Aromatic amidinov derivative and pharmaceutical composition

 

(57) Abstract:

Describes the new aromatic amidinov derivatives of General formula I, where R1is a hydrogen atom or a lower alkoxygroup; R2is a hydrogen atom, a lower alkyl group, lower alkoxygroup, carboxyl group, carboxialkilnuyu group with 2 to 5 carbon atoms or alkoxycarbonyl group with 2 to 5 carbon atoms; R3is a hydrogen atom, carboxyl group, carboxialkilnuyu group with 2 to 5 carbon atoms, alkoxycarbonylmethyl group with 3 to 6 carbon atoms, carboxyaniline group with 2 to 5 carbon atoms and alkoxycarbonylmethyl group with 3 to 6 carbon atoms; R4is a hydrogen atom, hydroxyl group or lower alkoxygroup; n = 0, 1, 2; And - Allenova group with 1 to 4 carbon atoms which may be substituted by one or two substituents selected from hydroxyalkyl group with 1 to 4 carbon atoms, carboxyl, alkoxycarbonyl group with 2 to 5 carbon atoms and carboxialkilnuyu group with 2 to 5 carbon atoms; X is a simple bond, oxygen atom or sulfur or a carbonyl group; Y is a saturated or unsaturated 5 - or 6-membered heterocyclic fragment, having one or two heteroatoms, selected and what oppai, carbamoyl, mono - or dialkylamino, alkanolamides, lower alkyl, lower alkanoyl, alkoxycarbonyl, benzimidazolium, alkanolamine, alkylamine; saturated or unsaturated 5 - or 6-membered cyclic hydrocarbon fragment, which can be substituted aminoalkyl group or alkanolammonium group, or Y is an amino group which may be substituted pyrrolidinyl or pyridinoline group; and a group of formula II is a group selected from indolyl, benzofuranyl, benzothiazyl, benzothiazolyl, naphthyl, tetrahydronaphthyl, benzimidazolyl, or its pharmaceutically acceptable salt. Target products have the ability to strong antikoaguliruyuschee action through reversible inhibition of activated coagulation factor ("F"). Also described anticoagula composition based on compounds of the formula (I). 11 C. and 1 C.p. f-crystals, 5 PL.

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The invention relates to aromatic amedieval derivatives and their salts, which have the ability to strong antikoaguliruyuschee action through reversible inhibition of activated coagulation factor, factor X (hereinafter referred to "FXA"), and to what their basis, intended for the treatment or prevention of thrombosis or embolism, and containing aromatic amidinov derivative or its salt as an active ingredient.

To date, attempts were made to develop antithrombin as antithrombotic agents. However, it is known that such an antithrombotic agent may cause bleeding and creates difficulties to stop the bleeding, because it inhibits blood clotting and platelet aggregation induced by thrombin. To solve this problem, attempts were made to obtain antikoaguliruyuschee means not by inhibiting thrombin, and by another inhibitory mechanism. As a result of the research was obtained 1,2-bis(5-amidino-2-benzofuranyl)-ethane (hereinafter referred to "DABE"), which has the following formula (2), and anticoagulate which is based on FXa-inhibiting (Thrombosis Research, vol. 19, pp. 339-34, 1980):

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However, the connection DABE has the disadvantages that it has any abscopal action against FXa, and thrombin, which may not be sufficiently separated from each other; in addition, it has a very niskayuna anticoagulative funds with good clinical effect special efforts should be devoted to the development of the medicinal product, with a highly specific and strong FXa - inhibiting activity, good solubility, and which is effective when administered orally.

Based on the above considerations, the authors of the present invention have conducted intensive studies related to the synthesis of various types of aromatic Akudovich derivatives and evaluation of their pharmacological properties. As a result of these studies it was found that aromatic amidowe derivative represented by the General formula (I) or its salt, has excellent solubility, strong antikoaguliruyuschim action, due to its highly specific and reversible FXa-inhibiting activity, even in the case of oral administration, and can therefore be used as pharmaceuticals for the prevention and treatment of various diseases associated with thrombosis and embolism. Based on the above research and has been developed by the present invention.

Thus, the present invention relates to aromatic medinova production, having the General formula (I):

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where R1represents a hydrogen atom or a lower alkoxygroup;

R2PR is alkiline group with 2-5 carbon atoms or alkoxycarbonyl group with 2-5 carbon atoms;

R3represents a hydrogen atom, carboxyl group, carboxialkilnuyu group with 2-5 carbon atoms, alkoxycarbonylmethyl group with 3-6 carbon atoms, carboxylcontaining group with 2-5 carbon atoms, alkoxycarbonylmethyl group with 3-6 carbon atoms or alkoxycarbonyl group with 2-5 carbon atoms;

R4represents a hydrogen atom, a hydroxyl group or a lower alkoxygroup;

n = 0, 1, 2;

A is alkalinous group with 1-4 carbon atoms which may be substituted by one or two substituents selected from hydroxyalkyl group with 1-4 carbon atoms, carboxyl, alkoxycarbonyl group with 2-5 carbon atoms and carboxialkilnuyu group with 2-5 carbon atoms;

X is a simple bond, oxygen atom or sulfur, or carbonyl group;

Y is a saturated or unsaturated 5 - or 6-membered heterocyclic fragment having one or two heteroatoms selected from nitrogen atoms, oxygen, sulfur, or cyclic hydrocarbon fragment, which can be substituted by aminogroups, carbamoyl, mono - or dialkylamino, alkanolamides, lower alkyl, lower alkanoyl, alkoxycarbonyl, benzylidene fragment can also be substituted aminoalkyl group or alkanolammonium group; or Y is an amino group which may be substituted pyrrolidinyl or pyridinoline group;

a group of the formula I

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is a group selected from indolyl, benzofuranyl, benzothiazyl, benzothiazolyl, naphthyl, tetrahydronaphthyl, benzimidazolyl; or its pharmaceutically acceptable salt.

The present invention also relates to a pharmaceutical composition having antikoaguliruyuschim action, containing the compound of General formula (I) or its salt as the active agent and special additives.

In the compound of the present invention represented by the General formula (I), any straight, branched or cyclic alkyl group with 1-6 carbon atoms can be used as a lower alkyl group. Examples of such alkyl groups can serve as methyl, ethyl, propyl, isopropyl, butyl, sec - or tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., Lower alkoxy group may have 1 to 6 carbon atoms. Examples of such groups can serve as methoxy, ethoxy-, propoxy-, isopropoxy, butoxy-, second - or tributoxy group, etc. Alkoxycarbonyl, alkoxycarbonylmethyl, carboxyaniline, alkoxide is Ino 1-4 carbon atoms. Examples alkoxycarbonyl groups are methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc. Examples carboxialkilnuyu groups are carboxymethyl, carboxyethyl, carboxypropyl, etc. Examples alkoxycarbonylmethyl groups are methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonyl, methoxycarbonylethyl, ethoxycarbonylethyl, methoxycarbonylpropionyl, ethoxycarbonylbutyl, etc., Examples of carboxylate groups are carboxymethoxy, carboxymethoxy, carboxyphenoxy group, etc., Examples of alkoxycarbonyl groups are ethoxycarbonylmethoxy, ethoxycarbonylmethoxy, propoxycarbonyl, ethoxycarbonylmethoxy, ethoxycarbonylmethoxy, etc., examples of the hydroxyalkyl groups are hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, etc. Examples alkalinous group, having 1-4 carbon atoms and represented by A are methylene, ethylene, trimethylene, tetramethylene etc.

Saturated or unsaturated heterocyclic fragment with 5 or 6 members may contain preferably one or two heteroatoms selected from nitrogen atoms, oxygen, sulfur. Examples of heterocyclic rings of the roll, imidazol, pyrazin, pyrrolidine, piperidine, morpholine, etc., Most preferred are pyrrolidine and piperidine containing as the heteroatom one nitrogen atom. Examples of saturated or unsaturated cyclic hydrocarbon moiety may serve as cyclopentyl, cyclohexyl, etc., Examples aminoalkyl groups are aminomethyl, aminoethyl, aminopropyl, etc., Examples of the substituents for the above-mentioned heterocyclic rings and cyclic hydrocarbon rings can serve preferably lower alkyl, lower alkanoyl, carbarnoyl, mono - or dialkylamino, alkanolamides, benzamido, alkylamino, alkanolamine, imino, alkoxycarbonyl, and more preferably, alkanolamides. Examples of the substituents for the above-mentioned amino groups and aminocyte aminoalkyl groups are pyridinyl or pyrrolidinyl.

The compounds of formula (I) of the present invention may be optical isomers or stereoisomers due to the presence of asymmetric carbon atom. Scope of the present invention includes optical isomers, stereoisomers of the compounds of the present invention, and their mixtures.

Salts of compounds of formula (I) of the present invention can bee suitable salts include: salts of inorganic acids, such as hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate, etc.; salt organicheskoi sulfonic acids, such as methanesulfonate, 2-hydroxyethanesulfonic, p-toluensulfonate and etc.; salts of organic carboxylic acids, such as acetate, propanoate, oxalate, malout, succinate, glutarate, adipate, tartarate, maleate, malate, mandelate, etc.

Below are examples of the most preferred compounds of the present invention, which can be represented by the formula (I):

2-[4[(1-acetimidoyl-3-pyrrolidinyl)oxy]phenyl]-3-(7-amidino - 2-naphthyl)propionic acid or its salt;

(+)-2-[4-[[((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy] -phenyl]- 3-(7-amidino-2-)naphthyl)propionic acid or its salt;

(2S)-2-[4-[(3S)-1-acetimidoyl-3-pyrrolidinyl)oxy]-phenyl]-3- (7-amidino-2-naphthyl)propionic acid or its salt;

(2R)-2-[4-[((3R)-1-acetimidoyl-3-pyrrolidinyl)oxy] -phenyl]-3- (7-amidino-2-naphthyl)propionic acid or its salt;

2-[4-[(1-acetimidoyl-2-pyrrolidinyl)methoxy] -phenyl] -3- (5-amidines[b]Tien-2-yl)propionic acid or its salt;

(+)-2-[4-[((2S)-1-acetimidoyl-2-pyrrolidinyl)methoxy] -phenyl]-3- (5-amidines[b]Tien-2-yl)propionic acid or its salt;

2-[4-[(1-acetimidoyl-4-piperidinyl)oxy] -phenyl] -3- (7-AMI is naphthyl)propionic acid or its salt;

the hydrochloride pentahydrate (2S)-2-[4-[((3S)-1-acetimidoyl-3 - pyrrolidinyl)oxy]-phenyl]-3-(7-amidino-2-naphthyl)propionic acid.

In General, the compound of formula (I) of the present invention can be obtained, for example, in accordance with the following reaction formulas. Namely, a nitrile compound of the formula (3) is subjected to interaction with alcohol (R5OH) in the presence of galgenwaard. The resulting imidate (4) is subjected to reaction with ammonia to obtain an aromatic amidnogo derivative (1a).

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In the above formulas, R1, R2, R3, R4, n, A, X, Y, and

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are the same as defined above, and R5is a lower alkyl group.

Below is a detailed description of the above reaction scheme. The reaction of the nitrile compound (3) with alcohol (R5OH) can be carried out, for example, by reaction of the nitrile (3) with an equimolar or excess amount of the alcohol (R5OH), having from 1 to 6 carbon atoms, such as methanol, ethanol, propanol, etc., in the presence of galgenwaard, such as hydrogen chloride, bromovalerate, etc. If necessary, can be used rastvorjaemyh hydrocarbons, such as chloroform, dichloromethane, etc.; aprotic solvents, such as benzene, etc. and mixtures thereof. In General, the reaction proceeds at temperatures from -20 to 60oC for from 3 to 220 hours. Preferably, if the reaction proceeds at temperatures from -8 to 30oC during the period of time from 10 to 96 hours, in the presence of excess methanol or ethanol, and halogenated hydrocarbon solvent such as chloroform or dichloromethane.

The reaction of the thus obtained of imidate (4) with ammonia can be carried out through the interaction of the specified imidate (4) with ammonia in a solvent or mixture of solvents selected from alcohols having 1-4 carbon atoms, such as ethanol, propanol, etc.; aliphatic ethers, such as diethyl ether and so on; halogenated hydrocarbons such as chloroform, etc.; aprotic solvents, such as benzene, etc. ; and N, N'-dimethylformamide and dimethyl sulfoxide. The reaction can be conducted at temperatures from -10 to 140oC during the period of time from 0.5 to 200 hours, and preferably at a temperature from -8oC to 30oC during the period of time from 10 to 96 hours in ethanol.

Eslicarbazepine group, this carboxyl or alkoxycarbonyl group is subjected to esterification by reaction of formation of imidate, or by interesterification in the interaction of ester with the alcohol (R5OH). As a result, since the carboxyl group in the compound (1a) obtained by this reaction is esterified, the compound (1a) it is necessary to hydrolyze if you get aromatic amidinov derivative having free hydroxyl group.

The hydrolysis reaction can be carried out by treating the compound (1a) in an aqueous solution of an inorganic acid, such as hydrochloric acid, sulfuric acid, etc. or organic acids, such as tolilsulfonil, etc. at a temperature of from -10oC to temperature distillation, and preferably from -5oC to a temperature of distillation, during the period of time from 0.5 to 550 hours, and preferably from 0.5 to 350 hours.

If the compound (1a) contains a group susceptible to hydrolysis with a strong acid, to the reaction of hydrolysis, it is preferable to block amidinopropane protecting group such as tert-butoxycarbonyl or similar group, followed by hydrolysis slena through reaction of the compound (1a) with 2-(tert-butoxycarbonyloxyimino)-2-phenyl-acetonitrile in water, methanol, ethanol, tetrahydrofuran, dioxane, acetone or their mixtures, in the presence of a base such as 1,8-diazabicyclo[5.4.0] -7-undecene or so on, This reaction can be carried out at a temperature of from 0oC to 50oC, and preferably from 5oC to 30oC, during the period of time from 0.5 to 48 hours, and preferably from 1 to 24 hours.

Ester hydrolysis protected connection and subsequent unlocking can be carried out by treating the protected compound with an aqueous solution of sodium hydroxide or potassium hydroxide, and then with hydrochloric acid, in water or water-containing solvent, such as ethanol, methanol, tetrahydrofuran, dioxane or similar hydrolysis Reaction of ester can be carried out at a temperature of from 0oC to 50oC, and preferably from 5oC to 30oC, during the period of time from 0.5 to 48 hours, and preferably from 1 to 24 hours. The reaction unlocking can be carried out at a temperature of from 0oC to 60oC, preferably at 25oC, during the period of time from 0.5 to 24 hours, and preferably from 1 to 6 hours.

If the group A compounds (1a) two alkoxycarbonyl group associated with one and the processes of reaction scheme:

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In the above formulas each l = 1, m = 0 or 1, and R1, R2, R3, R4, R5, n, X, Y, and

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are the same as defined above.

This reaction can be carried out in an aqueous solution of an inorganic acid, such as hydrochloric acid, sulfuric acid, etc. or organic acids, such as tolilsulfonil or etc., at temperatures from -20oC to temperature distillation, and preferably from -5oC to a temperature of distillation, during the period of time from 0.5 to 550 hours, and preferably from 0.5 to 350 hours.

If the compounds of the present invention of formula (I) obtain the compound (1e) having in its group isidorou group, it may be obtained by reaction of compound (1d) with a primary or secondary amino group in its group Y, with imitator compound (5) according to the following reaction scheme:

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In the above formulas, Y1represents the number of the aforementioned groups Y having as Deputy primary or secondary amino group, Y2represents another series of the aforementioned groups Y having as Deputy isidorou group; each of R6and R71, R2, R3, R4, n, A, X, and

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are the same as defined above.

This reaction can be carried out, for example, by reaction of the compound (1d) with an equimolar or excess amount of imidate (5) in the presence of a base such as triethylamine, hydroxyl sodium hydroxide or potassium, etc., in water or a solvent or mixture of solvents selected from, for example, alcohols having 1-4 carbon atoms, such as ethanol, propanol, etc., aliphatic ethers, such as diethyl ether, etc., halogenated hydrocarbons such as chloroform, etc., and N, N-dimethylformamide and dimethyl sulfoxide. This reaction can be carried out at temperatures from -20oC to 70oC during the period temporizing from 1 min to 168 hours, and preferably at a temperature of from -10oC to 40oC during the period of time from 1 minute to 72 hours.

When imicola form (1e) has alkoxycarbonyl group, this alkoxycarbonyl group can be either hydrolyzed to carboxyl group.

The hydrolysis reaction can be carried out by processing the compound (1e) in an aqueous solution of an inorganic acid, such as hydrochloric acid, -10oC to temperature distillation, and preferably from -5oC to a temperature of distillation, during the period of time from 0.5 to 550 hours, and preferably from 0.5 to 350 hours.

In accordance with the present invention, if the original connection has a Deputy, such as carboxyl group, amino group, or so on, before carrying out the desired reaction, it is preferable to protect this functional group, then the protective group is removed. On the other hand, the reaction of the educated amidine, the reaction of formation of imidate and similar reactions can be carried out without blocking such functional groups. In this case, the blocking of the primary or secondary amino group can be performed by using a protective group such as tert-butoxycarbonyl, benzyloxycarbonyl, p-nitrobenzenesulfonyl, triphenylmethyl, or etc.

In addition, alkoxycarbonyl-substituted compound can be obtained, for example, in accordance with the following reaction scheme, by carrying out hydrolysis of ester after the formation of amidine or imidate, followed by perestroika, if necessary:

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In the above formulas, R9is the th number 1 or 2, and R5, n, X, Y

and

are the same as defined above.

That is, a nitrile compound of the formula (6) is subjected to reaction with alcohol (R5OH) in the presence of galgenwaard, and the resulting connection "imitat, ester" hydrolized by treatment with base, getting derived "imitat carboxylic acid (7), which is then subjected to reaction with ammonia, resulting in a gain amidinothiourea aromatic compound (If). By esterification of the compound (If) receive the compound (Ig).

The reaction of the nitrile compound (6) with alcohol (R5OH) can be achieved by interaction of the specified nitrile compound (6) with an equimolar or excess amount of the alcohol (R5OH) having 1-6 carbon atoms, such as methanol, ethanol, propanol or etc., in the presence of galgenwaard, such as hydrogen chloride, bromovalerate, etc. If necessary, may be used a solvent or mixture of solvents, which are selected, for example, from aliphatic ethers, such as diethyl ether, etc., halogenated hydrocarbons such as chloroform, dichloromethane, etc. , aprotic solvents, such as benzene. This is the RC. Preferably, if the reaction proceeds at temperatures from -8oC to 30oC during the period of time from 10 to 96 hours in a halogenated hydrocarbon solvent such as chloroform or dichloromethane, in the presence of excess methanol or ethanol. After concentrating and drying the obtained reaction mixture, the solid residue is treated with a concentrated alkaline solution for the implementation of neutralization and ester hydrolysis, resulting in a gain derived "imitatione acid of formula (7). This reaction can be carried out, generally at a temperature of from -10oC to 60oC during the period of time from 0.2 to 5 hours, preferably at a temperature of from 0 to 25oC during the period of time from 0.5 to 2 hours, in an aqueous solution of sodium hydroxide or potassium hydroxide.

The reaction of the thus obtained derivative "imitatione acid having the formula (7), with ammonia can be carried out, for example, by interaction of a specified derivative (7) with ammonium chloride, ammonia, or mixtures thereof, in a solvent or mixture of solvents, which are selected, for example, from alcohols having 1-4 carbon atoms, such as Hatanaka as chloroform, etc.; aprotic solvents, such as benzene, etc., and N,N-dimethylformamide and dimethyl sulfoxide. This reaction typically occurs at a temperature of from -10oC to 140oC during the period of time from 0.5 to 200 hours, and preferably at a temperature from -8oC to 30oC during the period of time from 10 to 96 hours in ethanol.

Esterification amidino-the compounds of formula (1f) can be carried out, for example, through reaction of the compound (1f) with toniguy.com, such as thionyl chloride, thienylboronic and so on, in alcohol with 1-4 carbon atoms, such as ethanol, propanol, etc., This reaction is carried out mainly at a temperature of from 0oC to temperature distillation over a period of time from 10 minutes to 36 hours, preferably at a temperature of from 10oC to 60oC during the period of time from 10 minutes to 24 hours.

Crystallization of the compounds of formula (I) of the present invention may be implemented, for example, by treating the reaction solution after the reaction of the strong base (OH-type ion exchange resins, or sodium hydroxide, potassium hydroxide, etc. to bring the number of added salts, preferably up to 1. The resulting solution is treated at a temperature of from -10oC isopropanol, acetone, etc. or their mixtures, preferably in a mixture of water and ethanol.

Thus obtained aromatic amidinov derivative of the formula (I) or its salt has an excellent and specific capacity for inhibition of FXa and can be used as anticoagulative funds, as well as drugs for prevention and treatment of thrombosis and embolism. Since the compound of the formula (I) is active even when administered orally, it may be entered as oral and parenteral. The compound of the present invention can be introduced in various doses depending on symptoms, age, weight of the patient and other factors. In the case of oral administration, the usual dose of the compounds is from 5 to 1000 mg per day for an adult, and preferably from 10 to 500 mg per day for an adult. Examples of standard dosage forms of the input means are tablets, capsules, powders, granules, etc. that can be manufactured using commonly used additives, such as fillers, sizing, binders, etc. In the case of parenteral administration, the compounds of the present invention can be alausa from 0.1 to 100 mg per day, and preferably from 0.5 to 30 mg per day for an adult.

Because the connection of the present invention has a high antikoaguliruyuschim action based on its excellent FXa-inhibiting activity, it has no effect on platelets, and can be used for treatment of various diseases caused by thrombosis or embolism, such as cerebral infarction, cerebral thrombosis, cerebral embolism, transient ischemic stroke (TIA), myocardial infarction, unstable angina, infarction of the lungs, pulmonary embolism syndrome Berger, deep vein thrombosis, disseminated intravascular coagulation or generalized thrombohemorrhagic syndrome, thrombus formation after surgery on vessels, the introduction of artificial valve, percutaneous transluminal coronary angioplasty (PTCA) or percutaneous transluminal coronary recanalization (PTCP), occlusion after blood transfusion, blood clots in the artificial circulation, etc.

For a more complete illustration of the present invention listed below are reference examples, examples illustrating the present invention, and spaceytracey of the present invention, but in any case do not limit its scope.

Referential example 1. Receive (5-cyano-3-methyl-2-benzofuranyl)methyltriphenylphosphonium.

a) 13,31 g of 2-acetyl-4-bromophenol, 11,0 g ethylbromoacetate and 9.7 anhydrous potassium carbonate was heated under reflux in 70 ml of acetone for 2 hours. Any insoluble matter was removed by filtration, and the obtained filtrate was concentrated and dried off. The residue was dissolved in chloroform, washed with water, and then dried to remove solvent. The thus treated residue was washed mixed solvent consisting of ethanol and n-hexane, and any insoluble crystals were isolated by filtration. In the described procedure has been 16,82 g of ethyl 2-acetyl-4-bromophenyl of oxoacetate in the form of colorless plate crystals. So pl. 66-68oC.

b) to 16.8 g of ethyl (2-acetyl-4-bromophenyl)oxoacetate obtained according to the procedure described in stage (a), was dissolved in 100 ml of anhydrous ethanol, which previously was dissolved 1.2 g of metallic sodium, and the resulting solution was stirred at room temperature for 1.5 hours. The reaction solution was poured into water and was extracted with ethyl acetate, and the resulting organically and washed with ethanol, the result was received with 5.3 g of ethyl 5-bromo-3-methyl-2-benzophenoneoxymate in the form of colorless fine needle-shaped crystals. So pl. 96-97oC.

1H-NMR (CDCl3) : the 1.44 (3H, t, J = 8 Hz); of 2.54 (3H, c); of 4.45 (2H, square, J = 8 Hz); the 7.43 (2H); 7,73 (1H, s).

c) In a stream of nitrogen, 4.9 g of ethyl-5-bromo-3-methyl-2-benzophenoneoxymate received in accordance with the procedure described in stage (b), 2.0 g of copper cyanide and a catalytically effective amount of copper sulfate stirred in 40 ml of N-methyl-2-pyrrolidone for 6 hours at 200oC. After cooling, the reaction solution was poured into water, and insoluble substances were removed by filtration. The obtained filtrate was extracted with ethyl acetate, and the organic layer was washed with water, concentrated, drained and collected precipitated crystals. As a result of the treatment received, and 3.16 g of ethyl-5-cyano-3-methyl-2-benzophenoneoxymate in the form of slightly brownish crystals. So pl. 156-158oC.

1H-NMR (CDCl3) : of 1.45 (3H, t, J=8.0 Hz), 2,60 (3H, c); of 4.45 (2H, square, J = 8 Hz); to 7.67 (2H), to 7.99 (1H, s).

d) 3.1 g of ethyl 5-cyano-3-methyl-2-benzophenoneoxymate received in accordance with the procedure described in stage (c), was dissolved in 60 ml of tetrahydrofuran. To the resulting solution were added, oikeesto sodium bicarbonate. The resulting mixture was stirred at room temperature for 18 hours, then was added 2.1 g of calcium iodide (4H2O) and 0.63 g of sodium borohydride and stirred at room temperature for another 18 hours.

The resulting reaction solution was diluted with ethyl acetate, washed with water, and then dried by removing the solvent. Thus obtained residue was subjected to column chromatography on silica gel, elwira chloroform. The result of this procedure was given to 1.96 g of purified 2-hydroxymethyl-3-methyl-5-benzofurazanyl.

1H-NMR (CDCl3) : 1,8 (1H, Shir. C); of 2.28 (3H, s; 4,78 (2H, s); 7,52 (2H), 7,82 (1H, c).

e) 1.92 g of 2-hydroxymethyl-3-methyl-5-benzofurazanyl obtained according to the procedure described in stage (d) was added to 50 ml of diethyl ether and then added 3 drops of pyridine and of 1.65 ml of thionyl chloride, cooling the thus ice, and the mixture was stirred at room temperature for 4.5 hours. The reaction solution was poured into ice water and was extracted with chloroform, and the obtained organic layer was washed successively with water, saturated aqueous sodium bicarbonate and water, and then concentrated and dried off. The result of this procedure is carbonitrile, obtained according to the procedure described in stage (e), and 3 g of triphenylphosphine was heated under reflux in xylene for 5 hours. After cooling, precipitated crystals were collected by filtration, and was received in the 3,63 g of target compound. So pl. > 270oC.

1H-NMR (CDCl3) : 2,0 (1,5 H, C); 2,04 (1,5 H, C); 6,09 (2H, d, J = 16 Hz), and 7.7 (18H, m).

Referential example 2. Receive (5-cyano-3-benzofuranyl)methyltriphenylphosphonium bromide

a) 12,15 g of ethyl 5-cyano-3-methyl-2-benzophenoneoxymate obtained according to the procedure described in stage (c), reference example 1, was dissolved in 60 ml of ethanol and then added 5 g of sodium hydroxide and 100 ml of water, after which the resulting mixture was stirred at 30-40oC for 2 hours. After cooling with ice, the pH of the reaction solution was brought to 2 with dilute HCl, and the precipitated crystals thus collected by filtration and dried off. The result of this procedure was obtained 10.6 g of 5-cyano-3-methyl-2-benzofuranol acid as colorless pritvorenih crystals. So pl.: (sublimation at 275-285oC).

1H-NMR (CDCl3) : of 2.54 (3H, s), 7,88 (2H); 8,44 (1H).

b) at 10.64 g of 5-cyano-3-methyl-2-benzofuranol acid obtained submesible 30 minutes at 210oC. After cooling, ice water and bring the pH to 1 with HCl, the reaction mixture was extracted with chloroform, and the organic layer was dried under reduced pressure. Thus obtained residue was subjected to chromatography on a column of silica gel, elwira toluene. The result of this procedure received 6,89 g purified colorless 3-methyl-5-benzofurazanyl. So pl. 73oC.

1H-NMR (CDCl3) : of 2.26 (3H, d, J = 1.5 Hz), 7,53 (3H); a 7.85 (1H, s).

c) 7,28 g 3-methyl-5-benzofurazanyl, obtained as described in stage (b), was dissolved in 50 ml of carbon tetrachloride was heated under reflux under conditions of light irradiation. To the resulting reaction solution was gradually added a mixture of 8.25 g of N-bromosuccinimide and 160 g of 2,2-azobis-ISO-butyronitrile. After heating under reflux for 3 hours, the precipitated material was removed by filtration, and the obtained filtrate was drained. The dried residue was purified by chromatography on a column of silica gel, using as eluent toluene, and got so 8.65 g of a mixture (2:5) starting material and 3-bromomethyl-5-benzofurazanyl. 8.65 g thus obtained crude bromomethyl connection is Aravali for 20 minutes. After cooling, the precipitate was collected by filtration, resulting in a received 14,73 g of the target compound as colorless crystals. So pl. > 290oC.

1H-NMR (CDCl3) : 5,88 (2H, d, J = 16 Hz), 7,0 - 8,0 (19H, m).

Reference example 3. Receive (5-cyano-7-methoxy-2-benzofuranyl) methyltriphenylphosphonium.

a) 10.0 g of 5-bromo-2-hydroxy-3-methoxybenzaldehyde was dissolved in 39 ml of N,N-dimethylformamide, and the resulting solution was mixed with 11.9 g of anhydrous potassium carbonate and stirred at room temperature. Then, at the same temperature, to the resulting reaction solution drop by drop was added 5.0 g of chloroacetone, and stirred another hour at the elevated temperature 80oC. the resulting solution was diluted with ethyl acetate and the pH was brought to 2 with concentrated hydrochloric acid, and the obtained organic layer was collected. This organic layer was dried by distillation of the solvent, and the residue was purified by chromatography on silica gel, resulting in a 4.0 g of 2-acetyl-5-bromo-7-methoxybenzophenone. So pl. 107-109oC.

1H-NMR (CDCl3) : 2,62 (3H, c); a 3.83 (3H, s); 7,02 (1H), 7,39 (2H).

(b) to 107.6 ml of 5 n aqueous sodium hydroxide solution drop by drop) was added and 26.8 g of bromine p is containing 15.0 g of 2-cetyl-5-bromo-7-methoxy-benzofuran, obtained according to the procedure described in stage (a). After completion of this addition, the temperature of the reaction solution was gradually raised to 60oC, and then stirred for 30 minutes. After cooling, the pH of the resulting reaction solution was brought to 2 with concentrated hydrochloric acid, and then extracted with ethyl acetate. The obtained organic layer was concentrated to dryness, and the precipitated crystals thus collected by filtration, resulting in received 5-bromo-7-methoxy-2-benzofuranol acid. These crystals are suspended in 200 ml of ethanol, and stirring at room temperature, to this suspension drop was added 10 ml of thionyl chloride. The reaction solution was heated under reflux for 2 hours. After cooling, this reaction solution was neutralized with saturated aqueous sodium bicarbonate solution, then mixed with water, and precipitated crystals were collected by filtration. The obtained crystals were purified through column chromatography with silica gel, elwira chloroform, and resulted 11,33 g of ethyl 5-bromo-7-methoxy-2-benzophenoneoxymate.

1H-NMR (CDCl3) : of 1.41 (3H, t, J = 7,10 Hz); 4,00 (3H, s); 4,43 (2H, square , J = 7 Hz); 7,02 (1H, built in accordance with the procedure described in stage (b), 1.26 g of copper cyanide, 100 ml of N-methyl-2-pyrrolidone and a catalytically effective amount of copper sulfate, stirred for 2 hours at 180-190oC in a stream of argon. After cooling, to the reaction solution was added a mixture of toluene and ethyl acetate (1:1) and water to remove nerastvorimogo material, and the obtained organic layer was washed with water, and then drained. After removal of the solvent, the precipitated crystals were collected by filtration, washed with ethanol and was obtained 1.2 g of ethyl 5-cyano-7-methoxy - benzophenoneoxymate.

1H-NMR (CDCl3) : USD 1.43 (3H, t, J = 7.0 Hz); 4,06 (3H, s); to 4.46 (2H, t, J = 7.0 Hz); 7,10 (1H, d, J = 1.0 Hz); 7,53 (1H, s); to 7.64 (1H, d).

d) 8,55 g of ethyl 5-cyano-7-methoxy-2-benzophenoneoxymate obtained according to the procedure described in stage (c), was dissolved in 250 ml of tetrahydrofuran. While cooling in an ice bath, the resulting solution was mixed with 13,74 g of calcium iodide (4H2O), 2,12 g of sodium borohydride and a catalytically effective amount of sodium bicarbonate, and the mixture was stirred at room temperature for 1.5 hours, then was added 13,74 g of calcium iodide (4H2O) and 2.12 g of sodium borohydride, and the mixture was stirred at room temperature hydrochloric acid, and the solvent was removed by distillation. The residue was extracted with chloroform, washed with water, and was dried by distillation of the solvent. Thus obtained residue was purified by column chromatography on silica gel, using as eluent a mixture of chloroform and ethanol, and resulted from a 1.96 g of 2-hydroxymethyl-7-methoxy-5-benzofurazanyl.

T. p. 149-150oC.

1H-NMR (CDCl3) : 2,17 (1H, t, J = 6,1 Hz); was 4.02 (3H, c); 4,80 (2H, d, J = 6,1 Hz); of 6.71 (1H, s); 6,99 (1H, d, J = 1.3 Hz); 7,50 (1H, d, J = 1.3 Hz).

e) 5.0 g of 2-hydroxymethyl-7-methoxy-5-benzofuranyl received in accordance with the procedure described in stage (d), was dissolved in 100 ml of diethyl ether and then added a few drops of pyridine. Cooling in an ice bath and while stirring, to the resulting solution drop by drop) was added 5,86 g of thionyl chloride. After the addition, the temperature of the resulting solution was gradually raised to room temperature and continued to stir at room temperature for another 1 hour. While cooling in an ice bath, the reaction solution was added water, and the resulting organic layer was collected, washed with water, and then dried by removing the solvent, the resulting received is of Ivanishin was heated under reflux in 50 ml of xylene for 18 hours. After cooling, precipitated crystals thus collected by filtration and resulted 10,54 g of target compound.

1H-NMR (DMSO-d6) : the 3.89 (3H, s); 5,6-6,0 (2H, Shir. C).

Reference example 4. Receive (5-cyanobase [b] Tien-2-yl)methyltriphenylphosphonium chloride.

a) 8,13 g 5-bromosalicylaldehyde was dissolved in 100 ml of acetone, and then was added 6.7 g of anhydrous potassium carbonate. Stirring at room temperature, to the resulting solution was added 5.0 g of N,N-dimethylthiocarbamate, and then continued to stir for another two hours. The resulting reaction solution was poured into ice water, and precipitated crystals thus collected by filtration, dried off and got in the result of 9.2 g of 5-bromo-2-[N,N-diethylthiocarbamoyl)oxy]benzaldehyde.

So pl. 141-143oC.

IR (KBr): 1690, 1596, 1546, 1470, 1396 cm-1< / BR>
1H-NMR (CDCl3) : of 3.42 (3H, s); 3,47 (3H, s); 7,03 (1H, d, J = 8,3 Hz); 7,72 (1H, DD, J = 8.3 and 2.2 Hz); 8,01 (1H, d, J = 2.2 Hz).

b) 9.0 g of 5-bromo-2-[(N,N-diethylthiocarbamoyl)oxy]-benzaldehyde, obtained as described in stage (a) was melted by heating for 10 minutes at an oil bath at 210-220oC. the Obtained product was dissolved in 1 ml of toluene, and sago 5-bromo-2-[(N, N-dimethylcarbamoyl)thio]benzaldehyde.

So pl. 118-120oC.

IR (KBr): 1677, 1365, 1185 cm-1< / BR>
1H-NMR (CDCl3) : to 3.09 (6H, s); 7,31 (1H, d, J = 9.6 Hz); of 7.70 (1H, DD, J = 9.6 and 1.8 Hz); to 8.14 (1H, d, J = 1,8 Hz), of 10.25 (1H, s).

c) to 21.0 g of 5-bromo-2-[(N,N-dimethylcarbamoyl)thio]benzaldehyde was dissolved in 50 ml of methylacetate. The resulting solution was mixed with 1.0 g of p-toluensulfonate, and then was heated under reflux for 50 minutes. After cooling, the reaction solution was poured into saturated sodium bicarbonate solution and was extracted with benzene. The obtained organic layer was dried by removing the solvent. The precipitate was dissolved in 100 ml of methanol, after which was added 37 ml of 2n sodium hydroxide and heated under reflux in a stream of nitrogen for 1 hour. After cooling, the resulting reaction solution was adjusted to obtain a pH of 1 using concentrated hydrochloric acid, was extracted with benzene, and then dried to remove the solvent. The precipitate was dissolved in 20 ml of acetone, and one drop was added at room temperature to a stirred mixture consisting of 6,74 g chloroacetone, 22.1 g of anhydrous potassium carbonate, and 150 ml of acetone. After 30 minutes of stirring, the reaction mixture was heated compensation, and the obtained filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel, elwira toluene, and the obtained product was recrystallized from ethanol, resulting in a received 7.5 g of 2-acetyl-5-bromobenzo of thiophene. So pl. 120-121oC. IR (KBr): 1668, 1512, 1326, 1266 cm-1.

1H-NMR (CDCl3) : to 2.67 (3H, s); rate of 7.54 (1H, DD, J = 8.8 and 1.8 Hz); of 7.75 (1H, d, J = 8,8 Hz); a 7.85 (1H, s); 8,03 (1H, d, J = 1,8 Hz).

d) Stirring of 5.4 ml of bromine drop was added 5 n aqueous sodium hydroxide solution, which was cooled to-5-0oC. To this solution, at a temperature of -5oC or below, one drop was added 50 ml of a dioxane solution of 2-acetyl-5-bromobenzo /b/ thiophene obtained as described in stage (c). The resulting mixture was stirred for 30 minutes at room temperature and then for 30 minutes at 50oC. While cooling with ice, the pH of the reaction solution was brought to 2 with concentrated hydrochloric acid, and precipitated crystals were collected by filtration and washed with water. Thus obtained crystals were dissolved in ethyl acetate, and the solution was dried and concentrated. Precipitated crystals were collected by filtration and washed with toluene, which was obtained 6.6 g of 5- 1H-NMR (CDCl3) : EUR 7.57 (1H, DD, J = 8.6 and 1.8 Hz); of 7.82 (1H, d, J = 8.6 Hz); 8,00 (1H, s); 8,07 (1H, d, J = 1,8 Hz).

e) 6.4 g of 5-bromobenzo[b]thiophene-2-carboxylic acid, obtained in stage (d), suspended in 250 ml of ethanol. Cooling in an ice bath and stirring, to the resulting suspension drop was added of 4.45 g of thionyl chloride, and then heated under reflux for 1 hour. Then to the resulting mixture, cooling the thus ice, one drop was added 8,15 g of thionyl chloride, and then heated under reflux for 2 hours. The resulting reaction solution was concentrated, and the pH was brought to 9 with saturated aqueous sodium bicarbonate solution. Precipitated crystals were collected by filtration, dried off and got to 7.0 g of ethyl-5-bromobenzo of thiophene-2-carboxylate. Part of the thus obtained compound was recrystallized from methanol and received needle crystals. So pl. 94-95oC.

1H-NMR (CDCl3) : of 1.42 (3H, t, J = 7.0 Hz); to 4.41 (2H, square, J = 7,0 Hz); rate of 7.54 (1H, DD, J = 8.8 and 1.8 Hz); 7,73 (1H, d, J = 8,8 Hz); of 7.96 (1H, s); 8,01 (1H, d).

f) 7.0 g of ethyl-5-bromobenzo[b]thiophene-2-carboxylate, obtained in stage (a), and 5.4 g of copper cyanide suspended in 70 ml of N-methyl-2-pyrrolidone, and the resulting suspension stirred for 2 hours at tatom, any insoluble matter was removed by filtration and the resulting filtrate was washed with water and dried. After removal of the solvent, the precipitated crystals were collected by filtration and washed with ethanol, resulting in a received 5,02 g 5-dinobot of thiophene-2-carboxylate in the form of crystals. So pl. 138-139oC.

IR (KBr): 2232, 1728, 1262 cm-1< / BR>
1H-NMR (CDCl3) : USD 1.43 (3H, t, J = 7.0 Hz); of 4.45 (2H, square, J = 7,0 Hz); of 7.70 (1H, DD, J = 9.0 and 1.8 Hz), of 8.04 (1H, d, J = 9.0 Hz); 8,08 (1H), 8,20 (1H)

g) To 150 ml of tetrahydrofuran was added to 4.92 g of ethyl 5-cyanobase[b]thiophene-2-carboxylate, obtained in stage (f), and then was added 3.33 g of calcium iodide (4H2O). Cooling with ice and stirring, to the mixture was added 1.0 g of sodium borohydride and a catalytically effective amount of sodium bicarbonate, after which the mixture is stirred at room temperature for 1 hour. Then was added 3.33 g of calcium iodide (4H2O), and to the resulting mixture, which was cooled in an ice bath, while stirring, was added 1.0 g of sodium borohydride, after which the mixture is stirred at room temperature. After stirring for 1 hour, to the mixture was again added 3.33 g of calcium iodide (4H2O), and to the resulting mixture, which stirring, cooled on ice for one hour. Thus obtained reaction solution was diluted with water, extracted with ethyl acetate and dried to remove solvent. Then the precipitated crystals were collected by filtration and washed with a mixture of benzene and n-hexane, which was obtained 4.0 g of 2-hydroxymethylene[b]thiophene-5-carbonitrile. So pl. 78-79oC.

IR (KBr): 3496, 2236, 1026 cm-1< / BR>
1H-NMR (CDCl3) : equal to 4.97 (2H, s); 7,26 (1H), 7,51 (1H, DD, J = 8,3 and 1.8 Hz); of 7.90 (1H, d, J = 8,3 Hz); 8,03 (1H).

h) 4.0 g of 2-hydroxymethylene[b] thiophene-5-carbonitrile obtained in stage (g), was dissolved in 100 ml diethyl ether followed by the addition of 0.1 ml of pyridine. With ice cooling and stirring, to the resulting solution was added 5 ml diethylamino solution 5.5 thionyl chloride, and the mixture is stirred at room temperature for 2 hours. The resulting reaction solution was poured into ice water and was extracted with benzene. The organic layer was washed saturated aqueous sodium bicarbonate and concentrated to dryness. Thus obtained precipitate was dissolved in 100 ml of xylene, and the solution was mixed with 7.2 g of triphenylphosphine, and was heated under reflux for 10 hours. After that, the precipitated crystals were collected by filtration and 0 8,10 (19H, m).

Reference example 5. Obtaining (7-cyano-2-naphthyl)methyltriphenylphosphonium bromide

a) of 11.0 g of 7-methyl-2-naphthaleneboronic acid obtained according to the procedure described in Australian Journal of Chemistry (T. 18, pp. 1351-1364, 1965), was mixed with 70 ml of thionyl chloride and heated under reflux for 4 hours. The reaction solution was concentrated to dryness. To the residue was added 300 ml of concentrated aqueous ammonia, cooling at the same time. The mixture is stirred 3 hours at room temperature, and then was extracted with ethyl acetate. The organic layer was washed with water and then saturated aqueous sodium chloride, after which this layer was dried and the solvent was removed. The result of this procedure was obtained 8.5 g of 7-methyl-2-naphthaleneboronic in the form of colorless needle-like crystals. So pl. 210 - 212oC.

1H-NMR (DMSO-d6) : 2,50 (3H, s); 7,4 - 8,5 (6H, m).

b) 8.0 g of 7-methyl-2-naphthaleneboronic obtained in stage (a), suspended in 200 ml of tetrahydrofuran, to which was then added at room temperature, 100 ml of carbon tetrachloride containing cushion 22.66 g of triphenylphosphine. The resulting mixture was stirred at room temperature for 30 minutes and then at 60othe ation, and the resulting filtrate was concentrated under reduced pressure. 28,35 g obtained residue was chromatographically on a column of silica gel, elwira a mixture of n-hexane and ethyl acetate, and was received as a result of 5.73 g of 7-methyl-2-naphthaleneacetic in the form of colorless crystals. So pl. 134 - 136oC.

1H-NMR (CDCl3) : of 2.54 (4H, s); of 7.4 to 8.2 (6H, m).

c) 5.7 g of 7-methyl-2-naphthaleneacetic obtained in stage (b), suspended in 100 ml of carbon tetrachloride. To this suspension was added 6,37 g N bromosuccinimide and 30 mg of 2,2-azobis-ISO-butyronitrile. After 2 hour of heating under reflux, the reaction solution was diluted with dichloromethane, washed with water, and then saturated aqueous sodium chloride, and dried off. After removal of the solvent, received a 8.34 g of 7-bromomethyl-2-naphthaleneacetic in the form of pale yellow needle crystals. So pl. 110 - 116oC.

1H-NMR (CDCl3) : the 4.65 (2H, s); 7,55 - 8,25 (6H, m).

d) to 8.34 g of 7-bromomethyl-2-naphthaleneacetic obtained in stage (c), was dissolved in 200 ml of xylene, and then the solution was mixed with 11.6 g of triphenylphosphine, and the mixture was heated under reflux for 16 hours. To the reaction solution was added diethyl ether, and the ptx2">

1H-NMR (CDCl3) : 5,96 (3H, d, J = 15.3 Hz); 7,1 - 8,0 (2H, m).

Reference example 6. Obtain (6-cyano-1-methyl-2 - indolyl)methyltriphenylphosphonium bromide.

a) 1.5 g of methyl 6-cyano-2-indocarbocyanine received in accordance with the procedure described in Liebigs Annalen der Chemie (1986, page 438 - 455), was dissolved in 20 ml of N-dimethylformamide. 320 mg of 60% sodium hydride was added to the resulting solution, cooling the thus ice and stirring, and the mixture was stirred at room temperature for 10 minutes. To the mixture then were added to 0.47 ml under the conditions, and stirred at room temperature for 2 hours. To the resulting reaction solution was added saturated aqueous solution of ammonium chloride, and the precipitated crystals thus collected by filtration, and washed with methanol. The washed crystals are recrystallized from a mixture of dichloromethane and methanol, and was obtained 1.4 g of methyl 6-cyano-1-methyl-2-indocarbocyanine.

1H-NMR (CDCl3) : to 3.92 (3H, s); 4,10 (3H, s); 7,42 (1H, s); 7,52 (1H, DD); 7,98 (1H, DD); scored 8.38 (1H, Shir.).

b) 5.7 g of methyl 6-cyano-1-methyl-2-indocarbocyanine obtained in stage (a), was dissolved in 120 ml of tetrahydrofuran. Cooling in an ice bath and while stirring, to the resulting p is reed sodium, after which the mixture is stirred for 5 hours. The reaction solution was mixed with ice water and acetic acid, and then from a mixture drove tetrahydrofuran, and the resulting aqueous solution was extracted with ethyl acetate, and then dried. After removal of the solvent, the residue was dissolved in 50 ml of dichloromethane. With ice cooling and stirring, to the reaction solution drop by drop) was added 10 ml of dichloromethane solution containing 1 ml of tribromide phosphorus, and the resulting mixture was stirred at the same temperature for 2 hours and then another 2 hours at room temperature. The thus treated reaction solution was mixed with ice water, washed with an aqueous solution of sodium carbonate and dried off. The organic layer was concentrated under reduced pressure to reduce the amount of 2 times, then was mixed with 15 g of triphenylphosphine and heated under reflux for 12 hours. After that, the precipitate was collected by filtration and got a 10.5 g of the target compound.

1H-NMR (DMSO-d6) :/ (3H, s); of 5.55 (2H, d); of 6.26 (1H, s); 7,20 - 8,10 (18H, m).

Compounds of reference examples 7 and 8 were obtained in accordance with the procedure described in Comparative example 6.

Reference example 7. (6-cyano-1-ethyl-2 - indolyl)methyltriphenylphosphonium">

Reference example 8. [1-(2-chloromethyl)-6-cyano-2-indolyl] methyltriphenylphosphonium bromide.

1H-NMR (DMSO-d6) : 3,40 - of 3.80 (2H); 4,30 - 4,60 (2H); ceiling of 5.60 (2H, d); and 6.25 (1H, s); 7,10 - 8,00 (18H, m).

Reference example 9. Getting 2-bromomethyl-5-benzothiazolethiol

a) of 28.0 g of 5-bromo-2-methylbenzothiazole was dissolved in 200 ml of N-methyl-2-pyrrolidone, and the resulting solution was mixed with 13.8 g of copper cyanide and a catalytically effective amount of copper sulfate, after which the mixture is stirred for 4 hours with heating at a temperature of 180 - 190oC in a stream of nitrogen. The resulting reaction solution was poured into water, and any insoluble materials were collected by filtration. This nerastvorim material was mixed with a mixture containing 22 ml of Ethylenediamine and 50 ml of water, and the resulting mixture was thoroughly stirred. After extraction with benzene, the organic layer was washed with water, and was dried by distillation of benzene. Then the resulting residue was washed with ethanol and received 10,22 g 2-methyl-5-benzothiazolethiol in the form of slightly brownish crystals, So pl. 158 - 160oC.

1H-NMR (CDCl3) : 2,90 (3H, s); of 7.60 (1H, DD); to 7.95 (1H, d); of 8.25 (1H, d).

b) 7,46 g 2-methyl-5-benzothiazolethiol obtained in stage (a), was dissolved in 250 the mu reaction solution was gradually added to the mixture, containing a 7.62 g of N-bromosuccinimide and 150 mg of 2,2-azobis-isobutyronitrile, and then was heated under reflux for 20 hours. After cooling, any insoluble materials were removed by filtration and the solvent drove away. Formed in this way the residue was purified by column chromatography on silica gel, elwira toluene, and received in the result of 2.18 g of the target compound as a pale yellow pritvorenih crystals. So pl. 185 - 186oC.

1H-NMR (CDCl3) : a 4.83 (2H, s); to 7.67 (1H, DD); 8,02 (1H, d); a 8.34 (1H, d).

Reference example 10. Obtain (6-cyano-1,2,3,4-tetrahydro - 2-naphthyl)methyltriphenylphosphonium p-toluensulfonate.

a) 10.0 g of methyl 6-hydroxymethyl-5,6,7,8-tetrahydro-2 - naphthalenesulfonate added to 3,82 g of 2,3-dihydropyran. Then added 5 drops of concentrated sulfuric acid and the resulting mixture was stirred for 1 hour. To this mixture was added to 1.00 g of 2,3-dihydropyran and 3 drops of concentrated sulfuric acid, after which the mixture is stirred for 5 hours. The resulting reaction mixture was mixed with 100 ml of diethyl ether, and the mixture was washed with saturated aqueous sodium bicarbonate solution, then water, and then saturated aqueous sodium chloride, after which the mixture of stalinorgel in the form of a yellow oily substance.

1H-NMR (CDCl3) : 1,50 - 3,00 (13H, m); 3,30 - 4,10 (4H, m); 3,86 (3H, s); 4,60 (1H, width); 7,10 (1H, d); 7,80 - of 7.90 (2H, m).

b) 13,72 g of methyl 6-[(2-tetrahydrofuranyl)oxymethyl]-5,6,7,8 - tetrahydro-2-naphthalenesulfonate obtained in stage (a), was dissolved in 180 ml of methanol. After adding a solution 2,96 g of sodium hydroxide in 60 ml of water, the resulting mixture was heated under reflux for 3 hours. After cooling, the reaction solution was concentrated under reduced pressure, then was mixed with chloroform and water and neutralized with acetic acid. The obtained organic layer was washed with water and then saturated aqueous sodium chloride, and dried off. After removal of the solvent, the obtained residue was led in isopropyl ether and was obtained 10,51 g of 6-[(2-tetrahydropyranyl)oxymethyl] -5,6,7,8 - tetrahydro-2-naphthaleneboronic acid.

1H-NMR (CDCl3) : 1,50 - 3,00 (13H, m); 3,30 - 4,00 (4H, m); 4,60 (1H, width); 7,16 (1H, d); 7,80 - of 7.90 (2H, m).

c) 12.0 g of 6-[(2-tetrahydropyranyl)oxymethyl]-5,6,7,8 - tetrahydro-2-naphthaleneboronic acid, obtained in stage (b), and 4.1 g of triethylamine were dissolved in 100 ml of tetrahydrofuran, and the resulting solution was cooled to -15oC. Then, to this solution was added, stirring at the Etta same temperature, and then poured into 200 ml ice ethanol containing 14% (wt./about.) of ammonia. After removal nerastvorim materials by filtration, the obtained filtrate was dried under reduced pressure. The residue was purified by chromatography on silica gel, elwira a mixture of n-hexane and ethyl acetate, and the purified product was led in isopropyl ether, resulting in the received 7.20 g of 6-[(2-tetrahydropyranyl)oxymethyl]-5,6,7,8-tetrahydro-2 - naphthaleneboronic.

1H-NMR (CDCl3) : 1,40 - 3,00 (13H, m); 3,30 - 4,00 (4H, m); 4,60 (1H, width); 6,10 (2H, W); then 7.20 (1H, d); 7,50 - of 7.70 (2H, m).

b) 15.0 g of 6-[(2-tetrahydropyranyl)oxymethyl] -5,6,7,8 - tetrahydro-2-naphthaleneboronic obtained in stage (c), suspended in 60 ml of dioxane. After adding 8,35 ml of pyridine, the suspension was cooled to -8oC - 0oC.

Then, to this suspension, while stirring, was added drop 7,89 ml anhydrous trifenatate. The resulting reaction solution was stirred for 30 minutes at -5oC, then 2 hours at room temperature. The thus treated reaction solution was diluted with chloroform and then washed with water and saturated aqueous sodium chloride. The obtained organic layer was dried, RA is carbonitrile in the form of an oily product.

1H-NMR (CDCl3) : 1,50-3,00 (13H, m), 3,30-and 4.40 (4H, m); br4.61 (1H, width); 7,05 is 7.50 (3H, m).

e) 9,78 g of 6-[(2-tetrahydropyranyl)oxymethyl] -5,6,7,8-tetrahydro - 2-naphthaleneacetic was dissolved in 100 ml of ethanol. After adding 100 mg of p-toluensulfonate acid, the resulting mixture was stirred 15 hours at room temperature. Then the resulting reaction solution was neutralized with saturated aqueous sodium bicarbonate solution, followed by removal of solvent by distillation. Thus obtained residue was dissolved in chloroform, and the solution was washed with water and then saturated aqueous sodium chloride. The organic layer was dried and the solvent drove away. After crystallization from isopropanol received of 5.26 g of 6-hydroxymethyl-5,6,7,8-tetrahydro-2-naphthaleneacetic in the form of colorless crystals. So pl. 83-85oC.

1H-NMR (CDCl3) : 1,30 - of 3.00 (7H, m); of 3.64 (2H, d, J = 6.0 Hz); 7,05 is 7.50 (3H, m).

f) 15.0 g of 6-hydroxymethyl-5,6,7,8-tetrahydro-2-naphthaleneacetic obtained in stage (e), and 3.50 g of p-toluensulfonate was dissolved in 150 ml of pyridine, and the resulting solution was stirred at room temperature for 15 hours. The resulting reaction solution was poured into ice water, and precipitated creary received 24,72 g colorless 5,6,7,8 - tetrahydro-6-[(p-toluensulfonyl)oxymethyl]-2-naphthaleneacetic.

So pl. 100 - 102oC.

1H-NMR (CDCl3) : 1,20 - of 3.80 (7H, m); 2,47 (3H, s); 4,00 (2H, d, J = 6.0 Hz), 7,10 (1H, d, J = 9.0 Hz), 7,30 is 7.50 (4H, m), 7,80 (2H, d).

q) 24,00 g of 5,6,7,8-tetrahydro-6-[(p-toluensulfonyl)-oxymethyl]-2-naphthaleneacetic and 18,38 g of triphenylphosphine were mixed, and then heated for 15 hours at a temperature of 130-140oC in a tightly closed container. The resulting reaction product was led from a mixture of acetone and n-hexane, resulting in received 23.3 g of the target compound as a pale yellow powder.

1H-NMR (CDCl3) : 1,40 - 2,90 (7H, m); and 2.27 (3H, s); 3,60 - are 3.90 (2H, m); 6,80 - 7,30 (5H, m); 7,40 - 8,00 (17H, m).

Reference example 11. Obtain (6-cyano-2-naphthyl)methyltriphenylphosphonium bromide

a) 6.11 g of 6-methyl-2-naphthaleneacetic was dissolved in 100 ml of carbon tetrachloride, and the resulting solution was mixed with 6,63 g of N-bromosuccinimide and 30 g of 2,2-azobis-ISO-butyronitrile. After 4 hour of heating under reflux, the reaction solution was mixed with chloroform, washed with water, and then drained. After removal of the solvent was received 7,07 g colorless 6-bromomethyl-2-naphthaleneacetic.

So pl. 134-137oC.

1H-NMR (CDCl3) : the 4.65 (2H, s); 7,60 - 7,80 (2H, m); 7,80 - of 8.00 (3H, m); by 8.22 (1H, s).

b) 2.0 g of 6-the donkey 18 hours of heating under reflux, precipitated crystals were collected by filtration and was received of 3.31 g of the target compound. So pl. > 270oC.

1H-NMR (CDCL3) : to 5.93 (2H, d, J = 15.2 Hz); 7,40 - 8,00 (21H, m).

Referential example 12. Obtain (S)-(+)-3-hydroxymitragynine.

0,23 g R-toluensulfonate acid was added to 25 g of (S)-(-)-1,2,4-butanetriol, and the resulting mixture was stirred at 100oC for 5 minutes, and then at 180-200oC for 10 minutes. This reaction mixture was subjected to distillation and collecting the fraction at 95-100 C/300 mm RT.art., thereby 16.2 g of target compound in the form of an oily material.

1H-NMR (CDCl3) : 1,80 - 2,20 (2H, m); 3,76 (2H, d); 3,70 - 4,10 (2H, m); 4,40 - 4,60 (1H, m).

Reference example 13. Obtain ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl hydroxy]phenyl]-2-oxoacetate.

In 40 ml of tetrahydrofuran was dissolved 1.8 g of ethyl 2-(4-hydroxyphenyl)-2-oxoacetate, 1,74 g (3R)-1-tert-butoxycarbonyl-3-hydroxypyrrolidine and of 2.92 g of triphenylphosphine. To this solution, at room temperature, was added 1,94 g diethylazodicarboxylate, and the resulting mixture stirred 18 hours. After removal of the solvent, the residue was dissolved in ethyl acetate, and the solution was washed with water and then drained. After that, the solvent drove, and Parma, resulting received 2,53 g of target compound in the form of a viscous yellow oily substance.

1H-NMR (CDCl3) : of 1.41 (3H, t, J = 7,0 Hz) of 1.46 (9H, s); 2,00 - to 2.40 (2H, m); 3,00 - of 3.75 (4H, m); 4,43 (2H, square, J = 7,0 Hz); 5,00 (1H, width); 6,93 (2H, d, J = 9.0 Hz); 8,00 (2H, d, J = 9.0 Hz).

Connection represented in the reference examples 14-25, were obtained in accordance with the procedure described in reference example 13.

Reference example 14. Methyl-2-[4-[((3S)-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]-phenyl]-2 - oxoacetate, viscous yellow oily substance.

Reference example 15. Ethyl-2-[4-[((3R)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy] phenyl]-2-oxoacetate, viscous yellow oily substance.

1H-NMR (CDCL3) : of 1.40 (3H, t, J = 7.0 Hz); of 1.46 (9H, s); 2,00 -2,35 (2H, m); 3.45 points of 3.75 (4H, m); the 4.90 (2H, square, J=7,0 Hz); 4,9 - 5,1 (1H, Shir. ); 4,9 - 5,1 (1H, width); to 6.95 (2H, d, J = 9.0 Hz); 8,00 (2H, d, J = 9.0 Hz).

Reference example 16. Ethyl 2-[4-[((2S-1-tert-butoxycarbonyl-2-pyrrolidinyl))-methoxy]phenyl]-2 - oxoacetate, viscous yellow oily substance.

1H-NMR (CDCl3) : of 1.41 (3H, t); of 1.47 (9H, s); 2,0 (4H, W), 3,37 (2H, W); 4,20 (3H, width); 4,43 (2H, square), a 7.0 (2H, d), of 7.95 (2H, d).

Reference example 17. Ethyl 2-[4-[((2S, 4S)-1-tert-butoxycarbonyl-2-carbarnoyl-4-pyrrolidinyl)oxy] phenyl] -2 - oxoa (2H, W); 3,64 - 3,90 (2H, W); 4,30 - 4,60 (1H, width); was 4.42 (2H, square, J = 7,0 Hz); the ceiling of 5.60 (1H, width); 6,97 (2H, d, J = 9.0 Hz); 8,07 (2H, d, J = 9.0 Hz).

Reference example 18. Ethyl-2-[4-[((2S, 4S)-1-tert-butoxycarbonyl-2-dimethylcarbamoyl-4-pyrrolidinyl)oxy] phenyl] -2-oxoacetate, viscous yellow oily substance.

1H-NMR (CDCl3) : 1,37 of 1.50 (12H, m); 1,96 - of 2.30 (1H, m); 2,50 - 2,82 (1H, m); 2,90 is 3.15 (6H, W); 3,70 (1H, DD, J = 10,8 and 5.1 Hz); 3,90 - 4,16 (1H, m); to 4.46 (2H, square, J = 7,0 Hz); 4,60 - 5,14 (2H, m); 7,00 (2H, d, J = 9.4 Hz); 8,08 (2H, d, J = 9.4 Hz).

Reference example 19. Ethyl 2-[4-[2-(tert-butoxycarbonylamino)-1-(tert-butoxycarbonylamino) ethoxy] phenyl]-2-oxoacetate, viscous yellow oily substance.

1H-NMR (CDCl3) : 1,00 - 1,70 (21H, W); 2,80 - of 3.80 (4H, m); 4,20 - 4,60 (3H, m), 7,10 (2H, d, J=8,3 Hz); 7,98 (2H, d, J=8,3 Hz).

Reference example 20. Ethyl 2-[4-[(1-tert-butoxycarbonyl-4 - piperidinyl)oxy]phenyl]-2-oxoacetate, viscous yellow oily substance.

1H-NMR (CDCl3) : of 1.35 (3H, t, J=6 Hz); for 1.49 (9H, s); of 1.8 - 2.0 (4H, m), 3,2 - 4,0 (4H, m); to 4.46 (2H, square, J=6 Hz); 4,6 - 4,8 (1H, m); 7,01 (2H, d, J=9 Hz); 8,04 (2H, d, J=9 Hz).

Reference example 21. Ethyl 2-[4-(2-tert-butoxycarbonylamino)phenyl] -2-oxoacetate, viscous yellow oily substance.

1H-NMR (CDCl3) : of 1.42 (3H, t, J=7.0 Hz); of 1.46 (9H, s); of 3.56 (2H, square, J=5.4 Hz); of 4.12 (2H,� 2-[4-[(1- tert-butoxycarbonyl-4-piperidinyl)methoxy]phenyl]-2 - oxoacetate, viscous yellow oily substance.

1H-NMR (CDCl3) : 1,2 - 1,3 (2H, m); of 1.42 (3H, t, J=7,1 Hz); of 1.47 (9H, s); of 1.65 and 1.80 (2H, m); the 3.89 (2H, d); 4,10 - of 4.25 (2H, m); 4,43 (2H, square, J=7,1 Hz); to 6.95 (2H, d, J=8,8 Hz); 7,99 (2H, d, J=8,8 Hz).

Reference example 23. Ethyl 2-[4-[((2S)-1-tert-butoxycarbonyl-5-oxo-2-oxo-2-pyrrolidin) methoxy] phenyl] -2-oxoacetate, viscous yellow oily substance.

1H-NMR (CDCl3) : of 1.35 (3H, t); of 1.41 (9H); 1,80 - 2,20 (2H, m); 2,47 (2H, t); of 4.05 (2H, W); to 4.41 (2H, square); 4,70 - 5,00 (1H, m); 6,98 (2H, d); 8,00 (2H, d).

Reference example 24. Ethyl 2-[4-[(2R, 4S)-1-tert-butoxycarbonyl-2-methyl-4-pyrrolidinyl)oxy] phenyl] - 2-oxoacetate, viscous yellow oily substance.

1H-NMR (CDCl3) : 1,20 - of 1.42 (6H, m); of 1.47 (9H, s); 2,90 - 2,60 (1H, m); 3,50 - of 3.80 (2H, m); 3,90 - 4,22 (1H, m); was 4.42 (2H, square); 4,90 - 5,10 (1H, m); to 6.95 (2H, d); 8,00 (2H, d).

Reference example 25. Methyl 2-oxo-2-[4-[((3R)-tetrahydro-3 - furanyl)oxy]phenyl]acetate, viscous yellow oily substance.

Reference example 26. Ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl oxyphenyl]-2-ethoxycarbonylethyl.

a) to 27.7 g of ethyl 4-methoxyphenylacetate and 34 ml of diethylmalonate was dissolved in 150 ml of N,N-dimethylformamide, and the resulting solution was heated under reflux, gradually, within 1 hour by adding 6.5 g of hydride is whether in a mixture of ice water and hydrochloric acid and was extracted with ethyl acetate. The obtained organic layer was washed with water, was dried by distillation of the solvent. Thus obtained residue was purified by column chromatography on silica gel, elwira toluene, resulting in a received 26.7 g of ethyl 2-etoxycarbonyl-2-4-methoxyphenyl acetate as a pale yellow oily substance.

1H-NMR (CDCl3) : a 1.25 (6H, t, J=7.0 Hz); with 3.79 (3H, s); 4,20 (4H, square, J=7,0 Hz); 4,55 (1H, s); to 6.88 (2H, d, J=8.0 Hz); to 7.32 (2H, d, J=8.0 Hz).

b) 5.8 g of ethyl 2-etoxycarbonyl-2-4-methoxyphenyl acetate, obtained in stage (a), was dissolved in 70 ml of dichloromethane, and the solution was cooled to -40oC. To this solution, with stirring, this was added dropwise to 6.2 ml tribromide boron, dissolved in 5 ml of dichloromethane. After complete addition, the solution was heated to room temperature and stirred for 30 minutes. The resulting reaction solution was poured into a mixture of ice water and hydrochloric acid, then was extracted with chloroform. The obtained organic layer was dried by distillation of the solvent, and the residue was purified by column chromatography on silica gel, elwira chloroform, which was obtained 4.7 g of ethyl 2-etoxycarbonyl-2-4-hydroxyphenyl acetate as a colorless oily product.

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c) In 150 ml of tetrahydrofuran was dissolved 4.7 grams of ethyl-2-etoxycarbonyl-2-(4-hydroxyphenyl)acetate obtained in stage (b); to 6.58 g of triphenylphosphine and 4.7 g of (3R)-1-tert-butoxycarbonyl-3-hydroxypyrrolidine. To thus obtained solution, while stirring, was added 4,37 g diethylazodicarboxylate, and continued to stir for 18 hours. After removal of the solvent, the obtained residue was purified by column chromatography on silica gel, elwira mixture of toluene and ethyl acetate, which was obtained 4.0 g of the target compound as colorless oily substance.

1H-NMR (CDCl3) : a 1.25 (6H, t, J=7.0 Hz); of 1.46 (9H, s); 2,1 (2H, W); 3,55 (4H, Shir. ); 4,20 (4H, square, J=7,0 Hz); to 4.52 (1H, s); 4,82 (1H, width); PC 6.82 (2H, d, J=8.0 Hz); 7,28 (2H, d, J=8.0 Hz).

Reference example 27. Ethyl 2-[4-[(2R)-1-tert-butoxycarbonyl-2-pyrrolidinyl)-methoxy]phenyl]-2-ethoxycarbonylethyl.

This compound was obtained according to the procedure described in reference example 26, viscous oily substance.

1H-NMR (CDCl3) : a 1.25 (6H, t, J=7.0 Hz); of 1.47 (9H, s); 2,0 (4H, width); 3,40 (2H, W); of 3.9 (1H); 4,20 (6H); of 4.54 (1H, s); PC 6.82 (2H, d, J=8.0 Hz); 7,28 (2H, d, J=8.0 Hz).

Reference example 28. Ethyl 2-etoxycarbonyl-2-[4-[(2- imidazolin-2-yl)methoxy]phenyl acetate.


was removed by filtration, and the obtained filtrate was concentrated to dryness. The residue was purified by column chromatography, elwira toluene, and received in the result of 14.2 g of ethyl-2-[4-(cyanoethoxy)phenyl]-2-ethoxycarbonylethyl in the form of a colorless oily substance.

1H-NMR (CDCl3) : 1,26 ((6H, t, J=8.0 Hz); 4,22 (4H, square, J=8.0 Hz); 4,58 (1H, s); and 4.75 (2H, s); 7,02 (2H, d, J=9.0 Hz); of 7.36 (2H, d, J=9.0 Hz).

b) 14.2 g of ethyl 2-4-cinematographer-2-ethoxycarbonylethyl obtained in stage (a), was dissolved in a mixture consisting of 20 ml of ethanol and 150 ml of diethyl ether. The resulting solution was stirred at room temperature for 18 hours, cooling at this ice stream florodora. After removal of the solvent, got to 16.9 g of ethyl-2-etoxycarbonyl-2-[4-(2-ethoxy-2-aminoethoxy)phenyl]acetate hydrochloride as a solid substance.

c) Under cooling with ice and stirring, 40 ml of an ethanol solution containing 3.6 g of ethyl 2-etoxycarbonyl-2-[4-(2-ethoxy-2-aminoethoxy]phenyl] acetate obtained in stage (b), one drop was added to 10 ml of an ethanol solution containing 0.6 g of Ethylenediamine, and the resulting mixture was stirred at room the donkey cooling the pH of the resulting reaction solution was brought by the acid values using ethanol containing 13% (wt. /about.) hydrochloric acid, and the mixture is then concentrated to dryness. The residue was dissolved in water and washed with diethyl ether. After that, the pH of the resulting aqueous layer was brought to 9 to 10 with dilute aqueous sodium hydroxide solution, and the precipitated crystals were collected by filtration. The result of this procedure was given to 1.83 g of the target compound as colorless crystals.

So pl. 72 - 110oC gradual wetting

FAB-MS (mass spectroscopy by fast atom bombardment) (m/z): 335 (M++1).

1H-NMR (CDCl3) : of 1.23 (6H, t, J=8.0 Hz); 3,62 (4H, s); 4,10 (4H, square, J= 8.0 Hz); 5,52 (1H, s); and 4.68 (2H, s); 6,94 (2H, d, J=10 Hz); 7,26 (2H, d, J=10 Hz).

Reference example 29. Obtain ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-3-(5 - cyano-2-benzofuranyl)propionate

a) of 3.12 g of ethyl 2-[4-[((3S)-1-tertbutoxycarbonyl-3 - pyrrolidinyl)oxy] phenyl]-2-oxoacetate was dissolved in 100 ml of tetrahydrofuran, and then added with 4.65 g of 5-cyano-2-benzofuranyl methyltriphenylphosphonium chloride. To the resulting solution was added 400 mg of 60% sodium hydride. To this mixture, stirring, one drop was added 3 ml of ethanol, and n is th a 10% solution of citric acid, were extracted with ethyl acetate, and dried by removal of the solvent. The obtained residue was chromatographically on a column of silica gel, elwira mixture of toluene and ethyl acetate, which was obtained 3.1 g of ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl] -3-5 - cyano-2-benzofuranyl acrylate in the form of a viscous oily product, which is a mixture of E - and Z-forms. Part of the thus obtained compounds were divided into E - and Z - forms.

E-form (less polar):

1H-NMR (CDCl3) : of 1.32 (3H, t, J=7,6 Hz); for 1.49 (9H, s); 1.70 to to 2.40 (2H, m); 3,30-of 3.80 (4H, m); 4,30 (2H, square, J= 7,6 Hz); 4.92 in (1H, width); 6,62 (1H, s); 6,94 (2H, d, J=9.0 Hz); from 7.24 (2H, d, J=9.0 Hz); 7,38 (1H, d, J=8.6 Hz); 7,56 (1H, d, J=8.6 Hz); 7,74 (1H, s); to 7.77 (1H, s);

Z-form:

1H-NMR (CDCl3) : 1,10-to 1.60 (12H, m); 2,00-2,30 (2H, m); 3,30-of 3.80 (4H, m); 4,50 (3H, square, J=7.2 Hz); 4.92 in (1H, W), 6,76 (1H, s); for 6.81 (1H, s); to 6.88 (2H, d, J=8,75 Hz); 7,88 (2H, d, J=8,75 Hz); 7,31-of 7.60 (2H), a 7.85 (1H, s).

b) 3.1 g of ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3 - 5-cyano-2-benzofuranyl] acrylate obtained in stage (a), was dissolved in a mixture consisting of 100 ml of tetrahydrofuran and 100 ml of ethanol. To the resulting solution was added 700 mg of palladium oxide 1H2O barium sulfate, obtained according to the procedure described in Angewandte Chemie (vol.67, page 785, 1955). After 6-hour catalytic guy who Wali. After that, the rest was chromatographically on a column of silica gel, elwira mixture of toluene and ethyl acetate, which was obtained 1.9 g of target compound in the form of a viscous oily substance.

1H-NMR (CDCl3) : 1,00-1,40 (3H, m); of 1.46 (9H, s); 2,00-2,30 (2H, m); and 3.16 (1H, DD, J=14.4 and 7.2 Hz); 3,40-of 3.80 (5H, m); 3,90-4,30 (3H, m); 4,94 (1H, Shir. ); 6,40 (1H, s); to 6.80 (2H, d, J=8.7 Hz); of 7.25 (2H, d, J=8.7 Hz); 7,46 (2H, s); 7,76 (1H, s).

Reference example 30. Obtain ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]- 3-(7-cyano-2-naphthyl)propionate.

a) of 8.40 g of (7-cyano-2-naphthyl)methyltriphenylphosphonium bromide and 5.0 g of ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy] phenyl]-2-oxoacetate and suspended in a mixture of 100 ml of tetrahydrofuran and 100 ml of ethanol. To the resulting suspension were added, while stirring, of 2.51 g of 1,8-diazabicyclo[5.4.0]-7-undecene, and then stirred for 3 hours at room temperature. After removal of the solvent, the residue was chromatographically on a column of silica gel, elwira a mixture of n-hexane and ethyl acetate, the resulting received the 6.06 g of ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]- phenyl] -3-(7-cyano-2-naphthyl)acrylate in a mixture of E - and Z-forms. Part of the thus obtained compounds were divided into E - and Z-forms.

E-f, is); 3,45-3,70 (4H, m); or 4.31 (2H, square, J=7,3 Hz); 4.92 in (1H, width); 6,86 (2H, d, J= 8,8 Hz); 7,16 (2H, d, J=8,8 Hz); 7,20 (1H, DD, J=8.8 and 1.5 Hz); 7,56 (1H, DD, J=8.3 and 1.5 Hz); a 7.62 (1H, d, J=8,8 Hz); 7,73 (1H, s); 7,80 (1H, d, J=8,3 Hz); to 7.93 (1H, s); 8,07 (1H, s);< / BR>
Z-form:

1H-NMR (CDCl3) : to 1.19 (3H, t, J=7,3 Hz); to 1.48 (9H, s); 2,05-of 2.30 (2H, m); 3,45-3,70 (4H, m); the 4.29 (2H, square, J=7,3 Hz); is 4.93 (1H, width); make 6.90 (2H, d, J= 8,8 Hz); to 7.09 (1H, s); 7,44 (2H, d); of 7.60 (1H, DD, J=8.3 and 1.5 Hz); 7,63 (1H, s); of 7.90 (1H, d, J=8,3 Hz); 8,18 (1H, s).

b) the 6.06 g of ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy] phenyl]- 3-(7-cyano-2-naphthyl)acrylate obtained as a mixture of E - and Z-forms in stage (a) (see above), was dissolved in a mixture consisting of 80 ml of tetrahydrofuran and 80 ml of ethanol. To the resulting solution was added 2.0 g of palladium oxide 1H2O barium sulfate. After catalytic hydrogenation under normal pressure for 3.5 hours, the catalyst was removed by filtration and the solvent drove away. The obtained residue was subjected to column chromatography on silica gel, using as eluent a mixture of n-hexane and ethyl acetate, resulting in a received 6,24 g of target compound in a partially utverzhdenii form.

1H-NMR (CDCl3) : a 1.11 (3H, t, J=7,3 Hz); of 1.47 (9H, s); 2,00 is 2.33 (2H, m); 3,18 (1H, DD, J=14.2 per cent and 6.8 Hz); 3.40 in-the 3.65 (5H, m), 3,88 (1H, t, J=7.5 Hz); 4,06 (2H, square, J=7,3 Hz); 4,85 (1H, width); to 6.80 (2H, d, J=8,8 Hz); from 7.24 (2H, d); 7,4 zestawienie in the reference examples 31-39, received in accordance with the procedure described in reference example 30.

Reference example 31. Ethyl 2-[4-[((3R)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxyphenyl]-3- (7-cyano-2-naphthyl)propionate.

1H-NMR (CDCl3) : a 1.11 (3H, t, J=7,3 Hz); of 1.47 (9H, s); from 2.00 to 2.35 (2H, m); 3,18 (1H, DD, J=14.2 per cent and 6.8 Hz); 3.40 in-3,70 (5H, m); 3,38 (1H, width); 4,06 (2H, square , J= 7,3 Hz); 4,85 (1H, width); to 6.80 (2H, d, J=8,8 Hz); 7.24 to (2H); 7,42 (1H, DD, J=8,8 Hz and 1.5 Hz); rate of 7.54 (1H, DD, J=8.3 and 1.5 Hz); a 7.62 (1H, s); to 7.77 (1H, d, J=8,8 Hz), to 7.84 (1H, d, J=8,3 Hz); 8,11 (1H, s).

Reference example 32. Ethyl 2-[4-[(1-tert-butoxycarbonyl-4-piperidinyl)oxy]phenyl - 3-(7-cyano-2-naphthyl)propionate.

1H-NMR (CDCl3) : a 1.11 (3H, t); for 1.49 (9H, s); 1.70 to a 2.00 (4H, m); 3,00-4,10 (9H, m); of 4.45 (1H, width); 6,80-8,10 (10H, m);

FAB-MS (m/z): 418 (M++1).

Reference example 33. Ethyl 2-[4-[((2S, 4S)-1-tert-butoxycarbonyl-2-carbarnoyl-4-pyrrolidinyl)oxy] phenyl] - 3-(5-cyano-2-benzofuranyl)propionate, viscous oily substance.

1H-NMR (CDCl3) : of 1.16 (3H, t, J=7.0 Hz); of 1.47 (9H, s); 2,10 is 2.80 (2H, Shir. ); and 3.16 (1H, DD, J=14.4 and 7.2 Hz); 3.40 in-4,50 (6H, m); 5,08 (1H, width); to 6.39 (1H, s); 6,76 (2H, d, J=8.35 Hz); 7,26 (2H, d, J=8.35 Hz); 7,50 (2H, s); 7,80 (1H).

Reference example 34. Ethyl 2-[4-[((2S, 4S)-1-tert-butoxycarbonyl-2-dimethylcarbamoyl-4-pyrrolidinyl)oxy] phenyl]-3-5-cyano-2-benzofuranyl)propionate, viscous oily substance.

Reference example 35. Ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl - 3-pyrrolidinyl)oxy]phenyl]-3-(5-cyano-3-methyl-2 - benzofuranyl)propionate, viscous oily substance.

1H-NMR (CDCl3) : of 1.16 (3H, t); of 1.47 (9H, s); 2,02 (3H, s); 2,1 (2H, Shir. ); 3,1 (1H, width); 3,6 (5H, W); the 4.1 (3H, m); 4,85 (1H, width); 6,83 (2H, d); to 7.15 (2H, d); 7,46 (2H), and 7.7 (1H, s).

Reference example 36. Ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxyphenyl] -3-(5 - cyano-7-methoxy-2-benzofuranyl)propionate, viscous yellow oily substance.

1H-NMR (CDCl3) : of 1.17 (3H, t, J=7 Hz); of 1.46 (9H, s); 2,00-2,30 (2H, m); and 3.16 (1H, DD, J=14,5 and 7.4 Hz); 3,40 is 3.76 (5H, m); 3,80-4,30 (3H, m); was 4.02 (3H, s); 4,70-5,00 (1H, width); 6,37 (1H, s); to 6.80 (2H, d, J=8,75 Hz); to 6.95 (1H, d, J=1.3 Hz); 7.23 percent (2H, d, J=8,75 Hz); 7,41 (1H, d, J=1.3 Hz).

Reference example 37. Ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxyphenyl] -3- (5-cyano-3-benzofuranyl)propionate, viscous oily substance.

1H-NMR (CDCl3) : to 1.14 (3H, t); a 1.45 (9H, s); 2,12 (2H, W); 2,90-of 4.00 (7H, m); 4,08 (2H, square); 4,84 (1H, width); 6,85 (2H, d); to 7.2 (2H, d); 7,41 (1H, s); 7,50 (2H); 7,72 (1H).

Reference example 38. Ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl - 3-pyrrolidinyl)oxyphenyl]-3-(6-cyano-2-naphthyl)propionate.

1H-NMR (CDCl3) : a 1.25 (3H, t, J = 7.0 Hz); of 1.46 (9H is dicarbonyl-4 - piperidinyl)methoxy]phenyl]-3-(7-cyano-2-naphthyl)propionate.

1H-NMR (DMSO-d6) : a 1.01 (3H, t, J = 7,1 Hz); 1.1 to 1.2 (2H, m); of 1.39 (9H, s); by 1.68 to 1.76 (2H, m); 2,65 is 2.75 (2H, m); of 3.78 (2H, d); 3,9-4,1 (5H, m); 4,55 with 4.65 (1H, m); 6,85 (2H, d, J = 8,3 Hz); of 7.25 (2H, d, J = 8,3 Hz); 7,55-the 7.65 (1H, m); 7.68 per-7,73 (1H, m); of 7.82 (1H, s); of 7.90-of 7.95 (1H, m); 8,03 (1H, d, J = 8,8 Hz); 8,44 (1H, s).

Reference example 40. Getting ethyl(+)-2-[4-[((3S)-1 - tertbutoxycarbonyl-3-pyrrolidinyl)oxy] phenyl]-3-(7-cyano-2 - naphthyl)propionate and ethyl(-)-2-[4-[((3S)-1-tertbutoxycarbonyl-3 - pyrrolidinyl)-oxy]phenyl]-3-(7-cyano-2-naphthyl)propionate.

2.0 g of ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)- oxy] phenyl] -3-(7-cyano-2-naphthyl)propionate was dissolved in 10 ml of ethanol by heating. After cooling to room temperature, precipitated crystals were collected by filtration, and then recrystallized twice from ethanol, resulting in a received 640 mg of ethyl(+)-2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)- oxy] phenyl] -3-(7-cyano-2-naphthyl)propionate. So pl. 132-133,5oC.

[]2D4= = + 117,4 (c = 1,008, CHCl3)

1H-NMR (CDCl3) : a 1.11 (3H, t, J = 7,3 Hz); of 1.47 (9H, s ); 2,00-2,30 (2H, m); 3,18 (1H, DD, J = 14.2 per cent and 6.8 Hz); 3.40 in-3,70 (5H, m); a 3.87 (1H, t, J = 7,6 Hz); 4,00-4,10 (2H, m); 4,85 (1H, width); to 6.80 (2H, d, J = 8,8 Hz); 7,20-7,30 (2H, m); 7,42 (1H, d, J = 8,3 Hz); at 7.55 (1H, d, J = 8,3 Hz); 7,63 (1H, s); to 7.77 (1H, d, J = 8,3 Hz); a 7.85 (1H, d, J = 8,3 Hz); to 8.12 (1H, s).

HPLC: varicel: ISO-propanol:n-hexane = 15:85 (about./about.)

Flow rate: 1 ml/min

The column temperature: 25oC

Retention time: 31,37 minutes

The filtrate was concentrated to dryness and was led from a mixture of n-hexane and ethanol. The collected crystals are recrystallized from the same lump, and was obtained 80 mg of ethyl(-)-2-[4-[((3S)-1 - tert-butoxycarbonyl-3-pyrrolidinyl)-oxy]phenyl]-3-(7-cyano-2 - naphthyl)propionate. So pl. of 82.5-85,0oC

[]2D4= -85,0 (c = 0,53, CHCl3)

1H-NMR (CDCl3) : a 1.11 (3H, t, J = 7,3 Hz); of 1.47 (9H, s); 2,00-2,30 (2H, m); 3,18 (1H, DD, J = 14.2 per cent and 6.8 Hz); 3.40 in-3,66 (5H, m); a 3.87 (1H, t, J = 7,6 Hz); 4,00-4,10 (2H, m); 4,85 (1H, width); to 6.80 (2H, d, J = 8,8 Hz); 7,20-7,30 (2H, m); 7,42 (1H, d, J = 8,3 Hz); 7,56 (1H, d, J = 8,3 Hz); a 7.62 (1H, s); to 7.77 (1H, d, J = 8,3 Hz); a 7.85 (1H, d, J = 8,3 Hz); to 8.12 (1H, s).

HPLC: Column: column with aminosol for the separation of optical isomers (CHIPALPAK AD, 4.6 x 250 nm, Diacel Chemical Industries, Ltd.)

Solvent: isopropanol:n-hexane = 15:85.about.

Flow rate: 1 ml/min

The column temperature: 25oC

Retention time: 23,22 minutes

Reference example 41. Obtain ethyl 3-(5-cyano-2-benzofuranyl)- 2-[4-[((3S)-1-methyl-3-pyrrolidinyl)oxy]phenyl]propionate.

1.8 g of ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl] -3-(5 - cyano-2-benzofuranyl)propion the obtained reaction solution was concentrated to dryness, and the residue was dissolved in 8 ml of formic acid. To this solution was added to 0.29 ml 37% formaldehyde, and then was heated under reflux for 4 hours. After cooling, the reaction solution was mixed with chloroform and the pH of the mixture was brought to 10-11 using aqueous ammonia, and then the obtained organic layer was collected and dried. After removal of the solvent, the residue was purified by chromatography on silica gel, using as eluent a mixture of chloroform and methanol. In the described procedure was obtained 1.07 g of target compound in the form of an oily product.

1H-NMR (CDCl3) : of 1.16 (3H, t, J = 7.2 Hz); 1.60-to 2,30 (2H, m); of 2.38 (3H, s); 2,00-4,00 (7H, m), 4,11 (2H, square, J = 7,2 Hz), 4,60-of 4.90 (1H, width); to 6.39 (1H, s); is 6.78 (2H, d, J = 8,8 Hz); 7,21 (2H, d, J = 8,8 Hz); 7,47 (2H, s); to 7.77 (1H, s).

Reference example 42. Obtain ethyl 2-[4-[((3S)-1-acetyl-3 - pyrrolidinyl)oxy]phenyl]-3-(5-cyano-2-benzofuranyl)propionate.

2.3 g of ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)- oxy]phenyl]-3-(5-cyano-2-benzofuranyl)propionate was dissolved in 3 ml of anisole. To the resulting solution was added 25 ml triperoxonane acid, cooling the thus ice, and the mixture was stirred at room temperature for 1 hour. After distillation triperoxonane KIS is sodium, then was extracted with chloroform and dried off. At room temperature the organic layer was mixed with 2 ml of triethylamine and then with 555 ml acetylchloride, and then stirred at the same temperature for 0.5 hours. After removal of the solvent, the residue was chromatographically on a column of silica gel, elwira with a mixture of chloroform and ethanol, resulting in a received 1.8 g of the target compound.

1H-NMR (CDCl3) : of 1.17 (3H, t, J = 7.0 Hz); 2,04 (1,5 H); 2,08 (1,5 H); 3,14 (1H, DD, J = 15.1 and 3.6 Hz); 3.40 in-4,30 (8H, m); 4,70-5,04 (1H, width); 6,40 (1H, s); 6,60-6,92 (2H, m), 7,10 (2H, m); 7,47 (2H, s ); to 7.77 (1H, s).

Reference example 43. Obtain ethyl 3-(5-cyano-2-benzofuranyl)- 2-[4-[((3S)-1-dimethylcarbamoyl - 3-pyrrolidinyl)oxy]phenyl}propionate.

2.3 g of ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)- oxy} phenyl] -3-(5-cyano-2-benzofuranyl)propionate was dissolved in 3 ml of anisole. To the resulting solution was added 25 ml triperoxonane acid, cooling the thus ice, after which the mixture is stirred for 1 hour at room temperature. After distillation triperoxonane acid, the pH of the residue is brought up to 10-11 with saturated aqueous sodium bicarbonate solution and then was extracted with chloroform and dried off. At room temperature, the organic layer was mixed with 2 m is the atur. After removal of the solvent, the residue was chromatographically on a column of silica gel, elwira with a mixture of chloroform and ethanol, which was obtained 1.7 g of the target compound.

1H-NMR (CDCl3) : of 1.17 (3H, t, J = 7.0 Hz); 1,9-of 2.20 (2H, m); of 2.86 (6H, s); 3,14 (1H, DD, J = 16.0 and 7.2 Hz); 3,30-4,50 (8H, m); 4.72 in-4,96 (1H, Shir. ); 6,41 (1H, s); 6,83 (2H, d, J = 8.7 Hz); of 7.25 (2H, d, J = 8.7 Hz); 7,49 (2H, s); for 7.78 (1H, s).

Reference example 44. Obtain ethyl 2-(4-acetoxyphenyl)-2 - oxoacetate.

of 7.25 g of ethyl 2-(4-hydroxyphenyl)-2-oxoacetate was dissolved in 15 ml of pyridine, then added 4 ml of acetic anhydride, and stirred at room temperature for 1 hour. The resulting solution was poured into water and was extracted with diethyl ether. The organic layer was washed with water and concentrated to dryness. Then the residue was dissolved in benzene, concentrated, and received the score of 8.3 g of target compound in the form of an oily product.

1H-NMR (CDCl3) : of 1.41 (3H, t); 2,32 (3H, s); 4,43 (2H, square); 7,29 (2H, d); 8,01 (2H, d).

Reference example 45. Obtain ethyl 3-(5-cyano-2-benzofuranyl)-2-(4-hydroxyphenyl)propionate.

a) 15,93 g of 5-cyano-2-benzofuranyl methyltriphenylphosphonium chloride and 8,29 g of ethyl 2-(4-acetoxyphenyl)-2-oxoacetate was dissolved in a mixture consisting of 80 ml.0]-7-undecene, and the resulting mixture stirred at this temperature for 18 hours. Then the reaction solution was concentrated to dryness, the residue was purified through column chromatography with silica gel, using as eluent a mixture of toluene and ethyl acetate, which was given to 11.28 g of ethyl 2-4-acetoxyphenyl-3-5-cyano-2-benzofuranyl acrylate in the form of light yellow crystals, representing a mixture of E - and Z-forms.

1H-NMR (CDCl3) : of 1.32 (3H, t); a 2.36 (3H, s); 4,30 (2H, square); 6,30 (1H, s); 7,2-7,8 (8H, m).

b) 3.8 g of ethyl-2-4-acetoxyphenyl-3-5-cyano-2-benzofuranyl acrylate obtained in stage (a), was dissolved in a mixture solvent of ethanol and tetrahydrofuran. The resulting solution was mixed with 750 mg of palladium oxide 1H2O barium sulfate, and subjected to catalytic hydrogenation under normal pressure. After removal of the solvent by filtration, the filtrate was concentrated to dryness and was obtained 3.8 g of ethyl 2-(4-acetoxyphenyl)-3-(5-cyano-2-benzofuranyl)-propionate.

1H-NMR (CDCl3) : of 1.16 (3H, t, J = 7.2 Hz); of 2.25 (1H, s); 3,20 (1H, DD, J= 16.2 and a 7.0 Hz); 3.40 in-4,30 (4H, m); 6,50 (1H, s); 7,10 (2H, d, J=8,3 Hz); 7,40 (2H, d, J=8,3 Hz); 7,56 (2H, s); 7,86 (1H, s).

C) of 8.1 g of ethyl 2-(4-acetoxyphenyl)-3(5-cyano-2-benzofuranyl) propionate obtained in stage (b), the process is the temperature for 18 hours. Then the reaction solution was concentrated to dryness, and the residue was purified by column chromatography on silica gel, elwira chloroform. The result of this procedure received 5,62 g of the target compound as colorless crystals. So pl. 140-142oC.

1H-NMR(CDCl3) : to 1.15 (3H, t); 3,0-4,0 (3H, m), 2H, HF); to 4.98 (1H, s); to 6.39 (1H, s); 6,76 (2H, d); to 7.15 (2H, d), 7,45 (2H); of 7.75 (1H).

Reference example 46. Obtain ethyl 3-(5-cyano-2-benzofuranyl)-3-(4-hydroxyphenyl)propionate.

a) In 150 ml of acetone suspended 20 g of 5-bromosalicylaldehyde, 22.9 grams of 2-bromo-4-methoxyacetophenone and 27.6 g of anhydrous potassium carbonate. Then was stirred at room temperature for 4 hours, the reaction solution was concentrated to dryness, and then mixed with water and the precipitated crystals were collected by filtration. After washing with water and subsequent recrystallization from ethanol, got 14,02 g of 5-bromo-2-(4-methoxybenzoyl)benzofuran in the form of colorless pritvorenih crystals. So pl. 143-146oC.

IR (KBr): 1644, 1605, 1257 cm-1< / BR>
1H-NMR (DMSO-d6) : at 3.35 (3H, s); to 7.15 (2H, d, J=9 Hz); 7,72 (3H, m); 8,0-8,2 (3H)

b) 15.0 g of 5-bromo-2-(4-methoxybenzoyl)benzofuran obtained in stage (a), and 6,09 g of copper cyanide suspended in 75 ml of N-meth is ladenia, the reaction solution was diluted with chloroform, any insoluble materials were removed by filtration, and the obtained filtrate was washed with diluted hydrochloric acid. After drying of the organic layer, followed by concentration under reduced pressure, received 6.60 g of 2-(4-methoxybenzoyl)-5-benzofurazanyl in the form of a brown powder.

IR (KBr): 2224, 1644 cm-1< / BR>
1H-NMR (DMSO-d6) : 3,30 (3H, s); to 7.15 (2H, d, J = 9 Hz); 7,83 (1H, s); 8,00 (2H, d); 8,07 (2H, d, J= 9 Hz); 8,42 (1H, s).

c) 1.85 g of ethyldiethanolamine was dissolved in 20 ml of tetrahydrofuran. Stirring at room temperature, to the resulting solution was added 320 mg of 60% sodium hydride, and then continued to stir until you obtain a clear reaction solution. After 10 minutes, to this reaction solution was added 1.75 g of 2-(4-methoxybenzoyl)-5-benzofurazanyl obtained in stage C), and the mixture was heated under reflux for 30 minutes. After cooling, the reaction mixture was concentrated to dryness. The residue was mixed with diluted hydrochloric acid, was extracted with dichloromethane, washed with saturated aqueous sodium chloride and concentrated to dryness. The obtained residue was purified using a column of chrno-2-benzofuranyl)-3-(4-methoxyphenyl)acrylate in a mixture of E - and Z-isomers.

1H-NMR (CDCl3) : of 1.20 (3H, t, J= 7 Hz); of 3.84 (3H, s); 4,18 (2H, square, J= 7 Hz); 6,32 (1H, s); of 6.8 to 7.4 (5H, m); 7,56 (2H, s); to 7.93 (1H, Shir).

d) 1.78 g E/Z - mixture of ethyl 3-(5-cyano-2-benzofuranyl)-3-(4-methoxyphenyl)acrylate obtained in stage (C), was dissolved in a mixture of solvents consisting of 6 ml of tetrahydrofuran and 20 ml of ethanol. To the resulting solution were added 200 mg of 5% palladium carbon, and the mixture was subjected to catalytic hydrogenation under normal pressure for 1.5 hours. After removal of catalyst by filtration, the obtained filtrate was concentrated to dryness, resulting in a received 1,79 g of 3-(5-cyano-2-benzofuranyl)-3-(4-methoxyphenyl)propionate.

1H-NMR (CDCl3) : of 1.29 (3H, t, J=7 Hz); 2,9-3,1 (2H, m); of 3.78 (3H, s); 4.09 to (2H, square , J= 7 Hz); 4,5-4,7 (1H, m); 6,47 (1H, s); to 6.88 (2H, d, J= 9 Hz); 7,47 (2H, s); 7,80 (1H, s).

e) to 1.79 g of ethyl 3-(5-cyano-2-benzofuranyl)-3-(4-methoxyphenyl)propionate obtained in stage (d), was dissolved in 20 ml of anhydrous dichloromethane, and the resulting solution was cooled to -50oC. To this solution drop by drop) was added 10 ml of dichloromethane solution containing 1,36 ml tribromide boron. The resulting mixture was gradually heated and stirred 3 hours at room temperature. Then, the reaction solution was diluted with dichloromethane and extracting the sodium, then concentrated to dryness. The result of this procedure was given to 1.34 g of the target compound as an oily substance.

1H-NMR (CDCl3) : to 1.15 (3H, t, J=7 Hz); 2,9-3,3 (2H, m), 4.09 to (2H, square, J = 7 Hz); 4,5-4,7 (1H, m); x 6.15 (1H, width); 6,46 (1H, s); to 6.80 (2H, d, J = 9 Hz); to 7.15 (2H, d, J = 9 Hz); 7,42 (2H, s); 7,76 (1H, s).

Reference example 47. Getting ethyl-2-(2-(5-cyano-2-benzofuranyl)ethyl)-5-hydroxybenzoate.

a) to 4.87 g of 2-formyl-5-methoxybenzoic acid was dissolved in 30 ml of chloroform. Stirring at room temperature, a solution of a mixture of benzene and n-hexane (1: 1) containing diphenyldiazomethane received in accordance with the procedure described in Journal of Chemical Society (Parkin 1, pp. 2030-2033, 1975), was added to the resulting solution until until the reaction solution becomes purple-red color. This reaction solution was subjected to purification using column chromatography on silica gel, elwira mixture of toluene and ethyl acetate, and was received as a result of 8.2 g diphenylmethyl-2-formyl-5-methoxybenzoate in the form of a viscous oily substance.

1H - NMR (CDCl3) : a 3.87 (3H, s); 7,13 (1H, DD, J = 11.5 and 2.9 Hz); 7,20 (1H, s); from 7.24 (11H, m); of 7.97 (1H, d, J = 11.5 Hz); 10,45 (1H, s).

b) 6.0 g diphenyl 2-formyl-5-methoxybenzoate obtained in stage (a) and 8.1 g of (5-cyano-the Nola. Stirring at room temperature, only 2.91 g of 1,8-diazabicyclo [5.4.0]-7-undecene was added to the obtained solution, and the mixture is stirred 2 hours at the same temperature. After removal of the solvent, the obtained residue was purified by chromatography on silica gel, elwira mixture of toluene and chloroform, the resulting received 8,2 g diphenylmethyl 2-[2-(5-cyano-2-benzofuranyl)vinyl]-5-methoxybenzoate in the form of a mixture of E - and Z-isomers.

1H-NMR (CDCl3) : 3,84 (1H, s); 3,88 (3H, s); 6,20-8,28 (19H, m).

c) 8,2 g E/Z - mixture diphenylmethyl 2-[2-(5-cyano-2-benzofuranyl)vinyl]-5-methoxybenzoate obtained in stage b), was dissolved in a mixture solvent consisting of 60 ml of tetrahydrofuran and 60 ml of ethanol. To this solution was added 2.0 g of palladium oxide 1H2O barium sulfate, and the resulting mixture was subjected to catalytic hydrogenation under normal pressure. After removal of catalyst by filtration, the obtained filtrate was concentrated, precipitated crystals were collected by filtration, and was received as a result of 4.45 g of 2-[2-(5-cyano-2-benzofuranyl)ethyl] -5-methoxybenzoic acid. So pl. 179-182oC.

1H-NMR (CDCl3) : 2,90-of 3.42 (4H, m); of 3.75 (3H, s); to 6.67 (1H, s); 7,01 (1H, DD, J = 8.7 and 2.2 Hz); from 7.24 (1H, d, J = 8.7 Hz), 7,34 (1H, d, J=2.2 Hz); of 7.69 (2H, s)ethoxybenzoyl acid, obtained in stage (C), was dissolved in 200 ml of ethanol, and the resulting solution was mixed with 4 ml of concentrated sulfuric acid, and then the mixture was heated under reflux for 16 hours. After cooling, the reaction solution was neutralized with saturated aqueous sodium bicarbonate solution, and the ethanol was removed by distillation. The obtained residue was extracted with ethyl acetate and was dried by distillation of the solvent. The residue was purified by chromatography on silica gel and then recrystallized from n-hexane, resulting in received 4.11 g of ethyl 2-[2-(5-cyano-2-benzofuranyl)ethyl]5-methoxybenzoate in the form of colorless needle-like crystals. So pl. 92-93oC.

1H-NMR (CDCl3) : to 1.38 (3H, t, J= 7.0 Hz); 2,90-of 3.48 (4H, m), 3,82 (3H, s); 4,34 (2H, square, J = 7,0 Hz); 6,41 (1H, s); of 6.96 (1H, DD, J = 8.7 and 2.6 Hz); 7,10 (1H, d, J=8.7 Hz); 7,46 (1H, d, J = 2.6 Hz); of 7.48 (2H, s); 7,79 (1H, s).

e) 4.11 g of ethyl 2-[2-(5-cyano-2-benzofuranyl)ethyl]-5-methoxybenzoate obtained in stage (d), was dissolved in 40 ml of dichloromethane, and the resulting solution was cooled to -78oC. Then, at the same temperature, to this solution drop by drop) was added cent to 8.85 g tribromide boron, and the resulting mixture was gradually heated to -5oC - 0oC, after which it was stirred for 1 hour.washed with 4 n hydrochloric acid, and then water, then dried, and the solvent was removed. The residue was purified by column chromatography on silica gel, to deliver 2,80 g of target compound in the form of pritvorenih crystals.

So pl. 133-135oC.

1H NMR (CDCl3) : of 1.40 (3H, t, J = 7.0 Hz); 2,96 - to 3.50 (4H, m); 4,36 (2H, square , J = 7,0 Hz); of 6.45 (1H, s); 6,93 (1H, DD, J = 8.7 and 2.9 Hz); 7,13 (1H, d, J = 8.7 Hz); 7,50 (1H, d, J = 2,9 Hz); 7,56 (2H, s); to 7.84 (1H, s).

Reference example 48. Getting ethyl 2-[2-[2-(5-cyano-2-benzofuranyl)ethyl]-5-hydroxyphenyl]acetate.

a) 2.0 g of 2-[2-(5-cyano-2-benzofuranyl)ethyl]-5-methoxybenzoic acid suspended in 10 ml of benzene, and the resulting suspension was mixed with 1 ml of thionyl chloride. After 1 hour of heating the mixture under reflux and concentrating the mixture to dryness, received the crude acid chloride.

A mixed solution consisting of 10 ml of n-hexane containing 10% (wt. /about.) trimethylsilyldiazomethane, 1.3 ml of triethylamine, 10 ml of acetonitrile and 10 of tetrahydrofuran was cooled to -5oC. Then, to this solution, stirring, one drop was added 5 ml acetonitrile solution obtained above acid chloride. This reaction solution was stirred for 48 hours at 0oC, after which the solvent Tonala of 4 ml collidine and 4 ml of benzyl alcohol, and the solution stirred for 7 minutes at 180oC in a stream of nitrogen. The resulting reaction solution was dissolved in benzene, washed with 10% acetic acid, and then drained. After removal of the solvent, the residue was chromatographically on a column of silica gel, elwira mixture of toluene and ethyl acetate, resulting in a received 830 mg benzyl 2-[2-[2-(5-cyano-2-benzofuranyl)ethyl]-5-methoxyphenyl]-acetate. So pl. 127-128oC.

1H-NMR (CDCl3) : 3,00 (4H), 3,68 (2H, s); 3,76 (3H, s); 5,13 (2H, s); 6,32 (1H, c); 6,76 (1H, DD, J = 7,9 and 1.3 Hz); to 6.80 (1H, c); was 7.08 (1H, d, J = 7.9 Hz); 7,30 (5H, s); of 7.48 (1H, d, J = 1.3 Hz); to 7.77 (1H, c).

b) 855 mg benzyl 2-[2-[2-(5-cyano-2-benzofuranyl)-ethyl]-5-methoxyphenyl] acetate obtained in stage a), was dissolved in 20 ml of dichloromethane, and the resulting solution was cooled to -50oC. To this solution drop by drop) was added 5 ml of dichloromethane solution containing 1.75 g tribromide boron, and then gradually raise the temperature to 15oC and at this temperature, stirred for 20 minutes. The reaction solution was extracted with ethyl acetate, washed with diluted hydrochloric acid, and then drained. After concentration to dryness, the residue was dissolved in 30 ml of ethanol was mixed with 2 ml of thionyl chloride and heated under reflux for 1 hour. After ohlala by removal of the solvent. The residue was purified by column chromatography on silica gel, elwira chloroform. The result of this procedure received 680 mg of the target compound in powder form. So pl. 84-86oC.

1H-NMR (CDCl3) : a 1.25 (3H, t, J = 7.0 Hz); to 3.02 (4H) and 3.59 (2H, c); of 4.57 (2H, square, J = 7,0 Hz); to 6.19 (1H, s); 6,41 (1H, s); 6,55-6,84 (2H, m); 6,99 (1H, d, J = 7.9 Hz); of 7.48 (2H, s); to 7.77 (1H, s).

Reference example 49. Obtain ethyl 5-cyano-2-[2-(4-hydroxyphenyl)ethyl] -3-benzophenoneoxymate.

a) of 91.5 g of (5-bromo-2-benzofuranyl)methyltriphenylphosphonium chloride and 25 g of p-anisaldehyde was dissolved in a mixture of 180 ml of tetrahydrofuran and 180 ml of ethanol. To this solution, stirring at room temperature, was added 27,58 g of 1,8-diazabicyclo[3,4,0] -7-undecene, and the resulting mixture stirred 18 hours. After that, the reaction solution was concentrated, precipitated crystals were collected by filtration, and was received in the 32,8 g of 5-bromo-2-[2-(4-methoxyphenyl)-vinyl] benzofuran in the form of one of the stereoisomers.

So pl. 190-194oC.

1H-NMR (CDCl3) : a 3.83 (3H, s); is 6.54 (1H, s); 6,9 (3H); to 7.25 (1H, d, J = 17 Hz); 7,31 (2H); was 7.45 (2H, d); a 7.62 (1H).

The obtained filtrate was concentrated to dryness, and the residue was purified by column chromatography on silica gel, elwira tol.

1H-NMR (CDCl3) : of 3.84 (3H, s); 6,35 (1H, d, J = 14 Hz); 6,53 (1H, s); 6,62 (1H, d, J = 14 Hz); and 6.9 (2H, d); 7.24 to (2H); and 7.3 (2H, d); 7,38 (1H).

b) 84 g of a mixture of two stereoisomers of 5-bromo-2-[2-(4-methoxyphenyl)vinyl] benzofuran obtained in stage (a), was dissolved in 600 ml of dichloromethane. To this solution while cooling with ice and stirring at the same time, was added to 18.5 ml acetylchloride, and then one drop was added to 28.9 ml of titanium tetrachloride. The resulting reaction solution was poured into ice water, extracted with chloroform, and the obtained organic layer was washed with diluted hydrochloric acid and then with water, and then drained by removal of the solvent. After that, the residue suspended in ether, any insoluble crystals were collected by filtration, and was received as a result of 76 g of 3-acetyl-5-bromo-2-[2-(4-methoxyphenyl)vinyl]benzofuran in the form of light yellow needle-like crystals of the same isomer was formed from the E - and Z-forms. So pl. 163-165oC.

1H - NMR (CDCl3) : 2,69 (3H, s); of 3.85 (3H, s); to 6.95 (2H, d, J = 10 Hz); and 7.4 (2H, m); and 7.6 (2H, d, J = 10 Hz); the 7.65 (2H, s); 8,08 (1H).

c) a Mixture of 20.7 g of 3-acetyl-5-bromo-2-[2-(4-methoxyphenyl)-vinyl]benzofuran obtained in stage (b), 6 g of copper cyanide and 800 ml of N-methyl-2-pyrrolidone stirred in a stream of nitrogen for 8.5 hours at 210-220the initial filtrate was extracted with ethyl acetate. After removal nerastvorim materials by filtration, the obtained organic layer was washed with water and was dried by distillation of the solvent. Thus obtained residue was subjected to column chromatography on silica gel, elwira toluene, after which the obtained product was washed with methanol. The result of this procedure was given of 7.82 g of 3-acetyl-2-[2-(4-methoxyphenyl)vinyl]-5-benzofuranyl in the form of thin crystals. So pl. 190-191oC.

1H-NMR (CDCl3) : 2,69 (3H, s); of 3.85 (3H, s); 6,98 (2H, d, J = 10 Hz); 7.50 for -7,80 (6H, m); at 8.36 (1H).

d) of 7.8 g of 3-acetyl-2-[2-(4-methoxyphenyl)vinyl]-5-benzofuranyl obtained in stage c), was dissolved in a solvent mixture consisting of 600 ml of tetrahydrofuran and 500 ml of ethanol. To this solution was added 900 mg of palladium oxide 1H2O barium sulfate, and the resulting mixture was subjected to catalytic hydrogenation under normal pressure for 3.5 hours. After removal of catalyst by filtration, the filtrate was concentrated to dryness. The obtained residue was extracted with ethyl acetate, and the organic layer was washed with water and was dried by distillation of the solvent. After that, the precipitate was washed with methanol, precipitated crystals were collected by filtration, and was received in itallow. So pl. 130-131oC.

1H-NMR (CDCl3) : of 2.54 (3H, s); totaling 3.04 (2H, m); 3,4 (2H, m); of 3.77 (3H, s); 6,85 (2H, d, J = 10 Hz); 7,05 (2H, d); EUR 7.57 (2H, s); 8,33 (1H).

e) of 5.2 g of sodium hydroxide was dissolved in 30 ml of water, and the resulting solution was cooled to a temperature of 0oC or below. To this solution, while stirring, one drop was added to 2.7 ml of bromine, and then 40 ml of dioxane solution containing 4,14 g of 3-acetyl-2-[2-(4-methoxyphenyl)ethyl] 5-benzofurazanyl obtained in stage (d). The resulting mixture was stirred 45 minutes at 0oC, and then another 1 hour with ice cooling. The reaction solution was mixed with water, and the pH of the mixture was brought to 2 with concentrated hydrochloric acid, after which the mixture was extracted with chloroform. The obtained organic layer was washed with water and was dried by distillation of the solvent. Then, the residue was purified by column chromatography on silica gel, elwira chloroform, which was obtained 1.44 g of 5-cyano-2-[2-(4-methoxyphenyl)ethyl]-3-benzofuranol acid.

So pl. 205-208oC (after recrystallization from methanol, to obtain a thin pritvorenih crystals).

1H-NMR (CDCl3) : of 3.13 (2H, m); 3,5 (2H, m); of 3.78 (3H, s); 6,83 (2H, d); 7,07 (2H, d); 7,56 (2H, s); a 8.34 (1H).

f) of 1.81 g of 5-cyan, and the resulting mixture was heated under reflux for 1 hour. The resulting solution was concentrated to dryness, and the residue was mixed with ethanol and stirred for 30 minutes at 50oC. Precipitated crystals were collected by filtration, and resulted 1,82 g of ethyl 5-cyano-2-(2-(4-methoxyphenyl)ethyl)-3-benzophenoneoxymate.

So pl. 135-139oC (thin privorotnye crystals)

IR (KBr): 224, 1695, 1614, 1587, 1515 cm-1< / BR>
g) 1.78 g of ethyl 5-cyano-2-[2-(4-methoxyphenyl)ethyl]-3-benzophenoneoxymate obtained in stage f), were processed in accordance with the procedure described in stage e) of comparative example 46, received in the result of 2.27 g of target compound in the form of a thin needle-shaped crystals.

So pl. 182-183oC.

1H-NMR (CDCl3) : of 1.45 (3H, t, J = 8.0 Hz); 3,0 (2H, m); 3,4 (2H, m), 4,4 (2H, square, J = 8.0 Hz); 6,7 (2H, d); and 7.1 (2H, d); at 7.55 (2H); 8,29 (1H).

Reference example 50. Obtain ethyl[5-cyano-2-(2-(4-hydroxyphenyl)ethyl] -3-benzofuranyl)acetate.

a) 128 g of 5-bromo-2-[2-(4-methoxyphenyl)vinyl] benzofuran in the form of a mixture of two stereoisomers was dissolved in a mixture consisting of 1,3 l of tetrahydrofuran and 0.7 l of ethanol. The resulting solution was mixed with 3.0 g of platinum dioxide, and within 4 hours was subjected catalytically, and the precipitated crystals were collected by filtration and washed with ethanol. In the described procedure has been 97,08 g of 5-bromo-2-[2-(4-methoxyphenyl)ethyl]benzofuran. So pl. 109-111oC.

1H-NMR (CDCl3) : 3,00 (4H, s); of 3.77 (3H, s); 6,28 (1H, s); to 6.88 (2H, d, J = 9.0 Hz); was 7.08 (2H, d, J = 9.0 Hz); 7,32 (2H); 7,60 (1H).

b) 97 g of 5-bromo-2-[2-(4-methoxyphenyl)-ethyl]benzofuran obtained in stage a) was treated according to the procedure described in stage b) of reference example 49, resulting in the received 79,9 g of 3-acetyl-5-bromo-2-[2-(4-methoxyphenyl)ethyl]benzofuran. So pl. 100-101oC.

1H-NMR (CDCl3) : 2,52 (3H, s); 3,05 (2H, m); at 3.35 (2H, m); 3,76 (3H, s); to 6.80 (2H, d, J = 9.0 Hz); 7,10 (2H, d, J = 9.0 Hz); to 7.35 (2H, m); 8,05 (1H).

c) 79,9 g of 3-acetyl-5-bromo-2-[2-(4-methoxyphenyl)ethyl]-benzofuran obtained in stage b), were processed in accordance with the procedure described in stage e) of reference example 49, resulting in the received 64,2 g of 5-bromo-2-[2-(4-methoxyphenyl)ethyl]-3-benzofuranol acid.

1H-NMR (DMSO-d6) : of 3.00 (2H, m); at 3.35 (2H, m); of 3.69 (3H, s); to 6.80 (2H, d, J = 8.0 Hz); 7,07 (2H, d, J = 8.0 Hz); 7,50 (1H, DD); at 7.55 (1H, d); 8,00 (1H, d).

d) 64,2 g of 5-bromo-2-[2-(4-methoxyphenyl)ethyl]-3-benzofuranol acid, obtained in stage c), suspended in 900 ml of ethanol. the project under reflux, to the reaction mixture drop by drop was added 50 ml of thionyl chloride, and then the obtained mixture was heated under reflux for another 3 hours. The reaction solution was concentrated to dryness, and the residue was mixed with water and any insoluble materials were collected by filtration. These insoluble material was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate, then water, and then saturated aqueous sodium chloride, and the solvent drove away.

The resulting residue is suspended in ethanol, filtered and received 59,23 g of ethyl 5-bromo-2-[2-(4-methoxyphenyl)ethyl]-3-benzophenoneoxymate. So pl. 73-75oC.

1H-NMR (CDCl3) : USD 1.43 (3H, t, J = 8,9 Hz); 3,10 (2H, m); 3.40 in (2H, m); of 3.77 (3H, s); however, 4.40 (2H, square, J = 8,9 Hz); to 6.80 (2H, d); to 7.2 (2H, d); 7,33 (2H, m), 8,10 (1H).

e) 35.5 g of ethyl 5-bromo-2-[2-(4-methoxyphenyl)ethyl]-3-benzophenoneoxymate obtained in stage d), was dissolved in 400 ml of tetrahydrofuran, followed by the gradual addition of 3.5 g of lithium aluminum hydride, and then the resulting mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water, the pH was brought to 2 with hydrochloric acid, and the resulting solution was extracted with benzene. Then the organic layer is enyl)ethyl] benzofuran in the form of crystals. So pl. 65-75oC.

1H-NMR (CDCl3) : 2,95 (4H, s); of 3.69 (3H, m); 4,33 (2H, s); 6,77 (2H, d); make 6.90 (2H, d); 7,26 (2H, m); the 7.65 (1H).

f) 30 g of 5-bromo-3-hydroxymethyl-2-[2-(4-methoxyphenyl)-ethyl]benzofuran obtained in stage e), suspended in 150 ml of diethyl ether. To this suspension was added 12 drops of pyridine. Then, cooling with ice, drop by drop was added 12 ml of thionyl chloride. The reaction mixture was stirred at room temperature for 1 hour. Then the resulting reaction solution was poured into ice water and was extracted with diethyl ether. After that, the organic layer was washed with water and then saturated aqueous sodium bicarbonate, and then concentrated to dryness, resulting in a received 28,3 g of 5-bromo-3-chloromethyl-2-[2-(4-methoxyphenyl)ethyl]benzofuran. So pl. 70-75oC.

1H-NMR (CDCl3) : 3,00 (4H, s); 3,76 (3H, s); of 4.38 (2H, s); PC 6.82 (2H, d); 6,97 (2H, d); 7,31 (2H); to 7.68 (1H).

g) To 75 ml of acetonitrile was added was 10.82 g of 5-bromo-3-chloromethyl-2-[2-(4-methoxyphenyl)ethyl] benzofuran obtained in stage f), 3.7 g of potassium cyanide and 0.6 g of 18-crown-6-ether. The resulting mixture was heated under reflux for 2.5 hours. Then the reaction solution was mixed with water and was extracted with benzene, and the resulting organic layer prce silica gel, using as elution solvent a mixture of toluene and n-hexane, resulting in received 9,17 g of 5-bromo-3-cyanomethyl-2-[2-(4-methoxyphenyl)ethyl]benzofuran.

1H-NMR (CDCl3) : 2,95 (4H, s); 3,20 (2H, s); of 3.73 (3H, s); to 6.80 (2H, d); make 6.90 (2H, d); 7,33 (2H); to 7.61 (1H).

h) 9,17 g of 5-bromo-3-cyanomethyl-2-[2-(4-methoxyphenyl)ethyl]benzofuran obtained in stage (g), was added to a mixed solution consisting of 100 ml of ethanol and 5 ml of concentrated sulfuric acid, and the resulting mixture was heated under reflux for 18 hours. The reaction solution was poured into water and was extracted with ethyl acetate. Then the organic layer was washed with water, then saturated aqueous sodium bicarbonate and again with water, after which this layer was dried by distillation of the solvent. The result of this procedure received 8,96 g of ethyl 5-bromo-2-[2-(4-methoxyphenyl)ethyl]-3-benzofuranyl acetate.

1H-NMR (CDCl3) : to 1.21 (3H, t, J = 7.0 Hz); 2,96 (4H, s); to 3.34 (2H, s); 3,74 (3H, s); 4,10 (2H, square, J = 7,0 Hz); to 6.80 (2H, d, J = 9 HZ); 7,00 (2H, d, J = 7,0 Hz); 7,28 (2H); to 7.59 (1H).

i) of 8.2 g of ethyl [5-bromo-2-[2-(4-methoxyphenyl)ethyl]-3-benzofuranyl]acetate obtained in stage h), were processed in accordance with the procedure described in stage c) of reference example 49, the result of which was obtained 4.5 g of ethyl [. 5-86oC

1H-NMR (CDCl3) : of 1.23 (3H, t, J = 7.0 Hz); 3,01 (4H, s); 3.40 in (2H, s); of 3.75 (3H, s); 4,11 (2H, square, J = 7,0 Hz); to 6.80 (2H, d, J = 9 Hz); 7,00 (2H, d, J = 7,0 Hz); 7,47 (2H); 7,81 (1H).

j) of 4.45 g of ethyl[5-cyano-2-[2-(4-methoxyphenyl)ethyl]-3-benzofuranyl]acetate obtained in stage i) was treated according to the procedure described in stage e) of comparative example 46, resulting in a received 2,98 g of the target compound as colorless crystals.

So pl. 134-136oC

1H-NMR (CDCl3) : to 1.22 (3H, t, J = 7.0 Hz); 2,98 (4H, s); 3,39 (2H, s); of 4.12 (2H, square , J = 7,0 Hz); 6,74 (2H, q, J = 9 Hz); 6,91 (2H, d, J = 7,0 Hz); of 7.48 (2H); 7,80 (1H).

Reference example 51. Getting ethyl 3-[2-[2-(5-cyanobase[b]Tien-2-yl)ethyl]-4-ethoxy-5 - hydroxyethyl]propionate.

a) of 20.0 g of ferulic acid was dissolved in 250 ml of methanol and the resulting solution was subjected to catalytic recovery for 3 hours under normal pressure in the presence of 10% palladium carbon (catalyst, 50% wet). After removal of catalyst by filtration, the obtained filtrate was concentrated, and the precipitated crystals were collected by filtration, resulting in a received 19.3 g of 3-(4-hydroxy-3-methoxyphenyl)propionic acid.

So pl. 87 - 89oC.

1H-NMR (CDCl3

1H-NMR (CDCl3) : of 1.23 (3H, t, J = 7.2 Hz); 2,4 - 3,0 (4H, m); of 3.85 (3H, s); of 4.12 (2H, square, J = 7,12 Hz); 6,6 - 6,9 (3H, m).

c) 10.0 g of ethyl 3-(4-hydroxy-3-methoxyphenyl)propionate obtained in stage b), was dissolved in 300 ml of tetrahydrofuran. Then added a 1.96 g of 60% sodium hydride. Thus obtained mixture was stirred for 30 minutes at 50oC. thereafter, to the mixture drop by drop) was added 7,17 g ethylbromide. After 6 hours of heating under reflux, the reaction solution was poured into ice water, extracted with chloroform, washed with water, and then concentrated under reduced pressure. After that, the obtained residue was subjected to column chromatography on silica gel, elwira chloroform, and was obtained 5.6 g of oily ethyl 3-(4-ethoxy-3-methoxyphenyl)propionate.

1H-NMR (CDCl3

d) 9.3 g of ethyl 3-(4-ethoxy-3-methoxyphenyl)propionate obtained in stage c), was dissolved in 10 ml of acetic acid, followed by the addition of 7.4 g chlormethiazole methylether, and then stirred for 22 hours at room temperature. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with water and was dried by distillation of the solvent. Thus obtained residue was dissolved in 10 ml of xylene, and the solution was mixed with 8,54 g of triphenylphosphine. The resulting mixture was stirred at room temperature for 18 hours and then 5 hours at 70 - 80oC. After cooling, the xylene was removed by decantation, and the remaining part was utverjdali by adding n-hexane, which was obtained 6.0 g of crude [5-ethoxy-2-(2-ethoxycarbonylethyl)-4-methoxyphenyl]-methyltriphenylphosphonium chloride.

e) In a solution consisting of 50 ml of tetrahydrofuran and 50 ml of ethanol, was dissolved 1.5 g of 5-cyanobase[b]thiophene-2-carbaldehyde and 6,34 g of crude [5-ethoxy-2-(2-ethoxycarbonylethyl)-4-methoxyphenyl] methyltriphenylphosphonium chloride, obtained in stage d). To the resulting solution was added to 1.83 g of 1,8-diazabicyclo[5.4.0] -7-undecene, and stirred 18 hours at room temperature. The resulting reaction solution was concentrated at ponijiem, the solution was mixed with 1.70 g of 10% palladium carbon (catalyst at 50% wet), and subjected to catalytic hydrogenation under normal pressure until, until the absorption of hydrogen. After removal of catalyst by filtration, the solvent drove away. After chromatography of the resulting residue on a column of silica gel, was obtained 1.2 g of oily ethyl 3-[2-[2-(5-cyanobase[b]Tien-2-yl)ethyl]-4-ethoxy - 5-methoxyphenyl]propionate.

1H-NMR (CDCl3) : of 1.24 (3H, t, J = 7,1 Hz); of 1.36 (3H, t, J = 7.0 Hz); 2,4 - 3,3 (8H, m); a-3.84 (3H, s); 3,98 (2H, square, J = 7,0 Hz); 4,13 (2H, square, J = 7,1 Hz); only 6.64 (1H, s); 6,70 (1H, s);? 7.04 baby mortality (1H, s); 7,46 (1H, DD, J = 8.4 and 1.5 Hz); 7,83 (1H, d, J = 8,4 Hz); of 7.96 (1H, s).

f) 2.1 g of ethyl 3-[2-[2-(5-cyanobase[b]Tien-2-yl)ethyl]-4 - ethoxy-5-methoxyphenyl]propionate obtained in stage e), was dissolved in 20 ml collidine, followed by the addition 7,94 g of lithium iodide and then heated under reflux for 18 hours. The reaction solution was poured into ice water, extracted with chloroform, washed with water, and then drained. After removal of the solvent, the obtained residue was dissolved in 100 ml of ethanol, mixed with 0.3 ml of concentrated sulfuric acid, and then heated under reflux for 1 hour. After removal of the solvent under reduced pressure, the resulting reaction solution was diluted with chloroform, washing is adopted on a column of silica gel, elwira chloroform. In the described procedure was obtained 2.0 g of the target compound as an oily substance.

1H-NMR (CDCl3) : of 1.24 (3H, t, J = 7,1 Hz); of 1.35 (3H, t, J = 7.0 Hz); 2,4 - 3,3 (8H, m); 3,98 (2H, square, J = 7,0 Hz); 4,13 (2H, square, J = 7,1 Hz); 6,60 (1H, s); 7,44 (1H, DD, J = 8.4 and 1.5 Hz); of 7.82 (1H, d, J = 8,4 Hz); of 7.96 (1H, s); 7,94 (1H, s).

Reference example 52. Getting ethyl 3-[2-[2-(5-cyanobase[b]Tien-2-yl)ethyl]-5-hydroxyphenyl propionate.

a) of 33.5 g of 6-methoxy-2-tetralone was dissolved in a 27.6 ml of ethanol and then added of 37.8 ml of atlantogenata and one drop of concentrated sulfuric acid. The resulting mixture was stirred 4 hours at 100oC. After removal of the solvent under reduced pressure, the obtained residue was subjected to column chromatography on silica gel, elwira chloroform. The desired fractions were combined, concentrated, and precipitated crystals were collected, resulting in received of 5.82 g of 3,4-dihydro-2-ethoxy-6-methoxynaphthalene.

1H-NMR (CDCl3) : of 1.37 (3H, t, J = 7.0 Hz); 2,20 - of 3.00 (4H, m); with 3.79 (3H, s); a-3.84 (2H, square, J = 7,0 Hz); of 5.48 (1H, s); 6,60 - to 7.00 (3H, m).

b) 5.8 g of 3,4-dihydro-2-ethoxy-6-methoxynaphthalene obtained in stage (a), was dissolved in a mixture of 90 ml of ethanol and 10 ml of dichloromethane. Then, stirring at -20oC, the th same temperature, gradually, drop by drop was added 10 ml of dimethyl sulfide, after which the mixture stirred 30 min at room temperature. After removal of the solvent under reduced pressure, the residue was dissolved in 100 ml of a mixture of tetrahydrofuran and ethanol (1:1). To the resulting solution was added 12.5 g (5-cyanobase[b] Tien-2-yl)methyltriphenylphosphonium chloride, and then to 4.46 ml of 1,8-diazabicyclo[5.4.0] -7-undecene, after which the mixture is stirred for 5 hours. The resulting reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel, elwira chloroform. The purified product was dissolved in 60 ml of a mixture of ethanol and tetrahydrofuran (1:1), and the resulting solution was mixed with 3.9 g of 10% palladium carbon (catalyst at 50% wet). After 3 hours of catalytic hydrogenation of the mixture under normal pressure, received a 2.75 g of ethyl 3-[2-[2-(5-cyanobase[b]Tien-2-yl)ethyl]-5-methoxytryptamine.

1H-NMR (CDCl3) : to 1.22 (3H, t, J = 7.2 Hz); 2,2 - 3,4 (8H, m); 3,76 (3H, s); of 4.16 (2H, square, J = 7.2 Hz); 6,60 - 7,30 (4H, m); of 7.48 (1H, d, J = 8,2 Hz); a 7.85 (1H, d, J = 8,2 Hz); 7,99 (1H, s).

c) of 2.75 g of ethyl 3-[2-[2-(5-cyanobase[b]Tien-2-yl)ethyl]-5 - methoxyphenyl propionate obtained in stage [b] processed according to the procedure described in stage (e) with the>

1H-NMR (CDCl3) : of 1.23 (3H, t, J = 7,1 Hz); 2,4 - 3,34 (8H, m); 4,13 (2H, square, J = 7.2 Hz); the ceiling of 5.60 (1H, s); 6,50 - 7,20 (3H, m); of 7.25 (1H, s); 7,44 (1H, d, J = 8,3 Hz); of 7.82 (1H, d, J = 8,3 Hz), 7,92 (1H, s).

Reference example 53. Obtain ethyl 2-(5-cyanobase[b]Tien-2-yl)-3-(4-hydroxyphenyl)propionate.

a) 0.5 g of 5-bromo-2-hydroxymethylene[b] thiophene was dissolved in 20 ml of dichloromethane and then added 230 mg of tribromide phosphorus. After 1 hour stirring at room temperature, the reaction solution was mixed with water, washed with saturated aqueous sodium bicarbonate, and then dried by distillation of the solvent. The obtained residue was dissolved in a mixture consisting of 10 ml of acetonitrile and 3 ml of dimethylsulfoxide was then added 300 mg of copper cyanide, and was heated under reflux for 2 hours. After cooling, to the reaction solution was added toluene, any insoluble materials were removed by filtration, and the filtrate was washed with water, dried and concentrated. After collecting the precipitated crystals by filtration, received 200 mg of 5-bromo-2-cyanomethylene of thiophene. So pl. 94 - 96oC.

1H-NMR (CDCl3) : 3,98 (2H,s); of 7.25 (1H, s); 7,42 1H, DD, J = 8.5 and 1.8 Hz); the 7.65 (1H, d, J = 8.5 Hz); of 7.90 (1H, d, J = 1,8 Hz).

b) 12.0 g of 5-bromo-2-cyanomethylene[b]t is sulfuric acid. After 7 hours of heating under reflux, the reaction solution was mixed with 40 ml of ethanol, 15 ml of concentrated sulfuric acid and 0.5 ml of water, and the resulting mixture was heated under reflux for 2 hours. After cooling, the reaction solution was mixed with water and was extracted with an equal volume mixture of toluene and ethyl acetate. The obtained organic layer was washed with water and saturated aqueous sodium bicarbonate, and then dried by distillation of the solvent. After that, the residue was subjected to chromatography on silica gel and was obtained 8.0 g of ethyl 2-(5-bromobenzo[b]Tien-2-yl)acetate. So pl. 56 - 57oC.

1H-NMR (CDCl3) : of 1.28 (3H, t, J = 7.0 Hz); 3,88 (2H, s); to 4.23 (2H, square, J = 7,0 Hz); 7,11 (1H, s); 7,38 (1H, DD, J = 8,3 and 1.8 Hz); to 7.68 (1H, d, J = 8,3 Hz); of 7.82 (1H, d, J = 1,8 Hz).

c) 800 mg of ethyl 2-(5-bromobenzo[b]Tien-2-yl)acetate obtained in stage b), and 965 mg diethylmalonate was dissolved in 4 ml of N,N-dimethylformamide. To the resulting solution by heating in an oil bath at 120 - 130oC, was added 162 mg of sodium hydride (60%). After 10 minutes of stirring at the same temperature, to the reaction solution was added 30 mg of sodium hydride (60%), and stirring was continued for another 10 minutes. The resulting solution was diluted with an equal volume of a mixture a distillation of the solvent, the obtained residue was purified by chromatography on a column of silica gel, elwira mixture of toluene and ethyl acetate. The result of this procedure, received 600 mg of ethyl 2-(5-bromobenzo[b]Tien-2-yl)-2-ethoxycarbonylethyl.

1H-NMR (CDCl3) : of 1.28 (6H, t, J = 7.0 Hz); 4.25 in (4H, square, J = 7,0 Hz); of 4.95 (1H, s); 7,17 (1H, s); to 7.35 (1H, DD, J = 8.3 and 2.1 Hz); a 7.62 (1H, d, J = 8,3 Hz); 7,83 (1H, d, J = 2.1 Hz).

d) 6.2 g of ethyl 2-(5-bromobenzo[b] Tien-2-yl)-2-ethoxycarbonylethyl obtained in stage c), and 5.2 g of 4-methoxybenzylamine was dissolved in 30 ml of N, N-dimethylformamide. To the resulting solution at room temperature, was added to 1.34 g of sodium hydride (60%), and the mixture is stirred for 3 hours. Cooling with ice, the reaction solution was mixed with 10% aqueous citric acid solution, was extracted with toluene, washed with water, and then drained. After removal of the solvent, the obtained residue was chromatographically on a column of silica gel, elwira toluene, resulting in received of 8.2 g of ethyl 2-(5-bromobenzo[b] Tien-2-yl)-2-etoxycarbonyl-3-(4-methoxyphenyl) propionate. So pl. 58 - 60oC.

1H-NMR (CDCl3) : to 1.22 (6H, t, J = 7.0 Hz); the 3.65 (5H, s); 4,30 (4H,. square , J = 7,0 Hz); 6,60 (2H, d, J = 8.5 Hz); 6,79 (2H, d, J = 8.5 Hz); 7,31 (1H, s); to 7.35 (1H, DD, J = 8.8 and 1.8 Hz); of 7.60 (1H, d, J = 8,8 Hz); of 7.82 (1H, d, J = 1,8 Hz).

1H-NMR (CDCl3) : to 1.15 (3H, t, J = 7.0 Hz); is 3.08 (1H, DD. J = 13,5 and 7.3 Hz); 3,37 (1H, DD, J = 13.5 and the 7.3 Hz); 3,71 (3H, s); 4,10 (2H, square, J = 7,0 Hz); 4,14 (1H, t, J = 7,3 Hz); 6.75 in (2H, d, J = 8.7 Hz); 6,83 (1H, s); 7,05 (2H, d, J = 8.7 Hz); 7,30 (1H, DD, J = 8.8 and 2.3 Hz); EUR 7.57 (1H, d, J = 8,8 Hz); 7,74 (1H, d, J = 2.3 Hz).

f) 1.6 g of ethyl 2-(5-bromobenzo[b]Tien-2-yl)-3-(4-methoxyphenyl) propionate obtained in stage e), were processed in accordance with the procedure described in Ref is onata. So pl. 93 - 96oC.

1H-NMR (CDCl3) : of 1.17 (3H, t, J = 7.0 Hz); to 3.09 (1H, DD, J = 14.0 and 8.0 Hz); 3,39 (1H, DD, J = 14.0 and 8.0 Hz); of 3.73 (3H, s); of 4.12 (2H, square, J = 7,0 Hz); 4,16 (1H, t); to 6.75 (2H, d, J = 8,8 Hz); 7,05 (2H, d, J = 8,8 Hz); 7,13 (1H, s); the 7.43 (1H, DD, J = 8.3 and 1.3 Hz); 7,81 (1H, d, J = 8,3 Hz); a 7.92 (1H, Shir.).

g) of 3.3 g of ethyl-2-(5-cyanobase[b]Tien-2-yl)-3-(4-methoxyphenyl) propionate obtained in stage f), were processed in accordance with the procedure described in stage e) of reference example 46, the result of which was obtained 2.8 g of the target compound. So pl. 146 - 147oC.

1H-NMR (CDCl3) : to 1.19 (3H, t, J = 7.0 Hz); to 3.09 (1H, DD, J = 13.5 and 7.5 Hz); to 3.38 (1H, DD, J = 13.5 and 7.5 Hz); 4,13 (2H, square, J = 7,0 Hz); 4,18 (1H, t); 6,70 (2H, d, J = 8.5 Hz); 7,00 (2H, d, J = 8.5 Hz); to 7.15 (1H, s); 7,47 (1H, DD, J = 8.3 and 1.3 Hz); a 7.85 (1H, d, J = 8,3 Hz); of 7.95 (1H, Shir.).

Reference example 54. Obtain ethyl 2-[4-[((2S)-1-tert-butoxycarbonyl-2-pyrrolidinyl)methoxy]phenyl]-3- (5-cyano-2-benzofuranyl)propionate.

1.04 g of diethylazodicarboxylate was added to 300 ml of tetrahydrofuran containing 1 g of ethyl 3-(5-cyano-2-benzofuranyl)-2- (4-hydroxyphenyl)propionate, 1.2 g of (2S)-1-tert-butoxycarbonyl-2-pyrrolidineethanol and 1.56 g of triphenylphosphine, and the mixture was stirred at room temperature for 18 hours. To the reaction solution was added 0.6 g of (2S)-1-tert-what do 18 hours at room temperature. Then, the reaction solution was concentrated to dryness, and the residue was purified by chromatography on a column of silica gel, elwira mixture of toluene and ethyl acetate. In the described procedure received 790 mg of the target compound as colorless oily substance.

1H-NMR (CDCl3) : to 1.15 (3H, t); of 1.46 (9H, s); to 1.98 (4H, W), is 3.0 - 4.2 (8H, m); a 4.1 (2H), 6,37 (1H, s); 6,9 (2H, d); to 7.2 (2H, d); 7,45 (2H); 7,76 (1H, s).

Compounds of reference examples 55 to 61 were obtained in accordance with the procedure described in reference example 54.

Reference example 55. Ethyl 3-[4-[((3S)-1-tert-butoxycarbonyl-3 - pyrrolidinyl)oxy]phenyl]-3-(5-cyano-2-benzofuranyl)propionate,

1H-NMR (CDCl3) : of 1.16 (3H, t, J = 7 Hz); of 1.46 (9H, s); of 2.0 - 2.2 (2H, m); is 2.8 - 3.2 (2H, m); of 3.5 - 3.7 (4H, m); 4,10 (2H, square, J = 7 Hz); 4,5 - 4,7 (1H, m) and 4.9 (1H, m); of 6.49 (1H, s); PC 6.82 (2H, d, J = 9 Hz); 7.23 percent (2H, d, J = 9 Hz); 7,47 (2H, s); 7,80 (1H, s).

Reference example 56. Ethyl 5-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)hydroxy]-2-2-[2-(5- cyano-2-benzofuranyl)ethyl]benzoate.

1H-NMR (CDCl3) : to 1.38 (3H, t, J = 7.0 Hz); to 1.48 (9H, s); 2,00 - 2,30 (2H, m); 2,96 is 3.76 (8H, m); 4,36 (2H, square); the 4.90 (1H, width); 6,44 (1H, s); 6,93 (1H, DD, J = 8.8 and 2.7 Hz); to 7.15 (1H, d, J = 8,8 Hz); of 7.48 (1H, d, J = 2.7 Hz); 7,52 (2H, s); 7,80 (1H, s)

Reference example 57. Ethyl 2-[5-[((3S)-1-tert-butoxycarbonyl-3 - pyrrolidinyl)oxy]is 2.30 (2H, m); 3.04 from (4H, s); 3,36 - 3,70 (6H, m); 4,16 (2H, square, J = 7,0 Hz); 4,90 - 5,12 (2H, W); 6.42 per (1H, s); 6,60 - to 6.80 (2H, m); was 7.08 (1H, d, J = 7,6 Hz); the 7.43 (2H, s); to 7.77 (1H, d, J = 0,87 Hz).

Reference example 58. Ethyl 2-[2-[4-((3S)-1-tert-butoxycarbonyl - 3-pyrrolidinyl)oxy]phenyl]ethyl]-5-cyano-3-benzophenoneoxymate.

1H-NMR (CDCl3) : of 1.46 (12H, m); is 2.05 (2H, m); 2,95 (2H, m); 3,5 (6H, m), 4,4 (2H, square); 4,80 (1H, width); PC 6.82 (2H, d); was 7.08 (2H, d); at 7.55 (2H); 8,30 (1H).

Reference example 59. Ethyl 3-[5-[((3S)-1-tert-butoxycarbonyl - 3-pyrrolidinyl)hydroxy]-2-[2-(5-cyanobase[b]Tien-2-yl)ethyl]-4 - ethoxyphenyl]propionate.

1H-NMR (CDCl3) : of 1.23 (3H, t, J = 7.2 Hz); of 1.33 (3H, t, J = 7.0 Hz); of 1.47 (9H, s); 2,00 - 3,30 (10H, m); 3,4 - 3,7 (4H, m); of 3.94 (2H, square, J = 7,0 Hz); of 4.12 (2H, square, J = 7.2 Hz); 4,70 - 5,00 (1H, width); to 6.67 (1H, s); 6,72 (1H, s); 7,05 (1H, s); 7,46 (1H, DD, J = 8.4 and 1.6 Hz); to 7.84 (1H, DD, J = 8,4 Hz); of 7.95 (1H, d, J = 1.6 Hz).

Reference example 60. Ethyl 3-[5-[((3S)-1-tert-butoxycarbonyl - 3-pyrrolidinyl)hydroxy-2-[2-(5-cyanobase[b]Tien-2-yl)ethyl]phenyl]propionate.

So pl. 117 - 119oC

1H-NMR (CDCl3) : 1,24 (3H, so J = 7,1 Hz); for 1.49 (9H, s); 1,6 - 3,6 (14H, m); 4,13 (2H, square, J = 7,1 Hz); 4,6 - 4,9 (1H, m); 6,50 - 7,20 (4H, m); was 7.45 (1H, d, J = 8.5 Hz); 7,83 (1H, d, J = 8.5 Hz); of 7.95 (1H, s).

Reference example 61. Ethyl-3-[4-[((3S)-1-tert-butoxycarbonyl - 3-pyrrolidinyl)oxy]phenyl]-2-(5-cyanobase[b]Tien-2-yl)propionate.

1H-NMR (CDC, WHO); 7,07 (2H, d, J = 8,3 Hz); 7,10 (1H, s); 7,40 (1H, DD, J = 8.3 and 1.3 Hz); to 7.77 (1H, d, J = 8,3 Hz); 7,89 (1H, Shir.).

Reference example 62. Obtain methyl 3-(5-cyano-2-benzofuranyl)-2-[4-[(tetrahydro-3-furanyl)oxy] phenyl]propionate.

In 30 ml of tetrahydrofuran was dissolved 3 g of 3-hydroxymitragynine, 6.5 g of methyl 2-(4-hydroxyphenyl)-2-oxoacetate and 9 g of triphenylphosphine. The resulting solution was mixed with 6.5 g of diethylazodicarboxylate, and the mixture is stirred for 2 hours. After removal of the solvent, the obtained residue was subjected to purification using column chromatography on silica gel, elwira dichloromethane, resulting in received 7.5 g of methyl 2-[4-[(tetrahydro-3-furanyl)oxy]phenyl]-2-oxoacetate in the form of an oily substance.

In a mixture solvent consisting of 30 ml of tetrahydrofuran and 50 ml of methanol, was dissolved 2.2 g of methyl 2-[4-[(tetrahydro-3-furanyl) oxy)phenyl]-2-oxoacetate obtained above, and 3.6 g of (5-cyano-2-benzofuranyl)methyltriphenylphosphonium chloride. To this solution while cooling with ice, was added 1.5 ml of 1,8-diazabicyclo[5.4.0]-7-undecene. After 18 hours stirring at room temperature, the reaction solution was concentrated to dryness, the residue was purified by chromatography on silica gel, elwira with a mixture of chloroform and Azucena thus a derivative of acrylic acid was dissolved in 80 ml of methanol, was mixed with 4 g of palladium oxide 1H2O barium sulfate, and subjected to catalytic hydrogenation under normal pressure. Then, the catalyst was removed by filtration, the obtained filtrate was concentrated to dryness, and the residue was purified using column chromatography on silica gel, elwira with a mixture of chloroform and acetone. The result of this procedure, received 2.5 g of the target compound.

1H-NMR (CDCl3) : 2,0 - 2,3 (2H, m); 3,2 (1H, DD); 3,6 (1H, DD); the 3.65 (3H, s); of 3.97 (2H, d); 3,8 - 4,2 (1H, m); 4,8 - 5,0 (1H, m); 6,40 (1H, m); 6.8 cm (2H, d); of 7.25 (1H, d); 7,5 (2H, s); 7,79 (1H, s).

Reference example 63. Obtain methyl 3-(5-cyano-2-indolyl)-2-[4-[((3R)-tetrahydro-3-furanyl)oxy] phenyl]propionate.

In 30 ml of tetrahydrofuran was dissolved 3.0 g (S)-(+)-3 - hydroxymitragynine, 6.6 g of methyl 2-(4-hydroxyphenyl)-2-oxoacetate and 8.90 g of triphenylphosphine. The resulting solution was mixed with 6.0 g of diethylazodicarboxylate, and the mixture is stirred for 2 hours. After removal of the solvent, the residue was purified by column chromatography on silica gel, elwira chloroform, resulting in received 4,60 g of methyl 2- [4-[((3R)-tetrahydro-3-furanyl)oxy]phenyl]-2-oxoacetate in the form of an oily product.

In a mixture solvent consisting of 30 ml of methanol, RAL)methyl triphenylphosphine bromide. To the resulting solution was added to 2.1 ml of 1,8-diazabicyclo[5.4.0]-7-undecene, stirring under ice cooling, and the mixture is then stirred at room temperature for 2 hours. After removal of the solvent, the residue was purified by column chromatography on silica gel, elwira with a mixture of chloroform and acetone, which was obtained methyl 3-(5-cyano-2-indolyl)-2- [4-[((3R)-tetrahydro-3-furanyl)oxy] phenyl] acrylate in a mixture of E - and Z-forms. Thus obtained E/Z-mixture was dissolved in 50 ml of methanol, mixed with 4.0 g of palladium oxide 1H2O barium sulfate, and then subjected to catalytic hydrogenation under normal pressure for 3 hours. Thereafter, the catalyst was removed by filtration, the solvent in the resulting filtrate is kept off, and the residue was purified by chromatography on silica gel using as eluent a mixture of chloroform and acetone. In the described procedure received 1.50 g of target compound in the form of a viscous oily material.

1H-NMR (CDCl3) : 3,10 (1H, DD); of 3.60 (3H, s); 3,78 - 4,10 (5H, m); 4.75 V - 5,00 (1H, m); and 6.25 (1H, width); to 6.80 (2H, d); then 7.20 (2H, d); 7,30 - of 7.90 (3H, m); 10,00 (1H, s).

Reference example 64. Obtain methyl 3-(5-cyano-2-indolyl)-2-[4-[((3S)-tetrahydro-3-furanyl)oxy] phenyl]propilot and 17.0 g of triphenylphosphine. To this solution, stirring and cooling with ice, drop by drop was added 12.0 g of diethylazodicarboxylate. After 2 hours stirring at room temperature, the solvent is kept off, and the obtained residue was purified by column chromatography on silica gel, elwira chloroform, which was obtained (S)-(+)-tetrahydro-3-humaniform, which was then dissolved in 50 ml of ethanol. This ethereal solution, stirring, was added 5.0 g of sodium hydroxide dissolved in 5 ml of water, and then stirred for 3 hours. After dissolution in diethyl ether, any insoluble materials were removed by filtration. After removal of the solvent, got 4,50 g of crude (R)-(-)-3-hydroxymitragynine.

b) Crude (R)-(-)-3-hydroxymitragynine obtained in stage (a) was treated according to the procedure described in reference example 63, resulting in a received 1.50 g of target compound in the form of a viscous oily material.

1H-NMR (CDCl3) : 3.15 in (1H, DD); the 3.65 (3H, s); 3,30 - 4,20 (5H, m); 4.80 to of 5.05 (1H, m); 6,30 (1H, width); PC 6.82 (2H, d); 7,22 (2H, d); 7,30 - of 7.90 (3H, m); of 9.30 (1H, Shir.).

Reference example 65. Obtain methyl 3-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-2-(5-cyano-2-benzofuranyl)propionate.

a is the temperature -10oC, one drop was added 30 ml of dichloromethane solution containing 18.2 g of bromine. After gradual heating to a temperature of the cooling with ice, the resulting reaction solution was mixed with chloroform, and washed with 10% aqueous sodium thiosulfate solution. Then the organic layer was dried and concentrated to dryness, and the residue was recrystallized from a mixture of benzene and n-hexane, resulting in received 21,0 g 2-(2-bromo-1-oxoethyl)-5-benzofurazanyl in the form of colorless crystals. So pl. 156 - 158oC.

IR (KBr): 2228, 1696, 1616, 1564, 1290, 1166, 1122 cm-1.

1H-NMR (CDCl3) : of 4.44 (2H, s); 7,60 - of 7.90 (3H, m); 8,11 (1H, s).

FD-MS (m/z): 263 (M+), 265 (M+)

b) 444 mg of selenium dioxide was dissolved in 10 ml of dry methanol, by heating at the same time, and then added 1,056 g 2-(2-bromo-1-oxoethyl)-5-benzofurazanyl obtained in stage (a). Thus obtained mixture was heated under reflux for 12 hours. After cooling, any insoluble materials were removed by filtration, and the obtained filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel, elwira mixture of toluene and ethyl acetate, resulting in a received 129 mg of methyl 2-(5-cyano-2-benzo is 1614, 1552 cm-1.

1H-NMR (CDCl3) : a 4.03 (3H, s); 7,66 - of 7.96 2H, m), 8,17 (2H, s).

FD-MS (m/z): 321 (M++ 92), 229 (M+).

c) 3.1 g of methyl 2-(5-cyano-2-benzofuranyl)-2-oxoacetate obtained in stage b), and 6.2 g of (4-methoxyphenyl)methyltriphenylphosphonium chloride was dissolved in a mixture of solvents consisting of 100 ml of tetrahydrofuran and 100 ml of methanol. To this solution, stirring at room temperature, was added 2,19 g of 1,8-diazabicyclo[5.4.0]-undecene, and continued to stir for 1 hour. Then to this mixture was added 1.3 g (4-methoxyphenyl)methyltriphenylphosphonium chloride and 0.65 g of 1,8-diazabicyclo[5.4.0]-undecene. After 1 hour stirring, followed by distillation of the solvent, the obtained residue was purified by column chromatography, elwira chloroform, resulting in the received viscous oily olefinic compound in the form of a mixture of E - and Z-forms.

1H-NMR (CDCl3) : 3,78 (1,5 H, C); a-3.84 (3H, s); a 3.87 (1,5 H, C); 6,60 (9H, m).

The obtained olefinic compound was dissolved in a mixture of solvents consisting of 100 ml of methanol and 100 ml of tetrahydrofuran, followed by addition of 1.1 g of palladium oxide 1H2O barium sulfate, and then subjected to catalytic hydrogenation under normal pressure is omashu chromatography on silica gel, as a result, we received a 4.2 g of a viscous and oily methyl 2-(5-cyano-2-benzofuranyl)-2-(4-methoxyphenyl)propionate.

1H-NMR (CDCl3) : 3,20 (1H, DD, J=14,4 and 7.8 Hz); to 3.41 (1H, DD, J=14,4 and 7.4 Hz); of 3.69 (3H, s); of 3.75 (3H, s); 4,10 (1H, DD, J=7.8 and 7.4 Hz); 6,60 (1H, s); 6,76 (2H, d, J=8,8 Hz); 7,05 (2H, d, J=8,8 Hz); 7,53 (2H); of 7.82 (1H, s).

d) of 4.2 g of methyl 2-(5-cyano-2-benzofuranyl)-3-(4-methoxyphenyl) propionate obtained in stage (c), was dissolved in 150 ml of dichloromethane, and the resulting solution was cooled to -50oC. Then, to this solution, stirring, one drop was added 30 ml of dichloromethane solution containing becomes 9.97 g tribromide boron. Then the temperature of the reaction solution was gradually raised to 15oC. After 30 minutes stirring at this temperature, the reaction solution was diluted with chloroform, washed with diluted hydrochloric acid, and then was dried by distillation of the solvent. The obtained residue was chromatographically on a column of silica gel, elwira with a mixture of chloroform and ethanol, and the resulting combined desired fractions were concentrated by precipitation of crystals. These crystals were washed with benzene, and was collected by filtration, which was obtained 3.1 g of methyl 2-(5-cyano-2-benzofuranyl)-3-(4-hydroxyphenyl) propionate as colorless Chris is SUB>) : 3,18 (1H, DD, J=14,4 and 7.8 Hz); to 3.36 (1H, DD, J=14,4 and 7.4 Hz); of 3.69 (3H, s); 4.09 to (1H, DD, J=7.8 and 7.4 Hz); 6,60 (1H, s); 6,69 (2H, d, J=8,4 Hz); 7,00 (2H, d, J=8,4 Hz); 7,53 (2H, s); 7,83 (1H, s).

e) In 150 ml of dry tetrahydrofuran was dissolved 3.0 g of methyl 2-(5-cyano-2-benzofuranyl)-3-(4-hydroxyphenyl)-propionate obtained in stage d), 1.92 g (3R)-1-tert-butoxycarbonyl-3 - hydroxypyrrolidine and 2,69 g of triphenylphosphine. To the resulting solution, stirring at room temperature, was added to 1.79 g of diethylazodicarboxylate, and continued to stir for 1 hour. After removal of the solvent, the residue was subjected to column chromatography on silica gel, elwira mixture of toluene and ethyl acetate, which was obtained a mixture containing source compound methyl 2-(5-cyano-2-benzofuranyl)-3-(4-hydroxyphenyl)propionate and the target connection

Thus obtained mixture was dissolved in 100 ml of tetrahydrofuran. To this solution was added sequentially 0.95 g (3R)-1-tert-butoxycarbonyl-3-hydroxypyrrolidine, 1.35 g of triphenylphosphine and 0.85 grams of diethylazodicarboxylate. The resulting mixture was stirred at room temperature for 16 hours. Then the reaction solution was treated and purified in accordance with the procedure described above, resulting in a received 2,02 g target C0 - of 3.60 (6H, m); of 3.69 (3H, s); 4,10 (1H, t); to 4.81 (1H, width); 6,1 (1H, s); of 6.73 (2H, d, J=8,3 Hz);? 7.04 baby mortality (2H, d, J=8,3 Hz); 7,54 (2H, s); 7,83 (1H, s).

FD-MS (m/z): 321 (M+).

Reference example 66. Obtain ethyl 3-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-4- (5-cyanobase[b]Tien-2-yl)butyrate.

a) of 14.2 g of ethyl 2-etoxycarbonyl-2-4-methoxyphenyl acetate was dissolved in 150 ml of tetrahydrofuran. To this solution, while stirring with ice cooling, was added 2.6 g of sodium hydride (oily type, 60%), and then continued to stir for 2 minutes. Then, to the mixture was added to 17.2 g of 5-bromo-2 - bromomethyl-benzo[b]thiophene. After 18 hours stirring at room temperature, the reaction solution was mixed with an aqueous solution of ammonium chloride, and then extracted with ethyl acetate. After removal of the solvent, the residue was chromatographically on a column of silica gel, elwira chloroform, resulting in received 24.2 g ethyl-3-(5-bromobenzo[b]Tien-1-yl)-2-etoxycarbonyl-2-(4-methoxyphenyl) propionate.

1H-NMR (CDCl3) : 1,2 (6H, t); of 3.78 (3H, s); of 3.85 (2H, s); 6,76 - 7,0 (3H, m); 7,2 - 7,8 (5H, m).

b) a Solution of 7.3 g of potassium hydroxide dissolved in 20 ml of water was added to 200 ml of an ethanol solution containing 24.2 g of 3-(5-bromobenzo[b]Tien-2-yl)-2-etoki. Then the reaction solution was poured into a chilled dilute hydrochloric acid, and precipitated crystals were collected by filtration. These crystals were dissolved in ethyl acetate, and then dried. After removal of the solvent, the residue was dissolved in 200 ml of ethanol, were mixed in 3 ml of concentrated sulfuric acid and heated under reflux for 2 hours. After cooling, the reaction solution was concentrated, mixed with chloroform, washed with water and drained. After removal of the solvent, the obtained residue was purified by column chromatography on silica gel, elwira chloroform, resulting in received 20 g of ethyl 3-(5-bromobenzo[b]Tien-2-yl)-2-(4 - methoxyphenyl)propionate.

1H-NMR (CDCl3) : of 1.17 (3H, t); 3,2 (1H, DD); 3,55 (1H, DD); of 3.77 (3H, s); 3,81 (1H, DD); 4,10 (2H, square); PC 6.82 (2H, d); 7,2 - 7,8 (6H, m).

c) 20 g of ethyl 3-(5-bromobenzo[b]Tien-2-yl)-2-(4-methoxyphenyl) propionate obtained in stage b), was dissolved in 200 ml of tetrahydrofuran, and then added 12 g of sodium borohydride. To this mixture, cooling the thus ice, one drop was added 80 ml of methanol. After 3 hours stirring, the reaction solution was brought to pH 6 with concentrated hydrochloric acid, and then extracted with ethyl acetate. Received about wiroa with a mixture of chloroform and methanol, as a result, we obtained 16 g of 3-(5-bromobenzo[b]Tien-2-yl)-2-(4-methoxyphenyl)-1-propanol.

1H-NMR (CDCl3) : 2,9 - 3,4 (3H, m); to 3.73 (3H, s); 3,62 - 3,90 (2H, Shir. ); 6,70 - 7,80 (8H, m).

d) 16 g of 3-(5-bromobenzo[b]Tien-2-yl)-2-(4-methoxyphenyl)-1 - propanol obtained in stage c), was dissolved in 40 ml of dichloromethane. To this mixture, stirring with ice cooling, was added 6.3 ml of triethylamine and 4 ml of methanesulfonanilide. After 2-hour stirring at the same temperature, the reaction solution was mixed with dichloromethane, washed with water and drained. After removal of the solvent, the obtained residue was purified by column chromatography on silica gel, elwira chloroform, resulting in received of 18.5 g of 3-(5-bromobenzo[b]Tien-2-yl)-2-(4-methoxyphenyl)propylaminosulfonyl.

1H-NMR (CDCl3) : of 3.78 (3H, s); 3.9 to 4.5 (3H, m), 3,70 (3H, s), 4,3 (2H, m); 6,70 - 7,80 (8H, m).

e) 1.2 g of sodium cyanide was dissolved in 30 ml of dimethyl sulfoxide at a temperature of 90oC. To this solution was gradually added to 18.5 g of 3-(5-bromobenzo[b] Tien-2-yl-2-(4-methoxyphenyl)propylaminosulfonyl, and then stirred for 1 hour at 80oC. the Reaction solution was mixed with a mixture of ethyl acetate and toluene, washed with water, and then dried by distillation RA is Tien-2-yl)-2-yl-(4-methoxyphenyl)butyronitrile. The same compound was also obtained with a yield of 2 g by concentrating the ethanol solution obtained by washing the crystals, and chromatography was carried out concentrate on a column of silica gel, elwira chloroform.

1H-NMR (CDCl3) : 2,5 - 2,7 (2H, W); the 3.2 and 3.4 (3H, width); 3,76 (3H, s); 6,70 - 7,80 (8H, m).

MC m/z: 386, 388.

f) 7 g of 3-(5-bromobenzo[b]Tien-2-yl)-2-(4-methoxyphenyl) butyronitrile obtained in stage e), suspended in 80 ml of ethanol and then added 5 ml of concentrated sulfuric acid and a few drops of water. The resulting mixture was heated under reflux for 7 hours. After removal of the solvent, the reaction solution was mixed with chloroform and water, and the obtained organic layer was dried by distillation of the solvent. Then the residue was chromatographically on a column of silica gel, elwira chloroform, and obtained 6.3 g of ethyl 4-(5-bromobenzo[b]Tien-2-yl)-3-(4-methoxyphenyl)butyrate.

1H-NMR (CDCl3) : of 1.12 (3H, t); to 2.65 (2H, DD); 3,10 - of 3.80 (3H, m); 3,76 (3H, s); 4,01 (2H, square ); 6,70 - to 6.95 (3H, m), 7,10 (2H, d); 7,20 - 7,40 (1H); at 7.55 (1H, d); 7,72 (1H, d);

FAB-MS (m/z): 433, 435.

g) 6.0 g of ethyl 4-(5-bromobenzo[b]Tien-2-yl)-3-(4-methoxyphenyl) butyrate obtained in stage f, was dissolved in 50 ml of N-methyl-2-p is I. The resulting mixture was stirred at a temperature of 190 - 200oC in a stream of argon. After cooling, the reaction solution was mixed with ethyl acetate and toluene, and then washed with water, followed by distillation of the solvent. The obtained residue was purified by chromatography on silica gel, elwira with a mixture of chloroform and acetone, resulting in a received 4.5 g ethyl 4-(5-cyanobase[b]Tien-2-yl)-3-(4-methoxyphenyl)- butyrate

1H-NMR (CDCl3) : of 1.18 (3H, t); 2,70 (2H, DD); 3,16 - 3,70 (3H, m); of 3.78 (3H, s); was 4.02 (2H, square); 6,85 (2H, d); 6,98 (1H, s); to 7.18 (2H, d); 7,5 (1H, DD); 7,8 (1H, d); of 7.96 (1H, d).

h) 4.5 g ethyl 4-(5-cyanobase[b]Tien-2-yl)-3-(4-methoxyphenyl) butyrate obtained in stage g), was dissolved in 20 ml of dichloromethane. To the resulting solution was cooled to -70oC, was added 3.4 ml of tribromide boron. Thus obtained mixture was heated to room temperature and stirred for 1 hour. To the reaction solution was added crushed ice, and collected the dichloromethane layer which was then dried for removal of the solvent. The obtained residue was dissolved in 50 ml of tetrahydrofuran. To the mixture, stirring in a stream of argon and while cooling with ice, was added to 1.9 g of (3R)-1-tertbutoxycarbonyl-3-hydroxypyrrolidine, 3.2 g of triphenylphosphine and 2.3 g of diethylazodicarboxylate using column chromatography, elwira a mixture of n-hexane and ethyl acetate. The result of this procedure, received 4 g of target compound.

1H-NMR (CDCl3) : to 1.48 (9H, s); 1,95 - of 2.20 (2H, m); to 2.65 (2H, DD); 3,15 - 3,70 (7H, m); 4,78 - 5,00 (1H, m); to 6.80 (2H, d); 6,98 (1H, s); 7,17 (2H, d); 7,5 (1H, DD); of 7.82 (1H, d); 7,98 (1H, d).

Reference example 67. Obtain ethyl 2-[4-[((3S)-1-tert - butoxycarbonyl-3-pyrrolidinyl)thio] phenyl] -3-(5-cyanobase[b] thieno - 2-yl)-2-ethoxycarbonylpyrimidine.

a) a 20.2 g of ethyl 4-mercaptophenylacetic was dissolved in 450 ml of tetrahydrofuran. To this solution, stirring and cooling with ice, was added to 21.0 g of (3R)-1-tert-butoxycarbonyl-3-hydroxypyrrolidine, of 29.4 g of triphenylphosphine and 19.5 g of diethylazodicarboxylate. The resulting mixture was stirred at room temperature for 18 hours. After removal of the solvent, the residue was purified by chromatography on silica gel, elwira a mixture of n-hexane and ethyl acetate, which was obtained 7.0 g ethyl ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)thio]phenyl]acetate.

1H-NMR (CDCl3) : a 1.25 (3H, t, J = 7.2 Hz), a 1.45 (9H, s); of 1.7 - 2.4 (2H, m); a 3.2 and 4.4 (5H, m); to 3.58 (2H, s); 4,15 (2H, square, J = 7.2 Hz); of 7.0 and 7.6 (4H, m).

b) 4.0 g of ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl) thio] phenyl] acetate obtained in stage (a), was dissolved in 21 ml of N,N-di is 130oC, was added 530 mg (60%) sodium hydride, after which the mixture is stirred for 10 minutes, then added 106 mg of sodium hydride and again stirred for 10 minutes. The reaction solution was poured into ice water, neutralized with diluted hydrochloric acid, was extracted with ethyl acetate, and then dried. After removal of the solvent, the residue was purified by column chromatography on silica gel, elwira a mixture of n-hexane and ethyl acetate, resulting in a received 1,74 g of ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl) thio)phenyl] -2-ethoxycarbonylethyl in the form of an oily product.

1H-NMR (CDCl3) : of 1.27 (6H, t, J = 7.2 Hz); of 1.46 (9H, s); 1,4 - 2,4 (2H, m); 3,0 - 4,0 (5H, m), 4,22 (4H, square, J = 7.2 Hz); 4,58 (1H, s); 7,2 - 7,5 (4H, m).

c) 1.7 g of ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)thio]phenyl] -2-ethoxycarbonylethyl obtained in stage (b), was dissolved in a mixture solvent consisting of 20 ml of tetrahydrofuran and 1 ml of N,N-dimethylformamide, after which was added 155 mg of sodium hydride (60%), and the mixture was stirred for 20 minutes. To the reaction solution were added 980 mg of 2-bromoethylene[b] thiophene-5-carbonitrile, and then stirred for 24 hours. The resulting reaction solution was poured into ice water, extracted with ethyl acetate, and Zelyonaya a mixture of n-hexane and ethyl acetate, resulting received 2,05 g of target compound in the form of an oily substance.

1H-NMR (CDCl3) : of 1.23 (6H, t, J = 7.2 Hz), of 1.46 (9H, s); 1,50 - 2,50 (2H, m); a 3.2 and 4.4 (5H, m); the 3.89 (2H, s); 4.25 in (4H, square, J = 7.2 Hz); 7,28 (4H, s); 7,44 (1H, DD, J = 8.4 and 1.5 Hz); for 7.78 (1H, d, J = 8,4 Hz); to $ 7.91 (1H, DD).

Reference example 68. Obtain ethyl 2-[4-[((3S)-1-tert - butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-3-(5-cyanobase[b] Tien-2-yl)-2-propionate.

In a mixture consisting of 50 ml of tetrahydrofuran and 50 ml of ethanol, was dissolved 3.0 g (5-cyanobase[b]Tien-2-yl-methyltriphenylphosphonium chloride and 2.55 g of ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3 - pyrrolidinyl)oxy] phenyl] -2-oxoacetate. To the resulting solution, stirring at room temperature, was added 1.07 g of 1,8-diazabicyclo[5.4.0]-7-undecene, and the mixture is stirred at room temperature for 1 hour. After removal of the solvent, the obtained residue was purified by column chromatography on silica gel, elwira mixture of toluene and ethyl acetate, which was obtained ethyl-2-[4-[((3S)-1-tertbutoxycarbonyl-3-pyrrolidinyl] oxy] phenyl]-3-(5-cyanobase[b]Tien-2-yl)acrylate in a mixture of E - and Z-forms. Thus obtained compound was dissolved in a mixture consisting of 50 ml of tetrahydrofuran and 50 ml of ethanol, and this solution securizarii at normal pressure. After removal of catalyst by filtration and distillation of the solvent, the obtained residue was purified by chromatography on silica gel, elwira mixture of toluene and ethyl acetate, which was obtained 2.2 g of target compound in the form of a viscous oily substance.

1H-NMR (CDCl3) : of 1.17 (3H, t, J = 7.0 Hz); of 1.47 (9H, s); 1,90 - of 2.20 (2H, m); 3,10 - of 3.95 (7H, m); 4,10 (2H, square, J = 7,0 Hz); 4,84 (1H, width); for 6.81 (2H, d, J = 9.0 Hz); 7,20 (1H, s); of 7.25 (2H, d, J = 9.0 Hz); 7,44 (1H, DD, J = 9,0 and 1.6 Hz); 7,81 (1H, DD, J = 9,0 and 1.6 Hz); 7,94 (1H, s).

Compounds of reference examples 69-75 received in accordance with the procedure described in reference example 68.

Reference example 69. Ethyl 2-[4-[2-(tert-butoxycarbonylamino)- 1-(tert-butoxycarbonylamino)ethoxy] phenyl] -3-(5-cyanobase[b] Tien-2-yl)propionate, viscous oily substance

1H-NMR (CDCl3) : a 1.25 (3H, t, J = 7.0 Hz); of 1.45 (18H, s); 2,90 - 4,50 (8H, m); 6,80 - to 7.35 (5H); was 7.45 (1H, DD, J = 8.3 and 1.3 Hz); 7,80 (1H, d, J = 8,3 Hz); 7,93 (1H).

Reference example 70. Ethyl 2-[4-[((2S)-1 - butoxycarbonyl-2-pyrrolidinyl)-methoxy] phenyl]-3-(5-cyanobase[b]Tien-2-yl)propionate.

1H-NMR (CDCl3) : of 1.17 (3H, t); of 1.47 (9H, s); 2,00 (4H, Shir.C.); 3,40 (2H, Shir.C.); 3,60 - 4,30 (6H); make 6.90 (2H, d, J = 10 Hz); of 7.25 (2H, d, J = 10 Hz); 7,00 - 8,00 (4H, m).

Reference example 71. Ethyl 2-[4-[(1-tert-butoxycarbonyl) : 1,10 (3H, t, J = 6.0 Hz); a 1.50 (9H, s); 1.70 to a 2.00 (4H, m); 3,20 - 4,00 (4H, m); 4,15 (2H, square); 4,30 - 4,60 (1H, Shir.C); 6,80 - 8,10 (8H).

Reference example 72. Ethyl 2-[4-(2-tert - butoxycarbonylamino)phenyl] -3-(5-cyanobase[b] Tien-2-yl)propionate, viscous oily substance.

1H-NMR (CDCl3) : of 1.16 (3H, t, J = 7.0 Hz); of 1.45 (9H, s); 3,05 - 4,40 (9H); 5,12 (1H, Shir.C.); at 6.84 (2H, d, J = 8,3 Hz); 7,01 (1H, s); of 7.25 (2H, d, J = 8,3 Hz); 7,41 (1H, DD, J = 8,3 and 1.2 Hz); to 7.77 (1H, DD, J = 8,3 Hz); 7,89 (1H, s).

Reference example 73. Ethyl 2-[4-[((2S)-1-tert - butoxycarbonyl-5-oxo-2-pyrrolidinyl)methoxy]phenyl]- 3-(5-cyanobase[b]Tien-2-yl)propionate, viscous oily substance.

1H-NMR (CDCl3) : of 1.17 (3H, t); of 1.42 (9H, s); 1,80 was 2.25 (2H, m); 2,30 - 2,60 (2H, m); 3,20 (1H, DD); 3,37 (1H, DD); 3,50 - 3,82 (1H, DD); 3,82 - 4,50 (4H, m); 4.80 to 5,10 (1H, m); 6.75 in - 8,10 (8H, m).

Reference example 74. Ethyl 2-[4-[((2S,4S)-1-tert - butoxycarbonyl-2-methyl-4-pyrrolidin)oxy]phenyl]-3-(5-cyanobase[b]Tien-2-yl)propionate.

1H-NMR (CDCl3) : 1,15 - of 1.50 (6H, m); a 1.50 (9H, s); 1,80 - 2,60 (2H, m); 3,00 - 4,50 (8H, m); 4.80 to 5,10 (1H, m); 6,80 - to 8.20 (8H, m).

Reference example 75. Ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)-oxy]phenyl]- 3-(6-cyanobase[b]Tien-2-yl)propionate.

1H-NMR (CDCl3) : of 1.17 (3H, t); of 1.46 (9H, s); 2,10 (2H, m); of 3.60 (6H, m); a 3.83 (1H, m); 4,10 (2H); 4,85 (1H, Shir. C); 6,86 (2H, d);? 7.04 baby mortality (1H, s); 7,25 (2H); at 7.55 (1H, DD);ethoxy] phenyl]-3- (5-cyanobase[b]Tien-2-yl)propionate and ethyl(-)-2-[4-[((2S)-1-tert-butoxycarbonyl-2-pyrrolidinyl)methoxy]phenyl]- 3-(5-cyanobase[b]Tien-2-yl)propionate.

5.0 g of ethyl 2-[4-[((2S)-1-tert-butoxycarbonyl-2-pyrrolidinyl)methoxy] phenyl] -3- (5-cyanobase[b]Tien-2-yl)propionate was divided into (+) and (-) forms using a column for separating optical isomers, resulting received 2.5 g (+) and 1.7 (-) of target compound.

Isomer (-): so pl. 102-104oC

[]2D4= 142,00 (c = 1,000, EtOH).

1H-NMR (CDCl3) : 1,13-1,22 (3H, m); of 1.47 (8H, s); 1,80 - 2,10 (4H, m); 3,25 - 3,50 (4H, m); 3,64 of 3.75 (1H, m); 3,70 - 3,90 (1H, Shir. C); 3,90 (1H, Shir. C); 4,05 - 4,20 (4H, m); to 6.88 (2H, d, J = 8,3 Hz); 7,02 (1H, s); of 7.23 (2H, d, J = 8,3 Hz); was 7.45 (1H, d, J = 8,3 Hz); 7,80 (1H, d, J = 8,3 Hz), 7,94 (1H, s).

HPLC: Column; the column on amylase for use in breeding optical isomers (CHIPALPAK AD, 20 x 250 mm, Daicel Chemical Industries, Ltd.).

Solvent: n-hexane: ISO-propanol = 70:30.

Flow rate: 4 ml/min

Retention time: 20-23 minutes

Isomer (+): so pl. 111-112oC

[]2D4= +55,19 (c = 1,000, EtOH)

1H-NMR (CDCl3) : 1,13 - 1,22 (3H, m); of 1.47 (9H, s); 1,80 - 2,10 (4H, m); 3,25 - 3,50 (4H, m); 3,64 of 3.75 (1H, m); 3,70 - 3,90 (1H, Shir. C); 3,90 (1H, Shir. C); 4,05 - 4,20 (4H, m); to 6.88 (2H, d, J = 8,3 Hz); 7,02 (1H, s); of 7.23 (2H, d, J = 8,3 Hz); was 7.45 (1H, d, J = 8,3 Hz); 7,80 (1H, d, J = 8,3 Hz); 7,94 (1H, s).

HPLC: Column, a column on amylase for use in the separation of optical isomers (CHAPALPAK/min

Retention time: 23-27 minutes

Reference example 77. Getting ethyl(-)-2-[4-[(1-tert-butoxycarbonyl-3-piperidinyl)oxy] phenyl]-3- (7-cyano-2-naphthyl)propionate and ethyl(+)-2-[4-[(1-tert-butoxycarbonyl-4-piperidinyl)-oxy] phenyl] -3-(7-cyano-2 - naphthyl)propionate.

These compounds were obtained by the same method described in reference example 76.

Isomer (+):

[]2D4= -100,78o(c = 1,024, CHCl3).

1H-NMR (CDCl3) : a 1.11 (3H, t, J = 6.9 Hz); of 1.47 (9H, s); 1,70 - 1,80 (2H, m); 1.85 to 1,95 (2H, m); 3,15 - 3,20 (1H, m); 3,30 is 3.40 (2H, m); 3,50 - 3,60 (1H, m); 3,65 of 3.75 (2H, m); 3,85 - 3,90 (1H, Shir. C.); 4,0 - 4,1 (2H, m); 4,40 is 4.45 (1H, m); 6,85 (2H, h, J = 8,3 Hz); 7.23 percent (2H, d); 7,40 was 7.45 (1H, m); 7,53 - 7,58 (1H, m); a 7.62 (1H, s); to 7.77 (2H, d); a 7.85 (1H, d, J = 8,3 Hz); to 8.12 (1H, s).

HPLC: Column: column on amylose for the separation of optical isomers (CHIPALPAK, AD, 4.6 x 250 mm, Diacel Chemical Industries, Ltd.).

Solvent: n-hexane:ISO-propanol = 90:10

Flow rate: 1 ml/min

Retention time: 26.9 minutes

Isomer (+):

[]2D4= +95,84o(c = 1,010, CHCl3)

1H-NMR (CDCl3) : a 1.11 (3H, t, J = 7,3 Hz); 1,65 - 1,70 (2H, m); 1.85 to a 2.00 (2H, m); 3,15 - 3,20 (2H, m); 3,30 - to 3.35 (2H, m); 3,50 - 3,60 (1H, m); 3,65 of 3.75 (2H, m); 3,85 - 3,90 (1H, Shir. C); 4,0 - 4,1 (2H, m); 4,40 is 4.45 (1H, m); 6,85 (2H, d, J = 8,8 Hz); 7.23 percent (2H, d, J = 8,3 Hz); 7,40 was 7.45 (m, 1H, Ar-H); 7,52 - EUR 7.57 (nia optical isomers (CHIRALPAK AD, 4.6 x 250 mm, Daicel Chemical Industries, Ltd.).

Solvent: n-hexane: ISO-propanol = 90:10

Flow rate: 1 ml/min

Retention time: 31 min

Reference example 78. Getting ethyl(+)-2-[4-[((2S)-1-tert - butoxycarbonyl-2-pyrrolidinyl)methoxy] phenyl] -3-(5-cyanobase[b] -Tien-2-yl) propionate.

of 54.0 g of 2-[4-[((2S)-1-tert-butoxycarbonyl-2-pyrrolidinyl)-methoxy]phenyl] -3-5-cyanobase[b] Tien-2-yl-propionate was dissolved in 400 ml of dry ethanol while heating, and the resulting solution was added 800 ml of dry n-hexane. To the thus obtained mixture was added 100 mg of sodium hydride and the seed crystals of ethyl(+)-2-[4-[((2S)-1-tert-butoxycarbonyl-2-pyrrolidinyl)-methoxy] phenyl] - 3-(5-cyanobase[b]Tien-2-yl)propionate. After stirring at room temperature for 4 hours, thus obtained mixture was mixed with 100 mg of sodium hydride, and continued to stir 18 hours at room temperature, and collecting the precipitated crystals by filtration. Thus collected crystals are recrystallized from 22 volumes (m /Rev) a mixture of ethanol and n-hexane (30:70, m/Rev). The recrystallization process was repeated 3 times, and got 37,0 g of target compound with a purity of diastereoisomer of 99.5% or more.

opinaca.

This compound was obtained according to the procedure described in reference example 78.

Reference example 80. Obtain ethyl 2-[4-[((2R)-1-tert-butoxycarbonyl-2 - pyrrolidinyl)methoxy]phenyl]-3-(5-dinobot[b]Tien-2-yl)- 2-ethoxy-carbonylation.

4.1 g of ethyl-2-[4-[((2R)-1-tert-butoxycarbonyl-2-pyrrolidinyl)methoxy] phenyl] -2 - ethoxycarbonylethyl was dissolved in 100 ml of tetrahydrofuran. Thus obtained solution at room temperature was mixed from 0.38 g of 60% sodium hydride and stirred for 30 minutes. Stirring at room temperature, to the resulting reaction solution drop by drop) was added 10 ml of tetrahydrofuran containing 2.1 g of 2-bromoethylene[b]-thiophene-5-carbonitrile. After concentrating the reaction solution to dryness, the resulting residue was purified by column chromatography on silica gel using as eluting solvent mixture of toluene and chloroform, the resulting received 4,34 g of target compound in the form of an oily substance.

1H-NMR (CDCl3) : to 1.21 (6H); of 1.46 (9H, s); 2,0 (4H, Shir. C); 3,40 (2H, Shir. C); 3,88 (3H); 4,22 (6H); 6,90 (3H); then 7.20 (2H, d); 7,50 (1H); for 7.78 (1H, d); to 7.93 (1H, d).

In accordance with the procedure described in reference primer)-2-etoxycarbonyl-2-[4-[(2-imidazolin-2-yl) methoxy] phenyl] propionate, viscous oily substance.

1H-NMR (CDCl3) : to 1.22 (6H, t); 3,63 (4H, s); the 3.89 (2H, s); 4,24 (4H); 4,69 (2H, s); 6,86 (3H); 7,27 (2H); 7,42 (1H); 7,76 (1H); 7,88 (1H).

Reference example 82. Ethyl-2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)-oxy] phenyl] -3- (5-cyano-2-benzothiazolyl)-2-etoxycarbonyl-propionate, viscous oily substance.

1H-NMR (CDCl3) : to 1.22 (6H, t); of 1.46 (9H, s); 2,09 (2H, Shir.with); to 3.56 (4H, Shir.C); 4,13 (2H); to 4.28 (4H, d); is 4.85 (1H, Shir. C); PC 6.82 (2H, d); 7,26 (2H, d); 7,63 (1H, DD); to 7.95 (1H, d); of 8.25 (1H, d).

Reference example 83. Obtain ethyl 3-(5-cyanobase[b]Tien-2-yl)-2-[4-[[2-(ethoxycarbonylethyl) hexahydropirimidine series-5-yl]oxy]phenyl]propionate

1.0 g of ethyl 2-[4-[2-(tert-butoxycarbonylamino)-1-(tert - butoxycarbonylamino)-ethoxy] phenyl] -3-(5-cyanobase[b]Tien-2-yl) propionate was dissolved in 2 ml of anisole. To the above solution was added 10 ml triperoxonane acid, stirring under ice cooling, and the resulting mixture was stirred at room temperature for 1 hour. The resulting reaction solution was concentrated under reduced pressure, and thus obtained residue was dissolved in water and washed with n-hexane. The resulting aqueous layer was brought to pH 9-10 using concentrated aqueous solution th thus the residue was dissolved in 20 ml dry ethanol. To the thus obtained solution was added 300 mg of ethyl N-(ethoxy(methylthio)methylene)carbamate, which was synthesized according to the procedure described in Journal of the Chemical Society, Parkin 1, 1973, pp. 2644-2646. Then thus obtained mixture was stirred for 20 hours, and the precipitate was collected and as a result received 560 mg of the target compound.

So pl. 179-182oC.

IR (KBr): 2230, 1725, 1638, 1512, 1337 cm-1< / BR>
1H-NMR (CDCl3) : of 1.13 (3H, t, J = 7.0 Hz); of 1.17 (3H, t, J = 7.0 Hz), 3,10 - 4,30 (11H, m); 4,50 - 4,80 (1H, m); 6.89 in (2H, d, J = 8,75 Hz); 7.03 is (1H, s); 7,26 (2H, d, J = 8,75 Hz); 7,46 (1H, DD, J = 8,31 and 1.75 Hz); of 7.82 (1H, d, J = 8,31 Hz); of 7.95 (1H, d); 8,70 - 9,50 (2H, Shir. C).

Reference example 84. Obtain ethyl 3-(5-cyanobase[b]Tien-2-yl)-2-[4-[[2-(imino)-hexahydropirimidine series-5-yl]oxy]phenyl] propionate hydrochloride.

a) 2.9 g of potassium thiocyanate was dissolved in 150 ml of dry acetone. Stirring under ice cooling, to the above solution was added drop by drop to 6.8 g of p-nitrobenzenesulfonate, which was dissolved in 20 ml of acetone. Thus obtained mixture was stirred for 2 hours while cooling with ice, and mixed from 1.15 g of methanol, and then stirred at room temperature for 20 hours. Then, precipitated crystals thus collected by pharmamar)carbamate in the form of powder.

1H-NMR (CDCl3) : a 4.03 (3H, s; 5,33 (2H, s); of 7.70 (2H, d, J = 9.0 Hz); 8,80 (2H, d, J = 9.0 Hz).

b) 3.5 g of p-nitrobenzyloxy(thiocarbamoyl)carbamate, obtained in the above stage (a), and 1.79 g of anhydrous potassium carbonate was dissolved in a mixture solution of 40 ml water and 40 ml of dioxane. To thus obtained solution gradually to drop added 1,72 g dimethylsulfate, and the resulting mixture was stirred at room temperature for 30 minutes. To the resulting reaction solution was again added 300 mg of anhydrous potassium carbonate was added drop by drop 300 mg dimethylsulfate. Thus obtained reaction solution was diluted with ethyl acetate, washed with water and successively saturated aqueous solution of sodium chloride and then concentrated. After that, the precipitated crystals thus collected by filtration and thoroughly washed with n-pentane, resulting in received 3,23 g p-nitrobenzyl N-(methoxy methylthio)methylene)carbamate.

1H-NMR (CDCl3) : is 2.40 (3H, s); 4,00 (3H, s); 5,28 (2H, s); 7,56 (2H, d, J = 9.0 Hz); by 8.22 (2H, d, J = 9.0 Hz).

c) in 10 ml of anisole was dissolved 2.0 g of ethyl 2-[4-[2-(tert-butoxycarbonylamino)-1-(tert-butoxycarbonylamino-methyl) ethoxy]phenyl]-3-(5-cyanobase[b] Tien-2-yl)propion the camping was stirred at room temperature for 2 hours. The resulting reaction solution was concentrated under reduced pressure, and thus obtained residue was dissolved in water and washed with n-hexane. The resulting aqueous layer was brought to pH 10 using concentrated aqueous ammonia solution and then was extracted with chloroform. The obtained organic layer was concentrated to dryness, and the resulting residue was dissolved in 50 ml of tetrahydrofuran. To the thus obtained solution was added 921 mg p-nitrobenzyl N-(methoxy-(methylthio) methylene)carbamate, obtained in the above stage (b), stirring 18 hours. After removal of the solvent, the obtained residue was purified by column chromatography on silica gel using as eluting solvent mixture of chloroform and ethanol, resulting in a received 1.5 g of ethyl 3-(5-cyanobase[b] Tien-2-yl)-2-[4-[[2-(p-nitrobenzisoxazole) hexahydropirimidine series-5-yl]oxy]phenyl]propionate in the form of a viscous and oily substances.

1H-NMR (CDCl3) : of 1.17 (3H, t, J = 7.0 Hz); 3,00 - 4,30 (1H, m); 4,40 - 4,70 (1H, m); 5,08 (2H, c); for 6.81 (2H, d, J = 8,3 Hz); 7.03 is (1H, s); 7,10 - 7,56 (5H, m), 7,81 (1H, d, J = 9,3 Hz); 7,94 (1H, s); 8,10 (2H, d, J = 8,75 Hz); 8,70 - 9,40 (2H, Shir. C.).

d) In 100 ml of ethanol was dissolved 1.5 g of ethyl 3-(5-cyano-b the frame in the above stage c). To the thus obtained solution was added 0.5 g of ammonium chloride and 0.5 g of 10% palladium carbon (catalyst, 50% wet). The resulting mixture was subjected to 2 hours of catalytic hydrogenation under normal pressure. After removal of catalyst by filtration and removal of the solvent, the obtained residue was purified by column chromatography on silica gel using as eluting solvent mixture of chloroform and ethanol, resulting in a received 1.0 g of the target compound.

1H-NMR (CDCl3) : to 1.21 (3H, t, J = 7.0 Hz); 3,00 - are 3.90 (7H, m); 4,17 (2H, square, J = 7,0 Hz); 4,50 - 4,80 (1H, Shir. C); 6,87 (2H, d, J = 8,75 Hz); 7,01 (1H, s); 7,06 and 7.36 (5H); 7,44 (1H, DD, J = 7.0 and 1.3 Hz); 7,81 (1H, s); 8,07 (2H, s).

Reference example 85. Obtain ethyl 3-(5-cyanobase[b]Tien-2-yl)-2-[4-[2-(1-pyrrolin-2-yl)aminoethoxy]phenyl] propionate hydrochloride.

Stirring, 1.3 g of ethyl 2-[4-[2-tert-butoxycarbonyl-aminoethoxy)phenyl] -3-(5-cyanobase[b] Tien-2-yl) propionate was dissolved in 50 ml of ethanol and then mixed. To this solution was added 25 ml of ethanol containing 13% (m /about. ) hydrochloric acid. Thus obtained mixture was stirred at 50oC for 30 minutes. After removal of the solvent, the obtained residue was dissolved in 50 ml tarawali under reflux for 1.5 hours. After cooling, precipitated crystals were collected by filtration, which was obtained 1.1 g of the target compound.

so pl.: 212-215oC

1H-NMR (CDCl3) : 1.14 in (1,5 H, t, J = 7.0 Hz); 1,16 (1,5 H, t, J = 7.0 Hz); of 2.16 (2H, t, J = 7.5 Hz); 2,87 (2H, t, J = 8.0 Hz); 3,20 - 4,40 (9H); 6,87 (2H, d, J = 8,3 Hz); 7,13 (1H, s); 7,27 (2H, d, J = 8,3 Hz); of 7.48 (1H, DD, J = 8.3 and 1.3 Hz); a 7.92 (1H, d, J = 8,3 Hz); 8,04 (1H, s); 10,04 (1H, Shir. C.); the 10.40 (1H, Shir.S.).

Reference example 86. Obtain methyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-3-(5-cyano-2 - indolyl)propionate.

In a solvent mixture consisting of 50 ml of tetrahydrofuran and 50 ml of methanol, was dissolved 5.0 g (5-cyano-2-indolyl)-methyltriphenylphosphonium bromide and 3.6 g of methyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)-oxy]phenyl] -2 - oxoacetate. To thus obtained solution, stirring at room temperature, was added 1.07 g of 1,8-diazabicyclo[5.4.0]-7-undecene, and the mixture was stirred at the same temperature for 2 hours. After removal of the solvent, the obtained residue was purified by column chromatography on silica gel, using as eluent a mixture of dichloromethane and acetone, resulting in the obtained methyl 2-[4-[((3S)-1-tert-butoxy-carbonyl-3 - pyrrolidinyl)oxy] phenyl] -3-(5-cyano-2-indolyl)acrylic is x from 50 ml of tetrahydrofuran and 50 ml of methanol, and the resulting solution was mixed with 5.0 g of palladium oxide 1H2O barium sulfate and then subjected to catalytic hydrogenation under normal pressure. After removal of catalyst by filtration and removal of the solvent, the obtained residue was purified by column chromatography on silica gel using as eluent a mixture of dichloromethane and acetone. The result of this procedure was obtained 3.5 g of target compound in the form of a viscous and oily substances.

1H-NMR (CDCl3) : of 1.46 (9H, s), 2.00 in of 2.20 (2H, m); 2.95 and - 4,22 (7H, m); 4.75 V - 4,90 (1H, Shir.C); 6,23 (1H, d); to 6.80 (2H, d); to 7.18 (2H, d); 7,20 - 7,40 (2H, m), 7,80 (1H, s); 8,80 (1H, Shir. C).

Compounds of reference examples 87-92 received in accordance with the procedure described in reference example 86.

Reference example 87. Methyl-2-[4-[((3S)-1-tert-butoxycarbonyl-3 - pyrrolidinyl)-oxy]phenyl]-3-(6-cyano-2-indolyl)propionate, viscous oily substance.

1H-NMR (CDCl3) : of 1.50 (9H, s); 2,00 - 2,25 (2H, Shir.C); of 3.13 (1H, DD); 3,37 of 3.75 (3H, m); of 3.97 (1H, DD); 4,70 - of 4.90 (1H, Shir. C); 6,37 (1H, s); to 6.80 (2H, d); 7,10 - of 7.70 (5H, m); a 9.25 (1H).

Reference example 88. Methyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)-oxy] phenyl] -3- (6-cyano-1-methyl-2-indolyl)propionate, viscous oily substance

1H e); 7,10 - of 7.70 (5H, m); a 9.25 (1H).

Reference example 89. Methyl 2-[4-[((3R)-1-tert - butoxycarbonyl-3-pyrrolidinyl)-oxy]phenyl]-3-(6-cyano-1-ethyl-2 - indolyl)propionate, viscous oily substance.

1H-NMR (CDCl3) : of 1.34 (3H, t, J = 7.2 Hz); of 1.47 (9H, s); 2,00 - 2,30 (2H, m); 2,90 - 3,30 (3H, m); 3,40 - of 3.80 (4H, m), 3,66 (3H, m); 4,15 (2H, square , J = 7.2 Hz); 4,70 - 5,00 (1H, Shir.C.); 6,30 (1H, s); at 6.84 (2H, d, J = 8,8 Hz); 7,27 (2H, d, J = 8,8 Hz); 7,26 (1H, d, J = 7,0 Hz); rate of 7.54 (1H, d, J = 7,0 Hz).

Reference example 90. Methyl 2-[4-[((3S)-1-tert - butoxycarbonyl-3-pyrrolidinyl)-oxy]phenyl]-3-(6-cyano-1-ethyl-2 - indolyl)propionate, viscous oily substance

1H-NMR (CDCl3) : of 1.32 (3H, t, J = 7.2 Hz); to 1.48 (9H, s); 2,00 - 2,30 (2H, m); 2,90 - 3,30 (3H, m); 3,40 - of 3.80 (4H, m); of 3.64 (3H, c); 4,15 (2H, square , J = 7.2 Hz); 4,70 - 5,00 (1H, Shir.C.); 6,30 (1H, s); at 6.84 (2H, d, J = 8,8 Hz); 7,26 (2H, d, J = 8,8 Hz); 7,26 (1H, d, J = 7,0 Hz); rate of 7.54 (1H, d, J = 7,0 Hz).

Referential example 91. Methyl 2-[4-[((3S)-1-tert - butoxycarbonyl-3-pyrrolidinyl)-oxy] phenyl]-3- [1-(2-chloroethyl)-6-cyano-2-indolyl]propionate, viscous oily substance.

1H-NMR (CDCl3) : of 1.47 (9H, s); 2,00 - 2,30 (2H, m); 3,00 - 4,20 (9H, m), 3,66 (3H, s); 4,20 - 4,60 (2H, m); 4.80 to 5,00 (1H, m); 6,37 (1H, s); at 6.84 (2H, d); 7,20 - 7,80 (5H, m).

Reference example 92. Methyl 2-[4-[(1-tert - butoxycarbonyl-4-piperidinyl)oxy]phenyl]-3-(6-cyano-1-ethyl-2 - indolyl)propionate.

1H-NMR (CDCl<,30 (3H, m); rate of 7.54 (1H, d); 7,58 (1H, s).

Reference example 93. Obtain methyl 2-[4-[((3S)-1-tert - butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-3-(5-cyano-1-methyl - 2-indolyl)propionate.

3.0 g of methyl 2-[4-[(3S)-1-tert - butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl] -3-(5-cyano-2-indolyl) propionate was dissolved in 30 ml of N,N-dimethylformamide, and then stirred while cooling with ice. To the above solution was added 270 mg of 60% sodium hydride and stirred for 10 minutes. The resulting reaction solution was mixed with 0.4 ml under the conditions, and the mixture was stirred at room temperature for 1 hour. The thus treated reaction solution was diluted with a mixture of toluene and ethyl acetate, and then washed with an aqueous solution of ammonium chloride. After drying of the organic layer by distillation of the solvent, the thus obtained residue was purified by column chromatography on silica gel using as eluting solvent mixture of dichloromethane and acetone. The result of this procedure was obtained 2.0 g of target compound in the form of a viscous and oily substances.

1H-NMR (CDCl3) : of 1.45 (9H, s); 2,00 - 2,22 (2H, m); 3,05 (1H, DD); 3,35 - of 3.80 (5H, m), 3,63 (3H, s); 4,00 (1H, DD), 4.75 V - 5,00 (1H, Shir.C.); of 6.25 (1H, d); 6,85 (2H, d); 7,20 is 7.50 (2H, m); of 7.90 (1H, s).

-naphthyl)propionate.

9.0 g (6-cyano-1,2,3,4-tetrahydro-2-naphthyl) methyltriphenylphosphonium p-toluensulfonate suspended in 150 ml of tetrahydrofuran, gradually adding 600 mg of 60% sodium hydride. Thus obtained mixture was heated under reflux for 20 minutes. After cooling to room temperature, the resulting reaction solution was added 10 ml of tetrahydrofuran containing 4,16 g of ethyl 2-[4-[((3S)-1-tert - butoxycarbonyl-3-pyrrolidinyl)oxy] phenyl] -2-oxoacetate. The resulting reaction mixture was stirred for 10 minutes and then was heated under reflux for 2 hours. After cooling to room temperature, the thus obtained reaction product was dissolved in ethyl acetate and washed successively with water and saturated aqueous sodium chloride. After drying of the organic layer by distillation of the solvent, the thus obtained residue was purified by column chromatography on silica gel using as eluting solvent mixture of n-hexane and ethyl acetate, resulting in a received 3,90 g of ethyl 2-[4-[((3S)-1-tert - butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-3-(6-cyano-1,2,3,4 - tetrahydro-2-naphthyl) acrylate as a yellow oily substance Sali with 650 mg of palladium oxide 1H2O barium sulfate, and subjected to catalytic hydrogenation under normal pressure for about 5 hours. After removal of catalyst by filtration and removal of the solvent, the obtained residue was purified by column chromatography on silica gel using as eluting solvent mixture of n-hexane and ethyl acetate. The result of this procedure received 1,69 g of target compound as a yellow oily substance.

1H-NMR (CDCl3) : of 1.20 (3H, t, J = 7.0 Hz); of 1.45 (9H, s); 1,50 - 3,90 (16H, m); 4,10 (2H, square); 4,82 (1H, m); for 6.81 (2H, square, J = 9.0 Hz); 7,00 - 7,40 (5H, m).

Reference example 95. Obtain ethyl 2-[4-[((2S)-1-tert - butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-3-(5-cyano-2 - benzimidazolyl)propionate.

a) of 3.42 g of 3,4-diaminobenzanilide and 4,06 g metilhloroizolinona hydrochloride was dissolved in 100 ml of ethanol, and the solution was heated under reflux for 3 hours. After cooling and removal of the solvent, the obtained residue was dissolved in ethylacetate, washed with water, and then dried. After removal of the solvent, the precipitated crystals thus collected by filtration, which was obtained 2.7 g of 2-chloromethyl-5-benzenedicarbonitrile.

so pl.: 144-146oC

1H-carbonitrile, obtained in the above stage (a) and 2,19 g of triphenylphosphine were dissolved in 30 ml of 1,2-dichloroethane, and the resulting solution was heated at a temperature of 140oC for 1 hour. After cooling and removal of the solvent, the thus obtained residue and 2.03 g of ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy] phenyl] -2 - oxoacetate was dissolved in a mixture solvent consisting of 20 ml of tetrahydrofuran and 20 ml of ethanol. Stirring at room temperature, to thus obtained solution was added 1.1 g of 1,8-dieselbil[5.4.0] -7-undecene, and the mixture was stirred at the same temperature for 72 hours. After removal of the solvent, the obtained residue was purified by column chromatography on silica gel using as eluting solvent mixture of chloroform and ethanol, resulting in a received 1.5 g of oily ethyl-2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl] -3-(5-cyano-2-benzimidazolyl)acrylate in a mixture of E - and Z-forms. Thus obtained mixture of E/Z was dissolved in a mixture solvent consisting of 50 ml of tetrahydrofuran and 50 ml of ethanol, and the resulting solution was mixed with 1.5 g of palladium oxide 1H2O barium sulfate, and then plunged catalytic hydrogenation under normal pressure is th column chromatography on silica gel using as eluting solvent mixture of chloroform and ethanol. The result of this procedure was obtained target compound in the form of a viscous and oily substances.

1H-NMR (CDCl3) : to 1.14 (3H, t, J = 7.0 Hz); to 1.48 (9H, s); 1,90 - of 2.30 (2H, Shir. C.); 3,05 - are 3.90 (6H, m); of 4.12 (2H, square, J = 7,0 Hz); 4,00 - 4,30 (1H); 4,70 - of 4.95 (1H, Shir.C.); 6,79 (2H, d, J = 8,8 Hz); 7,19 (2H, d, J = 8,8 Hz); 7,35 - 8,10 (3H, m).

FD-MS (m/z): 504 (M+); 505 (M++ 1).

Reference example 96. Obtain (+)-((2S)-1-p-toluensulfonyl-2 - pyrrolidinyl methyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl) oxy]phenyl] -3-(6-cyano-2-indolyl)propionate and (-)-((2S)-1-p - toluensulfonyl-2-pyrrolidinyl methyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl) hydroxy]phenyl] -3-(6-cyano-2-indolyl)propionate.

a) an aqueous solution containing 3 g of sodium hydroxide dissolved in 10 ml of water was added to 100 ml of methanol containing 22 g of methyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl) oxy]phenyl]-3-(6-cyano-2-indolyl)propionate, and the mixture was stirred at room temperature for 24 hours. After removal of the solvent, the pH of the remaining part of the lead up to the values 4-5 using citric acid, and then extracted with ethyl acetate. By drying the extract by distillation of the solvent, was obtained 20 g of 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl) oxy]phenyl]-3-(6-tzia is 20 g of 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy] phenyl] -3- (6-cyano-2-indolyl)propionic acid, obtained in the above part (a) and 11.9 g ((2S)-1-p-toluensulfonyl-2-pyrrolidinyl)-methanol. Thus obtained solution was mixed with a catalytically effective amount of 4-dimethylaminopyridine and 9 g of 1,3-dicyclohexylcarbodiimide, stirring under ice cooling, and the mixture was stirred at room temperature for 24 hours. After removal of precipitated material by filtration and removal of the solvent, the obtained residue was purified by column chromatography on silica gel using as eluting solvent mixture of chloroform and acetone, resulting in received of 10.5 g of (+)-((2S)-1-p-toluensulfonyl-2-pyrrolidinyl)methyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy] phenyl] -3- (6-cyano-2-indolyl)propionate.

1H-NMR (CDCl3) : 1,00 - 1,80 (4H, m); of 1.46 (9H, s); 2,00 - 2,30 (2H, m); 2,43 (3H, s); 3,00 - 4,40 (12H, m); 4.75 V - 5,00 (1H, m); 6,30 (1H, s); PC 6.82 (2H, d); 7,10 - of 7.90 (9H, m); 9,00 (1H, s).

After re-elution of the column with the same solvent system, was obtained 9.5 g ((-)-((2S)-1-p-toluensulfonyl-2-pyrrolidinyl methyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-3- (6-cyano-2-indolyl)propionate.

1H-NMR (CDCl3) : 1,00 - 2,00 (4H, m); the 1.44 (9H, s); 2,00 - 2,25 (2H, m); to 2.41 (3H, s); 2.95 and - 4,10 (10H, m); 4,20 (2H, d); 4,70 - of 4.90 (1H arbonyl-3-pyrrolidinyl)-3-(6-cyano-1 - ethoxycarbonylmethyl-2-indolyl)propionate.

3.0 g of methyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl] -3- -3-(6-cyano-2-indolyl)propionate was dissolved in 30 ml of N,N-dimethylformamide. Thus obtained solution was mixed with 280 mg of 60% sodium hydride, stirring under ice cooling, and stirred for 20 minutes at the same temperature. The resulting reaction solution was mixed with 0.7 ml of bromoacetate and the mixture was stirred for 1 hour. The thus treated solution was mixed with diluted hydrochloric acid, was extracted with a mixture of ethyl acetate and toluene, washed with water and then dried. After removal of the solvent, the obtained residue was purified by column chromatography on silica gel using a mixture of dichloromethane and acetone as eluting solvent. The result of this procedure was obtained 3.2 g of target compound in the form of a viscous and oily substances.

1H-NMR (CDCl) : of 1.26 (3H, t); of 1.46 (9H, s); to 3.02 (1H, DD); 3,30 - 3,70 (5H, m), 3,66 (3H, s); 4,00 (1H, DD); 4,20 (2H, square); 4,80 (2H, s); 4,78 - of 4.90 (1H, m); 6,40 (1H, s); make 6.90 (2H, d); 7,20 - of 7.70 (5H, m).

Reference example 98. Getting 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]- -3-(6-cyano-2-indolyl)propanol.

2.7 g of methyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]Feria. To the thus obtained solution was added drop by drop 12 ml of methanol, stirring under ice cooling, and the mixture was stirred at room temperature for 3 hours. The resulting reaction solution was mixed with 10% aqueous citric acid solution, was extracted with dichloromethane and then dried. After removal of the solvent, the obtained residue was purified by column chromatography on silica gel using as eluting solvent mixture of dichloromethane and methanol. The result of this procedure was obtained 2.2 g of target compound in the form of a viscous oily substance.

1H-NMR (CDCl3) : to 1.48 (9H, s); 1,95 was 2.25 (2H, m); 2,48 (1H, t); 3,00 - up 3.22 (2H, m); 3.40 in at 3.69 (6H, m); 3,70 - are 3.90 (1H, m); 4,70 - of 4.90 (1H, m); 6,21 (1H, s); to 6.80 (2H, d); 7,00 - the 7.65 (5H, m); 9,20 (1H, s).

Reference example 99. Getting ethyl 2-[2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-3 - hydroxypropyl]-6-cyano-1-indoleacetate.

2.0 g of 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-3-(6-cyano-2-indolyl)propanol was dissolved in 30 ml of N,N-dimethylformamide. To the above solution was added 280 mg of 60% sodium hydride, stirring under ice cooling, and then stirred for 20 minutes at room temperature. Poluchennymi, the solution was mixed with an aqueous solution of ammonium chloride, were extracted with a mixture of toluene and ethyl acetate, washed with water, and then dried. After removal of the solvent, the obtained residue was purified by column chromatography on silica gel using as eluting solvent mixture of dichloromethane and acetone. The result of this procedure were given 1.5 g of target compound in the form of a viscous oily substance.

1H-NMR (CDCl3) : of 1.23 (3H, t); a 1.45 (9H, s); 1,90 - 2,20 (2H, s); 4,20 (2H, square); 4,50 - 4,90 (3H); of 6.20 (1H, s); is 6.78 (2H, d).

Reference example 100. Getting 2-[2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl] ethyl]-6-indocarbocyanine.

a) In 40 ml of tetrahydrofuran was dissolved 1,31 g R-hydroxybenzaldehyde, of 1.87 g of (3R)-1-tert-butoxycarbonyl-3-hydroxypyrrolidine and 2.88 g of triphenylphosphine. Stirring at room temperature, to thus obtained solution was added at 1.91 g of diethylazodicarboxylate, and the mixture was stirred for 45 minutes. After removal of the solvent, the obtained residue was purified by column chromatography on silica gel, using as eluent a mixture of benzene and ethyl acetate. The result of this procedure was obtained 2.9 g of [4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)-oxy] benzaldehyde in the form of oily ve is d, J = 9.0 Hz); of 9.89 (1H, s).

b) of 0.93 g of [4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)-oxy] benzaldehyde obtained in the above part (a), and 1.6 g (6-cyano-2-indolyl)methyltriphenylphosphonium bromide was dissolved in a mixture solvent consisting of 20 ml of methanol and 20 ml of tetrahydrofuran. In the thus obtained solution was dissolved 490 mg of 1,8-diazabicyclo[5.4.0]-7-undecene, mixed, cooling with this ice, and the resulting mixture was stirred at room temperature for 3 hours. After removal of the solvent, the obtained residue was purified by column chromatography on silica gel using as eluting solvent mixture of chloroform and methanol, resulting in a received 700 mg 2-[2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy] phenyl] vinyl]-6-indocarbocyanine in the form of a mixture of E - and Z-forms.

1H-NMR (CDCl3) : USD 1.43 (9H, s); 1,90 - of 2.23 (2H, m); 3,30 - 3,70 (4H, m); 4.75 V - of 4.95 (1H, m); 8,65 (1H, Shir.S.).

c) 700 mg 2-[2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl] vinyl]-6-endocervical obtained in the above (b), was dissolved in a mixture solvent consisting of 20 ml of methanol and 40 ml of tetrahydrofuran. To the resulting solution was added 70 mg of palladium oxide 1H2O barium sulfate, and cm is Isadora by filtration and removal of the solvent, the obtained residue was purified by column chromatography on silica gel using as eluting solvent mixture of chloroform and methanol. The result of this procedure was given 650 mg of target compound in the form of a viscous and oily substances.

1H-NMR (CDCl3) : of 1.50 (9H, s); 1,95 - of 2.20 (2H, m); 4,70 - of 4.90 (1H, m); 6,30 (1H, s); of 6.75 (2H, d); 7,10 (2H, d); 7,10 - the 7.65 (3H, m); 9,46 (1H, Shir.S.).

Reference example 101. Getting ethyl 2-[2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl] ethyl]-6-cyano-1-indoleacetate.

2.4 g 2-[2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl] ethyl] -6-endocervical was dissolved in 50 ml of N,N-dimethylformamide. To the thus obtained solution was added 300 mg of 60% sodium hydride and stirred while cooling with this ice, and then the obtained mixture was heated to room temperature and stirred at the same temperature for 20 minutes. To the above mixture was added 0,76 ml ethylbromoacetate and stirred while cooling with ice, and then stirred for another 1 hour. The resulting reaction solution was mixed with an aqueous solution of ammonium chloride and was extracted with a mixture of toluene and ethyl acetate, and the obtained organic layer was washed with water and dried. After the distillation process is wirausaha solvent mixture of dichloromethane and acetone. The result of this procedure has been the target connection 2.3 g in the form of a viscous and oily substances.

1H-NMR (CDCl3) : 1,2 (3H, t); 2,00 - of 2.20 (2H, m); 2.95 and (4H, s); 3,30 - of 3.60 (4H, m); 4,18 (2H, square); 4,70 (2H, s); 6,36 (1H, s); of 6.75 (2H, d); 7,00 - of 7.60 (5H, m).

Reference example 102. Getting 2-[4-[(1-tert-butoxycarbonyl-4-piperidinyl)oxy-phenyl]methyl]-5 - benzofurazanyl.

a) 5,07 g of potassium hydroxide was added to 30 ml of diethylene glycol, and the mixture was stirred at room temperature with the addition of 5.5 g of 80% hydrazine dihydrate 2H2O and 5.0 g of 5-bromo-2-(4-methoxybenzoyl)benzofuran. Thus obtained mixture was heated under reflux. After cooling, the resulting reaction solution was brought to pH 4-5, extracted with benzene, and then dried. After removal of the solvent, the obtained residue was purified by column chromatography on silica gel using as eluting solvent mixture of n-hexane and isopropanol, resulting in received of 3.95 g of 5-bromo-2-(4-methoxybenzyl)benzofuran in the form of a brown oily product.

1H-NMR (CDCl3) : of 3.80 (3H, s); was 4.02 (2H, s); 6,23 (1H, s); make 6.90 (2H, d, J = 9.0 Hz); 7,20 - 7,40 (4H, m); EUR 7.57 (1H, m).

b) of 3.95 g of 5-bromo-2-(4-methoxybenzoyl)benzofuran is the Zia was heated at a temperature of 200-220oC in a stream of nitrogen. After cooling, the resulting reaction product was dissolved in chloroform, and insoluble substances were removed by filtration. The obtained organic layer was washed with water and concentrated to dryness. After that, the thus obtained residue was purified by column chromatography on silica gel using as eluting solvent mixture of n-hexane and isopropyl ether, resulting in the received 3,10 g of 2-(4-methoxybenzyl)-5-benzofurazanyl, so pl. 78-80oC.

1H-NMR (CDCl3) : of 3.80 (3H, s); 4,10 (2H, s); to 6.39 (1H, s); make 6.90 (2H, d, J = 9.0 Hz); 7,22 (2H, d); 7,46 (2H); for 7.78 (1H, s).

c) 3.0 g of 2-(4-methoxybenzyl)-5-benzofurazanyl obtained in the above part (b), was dissolved in 30 ml of dichloromethane, and the solution was cooled to -50oC. To the solution under stirring was added drop by drop 20 ml of dichloromethane solution containing 2,23 ml tribromide boron. After gradual heating of the mixture to room temperature, it was stirred for 1 hour. The resulting reaction solution was diluted with chloroform, washed with diluted hydrochloric acid and then dried. After removal of the solvent, the precipitated crystals thus collected by filtration, cut the s.

1H-NMR (CDCl3) : as 4.02 (2H, s); of 6.45 (1H, s); 6,77 (2H, d, J = 9.0 Hz); 7,10 (2H, d); of 7.48 (2H); 7,81 (1H, s).

d) In 50 ml of tetrahydrofuran was dissolved 1.50 g of 2-(4-hydroxybenzoyl)-5-benzofurazanyl obtained in the above part c), 2.37 g of triphenylphosphine and to 1.21 g of 1-tert-butoxycarbonyl-4-hydroxypiperidine. Stirring at room temperature, the resulting solution was mixed with of 1.57 g of diethylazodicarboxylate, and stirred for 40 hours. After removal of the solvent, the obtained residue was purified by column chromatography on silica gel using as eluting solvent, a mixture of n-hexane and ethyl acetate. The result of this procedure, received of 1.30 g of target compound in the form of colorless needle-like crystals. So pl. 144-146oC.

1H-NMR (CDCl3) : of 1.47 (9H, s); 1,60 - 2,00 (4H, m); 3,20 - are 3.90 (4H, m); of 4.05 (2H, s); of 4.44 (1H, m); 6,41 (1H, s); 6.87 in (2H, d, J = 9.0 Hz); then 7.20 (2H, d, J = 9.0 Hz); 7,47 (2H); 7,79 (1H, s).

Reference example 103. Getting 3-[3-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl] propyl]-5-benzofurazanyl.

a) 2.14 g (5-cyano-3-benzofuranyl)methyltriphenylphosphonium chloride and 0.7 g of 4-methoxyphenylacetamide was dissolved in a mixture of solvents containing 100 ml of tetrahydrofuran and within 24 hours. After removal of the solvent, the obtained residue was purified by column chromatography on silica gel using as eluting solvent toluene, resulting in a received 0,86 g yellow oily 3-[3-(4-methoxyphenyl)allyl] -5-benzofuranyl in the form of a mixture of E - and Z-forms. Thus obtained mixture of E/Z was dissolved in 100 ml of ethanol, and the solution was subjected to catalytic hydrogenation under normal pressure in the presence of 370 mg of 5% palladium charcoal. Thereafter, the catalyst was removed by filtration and the solvent drove, which was obtained 0.6 g of 3-[3-(4-methoxyphenyl)propyl] -5-benzofurazanyl. Thus obtained methoxy-compound was dissolved in 20 ml of dichloromethane. Stirring at -40oC, to the resulting solution was added drop by drop 10 ml of dichloromethane solution containing 0.4 ml of tribromide boron. The resulting mixture was heated to room temperature and was stirred for 2 hours. The resulting reaction solution was poured into cold diluted hydrochloric acid and was extracted with chloroform. After drying the organic layer and removal of the solvent, the thus obtained residue was purified by column chromatography on silicagel is-(4-hydroxyphenyl)propyl]-5-benzofurazanyl.

1H-NMR (CDCl3) : a 2.0 (2H, m); of 2.64 (4H, m); to 6.80 (2H, d); 7,16 (2H, d); 7,52 (3H, m); 7,79 (1H).

b) In 20 ml of tetrahydrofuran was dissolved 280 mg of 3-[3-(4-hydroxyphenyl)propyl]-5-benzofuranyl obtained in the above part (a), 280 mg of (3R)-1-tert-butoxycarbonyl-3-hydroxypyrrolidine and 400 mg of triphenylphosphine. Stirring at room temperature, the resulting solution was mixed with 265 mg of diethylazodicarboxylate, and continued to stir for 24 hours. After removal of the solvent, the obtained residue was purified by column chromatography on silica gel using as eluting solvent mixture of n-hexane and ethyl acetate. The result of this procedure were given 400 mg of the target compound as a yellow oily substance.

1H-NMR (CDCl3) : of 1.46 (9H, s); is 2.05 (4H, m); of 2.66 (4H, m); of 3.60 (4H, Shir. C); is 4.85 (1H, Shir. C); 6,85 (4H, d); 7,05 (2H, d); 7,53 (3H, m); 7,83 (1H).

Reference example 104. Getting 4-[((3S)-1-tert - butoxycarbonyl-3-pyrrolidinyl)oxy]-3-methoxybenzaldehyde.

In 50 ml of tetrahydrofuran was dissolved totaling 3.04 g of vanillin, 3,74 g (3R)-1-tert-butoxycarbonyl-3-hydroxypyrrolidine and of 5.24 g of triphenylphosphine. Thus obtained solution was mixed with of 4.00 g of diethylazodicarboxylate, and the mixture, the residue was purified by column chromatography on silica gel, using as an eluting solvent mixture of ethanol and chloroform. The result of this procedure, received 5.0 g of the target compound as an oily substance.

1H-NMR (CDCl3) : of 1.47 (9H, s); 2,00 - to 2.40 (2H, m); 3,50 - of 3.80 (4H, m), 3,90 (3H, s); 5,02 (1H, Shir.C.); 6,80 - of 7.60 (3H, m); 9,86 (1H, s).

Reference example 105. Getting 4-[[4-(N-acetyl) aminoethylthiomethyl] methoxy]benzaldehyde.

Received target connection in accordance with the procedure described in reference example 104.

1H-NMR (CDCl3) : 0,80 - 2,10 (10H, m); of 3.13 (2H, DD, J = 6,1 Hz and 6.1 Hz); a-3.84 (2H, d, J = 6,1 Hz); to 5.56 (1H, Shir.C.); 6,97 (2H, d, J = 8.7 Hz); of 7.82 (2H, d, J = 8.7 Hz); 9,88 (1H, s).

Reference example 106. Obtain 3-acetoxy-4-[((3S)-1 - acetyl-3-pyrrolidinyl)oxy]-benzaldehyde.

a) 5.5 g of 4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)- oxy]-3-methoxybenzaldehyde was dissolved in 20 ml of dichloromethane, followed by adding 30 ml of formic acid. Thus obtained mixture was stirred at room temperature for 1 hour and then a further 1 hour at 50oC. the Solvent and formic acid was distilled under reduced pressure, and the obtained residue was dissolved in 100 ml of tetrahydrofuran. Thus obtained solution was mixed with 2,68 g acetylchloride drove away and the resulting residue was dissolved in chloroform, and washed with water, and drained the obtained organic layer. After removal of the solvent, the obtained residue was purified by column chromatography on silica gel, using as eluent toluene, which was obtained 4.3 g of 4-[((3S)-1-acetyl-3-pyrrolidinyl)oxy] -3-methoxybenzaldehyde in the form of oil viscous liquid.

1H-NMR (CDCl3) : 2,04 (5H, m); 3,50 - 4,00 (4H, m), 3,90 (3H, s); 5,10 (1H, Shir.C.); 6,80 - of 7.60 (3H, m); 9,86 (1H, s).

b) 4.3 g of 4-[((3S)-1-acetyl-3-pyrrolidinyl)oxy]-3-methoxybenzaldehyde obtained in the above part (a), was dissolved in 40 ml of dichloromethane, and the solution was cooled to -70oC. To the above solution under stirring was added drop by drop of 12.6 g of tribromide boron. Thus obtained reaction solution was heated to 0oC and then poured into ice water and was extracted with chloroform. The obtained organic layer was concentrated to dryness, and the resulting residue was led from the solvent system of chloroform and n-hexane, which was obtained 2.0 g of 4-[((3S)-1-acetyl-3-pyrrolidinyl) oxy]-3-hydroxybenzaldehyde. Thus obtained compound was used in subsequent reactions without further purification.

1H-NMR (CDCl3: [((3S)-1-acetyl-3-pyrrolidinyl)oxy]-3 - hydroentangled, obtained in the above (b), suspended in 5 ml of pyridine, followed by adding 0,86 g of acetic anhydride. Thus obtained mixture was stirred at room temperature for 1 hour. After drying the reaction solution under reduced pressure, the thus obtained residue was purified by column chromatography on silica gel, elwira mixture of ethanol and chloroform. The result of this procedure was given of 1.30 g of the target compound as an oily substance.

1H-NMR (CDCl3) : to 2.06 (3H, s); of 2.28 (3H, s); 2,00 - to 2.40 (2H, m); 3.40 in - 3,90 (4H, m); the ceiling of 5.60 (1H, Shir.C); 6,90 - of 7.90 (3H, m); for 9.90 (1H, s).

Reference example 107. Getting 4-[(1-trityl-4-imidazolyl) methoxy] benzaldehyde.

1.22 g of p-hydroxybenzaldehyde and 4,08 g of 4-chloromethyl-1-tritylimidazole was dissolved in 40 ml of N,N-dimethylformamide, followed by the addition of 1.66 g of anhydrous potassium carbonate and then stirred at room temperature for 40 hours. Thus obtained reaction solution was distributed between water and benzene, and the organic layer was concentrated to dryness. The obtained residue was purified by column chromatography on silica gel, elwira chloroform, and the purified product was led from the system of RPL. 181-182oC.

1H-NMR (CDCl3) : 5,09 (2H, c), of 6.90 (1H, d, J = 1.1 Hz); 7,00 - 7,40 (17H, m); 7,47 (1H, d, J = 1.1 Hz); 7,81 (2H, d, J = 8,8 Hz); 9,88 (1H, c).

Reference example 108. Getting 2-[2-[4-[(3S)-1-acetyl-3-pyrrolidinyl)oxy]-3-hydroxyphenyl]ethyl]-5 - benzofurazanyl.

a) 1.3 g of 3-atomic charges-4-[((3S)-1-acetyl-3-pyrrolidinyloxy] benzaldehyde and 2,22 g (5-cyano-2-benzofuranyl)methylcrotonyl-phosphonium chloride was dissolved in a mixture solvent consisting of 10 ml of tetrahydrofuran and 10 ml of ethanol, and then adding 0,943 g of 1,8-diazabicyclo[5.4.0]-7-undecene and then stirred at room temperature for 2 hours. To the resulting mixture then was added 1.88 g of 1,8-diazabicyclo [5.4.0]-7-undecene and 3 ml of water, followed by stirring at room temperature for 2 hours. Thus obtained reaction solution was brought to pH 4-5 with 10% aqueous citric acid solution and concentrated under reduced pressure, and the obtained residue was extracted with chloroform and then dried. After removal of the solvent, the obtained residue was purified by column chromatography on silica gel, elwira with a mixture of chloroform and ethanol, resulting in a received 1.8 g 2-[2-[4-[((3S)-pyrrolidinyl)oxy]-3-hydroxyphenyl] vinyl] -5 - b is (5H, m); 3,40 - 4,00 (4H, m); 5,00 (1H, Shir. C); 6,30 - of 7.90 (9H, m).

b) 1.8 g 2-[2-[4-[((3S)-1-acetyl-3-pyrrolidinyl)oxy]-3-hydroxyphenyl] vinyl] -4 - benzofurazanyl obtained in the above part (a), was dissolved in a solvent mixture consisting of 300 ml of tetrahydrofuran and 300 ml of ethanol, and the solution was subjected to catalytic recovery under normal pressure for 5 hours in the presence of 340 mg of palladium oxide 1H2Sulfate barium. After removal of catalyst by filtration and concentrating the obtained filtrate, and the precipitated crystals thus collected by filtration, which was obtained 1.6 g of the target compound as colorless crystals. So pl. 191-193oC.

IR (KBr): 2224, 1644, 1512 cm-1< / BR>
1H-NMR (CDCl3) : of 2.09 (3H, c); 2,00 - 2,50 (2H, m); 3.04 from (4H, c); 3,50 - are 3.90 (4H, m); 4,96 (1H, Shir.C); 6,40 (1H, s); 6,50 - of 6.90 (3H, m); 7,50 (2H, s); 7,80 (1H, s).

Further compounds of reference examples 109 and 110 received in accordance with the procedure described in reference example 108.

Reference example 109. 2-[2-[4-[[4-(N-Acetyl)aminoethylthiomethyl]methoxy]phenyl]ethyl]- 5-benzofurazanyl.

So pl.: 159-161oC

1H - NMR (CDCl3) : 0,80 - 2,10 (10H, m); 1,99 (3H, s); totaling 3.04 (4H, s); 3,19 (2H, DD, J = 6,1 and 6.1 Hz); 3,63 (2H, d, -[(1-Trityl-4-imidazolyl)methoxy]phenyl] ethyl]-5 - benzofurazanyl.

So pl. 165-167oC

1H-NMR (CDCl3) : 3,03 (4H, c); equal to 4.97 (2H, s); 6,38 (1H, c); 6.90 to - 7,70 (22H, m); for 7.78 (1H, s).

Reference example 111. Getting 2-[2-[4-[(1-imidazolyl)methyl)phenyl]ethyl] -5-benzofurazanyl.

a) 911 mg of 4-hydroxymethylbenzene and 2.0 g (5-cyano-2-benzofuranyl)-methyltriphenylphosphonium chloride was dissolved in a mixture solvent consisting of 10 ml of tetrahydrofuran and 10 ml of ethanol, was added 845 mg of 1,8-diazabicyclo[5.4.0]-7-undecene and stirred at room temperature for 1 hours. After removal of the solvent, the obtained residue was purified by column chromatography on silica gel, which was obtained 2.3 g of 2-[2-(4-hydroxymethylene)vinyl] -5-benzofuranyl in the form of a mixture of E and Z isomers. 2.3 g thus obtained a mixture of E/Z mixture was dissolved in a mixture solvent consisting of 10 ml of tetrahydrofuran and 10 ml of ethanol, and the solution was subjected to catalytic hydrogenation under normal pressure for 7 hours in the presence of 600 mg of palladium oxide 1H2O barium sulfate. After removal of catalyst by filtration and removal of the solvent, the obtained residue was purified by column chromatography on silica gel, elwira chloroform, resulting received.

1H-NMR (CDCl3) : 1,60 (1H, s); 3,10 (4H, s); of 4.67 (2H, s); 6,41 (1H, s); then 7.20 (2H, d, J = 8,2 Hz); 7,34 (2H, d, J = 8,2 Hz); 7,52 (2H, s); of 7.82 (1H, s).

b) 835 mg of 2-[2-(4-hydroxymethylene)ethyl]-5-benzofuran of carbonitrile obtained in the above part (a), was dissolved in 15 ml of thionyl chloride, and the solution was stirred at room temperature for 1 hour. Then thionyl chloride drove away, and the obtained residue was dissolved in 30 ml of acetonitrile, together with 550 mg of N-acetylimidazole and 600 mg of sodium iodide. Thus obtained solution was heated under reflux for 3 hours. After removal of the solvent, the obtained residue was purified by column chromatography on silica gel, elwira chloroform. The result of this procedure were given 300 mg of target compound in the form of brown crystals.

So pl.: 72-73oC.

1H-NMR (CDCl3) : is 3.08 (4H, s); 5,09 (2H, s); 6,40 (1H, s); 6.89 in (1H, s); 7,00 - to 7.18 (5H, m); 7,49 (2H, s); 7,56 (1H, s); 7,79 (1H, s).

Reference example 112. Getting 4-[2-(5-cyano-2-benzofuranyl)ethyl]benzoic acid

a) of 5.17 g of methyl 4-formylbenzoate and 13,97 g (5-cyano-2-benzofuranyl)methyltriphenylphosphonium chloride was dissolved in a mixture solvent consisting of 50 ml of tetrahydrofuran and 50 ml of methanol. 5,02 g of 1,8-diazabicyclo[5.4.0] -7-undeca matney temperature for 2 hours. By collecting the precipitated crystals through the filter, was obtained methyl 4-[2-(5-cyano-2-benzofuranyl)vinyl] benzoate in the form of a mixture of E - and Z-forms. The thus obtained crystals were dissolved in a solvent mixture consisting of 300 ml of tetrahydrofuran and 100 ml of ethanol, and the solution was subjected to catalytic hydrogenation under normal pressure for 2 hours in the presence of 2.0 g of palladium oxide 1H2O barium sulfate. After removal of catalyst by filtration and concentrating the obtained filtrate thus obtained residue was purified by column chromatography on silica gel, elwira benzene, resulting in received of 8.1 g of methyl 4-[2-(5 - cyano-2-benzofuranyl)ethyl] benzoate in the form of pritvorenih crystals, so pl.: 114-115oC.

1H-NMR (CDCl3) : 3,13 (4H, s); are 3.90 (3H, s); of 6.31 (1H, s); 7,26 (2H, d, J = 8.5 Hz); 7,50 (2H, s); 7,80 (1H, s); 7,98 (2H, d, J = 8,5 Hz).

b) 1.5 g of methyl 4-[2-(5-cyano-2-benzofuranyl)ethyl]benzoate, obtained in the above part (a), was dissolved in a mixture solvent consisting of 20 ml of tetrahydrofuran and 20 ml of ethanol, and then was added 11 ml of 1 N. aqueous sodium hydroxide solution and was stirred at room temperature for 14 hours. Thereafter, the resulting reaction Rast is istratii, washed with water, and then dried. The result of this procedure, received of 1.41 g of the target compound, so pl. 234-235oC.

1H-NMR (DMSO-d6) : 3,13 (4H, s); 6,70 (1H, s); 7,44 (2H, d, J = 8.0 Hz); of 7.69 (2H, s); 7,88 (2H, d, J = 8.0 Hz); of 8.06 (1H, s).

Reference example 113. Getting 2-[2-[4-[(4-methyl-1-piperazinil) carbonyl]phenyl]ethyl]-5-benzofurazanyl.

1.35 g of 4-[2-(5-cyano-2-benzofuranyl)ethyl]benzoic acid was heated under reflux for 2 hours in 15 ml of thionyl chloride. Then thionyl chloride drove, and thus obtained residue was dissolved in 10 ml of tetrahydrofuran. Received so the solution was added drop by drop to 20 ml of tetrahydrofuran containing 1.0 g 1-methyleneimine mixed under ice cooling. After stirring at room temperature for 1 hour and subsequent removal of the solvent by distillation, the resulting residue was dissolved in chloroform and washed with saturated aqueous sodium bicarbonate. After drying the organic layer and removal of the solvent, the obtained residue was purified by column chromatography on silica gel, elwira mixture of chloroform in ethanol. The result of this procedure was obtained 1.35 g Zeir. C); 3,11 (4H, s); of 3.64 (4H, Shir. C.); 6.42 per (1H, s); 7,26 (2H, d, J = 9.0 Hz); 7,40 (2H, d, J = 9.0 Hz); 7,50 (2H, s); 7,80 (1H, s).

Reference example 114. Getting 2-[2-[4-[[(2-pyrazinyl)amino]carbonyl] phenyl]ethyl]-5 - benzofurazanyl.

a) 1 g of 4-[2-(5-cyano-2-benzofuranyl)ethyl]benzoic acid and 573 mg of 1-hydroxybenzotriazole, at room temperature, dissolved in 100 ml of dichloromethane followed by the addition of 780 mg of 1,3-dicyclohexylcarbodiimide and then stirred at the same temperature for 3 hours. After removal of the solvent, the obtained residue was purified by column chromatography on silica gel, elwira with a mixture of chloroform and ethanol, and the thus purified product was led from a mixture of benzene and n-hexane. The result of this procedure was obtained 1.2 g 2-[2-[4-[[(1-benzotriazolyl)oxy] carbonyl]phenyl]-ethyl]-5-benzofuranyl in the form of powder, so pl.: 171-172oC.

1H-NMR (CDCl3) : 3,14 (4H, s); 6,48 (1H, s); 7,30-8,30 (11H, m);

MC (m/z): 409 (M++1).

b) 100 mg 2-[2-[4-[[(1-benzotriazolyl)oxy] carbonyl]phenyl] ethyl]-5-benzofuranyl obtained in the above part (a), and 23.3 mg aminopyrazine was dissolved in 2 ml N,N-dimethylformamide. Thus obtained solution was mixed with 13,0 mg (60%) of the hydride nitrocotton, washed with water, and then dried. After removal of the solvent, the obtained residue was purified by column chromatography on silica gel, resulting in a received 55 mg of target compound in the form of powder, so pl.: 183-185oC.

1H-NMR (CDCl3) : 3,17 (4H, s); 6.42 per (1H, s); 7,34 (2H, d, J=9.0 Hz); to 7.59 (2H, s); 7,81 (1H, s); of 7.90 (2H, d, J=9.0 Hz); compared to 8.26 (1H, DD, J=3.0 and 1.6 Hz); 8,40 (1H, DD, J=3.0 Hz); 8,65 (1H, Shir.C.); 9,74 (1H, d, J=1.6 Hz).

Reference example 115. Obtaining methyl[5-[((3S)-1-tert - butoxycarbonyl-3-pyrrolidinyl)hydroxy] -2-[2-(5-cyano-2 - benzofuranyl)ethyl]phenyl]oxoacetate.

a) In 40 ml of tetrahydrofuran was dissolved 1,38 g of 2,4-dihydroxybenzaldehyde, of 1.87 g of (3R)-1-tert-butoxycarbonyl-3-hydroxypyrrolidine and 2.88 g of triphenylphosphine. Thus obtained solution was mixed with 1,91 g diethylazodicarboxylate and stirred at room temperature for 1 hour. After removal of the solvent, the obtained residue was purified by column chromatography on silica gel, which was obtained 1.2 g of 4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl] -oxy] -2 - hydroxybenzaldehyde in the form of a viscous and oily substances.

1H-NMR (CDCl3) : of 1.47 (9H, s); 2,00-of 2.36 (2H, m); 3,30 of 3.75 (4H, m); 4,94 (1H, square); 6,38 (1H, d, J=2.1 Hz); of 6.52 (1H, DD, J=8.0 and 2.1 Hz is benzaldehyde, obtained in the above part (a), and 0,884 g ethylbromoacetate was dissolved in 100 ml of acetone. Thus obtained solution was mixed with 1.12 g of anhydrous potassium carbonate, and the mixture was heated under reflux for 1.5 hours. After cooling, any insoluble matter was removed by filtration and the solvent drove away. After that, the obtained residue was purified by column chromatography on silica gel, resulting in a received 1.44 g of ethyl[2-formyl-5-[((3S)-1-tert-butoxycarbonyl - 3-pyrrolidinyl)oxy] phenyl]oxoacetate in the form of a viscous and oily substances.

1H-NMR (CDCl3) : of 1.30 (3H, t, J=7.0 Hz); of 1.47 (9H, s); 2,00-of 2.28 (2H, m); 3,36-3,70 (4H, m), 4,28 (2H, square); 4,71 (2H, s); 4,94 (1H, Quint); of 6.31 (1H, d, J=2.2 Hz); 6,53 (1H, DD, J=8.8 and 2.2 Hz); to 7.84 (1H, s); accounted for 10.39 (1H, s).

c) 1.44 g of ethyl[2-formyl-5-[((3S)-1-tert-butoxycarbonyl-3 - pyrrolidinyl)oxy] phenyl] oxoacetate obtained in the above (b), and 1.71 g (5-cyano-2-benzofuranyl)methyltriphenylphosphonium chloride was dissolved in a mixture solvent consisting of 10 ml of tetrahydrofuran and 10 ml of methanol. Thus obtained solution was mixed with 0,664 g of 1,8-diazabicyclo[5.4.0]-7-undecene, and the mixture was stirred for 1 hour. After removal of the solvent, the resulting residue was purified using kleinova connection in the form of a mixture of E - and Z-forms. 1.8 g thus obtained olefin compounds were dissolved in a mixture solvent consisting of 40 ml of tetrahydrofuran and 40 ml of ethanol, and the resulting solution was subjected to catalytic hydrogenation under normal pressure in the presence 0,22 g oxide, palladium barium sulfate 1H2O. After removal of the catalyst by filtration, the obtained residue was purified by column chromatography on silica gel, elwira mixture of benzene and ethyl acetate. The result of this procedure was obtained 1.6 g of target compound in the form of a viscous oily substance. During the reaction was carried out by the transesterification.

1H-NMR (CDCl3) : of 1.46 (9H, s); 1,96-of 2.08 (2H, m); is 3.08 (4H, s); 3,36-3,68 (4H, m); of 3.80 (3H, m); to 4.62 (2H, s); 4,80 (1H, Shir. C); 6,30 (1H, s); 6,36 (1H, d, J=8.0 Hz); to 6.43 (1H, s); 7,02 (1H, d, J=8.0 Hz); 7,46 (2H, s); to 7.77 (1H, s).

Illustrative example 1 (invention). Ethyl 3-(5-amidino-2-benzofuranyl)-2-[4-[((3)-3-pyrrolidinyl)oxy]phenyl] propionate dihydrochloride.

a 1.96 g of ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl] -3- (5-cyano-2-benzofuranyl)propionate was dissolved in 150 ml of ethanol. While cooling with ice and stirring, hydrogen chloride was barbotirovany in the thus obtained solution to the saturated level, and then left for 18 hour, the residue was dissolved in 300 ml of ethanol, containing 15% (m/Rev) ammonia and then the solution was left for another 18 hours. After removal of the solvent, the obtained residue was subjected to column chromatography using a column Packed with a highly porous polymer (synthetic adsorbent; the polymer is a styrene-divinylbenzene Diaion HP-20), using as eluent a mixture of water and acetonitrile. Thus obtained the desired fractions were subjected to reversed-phase liquid chromatography high resolution (IHVR), using a column filled octadecyl-bound silica gel, elwira with a mixture of water and acetonitrile. After that erwerbende thus fractions were collected, mixed with diluted hydrochloric acid, and then concentrated to dryness. The result of this procedure received 610 mg of the target compound in the form of a solid substance.

1H-NMR (DMCO-d6) : a 1.08 (3H, t, J=7.0 Hz); 1,90-of 2.30 (2H, m); 3,00-of 3.80 (6H, m); 3,80-4,30 (3H, m); 5,08 (1H, Shir.C.); of 6.73 (1H, s); 6,93 (2H, d, J= 8,3 Hz); 7,33 (2H, d, J=8,3 Hz); 7,73 (2H, s); 8,08 (1H, s); a 9.25 (2H, Shir. C); 9,40 (2H, Shir.C); 9,50-10,00 (2H, Shir.S.).

Subsequent connections illustrative examples 2-17 were received in accordance with the procedure described in illustrative example 1.

Illustrative example 2. Ethyl 3-(5-amidino-2-benzofuranyl)- 2-[4-[((2S, (DMCO-d6) : of 1.10 (3H, t, J=7.0 Hz); 1.70 to 3,20 (2H, m); 3,00-4,50 (8H, m); 5,00-and 5.30 (1H, Shir.C.); of 6.71 (1H, s); 6.87 in (2H, d, J=8,3 Hz); 7,30 (2H, d, J=8,3 Hz); 7,72 (2H, s); 8,10 (1H, s); 9,00-10,00 (6H).

Illustrative example 3. Ethyl 3-(5-amidino-2-benzofuranyl)-2-[4-[((2S, 4S)-2-dimethylcarbamoyl - 4-pyrrolidinyl)oxy] phenyl]propionate dihydrochloride (solid).

1H-NMR (DMCO6) : a 1.11 (3H, t, J=7.0 Hz); 1.70 to 3,30 (2H, m); only 2.91 (3H, s); 2,96 (3H, s); 3,00-4,20 (7H, m), 4,70 (1H, Shir.C.); 5,10 (1H, Shir.C.); 6,69 (1H, s); 6,86 (2H, d, J=8.7 Hz); 7.29 trend (2H, d, J=8.7 Hz), 7,69 (2H, s); 8,07 (1H, s); 8,80 (1H, Shir.C.); 9,10 (2H, Shir.C.); 9,34 (2H, Shir.C.); 10,08 (1H, Shir.S.).

Illustrative example 4. Ethyl 2-(5-amidino-2-benzofuranyl)-3-[4- [((3S)-3-pyrrolidinyl)oxy] phenyl] propionate dihydrochloride (solid).

1H-NMR (DMSO-d6) : a 1.08 (3H, t, J = 7.0 Hz); 1,80-of 2.30 (2H, Shir. C); 2,70-3,70 (6H, m); 4,08 (2H, square, J = 7,0 Hz); of 4.35 (1H, t, J = 7.9 Hz); 5,08 (1H, Shir. C); at 6.84 (2H, d, J = 8,3 Hz); 6,9 (1H, c); 7,17 (2H, d, J = 8,3 Hz); 7,79 (2H, s); to 8.12 (1H, s); was 9.33 (2H, Shir. C); 9,51 (2H, Shir. C); 9,80 (2H, Shir. C).

Illustrative example 5. Ethyl 3-(5-amidino-2-benzofuranyl)-3- [4-[((3S)-3-pyrrolidinyl-hydroxy]phenyl]propionate dihydrochloride (solid)

1H-NMR (DMSO-d6) : of 1.17 (3H, t, J = 7 Hz); of 2.0-2.2 (2H, m); 3,0-3,8 (6H, m); 4,07 (2H, square); 4,5-4,7 (1H, m); 5,13 (1H, m); 6,94 (1H, s); 6,94 (2H, d, J = 9 Hz); to 7.32 (2H, d, J = 9 Hz); 7,73 (2H, s); 8,13 (1H, s); of 9.21 (2H, Shir. C); 9,40 (2H, Shir. C); and 9.4 to 10.0 is l] propionate dihydrochloride (solid).

1H-NMR (DMSO-d6) : of 1.06 (3H, t); 2,10 (2H, W); 3,0-3,7 (7H); of 4.05 (2H, square ); 5,09 (1H, Shir. with); to 6.95 (2H, d); 7,28 (2H, d); to 7.77 (3H); 8,21 (1H, s); 9,2-9,8 (6H).

Illustrative example 7. Ethyl 2-[2-(5-amidino-2-benzofuranyl)- ethyl]-5-[((3S)-3-pyrrolidinyl)oxy]benzoate the dihydrochloride (solid).

1H-NMR (DMSO-d6) : of 1.29 (3H, t, J = 7.0 Hz); from 2.00 to 2.35 (2H, m); 2,90-of 3.60 (8H, m); 4,18 (2H, square, J = 7,0 Hz); 5,20 (1H, Shir. with); to 6.75 (1H, c); then 7.20 (1H, DD, J = 7,9 and 2.8 Hz); 7,39 (1H, d, J = 7.9 Hz); 7,41 (1H, d, J = 2,8 Hz); 7,74 (2H, s); of 8.09 (1H, s); 9,23 (2H, Shir. C); 9,40 (2H, Shir. C.); 9,50-10,20 (2H, Shir. C).

Illustrative example 8. Ethyl[2-[2-(5-amidino-2-benzofuranyl)- ethyl]-5-[((3S)-3-pyrrolidinyl-hydroxy]phenyl]propionate dihydrochloride (solid)

1H-NMR (DMSO-d6) : of 1.18 (3H, t, J = 7.0 Hz); 2,0-of 2.30 (2H, m); to 3.02 (4H, c); 3,00-4,00 (6H, m); the 4.90 (2H, square, J = 7,0 Hz); 5,12 (1H, Shir. C); 6,80-to 7.00 (3H, m); from 7.24 (1H, d, J = 8,64 Hz); 7,76 (2H, s); to 8.12 (1H, s); 9,29 (1H, s); of 9.45 (2H, Shir. C); 9,40-10,10 (2H, Shir. C).

Illustrative example 9. Ethyl 5-amidino-2-[2-[4-[((3S)-3 - pyrrolidinyl)oxy] phenyl]ethyl]-3-benzophenoneoxymate the dihydrochloride (solid).

1H-NMR (DMSO-d6) : of 1.36 (3H, t); of 2.08 (2H, m); 4,30 (2H); 5,00 (1H, Shir. C); make 6.90 (2H, d); 7,10 (2H, d); 7,83 (2H); to 8.34 (1H, s); 9,27 (2H, Shir. C); 9,51 (4H, Shir. C).

Illustrative example 10. Ethyl 3-(5-amidines[b]Tien-2-yl)- 2-[4-[((3S)-3-pyrrolidinyl)OCN, m); 3,00-4,20 (9H, m); 5,08 (1H, Shir. C), 6,92 (2H, d, J = 8,75 Hz); 7,27 (1H, s); 7,31 (2H, d, J = 8,75 Hz); to 7.68 (1H, d, J = 8.3 and 1.5 Hz); 8,10 (1H, d, J = 8,3 Hz)); of 8.27 (1H, d, J = 1.5 Hz); 9,19 (2H, Shir. C.); 9,42 (2H, Shir. C); 9,10-10,00 (2H, Shir. C).

Illustrative example 11. Ethyl 3-(6-amidines[b]Tien-2 - yl)-2-[4-[((3S)-3-pyrrolidinyl-hydroxy]phenyl]propionate dihydrochloride (solid)

1H-NMR (DMSO-d6) : of 1.05 (3H, t); 2,10 (2H, m); 3,30 (7H, m); 4,0 (2H, m); of 5.05 (1H, Shir. C); make 6.90 (2H, d); 7,22 (3H, m); 7,60-of 7.90 (2H, m); scored 8.38 (1H, s); 9,10 (2H, Shir. C); a 9.35 (2H, Shir. C); 9,40 (2H, Shir. C).

Illustrative example 12. Ethyl 3-(6-amidino-1-ethyl-2-indolyl)- 2-[4-[(4-piperidinyl)oxy]phenyl]propionate dihydrochloride (solid).

1H-NMR (DMSO-d6) : of 1.05 (3H, t); 1.28 (in, 3H); to 1.83 (2H Shire. C); of 2.08 (2H, Shir. C); 2,90-3,20 (5H, Shir. C); 3,90-and 4.40 (3H, m); to 4.62 (1H, Shir. C); 6,34 (1H, s); 6,97 (2H, d); 7,34 (2H); 7,47 (1H, d); 7,58 (1H, d); 8,13 (1H, s); 8,90-9,40 (6H, Shir. C).

Illustrative example 13. Ethyl 3-(6-amidino-1-ethyl-2-indolyl)- 2-4-[((3R)-3-pyrrolidinyl)oxy]phenyl]propionate dihydrochloride (solid)

1H-NMR (DMSO-d6) : a 1.08 (3H, t, J = 7.0 Hz); of 1.31 (3H, t, J = 7.0 Hz); 2,10-of 2.30 (2H, Shir. C); 3,17 (1H, DD); 3,20-3,40 (2H, m); 3,90-and 4.40 (5H, m); 5,14 (1H, Shir. C); 6,37 (1H, s); 6,97 (2H, d, J = 8,8 Hz); 7,38 (2H, d, J = 8,8 Hz); 7,49 (1H, d, J = 8,3 Hz); a 7.62 (1H, d, J = 8,3 Hz); to 8.14 (1H, s); 8,99 (2H, Shir. C.); to 9.32 (2H, Shir. C); 9,50-to 9.70 (2H, Shir. C).

Illustrative eficacia using an ethanol solvent) (solid).

1H-NMR (DMSO-d6) : of 1.05 (3H, t); 1,95-of 2.30 (2H, m); 3,76 (3H, s); was 4.02 (2H, square); 4,00-4,30 (1H, m); 5,00-5,20 (1H, m); 6,38 (1H, s); 7,00 (2H, d); 7,40 (2H, d); 7,50-of 7.70 (2H, m); of 8.25 (1H, s); of 9.30-10,10 (6H).

Illustrative example 15. Ethyl 3-(6-amidino-2-naphthyl)-2- [4-((3S)-3-pyrrolidinyl)-oxy]-phenyl]propionate dihydrochloride (solid).

1H-NMR (DMSO-d6) : of 1.06 (3H, t, J = 7.0 Hz); 2,00-of 2.20 (2H, m); 3,00-4,00 (7H, m); 3,99 (2H, square, J = 7,0 Hz); 5,11 (1H, m), 6,92 (2H, d, J = 9.0 Hz); 7,31 (2H, d, J = 9.0 Hz); at 7.55 (1H, d, J = 8.0 Hz); 7,80-8,10 (4H, m); 8,51 (1H, C); 9,40 (2H, Shir. C); 9,58 (2H, Shir. C); 9,50-10,00 (2H, Shir. C).

Illustrative example 16. Ethyl 3-(7-amidino-2-naphthyl)-2- [4-[((3S)-3-pyrrolidinyl)-oxy]phenyl]propionate dihydrochloride (solid).

1H-NMR (DMSO-d6) : a 1.01 (3H, t, J = 7.0 Hz); 2,00-of 2.20 (2H, m); 3,10-of 3.80 (7H, m); 3,98 (2H, square, J = 7,0 Hz); 5,10 (1H, m); 6,93 (2H, d, J = 9.0 Hz); to 7.32 (2H, d, J = 9.0 Hz); 7,50-8,10 (5H, m); 8,44 (1H, m); 9,41 (2H, Shir. C); 9,59 (2H, Shir. C); of 9.30-10,00 (2H, Shir. C).

Illustrative example 17. Ethyl 3-(7-amidino-2-naphthyl)-2- [4-[(4-piperidinyl-methoxy]phenyl]propionate dihydrochloride (solid)

1H-NMR (DMSO-d6) : a 1.01 (3H, t, J = 7,1 Hz); 1,45-1,55 (2H, m); 1.85 to 1,95 (2H, m); 2,80-2,95 (2H, m); 3,15-3,50 (5H, m); 3,81 (2H, d); 3,95-of 4.05 (2H, m); 4,05-to 4.15 (1H, m); 6.87 in (2H, d, J = 8,3 Hz); 7,27 (2H, d, J = 8,3 Hz); 7,58-7,63 (1H, m); 7,75-7,80 (1H, m); to 7.84 (1H, s); of 7.95 (1H, d, J = 8,8 Hz); 8,07 (1H, d, J = 8,8 Hz); of 8.40 (1H, s); 9,29 (2H); at 9.53 is lots hydrochloride monohydrate.

1.51 g of ethyl 3-(7-amidino-2-naphthyl)-2-[4-[(4-piperidinyl)- methoxy]phenyl] propionate dihydrochloride was dissolved in 50 ml of concentrated hydrochloric acid, and the solution was left in a tightly closed container at room temperature for 62 hours. After drying the resulting reaction solution under reduced pressure, the thus obtained residue was purified by applying it to a column Packed with a highly porous polymer (synthetic adsorbent; a polymer of styrene and divinylbenzene HP-20). After that, erwerbende thus fractions were collected and mixed with a small amount of ethanol and then precipitated crystals were collected by filtration. The result of this procedure received 0,79 g of target compound in the form of crystals. So pl.: 285 - 287oC (with decomp.).

Since the solubility of the thus obtained product in any solvent is very low, the connection is handled by the dihydrochloride with hydrochloric acid and then to the measurement of NMR drained.

1H-NMR (DMSO-d6) : 1,45 - to 1.60 (2H, m); 1.85 to 1,95 (2H, m); 1,95 - 2,05 (1H, Shir. C); 2,8 - 2,9 (2H, m) 3,1 - 3,2 (1H, m); 3,2 - 3,3 (2H, m); 3,4 - 3,5 (1H, m); of 3.80 (2H, d, J = 6.4 Hz); 3,9 - 4,0 (1H, m); 6.87 in (2H, d, J = 8,8 Hz); 7,27 (2H, d, J = 8,8 Hz); of 7.60 (1H, d, J = 8,8 Hz); 7,75 - 7,80 (1H, m); 7,83 (1H, s); 7,94 (1H, d benzofuranyl)-2- [4-[((3S)-3-pyrrolidinyl)oxy]phenyl]propionic acid dihydrochloride.

3.2 g of ethyl 3-(5-amidino-2-benzofuranyl)-2- [4-[((3S)-3-pyrrolidinyl)oxy] phenyl] propionate dihydrochloride was dissolved in 80 ml of 2 N. hydrochloric acid, and the solution was heated under reflux for 30 minutes. After cooling and removal of the solvent, the obtained residue was purified by column chromatography using a column Packed with a highly porous polymer (synthetic adsorbent; a polymer of a styrene-divinylbenzene Diaion HP-20), and as the eluent used 5 - 10% acetonitrile. After that, erwerbende thus fractions were collected and brought to pH 2 to 3 with diluted hydrochloric acid, and then concentrated to dryness. The result of this procedure was given to 1.25 g of target compound in the form of a solid substance.

1H-NMR (DMSO-d6) : 2,00 - 2,30 (2H, m); 3,00 - of 3.80 (6H, m); 4,10 (1H, t, J = 7.2 Hz); 5,10 (1H, Shir. C); 6,74 (1H, s); 6,94 (2H, d, J = 8,3 Hz); 7,40 (2H, d, J = 8,3 Hz); 7,74 (2H, s); of 8.09 (2H, s); which 9.22 (2H, Shir. C); 9,40 (2H, Shir. C); 9,10 (2H, Shir. C).

Subsequent connections illustrative examples 20 to 26 received in accordance with the procedure described in illustrative example 19.

Illustrative example 20. 3-(5-Amidino-2-benzofuranyl)-2- [4-[((2S, 4S)-2-dimethylcarbamoyl-4-pyrrolidinyl)oxy] phenyl]propionic acid Digi is 4.09 to (1H, t, J = 7.9 Hz); 4,70 (1H, Shir. C); 5,12 (1H, Shir. C); of 6.71 (1H, s); 6,86 (2H, d, J = 8,3 Hz); 7,30 (2H, d, J = 8,3 Hz); 7,73 (2H, s); 8,10 (1H, s); 8,76 (1H, Shir. C); of 9.30 (2H, Shir. C); 9,46 (2H, Shir. C); 10,80 (1H, Shir. C).

Illustrative example 21. 2-(5-Amidino-2-benzofuranyl)-3- [4-[((3S)-3-pyrrolidinyl)oxy] phenyl] propionic acid dihydrochloride (solid).

1H-NMR (DMSO-d6) : 1,90 - of 2.30 (2H, m); 2,90 - 3,70 (6H, m), 4.26 deaths (1H, t, J = 7.9 Hz); of 5.06 (1H, Shir. C); 6,83 (2H, d, J = 8,3 Hz); 6,93 (1H, s); 7,17 (2H, d, J = 8,3 Hz); 7,78 (2H, s); to 8.14 (1H, s); of 9.30 (2H, Shir. C); for 9.47 (2H, Shir. C); 9,80 (2H, Shir. C).

Illustrative example 22. 3-(5-Amidino-2-benzofuranyl)-3- [4-[((3S)-3-pyrrolidinyl)oxy] phenyl] propionic acid dihydrochloride (solid).

1H-NMR (DMSO-d6) : of 2.0 - 2.2 (2H, m); 3,0 - 4,0 (6H, m); 4,6 (1H, m); 5,10 (1H, m), 6,92 (1H, s); 6,92 (2H, d, J = 9.0 Hz); to 7.32 (2H, d, J = 9.0 Hz); 7,73 (2H, s); 8,16 (1H, s); of 9.30 (2H, Shir. C); 9,46 (2H, Shir. C); 9,6 - 10,0 (2H, Shir. C).

Illustrative example 23. 2-[2-(5-Amidino-2-benzofuranyl) ethyl] -5-[((3S))-3-pyrrolidinyl)oxy] benzoic acid dihydrochloride (solid).

1H-NMR (DMSO-d6) : 1,90 - of 2.30 (2H, m); 2,90 - 3,70 (3H, m); 4,96 (1H, Shir. with); to 6.75 (1H, s); was 7.08 (1H, DD, J = 7,9 and 2.8 Hz); 7,28 (1H, d, J = 7.9 Hz); 7,41 (1H, d, J = 2,8 Hz); of 7.75 (2H, s); of 8.09 (1H, s); a 9.25 (2H, Shir. C); 9,42 (2H, Shir. C); 9,50 - 10,00 (2H, Shir. C).

Illustrative example 24. [2-[2-(5-Amidino 1H-NMR (DMSO-d6) : 1,95 - of 2.30 (2H, m); 3,03 (4H, s); 5,04 (1H, Shir. C); 6,68 - of 6.90 (3H, m); 7,14 (1H, d, J = 8,3 Hz); 7,74 (2H, s); 8,10 (1H, s); 9,38 (2H, Shir. C); 9,66 (2H, Shir. C); 9,00 - 10,00 (2H, Shir. C).

Illustrative example 25. 3-(5-Amidines[b]Tien-2-yl)- 2-[4-[((3S)-3-pyrrolidinyl)oxy] phenyl] propionic acid dihydrochloride (solid).

1H-NMR (DMSO-d6) : 1,90 - to 2.40 (2H, m); 3,00 - 4,10 (7H, m); 5,14 (1H, Shir. C); 6,93 (2H, d, J = 8,2 Hz); 7,28 (1H, s); 7,33 (2H, d, J = 8,2 Hz); of 7.70 (1H, d, J = 8,8 Hz); of 8.09 (1H, d, J = 8,8 Hz); compared to 8.26 (1H, s); 9,24 (2H, Shir. C); for 9.47 (2H, Shir. C); 9,00 - 10,20 (2H, Shir. C).

Illustrative example 26. 3-(7-Amidino-2-naphthyl)-2- [4-[((3S)-3-pyrrolidinyl)oxy]phenyl]propionic acid dihydrochloride (solid).

1H-NMR (DMSO-d6) : 2,00 - of 2.20 (2H, m); 3,00 - 3,70 (6H, m); free 5.01 (1H, m); 5,11 (1H, m), 6,92 (2H, d, J = 9.0 Hz); 7,33 (2H, d, J = 9.0 Hz); 7,50 - to 8.20 (5H, m); 8,43 (1H, s); 9,00 - 10,50 (6H).

Illustrative example 27. Ethyl (+)-3-(7-amidino-2-naphthyl)-2-[4-[((3S))-3-pyrrolidinyl)oxy]phenyl]propionate dihydrochloride.

123,1 g of ethyl(+)-2-[4-[((3S)-1-tert-butoxycarbonyl-3 - pyrrolidinyl)oxy]phenyl]-3-(7-cyano-2-naphthyl)propionate was dissolved in a mixture of solvents consisting of 480 ml of dichloromethane and 1286 ml of ethanol. Stirring at -10oC, hydrogen chloride was barbotirovany in thus obtained to the level of saturation, pay the solution was concentrated under reduced pressure at a temperature of from 10oC and below, resulting in a received 154 g of oily product. Thus obtained oily product was dissolved in 1480 ml of ethanol and, maintaining the internal temperature at -10oC or below, was introduced ammonia gas until the concentration becomes 21% (about. /about. ) or more. After conditioning at a temperature of -8oC to 5oC for 107 hours, the resulting reaction solution was concentrated under reduced pressure at a temperature of from 10oC or below for removal of the solvent, and the thus obtained residue was dissolved in 200 ml of water. After adjusting to pH 3 to 5 diluted hydrochloric acid, the resulting solution was purified by column chromatography using a column Packed with a highly porous polymer (synthetic adsorbent; the polymer is a styrene-divinylbenzene Diaion HP-20) and using as eluent a mixture of water and acetonitrile. After that erwerbende thus fractions were collected, mixed with a small amount of hydrochloric acid and concentrated to dryness. The result of this procedure received 107 g of the target compound as a colorless solid.

1H-NMR (DMSO-d6) : a 1.01 (3H, t, J = 7.2 Hz); 2,00 - 2,30 (2H, m) 3,1 - 3,6 (6H, m 8,3 Hz); 8,08 (1H, d, J = 8,3 Hz); to 8.41 (1H, s); 9,20 - of 9.30 (2H, Shir. C); 9,40 - 9,70 (4H, Shir. C).

Subsequent connections illustrative examples 28 to 32 were obtained in accordance with the procedure described in illustrative example 27.

Illustrative example 28. Ethyl (-)-3-(7-amidino-2-naphthyl)-2- [4-[((3S))-3-pyrrolidinyl)oxy] phenyl] propionate dihydrochloride (solid).

1H-NMR (DMSO-d6) : of 1.02 (3H, t, J = 7.2 Hz); 2,00 - 2,30 (2H, m) 3,1 - 3,6 (6H, m); 3,90 - of 4.05 (2H, m); 4,05 - to 4.15 (1H, m); 5,10 (1H, Shir. C); 6,94 (2H, d, J = 8,8 Hz); 7,32 (2H); of 7.60 (1H, d, J = 8,3 Hz); for 7.78 (1H, d, J = 8,3 Hz); 7,86 (1H, s); of 7.96 (1H, d, J = 8,3 Hz); 8,08 (1H, d, J = 8,3 Hz); 8,42 (1H, s); 9,20 - of 9.30 (2H, Shir. C); 9,40 - 9,70 (4H, Shir. C).

Illustrative example 29. Ethyl (+)-3-(5-amidines[b]Tien-2 yl)-2-4-[((2S)-2-pyrrolidinyl)methoxy] phenyl] propionate dihydrochloride (solid).

1H-NMR (DMSO-d6) : of 1.10 (3H, t, J = 7,3 Hz); 1,73 (1H, d sq J = 12.3 and 8,3 Hz); 1,84 - of 2.05 (2H, m); 2.06 to of 2.16 (1H, m); 3,12 - of 3.27 (2H, Shir. C); 3,39 (1H, DD, J = 15,0 and 7.8 Hz); of 3.64 (1H, DD, J = 15,0 and 7.8 Hz); 3,80 - 3,93 (1H, Shir. C); 4,00 - 4,24 (5H, m); 6,93 (2H, d, J = 8,3 Hz); 7,30 (1H, s); 7,31 (2H, d); to 7.67 (1H, d, J = 8,3 Hz); 8,11 (1H, d, J = 8,3 Hz); 8,23 (1H, s); 9,12 - of 9.30 (3H); to 9.45 (2H, s); 9,43 (2H, s); 9,74 - 9,94 (1H, Shir. C).

Illustrative example 30. Ethyl (-)-3-(5-amidines[b]Tien-2 - yl)-2-[4-[((2S)-2-pyrrolidinyl)methoxy] phenyl] propionate dihydrochloride (solid wishesto,27 (2H, Shir. C); 3,39 (1H, DD, J = 15,0 and 7.8 Hz); of 3.64 (1H, DD, J = 15,0 and 7.8 Hz); 3,80 - 3,93 (1H, Shir. C); 4,00 - 4,24 (5H, m); 6,93 (2H, d, J = 8,8 Hz, 2 AH); 7,30 (1H, s); 7,31 (2H, d, J = 8,8 Hz); to 7.67 (1H, DD, J = 8.3 and 1.5 Hz); 8,11 (1H, d, J = 8,3 Hz); 8,23 (1H, d, J = 1.5 Hz); 9,10 - to 9.25 (1H, Shir. C); of 9.21 (2H, s); 9,43 (2H, s); 9,74 - 9,84 (1H, Shir. C).

Illustrative example 31. Ethyl (+)-3-(7-amidino-2-naphthyl)-2-[4-[(4-piperidinyl)oxo]-phenyl]propionate dihydrochloride (solid).

1H-NMR (DMSO-d6) : a 1.01 (3H, t, J = 7,1 Hz); 1,75 - of 1.85 (2H, m); 2,05 - of 2.15 (2H, m); 3,0 - 3,1 (2H, m) 3,1 - 3,2 (3H, m); 3,9 - 4,0 (2H, m); 4,0 - 4,1 (1H, Shir. with); to 4.1 to 4.2 (1H, m); br4.61 (1H, Shir. with); to 6.95 (2H, d, J = 8,8 Hz); 7.29 trend (2H, d, J = 8,8 Hz); to 7.61 (1H, d, J = 8,3 Hz); for 7.78 (1H, d, J = 8,3 Hz); to 7.84 (1H, s); of 7.95 (1H, d, J = 8,3 Hz); 8,07 (1H, d, J = 8,8 Hz); scored 8.38 (1H, s); 8,9 - 9,1 (2H, Shir. C); 9,20 (2H, Shir. C); 9,49 (2H, Shir. C).

Illustrative example 32. Ethyl (-)-3-(7-amidino-2-naphthyl)-2-[4-[(4-piperidinyl)oxy]-phenyl] propionate dihydrochloride (solid).

1H-NMR (DMSO-d6) : a 1.01 (3H, t, J = 7,1 Hz); 1,75 - 1,80 (2H, m), 2.05 is - of 2.15 (2H, m); 3,0 - 3,1 (2H, m); for 3.1 to 3.3 (3H, m); 3,50 - 3,60 (1H, m); 3,65 of 3.75 (2H, m); 3,9 - 4,0 (2H, m); 4,0 - 4,1 (1H, Shir. with); to 4.1 to 4.2 (1H, m); br4.61 (1H, Shir. with); to 6.95 (2H, d, J = 8,3 Hz); 7.29 trend (2H, d, J = 8,3 Hz); to 7.61 (1H, d, J = 8,8 Hz); for 7.78 (1H, d, J = 8,3 Hz); to 7.84 (1H, s); of 7.95 (1H, d, J = 8,3 Hz); 8,07 (1H, d, J = 8,8 Hz); 8,39 (1H, s); 8,9 - 9,1 (2H, Shir. C); 9,23 (2H, Shir. C); 9,50 (2H, Shir. C).

Illustrative example 33. Ethyl(+)-2-[4-[((3S)-1-acetimidoyl-3-Pirro is ethyl (+)-3-(7-amidino-2-naphthyl)-2-[4-[((3S)-3-pyrrolidinyl)oxy] phenyl] propionate dihydrochloride. Stirring at room temperature, the resulting solution was mixed with 51,5 g ethylacetamide hydrochloride. Stirring and cooling with ice, to the above solution drop by drop) was added 89 ml of triethylamine, maintaining the internal temperature from 3 to 5oC, and was stirred for 2.5 hours, maintaining at a temperature of 5oC or below. After removal of the solvent under reduced pressure and low temperature, the resulting reaction solution was brought to pH 4-5 with diluted hydrochloric acid, then continued distillation under reduced pressure to remove solvent. The obtained residue was purified by column chromatography using a column Packed with a highly porous polymer (synthetic adsorbent; a polymer of a styrene-divinylbenzene Diaion HP-20) as eluent used a mixture of water and acetonitrile. After that, erwerbende fractions were collected, mixed with a small amount of diluted hydrochloric acid, and then concentrated to dryness. The result of this procedure received 110,1 g of target compound as a colorless solid.

1H-NMR (DMSO-d6) : of 1.02 (3H, m); of 2.10 to 2.35 (2H, m); 2.26 and (1,5 H, C); 2,30 (1,5 H, C); 3,19 (1H, m); 3,40 - of 3.85 (5H, m); 3,90 - 4,0); of 7.96 (1H, d, J = 8,3 Hz); 8,08 (1H, d, J = 8,3 Hz); 8,43 (1H, s); charged 8.52 (0.5 H, Shir. C); 8,61 (0.5 H, Shir. C); 9.28 are - 9,40 (3H, Shir. C); 9,50 - 9,60 (2H, Shir. C).

Subsequent connections illustrative examples 34 to 38 received in accordance with the procedure described in illustrative example 33.

Illustrative example 34. Ethyl(-)-2-[4-[((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy]phenyl]-3- (7-amidino-2-naphthyl)propionate dihydrochloride (solid).

1H-NMR (DMSO-d6) : of 1.02 (3H, m); of 2.10 to 2.35 (2H, m); 2.26 and (1,5 H, C); 2,30 (1,5 H, C); 3,19 (1H, m); 3,40 - of 3.85 (5H, m); 3,90 - of 4.05 (2H, m); 4,05 - to 4.15 (1H, m); 5,13 (0.5 H, Shir. C); 5,20 (0.5 H, Shir. s); 6.90 to - 6,97 (2H, m); to 7.32 (2H, m); to 7.61 (1H, d, J = 8,3 Hz); 7,80 (1H, DD, J = 8.3 and 1.5 Hz); to 7.84 (1H, s); of 7.96 (1H, d, J = 8,3 Hz); 8,08 (1H, d, J = 8,3 Hz); 8,42 (1H, s); charged 8.52 (0.5 H, Shir. C); 8,61 (0.5 H, Shir. C); 9.28 are - 9,40 (3H, Shir. C); 9,50 - 9,60 (2H, Shir. C).

Illustrative example 35. Ethyl(+)-2-[4-[((2S)-1-acetimidoyl-3-pyrrolidinyl)methoxy] phenyl] -3- (5-amidines[b]Tien-2-yl)propionate dihydrochloride (solid).

1H-NMR (DMSO-d6) : of 1.09 (3H, t, J = 7,3 Hz); 1,95 - 2,60 (4H, m); and 2.26 (1H, s); 2,47 (2H, s); 3,30 - 3,70 (4H, m); 3,90 - 4,10 (5H, m); 4,40 - 4,60 (1H, m); 6,85 - to 6.95 (2H, m); 7,28 - 7,33 (3H, m); to 7.67 (1H, d, J = 8,3 Hz); 8,11 (1H, d, J = 8,3 Hz); 8,23 (1H, s); 8,54 (2/3H, s); 8,69 (1/3H, s); 9,23 (2H, s); 9,35 - 9,50 (3H, m).

Illustrative example 36. Ethyl(-)-2-[4-[((2S)-1-acetimidoyl-3 - pyrrolidinyl)methoxy] phenyl] -3-(5-1,09 (3H, t, J = 7,3 Hz); 1,95 - 2,60 (4H, m); and 2.26 (1H, s); 2,47 (2H, s); 3,30 - 3,70 (4H, m); 3,90 - 4,10 (5H, m); 4,40 - 4,60 (1H, m); 6,85 - to 6.95 (2H, m); 7,28 - 7,33 (3H, m); to 7.67 (1H, d, J = 8,3 Hz); 8,10 (1H, d, J = 8,3 Hz); 8,23 (1H, s); 8,51 (2/3H, s); 8,66 (1/3H, s); 9,16 (2H, s); of 9.30 - 9,48 (3H, m).

Illustrative example 37 Ethyl(+)-2-[4-[(1-acetimidoyl-4 - piperidinyl)oxy]phenyl]-3-(7-amidino-2-naphthyl)propionate dihydrochloride (solid).

1H-NMR (DMSO-d6) : a 1.01 (3H, t, J = 6.9 Hz); of 1.65 and 1.80 (2H, m); 2,0 - 2,1 (2H, m); of 2.30 (3H, s); 3,1 - 3,2 (1H, m); a 3.2 to 3.8 (5H, m); 3,9 - 4,0 (2H, m); 4,0 - 4,1 (1H, Shir. C); of 4.67 (1H, Shir. with); to 6.95 (2H, d, J = 8,8 Hz); 7,30 (2H, d, J = 8,8 Hz); to 7.61 (1H, d, J = 8,3 Hz); 7,78 - to 7.84 (1H, m); to 7.84 (1H, s); of 7.95 (1H, d, J = 8,3 Hz); 8,08 (1H, d, J = 8,3 Hz); of 8.40 (1H, s); 8,80 - of 9.55 (6H).

Illustrative example 38. Ethyl(-)-2-[4-[(1-acetimidoyl-4-piperidinyl)-oxy] phenyl] -3- (7-amidino-2-naphthyl)propionate dihydrochloride (solid)

[]D= -67,69o(C = 0,585, H2O)

Illustrative example 39. (+)-2-[4-[((3S)-1-Acetimidoyl-3-pyrrolidinyl)-oxy]phenyl]-3- (7-amidino-2-naphthyl)propionic acid dihydrochloride.

While maintaining the internal temperature at -5oC or below, 110,1 g of ethyl(+)-2-[4-[((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy] phenyl]-3-(7-amidino-2-naphthyl)propionate dihydrochloride was dissolved in 3 300 ml of concentrated hydrochloric acid and the resulting solution was left still n the ri reduced pressure. The obtained residue was purified by column chromatography on a column filled with a synthetic adsorbent type of highly porous polymer (polymer of styrene-divinylbenzene Diaion HP-20), elwira with a mixture of water and acetonitrile. After that, erwerbende fractions were collected, mixed with a small amount of hydrochloric acid, and then concentrated to dryness. The result of this procedure, received 103,6 g of target compound as a pale yellow solid.

1H-NMR (DMSO-d6) : 2,10 - 2,4 (2H, m); 2,28 (1,5 H, C); 2,31 (1,5 H, C); 3,10 - 3,30 (1H, m); 3.40 in - 4,10 (6H, s); 5,14 (0.5 H, Shir. C); 5,20 (0.5 H, Shir. s); 6.90 to - 7,00 (2H, m); 7,35 - 7,40 (2H, m), 7,60 (1H, d, J = 8,3 Hz); 7,80 (1H, d, J = 8,3 Hz); to 7.84 (1H, s); 7,94 (1H, d, J = 8,3 Hz); of 8.06 (1H, d, J = 8,3 Hz); 8,42 (1H, s); 8,55 (0.5 H, Shir. C); 8,65 (0.5 H, Shir. C); of 9.30 - 9,70 (5H).

GHUR: Column: ligand-exchange type with D-penitsillamin as optically active center (SUMICHIPA OA-5000, 4,6 150 mm, Sumika Analysis Center

Solvent: 2 mm aqueous copper sulfate solution: acetonitrile = 85:15 (vol./about.)

Flow rate: 1 ml/min

Column temperature: 60oC

Holding time: 43,60 minutes

Subsequent connections illustrative examples 40 - 44 received in accordance with the procedure described in illustrative example 39.

Illustration the chloride (solid).

1H-NMR (DMSO-d6) : 2,05 - 2,4 (2H, m); 2,28 (1,5 H, C); 2,31 (1,5 H, C); 3,10 - 3,30 (1H, m); 3.40 in - 4,10 (6H, m); 5,13 (0.5 H, Shir. C); 5,20 (0.5 H, Shir. s); 6.90 to - 7,00 (2H, m); 3,5 - 7,40 (2H, m), 7,60 (1H, d, J = 8,3 Hz); 7,81 (1H, d, J = 8,3 Hz); to 7.84 (1H, s); 7,94 (1H, d, J = 8,3 Hz); of 8.06 (1H, d, J = 8,3 Hz); 8,42 (1H, s); 8,55 (0.5 H, Shir. C.); 8,64 (0.5 H, /Il. C.); of 9.30 - 9,70 (5H).

GHUR: Column: ligand-exchange type with D-penitsillamin as optically active center (SUMICHIPA OA-5000, 4,6 x 150 mm, Sumika Analysis Center)

Solvent: 2 mm aqueous copper sulfate solution: acetonitrile = 85:15 (vol./about.)

Flow rate: 1 ml/min

Column temperature: 60oC

Retention time: 38, 14 minutes.

Illustrative example 41. (+)-2-[4-[((2S)-1-Acetimidoyl-2 - pyrrolidinyl)methoxy] phenyl]-3-(5-amidines[b]Tien-2-yl)propionic acid dihydrochloride (solid).

1H-NMR (DMSO-d6) : 1,95 - 2,60 (4H, m); of 2.25 (1H, s); 2,44 (2H, s); 3,15 - of 3.80 (5H, m); 4,40 - 4,60 (1H, m); 6,83 - to 6.95 (2H, m); 7,26 (1H, s); to 7.32 (2H, d, J = 8,8 Hz); to 7.61 (1H, d, J = 8.5 Hz); 8,04 (1H, d, J = 8,50 Hz); 8,21 (1H, C); 8,40 - 10,90 (6H).

Illustrative example 42. (-)-2-[4-[((2S)-1-Acetimidoyl-2 - pyrrolidinyl)methoxy] phenyl]-3-(5-amidines[b]Tien-2-yl)propionic acid dihydrochloride (solid).

1H-NMR (DMSO-d6) : 1,95 - 2,60 (4H, m); of 2.25 (1H, s); 2,44 (2H, s); 3,15 - of 3.75 (4H, m), 3,82 (1H, t, J = 7.5 Hz); 4,40 - 4, the administrative example 43. (+)-2-[4-[(1-Acetimidoyl-4 - piperidinyl)oxy] phenyl]-3-(7-amidino-2-naphthyl)propionic acid dihydrochloride (solid).

1H-NMR (DMSO-d6) : of 1.65 and 1.80 (2H, m); 1,95 - of 2.05 (2H, m); 2,31 (3H, s); 3,1 - 3,2 (1H, m); 3,3 - 3,9 (5H, m); 3.95 to of 4.05 (1H, m); of 4.66 (1H, Shir. C.); to 6.95 (2H, d, J = 8,8 Hz); 7.29 trend (2H, d, J = 8,3 Hz); of 7.60 (1H, d, J = 8,8 Hz); 7,81 (1H, d, J = 8,8 Hz); to 7.84 (1H, s); of 7.95 (1H, d, J = 8,8 Hz); 8,07 (1H, d, J = 8,8 Hz); 8,43 (1H, s); 8,80 - 9,65 (6H).

Illustrative example 44. (-)-2-[4-[(1-Acetimidoyl-4 - piperidinyl)oxy] phenyl]-3-(7-amidino-2-naphthyl)propionic acid dihydrochloride (solid).

1H-NMR (DMSO-d6) : of 1.65 and 1.80 (2H, m); 2,00 is 2.10 (2H, m); of 2.30 (3H, s); 3,1 - 3,2 (1H, m); 3,3 - of 3.85 (5H, m); 3.95 to of 4.05 (1H, m); of 4.66 (1H, m); to 6.95 (2H, d, J = 8,8 Hz); 7,30 (2H, d, J = 8,8 Hz); to 7.61 (1H, d, J = 8,8 Hz); for 7.78 (1H, d, J = 8,8 Hz); a 7.85 (1H, s); of 7.95 (1H, d, J = 8,8 Hz); 8,08 (1H, d, J = 8,8 Hz); of 8.40 (1H, s); 8,60 - 9,65 (6H).

Illustrative example 45. (+)-2-[4-[((3S)-1-Acetimidoyl-3 - pyrrolidinyl)oxy] phenyl]-3-(7-amidino-2-naphthyl)propionic acid hydrochloride pentahydrate.

102,6 g(+)-2-[4-[((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy] phenyl] -3-(7-amidino-2-naphthyl)propionic acid dihydrochloride was dissolved in 1000 ml of water. Under stirring, the resulting solution was brought to pH values of 4.8, gradually adding highly basic ion-exchange resin (OH-type (Amberlite is obtained residue (94,6 g) was dissolved in 142 ml of water, and the solution was mixed with 1570 ml of ethanol, and stirred at room temperature for 1 hour. After removal of the crystals by filtration, the resulting stock solution was made of the seed crystals and stirred in 8oC for 40 hours. Then, precipitated crystals thus collected by vacuum filtration, washed with ethanol, and then dried by air for 6.5 hours at normal pressure and relative humidity from 60 to 70%. The result of this procedure, received 70,3 g of the target compound as colorless pritvorenih crystals.

[]2D4= +57,4 (C = 1000, H2O) (solubilization at 40oC, measured after 30 minutes of heating at this temperature)

1H-NMR (DMSO-d6) : of 2.20 to 2.35 (2H, m); 2,29 (1,5 H, C); 2,32 (1,5 H, C); 2,80 - 2,95 (1H, m); 3,30 - 4,00 (6H, m); 5,16 (0.5 H, Shir. C); 5,22 (0.5 H, Shir. s); 6.90 to - 7,00 (2H, m); 7,45 - 7,51 (2H, m); EUR 7.57 (1H, d, J = 8,3 Hz); 7,66 (1H, d, J = 8.0 Hz); to 7.93 (1H, d, J = 8,3 Hz); of 7.97 (1H, d, J = 8,3 Hz); 8,11 (1H, s); 8,68 (1H, Shir. C); 8,70 - of 9.30 (Shir. C.); 11,50 - 12,20 (Shir. C).

Elementary analysis for C26H28N4O3HCl 5H2O:

Calculated: C 54,68; H 6,88; N 9,80; Cl 6,21

Found: C 54,77; H 6,76; N 9,68; Cl 6.42 per

The results of x-ray crystallographic analysis confirmed the Teal)propionic acid.

Illustrative example 46. Methyl (+)-3-(6-amidino-2-indolyl)-2-[4-[((3S)-3-pyrrolidinyl)oxy]phenyl] propionate dihydrochloride.

Under ice cooling, hydrogen chloride was barbotirovany in a solvent mixture consisting of 10 ml dichloromethane and 20 ml of methanol. To saturated so the solution was added 10 ml of dichloromethane solution containing 450 mg of (+)-((2S)-1-p-toluensulfonyl-2-pyrrolidinyl)methyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy] phenyl]- 3-(6-cyano-2-indolyl)-propionate. Thus obtained mixture was left for another 72 hours in 5oC. After concentration to dryness under reduced pressure at a temperature of from 40oC or below, the resulting residue was dissolved in 20 ml of ethanol containing 14% (m /about. ) ammonia, and stirred at room temperature for 24 hours. After removal of the solvent, the thus obtained residue was subjected to reversed-phase GHUR using columns filled with octadecylsilane silica gel and elwira with a mixture of water and acetonitrile. After that erwerbende fractions were collected, mixed with diluted hydrochloric acid and then concentrated to dryness. The result of this procedure was obtained target compound (95 mg) as a solid.

Illustrative example 47. Methyl (-)-3-(6-amidino-2-indolyl)-2- [4-[((3S)-3-pyrrolidinyl)oxy]phenyl]propionate dihydrochloride.

This compound was obtained according to the procedure described in illustrative example 46 (a solid substance).

1H-NMR (DMSO-d6) : 2,30 (2H, m); 3,30 (1H, DD); 3,50 - 3,60 (5H, m), 3,70 (3H, s); 4,20 (1H, t); 5,20 (1H, m); 6,33 (1H, s); of 6.96 (2H, d); 7,33 (2H, d); 7,40 (1H, d); to 7.64 (1H, d); 7,80 (1H, s); of 9.30 - 9,80 (6H, m).

Illustrative example 48. (+)-3-(6-Amidino-2-indolyl)-2- [4-[((3S)-3-pyrrolidinyl)-oxy]phenyl]propionic acid dihydrochloride.

1.8 g of methyl (+)-3-(6-amidino-2-indolyl)-2-[4-[((3S)-3 - pyrrolidinyl)oxy] phenyl] propionate dihydrochloride was dissolved in 60 ml of concentrated hydrochloric acid, and the solution was stirred at 5oC for 7 days. After concentrating the reaction solution to dryness, under reduced pressure at a temperature of from 50oC or below, the resulting residue was subjected to reversed-phase GHUR using columns filled with octadecyl-bound silica gel, elwira with a mixture of water and acetonitrile. After that, erwerbende the desired fractions were combined, mixed with diluted hydrochloric acid, and then concentrated to dryness. In Rasul, 1730, 1680 cm-1< / BR>
Illustrative example 49. (-)-3-(6-Amidino-2-indolyl)-2-[4-[((3S)-3-pyrrolidinyl)oxy] phenyl]propionic acid dihydrochloride.

This compound was obtained according to the procedure described in illustrative example 48 (solid)

IR (KBr): 3600 - 3300, 1730, 1680 cm-1.

Illustrative example 50. 3-(5-Amidino-2-benzofuranyl)-2-[4-[((3S)-1-methyl-3-pyrrolidinyl)oxy]phenyl] propionic acid dihydrochloride.

1.0 g of Ethyl 3-(5-cyano-2-benzofuranyl)-2-[4-[((3S)-1-methyl-3-pyrrolidinyl)oxy]phenyl] propionate was dissolved in 70 ml of standard. Stirring and cooling with ice, the resulting solution was barbotirovany hydrogen chloride up to saturation level. Then a saturated solution was left for 20 hours at 25oC. After removal of the solvent, the residue was dissolved in 50 ml of ethanol containing 14 wt. -%/about. ammonia, and the resulting solution was left for 20 hours at 25oC. Then, the solvent was removed by distillation and obtained ethyl 3-(5-amidino-2-benzofuranyl)-2[4-[((3S)-1-methyl-3-pyrrolidinyl)oxy]phenyl] propionate-dihydrochloride. The obtained ester compound was dissolved in 50 ml of 2 N. hydrochloric acid, and heated under reflux for 30 minutes. After removal of the solvent is nnow synthetic adsorbent type of highly porous polymer (a polymer of styrene and divinylbenzene, Diaion HP-20), and elwira with a mixture of water and acetonitrile. The desired fractions were combined and subjected to reverse-phase GHUR using a column Packed with octadecylsilane silica gel, and elwira with a mixture of water and acetonitrile. After that erwerbende the desired fractions were combined, mixed with diluted hydrochloric acid and concentrated to dryness. In the described treatments received 200 mg of target compound in the form of a solid substance.

1H-NMR (DMCO-d6) : 2,40 is 3.40 (6H,m); 2,92 (3H, m); 5,10-of 5.40 (1H, Shir. s): PC 6.82 (1H, s); 7,01 (2H, d, J= 8,4 Hz); the 7.43 (2H, d, J = 8,4 Hz): of 7.82 (2H, s); 8,17 (1H, s); 9,34 (2H, width, C); 9,23 (2H, Shir. C).

Connection, presents illustrative examples 51-82, were obtained in accordance with the procedure described in illustrative example 50.

Illustrative example 51. 2-[4-[((3S)-1-Acetyl-3-pyrrolidinyl)oxy]phenyl]-3-(5-amidino-2-benzofuranyl) propionic acid dihydrochloride (solid)

1H-NMR (DMCO-d6) : 1,90-of 2.38 (5H, m); 3,00-are 3.90 (6H, m); 4,06 (1H, t, J = 7.2 Hz); 4,88 (1H, Shir. C) to 6.67 (1H, s); 6.87 in (2H, d, J = 8,3 Hz); 7.29 trend (2H, d, J = 8,3 Hz); of 7.70 (2H, s); 8,08 (1H, s); 9,20 (2H, width, C); 9,41 (2H, Shire, S.).

Illustrative example 52. 3-(5-Amidino-2-benzofuranyl)-2-[4-[((3S)-1-dimethylcarbamoyl-3-pyrrolidinyl) oxy]phenyl]propionic acid hydrochlo,10 (1H, W); of 6.68 (1H, s); 6.87 in (2H, d, J= 8,75 Hz); 7.29 trend (2H, d, J = 8,75 Hz); of 7.70 (2H, s); 8,07 (1H, s); 9,23 (2H, width, C); 9,39 (2H, Shire, S.).

Illustrative example 53. 3-(5-Amidino-2-benzofuranyl)-2-[4-[((2S)-2-pyrrolidinyl-methoxy] phenyl]propionic acid dihydrochloride (solid).

1H-NMR (DMSO-d6) : 1,95 (4H, width, C); of 6.71 (1H, s); 6,97 (2H, d); 7,27 (2H, d); 7,71 (2H, s); of 8.06 (1H, s); 9,15-9,35 (5H); and 9.7 (1H).

Illustrative example 54. 3-(5-Amidino-2-benzofuranyl)-2-[4-[(tetrahydro-3-furanyl)-oxy]phenyl] propionic acid hydrochloride (solid).

1H-NMR (DMSO-d6) : 1,6-2,4 (2H, m); 3,0-3,9 (6H, m); 4,0 (1H, DD); and 4.8 to 5.1 (1H, m); of 6.75 (1H, s); 6,9 (2H, d); to 7.32 (2H); to 7.77 (2H, s); 8,1 (1H, s); 9,37 (4H, d).

Illustrative example 55. 3-(5-Amidino-3-methyl-2-benzofuranyl)-2-[4-[((3S)-3-pyrrolidinyl)oxy]phenyl] propionic acid dihydrochloride (solid)

1H-NMR (DMSO-d6) : to 2.06(5H, m); of 5.05 (1H, width); 6,94 (2H, d); 7,22 (2H, d); of 7.70 (2H, s); 8,08 (1H, s); 9,10-9,50 (5H, m).

Illustrative example 56. 3-(5-Amidino-7-methoxy-2-benzofuranyl)-2-[4-[((3S)-3-pyrrolidinyl)oxy]phenyl] propionic acid dihydrochloride (solid).

1H-NMR (DMSO-d6) : 1,90-to 2.40 (2H, m); 2,90-of 3.80 (6H, m); a 4.03 (3H, s); 5,00-5,20 (1H, width); of 6.65 (1H, s); 6,91 (2H, d, J = 8,3 Hz); 7,31 (2H, d, J = 8,3 Hz); to 7.32 (1H, s); to 7.68 (1H, s); 9,16 (2H, W); 9,40 (2H, width); 9, propionic acid dihydrochloride (solid).

1H-NMR (DMSO-d6) : 2,1 (2H, W); 3,00-4,00 (7H, m)W 5,08 (1H, width); make 6.90 (2H, d, J = 8 Hz); 7,30 (2H, d, J = 8 Hz); to 7.77 (3H); by 8.22 (1H, s); 9,0-10,00 (6H).

Illustrative example 58. 5-Amidino-2-[2-[4-[((3S)-3-pyrrolidinyl)oxy] phenyl] ethyl] -3 - benzofuranol acid dihydrochloride (solid).

1H-NMR (DMSO-d6) : 2,07 (2H, m); 3,00-3,50 (8H), of 5.05 (1H, width); 6,85 (2H, sh, J = 8.0 Hz); to 7.15 (1H, d, J = 8.0 Hz); of 7.82 (2H, s); 8,35 (1H, s); of 9.30 (1H, s); 9,50 (2H, W).

Illustrative example 59. 3-[2-[2-(5-Amidines[b] Tien-2-yl ethyl]-4-ethoxy-5-[((3S)-3-pyrrolidinyl)oxy] phenyl]propionic acid dihydrochloride (solid).

1H-NMR (DMSO-d6) : of 1.30 (3H, t, J = 7.0 Hz); 2.00 in 3,90 (14H, m); 4,01 (2H, square , J = 7,0 Hz); 6,94 (1H, s); of 6.96 (1H, s); 7,39 (1H, s); 7,79 (1H, d, J = 9.0 Hz); to 8.20 (1H, d, J = 9.0 Hz); of 8.37 (1H, s); 9,41 (2H, W); 9,59 (2H, W); 9,0 - 10,0 (2H, W).

Illustrative example 60. 3-[2-[2-(5-Amidines[b]Tien-2-yl)ethyl]-5-[((3S)-3-pyrrolidinyl)oxy]phenyl] propionic acid dihydrochloride (solid),

1H-NMR (DMSO-d6) : 2,00 - 4,80 (14H, m); 5,08 (1H, m); 6,77 (1H, d, J = 8.5 Hz); PC 6.82 (1H, s); to 7.18 (1H, d, J = 8.5 Hz); to 7.35 (1H, s); 7,72 (1H, d, J = 8.7 Hz); 8,16 (1H, d, J = 8.7 Hz); 8,23 (1H, s); 9,31 (2H, W); 9,51 (2H, W); of 9.3 and 9.8 (2H, W).

Illustrative example 61. 4-(5-Amidines[b]Tien-2-yl)-3-[4-[((3S)-3-pyrrolidinyl)-oxy] phenyl] butyric key is then 7.20 (1H, with); to 7.25 (2H, d); the 7.65 (1H, DD); 8,05 is 8.25 (2H, m);

Illustrative example 62. 3-(5-Amidines[b]Tien-2-yl)2-[4-[(2-ethoxycarbonylethyl)- hexahydropirimidine series-5-yl] oxy] phenyl]propionic acid dihydrochloride (solid).

1H-NMR (DMSO-d6) : of 1.27 (3H, t, J=7.0 Hz); 3,00-4,04 (width); 4,24 (2H, square , J = 7,0 Hz); 4,90-5,10 (1H, width); 6,99 (2H, d, J = 8,3 Hz); 7,34 (2H, d, J = 8,3 Hz); 7,39 (1H, s); to 7.68 (1H, DD, J= 9.0 and 1.8 Hz); 8,10 (1H, d, J = 9.0 Hz); 8,24 (1H, d, J= 1.8 Hz); 8,98 (2H, W); 9,23 (2H, W); 9,44 (2H, W); 11,65 (1H, s).

Illustrative example 63. 3-(5-Amidines[b] Tien-2-yl)-2-[4-[(2-(imino-)hexahydropirimidine series-5-yl] oxo] phenyl] propionic acid dihydrochloride (solid).

1H-NMR (DMSO-d6) : 3,20 - 4,20 (3H, m); 3,44 (2H); 4.80 to 5,00 (1H, Shir. ); 6,98 (2H, d, J = 8,31 Hz); 7,17 (2H, s); 7,29 (1H, s); 7,34 (2H, d, J= 8,31 Hz); of 7.70 (1H, DD, J = 8,2 and 2.0 Hz); of 8.06 (2H, s); to 8.12 (1H, d, J = 8,2 Hz); of 8.25 (1H, s); 9,46 (2H, W); to 9.57 (2H, W).

Illustrative example 64. 3-(5-Amidines[b]Tien-2-yl)-2- [4-[((2S)-2-pyrrolidinyloxy] phenyl] propionic acid dihydrochloride (solid).

1H-NMR (DMSO-d6) : 1,95 (4H, m); 3,00 - 4,20 (8H, m); to 6.95 (2H, d, J= 8.0 Hz); 7,28 (3H); of 7.70 (1H, d, J=8.0 Hz); of 8.06 (1H, d, J=8.0 Hz); 8,23 (1H, s); 9,20 - 9,50 (6H).

Illustrative example 65. 3-(5-Amidines[b]Tien-2-yl)-2-[4- [(4-piperidinyl)oxy]phenyl]propionic acid-D4,70 (1H, m), 6,97 (2H, d, J=8,3 Hz); 7,31 (3H, m); of 7.69 (1H, DD); 8,13 (1H, d, J=8,8 Hz); compared to 8.26 (1H, s); 9,31 (2H, W); 9,50 (2H, W); 9,00 - 10,00 (2H, W).

Illustrative example 66. 3-(5-Amidines[b]Tien-2-yl)-2- [4-[(2-aminoethyl)-oxy]phenyl]propionic acid dihydrochloride (solid).

1H-NMR (DMSO-d6) : 3,00 - 4,40 (7H, m); 6,93 (2H, d, J=8,3 Hz); 7.29 trend (1H, s); to 7.32 (2H, d, J=8,3 Hz); to 7.67 (1H, DD, J=9.0 and 1.0 Hz); to 8.20 (1H, d, J= 9.0 Hz); 8,32 (1H, s); 8,10 at 8.60 (3H, width); 9,24 (2H, W); 9,46 (2H, W).

Illustrative example 67. 3-(5-Amidines[b]Tien-2-yl) -2-[4-(2-(1-pyrrolin-2-yl)-aminoethoxy] phenyl]propionic acid dihydrochloride (solid).

1H-NMR (DMSO-d6) : 1,88 - of 2.30 (2H, m); 2,60 - of 3.00 (2H, m); 3,00 - 4,30 (9H, m); make 6.90 (2H, d, J=8,3 Hz); 7,30 (1H, s); 7,31 (2H, d, J=8,3 Hz); of 7.70 (1H, DD, J=8,50 and 1.00 Hz); 8,11 (1H, d, J=8,50 Hz); of 8.25 (1H, s); 9.28 are (2H, Shir.); 9,48 (2H, W); 10,00 (1H, width); 10,19 (1H, Shir.).

Illustrative example 68. 3-(5-Amidino-2-indolyl)-2-[4-[((3S) -3-pyrrolidinyl)oxy]phenyl]propionic acid dihydrochloride (solid).

1H-NMR (DMSO-d6) : from 2.00 to 2.35 (2H, m); 4,00 - 4,30 (1H, m); 5,00 - and 5.30 (1H, Shir. ); 6,37 (1H, s); 7,00 (2H, d); 7,40 (2H, d); of 7.60 (2H, d); 8,10 (1H, s); 11,60 (1H, s).

Illustrative example 69. 3-(6-Amidino-2-indolyl)-2-[4-[((3S) -3-pyrrolidinyl)oxy]phenyl]propionic acid dihydrochloride (solid).

, the).

Illustrative example 70. 3-(5-Amidino-2-indolyl)-2-[4-[((3R) tetrahydro-3-furanyl]oxy]phenyl]propionic acid hydrochloride (solid).

1H-NMR (DMSO-d6) : 5,00 (1H, width); 6,28 (1H, s); PC 6.82 (2H, d); 7,30 (2H, d); 7,58 (2H, d); 8,00 (1H, s); 9,10 (4H); and 11.8 (1H, s).

Illustrative example 71. 3-(5-Amidino-2-indolyl)-2-[4- [((3S)-tetrahydro-3-furanyl] -oxy] phenyl] propionic acid hydrochloride (solid).

1H-NMR (DMSO-d6) : 5,10 (1H, width); 6,27 (2H, s); PC 6.82 (2H, d); 7,29 (2H, d); 7,58 (2H, s); 8,00 (1H, s); 9,12 (4H); and 11.8 (1H, s).

Illustrative example 72. 3-(5-Amidino-1-methyl-2-indolyl)-2-[4- [((3S)-3-pyrrolidinyl)-oxy]phenyl]propionic acid dihydrochloride (solid).

1H-NMR (DMSO-d6) : 1,90 - of 2.25 (2H, m); to 3.73 (3H, s); 5,00 - 5,20 (1H, width); 6,40 (1H, d); 6,95 (2H, s); 7,40 (2H, d); a 7.62 (2H, s); 8,10 (1H, s); 9,00 - 9,80 (6H, W).

Illustrative example 73. 3-(6-Amidino-1-ethyl-2-indolyl)-2-[4- [((3S)-3-pyrrolidinyl)-oxy] phenyl] propionic acid dihydrochloride (solid).

1H-NMR (DMSO-d6) : of 1.30 (3H, t); 1,95 - of 2.30 (2H, m); 5,10 (1H, m); 6,37 (1H, s); 6,92 (2H, d); 7,30 - of 7.70 (4H, m), 8,10 (1H, s); of 9.30 - 9,90 (6H, W).

Illustrative example 74. 3-(6-Amino-1-ethyl-2-indolyl)-2-[4- [((3S)-3-pyrrolidinyl)-oxy] phenyl] propionic acid, dihydrochloride is Hz); 7,30 - of 7.70 (4H, m), 8,17 (1H, s); 9,07 (2H, W); 9,34 (2H, W); of 9.30 - 10,00 (2H, W).

Illustrative example 75. 3-[6-Amidino-1-(2-chloroethyl)-2 - indolyl]-2-[4-[((3S)-3-pyrrolidinyl)oxy] phenyl] propionic acid dihydrochloride (solid).

1H-NMR (DMSO-d6) : 2,00 - 5,00 (13H); 5,13 (1H, width); 6.42 per (1H, s); 6,97 (2H, d, J=8,4 Hz); 7,50 - of 7.70 (2H, m); by 8.22 (1H, s); 9,13 (2H, W); 9,39 (2H, W); 9,50 - 10,00 (2H, W).

Illustrative example 76. 3-[6-Amidino-1,2,3,4-tetrahydro-2 - naphthyl]-2-[4-[((3S)-3-pyrrolidinyl)oxy] phenyl] propionic acid dihydrochloride (solid).

1H-NMR (DMSO-d6) : 1,30 - 4,00 (16H, m); 5,10 (1H, m); 6,94 (2H, d, J= 9.0 Hz); 7,20 - of 7.70 (5H, m); 9,18 (2H, W); 9,34 (2H, W); 9,50 - 10,00 (2H, W).

Illustrative example 77. 3-[5-Amidino-2-benzimidazolyl-2- [4-[((3S)-3-pyrrolidinyl)oxy] phenyl] propionic acid dihydrochloride (solid).

1H-NMR (DMSO-d6) : 1,98 - of 2.28 (2H, W); 3,00 - 4,80 (7H, m); 5,00 - 5,20 (1H, width); 6,93 (2H, d, J=9.0 Hz); 7,34 (2H, d, J=9.0 Hz); to $ 7.91 (2H, s); of 8.28 (1H, s); 9,36 (2H, W); being 9.61 (2H, W); 9,40 - 10,10 (2H, W).

Illustrative example 78. 3-(7-Amidino-2-naphthyl)-2-[4-[(3R)-3 - pyrrolidinyl)oxy]phenyl]- propionic acid dihydrochloride (solid).

1H-NMR (DMSO-d6) : 2,00 - of 2.20 (2H, m); 3,00 - 4,20 (7H, m); 5,10 (1H, Shir. ); 6,92 (2H, d, J=9.0 Hz); 7,33 (is midino-2-naphthyl)-2-[4-[(4- piperidinyl)oxy]phenyl]propionic acid dihydrochloride (solid).

1H-NMR (DMSO-d6) : 1,70 - of 2.20 (4H, m); 2,80 - 4,10 (7H, m); 4,50 - 4,80 (1H, m); to 6.95 (2H, d, J=8.0 Hz); 7,30 (2H, d, J=8.0 Hz); 7,60 - 8,50 (6H, m); a 9.35 (2H, W); to 9.57 (2H, W); 9,10 - 9,80 (2H, W).

Illustrative example 80. 3-(6-Amidino-1-carboxymethyl-2-indolyl)-2-[4-[((3S)-3-pyrrolidinyl)oxy] phenyl] propionic acid dihydrochloride (solid).

1H-NMR (DMSO-d6) : 1,93 - of 2.30 (2H, m); 2,80 - of 3.80 (6H, m); 3,90 - of 4.25 (1H, t); 5,00 - 5,50 (3H, Shir. C); 6,41 (1H, s); 7,00 (2H, d); 7,42 (2H, d); 7,60 - of 7.90 (2H, m); 8,30 (1H, s); 9,10 - 10,00 (6H, W).

Illustrative example 81. 6-Amidino-2-[3-hydroxy-2- [4-[((3S)-3-pyrrolidinyl)oxy] phenyl]propyl]-1-endolysosomal acid dihydrochloride (solid).

1H-NMR (DMSO-d6) : 1,95 - of 2.20 (2H, m); 4,90 - of 5.15 (3H, m); of 6.20 (1H, s); make 6.90 (2H, d); of 7.25 (2H, d); EUR 7.57 (2H, m); to 8.20 (1H, s); 9,20 - 9,90 (6H, W)

Illustrative example 82. 6-Amidino-2-[2-[4-[((3S)-3-pyrrolidinyl) oxy] phenyl]ethyl]-1-indoloquinone acid dihydrochloride (solid).

1H-NMR (DMSO-d6) : 1,90-of 2.30 (2H, m); 3,10 - to 3.50 (4H, m); 4.80 to and 5.30 (3H, Shir. ); 6.42 per (1H, s); make 6.90 (2H, d); of 7.25 (2H, d); of 7.60 (3H, m); of 8.25 (1H, s); 9,20-10,00 (6H, W).

Illustrative example 83. Ethyl 3-(5-amidines[b]Tien-2-yl)-2-etoxycarbonyl-2-[4-[((2R)-2-pyrrolidinyl) methoxy] phenyl] propionate dihydrochloride.

4,34 g of ethyl 2-[4-[((2R)-1-tert-butoxyethanol. Hydrogen chloride was barbotirovany in the resulting solution under ice cooling and stirring to a saturated level. A saturated solution was left at room temperature for 18 hours. After removal of the solvent under reduced pressure, the residue was dissolved in 100 ml of an ethanol solution containing 13% (m/Rev) ammonia, and the resulting solution was left still for 24 hours. After removal of the solvent, the obtained residue was chromatographically on a column with a synthetic adsorbent type of highly porous polymer (a polymer of styrene and divinylbenzene: Diaion HP-20) and elwira with a mixture of water and acetonitrile. The combined desired fractions were subjected to reversed-phase GHUR on the column with octadecyl-bound silica gel, elwira with a mixture of water and acetonitrile. After that erwerbende the desired fractions were combined, mixed with diluted hydrochloric acid and then concentrated to dryness. In the described procedure was obtained 1.0 g of the target compound as a pale yellow solid.

1H-NMR (DMSO-d6) : to 1.15 (6H, t, J = 7.0 Hz); 2,0 (4H, width); 3,00-4,00 (3H); 3.95 to (2H); 4,2 (4H); 7,00 (2H, d); 7,16 (1H); 7,31 (2H, d); of 7.70 (2H, DD); 8,10 (1H, d); compared to 8.26 (1H, d); 9,20-9,60 (5H); 9,9 (1H).

Illustrative example 84. 3-5 Amidines [b]Tien-2-yl-2-[4-[(2-imidazolin-2-yl)method is 4-[(2-imidazolin-2-yl)- methoxy] phenyl] propionate was dissolved in 100 ml of ethanol. Cooling with ice and stirring, hydrogen chloride was barbotirovany in the resulting solution up to the saturation level. A saturated solution was left for 18 hours at 5oC. After removal of the solvent under reduced pressure, the obtained residue was dissolved in 100 ml of an ethanol solution containing 13% (m/Rev) ammonia, and the solution was set aside at room temperature for another 24 hours. After that, the solvent drove to obtain ethyl 3-(5-aminobenzo [b]Tien-2-yl)-2-etoxycarbonyl-2-[4-[(2-imidazolin-2-yl)methoxy]phenyl] propionate dihydrochloride. The obtained ester compound was dissolved in 50 ml of 5 N. hydrochloric acid, and the solution was heated under reflux for 1 hour. After removal of the solvent, the residue was chromatographically on a column with a synthetic adsorbent type of highly porous polymer (a polymer of styrene and divinylbenzene: Diaion HP-20) and elwira with a mixture of water and acetonitrile. The combined desired fractions were subjected to reverse-phase GHUR on the column with octadecyl-bound silica gel, elwira with a mixture of water and acetonitrile. After that erwerbende the desired fractions were combined, mixed with diluted hydrochloric acid and then concentrated to dryness. In the described treatments received 200 mg of the target connection); to 3.99 (1H, t); 5,07 (2H, s); 6,98 (2H, d); to 7.32 (1H, s); 7,37 (2H, d); 7,66 (1H, d); to 8.12 (1H, d); 8,21 (1H, s); 9,10 (2H); 9,39 (2H); 10,38 (2H).

Subsequent connections illustrative examples 85 and 86 received in accordance with the procedure described in illustrative example 82.

Illustrative example 85. 3-(5-Amidines[b]Tien-2-yl)-2-[4-[((3S) -3-pyrrolidinyl)-thio] phenyl]propionic acid dihydrochloride (solid).

1H-NMR (DMSO-d6) : 1,5-4,5 (10H, m); to 6.95 (2H, d); to 7.32 (1H, s); 7,40 (2H, d); 7,71 (1H, d); 8,13 (1H, d); of 8.28 (1H, s); 9,3 (2H, W); 9,5 (2H, W); 9,8 (2H, W).

Illustrative example 86. 3-(5-Amidino-2-benzothiazolyl)-2-[4-[((3S)-3-pyrrolidinyl)-oxy] -phenyl] propionic acid dihydrochloride (solid).

1H-NMR (DMSO-d6) : of 2.08 (2H, W); 3,00-4,25 (7H); 5,10 (1H, width); to 6.95 (2H, d); 7,34 (2H, d); of 7.82 (1H, DD); 8,29 (1H, d); to 8.41 (1H, d); 9,20 - 9,60 (6H).

FAB MC (m/Z): 411 (M++1).

Illustrative example 87. 2-[4-((3S)-1-Acetimidoyl-3-pyrrolidinyl)oxy] phenyl]-3- (5-amidino-2-benzofuranyl)propionic acid dihydrochloride.

1.1 g (3-(5-amidino-2-benzofuranyl)-2-[4-[((3)-3-pyrrolidinyl)oxy]phenyl] propionic acid dihydrochloride was dissolved in 20 ml of water. Stirring and cooling with ice, 1.4 g of ethylacetamide hydrochloride was gradually added to the resulting plants the mixture was stirred 15 minutes, cooling with ice, and then brought the pH to 2.0 with diluted hydrochloric acid. After concentration to dryness the resulting reaction solution, the residue was subjected to reversed-phase GHUR on column octadecylsilane silica gel, elwira with a mixture of water and acetonitrile. After that, erwerbende the desired fractions were combined, mixed with diluted hydrochloric acid and then concentrated to dryness. In the described procedure received 780 mg of the target compound in the form of a solid substance.

1H-NMR (DMSO-d6) : 1,90-to 2.40 (5H, m); 2,90-4,30 (7H, W); 4,96 (1H, Shir. ); of 6.73 (1H, s); 6,93 (2H, d, J = 8,8 Hz); 7,33 (2H, d, J = 8,8 Hz); 7,73 (2H, s); 8,10 (1H, s); 8,50-8,80 (1H, width); was 9.33 (2H, W); 9,46 (3H, W).

Subsequent connections illustrative examples 88-91 were obtained in accordance with the procedure described in illustrative example 87.

Illustrative example 88. 2-[4-[((3S)-1-Acetimidoyl-3-pyrrolidinyl)oxy] phenyl]-3-5-aminobenzo[b]Tien-2-yl)propionic acid dihydrochloride (solid)

1H-NMR (DMSO-d6) : 2,00-2,50 (5H, m); 3,10-4,20 (7H, m); 4,96 (1H, Shir. ); 6,93 (2H, d, J = 7.9 Hz); 7.29 trend (1H, s); 7,34 (2H, d, J = 7.9 Hz); 7,73 (1H, d, J = 8,3 Hz); 8,10 (1H, d, J = 8,3 Hz); 8,30 (1H, s); 8,50-of 9.30 (1H, width); 9,37 (2H, W); 9,54 (2H, W).

Illustrative example 89. 2-[4[((3S)-1-Acetamido).

1H-NMR (DMSO-d6) : 2,00 (2H, W); of 2.26 (1,5 H); 2,30 (1,5 H); 3,00-4,25 (7H); to 5.17 (1H, width); of 6.99 (2H, d); 7,31 (2H, d); 7,88 (1H, d); of 8.25 (1H, d); 8,44 (1H, d); and 8.50 (1H); was 9.33 (2H, W); of 9.55 (2H, W).

Illustrative example 90. 2-[4-[((3S)-1-Acetimidoyl-3-pyrrolidinyl)oxy] phenyl] -3-(6-amidino-1-ethyl-2-indolyl)propionic acid dihydrochloride (solid).

1H-NMR (DMSO-d6) : of 1.31 (3H, t, J = 7.0 Hz); 2,15-to 2.40 (2H, m); 2,28 (1,5 H); 2,31 (1,5 H); 3.15 in (1H, DD); 3,40-of 4.05 (5H); 4,10 (1H, t); to 4.28 (2H, m); 5,16 (0.5 H, W); 5,22 (0.5 H, W); 6,40 (1H, s); 6,97 (2H, DD); 7,40 (2H); of 7.48 (1H, d, J = 8,3 Hz); a 7.62 (1H, d, J = 8,3 Hz); 8,13 (1H, s); 8,50 (0.5 H, s); 8,59 (0.5 H, s); 8,98 (2H, s); to 9.32 (2H, s); 9,25-a 9.35 (1H).

Illustrative example 91. 2-[4-[((3S)-1-Acetimidoyl-3-pyrrolidinyl)oxy] phenyl] -3-(7-amidino - 2-naphthyl)propionic acid dihydrochloride (solid).

1H-NMR (DMSO-d6) : 2,00-to 2.40 (5H, m); 2,90 - 4,10 (7H, m); further 5.15 (1H, Shir. ); 6,93 (2H, d, J = 8.0 Hz); 7,33 (2H, d, J = 8.0 Hz); 7,50 - 8,40 (6H, m); 8,50 - to 8.70 (1H); of 9.30 (3H, width); of 9.55 (2H, W).

Illustrative example 92. 2-[4-[(2R)-1-Acetimidoyl-2-pyrrolidinyl)methoxy] phenyl] -3-(5-amidines [b]Tien-2-yl)propionic acid hydrochloride.

1.0 g of ethyl 3-(5-amidines[b]Tien-2-yl)-2-etoxycarbonyl-2-[4-[(2R)-2-pyrrolidinyl) methoxy] phenyl]propionate dihydrochloride was dissolved in 20 ml of ethanol followed by the addition of 0.42 g e the amine, and the resulting mixture was heated to room temperature and stirred for 18 hours. After removal of the solvent was obtained ethyl 2-[4-[((2R)-1-acetimidoyl-2-pyrrolidin) methoxy] phenyl]-2-etoxycarbonyl-3-(5-amidino-benzo[b]Tien-2-yl) propionate dihydrochloride. Thus obtained ester compound was dissolved in 50 ml of 5 N. hydrochloric acid, and then heated under reflux for 60 minutes. After removal of the solvent, the residue was chromatographically on a column Packed with a highly porous polymer as a synthetic adsorbent (polymer of styrene and divinylbenzene: Diaion HP-20), elwira with a mixture of water and acetonitrile. The desired fractions were combined and concentrated, and the obtained residue was subjected to reversed-phase liquid chromatography high resolution (IHVR) on a column filled with octadecyl-bound silica gel, using as eluent a mixture of water and acetonitrile. Then, you need erwerbende fractions were combined, mixed with diluted hydrochloric acid and concentrated to dryness. In the described procedure received 360 mg of the target compound as a pale yellow solid.

1H-NMR (DMSO-d6) : 2,00 (4H, width); 2,24 is 2.43 (3H); 3,00 - 4,00 (5H); 4,00 (2H); 4,50 (1H, width); 6,2-Il)-2-[4-[((3S)-1-benzamido-3 - pyrrolidinyl)oxy]phenyl]propionic acid dihydrochloride.

1.0 g of ethyl 3-(5-amidines[b] Tien-2-yl)-2-[4-[((3S)- 3-pyrrolidinyl)oxy]phenyl]propionate dihydrochloride was dissolved in 15 ml of ethanol. To this solution was added 773 mg of ethyl benzimidazolone, which was obtained through the reaction of benzonitrile with ethanol in the presence of florodora. To the resulting solution, stirring under ice cooling, was added 631 mg of triethylamine, and the mixture was heated to room temperature, and then stirred for 18 hours. After removal of the solvent, was obtained ethyl 3-(5-amidines [b] Tien-2-yl)-2-[4-[((3S)-1-benzamido-3-pyrrolidinyl)oxy] phenyl] - propionate hydrochloride. Thus obtained ester compound was dissolved in 60 ml of 3n. hydrochloric acid and heated under reflux for 30 minutes. After removal of the solvent, the residue was subjected to column chromatography on a column filled with a synthetic adsorbent in the form of highly porous polymer (a polymer of styrene and divinylbenzene: Diaion HP-20), elwira with a mixture of water and acetonitrile. The desired fractions were combined and concentrated, and the obtained residue was subjected to reversed-phase GHUR, using a column filled with octadecyl-bound silica gel, and elwira with a mixture of water and acetonitrile. Need erwerbende Fi treatments received 350 mg of the target compound as a pale yellow solid.

1H-NMR (DMSO-d6) : 2,00 is 2.80 (2H, m); 3,00 - 3,30 (7H, m); 4,04 (0.5 H, W); 4,30 (0.5 H, W); 6,80 - of 7.90 (11H, m); to 8.12 (1H, d, J = 8,3 Hz); 8,30 (1H, s); 9,20 - 9,70 (6H, m).

Connection, presents illustrative examples 94 - 100 were obtained in accordance with the procedure described in illustrative example 93.

Illustrative example 94. 3-(5-Amidines [b]Tien-2-yl)-2-[4-[((3S)-1-n-hexane-imidoyl-3-pyrrolidinyl)oxy] phenyl] propionic acid dihydrochloride (solid).

1H-NMR (DMSO-d6) : to 0.80 - 0.95 (3H, m); 1,20 - 1,40 (4H, m); 1,45 is 1.70 (2H, m); 2,15 - to 2.40 (2H, m); 2,45 - 2,60 (2H, m); 3.25 to 3,90 (6H, m); of 3.96 (1H, t, J = 7.5 Hz); 6,85 - 7,00 (2H, m); 7,25 - 7,40 (3H, m); of 7.69 (1H, DD, J = 8.3 and 1.5 Hz); 8,11 (1H, d, J = 8,3 Hz); of 8.25 (1H, s); 8,58 (0.5 H, s); 8,66 (0.5 H, s); 9,20 - of 9.30 (3H, width); for 9.47 (2H, W).

Illustrative example 95. 3-(5-Amidines [b] Tien-2-yl)-2- [4-[((3S)-1-cyclo-propanecarboxylate-3-pyrrolidinyl)oxy] phenyl] propionic acid dihydrochloride (solid).

1H-NMR (DMSO-d6) : 0,90 - 1,30 (3H, m); 1,80 - 4,10 (10H, m); 5,10 - and 5.30 (1H, m); of 6.96 (2H, d, J = 8,4 Hz); to 7.32 (1H, s); of 7.36 (2H, d, J = 8,4 Hz); 7,71 (1H, d, J = 7,4 Hz); to 8.14 (1H, d, J = 7,4 Hz); 8,29 (1H, s); 8,40 - to 8.70 (2H, m); 9,36 (2H, W); 9,52 (2H, W).

Illustrative example 96. 2-[4-[((2S)-1-Acetimidoyl-2-pyrrolidinyl)methoxy] phenyl] -3- (5-amidines[b]Tien-2-yl) propionic kislotno); 7,30 (3H); of 7.70 (1H, d); 8,10 (1H, d); of 8.25 (1H, s); at 8.60 (1H, s); 9,20 - 9,60 (5H, m).

Illustrative example 97. 2-[4-[(1-Acetimidoyl-4-piperidinyl)oxy]phenyl] -3-5-amidines[b] Tien-2-yl propionic acid dihydrochloride.

1H-NMR (DMSO-d6) : 1,65 - 2,10 (4H, m); 2,32 (3H, s); 3,20 - of 4.00 (7H, m); 4,60 - 4,70 (1H, m); of 6.96 (2H, d, J = 8,3 Hz); 7,30 (3H, m); of 7.69 (1H, d, J = 8,3 Hz); 8,10 (1H, d, J = 8,3 Hz); compared to 8.26 (1H, s); of 8.95 (1H, s); to 9.32 (2H, Shir.); 9,52 (2H, W).

Illustrative example 98. 2-[4-[(1-Acetimidoyl-4-piperidinyl)oxy]phenyl] -3-(6-amidino-1-ethyl-2-indoyl)propionic acid dihydrochloride.

1H-NMR (DMSO-d6) : of 1.30 (3H, t, J = 7.0 Hz); 1,73 is 2.10 (4H, m); 2,31 (3H, s); 3,10 (1H, m); 3,30 - 3,30 (5H); of 4.05 (1H, t), 4,30 (2H, m), 4,70 (1H, Shir. ); 6,38 (1H, c); 6,97 (2H, d, J = 8.5 Hz); 7,37 (2H, d, J = 8.5 Hz); of 7.48 (1H, d, J = 8,3 Hz); to 7.61 (1H, d, J = 8,3 Hz); to 8.14 (1H, s); 8,86 (1H, width); 9,15 - 9,50 (5H, m).

Illustrative example 99. 3-(7-Amidino-2-naphthyl)-2-[4-[((3S)-1 - butanamide-3-pyrrolidinyl)oxy] phenyl] propionic acid dihydrochloride (solid).

1H-NMR (DMSO-d6) : 0,60 - 4,00 (16H); 5,00 (1H, width); 6,79 (2H, d, J = 8.0 Hz); 7,21 (2H, d, J = 8.0 Hz); 7,30 - 8,10 (5H, m); a 8.34 (1H, s); 8,30 (1H, s); 8,40 - to 8.70 (1H); 9,00 - 10,00 (5H).

Illustrative example 100. 3-(7-Amidino-2-naphthyl)-2-[4-[((3S)-1 - benzamido-3-pyrrolidinyl)oxy] phenyl] propionic acid dihydrochloride (solid).

Illustrative example 101. 3-(5-Amidines[b] Tien-2-yl)- 2-[4-[((3S)-1-(N-methylacetamide)-3-pyrrolidinyl]oxy]phenyl] propionic acid dihydrochloride

2.0 g of 3-(5-amidines[b] Tien-2-yl)-2-4-[((3S)-3 - pyrrolidinyl)oxy] phenyl] propionic acid dihydrochloride was dissolved in a mixture consisting of 10 ml of water and 10 ml of acetonitrile. To the resulting solution, stirring was gradually added to 20 g of ethyl (N-methyl)acetimidate hydrochloride obtained in accordance with the procedure described in The Journal of Organic Chemistry vol. 33, pp. 1679 - 1681, 1968), while maintaining the pH of the solution at 8,5 using 2 N. aqueous sodium hydroxide solution. After removal of the solvent, the residue was washed with dichloromethane and subjected to chromatography on a column filled with a synthetic adsorbent in the form of highly porous polymer (a polymer of styrene and divinylbenzene: Diaion HP-20), using as eluent a mixture of water and acetonitrile, thereby making desalination. The desired fractions were combined and subjected to reverse-phase GHUR, using a column filled with octadecyl-bound silica gel. Then erwerbende the desired fractions were combined and concentrated to dryness, passing through strong-base ion-exchange resin CI-type (Diaion SA-10, Nippon Rensui Co., Ltd.). In the op6) : 2,00 is 2.44 (2H, m); 2,30 (1,5 H); 2,33 (1,5 H); 2,98 (3H); 3,06 - 4,20 (7H, m); 5,00 - of 5.40 (1H, width); 6,92 (2H, d, J = 8,3 Hz); 7,28 (1H, s); 7,33 (2H, d, J = 8,3 Hz); 7,72 (1H, d J = 9.0 Hz); of 8.06 (1H, d, J = 9.0 Hz); of 8.28 (1H, s); 8,8 - 9,20 (1H, width); 9,23 (2H, Shir. C); 9,50 (2H, W).

Illustrative example 102. 3-(5-Amidino-2-benzofuranyl)-2- [4-[((2R)-2-amino-1-butyl)oxy]funil]propionic acid dihydrochloride.

In 300 ml of tetrahydrofuran was dissolved 1.1 g of ethyl 3-(5-cyano-2-benzofuranyl)-2-(4-hydroxyphenyl)propionate, 1.24 g (2R)-2-tert-butoxycarbonyl-amino-1-butanol, and 1,72 g of triphenylphosphine. Thus obtained solution was mixed with 1,14 g diethylazodicarboxylate and stirred at room temperature for 18 hours. Then the resulting solution was mixed from 0.83 g of (2R)-2-tert-butoxycarbonylamino-1-butanol, 1.2 g of triphenylphosphine and 0,76 g diethylazodicarboxylate, and the resulting mixture was stirred at room temperature for 18 hours. After concentrating the reaction solution to dryness, the residue was purified by column chromatography on silica gel, using as developing solvent a mixture of toluene and ethyl acetate, resulting in a received 660 mg of ethyl 2-[4-[((2R)-2-tert-butoxycarbonylamino-1-butyl)oxy] phenyl] -3-(5-cyano-2-benzofuranyl)propionate as colorless oily shall furanyl)propionate, obtained above, was treated and purified in accordance with the procedure described in illustrative example 50, resulting in a received 78 mg of the target compound in the form of a solid substance.

1H-NMR (DMSO-d6) : the 1.04 (3H, t); to 1.70 (2H); is 3.0 - 4.2 (6H); 6,41 (1H, s); 6,99 (2H, d); 7,27 (2H, d); 7,72 (2H, s); 8,07 (1H, s); 8,3 (3H, width); 9,34 - 9,40 (4H);

Illustrative example 103. 3-(5-Amidino-2-benzofuranyl)-2- [4-[((2S)-2-amino-1-butyl)oxy]phenyl]propionic acid dihydrochloride.

Repeating the procedure described in illustrative example 102, except that instead of (2R)-2-tert-butoxycarbonylamino-1 - butanol was used (2S)-2-tert-butoxycarbonylamino-1-butanol, resulting received 620 mg of the target compound in the form of a solid substance.

1H-NMR (DMSO-d6) : the 1.04 (3H, t); to 1.70 (2H); is 3.0 - 4.2 (6H); of 6.68 (1H, s); of 6.96 (2H, d); from 7.24 (2H, d); of 7.70 (2H, s); with 8.05 (1H, s); 8.4V (3H, width); 9,40 (4H, W).

Illustrative example 104. 3-[4-[((3S)-1-Acetimidoyl-3 - pyrrolidinyl]oxy]phenyl]-4-(5-amidines[b]Tien-2-yl)butyric acid dihydrochloride.

1 ml of thionyl chloride drop by drop) was added to 50 ml of ethanol. To this solution, stirring at room temperature, was added 1.0 g of 4-(5-amidines[b] Tien-2-yl)-3-[4-[((3S)-3-pyrrolidinyl)oxy] phenyl] butyric acid Digue is the total removal of the solvent by distillation, the resulting reaction solution was carefully dried under reduced pressure, resulting in the obtained ethyl 4-(5-amidines[b]Tien-2-yl)-3- [4-[((3S)-3-pyrrolidinyl)oxy] phenyl]butyrate-dihydrochloride. Thus obtained ester compound was dissolved in 20 ml of tetrahydrofuran. Stirring under ice cooling, the resulting solution was mixed with triethylamine, and then 360 mg ethylacetoacetate, and the mixture is stirred for 1 hour. After removal of the solvent, the obtained residue was chromatographically on a column filled with a synthetic adsorbent in the form of highly porous polymer (a polymer of styrene and divinylbenzene: Diaion HP-20), elwira with a mixture of water and acetonitrile. The desired fractions were collected and concentrated to dryness, and the residue was dissolved in 50 ml of 2 N. hydrochloric acid and heated under reflux for 1 hour. After removal of the solvent, the residue was chromatographically on a column filled with a synthetic adsorbent in the form of highly porous polymer (a polymer of styrene and divinylbenzene: Diaion HP-20), using as eluent a mixture of water and acetonitrile. The desired fractions were combined and subjected to reverse-phase GHUR on a column filled with octadecyl-bound silica gel, elwira mixture is acid and concentrated to dryness. In the described procedure received 850 mg of target compound in the form of a solid substance.

1H-NMR (DMSO-d6) : 2,0 at 2.45 (2H, m); 2,32 (3H, d); 2,5 - 2,9 (2H, m) 3,1 - 4,0 (7H, m); 5,1 to 5.35 (1H, m), 6,92 (2H, d); 7,30 (2H, d); 7,8 (1H, d); to 8.20 (1H, d); of 8.37 (1H, s); 8,6 - 8,9 (1H, m); of 9.30 - 9,80 (5H).

FAB-MS (m/z): 465.

Illustrative example 105. 2-[4-[((3S)-1-(Acetimidoyl-3 - pyrrolidinyl] oxy]phenyl]-3-(6-amidino-1-ethyl-2-indolyl)propionic acid dihydrochloride.

This compound was obtained according to the procedure described in illustrative example 104 (solid).

1H-NMR (DMSO-d6) : of 1.35 (3H, t); is 2.37 (3H); 4,10 - and 4.40 (1H, m), 6.42 per (1H, s); 7,00 (2H, d); was 7.45 (2H, d); of 7.60 (2H, m); 8,30 (1H, s); to 8.70 (1H, width); the 9.25 - 9,80 (5H).

Illustrative example 106. 3-[4-[((3S)-1-(Acetimidoyl-3 - pyrrolidinyl] oxy]phenyl]-2-(5-amidines[b]Tien-2-yl)propionic acid dihydrochloride.

2.0 g of ethyl 3-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl) oxy]phenyl]-2-(5-cyanobase[b]Tien-2-yl)propionate was dissolved in 100 ml of ethanol. Stirring under ice cooling, the resulting solution was barbotirovany hydrogen chloride up to saturation level. The resulting solution was left for 18 hours at room temperature. After removal of the solvent, the obtained residue was dissolved in 100 ml of e is La, the residue was chromatographically on a column filled with a synthetic adsorbent in the form of highly porous polymer (a polymer of styrene and divinylbenzene: Diaion HP-20), elwira with a mixture of water and acetonitrile, which was obtained 1.1 g of ethyl 2-(5-amidines[b] Tien-2-yl)-3-[4-[((3S)-3-pyrrolidinyl)oxy] phenyl] propionohydroxamic. 1.1 g of the obtained compound was dissolved in 15 ml of ethanol, and this solution was mixed with 566 mg ethylacetophenone, and then 694 mg of triethylamine, after which the resulting mixture was stirred at room temperature for 18 hours. After removal of the solvent, the obtained residue was dissolved in 50 ml of 2 N. hydrochloric acid, and then heated under reflux for 30 minutes. After cooling and subsequent removal of the solvent, the obtained residue was chromatographically on a column filled with a synthetic adsorbent in the form of highly porous polymer (a polymer of styrene and divinylbenzene: Diaion HP-20), suirou with a mixture of water and acetonitrile. The collected desired fraction was subjected to reverse-phase GHUR, using a column filled with octadecyl-bound silica gel, and elwira with a mixture of water and acetonitrile. Then erwerbende the desired fractions were combined, mixed with diluted hydrochloric acid and traducta.

1H-NMR (DMCO-d6) : of 2.1-2.4 (2H, m); 2,22 (1,5 H); 2,29 (1,5 H); is 3.08 (1H, DD, J= 13.7 and 7.8 Hz); 3,30-4,00 (5H, m); 4,36 (1H); 5,00-5,20 (1H); 6,80-of 6.90 (2H, m); 7,15-of 7.25 (2H, m); 7,44 (1H, s); 7,72 (1H, d, J=8,3 Hz); 8,15 (1H, d, J=8,3 Hz); 8,32 (1H, s); 8,58 (0.5 H); 8,66 (0.5 H); to 9.32 (2H, Shir. ); 9,38 (0.5 H); 9,45 (0.5 H); 9,50 (2H, W).

Compounds of the present invention, are presented for illustrative examples 107-110, were obtained in accordance with the procedure described in illustrative example 106.

Illustrative example 107. 2-[4-[((3R)-1-Acetimidoyl-3 - pyrrolidinyl)oxy] phenyl] -3-(7-amidino-2-naphthyl)propionic acid dihydrochloride (solid).

1H-NMR (DMCO-d6) : 2,00-to 2.40 (5H, m); 2,90-4,10 (7H, m); 5,20 (1H, Shir. ); 6,93 (2H, d, J=8.0 Hz); 7,33 (2H, d, J=8.0 Hz); 7,56 (1H, d); 7,70-to 8.20 (4H, m); to 8.45 (1H, s); 8,50-8,80 (1H); 9,45 (3H, width); 9,63 (2H, W).

Illustrative example 108. 2-[4-[(1-Acetimidoyl-4-piperidinyl)oxy]phenyl] -3-(7-amidino - 2-naphthyl)propionic acid dihydrochloride (solid).

1H-NMR (DMCO-d6) : 1,50-2,10 (4H, m); 2,31 (3H, s); 3,00-4,20 (7H, m); 4,60-4,80 (1H, m); to 6.95 (2H, d, J=9.0 Hz); 7,31 (2H, d, J=9.0 Hz); 7,50-8,50 (6H, m); 8,93 (1H); 9,45 (3H, width); 9,62 (2H, W).

Illustrative example 109. 3-(7-Amidino-2-naphthyl)- 2-[4-[(1-butanamide-4-piperidinyl)-oxy] phenyl] propionic acid dihydrochloride (solid).

1H-NMR (DMCO0 Hz); 7,30 (2H, d, J=8.0 Hz); 7,60-8,40 (6H, m); 8,86 (1H); to 9.32 (3H, width); 9,58 (2H, W).

Illustrative example 110. 2-[4-[((2R, 4S)-1-Acetimidoyl-2 - methyl-4-pyrrolidinyl)oxy] phenyl] -3-(5-amidines [b] Tien-2-yl) propionic acid dihydrochloride (solid).

1H-NMR (DMCO-d6) : of 1.85 (3H, m); 2,27 (1,5 H, C); 2,37 (1,5 H, C); 5,10-of 5.50 (1H, width); of 7.00 (2H, d); 7,10-8,70 (6H, m); 9,10-9,60 (6H, W).

FAB-MS (m/z): 465 (M++1).

Illustrative example 111. 3-(5-Aminobenzo [b] Tien-2-yl)-2-[4-[((2S)-5-oxo-2-pyrrolidinyl) methoxy]phenyl]propionic acid hydrochloride

a) 3.2 g of ethyl 2-[4-[((2S)-1-tert-butoxycarbonyl-5-oxo-2-pyrrolidinyl)methoxy] phenyl] -3-(5-cyanobase [b] Tien-2-yl propionate was dissolved in a mixture consisting of 50 ml ethanol and 50 ml of dichloromethane. Then, through this solution, stirring under ice cooling, was barbotirovany hydrogen chloride up to saturation level. The resulting reaction mixture was left for 48 hours in 5oC. After removal of the solvent, the residue was dissolved in 100 ml of an ethanol solution containing 13% (wt./about.) ammonia, and the resulting solution was kept at room temperature for 24 hours. After that, the solvent was removed by distillation and the obtained ethyl 3-(5-amidines[b]Tien-2-yl)-2-[4-[((2S)-5-oxo-2-pyrrolidinyl) methoxy]phenyl]propionate water. To the mixture was added 1.6 g of 2-(tert-butoxycarbonylamino)-2-phenylacetonitrile and 2 ml of 1,8-diazabicyclo[5.4.0]-7-undecene. After 24 hours stirring at room temperature, the reaction solution was extracted with ethyl acetate and dried off. After removal of the solvent, the residue was purified by chromatography on a column of silica gel, elwira with a mixture of chloroform and methanol, resulting in a 2.4 g of ethyl 3-[5-(N-tert-butoxycarbonyl)aminoiminomethyl[b] Tien-2-yl] - 2-[4-[((2S)-5-oxo-2-pyrrolidinyl)methoxy] phenyl] propionate in the form of a solid substance.

1H-NMR (CDCl3) : of 1.18 (3H, t); was 1.58 (9H, s); 1,80-of 2.50 (4H, m); for 3.28 (1H, DD); 3,70 (1H, DD); 3,80-4,50 (6H, m).

b) 2.4 g of ethyl 3-[5-(N-tert-butoxycarbonyl aminoiminomethyl[b]Tien-2-yl-2-[4-[((2S)-5-oxo-2-pyrrolidinyl)- methoxy] phenyl]propionate obtained in stage a), was dissolved in 30 ml of tetrahydrofuran. The resulting solution was mixed with an aqueous solution of 200 mg of sodium hydroxide dissolved in 5 ml of water, and the mixture is stirred for 72 hours. After removal of the solvent, the obtained residue was dissolved in 10 ml of concentrated hydrochloric acid, and the solution stirred at room temperature for 1 hour. After removal of the solvent, the residue was subjected to chromate divinylbenzene: Diaion HP-20), elwira with a mixture of water and acetonitrile. Then erwerbende the desired fractions were combined, mixed with hydrochloric acid and concentrated to dryness. In the described procedure was obtained 1.1 g of the target compound.

1H-NMR (DMCO-d6) : 1,70-of 2.30 (4H, m); make 6.90 (2H, d); 7,29 (2H, d); 7,30 (1H, s).

FAB-MS (m/z): 438 (M++1).

Illustrative example 112. 2-[2-[4-[(4-Imidazolyl)methoxy]phenyl]ethyl]-5-benzofuran-carboxamidine the dihydrochloride.

3,53 g part 2-[2-[4-[(1-trityl-4-imidazolyl)methoxy]-phenyl] ethyl]-5-benzofuranyl was dissolved in a mixture consisting of 150 ml of ethanol and 100 ml of dichloromethane. Then, stirring while cooling with ice, through this solution was barbotirovany gaseous hydrogen chloride, after which the solution is kept for 24 hours at room temperature. After removal of the solvent, the residue was dissolved in ethanol solution containing 15% (wt./about.) ammonia, and the resulting solution was stirred at room temperature for 80 hours. After removal of the solvent, the residue was dissolved in a mixture of 100 ml of formic acid and 2 ml of concentrated hydrochloric acid, and the resulting solution was stirred for 6 hours. After removal of formic acid by distillation, the resulting residue Astorga of the filtrate to dryness, the residue was chromatographically on a column filled with a synthetic adsorbent in the form of highly porous polymer (a polymer of styrene and divinylbenzene: Diaion HP-20), elwira with a mixture of water and acetonitrile. The desired fractions were combined and concentrated, and the residue was subjected to reversed phase GHUR on a column filled with octadecyl-bound silica gel, elwira with a mixture of water and acetonitrile. After this you need erwerbende fractions were combined, mixed with diluted hydrochloric acid and concentrated to dryness. In the described procedure received 730 mg of the target compound as a pale yellow solid.

1H-NMR (DMCO-d6) : 2,95 (4H, m); 5,12 (2H, s); 6,72 (1H, s); 6,94 (2H, d, J=8.7 Hz); then 7.20 (2H, d, J=8.7 Hz); 7,72 (2H, s); of 7.75 (1H, s); 8,08 (1H, s); 9,13 (3H, width); 9,38 (2H, W).

Illustrative example 113. 2-[2-[4-[((3S)-3-Pyrrolidinyl)oxy] phenyl] ethyl]-6-indocarbocyanine the dihydrochloride

650 mg 2-[2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl] -6-endocervical was dissolved in a mixture consisting of 100 ml of ethanol and 30 ml of dichloromethane. Stirring under ice cooling, the resulting solution was barbotirovany hydrogen chloride up to saturation level. The resulting solution was left for 24 hours at room temperature. After other stirred 24 hours at room temperature. After removal of the solvent, the residue was subjected to reversed-phase GHUR using a column Packed with octadecyl-bound silica gel, and elwira with a mixture of water and acetonitrile. After that, you need erwerbende fractions were combined, mixed with diluted hydrochloric acid and concentrated to dryness. In the described procedure received 90 mg of target compound in the form of crystals. So pl. 229-233oC.

1H-NMR (DMCO-d6) : of 1.95 to 2.35 (2H, m); 5,00-and 5.30 (1H, width); 6,36 (1H, s); 6,80-7,80 (7H, m); 8,00 (1H, s); of 9.30-9,60 (6H, W).

Connection represented in the illustrated examples, 114-121, were obtained in accordance with the procedure illustrated in example 113.

The illustrated example 114. 2-[3-Hydroxy-2-[4-[((3S)-3-pyrrolidinyl)oxy]phenyl]propyl-6 - indocarbocyanine the dihydrochloride (solid).

1H-NMR (DMCO-d6) : 1,97-of 2.30 (2H, m); 2,90-4,60 (9H, m); 5,00-5,20 (1H, Shir. with); to 6.22 (1H, s); make 6.90 (2H, d); 7,18-of 7.70 (2H, m); of 7.96 (1H, s); 9,10-9,90 (6H, Shir. C); 11,05 (1H, s).

Illustrative example 115. 2-[2-[4-[[(2-Pyrazinyl)amino]- carbonyl]phenyl]ethyl]-5-benzofuroxan the dihydrochloride (solid).

1H-NMR (DMSO-d6) : 3,20 (4H, s); is 6.78 (1H, s); was 7.08 (1H, Shir. C); of 7.48 (2H, d, J = 7.9 Hz); 7,80 (2H, s); 8,03 (2H, d, J = 7.9 Hz); 8 the Teal]- phenyl]ethyl]-5-benzofuroxan the dihydrochloride (solid )

1H-NMR (DMSO-d6) : 3,10 (4H, s); the 5.45 (2H, s); of 6.75 (1H, s); from 7.24 (2H, d, J = 8,3 Hz); 7,40 (2H, d, J = 8,3 Hz); 7,66 (1H, s); 7,72 (2H, s); 7,80 (1H, s); to 8.12 (1H, s); of 9.30 (2H, Shir. C.); 9,45 (3H, Shir. C).

Illustrative example 117. 2-[2-[4-[(4-Methyl-1-piperazinil)- carbonyl] phenyl]ethyl]-5-benzofuroxan the dihydrochloride.

1H-NMR (DMSO-d6) : 2,80 (3H, s); 4.09 to (4H, s); 3,10 (4H, Shir. C); 4,00 (4H, Shir. C); 6,74 (1H, s); of 7.36 (4H, s); 7,74 (2H, s); to 8.12 (1H, s); 9.28 are (2H, Shir. C); 9,48 (2H, Shir. C).

Illustrative example 118. 3-[3-[4-[((3S)-3-Pyrrolidinyl)oxy]- phenyl] propyl]-5-benzofuroxan the dihydrochloride (solid).

1H-NMR (DMSO-d6) : 2,10 (4H, m); 2,70 (4H, m); 3,30 (4H); 5,07 (1H, Shir. C); make 6.90 (2H, d); to 7.15 (2H, d); 7,79 (2H, s); 8,00 (1H, s); 8,23 (1H, s); 9,20-9,80 (6H, W).

Illustrative example 119. 2-[[4-[(4-Piperidinyl)oxy]phenyl]- methyl]-5-benzofuroxan the dihydrochloride (solid).

1H-NMR (DMSO-d6) : 1,70-of 2.20 (2H, m); 2,70-3,30 (4H, m), 4,14 (2H, s); 4,60-4,80 (1H, m); 6,79 (1H, s); 6,97 (2H, d, J = 9.0 Hz); 7,26 (2H, d, J = 9.0 Hz); 7,74 (2H, s); 8,13 (1H, s); of 9.30 (2H, W); 9,44 (2H, width); 9,00-9,60 (2H, W).

Illustrative example 120. 2-[2-[4-[(3S)-1-Acetyl-3 - pyrrolidinyl)oxy] -3-hydroxyphenyl]-ethyl]-5-benzofuroxan hydrochloride.

So pl. 175-176oC

1H-NMR (DMSO-d6) : 1,80-2,20 90-8,98 (1H); 9,23 (2H, W); 9,40 (2H, W).

Illustrative example 121. 2-[2-[4-(N-Acetyl)aminoethylthiomethyl methoxy phenyl ethyl-5 - benzofuroxan hydrochloride (solid).

1H-NMR (DMSO-d6) : 0,70 is 2.00 (10H, m); to 1.83 (3H, s); 2,75-3,20 (6H, m), 3,70 (2H, d, J = 5.7 Hz); only 6.64 (1H, s); 6,77 (2H, d, J = 8,8 Hz); to 7.15 (2H, d, J = 8,8 Hz); the 7.65 to 7.68 (3H); 8,04 (1H, s); 9,00 (2H, W); 9,31 (2H, W).

Illustrative example 122. 2-[2-[4-[((3S)-1-Formimidoyl-3 - pyrrolidinyl)-oxy]phenyl]ethyl]-5-benzofuroxan the dihydrochloride.

a) Repeating the procedure of illustrative example 100, and received 2-[2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-ethyl]-5-benzofurazanyl

1H-NMR (CDCl3) : of 1.66 (9H, s); totaling 3.04 (4H, s); 3,30-3,70 (4H, width); is 4.85 (1H); 6,40 (1H, s); to 6.80 (2H, d); for 7.12 (2H, d); 7,52 (2H, s); of 7.82 (1H, s).

b) 1.66 g 2-[2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)- oxy] phenyl] ethyl]-5-benzofuranyl obtained in stage a), was treated and purified in accordance with the procedure described in illustrative example 113, resulting in a received 800 mg 2-[2-[4-[((3S)-3-pyrrolidinyl)oxy] phenyl]ethyl]-5-benzofuroxan dihydrochloride.

1H-NMR (DMSO-d6) : 1,90-of 2.30 (2H, m); a 3.06 (4H, width); 3,00-of 3.80 (4H, Shir. ); to 5.08 (1H, width); of 6.73 (1H, s); to 6.88 (2H, d); 7,19 (2H, d); 7,74 (2H, with whom mydigitalmedia, obtained in stage b), was dissolved in 15 ml of water. Stirring and cooling with ice, to the resulting solution was added to 1.83 g of benzylmaleimide

hydrochloride, while maintaining the pH of the reaction solution at the value of 8 with 1 N. aqueous sodium hydroxide solution. The resulting mixture was stirred for 20 minutes in an ice bath. Then the pH of the reaction solution was brought to 2.0 with dilute hydrochloric acid, washed with diethyl ether and concentrated to dryness. The obtained residue was subjected to chromatography on a column filled with a synthetic adsorbent type of highly porous polymer (a polymer of styrene and divinylbenzene: Diaion HP-20), elwira with a mixture of water and acetonitrile. In the described procedure has been the target compound in the form of solids.

1H-NMR (DMSO-d6) : 1,80-2,60 (2H, m); is 3.08 (4H, width); 3,20-4,00 (4H, Shir. ); 5,14 (1H, width); to 6.80 (1H, s); 6,92 (2H, d); of 7.25 (2H, d); 7,76 (1H, d); 7,86 (1H, d); 8,21 (1H, s); of 8.40 (1H, width); the remaining 9.08 (1H, width); 9,18 (2H, W); to 9.57 (3H, W).

Illustrative example 123. 2-[2-[3-Hydroxy-4-[((3S)-3 - pyrrolidinyl)oxy]phenyl]ethyl]-5-benzofuroxan the dihydrochloride.

1.0 g 2-[2-[4-[((3S)-1-acetyl-3-pyrrolidinyl)oxy]-3 - hydroxyphenyl]-5-benzofuroxan hydrochloride was dissolved in 30 ml of 6 N. salaices, the obtained residue was subjected to column chromatography on a column with a synthetic adsorbent type of highly porous polymer (a polymer of styrene and divinylbenzene: Diaion HP-20), elwira with a mixture of water and acetonitrile. In the described procedure was 320 mg of target compound in the form of a solid product.

1H-NMR (DMSO-d6) : 1,90-of 2.20 (2H, m); 2,70-3,50 (8H, m); 5,08 (1H, Shir. ); 6,66 (1H, DD, J = 9.0 and 1.8 Hz); to 6.80 (2H, s); 6,94 (1H, s); 7,76 (2H, s); 8,12 (2H, s); 9,26 (2H, width); 9,44 (2H, W); 9,24 (2H, W).

Illustrative example 124. 2-[2-[4-[(4-Aminoethylthiomethyl)- methoxy] phenyl]ethyl]-5-benzofuroxan the dihydrochloride.

This compound was obtained according to the procedure described in illustrative example 123 (solid).

1H-NMR (DMSO-d6) : 0,80 is 2.00 (10H, m); 2,90-3,20 (4H, m); to 3.73 (4H, m); 6,72 (1H, s); 6,79 (2H, d, J = 8.5 Hz); 7,14 (2H, d, J = 8.5 Hz); 7,73 (2H, s); 8,07 (3H, width); 9,18 (2H, width); 9,38 (2H, W).

Illustrative example 125. [2-[2-(5-Amidino-2-benzofuranyl)- ethyl]-5-[((3S)-3-pyrrolidinyl)oxy]phenyl]exucuse acid dihydrochloride.

1.6 g of methyl [5-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)hydroxy]- 2-[2-(5-cyano-2-benzofuranyl)ethyl] phenyl] oxoacetate was dissolved in 100 ml of ethanol. Stirring and cooling with ice, obtained through the room temperature, and kept at this temperature for 18 hours. After removal of the solvent, the obtained residue was dissolved in 20 ml of ethanol, and this solution drop by drop) was added, while stirring, to an aqueous solution of 5 n sodium hydroxide. After 10 minutes of stirring, the resulting solution was saturated with sodium chloride, was extracted with chloroform three times with 200 ml, 100 ml and 100 ml), successively, and then dried in the presence of a mixture of potassium carbonate and magnesium sulfate. After removal of the solvent, the residue was dissolved in 50 ml of ethanol. The resulting solution was mixed with 1.0 g of ammonium chloride, and then with 200 ml of an ethanol solution containing 12% ammonia, and the mixture was stirred for 96 hours. After removal of the solvent, the residue was subjected to reversed-phase GHUR, using a column with octadecyl-bound silica gel, and elwira with a mixture of water and acetonitrile. After that, you need erwerbende fractions were combined, mixed with diluted hydrochloric acid and concentrated to dryness. In the described procedure was obtained 0.7 g of target compound in powder form.

1H-NMR (DMSO-d6) : 1,96 of-2.32 (2H, W); 2,80-of 3.60 (8H, width); at 4.75 (2H, s); 5,10 (1H, width); 6,48 (1H, d, J = 8,8 Hz); 6,51 (1H, s); 6,76 (1H, s); rate of 7.54 (1H, d, J = 8,8 Hz); 7,74 (2H, s); 8,10 (1H, s); 9,27 (2H, W); 9,42 (2H, W); l)oxy]phenyl]oxoacetate the dihydrochloride.

0.65 g of [2-[2-(5-amidino-2-benzofuranyl)ethyl-5-[((3S)-3 - pyrrolidinyl)oxy]phenyl]exucuse acid dihydrochloride was dissolved in 50 ml of ethanol. To this solution while cooling with ice, was added 0.2 ml of thionyl chloride, and the mixture was stirred at room temperature for 18 hours. Then the reaction solution was concentrated to dryness, dissolved in water and again concentrated to dryness. In the described procedure was obtained 0.65 g of target compound in the form of a solid substance.

1H-NMR (DMSO-d6) : of 1.20 (3H, t); 2,11 (2H, W); 3,30 (4H, width); 4,20 (2H, square ); 4,84 (2H, s); 5,08 (1H, width); 6,53 (2H, s); of 6.75 (1H, SG; 7,10 (1H, d); 7,72 (2H, s); 8,07 (1H, s); 9,18 (2H); 9,38 (2H); 9,66 (2H, W).

Illustrative example 127. The hydrochloride pentahydrate (2R)-2-[4-[[(3R)-1-acetimidoyl-3-pyrrolidinyl] oxy] phenyl]-3- (7-amidino-2-naphthyl)propanoic acid.

The structural formula is:

< / BR>
Molecular formula (M. C. ): C26H21N4O31HCl 5H2O (571.071) N 1730801

Properties: Colorless prismatic crystals

[]2D6.1= -42,78o(c = 0,984, MeOH)

1H-NMR (DMSO-d6) : 2,20 - 2,40 (m, 2H, pyrrolidine C4-H1), 2,28 (c. 1,5 H 1/2 x-CH2), 2,31 (c. 1,5 H 1/2 x-CH2), 2,83-of 2.93 (m, 1H, -C(COOH)C H-), 3,30 - a 4.03 (m , 6H, pyrrolidin C2-H1C5-H1 J = 7.8 Hz, ArH), 7,56 (D., 1H, J = 8,3 Hz), 7,65 (D., 1H, J = 8,3 Hz), 7,93 (D. , 1H, J = 8,8 Hz, ArH), of 7.96 (D., 1H, J = 8,8 Hz, ArH), 8,13 (C., 1H, ArH), 8,65 (c. 1H, ArH), 8,70 - 9,00 (width, 1H).

MS (FAB): m/z 445 (M+H)+.

IR (KBr): 1682, 1634, 1610, 1504, 1384, 1242 cm-1.

Analysis: Calculated C26H21N4O31HCl 5H2O: C 54,68; H 6,88; 9,81 N; Cl 6,21. Found: C 54,60; H 6,84; N 9,74; Cl 6,38

HPLC: column: SUMICHIRAL OA-5000L 4,6 x 150 mm

solvent: 2 mm CuSO4: MeOH = 83:17

flow rate: 1 ml/min

temperature: 50oC

detection: UV 254 nm

retention time: 55,28 minutes

Test example 1. Measurement of solubility in water.

Different quantities of each sample were added to a fixed amount of water, and the resulting mixture was stirred on the vibrator for 10 minutes at 25oC. the results Obtained are presented in table 1.

These results suggest that compounds of the present invention are more soluble in water than the connection of the prototype.

Test example 2. Measurement antikoaguliruyuschey activity.

Using centrifuges received a sample of human blood plasma. 100 μl of the drug in blood plasma was added to 100 μl of fisiologicas is at 37oC. Then, to this mixture was added 100 μl of 0.02 M solution of calcium chloride, pre-incubated at 37oC. then, using CLOTEC (Sanko Iunyaku, Co. Ltd) was measured coagulation time. The coagulation time measured without addition of the test compounds were examined as a control, and on this basis, the expected concentration of the test compound, which gave the coagulation time of blood, twice the reference time, and this concentration was adopted for the indicator antikoaguliruyuschey activity (also called "ST2"). The results obtained are shown in table 2.

Test example 3. Measurement of the ability to inhibition of activated coagulation factor X (FXa).

180 µl of physiological solution containing the test compound was mixed with 200 ál of Tris-HCl buffer (pH 8,4) and 100 μl of an aqueous solution of 1 mm S-2222 (Kabivitrum AB), and the mixture was incubated at 37oC. Then, to this mixture was added 20 μl of Tris-HCl-buffered saline (pH was 7.45), with 0.6 units/ml human FXa. After a 15 minute incubation at the same temperature, the reaction was stopped by adding 100 ál of 60% acetic acid and measured the optical density of reactio is the GUI of the reaction mixture, where 60% acetic acid was added before the addition of FXa, was used as control. As an indicator of FXa-inhibiting activity was calculated concentration of each test compound that is 50% inhibited FXa activity (this concentration was further marked "IC50"). Typical examples of obtained results are presented in table 2.

Test example 4. Measurement of thrombin-inhibiting activity.

100 μl of Tris-HCl-buffered saline (pH was 7.45) (TBS) containing 6 mg/ml of fibrinogen (type 1, Daiichi Pure Chemicals Co., Ltd.), was mixed with 100 μl of saline. At 37oC, 100 µl of Tris-HCl-buffered saline (pH was 7.45) (TBS) containing various amounts of thrombin (for outdoor use, Sankyo Co., Ltd.), was added to the mixture obtained above, and the measured coagulation time using CLOTEC (Sanko Junyak Co., Ltd), and then build the calibration curve. The degree of inhibition (%) of each test compound was determined by measuring the time of coagulation using 100 µl of saline solution, to which was added each of these compounds. The concentration of each connection, which is 50% inhibited activexcontrol of this compound was determined as an indicator antithrombine activity. Typical examples of obtained results are presented in table 2.

As can be seen from the results shown in table 2, each connection of the present invention has a strong antikoaguliruyuschey activity, due to its specific activity against FXa (compared with the connection DABE, which is known to experts as anticoagulate agent).

Test example 5. Measurement antikoaguliruyuschey activity when administered orally

An aqueous solution of each test compound was administered orally to each rat separately (males SID: Wistar) under anesthesia, the dose of 10 ml/kg of the body. Periodically collected blood samples, and the preparations of plasma obtained from these samples was measured to determine the time of formation and activity of thromboplastin (APTT). Similarly, APTT was determined in rats to clean water, and these measurements were used as control. Then calculate the ratio of ispytat. /control APTT, and this ratio was used as an indicator antikoaguliruyuschey activity. Typical examples of obtained results are presented in table 3.

As can be seen from table 3, when administered orally each connection of this from the>Test example 6. Testing for toxicity by a single injection of rats with oral doses.

Connection illustrative example 45 was dissolved in distilled water and orally was administered to each of two 6-week-old rats (males, SLc: CD) at a dose of 2000 mg/kg body weight. During the observation time of 14 days, no deaths were not registered.

Test example 7. Testing for toxicity by repeated administration to rats oral dose.

Each of the compounds of the present invention was dissolved in distilled water and administered orally to each of the five 5-week-old rats (males, Slc: SD) dose of 800 mg / kg body weight. This oral administration was performed once a day and repeated in the next 10 days in order to determine the possible mortality. Results of observations are presented in table 4.

Test example 8. Definition antithrombine activity by oral administration of the compound to rats in a model of arteriovenous anastomose.

Using a slightly modified procedure described in Thrombosis Research, vol. 54, pp. 399-410, 1989, determined antithrombin action of the compounds of the present invention when they are orally administered orally to male rats (STD : Wistar) and these rats were anestesiologi 15 minutes after injection of the compounds. Then, near the carotid artery anastasiosandy rats imposed arterial clamp to stop the blood, and entered, locking in this case, one end of the shunt, filled with saline, and the other end of the shunt was introduced, locking in the jugular vein. In these tests, the shunt consisted of a copper wire of length 20 cm and a diameter of 0.17 mm, placed in a polyethylene tube (Hibiki N 5), with an external diameter of 5/3 mm and a length of 21 cm), where each end of this tube is connected with a plastic tube (Hibiki N 3, with an external diameter of 11 mm and a length of 3 cm) using 3-mm silicone tube. After 30 minutes after administration, the arterial clamp was removed so that the blood flowed into the shunt. After 7 minutes after restoration of blood flow, a copper wire was taken out together with the formed clots and washed with 10 ml of saline. Thereafter, in accordance with the procedure described in Journal of Biological Chemistry, vol 193, pp. 265-275, 1951, determined the amount of thrombus formed on a fine wire, in the form of protein. When calculating the degree of inhibition of thrombosis after administration of the compounds used control option, where instead of the test compound was injected water. The results are presented in the table is boonratana.

Although the present invention is described in preferred examples of its implementation, however, any specialist clear that it can be made various changes or modifications not beyond being and scope of the present invention.

1. Aromatic amidinov derivative of General formula I

< / BR>
where R1is a hydrogen atom or a lower alkoxygroup;

R2is a hydrogen atom, a lower alkyl group, lower alkoxygroup, carboxyl group, carboxialkilnuyu group with 2-5 carbon atoms or alkoxycarbonyl group with 2-5 carbon atoms;

R3is a hydrogen atom, carboxyl group, carboxialkilnuyu group with 2-5 carbon atoms, alkoxycarbonylmethyl group with 3-6 carbon atoms, carboxyaniline group with 2-5 carbon atoms, alkoxycarbonylmethyl group with 3-6 carbon atoms or alkoxycarbonyl group of 2-5 carbon atoms;

R4is a hydrogen atom, hydroxyl group or lower alkoxygroup;

n = 0, 1, 2;

A - Allenova group with 1-4 carbon atoms which may be substituted by one or two substituents selected from hydroxyalkyl group with 1-4 carbon atoms, carboxyl, alkoxycarbonyl is Sloboda or sulfur or a carbonyl group;

Y is a saturated or unsaturated 5 - or 6-membered heterocyclic fragment having one or two heteroatoms selected from nitrogen atoms, oxygen, sulfur, or cyclic hydrocarbon fragment, which can be substituted by aminogroups, carbamoyl, mono - or dialkylamino, alkanolamides, lower alkyl, lower alkanoyl, alkoxycarbonyl, benzimidazolium, alkanolamine or alkylaminocarbonyl; where saturated or unsaturated 5 - or 6-membered cyclic hydrocarbon fragment can be substituted aminoalkyl group or alkanolammonium group, or Y is an amino group which may be substituted pyrrolidinyl or personalni group;< / BR>
a group of the formula

< / BR>
is a group selected from indolyl, benzofuranyl, benzothiazyl, benzothiazolyl, naphthyl, tetrahydronaphthyl, benzimidazolyl;

or its pharmaceutically acceptable salt.

2. Aromatic amidinov derivative or its salt under item 1, wherein said saturated or unsaturated 5 - or 6-membered heterocyclic fragment contains 1 or 2 heteroatoms selected from nitrogen atoms and oxygen.

3. Aromatic amidinov derived, representing 2">

4. Aromatic amidinov derived, representing(+)-2-[4-[((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy] -phenyl] -3-(7-amidino-2-naphthyl)propionic acid or its salt.

5. Aromatic amidinov derived, representing the (2S)-2-[4-[((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy] phenyl] -3-(7-amidino-2-naphthyl)propionic acid or its salt.

6. Aromatic amidinov derived, representing the (2R)-2-[4-[((3R)-1-acetimidoyl-3-pyrrolidinyl)-oxy] -phenyl] -3-(7-amidino-2-naphthyl)propionic acid or its salt.

7. Aromatic amidinov derived, representing 2-[4-[(1-acetimidoyl-2-pyrrolidinyl)methoxy]phenyl]-3-(5-amidines[b]Tien-2-yl)propionic acid or its salt.

8. Aromatic amidinov derived, representing(+)-2-[4-[((2S)-1-acetimidoyl-2-pyrrolidinyl)methoxy] -phenyl]-3-(5-amidines[b] Tien-2-yl)propionic acid or its salt.

9. Aromatic amidinov derived, representing 2-[4-[(1-acetimidoyl-4-piperidinyl)oxy] phenyl]-3-(7-amidino-2-naphthyl)propionic acid or its salt.

10. Aromatic amidinov derived, representing(+)-2-[4-[(1-acetimidoyl-4-piperidinyl)oxy]phenyl]-3-(7-amidino-2-naphthyl)poxy]phenyl]-3-(7-amidino-2-naphthyl)propionic acid.

12. Pharmaceutical composition having antikoaguliruyuschim action, including the active principle and the target additives, characterized in that the active agent it contains an effective amount of an aromatic amidnogo derived by PP. 1-5, 8, 10, or 11, or its pharmaceutically acceptable salt.

 

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