Derivatives of phenylglycine, method for their preparing, intermediate compounds, pharmaceutical composition and method for treatment

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of phenylglycine of the formula (I) , to their hydrates or solvates, and/or to physiologically acceptable salts and/or physiologically acceptable esters possessing inhibitory effect on amidolytic activity of the complex factor VIIa/tissue factor that can be used for therapeutic and/or prophylactic treatment of diseases, for example, thrombosis. In the formula (I) R1 means (C1-C6)-alkyl; R2 means hydrogen atom, hydroxy-(C1-C6)-alkoxy-, (C1-C6)-alkoxycarbonyloxy-, (C1-C6)-alkoxy-group or halogen-(C1-C6)-alkoxycarbonyloxy-(C1-C6)-alkoxy-group; R3 means hydrogen atom, (C1-C6)-alkoxy- or heterocycloalkyloxy-group wherein heterocycloalkyl group means 5-6-membered ring comprising a heteroatom taken among nitrogen and oxygen atom; R4 means hydrogen atom or ester residue that is cleaved off under physiological conditions. R5 means hydrogen atom, hydroxy-group, (C1-C6)-alkoxycarbonyl, halogen-(C1-C6)-alkoxycarbonyl, (C6)-aryloxycarbonyl,(C6)-arylalkoxycarbonyl, (C1-C6)-alkoxy-(C1-C6)-alkoxy(C1-C6)-alkoxycarbonyl, (C3-C6)-cycloalkyloxycarbonyl, (C2-C6)-alkynyloxycarbonyl, 5-methyl-2-oxo[1,3]dioxol-4-yl-methoxycarbonyl, (C6)-arylcarbonyloxy-, (C1-C6)-alkylaminocarbonyloxy-group, (C1-C6)-alkylcarbonyl, arylcarbonyl, arylaminocarbonyl or heteroarylcarbonyl wherein heteroaryl represents 5-6-membered ring comprising nitrogen atom the cycle; X means atom F, Cl or Br. Also, invention relates to a method for preparing compounds, intermediates substances and pharmaceutical composition and a method for treatment.

EFFECT: improved preparing method, valuable medicinal properties of agents and composition.

29 cl, 5 ex

 

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

where

R1means alkyl,

R2means hydrogen, hydroxyalkoxy, alkoxycarbonylmethyl or halogenocarboxylic,

R3means hydrogen, alkoxy or heterocyclizations,

R4means hydrogen or a residue of the ester group, which is cleaved under physiological conditions,

R5means hydrogen, hydroxy, alkoxycarbonyl, halogenosilanes, aryloxyalkyl, arylethoxysilanes, alkoxycarbonyl, cycloalkylcarbonyl, alkyloxyaryl, 5-methyl-2-oxo[1,3]dioxol-4-ylmethoxycarbonyl, arylcarboxylic, alkylaminocarbonyl, allmenareliars, alkylsulphonyl, arylcarbamoyl, heteroarylboronic or allumination,

X is F, Cl or Br,

and their hydrate or solvate and/or physiologically acceptable salts and/or physiologically acceptable esters,

provided that the compound of formula 1 is not selected from the group including

ethyl ester of (RS)-(4-carbamimidoyl)-(3,5-diethoxy-2-forfinal)acetic acid,

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

(RS)-(4-carbamimidoyl)-(2-fluoro-3,5-acid)of uksosn the Yu acid and

ethyl ester of (RS)-(4-carbamimidoyl)-(2-fluoro-3,5-acid)acetic acid.

In addition, the invention relates to a method for producing the above-mentioned compounds, pharmaceutical preparations which contain such compounds and to the use of these compounds for the manufacture of pharmaceutical products.

Examples of physiologically acceptable salts of these compounds of formula I are salts of physiologically acceptable mineral acids, such as hydrochloric acid, sulphuric acid, sulphurous acid or phosphoric acid, or 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 term "physiologically acceptable salts" means salts of these acids.

Examples of physiologically acceptable esters are esters of compounds of the formula I, in which the hydroxy-group converted into the corresponding esters with inorganic or organic acids, such as nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonate acid, para-oloololetova acid and the like, which are non-toxic to living organisms. The term "physiologically acceptable esters" means esters of these acids.

The compounds of formula I can be solvated, especially, gidratirovana. The term solvate and hydrate refers to compounds of the formula I, which include solvent molecules or in the case of hydrates, respectively, of the water molecules. Hydrating can occur in the process of obtaining or may occur gradually due to the hygroscopic properties of the initially anhydrous compound of formula I.

The compounds of formula I can have at least one asymmetric carbon atom and can therefore exist in the form of mixtures of enantiomers, diastereomers or in the form of optically pure compounds. The compounds of formula I may exist in tautomeric forms and the invention includes all such tautomeric forms.

In the scope of the present invention, the term alkyl used alone or in combination with other groups, such as alkoxy, alkoxycarbonyl etc., means a straight or branched hydrocarbon residue containing 1-6, preferably 1-4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl and isobutyl. Alkyl groups can be substituted, for example, by one or more halogen atoms, preferably chlorine is, for example, such as 2,2,2-trichlorethyl. Such groups are designated as halogenated. Alkyl groups may also be substituted by other groups, such as hydroxy, for example, can mean hydroxyethyl.

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

The term quinil used alone or in combination with other groups, means a straight or branched hydrocarbon residue containing a triple bond and up to 6, preferably up to 4 carbon atoms, such as ethinyl, butenyl or prop-2-inyl.

The term cycloalkyl means a cyclic alkyl group containing from three to six carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Such cyclic alkyl groups optionally can be substituted by one or more substituents such as alkyl, halogen or alkoxy, preferably alkyl.

The term cycloalkane or cycloalkane means cycloalkyl group, which is linked via oxy (-O-) group, such as cyclopentyloxy or cyclohexyloxy.

The term heteroseksualci means a cyclic alkyl group containing from three to six carbon atoms and from 1 to 2 atoms selected from the series nitrogen, oxygen or sulfur, such as tetrahydrof the Russian Academy of Sciences, pyrrolidine, morpholine, preferably tetrahydrofuran. Heterocytolysine groups can be substituted by the substituents mentioned above for group cycloalkyl.

The term aryl, as used alone or in combination with other terms, such as aryloxy, arylalkyl etc. means carbocyclic, aromatic residue 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; alkyl, such as methyl, propyl or butyl; halogenation, such as trifluoromethyl; alkoxygroup, such as methoxy, ethoxy or propoxy; and the groups hydroxy, nitro, amino, mono - or dialkylamino, phenyl, phenoxy, COOH or COO-alkyl, such as SOOSN3or COOC2H5. Preferred substituents are alkoxy, halogen or alkyl, more preferred fluorine. Examples arylalkyl groups are benzyl, phenethyl, mono - or dimethoxybenzyl, aminobenzyl or nitrobenzyl, preferably benzyl, examples of aryloxy are phenoxy or ethoxycarbonylmethoxy, preferred phenoxy, and examples of arylalkylamine are benzyloxy, methoxybenzyloxy, venetucci, preferably benzyloxy.

The term heteroaryl means 5 - or 6-membered cycle which may contain (in a loop), 1 or 2 atoms, selected from the series nitrogen, oxygen or sulphur, such as furyl, pyridyl, 1,2-, 1,3 - and 1,4-diazines, thiophenyl, isoxazolyl, oxazolyl or imidazolyl. Heteroaryl group may be substituted by the substituents described above for the aryl group.

The term halogen means fluorine, chlorine, bromine and iodine. Preferred fluorine and chlorine, more preferred fluorine.

Examples of the group R4that is formed by hydrolysis of the ester group under physiological conditions, are alkyl; hydroxyalkyl, such as hydroxyethyl; arylalkyl, such as morpholinoethyl; 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-(pilosellae)ethyl; dialkylaminomethyl; morpholine-4-ylcarbamate.

Preferred groups R4are methyl, ethyl, isopropyl, butyl, isobutyl or benzyl.

In more detail, the present invention relates to compounds of the formula

where

R1means alkyl,

R2means hydrogen, hydroxyalkoxy, alkoxycarbonylmethyl or halogenoacetyl is joxeankoret,

R3means hydrogen, alkoxy or heterocyclizations,

R4means hydrogen or a residue of the ester group, which is cleaved under physiological conditions,

R5means hydrogen, hydroxy, alkoxycarbonyl, halogenosilanes, aryloxyalkyl, arylethoxysilanes, alkoxycarbonyl, cycloalkylcarbonyl, alkyloxyaryl, 5-methyl-2-oxo[1,3]dioxol-4-ylmethoxycarbonyl, arylcarboxylic, alkylaminocarbonyl, allmenareliars, alkylsulphonyl, arylcarbamoyl, heteroarylboronic or allumination,

X is F, Cl or Br,

and their hydrate or solvate and/or physiologically acceptable salts and/or physiologically acceptable esters, provided that the compound of formula 1 is not selected from the group including

ethyl ester of (RS)-(4-carbamimidoyl)-(3,5-diethoxy-2-forfinal)acetic acid,

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

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

ethyl ester of (RS)-(4-carbamimidoyl)-(2-fluoro-3,5-acid)acetic acid.

Preferred compounds of formula I and their physiologically acceptable salts and/or physiologically acceptable esters, above all, preferred compounds forms the crystals I.

Preferred compounds of formula I, in which only one of R2and R3means hydrogen. Another preferred variant of the present invention are compounds described above, where R1means ethyl.

Another preferred variant of the present invention are compounds described above, where R2means hydrogen, 2-hydroxyethoxy or 2-(2,2,2-trichlorocarbanilide)ethoxy.

Preferred compounds in which R2means hydrogen, as well as such compounds, where R2means 2 hydroxyethoxy. Preferred compounds in which R3means hydrogen, as well as such compounds, where R3means ethoxy and compounds, where R3means tetrahydrofuran-3-yloxy.

The invention primarily relates to the compounds mentioned above, in which R4means hydrogen, alkyl or arylalkyl, preferably hydrogen, ethyl, isopropyl, butyl, isobutyl or benzyl, more preferably hydrogen, and more preferably ethyl.

In addition, the invention primarily relates to the compounds mentioned above, in which R5means hydrogen, hydroxy, etoxycarbonyl, 2,2,2-trichlorocyanuric, methoxycarbonyl, 4-forgenerations, benzyloxycarbonyl, 2-methoxyethoxymethyl, 2-isopropyl-5-methylcyclohexanecarboxylic, the ROP-2-indoxacarb, 5-methyl-2-oxo-[1,3]dioxol-4-ylmethoxycarbonyl, benzoyloxy, ethylenedicarboxylic, phenylenecarbonyl, benzoyl, 3-perbenzoic, 4-perbenzoic, 2,4-differentail, 3,4-dimethoxybenzyl, 3,5-dimethoxybenzoyl, 4-methylbenzoyl, 4-trifloromethyl, phenylenecarbonyl or isobutoxide. First of all, the preferred compounds described above, in which R5means hydrogen, and compounds in which R5means hydroxy, the compounds in which R5means benzoyl, and compounds in which R5means 2,2,2-trichlorocyanuric. Another preferred variant of the invention refers to compounds in which X is fluorine.

In the context of the present invention in accordance with the above values of preferred compounds of formula Ia

where R1, R2, R3, R4, R5and X have the meanings specified above.

Above all, preferred compounds of formula I described in examples in the form of individual compounds in the form of free acids, their esters, and their hydrate or solvate, and physiologically acceptable salts.

Preferred individual compounds are selected from the group including

the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)is enyl]acetic acid,

(RS)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

(S)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

(R)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

ethyl ester of(RS)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

ethyl ester of(S)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

ethyl ester of(R)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

(RS)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid with one equivalent of sodium chloride,

ethyl ester of(RS)-[4-(aminoethoxyethanol)phenylamino]-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

ethyl ester of(RS)-{4-[amino-(2,2,2-trichlorocarbanilide)methyl]phenylamino}-{5-ethoxy-2-fluoro-4-[2-(2,2,2-trichlorocarbanilide)ethoxy]phenyl}acetic acid,

ethyl ester of(RS)-{4-[amino-(2,2,2-trichlorocarbanilide)methyl]phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl}acetic acid,

ethyl ester of(S)-{4-[amino-(2,2,2-trichlorocarbanilide)methyl]phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl}of uksosn the th acid,

ethyl ester of(R)-{4-[amino-(2,2,2-trichlorocarbanilide)methyl]phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl}acetic acid,

ethyl ester of(RS)-[4-(aminoethoxyethanol)phenylamino]-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

ethyl ester of(RS)-{4-[amino-(4-perfeccionandome)methyl]phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

ethyl ester of(RS)-[4-(aminobenzenesulphonyl)phenylamino]-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

ethyl ester of(RS)-{4-[amino-(2-methoxyethoxymethyl)methyl]phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

ethyl ester{4-[amino-[1R-(2S-isopropyl-5R-methylcyclohexyl)oxycarbonyl]methyl]phenylamino}-α-(RS)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

ethyl ester of(RS)-[4-(aminopropyl-2-ineluctibility)phenylamino]-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

ethyl ester of(RS)-{4-[amino-(5-methyl-2-oxo-[1,3]dioxol-4-ylmethoxycarbonyl)methyl]phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

ethyl ester of(RS)-α-[[4-[[(benzoyloxy)amino]iminomethyl]phenyl]amino]-5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)benzooxazol acid,

ethyl ester of(RS)-5-ethoxy-α-[[4-[[[[(ethylamino)carbonyl]oxy]amino]they shall said;"] phenyl]amino]-2-fluoro-4-(2-hydroxyethoxy)benzooxazol acid,

ethyl ester of(RS)-5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)-α-[[4-[imino[[[(phenylamino)carbonyl]oxy]amino]methyl]phenyl]amino]benzene-acetic acid,

ethyl ester of(RS)-{4-[amino-(4-forbeswoman)methyl]phenylamino}-5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

ethyl ester of(RS)-[4-(aminobenzoylamino)phenylamino]-5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

ethyl ester of(S)-[4-(aminobenzoylamino)phenylamino]-5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

ethyl ester of(R)-[4-(aminobenzoylamino)phenylamino]-5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

ethyl ester of(RS)-[4-(aminopolycarboxylates)phenylamino]-5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

butyl ether(RS)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

butyl ether(S)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

butyl ether(R)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

isopropyl ether(RS)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

isopropyl ether(S)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)FeNi is amino]acetic acid,

isopropyl ether(R)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

benzyl ether of(RS)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

benzyl ether of(S)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

benzyl ether of(R)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

isobutyl ether(RS)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

isobutyl ether(S)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

isobutyl ether(R)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

ethyl ester of(RS)-{4-[amino-(2,4-diferentseerimine)methyl]phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

ethyl ester of(RS)-{4-[amino-(3,5-dimethoxyphenethylamine)methyl]phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

ethyl ester of(RS)-{4-[amino-(3,4-dimethoxyphenethylamine)methyl]phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

ethyl ester of(RS)-{4-[amino-(3-forbeswoman)methyl]phenylamino}-[5-ethoxy-2-fluoro-4-(hydroxyethoxy)phenyl]acetic acid,

ethyl ester of(RS)-{4-[amino-(4-triftormetilfullerenov)methyl]phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

ethyl ester of(RS)-{4-[amino-(4-methylbenzylamino)methyl]phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

(R)-(4-carbamimidoyl)-(3,5-diethoxy-2-forfinal)acetic ciloto,

(S)-(4-carbamimidoyl)-(3,5-diethoxy-2-forfinal)acetic ciloto,

ethyl ester of(RS)-(3,5-diethoxy-2-forfinal)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

ethyl ester of(R)-(3,5-diethoxy-2-forfinal)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

ethyl ester of(S)-(3,5-diethoxy-2-forfinal)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

(RS)-(3,5-diethoxy-2-forfinal)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

(R)-(3,5-diethoxy-2-forfinal)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

(S)-(3,5-diethoxy-2-forfinal)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

ethyl ester of(RS)-[4-(aminoethoxyethanol)phenylamino](3,5-diethoxy-2-forfinal)acetic acid,

ethyl ester of(RS)-{4-[amino-(4-perfeccionandome)methyl]phenylamino}-(3,5-diethoxy-2-forfinal)acetic acid,

ethyl ester of(RS)-{4-[amino-(2,2,2-trichlorocarbanilide)methyl]phenylamino}-(3,5-diethoxy-2-forfinal)acetic key is lots

ethyl ester of(RS)-{4-[amino-(5-methyl-2-oxo-[1,3]dioxol-4-ylmethoxycarbonyl)methyl]phenylamino}-(3,5-diethoxy-2-forfinal)acetic acid,

ethyl ester of(RS)-[4-(aminoethoxyethanol)phenylamino]-(3,5-diethoxy-2-forfinal)acetic acid,

ethyl ester of(RS)-[4-(aminophenoxyethanol)phenylamino]-(3,5-diethoxy-2-forfinal)acetic acid,

ethyl ester of(RS)-[4-(aminopolycarboxylates)phenylamino]-(3,5-diethoxy-2-forfinal)acetic acid,

ethyl ester of(RS)-{4-[amino-(4-forbeswoman)methyl]phenylamino}-(3,5-diethoxy-2-forfinal)acetic acid,

butyl ether(RS)-(3,5-diethoxy-2-forfinal)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

isopropyl ether(RS)-(3,5-diethoxy-2-forfinal)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

ethyl ester of(RS)-[5-ethoxy-2-fluoro-3-[(R)-tetrahydrofuran-3-yloxy]phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

ethyl ester of(R)-[5-ethoxy-2-fluoro-3-[(R)-tetrahydrofuran-3-yloxy]phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

ethyl ester of(S)-[5-ethoxy-2-fluoro-3-[(R)-tetrahydrofuran-3-yloxy]phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

the hydrochloride of the ethyl ester of(RS)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-3-[(R)-tetrahydrofuran-3-yloxy]phenyl]acetic acid,

(RS)-(4-CT is americoliberian)-[5-ethoxy-2-fluoro-3-[(R)-tetrahydrofuran-3-yloxy]phenyl]acetic acid,

(R)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-3-[(R)-tetrahydrofuran-3-yloxy]phenyl]acetic acid,

(S)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-3-[(R)-tetrahydrofuran-3-yloxy]phenyl]acetic acid,

the hydrochloride of the ethyl ester of(RS)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-3-[(S)-tetrahydrofuran-3-yloxy]phenyl]acetic acid,

(RS)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-3-[(S)-tetrahydrofuran-3-yloxy]phenyl]acetic acid,

(R)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-3-[(S)-tetrahydrofuran-3-yloxy]phenyl]acetic acid and

(S)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-3-[(S)-tetrahydrofuran-3-yloxy]phenyl]acetic acid.

Above all, preferred compounds selected from the group including

(R)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

(R)-(4-carbamimidoyl)-(3,5-diethoxy-2-forfinal)acetic acid,

(R)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-3-[(R)-tetrahydrofuran-3-yloxy]phenyl]acetic acid,

ethyl ester of(R)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

ethyl ester of(R)-{4-[amino-(2,2,2-trichlorocarbanilide)methyl]phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

ethyl ester of(R)-[4-(aminobenzoylamino)phenylamino]-[5-ethoxy-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

butyl ether(R)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

isopropyl ether(R)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

benzyl ether of(R)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid and

isobutyl ether(R)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid.

Other, above all, preferred compounds are compounds selected from the group including

ethyl ester of(R)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

(R)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid and

ethyl ester of(RS)-[5-ethoxy-2-fluoro-3-[(S)-tetrahydrofuran-3-yloxy]phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid.

Another preferred compound is ethyl ester of (S)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid.

A preferred variant of the present invention also includes physiologically acceptable salts of the aforementioned compounds.

In addition, in accordance with the above values are preferred compounds in which the R 3does not mean alkoxy, if R5means hydrogen.

In addition, the invention relates to a method for producing compounds of formula I, and the method includes the transformation of a nitrile group in a compound of formula II

where R1, R2, R3, R4and X have the meanings indicated above in carbamimidoyl or N-hydroxycarbamoyl group, and, if necessary, modification of reactive groups present in the resulting compound of formula I, and, if necessary, conversion of the compounds of formula I into a physiologically acceptable salt or conversion of salts of the compounds of formula I in free acid or base.

In addition, the invention relates to compounds of formula I, above, are obtained by a specified method. Another variant of the invention relates to compounds of formula II, where R1, R2, R3, R4and X have the meanings specified above.

The transformation of the nitrile group in a compound of formula II in group carbamimidoyl, -C(NH)NH2or the group N-hydroxycarbonylmethyl, -C(NOH)NH2can be performed by known methods. For example, the transformation of the group N-hydroxycarbonylmethyl can be performed after dissolution of the compounds of formula II in a solvent such as DMF, ethanol or methanol, processing the obtained solution g is doxylamine or hydroxylamine salt and an inorganic acid, such as hydroxylamine hydrochloride, and then a base, such as diisopropylethylamine or triethylamine, sodium hydride or methanolate sodium, preferably at a temperature of up to 80°C.

The conversion of nitrile groups in carbamimidoyl group can be, for example, treatment of 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, in a stream of dry gaseous hydrogen chloride, preferably at temperatures below 10°and then treating the reaction mixture with a solvent, such as diethyl ether, and subsequent separation of precipitated in the sediment of aminoether by filtration. The resulting material is treated in a solvent such as methanol or ethanol, gaseous ammonia or an ammonium salt such as ammonium chloride, preferably at a temperature of up to 80°C. In another embodiment, the solution aminoether can be was evaporated, and the residue is treated with gaseous ammonia or an ammonium salt in methanol or ethanol. Similarly, iminoethyl can be transformed into N-hydroxycarbonylmethyl derivative of the formula I, by treatment with hydroxylamine or its salt in the presence of a base.

For modifying functional groups present in the compound of formula I, first of all, use paragraph shall avramania N-hydroxycarbamoyl group in carbamimidoyl group, the esterification of the carboxyl group, the saponification of the ester group and a hydrolysis group of simple ether, such as arylalkyl group, for example, a simple ester with benzyl group. All these reactions are carried out by known methods.

For the conversion of N-hydroxycarbamoyl group in carbamimidoyl group amidoxime formula I hydronaut 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 palladium, platinum or Nickel. Similarly can be modified by other reactive groups present in the compound of formula I and is able to interact with the regenerating agent.

In the interaction of the compounds of formula I, where R5means hydrogen, with an appropriate complex ether of Harborview acid in which 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 connection the General formula I, where, R5as indicated above, means alkoxycarbonyl, halogenosilanes, aryloxyalkyl, arylethoxysilanes, alkoxycarbonyl, cycloalkylcarbonyl, alkyloxyalkyl or similar group, including oxycarbonyl balance. Similarly, the compound of formula I, where R5means hydrogen, can be converted by interaction with the corresponding para-nitrophenylarsonic into the corresponding compound of formula I, where R5as indicated above, means the group comprising oxycarbonyl balance. For example, the reaction can be carried out by interaction of para-nitrophenylphosphate in THF and DMF at first with N,N-diisopropylethylamine, and then with the compound of the formula I, where R5means hydrogen.

In the interaction of the compounds of formula I, where R5means hydrogen, acylchlorides can be obtained compound of formula I, where R5as indicated above, means acyl group. For example, the reaction is carried out by interaction of acylchlorides in THF and DMF at first with N,N-diisopropylethylamine, and then with the compound of the formula I, where R5means hydrogen.

In the interaction of the compounds of formula I, where R5means hydroxy, allelochemical can be obtained compound of formula I, where R5as indicated above, means arylcarboxylic or similar group, including the STATCOM of carbonyloxy. For example, the reaction is carried out by interaction of acylchlorides in THF and DMF at first with N,N-diisopropylethylamine, and then with the compound of the formula I, where R5means hydroxy.

In the interaction of the compounds of formula I, where R5means hydrogen, with an appropriate isocyanate can be obtained compound of formula I, where R5as indicated above, means the group comprising aminocarbonyl balance. The reaction is carried out by the interaction of the compounds of formula I, where R5means hydrogen, with an appropriate isocyanate in THF and DMF) in the presence of triethylamine.

In the interaction of the compounds of formula I, where R5means hydroxy, with an appropriate isocyanate can be obtained compound of formula I, where R5as indicated above, means the group comprising the remainder of aminocarboxylate. The reaction is carried out by the interaction of the compounds of formula I, where R5means hydroxy, with an appropriate isocyanate in THF.

The compounds of formula II can be obtained by known General methods, for example as described below and/or in the examples, or analogously to the methods shown. For example, the aldehyde of formula III

where R1, R2, R3and X have the meanings stated above, may be introduced into reaction with para-aminobenzonitrile formula IV

and benzylideneamino, colorselectiondialog or morpholinobenzenediazonium, and a primary alcohol, such as methanol or ethanol, in the presence of epirate of boron TRIFLUORIDE. Hydrolysis of the obtained aminoether water leads to the formation of compounds of formula II in which R4means methyl or ethyl. When the hydrolysis of the ester group R4for example, treatment with LiOH in tetrahydrofuran, get the connection formula II, where R4means hydrogen.

In addition, the compounds of formula II receive according to the following reactions.

Of the compounds of formula II, where R1together with attached oxygen atom and/or one or both of R2and R3means a hydroxy-group, by reaction

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 with alcohol in the presence of the DEAD, DIAD or di-tert-utilization.bacteria and triphenylphosphine in a solvent such as THF or dioxane,

get the compounds of formula II, in which the hydroxy-group transformed into alkoxygroup.

The compounds of formula III are known. For example, from compounds of the formula III,

where R1together with attached oxygen atom and/or one or both of R2and R3means a hydroxy-group, by reaction

- by the reaction of Mitsunobu with alcohol in the presence of the DEAD, DIAD or di-tert-utilization.bacteria and triphenylphosphine in a solvent such as THF or dioxane,

get the compounds of formula III, in which the hydroxy-group is replaced by alkoxygroup;

and if R1together with attached oxygen atom and/or one or both of R2and R3mean similarshow by reaction

with an alkylating agent, such as allylbromide, in an appropriate solvent, such as DMF, in the presence of potassium fluoride,

get the compounds of formula III, in which similartype replaced by alkoxygroup.

Starting materials for preparing compounds of formula III are commercial products or can be obtained by methods known in the art.

Because these materials are not described in the examples, the compounds of formulas I, II, III and IV can be obtained by similar methods or by the methods set forth above.

The compounds of formula I are active compounds and inhibit the formation of coagulation factors XA, IXa and thrombin induced by factor VIIa and TC is newim factor or such active compounds are formed under physiological conditions from the corresponding derivatives. Therefore, these compounds have an effect on platelet aggregation, which is induced by these factors, and plasmatic coagulation of blood. Therefore, they inhibit the formation of blood clots and can be used for the treatment or prevention of diseases, such as thrombosis, apoplexy, cardiac infarction, inflammation and arteriosclerosis. In addition, these compounds act on tumor cells and prevent the formation of metastases. Therefore, these compounds can be also used as protivoopuhulevyh agents.

Accordingly, the present invention relates also to pharmaceutical preparations comprising the compound described above and a pharmaceutically acceptable carrier and/or adjuvant.

The invention also includes compounds mentioned above for use as therapeutically active components, primarily as inhibitors of the formation of coagulation factors XA, IXa and thrombin induced by factor VIIa and tissue factor, especially as therapeutically active substances for the treatment or prevention of thrombosis, apoplexy, cardiac infarction, inflammation and/or atherosclerosis and/or as antitumoral the th agent.

Another preferred variant of the invention relates to a method of therapeutic and/or prophylactic treatment of thrombosis, apoplexy, cardiac infarction, inflammation, arteriosclerosis and/or cancer, and this method includes the introduction of the above compounds human or animal.

The invention also includes the use of the above compounds for the treatment or prevention of thrombosis, apoplexy, cardiac infarction, inflammation, arteriosclerosis and/or cancer.

The invention also relates to the use of the above compounds to obtain drugs for treatment or prevention of thrombosis, apoplexy, cardiac infarction, inflammation and arteriosclerosis or as an antitumor agent. Such medicines include the connection described above.

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, in each well of a tablet containing 25 μl of inhibitor solution in buffer solution (100 mm, pH 7.5, containing about 0.14 M NaCl, 0.1 M HEPES (N-(2-hydroxyethyl)piperazin the-N'-(2-econsultancy acid)), 0.5 mg/l BSA (bovine serum albumin)containing no fatty acid, and 0.05% NaN3] add 100 μl of a solution containing tissue factor (26 nm), soluble factor VIIa (9 nm) and calcium chloride (8 mm). After incubation for 15 min to initiate the hydrolysis reaction by adding 50 μl of chromogenic substrate Chromozym-tPA (3.5 mm MeSO2-D-Phe-Gly-Arg-para-nitroanilide) and the degree of hydrolysis of the substrate recorded spectrophotometrically using a reader to determine the kinetics of the reaction for 10 minutes values of Kidetermine, using the graph curves of inhibition according to the method described in the article Biochem. J., 55, 170-171 (1953).

Furthermore, the activity of low molecular weight compounds can be characterized "by the activation of prothrombin (VAP) in the test formation of fibrin clot. First prepare solutions of the analyzed compounds (10 mm) in DMSO or DMSO/0.1 M HCl (DHCl), and then the same solvent is brought to the required dilution. Then 0.25 ml of human plasma (obtained from whole blood treated with anticoagulant +1/10 volume 108 mm sodium citrate) placed in the sample container, provided by the instrumentation. Then in each case the plasma is mixed with 5 μl of a solution of the analyte at each dilution. The resulting mixture plasma/inhibitor incubated at 37°within minutes Then 50 μl of a mixture of plasma/inhibitor transferred into a semi-automatic device (ACL, Automated Coagulation Laboratory (Insrument Laboratory)) of the measuring container. The reaction of formation of fibrin clot initiated by adding 0.1 ml of the drug Innovin (recombinant tissue factor human in calcium buffer solution containing synthetic phospholipids (company Dade Behring Inc.)). Time to education fibrinous clot determined photometrically using ACL. The concentration of inhibitor at which time the activation of prothrombin doubles, determined by the chart.

Values of Kithe active compounds according to the present invention preferably comprise from about 0.1 to 500 nm, especially from about 0.1 to 150 nm. Values VAP preferably ranges from approximately 0.1 to 10 microns, especially from about 0.1 to 5 microns.

As noted above, the drug containing the compound of formula I, its MES or salt, are also the object of the present invention, the same applies to the method of obtaining such medicines, which comprises applying one or more such compounds, their salts or solvate, and, if necessary, other therapeutic substances in herbal form for injection. These medicines can be administered orally, for example in the form of pills, tverdykh soft gelatin capsules, solutions, emulsions or suspensions, or rectally way, for example, in the form of suppositories, or in the form of an aerosol. However, the introduction can be carried out also by parenteral way, for example, in the form of injection solutions. To obtain tablets, coated tablets, dragées and hard gelatin capsules the active ingredient is mixed with pharmaceutically inert, inorganic or organic excipients. Suitable eccipienti for tablets, coated tablets, dragées and hard gelatin capsules are, for example, lactose, corn starch or its derivatives, talc, stearic acid or its salts. Suitable excipients for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols; however, in the case of soft gelatin capsules, depending on the nature of the active ingredient is usually no need for the use of excipients. Suitable excipients upon receipt 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 hardened oils, waxes, fats, semi-solid and liquid polyols. In addition, FA the pharmaceutical preparations can include preservatives, solubilizing agents, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for regulating the osmotic pressure, buffer substances, covering substances or antioxidants.

The dosage of the active ingredient in the treatment or prophylaxis of the diseases mentioned above, can vary in a wide interval, and will vary in each case. In General, when oral or parenteral, e.g. intravenous or subcutaneous, the introduction of the adult patient sufficient dose is from about 0.1 to 20 mg/kg, preferably from about 0.6 to 5 mg/kg per day, while the upper limit may be exceeded or the dose may be reduced in accordance with the indications.

The present invention and its preferred options are illustrated by the following examples, without limiting its scope.

Examples

Example 1

1.1

To a solution of 2-bromo-4-terfenol (25,8 g) in DMF (100 ml) was added To a2CO3(20.5 g), ethyliodide (23,2 g) and the mixture was stirred at room temperature for 24 h Then was added water (400 ml) and was extracted with hexane. The organic phase is washed with water, dried, filtered through a layer of silica gel and evaporated, thus received to 30.1 g of 2-bromo-1-ethoxy-4-fervently in the form of a colorless oil. MS: 220 ([M+H]+).

12

2-Bromo-1-ethoxy-4-torbenson (3.1 g), described in example 1.1, was dissolved in THF (25 ml). The solution was cooled to -75°C, was slowly added a solution of n-BuLi (9,73 ml, 1.6 M solution in hexane) and the mixture was stirred at -75°C for 30 minutes and Then for 5 min was added trimethylboron (1,62 g) and successively added acetic acid (1.27 g) and 30%solution of H2O2(1.51 g). The mixture was stirred at 0°C for 30 min and at room temperature for 3 hours Then was added water and was extracted with ethyl acetate. The crude product was purified by chromatography on a column (n-hexane/ethyl acetate), was obtained 1,77 g 2 ethoxy-5-terfenol in the form of a colorless oil. MS: 156 ([M]+).

1.3

2 Ethoxy-5-terfenol (14.3 g), described in example 1.2, was dissolved in triperoxonane acid (90 ml) and the resulting solution was slowly added to a solution of hexamethylenetetramine (25,7 g) in triperoxonane acid (90 ml) at 80°C. the Mixture was stirred at 80°C for 1 h and concentrated. Then added water (250 ml)was stirred for 10 min, neutralized by adding Na2CO3and was extracted with ether. The crude product was purified by chromatography on a column (n-hexane/ethyl acetate), was obtained 9,43 g 5-ethoxy-2-fluoro-4-hydroxybenzaldehyde in a solid yellow color. MS: 184 ([M]+).

1.4

5-Ethoxy-2-fluoro-4-hydroxybenzaldehyde (9,15 g), described in example 1.3, was dissolved in toluene (80 ml). Then added ethylene carbonate resulting in (a 5.25 g), iodide tetrabutylamonium (1,83 g) and the mixture is boiled under reflux for 22 hours the Mixture was cooled to room temperature and filtered through a layer of silica gel. The product was suirable hexane/ethyl acetate, the solvent evaporated and the solid was washed with hot hexane, obtained 10.3 g of 5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)benzaldehyde in the form of a solid light orange color. MS: 228 ([M]+).

1.5

5-Ethoxy-2-fluoro-4-(2-hydroxyethoxy)benzaldehyde (10,34 g)described in example 1.4, was dissolved in ethanol (160 ml). Then were added 4-aminobenzonitrile (4,87 g) and stirred at room temperature. After 1 h was added 5,68 ml morpholinosydnonimine. The resulting solution was cooled to 0°and was added dropwise 15,53 ml epirate of boron TRIFLUORIDE, maintaining the temperature of the mixture not more than 5°C. the Reaction mixture was stirred at 0°C for 15 min and at room temperature for 1.5 hours Then added water (20 ml) and was stirred over night at room temperature. The crude product was isolated by extraction and purified by chromatography on silica gel, thus received 11,13 g of ethyl ester of(RS)-(4-cyanoaniline)[5 ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid in the form of a solid yellow is atogo color. MS: 425 ([M+Na]+).

1.6

Ethyl ester of(RS)-(4-cyanovinylene)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid (201 mg)described in example 1.5, was dissolved in a mixture of chloroform (1.9 ml) and ethanol (0,38 ml). The mixture was cooled to -10°and saturated with dry gaseous HCl. The flask was closed and kept at 4°With during the night. The mixture is then concentrated to dryness, was added ethanol (1.1 ml), a solution of ammonia (2 M solution in EtOH, 0.5 ml) and stirred at 65°for 2.5 hours the Mixture was concentrated, the reaction product was isolated by chromatography on a column (CH2Cl2/MeOH), received 182 mg of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)[5 ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid as colorless solid. MS: 420 ([M+H]+).

The compound obtained was separated into the enantiomers preparative GHUR on chiral stationary phase (Chiralpak AD) using as mobile phase heptane/ethanol/triperoxonane acid (60:40:0,2), received triptorelin ethyl ester (S)-(4-carbamimidoyl)[5 ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid and triptorelin ethyl ester(R)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid as colorless solids. The compounds can be neutralized received the eat, accordingly, the ethyl ester of(S)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid ethyl ester(R)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid.

1.7

The hydrochloride of the ethyl ester of(RS)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid (172 mg)described in example 1.6, suspended in THF (1.1 ml). Then added 1 M NaOH (0,82 ml)was stirred at 0°C for 30 min and at room temperature for 40 min and was added 1 M HCl (0,41 ml). The mixture was concentrated, the solid is washed with water, ether and dried, it was received 129 mg of (RS)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid as colorless solid. MS: 392 ([M+H]+).

The compound obtained was separated into the enantiomers preparative GHUR on chiral stationary phase (Chiralpak AD) using as mobile phase of heptane/ethanol/triperoxonane acid (50:50:0,2), after neutralization was obtained (S)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid and (R)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid acid as colorless solids.

1.8

Ethyl ester of(RS)-(4-cyanovinylene)-[5-ethoxy-2-fluoro-4-(2-Ki is roxilox)phenyl]acetic acid (177 mg), described in example 1.5, was dissolved in a mixture of chloroform (1.7 ml) and ethanol (0.3 ml). The mixture was cooled to -10°and saturated with dry gaseous HCl. The flask was closed and kept at 4°With during the night. The mixture is then concentrated to dryness, was added ethanol (13 ml), hydroxylamine hydrochloride (61 mg), triethylamine (222 mg) and the mixture was stirred at room temperature for 2 hours the Product was isolated by extraction and chromatography on a column (CH2Cl2/MeOH), received 116 mg of ethyl ester of(RS)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid as colorless foam. MS: 436 ([M+H]+).

The compound obtained was separated into the enantiomers preparative GHUR on chiral stationary phase (Chiralpak AD) using as mobile phase heptane/ethanol/triperoxonane acid (75:25:0,2), after neutralization received, respectively, ethyl ester of(S)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl][4-(N-hydroxycarbamoyl)phenylamino]acetic acid ethyl ester(R)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid as colorless foam.

1.9

Ethyl ester of(RS)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid (44 mg)described in example 1.8, suspended in THF (0, ml). Then added 1 M NaOH (0,101 ml) and the mixture was stirred at 0°C for 30 min and at room temperature for 2.5 hours the Mixture was neutralized 1 M HCl and concentrated, when it received 42 mg of (RS)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid as a colorless solid substance in a mixture with sodium chloride. MS: 408 ([M+H]+).

The compound obtained was separated into the enantiomers by the method GHUR on chiral stationary phase (Chiralpak AD) using as mobile phase n-hexane+triperoxonane acid(0,4%)/ethanol (85:15), after neutralization was obtained (R)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid as colorless solid.

1.10

The hydrochloride of the ethyl ester of(RS)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid (100 mg)described in example 1.6, was dissolved in DMF (1 ml). Then at 0°doebeli ethylchloride (24 mg) and triethylamine (67 mg) and the mixture was stirred at 0°C for 1 h the Product was isolated by extraction and chromatography on a column (CH2Cl2/acetone), was obtained 106 mg of ethyl ester of(RS)-[4-(aminoethoxyethanol)phenylamino]-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid as colorless foam. MS: 492 ([M+H]+).

1.11

Ethyl ester of(RS)-{4-[amino-(2,2,2-trichlorocarbanilide)methyl]-phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid, MS: 596 ([M+H]+), was obtained by the reaction of the hydrochloride of the ethyl ester of(RS)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid, described in example 1.6, 2,2,2-trichlorethylphosphate same way as described in example 1.10.

The compound obtained was divided into enantiomer preparative GHUR on chiral stationary phase (Chiralpak AD) using as mobile phase heptane/ethanol/diethylamine (60:40:0,2), received the ethyl ester of(S)-{4-[amino-(2,2,2-trichlorocarbanilide)methyl]phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid ethyl ester(R)-{4-[amino-(2,2,2-trichlorocarbanilide)methyl]phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid.

As a by-product has obtained the ethyl ester of(RS)-{4-[amino-(2,2,2-trichlorocarbanilide)methyl]phenylamino}-{5-ethoxy-2-fluoro-4-[2-(2,2,2-trichlorocarbanilide]phenyl}acetic acid. MS: 770.

1.12

Ethyl ester of(RS)-[4-(aminoethoxyethanol)phenylamino]-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid, MS: 478 ([M+H]+), was obtained by the reaction of the hydrochloride of the ethyl ester of(RS)-(4-carbamimidoyl)-[-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid, described in example 1.6, methylchloroform same way as described in example 1.10.

1.13

Ethyl ester of(RS)-{4-[amino-(4-perfeccionandome)methyl]phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid was obtained by the reaction of the hydrochloride of the ethyl ester of(RS)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid, described in example 1.6, 4-vtorganichoney.com same way as described in example 1.10.

1.14

Ethyl ester of(RS)-[4-(aminobenzenesulphonyl)-phenylamino]-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid, MS: 554 ([M+H]+), was obtained by the reaction of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid, described in example 1.6, benzylchloride same way as described in example 1.10.

1.15

Ethyl ester of(RS)-{4-[amino-(2-methoxyethoxymethyl)methyl]phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid, MS: 522 ([M+H]+), was obtained by the reaction of the hydrochloride of the ethyl ester of(RS)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid, described in example 1.6, 2-methoxyethylamine same way as described in example 1.10.

1.16

Ethyl ester{4-[amino-[1R-(2S-isopropyl-5R-methylcyclohexyl)oxycur is onlineno]methyl]phenylamino}-α -(RS)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid, MS: 602 ([M+H]+), was obtained by the reaction of the hydrochloride of the ethyl ester of(RS)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid, described in example 1.6, (- )- (1R)-methylchloroform same way as described in example 1.10.

1.17

Ethyl ester of(RS)-[4-(aminopropyl-2-ineluctibility)phenylamino]-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid, MS: 502 ([M+H]+), was obtained by the reaction of the hydrochloride of the ethyl ester of(RS)-(4-carbamimidoyl)[5 ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid, described in example 1.6, propargylation same way as described in example 1.10.

1.18

Ethyl ester of(RS)-{4-[amino-(5-methyl-2-oxo[1,3]dioxol-4-ylmethoxycarbonyl)methyl]phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid, MS: 576 ([M+H]+), was obtained by the reaction of the hydrochloride of the ethyl ester of(RS)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid, described in example 1.6, (5-methyl-2-oxo-1,3-dioxol-4-EN-4-yl)-para-nitrophenylarsonic same way as described in example 1.10.

1.19

Ethyl ester of(RS)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid (218 mg)described in example 1.8, was dissolved in the MF (2 ml). Then was added triethylamine (61 mg) and benzoyl chloride (77 mg). After stirring at room temperature for 1 h the mixture was poured into cold water and extracted with ethyl acetate. The product was purified by chromatography on a column (hexane/ethyl acetate), was obtained 230 mg of ethyl ester of (R,S)-α-[[4-[[(benzoyloxy)amino]iminomethyl]-phenyl]amino]-5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)benzooxazol acid in the form of a solid of light yellow color. MS: 540 ([M+H]+).

1.20

Ethyl ester of(RS)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid (300 mg)described in example 1.8, was dissolved in THF (3 ml). Then added utilizationa (54 mg) and the mixture was stirred at room temperature for 2 hours the Mixture was concentrated and the residue was purified by chromatography on a column (hexane/EtOAc), received 290 mg of ethyl ester of(R,S)-5-ethoxy-α-[[4-[[[[(ethylamino)carbonyl]oxy]amino]iminomethyl]phenyl]amino]-2-fluoro-4-(2-hydroxyethoxy)benzooxazol acid as a colourless foam, MS: 507 ([M+N]+).

1.21

Ethyl ester of(R,S)-5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)-α-[[4-[imino[[[(phenylamino)carbonyl]oxy]amino]methyl]phenyl]amino]benzoyloxy Noi acid, MS: 555 ([M+H]+), was obtained by the reaction of the ethyl ester of(RS)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]of the criminal code is usnei acid, described in example 1.8, phenylisocyanate same way as described in example 1.20.

1.22

Ethyl ester of(RS)-{4-[amino-(4-forbeswoman)methyl]phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid, MS: 542 ([M+Na]+), was obtained by the reaction of the hydrochloride of the ethyl ester of(RS)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid, described in example 1.6, 4-tormentilla same way as described in example 1.10.

1.23

Ethyl ester of(RS)-[4-(aminobenzoylamino)phenylamino]-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid, MS: 524 ([M+H]+), was obtained by the reaction of the hydrochloride of the ethyl ester of(RS)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid, described in example 1.6, with benzoyl chloride in the same way as described in example 1.10.

The compound obtained was separated into the enantiomers preparative GHUR on chiral stationary phase (Chiralpak AD) using as mobile phase heptane/isopropanol/diethylamine (60:40:0,2), received the ethyl ester of(S)-[4-(aminobenzoylamino)phenylamino][5 ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid ethyl ester(R)-[4-(aminobenzoylamino)phenylamino]-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid.

1.24

Hydrochloride ethyl ester(RS)(4 carbamimidoyl)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid (456 mg), described in example 1.6, was dissolved in THF (3 ml). Then added DMF (3 ml), triethylamine (106 mg), phenylisocyanate (131 mg) and the mixture was stirred at room temperature for 3 hours the Reaction mixture was concentrated and purified by chromatography on a column (hexane/ethyl acetate), was obtained 380 mg of ethyl ester of (RS)-[4-(aminophenylacetylene)phenylamino]-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid as colorless foam. MS: 539 ([M+H]+).

1.25

(RS)-(4-Cyanovinylene)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-acetic acid, MS: 373 ([M-H]-), was obtained by the reaction of the ethyl ester of (RS)-(4-cyanovinylene)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid, described in example 1.5, with LiOH in the same way as described in example 2.15.

1.26

(RS)-(4-Cyanovinylene)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid (226 mg)described in example 1.25, was dissolved in DMF (2 ml). Then was added potassium carbonate (167 mg), n-butylated (556 mg), tetrabutylammonium iodide (22 mg) and the mixture was stirred at room temperature overnight. Then added water and the mixture was extracted with EtOAc. The organic phase is washed with water, dried, filtered and concentrated. The product was purified by chromatography (SiO2, EtOAc/gscan), received 146 mg butyl ether(RS)-(4-cyanovinylene)-[5-ethoxy-2-fluoro-4-(2-HYDR is xiaoxi)phenyl]acetic acid as colorless solid. MS: 453 ([M+Na]+).

1.27

Butyl ether(RS)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid, MS: 464 ([M+H]+), was obtained by the reaction of butyl ether (RS)-(4-cyanovinylene)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid, described in example 1.26, with triethylamine and hydroxylamine hydrochloride in the same way as described in example 2.5.

The compound obtained was separated into the enantiomers preparative GHUR on chiral stationary phase (Chiralpak AD) using as mobile phase heptane/ethanol/triperoxonane acid (80:20:0,2), after neutralization received butyl ether(S)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid and (R)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid.

1.28

Isopropyl ether(RS)-(4-cyanovinylene)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid, MS: 439 ([M+Na]+), was obtained by the reaction of (RS)-(4-cyanovinylene)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid, described in example 1.25, isopropylidene same way as described in example 1.26.

1.29

Isopropyl ether(RS)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid, MS: 450 ([M+H]+) was obtained by the reaction of isopropyl ether(RS)-(4-cyanovinylene)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid, described in example 1.28, with triethylamine and hydroxylamine hydrochloride in the same way as described in example 2.5.

The compound obtained can be separated into the corresponding R - and S-enantiomers of known methods, for example, preparative GHUR on chiral stationary phase in the same way as described in example 1.27.

1.30

Benzyl ether of(RS)-(4-cyanovinylene)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid, MS: 487 ([M+Na]+), was obtained by the reaction of (RS)-(4-cyanovinylene)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid, described in example 1.25, benzylbromide same way as described in example 1.26.

1.31

Benzyl ether of(RS)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid, MS: 498 ([M+H]+), was obtained by the reaction of the benzyl ester of (RS)-(4-cyanovinylene)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid, described in example 1.30, with triethylamine and hydroxylamine hydrochloride in the same way as described in example 2.5.

The compound obtained can be separated into the corresponding R - and S-enantiomers of known methods, for example, preparative GHUR on chiral stationary phase in the same way as described in example 1.27.

1.32

Isobutyl ether (RS)-(4-cyanovinylene)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]kusnoy acid, MS: 430 ([M]+), was obtained by the reaction of (RS)-(4-cyanovinylene)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid, described in example 1.25, isobutylidene same way as described in example 1.26.

1.33

Isobutyl ether(RS)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid was obtained by the reaction of isobutyl ether(RS)-(4-cyanovinylene)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid, described in example 1.32, with triethylamine and hydroxylamine hydrochloride in the same way as described in example 2.5.

The compound obtained can be separated into the corresponding R - and S-enantiomers of known methods, for example, preparative GHUR on chiral stationary phase in the same way as described in example 1.27.

1.34

Ethyl ester of(RS)-{4-[amino-(2,4-diferentseerimine)methyl]-phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid, MS: 560 ([M+H]+), was obtained by the reaction of the hydrochloride of the ethyl ester of(RS)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid, described in example 1.6, 2.4-differentiaion same way as described in example 1.10.

1.35

Ethyl ester of(RS)-{4-[amino-(3,5-dimethoxyphenethylamine)methyl]phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid, MS: 584 ([M+H]+ ), was obtained by the reaction of the hydrochloride of the ethyl ester of(RS)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid, described in example 1.6, 3.5-dimethoxybenzonitrile same way as described in example 1.10.

1.36

Ethyl ester of(RS)-{4-[amino-(3,4-dimethoxyphenethylamine)methyl]phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid, MS: 584 ([M+H]+), was obtained by the reaction of the hydrochloride of the ethyl ester of(RS)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid, described in example 1.6, 3.4-dimethoxybenzonitrile same way as described in example 1.10.

1.37

Ethyl ester of(RS)-{4-[amino-(3-forbeswoman)methyl]phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid, MS: 542 ([M+H]+), was obtained by the reaction of the hydrochloride of the ethyl ester of(RS)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid, described in example 1.6, 3-tormentilla same way as described in example 1.10.

1.38

Ethyl ester of(RS)-{4-[amino-(4-triftormetilfullerenov)methyl]phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid, MS: 592 ([M+H]+), was obtained by the reaction of the hydrochloride of the ethyl ester of(RS)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid, described what about in example 1.6, 4-triftoratsetilatsetonom same way as described in example 1.10.

1.39

Ethyl ester of(RS)-{4-[amino-(4-methylbenzylamino)methyl]phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid, MS: 538 ([M+H]+), was obtained by the reaction of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid, described in example 1.6, with pair-colourglide same way as described in example 1.10.

Example 2

2.1

3,5-bis-(tert-butyldimethylsilyloxy)-2-forbindelse (19,51 g) was dissolved in DMF (100 ml)was added potassium fluoride (to 11.79 g), ethyliodide (18,99 g) and stirred at room temperature for 3.5 hours and Then the mixture was poured into water and was extracted with diethyl ether. The product was purified by chromatography on a column (hexane/ethyl acetate), was obtained 6,28 g of 3,5-diethoxy-2-forventelige in the form of a colorless solid.

2.2

Ethyl ester of(RS)-(4-cyanovinylene)-(3,5-diethoxy-2-forfinal)acetic acid, MS: 386 ([M]+), was obtained by the reaction of 3,5-diethoxy-2-fluoro-benzaldehyde described in example 2.1, 4-aminobenzonitrile and morpholinosydnonimine in the presence of epirate of boron TRIFLUORIDE in the same way as described in example 1.5.

2.3

The hydrochloride of the ethyl ester of(RS)-(4-carbamimidoyl)-(3,5-diethoxy-2-forfinal)acetic acid is: 404 ([M+H] +), was obtained by the reaction of the ethyl ester of(RS)-(4-cyanoaniline)(3,5-diethoxy-2-forfinal)acetic acid, described in example 2.2, with gaseous HCl and EtOH, and then with ammonia in the same way as described in example 1.6.

2.4

(RS)-(4-carbamimidoyl)-(3,5-diethoxy-2-forfinal)acetic acid, MS: 376 ([M+H]+), was obtained from hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)(3,5-diethoxy-2-forfinal)acetic acid, described in example 2.3, by hydrolysis in the presence of NaOH in the same way as described in example 1.7.

The compound obtained was separated into the enantiomers preparative GHUR on chiral stationary phase (Chiralpak AD) using as mobile phase heptane/ethanol/triperoxonane acid (75:25:0,2), after neutralization was obtained (R)-(4-carbamimidoyl)-(3,5-diethoxy-2-forfinal)acetic acid and (S)-(4-carbamimidoyl)-(3,5-diethoxy-2-forfinal)acetic acid.

2.5

Ethyl ester of(RS)-(4-cyanovinylene)-(3,5-diethoxy-2-forfinal)acetic acid (136 mg)described in example 2.2, was dissolved in ethanol. Then was added triethylamine (712 mg), hydroxylamine hydrochloride (245 mg), and stirred at room temperature for 18 hours the Mixture was concentrated, the residue was dissolved in CH2Cl2and washed with water. The obtained product was purified by chromatography on a column (the N 2Cl2/Meon), received 87 mg of ethyl ester of(RS)-(3,5-diethoxy-2-forfinal)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid as colorless foam. MS: 420 ([M+H]+).

The compound obtained was separated into the enantiomers preparative GHUR on chiral stationary phase (Chiralpak AD) using as mobile phase heptane/isopropanol/triperoxonane acid (80:20:0,2), after neutralization was obtained ethyl ester(R)-(3,5-diethoxy-2-forfinal)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid and ethyl ester of(S)-(3,5-diethoxy-2-forfinal)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid.

2.6

Ethyl ester of(RS)-(3,5-diethoxy-2-forfinal)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid (44 mg)described in example 2.5, was dissolved in THF (0.5 ml)was added 1 M NaOH (to 0.21 ml) and stirred at room temperature for 2 hours the mixture is Then neutralized 1 M HCl, concentrated and purified by chromatography on a column, while received 23 mg of (RS)-(3,5-diethoxy-2-forfinal)-[4-(N-hydroxycarbonylmethyl)phenylamino]acetic acid as colorless solid. MS: 392 ([M+H]+).

The compound obtained was separated into the enantiomers preparative GHUR on chiral stationary phase (Chiralpak AD) using as mobile phase heptane/isopropanol/triperoxonane KIS is the notes (60:40:0,2), after neutralization was obtained (R)-(3,5-diethoxy-2-forfinal)[4-(N-hydroxycarbamoyl)phenylamino]acetic acid and (S)-(3,5-diethoxy-2-forfinal)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid.

2.7

Ethyl ester of(RS)-[4-(aminoethoxyethanol)phenylamino]-(3,5-diethoxy-2-forfinal)acetic acid, MS: 476 ([M+H]+), was obtained by the reaction of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)(3,5-diethoxy-2-forfinal)acetic acid, described in example 2.3, etelcharge.com same way as described in example 1.10.

2.8

Ethyl ester of(RS)-{4-[amino-(4-perfeccionandome)methyl]phenylamino}-(3,5-diethoxy-2-forfinal)acetic acid, MS: 542 ([M+H]+), was obtained by the reaction of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3,5-diethoxy-2-forfinal)acetic acid, described in example 2.3, 4-vtorganichoney.com same way as described in example 1.10.

2.9

Ethyl ester of(RS)-{4-[amino-(2,2,2-trichlorocarbanilide)methyl]-phenylamino}-(3,5-diethoxy-2-forfinal)acetic acid, MS: 580 ([M+H]+), was obtained by the reaction of the hydrochloride of the ethyl ester of(RS)-(4-carbamimidoyl)-(3,5-diethoxy-2-forfinal)acetic acid, described in example 2.3, 2,2,2-trichlorethylphosphate same way as described in example 1.10.

2.10

Ethyl ester of(RS)-{4-[amino-(5-what ethyl-2-oxo[1,3]dioxol-4-ylmethoxycarbonyl)methyl]phenylamino}-(3,5-diethoxy-2-forfinal)acetic acid, MS: 560 ([M+H]+), was obtained by the reaction of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3,5-diethoxy-2-forfinal)acetic acid, described in example 2.3, with (5-methyl-2-oxo-1,3-dioxol-4-EN-4-yl)methyl-para-nitrophenylarsonic same way as described in example 1.10.

2.11

Ethyl ester of(RS)-[4-(amino-methoxycarbonylaminophenyl)phenylamino]-(3,5-diethoxy-2-forfinal)acetic acid, MS: 462 ([M+H]+), was obtained by the reaction of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3,5-diethoxy-2-forfinal)acetic acid, described in example 2.3, methylchloroform same way as described in example 1.10.

2.12

Ethyl ester of(RS)-[4-(aminophenoxyethanol)phenylamino]-(3,5-diethoxy-2-forfinal)acetic acid, MS: 524 ([M+H]+), was obtained by the reaction of the hydrochloride of the ethyl ester of(RS)-(4-carbamimidoyl)-(3,5-diethoxy-2-forfinal)acetic acid, described in example 2.3, phenylcarbamates same way as described in example 1.10.

2.13

Ethyl ester of(RS)-[4-(aminopolycarboxylates)phenylamino]-(3,5-diethoxy-2-forfinal)acetic acid, MS: 504 ([M+H]+), was obtained by the reaction of the hydrochloride of the ethyl ester of(RS)-(4-carbamimidoyl)(3,5-diethoxy-2-forfinal)acetic acid, described in example 2.3, isobutylparaben same way as described in the ore 1.10.

2.14

Ethyl ester of(RS)-{4-[amino-(4-forbeswoman)methyl]phenylamino}-(3,5-diethoxy-2-forfinal)acetic acid, MS: 526 ([M+H]+), was obtained by the reaction of the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-(3,5-diethoxy-2-forfinal)acetic acid, described in example 2.3, 4-tormentilla same way as described in example 1.10.

2.15

Ethyl ester of(RS)-(4-cyanovinylene)-(3,5-diethoxy-2-forfinal)acetic acid (1,02 g)described in example 2.2, was dissolved in THF. Then added 1 M LiOH (3,96 ml) and the mixture was stirred at room temperature for 2 hours Then was added 1 M HCl (4 ml) and the reaction product was extracted by ethyl acetate, to receive 970 mg (RS)-(4-cyanovinylene)-(3,5-diethoxy-2-forfinal)acetic acid, MS: 357 ([M-H]+), which was used in the next stage without additional purification.

2.16

(RS)-(4-cyanovinylene)-(3,5-diethoxy-2-forfinal)acetic acid (220 mg)described in example 2.15, was dissolved in THF (3.3 ml). Then was added n-butanol (64 mg), triphenylphosphine (179 mg) and diethylazodicarboxylate (122 mg) and the resulting mixture was stirred at room temperature for 3 hours the Mixture was concentrated and the obtained product was purified by chromatography on a column, it was received 109 mg butyl ether(RS)-(4-cyanovinylene)-(3,5-diethoxy-2-forfinal)acetic acid in the form of a solid which substances off-white color. MS: 414 ([M+H]+).

2.17

Butyl ether(RS)-(3,5-diethoxy-2-forfinal)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid, MS: 448 ([M+H]+), was obtained by the reaction of butyl ether(RS)-(4-cyanovinylene)-(3,5-diethoxy-2-forfinal)acetic acid, described in example 2.16, with triethylamine and hydroxylamine hydrochloride in the same way as described in example 2.5.

2.18

Isopropyl ether(RS)-(4-cyanovinylene)-(3,5-diethoxy-2-forfinal)acetic acid, MS: 400 ([M]+), was obtained by the reaction of (RS)-(4-cyanovinylene)-(3,5-diethoxy-2-forfinal)acetic acid, described in example 2.15, isopropanol, triphenylphosphine and diethylazodicarboxylate same way as described in example 2.16.

2.19

Isopropyl ether(RS)-(3,5-diethoxy-2-forfinal)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid, MS: 434 ([M]+), was obtained by the reaction of isopropyl ether (RS)-(4-cyanovinylene)-(3,5-diethoxy-2-forfinal)acetic acid, described in example 2.18, with triethylamine and hydroxylamine hydrochloride in the same way as described in example 2.5.

Example 3

3.1

The solution to 53.0 g of 5-(tert-butyldimethylsilyloxy)-2-terfenol (see .Kawase, A.K.Sinhababu, R.T.Borchardt, Chem. Pharm. Bull., 38, 2939 (1990)) in 120 ml of DMF was cooled to 0°C for 15 min was added 61,6 ml of tert-butyldiphenylsilyl, and then portions were added to 16.4 g of imidazole. P the obtained suspension was stirred over night, then the reaction was stopped by adding 150 ml of N2About at 0°C. the Crude product was extracted with hexane and purified by chromatography on silica gel (hexane), was obtained at 88.9 g of 4-(tert-butyldimethylsilyloxy)-2-(tert-butyldiphenylsilyl)fervently in the form of a colourless liquid.

3.2

The solution 55,0 g of 4-(tert-butyldimethylsilyloxy)-2-(tert-butyldiphenylsilyl)fervently described in example 3.1, in 120 ml of THF was cooled to -78°and within 30 minutes was added dropwise 97 ml of 1.3 M solution of sec-utility in cyclohexane. Then was stirred at -78°C for 1 h and for 20 min was added 9.7 ml DMF 18.3 ml of THF. The mixture was stirred at -78°C for 1 h, then was heated to room temperature over 90 min and the reaction was stopped by adding 300 ml of ice water. The obtained product was isolated by extraction Et2O, it was given to 60.6 g of 5-(tert-butyldimethylsilyloxy)-3-(tert-butyldiphenylsilyl)-2-forventelige liquid yellow color.

3.3

A solution of 35.0 g of 5-(tert-butyldimethylsilyloxy)-3-(tert-butyldiphenylsilyl)-2-forventelige described in example 3.2, and 8,13 g of 4-aminobenzonitrile in 250 ml of EtOH was stirred at room temperature for 1 h and Then added 13,43 g of toluene-4-sulfonylmethane and the solution was cooled to 0°C. Then added the 25,9 ml of titlefirst of boron TRIFLUORIDE, keeping the temperature no higher than 5°C. the Mixture was stirred at 0°C for 15 min and at room temperature for 2 h, then was added 25 ml of H2O and the solution was stirred at 50°With during the night. The crude product was extracted EtOAc and purified by chromatography on silica gel (cyclohexane/EtOAc), to receive 22,38 g of ethyl ester of(RS)-[3-(tert-butyldiphenylsilyl)-2-fluoro-5-hydroxyphenyl]-(4-cyanoaniline)acetic acid as an amorphous solid light yellow color.

3.4

To a solution of 49 g of ethyl ester of(RS)-[3-(tert-butyldiphenylsilyl)-2-fluoro-5-hydroxyphenyl]-(4-cyanoaniline)acetic acid, described in example 3.3, in 900 ml of THF was sequentially added 24,86 g of triphenylphosphine, of 5.53 ml EtOH and 21,82 g of di-tert-utilization.bacteria. The solution was stirred at room temperature for 4 h and then evaporated. The crude product was purified by chromatography on silica gel (cyclohexane/EtOAc), to receive of 27.6 g of ethyl ester of(RS)-[3-(tert-butyldiphenylsilyl)-5-ethoxy-2-forfinal](4 cyanovinylene)acetic acid as an amorphous solid light yellow color.

3.5

A solution of 27.6 g of ethyl ester of(RS)-[3-(tert-butyldiphenylsilyl)-5-ethoxy-2-forfinal]-(4-cyanoaniline)acetic acid, described in example 3.4, in 470 ml of THF was cooled to 0°and handling the Ali of 50.9 ml of 1 M solution of tetrabutylammonium fluoride in THF. The reaction mixture was stirred at 0°C for 4 h, the crude product was extracted EtOAc and purified by chromatography on silica gel (cyclohexane/EtOAc), to receive 12,89 g of ethyl ester of(RS)-(4-cyanoaniline)(5 ethoxy-2-fluoro-3-hydroxyphenyl)acetic acid in the form of a semi-solid substance is yellow.

3.6

To a solution 7,38 g of ethyl ester of(RS)-(4-cyanovinylene)-(5-ethoxy-2-fluoro-3-hydroxyphenyl)acetic acid, described in example 3.5, in 220 ml of THF was added by 1.68 ml (S)-(+)-3-hydroxymitragynine and 6,48 g of triphenylphosphine and the mixture was cooled to 0°C. Then added 3,84 ml of diethylazodicarboxylate, the solution was stirred at room temperature for 3 h, and then evaporated. The crude product was purified by chromatography on silica gel (cyclohexane/EtOAc), to receive 6,53 g of ethyl ester of(RS)-(4-cyanoaniline)[5 ethoxy-2-fluoro-3-[(R)-tetrahydrofuran-3-yloxy]phenyl]acetic acid in a solid off-white color.

3.7

To the mixture cent to 8.85 g of ethyl ester of(RS)-(4-cyanovinylene)-[5-ethoxy-2-fluoro-3-[(R)-tetrahydrofuran-3-yloxy]phenyl]acetic acid, described in example 3.6, in 515 ml of EtOH was added 20,21 g of hydroxylamine hydrochloride and 81.1 ml of triethylamine. The solution was stirred at 50°C overnight and then was evaporated. The crude product was extracted EtOAc and purified by chromatography on silica compound is barely (CH 2Cl2/Meon), when it got to 7.64 g of ethyl ester of(RS)-[5-ethoxy-2-fluoro-3-[(R)-tetrahydrofuran-3-yloxy]phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid as an amorphous solid light brown color.

The resulting mixture of isomers is separated into the diastereomers preparative GHUR on chiral stationary phase (Chiralpak AD) using as mobile phase heptane/isopropanol/triperoxonane acid (70:30:0,2), after neutralization was obtained ethyl ester(R)-[5-ethoxy-2-fluoro-3-[(R)-tetrahydrofuran-3-yloxy]phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid and ethyl ester of(S)-[5-ethoxy-2-fluoro-3-[(R)-tetrahydrofuran-3-yloxy]phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid in the form of amorphous solids.

3.8

A solution of 3.85 g of ethyl ester of(RS)-(4-cyanovinylene)-[5-ethoxy-2-fluoro-3-[(R)-tetrahydrofuran-3-yloxy]phenyl]acetic acid, described in example 3.6, was dissolved in 80 ml of CHCl3/EtOH (3:1) and cooled to -10°C. Then through the resulting mixture for 1 h was passed a stream of dry gaseous model HC1. The reaction mixture is kept at -4°during the night, and then was evaporated. The residue was transferred into a 35 ml of 2 M solution of NH3in EtOH and stirred at 60°C for 2 h, after which the reaction mixture was evaporated. The crude product was purified by chromatography n is silica gel (CH 2Cl2/Meon), received of 4.04 g of the hydrochloride of the ethyl ester of(RS)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-3-[(R)-tetrahydrofuran-3-yloxy]phenyl]acetic acid in a solid off-white color.

3.9

A suspension of 170 mg of the hydrochloride of the ethyl ester of(RS)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-3-[(R)-tetrahydrofuran-3-yloxy]phenyl]acetic acid, described in example 3.8, in 5 ml of THF was cooled to 0°and treated With 1.8 ml 1 N. LiOH. The mixture was stirred at 0°C for 2 h, and then neutralized 1 N. HCl. The precipitate was separated by filtration, washed with N2O and Et2O, it was received 129 mg of (RS)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-3-[(R)-tetrahydrofuran-3-yloxy]phenyl]acetic acid in a solid off-white color.

The resulting mixture of isomers is separated into the diastereomers preparative GHUR on chiral stationary phase (Chiralpak AD) using as mobile phase heptane/isopropanol/triperoxonane acid (75:25:0,2), after neutralization was obtained (R)-(4-carbamimidoyl)[5 ethoxy-2-fluoro-3-[(R)-tetrahydrofuran-3-yloxy]phenyl]acetic acid and (S)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-3-[(R)-tetrahydrofuran-3-yloxy]phenyl]acetic acid in the form of solid substances off-white color.

3.10

Ethyl ester of (R) and (S)-(4-cyanovinylene)-[5-ethoxy-2-f the PR-3-[(S)-tetrahydrofuran-3-yloxy]phenyl]acetic acid was obtained by the reaction of the ethyl ester of(RS)-(4-cyanovinylene)-(5-ethoxy-2-fluoro-3-hydroxyphenyl)acetic acid with (R)-(-)-3-hydroxymitragynine same as described in example 3.6. The obtained product was converted into (RS)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-3-[(S)-tetrahydrofuran-3-yloxy]phenyl]acetic acid via the hydrochloride of the ethyl ester of(RS)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-3-[(S)-tetrahydrofuran-3-yloxy]phenyl]acetic acid in the same way as described in examples 3.8 and 3.9.

The resulting mixture of isomers is separated into the diastereomers preparative GHUR on chiral stationary phase (Chiralpak AD) using as mobile phase heptane/isopropanol/triperoxonane acid (80:20:0,2), after neutralization was obtained (R)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-3-[(S)-tetrahydrofuran-3-yloxy]phenyl]acetic acid and (S)-(4-carbamimidoyl) [5 ethoxy-2-fluoro-3-[(S)-tetrahydrofuran-3-yloxy]phenyl]acetic acid in the form of solid substances off-white color.

3.11

Ethyl ester of(RS)-[5-ethoxy-2-fluoro-3-[(S)-tetrahydrofuran-3-yloxy]-phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid was obtained from ethyl ester of (RS)-(4-cyanoaniline)[5 ethoxy-2-fluoro-3-[(S)-tetrahydrofuran-3-yloxy]phenyl]acetic acid, described in example 3.10, in the same way as described in example 3.7.

Example

The pharmaceutical composition 1

In one pill
AK is active substance 200 mg
Microcrystalline cellulose155 mg
Corn starch25 mg
Talc25 mg
The hypromellose20 mg
425 mg

Example B

The pharmaceutical composition II

In one capsule
The active ingredient100.0 mg
Corn starch20.0 mg
Lactose95,0 mg
Talc4.5 mg
Magnesium stearate0.5 mg
220,0 mg

1. The compounds of formula I

where R1means1-6alkyl;

R2means hydrogen, hydroxy-C1-6alkoxy, C1-6alkoxycarbonyl,1-6alkoxy or halogen-C1-6alkoxycarbonyl-C1-6alkoxy;

R3means hydrogen, C1-6alkoxy or heterocyclizations where heteroseksualci means 5-6-membered ring containing a heteroatom selected from nitrogen and oxygen;

R4means hydrogen or the residue of sonoelastography, which is cleaved under physiological conditions;

R5means hydrogen, hydroxy, C1-6alkoxycarbonyl, halogen-C1-6alkoxycarbonyl,6aryloxyalkyl,6arylethoxysilanes,1-6alkoxy-C1-6alkoxycarbonyl,3-6cycloalkylcarbonyl,2-6alkyloxyaryl, 5-methyl-2-oxo[1,3]dioxol-4-ylmethoxycarbonyl,6arylcarboxylic,1-6alkylaminocarbonyl,1-6alkylsulphonyl, arylcarbamoyl, allumination or heteroarylboronic where heteroaryl represents a 5-6-membered ring containing in the cycle the nitrogen atom;

X is F, C1 or Br,

and their hydrate or solvate and/or physiologically acceptable salts and/or physiologically acceptable esters, provided that the compound of formula I is not selected from the group including

ethyl ester of (RS)-(4-carbamimidoyl)-(3,5-diethoxy-2-forfinal)acetic acid,

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

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

ethyl ester of (RS)-(4-carbamimidoyl)-(2-fluoro-3,5-acid)acetic acid.

2. Compounds according to claim 1, where only one of R2and R3means hydrogen.

3. Compounds according to claims 1-2, where R1who appoints ethyl.

4. Compounds according to any one of claims 1 to 3, where R2means hydrogen, 2-hydroxyethoxy or 2-(2,2,2-trichlorocarbanilide)ethoxy.

5. Compounds according to any one of claims 1 to 4, where R2means hydrogen.

6. Compounds according to any one of claims 1 to 4, where R2means 2 hydroxyethoxy.

7. Compounds according to any one of claims 1 to 6, where R3means hydrogen.

8. Compounds according to any one of claims 1 to 6, where R3means ethoxy.

9. Compounds according to any one of claims 1 to 6, where R3means tetrahydrofuran-3-yloxy.

10. Compounds according to any one of claims 1 to 9, where R4means hydrogen, C1-6alkyl or benzyl.

11. Compounds according to any one of claims 1 to 10, where R4means hydrogen, ethyl, isopropyl, butyl, isobutyl or benzyl.

12. Compounds according to any one of claims 1 to 11, where R4means ethyl.

13. Compounds according to any one of claims 1 to 11, where R4means hydrogen.

14. Compounds according to any one of claims 1 to 13, where R4means hydrogen, hydroxy, etoxycarbonyl, 2,2,2-trichlorocyanuric, methoxycarbonyl, 4-forgenerations, benzyloxycarbonyl, 2-methoxyethoxymethyl,2-isopropyl-5-methylcyclohexanecarboxylic, prop-2-indoxacarb, 5-methyl-2-oxo-[1,3]dioxol-4-ylmethoxycarbonyl,benzoyloxy, ethylenedicarboxylic, phenylenecarbonyl, benzoyl, 3-perbenzoic, 4-perbenzoic, 2,4-differentail, 3,4-dimethoxybenzyl, 3,5-dimethoxybenzoyl, 4-methylbenzoyl 4-trifloromethyl, phenylenecarbonyl or isobutoxide.

15. Compounds according to any one of claims 1 to 14, where R5means hydroxy.

16. Compounds according to any one of claims 1 to 14, where R5means 2,2,2-trichlorocyanuric.

17. Compounds according to any one of claims 1 to 14, where R5means benzoyl.

18. Compounds according to any one of claims 1 to 14, where R5means hydrogen.

19. Compounds according to any one of claims 1 to 18, where X is F.

20. Compounds according to any one of claims 1 to 19 formula Ia

where R1, R2, R3, R4, R5and X have the meanings indicated in claim 1.

21. Compounds according to any one of claims 1 to 20, selected from the group including

the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

(RS)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

(S)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

(R)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

ethyl ester of (RS)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

ethyl ester of (S)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

E. the silt ether (R)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

(RS)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic kislomolocnam equivalent of sodium chloride,

ethyl ester of (RS)-[4-(aminoethoxyethanol)phenylamino]-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

ethyl ester of (RS)-{4-[amino-(2,2,2-trichlorocarbanilide)methyl]phenylamino}-{5-ethoxy-2-fluoro-4-[2-(2,2,2-trichlorocarbanilide)ethoxy]phenyl} acetic acid,

ethyl ester of (RS)-{4-[amino-(2,2,2-trichlorocarbanilide)methyl]phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

ethyl ester of (S)-{4-[amino-(2,2,2-trichlorocarbanilide)methyl]phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

ethyl ester of (R)-{4-[amino-(2,2,2-trichlorocarbanilide)methyl]phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

ethyl ester of (RS)-[4-(aminoethoxyethanol)phenylamino]-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

ethyl ester of (RS)-{4-[amino-(4-perfeccionandome)methyl]phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

ethyl ester of (RS)-[4-(aminobenzenesulphonyl)phenylamino]-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

ethyl ester of (RS)-{4-[amino-(2-m is daxiaoxinanling)methyl]phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

ethyl ester {4-[amino-[1R-(2S-isopropyl-5R-methylcyclohexyl)oxycarbonyl]methyl]phenylamino}-α-(RS)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

ethyl ester of (RS)-[4-(aminopropyl-2-ineluctibility)phenylamino]-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

ethyl ester of (RS)-{4-[amino-(5-methyl-2-oxo-[1,3]dioxol-4-ylmethoxycarbonyl)methyl]phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

ethyl ester of (RS)-α-[[4-[[(benzoyloxy)amino]iminomethyl]phenyl]amino]-5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)benzooxazol acid,

ethyl ester of (RS)-5-ethoxy-α-[[4-[[[[(ethylamino)carbonyl]oxy]amino]iminomethyl]phenyl]amino]-2-fluoro-4-(2-hydroxyethoxy)benzooxazol acid,

ethyl ester of (RS)-5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)- α-[[4-[imino[[[(phenylamino)carbonyl]oxy]amino]methyl]phenyl]amino]benzooxazol acid,

ethyl ester of (RS)-{4-[amino-(4-forbeswoman)methyl]phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

ethyl ester of (RS)-[4-(aminobenzoylamino)phenylamino]-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

ethyl ester of (S)-[4-(aminobenzoylamino)phenylamino]-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

ethyl ester of (R)-[4-(Amin is antiliminal)phenylamino]-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

ethyl ester of (RS)-[4-(aminopolycarboxylates)phenylamino]-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

butyl ether (RS)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

butyl ether (S)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

butyl ether (R)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

isopropyl ether (RS)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

isopropyl ether (S)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

isopropyl ether (R)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

benzyl ether of (RS)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

benzyl ether of (S)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

benzyl ether of (R)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

isobutyl ether (RS)-[5-ethoxy-2-fluoro-4-(2-HYDR is xiaoxi)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

isobutyl ether (S)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

isobutyl ether (R)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

ethyl ester of (RS)-{4-[amino-(2,4-diferentseerimine)methyl]phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

ethyl ester of (RS)-{4-[amino-(3,5-dimethoxyphenethylamine)methyl]phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

ethyl ester of (RS)-{4-[amino-(3,4-dimethoxyphenethylamine)methyl]phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

ethyl ester of (RS)-{4-[amino-(3-forbeswoman)methyl]phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

ethyl ester of (RS)-{4-[amino-(4-triftormetilfullerenov)methyl]phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

ethyl ester of (RS)-{4-[amino-(4-methylbenzylamino)methyl]phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

(R)-(4-carbamimidoyl)-(3,5-diethoxy-2-forfinal)acetic acid,

(S)-(4-carbamimidoyl)-(3,5-diethoxy-2-forfinal)acetic acid,

ethyl ester of (RS)-(3,5-diethoxy-2-forfinal)-[4-(N-hydroxycarbamoyl)phenylamino]ssnoi acid,

ethyl ester of (R)-(3,5-diethoxy-2-forfinal)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

ethyl ester of (S)-(3,5-diethoxy hydroxycarbonylmethyl)phenylamino]acetic acid,

(RS)-(3,5-diethoxy-2-forfinal)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

(R)-(3,5-diethoxy-2-forfinal)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

(S)-(3,5-diethoxy-2-forfinal)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

ethyl ester of (RS)-[4-(aminoethoxyethanol)phenylamino]-(3,5-diethoxy-2-forfinal)acetic acid,

ethyl ester of (RS)-{4-[amino-(4-perfeccionandome)methyl]phenylamino} -(3,5-diethoxy-2-forfinal)acetic acid,

ethyl ester of (RS)-{4-[amino-(2,2,2-trichlorocarbanilide)methyl]phenylamino}-(3,5-diethoxy-2-forfinal)acetic acid,

ethyl ester of (RS)-{4-[amino-(5-methyl-2-oxo-[1,3]dioxol-4-ylmethoxycarbonyl)methyl]phenylamino}-(3,5-diethoxy-2-forfinal)acetic acid,

ethyl ester of (RS)-[4-(aminoethoxyethanol)phenylamino]-(3,5-diethoxy-2-forfinal)acetic acid,

ethyl ester of (RS)-[4-2-forfinal)-[4-(N- (aminophenoxyethanol)phenylamino]-(3,5-diethoxy-2-forfinal)acetic acid,

ethyl ester of (RS)-[4-(aminopolycarboxylates)phenylamino]-(3,diethoxy-2-forfinal)acetic acid,

ethyl ester of (RS)-{4-[amino-(4-forbeswoman)methyl]phenylamino}-(3,5-diethoxy-2-forfinal)acetic acid,

butyl ether (RS)-(3,5-diethoxy-2-forfinal)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

isopropyl ether (RS)-(3,5-diethoxy-2-forfinal)-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

ethyl ester of (RS)-[5-ethoxy-2-fluoro-3-[(R)-tetrahydrofuran-3-yloxy]phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

ethyl ester of (R)-[5-ethoxy-2-fluoro-3-[(R)-tetrahydrofuran-3-yloxy]phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

ethyl ester of (S)-[5-ethoxy-2-fluoro-3-[(R)-tetrahydrofuran-3-yloxy]phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-3-[(R)-tetrahydrofuran-3-yloxy]phenyl]acetic acid,

(RS)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-3-[(R)-tetrahydrofuran-3-yloxy]phenyl]acetic acid,

(R)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-3-[(R)-tetrahydrofuran-3-yloxy]phenyl]acetic acid,

(S)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-3-[(R)-tetrahydrofuran-3-yloxy]phenyl]acetic acid,

the hydrochloride of the ethyl ester of (RS)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-3-[(S)-tetrahydrofuran-3-yloxy]phenylacetic acid,

(RS)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-3-[(S)-tetrahydrofuran-3-yloxy]phenyl]acetic acid,

(R)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-3-[(S)-tetrahydrofuran-3-yloxy]phenyl]acetic acid and

(S)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-3-[(S)-tetrahydrofuran-3-yloxy]phenyl]acetic acid.

22. Compounds according to any one of claims 1 to 21, selected from the group including

(R)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

(R)-(4-carbamimidoyl)-(3,5-diethoxy-2-forfinal)acetic acid,

(R)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-3-[(R)-tetrahydrofuran-3-yloxy]phenyl]acetic acid,

ethyl ester of (R)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

ethyl ester of (R)-{4-[amino-(2,2,2-trichlorocarbanilide)methyl]phenylamino}-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

ethyl ester of (R)-[4-(aminobenzoylamino)phenylamino]-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

butyl ether (R)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid,

isopropyl ether (R)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic KIS is the notes,

benzyl ether of (R)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid and

isobutyl ether (R)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid.

23. Compounds according to any one of claims 1 to 21, selected from the group including

ethyl ester of (R)-(4-carbamimidoyl)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]acetic acid,

(R)-[5-ethoxy-2-fluoro-4-(2-hydroxyethoxy)phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid and

ethyl ester of (RS)-[5-ethoxy-2-fluoro-3-[(S)-tetrahydrofuran-3-yloxy]phenyl]-[4-(N-hydroxycarbamoyl)phenylamino]acetic acid.

24. Compounds according to any one of claims 1 to 23, where R3does not mean alkoxy, if R5means hydrogen.

25. Pharmaceutical composition having the effect of inhibitor amylolyticus activity of a complex of factor VIIa/tissue factor comprising compounds according to any one of claims 1 to 24 and a pharmaceutically acceptable carrier and/or adjuvant.

26. Compounds according to any one of claims 1 to 24, with the action of the inhibitor amylolyticus activity of a complex of factor VIIa/tissue factor, as therapeutically active substances for pharmaceutical compositions suitable for the treatment or prevention of diseases, such as thrombosis.

27. With the royals therapeutic and/or prophylactic treatment of diseases, such as thrombosis, the introduction of the human or animal a compound according to any one of claims 1 to 24.

28. Method of preparing compounds according to any one of claims 1 to 24, the transformation of the nitrile group in a compound of formula II

where R1, R2, R3, R4and X have the meanings indicated in claim 1, in carbamimidoyl or N-hydroxycarbamoyl group, and, if necessary, subjected to the modification of the available reactive groups present in the compound of formula I by the esterification of the carboxyl group in the ester group, saponification of the ester group to obtain a carboxyl group, hydrolysis Arakelova simple ether, recovery hydroxycarbonylmethyl group in carbamimidoyl group, and if necessary converting the resulting compound of formula I into a physiologically acceptable salt or converting the salt of the compounds of formula I in free acid or base.

29. The compounds of formula II

where R1, R2, R3, R4and X have the meanings indicated in claim 1.



 

Same patents:

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to new aromatic diketone derivatives of formula I

(R4, R5, R6, and R7 are independently H, OH, X-alkyl, wherein X represents oxygen; K is group of formula II

or III

;

L is group of formula IV

;

or K and L together form group of formula VI ,

wherein R1 and R3 are independently H or alkyl; R2 is H or alkyl; X1-X7 are independently O, NH; and ring "cyclus" together with carbon atom labeled with letters c and d represents anthraquinone, hydroquinone or phenyl, optionally substituted with one or more hydroxyl, alkoxyl, or alkyl groups), as well as pharmaceutically accepts salts thereof, ethers, esters, tautomers, stereomers and mixtures in any ratio. Derivatives of present invention are glucose-6-phosphatetranslocase inhibitors. Also disclosed are method for production of derivatives, pharmaceutical composition containing the same, and uses thereof as drugs, in particular for treatment of diabetes mellitus.

EFFECT: new compounds and pharmaceutical composition for treatment of diabetes mellitus.

20 cl, 4 tbl, 6 ex

The invention relates to a new therapeutic drug for diabetes and includes the compound of the formula I: R1-C(O)-C(R2')(R2)-X-C(O)-R3where X represents a group of formula-C(R4)(R5)-, -N(R6)-, -O-; where R4is a hydrogen atom, a C1-C5alkyl, carboxy, phenyl, C2-C5acyl, C2-C5alkoxycarbonyl, R5is a hydrogen atom, a C1-C5alkyl; R6is hydrogen; R1is phenyl, optionally substituted C1-C5by alkyl, hydroxy, hydroxyalkyl, C2-C6alkenyl, acyl, carboxy, teinila, C3-C7cycloalkyl; biphenyl, optionally substituted C1-C5the alkyl or hydroxy; naphthyl; terphenyl; C3-C7cycloalkyl, optionally substituted C1-C5the alkyl or phenyl; optionally substituted C1-C5alkyl; pyridyl; sensational; substituted; indanyl; fluorenyl or group; R2is hydrogen, C1-C5alkyl, optionally substituted by carboxy; R2'is hydrogen; R3- C1-C5alkyl, optionally substituted by phenyl or C1-C4alkoxy, C1-C4alkoxy; hydroxy; phenyl; C3-C72)2-; R2and R5taken together, form a simple bond or-CH2-, - (CH2)3-, -(CH2)4-; R2, R2', R4and R5taken together form =CH-CH=CH-CH=; R2' and R3taken together form a-CH(R8)-OH, -CH(R8)-CH(R9)-, -CH(R8)NH; R8and R9is hydrogen, and pharmaceutically acceptable salts

The invention relates to a new means of plant protection

The invention relates to substituted derivative of amidine possessing biological activity, in particular to new substituted derivative of benzamidine possessing biological activity, in particular antagonistic action on leukotriene receptors B4

The invention relates to new methods of producing pharmaceutically active bicyclic amidinothiourea of amidinohydrolase, and to new bicyclic to hydroxyamides, which are intermediate compounds for obtaining pharmaceutically active bicyclic amidinothiourea of amidinohydrolase, in the form of various tautomeric forms, as well as a mixture of tautomers; and/or, if they euda soleobrazutaya group, in the form of salts

The invention relates to organic synthesis and relates to a method (variants) obtain derivatives amidoxime O-(2-hydroxy-3-piperidino-1-propyl)-nicotinic acid and their salts

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to new compounds of formula

,

wherein A and B are independently CH or CR3; X is C=O or (CR4aR4b)m, (m = 1 or 2); Y is S(O)n-R2 (n = 1 or 2), S(O)n-NR2R2, or S(O)n-OR2; N1 and N2 are nitrogen atoms; Q and R1 are independently 1) optionally substituted C1-C10-alkyl; 2) optionally substituted aralkyl containing C6-C10-aryl, attached to C1-C10-alkyl; 3) optionally substituted aralkenyl containing C5-C10-aryl, attached to C1-C10-alkenyl; 4) optionally substituted C6-C10-aryl; 5) optionally substituted aryl, containing 5-10 ring atoms, selected from carbon and sulfur; each R2 and R3 are hydrogen; R4a, R4b, R5, and R6, are independently hydrogen; R2 and R3 are independently hydrogen or C1-C6-alkyl; as well as acid and base additive salts thereof. Also disclosed are method for production of claimed compounds, pharmaceutical composition inhibiting serine protease enzymes and therapeutic method based thereon.

EFFECT: new compounds and pharmaceutical composition for thrombosis preventing or abnormal thrombosis treatment.

11 cl, 7 tbl, 15 ex

The invention relates to a derivative of benzamidine formula I, where R1denotes-C(=NH)-NH2; R2denotes H; R3refers to -[C(R5)2]m-СООR5, R3and X together represent well-CO-N-, form a 5-membered ring, with R3refers to - C = O, and X denotes N, R4means And, cycloalkyl, -[C(R5)2]mAr; X represents O, NR5or CH2Y represents O, NR5N[C(R5)2]m-Ar, N[C(R5)2]m-Het, - N[C(R5)2]m-СООR5W represents a bond, -SO2-, -CO - or-СОNR5-

The invention relates to derivatives of N-(4-carbamimidoyl) glycinamide formula (I), where E denotes hydrogen or HE, Q denotes hydrogen or alkyl, R is aryl, cycloalkyl or alkyl substituted radicals R1, R2, R3, R1denotes hydrogen, COOH, COO-alkyl or aryl, R2denotes hydrogen, aryl, cycloalkyl or heteroaryl, R3denotes hydrogen, aryl or HE (in any position other thanposition relative to the nitrogen atom is attached to an alkyl group R) or optional substituted by an amino group, three of the radicals X1-X4denote the group of C(Ra), C(Rb) or C(Rc), and the fourth represents C(Rd), Ra-Rddenote H, HE, NO2dialkylamino, halogen, alkyl, alkoxy, aryloxy, aralkylated, heteroarylboronic, geterotsiklicheskikh, COOH, COO-alkyl, NH-SO2-alkyl, NH-SO2-aryl, two adjacent groups Ra-Rbdenote alkylenedioxy, G1and G2denote hydrogen, HE, the invention relates to intermediate compounds of the formula (IV), (V), (VI) used in the methods of making compounds of formula (I), and are in взаимодействCN, the nitrile of formula (IV) is transformed into amidinopropane C(N-G1)NH-G2

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 ring or aryl ring

The invention relates to a derivative of biphenylamine General formula (1), where R1represents a hydrogen atom; L represents a direct bond or C1-4-alkylenes group; R2represents a carboxyl group;1-8-alkoxycarbonyl group; karbamoilnuyu group, and a nitrogen atom that is part of carbamoyl group, may be substituted mono - or di-C1-8is an alkyl group or may be a nitrogen atom in the amino acid; C1-8-alkylcarboxylic group; R3represents a hydrogen atom; X represents any of the groups-O-, -NH-CO-NH-, -N(R4)-, -CO-N(R5)-, -N(R5)-CO-, in which R4represents a hydrogen atom, a C1-10is an alkyl group, a C1-10-alkylcarboxylic group1-10-alkylsulfonyl group, R5represents a hydrogen atom, a C1-10is an alkyl group, Y represents a C4-8-cycloalkyl the group in which the methylene group in the C4-8-cycloalkyl may be substituted WITH1-8is an alkyl group WITH1-8-CNS group, carbamoyl group1-8-alkoxycarbonyl group, a carboxyl group, or the following 5-8-membered ring of formula I-1

The invention relates to new derivatives of biphenylamine formula (I)

< / BR>
where a IS-O-CmH2m-X1-

or denotes the formula (II)

,

where X1oxygen,

or formula (III)

< / BR>
R1- cycloalkyl with 5-7 carbon atoms, Ar1, CR4R5AG2, (CH3)2R6, R2is hydrogen, alkyl, hydroxyl, halogen, O - alkyl, R3is hydrogen, alkyl, R4- alkyl, trifluoromethyl, CH2HE, R5is hydrogen, alkyl, trifluoromethyl, or R4and R5may together form alkylene, R6- CH2OH, CONR7R8CH2R7R8provided that R1means associated through alkylene unsubstituted phenyl residue, or their acid additive salts with pharmacologically acceptable acids

The invention relates to new chemical compounds with biological activity, in particular to new derivatives of phenylaniline, their tautomers and stereoisomers, including mixtures thereof, and their salts, pharmaceutical compositions with anti-thrombotic and anti antiaggregatory action

The invention relates to substituted derivative of amidine possessing biological activity, in particular to new substituted derivative of benzamidine possessing biological activity, in particular antagonistic action on leukotriene receptors B4

FIELD: medicine, hematology, cardiology, endocrinology.

SUBSTANCE: one should introduce individually matched hypocaloric diet calculated in kcal by the following formula for women: age of 18-30 - (0.0621 x body weight, kg + 2.0357) x 240; age of 31-60 - (0.0342 x body weight, kg + 3.5377) x 240; age above 60 - (0.0377 x body weight, kg + 2.7545) x 240; for men: age of 18-30 - (0.0630 x body weight, kg + 2.8957) x 240; age of 31-60 - (0.0484 x body weight, kg + 3.6534) x 240; age above 60 - (0.0491 x body weight, kg + 2.4587) x 240 and amlodipine 5 mg once at one and the same daytime. The present innovation enables to decrease adhesion and aggregation of thrombocytes at optimizing their intravascular activity, increase antioxidant protection of blood platelets and normalizing cholesterol/phospholipids gradient in their membranes that, in its turn, favors the prophylaxis of complications of cardio-vascular diseases, shortens invalidism and lethality.

EFFECT: higher efficiency of normalization.

2 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes a novel pentasaccharide conjugate of the formula (I):

wherein R represents independently -SO-3 or -CH3; insert represents a flexible insert of length 13-25 atoms. Charge of a pentasaccharide residue is equilibrated with positively charged counterions and the total amount of sulfate groups in a pentasaccharide residue is 4, 5 or 6. Also, invention relates to a method of its preparing and pharmaceutical composition based on thereof and used in treatment of diseases mediated or associated with thrombin.

EFFECT: improved preparing method, valuable medicinal properties of conjugate.

9 cl, 2 ex

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