Phenylglycine derivatives

 

(57) Abstract:

The invention relates to new compounds of the formula (I), where R1is hydrogen or a fragment of ester, E is hydrogen or hydroxy, three of X1-X4denote the group of C(Ra), C(Rb) or C(Rc), and the fourth represents C(Rdor N, where Ra-Rdis hydrogen, alkenyl, quinil, alkenylacyl, alkoxy, alkylamino, alkoxyalkyl, alkoxyalkanols, alkoxycarbonylmethyl, alkoxycarbonylmethyl, alkoxycarbonylmethyl, alkyl, alkoxycarbonylmethyl, alkylsulfanyl, alkylsulfonyl, alkylsulfonyl, allylurea, allylthiourea, alkylsulfonamides, alkylsulfonyl, aminoethoxy, arylalkyl, Allakaket, arylalkyl, arylalkylamine, arylcarboxylic, arylcarboxamide, aryloxy, aryloxyalkyl, arylsulfonyl, arylsulfonamides, carboxy, carboxylic, substituted alkyl, substituted amino, halogen, substituted halogen, cycloalkyl, substituted cycloalkyl, hydroxy, substituted hydroxy, heterocycle, substituted heterocycle, or two adjacent groups of Ra-Rdtogether form the fragment condensed di - or monooxygenase rings or arelikely factor and due to this property can be used as an active component in farbkomposition, and also for the treatment of various diseases caused by this activity. 4 C. and 20 C. p. F.-ly.

The invention relates to new N-(4-carbamimidoyl)glycine derivatives of the formula

< / BR>
where R1denotes hydrogen or a fragment of the ester group which can be split under physiological conditions;

E represents hydrogen or hydroxy;

three characters from the X1-X4independently from each other represent a group C(Ra), C(Rb) or C(Rc), and the fourth refers to the group C(Rdor N;

Ra-Rdeach independently of one another denotes hydrogen, alkenyl, alkenylboronic, alkenylacyl, quinil, alkylalkoxy, alkoxy, alkoxyalkyl, alkoxyalkyl, alkoxyalkyl, alkoxyalkyl(alkyl)aminoalkyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonylmethyl, alkoxycarbonylmethyl, alkoxycarbonylmethyl, alkoxycarbonylmethyl, alkoxycarbonylmethyl, alkoxycarbonylmethyl, alkyl, alkyl(alkylsulphonyl)amino, alkylsulphonyl, alkylcarboxylic, alkylcarboxylic, alkylcarboxylic, alkylcarboxylic, alkylsulfanyl, alkylsulfonyl, alkylsulfanyl, alkoxy, aryl, arylalkyl, arylalkyl, Allakaket, allakariallak, arylalkyl, arylalkylamine, arylcarboxylic, arylcarboxamide, arylcarboxamide, aryloxy, aryloxyalkyl, arylsulfonyl, arylsulfonamides, carboxy, carboxylic, carboxylicacid, carboxylate, carboxycellulose, carboxyaniline, carboxyacid, carbamoylphenoxy, cycloalkyl, cycloalkene, cycloalkylation, cyclooctylamine, cycloalkylation, cycloalkylcarbonyl, cycloalkylcarbonyl, cycloalkylcarbonyl, dihydroxyacetone, halogen, haloalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkoxy, hydroxyalkyloxy, hydroxyalkyl, hydroxyalkoxy, hydroxycyclohexanone, mono - or dialkylamino, mono - or dialkylaminoalkyl, mono - or dialkylaminoalkyl, mono - or dialkylaminomethylcalix, 2,2,2-triftoratsetilatsetonom or heterocyclic Deputy, selected from the group consisting of useparalleloldgc, benzoimidazolyl, morpholinoethoxy, morpholinylmethyl, morpholinoethoxy, piperidinyloxy, piperidylamine, piperidinylmethyl, piperidinyloxy, alkylsulfonamides, furnell is, piperazinil, piperazinylmethyl, pyridinylamino, piperidinylidene, pyridyloxy, pyrimidinylpiperazine, pyrrolidinyl, pyrrolidinyloxy, pyrrolidinyloxy, pyrrolidinyloxy, pyrrolidinyloxy, oxopyrrolidin, oxadiazolyl, tetrahydropyranyloxy, tetrahydropyranyloxy, tetrahydropyranyloxy, tetrahydrofurfurylamine, tetrahydrothiopyrano, tetrahydropyranyloxy, dioxotetrahydrofuran, thiazoleacetic and thiophenyl, where the heterocyclic substituents optionally substituted by alkyl, alkoxygroup, carboxylation, hydroxy-, tetraallyloxyethane, alkylsulfonyl or alkoxycarbonylmethyl or two adjacent groups of Ra-Rdtogether form the fragment condensed 1,4-dioxane, 1,3-dioxolane, 1-oksanalove or aryl ring,

provided that not more than three groups of Ra-Rdhave the same values and X1not substituted by aryl, carboxypropyl or alkoxycarbonyl, and

one of the symbols G1and G2denotes hydrogen and the other denotes hydrogen, alkyl, hydroxy, alkoxy, aroyl or a group COO-Reor OCO-Reand Redenotes alkyl, neobyazatelnostyu,

and their hydrate or solvate, and physiologically acceptable salts.

In addition, the invention relates to a method for producing the above compounds, to pharmaceutical compositions containing the above compounds and to the use of these compounds for preparing pharmaceutical compositions.

Examples of physiologically acceptable salts of these compounds of formula I are salts with physiologically compatible mineral acids such as hydrochloric acid, sulphuric acid, sulphurous acid or phosphoric acid, or with organic acids, such as methanesulfonate acid, para-toluensulfonate acid, acetic acid, triperoxonane acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid.

The compounds of formula I can be solvated, especially gidratirovana. Hydration can be carried out in the manufacturing process or can occur due to the hygroscopic properties of the initially anhydrous compound of formula I.

The compounds of formula I contain at least one asymmetric carbon atom and therefore can am is 2">

In the context of the present invention the term "alkyl", either individually or in combination with other groups, such as alkoxy, alkoxycarbonyl and so on, refers to a hydrocarbon radical straight or branched chain containing 1-6, preferably 1-4 carbon atoms, such as methyl, ethyl, propyl, isopropyl and butyl.

The term "alkoxy" refers to the group alkyl-O-, where alkyl has the above values, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy.

The concept of "alkenyl individually or in combination with other groups, refers to a hydrocarbon radical straight or branched chain containing olefinic bond and up to 6, preferably up to 4, carbon atoms.

The concept of "quinil individually or in combination with other groups, refers to a hydrocarbon radical straight or branched chain, containing a triple bond and up to 6, preferably up to 4, carbon atoms.

The concept of "cycloalkyl" denotes a cyclic alkyl group containing from three to six carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The notion of "cycloalkane" or "cycloalkane" means cycloalkyl group, the light is with other groups, such as aryloxy, aralkyl and so on, refers to carbocyclic aromatic radical, such as phenyl, naphthyl or indanyl, preferably phenyl and naphthyl, especially phenyl, which may be substituted, e.g. by halogen, such as bromine, fluorine or chlorine, alkoxygroup, for example methoxy-, ethoxy or propoxyphene, alkylenedioxy, such as methylendioxyphenyl, hydroxy-, nitro-, amino-, mono - or dialkylamino, phenyl, fenoxaprop, COOH or COO-alkyl, for example COOCH3or SOOS2H5. Preferred substituents are alkoxy, halogen, preferably fluorine, alkyl, amino, nitro, dialkylamino and carboxy, primarily alkoxy, halogen and alkyl. Examples Uralkalij groups are benzyl, phenethyl, mono - or dimethoxybenzyl, aminobenzyl or nitrobenzyl, examples of aryloxy are phenoxy or methoxycarbonylbenzyl, and examples of aralkylated are benzyloxy, methoxybenzyloxy and ventocilla.

The term "halogen" denotes fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.

The term "hydroxy" refers to a group-IT.

The term "carbonyl" refers to a group-C(O)-.

The term "carboxy" obozy" refers to a group NH2-C(O)-.

The term "oxo" refers to a group-O-.

The term "amino" denotes the group-NH2.

The concept of "sulfanyl" denotes the group-S-.

The concept of "sulfinil" refers to a group-SO-.

The concept of "sulfonyl" denotes the group-SO2-.

The concept of "Reidel" refers to a group NH2-C(O)-NH-.

The concept of "teoretical" refers to a group NH2-C(S)-NH-.

Examples of haloalkyl are trifluoromethyl and pentafluoroethyl; examples of haloalkoxy are triptoreline, pentaverate.

Examples of ester groups that are cleaved under physiological conditions, which are indicated by the symbol R1are alkyl, especially methyl and ethyl; morpholinyl; tetrahydropyranyl; alkoxycarbonyl, such as tert-butoxycarbonylmethyl (pivoxil); alkoxycarbonylmethyl, such as 1-(ethoxycarbonyl)ethyl, hexyloxyethoxy (Exeter) and 1-(isopropoxycarbonyl)ethyl (proxetil); alkylcarboxylic, such as 1-acetoxyethyl (aksetil), 1-(pivaloyloxy)ethyl and 1-(cyclohexyloxy)ethyl. The most preferred ester groups are methyl and ethyl, especially ethyl group.

-X4independently from each other represent a group C(Ra), C(Rb) or C(Rc), and the fourth refers to the group C(Rd).

In a preferred embodiment, the invention includes first of all the above compounds in whicha-Rdindependently of one another denote hydrogen, alkenyl, alkenylboronic, alkenylacyl, quinil, alkoxy, alkoxyalkyl, alkoxyalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylmethyl, alkoxycarbonyl, alkyl, alkylcarboxylic, alkylcarboxylic, alkylcarboxylic, alkylsulfonates, aminoethoxy, aryl, arylalkyl, Allakaket, allakariallak, arylalkyl, arylcarboxylic, arylcarboxamide, aryloxy, aryloxyalkyl, carboxy, carboxylic, carboxylate, carboxycellulose, carboxyaniline, carbamoylphenoxy, cycloalkyl, cycloalkene, cycloalkylation, cyclooctylamine, cycloalkylation, cycloalkylcarbonyl, cycloalkylcarbonyl, dihydroxyacetone, halogen, haloalkyl, haloalkoxy, haloalkyl, hydroxyalkoxy, hydroxyalkyloxy, hydroxyalkyl, hydroxyalkoxy, mono - or dialkylamino is, is selected from the group consisting of morpholinoethoxy, morpholinylmethyl, morpholinoethoxy, piperidinyloxy, piperidinyloxy, pyridinylamino, alkylsulfonamides, fornillos, imidazolylalkyl, isothiazolinone, pyrrolidinyl, pyrrolidinyloxy, pyrrolidinyloxy, pyrrolidinyloxy, pyrrolidinyloxy, oxadiazolyl, tetrahydropyranyloxy, tetrahydropyranyloxy, tetrahydropyranyloxy, tetrahydropyranyloxy, thiazoleacetic, where the heterocyclic substituents optionally substituted by alkyl, alkoxy, tetraallyloxyethane, alkylsulfonyl or alkoxycarbonylmethyl or two adjacent groups of Ra-Rdtogether form the fragment condensed 1,4-dioxane, 1,3-dioxolane, 1-oksanalove or aryl ring.

Particularly preferred are the above compounds in which Ra-Rdindependently of one another denote hydrogen, alkenyl, alkenylacyl, quinil, alkoxy, alkoxyalkyl, alkoxyalkyl, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarboxylic, alkylsulfonates, arylcarboxamide, carbamoylphenoxy, carbonyloxy, cycloalkane, cycloalkylation, is hydroxy, haloalkyl, hydroxyalkoxy, hydroxyalkyloxy, hydroxyalkyl, hydroxyalkoxy, mono - or dialkylaminoalkyl or heterocyclic Deputy, selected from the group consisting of piperidinyloxy, fornillos, isothiazolinone, morpholinylmethyl, pyridinylamino, pyrrolidinyloxy, pyrrolidinyloxy, tetrahydropyranyloxy, tetrahydropyranyloxy, where the heterocyclic substituents optionally substituted by alkyl, alkoxy, tetraallyloxyethane, alkylsulfonyl or alkoxycarbonylmethyl.

Other preferred compounds are compounds in which Ra-Rdindependently of one another denote hydrogen, alkenyl, alkenylacyl, quinil, alkoxy, alkoxyalkyl, alkoxyalkyl, alkoxyalkyl, alkyl, alkylcarboxylic, alkylsulfonates, arylcarboxamide, alkoxycarbonylmethyl, carbamoylphenoxy, carboxycellulose, cycloalkane, cycloalkylation, cycloalkylation-bonelace, cycloalkylcarbonyl, dihydroxyacetone, halogen, haloalkyl, haloalkoxy, haloalkyl, hydroxyalkoxy, hydroxyalkyloxy, hydroxyalkyl, hydroxyalkoxy, mono - or dialkylaminoalkyl or heterocyclic Zam is, originalemonholes, pyrrolidinyloxy, pyrrolidinyloxy, tetrahydropyranyloxy, tetrahydropyranyloxy, where the heterocyclic substituents optionally substituted by alkyl, alkoxy, tetraallyloxyethane, alkylsulfonyl or alkoxycarbonylmethyl.

The most preferred compounds are compounds in which Ra-Rdindependently of one another denote hydrogen, alkenyl, quinil, alkoxy, alkyl, carbamoylphenoxy, cycloalkane, cycloalkylation, dihydroxyacetone, halogen, haloalkoxy, haloalkyl, hydroxyalkoxy, hydroxyalkyl, hydroxyalkoxy, mono - or dialkylaminoalkyl or heterocyclic Deputy selected from the group comprising morpholinylmethyl, piperidinyloxy, pyridinylamino, pyrrolidinyloxy, pyrrolidinyloxy, tetrahydropyranyloxy, where the heterocyclic substituents optionally substituted by alkyl, alkoxy, tetraallyloxyethane, alkylsulfonyl or alkoxycarbonylmethyl.

According to another preferred variant of the invention, preferred are compounds in which Ra-Rdindependently of one another denote hydrogen, alkenyl, quinil, alkoxy, and teracycline Deputy, selected from the group comprising morpholinylmethyl, piperidinyloxy, pyridinylamino, pyrrolidinyloxy, tetrahydropyranyloxy, where the heterocyclic Deputy optionally substituted by alkyl, alkoxy, tetraallyloxyethane, alkylsulfonyl or alkoxycarbonylmethyl.

In the most preferred embodiment, the invention relates to the above compounds in which X1refers to the group C(Ra), X2refers to the group C(Rb), X3refers to the group C(Rcand X4refers to a group (C(Rd).

The invention preferably includes the above compounds in which Radenotes hydrogen, carbamoylphenoxy, hydroxyalkoxy or halogen, preferably hydrogen.

In addition, the invention also preferably relates to the above compounds in which Rbdenotes hydrogen, alkenyl, quinil, alkoxy or alkyl, preferably alkoxy.

Further, the invention preferably relates to the above compounds in which Rcdenotes hydrogen, alkoxy, mono - or dialkylaminoalkyl or hydroxyalkoxy, preferably hydrogen or alkoxy.

Still in the Rddenotes hydrogen, alkoxy, hydroxyalkoxy, mono - or dialkylaminoalkyl or heterocyclic Deputy selected from the group comprising morpholinylmethyl, piperidinyloxy, pyridinylamino, pyrrolidinyloxyl or tetrahydropyranyloxy, where the heterocyclic substituents optionally substituted by alkyl or alkylsulfonyl.

In addition, the invention preferably relates to the above compounds in which one of the symbols G1and G2denotes hydrogen and the other denotes hydrogen, alkyl, hydroxy, alkoxy, aroyl or a group COO-Reor OCO-Reand Redenotes alkyl, optionally substituted with halogen, hydroxy-, alkoxy-, carboxypropyl, alkylcarboxylic or arylcarboxylic.

Preferred above compounds are compounds in which one of the symbols G1and G2denotes hydrogen or hydroxy and the other represents hydrogen. In a particularly preferred embodiment, both the symbol G1and G2denote hydrogen.

Also preferred are the above compounds in which R1denotes hydrogen.

Before the.

In the most preferred embodiment, preferred above compounds are compounds in which not more than two of the radicals Ra-Rdsimultaneously denote hydrogen.

According to another variant implementation of the invention includes the above compounds in which X1refers to the group C(Raand X2X3and X4independently of one another denote a group selected from the groups C(Rd), C(Rb) and C(Rc). In addition, the invention relates to the above compounds in which X2refers to the group C(Rband X1X3and X4independently of one another denote a group selected from the groups C(Rd), C(Ra) and C(Rc). In addition, the invention relates to the above compounds in which X3refers to the group C(Rcand X1X2and X4independently of one another denote a group selected from the groups C(Rd), C(Rb) and C(Ra). In addition, the invention relates to the above compounds in which X4refers to the group C(Rdand X1X2and X3independently of one another denote a group selected from the groups C (Ra), With (R

Preferred individual compounds are compounds selected from the group including:

a) (RS)-(4-carbamimidoyl)-[4-(2-dimethylaminoethoxy)-3-ethoxyphenyl] acetic acid;

b) (RS)- and (SR)-(4-carbamimidoyl)-[3-ethoxy-5-[(1-RS,2RS)-2-hydroxycyclopent]phenyl]acetic acid;

in) (RS)-(4-carbamimidoyl)-(3,5-diethoxy-2-forfinal)acetic acid;

g) (RS)-(4-carbamimidoyl)-[3-ethoxy-5-[(1-methylpiperidin-4-yloxy)phenyl]acetic acid;

d) (RS)- and (SR)-(4-carbamimidoyl)-[3-ethoxy-4-[(RS)-2-hydroxy-1-methylethoxy]phenyl]acetic acid;

e) (RS)- and (SR)-(4-carbamimidoyl)-[3-ethoxy-5-[(1RS,2RS)-2-hydroxycyclohexyl]phenyl]acetic acid;

W) (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(1-methanesulfonamido-4-yloxy)phenyl]acetic acid;

C) (4 carbamimidoyl)-[3-ethoxy-5-(tetrahydropyran-4-yloxy)phenyl]acetic acid;

and) (RS)-(4-carbamimidoyl)-(3-ethinyl-5-pyrrolidin-1-ylmethylene) acetic acid;

K) (RS)-(4-carbamimidoyl the laminitis)-(3-ethoxy-4-methoxyphenyl)acetic acid;

m) (RS)-(4-carbamimidoyl)-(2-fluoro-3,5-acid)acetic acid;

n) (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(pyridine-2-illuminometer)phenyl]acetic acid;

a) (RS)-(4-carbamimidoyl)-(3-ethoxy-5-morpholine-4-ylmethylene)acetic acid;

p) (RS)-(4-carbamimidoyl)-[3-ethoxy-4-(2-hydroxyethoxy)phenyl] acetic acid;

R) (RS)-(4-carbamimidoyl)-[4,5-diethoxy-2-(2-hydroxyethoxy)phenyl]acetic acid;

C) (RS)-(4-carbamimidoyl)-[3-(3-dimethylamino-2,2-DIMETHYLPROPANE)-5-ethylphenyl]acetic acid;

t) (RS)-(4-carbamimidoyl)-[3-ethoxy-4-(2-hydroxyethoxy)phenyl] acetic acid;

y) (RS)-(4-carbamimidoyl)-[4,5-diethoxy-2-(3-hydroxypropoxy)phenyl] acetic acid and

f) (RS)-(4-carbamimidoyl)-(2-carbamoylphenoxy-4,5-dioxyphenyl)acetic acid.

The compounds of formula I can be obtained by conversion of the nitrile group in a compound of formula II

< / BR>
where X1X2X3X4, R1and E have the above values,

in carbamimidoyl group or N-hydroxycarbamoyl group and, if necessary, by modification of reactive groups, prisutstvuut physiologically compatible salt or conversion of salts of the compounds of formula I in free acid or base.

The transformation of the nitrile group in a compound of formula II in carbamimidoyl group-C(NH)NH2or N-hydroxycarbamoyl group-C(NOH)NH2can be made well-known methods. For example, the conversion of N-hydroxycarbamoyl group can be carried out by dissolving the compounds of formula II in a solvent such as DMF, ethanol or methanol, treatment of a solution of hydroxylamine or hydroxylamine salt with inorganic acid, such as hydroxylamine hydrochloride, and after this grounds, such as diisopropylethylamine or triethylamine, sodium hydride or methanolate sodium, usually at a temperature of 80oC.

The conversion of nitrile groups in carbamimidoyl group can be carried out, for example, by treating the compounds of formula II in a solvent such as ethanol or methanol, or a mixture of solvents, such as chloroform and methanol or chloroform and ethanol stream of anhydrous hydrogen chloride, usually at temperatures below 10oWith subsequent processing of the reaction solution with a solvent, such as diethyl ether, and filtration sudivshegosya of aminoether. Thus obtained product is treated in a solvent such atemperature up to 80oC. In the alternative containing iminoethyl solution can be one stripped off and the residue may be treated with gaseous ammonia or an ammonium salt in methanol or ethanol. Similarly, iminoethyl can be converted into N-hydroxycarbonylmethyl derivative of the formula I with hydroxylamine or its salts in the presence of a base.

As modifications of functional groups present in the compound of formula I, can be considered first and foremost the transformation of N-hydroxycarbamoyl group in carbamimidoyl group, etherification of carboxypropyl to complex ester, saponification of the ester group and the splitting of groups of simple ether, such as simple arylalkyl ether group, for example a simple benzyl ether. All these reactions can be carried out in well-known methods.

For the conversion of N-hydroxycarbamoyl group in carbamimidoyl group amidoxime formula I may be subjected to hydrogenation in a solvent such as ethanol, methanol, dioxane, THF or glacial acetic acid, or a mixture of solvents, such as ethanol and glacial acetic acid, with hydrogen in the presence of a catalyst, such as PA is adequate in the compound of formula I, which have reactivity against reductant. For example, in the case of hydrogenation in the presence of palladium benzyloxy Ra, Rd, Rcor Rdturn to the hydroxy-group.

By reacting the compounds of formula I, in which G1and G2denote hydrogen, ether Harborview acid of the formula Cl(O)O-Rewhere Rehas the above values and where the hydroxy - or carboxypropyl present in protected form, in a solvent such as dichloromethane, dioxane or DMF, or a mixture of solvents, such as dichloromethane and water or ethyl acetate and water, in the presence of an organic base such as pyridine or triethylamine, or inorganic bases such as sodium hydroxide, sodium carbonate or potassium bicarbonate, receive a corresponding compound of formula I, in which G1and G2denotes the group-C(O)O-Re. Similarly, the compound of formula I, where G1and G2denote hydrogen, can be converted by means of steam-nitrophenylarsonic formulas para-NO2C6H4OCOO-Reinto the corresponding compound of formula I, where one of the radicals G1and G2denotes-CO is tiramina, and then the compound of the formula I, where1and G2denote hydrogen.

By reacting the compounds of formula I, in which G1and G2denote hydrogen, acylchlorides, such as Aronhold, receive a corresponding compound of formula I in which one of the radicals G1and G2denotes hydrogen and the other represents acyl. The reaction is carried out by processing acylchlorides in THF and DMF first N,N-diisopropylethylamine, and then the compound of the formula I, where G1and G2denote hydrogen.

The compounds of formula I, in which G1or G2denote the group-COO-Reand Redenotes alkyl, substituted alkylcarboxylic or aroiaterapii, can be obtained by well known methods (Synthesis, 1990, S. 1159-1166; J. Med. Chem. 31, S. 318-322, 1988) by reacting carbamimidoyl derived from steam-nitrophenylacetylene.

By reacting the compounds of formula I in which one of the radicals G1and G2represents hydroxy and the other represents hydrogen, allelochemical can be obtained compound of formula I, where one of the radicals G1and G2means-OCORe. The reaction is carried out by processing SUP> denote hydrogen.

The compounds of formula II can be obtained by well known methods, for example, presented below in the present description and/or described in the examples or in analogy to these methods. For example, the aldehyde of formula III

< / BR>
where X1X2X3and X4have the above values,

may be subjected to interaction with para-aminobenzonitrile formula IV

< / BR>
where E has the above value,

and benzylideneamino and primary alkanols, such as methanol or ethanol, in the presence of epirate of boron TRIFLUORIDE. By hydrolysis of the resulting aminoether with water get compound of formula II in which R1denotes methyl or ethyl. By hydrolysis of the ester group R1, for example by treatment with LiOH in tetrahydrofuran, get the connection formula II in which R1denotes hydrogen.

To obtain compounds of the formula II used the following reactions.

By reacting compounds of formula II in which one or more radicals Ra-Rd< / BR>
means(ut) allylthiourea, with an oxidant such as meta-chloroperbenzoic acid or ozone, in a suitable rastvoritelyami in alkylsulfonyl or alkylsulfonyl group;

means(ut) alkoxygroup, such as methoxy, isopropoxy or benzyloxy, with a Lewis acid, such as tribromide bromine or trichloride bromine, in a suitable solvent, such as methylene chloride, or optional by catalytic hydrogenation, for example, ethyl acetate or ethanol, to obtain the compounds of formula II in which alkoxygroup converted into the hydroxy-group;

means(comply) with the hydroxy-group,

with an alkylating agent such as allylbromide, alkylated or alkalmazasa, in the presence of a base such as potassium carbonate or cesium carbonate, in a solvent such as DMF or acetone, or

by the reaction of Mitsunobu using alcohol in the presence of DEAD and triphenylphosphine in a solvent such as THF or dioxane, or

through interaction with the epoxide, such as Cyclopentanone, in the presence of a base such as potassium carbonate, preferably at temperatures up to 150oTo obtain compounds of formula II, in which the hydroxy-group transformed into alkoxygroup;

means(comply) with the hydroxy-group, with an aryl - or heteroarylboronic acid, such as phenylboronic acid or 3-pyridylboron acid, in the presence of copper acetate and a base such is x converted into a hydroxy-group aryloxy or heteroepitaxy;

means(ut) hydroxy, anhydride triftormetilfullerenov acid in the presence of a base such as pyridine or triethylamine, in a suitable solvent, such as methylene chloride or THF, and by subsequent interaction with the aryl or heteroarylboronic acid, such as pyridineboronic acid or tiefenbronn acid, in the presence of a suitable catalyst, such as tetrakis(triphenylphosphine) palladium, in a solvent such as toluene, preferably at a temperature of up to 100oTo obtain compounds of formula II, in which the hydroxy-group converted into aryl or heteroaryl group;

means(comply) with the nitro-group by catalytic hydrogenation in the presence of a catalyst, for example palladium on charcoal, in a solvent such as ethanol or THF, to obtain the compounds of formula II, in which the nitro-group is converted into the amino group;

denotes an amino group,

with an alkylating agent such as alkylhalogenide or alkalmazasa, in the presence of a base, such as base Hunga or triethylamine, in a solvent such as THF, preferably at elevated temperature, or

- with carbonyl derivatives, such as pyridinecarboxamide or 1-methyl-4-PI is com as ethyl acetate, or

- epoxide, such as, for example, Cyclopentanone, in the presence of perchlorate, such as lithium perchlorate in a solvent such as acetonitrile, preferably at elevated temperature, obtain the compounds of formula II in which the amino group is transformed into alkylamino or dialkylamino;

means(comply) with the amino group, with an acid chloride, such as the acid chloride cyclopentanecarbonyl acid, vinylsulfonate or butylsulfide-illorin, in the presence of a base such as triethylamine or base Hunya, in an inert solvent, such as THF or methylene chloride, to obtain the compounds of formula II in which the amino group is transformed into amide or sulfonamidnuyu, or sulfa group;

means(comply) with the amino group, with an isocyanate, such as, for example, utilitzant, in a suitable solvent, such as THF, to obtain the compounds of formula II in which the amino group is transformed into urea;

means(ut) halogen,

from a derivative of acetylene, such as, for example, trimethylsilylacetamide, in the presence of palladium acetate and triphenylphosphine in a solvent such as triethylamine,

by reaction the Steele with stannane, such as, for example, allyltrimethylsilane or three is rastvoritele, such as dimethylacetamide, preferably at elevated temperatures, get the compounds of formula II, in which Deputy representing halogen, converted into allyl, or alkylamino, or vinyl group;

means(ut) halogen, by a Suzuki reaction with an aryl - or heteroarylboronic acid, such as phenylboronic acid or 3-pyridylboron acid, in the presence of tetrakis(triphenylphosphine)palladium and a base such as potassium carbonate, in a solvent such as toluene or dioxane, to obtain the compounds of formula II, in which Deputy representing halogen, converted into aryl or heteroaryl group;

means(ut) halogen, ether Bronevoy acid, such as bis(pinacolato)diboron, in the presence of potassium acetate and chloride bis(triphenylphosphine)palladium(II) in a solvent such as dioxane, and the subsequent interaction with the aryl - or heteroarylboronic, such as, for example, 3-bromopyridin, in the presence of potassium carbonate and tetrakis(triphenylphosphine)palladium in a solvent such as toluene, at elevated temperature produces the compounds of formula II, in which Deputy representing halogen, converted into aryl or heteroarylboronic, for example palladium on charcoal, in a solvent such as ethanol, ethanolicus acid or THF, to obtain the compounds of formula II in which Alchemilla or Alchemilla group is restored to the alkyl group;

means(ut) vinyl, by the reaction of adding rings (3+2) using, for example, nitroethane and di-tert-BUTYLCARBAMATE, in the presence of dimethylaminopyridine in a solvent such as acetonitrile, to obtain the compounds of formula II, in which the vinyl group is converted into dihydroisoxazole group;

means(ut) hydroxymethyl, methanesulfonamido in the presence of a base such as triethylamine and in a solvent such as methylene chloride or THF, and the subsequent interaction with a suitable amine, such as, for example, pyrrolidine or morpholine in a solvent such as THF, to obtain the compounds of formula II in which hydroxymethylene group is converted into a mono - or dialkylaminomethyl group;

mark(s) hydroxymethyl, with an oxidant, such as oxacillin and dimethylsulfoxide, in the presence of triethylamine and in a solvent such as methylene chloride, preferably at a low temperature, obtain the compounds of formula II in which hydroxymethylene group turned into siltstone, such as, for example, bromide methyldiphenylphosphine, in the presence of a base, such as potassium carbonate, in a solvent such as a mixture of dioxane-water, preferably at elevated temperature, obtain the compounds of formula II, in which the formyl group is converted into alkenylphenol group;

means(ut) formyl, with an amine, such as, for example, pyrrolidin, and with a suitable reducing agent, such as, for example, lambrogini sodium in a solvent such as methanol, when the pH value is brought to 6, for example, using acetic acid to obtain compounds of formula II, in which the formyl group is converted into acylaminoalkyl group;

means(ut) formyl,

- 1,2-diamine, such as, for example, 1,2-phenylenediamine in the presence of an oxidant such as DDQ, in a solvent such as acetonitrile, or

with glyoxal and ammonia in a mixture of water-ethanol compounds of the formula II, in which the formyl group is converted into imidazolidinyl group;

means(ut) benzyloxycarbonyloxy, by catalytic hydrogenation in the presence of a catalyst, for example palladium on charcoal, in a solvent such as a mixture of ethanol-acetic acid to obtain the compounds of formula II, in which alkoxygroup, with an amine, such as, for example, pyrrolidine or morpholine, and a binder, such as, for example, BOP, in the presence of a base such as 4-ethylmorpholine, and in a solvent such as DMF, to obtain the compounds of formula II in which carboxitherapy turned into carbamoyloximes.

The compounds of formula III are well known. They can be obtained, for example, by reacting compounds of the formula III, in which one or more radicals Ra-Rdmeans(comply) with the hydroxy-group,

with an alkylating agent such as, for example, benzylbromide or ethylbromide, in the presence of a base such as potassium carbonate or cesium carbonate, in a suitable solvent, such as DMF or acetone, preferably at elevated temperature, or

by the reaction of Mitsunobu with alcohol in the presence of DEAD and triphenylphosphine in a solvent such as THF or dioxane, to obtain the compounds of formula II, in which the hydroxy-group transformed into alkoxygroup;

means(ut) formyl group, through a Wittig reaction with a halide alkyldiphenylamine, such as, for example, bromide methyldiphenylphosphine, in the presence of a base, such as potassium carbonate, in races of the formula II, in which the formyl group is converted into alkenylphenol group.

The compounds of formula III in which one of the radicals Ra-Rdindicates alkylthio or 1-hydroxyalkyl, can also be obtained by reacting aldehyde protected as acetal or amines, where considered radical of Ra-Rddenotes hydrogen, bromine or iodine, with a strong base, such as, for example, utility, for example, THF, and then interact with disulfides, such as, for example, dimethyl disulfide in a solvent such as THF, or aldehydes, such as acetaldehyde, and subsequent removal of the protective group of the aldehyde function with aqueous acid.

The compounds of formula III can also be obtained by

- formirovaniya appropriately substituted aromatic compounds using conventional methods such as reaction of Vilsmeier, interaction with titanium tetrachloride and simple methyldichlorosilane ether, interaction with chloroform-sodium hydroxide or with hexamethylenetetramine and acetic acid;

- oxidation of benzyl alcohol with known methods, for example with manganese dioxide;

interaction that is to interact with 2-nitropropane in the presence of a base, such as sodium ethylate.

In that case, if their receipt is not described in the examples, the compounds of formulas III and IV can be obtained by the above methods or similar methods.

The compounds of formula I, a solvate and salts inhibit the formation of coagulation factors XA, Ha and thrombin induced by factor VIIa and tissue factor. Therefore, these compounds have an effect on platelet aggregation, which is induced by these factors, and plasma coagulating blood. As a result, they inhibit the formation of blood clots and can be used for treating or preventing diseases such as thrombosis, apoplexy, heart attack, inflammation and arteriosclerosis. In addition, these compounds have effects on tumor cells and prevent metastases. Therefore, they can also be used as antitumor agents.

Thus, the present invention relates also to pharmaceutical compositions containing the above-described connection, intended for the introduction of the galenical form.

The invention also includes the above-described compounds intended for use as medicines, pria and tissue factor primarily as medicines for the treatment or prevention of thrombosis, apoplexy, heart attack, inflammation and arteriosclerosis or as anticancer agents.

In addition, the invention relates to the use of the above compounds for the preparation of medicines containing the above compound for the treatment or prevention of thrombosis, apoplexy, heart attack, inflammation and arteriosclerosis or as anticancer agents.

Inhibition amylolyticus activity of a complex of factor VIIa/tissue factor compounds according to the invention can be demonstrated using the chromogenic peptide substrate as described below.

The measurements were carried out using titration microplate at room temperature. For this purpose, 100 μl of a solution containing 26 nm tissue factor, 9 nm soluble factor VIIa and 8 mm of calcium chloride, was added to each well of the tablet to 25 μl of a solution of the inhibitor in the buffer [pH 7.5, 100 mm buffer containing about 0.14 M NaCl, 0.1 M N-(2-hydroxyethyl)piperazine-N'-(2-econsultancy acid) (HEPES), 0.5 mg/l not containing fatty acid bovine serum is i.i.d. substrate Chromozym-tPA (3.5 mm, MeSO2-D-Phe-Gly-Arg-para-nitroanilide) and within 10 min were evaluated by the hydrolysis of the substrate by a spectrophotometric method using kinetic tablet reader for titration microplate. The values of Ki were determined based on the dependency graph of inhibition according to the method described in Biochem. J. 55, 170-171, 1953. The results are presented below (Ki expressed in μm/l):

Example - Ki

4.e - 0,061

15 - 0,084

17 - 0,0385

26.e - 0,1144

Furthermore, the activity of substances with low molecular weight can be determined in the experience of assessment of coagulation with the definition of "prothrombin time" (RT). Substances used in the form of a 10 mm solution in DMSO or DMSO/0.1 M Hcl (DHCl) and then prepare the required dilution with the same solvent. Then 0.25 ml of human plasma obtained from whole blood, antikoagulyantnoe using 1/10 volume 108 mm sodium citrate) were placed in special designed for the measurement container. Then with this plasma for each variant were mixed in 5 μl of each serial dilution of the substance. The resulting mixture plasma/inhibitor were incubated for 2 min at 37oC. After that, in the measuring container semi-automatic device (firm ACL by adding 0.1 ml of Innovin(recombinant human tissue factor, combined with the calcium buffer and synthetic phospholipids (company Dade Behring, Inc.). The period of time prior to the crosslinking of fibrin was determined by photo-optical device firms ACL. The concentration of inhibitor that causes a doubling of the clotting time RT were determined using the graph.

The value of Ki compounds of the present invention is preferably about 0.1 to 500 nm, more preferably approximately 0.1-100 nm. The value of RT is preferably approximately 0.1 to 10 μm, more preferably about 0.1-5 microns.

As described above, an object of the present invention are also medicinal product containing a compound of formula I, its MES or salt, as well as the method of obtaining such medicines, providing for the preparation of galenical form for introduction on the basis of one or more such compounds, solvate, or salt, and optionally with other therapeutic active substances. These drugs can be administered orally, for example in the form of tablets, gelatin capsules, hard and soft coating solutions, em who may be parenteral, for example in the form of injectable solutions.

For the preparation of tablets, coated tablets (filmtabletten), tablets and gelatin capsules with solid surface active substance can be mixed with pharmaceutically inert inorganic or organic excipients. Suitable excipients for tablets, filmtabletten, tablets and gelatin capsules with a hard coating are, for example, lactose, corn starch or its derivatives, talc, stearic acid or its salts. Suitable excipients for gelatin capsules with a soft coating are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols; however, depending on the nature of the active substance for gelatin capsules, soft coated usually do not require any of the excipients. Suitable excipients for the preparation of solutions and syrups are, for example, water, polyols, saccharose, invert sugar and glucose; suitable excipients for injection solutions are, for example, water, alcohols, polyols, glycerine and vegetable oils, and suitable excipients for suppositories are natural and hydrogenated oils, waxes, fats, semi-liquid or liquid polyols. In addition, plenty, emulsifiers, sweeteners, colorants, corrigentov, salts for modifying the osmotic pressure, buffers, agents for coating or antioxidants.

The dose of the active substance for treating or preventing the above diseases may vary within wide limits and should, of course, be adapted to the individual requirements in each particular case. As a rule, in the case of oral or parenteral, e.g. intravenous or subcutaneous injection, for adults suitable dose of approximately 0.1 to 20 mg/kg, preferably approximately 0.6 to 4 mg/kg per day, although the above upper limit may be exceeded, or the dose may be reduced if it is shown.

Below the invention is illustrated in the examples.

Example 1.

1.1. A solution of 1.19 g of 3,5-dimethoxybenzaldehyde and 0,7234 g of 4-aminobenzonitrile in 20 ml of methanol was stirred at room temperature. After 1 h was added 0.75 ml of benzylideneamino. The resulting solution was cooled to 0oWith, and then was added dropwise 2,33 ml epirate boron TRIFLUORIDE such a way that the temperature did not exceed 10oC. the Reaction mixture was stirred at room temperature the received solution was stirred at room temperature for 2 h, and then concentrated. The crude product was isolated by extraction and purified by chromatography on silica gel, thus received 1.66 g of methyl ester of (RS)-(4-cyanovinylene)-(3,5-dioxyphenyl)acetic acid in the form of a brown foam.

1.2. 22,9 ml of 1 n LiOH solution was added to a solution of the compound obtained as described in example 1.1, in 25 ml of tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 h THF is evaporated, the resulting aqueous solution was acidified using 1 ad model HC1 and extracted with ethyl acetate. The crude product is precipitated with addition of a mixture of ethyl ether and cyclohexane, were received 1.29 g (RS)-(4-cyanovinylene)-(3,5-dioxyphenyl)acetic acid as a solid substance.

1.3. 2,61 g of hydroxylamine hydrochloride and 10.5 ml of triethylamine was added to a solution of 1.28 g of the compound obtained as described in example 1.2, in 26 ml of ethanol. The resulting solution was boiled under reflux overnight and then concentrated. The obtained residue was purified by chromatography on silica gel, thus received 0.74 g (E)- and/or (Z)-(RS)-(3,5-dioxyphenyl)-[4-(N-hydroxycarbamoyl)phenylamino]exuses 4 ethoxy-3-methoxybenzaldehyde, 4-aminobenzonitrile and benzylideneamino received the methyl ester of (RS)-(4-cyanovinylene)-(4-ethoxy-3-methoxyphenyl)acetic acid, from which through the intermediate formation of (RS)-(4-cyanovinylene)-(4-ethoxy-3-methoxyphenyl)acetic acid was obtained (E)- and/or (Z)-(RS)-(4-ethoxy-3-methoxyphenyl)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid;

2. b) from 4-benzyloxy-3-ethoxybenzaldehyde, 4-aminobenzonitrile and benzylideneamino received the methyl ester of (RS)-(4-benzyloxy-3-ethoxyphenyl)-(4-cyanoaniline) acetic acid, from which through the intermediate formation of (RS)-(4-benzyloxy-3-ethoxyphenyl)-(4-cyanoaniline)acetic acid was obtained (E)- and/or (Z)-(RS)-(4-benzyloxy-3-ethoxyphenyl)-[4-(N-hydroxycarbamoyl)phenylamino] acetic acid;

2. in) from 3,5-dimethoxybenzaldehyde, 4-amino-2-hydroxybenzonitrile (obtained by hydrogenation over Pd/C 2-hydroxy-4-nitrobenzonitrile (W. Borsche, Ann. Chem. , 390, 1 (1912)) and benzylideneamino received the methyl ester of (RS)-(4-cyano-3-hydroxytyramine)-(3,5-acid) acetic acid, from which through the intermediate formation of (RS)-(4-cyano-3-hydroxytyramine)-(3,5-acid)acetic acid was obtained (E)- and/or (Z)-(RS)-(3,5-acid)-[3-hydroxy-4-(N-hydroxycarbamoyl)-(4-cyano-3-hydroxytyramine)-(3,5-acid)acetic acid, from which through the intermediate formation of (RS)-(4-cyanoaniline)phenylacetic acid was obtained (E)- and/or (Z)-(RS)-[4-(N-hydroxycarbamoyl)phenylamino]phenylacetic acid;

2. d) from 4-benzyloxy-3-methoxybenzaldehyde, 4-aminobenzonitrile and benzylideneamino received the methyl ester of (RS)-(4-benzyloxy-3-methoxyphenyl)-(4-cyanoaniline)acetic acid, from which through the intermediate formation of (RS)-(4-benzyloxy-3-methoxyphenyl)-(4-cyanoaniline)acetic acid was obtained (E)- and/or (Z)-(RS)-(4-benzyloxy-3-methoxyphenyl)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid;

2.e) of the methyl ester of 4-(4-formyl-2-methoxyphenoxy)benzoic acid, 4-aminobenzonitrile and benzylideneamino received methyl ether (RS)-4-[4-[(4-cyanoaniline)methoxycarbonylmethyl] -2-methoxyphenoxy] benzoic acid, from which through the intermediate formation of (RS)-4-[4-[carboxy(4-cyanoaniline)methyl] -2-methoxyphenoxy] benzoic acid was obtained (E)- and/or (Z)-(RS)-4-[4-[carboxy[4-(N-hydroxycarbamoyl)phenylamino] methyl] -2-methoxyphenoxy]benzoic acid;

2.g of 3,5-triftormetilfullerenov, 4-aminobenzonitrile and benzylideneamino received the methyl ester of (RS)-(3,5-bis-triptoreline)-(4-cyanoaniline) acetic Ki is islote was obtained (E)- and/or (Z)-(RS)-(3,5-bis-triptoreline)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid.

Example 3.

A solution of 0.3 g of the compound obtained as described in example 1.3, 6 ml of ethanol, 3 ml of dimethylformamide (DMF), 5 ml water and 5 ml of acetic acid was first made for 4 h in the presence of catalytic amounts of one of the catalytic amount of Raney Nickel. Then the reaction mixture was filtered, the crude product was purified by chromatography on silica gel, was obtained 0.12 g of (RS)-(4-carbamimidoyl)-3,5-dioxyphenyl)acetic acid in the form of a solid light gray color.

Example 4. Analogously to example 3

4. a) from the compound obtained as described in example 2.and got acetate (RS)-(4-carbamimidoyl)-(4-ethoxy-3-methoxyphenyl)acetic acid (1:1);

4. b) from the compound obtained as described in example 2.6, got acetate (RS)-(4-benzyloxy-3-ethoxyphenyl)-(4-carbamimidoyl)acetic acid (1:1);

4. in) from the compound obtained as described in example 2.in, got acetate (RS)-(4-carbamimidoyl-3-hydroxytyramine)-(3,5-acid)acetic acid (1:1);

4. g) from the compound obtained as described in example 2.g was obtained (RS)-(4-carbamimidoyl)phenylacetic acid;

4. d) from the compound obtained as described in example 2D, is obtained, as described in example 2.E., got acetate (RS)-4-[4-[(4-carbamimidoyl)carboxymethyl]-2-methoxyphenoxy] benzoic acid (1:1);

4. W) of the compound obtained as described in example 2.W, was obtained (RS)-(3,5-bis-triptoreline)-(4-carbamimidoyl)acetic acid.

Example 5.

5.1. Analogously to example 1.1 methyl ester 5-formyl-2,3-dimethoxybenzoic acid (Wu F. Y., D. L. Brink, J. Agric. Food. Chem., 25, 692 (1977)) were introduced in the reaction with 4-aminobenzonitrile and benzylideneamino, when it received the methyl ester of (RS)-5-[(4-cyanoaniline)methoxycarbonylmethyl] -2,3-dimethoxybenzoic acid.

5.2. Analogously to example 1.2 from the compound obtained as described in example 5.1, obtained methyl ester (E)- and/or (Z)-(RS)-5-[[4-(N-hydroxycarbamoyl)phenylamino] methoxycarbonylmethyl] -2,3-dimethoxybenzoic acid.

5.3. Analogously to example 3 from the compound obtained as described in example 5.2, got acetate methyl ester (RS)-5-[(4-carbamimidoyl)methoxycarbonylmethyl]-2,3-dimethoxybenzoic acid (1:1).

5.4. Analogously to example 1.2 from the compound obtained as described in example 5.3, received the methyl ester of (RS)-5-[(4-carbamimidoyl)carboxymethyl]-2,3-dimethoxy is eakly 4-aminobenzonitrile and benzylideneamino, it was obtained methyl ester of (RS)-(4-cyanovinylene)-(3, 5dimethylphenyl)acetic acid. Analogously to example 1.2 from this compound was obtained (RS)-(4-cyanovinylene)-(3, 5dimethylphenyl)acetic acid.

6.2. A solution of 0.5 g of the compound obtained as described in example 6.1, 20 ml l3/methanol (5:1) was cooled to 0oC. Then through the reaction mixture for 20 min was passed dry gaseous hydrogen chloride, kept at 4oC for 2 days and concentrated. The residue was dissolved in 200 ml of a saturated solution of ammonia in methanol was heated under reflux for 3 h and concentrated. The residue was led from ethyl acetate, to receive 0,552 g of methyl ester hydrochloride (RS)-(4-carbamimidoyl)-(3, 5dimethylphenyl)acetic acid (1:1) in the form of a solid crystalline substance.

6.3. Analogously to example 1.3 from the compound obtained as described in example 6.2, got hydrochloride, (RS)-(4-carbamimidoyl)-(3, 5dimethylphenyl)acetic acid (1:1).

Example 7. Analogously to example 6

7. a) 3,4-dimethylbenzaldehyde was introduced in the reaction with 4-aminobenzonitrile and benzylideneamino, when it received the methyl ester of (RS)-(4-cyanovinylene)-(3,4-Enyl)acetic acid and methyl ester hydrochloride (RS)-(4-carbamimidoyl)-(3,4-dimetilfenil)acetic acid (1: 1) received hydrochloride, (RS)-(4-carbamimidoyl)-(3,4-dimetilfenil)acetic acid (1:1);

7.b) 3,4-diethoxybenzene was introduced in the reaction with 4-aminobenzonitrile and benzylideneamino, when it received the methyl ester of (RS)-(4-cyanovinylene)-(3,4-dioxyphenyl)acetic acid, from which through the intermediate formation of (RS)-(4-cyanovinylene)-(3,4-dioxyphenyl)acetic acid and methyl ester hydrochloride (RS)-(4-carbamimidoyl)-(3,4-dioxyphenyl)acetic acid (1: 1) was obtained (RS)-(4-carbamimidoyl)-(3,4-dioxyphenyl)acetic acid;

7. C) 3,4-dimethoxybenzaldehyde was introduced in the reaction with 4-aminobenzonitrile and benzylideneamino, when it received the methyl ester of (RS)-(4-cyanovinylene)-(3,4-acid)acetic acid, from which through the intermediate formation of (RS)-(4-cyanovinylene)-(3,4-acid) acetic acid and methyl ester hydrochloride (RS)-(4-carbamimidoyl)-(3,4-acid)acetic acid (1: 1) received hydrochloride, (RS)-(4-carbamimidoyl)-(3,4-acid)acetic acid (1:1);

7. g) 3,5-dimethoxybenzaldehyde was introduced in the reaction with 4-aminobenzonitrile and benzylideneamino, when it received the methyl ester of (RS)-(4-cyanovinylene)-(3,5-acid)acetic acid, from which through the intermediate formation of (RS)-(4-CANopen,5-acid)acetic acid (1: 1) received hydrochloride, (RS)-(4-carbamimidoyl)-(3,5-acid)acetic acid (1:1);

7. d) 3,5-dichlorobenzaldehyde was introduced in the reaction with 4-aminobenzonitrile and benzylideneamino, when it received the methyl ester of (RS)-(4-cyanovinylene)-(3,5-dichlorophenyl)acetic acid, from which through the intermediate formation of (RS)-(4-cyanovinylene)-(3,5-dichlorophenyl)acetic acid and methyl ester hydrochloride (RS)-(4-carbamimidoyl)-(3,5-dichlorophenyl)acetic acid (1: 1) received hydrochloride, (RS)-(4-carbamimidoyl)-(3,5-dichlorophenyl)acetic acid (1:1);

7.(e) 4,5-dimethoxy-2-forbindelse was introduced in the reaction with 4-aminobenzonitrile and benzylideneamino, when it received the methyl ester of (RS)-(4-cyanovinylene)-(2-fluoro-4,5-acid)acetic acid, from which through the intermediate formation of (RS)-(4-cyanovinylene)-(2-fluoro-4,5-acid)acetic acid and methyl ester hydrochloride (RS)-(4-carbamimidoyl)-(2-fluoro-4,5-acid)acetic acid (1:1) received hydrochloride, (RS)-(4-carbamimidoyl)-(2-fluoro-4,5-acid)acetic acid (1:1);

7.g) 3-ethoxy-4-methoxybenzaldehyde was introduced in the reaction with 4-aminobenzonitrile and benzylideneamino, when it received the methyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-4-methoxyphenyl)acetic acid, from which cartilage ether (RS)-(4-carbamimidoyl)-(3-ethoxy-4-methoxyphenyl)acetic acid (1: 1) received hydrochloride, (RS)-(4-carbamimidoyl)-(3-ethoxy-4-methoxyphenyl) acetic acid (1:1);

7. C) 2,6-dimethoxypyridine-4-aldehyde (Kompis I., Muller W., Bohni E., R. Then , Montavon, M., Eur. J. Chem.-Chim. Ther., 12, 531 (1977)) were introduced in the reaction with 4-aminobenzonitrile and benzylideneamino, when it received the methyl ester of (RS)-(4-cyanovinylene)-(2,6-dimethoxypyridine-4-yl)acetic acid, from which through the intermediate formation of (RS)-(4-cyanovinylene)-(2,6-dimethoxypyridine-4-yl)acetic acid and methyl ester hydrochloride (RS)-(4-carbamimidoyl)-(2,6-dimethoxypyridine-4-yl)acetic acid (1: 1) received hydrochloride, (RS)-(4-carbamimidoyl)-(2,6-dimethoxypyridine-4-yl)acetic acid (1:1) and

7. and 3,5-dimethoxybenzaldehyde was introduced in the reaction with 3-aminobenzonitrile and benzylideneamino, when it received the methyl ester of (RS)-(3-cyanovinylene)-(3,5-acid)acetic acid, from which through the intermediate formation of (RS)-(3-cyanovinylene)-(3,5-acid)acetic acid and methyl ester hydrochloride (RS)-(3-carbamimidoyl)-(2,6-acid)acetic acid (1: 1) received hydrochloride, (RS)-(3-carbamimidoyl)-(3,5-acid)acetic acid (1:1).

Example 8.

8.1. Analogously to example 1.1, the 3-benzyloxy-5-methoxybenzaldehyde was introduced in the reaction with 4-aminobenzonitrile and basilicon

8.2. Analogously to example 1.2 from the compound obtained as described in example 8.1 was obtained (RS)-(3-benzyloxy-5-methoxyphenyl)-(4-cyanoaniline)acetic acid.

8.3. Analogously to example 1.2 from the compound obtained as described in example 8.2, got hydrochloride methyl ester (RS)-(3-benzyloxy-5-methoxyphenyl)-(4-carbamimidoyl)acetic acid (1:1) and the hydrochloride of the methyl ester of (RS)-(4-carbamimidoyl)-(3-hydroxy-5-methoxyphenyl)acetic acid (1:1).

8.4. Analogously to example 1.2 from the first compound, obtained as described in example 8.3, got hydrochloride, (RS)-(3-benzyloxy-5-methoxyphenyl)-(4-carbamimidoyl)acetic acid (1:1), and from the second connection, obtained as described in example 8.3, got hydrochloride, (RS)-(4-carbamimidoyl)-(3-hydroxy-5-methoxyphenyl)acetic acid (1:1).

Example 9.

Analogously to example 8 3-benzyloxy-5-methoxybenzaldehyde was introduced in the reaction with 4-aminobenzonitrile and benzylideneamino, when it received the methyl ester of (RS)-(3-benzyloxy-5-methoxyphenyl)-(4-cyanoaniline)acetic acid. Then from this compound was obtained (RS)-(3-benzyloxy-5-ethoxyphenyl)-(4-cyanoaniline)acetic acid, from which catiline)acetic acid (1:1) received hydrochloride, (RS)-(3-benzyloxy-5-ethoxyphenyl)-(4-carbamimidoyl)acetic acid (1:1), and through the intermediate formation of methyl ester hydrochloride (RS)-(4-carbamimidoyl)-(3-ethoxy-5-hydroxyphenyl)acetic acid (1: 1) received hydrochloride, (RS)-(4-carbamimidoyl)-(3-ethoxy-5-hydroxyphenyl)acetic acid (1:1).

Example 10.

10.A. A solution of 0.5 g of (RS)-(4-cyanovinylene)-(3,4-dioxyphenyl)acetic acid (see example 7. b) in 24 ml l3/methanol (5:1) was cooled to 0oAnd then after the solution was passed a stream of dry gaseous model HC1. Then the reaction mixture is kept atoC for 1 day and concentrated. The residue was dissolved in CH2Cl2and washed with saturated solution of NaHCO3. The organic phase was dried over Na2SO4and filtered. The filtrate was concentrated, the residue was dissolved in ethanol. The solution was treated 1,02 g of hydroxylamine hydrochloride and 4.1 ml of triethylamine. The reaction mixture is boiled under reflux for 3 hours the Crude product was extracted and was led from diethyl ether, was obtained 0.27 g of methyl ester of (E)- and/or (Z)-(RS)-(3,4-dioxyphenyl)-[4-(N-hydroxycarbamoyl)phenylamino] acetic acid in the form of a crystalline solid.

10.B. Analogously to example 17.and hydrochlorid (E)- and/or (Z)-(RS)-(3,5-acid)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid (1:1).

Example 11. Analogously to example 1.3

11. (a) from (RS)-(4-cyanovinylene)-(3,4-dioxyphenyl)acetic acid (see example 7. b) was obtained (E)- and/or (Z)-(RS)-(3,4-dioxyphenyl)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid and

11.6) of (RS)-(4-cyanovinylene)-(3,5-acid)acetic acid (see example 7.g) was obtained (E)- and/or (Z)-(RS)-(3,5-acid)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid.

Example 12.

12.1. 0,808 ml of ethyl ether bromoxynil acid and 1 g of potassium carbonate were added to a solution of 838 mg of 2-hydroxy-4,5-dimethylbenzaldehyde (J. Chem. Soc. , 820 (1953)) in 150 ml of acetone. The resulting suspension was heated under reflux overnight, filtered and the obtained filtrate was concentrated. The crude product was isolated by extraction and purified by chromatography on silica gel, thus received 952 mg of ethyl ester of (2-formyl-4,5-dimethylphenoxy)acetic acid in the form of a solid of light yellow color.

12.2. Analogously to example 1, the compound obtained as described in example 12.1, was introduced in the reaction with 4-aminobenzonitrile and benzylideneamino, when it received the methyl ester of (RS)-(4-cyanovinylene)-(2-ethoxycarbonylmethoxy-4,5-dimetilfenil)acetic acid. Then what about)acetic acid was obtained (E)- and/or (Z)-(RS)-(2-carboxymethoxy-4,5-dimetilfenil)-[4-(N-hydroxycarbamoyl)phenylamino] acetic acid.

Example 13.

Analogously to example 12.1 of 2-hydroxy-3,5-dimethoxybenzaldehyde (Sinhababu, A. K., Borchardt R. T., J. Org. Chem., 48, 1941-1944 (1983)) was obtained ethyl ester of (2-formyl-4,6-dimethoxyphenoxy)acetic acid. Analogously to example 1 the compound obtained was introduced into a reaction with 4-aminobenzonitrile, when it received the methyl ester of (RS)-(4-cyanovinylene)-(2-ethoxycarbonylmethoxy-3,5-acid)acetic acid. Then, from the connection via the intermediate formation of (RS)-(2-carboxymethoxy-3,5-acid)-(4-cyanoaniline)acetic acid was obtained (E)- and/or (Z)-(RS)-(2-carboxymethoxy-3,5-acid)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid.

Example 14.

Analogously to example 3 from the compound obtained as described in example 12.2, was obtained (RS)-(4-carbamimidoyl)-(2-carboxymethoxy-4,5-dimetilfenil)acetic acid.

Example 15.

Analogously to example 3 from the compound obtained as described in example 13, was obtained (RS)-(4-carbamimidoyl)-(2-carboxymethoxy-3,5-acid)acetic acid.

Example 16.

Suspension 10,88 g of 2-benzyloxy-4,5-dimethoxybenzaldehyde and 4,72 g of 4-aminobenzonitrile intensively stirred when com
With, and then added 15 ml of epirate boron TRIFLUORIDE such a way that the temperature did not exceed 10oC. the resulting brown solution was stirred at 5oC. After 15 min began to precipitate. Then the mixture was stirred at 5oEven for 3 h, the solid was separated by filtration and dried. When it got to 19.1 g of the complex methyl ester (E)- and/or (Z)-(RS)-N-benzyl-2-(2-benzyloxy-4,5-acid)-2-(4-cyanoaniline)iminoxyl acid with boron TRIFLUORIDE in the form of a crystalline substance of a light grey color.

16.2. A suspension of 13.1 g of the compound obtained as described in example 16.1, in 1300 ml of methanol and 130 ml of water was boiled under reflux for 1 h the resulting solution was concentrated under reduced pressure. After evaporation of almost all the methanol had begun to fall out of the precipitate, which was separated by filtration and dried. It was obtained 9.6 g of methyl ester of (RS)-(2-benzyloxy-4,5-acid)-(4-cyanoaniline)acetic acid.

16.3. 400 mg of palladium on coal was added to a solution of 3.8 g of the compound obtained as described in example 16.2, in 170 ml of methanol and 17 ml of THF. The reaction mixture was first made for 5 h, then filtered and nonlocal 1.5 g of methyl ester of (RS)-(4-cyanovinylene)-(2-hydroxy-4,5-acid)acetic acid.

16.4. Analogously to example 12.1 of the compound obtained as described in example 16.3, received the methyl ester of (RS)-(4-cyanovinylene)-(4,5-dimethoxy-2-methoxycarbonylaminophenyl)acetic acid.

16.5. Analogously to examples 1.2 and 1.3 of the compound obtained as described in example 16.4, through the intermediate formation of (RS)-(2-carboxymethoxy-4,5-acid)-(4-cyanoaniline)acetic acid was obtained (E)- and/or (Z)-(RS)-(2-carboxymethoxy-4,5-acid)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid.

Example 17.

Analogously to example 3 from the compound obtained as described in example 16.5, was obtained (RS)-(4-carbamimidoyl)-(2-carboxymethoxy-4,5-acid)acetic acid.

Example 18.

18.1. 0,49 ml methyl ester R-lactic acid, 1.26 g of triphenylphosphine and from 0.76 mmole of diethylazodicarboxylate was added to a solution of 1.06 g of the compound obtained as described in example 16.3, in 14 ml of THF. The reaction mixture was stirred at room temperature for 1 h, and then concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel, thus received of 0.91 g of a mixture of 1:1 methyl esters (S)-2-[2-[(R)- and -[(S)-(4-cyanoaniline)methoxycarbonyl the 1.2 from the connection, obtained as described in example 18.1, received two epimer: (S)-2-[2-[(R) -, or -[(S)-carboxy(4-cyanoaniline)methyl] -4,5-dimethoxyphenoxy] propionic acid and (S)-2-[2-[(S) -, or -[(R)-carboxy(4-cyanoaniline)methyl] -4,5-dimethoxyphenoxy] propionic acid. Epimer were separated by chromatography on silica gel.

18.3. Analogously to example 1.3 from the first epimer mentioned in example 18.2, was obtained (E)- and/or (Z)-(S)-2-[2-[(R) -, or - [(S)-carboxy[4-(N-hydroxycarbamoyl)phenylamino] methyl] -4,5-dimethoxyphenoxy] propionic acid, and from the second epimer mentioned in example 18.2, was obtained (E)- and/or (Z)-(S)-2-[2-[(S) -, or -[(R)-carboxy[4-(N-hydroxycarbamoyl)phenylamino]methyl]-4,5-dimethoxyphenoxy]propionic acid.

Example 19.

Analogously to example 3 of the first epimer mentioned in example 18.3, was obtained (S)-2-[(S) -, or -[(R)-2-[(4-carbamimidoyl)carboxymethyl] -4,5-dimethoxyphenoxy]propionic acid, and from the second epimer mentioned in example 18.3, was obtained (S)-2-[(R) -, or -[(S)-2-[(4-carbamimidoyl)carboxymethyl]-4,5-dimethoxyphenoxy]propionic acid.

Example 20.

20.1. Analogously to example 1.1 2-hydroxy-3,5-dimethylbenzaldehyde (G. Casiraghi, Casnatti G., J. Chem. Soc., 1862 (1980)) were introduced in the reaction with 4-amino fenil)acetic acid.

20.2. Similar examples 16.4-16.6 from the compound obtained as described in example 20.1, through the intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-(2-ethoxycarbonylmethoxy-4,5-dimetilfenil)acetic acid and (RS)-(2-carboxymethoxy-4,5-dimetilfenil) (4 cyanovinylene)acetic acid was obtained (E)- and/or (Z)-(RS)-(2-carboxymethoxy-3, 5dimethylphenyl)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid.

Example 21.

Analogously to example 3 from the compound obtained as described in example 20.2, got acetate (RS)-(4-carbamimidoyl)-(2-carboxymethoxy-3, 5dimethylphenyl)acetic acid (1:1).

Example 22.

22.1. 2.35 ml diisopropylethylamine and of 0.83 mmole of phenylacetylene was added to a solution of 2.3 g of methyl ester of (RS)-(2-amino-4-benzyloxy-5-methoxyphenyl)-(4-cyanoaniline)acetic acid (obtained by the reaction of 4-benzyloxy-5-methoxy-2-nitrobenzaldehyde 4-aminobenzonitrile and benzylideneamino with the formation of the methyl ester of (RS)-(4-benzyloxy-5-methoxy-2-nitrophenyl)-(4-cyanoaniline)acetic acid and hydrogenation of the nitro group in the presence of Pt/C) in 60 ml of THF. The resulting solution was stirred at 50oC for 3 h and then at room temperature in those who received 2,05 g of methyl ester of (RS)-(4-benzyloxy-5-methoxy-2-phenylacetylamino)-(4-cyanoaniline)acetic acid as a colourless crystalline substance.

22.2. Analogously to examples 1.2 and 1.3 of the compound obtained as described in example 22.1, through the intermediate formation of (RS)-(4-benzyloxy-5-methoxy-2-phenylacetylamino)-(4-cyanoaniline)acetic acid was obtained (E)- and/or (Z)-(RS)-(4-benzyloxy-5-methoxy-2-phenylacetylamino)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid.

Example 23.

Analogously to example 22 methyl ester of (RS)-(2-amino-4-benzyloxy-5-methoxyphenyl)-(4-cyanoaniline)of acetic acid were introduced into a reaction:

23. a) acetylchloride, when it received the methyl ester of (RS)-(2-acetylamino-4-benzyloxy-5-methoxyphenyl)-(4-cyanoaniline)acetic acid, from which through the intermediate formation of (RS)-(2-acetylamino-4-benzyloxy-5-methoxyphenyl)-(4-cyanoaniline)acetic acid was obtained (E)- and/or (Z)-(RS)-(2-acetylamino-4-benzyloxy-5-methoxyphenyl)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid;

23. (b) methoxyacetanilide, when it received the methyl ester of (RS)-[4-benzyloxy-5-methoxy-2-(2-methoxyethylamine)phenyl] -(4-cyanoaniline)acetic acid, from which through the intermediate formation of (RS)-[4-benzyloxy-5-methoxy-2-(2-methoxyethylamine)phenyl] -(4-cyanoaniline)acetic acid was obtained (E)- and/or the GTC;

23. C) methanesulfonanilide, when it received the methyl ester of (RS)-[4-benzyloxy-2-(bistanbulholiday)-5-methoxyphenyl] -(4-cyanoaniline)acetic acid, from which through the intermediate formation of (RS)-(4-benzyloxy-2-methanesulfonamido-5-methoxyphenyl)-(4-cyanoaniline)acetic acid was obtained (E)- and/or (Z)-(RS)-(4-benzyloxy-2-methanesulfonamido-5-methoxyphenyl)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid.

Example 24. Analogously to example 3

24. a) from the compound obtained as described in example 22.2, was obtained (RS)-(4-benzyloxy-5-methoxy-2-phenylacetylamino)-(4-carbamimidoyl)acetic acid;

24. b from the compound obtained as described in example 23.and received (RS)-(2-acetylamino-4-benzyloxy-5-methoxyphenyl)-(4-carbamimidoyl)acetic acid;

24. in) from the compound obtained as described in example 23.b, was obtained [4-benzyloxy-5-methoxy-2-(2-methoxyethylamine)phenyl] -(4-carbamimidoyl)acetic acid and

24. g) from the compound obtained as described in example 23.in received (RS)-(4-benzyloxy-2-methanesulfonamido-5-methoxyphenyl)-(4-carbamimidoyl)acetic acid.

Example 25.

25.1. Analogously to example and methyl ester of (RS)-[2-(2-benzyloxyethyl)-4,5-acid]-(4-cyanoaniline)acetic acid.

25.2. Analogously to examples 1.2 and 1.3 of the compound obtained as described in example 25.1, through the intermediate formation of (RS)-[2-(2-benzyloxyethyl)-4,5-acid] -(4-cyanoaniline)acetic acid was obtained (E)- and/or (Z)-(RS)-[2-(2-benzyloxyethyl)-4,5-acid]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid.

Example 26.

26. A. Analogously to example 3 from the compound obtained as described in example 25.2, was obtained (RS)-[2-(2-benzyloxyethyl)-4,5-acid]-(4-carbamimidoyl)acetic acid.

26. B. 11 mg of 10% palladium on coal was added to a solution of 100 mg of the compound obtained as described in example 25.2, 5 ml ethanol, 5 ml THF, 2 ml water and 1 ml of acetic acid. The reaction mixture was first made during the night, and then filtered. The filtrate was concentrated under reduced pressure, the residue was led from methanol/acetone, to receive 30 mg of (RS)-(4-carbamimidoyl)-[2-(2-hydroxyethoxy)-4,5-acid] acetic acid as a colourless crystalline substance.

Example 27.

27.1. 6.2 ml of methyl acrylate, 25 ml of triethylamine, 270 mg of PD(SLA)2and 1.5 g three(ortho-tolyl)phosphine were added to a solution of 14.7 g of 6-bromoveratrole aldehyde howl temperature and was poured into a mixture of ethyl acetate with water. The crude product was extracted and purified by chromatography on silica gel, was obtained 10.8 g of methyl ester of (E)-3-(2-formyl-4,5-acid)acrylic acid in a solid yellow color.

27.2. 1.1 g of magnesium powder was added to a solution of 1.15 g of the compound obtained as described in example 27.1, 20 ml of methanol. The reaction mixture was stirred at room temperature for 2 h, and treated with 25 ml of 3 N. Hcl and was extracted with ethyl acetate. The crude product was purified by chromatography on silica gel, thus received 776 mg of methyl ester of 3-(2-hydroxymethyl-4,5-acid)propionic acid in the form of a yellow oil.

27.3. 1.5 mg Mno2was added to a solution of 812 mg of the compound obtained as described in example 27.2, in 15 ml of 1,2-dichloroethane. The reaction mixture was stirred at 50oC for 3 h, filtered and concentrated. The residue was purified by chromatography on silica gel, thus received 671 mg of methyl ester of 3-(2-formyl-4,5-acid)propionic acid as a colourless resin.

27.4. Analogously to example 1.1 the compound obtained as described in example 27.3, was introduced in the reaction with 4-aminobenzonitrile and benzylideneamino, methyl received the frames 1.2 and 1.3 of the compounds obtained via the intermediate formation of (RS)-3-[2-[carboxy(4-cyanoaniline)methyl] -4,5-acid]propionic acid was obtained (E)- and/or (Z)-(RS)-3-[2-[carboxy[4-(N-hydroxycarbamoyl)phenylamino]methyl]-4,5-acid]propionic acid.

Example 28.

Analogously to example 3 from the compound obtained as described in example 27.4 received (RS)-3-[2-[(4-carbamimidoyl)carboxymethyl] -4,5-acid]propionic acid.

Example 29.

29.1. Analogously to example 27 from 2-bromo-3,5-dimethoxybenzaldehyde (J. Org. Chem. , 48, 1941 (1983)) was obtained methyl ester (E)-3-(2-formyl-4,6-acid)acrylic acid.

29.2. 160 mg of 10% palladium on coal was added to a solution of 3.7 g of the compound obtained as described in example 29.1, in 60 ml of THF. The reaction mixture was first made for 5 h, then filtered and concentrated. The residue was purified by chromatography on silica gel, was obtained methyl ester 3-(2-hydroxymethyl-4,6-acid)propionic acid as colorless oil.

29.3 Analogously to example 27.3 of the compound obtained as described in example 29.2, received methyl ester 3-(2-formyl-4,6-acid)propionic acid.

29.4. Analogously to example 1.1 the compound obtained as described in example 29.3, was introduced in the reaction with 4-aminobenzonitrile and benzylideneamino, received methyl ether (RS)-3-[2-[(4-cyanoaniline)methoxycarbonylmethyl] -4,6-acid]propionic acid. Similarly, the,6-acid]propionic acid was obtained (E)- and/or (Z)-(RS)-3-[2-[carboxy [4-(N-hydroxycarbamoyl)phenylamino]methyl] -4,6-acid]propionic acid.

Example 30.

Analogously to example 3 from the compound obtained as described in example 29.4 received (RS)-3-[2-[(4-carbamimidoyl)carboxymethyl] -4,6-acid]propionic acid.

Example 31.

31.1. 6,27 g of tert-butyldimethylsilyloxy, 6,63 ml of triethylamine and 270 mg of imidazole was added to a solution of 10 g of diethyl ether 5-(hydroxymethyl)isophthalic acid in 100 ml of DMF. The reaction mixture was stirred at room temperature for 4 h, and then were extracted. Sililirovany the crude product was dissolved in 150 ml of THF. To the resulting solution was added 17.8 g Li4and the reaction mixture was stirred at 40oWith during the night. Then at 0oWith carefully added a saturated solution of NH4Cl. The crude product was isolated by extraction and purified by chromatography on silica gel, thus received is 4.93 g of tert-butyl(3,5-dimethoxybenzoate)dimethylsilane and 5.31g ethyl ester 3- (tert-butyldimethylsilyloxy)-5-hydroxymethylbenzene acid.

31.2. of 0.64 ml oxalicacid was added at -60oWith the solution 0,76 ml of DMSO in 10 ml of CH2CL2. After 5 min for 5 min was added 2 g of ethyl ester of 3-(tert-butyldimethylsilyloxy exceed -60oC. After 15 min was added 4,295 ml of triethylamine. Then the reaction mixture was heated to room temperature and was extracted, it was obtained 2.0 g of ethyl ester of 3-(tert-butyldimethylsilyloxy)-5-formylbenzoate acid.

31.3. Analogously to example 1, the compound obtained as described in example 31.2, was introduced in the reaction with 4-aminobenzonitrile and benzylideneamino, received ethyl ester of (RS)-3-[(4-cyanoaniline)methoxycarbonylmethyl]-5-hydroxymethylbenzene acid. Then connect via the intermediate formation of (RS)-3-[carboxy(4-cyanate-ylamino)methyl] -5-hydroxymethylbenzene acid was obtained (E)- and/or (Z)-(RS)-3-[carboxy [4-(N-hydroxycarbamoyl)phenylamino]methyl]-5-hydroxymethylbenzene acid.

Example 32.

32. A. Analogously to example 3 from the compound obtained as described in example 31.3, was obtained (RS)-3-[(4-carbamimidoyl)carboxymethyl]-5-hydroxymethylbenzene acid.

32. B. 0,42 ml of thionyl chloride was added to a solution of 0.2 g of the compound obtained as described in example 32.A. The reaction mixture was stirred at room temperature overnight, and then concentrated. The residue was treated with diethyl ether, while p is ethylbenzoic acid (1:1).

Example 33.

33.1. Analogously to example 31.2 of tert-butyl(3,5-dimethoxybenzoate)dimethylsilane (see example 31.1) was obtained 3,5-bis-(tert-butyldimethylsilyloxy)benzaldehyde.

33.2. Analogously to example 1, the compound obtained as described in example 33.1, was introduced in the reaction with 4-aminobenzonitrile and benzylideneamino, when it received the methyl ester of (RS)-(3,5-bis-hydroxymethylene)-(4-cyanoaniline)acetic acid. This connection through the intermediate formation of (RS)-(3,5-bis-hydroxymethylene)-(4-cyanoaniline)acetic acid was obtained (E)- and/or (Z)-(RS)-(3,5-bis-hydroxymethylene)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid.

Example 34.

Analogously to example 3 from the compound obtained as described in example 33.2, was obtained (RS)-(3,5-bis-hydroxymethylene)-(4-carbamimidoyl)acetic acid.

Example 35. The following compounds were obtained analogously to example 1:

a) (E)- and/or (Z)-(RS)-(3,4-dibromobiphenyl)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid, MS:402 (M+N+), was obtained from 3,4-di-n-propoxybenzaldehyde through intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-(3,4-dibromobiphenyl)acetic acid and (RS)-(4-zydol)phenylamino] acetic acid, MS:402 (M+N+), was obtained from 3,4-diisopropylbenzamide through intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-(3,4-diisopropylphenyl)acetic acid and (RS)-(4-cyanovinylene)-(3,4-diisopropylphenyl)acetic acid;

in) (RS)-(3,5-diisopropylphenyl)-[4-(N-hydroxycarbamoyl)phenylamino] acetic acid, MS:402 (M+N+), was obtained from 3,5-diisopropylsalicylic through intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-(3,5-diisopropylphenyl)acetic acid and (RS)-(4-cyanovinylene)-(3,5-diisopropylphenyl)acetic acid;

g) (RS)-[4-(N-hydroxycarbamoyl)phenylamino] -(4-methoxy-3-propoxyphenyl)acetic acid, MS: 372 (M+N+), was obtained from 3-propoxy-4-methoxybenzaldehyde through intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-(4-methoxy-3-propoxyphenyl)acetic acid and (RS)-(4-cyanovinylene)-(4-methoxy-3-propoxyphenyl)acetic acid;

d) (RS)-[4-(N-hydroxycarbamoyl)phenylamino] -(4-isopropoxy-3-methoxyphenyl)acetic acid, MS: 374 (M+N+), was obtained from 4-isopropoxy-3-methoxybenzaldehyde through intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-(4-isopropoxy-3-methoxyphenyl)acetic acid and (RS)-(4-tzia is phenylamino] naphthalene-2-luksusowe acid, MS:336 (M+N+), was obtained from 2-naphthaldehyde through intermediate formation of methyl ester of (RS)-(4-cyanoaniline)naphthalene-2-luxusni acid and (RS)-(4-cyanoaniline)naphthalene-2-luxusni acid.

Example 36.

Below amidine was obtained analogously to example 3 from amidoximes, obtained as described in example 35:

a) (RS)-(4-carbamimidoyl)-(3,4-dibromobiphenyl)acetic acid, MS:386 (M+N+);

b) (RS)-(4-carbamimidoyl)-(3,4-diisopropylphenyl)acetic acid, MS:386 (M+N+);

in) (RS)-(4-carbamimidoyl)-(3,5-diisopropylphenyl)acetic acid, MS:386 (M+N+);

g) (RS)-(4-carbamimidoyl)-(4-methoxy-3-propoxyphenyl)acetic acid, MS:358 (M+N+);

d) (RS)-(4-carbamimidoyl)-(4-isopropoxy-3-methoxyphenyl)acetic acid, MS:358 (M+N+);

e) (RS) - (4-carbamimidoyl)naphthalene-2-ilocana acid, MS: 320 (M+H+).

Example 37.

a) Methyl ester of (RS)-[4-(N-hydroxycarbamoyl)phenylamino]-(6-methoxynaphthalene-2-yl)acetic acid was obtained from 6-methoxy-2-naphthaldehyde analogously to example 1.3 through intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-(6-methoxynaphthalene-2-yl)acetic acid.+).

Example 38.

Amidoxime, obtained as described in example 37.and, hydrolyzed analogously to example 3, was obtained (RS)-(4-carbamimidoyl)-(6-methoxynaphthalene-2-yl)acetic acid, MS:350 (M+N+).

Example 39.

39.1. Analogously to example 1.1 from 3-benzyloxybenzaldehyde and 4-aminobenzonitrile received the methyl ester of (RS)-(3-benzyloxyphenyl)-(4-cyanoaniline)acetic acid, MS:373 (M+N)+.

39.2. Hydrogen chloride was passed through the solution for 2.01 g of methyl ester of (RS)-(3-benzyloxyphenyl)-(4-cyanoaniline)acetic acid in 25 ml of methylene chloride and 5 ml of methanol at 0oWith over 75 minutes the Solution was kept at 4oC for 23 h, and then evaporated in vacuum. The residue was treated with 20 ml of methanol, 1.66 g of ammonium acetate and boiled under reflux for 3.5 hours and Then the solution was evaporated in vacuo, the residue was dissolved in 95 ml of methylene chloride, 75 ml of water and 19 ml of a saturated solution of sodium carbonate was treated with 3.1 g of di-tert-BUTYLCARBAMATE and intensively stirred at 20oWith over 3.5 hours After extraction and chromatography on silica gel was obtained methyl ester (E)/(Z)-(RS)-(3-benzyloxyphenyl)-[4-(tert-LASS="ptx2">

39.3. 655 mg methyl ester (E)/(Z)-(RS)-(3-benzyloxyphenyl)-[4-(tert-butoxycarbonylamino-tert-butoxycarbonylamino)phenylamino] acetic acid was dissolved in 3 ml of methylene chloride containing 3 ml triperoxonane acid, and kept at room temperature for 50 minutes Then the solution was evaporated in vacuo, the residue was chromatographically on silica gel, thus received 440 mg trifenatate methyl ester (RS)-(3-benzyloxyphenyl)-(4-carbamimidoyl)acetic acid, tPL162oC, MS:390 (M+N)+.

39.4. Analogously to example 70 from trifenatate methyl ester (RS)-(3-benzyloxyphenyl)-(4-carbamimidoyl)acetic acid was obtained (RS)-(3-benzyloxyphenyl)-(4-carbamimidoyl)acetic acid, tPL306oC, MS:376 (M+N)+.

Example 40.

40.1. Analogously to example 1.1 from 2-(ethoxycarbonylmethoxy)benzaldehyde, 4-aminobenzonitrile, toluene-4-sulfonylmethane and F3t2in ethanol was obtained ethyl ester of (RS)-(4-cyanovinylene)-(2-ethoxycarbonylmethoxy)acetic acid, tPL108oC, MS:383 (M+N)+.

40.2. Hydrogen chloride was passed through a solution of 1.5 g of ethyl ester of (RS)-(4-cyanoaniline the solution was kept for 6 h at room temperature and was evaporated. The residue was treated with 15 ml of ethanol and 1.2 g of ammonium acetate and boiled under reflux for 3.5 hours, the Reaction mixture was evaporated, the residue was treated with 35 ml of methylene chloride, 17 ml of water and 17 ml of a saturated solution of sodium carbonate containing 916 mg of di-tert-BUTYLCARBAMATE, and intensively stirred at room temperature for a period of 2.25 hours After extraction and chromatography on silica gel was obtained 1.7 g of ethyl ester of (RS)-[4-(tert-butoxycarbonyloxyimino)phenylamino]-(2-ethoxycarbonylmethoxy)acetic acid as a white foam, MS:500 (M+N)+.

40.3. 499 mg of ethyl ester of (RS)-[4-(tert-butoxycarbonyloxyimino)phenylamino] -(2-ethoxycarbonylmethoxy)acetic acid was treated with 14 ml of THF and 2 ml of 1 N. LiOH, after 4 h was added 2 ml of 1 ad model HC1 to pH 4 and the reaction mixture was evaporated in vacuum. Then from acetonitrile/water received 182 mg of (RS)-(4-carbamimidoyl)-(2-carboxymethoxy)acetic acid, tPL223oC, MS:344 (M+H)+.

Example 41.

41.1. Analogously to example 1.1 from 2,5-dimethoxybenzaldehyde and 4-aminobenzonitrile received the methyl ester of (RS)-(4-cyanovinylene)-(2,5-acid)acetic acid, MS:327 (M+H)+.

41.2. Analogs+.

41.3. Analogously to example 1.3 of this compound was obtained (Z)-(RS)-(2,5-acid)-[4-(N-hydroxycarbamoyl)phenylamino] acetic acid, MS:346 (M+H)+.

41.4. 555 mg of (Z)-(RS)-(2,5-acid)-[4-(N-hydroxycarbamoyl)phenylamino] acetic acid in 8 ml of acetic acid and 16 ml of water was stirred in hydrogen atmosphere in the presence of Raney Nickel. After adding 13 ml of acetic acid, the solution was filtered and evaporated in vacuum. The residue is triturated in water and then in methanol, was filtered under vacuum and dried. When it got 404 mg (RS)-(4-carbamimidoyl)-(2,5-acid)acetic acid, tPL310oC, MS:330 (M+N)+.

Example 42.

42.1. Analogously to example 52.1 from 5-benzyloxy-2-hydroxybenzaldehyde and ethyl ether bromoxynil acid was obtained ethyl ester (4-benzyloxy-2-formylphenoxy)acetic acid, tPL65oC, MS:314 (M)+.

42.2. Analogously to example 1.1 from ethyl ether (4-benzyloxy-2-formylphenoxy)acetic acid and 4-aminobenzonitrile in ethanol was obtained ethyl ester of (RS)-(5-benzyloxy-2-ethoxycarbonylmethoxy)-(4-cyanoaniline)acetic acid in the form of a yellow resin, MS:489 (M+H)+.

oC for 2 h Then the reaction mixture was diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate solution, water and saturated sodium chloride solution, dried and evaporated in vacuum. After chromatography on silica gel was obtained 1.6 g of ethyl ester of (RS)-(5-benzyloxy-2-ethoxycarbonylmethoxy)-(4-thiocarbamoylation)acetic acid, tPL166oC, MS:523 (M+H)+.

42.4. 1.6 g of ethyl ester of (RS)-(5-benzyloxy-2-ethoxycarbonylmethoxy)-(4-thiocarbamoylation)acetic acid, 25 ml of acetone and 1.95 ml iodotope bromide was stirred at 40oWith over 3.5 hours and Then the solution was evaporated, the residue was immediately dissolved in ethanol, treated of 0.18 ml of acetic acid and 720 mg of ammonium acetate was heated to 60oC for 1.5 hours Then the reaction mixture was evaporated in vacuo, and treated with 27 ml of methylene chloride and 14 ml of water, 14 ml of a saturated solution of sodium bicarbonate and 740 mg of di-tert-BUTYLCARBAMATE and intensively stirred at room temperature for 5 hours After extraction and chromatography on silica gel was obtained 1.4 g of ethyl ester of (RS)-(5-benzyloxy-2-ethoxycarbonylmethoxy)-[4-(tert-butano example 40.3 after neutralization of the mixture with acetic acid and evaporation of the solvent in vacuo from the ethyl ester of (RS)-(5-benzyloxy-2-ethoxycarbonylmethoxy)-[4-(tert-butoxycarbonyloxyimino)phenylamino] acetic acid was obtained (RS)-(5-benzyloxy-2-hydroxycarbonylmethyl)-[4-(tert-butoxycarbonyloxyimino)phenylamino] acetic acid, which was dissolved in methylene chloride/TFU (1:1) and stirred at room temperature for 1.5 hours the resulting solution was evaporated, to the residue water was added to the ammonia solution to pH 8 and the solution was again evaporated. (RS)-(5-Benzyloxy-2-carboxymethoxy)-(4-carbamimidoyl] acetic acid was led out of the water and to clean several times triturated in ethanol, tPL258oC, MS:450 (M+N)+.

Example 43.

43.1. Analogously to example 42.2 of the ethyl ester of (2-formyl-4-methoxyphenoxy)acetic acid and 4-aminobenzonitrile received ethyl ester of (RS)-(4-cyanovinylene)-(2-ethoxycarbonylmethoxy-5-methoxyphenyl)acetic acid, MS:413 (M+N)+.

43.2. Analogously to example 40.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(2-ethoxycarbonylmethoxy-5-methoxyphenyl)acetic acid was obtained ethyl ester of (RS)-[4-(tert-butoxycarbonyloxyimino)phenylamino]-(2-ethoxycarbonylmethoxy-5-methoxyphenyl)acetic acid, MS:530 (M+N)+.

43.3. Analogously to example 1.2 from this compound was obtained (RS)-[4-(tert-butoxycarbonyloxyimino)phenylamino] -(2-carboxymethoxy-5-methoxyphenyl)acetic acid.

43.4. 356 mg (RS)-[4-(tert-butoxycarbonyloxyimino the ml TFU within 1 hour Then the reaction mixture was evaporated in vacuo, the residue was chromatographically on silica gel in ethyl acetate/acetone/water/acetic acid(6:2:1:1). From ethyl acetate/acetone/water/acetic acid (12:2:1:1) received the crystal (RS)-(4-carbamimidoyl)-(2-carboxymethoxy-5-methoxyphenyl)acetic acid, tPL213oC, MS:374 (M+N)+.

Example 44.

44.1. Analogously to example 50.1 from 5-ethoxy-2-hydroxybenzaldehyde and ethyl ether bromoxynil acid was obtained ethyl ester (4-ethoxy-2-formylphenoxy)acetic acid, tPL61-62oC, MS:252 (M)+.

44.2. Analogously to example 50.2 from ethyl ether (4 ethoxy-2-formylphenoxy)acetic acid and 4-aminobenzonitrile in the presence of 2-morpholinosydnonimine and BF3OEt2in ethanol was obtained ethyl ester of (RS)-(4-cyanovinylene)-(5-ethoxy-2-ethoxycarbonylmethoxy)acetic acid, MS: 427 (M+N)+.

44.3. Analogously to example 40,2 of the ethyl ester of (RS)-(4-cyanovinylene)-(5-ethoxy-2-ethoxycarbonylmethoxy)acetic acid was obtained ethyl ester of (RS)-[4-(tert-butoxycarbonylamino-methyl)phenylamino] -(5-ethoxy-2-ethoxycarbonylmethoxy)acetic acid, MS:544 (M+N)+.

44.4. 617 mg of ethyl what usnei acid was treated to 15.8 ml of THF and 2.26 ml of 1 N. LiOH and stirred at room temperature for 3 h Then the reaction mixture was added TFU to pH 7 and evaporated in vacuum. The residue was dissolved in 4.5 ml of methylene chloride and 4.5 ml of TFU, after 1 h, the reaction mixture was evaporated in vacuum. The residue was dissolved in water and again evaporated, and then neutralized with a solution of ammonia in methanol. (RS)-(4-Carbamimidoyl)-(2-carboxymethoxy-5-ethoxyphenyl)acetic acid was led from methanol and was purified by rubbing in ethyl acetate/acetone/water/acetic acid(12:2:1:1), tPL241oC, MS:388 (M+H)+.

Example 45.

45.1. 2,49 g 5-ethoxy-2-hydroxybenzaldehyde, 2,7 ml ethyl ester 5-bombalurina acid, 15 ml of DMSO, 3.1 g K3CO3and 75 g of KI was stirred at 55oWith within 2.5 hours After treatment and chromatography on silica gel was obtained 4.7 g of ethyl ester of 5-(4-ethoxy-2-formylphenoxy)pentanol acid, MS:294 (M)+.

45.2. Analogously to example 40.1 of the ethyl ester of 5-(4-ethoxy-2-formylphenoxy)pentanol acid and 4-aminobenzonitrile received ethyl ester (RS)-5-{ 2-[(4-cyanoaniline)ethoxycarbonylmethyl] -4-ethoxyphenoxy} pentanol acid, tPL80-81oC, MS:469 (M+N)+.

45.3. Analogously to example 40.2 arbonelli}-4-ethoxyphenoxy)pentanol acid, MS:586 (M+N)+.

45.4. Analogously to example 44.4 of this compound was obtained (RS)-5-{2-[(4-carbamimidoyl)carboxymethyl]-4-ethoxyphenoxy}pentane acid, tPL260oC, MS:428 (M-N)-.

Example 46.

46.1. Analogously to example 45.1 5-ethoxy-2-hydroxybenzaldehyde and 2-pomatoleios of ether there was obtained 5-ethoxy-2-(2-methoxyethoxy)benzaldehyde; MS:224 (M)+.

46.2. Analogously to example 1.1 from 5-ethoxy-2-(2-methoxyethoxy)benzaldehyde, 4-amino-N-hydroxybenzamide, 2-morpholinosydnonimine and BF3OEt2in methanol was obtained methyl ester (E)/(Z)-(RS)-[5-ethoxy-2-(2-methoxyethoxy)phenyl] -[4-(N-hydroxycarbamoyl)phenylamino]acetic acid, MS:418 (M+N)+.

46.3. Methyl ester (E)/(Z)-(RS)-[5-ethoxy-2-(2-methoxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino] acetic acid hydrolyzed in THF and 1 N. LiOH, it was received (E)/(Z)-(RS)-[5-ethoxy-2-(2-methoxyethoxy)phenyl] -[4-(N-hydroxycarbamoyl)phenylamino] acetic acid. The reaction mixture was neutralized with acetic acid, the solution was evaporated, the crude product is used as described in example 46.4.

46.4. Analogously to example 50.5 from this compound was obtained (RS)-(4-carbamimidoyl)-[obyvali vacuum filtration and dried, tPL275oC, MS:388 (M+N)+.

Example 47.

47.1. Analogously to example 52.1 5-ethoxy-2-hydroxybenzaldehyde and methyl ester 3-bromomethylphenyl acid was obtained methyl ester 3-(4-ethoxy-2-formylphenoxy)benzoic acid, tPL67-69oC, MS:314 (M)+.

47.2. Analogously to example 52.2 of the methyl ester of 3-(4-ethoxy-2-formylphenoxy)benzoic acid and 4-aminobenzonitrile in methanol was obtained methyl ether (RS)-3-{2-[(4-cyanoaniline)methoxycarbonylmethyl]-4-ethoxyphenoxy}benzoic acid, MS:475 (M+N)+.

47.3. Analogously to example 50.3 of the methyl ester (RS)-3-{2-[(4-cyanoaniline)methoxycarbonylmethyl] -4-ethoxyphenoxy} benzoic acid was obtained methyl ester (E)/(Z)-(RS)-3-(4-ethoxy-2-{[4-(N-hydroxycarbamoyl)phenylamino] methoxycarbonylmethyl} phenoxymethyl)benzoic acid, MS: 508 (M+N)+.

47.4. Analogously to example 46.3 of the methyl ester (E)/(Z)-(RS)-3-(4-ethoxy-2-{ [4-(N-hydroxycarbamoyl)phenylamino] methoxycarbonylmethyl} phenoxymethyl)benzoic acid was obtained (E)/(Z)-(RS)-3-(4-ethoxy-2-{[4-(N-hydroxycarbamoyl)phenylamino] carboxymethyl} phenoxymethyl)benzoic acid.

47.5. Analogously to example 50.5 of this Crude product is triturated in water, and then in ethanol, tPL260oC, MS:464 (M+N)+.

Example 48.

48.1. Analogously to example 45.1 5-ethoxy-2-hydroxybenzaldehyde and chloracetamide received 2-(4-ethoxy-2-formylphenoxy)ndimethylacetamide, tPL127-129oC, MC:223 (M)+.

48.2. Analogously to example 1.1 from 2-(4-ethoxy-2-formylphenoxy)ndimethylacetamide, 4-aminobenzonitrile, 2-morpholinosydnonimine and F3t2in methanol was obtained methyl ester of (RS)-(2-carbamoylmethyl-5-ethoxyphenyl)-(4-cyanoaniline)acetic acid as a white foam, MS:384 (M+H)+.

48.3. Analogously to example 1.3 of the methyl ester of (RS)-(2-carbamoylmethyl-5-ethoxyphenyl)-(4-cyanoaniline)acetic acid, hydroxylamine hydrochloride and triethylamine in methanol was obtained methyl ester (Z)-(RS)-(2-carbamoylmethyl-5-ethoxyphenyl)-[4-(N-hydroxyurea-imidoyl)phenylamino] acetic acid, tPL175oC, MS:417 (M+N)+.

48.4. 305 mg of ethyl ester of (Z)-(RS)-(2-carbamoylmethyl-5-ethoxyphenyl)-[4-(N-hydroxycarbamoyl)phenylamino] acetic acid were treated in 8 ml of methanol/acetic acid (1:1) Raney Nickel and stirred in a hydrogen atmosphere. Then the reaction mixture was filtered, evaporated in vacuo, the residue was purified of raster and-5-ethoxyphenyl)acetic acid, tPL200oC (decomp.), MS:401 (M+N)+.

48.5. Methyl ester of (RS)-(4-carbamimidoyl)-(2-carbamoylmethyl-5-ethoxyphenyl)acetic acid hydrolyzed in THF with 1 N. LiOH, it was received (RS)-(4-carbamimidoyl)-(2-carbamoylmethyl-5-ethoxyphenyl)acetic acid, which was purified by rubbing in water and dilute ammonia solution, tPL266oC, MS:387 (M+N)+.

Example 49.

49.1. Analogously to example 50.1 from 5-benzyloxy-2-hydroxybenzaldehyde received 5-benzyloxy-2-(2-hydroxyethoxy)benzaldehyde, tPL83oC, MS:272 (M)+.

49.2. Analogously to example 1.1 from 5-benzyloxy-2-(2-hydroxyethoxy)benzaldehyde, 4-aminobenzonitrile, 2-morpholinosydnonimine and BF3OEt2in methanol was obtained methyl ester of (RS)-[5-benzyloxy-2-(2-hydroc-setacci)phenyl]-(4-cyanoaniline)acetic acid, MS:433 (M+N)+.

49.3 Catalytic hydrogenation of the methyl ester of (RS)-[5-benzyloxy-2-(2-hydroxyethoxy)phenyl]-(4-cyanoaniline)acetic acid in the presence of Pd/C in ethyl acetate/ethanol led to a methyl ester of (RS)-(4-cyanovinylene)-[5-hydroxy-2-(2-hydroxyethoxy)phenyl]acetic acid, MS:343 (M+N)+.

49.4. Analogues of the and ethylbromide in DMF in the presence of sodium iodide was obtained methyl ester of (RS)-(4-cyanovinylene)-[5-ethoxy-2-(2-hydroxyethoxy)phenyl]acetic acid, MS:370 (M)+.

49.5. Analogously to example 1.3 of the methyl ester of (RS)-(4-cyanovinylene)-[5-ethoxy-2-(2-hydroxyethoxy)phenyl] acetic acid, hydroxylamine hydrochloride and triethylamine in methanol was obtained methyl ester of (RS)-(E)/(Z)-[5-ethoxy-2-(2-hydroxyethoxy)phenyl] -[4-(N-hydroxycarbamoyl)phenylamino]acetic acid, MS:404 (M+N)+.

49.6. Analogously to example 48.4 of the methyl ester of (RS)-(E)/(Z)-[5-ethoxy-2-(2-hydroxyethoxy)phenyl] -[4-(N-hydroxycarbamoyl)phenylamino] acetic acid was obtained acetate methyl ester (RS)-(4-carbamimidoyl)-[5-ethoxy-2-(2-hydroxyethoxy)phenyl] acetic acid, tPL183oC, MS:388 (M+N)+.

49.7. Analogously to example 48.5 from acetate methyl ester (RS)-(4-carbamimidoyl)-[5-ethoxy-2-(2-hydroxyethoxy)phenyl] acetic acid was obtained (RS)-(4-carbamimidoyl)-[5-ethoxy-2-(2-hydroxyethoxy)phenyl]acetic acid, tPL268oC, MS:374 (M+N)+.

Example 50.

50.1. 2.5 g of 2-hydroxy-4-methoxybenzaldehyde, 6.8 g3CO3, 3,3 ml chloroethanol and 33 ml of DMSO was heated at 80oC for 8 hours After extraction with ethyl acetate and chromatography on silica gel in methylene chloride/acetone was obtained 2.1 g of 2-(2 the ru 1.1 from 2-(2-hydroxyethoxy)-4-methoxybenzaldehyde, 4-aminobenzonitrile, 2-morpholinosydnonimine and F3t2received the methyl ester of (RS)-(4-cyanovinylene)-[2-(2-hydroxyethoxy)-4-methoxyphenyl]acetic acid, MS:357 (M+N)+.

50.3. Analogously to example 1.3 of the methyl ester of (RS)-(4-cyanovinylene)-[2-(2-hydroxyethoxy)-4-methoxyphenyl] acetic acid, hydroxylamine hydrochloride and triethylamine in methanol was obtained methyl ester (Z)-(RS)-[4-(N-hydroxycarbamoyl)phenylamino] -[2-(2-hydroxyethoxy)-4-methoxyphenyl]acetic acid, tPL92oC, MS:390 (M+N)+.

50.4. Methyl ester (Z)-(RS)-[4-(N-hydroxycarbamoyl)phenylamino]-[2-(2-hydroxyethoxy)-4-methoxyphenyl] acetic acid hydrolyzed in THF with 1 N. LiOH, were obtained (Z)-(RS)-[4-(N-hydroxycarbamoyl)phenylamino]-[2-(2-hydroxyethoxy)-4-methoxyphenyl]acetic acid.

50.5. Analogously to example 3 from this compound in acetic acid/water (2: 1) was obtained acetate (RS)-(4-carbamimidoyl)-[2-(2-hydroxyethoxy)-4-methoxyphenyl] acetic acid (1:2). The crude product was chromatographically on silica gel 100 with reversed phase C18, water/methanol (19:1 to 4:1) and then purified by chromatography on silica gel in ethyl acetate/acetone/water/acetic acid (12:2:1:1 to 6:2:logiczne example 50.1 from 4-benzyloxy-2-hydroxybenzaldehyde and 2-chloroethanol was obtained 4-benzyloxy-2-(2-hydroxyethoxy)benzaldehyde, tPL95oC, MS:272 (M)+.

51.2. Analogously to example 1.1 from 4-benzyloxy-2-(2-hydroxyethoxy)benzaldehyde, 4-aminobenzonitrile, 2-morpholinosydnonimine and BF3OEt2received the methyl ester of (RS)-[4-benzyloxy-2-(2-hydroxyethoxy)phenyl]-(4-cyanoaniline)acetic acid, MS:432 (M)+.

51.3. Analogously to example 50.3 of the methyl ester of (RS)-[4-benzyloxy-2-(2-hydroxyethoxy)phenyl] -(4-cyanoaniline)acetic acid was obtained methyl ester of (RS)-(E)/(Z)-[4-benzyloxy-2-(2-hydroxyethoxy)phenyl] -[4-(N-hydroxycarbamoyl)phenylamino] acetic acidPL90oC, MS: 466 (M+H)+.

51.4. Analogously to example 50.4 this compound is hydrolyzed in THF with 1 N. LiOH, it was received (RS)-(E)/(Z)-[4-benzyloxy-2-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid.

51.5. Analogously to example 50.5 from this compound was obtained (RS)-[4-benzyloxy-2-(2-hydroxyethoxy)phenyl] -(4-carbamimidoyl)acetic acid. The crude product was led out of the water and was purified by rubbing in methanol, MS:436 (M+N)+.

Example 52.

52.1. Analogously to example 12.1 and adding 3 mol.% KI, 2-hydroxy-4,5-dimethoxybenzaldehyde and methyl efiy, tPL144oC, MS:330 (M)+.

52.2. Analogously to example 1.1 from methyl ester 3-(2-formyl-4,5-dimethoxyphenoxy)benzoic acid, 4-aminobenzonitrile, 2-morpholinosydnonimine and F3t2received methyl ether (RS)-3-{2-[(4-cyanoaniline)methoxycarbonylmethyl]-4,5-dimethoxyphenoxy}benzoic acid, MS:513 (M+Na)+.

52.3. Analogously to example 1.3 of the methyl ester (RS)-3-{2-[(4-cyanoaniline)methoxycarbonylmethyl]-4,5-dimethoxyphenoxy}benzoic acid in methanol was obtained methyl ester (Z)-(RS)-3-(2- {[4-(N-hydroxycarbamoyl)phenylamino] methoxycarbonylmethyl} -4,5-dimethoxyphenoxy)benzoic acid, tPL173oC, MS:524 (M+H)+.

Example 53.

53.1. Analogously to example 18.1 of 5-ethyl-2,4-dihydroxybenzaldehyde, ethanol, triphenylphosphine and diethylazodicarboxylate received 4 ethoxy-5-ethyl-2-hydroxybenzaldehyde, MS:194 (M)+.

53.2. Analogously to example 45.1 4-ethoxy-5-ethyl-2-hydroxybenzaldehyde and chloracetamide received 2-(5-ethoxy-4-ethyl-2-formylphenoxy)ndimethylacetamide, tPL163-164oC, MS:251 (M)+.

53.3. Analogously to example 1.1 from 2-(5-ethoxy-4-ethyl-2-formylphenoxy)ndimethylacetamide, 4-aminobenzonitrile, 2-morpholinoethyl)-(4-cyanoaniline)acetic acid, tPL150-152oC, MS:412 (M+N)+.

53.4. Analogously to example 1.3 of the methyl ester of (RS)-(2-carbamoylmethyl-4-ethoxy-5-ethylphenyl)-(4-cyanoaniline)acetic acid, hydroxylamine hydrochloride and triethylamine in methanol was obtained methyl ester of (RS)-(E/Z)-(2-carbamoylmethyl-4-ethoxy-5-ethylphenyl)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid, tPL130-133oC, MS:445 (M+H)+.

53.5. Analogously to example 48.4 of the methyl ester of (RS)-(E/Z)-(2-carbamoylmethyl-4-ethoxy-5-ethylphenyl)-[4-(N-hydroxycarbamoyl)phenylamino] acetic acid was obtained acetate methyl ester (RS)-(4-carbamimidoyl)-(2-carbamoylmethyl-4-ethoxy-5-ethylphenyl)acetic acid, tPL230oC, MS:429 (M+H)+.

53.6. Analogously to example 48.5 from acetate methyl ester (RS)-(4-carbamimidoyl)-(2-carbamoylmethyl-4-ethoxy-5-ethylphenyl)acetic acid was obtained (RS)-(4-carbamimidoyl)-(2-carbamoylmethyl-4-ethoxy-5-ethylphenyl)acetic acid, tPL299oC, MS:415 (M+N)+.

Example 54.

54.1. Analogously to example 50.1 4-ethoxy-5-ethyl-2-hydroxybenzaldehyde received 4 ethoxy-5-ethyl-2-(2-hydroxyethoxy)benzaldehyde; MS:238 (M)+.

54.2. The Academy of Sciences of the cyanide and BF3OEt2in methanol was obtained methyl ester of (RS)-(4-cyanovinylene)-[4-ethoxy-5-ethyl-2-(2-hydroxyethoxy)phenyl]acetic acid, MS:399 (M+H)+.

54.3. Analogously to example 1.3 of the methyl ester of (RS)-(4-cyanovinylene)-[4-ethoxy-5-ethyl-2-(2-hydroxyethoxy)phenyl]acetic acid, hydroxylamine hydrochloride and triethylamine in methanol was obtained methyl ester of (RS)-(E/Z)-[4-ethoxy-5-ethyl-2-(2-hydroxyethoxy)phenyl] -[4-(N-hydroxycarbamoyl)phenylamino]acetic acid, MS:432 (M+N)+.

54.4. Analogously to example 48.4 of the methyl ester of (RS)-(E/Z)-[4-ethoxy-5-ethyl-2-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino] acetic acid was obtained acetate methyl ester (RS)-(4-carbamimidoyl)-[4-ethoxy-5-ethyl-2-(2-hydroxyethoxy)phenyl] acetic acid, tPL188oC, MS:416 (M+N)+.

54.5. Analogously to example 48.5 from acetate methyl ester (RS)-(4-carbamimidoyl)-[4-ethoxy-5-ethyl-2-(2-hydroxyethoxy)phenyl] acetic acid was obtained (RS)-(4-carbamimidoyl)-[4-ethoxy-5-ethyl-2-(2-hydroxyethoxy)phenyl]acetic acid, tPL271oC, MS:402 (M+N)+.

Example 55.

55.1. Analogously to example 52.1 4-ethoxy-5-ethyl-2-hydroxybenzaldehyde, Atila the l99-101oC, MS:280 (M)+.

55.2. Analogously to example 1.1 from ethyl ether (5 ethoxy-4-ethyl-2-formylphenoxy)acetic acid, 4-amino-N-hydroxybenzamide, 2-morpholinosydnonimine and F3t2in ethanol was obtained ethyl ester of (RS)-(E/Z)-(4-ethoxy-2-ethoxycarbonylmethoxy-5-ethylphenyl)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid, MS:488 (M+N)+.

55.3. Analogously to example 48.4 of the ethyl ester of (RS)-(E/Z)-(4-ethoxy-2-ethoxycarbonylmethoxy-5-ethylphenyl)-[4-(N-hydroxycarbamoyl)phenylamino] acetic acid was obtained acetate ethyl ether (RS)-(4-carbamimidoyl)-(4-ethoxy-2-ethoxycarbonylmethoxy-5-ethylphenyl)acetic acid, tPL195oC, MS:472 (M+H)+.

55.4. Analogously to example 48.5 from ethyl ether (4 carbamimidoyl)-(4-ethoxy-2-ethoxycarbonylmethoxy-5-ethylphenyl)acetic acid was obtained (4-carbamimidoyl)-(2-carboxymethoxy-4-ethoxy-5-ethylphenyl)acetic acid, which was purified by rubbing in water, tPL252oC.

Example 56.

56.1. Analogously to example 52.1 2-hydroxy-5-methyl-3-propylbenzamide and 2-chloroethanol received 2-(2-hydroxyethoxy)-5-methyl-3-propylbenzamide, MS:222 (M)+.

56.2. levy ether (RS)-(4-cyanovinylene)-[2-(2-hydroxyethoxy)-5-methyl-3-propylphenyl] acetic acid, tPL137-139oC, MS:382 (M)+.

56.3. Analogously to example 52.3 of the methyl ester of (RS)-(4-cyanovinylene)-[2-(2-hydroxyethoxy)-5-methyl-3-propylphenyl] acetic acid was obtained methyl ester (E)/(Z)-(RS)-[4-(N-hydroxycarbamoyl)phenylamino]-[2-(2-hydroxyethoxy)-5-methyl-3-propylphenyl]acetic acid, MS:416 (M+H)+.

56.4. Analogously to example 52.4 this compound is hydrolyzed in THF with 1 N. LiOH, it was received (E)/(Z)-(RS)-[4-(N-hydroxycarbamoyl)phenylamino] -[2-(2-hydroxyethoxy)-5-methyl-3-propylphenyl]acetic acid.

56.5. Analogously to example 52.5 from this compound was obtained (RS)-(4-carbamimidoyl)-[2-(2-hydroxyethoxy)-5-methyl-3-propylphenyl] acetic acid, which was led out of the water and was purified by rubbing in ethanol, tPL240oC, MS:386 (M+N)+.

Example 57.

57.1. Analogously to example 52.1 3-allyl-5-methylsalicylate aldehyde was obtained 3-allyl-2-(2-hydroxyethoxy)-5-methylbenzaldehyde, MS:220 (M)+.

57.2. Analogously to example 52.2 3-allyl-2-(2-hydroxyethoxy)-5-methylbenzaldehyde and 4-aminobenzonitrile received the methyl ester of (RS)-[3-allyl-2-(2-hydroxyethoxy)-5-were] -(4-cyanoaniline)acetic acid, tPL123oC, MS:381 amino)acetic acid in methylene chloride/methanol (5:1) at 0oWith saturated hydrogen chloride and kept at room temperature for 1 day. Then, the solution was evaporated in vacuum, the residue in methanol with ammonium acetate was heated under reflux. After evaporation of the solution and chromatography on silica gel in methylene chloride/methanol was obtained methyl ester of (RS)-[3-allyl-2-(2-hydroxyethoxy)-5-were]-(4-carbamimidoyl)acetic acid.

57.4. This compound is hydrolyzed in THF with 1 N. LiOH, it was received (RS)-[3-allyl-2-(2-hydroxyethoxy)-5-were] -(4-carbamimidoyl)acetic acid, tPL228o(Out of water), MS:384 (M+N)+.

Example 58.

58.1. of 4.2 g of hexamethylenetetramine was carefully added to 1.5 g of 2-methyl-4-propylene in 11 ml triperoxonane acid and the resulting mixture was heated at 120oC for 5 hours After adding 11 ml of 1 N. hydrochloric acid and the mixture was stirred at 107oC for 1 h Then the mixture was cooled to room temperature, diluted with ethyl acetate and then washed with water, dilute sodium hydrogen carbonate solution, water and sodium chloride solution. After evaporation of the solution and chromatography on silica gel in hexane/toluene was obtained 2-hydroxy-3-methyl-5-Pryda and 2-chloroethanol received 2-(2-hydroxyethoxy)-3-methyl-5-propylbenzamide, MS:222 (M)+.

58.3. Analogously to example 52.2 2-(2-hydroxyethoxy)-3-methyl-5-propylbenzamide and 4-aminobenzonitrile received the methyl ester of (RS)-(4-cyanovinylene)-[2-(2-hydroxyethoxy)-3-methyl-5-propylphenyl] acetic acid, tPL100oC, MS:382 (M)+.

58.4. Analogously to example 57.3 of the methyl ester of (RS)-(4-cyanovinylene)-[2-(2-hydroxyethoxy)-3-methyl-5-propylphenyl] acetic acid was obtained methyl ester of (RS)-(4-carbamimidoyl)-[2-(2-hydroxyethoxy)-3-methyl-5-propylphenyl]acetic acid.

58.5. This compound is hydrolyzed in THF with 1 N. LiOH, it was received (RS)-(4-carbamimidoyl)-[2-(2-hydroxyethoxy)-3-methyl-5-propylphenyl]acetic acid, tPL230o(Out of water), MS:386 (M+N)+.

Example 59.

59.1. Analogously to example 1.1, the 3-nitrobenzaldehyde was introduced in the reaction with 4-aminobenzonitrile and benzylideneamino, when it received the methyl ester of (RS)-(4-cyanovinylene)-(3-nitrophenyl)acetic acid.

59.2. 600 mg of 10% palladium on coal was added to a solution of 6.2 g of the nitro compounds obtained as described in example 59.1, in 150 ml of THF. The mixture was first made for 5 h at atmospheric pressure. Then the catalyst was separated by filtration, plucene, as described in example 59.2, was introduced into the reaction with acetylchloride, when it received the methyl ester of (RS)-(3-acetylaminophenol)-(4-cyanoaniline)acetic acid.

59.4. Analogously to example 1.2, then 1.3 from the compound described in example 59.3 via the intermediate formation of (RS)-(3-acetylaminophenol)-(4-cyanoaniline)acetic acid was obtained (E)-and/or (Z)-(RS)-(3-acetylaminophenol)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid.

Example 60.

60.1. Analogously to example 3 from the compound described in example 59.4, got acetate (RS)-(3-acetylaminophenol)-(4-carbamimidoyl)acetic acid (1:1).

Example 61.

61.1. 1.7 ml of diisopropylethylamine and 1.2 ml iodotope bromide was added to a solution of 2.8 g of aniline described in example 54.2, in 15 ml THF and the reaction mixture is boiled under reflux during the night. The crude product was isolated by extraction. After chromatography on silica gel received 0,59 g of methyl ester of (RS)-(4-cyanovinylene)-(3-methylaminophenol)acetic acid in a solid yellow color and 1,49 g of methyl ester of (RS)-(4-cyanovinylene)-(3-dimethylaminophenyl)acetic acid as a white powder.

61.2. Analogously to example 1.2, then 1.3 ethylaminomethyl)acetic acid was obtained (E)- and/or (Z)-(RS)-[4-(N-hydroxycarbamoyl)phenylamino] -(3-methylaminophenol)acetic acid, and from the corresponding DIMETHYLPROPANE through the intermediate formation of (RS)-(4-cyanovinylene)-(3-dimethylaminophenyl)acetic acid was obtained (E)- and/or (Z)-(RS)-(3-dimethylaminophenyl)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid.

Example 62.

Analogously to example 61 from the methyl ester of (RS)-(3-AMINOPHENYL)-(4-cyanoaniline)acetic acid and iodine ethyl received the methyl ester of (RS)-(4-cyanovinylene)-(3-diethylaminophenyl)acetic acid, from which then, through the intermediate formation of (RS)-(4-cyanovinylene)-(3-diethylaminophenyl)acetic acid was obtained (E)- and/or (Z)-(RS)-(3-diethylaminophenyl)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid.

Example 63. Analogously to example 3

63. a) from monomethylester described in example 61.2, got hydrochloride, (RS)-(4-carbamimidoyl)-(3-methylaminophenol)acetic acid (1:1);

63. b) from DIMETHYLPROPANE described in example 61.2, got hydrochloride, (RS)-(4-carbamimidoyl)-(3-dimethylaminophenyl)acetic acid (1:1);

63. in) from the compound described in example 62, received hydrochloride, (RS)-(4-carbamimidoyl)-(3-diethylaminophenyl)acetic acid (1:1).

Example 64.

64.1. 2.76 ml 2-brow the mixture was heated at 70oWith during the night, and then at 120oC for another 4 h and Then the mixture was cooled to room temperature, filtered and concentrated in high vacuum. The crude product was isolated by extraction and purified by chromatography on silica gel, thus received 6,09 g 3 ethoxy-4-(2-hydroxyethoxy)benzaldehyde in the form of a solid white color.

64.2. Analogously to example 1.1 from the aldehyde described in example 64.1, 4-aminobenzonitrile and benzylideneamino received the methyl ester of (RS)-(4-cyanovinylene)-[3-ethoxy-4-(2-hydroxyethoxy)phenyl]acetic acid.

64.3. Dry gaseous model HC1 was passed within 20 min after cooled to -10oWith the solution 926 mg of the compound obtained as described in example 64.2, in 10 ml of CHCl3/MeOH (3:1). The reaction mixture is kept at 4oWith overnight, and then concentrated. The residue was dissolved in 5 ml of methanol and treated with 5 ml of saturated solution of ammonia in methanol. The resulting solution was stirred at room temperature for 3 h, and then evaporated. The crude product was purified by chromatography on silica gel, thus received 391 mg of methyl ester hydrochloride (RS)-(4-carbamimidoyl)-[3-ethoxy-4-(2-hydroxyethoxy)phenyl] acetic acid a) 3-ethoxy-4-hydroxybenzaldehyde hydrochloride and 1-chloro-2-dimethylaminoethanol received 4-(2-dimethylaminoethoxy)-3-ethoxybenzaldehyde, which on reaction with 4-aminobenzonitrile and benzylideneamino received the methyl ester of (RS)-(4-cyanovinylene)-[4-(2-dimethylaminoethoxy)-3-ethoxyphenyl] acetic acid, and then the hydrochloride of the methyl ester of (RS)-(4-carbamimidoyl)-[4-(2-dimethylaminoethoxy)-3-ethoxyphenyl]acetic acid (1:2);

65. b) from 3-hydroxy-4-isopropoxybenzonitrile (obtained with a yield of 75% monoalkylammonium 3,4-dihydroxybenzaldehyde in the presence of Isopropylamine and K2CO3in DMF) and 2-bromoethanol was obtained 3-(2-hydroxyethoxy)-4-isopropoxybenzonitrile, which on reaction with 4-aminobenzonitrile and toluene-4-sulfonylmethane received the methyl ester of (RS)-(4-cyanovinylene)-[3-(2-hydroxyethoxy)-4-isopropoxyphenyl] acetic acid, and then the hydrochloride of the methyl ester of (RS)-(4-carbamimidoyl)-[3-(2-hydroxyethoxy)-4-isopropoxyphenyl]acetic acid (1:1);< / BR>
65. C) from 3-hydroxy-4-isopropoxybenzonitrile and iodoacetamide received 2-(5-formyl-2-isopropoxyphenoxy)ndimethylacetamide, which on reaction with 4-aminobenzonitrile and toluene-4-sulfonylmethane received the methyl ester of (RS)-(3-carbamoylmethyl-4-isopropoxyphenyl)-(4-cyanoaniline)acetic acid hydrochloride and then m is/BR> 65. g) of 3,4-dihydroxybenzaldehyde and 1-bromobutane received 3,4-dimetocsibenzoy, which on reaction with 4-aminobenzonitrile and benzylideneamino received the methyl ester of (RS)-(4-cyanovinylene)-(3,4-dibutoxy)acetic acid, and then the methyl ester of (RS)-(4-carbamimidoyl)-(3,4-dibutoxy)acetic acid.

Example 66.

66.1. Analogously to example 59.1 of the methyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-4-hydroxyphenyl)acetic acid (see example 350.1) and 2-chloro-1-propanol was obtained a mixture of the methyl esters of (RS)- and (SR)-(4-cyanovinylene)-[3-ethoxy-4-[(RS)-2-hydroxy-1-methylethoxy]phenyl]acetic acid.

66.2. Analogously to example 64.3 from the compound described in example 66.1, received a mixture of hydrochloride methyl ester of (RS)- and (SR)-(4-carbamimidoyl)-[3-ethoxy-4-[(RS)-2-hydroxy-1-methylethoxy] phenyl] acetic acid (1:1).

Example 67.

67.1. Analogously to example 64.1 3-ethoxy-4-hydroxybenzaldehyde and 1-chloro-2-methyl-2-propanol was obtained 3-ethoxy-4-(2-hydroxy-2-methylpropoxy)benzaldehyde.

67.2. Analogously to example 1.1 from aldehyde obtained as described in example 62.1, 4-amino-N-hydroxybenzamide and toluene-4-sulfonylmethane received ethyl the red acid.

67.3. Analogously to example 3 from amidoxime, obtained as described in example 67.2, received the ethyl ester of (RS)-(4-carbamimidoyl)-[3-ethoxy-4-(2-hydroxy-2-methylpropoxy)phenyl]acetic acid.

Example 68.

68.1. Analogously to example 64.1 of 3-hydroxy-4-nitrobenzaldehyde and iodine ethyl received 3 ethoxy-4-nitrobenzaldehyde.

68.2. Analogously to example 1 from aldehyde obtained as described in example 68.1, 4-aminobenzonitrile and toluene-4-sulfonylmethane received the methyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-4-nitrophenyl)acetic acid.

68.3. Analogously to example 54.2 of nitro-derivatives, obtained as described in example 68.2, received the methyl ester of (RS)-(4-amino-3-ethoxyphenyl)-(4-cyanoaniline)acetic acid.

68.4. Analogously to example 61.1 of the aniline described in example 68.3, and Isopropylamine received the methyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-4-isopropylaminomethyl)acetic acid.

68.5. Analogously to example 64.3 from the compound described in example 68.4, got hydrochloride methyl ester (RS)-(4-carbamimidoyl)-(3-ethoxy-4-isopropylaminomethyl)acetic acid (1:1).

Example 69. Similarly, examples of 68.4 and 68.5

Ali methyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-4-ethylaminomethyl)acetic acid, which then got hydrochloride methyl ester (RS)-(4-carbamimidoyl)-(3-ethoxy-4-ethylaminomethyl)acetic acid (1:1);

69.b) methyl ester of (RS)-(4-amino-3-ethoxyphenyl)-(4-cyanoaniline)acetic acid and iodine ethyl received the methyl ester of (RS)-(4-cyanovinylene)-(4-diethylamino-3-ethoxyphenyl)acetic acid, which then received hydrochloride methyl ester (RS)-(4-carbamimidoyl)-(4-diethylamino-3-ethoxyphenyl)acetic acid (1:1);

69.in) of the methyl ester of (RS)-(3-amino-4-ethoxyphenyl)-(4-cyanoaniline)acetic acid [obtained analogously to examples 68.1-3 of 5-hydroxy-3-nitrobenzaldehyde and methyl ethyl via the intermediate formation of 4-ethoxy-3-nitrobenzaldehyde and methyl ester of (RS)-(4-cyanovinylene)-(4-ethoxy-3-nitrophenyl)acetic acid] and under the conditions received the methyl ester of (RS)-(4-cyanoaniline)-(4-ethoxy-3-methylaminophenol)acetic acid, which then received hydrochloride methyl ester (RS)-(4-carbamimidoyl)-(4-ethoxy-3-methylaminophenol)acetic acid (1:1);

69.g) of the methyl ester of (RS)-(3-amino-4-ethoxyphenyl)-(4-cyanoaniline)acetic acid (see example 69.in) and under the conditions received the methyl ester of (RS)-(4-cyanophenyl the S)-(4-carbamimidoyl)-(3-dimethylamino-4-ethoxyphenyl)acetic acid (1:2);

69. d) of the methyl ester of (RS)-(3-amino-4-ethoxyphenyl)-(4-cyanoaniline)acetic acid (see example 69.in) and ethyliodide received the methyl ester of (RS)-(4-cyanovinylene)-(4-ethoxy-3-ethylaminomethyl)acetic acid, which then received hydrochloride methyl ester (RS)-(4-carbamimidoyl)-(4-ethoxy-3-ethylaminomethyl)acetic acid (1:1);

69. e) of the methyl ester of (RS)-(3-amino-4-ethoxyphenyl)-(4-cyanoaniline)acetic acid (see example 69.in) and ethyliodide received the methyl ester of (RS)-(4-cyanovinylene)-(3-diethylamino-4 ethoxyphenyl)acetic acid, which then received hydrochloride methyl ester (RS)-(4-carbamimidoyl)-(3-diethylamino-4-ethoxyphenyl)acetic acid (1:1).

Example 70.

70.1. Analogously to example 64.1 of 4-hydroxy-3-nitrobenzaldehyde by reaction with methyliodide was obtained 3-nitro-para-anisic aldehyde.

70.2. Analogously to example 1.1 from aldehyde obtained as described in example 70.1, 4-aminobenzonitrile and benzylideneamino received the methyl ester of (RS)-(4-cyanovinylene)-(4-methoxy-3-nitrophenyl)acetic acid.

70.3. Analogously to example 59.2 of the nitro-derivatives described in example 70.2, received the methyl ester of (RS)-(3-amino-4-methoxyphenyl)-(4-letterhead received the methyl ester of (RS)-(3-acetylamino-4-methoxyphenyl)-(4-cyanoaniline)acetic acid.

70.5 Analogously to example 1.2 of the complex ester described in example 70.4, was obtained (RS)-(3-acetylamino-4-methoxyphenyl)-(4-cyanoaniline)acetic acid.

70.6. Analogously to example 1.3 of the nitrile described in example 70.5, was obtained (E)- and/or (Z)-(RS)-(3-acetylamino-4-methoxyphenyl)- [4-(N-hydroxycarbamoyl)phenylamino]acetic acid.

Example 71.

71. A. Similar examples 70.2-6 of 4-methyl-3-nitrobenzaldehyde, 4-aminobenzonitrile and benzylideneamino received the methyl ester of (RS)-(4-cyanovinylene)-(4-methyl-3-nitrophenyl)acetic acid, which then received the methyl ester of (RS)-(3-amino-4-were)-(4-cyanoaniline)acetic acid. Then from this compound by reaction with acetylchloride received the methyl ester of (RS)-(3-acetylamino-4-were)-(4-cyanoaniline)acetic acid, and then through the intermediate formation of (RS)-(3-acetylamino-4-were)-(4-cyanoaniline)acetic acid was obtained (E)- and/or (Z)-(RS)-(3-acetylamino-4-were)-[4-(N-hydroxycarbamoyl)phenylamino] acetic acid.

71. B. Similar examples 70.4-6 methyl ether (RS)-(3-amino-4-methoxyphenyl)-(4-cyanoaniline)acetic acid, described in example 70.3, anhydride glutaric acids and bases Honig, then through the intermediate formation of (RS)-4-{ 5-[carboxy-(4-cyanoaniline)methyl] -2-methoxyphenylacetyl} butyric acid was obtained (RS)-(E)- and/or -(Z)-4-(5-{carboxy-[4-(N-hydroxycarbamoyl)phenylamino]methyl}-2-methoxyphenylacetyl)butyric acid.

71. C. Analogously to examples 70.4-6 methyl ether (RS)-(3-amino-4-methoxyphenyl)-(4-cyanoaniline)acetic acid, described in example 70.3, anhydride of succinic acid and base Chunga was obtained (RS)-N-{5-[(4-cyanoaniline) methoxycarbonylmethyl] -2-methoxyphenyl} succinimido acid, from which then, through the intermediate formation of (RS)-N-{5-[carboxy-(4-cyanoaniline)methyl] -2-methoxyphenyl} succinamides acid was obtained (RS)-(E)- and/or - (Z)-N-(5-{carboxy-[4-(N-hydroxycarbamoyl)phenylamino]methyl}-2-methoxyphenyl)succinimido acid.

Example 72.

72.1. Analogously to example 22.1 of the methyl ester of (RS)-(4-cyanovinylene)-(4-ethoxy-3-ethylaminomethyl)acetic acid obtained as the intermediate in example 69.d by reaction with acetylchloride received the methyl ester of (RS)-[3-(acetylamino)-4-ethoxyphenyl]-(4-cyanoaniline)acetic acid.

72.2. Analogously to example 64.3 nitrile obtained as op is

Example 73.

73.1. Analogously to example 22.1 of the methyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-4-hydroxyphenyl)acetic acid, described in example 350, by reaction with anhydride triftormetilfullerenov acid in CH2Cl2in the presence of triethylamine was obtained methyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-4-triftoratsetilatsetonom)acetic acid.

73.2. 118 mg of phenylboronic acid and 101 mg of potassium carbonate were added to a solution of 222 mg of the compound described in example 72.1, in 5 ml of toluene. The reaction mixture was purged with argon for 15 min and then was treated with 17 mg of tetrakis (triphenyl) palladium and heated at 90oC for 5 hours the Crude product was isolated by extraction and purified by chromatography on silica gel, thus received 166 mg of methyl ester of (RS)-(4-cyanovinylene)-(2-ethoxymethyl-4-yl)acetic acid in a solid white color.

73.3. Analogously to example 59.3 nitrile obtained as described in example 68.2, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(2-ethylbiphenyl-4-yl)acetic acid (1:1).

Example 74.

Analogously to example 73 from the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethyl-4-hydroxyphenyl)exfoilation)acetic acid, from which then, through the intermediate formation of ethyl ester of (RS)-(4-cyanovinylene)-(2-ethylbiphenyl-4-yl)acetic acid was obtained the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(2-ethylbiphenyl-4-yl)acetic acid (1:1).

Example 75.

A solution of 271 mg of ester, obtained as described in example 64.3, in 5 ml of THF was cooled to 0oAnd was treated with 3.5 ml of 1 N. LiOH. Then the mixture was stirred for 2 h, neutralized 1 N. Hcl and the THF evaporated. The resulting colorless precipitate was separated by filtration and thoroughly washed with water and diethyl ether. It was given 195 mg of (RS)-(4-carbamimidoyl)-[3-ethoxy-4-(2-hydroxyethoxy)phenyl] acetic acid in a solid white color.

Example 76. Analogously to example 75

76. a) of ester obtained as described in example 65.and received (RS)-(4-carbamimidoyl)-[4-(2-dimethylaminoethoxy)-3-ethoxyphenyl]acetic acid;

76. b) of ester obtained as described in example 65.b, was obtained (RS)-(4-carbamimidoyl)-[3-(2-hydroxyethoxy)-4-isopropoxyphenyl]acetic acid;

76. o) of ester obtained as described in example 60.in received (RS)-(4-carbamimidoyl)-(aproportional)acetic acid;

76. g) of ester obtained as described in example 65.g was obtained (RS)-(4-carbamimidoyl)-(3,4-dibutoxy)acetic acid;

76. d) of ester obtained as described in example 61.2, received a mixture of (RS)- and (SR)-(4-carbamimidoyl)-[3-ethoxy-4-[(RS)-2-hydroxy-1-methylethoxy]phenyl]acetic acid;

76. e) of ester obtained as described in example 67.3, was obtained (RS)-(4-carbamimidoyl)-[3-ethoxy-4-(2-hydroxy-2-methylpropoxy)phenyl]acetic acid;

76. W) of ester obtained as described in example 68.5, was obtained (RS)-(4-carbamimidoyl)-(3-ethoxy-4-isopropylaminomethyl)acetic acid;

76. C) of ester obtained as described in example 69.and received (RS)-(4-carbamimidoyl)-(3-ethoxy-4-ethylaminomethyl)acetic acid;

76. s) of ester obtained as described in example 69.b, was obtained (RS)-(4-carbamimidoyl)-(4-diethylamino-3-ethoxyphenyl)acetic acid;

76. K) of the complex ester, obtained as described in example 69.in received hydrochloride methyl ester (RS)-(4-carbamimidoyl)-(4-ethoxy-3-methylaminophenol)acetic acid (1:1);

76. l) of ester obtained as described in example 69.g, ether, obtained as described in example 69.d, was obtained (RS)-(4-carbamimidoyl)-(4-ethoxy-3-ethylaminomethyl)acetic acid;

76. n) of the complex ester, obtained as described in example 69.e, was obtained (RS)-(4-carbamimidoyl)-(3-diethylamino-4-ethoxyphenyl)acetic acid;

76. o) of ester obtained as described in example 72.2, was obtained (RS)-[3-(acetylamino)-4-ethoxyphenyl] -(4-carbamimidoyl)acetic acid;

76. p) of the complex ester, obtained as described in example 73.3, was obtained (RS)-(4-carbamimidoyl)-(2-ethoxymethyl-4-yl)acetic acid;

76.R) of ester obtained as described in example 74 was obtained (RS)-(4-carbamimidoyl)-(2-ethylbiphenyl-4-yl)acetic acid.

Example 77. Analogously to example 3

77. a) from amidoxime, obtained as described in example 70.6, was obtained (RS) - (3-acetylamino-4-methoxyphenyl)-(4-carbamimidoyl)acetic acid;

77. b) from amidoxime, obtained as described in example 71.and received (RS)-(3-acetylamino-4-were)-(4-carbs-methylphenylimino)acetic acid;

77. o) of ester obtained as described in example 71.b, received hydrochloride (RS)-4-{5-[(4-carbamimidoyl)carboxymethyl] is 71.in, received hydrochloride, (RS)-N-{5-[(4-carbamimidoyl)carboxymethyl]-2-methoxyphenyl}succinamide acid (1:2).

Example 78.

78.1. Analogously to example 64.1 3.5-dihydroxybenzaldehyde and ethyliodide received 3 ethoxy-5-hydroxybenzaldehyde.

78.2. Analogously to example 18.1 of phenol, obtained as described in example 78.1, 2-benzyloxyethanol was obtained 3-(2-benzyloxyethyl)-5-ethoxybenzaldehyde.

78.3. Analogously to example 1.1 from benzaldehyde, obtained as described in example 78.2, 4-aminobenzonitrile and benzylideneamino received the methyl ester of (RS)-[3-(2-benzyloxyethyl)-5-ethoxyphenyl]-(4-cyanoaniline)acetic acid.

78.4. Analogously to example 1.2 of the complex ester, obtained as described in example 78.3, was obtained (RS)-[3-(2-benzyloxyethyl)-5-ethoxyphenyl]-(4-cyanoaniline)acetic acid.

78.5. Analogously to example 1.3 of the nitrile obtained as described in example 78.4, was obtained (E)- and/or (Z)-(RS)-[3-(2-benzyloxyethyl)-5-ethoxyphenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid.

Example 79.

79.1. Analogously to example 64.1 of phenol, obtained as described in example 78.1, and ethyl ether bromoxynil acid was obtained ethyl ether, as described in example 79.1, 4-aminobenzonitrile and benzylideneamino received ethyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-5-ethoxycarbonylmethoxy)acetic acid.

79.3. Analogously to example 1.2 of the complex ester, obtained as described in example 79.2, was obtained (RS)-(3-carboxymethoxy-5-ethoxyphenyl)-(4-cyanoaniline)acetic acid.

79.4. Analogously to example 1.3 of the nitrile obtained as described in example 79.3, was obtained (RS)-(3-carboxymethoxy-5-ethoxyphenyl)-(4-cyanoaniline)acetic acid.

Example 80. Analogously to example 67

80. a) of the phenol described in example 78.1, and ethyl ester of 4-pamakani acid was obtained ethyl ester 4-(3-ethoxy-5-formylphenoxy)butyric acid, which then reacts with 4-amino-N-hydroxybenzamide and toluene-4-sulfonylmethane received ethyl ester of (RS)-(E)- and/or -(Z)-4-(3-ethoxy-5-{ etoxycarbonyl-[4-(N-hydroxycarbamoyl)phenylamino] methyl} phenoxy)butyric acid, acetate and then ethyl ether (RS)-4-{3-[(4-carbamimidoyl)ethoxycarbonylmethyl] -5-ethoxyphenyl} butyric acid (1:1);

80. b) from 3,5-dihydroxybenzaldehyde and 1-bromobutane received a 3.5-dimetocsibenzoy, which on reaction with 4-amino-N-hidrocarbonetos)phenylamino] acetic acid, and then methyl ether (4 carbamimidoyl)-(3,5-dibutoxy)acetic acid (compound includes acetic acid).

Example 81.

81.1. A solution of dimethyl-5-idsoftware in 800 ml of THF was treated 22,2 g l2and then portions were added 15.2 g NaBH4. The resulting mixture was stirred at room temperature for 1 day. Then the mixture was acidified with 250 ml 3 N. Hcl and diluted with 2 l of water. The crude product was isolated by extraction and purified by crystallization from THF/hexane. It was obtained 11.2 g (3-hydroxymethyl-5-itfeel)methanol as white crystals.

81.2. of 4.13 g of tetrakis(triphenyl)palladium was added to saturated with argon to a solution of 4.72 in g improsoned described in example 76.1, 250 ml of toluene. The mixture is then saturated WITH heated up to 70oWith, and using a spray pump within 6 h was added 6,15 ml of the hydride tributyl tin. Then the mixture was cooled to room temperature and filtered. The solid was dissolved in methanol and stirred with activated charcoal. After filtration through Dicalite product has led adding methanol. It was obtained 3,5-bis-hydroxymethylbenzene in the form of a solid light gray color.

nitrile and benzylideneamino, it was obtained methyl ester of (RS)-(3,5-bis-hydroxymethylene)-(4-cyanoaniline)acetic acid.

81.4. The solution is 1.82 ml DMSO in 150 ml of CH2CL2at -78oWith the handle of 1.86 ml of oxalicacid and the resulting mixture was stirred at -78oC for 30 minutes Then added dropwise 2,62 g of the compound described in example 81.3, in 50 ml of CH2Cl2and the resulting mixture was stirred at -78oC for 30 minutes and Then was added dropwise 17,88 ml of triethylamine and the reaction mixture was stirred at -78oC for another 2 hours Then the mixture was heated to room temperature and was evaporated. The residue was purified by chromatography on silica gel. When this was received of 2.34 g of methyl ester of (RS)-(4-cyanovinylene)-(3,5-deformity)acetic acid in the form of a solid foam light yellow color.

81.5. Suspension 425 mg dialdehyde described in example 81.4, 456 mg of potassium carbonate and 943 mg bromide methyltriphenylphosphonium in 17 ml of dioxane containing 1.5% of water, was heated at 110oC for 16 h Then the reaction mixture was concentrated, the crude product was isolated by chromatography on silica gel. When this was received 293 mg of methyl ester of (RS)-(4-cyanovinylene)-(3,5-diphenylphenol)acetic acid as Tverdov in example 81.5, received the methyl ester of (RS)-(4-cyanovinylene)-(3,5-diethylphenyl)acetic acid.

81.7. Analogously to example 59.3 nitrile obtained as described in example 81.6, received the methyl ester of (RS)-(4-carbamimidoyl)-(3,5-diethylphenyl)acetic acid.

Example 82.

Similar examples 81.5-7 of dialdehyde described in example 81.4, and bromide ethyltriphenylphosphonium received methyl ether (4 cyanovinylene)-(3,5-depropaniser)acetic acid, from which through the intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-(3,5-DIPROPYLENE)acetic acid was obtained methyl ether (4 carbamimidoyl)-(3,5-DIPROPYLENE)acetic acid.

Example 83.

Analogously to example 64.3 of the methyl ester (4 cyanovinylene)-(3,5-depropaniser)acetic acid, described as an intermediate compound in example 82, received hydrochloride methyl ester (RS)-(4-carbamimidoyl)-(3,5-depropaniser)acetic acid (1: 1) (in the configuration of the E and Z).

Example 84.

84.1. A solution of 130 mg of the aldehyde described in example 81.2, in 10 ml of DMF obrabatyvali 62 mg of NaH and the reaction mixture was stirred at room temperature for 10 minutes Then add rivali, the crude product was purified by chromatography on silica gel. When this was received 85 mg of 3,5-bis-methoxysalicylaldehyde.

84.2. Analogously to example 1.1 from benzaldehyde described in example 84.1, 4-aminobenzonitrile and toluene-4-sulfonylmethane received the methyl ester of (RS)-(3,5-bis-methoxymethyl)-(4-cyanoaniline)acetic acid.

84.3. Analogously to example 64.3 nitrile obtained as described in example 84.2, got hydrochloride methyl ester (RS)-(3,5-bis-methoxymethyl)-(4-carbamimidoyl)acetic acid (1:1).

Example 85.

85.1. The solution 2,87 g of methyl ester of (RS)-(4-cyanovinylene)-(3,5-deformity)acetic acid in 20 ml of dioxane and 1.3 ml of DMF was treated 3,18 g of bromide methyltriphenylphosphonium and 1.84 g of potassium carbonate. Suspensio was heated to 100oC for 3 days, then cooled to room temperature, filtered and concentrated. The crude product was isolated by extraction and purified by chromatography on silica gel. When it got to 1.31 g of methyl ester of (RS)-(4-cyanovinylene)-(3-formyl-5-vinylphenol)acetic acid in the form of a solid of light yellow color.

85.2. To a suspension of 200 mg of the aldehyde described in example 80.1, and 0,062 ml Patria, the resulting mixture was stirred at room temperature overnight, acidified 1 N. Hcl to pH 3 and evaporated. The crude product was isolated by extraction and purified by chromatography on silica gel. It was given 200 mg of methyl ester of (RS)-(4-cyanovinylene)-(3-pyrrolidin-1-ylmethyl-5-vinylphenol)acetic acid as colorless oil.

85.3. Analogously to example 64.3 from the compound described in example 85.2, got hydrochloride methyl ester (RS)-(4-carbamimidoyl)-(3-pyrrolidin-1-ylmethyl-5-vinylphenol)-acetic acid (1:2).

Example 86. Analogously to example 3

86.1) from amidoxime described in example 78.5, was obtained (RS)-[3-(2-benzyloxyethyl)-5-ethoxyphenyl]-(4-carbamimidoyl)acetic acid;

86.2) from amidoxime described in example 79.4, was obtained (RS)-(4-carbamimidoyl)-(3-carboxymethoxy-5-ethoxyphenyl]acetic acid.

Example 87. Analogously to example 16.3

87. a) from the compound described in example 78.5, was obtained (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(2-hydroxyethoxy)phenyl]acetic acid;

87. b) from the compound described in example 88.well, got acetate (RS)-(4-carbamimidoyl)-(3-ethyl-5-pyrrolidin-1-ylmethylene)acetic acid (1:1).

Example 89.

89.1. 114 g of hexamethylenetetramine was added to a solution of 20 g of 4-ethylphenol 400 ml Asón and the reaction mixture was stirred at 100oC for 5 h and Then was added 150 ml of water and 150 ml of 25% Hcl solution. The mixture was stirred at 100oC for 1 h, and then cooled to room temperature. The crude product was isolated by extraction of dietro is light yellow liquid.

89.2. Analogously to example 64.1 of phenol, obtained as described in example 89.1, and iodoacetamide received 2-(4-ethyl-2-formylphenoxy)ndimethylacetamide.

89.3. Analogously to example 1.1 from benzaldehyde described in example 89.2, 4-aminobenzonitrile and benzylideneamino received ethyl ester of (RS)-(2-carbamoylmethyl-5-ethylphenyl)-(4-cyanoaniline)acetic acid.

89.4. Analogously to example 64.3 nitrile described in example 89.3, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(2-carbamoylmethyl-5-ethylphenyl)acetic acid (1:1).

Example 90.

90. A. Similar examples 89.2-4 from the aldehyde described in example 89.1, and hydrochloride of 1-chloro-2-dimethylaminoethanol received 2-(2-dimethylaminoethoxy)-5-ethylbenzaldehyde, which on reaction with 4-aminobenzonitrile and toluene-4-sulfonylmethane received the methyl ester of (RS)-(4-cyanovinylene)-[2-(2-dimethylaminoethoxy)-5-ethylphenyl] acetic acid, and then the hydrochloride of the methyl ester of (RS)-(4-carbamimidoyl)-[2-(2-dimethylaminoethoxy)-5-ethylphenyl]acetic acid (1:1).

90.B. Analogously to example 89 4-propylene received 2-hydroxy-5-propylbenzamide, which on reaction with 2-bromoethanol received 2-(2-hydro who were given methyl ester of (RS)-(4-cyanovinylene)-[2-(2-hydroxyethoxy)-5-propylphenyl] acetic acid, and then the acetate methyl ester (RS)-(4-carbamimidoyl)-[2-(2-hydroxyethoxy)-5-propylphenyl]acetic acid (1:1).

90. C. Analogously to examples 89.2-4 of 2-hydroxy-5-propylbenzamide, the intermediate described in example 90.b, and iodoacetamide received 2-(2-formyl-4-propylenoxide)ndimethylacetamide, which on reaction with 4-aminobenzonitrile and toluene-4-sulfonylmethane received the methyl ester of (RS)-(2-carbamoylmethyl-5-propylphenyl)-(4-cyanoaniline)acetic acid, and then the hydrochloride of the methyl ester of (RS)-(4-carbamimidoyl)-(2-carbamoylmethyl-5-propylphenyl)acetic acid (1:1).

90. Similarly, example 89 4-(2-hydroxyethyl)phenol was obtained 5-(2-hydroxyethyl)salicylic aldehyde, which on reaction with 2-bromoethanol received 2-(2-hydroxyethoxy)-5-(2-hydroxyethyl)benzaldehyde. Then from this compound by the reaction with 4-aminobenzonitrile and benzylideneamino received ethyl ester of (RS)-(4-cyanovinylene)-[2-(2-hydroxyethoxy)-5-(2-hydroxyethyl)phenyl] acetic acid, and then the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-[2-(2-hydroxyethoxy)-5-(2-hydroxyethyl)phenyl] acetic acid (1:1).

90. D. Analogously to example 89 4-isopropylphenol poluprofessionalnaya. Then from this compound by the reaction with 4-aminobenzonitrile and benzylideneamino received the methyl ester of (RS)-(4-cyanovinylene)-[2-(2-hydroxyethoxy)-5-isopropylphenyl] acetic acid, and then the methyl ester of (RS)-(4-carbamimidoyl)-[2-(2-hydroxyethoxy)-5-isopropylphenyl]acetic acid.

Example 91.

91.1. 21 ml l3was added dropwise within 30 min to heated to 55oFrom a suspension of 20 g of 4-hydroxypropiophenone in 95 ml of 28% NaOH. The yellow suspension was heated at 55oC for 1.5 h, and then was added dropwise 5 ml l3, kept at 60oC for 5 h, cooled to room temperature and was poured into a mixture containing 70 ml of concentrated hydrochloric acid and 200 ml of water. The resulting yellow precipitate was separated by filtration. The remaining crude product was isolated from the filtrate by extraction. The residue and the extract were combined and purified by chromatography on silica gel. When this was received 2.24 g of 2-hydroxy-5-Propionaldehyde in a solid green color.

91.2. Similar examples 89.2-4 of the phenol described in example 91.1, 2-bromoethanol received 2-(2-hydroxyethoxy)-5-propenylbenzene. This is connected is enylamine)-[2-(2-hydroxyethoxy)-5-propionitrile] acetic acid, and then the hydrochloride of the methyl ester of (RS)-(4-carbamimidoyl)-[2-(2-hydroxyethoxy)-5-propionitrile]acetic acid (1:1).

Example 92.

92.1. Analogously to example 64.1 of the phenol described in example 89.1, and N-(2-bromacil)phthalimide was obtained 2-[2-(1,3-dioxo-1,3-dihydroindol-2-yl)ethoxy]-5-ethylbenzaldehyde.

92.2. Analogously to example 1.1 from benzaldehyde, obtained as described in example 92.1, 4-aminobenzonitrile and benzylideneamino received the methyl ester of (RS)-(4-cyanovinylene)-{ 2-[2-(1,3-dioxo-1,3-dihydroindol-2-yl)ethoxy]-4,5-acid}acetic acid.

92.3. of 0.82 ml) was added hydrazine hydrate is added to a solution 2,73 g phthalimide described in example 92.2, 20 ml Meon and 20 ml of CHCl3. The reaction mixture was stirred at room temperature for 1 day, then was treated with 10 ml of acetic acid in 20 ml of Meon and stirred at room temperature overnight. Then dropped in the sediment hydrazinoacetate was separated by filtration, the filtrate is evaporated. The crude product was isolated by chromatography on silica gel. It was obtained 1.48 g of the acetate methyl ester (RS)-[2-(2-aminoethoxy)-5-ethylphenyl] -(4-cyanoaniline)acetic acid (1:1) in the form of dried white product. methyl ester of (RS)-[2-(2-aminoethoxy)-5-ethylphenyl]-(4-carbamimidoyl)acetic acid (1:3).

Example 93.

Analogously to example 64.3 nitrile obtained as described in example 92.2, got hydrochloride methyl ester (RS)-(4-carbamimidoyl)-{ 2-[2-(1,3-dioxo-1,3-dihydroindol-2-yl)ethoxy]-5-ethylphenyl}acetic acid (1:1).

Example 94.

94.1. Analogously to example 22.1 of the amine obtained as described in example 92.3, and acetylchloride received the methyl ester of (RS)-[2-(2-acetylbenzoate)-5-ethylphenyl]-(4-cyanoaniline)acetic acid.

94.2. Analogously to example 64.3 nitrile obtained as described in example 94.1, got hydrochloride methyl ester (RS)- [2-(2-acetylbenzoate)-5-ethylphenyl]-(4-carbamimidoyl)acetic acid (1:1).

Example 95.

Analogously to example 94

95. a) of the amine obtained as described in example 92.3, and anhydride triperoxonane acid was obtained methyl ester of (RS)-(4-cyanovinylene)-{ 5-ethyl-2-[2-(2,2,2-triptoreline)ethoxy] phenyl} acetic acid, which then received hydrochloride methyl ester (RS)-(4-carbamimidoyl)-{ 5-ethyl-2-[2-(2,2,2-triptoreline)ethoxy] phenyl}acetic acid (1:1);

95. b) of the amine obtained as described in example 92.3, and methanesulfonanilide received the methyl Akali hydrochloride methyl ester (RS)-(4-carbamimidoyl)-[5-ethyl-2-(2-methanesulfonylaminoethyl)phenyl]acetic acid (1:1);

95. in) of the amine obtained as described in example 92.3, and phenylsulfonylacetate received the methyl ester of (RS)-[2-(2-Ben-solarpowergetics)-5-ethylphenyl] -(4-cyanoaniline)acetic acid, which then received hydrochloride methyl ester (RS)-[2-(2-benzosulfimide-aminoethoxy)-5-ethylphenyl]-(4-carbamimidoyl)acetic acid (1:1).

Example 96. Analogously to example 75

96. a) of ester obtained as described in example 89.4, was obtained (RS)-(4-carbamimidoyl)-(2-carbamoylmethyl-5-ethylphenyl)acetic acid;

96. b) of ester obtained as described in example 89.and received (RS)-(4-carbamimidoyl)-[2-(2-dimethylaminoethoxy)-5-ethylphenyl]acetic acid;

96. o) of ester obtained as described in example 90.b, was obtained (RS)-(4-carbamimidoyl)-[2-(2-hydroxyethoxy)-5-propylphenyl] acetic acid;

96. g) of ester obtained as described in example 90.in received (RS)-(4-carbamimidoyl)-(2-carbamoylmethyl-5-propylphenyl)acetic acid;

96. d) of ester obtained as described in example 89.g was obtained (RS)-(4-carbamimidoyl)-[2-(2-hydroxyethoxy)-5-(2-hydroxyethyl)phenyl]acetic acid;

96. e) Itaxi)-5-isopropylphenyl]acetic acid;

96. W) of ester obtained as described in example 92.4, got acetate (RS)-[2-(2-aminoethoxy)-5-ethylphenyl]-(4-carbamimidoyl)acetic acid (1:1);

96.C) of ester obtained as described in example 92 was obtained (RS)-N-(2-{ 2-[(4-carbamimidoyl)carboxymethyl] -4-ethylenoxy} ethyl)talimena acid;

96. s) of ester obtained as described in example 94.2, was obtained (RS)-[2-(2-acetylbenzoate)-5-ethylphenyl] -(4-carbamimidoyl)acetic acid;

96. K) of the complex ester, obtained as described in example 95.and received (RS)-(4-carbamimidoyl)-{ 5-ethyl-2-[2-(2,2,2-triptoreline)ethoxy]phenyl}acetic acid;

96. l) of ester obtained as described in example 95.b, was obtained (RS)-(4-carbamimidoyl)-[5-ethyl-2-(2-methanesulfonylaminoethyl)phenyl]acetic acid;

96. m) of ester obtained as described in example 95.in received (RS)-[2-(2-benzensulfonamidelor)-5-ethylphenyl] -(4-carbamimidoyl)acetic acid;

96. n) of the complex ester, obtained as described in example 91.2, got hydrochloride methyl ester (RS)-(4-carbamimidoyl)-[2-(2-hydroxyethoxy)-5-propionitrile]acetic acid (1:1).

Example 98.

98.1. Analogously to example 1.1 from 4,5-dimethoxy-2-methylbenzaldehyde, 4-aminobenzonitrile and toluene-4-sulfonylmethane received the methyl ester of (RS)-(4-cyanovinylene)-(4,5-dimethoxy-2-were)acetic acid, from which then, analogously to example 64.3 received hydrochloride methyl ester (RS)-(4-carbamimidoyl)-(4,5-dimethoxy-2-were)acetic acid (1:1).

98.2. Analogously to example 98.1 of 2,5-dimethyl-4-methoxybenzaldehyde, 4-aminobenzonitrile and toluene-4-sulfonylamino-cyanide was obtained methyl ester of (RS)-(4-cyanovinylene)-(4-methoxy-2,5-dimetilfenil)acetic acid, which then received the acetate methyl ester (RS)-(4-carbamimidoyl)-(4-methoxy-2,5-dimetilfenil)acetic acid (1:1).

Example 99.

99.1. Analogously to example 64.1 4.5-diethoxy-2-hydroblasting acid in methanol, subsequent hydrolysis of the resulting ester formylphenol using KOH in methanol to obtain 3,4-detoxifier and subsequent formirovanie on Gatterman (Gattermann) cyanide zinc, KCl and Hcl in diethyl ether] and 2-bromoethanol received 4,5-diethoxy-2-(2-hydroxyethoxy)benzaldehyde.

99.2. Analogously to example 1.1 from benzaldehyde, obtained as described in example 99.1, 4-amino-N-hydroxybenzamide and benzylideneamino received ethyl ester (E)- and/or (Z)-(RS)-[4,5-diethoxy-2-(2-hydroxyethoxy)phenyl] -[4-(N-hydroxycarbamoyl)phenylamino]acetic acid.

99.3. Analogously to example 3 from amidoxime, obtained as described in example 99.2, got acetate ethyl ether (RS)-(4-carbamimidoyl)-[4,5-diethoxy-2-(2-hydroxyethoxy)phenyl]acetic acid (1:1).

Example 100. Analogously to example 99

100. a) from 4,5-diethoxy-2-hydroxybenzaldehyde and 3-bromo-1-propanol was obtained 4,5-diethoxy-2-(3-hydroxypropoxy)benzaldehyde, which on reaction with 4-amino-N-hydroxybenzamide and benzylideneamino received ethyl ester of (RS)-(E)- and/or -(Z)-[4,5-diethoxy-2-(3-hydroxypropoxy)phenyl] -[4-(N-hydroxycarbamoyl)phenylamino] acetic acid, and then acetate ethyl ether (RS)-(4-carbamimidoyl)-[4, ethyl ester bromoxynil acid was obtained ethyl ester (4,5-diethoxy-2-formylphenoxy)acetic acid, from which on reaction with 4-amino-N-hydroxybenzamide and benzylideneamino received ethyl ester of (RS)-(E)- and/or -(Z)-(4,5-diethoxy-2-ethoxycarbonylmethoxy)-[4-(N-hydroxycarbamoyl)phenylamino] acetic acid, acetate and then ethyl ether (RS)-(4-carbamimidoyl)-(4,5-diethoxy-2-ethoxycarbonylmethoxy)acetic acid (1:1);

100. in) from 4,5-diethoxy-2-hydroxybenzaldehyde and ethyl ester of 2-promisable acid was obtained ethyl ester of 2-(4,5-diethoxy-2-formylphenoxy)-2-methylpropionic acid, which on reaction with 4-amino-N-hydroxybenzamide and benzylideneamino received ethyl ester of (RS)-(E)- and/or (Z)-2-(4,5-diethoxy-2-{[4-(N-hydroxycarbamoyl)phenylamino]methoxycarbonylmethyl} phenoxy)-2-methylpropionic acid, and then ethyl ether (RS)-2-{ 2-[(4-carbamimidoyl)methoxycarbonylmethyl] -4,5-dioxygenase} -2-methylpropionic acid;

100. g) of 4,5-diethoxy-2-hydroxybenzaldehyde and iodoacetamide received 2-(4,5-diethoxy-2-formylphenoxy)ndimethylacetamide, which on reaction with 4-amino-N-hydroxybenzamide and benzylideneamino received ethyl ester (2-carbamoylphenoxy-4,5-dioxyphenyl)-[4-(N-hydroxycarbamoyl)phenylamino] acetic acid, hydrochloride and then atrophogenic 101.

101.1. Similar examples 16.1-2 of 6-bromoveratrole aldehyde, 4-aminobenzonitrile and benzylideneamino received the methyl ester of (RS)-(2-bromo-4,5-acid)-(4-cyanoaniline)acetic acid.

101.2. Analogously to example 64.3 nitrile obtained as described in example 101.1, got hydrochloride methyl ester (RS)-(2-ROM-4,5-acid)-(4-carbamimidoyl)acetic acid (1:1).

Example 102.

102.1. A solution of 0.91 mg of the bromide described in example 101.1, in 20 ml of 1,2-dimethoxyethane was treated with 0.32 g of 3-tiefenbronn acid and 0,76 mg CsF. Through the resulting suspension for 30 min missed argon. Then was added 87 mg of tetrakis(triphenylphosphine)palladium and the reaction mixture is boiled under reflux during the night. The crude product was isolated by extraction and purified by chromatography on silica gel. When this was received 241 mg of methyl ester of (RS)-(4-cyanovinylene)-(4,5-dimethoxy-2-thiophene-3-ylphenyl)acetic acid in a solid gray color.

102.2. Analogously to example 64.3 from the compound described in example 101.1, got acetate methyl ester (RS)-(4-carbamimidoyl)-(4,5-dimethoxy-2-thiophene-3-ylphenyl)acetic acid (1:1).

Example 103.

.1, in 100 ml of dioxane and through the reaction mixture for 15 min missed argon. Then was added 0.52 g of chloride bis(triphenylphosphine)palladium (II), the reaction mixture was heated at 80oWith over night, filtered and evaporated. The crude product was isolated by chromatography on silica gel. When this was received 3.89 g of methyl ester of (RS)-(4-cyanovinylene)-[4,5-dimethoxy-2-(4,4,5,5-tetramethyl[1,3,2] dioxaborolan-2-yl)phenyl]acetic acid in the form of foam pink.

103.2. Analogously to example 73.2 from ether Bronevoy acid described in example 102.1, received the methyl ester of (RS)-(4-cyanovinylene)-(4,5-dimethoxy-2-pyridine-3-ylphenyl)acetic acid.

103.3. Analogously to example 64.3 of the compound obtained as described in example 103.2, got hydrochloride methyl ester (RS)-(4-carbamimidoyl)-(4,5-dimethoxy-2-pyridine-3-ylphenyl)acetic acid (1:1).

Example 104.

104. A. Analogously to example 102 of the bromide described in example 101.1, and phenylboronic acid was obtained methyl ester of (RS)-(4-cyanovinylene)-(4,5-dimethoxybiphenyl-2-yl)acetic acid, which then received hydrochloride methyl ester (RS)-(4-carbamimidoyl)-(4,5-dimethoxybiphenyl-2-yl)acetic acid (1:1).

Example 105. Analogously to example 75

105. a) of ester described in example 98.1, was obtained (RS)-(4-carbamimidoyl)-(4,5-dimethoxy-2-were)acetic acid;

105. b) of ester described in example 98.2, was obtained (RS)-(4-carbamimidoyl)-(4-methoxy-2,5-dimetilfenil)acetic acid;

105. o) of ester described in example 99.3, was obtained (RS)-(4-carbamimidoyl)-[4,5-diethoxy-2-(2-hydroxyethoxy)phenyl] acetic acid;

105. g) of the complex ester described in example 100.and received (RS)-(4-carbamimidoyl)-[4,5-diethoxy-2-(3-hydroxypropoxy)phenyl] acetic acid;

105. d) of ester described in example 100.b, was obtained (RS)-(4-carbamimidoyl)-(2-carboxymethoxy-4,5-dioxyphenyl)acetic acid;

105. e) of the complex ester described in example 100.in received (RS)-2-{ 2-[(4-carbamimidoyl)carboxymethyl] -4,5-dioxygenase} -2-methylpropionic acid;

105. W) of the complex ester described in example 100.g was obtained (RS)-(4-carbamimidoyl)-(2-carbamoylphenoxy-4,5-dioxyphenyl)exurbanization)acetic acid;

105. s) of ester described in example 102.2, was obtained (RS)-(4-carbamimidoyl)-(4,5-dimethoxy-2-thiophene-3-ylphenyl)acetic acid;

105. K) of the complex ester described in example 104.and received (RS)-(4-carbamimidoyl)-(4,5-dimethoxybiphenyl-2-yl)acetic acid;

105. l) of the complex ester described in example 104.b, was obtained (RS)-(4-carbamimidoyl)-(4,5-dimethoxy-2-thiophene-2-ylphenyl)acetic acid;

105. m) of the complex ester described in example 103.3, was obtained (RS)-(4-carbamimidoyl)-(4,5-dimethoxy-2-pyridine-3-ylphenyl)acetic acid.

Example 106.

106.1. Analogously to example 102.1 of the bromide described in example 103.1, and 2-Farnborough acid was obtained (RS)-(4-cyanovinylene)-(2-furan-2-yl-4,5-acid)acetic acid.

106.2. Analogously to example 1.2 from the compound described in example 106.1, was obtained (RS)-(4-cyanovinylene)-(2-furan-2-yl-4,5-acid)acetic acid.

106.3. Analogously to example 1.3 from the compound described in example 106.2, received (2-furan-2-yl-4,5-acid)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid.

106.4. Analogously to example 3 from amidoxime, obtained as described in example 106.3, was obtained (RS)-(47.1. 2.13 ml conc. nitric acid was added over 30 min to a cooled to -30oWith a solution of 10 g of 3,4-diethoxyaniline in 185 ml of 1,2-dichloroethane. Then the reaction mixture was heated to 0oC and poured into ice. The reaction product was extracted, it was received 12,06 g of 4,5-diethoxy-2-nitrobenzaldehyde.

107.2. Analogously to example 1.1 from benzaldehyde, obtained as described in example 107.1, 4-aminobenzonitrile and benzylideneamino received the methyl ester of (RS)-(4-cyanovinylene)-(4,5-diethoxy-2-nitrophenyl)acetic acid.

107.3. Analogously to example 59.2 recovery nitro compounds, obtained as described in example 107.2, in the presence of platinum on coal was obtained methyl ester of (RS)-(2-amino-4,5-dioxyphenyl)-(4-cyano-phenylamino)acetic acid.

107.4. Analogously to example 22.1 prepared from aniline as described in example 107.3, anhydride and glutaric acid was obtained (RS)-4-{2-[carboxy-(4-cyanoaniline)methyl]-4,5-diethoxyaniline}butyric acid.

107.5. Analogously to example 1.3 from the compound obtained as described in example 107.4, was obtained (RS)-4-(2-{ carboxy[4-(N-hydroxycarbamoyl)phenylamino]methyl}-4,5-diethoxyaniline)butyric acid.

107.6. Analogic kemetyl]-4,5-diethoxyaniline} butyric acid (compound includes acetic acid).

Example 108.

108.1. Analogously to example 22.1 of the aniline described in example 107.3, and monomethylethanolamine was obtained (RS)-(4-cyanovinylene)-[4,5-diethoxy-2-(oxalylamino)phenyl]acetic acid.

108.2. Analogously to example 64.3 of the compound obtained as described in example 107.1, got hydrochloride methyl ester (RS)-(4-carbamimidoyl)-[4,5-diethoxy-2-(methoxycarbonylamino)phenyl] acetic acid (1:1).

108.3. Analogously to example 1.2 of the complex ester, obtained as described in example 107.2, was obtained (RS)-(4-carbamimidoyl)-[4,5-diethoxy-2-(oxalylamino)phenyl]acetic acid.

Example 109.

109.1. Cooled to 0oWith the solution for 6.81 g of 3,4-dimethylbenzyl alcohol and are 11.62 ml of N, N, N',N'-tetramethylethylenediamine in 150 ml of pentane was treated with 62.5 ml of 1.6 M solution of n-utility in hexane and the reaction mixture is boiled under reflux for 11 hours and Then at -30oWith added dropwise 12,69 g of iodine in 50 ml of THF, after which the mixture was stirred at -30oC for 15 min and warmed up to room temperature. Then the reaction mixture was added to 100 ml of 10% sulfuric acid. The crude product was isolated by extraction and purified by chromatography on silica gel. Pri.2. Analogously to example 27.1 of iodide, obtained as described in example 109.1, and methyl acrylate was obtained methyl ester (E)-3-(2-hydroxymethyl-4,5-dimetilfenil)acrylic acid.

109.3. Analogously to example 27.2 from the compound described in example 109.2 received methyl ester 3-(2-hydroxymethyl-4,5-dimetilfenil)propionic acid.

109.4. Analogously to example 27.3 from the compound described in example 109.3, received methyl ester 3-(2-formyl-4,5-dimetilfenil)propionic acid.

109.5. Analogously to example 1 from benzaldehyde, obtained as described in example 109.4, 4-aminobenzonitrile and benzylideneamino received methyl ether (RS)-3-[2-[(4-cyanoaniline)methoxycarbonylmethyl] -4,5-dimetilfenil] propionic acid, from which through the intermediate formation of (RS)-3-[2-[carboxy(4-cyanoaniline)methyl] -4,5-dimetilfenil] propionic acid was obtained (E)- and/or (Z)-(RS)-3-[2-[carboxy[4-(N-hydroxycarbamoyl)phenylamino]methyl]-4,5-dimetilfenil]propionic acid.

109.6. Analogously to example 3 from amidoxime, obtained as described in example 109.5, received (RS)-3-{2-[(4-carbamimidoyl)carboxymethyl] -4,5-dimetilfenil}propionic acid.

Example 110.

110.1. Analogously to example dinnie, 2-buta-2-enyloxy-5-ethylbenzaldehyde, was extracted, was heated at 200oWith in one day and were directed into the mantle (bulb-tube oven). When this was received 3,39 g of (RS)-5-ethyl-2-hydroxy-3-(1-methylallyl)benzaldehyde as a yellow liquid.

110.2. Analogously to example 64.1 of the phenol described in example 110.1, and 2-bromoethanol was obtained (RS)-5-ethyl-2-(2-hydroxyethoxy)-3-(1-methylallyl)benzaldehyde.

110.3. Analogously to example 1.1 from benzaldehyde described in example 110.2, 4-amino-N-hydroxybenzamide and benzylideneamino received ethyl ester [5-ethyl-2-(2-hydroxyethoxy)-3-(1-methylallyl)phenyl] -[4-(N-hydroxycarbamoyl)phenylamino]acetic acid.

110.4. Analogously to example 3 from amidoxime, obtained as described in example 110.3, received a mixture of ethyl ester of (RS)- and (SR)-[(RS)-3-sec-butyl-5-ethyl-2-(2-hydroxyethoxy)phenyl] -(4-carbamimidoyl)acetic acid.

Example 111.

Analogously to example 110 of the phenol described in example 87.b, by alkylation of CIS, TRANS-crotylboration and subsequent heating at 200oWith received (RS)-2-hydroxy-3-(1-methylallyl)-5-propylbenzamide. From this phenol by reaction with 2-bromoethanol was obtained (RS)-2-(2-hydroxyethoxy)-3-(1-meth what onitrile received ethyl ester [4-(N-hydroxycarbamoyl)phenylamino] -[2-(2-hydroxyethoxy)-3-(1-methylallyl)-5-propylphenyl] acetic acid, which then received a mixture of acetates ethyl ester of (RS)- and (SR)-[(RS)-3-sec-butyl-2-(2-hydroxyethoxy)-5-propylphenyl]-(4-carbamimidoyl)acetic acid (1:1).

Example 112.

112.1. Analogously to example 1.1 from benzaldehyde, obtained as described in example 110.2, 4-aminobenzonitrile and benzylideneamino received a mixture of ethyl ester of (RS)- and (SR)-(4-cyanovinylene)-[5-ethyl-2-(2-hydroxyethoxy)-3-[(RS)-1-methylallyl]phenyl]acetic acid.

112.2. Analogously to example 59.3 nitrile obtained as described in example 112.1, received a mixture of hydrochloride ethyl ester of (RS)- and (SR)-(4-carbamimidoyl) - [5-ethyl-2-(2-hydroxyethoxy)-3-[(RS)-1-methylallyl]phenyl]acetic acid (1:1).

Example 113.

113.1. Analogously to example 89.1 of the methyl ester 5-methoxysalicylaldehyde acid was obtained methyl ester of 3-formyl-2-hydroxy-5-methoxybenzoic acid.

113.2. Analogously to example 64.1 of phenol, obtained as described in example 113.1, and 2-bromoethanol received 7-methoxy-5-oxo-2,3-dihydro-5H-benzo[e] [1,4]doxepin-9-carbaldehyde.

113.3. Analogously to example 1.1 from benzaldehyde, obtained as described in example 113.2, 4-amino-N-hydroxybenzamide and benzylideneamino received methyl is an Example 114.

114.1. to 8.41 ml of bromine in 100 ml l3was added dropwise over 2 h to a cooled to 0oWith a solution of 10 g of 4-ethylphenol 200 ml l3and 100 ml of methanol. Then the reaction mixture was heated to room temperature and concentrated. The reaction product was isolated by extraction. When this was received 33,14 g of 2-bromo-4-ethylphenol in the form of butter a light brown color.

114.2. Analogously to example 89.1 of the phenol described in example 114.1, received 3-bromo-5-ethyl-2-hydroxybenzaldehyde.

114.3. Analogously to example 59.1 of the phenol described in example 114.2, and 2-bromoethanol received 3-bromo-5-ethyl-2- (2-hydroxyethoxy)benzaldehyde.

114.4. Analogously to example 1.1 from benzaldehyde, obtained as described in example 114.3, 4-aminobenzonitrile and benzylideneamino received the methyl ester of (RS)-[3-bromo-5-ethyl-2-(2-hydroxyethoxy)phenyl] -(4-cyanoaniline)acetic acid.

114.5. Analogously to example 69.3 of the nitrile obtained as described in example 114.4, got hydrochloride methyl ester (RS)-[3-bromo-5-ethyl-2-(2-hydroxyethoxy)phenyl] -(4-carbamimidoyl)acetic acid (1: 1).

Example 115.

115.1. Analogously to example 73.1 of the bromide described in example 110.4, and phenylboronic acid recip.3 from the connection, described in example 115.1, got hydrochloride methyl ester (RS)-(4-carbamimidoyl)-[5-ethyl-2-(2-hydroxyethoxy)biphenyl-3-yl]acetic acid (1:1).

Example 116. Analogously to example 75

116. a) of ester described in example 110.4, received a mixture of (RS)- and (SR)-[(RS)-3-sec-butyl-5-ethyl-2-(2-hydroxyethoxy)phenyl] -(4-carbamimidoyl)acetic acid;

116. b) of ester described in example 111 was obtained a mixture of (RS)-and (SR)-[(RS)-3-sec-butyl-2-(2-hydroxyethoxy)-5-propylphenyl] -(4-carbamimidoyl)acetic acid;

116. o) of ester described in example 112.2, received a mixture of (RS)- and (SR)-(4-carbamimidoyl)-[5-ethyl-2-(2-hydroxyethoxy)-3-[(RS)-1-methylallyl]phenyl]acetic acid;

116. g of the complex ester described in example 113.4, was obtained (RS)-(4-carbamimidoyl)-(7-methoxy-5-oxo-2,3-dihydro-5H-benzo[e] [1,4] doxepin-9-yl)acetic acid and (RS)-3-[(4-carbamimidoyl)carboxymethyl]-2-(2-hydroxyethoxy)-5-methoxybenzoic acid;

116. d) of ester described in example 114.5, was obtained (RS)-[3-bromo-5-ethyl-2-(2-hydroxyethoxy)phenyl] -(4-carbamimidoyl)acetic acid;

116. e) of the complex ester described in example 115.2, was obtained (RS)-(4-carbamimidoyl method described in example 64.1, but using the following hydroxyaldehyde and alkylating agents were aldehydes, of which, analogously to example 1 was received appropriate amidoxime:

117. a) from 3-ethoxy-4-hydroxybenzaldehyde and 2-bromopropane received 3 ethoxy-4-isopropoxybenzonitrile, which through the intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-4-isopropoxyphenyl)acetic acid and (RS)-(4-cyanovinylene)-(3-ethoxy-4-isopropoxyphenyl)acetic acid was obtained (E)- and/or (Z)-(RS)-(3-ethoxy-4-isopropoxyphenyl)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid;

117. b) from 3-allyl-4-hydroxybenzaldehyde and 2-bromopropane received 3-allyl-4-isopropoxybenzonitrile, which through the intermediate formation of methyl ester of (RS)-(3-allyl-4-isopropoxyphenyl)-(4-cyanoaniline)acetic acid and (RS)-(3-allyl-4-isopropoxyphenyl)-(4-cyanoaniline)acetic acid was obtained (E)- and/or (Z)-(RS)-(3-allyl-4-isopropoxyphenyl)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid;

117. C) from 3-ethoxy-4-hydroxybenzaldehyde and bromocyclopropane received 3 ethoxy-4-cyclopropanecarboxaldehyde, which through the intermediate formation of methyl ester of (RS)-(4-laniel)acetic acid was obtained (RS)-(4-cyclopropane-3-ethoxyphenyl)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid.

Example 118.

Analogously to example 3 of the compounds obtained as described in example 117, received the appropriate amidine:

118. a) from the compound described in example 117.and received (RS)-(4-carbamimidoyl)-(3-ethoxy-4-isopropoxyphenyl)acetic acid;

118. b) from the compound described in example 117.b, was obtained (RS)-(4-carbamimidoyl)-(4-isopropoxy-3-propylphenyl)acetic acid;

118. in) from the compound described in example 117.in received (RS)-(4-carbamimidoyl)-(4-cyclopropane-3-ethoxyphenyl)acetic acid.

Example 119.

119.1. Similarly to the method described in example 64.1, from 3-allyl-4-hydroxybenzaldehyde and benzylbromide received 3-allyl-4-benzyloxybenzaldehyde.

119.2. Similarly to the method described in example 1.1, but substituting 3,5-dimethoxybenzaldehyde 3-allyl-4-benzyloxybenzaldehyde, received the methyl ester of (RS)-(3-allyl-4-benzyloxyphenyl)-(4-cyanoaniline)acetic acid.

119.3. Similarly to the method described in example 6.2, from the compound described in example 119.2, got ether of amidine, namely methyl ester of (RS)-(3-allyl-4-benzyloxyphenyl)-(4-carbamimidoyl)acetic acid.

Example 120.

SL-4-benzyloxyphenyl)-(4-carbamimidoyl)acetic acid.

Example 121.

121.1. Similarly to the method described in example 64.1, by the reaction of 3,5-dihydroxybenzaldehyde with 1.3 equivalents of 2-bromopropane at 60oC for 4 h was obtained 3-hydroxy-5-isopropoxybenzonitrile. According to a similar method in the interaction of the compounds with 1.5 equivalents of ethylbromide received 3 ethoxy-5-isopropoxybenzonitrile.

121.2. A solution of 1.2 g of 3-ethoxy-5-isopropoxybenzonitrile (see example 117.1) in 35 ml of methanol was treated with 0.87 g of 4-amino-N-hydroxybenzamide and stirred at room temperature for 1 h and Then added to 0.70 ml benzylideneamino, the resulting solution was cooled to 0oWith and was added dropwise at 2.45 ml epirate boron TRIFLUORIDE such a way that the temperature did not exceed 10oC. the Reaction mixture was stirred at room temperature for 1 h, and then concentrated under reduced pressure. The residue was transferred into 21 ml of methanol and 2.1 ml of water, the resulting solution was stirred at room temperature for 1 h, and then concentrated. The crude product was isolated by extraction and purified by chromatography on silica gel. When this was received of 0.44 g of methyl ester of (E)- and/or (Z)-(RS)-(3-ethoxy-5-isopropoxyphenyl)-[4-(N-hydroxyketones 122.

Similarly to the method described in example 75, ester, obtained as described in example 121.2, hydrolyzed to obtain (E)- and/or (Z)-(RS)-(3-ethoxy-5-isopropoxyphenyl)-[4-(N-hydroxycarbamoyl)phenylamino] acetic acid.

Example 123.

Analogously to example 3 from the product described in example 122 was obtained (RS)-(4-carbamimidoyl)-(3-ethoxy-5-isopropoxyphenyl)acetic acid.

Example 124.

124.1. of 7.3 g of methyl ester of (RS)-(3-benzyloxy-5-ethoxyphenyl)-(4-cyanoaniline)acetic acid was dissolved in 146 ml of ethanol and 146 ml of acetic acid, then was treated with 0.7 g of palladium catalyst on an angle and was first made at room temperature. After separation of the catalyst by filtration, the filtrate was concentrated, the residue was chromatographically on silica gel in hexane/ethyl acetate (3: 1). When this was received of 5.1 g of colorless methyl ester (RS)-(4-cyanovinylene)-(3-ethoxy-5-hydroxyphenyl)acetic acid.

124.2. Similarly to the method described in example 18, but substituting the methyl ester of lactic acid on phenol, obtained as described in example 124.1, and 4-morpholinoethyl, received the methyl ester of (RS)-(4-cyanovinylene)-[3-ethoxy-5-(2-morpholine-4-ylethoxy)phenyl]acetic acid is e 124.1, received hydrochloride methyl ester (4 carbamimidoyl)-[3-ethoxy-5-(2-morpholine-4-ylethoxy)phenyl] acetic acid (1:1).

Example 125.

Similarly to the method described in example 75, ester, described in example 124.3, hydrolyzed to obtain (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(2-morpholine-4-ylethoxy)phenyl]acetic acid.

Example 126.

Similarly to the method described in example 18, but substituting the methyl ester of lactic acid to the phenol described in example 125.1, and tert-butyl-4-hydroxy-1-piperidinylcarbonyl acid, was obtained tert-butyl ether (RS)-4-{ 3-[(4-cyanoaniline)methoxycarbonylmethyl] -5-ethoxyphenoxy} piperidine-1-carboxylic acid.

126.2. 1.5 g of the compound obtained as described in example 126.1, was stirred at 0oWith 13 ml of 2 M hydrochloric acid in ethyl acetate for 1.5 hours Then the reaction mixture was evaporated, it was obtained 1.0 g of methyl ester hydrochloride (RS)-(4-cyanovinylene)-[3-ethoxy-5-(piperidine-4-yloxy)phenyl]acetic acid.

126.3. 0,93 g amine, obtained as described in example 126.2, was dissolved in 15 ml of tetrahydrofuran and treated 0,78 ml of N-ethyldiethanolamine. Then at 0oWith injected to 0.19 ml m alibali cooled in ice 2 M hydrochloric acid and was extracted with ethyl acetate. After evaporation of the organic phase and chromatography of the residue on silica gel in ethyl acetate/hexane (1:1) was obtained 0.45 g of methyl ester of (RS)-(4-cyanovinylene)-[3-ethoxy-5-(1-methanesulfonamido-4-yloxy)phenyl] acetic acid.

126.4. Similarly to the method described in example 6.2, from the compound described in example 126.3, got hydrochloride methyl ester (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(1-methanesulfonamido-4-yloxy)phenyl]acetic acid.

Example 127.

Analogously to example 197, using phenol, obtained as described in example 124.1 via the intermediate formation of a mixture of ethyl ester of (RS)- and (SR)-(4-cyanovinylene)-[3-ethoxy-5-[(1RS,2RS)-2-hydroxycyclopent] phenyl] acetic acid was obtained a mixture of hydrochloride ethyl ester of (RS)- and (SR)-(4-carbamimidoyl)-[3-ethoxy-5-[(1RS,2RS)-2-hydroxycyclopent]phenyl]acetic acids.

Example 128.

Similarly to the method described in example 127, but substituting Cyclopentanone on cyclohexanone via the intermediate formation of a mixture of ethyl ester of (RS)- and (SR)-(4-cyanovinylene)-[3-ethoxy-5-[(1RS,2RS)-2-hydroxycyclohexyl] phenyl]acetic acid was obtained a mixture of hydrochloride ethyl S="ptx2">

Example 129.

Similarly to the method described in example 206, but when using phenol, obtained as described in example 124.1 via the intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-[3-ethoxy-5-(4-trithiacyclononane)phenyl] acetic acid was obtained methyl ester of (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(4-hydroxycyclohexyl)phenyl] acetic acid.

Example 130.

Similarly to the method described in examples 200.2 and 200.3, but when using phenol, obtained as described in example 124.1 via the intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-5-isobutoxide)acetic acid was obtained the hydrochloride of the methyl ester of (RS)-(4-carbamimidoyl)-(3-ethoxy-5-isobutoxide)acetic acid.

Example 131.

Similarly to the method described in example 75, the compounds described in the examples 126.4, 127, 128 and 129, hydrolyzed to the corresponding acids:

131.1) of the product described in example 126.4, was obtained (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(1-methanesulfonamido-4-yloxy)phenyl] acetic acid;

131.2) of the product described in example 127, received a mixture of (RS)- and (SR)-(4-carbamimidoyl 128, received a mixture of (RS)- and (SR)-(4-carbamimidoyl)-[3-ethoxy-5-[(1RS, 2RS)-2-hydroxycyclohexyl]phenyl]acetic acid;

131.4) of the product described in example 129 was obtained (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(4-hydroxycyclohexyl)phenyl] acetic acid;

131.5) of the product described in example 130 was obtained (RS)-(4-carbamimidoyl)-(3-ethoxy-5-isobutoxide)acetic acid.

Example 132.

Analogously to example 64.1 of the aldehyde described in example 89.1, and ethyl ether bromoxynil acid was obtained ethyl ester (4-ethyl-2-formylphenoxy)acetic acid, which, according to the method described in example 1, was obtained methyl ester of (RS)-(4-cyanovinylene)-(2-ethoxycarbonylmethoxy-5-ethylphenyl)acetic acid, which was obtained (RS)-(2-carboxymethoxy-5-ethylphenyl)-(4-cyanoaniline)acetic acid, from which the result was obtained (E)and/or (Z)-(RS)-(2-carboxymethoxy-5-ethylphenyl)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid.

Example 133.

Analogously to example 3 from the compound obtained as described in example 132 was obtained (RS)-(4-carbamimidoyl)-(2-carboxymethoxy-5-ethylphenyl)acetic acid.

Example 134.

134.1. Analogues is.

134.2. Analogously to example 1.1 from the aldehyde described in example 134.1, 4-aminobenzonitrile and toluene-4-sulfonylmethane received the methyl ester of (RS)-(2-benzyloxy-5-ethylphenyl)-(4-cyanoaniline)acetic acid.

134.3. Similarly to the method described in example 124.1, the product described in example 134.2, was first made to obtain methyl ester of (RS)-(4-cyanovinylene)-(5-ethyl-2-hydroxyphenyl)acetic acid.

134.4. Analogously to example 59.1 of the phenol described in example 134.3, and 2-pomatoleios of ether there was obtained methyl ester of (RS)-(4-cyanovinylene)-[5-ethyl-2-(2-methoxyethoxy)phenyl]acetic acid.

134.5. Similarly to the method described in example 6.2, from the compound described in example 134.4, got hydrochloride methyl ester (RS)-(4-carbamimidoyl)-[5-ethyl-2-(2-methoxyethoxy)phenyl] acetic acid (1:1).

Example 135.

Similar examples 89.2-4 from the aldehyde described in example 89.1, and 2-bromoethanol received 5-ethyl-2-(2-hydroxyethoxy)benzaldehyde, which on reaction with 4-aminobenzonitrile and toluene-4-sulfonylmethane received the methyl ester of (RS)-(4-cyanovinylene)-[5-ethyl-2-(2-hydroxyethoxy)phenyl]acetic acid, and then the hydrochloride metrolog is 136.

Similarly to the method described in example 18, but substituting the methyl ester of lactic acid to the phenol described in example 143.3, and 4-morpholinoethyl, received the methyl ester of (RS)-(4-cyanovinylene)-[5-ethyl-2-(2-morpholine-4-ylethoxy)phenyl] acetic acid, from which then, according to the method described in example 64.3, got hydrochloride methyl ester (RS)-(4-carbamide-dolphinling)-[5-ethyl-2-(2-morpholine-4-ylethoxy)phenyl]acetic acid (1:1).

Example 137.

Similarly to the method described in example 75, esters obtained in examples 134.5, 135 and 136, hydrolyzed with obtaining the following acids:

137. a) from the product described in example 134.5, was obtained (RS)-(4-caramelization)-[5-ethyl-2-(2-methoxyethoxy)phenyl]acetic acid;

137. b) from the product described in example 135 was obtained (RS)-(4-carbamimidoyl)-[5-ethyl-2-(2-hydroxyethoxy)phenyl]acetic acid;

137. from the product described in example 136 was obtained (RS)-(4-carbamimidoyl)-[5-ethyl-2-(2-morpholine-4-ylethoxy)phenyl]acetic acid.

Example 138.

138.1. Analogously to example 69.1 of 2-allyl-4-benzyloxyphenol and ethylbromide was obtained 2-allyl-4-benzyloxy-1-ethoxybenzoyl.

138.2. Similarly, the method opisane.3. Similarly to the method described in example 94.1, of the product described in example 138.2, received 5-ethoxy-2-hydroxy-4-propylbenzamide.

138.4. Analogously to example 64.1 of the product described in example 138.3, received 5-ethoxy-2-(2-hydroxyethoxy)-4-propylbenzamide.

138.5. Analogously to example 1 from the aldehyde described in example 138.4 via the intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-[5-ethoxy-2-(2-hydroxyethoxy)-4-propylphenyl] acetic acid and methyl ester of (RS)-(4-cyanovinylene)-[5-ethoxy-2-(2-hydroxyethoxy)-4-propylphenyl] acetic acid was obtained (RS)-[5-ethoxy-2-(2-hydroxyethoxy)-4-propylphenyl] -[4-(N-hydroxycarbamoyl)phenylamino]acetic acid.

Example 139.

Analogously to example 3 from the product described in example 138.5, was obtained (RS)-(4-carbamimidoyl)-[5-ethoxy-2-(2-hydroxyethoxy)-4-propylphenyl]acetic acid.

Example 140.

140.1. Similarly to the method described in examples 140.1-3, from 2-benzyloxy-2-(2-methylallyl)phenol via the intermediate formation of 1-benzyloxy-4-ethoxy-3-(2-methylallyl)benzene and 4-ethoxy-3-isobutylphenyl received 5-ethoxy-2-hydroxy-4-isobutylbenzene.

140.2. Analogously to example 64.1 from products>140.3. Analogously to example 1.1 from the aldehyde described in example 140.2, received the methyl ester of (RS)-(2-benzyloxy-5-ethoxy-4-isobutylphenyl)-(4-cyanoaniline)acetic acid.

140.4. Similarly to the method described in example 124.1, but replacing the solvent ethanol/acetic acid in ethanol/THF, the product described in example 140.3, was first made to obtain methyl ester of (RS)-(4-cyanovinylene)-(5-ethoxy-2-hydroxy-4-isobutylphenyl)acetic acid.

140.5. Similarly to the method described in example 18, of the product described in example 140.4, and 2-(benzyloxy)ethanol was obtained methyl ester of (RS)-[2-(2-benzyloxyethyl)-5-ethoxy-4-isobutylphenyl)] -(4-cyanoaniline)acetic acid.

140.6. Analogously to example 64.3 of the product described in example 140.5, got hydrochloride methyl ester (RS)-[2-(2-benzyloxyethyl)-5-ethoxy-4-isobutylphenyl)]-(4-carbamimidoyl)acetic acid (1:1).

140.7. Analogously to example 140.4 product obtained as described in example 140.7, was first made to obtain methyl ester hydrochloride (RS)-(4-carbamimidoyl)-[5-ethoxy-2-(2-hydroxyethoxy)-4-isobutylphenyl]acetic acid (1:1).

Example 141.

Ester described in example 140.7, hydro is-2-(2-hydroxyethoxy)-4-isobutylphenyl)] acetic acid (1:1).

Example 142.

142.1. Similarly to the method described in example 124.1, but replacing the solvent ethanol/acetic acid to ethyl acetate, 2-allyl-4-ethylphenol was first made to obtain 4-ethyl-2-propylene.

142.2. Similarly to the method described in example 94.1, of the product described in example 142.1, received 5-ethyl-2-hydroxy-3-propylbenzamide.

142.3. Analogously to example 132 of the aldehyde obtained as described in example 142.2 via the intermediate formation of ethyl ester (4-ethyl-2-formyl-6-propylenoxide)acetic acid, methyl ester (RS)-(4-cyanovinylene)-(2-ethoxycarbonylmethoxy-5-ethyl-3-propylphenyl)acetic acid and (RS)-(2-carboxymethoxy-5-ethyl-3-propylphenyl)-(4-cyanoaniline)acetic acid was obtained (E)- and/or (Z)-(RS)-(2-carboxymethoxy-5-ethyl-3-propylphenyl)-[4- (N-hydroxycarbamoyl)phenylamino]acetic acid.

Example 143.

Analogously to example 142.3 of the aldehyde obtained as described in example 142.2, but replacing bromoacetate on benzylbromide via the intermediate formation of 2-benzyloxy-5-ethyl-3-propylbenzamide, methyl ester (RS)-(2-benzyloxy-5-ethyl-3-propylphenyl)-(4-cyanoaniline)acetic acid and (RS)-(2-benzyloxy-5-ethyl-3-propylphenyl)-(4-cyanovinylene]acetic acid.

Example 144.

Analogously to example 3 of the following amidoximes received appropriate amidine:

144. a) from the product described in example 142.3, was obtained (RS)-(4-carbamimidoyl)-(2-carboxymethoxy-5-ethyl-3-propylphenyl)acetic acid;

144. b) from the product described in example 143 was obtained (RS)-(4-carbamimidoyl)-(5-ethyl-2-hydroxy-3-propylphenyl)acetic acid.

Example 145.

145.1. 25 g of 2-(2-methyl-2-propenyl)-4-ethylphenol was stirred at 195oWith in 48 hours After chromatography of the reaction mixture on silica gel in hexane/ethyl acetate (19:1) received 22.9 grams of 2-(2-methyl-2-propenyl)-4-ethylphenol in the form of butter.

145.2. Similarly to the method described in example 94.1, the product described in example 145.1, formulirovalis obtaining 5-ethyl-2-hydroxy-3-(2-methylallyl)benzaldehyde.

145.3. Similar examples 89.2-4 from the aldehyde described in example 145.2, and 2-pomatoleios of ether there was obtained 5-ethyl-2-(2-methoxyethoxy)-3-(2-methylallyl)benzaldehyde, which on reaction with 4-aminobenzonitrile and toluene-4-sulfonylmethane received the methyl ester of (RS)-(4-cyanovinylene)-[5-ethyl-2-(2-methoxyethoxy)-3-(2-methylallyl)phenyl] acetic acid, and then the hydrochloride meter CLASS="ptx2">

Example 146.

Similar examples 134.1-5 of 5-ethyl-2-hydroxy-3-(2-propenyl)benzaldehyde and benzylbromide received 3-allyl-2-benzyloxy-5-ethylbenzaldehyde, from which was obtained the methyl ester of (RS)-(3-allyl-2-benzyloxy-5-ethylphenyl)-(4-cyanoaniline)acetic acid, and then the methyl ester of (RS)-(4-cyanovinylene)-(5-ethyl-2-hydroxy-3-propylphenyl)acetic acid, from which on reaction with 2-(benzyloxy)ethanol was obtained methyl ester of (RS)-[2-(2-benzyloxyethyl)-5-ethyl-3-propylphenyl] -(4-cyanoaniline)acetic acid and, finally, the hydrochloride of the methyl ester of (RS)-[2-(2-benzyloxyethyl)-5-ethyl-3-propylphenyl] -(4-carbamimidoyl)acetic acid (1:1).

Example 147.

Similarly to the method described in example 124.1, but replacing the solvent ethanol/acetic acid to ethyl acetate/THF, the product described in example 136, was first made to obtain methyl ester hydrochloride (RS)-(4-carbamimidoyl)-[5-ethyl-2-(2-hydroxyethoxy)-3-propylphenyl] acetic acid (1:1).

Example 148.

Similarly to the method described in example 146, from the aldehyde described in example 145.2, received 2-benzyloxy-5-ethyl-3-(2-methylallyl)benzaldehyde, which was obtained methyl ester of (RS)-[2-benzyloxy is naftilamina)-(5-ethyl-2-hydroxy-3-isobutylphenyl)acetic acid, which then received the methyl ester of (RS)-[2-(2-benzyloxyethyl)-5-ethyl-3-isobutylphenyl] -(4-cyanoaniline)acetic acid and, finally, the hydrochloride of the methyl ester of (RS)-[2-(2-benzyloxyethyl)-5-ethyl-3-isobutylphenyl] -(4-carbamimidoyl)acetic acid (1:1).

Example 149.

Esters described in the following examples, hydrolyzed to the corresponding acid by the method described in example 75:

149.a) from the product described in example 145.3, was obtained (RS)-(4-carbamimidoyl)-[5-ethyl-2-(2-methoxyethoxy)-3-(2-methylallyl)phenyl] acetic acid;

149.b) from the product described in example 147 was obtained (RS)-(4-carbamimidoyl)-[5-ethyl-2-(2-hydroxyethoxy)-3-propylphenyl] acetic acid;

149. from the product described in example 148, received hydrochloride, (RS)-[2-(2-benzyloxyethyl)-5-ethyl-3-isobutylphenyl] -(4-carbamimidoyl)acetic acid (1:1).

Example 150.

Acid, described in the following examples, was first made by obtaining the appropriate products according to the method described in example 124.1:

150. a) of the acid described in example 149.and received (RS)-(4-carbamimidoyl)-[5-ethyl-3-isobutyl-2-(2-methoxyethoxy)phenyl] acetic, colotox)-3-isobutylphenyl] acetic acid.

Example 151.

151.1. Similarly to the method described in example 12.1, but replacing ethyl ester bromoxynil acid benzyl ester bromoxynil acid, methyl ester (RS)-(4-cyanovinylene)-(5-ethyl-2-hydroxy-3-propylphenyl)acetic acid (obtained as described in example 146) was obtained methyl ester of (RS)-(2-benzyloxycarbonyloxy-5-ethyl-3-propylphenyl)-(4-cyanoaniline)acetic acid.

151.2. The product described in example 141.1, was first made by the method described in example 124.1, but replacing the solvent ethanol/acetic acid to ethyl acetate/THF, to obtain the methyl ester of (RS)-(2-carboxymethoxy-5-ethyl-3-propylphenyl)-(4-cyanoaniline)acetic acid.

151.3. A solution of 0.8 g of the product obtained as described in example 151.2, in 8 ml of DMF was treated 0,86 g a THIEF, 0.3 ml of 4-ethylmorpholine and to 0.19 ml pyrrolidine and stirred at room temperature overnight. Then the reaction mixture was evaporated, the residue was transferred into ethyl acetate and once was extracted with a 5% solution of hydrosulfate/10% solution of potassium sulfate and twice with water. The organic phase was dried and evaporated, the residue was chromatographically in hexane/ethyl acetate (1:1). When this was received of 0.58 g of methyl ester of (RS)-(4-cyan 151.4. Analogously to example 64.3 of the product obtained as described in example 151.3, got hydrochloride methyl ester (RS)-(4-carbamimidoyl)-[5-ethyl-2-(2-oxo-2-pyrrolidin-1 ylethoxy)-3-propylphenyl] acetic acid (1:1).

Example 152.

The following products have obtained analogously to the method described in examples 151.3-4, but replacing pyrrolidin the following basis:

152. a) hydrochloride of the methyl ester of (RS)-(4-carbamimidoyl)-[5-ethyl-2-(2-morpholine-4-yl-2-oksidoksi)-3-propylphenyl] acetic acid (1: 1) was obtained with the use of the research through the intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-[5-ethyl-2-(2-morpholine-4-yl-2-oksidoksi)-3-propylphenyl]acetic acid;

152. b) hydrochloride of the methyl ester of (RS)-[2-(2-azepin-1-yl-2-oksidoksi)-5-ethyl-3-propylphenyl] -(4-carbamimidoyl)acetic acid (1:1) was obtained with the use of hexamethylenimine through intermediate formation of methyl ester of (RS)-[2-(2-azepin-1-yl-2-oksidoksi)-5-ethyl-3-propylphenyl] -(4-cyanoaniline)acetic acid;

152. b) hydrochloride of the methyl ester of (RS)-(4-carbamimidoyl)-(2-cyclopropylmethoxy-5-ethyl-3-propylphenyl)acetic acid (1:1) was obtained with the use of cyclepro the xylose-5-ethyl-3-propylphenyl)acetic acid.

Example 153.

Esters in the following examples, hydrolyzed to the corresponding acid by the method described in example 75:

153. a) from the product described in example 151.4, was obtained (RS)-(4-carbamimidoyl)-[5-ethyl-2-(2-oxo-2-pyrrolidin-1 ylethoxy)-3-propylphenyl]acetic acid;

153.b) from the product described in example 152.and received (RS)-(4-carbamimidoyl)-[5-ethyl-2-(2-morpholine-4-yl-2-oksidoksi)-3-propylphenyl] acetic acid;

153.from the product described in example 152.b, was obtained (RS)-[2-(2-azepin-1-yl-2-oksidoksi)-5-ethyl-3-propylphenyl] -(4-carbamimidoyl-phenylamino)acetic acid;

153. g) of the product described in example 152.in received (RS)-(4-carbamimidoyl)-(2-cyclopropylmethoxy-5-ethyl-3-propylphenyl)acetic acid.

Example 154.

The racemates can be separated into individual isomers by chromatography in heptane/ethanol (83:17) with the addition of 0.4% of TFU on a column with a chiral material (Chiralpak AD).

154. A. From (RS)-(4-carbamimidoyl)-(3,4-dioxyphenyl)acetic acid was obtained (R)-(4-carbamimidoyl)-(3,4-dioxyphenyl)acetic acid and (S)-(4-carbamimidoyl)-(3,4-dioxyphenyl)acetic sour what you got (R)-(4-carbamimidoyl)-[3-ethoxy-5-(tetrahydropyran-4-yloxy)phenyl] acetic acid and (S)-(4-carbamimidoyl)-[3-ethoxy-5-(tetrahydropyran-4-yloxy)phenyl] acetic acid.

154. V. From (RS)-(4-carbamimidoyl)-(2-carboxymethoxy-5-ethoxyphenyl)acetic acid was obtained (S)-(4-carbamimidoyl)-(2-carboxymethoxy-5-ethoxyphenyl)acetic acid and (R)-(4-carbamimidoyl)-(2-carboxymethoxy-5-ethoxyphenyl)acetic acid.

Example 155.

155.1. Analogously to example 22.1 of 5.00 g of methyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-5-hydroxyphenyl)acetic acid, described in example 124.1, was introduced into the reaction with 3,29 ml of anhydride triftormetilfullerenov acid in CH2CL2in the presence of 5.34 ml of triethylamine. When it got to 6.19 g of methyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-5-triftoratsetilatsetonom)acetic acid in the form of a solid of light yellow color, MS:457 [(M-N)-].

155.2. Analogously to example 73.2 of the methyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-5-triftoratsetilatsetonom)acetic acid, described in example 155.1 by reaction with phenylboronic acid was obtained methyl ether (RS-(4-cyanovinylene)-(5-ethoxymethyl-3-yl)acetic acid, MS:386 ([M]+).

155.3. Analogously to example 6.2 of the methyl ester of (RS)-(4-cyanovinylene)-(5-ethoxymethyl-3-yl)acetic acid, described in example 155.2, produces the/SUP>).

Similar examples.

155. A. Analogously to example 155 of the methyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-5-hydroxyphenyl)acetic acid via the intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-5-triftoratsetilatsetonom)acetic acid by the reaction with 3-aminophenylarsonic acid was obtained methyl ester of (RS)-(3'-amino-5-ethoxymethyl-3-yl)-(4-cyanoaniline)acetic acid, which then received hydrochloride methyl ester (RS)-(3'-amino-5-ethoxymethyl-3-yl)-(4-carbamimidoyl)acetic acid, MS:419 ([M+H]+).

155. B. Analogously to example 145 methyl ester (RS)-(4-cyanovinylene)-(3-ethoxy-5-hydroxyphenyl)acetic acid via the intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-5-triftoratsetilatsetonom)acetic acid by the reaction with thiophene-2-Bronevoy acid was obtained methyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-5-thiophene-2-ylphenyl)acetic acid, which then got hydrochloride methyl ester (RS)-(4-carbamimidoyl)-(3-ethoxy-5-thiophene-2-ylphenyl)acetic acid.

155. C. Analogously to example 155 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-hydroxy-5-methylphen unsulfonated)acetic acid, from which on reaction with 4-N,N-dimethylaminopropionic acid was obtained ethyl ester of (RS)-(4-cyanovinylene)-(4'-dimethylamino-5-methylbiphenyl-3-yl)acetic acid and, finally, the ethyl ester of (RS)-(4-carbamimidoyl)-(4'-dimethylamino-5-methylbiphenyl-3-yl)acetic acid.

155. g Analogously to example 155 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-hydroxy-5-were)acetic acid, described in example 156, received the ethyl ester of (RS)-(4-cyanovinylene)-(3-methyl-5-triftoratsetilatsetonom)acetic acid, from which on reaction with 3-N,N-dimethylaminopropionic acid was obtained ethyl ester of (RS)-(4-cyanovinylene)-(3'-dimethylamino-5-methylbiphenyl-3-yl)acetic acid and, finally, the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3'-dimethylamino-5-methylbiphenyl-3-yl)acetic acid.

155. D. Analogously to example 155 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-hydroxy-5-were)acetic acid, described in example 181.1 received ethyl ester of (RS)-(4-cyanovinylene)-(3-methyl-5-triftoratsetilatsetonom)acetic acid, from which on reaction with 3-aminophenylarsonic acid was obtained ethyl ester of (RS)-(3'-amino-5-methylbiphenyl-3-yl)-(4-cyanoaniline)acetic sour which includes acetic acid), MS:403 ([M+H]+).

Example 156.

156.1. A solution of 5.00 g of 1-bromo-3,5-xylene in CCL4processed 20,20 g of N-bromosuccinimide and 0,655 g of peroxide of Dibenzoyl and boiled under reflux for 5 hours Then the mixture was cooled to room temperature, separated by filtration of the resulting succinimide, the solvent evaporated in vacuum. After chromatography on a column (cyclohexane/ethyl acetate) was isolated a 3.87 g of 1-bromo-3-methyl bromide-5-dibromothiazole, which is suspended in water and boiled under reflux in the presence of 1.74 g of calcium carbonate, 2,73 g of sodium acetate and of 0.58 g of tetrabutylammonium bromide for 15 hours and Then the mixture was cooled to room temperature, filtered and the filtrate was acidified with diluted model HC1 to pH 2. The crude product obtained by extraction of CH2Cl2was purified by chromatography on a column (cyclohexane/ethyl acetate). When it got to 0.80 g of 3-bromo-5-hydroxymethylbenzene, MS:214/216 ([M]+).

156.2. Analogously to example 27.2 of 3-bromo-5-hydroxymethylbenzene described in example 156.1 by reaction with 4-aminobenzonitrile and benzylideneamino received ethyl ester (3-bromo-5-hydroxymethylene)-(4-cyanoaniline)acetic acid.

as 156.2, suspended in 3.1 ml of triethylamine, was added 4 mg of triphenylphosphine and through the reaction mixture missed argon for 30 minutes Then added 7 mg of palladium acetate (II) and 0.22 ml of trimethylsilylacetamide and the mixture was heated at 80oWith over 26 hours Then the mixture was cooled to room temperature, the crude product was isolated by extraction and purified by chromatography on a column (n-hexane/ethyl acetate). When this was received 398 mg of ethyl ester of (RS)-(4-cyanovinylene)-(3-hydroxymethyl-5-trimethylsilylethynyl)acetic acid in the form of a brown oil, MS:406 ([M]+).

156.4. 398 mg of ethyl ester of (RS)-(4-cyanovinylene)-(3-hydroxymethyl-5-trimethylsilylethynyl)acetic acid, described in example 156.3, was dissolved in 6 ml of CH2Cl2and 0.41 ml of triethylamine, and then at 0oWith added dropwise 0.1 ml methanesulfonanilide. The mixture was stirred over night, the intermediate compound was isolated by extraction. The intermediate compound was dissolved in 5 ml THF and stirred in the presence of 0.41 ml of triethylamine and 0.32 ml of pyrrolidine. Re-extraction was obtained the crude product, which was purified by chromatography on a column (cyclohexane/ethyl acetate). It was obtained 130 mg of ethyl EF is about substance, light brown, MS:460 ([M]+).

156.5. 130 mg of ethyl ester of (RS)-(4-cyanovinylene)-(3-pyrrolidin-1-ylmethyl-5-trimethylsilylethynyl)acetic acid, described in example 156.4, was dissolved in 2 ml of THF and treated at 0oFrom 0.43 ml of 1 M solution of tetrabutylammonium fluoride in THF. The reaction mixture was stirred at 0oC for 5 h, then was added water and the intermediate product was extracted with ethyl acetate. The obtained intermediate product was treated at 0oWith 31 mg of cyanoborohydride sodium in 5 ml of Meon. Then was added a methanol solution model HC1 up to pH 6 and the reaction mixture was stirred at room temperature overnight. The reaction mixture was podslushivaet methanol solution of knso3the solvent is evaporated in vacuo, the residue was purified by chromatography on a column (CH2CL2/methanol). It was given to 27 mg of ethyl ester of (RS)-(4-cyanovinylene)-(3-ethinyl-5-pyrrolidin-1-ylmethylene)acetic acid in the form of a solid of light yellow color, MS:374 ([M+H]+).

156.6. From the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethinyl-5-pyrrolidin-1-ylmethylene)acetic acid, described in example 156.5, similar to the examples 6.2 and 1.2 was obtained (RS)-(4-carbamimidoyl)-(3-ethinyl-5-pimero 1.2 of the methyl ester of (RS)-(4-carbamimidoyl)-(5-ethoxymethyl-3-yl)acetic acid (compound includes acetic acid), described in example 155.3, was obtained (RS)-(4-carbamimidoyl)-(5-ethoxymethyl-3-yl)acetic acid; MS:390 ([M+H]+).

Similar examples.

157. A. In a similar manner from methyl ester hydrochloride (RS)-(3'-amino-5-ethoxymethyl-3-yl)-(4-carbamimidoyl)acetic acid, described in example 155.and received (RS)-(3'-amino-5-ethoxymethyl-3-yl)-(4-carbamimidoyl)acetic acid, MS:405 ([M+H]+).

157. B. In a similar manner from methyl ester hydrochloride (RS)-(4-carbamimidoyl)-(3-ethoxy-5-thiophene-2-ylphenyl)acetic acid, described in example 155. b, was obtained (RS)-(4-carbamimidoyl)-(3-ethoxy-5-thiophene-2-ylphenyl)acetic acid, MS:396 ([M+H]+).

157. C. in a Similar manner from the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(4'-dimethylamino-5-methylbiphenyl-3-yl)acetic acid, described in example 155.in received (RS)-(4-carbamimidoyl)-(4'-dimethylamino-5-methylbiphenyl-3-yl)acetic acid, MS:404 ([M+H]+).

157. the Similar way of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3'-dimethylamino-5-methylbiphenyl-3-yl)acetic acid, described in example 155.g was obtained (RS)-(4-carbamimidoyl cnym way of ethyl ester of (RS)-(3'-amino-5-methylbiphenyl-3-yl)-(4-carbamimidoyl)acetic acid (compound includes acetic acid), described in example 155.d, was obtained (RS)-(3'-amino-5-methylbiphenyl-3-yl)-(4-carbamimidoyl)acetic acid, MS: 375 ([M+H]+).

Example 158.

158.1. Analogously to example 12.1 of 4-bromo-2-hydroxy-5-methoxybenzaldehyde (CAS 63272-66-2) by reaction with bromethalin received 4-bromo-2-(2-hydroxyethoxy)-5-methoxybenzaldehyde, MS:274/276 ([M]+).

158.2. Analogously to example 27.2 of 4-bromo-2-(2-hydroxyethoxy)-5-methoxybenzaldehyde, obtained as described in example 158.1 by reaction with 4-aminobenzonitrile and benzylideneamino received the methyl ester of (RS)-[4-bromo-2-(2-hydroxyethoxy)-5-methoxyphenyl] -(4-cyanoaniline)acetic acid, MS:434/436 ([M]+).

158.3. Of the methyl ester of (RS)-[4-bromo-2-(2-hydroxyethoxy)-5-methoxyphenyl] -(4-cyanoaniline)acetic acid, described in example 158.2, analogously to example 68.2 reaction with 3-aminophenylarsonic acid, was obtained methyl ester of (RS)-[3'-amino-5-(2-hydroxyethoxy)-2-methoxybiphenyl-4-yl]-(4-cyanoaniline)acetic acid, MS:448 ([M+H]+).

158.4. Analogously to example 6.2 of the methyl ester of (RS)-[3'-amino-5-(2-hydroxyethoxy)-2-methoxybiphenyl-4-yl] -(4-cyanoaniline)acetic acid, described in example 158.3, received the methyl ester of (RS)-[3'-amino-5-(snow acid), MS:456 ([M+H]+).

Example 159.

Analogously to example 1.2 of the methyl ester of (RS)-[3'-amino-5-(2-hydroxyethoxy)-2-methoxybiphenyl-4-yl]-(4-carbamimidoyl)acetic acid (compound includes acetic acid, described in example 158 was obtained (RS)-[3'-amino-5-(2-hydroxyethoxy)-2-methoxybiphenyl-4-yl] -(4-carbamimidoyl)acetic acid, MS:451 ([M+H]+).

Example 160

160.1. 3.6 g of 2-bromo-4,5-dimethoxybenzaldehyde and 3.22 g of 2,2-dimethyl-1,3-propane diol was dissolved in 200 ml of toluene and boiled under reflux in the presence of 0.8 g of para-toluensulfonate acid for 3 h Then the reaction mixture was cooled to room temperature and washed with a solution Panso3, water and saturated NaCl solution. The solvent is evaporated in vacuum, thus received of 5.1 g of 2-(2-bromo-4,5-acid)-5,5-dimethyl[1,3]dioxane in the form of needles are yellow-green.

160.2. 1.0 g of 2-(2-bromo-4,5-acid)-5,5-dimethyl[1,3] dioxane as described in example 160.1, was dissolved in 10 ml of 1-methyl-2-pyrrolidone and process of 0.54 g of CuCN. The reaction mixture is boiled under reflux for 3 h, after cooling, the crude product was obtained by extraction. Purification was performed by chromatography on a column of (n-altago oil.

160.3. Analogously to example 1.3 from 2,77 g of 2-(5,5-dimethyl[1,3]dioxane-2-yl)-4,5-dimethoxybenzonitrile by the reaction with H2NOH HC1 received 1.47 g (E)- and/or (Z)-2-(5,5-dimethyl[1,3] dioxane-2-yl)-N-hydroxy-4,5-dimethoxybenzamide resin greenish, MS:293 ([M-IT]-).

160.4. A mixture of 1.34 g of (E)- and/or (Z)-2-(5,5-dimethyl[1,3]dioxane-2-yl)-N-hydroxy-4,5-dimethoxybenzamide, 1,20 ml of DBU (1,8-diazabicyclo[5,4,0]undecene-7-ene) and 0.61 ml of acetic anhydride in 50 ml of DMF was stirred at room temperature for 1 h and then at 80oC for 2 h and Then DMF was removed in vacuo, the residue was dissolved in ethyl acetate. The solution in ethyl acetate was washed with water and saturated NaCl solution, after removal of solvent the residue was purified by chromatography on a column (CH2WITH2/ethyl acetate). When this was received of 0.43 g of 3-[2-(5,5-dimethyl[1,3]dioxane-2-yl)-4,5-acid]-5-methyl[1,2,4] oxadiazole in a solid white color, MS:334 ([M] +).

160.5. 2.0 g of 3-[2-(5,5-dimethyl[1,3]dioxane-2-yl)-4,5-acid]-5-methyl[1,2,4] oxadiazole was stirred in 100 ml of acetone in the presence of 10 ml of concentrated HC1 at room temperature for 3 h Then the reaction mixture was added a saturated solution of NaHCO3to pH 7, the acetone was removed in vacuum and n is the column (CH2WITH2/ethyl acetate), was obtained 1.12 g of 4,5-dimethoxy-2-(5-methyl[1,2,4]oxadiazol-3-yl)benzaldehyde in the form of solid white, MS:248 ([M]+).

160.6. Analogously to example 141 27.2 mg of 4,5-dimethoxy-2-(5-methyl[1,2,4] oxadiazol-3-yl)benzaldehyde described in example 160.5, received 56 mg of methyl ester of (RS)-(4-cyanovinylene)-[4,5-dimethoxy-2-(5-methyl[1,2,4] oxadiazol-3-yl)phenyl] acetic acid in the form of a yellow foam, MS:409 ([M+H]+).

160.7. Analogously to example 6.2 of the methyl ester of (RS)-(4-cyanovinylene)-[4,5-dimethoxy-2-(5-methyl[1,2,4] oxadiazol-3-yl)phenyl] acetic acid, described in example 160.6, received the methyl ester of (RS)-(4-carbamimidoyl)-[4,5-dimethoxy-2-(5-methyl[1,2,4] oxadiazol-3-yl)phenyl] acetic acid (compound includes acetic acid), MS:426 ([M+H]+).

Example 161.

Analogously to example 1.2 of the methyl ester of (RS)-(4-carbamimidoyl)-[4,5-dimethoxy-2-(5-methyl[1,2,4] oxadiazol-3-yl)phenyl] acetic acid, described in example 160 was obtained (RS)-(4-carbamimidoyl)-[4,5-dimethoxy-2-(5-methyl[1,2,4] oxadiazol-3-yl)phenyl]acetic acid, MS:412 ([M+H]+).

Example 162.

162.1. 3-Methylsulfonylbenzoyl was obtained from 2-(3-br 41, 373 (1998)).

162.2. Analogously to example 1.1 from 3-methylsulfonylbenzoyl, obtained as described in example 162.1 by reaction with 4-aminobenzonitrile and benzylideneamino in EtOH was obtained ethyl ester of (RS)-(4-cyanovinylene)-(3-methylsulfinylphenyl)acetic acid, MS:344 ([M+NH4]+).

162.3. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-methylsulfinylphenyl)acetic acid obtained as described in example 163.2, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(3-methylsulfinylphenyl)acetic acid (1:1), MS:344 ([M+H]+).

Example 163.

163.1. Analogously to example 162.1 3-metilsulfonilmetane was obtained from 2-(3-bromophenyl)-1,3-dioxolane by reaction with n-butyllithium, diethyldithio and subsequent processing of 1 M Hcl, MS:166 ([M]+).

163.2. Analogously to example 1.1 from 3-metilsulfonilmetane, obtained as described in example 163.1 by reaction with 4-aminobenzonitrile and benzylideneamino in EtOH was obtained ethyl ester of (RS)-(4-cyanovinylene)-(3-ethylsulfanyl)acetic acid, MS:340 ([M]+).

163.3. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethylsulfanyl)acetic acid, polycentricity)acetic acid (1:1), MS:358 ([M+H]+).

Example 164.

The hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3-ethylsulfanyl)acetic acid (1: 1), described in example 163.3 (150 mg, 0,381 mmole), was dissolved in acetone (3 ml), was added water (1.5 ml) and the resulting mixture was cooled to 0oC. Then was added ozone (261 mg, 0,404 mmole) and the mixture was stirred at 0oC for 40 minutes and Then the reaction mixture was concentrated and the product was purified by chromatography on a column (SiO2CH2Cl2= >CH2Cl2/MeOH 4: 1). When this was received 91 mg (56%) of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3-ethanolgasoline)acetic acid (1:1) in the form of a yellow foam.

Example 165.

165.1. Analogously to example 164.1 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3-ethylsulfanyl)acetic acid (1: 1), described in example 163.3 by reaction with ozone (0.53 equivalent) received a mixture of hydrochloride ethyl ester of (RS)- and (SR)-(4-carbamimidoyl)-[(RS)-3-econsultanty]acetic acid (1:1).

Example 166.

166. A. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3-methylsulfinylphenyl)acetic acid (1: 1), receive the GTC, MS:316 ([M+H]+).

166. B. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3-ethylsulfanyl)acetic acid (1:1) obtained as described in example 163.3, was obtained (RS)-(4-carbamimidoyl)-(3-ethylsulfanyl)acetic acid, MS:330 ([M+H]+).

166. C. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3-ethanolgasoline)acetic acid (1:1) obtained as described in example 164.1, was obtained (RS)-(4-carbamimidoyl)-(3-ethanolgasoline)acetic acid, MS:362 ([M+H]+).

166. Similarly, example 75 from a mixture of hydrochloride ethyl ester of (RS)- and (SR)-(4-carbamimidoyl)-[(RS)-3-econsultanty]acetic acid (1:1) obtained as described in example 165.1, received a mixture of (RS)- and (SR)-(4-carbamimidoyl)-[(RS)-3-econsultanty] acetic acid, MS:346 ([M+H]+).

Example 167.

167.1. The solution anisic aldehyde (to 13.6 g, 100 mmol) and N,N'-diisopropylethylamine (14.4 g, 100 mmol) in toluene (100 ml) was boiled under reflux with a nozzle for the Department of water for 10 hours and Then the reaction mixture was concentrated (dry) and dried under high vacuum. Part of alterationin (3.5 ml, of 41.7 mmole) and the mixture was cooled to -78oC. Then at -78oWith slowly added 1.6 M solution of n-utility in hexane (26,1 ml, 41.7 mmol). After 30 min the mixture was heated to room temperature. After 1 h the mixture was again cooled to -78oC, was added dimethyl disulfide (3,71 ml of 41.7 mmole) and slowly heated to room temperature. After 1 h of incubation at room temperature was added water and the mixture was extracted three times with diethyl ether. The organic phase was concentrated, the residue was stirred with 10% Hcl for 2 h, and then was extracted with diethyl ether. The organic phase was dried, filtered, the resulting filtrate was concentrated. The residue was purified by chromatography (SiO2, hexane/CH2CL21:1), when it got to 2.99 g of 4-methoxy-3-methylsulfonylbenzoyl in a solid yellow color.

167.2. Analogously to example 1.1 from 4-methoxy-3-methylsulfonylbenzoyl, obtained as described in example 167.1 by reaction with 4-aminobenzonitrile and benzylideneamino in EtOH was obtained ethyl ester of (RS)-(4-cyanovinylene)-(4-methoxy-3-methylsulfinylphenyl)acetic acid, MS:379 ([M+Na]+).

167.3. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(4-matakohe ether (RS)-(4-carbamimidoyl)-(4-methoxy-3-methylsulfinylphenyl)acetic acid (1:1), MS:374 ([M+H]+).

Example 168.

168.1. 1 M solution of BBr3in CH2Cl2(4.5 ml, 4.5 mmole) was added at -78oTo a solution of ethyl ester of (RS)-(4-cyanovinylene)-(4-methoxy-3-methylsulfinylphenyl)acetic acid (320 mg, 0,899 mmole), obtained as described in example 167.2, CH2Cl2(10 ml). The mixture was stirred at -78oC for 5 min, at 0oC for 30 min and at room temperature for 2 hours and Then added to ice water, the mixture was stirred for 10 min and was extracted with CH2CL2. The organic phase was dried, filtered and concentrated. The residue was purified by chromatography (SiO2, hexane/EtOAc 2:1), was obtained ethyl ester of (RS)-(4-cyanovinylene)-(4-hydroxy-3-methylsulfinylphenyl)acetic acid as a colourless oil (198 mg, 64%), MS:343 ([M+H]+).

168.2. A suspension of ethyl ester of (RS)-(4-cyanovinylene)-(4-hydroxy-3-methylsulfinylphenyl)acetic acid (198 mg, of 0.58 mmole) as described in example 168.1, Cs2CO2(227 mg, of 0.64 mmole) and isopropylidene (58 μl, of 0.58 mmole) in acetone (3 ml) was boiled under reflux for 4 hours Then added water and the mixture was extracted with CH2CL2. The organic phase was dried, filterweir (RS)-(4-cyanovinylene)-(4-isopropoxy-3-methylsulfinylphenyl)acetic acid as a colorless oil (140 mg, 63%), MS:443 ([M+SLA]+).

168.3. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(4-isopropoxy-3-methylsulfinylphenyl)acetic acid obtained as described in example 168.2, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(4-isopropoxy-3-methylsulfinylphenyl)acetic acid (1:1), MS:402 ([M+H]+).

Example 169.

169.1. Analogously to example 168.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(4-hydroxy-3-methylsulfinylphenyl)acetic acid obtained as described in example 168.1, by reaction with ethyliodide and Cs2CO3in acetone was obtained ethyl ester of (RS)-(4-cyanovinylene)-(4-ethoxy-3-methylsulfinylphenyl)acetic acid.

169.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(4-ethoxy-3-methylsulfinylphenyl)acetic acid obtained as described in example 169.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(4-ethoxy-3-methylsulfinylphenyl)acetic acid (1:1), MS:388 ([M+H]+).

Example 170.

170.1. Analogously to example 168.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(4-hydroxy-3-methylsulfinylphenyl)acetic acid obtained as described in example 168.1, by reaction with 2-methyl-3-llanerfyl)acetic acid.

170.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(4-isobutoxy-3-methylsulfinylphenyl)acetic acid obtained as described in example 170.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(4-isobutoxy-3-methylsulfinylphenyl)acetic acid (1: 1), MS:416 ([M+H]+).

Example 171.

171.1. Analogously to example 168.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(4-hydroxy-3-methylsulfinylphenyl)acetic acid obtained as described in example 168.1, by reaction with ethyl ether bromoxynil acid and Cs2CO3in acetone was obtained ethyl ester of (RS)-(4-cyanovinylene)-(4-ethoxycarbonylmethoxy-3-methylsulfinylphenyl)acetic acid.

171.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(4-ethoxycarbonylmethoxy-3-methylsulfinylphenyl)acetic acid obtained as described in example 171.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(4-ethoxycarbonylmethoxy-3-methylsulfinylphenyl)acetic acid (1:1), MS:446 ([M+H]+).

Example 172.

172.1. Analogously to example 168.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(4-hydroxy-3-methylsulfinylphenyl)acetic acid obtained as opisaniya)-(4-carbamoylmethyl-3-methylsulfinylphenyl)acetic acid, MS:417 ([M+NH4]+).

172.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(4-carbamoylmethyl-3-methylsulfinylphenyl)acetic acid obtained as described in example 162.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(4-carbamoylmethyl-2-methylsulfinylphenyl)acetic acid (1:1), MS:417 ([M+H]+).

Example 173.

173.1. Analogously to example 167.1 anisic aldehyde was introduced in the reaction with N, N'-diisopropylethylamine and then with N, n, N',N'-tetramethylethylenediamine/n-BuLi and diethyldithio. After removal of the protective groups in 10% Hcl and chromatography was obtained 3-ethylsulfanyl-4-methoxybenzaldehyde in the form of a yellow oil, MS:196 ([M]+).

173.2. Analogously to example 1.1 from 3-ethylsulfanyl-4-methoxybenzaldehyde, obtained as described in example 173.1 by reaction with 4-aminobenzonitrile and benzylideneamino in EtOH was obtained ethyl ester of (RS)-(4-cyanovinylene)-(3-ethylsulfanyl-4-methoxyphenyl)acetic acid, MS:393 ([M+Na]+).

173.3. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethylsulfanyl-4-methoxyphenyl)acetic acid obtained as described in example 173.2, got hydrochloride ethyl ester of (RS)-(4-Example 174.

174.1. Analogously to example 168.1 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethylsulfanyl-4-methoxyphenyl)acetic acid obtained as described in example 173.2 by reaction with VVG3in CH2CL2received ethyl ester of (RS)-(4-cyanovinylene)-(3-ethylsulfanyl-4-hydroxyphenyl)acetic acid, MS:357 ([M+H]+).

174.2. Analogously to example 168.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethylsulfanyl-4-hydroxyphenyl)acetic acid obtained as described in example 174.1 by reaction with isopropylidene and Cs2CO3in acetone was obtained ethyl ester of (RS)-(4-cyanovinylene)-(3-ethylsulfanyl-4-isopropoxyphenyl)acetic acid, MS:421 ([M+Na]+).

174.3. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethylsulfanyl-4-isopropoxyphenyl)acetic acid obtained as described in example 164.2, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(3-ethylsulfanyl-4-isopropoxyphenyl)acetic acid (1: 1), MS:416 ([M+H]+).

Example 175.

175.1. Analogously to example 167.1 anisic aldehyde was introduced in the reaction with N, N'-diisopropylethylamine and then with N, N,N',N'-tetramethylethylenediamine/n-BuLi and acetaldehyde. After removal of the protective FCU is one MS:180 ([M]+).

175.2. Analogously to example 1.1 from (RS)-3-(1-hydroxyethyl)-4-methoxybenzaldehyde, obtained as described in example 175.1 by reaction with 4-aminobenzonitrile and benzylideneamino in EtOH was obtained a mixture of ethyl ester of (RS)- and (SR)-(4-cyanovinylene)-[3-[(RS)-1-hydroxyethyl] -4-methoxyphenyl] acetic acid, MS:405 ([M+Na]+).

175.3. Analogously to example 6.2, the mixture of ethyl esters of (RS)- and (SR)-(4-cyanovinylene)-[3-[(RS)-1-hydroxyethyl] -4-methoxyphenyl] acetic acid obtained as described in example 165.2, received a mixture of hydrochloride ethyl ester of (RS)- and (SR)-(4-carbamimidoyl)-[3-[(RS)-1-ethoxyethyl]-4-methoxyphenyl]acetic acid (1:1), MS:400 ([M+H]+).

Example 176.

176.1. Analogously to example 178.1 from 4-bromo-1-isopropoxy-2-isopropylbenzene (obtained from 2-isopropylphenol alkylation by isopropylidene/K2CO3and then bromirovanii CVG/MSRV) by reaction with n-BuLi and DMF was obtained 4-isopropoxy-3-isopropylbenzaldehyde, MS:206 ([M]+).

176.2. Analogously to example 1.1 from 4-isopropoxy-3-isopropylbenzyl-degidi, obtained as described in example 176.1 by reaction with 4-aminobenzonitrile and benzylideneamino in EtOH was obtained ethyl ester of (RS)-(4-cyanovinylene)-(4-isopro ether (RS)-(4-cyanovinylene)-(4-isopropoxy-3-isopropylphenyl)acetic acid was obtained the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(4-isopropoxy-3-isopropylphenyl)acetic acid (1:1).

Example 177.

177.1. Analogously to example 168.1 of the ethyl ester of (RS)-(4-cyanovinylene)-(4-isopropoxy-3-isopropylphenyl)acetic acid obtained as described in example 176.2 by reaction with VVG3in CH2Cl2received ethyl ester of (RS)-(4-cyanovinylene)-(4-hydroxy-3-isopropylphenyl)acetic acid.

177.2. Analogously to example 168.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(4-hydroxy-3-isopropylphenyl)acetic acid obtained as described in example 177.1 by reaction with iodoacetamide and Cs2CO3in acetone was obtained ethyl ester of (RS)-(4-carbamoylmethyl-3-isopropylphenyl)-(4-cyanoaniline)acetic acid, MS:413 ([M+NH4]+).

177.3. Analogously to example 6.2 of the ethyl ester of (RS)-(4-carbamoylmethyl-3-isopropylphenyl)-(4-cyanoaniline)acetic acid obtained as described in example 177.2, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(4-carbamoylmethyl-3-isopropylphenyl)acetic acid (1:1).

Example 178.

178.1. A solution of 4-bromo-2-ethyl-1-methoxybenzene (J. Chem. Soc., Perkin Trans. 1, 1423 (1987)) (2,13 g, a 9.9 mmole) in THF (30 ml) was cooled to -78oC. and Then slowly added 1.6 M solution of n-BuLi in hexane (7,42 ml, 11.9 mmole) and the mixture was stirred who eat slowly added DMF (2,29 ml, for 29.7 mmole) and the mixture was stirred at -78oC for 1 h and at 0oC for 1 h, the Reaction mixture was poured into ice-cold 3 M Hcl and was extracted with diethyl ether. The organic phase was dried and filtered, the filtrate was concentrated. The residue was purified by chromatography (SiO2, hexane/AcOEt 8:1 = > 2: 1). When this was received 690 mg (42%) of 3-ethyl-4-methoxybenzaldehyde liquid yellowish color.

178.2. Analogously to example 1.1 from 3-ethyl-4-methoxybenzaldehyde, obtained as described in example 178.1 by reaction with 4-aminobenzonitrile and benzylideneamino in EtOH was obtained ethyl ester of (RS)-(4-cyanovinylene)-(3-ethyl-4-methoxyphenyl)acetic acid, MS:337 ([M-H]-).

178.3. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethyl-4-methoxyphenyl)acetic acid obtained as described in example 178.2, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(3-ethyl-4-methoxyphenyl)acetic acid (1:1).

Example 179.

179.1. TiCl4(45.6 g, 238 mmol) was slowly added to a solution of 2-ethylphenol (15 g, 119 mmol) in 150 ml of CH2Cl2at 0oC. the Mixture was heated to room temperature and added dichlorodimethyl ether (18.3 ml, 200 mmol) (intensive SUP>oWith and was added dropwise 1 M Hcl (119 ml, 119 mmol). The mixture was stirred for 10 min and then was extracted with diethyl ether. The organic phase was washed with saturated solution of NaHCO3and NaCl solution, dried, filtered and concentrated. The residue was purified by chromatography (SiO2CH2Cl2= > CH2Cl2/MeOH 9:1). It was obtained 3-ethyl-4-hydroxybenzaldehyde in the form of a brown oil (of 7.97 g, 45%).

179.2. A mixture of 3-ethyl-4-hydroxybenzaldehyde (7,8 g, 51,9 mmole), obtained as described in example 179.1, K2CO3(10.8 g, 78 mmol) and Isopropylamine (7,86 ml, 78 mmol) was heated in DMF (65 ml) at 80oC for 3 h, and then stirred at room temperature for 12 hours, the Reaction mixture was poured into ice-cold 0.5 M Hcl and was extracted with diethyl ether. The organic phase is washed with NaCl solution, dried, filtered and concentrated. The residue was purified by chromatography (SiO2, hexane/AcOEt 4:1). It was obtained 3-ethyl-4-isopropoxybenzonitrile in the form of an orange oil (6,12 g, 61%), MS:192 ([M]+).

179.3. Analogously to example 1.1 from 3-ethyl-4-isopropoxybenzonitrile, obtained as described in example 179.2 by reaction with 4-aminobenzonitrile and benzylideneamino

179.4. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethyl-4-isopropoxyphenyl)acetic acid obtained as described in example 179.3, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(3-ethyl-4-isopropoxyphenyl)acetic acid (1: 1), MS: 384 ([M+H]+).

Example 180.

180.1. Analogously to example 168.1 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethyl-4-isopropoxyphenyl)acetic acid obtained as described in example 179.3 by reaction with BBr3in CH2CL2received ethyl ester of (RS)-(4-cyanovinylene)-(3-ethyl-4-hydroxyphenyl)acetic acid, MS: 325 ([M+H]+).

180.2. Analogously to example 168.2, the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethyl-4-hydroxyphenyl)acetic acid obtained as described in example 180.1, by reaction with iodoacetamide and Cs2CO3in acetone was obtained ethyl ester of (RS)-(4-carbamoylmethyl-3-ethylphenyl)-(4-cyanoaniline)acetic acid, MS:380 ([M-H]-).

180.3. Analogously to example 6.2 of the ethyl ester of (RS)-(4-carbamoylmethyl-3-ethylphenyl)-(4-cyanoaniline)acetic acid obtained as described in example 180.2, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(4-carbamoylmethyl the ru 168.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethyl-4-hydroxyphenyl)acetic acid, obtained as described in example 180.1, by reaction with propyliodide and Cs2CO3in acetone was obtained ethyl ester of (RS)-(4-cyanovinylene)-(3-ethyl-4-propoxyphenyl)acetic acid, MS:366 ([M]+).

181.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethyl-4-propoxyphenyl)acetic acid obtained as described in example 171.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(3-ethyl-4-propoxyphenyl)acetic acid (1:1), MS:384 ([M+H]+).

Example 182.

182.1. A suspension of ethyl ester of (RS)-(4-cyanovinylene)-(3-ethyl-4-hydroxyphenyl)acetic acid, described in example 180.1, (328 mg, 1,01 mmole) and2CO3(89 mg, 0.25 mmole) in Cyclopentanone (0,896 ml, 10.1 mmole) and EtOH (0.5 ml) was boiled under reflux for 9 hours and Then the reaction mixture was concentrated and dried under high vacuum. The residue was purified by chromatography (SiO2, hexane/AcOEt 1:1). It was obtained a mixture of ethyl ester of (RS)- and (SR)-(4-cyanovinylene)-[3-ethyl-4-[(RS, 2RS)-2-hydroxycyclopent] phenyl] acetic acid (226 mg, 55%) as a colourless foam, MS:407 ([M-H]-).

182.2. Analogously to example 6.2, the mixture of ethyl esters of (RS)- and (SR)-(4-cyanovinylene)-[3-ethyl-4-[(RS, 2RS)-2-gorodov ethyl ester of (RS)- and (SR)-(4-carbamimidoyl)-[3-ethyl-4-[(1RS,2RS)-2-hydroxycyclopent]phenyl]acetic acid (1:1), MS: 426 ([M+H]+).

Example 183.

183.1. A solution of ethyl ester of (RS)-(4-cyanovinylene)-(3-ethyl-4-hydroxyphenyl)acetic acid (400 mg, of 1.23 mmole, described in example 180.1, ethylene carbonate resulting in (110 mg, of 1.23 mmole) and tetrabutylammonium bromide (264 mg, of 1.23 mmole) in DMF (0.6 ml) was heated for 6 h at 155oC. the Reaction mixture was concentrated and the residue was purified by chromatography (SiO2, hexane/AcOEt 9: 1). It was obtained ethyl ester of (RS)-(4-cyanovinylene)-[3-ethyl-4-(2-hydroxyethoxy)phenyl] acetic acid (111 mg, 24%) as a yellow oil.

183.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-[3-ethyl-4-(2-hydroxyethoxy)phenyl] acetic acid obtained as described in example 183.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-[3-ethyl-4-(2-hydroxyethoxy)phenyl] acetic acid (1: 1).

Example 184.

184.1. Analogously to example 18.1 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethyl-4-hydroxyphenyl)acetic acid obtained as described in example 180.1 by reaction with N-(2-hydroxyethyl)pyrrolidine, diethylazodicarboxylate and triphenylphosphine in THF was obtained ethyl ester of (RS)-(4-cyanovinylene)-[3-ethyl-4-(2-pyrrolidin-1 ylethoxy)phenyl]acetic Kisaki)phenyl] acetic acid, obtained as described in example 184.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-[3-ethyl-4-(2-pyrrolidin-1 ylethoxy)phenyl] acetic acid (1:1), MS:439 ([M+H]+).

Example 185.

185.1. 3-Ethyl-4-nitrobenzaldehyde was obtained from 4-nitrobenzaldehyde introduction of protective groups with the use of ethylene glycol by reaction with ethylmagnesium and DDQ, followed by removal of protective groups in Hcl (J. were obtained. Chem., 447, 1 (1993)), MS:179 ([M]+).

185.2. Analogously to example 1.1 from 3-ethyl-4-nitrobenzaldehyde, obtained as described in example 185.1 by reaction with 4-aminobenzonitrile and benzylideneamino in EtOH was obtained ethyl ester of (RS)-(4-cyanovinylene)-(3-ethyl-4-nitrophenyl)acetic acid, MS:354 ([M+H]+).

185.3 Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethyl-4-nitrophenyl)acetic acid obtained as described in example 185.2, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(3-ethyl-4-nitrophenyl)acetic acid (1:1), MS:371 ([M+H]+).

Example 186.

186.1. Analogously to example 59.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethyl-4-nitrophenyl)acetic acid obtained as described in example 185.2 by reaction with N-).

186.2. Analogously to example 61.1 of the ethyl ester of (RS)-(4-amino-3-ethylphenyl)-(4-cyanoaniline)acetic acid obtained as described in example 186.1 by reaction with ethyliodide and diisopropylethylamine in THF was obtained ethyl ester of (RS)-(4-cyanovinylene)-(3-ethyl-4-ethylaminomethyl)acetic acid, MS:352 ([M+H]+).

186.3. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethyl-4-ethylaminomethyl)acetic acid obtained as described in example 186.2, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(3-ethyl-4-ethylaminomethyl)acetic acid (1:1), MS:369 ([M+H]+).

Example 187.

187.1. Analogously to example 61.1 of the ethyl ester of (RS)-(4-amino-3-ethylphenyl)-(4-cyanoaniline)acetic acid obtained as described in example 186.1 by reaction with isopropylidene and diisopropylethylamine in THF was obtained ethyl ester of (RS)-(4-cyanovinylene)-(3-ethyl-4-isopropylaminomethyl)acetic acid, MS:366 ([M+H]+).

187.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethyl-4-isopropylaminomethyl)acetic acid obtained as described in example 187.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl 188.1. The solution isopropylmalate (130 mg, of 1.55 mmole) in THF (2 ml) was added to a solution of ethyl ester of (RS)-(4-amino-3-ethylphenyl)-(4-cyanoaniline)acetic acid (500 mg, of 1.55 mmole, described in example 186.1, in THF (10 ml). The mixture was stirred at room temperature overnight. Then add an additional amount isopropylmalate (260 mg, 3.1 mmole) and the mixture was stirred at 50oWith during the night. Then the reaction mixture was concentrated. The residue is suspended in CH2Cl2/MeOH (98:2) and was filtered colorless solid. The obtained solid is washed with EtOH and dried under high vacuum. It was obtained ethyl ester of (RS)-(4-cyanovinylene)-[3-ethyl-4-(3-isopropylamino)phenyl]acetic acid (395 mg, 62%) as a colourless solid, MS:409 ([M+H]+).

188.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-[3-ethyl-4-(3-isopropylamino)phenyl] acetic acid obtained as described in example 188.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-[3-ethyl-4-(isopropylamino)phenyl]acetic acid (1:1).

Example 189.

189. A. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(4-methoxy-leilanie)-(4-methoxy-3-methylsulfinylphenyl)acetic acid, MS:346 ([M+H]+).

189. B. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(4-isopropoxy-3-methylsulfinylphenyl)acetic acid (1:1) obtained as described in example 168.3, was obtained (RS)-(4-carbamimidoyl)-(4-isopropoxy-3-methylsulfinylphenyl)acetic acid, MS:374 ([M+H]+).

189. C. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(4-ethoxy-3-methylsulfinylphenyl)acetic acid (1: 1) obtained as described in example 169.2, was obtained (RS)-(4-carbamimidoyl)-(4-ethoxy-3-methylsulfinylphenyl)acetic acid, MS:360 ([M+H]+).

189. Similarly, example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(4-isobutoxy-3-methylsulfinylphenyl)acetic acid (1:1) obtained as described in example 170.2, was obtained (RS)-(4-carbamimidoyl)-(4-isobutoxy-3-methylsulfinylphenyl)acetic acid, MS:388 ([M+H]+).

189. D. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(4-ethoxycarbonylmethoxy-3-methylsulfinylphenyl)acetic acid (1:1) obtained as described in example 171.2, was obtained (RS)-(4-carbamimidoyl)-(4-carboxymethylated ethyl ester of (RS)-(4-carbamimidoyl)-(4-carbamoylmethyl-3-methylsulfinylphenyl)acetic acid (1:1), obtained as described in example 172.2, was obtained (RS)-(4-carbamimidoyl)-(4-carbamoylmethyl-3-methylsulfinylphenyl)acetic acid, MS:389 ([M+H]+).

189. W. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3-ethylsulfanyl-4-methoxyphenyl)acetic acid (1: 1) obtained as described in example 173.3, was obtained (RS)-(4-carbamimidoyl)-(3-ethylsulfanyl-4-methoxyphenyl)acetic acid, MS:360 ([M+H]+).

189. C. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3-ethylsulfanyl-4-isopropoxyphenyl)acetic acid (1:1) obtained as described in example 174.3, received the ethyl ester of (RS)-(4-carbamimidoyl)-(3-ethylsulfanyl-4-isopropoxyphenyl)acetic acid, MS:388 ([M+H]+).

189. I. Analogously to example 75 from a mixture of hydrochloride ethyl ester of (RS)- and (SR)-(4-carbamimidoyl)-[3-[(RS)-1-ethoxyethyl]-4-methoxyphenyl]acetic acid (1:1) obtained as described in example 175.3, received a mixture of (RS)- and (SR)-(4-carbamimidoyl)-[3-[(RS)-1-ethoxyethyl] -4-methoxyphenyl]acetic acid, MS:372 ([M+H]+).

189. K. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(4-carbamimidoyl)-(4-isopropoxy-3-isopropylphenyl)acetic acid, MS:370 ([M+H]+).

189. L. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(4-carbamoylmethyl-3-isopropylphenyl)acetic acid (1:1) obtained as described in example 177.3, was obtained (RS)-(4-carbamimidoyl)-(4-carbamoylmethyl-3-isopropylphenyl)acetic acid, MS:385 ([M+H]+).

189. m Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3-ethyl-4-methoxyphenyl)acetic acid (1: 1) obtained as described in example 178.3, was obtained (RS)-(4-carbamimidoyl)-(3-ethyl-4-methoxyphenyl)acetic acid, MS:328 ([M+H]+).

189. N. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3-ethyl-4-isopropoxyphenyl)acetic acid (1:1) obtained as described in example 179.4 was obtained (RS)-(4-carbamimidoyl)-(3-ethyl-4-isopropoxyphenyl)acetic acid, MS:354 ([M+H]+).

189. acting Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(4-carbamoylmethyl-3-ethylphenyl)acetic acid (1: 1) obtained as described in example 180.3, was obtained (RS)-(4-carbamimidoyl)-(4-carbamoylmethyl-3-ethylphenyl)acetic acid, MS:371 ([M+H]+).+).

189. R. Analogously to example 75 from a mixture of hydrochloride ethyl ester of (RS)- and (SR)-(4-carbamimidoyl)-[3-ethyl-4-[(1RS, 2RS)-2-hydroxycyclopent] phenyl] acetic acid (1: 1) obtained as described in example 182.2, received a mixture of (RS)- and (SR)-(4-carbamimidoyl)-[3-ethyl-4-[(1RS, 2RS)-2-hydroxycyclopent] phenyl] acetic acid, MS:398 ([M+H]+).

189. C. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-[3-ethyl-4-(2-hydroxyethoxy)phenyl] acetic acid (1: 1) obtained as described in example 183.2, was obtained (RS)-(4-carbamimidoyl)-[3-ethyl-4-(2-hydroxyethoxy)phenyl]acetic acid, MS:358 ([M+H]+).

189. so Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-[3-ethyl-4-(2-pyrrolidin-1 ylethoxy)phenyl] acetic acid (1:1) obtained as described in example 184.2, was obtained (RS)-(4-carbamimidoyl)-[3-ethyl-4-(2-pyrrolidin-1 ylethoxy)phenyl] acetic acid, MS:411 ([M+H]+).

189. . Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl is americoliberian)-(3-ethyl-4-ethylaminomethyl)acetic acid, MS:341 ([M+H]+).

189. F. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3-ethyl-4-isopropylaminomethyl)acetic acid (1: 1) obtained as described in example 187.2, was obtained (RS)-(4-carbamimidoyl)-(3-ethyl-4-isopropylaminomethyl)acetic acid, MS: 355 ([M+H]+).

189. X. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-[3-ethyl-4-(isopropylamino)phenyl] acetic acid (1: 1) obtained as described in example 188.2, was obtained (RS)-(4-carbamimidoyl)-[3-ethyl-4-(3-isopropylamino)phenyl] acetic acid, MS: 398 ([M+H]+).

Example 190.

190.1. A suspension of 3,5-dimethylanisole (13,60 g, 100 mmol), N-bromosuccinimide (18,35 g, 100 mmol) and 2,2'-azobis-(2-methylpropionitrile) in CCL4boiled under reflux for 1 h Succinimide was filtered, the filtrate was concentrated and the residue was chromatographically (SiO2CH2CL2/hexane 1:4). When this was received 14,61 g (68%) of 1-methyl bromide-3-methoxy-5-methylbenzene.

2-Nitropropane (6,77 ml, 71.3 mmole), and then 1-methyl bromide-3-methoxy-5-methylbenzo (14.6 g, 67,9 mmole) was added to a solution of NaOEt (4.72 in g, 67,9 mmole) in EtOH (60 ml). The mixture was heated at 65oWith those who t was purified by chromatography (SiO2CH2CL2/hexane 1:2). When this was received 7,87 g (77%) of 3-methoxy-5-methylbenzaldehyde in the form of a colourless liquid.

190.2. Analogously to example 1.1 from 3-methoxy-5-methylbenzaldehyde, obtained as described in example 190.1 by reaction with 4-aminobenzonitrile and benzylideneamino in EtOH was obtained ethyl ester of (RS)-(4-cyanovinylene)-(3-methoxy-5-were)acetic acid, MS:324 ([M]+).

190.3. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-methoxy-5-were)acetic acid obtained as described in example 180.2, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(3-methoxy-5-were)acetic acid (1:1), MS:342 ([M+H]+).

Example 191.

191.1. Analogously to example 168.1 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-methoxy-5-were)acetic acid obtained as described in example 190.2, received the ethyl ester of (RS)-(4-cyanovinylene)-(3-hydroxy-5-were)acetic acid, MS:310 ([M+H]+).

191.2. Analogously to example 168.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-hydroxy-5-were)acetic acid obtained as described in example 191.1 by reaction with isopropylidene and Cs2CO3in acetone received these is.3. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-isopropoxy-5-were)acetic acid obtained as described in example 191.2, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(3-isopropoxy-5-were)acetic acid (1: 1), MS:370 ([M+H]+).

Example 192.

192.1. Analogously to example 168.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-hydroxy-5-were)acetic acid obtained as described in example 191.1 by reaction with iodoacetamide and Cs2CO3in acetone was obtained ethyl ester of (RS)-(3-carbamoylmethyl-5-were)-(4-cyanoaniline)acetic acid, MS:366 ([M-H]-).

192.2. Analogously to example 6.2 of the ethyl ester of (RS)-(3-carbamoylmethyl-5-were)-(4-cyanoaniline)acetic acid obtained as described in example 192.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(3-carbamoylmethyl-5-were)acetic acid (1:1), MS:385 ([M+H]+).

Example 193.

193.1. Analogously to example 168.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-hydroxy-5-were)acetic acid obtained as described in example 191.1 by reaction with ethyliodide and Cs2CO3in acetone was obtained ethyl EF the example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-5-were)acetic acid, obtained as described in example 193.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(3-ethoxy-5-were)acetic acid (1:1), MS:356 ([M+H]+).

Example 194.

194.1. Analogously to example 18.1 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-hydroxy-5-were)acetic acid obtained as described in example 191.1 by reaction with N-(2-hydroxyethyl)pyrrolidine, diethylazodicarboxylate and triphenylphosphine in THF was obtained ethyl ester of (RS)-(4-cyanovinylene)-[3-methyl-5-(2-pyrrolidin-1 ylethoxy)phenyl]acetic acid, MS:408 ([M+H]+).

194.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-[3-methyl-5-(2-pyrrolidin-1 ylethoxy)phenyl] acetic acid obtained as described in example 194.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-[3-methyl-5-(2-pyrrolidin-1 ylethoxy)phenyl] acetic acid (1:1).

Example 195.

195.1. Analogously to example 18.1 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-hydroxy-5-were)acetic acid obtained as described in example 191.1 by reaction with Cyclopentanol, diethylazodicarboxylate and triphenylphosphine in THF was obtained ethyl ester of (RS)-(4-cyanovinylene)-(3-cyclopentyloxy-5-methylphenylimino)-(3-cyclopentyloxy-5-were)acetic acid, obtained as described in example 195.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(3-cyclopentyloxy-5-were)acetic acid (1:1), MS:396 ([M+H]+).

Example 196.

196.1. Analogously to example 18.1 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-hydroxy-5-were)acetic acid obtained as described in example 191.1 by reaction with 4-hydroxy-N-methylpiperidine, diethylazodicarboxylate and triphenylphosphine in THF was obtained ethyl ester of (RS)-(4-cyanovinylene)-[3-methyl-5-(1-methylpiperidin-4-yloxy)phenyl] acetic acid, MS: 408 ([M+H]+).

196.2 Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-[3-methyl-5-(1-methylpiperidin-4-yloxy)phenyl] acetic acid obtained as described in example 196.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-[3-methyl-5-(1-methylpiperidin-4-yloxy)phenyl]acetic acid (1:1), MS:425 ([M+H]+).

Example 197.

197.1. Analogously to example 182.1 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-hydroxy-5-were)acetic acid obtained as described in example 191.1 by reaction with cyclopentenone and K2CO3in EtOH was obtained a mixture of ethyl ester of (RS)- and (SR)-(4-cyanovinylene)-[3-[(imeru 6.2 from a mixture of ethyl ester of (RS)-and (SR)-(4-cyanovinylene)-[3-[(1RS, 2RS)-2-hydroxycyclopent] -5-were]acetic acid obtained as described in example 197.1 received a mixture of hydrochloride ethyl ester of (RS)- and (SR)-(4-carbamimidoyl)-[3-[(1RS, 2RS)-2-hydroxycyclopent] -5-were] acetic acid (1:1), MS:412 ([M+H]+).

Example 198.

198.1. Analogously to example 190.1 of the 3.5-dimethylanisole received 5-methoxybenzo-1,3-dicarbollide.

198.2. A mixture of 5-methoxybenzo-1,3-dicarbollide (3,68 g, 22.4 mmole), obtained as described in example 198.1, bromide methyltriphenylphosphonium (8,17 g, 22.4 mmole)2CO3(3,10 g, 22.4 mmole), water (0.68 ml) and dioxane (51 ml) was heated at 90oC for 2 h, the Reaction mixture was concentrated, and the obtained product was purified by chromatography (SiO2, hexane/CH2Cl24:1). When this was received 1,74 g (48%) of 3-methoxy-5-universalized in the form of a colorless oil, MS:162 ([M]+).

198.3. Analogously to example 1.1 from 3-methoxy-5-Universalnaya, obtained as described in example 198.2 by reaction with 4-aminobenzonitrile and benzylideneamino in EtOH was obtained ethyl ester of (RS)-(4-cyanovinylene)-(3-methoxy-5 - vinylphenol)acetic acid, MS:336 ([M]+).

198.4. Analogously to example 6.2 of the ethyl ester (R ethyl ester of (RS)-(4-carbamimidoyl)-(3-methoxy-5-vinylphenol)acetic acid (1:1), MS:354 ([M+H]+).

Example 199.

199.1. To 10% final Pd/C (236 mg and 0.22 mole) was added to a solution of ethyl ester of (RS)-(4-cyanovinylene)-(3-methoxy-5-vinylphenol)acetic acid (1,495 g of 4.44 mmole), obtained as described in example 198.3, in EtOH (40 ml) and THF (4 ml) and the mixture was first made at room temperature for 1 h Then the reaction mixture was filtered, the filtrate was concentrated and the residue was purified by filtration through a SiO2(eluent: AcOEt/hexane 1:1). It was obtained 1.5 g (99%) of ethyl ester of (RS)-(4-cyanovinylene)-(3-ethyl-5-methoxyphenyl)acetic acid in a solid beige, MS: 338 ([M]+).

199.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethyl-5-methoxyphenyl)acetic acid obtained as described in example 199.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(3-ethyl-5-methoxyphenyl)acetic acid (1:1), MS:356 ([M+H]+).

Example 200.

200.1. Analogously to example 168.1 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethyl-5-methoxyphenyl)acetic acid obtained as described in example 199.1, received the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethyl-5-hydroxyphenyl)acetic acid, MS:325 ([M+H]+).

200.2. An the tion, as described in example 200.1 by reaction with 2-methyl-3-iodopropane and Cs2CO3in acetone was obtained ethyl ester of (RS)-(4-cyanovinylene)-(3-ethyl-5-isobutoxide)acetic acid, MS:381 ([M+H]+).

200.3. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethyl-5-isobutoxide)acetic acid obtained as described in example 200.2, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(3-ethyl-5-isobutoxide)acetic acid (1:1), MS:398 ([M+H]+).

Example 201.

201.1. Analogously to example 18.1 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethyl-5-hydroxyphenyl)acetic acid obtained as described in example 200.1 by reaction with 4-hydroxy-N-methylpiperidine, diethylazodicarboxylate and triphenylphosphine in THF was obtained ethyl ester of (RS)-(4-cyanovinylene)-[3-ethyl-5-(1-methylpiperidin-4-yloxy)phenyl] acetic acid, MS: 422 ([M+H]+).

201.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-[3-ethyl-5-(1-methylpiperidin-4-yloxy)phenyl] acetic acid obtained as described in example 201.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-[3-ethyl-5-(1-methylpiperidin-4-yloxy)phenyl] acetic acid (1:1), MS:439 ([M+H]+).

202.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-[3-ethyl-5-(2-pyrrolidin-1 ylethoxy)phenyl] acetic acid obtained as described in example 202.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-[3-ethyl-5-(2-pyrrolidin-1 ylethoxy)phenyl] acetic acid (1:1), MS:439 ([M+H]+).

Example 203.

203.1. Analogously to example 18.1 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethyl-5-hydroxyphenyl)acetic acid obtained as described in example 200.1 by reaction with tetrahydro-2H-Piran-4-I, diethylazodicarboxylate and triphenylphosphine in THF was obtained ethyl ester of (RS)-(4-cyanovinylene)-[3-ethyl-5-(tetrahydropyran-4-yloxy)phenyl] acetic acid, MS:409 ([M+H]+).

203.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-[3-ethyl-5-(tetrahydropyran-4-yloxy)phenyl] acetic acid obtained as described in example 203.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl the

204.1. Analogously to example 18.1 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethyl-5-hydroxyphenyl)acetic acid obtained as described in example 200.1 by reaction with tetrahydrofurfuryl alcohol, diethylazodicarboxylate and triphenylphosphine in THF was obtained a mixture of ethyl ester of (RS)- and (SR)-(4-cyanovinylene)-[3-ethyl-5-[(RS)-tetrahydrofuran-2-ylethoxy] phenyl] acetic acid, MS:408 ([M]+).

204.2. Analogously to example 6.2, the mixture of ethyl esters of (RS)- and (SR)-(4-cyanovinylene)-[3-ethyl-5-[(RS)-tetrahydrofuran-2-ylethoxy] phenyl] acetic acid obtained as described in example 204.1, received a mixture of hydrochloride ethyl ester of (RS)- and (SR)-(4-carbamimidoyl)-[3-ethyl-5-[(RS)-tetrahydrofuran-2-ylethoxy] phenyl]acetic acid (1:1), MS:426 ([M+H]+).

Example 205.

205.1. Analogously to example 18.1 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethyl-5-hydroxyphenyl)acetic acid obtained as described in example 200.1, by reaction with Cyclopentanol, diethylazodicarboxylate and triphenylphosphine in THF was obtained ethyl ester of (RS)-(4-cyanovinylene)-(3-cyclopentyloxy-5-ethylphenyl)acetic acid, MS:392 ([M]+).

205.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-cyclopen the Fira (RS)-(4-carbamimidoyl)-(3-cyclopentyloxy-5-ethylphenyl)acetic acid (1:1), MS:410 ([M+H]+).

Example 206.

206.1. Analogously to example 18.1 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethyl-5-hydroxyphenyl)acetic acid obtained as described in example 200.1 by reaction with TRANS-4-trithiacyclononane (Synth. Commun. , 24, 2399, (1994)), diethylazodicarboxylate and triphenylphosphine in THF was obtained ethyl ester of (RS)-(4-cyanovinylene)-[3-ethyl-5-(4-trithiacyclononane)phenyl]acetic acid, MS:687 ([M+Na]+).

206.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-[3-ethyl-5-(4-trithiacyclononane)phenyl] acetic acid obtained as described in example 206.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-[3-ethyl-5-(4-hydroxycyclohexyl)phenyl] acetic acid (1:1), MS:440 ([M+H]+).

Example 207.

207.1. Analogously to example 18.1 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethyl-5-hydroxyphenyl)acetic acid obtained as described in example 200.1 by reaction with tert-butyl-4-hydroxy-1-piperidinecarboxylate, diethylazodicarboxylate and triphenylphosphine in THF was obtained tert-butyl ether (RS)-4-{ 3-[(4-cyanoaniline)ethoxycarbonylmethyl]-5-ethylenoxy} piperidine-1-carboxylic acid, MS:508 ([M+H]++).

Example 208.

208.1. Analogously to example 18.1 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethyl-5-hydroxyphenyl)acetic acid obtained as described in example 200.1 by reaction with 3-dimethylamino-2,2-dimethyl-1-propanol, diethylazodicarboxylate and triphenylphosphine in THF was obtained ethyl ester of (RS)-(4-cyanovinylene)-[3-(3-dimethylamino-2,2-DIMETHYLPROPANE)-5-ethylphenyl]acetic acid, MS:438 ([M+H]+).

208.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-[3-(3-dimethylamino-2,2-DIMETHYLPROPANE)-5-ethylphenyl] acetic acid obtained as described in example 208.1, received the ethyl ester of (RS)-(4-carbamimidoyl)-[3-(3-dimethylamino-2,2-DIMETHYLPROPANE)-5-ethylphenyl]acetic acid, MS:456 ([M+H]+).

Example 209.

209.1. Triperoxonane acid (1,67 ml of 21.7 mmole) was added dropwise at 0oTo a solution of tert-butyl methyl ether (RS)-4-{ 3-[(4-cyanoaniline)ethoxycarbonylmethyl]-5-ethylenoxy}piperidine-1-carboxylic acid (1.1 g, 2,17 mmole), obtained as described in primarey saturated solution Panso3and ice. The resulting mixture was extracted with CH2Cl2. The organic phase was dried and filtered, the filtrate was concentrated. The obtained amine was used without further purification.

209.2. Methanesulfonanilide (71 mg, and 0.61 mmole) was slowly added at 0oTo a solution of amine (250 mg, of 0.51 mmole), obtained as described in example 209.1, and N-ethyldiethanolamine (81 mg, and 0.61 mmole) in THF (3.5 ml). The mixture was stirred at 0oC for 1.5 h and at room temperature for 1.5 hours Then the reaction mixture was concentrated and the residue was purified by chromatography (SiO2CH2Cl2= >CH2Cl2/MeOH 95:5). When this was received 201 mg (81%) of ethyl ester of (RS)-(4-cyanovinylene)-[3-ethyl-5-(1-methanesulfonamido-4-yloxy)phenyl]acetic acid in the form of a beige foam, MS: 486 ([M+H]+).

209.3. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-[3-ethyl-5-(1-methanesulfonamido-4-yloxy)phenyl] acetic acid obtained as described in example 209.2, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-[3-ethyl-5-(methanesulfonamido-4-yloxy)phenyl] acetic acid (1:1), MS:503 ([M+H]+).

Example 210.

210.1. Ethylbromoacetate (104 mg, 0,61 .1, and N-ethyldiethanolamine (81 mg, and 0.61 mmole) in THF (3.5 ml). The mixture was stirred at 0oC for 1 h and at room temperature for 3 h Then the reaction mixture was concentrated and the residue was purified by chromatography (SiO2CH2Cl2= >CH2CL2/Meon 95:5). When this was received 176 mg (69%) of ethyl ester of (RS)-(4-cyanovinylene)-[3-(1-ethoxycarbonylmethylene-4-yloxy)-5-ethylphenyl] acetic acid in the form of a yellow oil, MS:494 ([M+H]+).

210.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-[3-(1-ethoxycarbonylmethylene-4-yloxy)-5-ethylphenyl] acetic acid obtained as described in example 210.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-[3-(1-ethoxycarbonylmethylene-4-yloxy)-5-ethylphenyl]acetic acid (1:1), MS:511 ([M+H]+).

Example 211.

211.1. Analogously to example 182.1 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethyl-5-hydroxyphenyl)acetic acid obtained as described in example 200.1, by reaction with cyclopentenone and K2CO3in EtOH was obtained a mixture of ethyl ester of (RS)- and (SR)-(4-cyanovinylene)-[3-ethyl-5-[(1RS,2RS)-2-hydroxycyclopent]phenyl]acetic acid, MS:409 ([M+H]+).

is nilakshi] phenyl] acetic acid, obtained as described in example 211.1, received a mixture of hydrochloride ethyl ester of (RS)- and (SR)-(4-carbamimidoyl)-[3-ethyl-5-[(1RS, 2RS)-2-hydroxycyclopent]phenyl]acetic acid (1:1), MS: 426 ([M+H]+).

Example 212.

212.1. The copper acetate (II) (223 mg, 1.20 mmole), phenylboronic acid (164 mg, 1,32 mmole) and molecular sieve 4 was added to a solution of ethyl ester of (RS)-(4-cyanovinylene)-(3-ethyl-5-hydroxyphenyl)acetic acid (390 mg, 1.20 mmole), obtained as described in example 200.1, CH2Cl2(12 ml). Then was added dropwise pyridine (476 mg, 6,01 mmole) and the mixture was stirred in open air for 60 hours, the Reaction mixture was concentrated, the residue was purified by chromatography (SiO2CH2Cl2). When this was received 391 mg (81%) of ethyl ester of (RS)-(4-cyanovinylene)-(3-ethyl-5-phenoxyphenyl)acetic acid in the form of beige crystals, MS:401 ([M+H]+).

212.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanophenyl-Mino)-(3-ethyl-5-phenoxyphenyl)acetic acid obtained as described in example 212.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(3-ethyl-5-phenoxyphenyl)acetic acid (1:1), MS:418 ([M+H]+).

Example 213.

213.1. Anal is th, as described in example 200.1 by reaction with 3-pyridylamino acid was obtained ethyl ester of (RS)-(4 - cyanovinylene)-[3-ethyl-5-(pyridine-3-yloxy)phenyl] acetic acid.

213.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-[3-ethyl-5-(pyridine-3-yloxy)phenyl] acetic acid obtained as described in example 213.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-[3-ethyl-5-(pyridine-3-yloxy)phenyl] acetic acid (1: 1).

Example 214.

214.1. Analogously to example 198.2 from 5-methoxybenzo-1,3-dicarbollide, obtained as described in example 198.1 by reaction with bromide ethyltriphenylphosphonium received 3-methoxy-5-propenylbenzene.

214.2. Analogously to example 1.1 from 3-methoxy-5-propenylbenzene, obtained as described in example 214.1 by reaction with 4-aminobenzonitrile and benzylideneamino in tO received ethyl ester of (RS)-(E/Z)-(4-cyanovinylene)-(3-methoxy-5-propylphenyl)acetic acid.

214.3. Analogously to example 199.1 of the ethyl ester of (RS)-(E/Z)-(4-cyanovinylene)-(3-methoxy-5-propylphenyl)acetic acid obtained as described in example 214.2 received ethyl ester of (RS)-(4-cyanovinylene)-(3-methoxy-5-propylphenyl)acetic acid, MS:353 ([M+nil)acetic acid, obtained as described in example 214.3, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(3-methoxy-5-propylphenyl)acetic acid (1:1), MS:370 ([M+H]+).

Example 215.

215.1. Analogously to example 168.1 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-methoxy-5-propylphenyl)acetic acid obtained as described in example 214.3 received ethyl ester of (RS)-(4-cyanovinylene)-(3-hydroxy-5-propylphenyl)acetic acid.

215.2. Analogously to example 168.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-hydroxy-5-propylphenyl)acetic acid obtained as described in example 215.1, by reaction with ethyliodide and Cs2CO3in acetone, was obtained ethyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-5-propylphenyl)acetic acid, MS:366 ([M]+).

215.3. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-5-propylphenyl)acetic acid obtained as described in example 215.2, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(3-ethoxy-5-propylphenyl)acetic acid (1:1), MS:384 ([M+H]+).

Example 216.

216.1. Analogously to example 190.1 of 5-nitro-meta-xylene was obtained 3-methyl-5-nitrobenzaldehyde, MS:165 ([M]+).

216.2. the robinsoniana and benzylideneamino in EtOH was obtained ethyl ester of (RS)-(4-cyanovinylene)-(3-methyl-5-nitrophenyl)acetic acid, MS:340 ([M+H]+).

216.3. Analogously to example 59.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-methyl-5-nitrophenyl)acetic acid obtained as described in example 216.2 by reaction with N2in EtOH (1:1) in the presence of Pd/C catalyst was obtained ethyl ester of (RS)-(3-amino-5-were)-(4-cyanoaniline)acetic acid, MS:309 ([M]+).

216.4. Analogously to example 61.1 of the ethyl ester of (RS)-(3-amino-5-were)-(4-cyanoaniline)acetic acid obtained as described in example 216.3 by reaction with ethyliodide and diisopropylethylamine in THF was obtained ethyl ester of (RS)-(4-cyanovinylene)-(3-ethylamino-5-were)acetic acid, MS:338 ([M+H]+).

216.5. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethylamino-5-were)acetic acid obtained as described in example 216.4, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(3-ethylamino-5-were)acetic acid (1:1), MS:355 ([M+H]+).

Example 217.

217.1. Analogously to example 61.1 of the ethyl ester of (RS)-(3-amino-5-were)-(4-cyanoaniline)acetic acid obtained as described in example 216.3 by reaction with ethyliodide and diisopropylethylamine in THF was obtained ethyl africna example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-diethylamino-5-were)acetic acid, obtained as described in example 217.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(3-diethylamino-5-were)acetic acid (1: 1), MS:383 ([M+H]+).

Example 218.

218.1. Analogously to example 61.1 of the ethyl ester of (RS)-(3-amino-5-were)-(4-cyanoaniline)acetic acid obtained as described in example 216.3 by reaction with cyclopentylamine and diisopropylethylamine in THF was obtained ethyl ester of (RS)-(4-cyanovinylene)-(3-cyclopentylamine-5-were)acetic acid, MS:378 ([M+H]+).

218.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-cyclopentylamine-5-were)acetic acid obtained as described in example 218.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(3-cyclopentylamine-5-were)acetic acid (1:1), MS:395 ([M+H]+).

Example 219.

219.1. Analogously to example 61.1 of the ethyl ester of (RS)-(3-amino-5-were)-(4-cyanoaniline)acetic acid obtained as described in example 216.3 by reaction with 1,4-dibromobutane and diisopropylethylamine in THF was obtained ethyl ester of (RS)-(4-cyanovinylene)-(3-methyl-5-pyrrolidin-1-ylphenyl)acetic acid, MS:363 ([M]+).

219 the s, obtained as described in example 219.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl) - (3-methyl-5-pyrrolidin-1-ylphenyl)acetic acid (1: 1), MS:381 ([M+H]+).

Example 220.

220.1. Analogously to example 188.1 of the ethyl ester of (RS)-(3-amino-5-were)-(4-cyanoaniline)acetic acid obtained as described in example 216.3 by reaction with n-utilitarianism in THF was obtained ethyl ester of (RS)-[3-(3-butylurea)-5-were] -(4-cyanoaniline)acetic acid, MS:409 ([M+H]+).

220.2. Analogously to example 6.2 of the ethyl ester of (RS)-[3-(3-butylurea)-5-were] -(4-cyanoaniline)acetic acid obtained as described in example 211.1, got hydrochloride ethyl ester of (RS)-[3-(3-butylurea)-5-were] -(4-carbamimidoyl)acetic acid (1:1), MS:426 ([M+H]+).

Example 221.

221.1. A solution of ethyl ester of (RS)-(3-amino-5-were)-(4-cyanoaniline)acetic acid (500 mg, of 1.62 mmole), obtained as described in example 216.3, cyclopentenone (136 mg, of 1.62 mmole) and LiClO4(172 mg, of 1.62 mmole) in acetonitrile (1.5 ml) was stirred for 70 h at room temperature. Then the mixture was heated at 60oC for 24 h, was added 1 tsp Chia After cooling, was added water and the mixture was extracted with diethyl ether. The organic phase was dried, filtered and concentrated, the residue was purified by chromatography (SiO2CH2Cl2/MeOH 98: 2). When this was received 272 mg (43%) of a mixture of ethyl ester of (RS)- and (SR)-(4-cyanovinylene)-[3-[(1RS,2RS)-2-hydroxycyclophosphamide] -5-were] acetic acid in the form of a solid yellowish, MS:394 ([M+H]+).

221.2. Analogously to example 6.2, the mixture of ethyl esters of (RS)- and (SR)-(4-cyanovinylene)-[3-[(1RS, 2RS)-2-hydroxycyclophosphamide]-5-were] acetic acid obtained as described in example 221.1, received a mixture of hydrochloride ethyl ester of (RS)- and (SR)-(4-cyanovinylene)-[3-[(1RS, 2RS)-2-hydroxycyclophosphamide] -5-were]acetic acid (1:1), MS:411 ([M+H]+).

Example 222.

222.1. A solution of ethyl ester of (RS)-(3-amino-5-were)-(4-cyanoaniline)acetic acid (475 mg, and 1.54 mmole), obtained as described in example 216.3, 2-chloropyrimidine (400 mg, to 3.38 mmole), diisopropylethylamine (317 μl, of 1.85 mmole) and 1,8-diazabicyclo[5.4.0]undec-7-ene (276 μl, of 1.85 mmole) in THF (4 ml) was boiled under reflux for 2 hours the Reaction mixture was concentrated, the residue was purified by chromatography (SiO2hexane)propyl] azepin-2-ylideneamino] phenyl}acetic acid in the form of a yellowish foam, MS: 540 ([M+H]+).

222.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-methyl-5-{ 1-[3-(pyrimidine-2-ylamino)propyl] azepin-2-ylideneamino} phenyl)acetic acid obtained as described in example 222.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(2-methyl-5-{ 1-[3-(pyrimidine-2-ylamino)propyl]azepin-2-ylideneamino}phenyl)acetic acid (1:1), MS:557 ([M+H]+).

Example 223.

223.1. From isophthalaldehyde by reaction with NGO3/N2SO4and ammonium sulfate was obtained 5-nitrobenzene-1,3-dicarbollide (Inorganic Chem. , 37, 2134 (1998)).

223.2. Analogously to example 198.2 from 5-nitrobenzene-1,3-dicarbollide, obtained as described in example 223.1 by reaction with bromide methyltriphenylphosphonium was obtained 3-nitro-5-vinylbenzene, MS:177 ([M]+).

223.3. Analogously to example 1.1 from 3-nitro-5-Universalnaya, obtained as described in example 223.2 by reaction with 4-aminobenzonitrile and benzylideneamino in EtOH was obtained ethyl ester of (RS)-(4-cyanovinylene)-(3-nitro-5-vinylphenol)acetic acid, MS:351 ([M]+).

223.4. Analogously to example 59.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-nitro-5-vinylphenol)acetic acid obtained as described is phenyl)-(4-cyanoaniline)acetic acid, MS:323 ([M]+).

223.5. Analogously to example 61.1 of the ethyl ester of (RS)-(3-amino-5-ethylphenyl)-(4-cyanoaniline)acetic acid obtained as described in example 223.4 by reaction with 1,4-dibromobutane and diisopropylethylamine in THF was obtained ethyl ester of (RS)-(4-cyanovinylene)-(3-ethyl-5-pyrrolidin-1-ylphenyl)acetic acid, MS:378 ([M+H]+).

223.6. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethyl-5-pyrrolidin-1-ylphenyl)acetic acid obtained as described in example 223.5, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(3-ethyl-5-pyrrolidin-1-ylphenyl)acetic acid (1:1), MS:395 ([M+H]+).

Example 224.

224.1. A mixture of ethyl ester of (RS)-(3-amino-5-ethylphenyl)-(4-cyanoaniline)acetic acid (500 mg, of 1.55 mmole), obtained as described in example 223.4, hydrochloride of bis-(2-chloroethylamine) (276 mg, of 1.55 mmole) and chlorobenzene (5 ml) was boiled under reflux for 18 hours the Reaction mixture was concentrated, the residue was purified by chromatography (SiO2CH2Cl2/MeOH 9: 1). When this was received 385 mg (63%) of ethyl ester of (RS)-(4-cyanovinylene)-(3-ethyl-5-piperazine-1-ylphenyl)acetic acid in the form of a solid brownish, MS:393 ([M+is fenil)acetic acid, obtained as described in example 224.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(3-ethyl-5-piperazine-1-ylphenyl)acetic acid (1: 1), MS:410 ([M+H]+).

Example 225.

225.1. Cyclopentanecarbonitrile (0.104 g ml of 0.85 mmole) was added dropwise at 0oTo a solution of ethyl ester of (RS)-(3-amino-5-ethylphenyl)-(4-cyanoaniline)acetic acid (250 mg, 0,772 mmole), obtained as described in example 223.4, and diisopropylethylamine (0,146 ml of 0.85 mmole) in CH2Cl2(5 ml). The reaction mixture was slowly heated (2 h) at room temperature. Then was added a saturated aqueous solution of KHSO4and the resulting mixture was extracted with AcOEt. The organic phase is washed with water, dried and filtered, the filtrate was concentrated. The residue was purified by chromatography (SiO2, hexane= >hexane/AcOEt 2: 1). It was obtained 215 mg (66%) of ethyl ester of (RS)-(4-cyanovinylene)-[3-(cyclopentanecarbonyl)-5-ethylphenyl] acetic acid as a colourless foam, MS:418 ([M-H]-).

225.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-[3-(cyclopentanecarbonyl)-5-ethylphenyl] acetic acid obtained as described in example 225.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl the p 226.

226.1. Analogously to example 225.1 of the ethyl ester of (RS)-(3-amino-5-ethylphenyl)-(4-cyanoaniline)acetic acid obtained as described in example 223.4 by reaction with benzosulphochloride and diisopropylethylamine in CH2Cl2received ethyl ester of (RS)-(4-cyanovinylene)-(3-benzosulfimide-5-ethylphenyl)acetic acid.

226.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-benzosulfimide-5-ethylphenyl)acetic acid obtained as described in example 226.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(3-benzosulfimide-5-ethylphenyl)acetic acid (1: 1), MS:481 ([M+H]+).

Example 227.

227.1. Analogously to example 225.1 of the ethyl ester of (RS)-(3-amino-5-ethylphenyl)-(4-cyanoaniline)acetic acid obtained as described in example 223.4 by reaction with butylsulfonyl and diisopropylethylamine in CH2Cl2received ethyl ester of (RS)-(4-cyanovinylene)-(3-butylsulfonyl-5-ethylphenyl)acetic acid.

227.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-butylsulfonyl-5-ethylphenyl)acetic acid obtained as described in example 227.1, got hydrochloride ethyl is SUP>+).

Example 228.

228.1. Na2SO4(1,09 g, 7.7 mmole) was added to a solution of ethyl ester of (RS)-(3-amino-5-ethylphenyl)-(4-cyanoaniline)acetic acid (250 mg, 0.77 mmole), obtained as described in example 223.4, and 1-methyl-4-piperidone (174 mg, and 1.54 mmole) in acetic acid (5 ml), the mixture was stirred at room temperature for 15 minutes Then the mixture was cooled to 0oAnd the portions were slowly added N(SLA)3(489 mg, 2,31 mmole). After 30 min was added a saturated solution of NaHCO3and the mixture was extracted with AcOEt. The organic phase was dried and filtered, the filtrate was concentrated. The residue was purified by chromatography (SiO2CH2Cl2/MeOH 9:1). When this was received 287 mg (89%) of ethyl ester of (RS)-(4-cyanovinylene)-[3-ethyl-5-(1-methylpiperidin-4-ylamino)phenyl] acetic acid in the form of a solid yellowish, MS:421 ([M+H]+).

228.2 Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-[3-ethyl-5-(1-methylpiperidin-4-ylamino)phenyl] acetic acid obtained as described in example 228.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-[3-ethyl-5-(1-methylpiperidin-4-ylamino)phenyl] acetic acid (1:1).

Example 229.

229 the frame, as described in example 223.4 by reaction with 3-pyridinecarboxamide, N(SLA)3in the Asón received ethyl ester of (RS)-(4-cyanovinylene)-{3-ethyl-5-[(pyridine-3-ylmethyl)amino]phenyl}acetic acid, MS:415 ([M+H]+).

229.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-{ 3-ethyl-5-[(pyridine-3-ylmethyl)amino] phenyl}acetic acid, obtained as described in example 229.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-[3-ethyl-5-[(pyridine-3-ylmethyl)amino] phenyl} acetic acid (1:1), MS:432 ([M+H]+).

Example 230.

230.1. Analogously to example 228.1 of the ethyl ester of (RS)-(3-amino-5-ethylphenyl)-(4-cyanoaniline)acetic acid obtained as described in example 223.4 by reaction with 3-pyridinecarboxamide and NaHB(OAc)3in the Asón received ethyl ester of (RS)-[3-(bis-pyridin-3-ylmethylamino)-5-ethylphenyl]-(4-cyanoaniline)acetic acid, MS:506 ([M+H]+).

230.2. Analogously to example 6.2 of the ethyl ester of (RS)-[3-(bis-pyridin-3-ylmethylamino)-5-ethylphenyl]-(4-cyanoaniline)acetic acid obtained as described in example 230.1, got hydrochloride ethyl ester of (RS)-[3-(bis-pyridin-3-ylmethylamino)-5-ethylphenyl] -(4-carbamimidoyl)acetic acid(1:1 which is 5-ethylphenyl)-(4-cyanoaniline)acetic acid, obtained as described in example 223.4 by reaction with tetrahydro-4H-Piran-4-one, N(SLA)3in the Asón received ethyl ester of (RS)-(4-cyanovinylene)-[3-ethyl-5-(tetrahydropyran-4-ylamino)phenyl]acetic acid, MS:408 ([M+H]+).

231.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-[3-ethyl-5-(tetrahydropyran-4-ylamino)phenyl]acetic acid obtained as described in example 231.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-[3-ethyl-5-(tetrahydropyran-4-ylamino)phenyl] acetic acid (1:1), MS:425 ([M+H]+).

Example 232.

232.1. Analogously to example 228.1 of the ethyl ester of (RS)-(3-amino-5-ethylphenyl)-(4-cyanoaniline)acetic acid obtained as described in example 223.4 by reaction with tetrahydro-4H-thiopyran-4-one, N(SLA)3in the Asón received ethyl ester of (RS)-(4-cyanovinylene)-[3-ethyl-5-(tetrahydrothiopyran-4-ylamino)phenyl]acetic acid, MS:424 ([M+H]+).

232.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-[3-ethyl-5-(tetrahydrothiopyran-4-ylamino)phenyl] acetic acid obtained as described in example 232.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-[3-ethyl-5-(tetrahydrothiopyran-4-Ilam is of the ethyl ester of (RS)-(4-cyanovinylene)-[3-ethyl-5-(tetrahydrothiopyran-4-ylamino)phenyl] acetic acid, obtained as described in example 232.1 by reaction with ozone in acetone/water was obtained ethyl ester of (RS)-(4-cyanovinylene)-[3-(1,1-dioxotetrahydrofuran-4-ylamino)-5-ethylphenyl]acetic acid, MS:456 ([M+H]+).

233.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-[3-(1,1-dioxotetrahydrofuran-4-ylamino)-5-ethylphenyl] acetic acid obtained as described in example 233.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-[3-(1,1-dioxotetrahydrofuran-4-ylamino)-5-ethylphenyl]acetic acid (1:1), MS:473 ([M+H]+).

Example 234.

234.1. MnO2(of 8.37 g, 96,3 mmole) was added to a solution of (3-ethoxy-5-hydroxymethylene)methanol (17,55 g, 96,3 mmole) in CH2Cl2(175 ml) and the mixture was stirred at room temperature for 64 hours and Then added an additional amount of Mno2(of 8.37 g, 96,3 mmole) and the mixture was stirred for 6 hours the Mixture was filtered through celite and the filtrate was concentrated. The product was purified by chromatography, thus received 8,32 g (48%) of 3-ethoxy-5-hydroxymethylbenzene in the form of a colorless oil.

234.2. Analogously to example 1.1 from 3-ethoxy-5-hydroxymethylbenzene, obtained as described in example 234.1 by reaction with 4-amylphenol)acetic acid, MS:355 ([M+H]+).

234.3. Methanesulfonanilide was slowly added at 0oTo a solution of ethyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-5-hydroxymethylene)acetic acid (200 mg, 0,564 mmole), obtained as described in example 234.2, and N-ethyldiethanolamine (88 mg, 0.68 mmole) in THF (3 ml). The mixture was stirred at 0oC for 1.5 h and at room temperature for 1.5 hours the Mixture was poured into ice water/1 M Hcl and was extracted with AcOEt. The organic phase is washed with water, dried and filtered, the filtrate was concentrated. When this was received 232 mg of ethyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-5-methanesulfonylaminoethyl)acetic acid in the form of a yellow oil, which was used in subsequent reactions without further purification.

234.4. N-Ethyldiethanolamine (132 mg, of 1.02 mmole) and pyrrolidine (145 mg, 2,04 mmole) was added to a solution of ethyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-5-methanesulfonylaminoethyl)acetic acid (221 mg, 0,511 mmole), obtained as described in example 234.3, in THF (2 ml) and the mixture was stirred at room temperature for 1 h the Reaction mixture was concentrated, the residue was purified by chromatography (SiO2CH2Cl2/MeOH 99:1). When this was received 153 mg (73%) this is the first color, MS:408 ([M+H]+).

234.5. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-5-pyrrolidin-1-ylmethylene)acetic acid obtained as described in example 234.4, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(3-ethoxy-5-pyrrolidin-1-ylmethylene)acetic acid (1:1).

Example 235.

235.1. Analogously to example 234.4 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-5-methanesulfonylaminoethyl)acetic acid obtained as described in example 234.3, by reaction with cyclobutylamine and N-ethyldiethanolamine in THF was obtained ethyl ester of (RS)-(4-cyanovinylene)-(3-cyclobutylmethyl-5-ethoxyphenyl)acetic acid, MS:408 ([M+H]+).

235.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-cyclobutylmethyl-5-ethoxyphenyl)acetic acid obtained as described in example 235.1, received the ethyl ester of (RS)-(4-carbamimidoyl)-(3-cyclobutylmethyl-5-ethoxyphenyl)acetic acid.

Example 236.

236.1. Analogously to example 234.4 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-5-methanesulfonylaminoethyl)acetic acid obtained as described in example 234.3, by reaction with morpholine the Nile)acetic acid, MS:424 ([M+H]+).

236.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-5-morpholine-4-ylmethylene)acetic acid obtained as described in example 236.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(3-ethoxy-5-morpholine-4-ylmethylene)acetic acid, MS:441 ([M+H]+).

Example 237.

237.1. Analogously to example 234.4 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-5-methanesulfonylaminoethyl)acetic acid obtained as described in example 234.3, by reaction with Isopropylamine and N-ethyldiethanolamine in THF was obtained ethyl ester of (RS)-(4-cyanovinylene)-[3-ethoxy-5-(isopropylaminomethyl)phenyl]acetic acid, MS:396 ([M+H]+).

237.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-[3-ethoxy-5-(isopropylaminomethyl)phenyl] acetic acid obtained as described in example 237.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(isopropylaminomethyl)phenyl] acetic acid (1:1), MS:413 ([M+H]+).

Example 238.

238.1. Analogously to example 234.4 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-5-methanesulfonylaminoethyl)acetic acid obtained is p (RS)-(4-cyanovinylene)-[3-ethoxy-5-(pyridine-2-illuminometer)phenyl]acetic acid, MS:431 ([M+H]+).

238.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-[3-ethoxy-5-(pyridine-2-illuminometer)phenyl] acetic acid obtained as described in example 238.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(pyridine-2-illuminometer)phenyl] acetic acid (1:1).

Example 239.

239.1. Analogously to example 234.4 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-5-methanesulfonylaminoethyl)acetic acid obtained as described in example 234.3, by reaction with imidazole and N-ethyldiethanolamine in THF was obtained ethyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-5-imidazol-1-ylmethylene)acetic acid, MS:405 ([M+H]+).

239.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-5-imidazol-1-ylmethylene)acetic acid obtained as described in example 239.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(3-ethoxy-5-imidazol-1-ylmethylene)acetic acid (1: 1), MS:422 ([M+H]+).

Example 240.

240.1. Analogously to example 234.4 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-5-methanesulfonylaminoethyl)acetic acid obtained as described in the example is openline)-(3-ethoxy-5-{[(2-methoxyethyl)methylamino]were)acetic acid, MS:426 ([M+H]+).

240.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-5-{ [(2-methoxyethyl)methylamino]methyl}phenyl)acetic acid obtained as described in example 240.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(3-ethoxy-5-{[(2-methoxyethyl)methylamino]methyl}phenyl)acetic acid (1:1), MS:443 ([M+H]+).

Example 241.

241.1. Analogously to example 234.4 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-5-methanesulfonylaminoethyl)acetic acid obtained as described in example 234.3, by reaction with diethylamine and N-ethyldiethanolamine in THF was obtained ethyl ester of (RS)-(4-cyanovinylene)-(3-diethylaminomethyl-5-ethoxyphenyl)acetic acid, MS:410 ([M+H]+).

241.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-diethylaminomethyl-5-ethoxyphenyl)acetic acid obtained as described in example 241.1, got acetate (hydrochloride) ethyl ester of (RS)-(4-carbamimidoyl)-(3-diethylaminomethyl-5-ethoxyphenyl)acetic acid (1:1), MS:428 ([M+H]+).

Example 242.

242.1. Analogously to example 234.4 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-5-methanesulfonylaminoethyl)acetic the GF got the ethyl ester of (RS)-(4-cyanovinylene)-[3-ethoxy-5-(4-methylpiperazin-1-ylmethyl)phenyl] acetic acid, MS:437 ([M+H]+).

242.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-[3-ethoxy-5-(4-methylpiperazin-1-ylmethyl)phenyl] acetic acid obtained as described in example 242.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(4-methylpiperazin-1-ylmethyl)phenyl]acetic acid (1:1), MS:455 ([M+H]+).

Example 243.

243.1. Analogously to example 234.4 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-5-methanesulfonylaminoethyl)acetic acid obtained as described in example 234.3, by reaction with cyclopentylamine and N-ethyldiethanolamine in THF was obtained ethyl ester of (RS)-(4-cyanovinylene)-(3-cyclopentylmethyl-5-ethoxyphenyl]acetic acid, MS:422 ([M+H]+).

243.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-cyclopentylmethyl-5-ethoxyphenyl)acetic acid obtained as described in example 243.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(3-cyclopentylmethyl-5-ethoxyphenyl)acetic acid (1:1), MS:439 ([M+H]+).

Example 244.

244.1. Analogously to example 75.4 of the ethyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-5-hydroxymethylene)acetic acid ester of (RS)-(4-cyanovinylene)-(3-ethoxy-5-formylphenyl)acetic acid, MS:352 ([M]+).

244.2. A solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in acetonitrile (1.5 ml) very slowly (over 2 h) was added dropwise to a solution of ethyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-5-formylphenyl)acetic acid (460 mg, 1,305 mmole), obtained as described in example 244.1, and 1,2-phenylenediamine in acetonitrile (2 ml). The reaction mixture was stirred at room temperature for 4 h and Then was added a mixture of water/saturated solution PA2CO3(1: 1) and was extracted with CH2CL2. The organic phase is washed with N2Oh, dried, filtered and concentrated. The residue was purified by chromatography (SiO2, hexane/AcOEt 3: 2). When this was received 173 mg (30%) of ethyl ester of (RS)-[3-(1H-benzimidazole-2-yl)-5-ethoxyphenyl] -(4-cyanoaniline)acetic acid as colorless solid, MS:441 ([M+H]+).

244.3. Analogously to example 6.2 of the ethyl ester of (RS)-[3-(1H-benzoimidazol-2-yl)-5-ethoxyphenyl]-(4-cyanoaniline)acetic acid obtained as described in example 244.2, got hydrochloride ethyl ester of (RS)-[3-(1H-benzoimidazol-2-yl)-5-ethoxyphenyl] -(4-carbamimidoyl)acetic acid (1:1), MS:458 ([M+H]+).

Example 245.

245.1. To a suspension of ethyl e the least 244.1, in EtOH (1 ml) at -10oWith the first, was added 2 M NH3in EtOH (2.9 ml of 5.75 mmole) and then 8.8 M glyoxal in N2On (0,32 ml, and 2.79 mmole). The mixture was stirred at room temperature for 1 h Then was added an additional amount of 2 M NH3in EtOH (2.9 ml of 5.75 mmole) and 8.8 M glyoxal in N2On (0,32 ml, and 2.79 mmole), the mixture was stirred at room temperature for 2 h, was added water and was extracted with AcOEt. The organic phase was dried, filtered and concentrated. The residue was purified by chromatography (SiO2, hexane/AcOEt 1:1). When this was received 179 mg (40%) of ethyl ester of (RS)-(4-cyanovinylene)-[3-ethoxy-5-(1H-imidazol-2-yl)phenyl]acetic acid as a colourless solid, MS:391 ([M+H]+).

245.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-[3-ethoxy-5-(1H-imidazol-2-yl)phenyl]acetic acid obtained as described in example 245.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(1H-imidazol-2-yl)phenyl]acetic acid (1: 1), MS:408 ([M+H]+).

Example 246.

246.1. Analogously to example 198.2 from 5-ethoxybenzo-1,3-dicarbollide by reaction with bromide methyltriphenylphosphonium received 3 ethoxy-5-vinylbenzene.

246.2. Similar is the Rila and benzylideneamino in EtOH was obtained ethyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-5-vinylphenol)acetic acid, MS:350 ([M]+).

246.3. To a solution of ethyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-5-vinylphenol)acetic acid (300 mg, 0,856 mmole), obtained as described in example 246.2, and di-tert-BUTYLCARBAMATE (280 mg, of 1.28 mmole) in acetonitrile (6 ml) at 0oWith added 4-dimethylaminopyridine (11 mg, of 0.085 mmole) and then slowly added nitroethane (66 mg, 0,856 mmole). The mixture was stirred at room temperature for 22 h and Then was added an additional amount of di-tert-BUTYLCARBAMATE (224 mg, of 1.03 mmole) and nitroethane (33 mg, 0.43 mmole) and the mixture was stirred at room temperature overnight. Then add an additional amount of 4-dimethylaminopyridine (11 mg, of 0.085 mmole) and the mixture was stirred at room temperature for 6 hours the Reaction mixture was concentrated, the residue was purified by chromatography (SiO2, hexane/AcOEt 2:1=>AcOEt). When this was received 200 mg (46%) of a mixture of ethyl ester of (RS)- and (SR)-[tert-butoxycarbonyl-(4-cyanophenyl)amino]-[3-ethoxy-5-[(RS)-3-methyl-4,5-dihydroisoxazole-5-yl] phenyl]acetic acid in the form of a yellowish foam, MS:508 ([M+H]+).

246.4. Analogously to example 6.2, the mixture of ethyl esters of (RS)- and (SR)-[tert-butoxycarbonyl-(4-cyanophenyl)amino] -[3-ethoxy-5-[(RS)-3-methyl-4,5-dihydroisoxazole-5-and(RS)- and (SR)-(4-carbamimidoyl)-[3-ethoxy-5-[(RS)-3-methyl-4,5-dihydroisoxazole-5-yl]phenyl]acetic acid (1:1), MS:425 ([M+H]+).

Example 247.

247.1. A solution of ethyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-5-vinylphenol)acetic acid (300 mg, 0,856 mmole), obtained as described in example 236.2 in acetonitrile (2 ml) slowly dropwise at -30oC was added to solution of nitroterephthalate (112 mg, 0,942 mmole) in acetonitrile (3 ml). The mixture was stirred atoC for 2 h and at room temperature for 1.5 hours the Reaction mixture was concentrated, the residue was purified by chromatography (SiO2CH2Cl2=>CH2Cl2/MeOH 4:1). When this was received 135 mg (38%) of ethyl ester of (RS)-(4-cyanovinylene)-[3-ethoxy-5-(3-hydroxy-2-methyl-3H-imidazol-4-yl)phenyl] acetic acid in the form of a yellowish foam, MS: 421 ([M+H]+).

247.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-[3-ethoxy-5-(3-hydroxy-2-methyl-3H-imidazol-4-yl)phenyl] acetic acid obtained as described in example 247.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(3-hydroxy-2-methyl-3H-imidazol-4-yl)phenyl]acetic acid (1:1), MS:438 ([M+H]+).

Example 248.

248.1. 20% solution of TiCl3in N2Oh was added dropwise at 0oTo a solution of ethyl evolucionado, as described in example 247.1, in methanol (4,2 ml). The mixture was stirred at room temperature for 3 h, and then poured into a solution Panso3/ice water and was extracted with CH2Cl2. The organic phase was dried, filtered and concentrated. The residue was purified by chromatography (SiO2CH2Cl2= >CH2Cl2/MeOH 95:5). It was obtained 50 mg (75%) of the ethyl ester of (RS)-(4-cyanovinylene)-[3-ethoxy-5-(2-methyl-3H-imidazol-4-yl)phenyl] acetic acid in the form of a solid yellowish, MS:405 ([M+H]+).

248.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-[3-ethoxy-5-(2-methyl-3H-imidazol-4-yl)phenyl] acetic acid obtained as described in example 248.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(2-methyl-3H-imidazol-4-yl)phenyl] acetic acid (1:1), MS:422 ([M+H]+).

Example 249.

249. A. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3-methoxy-5-were)acetic acid (1: 1) obtained as described in example 190.3, was obtained (RS)-(4-carbamimidoyl)-(3-methoxy-5-were)acetic acid, MS:314 ([M+H]+).

249. B. Analogously to example 70 from hydrochlori is, as described in example 181.3, was obtained (RS)-(4-carbamimidoyl)-(3-isopropoxy-5-were)acetic acid, MS:342 ([M+H]+).

249. C. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3-carbamoylmethyl-5-were)acetic acid (1: 1) obtained as described in example 192.2, was obtained (RS)-(4-carbamimidoyl)-(3-carbamoylmethyl-5-were)acetic acid, MS:357 ([M+H]+).

249. Similarly, example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3-ethoxy-5-were)acetic acid (1: 1) obtained as described in example 193.2, was obtained (RS)-(4-carbamimidoyl)-(3-ethoxy-5-were)acetic acid, MS:326 ([M-H]-).

249. D. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-[3-methyl-5-(2-pyrrolidin-1 ylethoxy)phenyl] acetic acid (1:1) obtained as described in example 194.2, was obtained (RS)-(4-carbamimidoyl)-[3-methyl-5-(2-pyrrolidin-1 ylethoxy)phenyl] acetic acid; MS:397 ([M+H]+).

249. that is, Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3-cyclopentyloxy-5-were)acetic acid (1: 1) obtained as ops:368 ([M+H]+).

249. W. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-[3-methyl-5-(1-methylpiperidin-4-yloxy)phenyl] acetic acid (1: 1) obtained as described in example 196.2, was obtained (RS)-(4-carbamimidoyl)-[3-methyl-5-(1-methylpiperidin-4-yloxy)phenyl]acetic acid; MS:397 ([M+H]+).

249. C. Analogously to example 75 from a mixture of hydrochloride ethyl ester of (RS)- and (SR)-(4-carbamimidoyl)-[3-[(1RS,2RS)-2-hydroxycyclopent] -5-were] acetic acid (1: 1) obtained as described in example 197.2, received a mixture of (RS)- and (SR)-(4-carbamimidoyl)-[3-[(1RS, 2RS)-2-hydroxycyclopent] -5-were]acetic acid, MS:382 ([M-H]-).

249. I. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3-methoxy-5-vinylphenol)acetic acid (1: 1) obtained as described in example 198.4, was obtained (RS)-(4-carbamimidoyl)-(3-methoxy-5-vinylphenol)acetic acid, MS:326 ([M+H]+).

249. K. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3-ethyl-5-methoxyphenyl)acetic acid (1: 1) obtained as described in example 199.2, was obtained (RS)-(4-carbamimidoyl)-(3-ethyl-5-methox the Fira (RS)-(4-carbamimidoyl)-(3-ethyl-5-isobutoxide)acetic acid (1:1), obtained as described in example 200.3, was obtained (RS)-(4-carbamimidoyl)-(3-ethyl-5-isobutoxide)acetic acid, MS:370 ([M+H]+).

249. m Analogously to example 70 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-[3-ethyl-5-(1-methylpiperidin-4-yloxy)phenyl]acetic acid (1:1) obtained as described in example 201.2, was obtained (RS)-(4-carbamimidoyl)-[3-ethyl-5-(1-methylpiperidin-4-yloxy)phenyl]acetic acid, MS:409 ([M+H]+).

249. N. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-[3-ethyl-5-(2-pyrrolidin-1 ylethoxy)phenyl] acetic acid (1:1) obtained as described in example 202.2, was obtained (RS)-(4-carbamimidoyl)-[3-ethyl-5-(2-pyrrolidin-1 ylethoxy)phenyl] acetic acid, MS:411 ([M+H]+).

249. acting Analogously to example 70 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-[3-ethyl-5-(tetrahydropyran-4-yloxy)phenyl] acetic acid (1:1) obtained as described in example 203.2, was obtained (RS)-(4-carbamimidoyl)-[3-ethyl-5-(tetrahydropyran-4-yloxy)phenyl] acetic acid, MS:398 ([M+H]+).

249. p. Analogously to example 75 from a mixture of hydrochloride ethyl ester of (RS)- and (SR)-(4-carbamimidoyl)-who made (4 carbamimidoyl)-[3-ethyl-5-(tetrahydrofuran-2-ylethoxy)phenyl]acetic acid, MS:398 ([M+H]+).

249.R. Analogously to example 70 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3-cyclopentyloxy-5-ethylphenyl)acetic acid (1: 1) obtained as described in example 205.2, was obtained (RS)-(4-carbamimidoyl)-(3-cyclopentyloxy-5-ethylphenyl)acetic acid, MS: 382 ([M+H]+).

249. C. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-[3-ethyl-5-(4-hydroxycyclohexyl)phenyl]acetic acid (1:1) obtained as described in example 206.2 received (4 carbamimidoyl)-[3-ethyl-5-(4-hydroxycyclohexyl)phenyl]acetic acid, MS:412 ([M+H]+).

249. so Analogously to example 70 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-[3-ethyl-5-(piperidine-4-yloxy)phenyl] acetic acid (1:1) obtained as described in example 207.2, was obtained (RS)-(4-carbamimidoyl)-[3-ethyl-5-(piperidine-4-yloxy)phenyl] acetic acid; MS:397 ([M+H]+).

249. . Analogously to example 75 of the ethyl ester of (RS)-(4-carbamimidoyl)-[3-(3-dimethylamino-2,2-DIMETHYLPROPANE)-5-ethylphenyl] acetic acid obtained as described in example 208.2, was obtained (RS)-(4-carbamimidoyl)-[3-(3-dimethylamino-2,2-timetype ethyl ester of (RS)-(4-carbamimidoyl)-[3-ethyl-5-(1-methanesulfonamido-4-yloxy)phenyl] acetic acid (1:1), obtained as described in example 209.3, was obtained (RS)-(4-carbamimidoyl)-[3-ethyl-5-(1-methanesulfonamido-4-yloxy)phenyl]acetic acid, MS:475 ([M+H]+).

249. X. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-[3-(1-ethoxycarbonylmethylene-4-yloxy)-5-ethylphenyl] acetic acid (1:1) obtained as described in example 210.2, was obtained (RS)-(4-carbamimidoyl)-[3-(1-carboxyethylidene-4-yloxy)-5-ethylphenyl]acetic acid, MS:455 ([M+H]+).

249. C. Analogously to example 75 from a mixture of hydrochloride ethyl ester of (RS)- and (SR)-(4-carbamimidoyl)-[3-ethyl-5-[(1RS, 2RS)-2-hydroxycyclopent] phenyl] acetic acid (1:1) obtained as described in example 211.2, received a mixture of (RS)- and (SR)-(4-carbamimidoyl)-[3-ethyl-5-[(1RS, 2RS)-2-hydroxycyclopent] phenyl] acetic acid, MS:398 ([M+H]+).

249. H. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3-ethyl-5-phenoxyphenyl)acetic acid (1: 1) obtained as described in example 212.2, was obtained (RS)-(4-carbamimidoyl)-(3-ethyl-5-phenoxyphenyl)acetic acid, MS:390 ([M+H]+).

249. W. Analogously to example 75 of the hydrochloride Adilov is described in example 213.2, was obtained (RS)-(4-carbamimidoyl)-[3-ethyl-5-(pyridine-3-yloxy)phenyl]acetic acid, MS:391 ([M+H]+).

249. Sch. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3-ethoxy-5-propylphenyl)acetic acid (1: 1) obtained as described in example 214.4, was obtained (RS)-(4-carbamimidoyl)-(3-methoxy-5-propylphenyl)acetic acid, MS:342 ([M+H]+).

249. AA. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3-ethoxy-5-propylphenyl)acetic acid (1: 1) obtained as described in example 215.3, was obtained (RS)-(4-carbamimidoyl)-(3-ethoxy-5-propylphenyl)acetic acid, MS:356 ([M+H]+).

249. AB. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3-ethylamino-5-were)acetic acid (1:1) obtained as described in example 216.5, was obtained (RS)-(4-carbamimidoyl)-(3-ethylamino-5-were)acetic acid, MS:327 ([M+H]+).

249. AV. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3-diethylamino-5-were)acetic acid (1:1) obtained as described in example 217.2, was obtained (RS)-(4-carbamimidoyl)-(3-diethyl-ethyl ester of (RS)-(4-carbamimidoyl)-(3-cyclopentylamine-5-were)acetic acid (1: 1), obtained as described in example 218.2, was obtained (RS)-(4-carbamimidoyl)-(3-cyclopentylamine-5-were)acetic acid, MS:367 ([M+H]+).

249. hell. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3-methyl-5-pyrrolidin-1-ylphenyl)acetic acid (1: 1) obtained as described in example 219.2, was obtained (RS)-(4-carbamimidoyl)-(3-methyl-5-pyrrolidin-1-ylphenyl)acetic acid, MS:353 ([M+H]+).

249. AE Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-[3-(3-butylurea)-5-were] -(4-carbamimidoyl)acetic acid (1: 1) obtained as described in example 220.2, was obtained (RS)-[3-(3-butylurea)-5-were] -(4-carbamimidoyl)acetic acid, MS:398 ([M+H]+).

249. all the way. Analogously to example 75 from a mixture of hydrochloride ethyl ester of (RS)- and (RS)-(4-cyanovinylene)-[3-[(1RS,2RS)-2-hydroxycyclophosphamide] -5-were] acetic acid (1: 1) obtained as described in example 221.2 received (4 carbamimidoyl)-[3-(2-hydroxycyclophosphamide)-5-were]acetic acid, MS:383 ([M+H]+).

249. AZ. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3-methyl-5-{ 1-[3-(pyrimidine-2-what if (RS)-(4-carbamimidoyl)-(3-methyl-5-{1-[3-(pyrimidine-2-ylamino)propyl] azepin-2-ylideneamino} Fe-nil)acetic acid, MS:529 ([M+H]+).

249. the AI. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3-ethyl-5-pyrrolidin-1-ylphenyl)acetic acid (1: 1) obtained as described in example 223.6 was obtained (RS)-(4-carbamimidoyl)-(3-ethyl-5-pyrrolidin-1-ylphenyl)acetic acid, MS: 367 ([M+H]+).

249. AK. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3-ethyl-5-piperazine-1-ylphenyl)acetic acid (1: 1) obtained as described in example 224.2, was obtained (RS)-(RS)-(4-carbamimidoyl) - (3-ethyl-5-piperazine-1-ylphenyl)acetic acid, MS:382 ([M+H]+).

249. al. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-[3-(cyclopentanecarbonyl)-5-ethylphenyl] acetic acid obtained as described in example 225.2, was obtained (RS)-(4-carbamimidoyl)-[3- (cyclopentanecarbonyl)-5-ethylphenyl] acetic acid, MS:409 ([M+H]+).

249. am. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3-benzosulfimide-5-ethylphenyl)acetic acid (1:1) obtained as described in example 226.2, was obtained (RS)-(3-benzosulfimide-5-ethylphenyl)-(4-carbamimidoyl the RA (RS)-(4-carbamimidoyl)-(3-butylsulfonyl-5-ethylphenyl)acetic acid (1:1), obtained as described in example 227.2 was obtained (RS)-(4-carbamimidoyl)-(3-butylsulfonyl-5-ethylphenyl)acetic acid, MS:448 ([M+H]+).

249. the AO. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-[3-ethyl-5-(1-methylpiperidin-4-ylamino)phenyl] acetic acid (1: 1) obtained as described in example 228.2, was obtained (RS)-(4-carbamimidoyl)-[3-ethyl-5-(1-methylpiperidin-4-ylamino)phenyl]acetic acid, MS:410,6 ([M+H]+).

249. AP. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-{ 3-ethyl-5-[(pyridine-3-ylmethyl)amino]phenyl}acetic acid (1:1) obtained as described in example 229.2, was obtained (RS)-(4-carbamimidoyl)-[3-ethyl-5-[(pyridine-3-ylmethyl)amino] phenyl]acetic acid, MS:404 ([M+H]+).

249. ar. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-[3-(bis-pyridin-3-ylmethylamino)-5-ethylphenyl] -(4-carbamimidoyl)acetic acid (1:1) obtained as described in example 230.2, was obtained (RS)-[3-(bis-pyridin-3-ylmethylamino)-5-ethylphenyl] -(4-carbamimidoyl)acetic acid, MS:495 ([M+H]+).

249. the AU. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl 231.2, was obtained (RS)-(4-carbamimidoyl)-[3-ethyl-5-(tetrahydropyran-4-ylamino)phenyl]acetic acid; MS:397 ([M+H]+).

249. the ATA. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-[3-ethyl-5-(tetrahydrothiopyran-4-ylamino)phenyl] acetic acid (1: 1) obtained as described in example 232.2, was obtained (RS)-(4-carbamimidoyl)-[3-ethyl-5-(tetrahydrothiopyran-4-ylamino)phenyl]acetic acid, MS:413 ([M+H]+).

249. AU. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-[3-(1,1-dioxotetrahydrofuran-4-ylamino)-5-ethylphenyl] acetic acid (1:1) obtained as described in example 233.2, was obtained (RS)-(4-carbamimidoyl)-[3-(1,1-dioxotetrahydrofuran-4-ylamino)-5-ethylphenyl]acetic acid, MS:445 ([M+H]+).

249. AF. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3-ethoxy-5-pyrrolidin-1-ylmethylene)acetic acid (1:1) obtained as described in example 234.5, was obtained (RS)-(4-carbamimidoyl)-(3-ethoxy-5-pyrrolidin-1-ylmethylene)acetic acid; MS:397 ([M+H]+).

249. Ah. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-karbamidoformaldegidnye)-(3-cyclobutylmethyl-5-ethoxyphenyl)acetic acid, MS:397 ([M+H]+).

249. AC. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3-ethoxy-5-morpholine-4-ylmethylene)acetic acid obtained as described in example 236.2, was obtained (RS)-(4-carbamimidoyl)-(3-ethoxy-5-morpholine-4-ylmethylene)acetic acid, MS: 413 ([M+H]+).

249. Ah. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(isopropylaminomethyl)phenyl] acetic acid (1:1) obtained as described in example 237.2, was obtained (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(isopropylaminomethyl)phenyl] acetic acid, MS:385 ([M+H]+).

249. al. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(pyridine-2-illuminometer)phenyl] acetic acid (1:1) obtained as described in example 238.2, was obtained (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(pyridine-2-illuminometer)phenyl] acetic acid, MS:420 ([M+H]+).

249. as. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3-ethoxy-5-imidazol-1-ylmethylene)acetic acid (1:1) obtained as described in example 239.2, was obtained (RS)-(4-carbamimidoyl)-(3-etox is ochloride ethyl ester of (RS)-(4-carbamimidoyl)-(3-ethoxy-5-{ [(2-methoxyethyl)methylamino] methyl}phenyl)acetic acid (1: 1), obtained as described in example 240.2, was obtained (RS)-(4-carbamimidoyl)-(3-ethoxy-5-{[(2-methoxyethyl)methylamino]methyl]phenyl)acetic acid, MS:415 ([M+H]+).

249. BB's. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3-diethylaminomethyl-5-ethoxyphenyl)acetic acid (1: 1) obtained as described in example 241.2, was obtained (RS)-(4-carbamimidoyl)-(3-diethylaminomethyl-5-ethoxyphenyl)acetic acid, MS:399 ([M+H]+).

249. BV. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(4-methylpiperazin-1-ylmethyl)phenyl] acetic acid (1: 1) obtained as described in example 242.2, was obtained (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(4-methylpiperazin-1-ylmethyl)phenyl]acetic acid, MS:426 ([M+H]+).

249. the BG. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3-cyclopentylmethyl-5-ethoxyphenyl)acetic acid (1:1) obtained as described in example 243.2, was obtained (RS)-(4-carbamimidoyl)-(3-cyclopentylmethyl-5-ethoxyphenyl)acetic acid, MS:411 ([M+H]+).

249. dB. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-[3-(1H-benzamid.3, was obtained (RS)-[3-(1H-benzoimidazol-2-yl)-5-ethoxyphenyl] -(4-carbamimidoyl)acetic acid, MS:430 ([M+H]+).

249. company code. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(1H-imidazol-2-yl)phenyl] acetic acid (1:1) obtained as described in example 245.2, was obtained (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(1H-imidazol-2-yl)phenyl] acetic acid, MS:380 ([M+H]+).

249. BJ. Analogously to example 75 from a mixture of hydrochloride ethyl ester of (RS)- and (SR)-(4-carbamimidoyl)-[3-ethoxy-5-[(RS)-3-methyl-4,5-dihydroisoxazole-5-yl] phenyl] acetic acid (1:1) obtained as described in example 246.4 received a mixture of (RS)- and (SR)-(4-carbamimidoyl)-[3-ethoxy-5-[(RS)-3-methyl-4,5-dihydroisoxazole-5-yl] phenyl]acetic acid; MS: 397 ([M+H]+).

249. br. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(3-hydroxy-2-methyl-3H-imidazol-4-yl)phenyl] acetic acid (1:1) obtained as described in example 247.2, was obtained (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(3-hydroxy-2-methyl-3H-imidazol-4-yl)phenyl]acetic acid, MS:410 ([M+H]+).

249. bi. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbs the least 248.2, was obtained (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(2-methyl-3H-imidazol-4-yl)phenyl]acetic acid, MS:394 ([M+H]+).

Example 250.

250.1. Analogously to example 18.1 of the methyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-5-hydroxyphenyl)acetic acid obtained as described in example 124.1, by reaction with 4-hydroxy-N-methylpiperidine, diethylazodicarboxylate and triphenylphosphine in THF was obtained methyl ester of (RS)-(4-cyanovinylene)-[3-ethoxy-5-(1-methylpiperidin-4-yloxy)phenyl] acetic acid, MS:424 ([M+H]+).

250.2. Analogously to example 6.2, of the methyl ester of (RS)-(4-cyanovinylene)-[3-ethoxy-5-(1-methylpiperidin-4-yloxy)phenyl] acetic acid obtained as described in example 250.1, got hydrochloride methyl ester (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(1-methylpiperidin-4-yloxy)phenyl]acetic acid (1:1), MS:441 ([M+H]+).

Example 251.

251.1. 3,5-Bis-(tert-butyldimethylsilyloxy)-2-forbindelse was obtained from 4-terfenol according to the method described in Chem. Pharm. Bull., 38, 2939-2946 (1990).

251.2. A mixture of 3,5-bis-(tert-butyldimethylsilyloxy)-2-forventelige (3.0 g, 7,8 mmole), obtained as described in example 251.1, potassium fluoride (1,81 g, and 31.2 mmole), under the conditions (1,17 ml, 18,7 mm which was garofali diethyl ether. The organic phase is washed with water, dried, filtered and concentrated. The residue was purified by chromatography (SiO2, cyclohexane/AcOEt 18: 1= >1: 1). It was obtained 0.87 g (60%) of 2-fluoro-3,5-dimethoxybenzaldehyde in the form of a colorless solid.

251.3. Analogously to example 1.1 from 2-fluoro-3,5-dimethoxybenzaldehyde, obtained as described in example 251.2 by reaction with 4-aminobenzonitrile and benzylideneamino in EtOH was obtained ethyl ester of (RS)-(4-cyanovinylene)-(2-fluoro-3,5-acid)acetic acid, MS:358 ([M]+).

251.4. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(2-fluoro-3,5-acid)acetic acid obtained as described in example 251.3, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(2-fluoro-3,5-acid)acetic acid (1: 1), MS: 376 ([M+H]+).

Example 252.

252.1. Analogously to example 251.2 from 3,5-bis-(tert-butyldimethylsilyloxy)-2-forventelige, obtained as described in example 251.1, by reaction with potassium fluoride and ethyliodide in DMF) was obtained 3,5-diethoxy-2-forbindelse.

252.2. Analogously to example 1.1 from 3,5-diethoxy-2-forventelige, obtained as described in example 252.1 by reaction with 4-aminobenzonitrile, MS:386 ([M]+).

252.3. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3,5-diethoxy-2-forfinal)acetic acid obtained as described in example 252.2, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(3,5-diethoxy-2-forfinal)acetic acid (1:1), MS:404 ([M+H]+).

Example 253.

253. A. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(1-methylpiperidin-4-yloxy)phenyl] acetic acid (1: 1) obtained as described in example 252.3, was obtained (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(1-methylpiperidin-4-yloxy)phenyl]acetic acid, MS:427 ([M+H]+).

253. B. Analogously to example 70 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(2-fluoro-3,5-acid)acetic acid (1:1) obtained as described in example 251.4, was obtained (RS)-(4-carbamimidoyl)-(2-fluoro-3,5-acid)acetic acid, MS:348 ([M+H]+).

253. C. Analogously to example 70 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3,5-diethoxy-2-forfinal)acetic acid (1:1) obtained as described in example 252.3, was obtained (RS)-(4-carbamimidoyl)-(3,5-diethoxy-2-forfinal)acetic sour is albenzaalbenza (obtained by formirovanie thymol iCl4/dichlorodimethyl ether, as described in Chem. Z., 114, 144 (1990), by reaction with isopropylidene and K2CO3in DMF) was obtained 4-isopropoxy-5-isopropyl-2-methylbenzaldehyde.

254.2. Analogously to example 1.1 from 4-isopropoxy-5-isopropyl-2-methylbenzaldehyde, obtained as described in example 253.1 by reaction with 4-aminobenzonitrile and benzylideneamino in EtOH was obtained ethyl ester of (RS)-(4-cyanovinylene)-(4-isopropoxy-5-isopropyl-2-were)acetic acid, MS: 394 ([M]+).

254.3. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(4-isopropoxy-5-isopropyl-2-were)acetic acid obtained as described in example 253.2, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(4-isopropoxy-5-isopropyl-2-were)acetic acid (1:1).

Example 255.

255.1. Ethyl ester of (RS)-(4-cyanovinylene)-(4-isopropoxy-5-isopropyl-2-were)acetic acid (921 mg, of 2.34 mmole), obtained as described in example 254.2, was dissolved with CH2Cl2and was cooled to -78oC. and Then slowly was added dropwise a 1 M solution VVG3in CH2Cl2(9.4 ml, 9.4 mmole). After 15 min the reaction mixture was heated to 0oC and was stirred at 0oWith for the ABC separated, the aqueous phase was extracted with CH2Cl2. The organic phase was dried, filtered and concentrated. The crude product was dissolved in acetone, was added Cs2CO3(918 mg, was 2.76 mmole) and iodoacetamide (447 mg, 2,41 mmole), the mixture was stirred at room temperature for 6 hours and Then added to a dilute aqueous solution of KHSO4and the mixture was extracted with CH2CL2. The organic phase was dried, filtered and concentrated, the residue was purified by chromatography (SiO2, hexane/AcOEt 1:1=>1:2). When this was received 704 mg (73%) of ethyl ester of (RS)-(4-cyanovinylene)-(4-carbamoylmethyl-5-isopropyl-2-were)acetic acid as colorless foam.

255.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(4-carbamoylmethyl-5-isopropyl-2-were)acetic acid obtained as described in example 255.1, got hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-(4-carbamoylmethyl-5-isopropyl-2-were)acetic acid (1:1), MS:427 ([M+H]+).

Example 256.

256. A. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(4-isopropoxy-5-isopropyl-2-were)acetic acid (1:1) obtained as described in example 254.3 +).

256. B. Analogously to example 75 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(4-carbamoylmethyl-5-isopropyl-2-were)acetic acid (1:1) obtained as described in example 255.2, was obtained (RS)-(4-carbamimidoyl)-(4-carbamoylmethyl-5-isopropyl-2-were)acetic acid, MS:399 ([M+H]+).

Example 257.

257.1. Analogously to example 1.1 piperonal was introduced in the reaction with 4-aminobenzonitrile and benzylideneamino, substituting methanol for ethanol. It was obtained ethyl ester of (RS)-benzo[1,3]dioxol-5-yl-(4-cyanoaniline)acetic acid, MC(ISP) m/z 325 (M+N)+, 347 (M+Na)+.

257.2. Analogously to example 1.2 ethyl ester of (RS)-benzo[1,3]dioxol-5-yl-(4-cyanoaniline)acetic acid hydrolyzed in the presence of lithium hydroxide to obtain (RS)-benzo[1,3]dioxol-5-yl-(4-cyanoaniline)acetic acid, MC(ISP) m/z 297 (M+N)+, 314 (M+NH4)+.

257.3. Analogously to example 1.3 from (RS)-benzo[1,3]dioxol-5-yl-(4-cyanoaniline)acetic acid by reaction with hydroxylamine hydrochloride and triethylamine were obtained (E)- and/or (Z)-(RS)-benzo[1,3]dioxol-5-yl-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid, MC(ISP) m/z 330 (M+N)+.

Example 258.

(see example 257.3) was first made over Raney Nickel to obtain (RS)-benzo[1,3]dioxol-5-yl-(4-carbamimidoyl)acetic acid, MC(ISP) m/z 314 (M+H)+.

Example 259.

259.1. Analogously to example 1.1, the 3-fluoro-para-anisic aldehyde was introduced in the reaction with 4-aminobenzonitrile and benzylideneamino, substituting methanol for ethanol. It was obtained ethyl ester of (RS)-(4-cyanovinylene)-(3-fluoro-4-methoxyphenyl)acetic acid, MS (EI) m/z 328 M+.

259.2. Analogously to example 1.2 ethyl ester of (RS)-(4-cyanovinylene)-(3-fluoro-4-methoxyphenyl)acetic acid hydrolyzed in the presence of lithium hydroxide to obtain (RS)-(4-cyanovinylene)-(3-fluoro-4-methoxyphenyl)acetic acid, MC(ISP) m/z 300 (M+N)+, 318 (M+NH4)+.

259.3. Analogously to example 1.3 from (RS)-(4-cyanovinylene)-(3-fluoro-4-methoxyphenyl)acetic acid by reaction with hydroxylamine hydrochloride and triethylamine were obtained (E)- and/or (Z)-(RS)-(3-fluoro-4-methoxyphenyl)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid, MC(ISP) m/z 334 (M+H)+.

Example 260.

Analogously to example 3 (E)- and/or (Z)-(RS)-(3-fluoro-4-methoxyphenyl)-[4-(N-hydroxycarbamoyl)phenylamino] acetic acid (see example 259.3) was first made over Raney Nickel to obtain (RS)-(4-ASS="ptx2">

261.1. Analogously to example 1.1 1,4-benzodioxan-6-carboxaldehyde was introduced in the reaction with 4-aminobenzonitrile and benzylideneamino, substituting methanol for ethanol. It was obtained ethyl ester of (RS)-(4-cyanovinylene)-(2,3-dihydrobenzo[1,4] dioxin-6-yl)acetic acid, MC(ISP) m/z 339 (M+H)+, 361 (M+Na)+.

261.2. Analogously to example 1.2 ethyl ester of (RS)-(4-cyanovinylene)-(2,3-dihydrobenzo[1,4] dioxin-6-yl)acetic acid hydrolyzed in the presence of lithium hydroxide to obtain (RS)-(4-cyanovinylene)-(2,3-dihydrobenzo[1,4]dioxin-6-yl)acetic acid, MC(ISN) m/z 3309 (M-N)-.

261.3. Analogously to example 1.3 from (RS)-(4-cyanovinylene)-(2,3-dihydrobenzo[1,4] dioxin-6-yl)acetic acid by reaction with hydroxylamine hydrochloride and triethylamine were obtained (RS)-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-[4-(N-hydroxycarbamoyl)phenylamino] acetic acid, MC(ISP) m/z 344 (M+N)+.

Example 262.

Analogously to example 3 (RS)-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-[4-(N-hydroxycarbamoyl)phenyl] acetic acid (see example 261.3) was first made over Raney Nickel to obtain (RS)-(4-carbamimidoyl)-(2,3-dihydrobenzo[1,4]dioxin-6-yl)acetic acid, MC(ISP) m/z 328 (M+H)+.

Example 263.

Similarly, primitivization, substituting methanol for ethanol. It was obtained ethyl ester of (RS)-[4-(N-hydroxycarbamoyl)phenylamino] -(3-hydroxymethyl-4-isopropoxyphenyl)acetic acid, MS (ISP) m/z 402 (M+N)+.

Example 264.

Analogously to example 3 ethyl ester of (RS)-[4-(N-hydroxycarbamoyl)phenylamino] -(3-hydroxymethyl-4-isopropoxyphenyl)acetic acid (see example 263) was first made over Raney Nickel with obtaining the ethyl ester of (RS)-(4-carbamimidoyl)-(3-hydroxymethyl-4-isopropoxyphenyl)acetic acid, MC(ISP) m/z 386 (M+N)+.

Example 265.

Analogously to example 75 ethyl ester of (RS)-(4-carbamimidoyl)-(3-hydroxymethyl-4-isopropoxyphenyl)acetic acid (see example 264) hydrolyzed in the presence of lithium hydroxide to obtain (RS)-(4-carbamimidoyl)-(3-hydroxymethyl-4-isopropoxyphenyl)acetic acid. The product was led out of the water, MC(ISP) m/z 358 (M+N)+, 375 (M+NH4)+.

Example 266.

266.1. Analogously to example 1.1 4 isopropoxy-3-methoxysalicylaldehyde was introduced in the reaction with 4-aminobenzonitrile and toluene-4-sulfonylmethane, substituting methanol for ethanol. It was obtained ethyl ester of (RS)-(4-cyanovinylene)-(4-isopropoxy-3-ethoxymethyleneamino)-(4-isopropoxy-3-ethoxymethylene)acetic acid by the reaction of Pinner received hydrochloride ethyl ester of (RS)-(4-carb-minigolfanlagen)-(4-isopropoxy-3-ethoxymethylene)acetic acid (1: 1), MC(ISP) m/z 400 (M+N)+.

Example 267.

Analogously to example 75, the ethyl ester hydrochloride (RS)-(4-carbamimidoyl)-(4-isopropoxy-3-ethoxymethylene)acetic acid (1:1) (see example 266.2) hydrolyzed in the presence of lithium hydroxide to obtain (RS)-(4-carbamimidoyl)-(4-isopropoxy-3-ethoxymethylene)acetic acid. The product was led out of the water, MC(ISP) m/z 372 (M+N)+.

Example 268.

268.1. Analogously to example 1.1 3,4-dichlorobenzaldehyde was introduced in the reaction with 4-aminobenzonitrile and benzylideneamino, substituting methanol for ethanol. It was obtained ethyl ester of (RS)-(4-cyanovinylene)-(3,4-dichlorophenyl)acetic acid, MC(ISP) m/z 349,3 (M+N)+, 366,1 (M+NH4)+.

268.2. Analogously to example 6.2 of the ethyl ester of (RS)-(4-cyanovinylene)-(3,4-dichlorophenyl)acetic acid by the reaction of Pinner received ethyl ester of (RS)-(4-carbamimidoyl)-(3,4-dichlorophenyl)acetic acid, MC(ISP) m/z 366,2 (M+N)+.

Example 269.

Analogously to example 75 ethyl ester of (RS)-(4-carbamimidoyl)-(3,4-dichlorophenyl)acetic acid (see example 268.2) hydrolyzed in the presence of lithium hydroxide to obtain (RS)-(4-carbamimidoyl)-(3,4-dichlorophenyl)at the th ether (2-formyl-4-triftormetilfosfinov)acetic acid by the reaction with 4-aminobenzonitrile and benzylideneamino, substituting methanol for ethanol, was obtained ethyl ester of (RS)-(4-cyanovinylene)-(2-ethoxycarbonylmethoxy-5-trifloromethyl)acetic acid, MC(ISP) m/z 467 (M+N)+, 489 (M+Na)+.

270.2. Analogously to example 1.2 ethyl ester of (RS)-(4-cyanovinylene)-(2-ethoxycarbonylmethoxy-5-trifloromethyl)acetic acid hydrolyzed in the presence of lithium hydroxide to obtain (RS)-(2-carboxymethoxy-5-trifloromethyl)-(4-cyanoaniline)acetic acid, MC(ISP) m/z 411 (M+N)+, 433 (M+Na)+.

270.3. Analogously to example 1.3 of the ethyl ester of (RS)-(2-carboxymethoxy-5-trifloromethyl)-(4-cyanoaniline)acetic acid by reaction with hydroxylamine hydrochloride and triethylamine were obtained (E)- and/or (Z)-(RS)-(2-carboxymethoxy-5-trifloromethyl)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid, MC(ISP) m/z 444 (M+N)+, 466 (M+Na)+.

Example 271.

Analogously to example 3 (E)- and/or (Z)-(RS)-(2-carboxymethoxy-5-trifloromethyl)-[4-(N-hydroxycarbamoyl)phenylamino] acetic acid (see example 270.3) was first made over Raney Nickel to obtain (RS)-(4-carbamimidoyl)-(2-carboxymethoxy-5-trifloromethyl)acetic acid, MC(ISP) m/z 428 (M+N)+.

Example 272.

+.

272.2. Analogously to example 1.1 from 5-chloro-2-(2-hydroxyethoxy)benzaldehyde by reaction with 4-aminobenzonitrile and toluene-4-sulfonylmethane, substituting methanol for ethanol, was obtained ethyl ester of (RS)-[5-chloro-2-(2-hydroxyethoxy)phenyl]-(4-cyanoaniline)acetic acid, MC(ISN) m/z 373 (M-N)-.

272.3. Analogously to example 6.2 of the ethyl ester of (RS)-[5-chloro-2-(2-hydroxyethoxy)phenyl]-(4-cyanoaniline)acetic acid by the reaction of Pinner received hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-[5-chloro-2-(2-hydroxyethoxy)phenyl] acetic acid (1: 1), MC(ISP) m/z 392 (M+N)+.

Example 273.

Analogously to example 75, the ethyl ester hydrochloride (RS)-(4-carbamimidoyl)-[5-chloro-2-(2-hydroxyethoxy)phenyl] acetic acid (1:1) (see example 272.3) hydrolyzed in the presence of lithium hydroxide to obtain (RS)-(4-carbamimidoyl)-[5-chloro-2-(2-hydroxyethoxy)phenyl] acetic acid, MS (ISP) m/z 364 (M+N)+.

Example 274.

274.1. Analogously to example 1.1 from 5-methoxypiperidine by the reaction with 4-aminobenzonitrile and benzylideneamino, substituting methanol for ethanol, was obtained ethyl ester of (RS)-(4-cyanovinylene)-(7 methoxybenzo[1,3] dioxol-5-yl)acetic KIS is Mino)-(7 methoxybenzo[1,3] dioxol-5-yl)acetic acid hydrolyzed in the presence of lithium hydroxide to obtain (RS)-(4-cyanovinylene)-(7 methoxybenzo[1,3]dioxol-5-yl)acetic acid, MC(ISN) m/z 325 (M-N)-.

274.3. Analogously to example 1.3 from (RS)-(4-cyanovinylene)-(7 methoxybenzo[1,3]dioxol-5-yl)acetic acid by reaction with hydroxylamine hydrochloride and triethylamine were obtained (E)- and/or (Z)-(RS)-[4-(N-hydroxycarbamoyl)phenylamino] -(7-methoxybenzo[1,3] dioxol-5-yl)acetic acid, MC(ISP) m/z 360 (M+N)+, 382 (M+Na)+.

Example 275.

Analogously to example 3 (E)- and/or (Z)-(RS)-[4-(N-hydroxycarbamoyl)phenylamino]-(7-methoxybenzo[1,3]dioxol-5-yl)acetic acid (see example 274.3) was first made over Raney Nickel to obtain (RS)-(4-carbamimidoyl)-(7 methoxybenzo[1,3]dioxol-5-yl)acetic acid, MC(ISP) m/z 344 (M+H)+.

Example 276.

276.1 Analogously to example 12.1 3.5-dichlorosalicylic aldehyde by reaction with tert-butylbromide in methyl ethyl ketone boiling under reflux for 4 h was obtained tert-butyl ester (2,4-dichloro-6-formylphenoxy)acetic acid, MS(EI) m/z 304 (M) 248/250 (M-tert-butyl).

276.2 Analogously to example 1.1 from tert-butyl ether (2,4-dichloro-6-formylphenoxy)acetic acid by the reaction with 4-amino-N-hydroxybenzamide and benzylideneamino received the methyl ester of (RS)-(2-tert-butoxycarbonylamino-3,5-dichlorophenyl)-[4-(N-g.

Analogously to example 75 methyl ester of (RS)-(2-tert-butoxycarbonylamino-3,5-dichlorophenyl)-[4-(N-hydroxycarbamoyl)phenylamino] acetic acid hydrolyzed in the presence of lithium hydroxide to obtain (RS)-(2-carboxymethoxy-3,5-dichlorophenyl)-[4-(N-hydroxycarbamoyl)phenylamino] acetic acid, the crude product was purified by treatment THF and acetone, MC(ISP) m/z 428,4 (M+N)+, 450,3 (M+Na)+.

Example 278.

3.7 g of fine powder of lithium carbonate was added to solution a 1.96 g of methyl ester of (RS)-(2-tert-butoxycarbonylamino-3,5-dichlorophenyl)-[4-(N-hydroxycarbamoyl)phenylamino] acetic acid (see example 276.2) in 200 ml THF and 100 ml of water and the suspension was stirred at 55-60oC for 8 h and Then the reaction mixture was concentrated and the resulting aqueous suspension was neutralized with 100 ml of 1 N. Hcl. The precipitate was filtered, washed with water and dried over night at 50oWith in high vacuum. When it got to 1.59 g of (RS)-(2-tert-butoxycarbonylamino-3,5-dichlorophenyl)-[4-(N-hydroxycarbamoyl)phenylamino] acetic acid, MC(ISP) m/z 484,3 (M+N)+, 506,2 (M+Na)+.

Example 279.

Analogously to example 3 (RS)-(2-tert-butoxycarbonylamino-3,5-dichlorophenyl)-[4-(N-hydroxy-butoxycarbonylamino-3,5-dichlorophenyl)-(4-carbamimidoyl)acetic acid, MC(ISP) m/z 468,2 (M+N)+, 490,2 (M+Na)+.

Example 280.

Analogously to example 75 (RS)-(2-tert-butoxycarbonylamino-3,5-dichlorophenyl)-(4-carbamimidoyl)acetic acid (see example 279) hydrolyzed in the presence of lithium hydroxide to obtain (RS)-(4-carbamimidoyl)-(2-carboxymethoxy-3,5-dichlorophenyl)acetic acid, MC(ISP) m/z 412,3 (M+N)+, 468,1 (M-H+Ni)+.

Example 281.

281.1. Analogously to example 12.1 of 5-bromo-2-hydroxy-3-methoxime-zaldehyde by the reaction with tert-butylbromide in methyl ethyl ketone boiling under reflux for 3 h was obtained ethyl ester (4-bromo-2-formyl-6-methoxyphenoxy)acetic acid, MS(EI) m/z 316/318 M+.

281.2. Analogously to example 1.1 from ethyl ether (4-bromo-2-formyl-6-methoxyphenoxy)acetic acid by the reaction with 4-aminobenzonitrile and toluene-4-sulfonylmethane, substituting methanol for ethanol, was obtained ethyl ester of (RS)-(5-bromo-2-ethoxycarbonylmethoxy-3-methoxyphenyl)-(4-cyanoaniline)acetic acid, MS (ISP) m/z 491/493 (M+N)+, 513/515 (M+Na)+.

281.3. Analogously to example 1.2 ethyl ester of (RS)-(5-bromo-2-ethoxycarbonylmethoxy-3-methoxyphenyl)-(4-cyanoaniline)acetic acid hydrolyzed in presilati, MC(ISN) m/z 433/435 (M-N)-.

281.4. Analogously to example 1.3 from (RS)-(5-bromo-2-carboxymethoxy-3-methoxyphenyl)-(4-cyanoaniline)acetic acid by reaction with hydroxylamine hydrochloride and triethylamine were obtained (E)- and/or (Z)-(RS)-(5-bromo-2-carboxymethoxy-3-methoxyphenyl)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid, MC(ISP) m/z 468/470 (M+N)+, 490/492 (M+Na)+.

Example 282.

Analogously to example 3 (E)- and/or (Z)-(RS)-(5-bromo-2-carboxymethoxy-3-methoxyphenyl)-[4-(N-hydroxycarbamoyl)phenylamino] acetic acid (see example 281.4) was first made over Raney Nickel to obtain (RS)-(5-bromo-2-carboxymethoxy-3-methoxyphenyl)-(4-carbamimidoyl)acetic acid, MS (ISP) m/z 452/454 (M+N)+.

Example 283.

283.1. Analogously to example 1.1 from ethyl ether (4-chloro-2-formyl-6-methoxyphenoxy)acetic acid by the reaction with 4-aminobenzonitrile and toluene-4-sulfonylmethane, substituting methanol for ethanol, was obtained ethyl ester of (RS)-(5-chloro-2-ethoxycarbonylmethoxy-3-methoxyphenyl)-(4-cyanoaniline)acetic acid, MS (ISN) m/z 445/447 (M-N)-.

283.2. Analogously to example 6.2 of the ethyl ester of (RS)-(5-chloro-2-ethoxycarbonylmethoxy-3-methoxyphenyl)-(4-cyanoaniline] acetic acid p is methoxy-3-methoxyphenyl)acetic acid (1:1), MS (ISP) m/z 464/466 (M+N)+.

Example 284.

Analogously to example 75, the ethyl ester hydrochloride (RS)-(4-carbamimidoyl)-(5-chloro-2-ethoxycarbonylmethoxy-3-methoxyphenyl)acetic acid (1:1) (see example 283.2) hydrolyzed in the presence of lithium hydroxide with polucheniem (RS)-(4-carbamimidoyl)-(2-carboxymethoxy-5-chloro-3-methoxyphenyl)acetic acid, MC(ISP) m/z 408/410 (M+N)+, 430/432 (M+Na)+.

Example 285.

285.1. Analogously to example 12.1 3.5-dichlorosalicylic aldehyde by reaction with iotechnology in ethylmethylketone boiling under reflux for 18 h was obtained 3,5-dichloro-2-(2-hydroxyethoxy)benzaldehyde; MS(E1) m/z 234/236 (M)+.

285.2. Analogously to example 1.1 from 3,5-dichloro-2-(2-hydroxyethoxy) benzaldehyde by reaction with 4-amino-N-hydroxybenzamide and benzylideneamino received ethyl ester of (RS)-[3,5-dichloro-2-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino] acetic acid, MC(ISP) m/z 442,3 (M+N)+, 464,1 (M+Na)+.

Example 286.

Analogously to example 75 ethyl ester of (RS)-[3,5-dichloro-2-(2-hydroxyethoxy)phenyl] -[4-(N-hydroxycarbamoyl)phenylamino] acetic acid (see example 285.2) hydrolyzed in the presence of hydroxide whether the s, the crude product was purified by chromatography, MC(ISP) m/z level of 414.2 (M+N)+, 436,3 (M+Na)+.

Example 287.

Analogously to example 3 (RS)-[3,5-dichloro-2-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino] acetic acid (see example 286) was first made over Raney Nickel to obtain (RS)-(4-carbamimidoyl)-[3,5-dichloro-2-(2-hydroxyethoxy)phenyl] acetic, acid, MC(ISP) m/z 398,2 (M+H)+, 420,2 (M+Na)+.

Example 288.

288.1. Analogously to example 12.1 3.5-dichlorosalicylic aldehyde by reaction with tert-butylbromide in ethylmethylketone boiling under reflux for 2 h was obtained tert-butyl ester (2,4-dibromo-6-formylphenoxy)acetic acid, (MS(EI) m/z 394 (M) 338/340 (M-tert-butyl).

288.2. Analogously to example 1.1 from tert-butyl ether (2,4-dibromo-6-formylphenoxy)acetic acid by the reaction with 4-amino-N-hydroxybenzamide and benzylideneamino received ethyl ester of (RS)-(3,5-dibromo-2-tert-butoxycarbonylmethylene)-[4-(N-hydroxycarbamoyl)phenylamino] acetic acid.

Example 289.

Analogously to example 75 ethyl ester of (RS)-(3,5-dibromo-2-tert-butoxycarbonylmethylene)-[4-(N-hydroxycarbamoyl)phenylamino] acetic acid (see primoscenidae)phenylamino]acetic acid, MC(ISP) m/z 518,0 (M+N)+, 540,1 (M+Na)+.

Example 290.

Analogously to example 3 (RS)-(3,5-dibromo-2-carboxymethoxy)-[4-(N-hydroxycarbamoyl)phenylamino] acetic acid (see example 289) was first made over Raney Nickel to obtain (RS)-(4-carbamimidoyl)-(3,5-dibromo-2-carboxymethoxy)acetic acid, MC(ISP) m/z 502,0 (M+N)+.

Example 291.

291.1. Analogously to example 12.1 of 5-bromo-2-hydroxy-3-methoxybenzaldehyde by reaction with bromoethanol in DMF at 85oC for 5 h was obtained 5-bromo-2-(2-hydroxyethoxy)-3-methoxybenzaldehyde, MS(EI) m/z 274/276 M+.

291.2. Analogously to example 1.1 from 5-bromo-2-(2-hydroxyethoxy)-3-methoxybenzaldehyde by the reaction with 4-aminobenzonitrile and toluene-4-sulfonylmethane, substituting methanol for ethanol, was obtained ethyl ester of (RS)-[5-bromo-2-(2-hydroxyethoxy)-3-methoxyphenyl] -(4-cyanoaniline)acetic acid, MC(ISP) m/z 449/451 (M+N)+, 471/473 (M+Na)+.

291.3. Analogously to example 6.2 of the ethyl ester of (RS)-[5-bromo-2-(2-hydroxyethoxy)-3-methoxyphenyl] -(4-cyanoaniline)acetic acid by the reaction of Pinner received hydrochloride ethyl ester of (RS)-[5-bromo-2-(2-hydroxyethoxy)-3-methoxyphenyl]-(4-carbamimidoyl)acetic acid is RA (RS)-[5-bromo-2-(2-hydroxyethoxy)-3-methoxyphenyl] -(4-carbamimidoyl)acetic acid (1: 1) (see example 291.3) hydrolyzed in the presence of lithium hydroxide to obtain (RS)-[5-bromo-2-(2-hydroxyethoxy)-3-methoxyphenyl] -(4-carbamimidoyl)acetic acid, MC(ISP) m/z 438/440 (M+N)+.

Example 293.

293.1. A solution of 5 g of 3,5-dichlorosalicylic aldehyde in 50 ml of DMF was treated 3,23 g of potassium tert-butylate and 6.6 g of alreadyd and stirred in an argon atmosphere at 65oC. After 2 h the reaction mixture was concentrated, treated with ice water and was extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. The residue was chromatographically on silica gel, was obtained 5.5 g of 2-allyloxy-3,5-dichlorobenzaldehyde, MC(EI) m/z 230/232 M+.

293.2. Analogously to example 1.1 from 2-allyloxy-3,5-dichlorobenzaldehyde by the reaction with 4-aminobenzonitrile and toluene-4-sulfonylmethane, substituting methanol for ethanol, was obtained ethyl ester of (RS)-(2-allyloxy-3,5-dichlorophenyl)-(4-cyanoaniline)acetic acid, MS(EI) m/z 404/406 M+.

293.3. Analogously to example 6.2 of the ethyl ester of (RS)-(2-allyloxy-3,5-dichlorophenyl)-(4-cyanoaniline)acetic acid by the reaction of Pinner received hydrochloride ethyl ester of (RS)-(2-allyloxy-3,5-dichlorophenyl)-(4-carbamimidoyl)uksosn the gross ether (RS)-(2-allyloxy-3,5-dichlorophenyl)-(4-carbamimidoyl)acetic acid (1: 1) (see example 293.3) hydrolyzed in the presence of hydrochloride lithium to obtain (RS)-(2-allyloxy-3,5-dichlorophenyl)-(4-carbamimidoyl)acetic acid, MC(ISP) m/z 394/396 (M+N)+.

Example 295.

A solution of 300 mg of the hydrochloride of the ethyl ester of (RS)-(2-allyloxy-3,5-dichlorophenyl)-(4-carbamimidoyl)acetic acid (1: 1) (see example 293.3) in 5 ml of ethanol was treated with hydrogen in the presence of catalytic amount of platinum dioxide for 45 minutes under stirring. The reaction mixture was filtered under vacuum through Spidex (Speedex). The filtrate was concentrated, it was obtained 270 mg of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3,5-dichloro-2-hydroxyphenyl)acetic acid (1: 1), MC(ISP) m/z 382/384 (M+N)+.

Example 296.

Analogously to example 75, the ethyl ester hydrochloride (RS)-(4-carbamimidoyl)-(3,5-dichloro-2-hydroxyphenyl)acetic acid (1:1) (see example 295) hydrolyzed in the presence of lithium hydroxide to obtain (RS)-(4-carbamimidoyl)-(3,5-dichloro-2-hydroxyphenyl)acetic acid, MC(ISP) m/z 354/356 (M+N)+.

Example 297.

A solution of 275 mg of the hydrochloride of the ethyl ester of (RS)-(2-allelic-si-3,5-dichlorophenyl)-(4-carbamimidoyl)acetic acid (Alicia for 30 min under stirring. The reaction mixture was filtered under vacuum through Spidex (Speedex). The filtrate was concentrated and after chromatographic separation on silica gel was obtained 210 mg of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3,5-dichloro-2-propoxyphenyl)acetic acid (1:1), MC(ISP) m/z 424/426 (M+N)+.

Example 298.

Analogously to example 75, the ethyl ester hydrochloride (RS)-(4-carbamimidoyl)-(3,5-dichloro-2-propoxyphenyl)acetic acid (1:1) (see example 297) hydrolyzed in the presence of lithium hydroxide to obtain (RS)-(4-carbamimidoyl)-(3,5-dichloro-2-propoxyphenyl)acetic acid, MC(ISP) m/z 396/398 (M+N)+.

Example 299.

299.1. Analogously to example 293.1 of the 3.5-dichlorosalicylic aldehyde by reaction with diethylene glycol in DMF at 100oC for 16 h was obtained 3,5-dichloro-2-[2-(2-hydroxyethoxy)ethoxy] benzaldehyde; MS(EI) m/z 278 (M), 190 (M-88).

299.2. Analogously to example 1.1 from 3,5-dichloro-2-[2-(2-hydroxyethoxy)ethoxy] benzaldehyde by reaction with 4-aminobenzonitrile and benzylideneamino, substituting methanol for ethanol, was obtained ethyl ester of (RS)-(4-cyanovinylene)-{ 3,5-dichloro-2-[2-(2-hydroxyethoxy)ethoxy]phenyl}acetic acid, MC(ISP) m/z 453,2 (M+N)+, 475,2 (M+Na)+.

299.3. Similar acid by the reaction of Pinner received hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-{ 3,5-dichloro-2-[2-(2-hydroxyethoxy)ethoxy] phenyl] acetic acid, MC(ISP) m/z 470,2 (M+N)+, 492,2 (M+Na)+.

Example 300.

Analogously to example 75, the ethyl ester hydrochloride (RS)-(4-carbamimidoyl)-{ 3,5-dichloro-2-[2-(2-hydroxyethoxy)ethoxy] phenyl} acetic acid (see example 299.3) hydrolyzed in the presence of lithium hydroxide to obtain (RS)-(4-carbamimidoyl)-{ 3,5-dichloro-2-[2-(2-hydroxyethoxy)ethoxy] phenyl} acetic acid, MC(ISP) m/z 442,3 (M+N)+, rub464.3 (M+Na)+.

Example 301.

301.1. Analogously to example 293.1 from 5-bromo-3-ethylcellulose aldehyde (catalog number 57704-12-8) by reaction with 2-iotechnology in DMF at 80oC for 6 h was obtained 5-bromo-3-ethyl-2-(2-hydroxyethoxy)benzaldehyde, MC(ISN) m/z 451,0 (M-N)+.

301.2. Analogously to example 1.1 from 5-bromo-3-ethyl-2-(2-hydroxyethoxy)benzaldehyde by reaction with 4-aminobenzonitrile and benzylideneamino, substituting methanol for ethanol, was obtained ethyl ester of (RS)-[5-bromo-3-ethyl-2-(2-hydroxyethoxy)phenyl]-(4-cyanoaniline)acetic acid, MC(ISP) m/z 449,3 (M+N)+, 471,0 (M+Na)+.

301.3. Analogously to example 6.2 of the ethyl ester of (RS)-[5-bromo-3-ethyl-2-(2-hydroxyethoxy)phenyl] -(4-cyanoaniline)acetic acid by the reaction of Pinner received hydrochloride ethyl ester of (RS)-[5-bromo-3-ethyl-2-(2-hydrogr CLASS="ptx2">

Analogously to example 75, the ethyl ester hydrochloride (RS)-[5-bromo-3-ethyl-2-(2-hydroxyethoxy)phenyl] -(4-carbamimidoyl)acetic acid (see example 301.3) hydrolyzed in the presence of lithium hydroxide to obtain (RS)-[5-bromo-3-ethyl-2-(2-hydroxyethoxy)phenyl] -(4-carbamimidoyl)acetic acid, MC(ISP) m/z 436,2, 438,3 (M+N)+, 458,3, 460,4 (M+Na)+.

Example 303.

303.1. Analogously to example 293.1 from 3-bromo-5-chlorosalicylic aldehyde by reaction with 2-iodine-O-tetrahydropyrimidine (catalog number 96388-83-9) in DMF at 80oC for 4 h was obtained (RS)-3-bromo-5-chloro-2-[2-(tetrahydropyran-2-yloxy)ethoxy] benzaldehyde, MC(EI) m/z 362 (M), 261 (M-99).

303.2. Analogously to example 1.1 from (RS)-3-bromo-5-chloro-2-[2-(tetrahydropyran-2-yloxy)ethoxy]benzaldehyde by reaction with 4-aminobenzonitrile and benzylideneamino, substituting methanol for ethanol, was obtained ethyl ester of (RS)-[3-bromo-5-chloro-2-(2-hydroxyethoxy)phenyl] -(4-cyanoaniline)acetic acid, MS(EI) m/z 454 (M), 379 (M-75).

303.3. Analogously to example 6.2 of the ethyl ester of (RS)-[3-bromo-5-chloro-2-(2-hydroxyethoxy)phenyl] -(4-cyanoaniline)acetic acid by the reaction of Pinner received hydrochloride ethyl ester of (RS)-[3-bromo-5-chloro-2-(2-hydroxyethoxy)phenyl] -(4-carbamimidoyl 75 hydrochloride ethyl ester of (RS)-[3-bromo-5-chloro-2-(2-hydroxyethoxy)phenyl] -(4-carbamimidoyl)acetic acid (see example 303.3) hydrolyzed in the presence of lithium hydroxide to obtain (RS)-[3-bromo-5-chloro-2-(2-hydroxyethoxy)phenyl] -(4-carbamimidoyl)acetic acid, MC(ISP) m/z 442/444,2 (M+N)+, 464/466,1 (M+Na)+.

Example 305.

305.1. Analogously to example 293.1 from 5-chloro-6-hydroxy-meta-anisic aldehyde (catalog number 90110-33-1) by reaction with 2-iotechnology in DMF at 70oC for 3 h was obtained 3-chloro-2-(2-hydroxyethoxy)-5-methoxybenzaldehyde, MS(EI) m/z 230 M+.

305.2. Analogously to example 1.1 from 3-chloro-2-(2-hydroxyethoxy)-5-methoxybenzaldehyde by the reaction with 4-aminobenzonitrile and toluene-4-sulfonylmethane, substituting methanol for ethanol, was obtained ethyl ester of (RS)-[3-chloro-2-(2-hydroxyethoxy)-5-methoxyphenyl] -(4-cyanoaniline)acetic acid, MC(ISP) m/z 405 (M+N)+, 427 (M+Na)+.

305.3. Analogously to example 6.2 of the ethyl ester of (RS)-[3-chloro-2-(2-hydroxyethoxy)-5-methoxyphenyl] -(4-cyanoaniline)acetic acid by the reaction of Pinner received hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-[3-chloro-2-(2-hydroxyethoxy)-5-methoxyphenyl]acetic acid (1: 1), MC(ISP) m/z 422 (M+N)+.

Example 306.

Analogously to example 75, the ethyl ester hydrochloride (RS)-(4-carbamide risotti of lithium hydroxide to obtain (RS)-(4-carbamimidoyl)-[3-chloro-2-(2-hydroxyethoxy)-5-methoxyphenyl]acetic acid, MC(ISP) m/z 394 (M+N)+.

Example 307.

307.1. Analogously to example 293.1 of the 3.5-dichlorosalicylic aldehyde by reaction with 2-iodoacetamide in DMF at 70oC for 4 h was obtained 2-(2,4-dichloro-6-formylphenoxy)ndimethylacetamide, MS(E1) m/z 247 (M), 189 (M-58).

307.2. Analogously to example 1.1 from 2-(2,4-dichloro-6-formylphenoxy)ndimethylacetamide by the reaction with 4-aminobenzonitrile and benzylideneamino received the methyl ester of (RS)-(2-carbamoylphenoxy-3,5-dichlorophenyl)-(4-cyanoaniline)acetic acid, MC(ISP) m/z 408,2 (M+N)+, 430,3 (M+Na)+.

307.3. Analogously to example 6.2 of the methyl ester of (RS)-(2-carbamoylphenoxy-3,5-dichlorophenyl)-(4-cyanoaniline)acetic acid by the reaction of Pinner received hydrochloride methyl ester (RS)-(4-carbamimidoyl)-(2-carbamoylphenoxy-3,5-dichlorophenyl)acetic acid, MC(ISP) m/z 425,4 (M+N)+, 427,1 (M+Na)+.

Example 308.

Analogously to example 75 methyl ester hydrochloride (RS)-(4-carbamimidoyl)-(2-carbamoylphenoxy-3,5-dichlorophenyl)acetic acid (see example 307.3) hydrolyzed in the presence of lithium hydroxide to obtain (RS)-(4-carbamimidoyl)-(2-carbamoylphenoxy-3,5-dichlorophenyl)acetic acid, MC(ISP) m/z 411,3 (M+N)+.

Example 309.

F. at 100oC for 3 h was obtained 2-(2,4-dichloro-6-formylphenoxy)-N,N-dimethylacetamide, MS(EI) m/z 275 (M), 240 (M-CL).

309.2. Analogously to example 1.1 from 2-(2,4-dichloro-6-formylphenoxy)-N,N-dimethylacetamide by the reaction with 4-aminobenzonitrile and benzylideneamino received the methyl ester of (RS)-(4-cyanovinylene)-(3,5-dichloro-2-dimethylcarbamoyl)acetic acid, MC(EI) m/z 435 (M), 376 (M-59).

309.3. Analogously to example 6.2 of the methyl ester of (RS)-(4-cyanovinylene)-(3,5-dichloro-2-dimethylcarbamoyl)acetic acid by the reaction of Pinner received hydrochloride methyl ester (RS)-(4-carbamimidoyl)-(3,5-dichloro-2-dimethylcarbamoyl)acetic acid, MC(ISP) m/z 453,4 (M+N)+, 475,2 (M+Na)+.

Example 310.

Analogously to example 75 methyl ester hydrochloride (RS)-(4-carbamimidoyl)-(3,5-dichloro-2-dimethylcarbamoyl)acetic acid (see example 309.3) hydrolyzed in the presence of lithium hydroxide to obtain (RS)-(4-carbamimidoyl)-(3,5-dichloro-2-dimethylcarbamoyl)acetic acid, MC(ISP) m/z RUR 439,3 (M+H)+, 461,1 (M+Na)+.

Example 311.

311.1. Analogously to example 293.1 of the 3.5-dichlorosalicylic aldehyde by reaction with 2-chloro-N-cyclopropylamino)+, 310,0 (M+Na)+.

311.2. Analogously to example 1.1 from N-cyclopropyl-2-(2,4-dichloro-6-formylphenoxy)ndimethylacetamide by the reaction with 4-aminobenzonitrile and benzylideneamino received the methyl ester of (RS)-(4-cyanovinylene)-(3,5-dichloro-2-cyclopropanecarbonitrile)acetic acid, MC(ISP) m/z 448,31 (M+N)+, 470,3 (M+Na)+.

311.3. Analogously to example 6.2 of the methyl ester of (RS)-(4-cyanovinylene)-(3,5-dichloro-2-cyclopropanecarbonitrile)acetic acid by the reaction of Pinner received hydrochloride methyl ester (RS)-(4-carbamimidoyl)-(3,5-dichloro-2-cyclopropylamino-maailmatasemel)acetic acid, MC(ISP) m/z 465,2 (M+N)+, 487,2 (M+Na)+.

Example 312.

Analogously to example 75 methyl ester hydrochloride (RS)-(4-carbamimidoyl)-(3,5-dichloro-2-cyclopropanecarbonitrile)acetic acid (see example 311.3) hydrolyzed in the presence of lithium hydroxide to obtain (RS)-(4-carbamimidoyl)-(3,5-dichloro-2-cyclopropanecarbonitrile)acetic acid, MC(ISP) m/z 451,3 (M+N)+.

Example 313.

313.1. 61 mg of potassium chlorate and 0.5 ml of 2.5% solution of osmium tetroxide in tert-butanol was added to a solution of 202 mg of ethyl ester of (RS)-(2-allyloxy-3,5-dichlorsilane at room temperature for 16 h, concentrated and extracted with a mixture of ice water and chloroform. The organic phase was concentrated, the residue was chromatographically on silica gel, was obtained 170 mg of the mixture of ethyl esters of (RS)- and (RS)-(4-cyanovinylene)-[3,5-dichloro-2-[(RS)-2,3-dihydroxypropane] phenyl] acetic acid, MC(ISP) m/z 439/441 (M+N)+, 461/463 (M+Na)+.

313.2. Analogously to example 6.2, the mixture of ethyl esters of (RS)- and (SR)-(4-cyanovinylene)-[3,5-dichloro-2-[(RS)-2,3-dihydroxypropane] phenyl] acetic acid by the reaction of Pinner received a mixture of hydrochloride ethyl ester of (RS)- and (SR)-(4-carbamimidoyl)-[3,5-dichloro-2-[(RS)-2,3-dihydroxypropane]phenyl]acetic acid (1:1), MC(ISP) m/z 456/458 (M+N)+.

Example 314.

Analogously to example 75, the mixture of hydrochloride ethyl ester of (RS)- and (SR)-(4-carbamimidoyl)-[3,5-dichloro-2-[(RS)-2,3-dihydroxypropane] phenyl] acetic acid (1:1) (see example 311.3) hydrolyzed in the presence of lithium hydroxide to obtain a mixture of (RS)- and (SR)-(4-carbamimidoyl)-[3,5-dichloro-2-[(RS)-2,3-dihydroxypropane] phenyl] acetic acid, MC(ISP) m/z 428/430 (M+N)+.

Example 315.

315.1. Analogously to example 12.1 3.5-dibromosalicylic aldehyde by reaction with iotechnology in ethylmethylketone when copaceni).

315.2. Analogously to example 1.1 from 3,5-dibromo-2-(2-hydroxilic-si)benzaldehyde by reaction with 4-aminobenzonitrile and benzylideneamino, substituting methanol for ethanol, was obtained ethyl ester of (RS)-(4-cyanovinylene)-[3,5-dibromo-2-(2-hydroxyethoxy)phenyl]acetic acid.

315.3. Analogously to example 1.2 ethyl ester of (RS)-(4-cyano-phenylamino)-[3,5-dibromo-2-(2-hydroxyethoxy)phenyl] acetic acid hydrolyzed in the presence of lithium hydroxide to obtain (RS)-(4-cyanovinylene)-[3,5-dibromo-2-(2-hydroxyethoxy)phenyl]acetic acid, MC(ISN) m/z 469,0 (M-N)-, 425,1 (M-CO2).

315.4. Analogously to example 6.2 from (RS)-(4-cyanovinylene)-[3,5-dibromo-2-(2-hydroxyethoxy)phenyl] acetic acid by the reaction of Pinner received hydrochloride methyl ester (RS)-(4-carbamimidoyl)-[3,5-dibromo-2-(2-hydroxyethoxy)phenyl]acetic acid, MC(ISP) m/z 502,1 (M+H)+.

Example 316.

Analogously to example 75 methyl ester hydrochloride (RS)-(4-carbamimidoyl)-[3,5-dibromo-2-(2-hydroxyethoxy)phenyl] acetic acid (see example 315.4) hydrolyzed in the presence of lithium hydroxide to obtain (RS)-(4-carbamimidoyl)-[3,5-dibromo-2-(2-hydroxyethoxy)phenyl] acetic acid, MS (ISP) m/z 488,1 (M+N)+, 510,1 (M+Na)+.

Note the ri 75oC for 6 h was obtained 5-chloro-3-ethyl-2-(2-hydroxyethoxy)benzaldehyde, MC(EI) m/z 228 (M), 210 (M-H2O).

317.2. Analogously to example 1.1 from 5-chloro-3-ethyl-2-(2-hydroxyethoxy)benzaldehyde by reaction with 4-aminobenzonitrile and benzylideneamino received the methyl ester of (RS)-[5-chloro-3-ethyl-2-(2-hydroxyethoxy)phenyl]-(4-cyanoaniline)acetic acid, MS (ISP) m/z 389,3 (M+N)+, 411,3 (M+Na)+.

317.3. Analogously to example 6.2 of the methyl ester of (RS)-[5-chloro-3-ethyl-2-(2-hydroxyethoxy)phenyl] -(4-cyanoaniline)acetic acid by the reaction of Pinner received hydrochloride methyl ester (RS)-(4-carbamimidoyl)-[5-chloro-3-ethyl-2-(2-hydroxyethoxy)phenyl] acetic acid, MS (ISP) m/z to 406.4 (M+N)+.

Example 318.

Analogously to example 75 methyl ester hydrochloride (RS)-(4-carbamimidoyl)-[5-chloro-3-ethyl-2-(2-hydroxyethoxy)phenyl] acetic acid (see example 317.3) hydrolyzed in the presence of lithium hydroxide to obtain (RS)-(4-carbamimidoyl)-[5-chloro-3-ethyl-2-(2-hydroxyethoxy)phenyl] acetic acid, MC(ISP) m/z 392,2 (M+N)+, 414,3 (M+Na)+.

Example 319.

319.1. Analogously to example 18.1 of 5-chloro-3-iodosalicylic aldehyde by the reaction Mitsunobu (Mitsonobu) with Diisopropylamine the2O).

319.2. Analogously to example 1.1 from 2-(2-benzyloxyethyl)-5-chloro-3-iodobenzaldehyde by the reaction with 4-aminobenzonitrile and toluene-4-sulfonylmethane received the methyl ester of (RS)-[2-(2-benzyloxyethyl)-5-chloro-3-itfeel] -(4-cyanoaniline)acetic acid, MS(EI) m/z 576 (M), 517 (M-SOON3).

319.3. Analogously to example 6.2 of the methyl ester of (RS)-[2-(2-benzyloxyethyl)-5-chloro-3-itfeel] -(4-cyanoaniline)acetic acid by the reaction of Pinner received hydrochloride methyl ester (RS)-[2-(2-benzyloxyethyl)-5-chloro-3-itfeel] -(4-carbamimidoyl)acetic acid, MC(ISP) m/z 594.1 nm (M+N)+, 615,9 (M+Na)+.

Example 320.

Analogously to example 75 methyl ester hydrochloride (RS)-[2-(2-benzyloxyethyl)-5-chloro-3-itfeel] -(4-carbamimidoyl)acetic acid (see example 319.3) hydrolyzed in the presence of lithium hydroxide to obtain (RS)- [2-(2-benzyloxyethyl)-5-chloro-3-itfeel] -(4-carbamimidoyl)acetic acid, MC(ISP) m/z 580,0 (M+N)+, 601,9 (M+Na)+.

Example 321.

place 321.1. Analogously to example 293.1 from 5-chloro-3-iodosalicylic aldehyde (catalog number 215124-03-1) by reaction with 1-(tert-butyldimethylsilyloxy)-2-iodatum (catalog number 101166-65-8) dim is digid, MS(EI) m/z 439 (M-1), 383 (M-tert-butyl).

321.2. Analogously to example 1.1 from 2-[2-(tert-butyldimethylsilyloxy)ethoxy] -5-chloro-3-iodobenzaldehyde by the reaction with 4-aminobenzonitrile and toluene-4-sulfonylmethane received meta-levy ether (RS)-[5-chloro-2-(2-hydroxyethoxy)-3-itfeel]-(4-cyanoaniline)acetic acid, MS(EI) m/z 486 (M+1), 427 (M-SOON3).

321.3. Analogously to example 6.2 of the methyl ester of (RS)- [5-chloro-2-(2-hydroxyethoxy)-3-itfeel] -(4-cyanoaniline)acetic acid by the reaction of Pinner received hydrochloride methyl ester (RS)-(4-carbamimidoyl)-[5-chloro-2-(2-hydroxyethoxy)-3-itfeel] acetic acid, MC(ISP) m/z 504,1 (M+N)+.

Example 322.

Analogously to example 75 methyl ester hydrochloride (RS)-(4-carbamimidoyl)-[5-chloro-2-(2-hydroxyethoxy)-3-itfeel] acetic acid (see example 321.3) hydrolyzed in the presence of lithium hydroxide to obtain (RS)-(4-carbamimidoyl)-[5-chloro-2-(2-hydroxyethoxy)-3-itfeel] acetic acid, MC(ISP) m/z 490,2 (M+N)+, 512,1 (M+Na)+.

Example 323.

323.1. The solution 119,9 ml of 2-ethylphenol in 500 ml of chlorobenzene was treated 126,9 g of iodine and 134,5 g of copper chloride (II), was stirred while boiling under reflux in techee the filtrate was washed with an aqueous solution of sodium thiosulfate and ice water. The organic phase was dried over sodium sulfate and concentrated. The residue was led from hexane, it was given to 79.3 g of 2-ethyl-4-itfinal. Uterine fluid chromatographically on silica gel, with additional 41 g of 2-ethyl-4-itfinal, MS(E1) m/z 248 (M).

323.2. A solution of 19.5 g of 2-ethyl-4-itfeel in 150 ml of DMF was treated in portions at 0oC for 15 min 9,37 g of potassium tert-butylate and the mixture was stirred for 30 minutes Then in high vacuum was removed approximately 100 ml of solvent. The residue was treated dropwise at 0oC for 1 h 12,66 g chloromethylmethylether ether, then was poured into ice water and was extracted with ether/hexane (1:2). The organic phase was washed with sodium chloride solution and water and then concentrated. The residue was chromatographically on silica gel, thus received 21.8 g of 2-ethyl-4-iodine-1-methoxyethoxymethyl, MS(EI) m/z 292 (M).

323.3. The solution cyclopropylmagnesium, freshly prepared from 2,49 g of magnesium and 13.3 g of cyclopropylamine in 40 ml of THF, was treated with 1.2 g of chloride bis-triphenylphosphine and 35-45oWith over 20 min a solution of 20.8 g of 2-ethyl-4-iodine-1-methoxyethoxymethyl in 40 ml of toluene. After stirring for 2 h the reaction mixture was poured in water is the target of sodium bicarbonate, a solution of sodium chloride, dried over magnesium sulfate and concentrated. The residue was chromatographically on silica gel, was obtained 12.7 g of 4-cyclopropyl-2-ethyl-1-methoxyethoxymethyl, MC(EI) m/z 206 (M), 176 (M-CH2O).

323.4. A solution of 12.0 g of 4-cyclopropyl-2-ethyl-1-methoxyethoxymethyl in 240 ml of 2 N. acetic acid was stirred for 24 h at 90oC. the Reaction mixture was poured into ice water and was extracted with dichloromethane. The organic phase was washed with water, saturated aqueous sodium bicarbonate solution and sodium chloride solution, dried over magnesium sulfate and concentrated. The residue was chromatographically on silica gel, was obtained 8.7 g of 4-cyclopropyl-2-ethylphenol, MS(EI) m/z 162 (M), 147 (M-CH3).

323.5. Analogously to example 89.1 4-cyclopropyl-2-ethylphenol was formulirovalis obtaining 5-cyclopropyl-3-ethyl-2-hydroxybenzaldehyde, MS(EI) m/z 190 (M), 175 (M-CH3).

323.6. Analogously to example 293.1 from 5-cyclopropyl-3-ethyl-2-hydroxybenzaldehyde by reaction with 2-iotechnology at 60oC for 6 h was obtained 5-cyclopropyl-3-ethyl-2-(2-hydroxyethoxy)benzaldehyde; MS(EI) m/z 234 (M), 216 (M-N2O).

323.7. Analogously to example 1.1 from 5-cyclopropyl-3-ethyl-2-(2-hydroxyethoxy)benzaldehyde according to R is l-3-ethyl-2-(2-hydroxyethoxy)phenyl] acetic acid, MC(ISP) m/z 395,4 (M+N)+, 417,4 (M+Na)+.

323.8. Analogously to example 6.2 of the methyl ester of (RS)-(4-cyanovinylene)-[5-cyclopropyl-3-ethyl-2-(2-hydroxyethoxy)phenyl] acetic acid by the reaction of Pinner received hydrochloride methyl ester (RS)-(4-carbamimidoyl)-[5-cyclopropyl-3-ethyl-2-(2-hydroxyethoxy)phenyl] acetic acid, MC(ISP) m/z 412,2 (M+N)+.

Example 324.

Analogously to example 75 methyl ester hydrochloride (RS)-(4-carbamimidoyl)-[5-cyclopropyl-3-ethyl-2-(2-hydroxyethoxy)phenyl] acetic acid (see example 336.3) hydrolyzed in the presence of lithium hydroxide to obtain (RS)-(4-carbamimidoyl)-[5-cyclopropyl-3-ethyl-2-(2-hydroxyethoxy)phenyl] acetic acid, MC(ISP) m/z 398,4 (M+N)+, 420,4 (M+Na)+.

Example 325.

325.1. Analogously to example 293.1 from 5-bromo-3-ethylcellulose aldehyde (catalog number 57704-12-8) by reaction with 2-iodoacetamide in dimethylacetamide at 40oC for 2 h was obtained 2-(4-bromo-2-ethyl-6-(formylphenoxy)ndimethylacetamide, MS(EI) m/z 285 (M), 241 (M-CONH2).

325.2. Analogously to example 1.1 from 2-(4-bromo-2-ethyl-6-formylphenoxy)ndimethylacetamide by the reaction with 4-aminobenzonitrile and benzylideneamino received the methyl ester of (RS)-(5-bromo-2-carbamoylmethyl.

Analogously to example 75 methyl ester hydrochloride (RS)-(5-bromo-2-carbamoylmethyl-3-ethylphenyl)-(4-carbamimidoyl)acetic acid (see example 325.3) hydrolyzed in the presence of lithium hydroxide to obtain (RS)-(5-bromo-2-carbamoylmethyl-3-ethylphenyl)-(4-carbamimidoyl)acetic acid, MC(ISP) m/z 449, 451,3 (M+N)+, 471,1 (M+Na)+.

Example 327.

327.1. Analogously to example 18.1 of 5-chloro-3-iodosalicylic aldehyde by the reaction Mitsunobu with diisopropylcarbodiimide (DIAD) and ethyl ether 2-hydroxymetoprolol acid was obtained 2-(4-chloro-2-formyl-6-iodinase) ethyl ester 2-methylacrylate acid, MS(EI) m/z 394 (M), 281 (M-113).

327.2. Analogously to example 1.1 from 2-(4-chloro-2-formyl-6-iodinase)ethyl ester 2-methylacrylate acid by reaction with 4-aminobenzonitrile and toluene-4-sulfonylmethane was obtained 2- {4-chloro-2-[(4-cyanoaniline)methoxycarbonylmethyl]-6-iodinate}ethyl ester of (RS)-2-methylacrylate acid, MC(ISP) m/z 555,1 (M+N)+, 576,9 (M+Na)+.

327.3. 1,99 g allyltrimethylsilane and 0.35 g of tetrakis(triphenylphosphine)palladium were added to a solution of 1.66 g of 2-{4-chloro-2-[(4-cyanoaniline)methoxycarbonylmethyl] -6-iodinate} ethyl ester of (RS)-2-methylacrylate acid in 15 ml of abs the juice vacuum. The residue was treated with ice water and was extracted with ethyl acetate. The organic phase was washed with sodium chloride solution, water and then concentrated. The residue was chromatographically on silica gel, was obtained 1.3 g of 2-{2-allyl-4-chloro-6-[(4-cyanoaniline)methoxycarbonylmethyl] phenoxy} ethyl ester of (RS)-2-methylacrylate acid.

327.4. Analogously to example 6.2 of 2-{2-allyl-4-chloro-6-[(4-cyanoaniline)methoxycarbonylmethyl] phenoxy} ethyl ester of (RS)-2-methylacrylate acid by the reaction of Pinner received hydrochloride, 2-{2-allyl-6-[(4-carbamimidoyl)methoxycarbonylmethyl] -4-chlorophenoxy}ethyl ester of (RS)-2-methylacrylate acid, MC(ISP) m/z 486,3 (M+N)+.

Example 328.

Analogously to example 75 hydrochloride, 2-{2-allyl-6-[(4-carbamimidoyl)methoxycarbonylmethyl] -4-chlorophenoxy} ethyl ester of (RS)-2-methylacrylate acid (see example 327.3) hydrolyzed in the presence of lithium hydroxide to obtain (RS)-[3-allyl-5-chloro-2-(2-hydroxyethoxy)phenyl]-(4-carbamimidoyl)acetic acid, MC(ISP) m/z 404,4 (M+N)+, 426,4 (M+Na)+.

Example 329.

329.1. A solution of 30.0 g of 5-ethylcellulose aldehyde (catalog number 52411-35-5) in 500 ml of DMF was treated to 36.0 g of sodium iodide and of 67.6 g hlaka vacuum, was poured into ice water, acidified 2 N. hydrochloric acid and was extracted with ethyl acetate. The organic phase was washed with an aqueous solution of sodium thiosulfate, a saturated solution of sodium chloride and ice water, dried over sodium sulfate and concentrated. The residue was dissolved in ether/hexane (1:1) and filtered. The filtrate was concentrated to obtain the 45.8 g of 5-ethyl-2-hydroxy-3-iodobenzaldehyde, MC(EI) m/z 276 M+.

329.2. Analogously to example 18.1 of 5-ethyl-2-hydroxy-3-iodobenzaldehyde reaction Mitsunobu with DIAD and 2-benzyloxyethanol received 2-(2-benzyloxyethyl)-5-ethyl-3-iodobenzaldehyde, MS(EI) m/z 410 M+.

329.3. Analogously to example 1.1 from 2-(2-benzyloxyethyl)-5-ethyl-3-iodobenzaldehyde by the reaction with 4-aminobenzonitrile and toluene-4-sulfonylmethane, substituting methanol for ethanol, was obtained ethyl ester of (RS)-[2-(2-benzyloxyethyl)-5-ethyl-3-itfeel]-(4-cyanoaniline)acetic acid, MC(ISP) m/z 585 (M+N)+.

329.4. A solution of 7.1 g of ethyl ester of (RS)-[2-(2-benzyloxyethyl)-5-ethyl-3-itfeel] -(4-cyanoaniline)acetic acid in 50 ml of dichloromethane was treated 7,29 g attributively. After 12 h at room temperature was added the same amount of attributively and the mixture was stirred is in a mixture of ice with an aqueous solution of sodium bisulfite and extracted with ethyl acetate. The organic phase was washed with an aqueous solution of sodium bicarbonate and ice water, dried over sodium sulfate and concentrated. After crystallization of the residue was obtained 3.8 g of ethyl ester of (RS)-(4-cyanovinylene)-[5-ethyl-2-(2-hydroxyethoxy)-3-itfeel] acetic acid. After chromatography of the mother liquor on silica gel got additionally to 1.83 g, MC(ISP) m/z 495 (M+N)+, 517 (M+Na)+.

329.5. Analogously to example 293.3 of the ethyl ester of (RS)-(4-cyanovinylene)-[5-ethyl-2-(2-hydroxyethoxy)-3-itfeel] acetic acid by the reaction of Still (Stille) allyltrimethylsilane and tetrakis(3-phenylphosphine)palladium was obtained ethyl ester of (RS)-[3-allyl-5-ethyl-2-(2-hydroxyethoxy)phenyl]-(4-cyanoaniline)acetic acid, MC(ISP) m/z 409 (M+H)+.

329.6. Analogously to example 6.2 of the ethyl ester of (RS)-[3-allyl-5-ethyl-2-(2-hydroxyethoxy)phenyl] -(4-cyanoaniline)acetic acid by the reaction of Pinner received hydrochloride ethyl ester of (RS)-[3-allyl-5-ethyl-2-(2-hydroxyethoxy)phenyl] -(4-carbamimidoyl)acetic acid, MC(ISP) m/z 426 (M+N)+.

Example 330.

Analogously to example 75, the ethyl ester hydrochloride (RS)-[3-allyl-5-ethyl-2-(2-hydroxyethoxy)phenyl] -(4-carbamimidoyl)acetic is etoxy)phenyl] -(4-carbamimidoyl)acetic acid, MC(ISP) m/z 398 (M+N)+.

Example 331.

331.1. Analogously to example 293.1 of the 3.5-diiodosalicylic aldehyde by reaction with 2-iodine-O-tetrahydropyrimidine (catalog number 96388-83-9) in DMF at 80oC for 6 h was obtained (RS)-3,5-diid-2-[2-(tetrahydropyran-2-yloxy)ethoxy]benzaldehyde; MS(EI) m/z 502 M+.

331.2. Analogously to example 1.1 from (RS)-3,5-diid-2-[2-(tetrahydropyran-2-yloxy)ethoxy] benzaldehyde by reaction with 4-aminobenzonitrile and toluene-4-sulfonylmethane received the methyl ester of (RS)-(4-cyanovinylene)-[2-(2-hydroxyethoxy)-3,5-diiodophenyl] acetic acid, MC(ISP) m/z 579 (M+N)+.

331.3. Analogously to example 6.2 of the methyl ester of (RS)-(4-cyanovinylene)-[2-(2-hydroxyethoxy)-3,5-diiodophenyl] acetic acid by the reaction of Pinner received hydrochloride methyl ester (RS)-(4-carbamimidoyl)-[2-(2-hydroxyethoxy)-3,5-diiodophenyl]acetic acid, MC(ISP) m/z 596 (M+N)+.

331.4. Analogously to example 327.3 hydrochloride methyl ester (4 carbamimidoyl)-[2-(2-hydroxyethoxy)-3,5-diiodophenyl] acetic acid was injected into the reaction Stille with tributylstannyl and tetrakis(triphenylphosphine) palladium, after concentration the crude mixture was chromatographically on si-diphenylvinyl]acetic acid, MC(ISP) m/z 396 (M+N)+.

Example 332.

Analogously to example 75 methyl ester hydrochloride (RS)-(4-carbamimidoyl)-[2-(2-hydroxyethoxy)-3,5-diphenylphenol]acetic acid (see example 327.3) hydrolyzed in the presence of lithium hydroxide to obtain (RS)-(4-carbamimidoyl)-[2-(2-hydroxyethoxy)-3,5-diphenylphenol] acetic acid, MS (ISP) m/z 382 (M+N)+, 404 (M+Na)+.

Example 333.

333.1. Analogously to example 293.3 from 2-{ 4-chloro-2-[(4-cyanoaniline)methoxycarbonylmethyl] -6-iodinate}ethyl ester of (RS)-2-methylacrylate acid (see example 327.2) by the reaction of Style with tributyl(phenylethynyl)stannane and tetrakis(3-phenylphosphine)palladium was obtained 2-{ 4-chloro-2-[(4-cyanoaniline)methoxycarbonylmethyl]-6-phenylethylene}ethyl ester of (RS)-2-methylacrylate acid, MC(ISP) m/z 529,2 (M+N)+, 551,0 (M+Na)+.

333.2. Analogously to example 6.2 of 2-{ 4-chloro-2-[(4-cyanoaniline)methoxycarbonylmethyl]-6-phenylethylene}ethyl ester of (RS)-2-methylacrylate acid by the reaction of Pinner received hydrochloride, 2-{2-[(4-carbamimidoyl)methoxycarbonylmethyl]-4-chloro-6-phenylethylene}ethyl ester of (RS)-2-methylacrylate acid, the product was purified by chromatography on silica gel, MC(ISP) m/z 546 arylmethyl] -6-phenylethylene} ethyl ester of (RS)-2-methylacrylate acid (see example 333.1) was introduced in the Pinner reaction and after chromatography on silica gel as a side product was isolated hydrochloride methyl ester (RS)-(4-carbamimidoyl)-[5-chloro-2-(2-hydroxyethoxy)-3-phenylethylene]acetic acid, MC(ISP) m/z 478,3 (M+N)+.

Example 335.

Analogously to example 75 hydrochloride, 2-{ 2-[(4-carbamimidoyl)methoxycarbonylmethyl] -4-chloro-6-phenylethylene}ethyl ester of (RS)-2-methylacrylate acid (see example 333.2) hydrolyzed in the presence of lithium hydroxide to obtain (RS)-(4-carbamimidoyl)-[5-chloro-2-(2-hydroxyethoxy)-3-phenylethylene] acetic acid, MC(ISP) m/z 464,2 (M+N)+, 486,1 (M+Na)+.

Example 336.

A solution of 210 mg of the hydrochloride of 2-{2-[(4-carbamimidoyl)methoxycarbonylmethyl] -4-chloro-6-phenylethylene}ethyl ester of (RS)-2-methylacrylate acid (see example 333.2) in 5 ml methanol and 5 ml of THF was first made in the presence of catalytic amount of Raney Nickel at room temperature under stirring for 5 hours Then the reaction mixture was filtered under vacuum, the filtrate was concentrated and after lyophilization from water received 190 mg of the hydrochloride of 2-{2-[(4-carbamimidoyl)methoxycarbonylmethyl]-4-chloro-6

Analogously to example 75 hydrochloride, 2-{ 2-[(4-carbamimidoyl)methoxycarbonylmethyl] -4-chloro-6-sterigenics} ethyl ester of (RS)-Z-somaclonal acid (see example 336) hydrolyzed in the presence of lithium hydroxide to obtain (RS)-Z-(4-carbamimidoyl)-[5-chloro-2-(2-hydroxyethoxy)-3-stillfeel] acetic acid, MC(ISP) m/z 466,3 (M+N)+.

Example 338.

Analogously to example 29.2 hydrochloride, 2-{ 2-[(4-carbamimidoyl)methoxycarbonylmethyl] -4-chloro-6-phenylethylene}ethyl ester of (RS)-2-methylacrylate acid (see example 333.2) was first made in methanol/dioxane to obtain hydrochloride of 2-{2-[(4-carbamimidoyl)methoxycarbonylmethyl] -4-chloro-6-penicillinase} ethyl ester of (RS)-somaclonal acid, MC(ISP) m/z 552,4 (M+H)+.

Example 339.

Analogously to example 75 hydrochloride, 2-{ 2-[(4-carbamimidoyl)methoxycarbonylmethyl] -4-chloro-6-penicillinase} ethyl ester of (RS)-somaclonal acid (see example 338) hydrolyzed in the presence of lithium hydroxide to obtain (RS)-(4-carbamimidoyl)-[5-chloro-2-(2-hydroxyethoxy)-3-fenetylline]acetic acid, MC(ISP) m/z 468,3 (M+N)+.

Example 340.

340.1. Analogously to example 18.1 of 5-ethyl-2-hydroxy-3-yodle 2-(4-ethyl-2-formyl-6-iodophenoxy)ethyl ester 2-methylacrylate acid, MS(EI) m/z 388,2 (M), 358,9 (M-CH2O).

340.2. Analogously to example 1.1 from 2-(4-ethyl-2-formyl-6-iodine-phenoxy) ethyl ester 2-methylacrylate acid by reaction with 4-aminobenzonitrile and benzylideneamino was obtained 2-{2-[(4-cyanoaniline)methoxycarbonylmethyl]-4-ethyl-6-iodinate}ethyl ester of (RS)-2-methylacrylate acid, MC(ISP) m/z 549,1 (M+N)+, 571,2 (M+Na)+.

340.3. Analogously to example 327.3 of 2-{2-[(4-cyanoaniline)methoxycarbonylmethyl] -4-ethyl-6-iodinate}ethyl ester of (RS)-2-methylacrylate acid by the reaction of Style with tributyl(phenylethynyl)stannane and tetrakis(triphenylphosphine)palladium was obtained 2-{2-[(4-cyanoaniline)methoxycarbonylmethyl] -4-ethyl-6-phenylethylene}ethyl ester of (RS)-2-methylacrylate acid, MC(ISP) m/z 523,3 (M+N)+, 545,3 (M+Na)+.

340.4. Analogously to example 6.2 of 2-{2-[(4-cyanoaniline)methoxycarbonylmethyl] -4-ethyl-6-phenylethylene}ethyl ester of (RS)-2-methylacrylate acid by the reaction of Pinner received hydrochloride, 2-{2-[(4-carbamimidoyl)methoxycarbonylmethyl] -4-ethyl-6-phenylethylene} ethyl ester of (RS)-2-methylacrylate acid, the product was purified by chromatography on silica gel, MS (ISP) m/z 540,3 (M+N)+.

Example 341.

Analogously to example 6.2 lots (see example 340.4) was introduced in the Pinner reaction and after chromatography on silica gel as a side product was isolated hydrochloride methyl ester (RS)-(4-carbamimidoyl)-[5-ethyl-2-(2-hydroxyethoxy)-3-phenylethylene] acetic acid, MC(ISP) m/z 472,3 (M+N)+.

Example 342.

Analogously to example 75 methyl ester hydrochloride (RS)-(4-carbamimidoyl)-[5-ethyl-2-(2-hydroxyethoxy)-3-phenylethylene] acetic acid (see example 341) hydrolyzed in the presence of lithium hydroxide to obtain hydrochloride of (RS)-(4-carbamimidoyl)-[5-ethyl-2-(2-hydroxyethoxy)-3-phenylethylene] acetic acid, MC(ISP) m/z 458,4 (M+H)+, 480,3 (M+Na)+.

Example 343.

343.1. Analogously to example 89.1 2-ethyl-4-itfinal (see example 323.1) was formulirovalis with 3-ethyl-2-hydroxy-5-iodobenzaldehyde, MS(EI) m/z 276 M+.

343.2. Analogously to example 18.1 of 3-ethyl-2-hydroxy-5-iodobenzaldehyde reaction Mitsunobu with DIAD and 2-benzimidazole received 2-(2-benzyloxyethyl)-3-ethyl-5-iodobenzaldehyde, MS(EI) m/z 410 M+.

343.3. Analogously to example 1.1 from 2-(2-benzyloxyethyl)-3-ethyl-5-iodobenzaldehyde by the reaction with 4-aminobenzonitrile and toluene-4-sulfonylmethane received ethyl +.

343.4. Analogously to example 6.2 of the ethyl ester of (RS)-[2-(2-benzyloxyethyl)-3-ethyl-5-itfeel] -(4-cyanoaniline)acetic acid by the reaction of Pinner received hydrochloride ethyl ester of (RS)-[2-(2-benzyloxyethyl)-3-ethyl-5-itfeel] -(4-carbamimidoyl)acetic acid, the product was purified by chromatography on silica gel, MC(ISP) m/z 602 (M+N)+.

343.5. Analogously to example 329.4 of the hydrochloride of the ethyl ester of (RS)-[2-(2-benzyloxyethyl)-3-ethyl-5-itfeel] -(4-carbamimidoyl)acetic acid by the reaction with trimethylsilylimidazole received hydrochloride ethyl ester of (RS)-(4-carbamimidoyl)-[3-ethyl-2-(2-hydroxyethoxy)-5-itfeel]acetic acid, MC(ISP) m/z 512 (M+N)+.

343.6. Analogously to example 327.3 of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-[3-ethyl-2-(2-hydroxyethoxy)-5-itfeel]acetic acid by the reaction of Style with tributylstannyl and tetrakis(triphenylphosphine) palladium was obtained the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-[3-ethyl-2-(2-hydroxyethoxy)-5-vinylphenol] acetic acid, MC(ISP) m/z 412 (M+N)+.

Example 344.

Analogously to example 75, the ethyl ester hydrochloride (RS)-(4-carbamimidoyl)-[3-ethyl-2-(2-gr is the receive (RS)-(4-carbamimidoyl)-[3-ethyl-2-(2-hydroxyethoxy)-5-vinylphenol] acetic acid, MC(ISP) m/z 384 (M+N)+.

Example 345.

345.1. Analogously to example 327.3 of 2-{2-[(4-cyanoaniline)methoxycarbonylmethyl] -4-ethyl-6-iodinate}ethyl ester of (RS)-2-methylacrylate acid (see example 342.2) by the reaction of Style with tributylstannyl and tetrakis(triphenylphosphine)palladium was obtained 2-{2-[(4-cyanoaniline)methoxycarbonylmethyl]-4-ethyl-6-ethynylene}ethyl ester of (RS)-2-methylacrylate acid, MC(ISP) m/z 447,4 (M+N)+, 469,4 (M+Na)+.

345.2. Analogously to example 6.2 of 2-{2-[(4-cyanoaniline)methoxycarbonylmethyl]-4-ethyl-6-ethynylene}ethyl ester of (RS)-2-methylacrylate acid by the reaction of Pinner received hydrochloride 2-[2-[(4-carbamimidoyl)methoxycarbonylmethyl] -6-(1-vinyl chloride)-4-ethylenoxy] ethyl ester of (RS)-2-methylacrylate acid, the product was purified by chromatography on silica gel, MC(ISP) m/z 500,3 (M+N)+.

Example 346.

Analogously to example 6.2 2-{2-[(4-cyanoaniline)methoxycarbonylmethyl]-4-ethyl-6-ethynylene}ethyl ester of (RS)-2-methylacrylate acid (see example 343.1) was introduced in the Pinner reaction and after chromatography on silica gel as a side product was isolated hydrochloride methyl ester (RS)-(4-carbamimidoyl)-[3-(1-vinyl chloride)-5-ethyl-2-(2-gidro 75 hydrochloride 2-[2-[(4-carbamimidoyl)methoxycarbonylmethyl] -6-(1-vinyl chloride)-4-ethylenoxy] ethyl ester of (RS)-2-methylacrylate acid (see example 345.2) hydrolyzed in the presence of lithium hydroxide to obtain (RS)-(4-carbamimidoyl)-[3-(1-vinyl chloride)-5-ethyl-2-(2-hydroxyethoxy)phenyl] acetic acid, MC(ISP) m/z 418,2 (M+N)+, 440,2 (M+Na)+.

Example 348.

348.1. Analogously to example 327.3 of 2-{2-[(4-cyanoaniline)methoxycarbonylmethyl]-4-ethyl-6-iodinate}ethyl ester (RS) 2-methylacrylate acid (see example 340.2) by the reaction of Style with tributyl(1-ethoxyphenyl)stannane and tetrakis(triphenylphosphine)palladium was obtained 2-[2-[(4-cyanoaniline)methoxycarbonylmethyl] -6-(1-ethoxyphenyl)-4-ethylenoxy]ethyl ester of (RS)-2-methylacrylate acid, MC(ISP) m/z 493,2 (M+N)+, 515,2 (M+Na)+.

348.2. Analogously to example 6.2 of 2-[2-[(4-cyanoaniline)methoxycarbonylmethyl] -6-(1-ethoxyphenyl)-4-ethylenoxy] ethyl ester of (RS)-2-methylacrylate acid by the reaction of Pinner received hydrochloride, 2-{ 2-acetyl-6-[(4-carbamimidoyl)methoxycarbonylmethyl] -4-ethylenoxy} ethyl ester of (RS)-2-methylacrylate acid, the product was purified by chromatography on silica gel, MC(ISP) m/z 482,4 (M+N)+, 512,3 (M+Na)+.

Example 349.

Analogously to example 75 hydrochloride, 2-{2-acetyl-6-[(4-carbamimidoyl)methoxycarbonylmethyl]-4-ethylenoxy}ethyl e-[3-acetyl-5-ethyl-2-(2-hydroxyethoxy)phenyl]-(4-carbamimidoyl)acetic acid, MC(ISP) m/z 400,4 (M+H)+, 422,3 (M+PA)+.

Example 350.

Analogously to example 29.2 hydrochloride, 2-{ 2-[(4-carbamimidoyl)methoxycarbonylmethyl] -4-ethyl-6-phenylethylene}ethyl ester of (RS)-2-methylacrylate acid (see example 340.4) was first made in methanol/dioxane to obtain hydrochloride of 2-{2-[(4-carbamimidoyl)methoxycarbonylmethyl] -4-ethyl-6-penicillinase} ethyl ester of (RS)-somaclonal acid, MC(ISP) m/z 546,3 (M+N)+.

Example 351.

Analogously to example 75 hydrochloride, 2-{ 2-[(4-carbamimidoyl)methoxycarbonylmethyl] -4-ethyl-6-penicillinase} ethyl ester of (RS)-somaclonal acid (see example 350) hydrolyzed in the presence of lithium hydroxide to obtain (RS)-(4-carbamimidoyl)-[5-ethyl-2-(2-hydroxyethoxy)-3-fenetylline] acetic acid, MC(ISP) m/z 462,2 (M+H)+, 484,3 (M+Na)+.

Example 352.

352.1. Analogously to example 124.1 methyl ester of (RS)-(4-benzyloxy-3-ethoxyphenyl)-(4-cyanoaniline)acetic acid (example 2.b) was first made to obtain (RS)-(4-cyanovinylene)-(3-ethoxy-4-hydroxyphenyl)acetic acid.

352.2. 0.3 mmole of phenol, obtained as described in example 352.1, was dissolved in 1000 μl of DMF and was treated with a small quantity is ion mixture was stirred at room temperature for 6 hours Then add 50 ál of formic acid, the reaction mixture was filtered, the reaction product was purified preparative GHUR (RP18, from 20% to 95% acetonitrile). It was obtained methyl ester of (RS)-(4-cyanovinylene)-[3-ethoxy-4-(3-methylbutoxy)phenyl]acetic acid.

352.3. 60 mg of the material obtained as described in example 352.2, was dissolved in 400 μl of chloroform and 1500 μl of a solution of dry hydrochloric acid in methanol (Hcl content=27% by weight). The reaction mixture was stirred at room temperature for 5 h, then concentrated. The residue was dissolved in 500 μl of THF and 1500 μl of 2 M solution of dry ammonia in ethanol and heated at 45oC for 5 h Then at room temperature was added 500 μl of 2 M sodium hydroxide solution. After 30 min the reaction mixture was neutralized with 200 μl of formic acid and concentrated. The residue was dissolved in formic acid and subjected to preparative GHUR (RP18, 10% to 95% acetonitrile). It was obtained (RS)-(4-carbamimidoyl a melamine)-[3-ethoxy-4-(3-methylbutoxy)phenyl]acetic acid.

Example 353.

The following compounds were obtained according to the method described in example 352, using appropriate were synthesized:

353. a) using 3-fenoxi the XI)phenyl] acetic acid was obtained (RS)-(4-carbamimidoyl)-[3-ethoxy-4-(3-phenoxypropane)phenyl]acetic acid;

353. b) when using 2-cyclohexylethylamine through the intermediate formation of (RS)-(4-cyanovinylene)-[4-(2-cyclohexylmethoxy)-3-ethoxyphenyl] acetic acid was obtained (RS)-(4-carbamimidoyl)-[4-(2-cyclohexylmethoxy)-3-ethoxyphenyl]acetic acid;

353. C) using 2-phenoxyethylamine through the intermediate formation of (RS)-(4-cyanovinylene)-[3-ethoxy-4-(2-phenoxyethoxy)phenyl] acetic acid was obtained (RS)-(4-carbamimidoyl)-[3-ethoxy-4-(2-phenoxyethoxy)phenyl]acetic acid.

Example 354.

354.1. 0.3 mmole of phenol, obtained as described in example 352.1, was dissolved in 1000 μl of DMF and treated by 0,6 mmol of potassium carbonate, and then with 0.3-mmol of 2-bromo-2'-methoxyacetophenone. The reaction mixture was stirred at 60oC for 5 h, and then filtered. To the filtrate was added 50 μl of formic acid and the reaction mixture was subjected to preparative GHUR (RP 18, from 20% to 95% acetonitrile). It was obtained methyl ester of (RS)-(4-cyanovinylene)-{3-ethoxy-4-[2-(2-methoxyphenyl)-2-oksidoksi]phenyl}acetic acid.

354.2. Similarly to the method described in example 352.3, from the product obtained as described above was obtained (RS)-(4-carbamimidoyl)-{ 3-ethoxy-4-[2-(2-methoxyp is according to the method, described in example 354, using appropriate were synthesized:

355. a) using 2-bromo-4'-methoxyacetophenone through the intermediate formation of (RS)-(4-cyanovinylene)-{ 3-ethoxy-4-[2-(4-methoxyphenyl)-2-oksidoksi] phenyl} acetic acid was obtained (RS)-(4-carbamimidoyl)-{ 3-ethoxy-4-[2-(4-methoxyphenyl)-2-oksidoksi] phenyl}acetic acid;

355. b) using 4-(2-oxobutyl)bromide via the intermediate formation of (RS)-(4-cyanovinylene)-[3-ethoxy-4-(2-oxopentanoic)phenyl] acetic acid was obtained (RS)-(4-carbamimidoyl)-[3-ethoxy-4-(2-oxopentanoic)phenyl]acetic acid.

Example 356.

356.1. 131 mg (0.5 mmole) of triphenylphosphine were dissolved in 650 μl of tetrahydrofuran and cooled to 0oC in argon atmosphere. To the resulting solution was added 78 μl (0.5 mmole) of diethylazodicarboxylate dissolved in 650 μl of tetrahydrofuran and the reaction mixture was stirred for 1 h Then was added 0.5 mmole of 2-(4-forfinal)ethanol, dissolved in 500 μl of dioxane, and 0.33 mmole of phenol, obtained as described in the example of 124.1, 700 μl of tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 h, and then subjected to preparative GHUR (RP18, from 20% to 95% of the CLASS="ptx2">

356.2. Similarly to the method described in example 352.3, of the product obtained above, was obtained (RS)-(4-carbamimidoyl)-{3-ethoxy-5-[2-(4-forfinal)ethoxy]phenyl}acetic acid.

Example 357.

The following compounds were obtained according to the method described in example 356, using the appropriate alcohols:

357. a) when using (RS)-3-hydroxymitragynine through the intermediate formation of a mixture of ethyl ester of (RS)-(4-cyanovinylene)-[5-ethyl-2-[(RS)-(tetrahydrofuran-3-yloxy)] phenyl]acetic acid was obtained a mixture of (RS)-(4-carbamimidoyl)-[5-ethyl-2-[(RS)-(tetrahydrofuran-3-yloxy)] phenyl]acetic acid;

357. b) when using tetrahydro-4H-Piran-4-ol via the intermediate formation of ethyl ester of (RS)-(4-cyanovinylene)-[5-ethyl-2-(tetrahydropyran-4-yloxy)phenyl] acetic acid was obtained (RS)-(4-carbamimidoyl)-[5-ethyl-2-(tetrahydropyran-4-yloxy)phenyl] acetic acid;

357. C) using 2-(hydroxymethyl)pyridine via the intermediate formation of ethyl ester of (RS)-(4-cyanovinylene)-[5-ethyl-2-(pyridine-2-ylethoxy)phenyl] acetic acid was obtained (RS)-(4-carbamimidoyl)-[5-ethyl-2-(pyridine-2-ylethoxy)phenyl]acetic acid;

357. g) using N - [2-(2-oxopyrrolidin-1-yl)ethoxy] phenyl} acetic acid was obtained (RS)-(4-carbamimidoyl)-{ 5-ethyl-2-[2-(2-oxopyrrolidin-1-yl)ethoxy] phenyl] acetic acid.

Example 358.

The following compounds were obtained according to the method described in the examples 352.2 and 352.3 of phenol, obtained as described in example 124, and relevant were synthesized:

358.a) using 4-bromo-1-butene via the intermediate formation of methyl ester of (RS)-(3-but-3-enyloxy-5-ethoxyphenyl)-(4-cyanoaniline)acetic acid was obtained (RS)-(3-but-3-enyloxy-5-ethoxyphenyl)-(4-carbamimidoyl)acetic acid;

358. b) when using 1-bromo-3-methylbutane through intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-[3-ethoxy-5-(3-methylbutoxy)phenyl] acetic acid was obtained (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(3-methylbutoxy)phenyl]acetic acid;

358. C) when using bromeilles through intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-(3-cyclohexylmethoxy-5-ethoxyphenyl)acetic acid was obtained (RS)-(4-carbamimidoyl)-(3-cyclohexylmethoxy-5-ethoxyphenyl)acetic acid;

358. g) using 1-butylbromide through intermediate formation of methyl ester of (RS)-(3-butoxy-5-ethoxyphenyl)-(4-cyanoaniline)acetic acid was obtained (RS)-(3-butoxy-5-ethoxyphenyl)-(4-carbamimidoyl)acetic RS)-(4-cyanovinylene)-[3-ethoxy-5-(2-methoxyethoxy)phenyl] acetic acid was obtained (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(2-methoxyethoxy)phenyl]acetic acid;

358. e) using 3-phenoxypropylamine through intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-[3-ethoxy-5-(3-phenoxypropane)phenyl] acetic acid was obtained (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(3-phenoxypropane)phenyl]acetic acid;

358. g) using 2-cyclohexylethylamine through intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-[3-(2-cyclohexylmethoxy)-5-ethoxyphenyl] acetic acid was obtained (RS)-(4-carbamimidoyl)-[3-(2-cyclohexylmethoxy)-5-ethoxyphenyl]acetic acid;

358. C) when using cyclopropanemethylamine through the intermediate formation of (RS)-(4-cyanovinylene)-(3-cyclopropylmethoxy-5-ethoxyphenyl)acetic acid was obtained (RS)-(4-carbamimidoyl)-(3-cyclopropylmethoxy-5-ethoxyphenyl)acetic acid;

358. and when using 2-phenoxyethylamine through intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-[3-ethoxy-5-(2-phenoxyethoxy)phenyl] acetic acid was obtained (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(2-phenoxyethoxy)phenyl]acetic acid;

358.K) when using 1-hexylboronic through intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-5-hexiloc.

Example 359.

The following compounds were obtained according to the method described in the examples 354.1 and 354.2, phenol, obtained as described in example 124, and relevant were synthesized:

359.a) when using 2-bromoacetophenone through intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-[3-ethoxy-5-(2-oxo-2-phenylethane)phenyl] acetic acid was obtained (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(2-oxo-2-phenylethane)phenyl]acetic acid;

359.b) using 2-bromo-2'-methoxyacetophenone through intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-{3-ethoxy-5-[2-(2-methoxyphenyl)-2-oksidoksi] phenyl} acetic acid was obtained (RS)-(4-carbamimidoyl)-{ 3-ethoxy-5-[2-(2-methoxyphenyl)-2-oksidoksi] phenyl} acetic acid;

359.C) using 2-bromo-4'-methoxyacetophenone through intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-{3-ethoxy-5-[2-(4-methoxyphenyl)-2-oksidoksi] phenyl} acetic acid was obtained (RS)-(4-carbamimidoyl)-{ 3-ethoxy-5-[2-(4-methoxyphenyl)-2-oksidoksi] phenyl} acetic acid;

359. g) using 3-methyl-2-oxobutanamide through intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-[3-ethoxy-5-(3-methyl-2-ox is]acetic acid;

359.d) using 4-methyl-2-oxapentane through intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-[3-ethoxy-5-(4-methyl-2-oxopentanoic)phenyl] acetic acid was obtained (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(4-methyl-2-oxopentanoic)phenyl]acetic acid;

359. e) using 2-oxapentane through the intermediate formation of (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(2-oxopentanoic)phenyl] acetic acid was obtained (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(2-oxopentanoic)phenyl]acetic acid;

359. g) using 2-oxobutanamide through the intermediate formation of (RS)-(4-cyanovinylene)-[2-ethoxy-5-(2-oxobutanoic)phenyl] acetic acid was obtained (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(2-oxobutanoic)phenyl]acetic acid.

Example 360.

The following compounds were obtained according to the method described in the examples 354.1 and 354.2, phenol, obtained as described in example 148, and the corresponding alcohols:

360.a) when using 2-methylthioethyl through intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-[5-ethyl-2-(2-methylsulfonylmethane)-3-propylphenyl] acetic acid was obtained (RS)-(4-carbamimidoyl)-[5-ethyl-2-(2-IU is through the intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-[5-ethyl-3-propyl-2-(pyridine-4-ylethoxy)phenyl] acetic acid was obtained (RS)-(4-carbamimidoyl)-[5-ethyl-3-propyl-2-(pyridine-4-ylethoxy)phenyl] acetic acid;

360. C) when using benzyl alcohol via the intermediate formation of methyl ester of (RS)-(2-benzyloxy-5-ethyl-3-propylphenyl)-(4-cyanoaniline)acetic acid was obtained (RS)-(2-benzyloxy-5-ethyl-3-propylphenyl)-(4-carbamimidoyl)acetic acid;

360. g) using 3-furanmethanol through intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-[5-ethyl-2-(furan-3-ylethoxy)-3-propylphenyl] acetic acid was obtained (RS)-(4-carbamimidoyl)-[5-ethyl-2-(furan-3-ylethoxy)-3-propylphenyl]acetic acid;

360. d) using 3-(hydroxymethyl)pyridine via the intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-[5-ethyl-3-propyl-2-(pyridine-3-ylethoxy)phenyl] acetic acid was obtained (RS)-(4-carbamimidoyl)-[5-ethyl-3-propyl-2-(pyridine-3-ylethoxy)phenyl] acetic acid;

360. e) using 4-methyl-5-thiazoleethanol through intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-{5-ethyl-2-[2-(4-methylthiazole-5-yl)ethoxy] -3-propylphenyl} acetic acid was obtained (RS)-(4-carbamimidoyl)-{ 5-ethyl-2-[2-(4-methylthiazole-5-yl)ethoxy] -3-propylphenyl}acetic acid;

360. W) when using Cyclopentanol through intermediate obrazovanie-carbamimidoyl)-(2-cyclopentyloxy-5-ethyl-3-propylphenyl)acetic acid;

360.C) using (hydroxymethyl)cyclopropane via the intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-(2-cyclopropylmethoxy-5-ethyl-3-propylphenyl)acetic acid was obtained (RS)-(4-carbamimidoyl)-(2-cyclopropylmethoxy-5-ethyl-3-propylphenyl)acetic acid;

360.and when using (hydroxymethyl)cyclohexane via the intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-(2-cyclohexylmethoxy-5-ethyl-3-propylphenyl)acetic acid was obtained (RS)-(4-carbamimidoyl)-(2-cyclohexylmethoxy-5-ethyl-3-propylphenyl)acetic acid;

360.K) using (hydroxymethyl)cyclopentane through intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-(2-cyclopentyloxy-5-ethyl-3-propylphenyl)acetic acid was obtained (RS)-(4-carbamimidoyl)-(2-cyclopentyloxy-5-ethyl-3-propylphenyl)acetic acid;

360. l) when using 2-(3-forfinal)ethanol via the intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-{ 5-ethyl-2-[2-(3-forfinal)ethoxy] -3-propylphenyl} acetic acid was obtained (RS)-(4-carbamimidoyl)-{ 5-ethyl-2-[2-(3-forfinal)ethoxy] -3-propylphenyl}acetic acid;

360. m) using 2-(hydroxymethyl)Piri is XI)phenyl] acetic acid was obtained (RS)-(4-carbamimidoyl)-[5-ethyl-3-propyl-2-(pyridine-2-ylethoxy)phenyl] acetic acid;

360. h) using 2-isopropoxyethanol through intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-[5-ethyl-2-(2-isopropoxyphenoxy)-3-propylphenyl] acetic acid was obtained (RS)-(4-carbamimidoyl)-[5-ethyl-2-(2-isopropoxyphenoxy)-3-propylphenyl] acetic acid;

360. a) when using 2-methoxyethanol through intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-[5-ethyl-2-(2-methoxyethoxy)-3-propylphenyl] acetic acid was obtained (RS)-(4-carbamimidoyl)-[5-ethyl-2-(2-methoxyethoxy)-3-propylphenyl]acetic acid;

360. p) when using 2-(2-forfinal)ethanol via the intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-{ 5-ethyl-2-[2-(2-forfinal)ethoxy] -3-propylphenyl] acetic acid was obtained (RS)-(4-carbamimidoyl)-{ 5-ethyl-2-[2-(2-forfinal)ethoxy] -3-propylphenyl}acetic acid;

360. p) when using 2-(4-forfinal)ethanol via the intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-{ 5-ethyl-2-[2-(4-forfinal)ethoxy] -3-propylphenyl} acetic acid was obtained (RS)-(4-carbamimidoyl)-{ 5-ethyl-2-[2-(4-forfinal)ethoxy] -3-propylphenyl}acetic acid;

360. C) when using tetrahydro-4H-Piran-4-ol via an intermediate acid was obtained (RS)-(4-carbamimidoyl)-[5-ethyl-3-propyl-2-(tetrahydropyran-4-yloxy)phenyl] acetic acid;

360.t) using 2,5-differenziava alcohol through the intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-[2-(2,5-deferasirox)-5-ethyl-3-propylphenyl] acetic acid was obtained (RS)-(4-carbamimidoyl)-[2-(2,5-deferasirox)-5-ethyl-3-propylphenyl] acetic acid;

360.y) using 3,4-differenziava alcohol through the intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-[2-(3,4-deferasirox)-5-ethyl-3-propylphenyl] acetic acid was obtained (RS)-(4-carbamimidoyl)-[2-(3,4-deferasirox)-5-ethyl-3-propylphenyl] acetic acid;

360. f) using (RS)-1-isopropyl-3-pyrrolidinone through the intermediate formation of a mixture of the methyl esters of (RS)- and (SR)-(4-cyanovinylene)-[5-ethyl-2-[(RS)-(1-isopropylpyrimidine-3-yloxy)]-3-propylphenyl]acetic acid was obtained a mixture of (RS)- and (SR)-(4-carbamimidoyl)-[5-ethyl-2-[(RS)-(1-isopropylpyrimidine-3-yloxy)]-3-propylphenyl]acetic acid;

360.x) using (RS)-3-hydroxymitragynine through the intermediate formation of a mixture of the methyl esters of (RS)- and (SR)-(4-cyanovinylene)-[5-ethyl-3-propyl-2-[(RS)-(tetrahydrofuran-3-yloxy)] phenyl] acetic acid was obtained a mixture of (RS)- and (SR)-(4-carbamimidoyl)-[5-ethyl-3-propyl-2-[(RS)-(tetragoniaceae the formation of a mixture of the methyl esters of (RS)- and (SR)-(4-cyanovinylene)-[5-ethyl-3-propyl-2-[(RS)-(tetrahydrofuran-3-ylethoxy)]phenyl]acetic acid was obtained a mixture of (RS)- and (SR)-(4-carbamimidoyl)-[5-ethyl-3-propyl-2-[(RS)-(tetrahydrofuran-3-ylethoxy)]phenyl]acetic acid.

Example 361.

The following compounds were obtained according to the method described in the examples 354.1 and 354.2, phenol, obtained as described in example 134.3, and the corresponding alcohols:

361.a) using 3,4-differenziava alcohol through the intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-[2-(3,4-deferasirox)-5-ethylphenyl] acetic acid was obtained (RS)-(4-carbamimidoyl)-[2-(3,4-deferasirox)-5-ethylphenyl]acetic acid;

361.b) when using 2-methylthioethyl through intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-[5-ethyl-2-(2-methylsulfonylmethane)phenyl] acetic acid was obtained (RS)-(4-carbamimidoyl)-[5-ethyl-2-(2-methylsulfonylmethane)phenyl]acetic acid;

361. C) using 4-(hydroxymethyl)pyridine via the intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-[5-ethyl-2-(pyridine-4-ylethoxy)phenyl] acetic acid was obtained (RS)-(4-carbamimidoyl)-[5-ethyl-2-(pyridine-4-ylethoxy)phenyl]acetic acid;

361.g) using 3-furanmethanol through intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-[5-ethyl-2-(furan-3-ylethoxy)phenyl] acetic acid was obtained (RS)-(4-carbamimidoyl intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-[5-ethyl-2-(pyridine-3-ylethoxy)phenyl] acetic acid was obtained (RS)-(4-carbamimidoyl)-[5-ethyl-2-(pyridine-3-ylethoxy)phenyl]acetic acid;

361. e) when using Cyclopentanol through intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-(2-cyclopentyloxy-5-ethylphenyl)acetic acid was obtained (RS)-(4-carbamimidoyl)-(2-cyclopentyloxy-5-ethylphenyl)acetic acid;

361.W) using (hydroxymethyl)cyclopropane via the intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-(2-cyclopropylmethoxy-5-ethylphenyl)acetic acid was obtained (RS)-(4-carbamimidoyl)-(2-cyclopropylmethoxy-5-ethylphenyl)acetic acid;

361.C) using (hydroxymethyl)cyclopentane through intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-(2-cyclopentyloxy-5-ethylphenyl)acetic acid was obtained (RS)-(4-carbamimidoyl)-(2-cyclopentyloxy-5-ethylphenyl)acetic acid;

361. and when using 2-(3-forfinal)ethanol via the intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-{ 5-ethyl-2-[2-(3-forfinal)ethoxy] phenyl} acetic acid was obtained (RS)-(4-carbamimidoyl)-{5-ethyl-2-[2-(3-forfinal)ethoxy]phenyl}acetic acid;

361. K) when using 2-propargilovyh alcohol through the intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-(5-ethyl-2-ol is strong acid;

361. l) when using 2-(2-forfinal)ethanol via the intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-{ 5-ethyl-2-[2-(2-forfinal)ethoxy] phenyl} acetic acid was obtained (RS)-(4-carbamimidoyl)-{5-ethyl-2-[2-(2-forfinal)ethoxy]phenyl}acetic acid;

361. m) using 2-(4-forfinal)ethanol via the intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-{ 5-ethyl-2-[2-(4-forfinal)ethoxy] phenyl} acetic acid was obtained (RS)-(4-carbamimidoyl)-{5-ethyl-2-[2-(4-forfinal)ethoxy]phenyl}acetic acid;

361.h) using 2,5-differenziava alcohol through the intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-[2-(2,5-deferasirox)-5-ethylphenyl] acetic acid was obtained (RS)-(4-carbamimidoyl)-[2-(2,5-deferasirox)-5-ethylphenyl]acetic acid;

361.o) using 2,5-differenziava alcohol through the intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-[2-(2,5-deferasirox)-5-ethylphenyl] acetic acid was obtained (RS)-(4-carbamimidoyl)-[2-(2,5-deferasirox)-5-ethylphenyl]acetic acid;

361. p) using (RS)-1-isopropyl-3-pyrrolidinone through the intermediate formation of a mixture of methyl RS)- and (SR)-(4-carbamimidoyl)-[5-ethyl-2-[(RS)-(1-isopropylpyrimidine-3-yloxy)]phenyl]acetic acid;

361.p) using (RS)-tetrahydro-3-furanmethanol through the intermediate formation of a mixture of the methyl esters of (RS)- and (SR)-(4-cyanovinylene)-[5-ethyl-2-[(RS)-(tetrahydrofuran-3-ylethoxy)]phenyl]acetic acid was obtained a mixture of (RS)- and (SR)-(4-carbamimidoyl)-[5-ethyl-2-[(RS)-(tetrahydrofuran-3-ylethoxy) ]phenyl]acetic acid;< / BR>
361. (C) using (RS)-(2-forfinal)methylcarbazole through the intermediate formation of a mixture of the methyl esters of (RS)- and (SR)-(4-cyanovinylene)-{ 5-ethyl-2-[(RS)-[1-(2-forfinal)ethoxy] ]phenyl}acetic acid was obtained a mixture of (RS)- and (SR)-(4-carbamimidoyl)-{5-ethyl-2-[(RS)-[1-(2-forfinal)ethoxy]]phenyl}acetic acid.

Example 362.

The following compounds were obtained according to the method described in the examples 354.1 and 354.2, phenol, obtained as described in example 124, and the corresponding alcohols:

362. a) when using 2-methylthioethyl through intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-[3-ethoxy-5-(2-methylsulfonylmethane)phenyl] acetic acid was obtained (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(2-methylsulfonylmethane)phenyl]acetic acid;

362. b) using 4-(hydroxymethyl)pyridine via the intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-[3 is n-4-ylethoxy)phenyl]acetic acid;

362. C) using 4-methyl-5-thiazoleethanol through intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-{3-ethoxy-5-[2-(4-methylthiazole-5-yl)ethoxy] phenyl} acetic acid was obtained (RS)-(4-carbamimidoyl)-{ 3-ethoxy-5-[2-(4-methylthiazole-5-yl)ethoxy] phenyl} acetic acid;

362.g) using (hydroxymethyl) cyclopentane through intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-(3-cyclopentyloxy-5-ethoxyphenyl)acetic acid was obtained (RS)-(4-carbamimidoyl)-(3-cyclopentyloxy-5-ethoxyphenyl)acetic acid;

362. e) using 2-(3-forfinal)ethanol via the intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-{3-ethoxy-5-[2-(3-forfinal)ethoxy] phenyl} acetic acid was obtained (RS)-(4-carbamimidoyl)-{3-ethoxy-5-[2-(3-forfinal)ethoxy]phenyl}acetic acid;

362. e) using 2-(hydroxymethyl)pyridine via the intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-[3-ethoxy-5-(pyridine-2-ylethoxy)phenyl] acetic acid was obtained (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(pyridine-2-ylethoxy)phenyl]acetic acid;

362. g) using 2-isopropoxyethanol through intermediate formation IU is americoliberian)-[3-ethoxy-5-(2-isopropoxyphenoxy)phenyl]acetic acid;

362. C) when using propargilovyh alcohol through the intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-(3-ethoxy-5-prop-2-injectively)acetic acid was obtained (RS)-(4-carbamimidoyl)-(3-ethoxy-5-prop-2-injectively)acetic acid;

362. and when using 2-(2-forfinal)ethanol via the intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-{3-ethoxy-5-[2-(2-forfinal)ethoxy] phenyl} acetic acid was obtained (RS)-(4-carbamimidoyl)-{3-ethoxy-5-[2-(2-forfinal)ethoxy]phenyl}acetic acid;

362. K) when using 2-indanol through intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-[3-ethoxy-5-(indan-2-yloxy)phenyl] acetic acid was obtained (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(indan-2-yloxy)phenyl]acetic acid;

362. l) when using tetrahydro-4H-Piran-4-ol via the intermediate formation of methyl ester of (RS)-(4-cyanovinylene)-[3-ethoxy-5-(tetrahydropyran-4-yloxy)phenyl] acetic acid was obtained (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(tetrahydropyran-4-yloxy)phenyl] acetic acid.

Example A. Pharmaceutical composition I, in one tablet, mg:

Active component - 200

Microcrystalline CE the BR>
Example B. Pharmaceutical composition II, in one capsule, mg:

Active component - 100,0

Corn starch - 20,0

Lactose - 95,0

Talc - 4,5

Magnesium stearate and 0.5

Total - 220,0 s

1. The compounds of formula

< / BR>
where R1is hydrogen or a fragment group of ester, which can be split under physiological conditions;

E is hydrogen or hydroxy;

three of the symbols X1-X4independently represent a group C(Ra), C(Rb) or C(Rc), and the fourth refers to the group C(Rdor N;

Ra-Rdeach independently represents hydrogen, alkenyl, alkenylboronic, alkenylacyl, quinil, alkylalkoxy, alkoxy, alkoxyalkyl, alkoxyalkyl, alkoxyalkyl, alkoxyalkyl(alkyl)aminoalkyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonylmethyl, alkoxycarbonylmethyl, alkoxycarbonylmethyl, alkoxycarbonylmethyl, alkoxycarbonylmethyl, alkoxycarbonylmethyl, alkyl, alkyl(alkylsulphonyl)amino, alkylsulphonyl, alkylcarboxylic, alkylcarboxylic, alkylcarboxylic, alkylcarboxylic, alkylsulfanyl, alkylsulfonyl, alkylsulfanyl, alkylsulfonyl, arylalkyl, arylalkyl, Allakaket, allakariallak, arylalkyl, arylalkylamine, arylcarboxylic, arylcarboxamide, arylcarboxamide, aryloxy, aryloxyalkyl, arylsulfonyl, arylsulfonamides, carboxy, carboxylic, carboxylicacid, carboxylate, carboxycellulose, carboxyaniline, carboxyacid, carbamoylphenoxy, cycloalkyl, cycloalkene, cycloalkylation, cyclooctylamine, cycloalkylation, cycloalkylcarbonyl, cycloalkylcarbonyl, cycloalkylcarbonyl, dihydroxyacetone, halogen, haloalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkoxy, hydroxyalkyloxy, hydroxyalkyl, hydroxyalkoxy, hydroxycyclohexanone, mono - or dialkylamino, mono - or dialkylaminoalkyl, mono - or dialkylaminoalkyl, mono - or dialkylaminomethylcalix, 2,2,2-triftoratsetilatsetonom or heterocyclic Deputy, selected from the group consisting of useparalleloldgc, benzoimidazolyl, morpholinoethoxy, morpholinylmethyl, morpholinoethoxy, piperidinyloxy, piperidylamine, piperidinylmethyl, piperidinyloxy, alkylsulfonamides, fornillos, 1,3-dioxo-1,3-arsenicalis, pyridinylamino, piperidinylidene, pyridyloxy, pyrimidinamine-alkylenediamine, pyrrolidinyl, pyrrolidinyloxy, pyrrolidinyloxy, pyrrolidinyloxy, pyrrolidinyloxy, oxopyrrolidin, oxadiazolyl, tetrahydropyranyloxy, tetrahydropyranyloxy, tetrahydropyranyloxy, tetrahydrofurfurylamine, tetrahydrothiopyrano, tetrahydropyranyloxy, dioxotetrahydrofuran, thiazoleacetic and thiophenyl, where the heterocyclic substituents optionally substituted by alkyl, alkoxygroup, carboxylation, hydroxy-, tetraallyloxyethane, alkylsulfonyl or alkoxycarbonylmethyl or two adjacent groups of Ra-Rdtogether form the fragment condensed 1,4-dioxane, 1,3-dioxolane, 1-oksanalove or aryl ring, provided that not more than three of Ra-Rdhave the same values and X1not substituted by aryl, carboxypropyl or alkoxycarbonyl;

one of the G1and G2is hydrogen and the other is hydrogen, alkyl, hydroxy, alkoxy, aroyl or a group COO-Reor OCO-Rewhere Re- alkyl, optionally substituted with halogen, hydroxy-, alkoxy-, carboxypropyl, alkylcarboxylic the E. of salt.

2. Connection on p. 1, where Ra-Rdeach independently of one another denotes hydrogen, alkenyl, alkenylboronic, alkenylacyl, quinil, alkoxy, alkoxyalkyl, alkoxyalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylmethyl, alkoxycarbonyl, alkyl, alkylcarboxylic, alkylcarboxylic, alkylcarboxylic, alkylsulfonates, aminoethoxy, aryl, arylalkyl, Allakaket, allakariallak, arylalkyl, arylcarboxylic, arylcarboxamide, aryloxy, aryloxyalkyl, carboxy, carboxylic, carboxylate, carboxycellulose, carboxyaniline, carbamoylphenoxy, cycloalkyl, cycloalkene, cycloalkylation, cyclooctylamine, cycloalkylation, cycloalkylcarbonyl, cycloalkylcarbonyl, dihydroxyacetone, halogen, haloalkyl, haloalkoxy, haloalkyl, hydroxyalkoxy, hydroxyalkyloxy, hydroxyalkyl, hydroxyalkoxy, mono - or dialkylaminoalkyl, mono - or dialkylaminoalkyl, mono - or dialkylaminomethylcalix or heterocyclic Deputy, selected from the group consisting of morpholinoethoxy, morpholinylmethyl, morpholinoethoxy, piperidinyloxy, pipsology, pyrrolidinyl, pyrrolidinyloxy, pyrrolidinyloxy, pyrrolidinyloxy, pyrrolidinyloxy, oxadiazolyl, tetrahydropyranyloxy, tetrahydropyranyloxy, tetrahydropyranyloxy, tetrahydropyranyloxy, thiazoleacetic, where the heterocyclic substituents optionally substituted by alkyl, alkoxy, tetraallyloxyethane, alkylsulfonyl or alkoxycarbonylmethyl or two adjacent groups of Ra-Rdtogether form the fragment condensed 1,4-dioxane, 1,3-dioxolane, 1-oksanalove or aryl ring.

3. Connection on p. 2, where Ra-Rdeach independently of one another denotes alkenyl, alkenylacyl, quinil, alkoxy, alkoxyalkyl, alkoxyalkyl, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarboxylic, alkylsulfonates, arylcarboxamide, carbamoylphenoxy, carboxycellulose, cycloalkane, cycloalkylation, cycloalkylcarbonyl, cycloalkylcarbonyl, dihydroxyacetone, halogen, haloalkyl, haloalkoxy, haloalkyl, hydroxyalkoxy, hydroxyalkyloxy, hydroxyalkyl, hydroxyalkoxy, mono - or dialkylaminoalkyl or heterocyclic Deputy selected from the group shall originally, pyrrolidinyloxy, tetrahydropyranyloxy, tetrahydropyranyloxy, where the heterocyclic substituents optionally substituted by alkyl, alkoxy, tetraallyloxyethane, alkylsulfonyl or alkoxycarbonylmethyl.

4. Connection on p. 3, where Ra-Rdeach independently of one another denotes hydrogen, alkenyl, quinil, alkoxy, alkyl, carbamoylphenoxy, cycloalkane, cycloalkylation, dihydroxyacetone, halogen, haloalkoxy, haloalkyl, hydroxyalkoxy, hydroxyalkyl, hydroxyalkoxy, mono - or dialkylaminoalkyl or heterocyclic Deputy selected from the group comprising morpholinylmethyl, piperidinyloxy, pyridinylamino, pyrrolidinyloxy, pyrrolidinyloxy, tetrahydropyranyloxy, where the heterocyclic substituents optionally substituted by alkyl, alkoxy, tetraallyloxyethane, alkylsulfonyl or alkoxycarbonylmethyl.

5. Connection on p. 4, where Ra-Rdeach independently of one another denotes hydrogen, alkenyl, quinil, alkoxy, alkyl, carbamoylphenoxy, halogen, hydroxyalkoxy, hydroxyalkoxy, mono - or dialkylaminoalkyl or heterocyclic Deputy selected from the group comprising morpholine the definition of the substituents optionally substituted by alkyl, alkoxy-, tetraallyloxyethane, alkylsulfonyl or alkoxycarbonylmethyl.

6. Compounds according to any one of paragraphs.1-5, where X1- group C(Ra), X2group C(Rb), X3- group C(Rcand X4group C(Rd).

7. Compounds according to any one of paragraphs.1-6, where Rais hydrogen, carbamoylphenoxy, hydroxyalkoxy or halogen.

8. Compounds according to any one of paragraphs.1-7, where Ra- hydrogen.

9. Compounds according to any one of paragraphs.1-8, where Rbis hydrogen, alkenyl, quinil, alkoxy or alkyl.

10. Compounds according to any one of paragraphs.1-9, where Rb- alkoxy.

11. Compounds according to any one of paragraphs.1-10, where Rcis hydrogen, alkoxy, mono - or dialkylaminoalkyl or hydroxyalkoxy.

12. Compounds according to any one of paragraphs.1-11, where Rcis hydrogen or alkoxy.

13. Compounds according to any one of paragraphs.1-12, where Rdis hydrogen, alkoxy, hydroxyalkoxy, mono - or dialkylaminoalkyl or heterocyclic Deputy selected from the group comprising morpholinylmethyl, piperidinyloxy, pyridinylamino, pyrrolidinyloxyl or tetrahydropyranyloxy, where the heterocyclic substituents optionally substituted by alkyl or alkylsulfonyl.

Cocci, aroyl or a group COO-Reor OCO-Rewhere Re- alkyl, optionally substituted with halogen, hydroxy-, alkoxy-, carboxypropyl, alkylcarboxylic or arylcarboxylic.

15. Compounds according to any one of paragraphs.1-14, where one of the G1and G2is hydrogen or hydroxy and the other is hydrogen.

16. Compounds according to any one of paragraphs.1-15, where G1and G2- hydrogen.

17. Compounds according to any one of paragraphs.1-16, where R1- hydrogen.

18. Compounds according to any one of paragraphs.1-17, where E is hydrogen.

19. Compounds according to any one of paragraphs.1-18 selected from the group including

a) (RS)-(4-carbamimidoyl)-[4-(2-dimethylaminoethoxy)-3-ethoxyphenyl]acetic acid;

b) (RS)- and (SR)-(4-carbamimidoyl)-[3-ethoxy-5-[(1-RS,2RS)-2-hydroxycyclopent]phenyl]acetic acid;

in) (RS)-(4-carbamimidoyl)-(3,5-diethoxy-2-forfinal) acetic acid;

g) (RS)-(4-carbamimidoyl)-[3-ethoxy-5-[(1-methylpiperidin-4-yloxy)phenyl]acetic acid;

d) (RS)- and (SR)-(4-carbamimidoyl)-[3-ethoxy-4-[(RS)-2-hydroxy-1-methylethoxy] phenyl]acetic acid;

e) (RS)- and (SR)-(4-carbamimidoyl)-[3-ethoxy-5-[(1RS,2RS)-2-hydroxycyclohexyl]phenyl]acetic acid;

is) (4 carbamimidoyl)-[3-ethoxy-5-(tetrahydropyran-4-yloxy)phenyl]acetic acid;

and) (RS)-(4-carbamimidoyl)-(3-ethinyl-5-pyrrolidin-1-ylmethylene)acetic acid;

K) (RS)-(4-carbamimidoyl)-(3-pyrrolidin-1-ylmethyl-5-vinylphenol)acetic acid;

l) hydrochloride, (RS)-(4-carbamimidoyl)-(3-ethoxy-4-methoxyphenyl)acetic acid;

m) (RS)-(4-carbamimidoyl)-(2-fluoro-3,5-acid)acetic acid;

n) (RS)-(4-carbamimidoyl)-[3-ethoxy-5-(pyridine-2-illuminometer)phenyl]acetic acid;

a) (RS)-(4-carbamimidoyl)-(3-ethoxy-5-morpholine-4-ylmethylene)acetic acid;

p) (RS)-(4-carbamimidoyl)-[3-ethoxy-4-(2-hydroxyethoxy)phenyl] acetic acid;

R) (RS)-(4-carbamimidoyl)-[4,5-diethoxy-2-(2-hydroxyethoxy)phenyl]acetic acid;

C) (RS)-(4-carbamimidoyl)-[3-(3-dimethylamino-2,2-DIMETHYLPROPANE)-5-ethylphenyl]acetic acid;

t) (RS)-(4-carbamimidoyl)-[3-ethoxy-4-(2-hydroxyethoxy)phenyl] acetic acid;

y) (RS)-(4-carbamimidoyl)-[4,5-diethoxy-2-(3-hydroxypropoxy)phenyl]acetic acid; and

f) (RS)-(4-carbamimidoyl)-(2-carbamoylphenoxy-4,5-dioxyphenyl)acetic acid.

20. Compounds according to any one of paragraphs.1-19, with the ability to inhibit the mod is installed for the treatment and prevention of thrombosis, apoplexy, heart attack, inflammation or atherosclerosis.

21. Pharmaceutical composition having the ability to inhibit the formation of coagulation factors XA, Ha and thrombin induced by factor VII and tissue factor containing the compound according to any one of paragraphs.1-19 and pharmaceutically acceptable excipient, in the form of a galenical form for injection.

22. Method of preparing compounds according to any one of paragraphs.1-19, providing for the conversion of nitrile groups in the compound of formula II

< / BR>
where X1- X4, R1and E have the values specified in paras.1-19,

in carbamimidoyl group or N-hydroxycarbamoyl group and, if necessary, modification of reactive groups present in the resulting compound of formula I, and optionally conversion of the compounds of the formula I into a physiologically compatible salt or the conversion of salts of the compounds of formula I in free acid or base.

25. Compounds according to any one of paragraphs.1-19, obtained by the method according to p. 22.

24. The compounds of formula II according to p. 22, where X1- X4, R1and E have the values specified in paras.1-19.

 

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< / BR>
in which R1denotes a group R6-SO2-NR7-; R6-NR7-SO2-; R6-SO2-O-; R6-O-SO2-;

R2denotes a hydrogen atom or halogen, cyano, alkyl, CNS or halogenation group;

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R3and R4are identical or different and denote hydrogen atoms or alkyl groups;

R5denotes a hydrogen atom, alkyl group or aracelio group;

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The invention relates to new cycloalkenes and cycloalkanes, suitable as pharmaceutically active substances, more particularly to derivatives of 1,3-substituted of cycloalkene and cycloalkane formula (I)

Z-CH2-Y (I)

where Z stands for a group

< / BR>
where

where R is aryl, 2-, 3 - or 4-pyridinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2-, 4 - or 5-pyrimidinyl, unsubstituted or substituted lower alkyl, lower alkoxide, hydroxyl or halogen, 2-pyrazinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2 - or 3-thienyl, unsubstituted go substituted lower alkyl or halogen, 2 - or 3-furanyl, unsubstituted or substituted lower alkyl or halogen, 2-, 4 - and 5-thiazolyl, unsubstituted or substituted lower alkyl or halogen, 3-indolyl, 2-, 3 - or 4-chinoline, and m is the number 1, 2, or 3, or group

< / BR>
in which R and m have the above meanings;

Y - group

< / BR>
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mixtures of their isomers or the individual is

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< / BR>
where a IS-O-CmH2m-X1-

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,

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< / BR>
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