-alkyl.

32. Connection PP.1, 30 or 31, characterized in that the a group of the formula IIc, and R3is hydrogen, C1- C4-alkyl, carboxypropyl, protected carboxypropyl or tetrazol-5-yl.

33. The compound according to any one of paragraphs.1 - 30 to 32, characterized in that the a group of the formula IIc, and X is a group of formula-CH= or-N=.

34. The compound according to any one of paragraphs.1 or 30 to 33, characterized in that the a group of the formula IIc, and Z is a simple bond, methylene or vinile.

35. The compound according to any one of paragraphs.1 - 30 to 34, characterized in that the a group of the formula IIc, and R1is ethyl, propyl, butyl, 2-methoxyethyl or 2-methylthioethyl.

3l, 2-methoxyethyl or 2-methylthioethyl.

37. The compound according to any one of paragraphs.1 - 30 to 36, characterized in that the a group of the formula IIc, and R2is hydrogen, fluorine, chlorine, methyl, ethyl or isopropyl.

38. The compound according to any one of paragraphs.1 - 30 to 37, characterized in that the a group of the formula IIc, and R2is hydrogen or methyl.

39. The compound according to any one of paragraphs.1 - 30 to 38, characterized in that the a group of the formula IIc, and R3is hydrogen, methyl, ethyl, carboxypropyl, protected carboxypropyl or tetrazol-5-yl.

40. The compound according to any one of paragraphs.1 - 30 to 39, characterized in that the a group of the formula IIc, and R3- carboxypropyl, protected carboxypropyl or tetrazol-5-yl.

41. The compound according to any one of paragraphs.1 30 or 40, characterized in that the a group of the formula IIc, and X is a group of formula-CH=.

42. The compound according to any one of paragraphs.1 - 30 to 41, characterized in that the a group of the formula IIc, and R1is ethyl, propyl, butyl, 2-methoxyethyl or 2-methylthioethyl, R2is hydrogen, fluorine, chlorine, methyl, ethyl or isopropyl, R3is hydrogen, methyl, ethyl, carboxypropyl, protected carboxypropyl or tetrazol-5-yl, X is a group of formula-CH= or-N=, and Z is a simple bond or methylene.

43. The compound according to any one of paragraphs.1 - 30 of 42 different teli methyl, R3- carboxypropyl, protected carboxypropyl or tetrazol-5-yl, X is a group of formula-CH=, and Z is a simple bond.

44. The compound according to any one of paragraphs.1 to 43, wherein R3or In a protected carboxypropyl or R6- protective radical; alkanoyloxy in which alkanoyl has 2 to 5 carbon atoms and the alkyl has 1 to 2 carbon atoms, alkoxycarbonylmethyl in which alkoxygroup has 1 to 4 carbon atoms and the alkyl has 1 to 2 carbon atoms, cycloalkylcarbonyl in which cycloalkyl has 5 to 6 carbon atoms and the alkyl has 1 to 2 carbon atoms or (5-methyl-2-oxo-1,3 - dioxolan-4-yl)methyl.

45. The compound according to any one of paragraphs.1 - 44, characterized In that carboxypropyl or tetrazol-5-yl.

46. The compound according to any one of paragraphs.1 to 45, wherein R3or In a protected carboxypropyl or R6- protective radical for carboxypropyl and protective radical: acetoxymethyl, pivaloyloxymethyl, ethoxycarbonylethyl, isopropoxycarbonyloxymethyl, 1-ethoxycarbonylethyl, 1-isopropoxycarbonyloxymethyl, cyclohexyloxycarbonyloxy, 1-cyclohexyloxycarbonyloxy or (5-methyl-2-oxo-1,3 - dioxolan-4-yl)methyl.

47. Connection on p. 1, chosen from:
the oxyethyl)-1-[2'- oxalobacter-4-yl)methyl]-2-propylimidazol-5 - carboxylic acid,

4-isopropyl-1-[(2'-oxalobacter - 4-yl)methyl]-2 - propylimidazol-5-carboxylic acid,

4-(1-hydroxy-2-methylpropyl)-1- [(2'-oxalobacter-4-yl)methyl]- 2-propylimidazol-5-carboxamide,

4-(1-hydroxy-2,2-dimethylpropyl)- 1-[(2'-oxalobacter-4-yl)- methyl]-2-propylimidazol-5-carboxamide,

pivaloyloxymethyl-4-(1-hydroxy - 1-methylethyl)-1-[2'- oxalobacter-4-yl)methyl]- 2-propylimidazol-5-carboxylate,

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

{ 4'-[4-(1-hydroxy-1-methylethyl)- 2-propyl-5-(tetrazol-5-yl)- imidazol-1-ylmethyl]biphenyl-2-yl} Glyoxylic acid,

2-ethyl-5,7-dimethyl-3(2'- oxalobacter-4-yl)methyl - 3H-imidazo-[4,5-b] pyridine,

5,7-dimethyl-3-(2'-oxalobacter - 4-yl)methyl-2-propyl - 3H-imidazo[4,5-b] pyridine,

2-ethyl-1-[(2'-oxalobacter-4 - yl)methyl]benzimidazole-7-carboxylic acid,

pivaloyloxymethyl-2-ethyl-1- [(2'-oxalobacter-4-yl) methyl] benzimidazole-7-carboxylate,

(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl - 2-ethoxy-1-[(2'- oxalobacter-4-yl)methyl]benzimidazole - 7-carboxylate,

2-{N - [(2'-oxalobacter - 4-yl)methyl]-N - propylamino}nicotinic acid and

(N-propyl-N-{4'- [3-(tetrazol-5-yl)pyrid-2 - yl}aminomethyl]biphenyl - 2-yl)gli is the treatment of compounds PP.1 - 47, characterized in that carry out the reaction of the compound of formula III

Ax- H, III

where Axmatter And above

or group of formulas

< / BR>
< / BR>
< / BR>
where R1a, R2aand X1have the meanings given for R1, R2and X respectively, but in which any primary or secondary amino group, any carboxypropyl or any tetrazol-5-yl protected;

Z has the value

with the compound of the formula IV

< / BR>
where B1protected carboxypropyl or protected tetrazol-5-yl;

V - halogen,

and, if necessary, turn the CN-group of compound III in the appropriate group, R3remove the protective group from the selection of the target product in a free form, a salt or ester.

49. The method of obtaining the compounds according to paragraphs.1 - 47, in which a represents a group of formula IIb, wherein carry out the reaction of the compound of formula III

< / BR>
where the precursor groups of formula IIb and has the formula VI'

< / BR>
where R2a, R3aX' have the meanings given for R2, R3and X respectively, but in which any primary or secondary amino group, any carboxypropyl or luminaries formula IV

< / BR>
where B1protected carboxypropyl or protected tetrazol-5-idgruppo;

V is a halogen atom,

obtaining the compounds of formula VII

< / BR>
then remove the protective group R7in the resulting compound of the formula VII and receive compound of the formula VIII

< / BR>
then restore the nitro-group in the compound of formula VIII to obtain the compounds of formula IX

< / BR>
and spend the reaction of compound IX with the compound of the formula XIV

R1aC(OR8)3XIV

where R1ahas the meaning specified in paragraph 48;

R8- C1- C6-alkyl,

obtaining the compounds of formula X

< / BR>
and, if necessary, remove any protective group and/or receive salt, etherification or diesterification compound of formula X.

 

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< / BR>
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