Amino acid derivatives or their pharmaceutically acceptable salts and pharmaceutical compositions on their basis

 

(57) Abstract:

Usage: as a drug for the treatment of hypertension and heart failure in humans or animals. The inventive amino acid derivatives f-ly I, where the radicals have the appropriate values. The pharmaceutical composition inhibiting the action of renin, containing as the active ingredient of amino acid derivatives of f-crystals I. 2 C. and 6 C. p. F.-ly, 3 tables. Connection structure of f-crystals I:

The invention relates to new amino acid derivatives and their pharmaceutically acceptable salts, specifically to new amino acid derivatives and their pharmaceutically acceptable salts, which have an inhibiting activity against renin, to methods for their preparation, to pharmaceutical compositions containing them and to a method for the treatment of hypertension and heart failure in humans or animals.

The purpose of the invention to provide new and valuable amino acid derivatives and their pharmaceutically acceptable salts, which possess inhibitory activity against renin and are useful as antihypertensives and therapeutic agent in heart failure, especially DL the x amino acid derivatives and their salts.

An additional aim of the invention is pharmaceutical compositions containing as an active ingredient the above amino acid derivatives and their pharmaceutically acceptable salts.

Another aim of the invention is to provide a therapeutic method for the treatment of hypertension and congestive heart failure.

Some of the renin inhibitors having structures similar to the structures of the claimed amino acid derivatives known from the description in applications for Europatent N 172346 and N 229667.

The target amino acid derivatives of the invention are new and can be represented by the following General formula:

(I)

where R1denotes lower alkyl, optionally substituted Deputy selected from the group consisting of acyl, hydroxy, lower alkoxy, aryl, lower alkylthio and groups of the formula

< / BR>
where R5denotes hydrogen or acyl;

R6denotes hydrogen or lower alkyl, aryl or amino, optionally substituted by substituent (substituents), selected from the group consisting of lower alkyl and acyl;

R2denotes hydrogen or lower alkyl, or R1and R2taken together with prisoedinneny is selected from the group consisting of lower alkyl, hydroxy (lower) alkyl, lower alkoxy (lower) alkyl, acyl (lower) alkyl, oxo, and acyl;

R3denotes hydrogen or lower alkyl;

R4denotes lower alkyl.

The target compound I or its salt can be obtained by the methods illustrated in the following reaction schemes, however, obtaining the target compound I is not limited in the following ways:

Method 1.

Stage 1.

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Stage 2

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Stage 3

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< / BR>
Method 2

< / BR>
< / BR>
where R7denotes the N-protective group;

R8denotes hydrogen or an N-protective group; A represents a lower alkylene;

R1, R2, R3, R4and R6have the above values.

In the above and subsequent description is explained in detail suitable examples of the various definitions included in the scope of the invention.

The term "lower" means a group having 1 to 7 carbon atoms, unless stated otherwise.

Suitable "lower alkyl" may be Premiery or branched methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, etylhexyl, EGPA formula:

,

R11-CO - and R11-SO2-,

where R9and R10each denotes hydrogen, aryl, cyclo(lower) alkyl, heterocyclic group or lower alkyl, optionally substituted Deputy selected from the group consisting of alkoxycarbonyl, lower alkoxy, aryl and heterocyclic group, or R9and R10taken together with the attached nitrogen atom, form a heterocyclic group, optionally substituted lower alkyl, and R11denotes aryl, lower alkyl, optionally substituted Deputy selected from the group consisting of lower alkoxy and mono - or di(lower)-alkylamino, or lower alkoxy, optionally substituted Deputy selected from the group consisting of lower alkanoyl and aryl, aminosidine or unprotected amino acid residue or the like.

Suitable "aryl" may be phenyl, naphthyl, tolyl, xylyl, mesityl, cumenyl and the like, and preferred is phenyl.

Suitable "cyclo(lower) alkyl" is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the like.

Suitable "heterocyclic group" for R9and R10and such as Deputy pitsillides group, containing at least one heteroatom such as nitrogen atom, oxygen atom or sulfur atom, preferably N, O and/or S-containing 5 - or 6-membered heterocyclic group, where preferred are morpholino, pyridyl and thiazolyl.

Suitable "lower alkoxy" and part of "lower alkoxy" in the term "lower alkoxycarbonyl" can be premazepam or branched, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy and the like, with the most preferred can be1-C4alkoxy.

Suitable "heterocyclic group" formed by using R9, R10and the attached nitrogen atom, can be morpholino, thiomorpholine, its 1-oxide or 1,1-dioxide, pyrrolidin-1-yl, pyrazolin-1-yl, piperidino, piperazine-1-yl, pyrrolin-1-yl, thiazolidin-3-yl, its oxide or 1,1-dioxide, oxazolidin-3-yl, targetability-1-yl, 1,4-dihydropyridines-1-yl, 1,2,3,6-tetrahydropyridine-1-yl, 1,2,3,4-tetrahydroisoquinoline-2-yl, 1,2,3,4-tetrahydroquinolin-1-yl, hexamethylenimine, 1,4-diazabicyclo-[4.3.0]-nonan-4-yl and the like.

Suitable mono - or di(lower) alkylamino" can be methylamino, ethylamino, Pratolino or the like.

Suitable "lower alkanoyl" may be formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, 4-methylmalonyl or the like.

Suitable "aminosidine or unprotected amino acid residue" may be glycine, alanyl, -ananel, poured, leucyl, isoleucyl, histidyl, propyl, seril, threonyl, cystyl, i.e. phenylalanyl, aspartyl, glutamyl, tryptophyl or the like, and each amino group of this number can be protected N-protective group as mentioned below.

Preferred examples of the above-mentioned acyl groups may be lower alkanoyl, for example formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, 4-methylmalonyl etc., mono - or di(lower)alkylamino (lower)alkanoyl, such as methylaminomethyl, methylaminopropyl, dimethylaminobutyric etc., lower alkoxy (lower)alkanoyl, such as methoxyacetyl, methoxypropanol, ethoxypropanol etc aroyl, for example benzoyl, toluoyl etc., cyclo(lower)alkylaryl, such as cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexylcarbonyl etc. aminosidine or unprotected amino acid residue, for example, glycyl, benzoylglycine, t-butori di(lower) allylcarbamate, for example, methylcarbamoyl, ethylcarbitol, propellerblades, isopropylcarbamate, butylcarbamoyl, intercalator, isobutylamino, tert-butylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, methylethylketon, methylisobutylcarbinol, methylisobutylcarbinol etc., heterocyclic (lower) allylcarbamate, such as Pololikashvili, pyridylcarbinol, thiazolinediones, morpholinomethyl, morpholinoethyl, etc. N-heterocyclic (lower) alkyl-N-lower allylcarbamate, for example N-picolyl-N-methylcarbamoyl, N-pyridylmethyl-N-methylcarbamoyl, N-morpholinomethyl-N-ethyl-carbarnoyl, N-morpholinoethyl-N-methylcarbamoyl etc. ar-lower/allylcarbamate, such as benzylcarbamoyl, phenetically, benzylaminocarbonyl, etc. N-ar(lower)alkyl-N-lower allylcarbamate, for example N-benzyl-N-methylcarbamoyl, N-phenethyl-N-methylcarbamoyl, N-phenethyl-N-ethylcarbamate etc., N-aryl-N-lower allylcarbamate, for example N-phenyl-N-methylcarbamoyl etc. lowest alkoxycarbonyl (lower) allylcarbamate, such as methoxycarbonylmethylene, ethoxycarbonylmethylene, ethoxycarbonylmethylene etc., lower alkoxy (lower) allylcarbamate, such as methoxymethanol, methoxyethanol, e is a mini-carbarnoyl, for example, pyridylcarbinol, morpholinomethyl, thiazolecarboxamide, etc. N-heterocyclic-N-lower allylcarbamate, for example N-pyridyl-N-methylcarbamoyl, N-thiazolyl-N-methylcarbamoyl etc., heterocyclic carbonyl, preferably N-containing heterocyclic-N-ylcarbonyl, which may be substituted by lower alkyl, such as morpholinomethyl, thiomorpholine, piperidinylcarbonyl, 4-methyl-1-piperazinylcarbonyl, 1,2,3,6-tetrahydro-1-pyridylcarbonyl etc. lowest alkoxycarbonyl, such as methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxide, tert-butoxycarbonyl, pentyloxybenzoyl, hexyloxybenzoyl etc., mono-, or di, or three/halo/lower/alkoxycarbonyl, such as iododeoxyuridine, dichlorocarbene, trichlorocyanuric, trifloromethyl etc., hydroxy (lower) alkoxycarbonyl, such as hydroxyethoxymethyl, hydroxyethoxyethyl, hydroxyprogesterone, hydroxyethoxyethyl etc. ar-(lower)-alkoxycarbonyl, such as benzyloxycarbonyl, ventilatsioonil, 4-nitrobenzenesulfonyl, trisiloxanes, benzylaminocarbonyl etc. lowest alkenylacyl, such as vinyloxycarbonyloxy, acetylethanolamine etc. lower Acesulfame, for example, mesyl, ethylsulfonyl, propylsulfonyl, isopropylphenyl, butylsulfonyl, isobutylphenyl, tertbutylphenyl, peterculter, hexylsilane etc. arylsulfonyl, for example phenylsulfonyl, tosyl etc. or the like.

Suitable "lower alkylthio" can be Premiery or branched methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutyric, tert-butylthio, pentylthio, hexylthio and the like, of which more is preferred TO1-C4-alkylthio.

Preferred "heterocyclic group" formed by R1and R2and the attached nitrogen atom may be a group formed by R9, R10and the attached nitrogen atom shown in the example above.

Suitable "hydroxy (lower) alkyl can be hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, hydroxybutyl and the like.

Suitable (lower) alkoxy (lower) alkyl" may be methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, methoxypropyl and the like.

Suitable "N-protective group" may be zamestnanosti [for example, tert-butoxycarbonyl, tert-aryloxyalkyl etc., substituted or unsubstituted Uralelectromed, such as benzyloxycarbonyl, p-nitrobenzenesulfonyl etc., substituted or unsubstituted arenesulfonyl, for example benzazolyl, toil and so on nitrophenyloctyl, aralkyl, for example, trityl, benzyl, etc. or the like.

Suitable "lower alkylene" can be Premiery or branched methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, propylene, METROTILE, utilitiles, Propylamine and the like, of which the preferred is1-C4-alkylene and most preferred methylene, ethylene, trimethylene, tetramethylene, METROTILE.

Suitable pharmaceutically acceptable salts of the target compounds I are conventional non-toxic salts including organic acid additive salt, for example formate, acetate, triptorelin, maleate, tartrate, methanesulfonate, bansilalpet, toluensulfonate etc., inorganic acid additive salt, such as hydrochloride, hydrobromide, sulfate, phosphate, etc. salt with amino acid such as salt, aspartic acid salt, glutamic acid, etc. or the like.

Compound IV or its salt can be obtained by reacting the compound (II) or its reactive production at the carboxyl group, or its salt with the compound III, or its reactive derivative at the amino group or its salt.

Suitable salts of the compounds IV can be salts mentioned as examples for compounds I.

Suitable reactive derivative at the carboxyl group of compound (II) may include galoyanized, acid anhydride, activated amide, an activated ester, and the like. Suitable examples of the reactive derivatives may be an acid chloride, acid azide, mixed acid anhydride with an acid such as substituted phosphoric acid, for example dialkylphosphinate acid, phenylphosphine acid, diphenylphosphoryl acid, dibenzylamine acid, galizana phosphoric acid, etc. dialkylphosphorous acid, sulfurous acid, tisera acid, sulfuric acid, acid, such as methanesulfonate etc., aliphatic carboxylic acid, for example acetic acid, propionic acid, butyric acid, somalina acid, pavlikova acid, pentane Ki the OIC acid, for example benzoic acid, etc. symmetric acid anhydride, activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole, or activated ester, such as complex cinematology ether complex methoxymethyl ether complex dimethylaminomethylene [(CH3)2N=CH-] ether complex vinyl ether complex propargilovyh ether complex p-nitrophenyloctyl ether complex of 2,4-dinitrophenolate ether complex trichloranisole ether complex pentachlorphenol ether complex methylphenylene ether complex phenylazophenyl ether, phenylthiomethyl, p-nitrophenylthio, p-crazily tiefer, carboxymethoxy tiefer, complex pyranyloxy ether complex pyridyloxy ether complex pyridyloxy ether, 8-finalities etc. or ester 11-hydroxidealuminum, for example N, N-dimethyl-hydroxylamine, 1-hydroxy-2-/1H/-pyridone, N-hydroxy-succinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole and so on and so forth. These reactive derivatives can be arbitrarily selected from those listed in accordance with the type of compound (II).

Suitable salts of the compound (II) and its reactive derivative can be the main Sol is metal, for example, calcium salt, magnesium salt etc., ammonium salt, salt with organic base, such as salt, trimethylamine salt of triethylamine, pyridine salt, picolina salt, salt dicyclohexylamine, salt N,N-dibenziletilendiaminom and so forth, or the like, and acid additive salts described for compound I.

Suitable reactive derivative at the amino group of compound III may include imino type shiftwork Foundation or its tautomeric isomer type of enamine formed by reacting compound III with a carbonyl compound such as aldehyde, ketone or the like; a derivative Silla formed by reacting compound III with a silyl compound such as bis-(trimethylsilyl)-ndimethylacetamide, mono-(trimethylsilyl)-ndimethylacetamide, bis-(trimethylsilyl) urea or the like; a derivative, formed by reacting compound III with phosphorus trichloride or phosgene, etc.

Suitable salts of the compound III and its reactive derivative can be referred to for compounds I.

The reaction is usually carried out in a conventional solvent such as water, alcohol, for example methanol, ethanol, etc., armaid, pyridine or any other organic solvent which does not adversely influence the reaction. These traditional solvents can also be used in mixture with water.

In this reaction, when compound II is used in the form of the free acid form or its salt, the reaction is preferably carried out in the presence of a conventional condensing agents, such as N,N-dicyclohexylcarbodiimide; N-cyclohexyl-N'-morpholinobutyrophenone; N-cyclohexyl-N'-(4-diethylaminoethoxy)-carbodiimide; N, N'-diethylcarbamoyl; N,N'-diisopropylcarbodiimide; N-ethyl-N'-/3-dimethylaminopropyl/-carbodiimide; N,N'-carbonyl-bis-/2-Mei/; pentamethylene-N-cyclohexylamine; diphenylethan-N-cyclohexylamine; ethoxyacetylene; 1-alkoxy-1-chlorethylene; trialkylphosphine; etiloleat; isopropylpalmitate; phosphorus oxychloride (chlorine phosphoryl); phosphorus trichloride; diphenylphosphoryl; thionyl chloride; oxacillin; lower alkylsulfonic, such as ethylchloride, isopropylcarbamate etc. triphenylphosphine; 2-ethyl-7-hydroxybenzotriazole salt; intramolecular salt of 2-ethyl-5-/m-sulfenyl/isoxazole hydroxide; 1-/p-chlorobenzenesulfonate/-6-chloro-1H-benzotriazole; so we, trichloromethylcarbonate, phosphorus oxychloride, oxalylamino and so on and so forth.

The reaction may also be carried out in the presence of inorganic or organic bases such as bicarbonate of an alkali metal, three(lower)alkylamine, pyridine N-(lower) alkalifying, N,N-di(lower)alkylbenzene or the like.

The reaction temperature is not critical and the reaction is usually carried out in the range of from cooling to heating.

Stage 2.

Compound V or its salt can be obtained by subjecting compound IV or its salt elimination reactions of N-protective group.

Suitable salts of the compounds V can be attributed to the salts are provided for connection I.

This reaction is carried out in accordance with a conventional method such as hydrolysis, recovery and the like.

The hydrolysis preferably takes place in the presence of a base or an acid including Lewis acid.

Suitable base may include an inorganic base and organic base such as alkali metal, e.g. sodium, potassium etc., alkaline-earth metal, e.g. magnesium, calcium, etc. hydroxide or carbon is lo[4.3.0]-non-5-ene, 1,4-diazabicyclo-[2.2.2]-octane, 1,8-diazabicyclo-[5.4.0]-undec-7-ene or the like.

Suitable acid may include an organic acid such as formic acid, acetic acid, propionic acid, trichloroacetic acid, triperoxonane acid etc., inorganic acid, for example hydrochloric acid, Hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, hydrogen fluoride, etc., and compound acid salt additive, such as piridinkarboksamid etc.

The elimination using Lewis acid, such as triglossia acid, such as trichloroacetic acid, triperoxonane acid, etc. is preferably carried out in the presence of casinoenlinea tools, such as anisole, phenol, etc.

The reaction is usually carried out in a solvent such as water, alcohol, for example methanol, ethanol etc., methylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran, a mixture of them or any other solvent which does not adversely affect the reaction. Liquid base or acid can also be used as solvent. The reaction temperature is not critical and the reaction is usually the treatment, may include chemical reduction and catalytic reduction.

Suitable reducing agents used in chemical reduction are a combination of metal, e.g. tin, zinc, iron, etc. or metal compounds, such as chromium chloride, chromium acetate, etc., and organic or inorganic acids, for example formic acid, acetic acid, propionic acid, triperoxonane acid, p-toluenesulfonic acid, hydrochloric acid, Hydrobromic acid, etc.

Suitable catalysts used in catalytic reduction are conventional catalysts such as platinum catalysts, e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc., palladium catalysts, for example teeth, palladium, palladium black, palladium oxide, palladium carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc. Nickel catalysts, for example, the recovered Nickel, Nickel oxide, skeletal Nickel catalyst for hydrogenation, etc. cobalt catalysts, for example vosstanovlenie iron, the skeletal iron catalyst for hydrogenation, etc. copper catalysts, such as the recovered copper, skeletal copper catalyst for the hydrogenation, Ullman copper, etc., and the like.

Recovery is usually carried out in a conventional solvent which does not adversely affect the reaction, for example water, methanol, ethanol, propanol, N,N-dimethylformamide or a mixture thereof. In addition, the above-mentioned acid used in the liquid in the catalytic reduction, they can also be used as solvent. In addition, the suitable solvent used in the catalytic reduction may be the above-mentioned solvent and other conventional solvent such as diethyl ether, dioxane, tetrahydrofuran, etc. or a mixture thereof.

The reaction temperature for this reaction is not critical and the reaction is usually carried out in the range of from cooling to heating.

Stage 3.

The target compound I or its salt can be obtained by reacting compound V or its reactive derivative at the amino group or its salt with the compound VI or its reactive derivative at carboxylase compounds VI can be the salt of the base, given as an example for compound (II).

This reaction can be performed basically as described for the reaction in stage 1, and therefore the way of reaction and reaction conditions, such as reactive derivative, condensing agents, solvents, reaction temperature and so on, this reaction should be gathered in the description of stage I.

When protected imidazolyl-connection group V, the target compound I can be obtained by further elimination of the N-protective group of the reaction product of compound V and compound VI.

This elimination reaction can be performed basically as described in stage 2 in this way, and therefore the way of reaction and reaction conditions, such as bases, acids, reducing agents, catalysts, solvents, reaction temperature and so on, this reaction should be gathered in the description of stage 2 in this way.

Method 2.

The target compound 1b or its salt can be obtained by subjecting compound 1a or its salt elimination reactions of N-protective group.

Suitable salts of the compounds 1a and 1b can be those mentioned for compound I.

This reaction Eli reaction conditions, for example, bases, acids, reducing agents, catalysts, solvents, reaction temperature and so on, this reaction should be gathered in the description of step 2 of method 1.

Among the starting compound VI, some of them are new and can be obtained as illustrated in the following reaction schemes.

Method A.

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Method B.

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< / BR>
Method C.

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where R12indicates a protected carboxy,

R1, R2, R9, R10and a have the above values.

Among the compounds VII some of them are new and can be obtained as illustrated in the following reaction schemes.

Method D.

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< / BR>
Method E.

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Method F.

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Method G.

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Method H.

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where R5adenotes acyl;

R13denotes lower alkyl;

R2, R5, R6, R7, R9, R10and While everyone has the above value.

Suitable "protected carboxy" may be a carboxyl group protected by conventional protecting group such as lower alkoxycarbonyl, such as methoxycarbonyl, ronil, tert-butoxycarbonyl, pentyloxybenzoyl, neopentylglycol, hexyloxymethyl, etc. arbitrarily substituted ar(lower)-alkoxycarbonyl, for example mono - or di - or triphenyl(lower)alkoxycarbonyl, which may be substituted by nitro, for example benzyloxycarbonyl, 4-nitrobenzenesulfonyl, benzylaminocarbonyl, trisiloxanes etc. or the like.

The above mentioned ways of obtaining the source compounds are explained in detail below.

Method A.

Compound IX can be obtained by subjecting compound VII or its salt and the compound VIII to formation of carbamoylated group.

Suitable salts of the compounds VII can be those described for compound I.

This reaction is carried out in the presence of the reagent, which introducere carbonyl group, such as phosgene, californiathe connection, such as ethylchloride, trichloromethylcarbonate etc., N,N'-carbonyldiimidazole, metallacarborane compounds, such as cobalt carbonyl, carbonyl manganese, etc. the combination of carbon monoxide and a catalyst, such as palladium chloride, etc. or the like.

This reaction is usually carried out in a solvent such as is practical solvent, which does not adversely affect the reaction.

The reaction temperature is not critical and the reaction is usually carried out in the range of from cooling to heating.

Method B.

Compound IXa can be obtained by reacting compound X or its reactive derivative at the carboxy group or its salt, with a compound XI or its reactive derivative at the amino group or its salt.

Suitable salts of the compounds X and its reactive derivative can be referred to compound II as basic salts.

Suitable salts of the compounds XI and its reactive derivative can be referred to for compounds I.

This reaction can be performed basically as described in stage 1 of method 1 and therefore the way of reaction and reaction conditions, such as reactive derivative, condensing agents, solvents, reaction temperature and so on, this reaction can be derived from the description of stage 1 of method 1.

Method C.

Compound VI or its salt can be obtained by subjecting compound (IX reaction of elimination of karbasova 1, and so the way of reaction and reaction conditions, such as bases, acids, reducing agents, catalysts, solvents, reaction temperature and so on, this reaction can be derived from the description of step 2 of method 1.

Method D.

Compound XIII can be obtained by reacting compound XII or its reactive derivative at the carboxy group or its salt, with a compound XI or its reactive derivative at the amino group or its salt.

Suitable salts of the compounds XII and its reactive derivative can be referred to compound (II) in the form of salts of the base.

This reaction can be performed basically as described in stage 1 of method 1, and therefore the way of reaction and reaction conditions, such as reactive derivative, condensing agents, solvents, reaction temperature and so on, this reaction can be derived in the description of stage 1 of method 1.

The way it Is.

Compound VIIa or its salt can be obtained by subjecting compound XIII of the elimination reaction of the N-protective group.

Suitable salts of the compounds VIIa can be salts described for compound I.

Method F.

Compound XVI can be obtained by reacting compound XIV or its reactive derivative at the amino group or its salt, with a compound XV or its reactive derivative, or its salt.

Suitable salts of the compounds XIV and its reactive derivative can be salts described for compound I.

Suitable salts of the compounds XV and its reactive derivative can be basic salts described for compound II.

This reaction can be performed basically as described for stage 1 of method 1, and therefore the way of reaction and reaction conditions, such as reactive derivative, condensing agents, solvents, reaction temperature and so on, this reaction can be derived in the description of stage 1 of method 1.

Method G.

Compound XVIb or its salt can be obtained by subjecting compound XVIa or its salt of the reaction of the lower alkylation.

Suitable lower alkylating substances is d, mutilated, butyl chloride, pantellaria etc. or the like.

This reaction is usually carried out in the presence of a base, such as alkali metal, e.g. sodium, potassium, etc., alkaline-earth metal such as magnesium, calcium, etc. nitride or hydroxide him, alkali metal alkoxide, such as nutrimetics, materialised, tert-piperonyl potassium, etc. or the like.

This reaction is usually carried out in a conventional solvent such as water, alcohol, for example methanol, ethanol, propanol etc., tetrahydrofuran, dioxane, ethyl acetate, methylene chloride, N,N-dimethylformamide, dimethyl sulfoxide, diethyl ether or any other organic solvent which does not adversely affect the reaction. In the case when the above-mentioned lower alkylating agent is in liquid, it can also be used as solvent.

The reaction temperature is not critical and the reaction is usually carried out under cooling, at ambient temperature or under heating or heating.

Way N.

Compound VIIb or its salt can be obtained by subjecting compound XVI of the elimination reaction of the N-protective group. When the out mostly so, as described in step 2 of method 1, and therefore the way of reaction and reaction conditions, such as bases, acids, reducing agents, catalysts, solvents, reaction temperature and so on, this reaction can be borrowed in the description of step 2 of method 1.

The compound obtained above methods can be isolated and purified by the conventional method, such as spraying, recrystallization, column chromatography, pereosazhdeniya or the like.

It should be noted that the connection I and other compounds can include one or more stereoisomers due to asymmetric carbon atoms, and all of such isomers and mixtures thereof are included in the scope of the invention.

Target compounds I and their pharmaceutically acceptable salts possess any abscopal strong action against renin and are useful as antihypertensives and therapeutic agent in heart failure, especially for oral administration.

For therapeutic purposes, the compounds I and its pharmaceutically acceptable salts of the invention can be used in the form of pharmaceutical preparation containing one of these compounds as an active component is a liquid filler, suitable for oral administration, parenteral or external use.

Test 1.

Test method.

The human plasma collected from male volunteers without first receiving no treatment and used as a pool. Disodium salt of ethylenediaminetetraacetic acid (adtc) is used as anticoagulant. The plasma renin activity was measured as the rate of formation of angiotensin I (Ang I) after incubation (37o(C) endogenous renin and angiotensinogen in plasma at pH 6.0. The incubation mixture contains 250 ál of plasma, 5 μl (phenylmethyl)sulfonyl fluoride, 30 μl of buffer (sodium, potassium-phosphate, pH 6.0) and 15 μl of the appropriate concentration of test compound in 50 media ethyl alcohol water. Ang I formed after 90 min incubation, measured by radioimmunoassay (RIA), which carry out commercial set, RENCTK 100 (manufacturer mmissariat Al energic Atomique. Samples incubated sparano and each tube is measured sparano in the RIA. The percentage of inhibition of plasma renin activity is calculated by comparing the amount of Ang I produced with and without the test compound. The concentration of test compound that inhibits the activity re the(known connection L-3-phenyllactic-histidyl (PB-AIS) amide of 2-amino-1-cyclo-hexyl-3-hydroxy-6-methylheptane described in example 16 in EP-172 346).

Test 2.

Test method.

Use male or female cynomolgus monkeys (Maccaca fascicularis weighing about 2.5 to 3.5 kg). Sodium depletion reach by introducing furosemide 15 mg/kg subcutaneously one day before and then 10 mg/kg intravenously 30 min prior to injection of the test compounds.

Test compounds are dissolved in dilute equimolar hydrochloric acid (pH 5 to 6) and orally administered in consciousness and trained monkeys placed in the machine for fixing with a pneumatic cuff placed around the upper limb for oscillometric measurement of mean arterial blood pressure (MAP) (Model VR-203 NPJ, manufacturer Nippon Colin).

MAR measured at 0 (baseline pre-dose), 0,5, 1, 2, 3, 4 and 6 h after injection of the test compounds. The maximum antihypertensive effect is calculated as the maximum percentage fall MAR from pre-treatment values.

Blood samples collected at 0, 0,5, 1, 2, 4 and 6 h after dosing located anterior to the elbow joint Vienna monkeys in and get plasma for determination of plasma renin activity (BDA) the BDA is measured as the rate of formation of APD I as described in test 1. 100 μl of an exemplary plasma is mixed with 100 μl of a solution of inhibitors angiotensinase (3mm 8-hydroxyanisole and 5 mm 2,3-dimercaptopropanol, SB-REN-I SORIN BIOMED ICA, ICA, Italy). Half (100 μl) of the mixture is incubated at a temperature of 37oC for one hour and educated APD I define commercial kit RIA /D INABOTT/. The remaining half (100 μl) of the reaction mixture is stored at a temperature of 4oC for one hour to measure and adjustments to previously existing Ang I in the plasma. The percentage inhibition of the BDA is calculated by the following formula

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AND37the amount of angiotensin 1, formed upon incubation at a temperature of 37oWith plasma collected before dosing the test compound;

A4the amount of angiotensin I formed while maintaining at a temperature of 4oWith plasma collected before dosing the test compound;

D37the amount of angiotensin I formed during incubation at a temperature of 37oWith plasma collected after dosing the test compound;

D4the amount of angiotensin I formed while maintaining at a temperature of 4oWith plasma collected after dosing, ispytyvau the factors shown are for illustration purpose preferred drugs target compounds I and preparations of these compounds are not limited to, the following preparations and examples.

Test for acute toxicity.

1. Description of the method.

Five rats (j DM(S)line) of both sexes were taken for the group. Solutions of the test compound in saline solution was administered to rats intravenously. For rats then were observed for 14 days. Values LD50were calculated using the probit method.

Test the connection.

1) 2(S)-[N-[2(S)-N-(2-morpholinylcarbonyl)-N-methylaminorex} -3-phenylpropionyl] - N-methyl-L-histidyl] -amino-1-cyclohexyl-3(S)-hydroxy-6 are formed hydrochloride

2) 2(S)-[N-[2(S)-[N-methyl-N-[2-N-(morpholinoethyl)-N-methylamino}-ethyl]-aminocarbonyl]-3 - phenylpropionyl]-N-methyl-L-histidyl]-amino-1-cyclohexyl-3(S)- hydroxy-6 are formed hydrochloride

II. The results are given in table. 3.

Examples of formulations.

Example 12.

2(S)-[N-[2(S)-{ N-(2-morpholinylcarbonyl)-N-methylaminorex} - 3-phenylpropionyl] -N-methyl-L-histidyl]-amino-1-cyclohexyl-3(S)- hydroxy-6 are formed hydrochloride 5 mg

Lactose 80 mg

The above ingredients were mixed and the mixture was enclosed in a capsule with getting capsuel]-aminocarbonyl]-3 - phenylpropionyl]-N-methyl-L-histidyl]-amino-1-cyclohexyl-3(S)- hydroxy-6 are formed hydrochloride 90 mg

Lactose 30 mg

The above ingredients were mixed and the mixture was sealed in a capsule to obtain a capsule.

In the following preparations and examples as plates for thin-layer chromatography using Kieselgel 254 (trademark: manufacturer Merck L Co (thickness 0.25 mm).

Preparation 1.

To a mixture of N-tert-butoxycarbonyl-N-methyl-beta-alanine (1,02 g) and research (0,48 g) in dry methylene chloride, was added the hydrochloride of N-ethyl-N-(3-dimethylaminopropyl) carbodiimide (1,05 g) followed by stirring at ambient temperature overnight. After evaporation of the solvent the residue is dissolved in ethyl acetate. The resulting solution was successively washed with 1 aqueous citric acid solution, saturated sodium bicarbonate solution and saturated sodium chloride solution. Then the solution is dried over magnesium sulfate and evaporated under reduced pressure to yield 4-(N-tert-butoxycarbonyl-N-methyl-beta-alanine) of the research (1,36 g).

Rf: 0,57 (methanol chloroform, 10 V/V).

Preparation 2.

A solution containing 4-(N-tert-butoxycarbonyl-N-the Les evaporation of the solvent receive triptorelin 4-(N-methyl-beta-alanine) of the research (1.44 g).

Rf: to 0.17 (chloroform, methanol, acetic acid, 8 1 1, V/V).

Preparation of 3.

In accordance with the method of preparation 1, the following compounds:

1) 4-(N-tert-butoxycarbonyl-N-methyl-beta-alanine) thiomorpholine (798 g) is obtained from a mixture of N-tert-butoxycarbonyl-N-methyl-beta-alanine (610 mg) and thiomorpholine (372 mg).

Rf: 0,79 (chloroform methanol, 9 1 V/V).

2) 2-(N-tert-butoxycarbonyl-N-methyl-beta-alanyl)-amino]-thiazole (639 mg) is prepared from a mixture of N-tert-butoxycarbonyl-N-methyl-beta-alanine (610 mg) and 2-aminothiazole (361 mg).

Rf: 0,63 (chloroform methanol, 9 1, V/V).

3) 2-[(N-tert-butoxycarbonyl-N-methyl-beta-alanyl)-aminomethyl] -pyridine (902 mg) is prepared from a mixture of N-tert-butoxycarbonyl-N-methyl-beta-alanine (610 mg) and 2-picolylamine (389 mg).

Rf: 0,55 (chloroform methanol, 9 1, V/V).

4) 4-[2-(N-tert-butoxycarbonyl-N-methyl-beta-alanyl)-amino-ethyl]-morpholine (931 mg) is prepared from a mixture of N-methyl-butoxycarbonyl-N-methyl-beta-alanine (610 mg) and 4-(2-amino-ethyl)-research (469 mg).

Rf: of 0.53 (chloroform methanol, 9 1, V/V).

5) 2-[2-{N-(N-tert-butoxycarbonyl-N-methyl-beta-alanyl)-N-methylamino}-ethyl] pyridine (1.08 g) obtained from a mixture of N-tert-butter, 9 1, V/V).

6) 1-(N-tert-butoxycarbonyl-N-methyl-beta-alanyl)-4-methylpiperazine (460 mg) is prepared from a mixture of N-tert-butoxycarbonyl-N-methyl-beta-alanine (711) and 4-methylpiperazine (421 mg).

7) 2-[N-(N-tert-butoxycarbonyl-N-methyl-beta-alanyl)-N-methylamino]- pyridine (324,3 mg) is obtained from N-tert-butoxycarbonyl-N-methyl-beta-alanine (508 mg) and 2-(methylamino)-pyridine (325 mg).

Rf: 0,63 (chloroform methanol, 9 1, V/V).

8) 3-[(N-tert-butoxycarbonyl-N-methyl-beta-alanyl)-aminomethyl] -pyridine (1,03 g) is obtained from a mixture of N-tert-butoxycarbonyl-N-methyl-beta-alanine (711 mg) and 3-picolylamine (454 mg).

Rf: 0,43 (chloroform methanol, 9 1, V/V).

9) 1-(N-tert-butoxycarbonyl-N-methyl-beta-alanyl)-1,2,3,6 - tetrahydropyran (645 mg) is prepared from a mixture of N-tert-butoxycarbonyl-N-methyl-beta-alanine (813 mg) and 1,2,3,6-tetrahydropyridine (399 mg).

Rf: to 0.68 (chloroform methanol 9 1, V/V).

10) N-isopropyl-Na-tert-butoxycarbonyl-N-methyl-beta-alaninate (893 mg) is obtained from N-tert-butoxycarbonyl-N-methyl-beta-alanine (813 mg) and Isopropylamine (284 mg).

Rf: of 0.62 (chloroform methanol 9 1, V/V).

11) Complex ethyl ester (N-tert-butoxycarbonyl-N-methyl-beta-alanyl)-glycine get the 495 mg).

Rf: 0,50 (ethyl acetate).

(12) N,N-dimethyl-N-tert-butoxycarbonyl-N-tert-butoxycarbonylamino (1.08 g) obtained from a mixture of N-tert-butoxycarbonylamino (0.95 g) and dimethylamine hydrochloride (0.45 g).

Rf: 0,41 (methanol chloroform, 10 V/V).

17) N-n-butyl-N-tert-butoxycarbonylamino (473 mg) and n-butylamine (201 mg).

Rf: 0,50 (ethyl acetate benzene acetic acid: 20 20 1, V/V).

18) 4-[(N-tert-butoxycarbonylmethyl)-aminomethyl)-pyridine (595,3 mg) is prepared from a mixture of N-tert-butoxycarbonylamino (473 mg) and 4-picolylamine (297 mg).

So pl. 115 116oC.

Rf: 0,50 (methanol-chloroform, 1 6, V/V).

19) N,N-dimethyl-N-tert-butoxycarbonyl-D-prolinamide) (519,1 mg) is prepared from a mixture of N-tert-butoxycarbonyl-D-Proline (455 mg) and dimethylamine hydrochloride (180 mg).

Rf: a 0.27 (ethyl acetate, benzene, acetic acid, 20 20 1, V/V).

Tert-butoxycarbonyl group obtained in the preparation of the compounds removed by the method of preparation 2 and the resulting derivative salt triperoxonane acid used as starting material in the preparation of 33.

Photometering ester of glycine (of 1.62 g) in methanol (60 ml) was added cyanoborohydride sodium (544 mg) in methanol (10 ml) at ambient temperature. The reaction mixture was stirred overnight at the same temperature. After evaporation of the solvent the residue is dissolved in ethyl acetate (50 ml) with subsequent washing with 1 M sodium bicarbonate solution and water, drying over magnesium sulfate and concentration under reduced pressure. The residue purified column chromatography on silica gel (eluent used chloroform) to yield N-[2-(N-tert-butoxycarbonyl-N-methylamino)-ethyl] -glycine methyl ester (1.04 g) in the form of butter.

Rf: 0,69 (chloroform acetic acid methanol 8 1 1, V/V).

2) Solution of complex methyl ester. N-[2-(N-tert-butoxycarbonyl-N-methylamino)-ethyl] -glycine (1.06 g) in triperoxonane acid (15 ml) stirred at 0oC for 1 h After evaporation of the solvent in vacuo the residue is dissolved in 6 N. solution of ammonia in methanol (20 ml). The resulting solution was stirred at ambient temperature for 30 min and after concentration in vacuum to obtain 1-methyl-2-piperazinone (490 mg) as oil. Rf: 0,28 (chloroform methanol, 10 1, V/V).

Preparation 5.

1) methyl ester. N-(N-tert-butoxycarbonyl-2(S)-pyrrolidinyloxy)-glycine (808 mg) PIDA difficult methyl ester of glycine (1.88 g).

Rf: 0,31 (ethyl acetate).

2) 6 (S)-2-2-oxo-1,4-diazabicyclo-[4.3.0] -nonan (410 mg) are obtained by the method similar to preparation 4 (2) of a mixture of N-(N-tert-butoxycarbonyl-2(S)-pyrrolidinyloxy)-glycine complex methyl ester (800 mg).

Rf: 0,52 (chloroform, methanol, acetic acid, 8 1 1, V/V).

Preparation of 6.

To the solution containing dichlorhydrate N,N'-dimethyl hydrazine (40 mg) and triethylamine (2.15 g) in methylene chloride (30 ml), cooled to 0oWith added isobutyl ether of Harborview acid (970 mg). The mixture was stirred at 0oC for 1 h After evaporation of the solvent the residue is dissolved in ethyl acetate (50 ml) with subsequent washing with 1 M sodium bicarbonate and water and dried over sodium sulfate. After evaporation of the solvent receive N-isobutoxide-N,N'-dimethyl (922 mg) in the form of butter.

Rf: 0,78 (chloroform methanol, 10 1, V/V).

Preparation 7.

In accordance with the method of preparation 6, the following compounds:

1) N-(morpholinoethyl)-N,N'-dimethyl (1.70 g) obtained from a mixture of dichlorhydrate N, N-dimethylhydrazine (1,33 g) and chloride morpholinylcarbonyl (1.50 g).

R

Rf: 0,56 (chloroform methanol, 10 1, V/V).

3) 1 - benzyloxycarbonylation (compared to 8.26 g) receive from dichlorhydrate of pyrazolidine (of 5.81 g) and benzyloxycarbonylamino (6,624 g).

Rf: 0,61 (chloroform methanol, 9 1, V/V).

4) 1-benzyloxycarbonylglycine (9,20 g) is prepared from a mixture of dichlorhydrate perhydrophenanthrene (of 6.68 g) and benzyloxycarbonylamino (7,123 g).

Rf: 0,29 (n-hexane ethyl acetate, 1 1, V/V).

Preparation of 8.

To a solution of dichlorhydrate N,N'-dimethylhydrazine (1,33 g) and triethylamine (2,02 g) in dry tetrahydrofuran (20 ml), cooled to 0oC, add isopropyltoluene (851 mg). The reaction mixture was stirred at 0oC for 2 h After evaporation of the solvent the residue is dissolved in ethyl acetate (50 ml). The solution is then washed successively 1 M sodium bicarbonate solution and water and dried over magnesium sulfate. After evaporation of the solvent to obtain N-(isopropylcarbamate)-N,N'-dimethyl (771 mg) in the form of butter.

Rf: to 0.48 (chloroform methanol, 10 1, V/V).

Preparation of 9.

N-(benzylcarbamoyl)-N, N'-dimethyl (1,07) are obtained according to the method described in preparation 8, of a mixture of d is 0 1, about/about).

Preparation 10.

To a solution of N-benzyloxycarbonyl-N, N'-dimethyl hydrazine (1.2 g) in dry tetrahydrofuran (20 ml) was added methyl isocyanate (352 mg) at 0oC. the Reaction mixture was stirred at 0oC for 6 hours After evaporation of the solvent, the obtained residue is dissolved in ethyl acetate (50 ml). The solution is successively washed with 5 hydrochloric acid, 1 M sodium bicarbonate solution and water, then dried over magnesium sulfate. After evaporation of the solvent, the residue is dissolved in methanol (20 ml), water (2 ml). The solution hydronaut 10 palladium on coal (100 mg) under hydrogen pressure of 3 ATM for 1 hour the Solution is filtered and concentrated in vacuo to yield N-(methylcarbamoyl)-N,N'-dimethylhydrazine (592 mg) in the form of butter.

Rf: 0,42 (chloroform methanol, 10 1, V/V).

Preparation of 11.

In accordance with the method of preparation of 10 receive the following connections:

1) 1-isopropylcarbodiimide (845 mg) obtained from a mixture of 1-benzyloxycarbonylglycine (1,237 g) and isopropylmalate (510,6 mg).

Rf: 0,52 (chloroform methanol, 9 1, V/V).

2) 1-methylcarbamoylmethyl (774 mg) obtained from a mixture of 1-benzyloxycarbonylglycine (1,237 g) and SS="ptx2">

To a solution of N-benzyloxycarbonyl-N,N'-dimethyl hydrazine (1.6 g) in toluene (30 ml) was added trichloromethylcarbonate (0,553). After heating the solution under reflux for 30 min thereto was added dimethylamine (672 mg) and triethylamine (2.0 g) at 0oC. After evaporation of the solvent the residue is dissolved in ethyl acetate (50 ml). The resulting mixture was sequentially washed with 5 hydrochloric acid, a solution of 1 M sodium bicarbonate and water followed by drying over magnesium sulfate. Field evaporation of the solvent the residue is dissolved in methanol (20 ml) with water (20 ml). Then the reaction solution hydronaut 10 palladium on coal (100 mg) under hydrogen pressure of 3 ATM for 1 h After filtering and concentrating the solution in vacuo get N-(N,N'-dimethylcarbamoyl)-N,N'-dimethyl (820 mg) as oil.

Rf: to 0.47 (chloroform methanol, 10 1, V/V).

Preparation 13.

To a solution of N-tert-butoxycarbonylamino (of 3.46 g) in dry tetrahydrofuran (100 ml), cooled to -78oWith that added dropwise a solution of isopentylamine obtained from isopentylamine (30,8 g) and magnesium (a 4.86 g) in dry tetrahydrofuran (200 ml). After the introduction of the reagents, the reaction mixture is heated by Donau mixture of a saturated aqueous solution of ammonium chloride (200 ml) the resulting solution was extracted with simple diethyl ether (300 ml x 2). Coupled extract was dried over magnesium sulfate and concentrate under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent used 20 ethyl acetate in n-hexane) to obtain 1-(N-tert-butoxycarbonyl-N-methylamino)-2-hydroxy-5-methylhexane (3,96 g).

Rf: of 0.53 (hexane ethyl acetate, 2 1, V/V).

Preparation 14.

To a solution of 1-(N-tert-butoxycarbonyl-N-methylamino)-2-hydroxy-5-methylhexane (2,45 g) and triethylamine (3.03 g) in dimethyl sulfoxide (20 ml) was added sulfur trioxide-pyridine complex (4.77 g) under cooling in an ice bath. After stirring the mixture at ambient temperature during the night it poured into ice water (100 ml). The reaction mixture was extracted with simple diethyl ether (100 ml x 2). The extract is washed with water, dried over magnesium sulfate and concentrate under reduced pressure. The residue purified by chromatography on a column of silica gel (eluent used 20 ethyl acetate in n-hexane) to yield 1-(N-tert-butoxycarbonyl-N-methylamino)-2-oxo-5-methylhexane (2.15 g),

Rf: 0,73 (hexane ethyl acetate, 5 2, V/V).

Preparation 15.

To a solution of N-tert-butoxycarbonyl-N-N'-dimethylethylenediamine chloride (794 g). The resulting mixture was stirred at 0oC for 1 h After evaporation of the solvent, the residue is dissolved in ethyl acetate (30 ml) followed by washing in turn 5 with hydrochloric acid, a solution of 1 M bicarbonate of sodium and water and drying over magnesium sulfate. In the process of evaporation of solvent to obtain N-tert-butoxycarbonyl-N-(morpholinoethyl)-N,N'-dimethylethylenediamine (1,11 g) in the form of butter.

Rf: of 0.62 (chloroform methanol, 10 1, V/V).

Preparation 16.

In accordance with the method of preparation 15 receive the following connections:

1) N-tert-butoxycarbonyl-N'-isobutyl-N,N'-dimethylethylenediamine (1.42 g) of N-tert-butoxycarbonyl-N,N'-dimethylethylenediamine (1.2 g) and isobutylamine (668 ml).

Rf: 0,31 (n-hexane ethyl acetate, 1 1, V/V).

2) N-tert-butoxycarbonyl-N-isovaleryl-N,N'-dimethylethylenediamine (1,17 g) and N-tert-butoxycarbonyl-N, N'-dimethylethylenediamine (850 mg) and chloride isovaleryl (0,55 ml).

Rf: 0,75 (chloroform methanol, 10 1, V/V).

3) 1-[(N-tert-butoxycarbonyl)-N-methylamino]-4- [N-(morpholinoethyl)-N-methylamino] -butane (478 mg) of 1-[N-(tert-butoxycarbonyl)-N-methylamino] -4-methylaminoethanol (500 mg) and morpholinosydnonimine (363 mg).

Rf: 0,34 (ethyl acetate).

5) 1-[N-(tert-butoxycarbonyl)-N-methylamino] -5-[N-(morpholinoethyl) -N-methylamino] -pentane (881 mg) of 1-[N-(tert-butoxycarbonyl)-N-methylamino] -5-methylaminoethanol (576 mg), morpholinosydnonimine (374 mg) and triethylamine (253 mg).

Rf: 0,74 (chloroform methanol, 10 1, V/V).

Preparation 17.

To a mixture of 5-(N-tert-butoxycarbonylamino) valerianic acid (2,173 g) and research (1,045 g) in anhydrous methylene chloride (22 ml) was added the hydrochloride of N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide (2.30 g) in portions at a temperature in the range of 0 to 5oC. After stirring at the same temperature for 3 h the solvent is evaporated in vacuum and the residue dissolved in a mixture of ethyl acetate (100 ml) with water (100 ml). The organic layer is washed successively with 0.5 G. hydrochloric acid (100 ml), water (100 ml), aqueous sodium bicarbonate solution (100 ml), water (100 ml) and with brine (100 ml) and then dried over magnesium sulfate. After evaporation of the solvent to obtain 4-[5-(N-tert-butoxycarbonylamino)-valeryl]-morpholine (1,668 g) in the form of butter.

Rf: 0,37 (ethyl acetate).

Preparation 18.

To a solution of 4-[5-(N-tert-butoxycarbonylamino)-valeryl]-47 mg) and modesty methyl (2,462 g) at 0 - 5oC in nitrogen atmosphere. After stirring the mixture for 6 h at room temperature, it was added to ethyl acetate (200 ml) with water (200 ml). The organic layer is washed successively with 0.5 G. hydrochloric acid (200 ml), water (200 ml), aqueous sodium bicarbonate solution (200 ml), water (200 ml) and with brine (200 ml) and then dried over magnesium sulfate. After evaporation of the solvent to obtain 4-[5-(N-methyl-N-tert-butoxycarbonylamino)-valeryl]-morpholine (1,093 g) in the form of butter.

Rf: 0,38 (ethyl acetate).

Preparation 19.

To a mixture of N-tert-butoxycarbonyl-N-methyl-beta-alanine (6,097 g) and triethylamine (4,18 ml) in ethyl acetate (60 ml) was added in portions of 2-bromoacetophenone (5,972 g) at a temperature of 0 to 5oC. After stirring overnight at ambient temperature, the solvent evaporated, and the obtained residue was dissolved in ethyl acetate (200 ml). The solution is washed successively with 0.5 G. hydrochloric acid (200 ml), water (200 ml) and with brine (200 ml) and dried over magnesium sulfate. After evaporation of the solvent receive N-tertbutoxycarbonyl-N-methyl-beta-alanine complex finally ether (8,54 g) in the form of butter.

Rf: 0,53 (n-hexane ethyl acetate, 1 1, V/V).

e, described in preparation 17, from 5-(N-tert-butoxycarbonylamino) valerianic acid (2,173 g) and Isopropylamine (673 mg).

So pl. 93,5 95oC.

Rf: 0,46 (ethyl acetate).

2) Amide-N-isopropyl-N-methyl-5-(N-methyl-N-tert-butoxycarbonylamino) valerianic acid (1,399 g) are obtained according to the method described in preparation 18, of amide-N-isopropyl-5-(N-tertbutoxycarbonyl) valerianic acid (1,502 g) and iodotope bromide (4,951 g).

Rf: 0,19 (n-hexane ethyl acetate, 1 1, V/V).

Preparation 21.

1) Methyl-5-(N-tert-butoxycarbonyl-N-methylamino)-valerate (563 mg) are obtained according to the method described in preparation 18, from 5-(N-tert-butoxycarbonylamino) valerianic acid (2,716 g) and iodotope bromide (14,20 g).

Rf: 0,62 (n-hexane ethyl acetate, 1 1, V/V).

2) a Mixture of methyl-5-(N-tert-butoxycarbonyl-N-methylamino)-valerate (557 mg) in methanol (6 ml) and 1 n sodium hydroxide solution (3,41 ml) was stirred at ambient temperature for 1 h the Solution was concentrated in vacuo and the resulting residue is poured into a mixture of water (20 ml) and diethyl ether (20 ml). The aqueous layer was separated and acidified with 1 N. hydrochloric acid, and then extracted with ethyl acetate (20 ml x ywaniem over magnesium sulfate. After evaporation of the solvent leaves 5-(N-tert-butoxycarbonyl-N-methylamino) valeric acid (470 mg) as oil.

Rf: 0,43 (chloroform, methanol, acetic acid, 16 1 1, V/V).

3) Amide valerianic acid (384 mg) are obtained according to the method described in preparation 17, from 5-(N-tert-butoxycarbonyl-N-methylamino) valerianic acid (454 mg) and Isopropylamine (132 mg).

Rf: to 0.17 (n-hexane ethyl acetate, 1 1, V/V).

Preparation 22.

1) 4-[4-(N-tert-butoxycarbonylamino)-butyryl] -morpholine (1.73 g) are obtained by the procedure described in preparation 17, from 4-(N-tert-butoxycarbonylamino)-butyric acid (2,03 g) and research (0.88 g).

Rf: of 0.50 (chloroform methanol, 10 1, V/V).

2) 4-[4-(N-tert-butoxycarbonyl-N-methylamino)-butyryl]-morpholine get on the method of preparation 18.

Rf: 0 58 (chloroform methanol, 10 1, V/V).

Preparation 23.

1) N-isopropyl-4-(N-tert-butoxycarbonyl-N-methylamino)-butyramide (3.13 g) are obtained according to the method of preparation 17, from 4-(N-tert-butoxycarbonyl-N-methylamino) butyric acid (3,26 g) and Isopropylamine (0,91 g).

Rf: of 0.62 (chloroform methanol, 10 1, V/V).

2) N-isopropyl-N-methyl-4-(N-tert-b the RM methanol 10 1, about/about).

Preparation 24.

(1 N-tert-butoxycarbonyl-N-methyl-beta-alanine methyl ester (15,12 g) are obtained according to the method of preparation 18 from N-tert-butoxycarbonyl-beta-alanine (28,38 g) and iodotope bromide (102,1 g).

Rf: 0,61 (n-hexane ethyl acetate, 1 1, V/V).

To a solution of complex methyl ester of N-tert-butoxycarbonyl-N-methyl-beta-alanine (3,911 g) in methanol (20 ml) with water (20 ml) was added to borohydride sodium (6.81 in) portions at a temperature of 4oC, followed by stirring the reaction mixture at room temperature for 3 hours the Solution was concentrated in vacuo, and the residue is divided between ethyl acetate (100 ml) and 0.5 G. hydrochloric acid (100 ml). Selected organic layer is washed successively with 0.5 G. hydrochloric acid (100 ml), water (100 ml), aqueous sodium bicarbonate solution (100 ml), water (100 ml) and with brine (100 ml) and then dried over magnesium sulfate. After evaporation of the solvent to obtain 3-(N-tert-butoxycarbonyl-N-methylamino)-propanol (2,48 g) in the form of butter.

Rf0,28 (n-hexane ethyl acetate, 1 1, V/V).

3) Solution containing 3-(N-tert-butoxycarbonyl-N-methylamino)-propanol (2,40 g) and triethylamine (2,07 g) in methylene chloride (25 ml), cooled to 4othe solution is evaporated in vacuum. The remainder is divided into phases with ethyl acetate (25 ml) and water (50 ml). The separated organic layer is washed successively with 0.5 G. hydrochloric acid (50 ml), water (50 ml), aqueous sodium bicarbonate solution (50 ml), water (50 ml) and with brine (50 ml) and dried over magnesium sulfate. After evaporation of the solvent to obtain 3-(N-tert-butoxycarbonyl-N-methylamino) propylaminosulfonyl (3,742 g) in the form of oil

Rq: to 0.18 (ethyl acetate).

4) To a thoroughly stirred suspension of sodium hydride (336 mg: 60 dispersion in oil) in anhydrous tetrahydrofuran (12 ml) was added dropwise a solution of 3-(N-tert-butoxycarbonyl-N-methylamino)-propylaminosulfonyl (2,139 g) in tetrahydrofuran (10 ml) for 5 minutes After stirring for 30 min the reaction mixture was cooled to 0oC and added dropwise 2-methyl-1-propanethiol (758 mg) at 0, 5oC. the mixture is Then heated to ambient temperature and stirred for 24 h and Then under the same conditions add another 168 mg of sodium hydride and 379 mg of 2-methyl-1-propanethiol. After stirring for an additional 16 h, the solvent evaporated, and the obtained residue was dissolved in ethyl acetate (100 ml). The solution is successively washed with 0.5 G. hydrochloric acid (100 ml), water is magnesium and concentrate. The remainder chromatographic on a column of silica gel with elution with a mixture of g-hexane and ethyl acetate (6 4, V/V). Get 3-(N-tert-butoxycarbonyl-N-methylamino)-proprietorship (595 mg) in the form of butter.

Rf: 0,83 (n-hexane ethyl acetate, 1 1, V/V).

Preparation of 25.

1) To a solution of 2-(N-tert-butoxycarbonyl)-aminoethanethiol (3.55 g) in N, N-dimethylformamide (10 ml) was added a solution of 2,2 N. sodium hydroxide (10 ml) under cooling in an ice bath. The reaction mixture was stirred at ambient temperature for 20 min followed by the addition of a solution of 2-iodopropane (3,74 g) in N,N-dimethylformamide (2 ml) under cooling in an ice bath. After stirring at ambient temperature for 1 h, the Reaction mixture was poured into ice water (20 ml). The mixture was then neutralized 10 hydrochloric acid and extracted with ethyl acetate (40 ml x 2). The extract is washed with water, dried over magnesium sulfate and concentrate under reduced pressure. The residue is purified column chromatography on silica gel with elution with a mixture of hexane and ethyl acetate (8 1, V/V). Get 2-(N-tert-butoxycarbonylamino)-ethylisopropylamine (3.88 g).

Rf: 0,46 (hexane ethyl acetate, 5 1, V/V).

2-(N-CLASS="ptx2">

Rf: 0,55 (hexane ethyl acetate, 5 1, V/V).

Preparation 26.

1) To a solution of N-tert-butoxycarbonyl-N-methyl-beta-alanine (610 mg) in dry methylene chloride (10 ml), cooled to 0oC, add oxalicacid (439 ml) and three drops of N,N-dimethylformamide. The mixture is stirred at the same temperature for 30 minutes After evaporation of the solvent the residue is dissolved in dry methylene chloride (10 ml) and the resulting solution was added 2-mercaptopyridine (350 mg) at 0oC. the Mixture is stirred at the same temperature for 4 hours After evaporation of the solvent the residue is dissolved in ethyl acetate (50 ml) followed by washing successively with 0.5 solution of hydrochloric acid, 1 M sodium bicarbonate solution and water, and then dried over magnesium sulfate. After evaporation of the solvent receive S-2-pyridyl 3-(N-tert-butoxycarbonyl-N-methylamino)-propertyof (490 mg) as amorphous powder.

Rf: 0,61 (n-hexane ethyl acetate, 1 1, V/V).

2) To a solution of 3-(N-tert-butoxycarbonyl-N-methylamino)-propanoate S-2-pyridyl (490 mg) in dry tetrahydrofuran (20 ml), cooled to 0oWith that added dropwise a solution of isobutylamine obtained from isobutyramide (1, 13 g) and magnesium (200 mg is e 1 o'clock The mixture is then poured into a saturated aqueous solution of ammonium chloride (50 ml). The resulting suspension is extracted with a simple diethyl ether (50 ml x 2), and the combined extract was dried over magnesium sulfate and concentrated to yield 1-(N-tert-butoxycarbonyl-N-methylamino)-3-oxo-5-methyl-hexane (400 mg) in the form of butter.

Rf: 0,64 (n-hexane ethyl acetate, 2 1, V/V).

Preparation 27.

1) a Mixture consisting of ethylendiamine (308 g) and methylisobutyl (87,15 g) was stirred at 80oWith over 15 hours After removal of excess Ethylenediamine under reduced pressure the residue is dissolved in ethyl acetate (100 ml). The precipitate was filtered, and the filtrate is evaporated and after distillation N-isobutylmethylxanthine (84,45 g).

So pl. 106 108oC/mm RT. Art.

2) Solution of di-tert-BUTYLCARBAMATE (137,5 g) in methylene chloride (1 l) was added dropwise to a solution of N-isobutylmethylxanthine (82,02 g) in methylene chloride (1 l) under cooling in an ice bath. The mixture is then stirred for 3 h at ambient temperature and the solvent evaporated under reduced pressure. The residue is recrystallized from a solvent mixture of n-hexane-ethyl acetate (2 1, V/V, 1.6 l) c output N-tert-butoxycarbonyl-N-and-N N-dimethylethylenediamine (129 g) are obtained according to the method of preparation 18 from a mixture of tert-butoxycarbonyl-N'-isobutylacetophenone (105 g), iodotope bromide (to 85.2 ml) and 60 solution of sodium hydride (38,3 g)

Rf: 0,59 (chloroform methanol, 10 1, V/V).

Tert-butoxycarbonyl group of the compounds obtained in preparation 13 27 is removed by the procedure described in preparation 2, and the resulting derivative salts triperoxonane acid used as starting compounds in the preparation of 33.

Preparation 28.

In accordance with the method of preparation 15, the following compounds:

1) 1-acetyl-2-benzyloxycarbonylglycine (647 mg) of acetyl chloride (195,5 μl) and 1-benzyloxycarbonylglycine (550,7 mg).

Rf: to 0.68 (chloroform methanol 9 10 on/about).

2) 1-benzyloxycarbonyl-2-butylphenoxyacetyl (782 mg) is prepared from a mixture of chloride butyryl (287,3 μl) and 1-benzyloxycarbonylglycine (550,7 mg).

Rf: 0,79 (chloroform methanol, 9 1, V/V).

3) 1-benzyloxycarbonyl-2-isobutylpyrazine (320 mg) obtained from a mixture of 1-benzyloxycarbonylglycine (220, 3 mg) and chloride isobutyrylacetate (350 mg) obtained from a mixture of 1-benzyloxycarbonylglycine (to 220.3 mg) and benzoyl chloride (127 μl).

Rf: 0,76 (chloroform methanol, 9 1, V/V).

5) 1-benzyloxycarbonyl-2-cyclohexylcarbodiimide (427 mg) obtained from a mixture of 1-benzyloxycarbonylglycine (to 220.3 mg) and chloride cyclohexylcarbonyl (148 μl).

Rf: 0.83 (chloroform methanol, 9 1, V/V).

6) 1-acetyl-2-benzyloxycarbonylation (222 mg) obtained from acetylchloride (78,2 μl) and 1-benzyloxycarbonylglycine (206,2 mg).

Rf: 0,66 (chloroform methanol, 9 1, V/V).

7) 1-benzyloxycarbonyl-2-isobutylpyrazine (1,796 g) is obtained from a mixture of 1-benzyloxycarbonylglycine (1,237 g) and chloride isobutyryl (696 μl).

Rf: 0,82 (chloroform methanol, 9 1, V/V).

8) 1-benzyloxycarbonyl-2-methoxyacetanilide (937 mg) obtained from a mixture of 1-benzyloxycarbonylglycine (825 mg) and methoxyacetanilide (366 μl).

Rf: 0,74 (chloroform methanol, 9 1, V/V).

9) 1-benzyloxycarbonyl-2-morpholinobenzenediazonium (1,797 g) is obtained from 1-benzyloxycarbonylglycine (1,237 g) and morpholinosydnonimine (0,897 g).

Rf: 0,76 (chloroform methanol, 9 1, V/V).

Preparation 29.

In accordance with the method of preparation 1 proxyconnection (1,237 g) and 4-dimethylaminomethylene acid hydrochloride (1.01 g).

Rf: of 0.62 (chloroform methanol, 9,1, about/about).

2) 1-benzyloxycarbonyl-2-benzylaminocarbonyl (1,36 g) is obtained from a mixture of 1-benzyloxycarbonylglycine (825 mg) and the hippuric acid (717 mg).

Rf: to 0.68 (chloroform methanol, 9 1, V/V).

3) 1-benzyloxycarbonyl-2-(N-tert-butoxycarbonyl-1-leucyl) pyrazolidine (4,25 g) is obtained from a mixture of 1-benzyloxycarbonylglycine (2,475 g) and N-tert-butoxycarbonyl-L-leucine (2,988 g).

Rf: 0,88 (chloroform methanol, 9 1, V/V).

4) 1-benzyloxycarbonyl-2-(N-acetyl-1-leucyl)-pyrazolidine (2,35) obtained from 1-benzyloxycarbonylglycine (1,718 g) and N-acetyl-L-leucine (1,422 g).

Rf: 0,70 (chloroform methanol, 9 1, V/V).

5) 1-benzyloxycarbonyl-2- (N-tert-butoxycarbonyl-Nim-tosyl-1-L-histidyl)-pyrazolidine (2,442 g) is obtained from a mixture of 1-benzyloxycarbonylglycine (2,475 g) and N-tert-butoxycarbonyl-Nim-tosyl-L-histidine (4,913 g).

Rf: to 0.72 (chloroform methanol, 9 1, V/V).

Benzyloxycarbonyl group of the compounds obtained in preparation 28 and 29 are removed by the procedure described in preparation 10, and the thus obtained compounds are used as Israir (2,13 g) are obtained according to the method of preparation 1 from a mixture of piperazine (to 1.034 g).

So pl. 169 170,5oC.

Rf: to 0.48 (chloroform methanol, 9 1, V/V).

Preparation 31.

To a solution of benzyl 2(S)-hydroxy-3-phenylpropanoate (256 mg) in dry tetrahydrofuran (10 ml) is added trichlorethylene ether of Harborview acid (0,122 ml). The reaction mixture was cooled to 0oWith, and then added morpholine (348 mg). The mixture is stirred at the same temperature for 3 hours After evaporation of the solvent the residue is dissolved in ethyl acetate (40 ml) the resulting solution was sequentially washed with 5 hydrochloric acid, a solution of 1 M sodium bicarbonate and water, and then dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue is purified column chromatography on silica gel (eluent used 25 ethyl acetate in n-hexane) to give benzyl 2(S)-morpholinoethoxy-3-phenylpropionate (367 mg) in the form of butter.

Rf: 0,52 (ethyl acetate n-hexane, 2 1, V/V).

Preparation 32.

To a solution of benzyl 2(S)-hydroxy-3-phenylpropionate (513 mg) in dry tetrahydrofuran (10 ml) was added trichlorethylene ether of Harborview acid (0,244 ml). The resulting mixture was heated under reflux for 18 hours the Mixture is cooled to 0oSlamin (701 mg) in dry tetrahydrofuran (10 ml). The reaction mixture was stirred at ambient temperature for 2 hours After evaporation of the solvent the residue is dissolved in ethyl acetate (150 ml). The solution is washed successively with 50 hydrochloric acid 1 M solution of bicarbonate sodium and water, and then dried over magnesium sulfate and concentrate under reduced pressure. The residue is purified column chromatography on silica gel (eluent used 50 ethyl acetate in n-hexane) to yield benzyl 2(S)-[N-2-(-morpholinoethyl)-N-methylaminorex] -3 - phenylpropionate (726 mg) in the form of butter.

Rf: 0,49 (ethyl acetate).

Preparation 33.

In accordance with the method of preparation 31 or 32 will receive the following compounds.

1) Benzyl 2(S)-N,N-diethylaminoethoxy)-3-phenylpropionate.

Rf: 0,64 (n-hexane ethyl acetate, 2 1, V/V).

2) Benzyl 2(S)-(2-methoxymethylethoxy)-3-phenylpropionate.

Rf: 0,63 (n-hexane ethyl acetate, 2 1, V/V).

3) Benzyl 2(S)-(N-methoxycarbonylmethyl-N-methylaminorex)-3-phenylpropionate.

Rf: 0,29 (n-hexane ethyl acetate, 2 1, V/V).

4) Benzyl 2(S)-N-(2-oxyethyl)-N-methylaminorex-3-phenylpropionate.

RP CLASS="ptx2">

Rf: 0,38 (n-hexane ethyl acetate, 1 1, V/V).

6) Benzyl 2 (S)-(2(S)-ethoxycarbonylpyrimidine-1 carbonyloxy)-3-phenylpropionate.

Rf: 0,36 (n-hexane ethyl acetate, 2 1, V/V).

7) Benzyl 2(S)-(N-n-butyl-N-ethylenedicarboxylic)-3-phenylpropionate.

Rf: 0.69 (n-hexane ethyl acetate, 2 1, V/V)

8) Benzyl 2 (S)-(N-methyl-N-Hairdryer-ethylenedicarboxylic)-3-phenylpropionate.

Rf: 0,58 (n-hexane ethyl acetate, 2 1, V/V).

9) Benzyl 2 (S)-(2)-(R)-ethoxycarbonylpyrimidine-1 carbonyloxy)-3-phenylpropionate.

Rf: of 0.35 (n-hexane ethyl acetate, 2 1, V/V).

10) Benzyl 2(S)-(N-n-butyl-N-methylaminorex)-3-phenylpropionate.

Rf: 0,67 (n-hexane ethyl acetate, 2 1, V/V).

11) Benzyl 2(S)-(N-methyl-N-phenylenecarbonyl)-3-phenylpropionate.

Rf: 0,65 (n-hexane ethyl acetate, 2 1, V/V)

12) Benzyl 2(S)-(2S)-ximetilpropan-1 carbonyloxy-3-phenylpropionate.

Rf: 0,19 (n-hexane ethyl acetate, 2 1, V/V).

13) Benzyl 2(S)-hexamethylenediisocyanate-3-phenyl-propionate.

Rf: 0,19 (n-hexane ethyl acetate, 2 1, V/V).

14) Benzyl 2(S)-(2R)-ximetilpropan-1 carbonyloxy)-3-phenylpropionate.

R

Rf: 0,58 (n-hexane ethyl acetate, 1 3, V/V).

16) Benzyl 2(S)-[N-(2-dimethylaminocarbonylmethyl)-N-methylaminorex]-3 - phenylpropionate.

Rf: 0,43 (ethyl acetate).

17) Benzyl 2(S)-(N-morpholinosydnonimine-N-methylaminorex)-3 - phenylpropionate.

Rf: of 0.35 (ethyl acetate).

18) Benzyl 2(S)-(N-dimethylaminocarbonylmethyl-N-methylaminorex)-3 - phenylpropionate.

Rf: of 0.44 (ethyl acetate)

19) Benzyl 2(S)-[N-(n-butylaminoethyl)-N-methylaminorex] -3 - phenylpropionate.

So pl. 48 50oC.

Rf: 0,61 (ethyl acetate hexane, 3 1, V/V).

20) Benzyl 2(S)-[N-(4-pilleriinikeolen)-N-methylaminorex]-3 - phenylpropionate.

So pl. 98 100oC.

Rf: of 0.60 (chloroform methanol, 6 1, V/V).

21) Benzyl 2(S)-[N-(N-methyl-N-penicillincephalexin)- N-methylaminorex]-3-phenylpropionate.

Rf: 0,52 (n-hexane ethyl acetate, 1 3, V/V).

22) Benzyl 2(S)-(2(R)-dimethylaminocarbonylmethyl-1 carbonyloxy)-3 - phenylpropionate.

Rf: 0,31 (ethyl acetate).

23) Benzyl 2(S)-(6(S)-2-oxo-1,4-diazabicyclo-[4.3.0]-nonan-4-carbonyloxy)-3 - phenylpropionate.

CLASS="ptx2">

Rf: 0,41 (ethyl acetate).

25) Benzyl 2(S)-(3-oxopiperidin-1 carbonyloxy)-3-phenylpropionate.

Rf: 0,38 (ethyl acetate).

26) Benzyl 2(S)-(N-isobutoxyethanol-N-methylaminorex)-3 - phenylpropionate.

Rf: 0.69 (n-hexane ethyl acetate, 2 1, V/V).

27) Benzyl 2(S)-(N-methyl-N-ventilatsiooniinseneride)-3 - phenylpropionate.

Rf: 0,72 (n-hexane ethyl acetate, 2 1, V/V).

28) Benzyl 2(S)-[N-methyl-N-(5-methyl-2-oxoethyl)-aminocarbonyl] -3 - phenylpropionate.

Rf: 0,62 (n-hexane ethyl acetate, 2 1 V/V).

29) Benzyl 2(S)-[N-methyl-N-(2-hydroxy-5-methylhexan)-aminocarbonyl]-3 - phenylpropionate.

Rf: 0,42 (n-hexane ethyl acetate, 2 1, V/V).

30) Benzyl 2(S)-[N-methyl-N-(2-oxopropanenitrile)-aminocarbonyl]-3 - phenylpropionate.

Rf: 0,82 (chloroform methanol, 10 1, V/V).

31) Benzyl 2(S)-N-{2-(ethoxycarbonylmethylene)-ethyl} -N-methylaminorex]-phenylpropionate.

Rf: 0,88 (chloroform methanol, 10 1, V/V).

32) Benzyl 2(S)-(2(S)-methoxypiperidine-1-carbonyl-oxy)-3-phenylpropionate.

Rf: 0,92 (ethyl acetate).

33) Benzyl 2(S)-[N-{2-(2-norm methanol, 9 1, V/V).

34) Benzyl 2(S)-[N-{2-(2-picolylamine)-ethyl}-N-methylaminorex]-3 - phenylpropionate.

Rf: of 0.21 (ethyl acetate).

35) Benzyl 2(S)-[N-[2-(2-pyridyl)-ethyl} -N-methylaminomethyl] -ethyl]- N-methylaminorex]-3-phenylpropionate.

Rf: 0,15 (ethyl acetate).

36) Benzyl 2(S)-[N-{2-(3-picolylamine)-ethyl}-N-methylaminorex]-3 - phenylpropionate.

Rf: 0,15 (ethyl acetate).

37) Benzyl 2(S)-[N-[2-{N-(2-pyridyl)-N-methylaminomethyl}-ethyl]-N - methylaminorex]-3-phenylpropionate.

Rf: of 0.25 (ethyl acetate).

38) Benzyl 2(S)-[N-(2-isopropylaminocarbonyl)-N-methylaminorex]-3 - phenylpropionate.

Rf: to 0.67 (ethyl acetate).

39) Benzyl 2(S)-[N-{2-(4-methylpiperazin-1-carbonyl)-ethyl}- N-methylaminorex]-3-phenylpropionate.

Rf: to 0.47 (chloroform methanol, 9 1, V/V).

40) Benzyl 2(S)-[N-(2-dimorpholinyldiethyl)-N-methylaminorex]-3 - phenylpropionate.

Rf: 0,76 (ethyl acetate).

41) Benzyl 2(S)-[N-{2-(2-thiazolidinethione)-ethyl}-N-methylaminorex]-3 - phenylpropionate.

Rf: 0.83 (ethyl acetate).

42) Benzyl 2(S)-[N-{2-(1,2,3,6-tetrahed the ASS="ptx2">

43) Benzyl 2(S)-(2-isopropylcarbodiimide-1 carbonyloxy)-3-phenylpropionate.

Rf: to 0.73 (chloroform methanol, 9 1, V/V).

44) Benzyl 2(S)-[N-(methylcarbamoyl)-N,N-dimethyl-4-hydrazinecarbothioamide] -3 - phenylpropionate.

Rf: 0,68 (ethyl acetate).

45) Benzyl 2(S)-[N'-(N,N-dimethylcarbamoyl)-N,N'-dimethyldithiocarbamate]-3 - phenylpropionate.

Rf: 0,79 (ethyl acetate).

46) Benzyl 2(S)-[N-'(morpholinoethyl)-N,N'-dimethyldithiocarbamate]-3 - phenylpropionate.

Rf: 0,36 (chloroform methanol, 10 1, V/V).

47) Benzyl 2(S)-[N'-(isopropylcarbamate)-N, N-dimethyldithiocarbamate]-3 - phenylpropionate.

Rf: 0,77 (ethyl acetate).

48) Benzyl 2(S)-[N'-(benzylcarbamoyl)-N,N-dimethyldithiocarbamate] -3 - phenylpropionate.

Rf: 0,42 (chloroform methanol, 10 1, V/V).

49) Benzyl 2(S)-(N'-isobutoxide-N,N'-dimethyldithiocarbamate)-3 - phenylpropionate.

Rf: 0,36 (chloroform methanol, 10 1, V/V).

50) Benzyl 2(S)-[N-(2-oxyethyl)-N-ethylenedicarboxylic]-3-phenylpropionate.

Rf: of 0.64 (ethyl acetate).

51) Benzyl 2(S)-[N-methyl-N-[2-{N-(morpholinoethyl)-N-methylamino}-ethyl]

aminocarbonyl the N-methylamino)-ethyl}- aminocarbonyl]-3-phenylpropionate.

Rf: or 0.57 (ethyl acetate).

53) Benzyl 2(S)-[N-methyl-N-{2-(N-isovaleryl-N-methylamino)-ethyl}- aminocarbonyl]-3-phenylpropionate.

Rf: of 0.64 (ethyl acetate).

54) Benzyl 2(S)-[N-methyl-N-[4-{N-(morpholinoethyl)-N-methylamino}-butyl] aminocarbonyl]-3-phenylpropionate.

Rf: 0,34 (ethyl acetate).

55) Benzyl 2(S)-[N-(4-morpholinoethyl)-N-methylaminorex] -3 - phenylpropionate.

Rf: 0,34 (ethyl acetate).

56) Benzyl 2(S)-(3-oxopiperidine)-3-phenylpropionate (490 mg) obtained from the benzyl ester 2(S)-hydroxy-3-phenylpropionic acid (513 mg), hydrochloride 3-oxopiperidine (551 mg) and triethylamine (405 mg)

Rf: 0,70 (ethyl acetate).

57) Benzyl 2(S)-[N-methyl-N-(2-ventilatsioonile)-aminocarbonyl]-3 - phenylpropionate.

Rf: 0,78 (ethyl acetate).

58) Benzyl 2(S)-[N-{4-(N-methyl-N-isopropylcarbamate)-butyl}- N-methylaminorex]-3-phenylpropionate.

Rf: 0,59 (ethyl acetate).

59) Benzyl 2(S)-[N-(4-isopropylcarbamate)-N-methylaminorex] -3 - phenylpropionate.

Rf: of 0.56 (ethyl acetate).

60) Benzyl 2(S)-[N-methyl-N-[3-{N-(morpholinoethyl)-N-methylamino}-propyl] aminocarbonylmethyl)-aminocarbonyl] -3 - phenylpropionate.

Rf: 0,20 (ethyl acetate: hexane, 5:1, V/V).

62) Benzyl 2(S)-[N-methyl-N-{ 3-(N-isopropyl-N-methylcarbamoyl)-propyl}- aminocarbonyl]-3-phenylpropionate.

Rf: to 0.48 (ethyl acetate n-hexane, 5 1, V/V).

63) Benzyl 2(S)-[N-methyl-N-{2-(N-tert-butoxycarbonyl-N-methylamino)-ethyl} aminocarbonyl] -3-phenylpropionate (1.6 g) is obtained from a mixture of benzyl 2(S)-hydroxy-3-phenylpropionate (1,36 g) and N-tert-butoxycarbonyl-N,N'-dimethylethylenediamine (1.0 g).

Rf: 0,59 (n-hexane ethyl acetate, 1 1, V/V).

64) Benzyl 2(S)-[N-(3-isobutyryl)-N-methylaminorex] -3 - phenylpropionate.

Rf: 0,53 (n-hexane ethyl acetate, 1 1, V/V).

65) Benzyl 2(S)-[N-methyl-N-[5-{N-morpholinoethyl)-N-methylamino}-pentyl] aminocarbonyl]-3-phenylpropionate.

Rf: 0,43 (ethyl acetate).

66) Benzyl 2(S)-[N-methyl-N-(3-isopropylcarbamate)-aminocarbonyl]-3 - phenylpropionate.

Rf: 0,32 (ethyl acetate n-hexane, 5 1, V/V).

67) Benzyl 2(S)-[N-methyl-N-(3-oxo-5-etylhexyl)-aminocarbonyl]-3 - phenylpropionate.

Rf: 0,52 (n-hexane ethyl acetate, 2 1, V/V).

68) Benzyl 2(S)-[N-(2-isopropylaminoethyl)-N-methylaminorex] -3-phenylpropionate.

Rf:opional.

Rf: 0,41 (ethyl acetate n-hexane, 1 1, V/V).

70) Benzyl 2(S)-(2-butylphenoxyacetyl-1 carbonyloxy)-3-phenylpropionate.

Rf: 0,68 (ethyl acetate n-hexane, 1 1, V/V).

71) Benzyl 2(S)-(2-isobutylpyrazine-1 carbonyloxy)-3-phenylpropionate.

Rf: 0,66 (ethyl acetate n-hexane, 1 1, V/V).

72) Benzyl 2(S)-(2-benzoylpiperidine-1 carbonyloxy)-3-phenylpropionate.

Rf: 0,66 (ethyl acetate: n-hexane, 1 1, V/V).

73) Benzyl 2(S)-(2-cyclohexylcarbodiimide-1 carbonyloxy)-3 - phenylpropionate.

Rf: 0,72 (ethyl acetate n-hexane, 1 1, V/V).

74) Benzyl 2(S)-(2-acetylpyrrolidine-1 carbonyloxy)-3-phenylpropionate.

Rf: of 0.25 (ethyl acetate n-hexane, 1 1, V/V).

75) Benzyl 2(S)-(2-isobutylpyrazine-1 carbonyloxy)-3-phenylpropionate.

Rf: 0,50 (ethyl acetate n-hexane, 1 1, V/V).

76) Benzyl 2(S)-(2-methoxyacetanilide-1 carbonyloxy)-3-phenylpropionate.

Rf: 0,20 (ethyl acetate n-hexane, 1 1, V/V).

77) Benzyl 2(S)-[2-(4-dimethylaminostyryl)-pyrazolidine-1 carbonyloxy] -3 - phenylpropionate.

Rf: to 0.17 (chloroform methanol, 9 1, V/V).

78) Benzyl 2 the San, 1 1, V/V).

79) Benzyl 2(S)-(2-methylcarbamoylmethyl-1 carbonyloxy)-3-phenylpropionate.

Rf: 0,67 (chloroform methanol, 9 1, V/V).

80) Benzyl 2(S)-(2-morpholinobenzenediazonium-1 carbonyloxy)-3-phenylpropionate.

Rf: of 0.45 (ethyl acetate).

81) Benzyl 2(S)-[2-(N-tert-butoxycarbonyl-1-leucyl)- pyrazolidine-1 carbonyloxy]-3-phenylpropionate.

Rf: 0,50 (ethyl acetate n-hexane, 1 1, V/V).

82) Benzyl 2(S)-[2-(N-acetyl-1-leucyl)- pyrazolidine-1 carbonyloxy]-3-phenylpropionate.

Rf: 0,30 (ethyl acetate).

83) Benzyl 2(S)-[2-(N-tert-butoxycarbonyl-Nim-tosyl-1 histidyl)- pyrazolidine-1 carbonyloxy]-3-phenylpropionate.

Rf: of 0.18 (ethyl acetate n-hexane, 1 1, V/V).

84) Benzyl 2(S)-(4-methylpiperazin-1 carbonyloxy)-3-phenylpropionate.

Rf: of 0.25 (ethyl acetate).

85) Benzyl 2(S)-(4-methylcarbamoylmethyl-1 carbonyloxy)-3-phenylpropionate.

Rf: of 0.21 (ethyl acetate).

86) Benzyl 2(S)-[4-(tert-butoxycarbonylamino)-piperazine-1-carbonyloxy]-3 - phenylpropionate.

Rf: 0,33 (ethyl acetate n-hexane, 1 1, V/V).

87) Benzyl 2 (S)-[4-(morpholinomethyl)-piperazine-1-carbonyloxy)-3-phenylpropionate.

Rf: 0,61 (ethyl acetate).

89) Benzyl 2(S)-(2-oxazolidinone-3-carbonyloxy)-3-phenylpropionate.

Rf: 0,41 (ethyl acetate n-hexane, 1 1, V/V).

90) Benzyl 2(S)-(1,2,3,6-tetrahydropyridine-1-carbonyloxy)-3-phenylpropionate.

Rf: 0,81 (ethyl acetate n-hexane, 1 1, V/V).

91) Benzyl 2(S)-(3-thiazolidinethione)-3-phenylpropionate.

So pl. 75 75,5oC.

Rf: 0,75 (ethyl acetate n-hexane, 1 1, V/V).

92) Benzyl 2(S)-timorgaleevich-3-phenylpropionate.

Rf: 0,82 (ethyl acetate n-hexane, 1 1, V/V).

93) Benzyl 2(S)-(2-(R)-methyl-3-(R)-dimethylcyclopropanecarboxylate)-3 - phenylpropionate.

Rf: of 0.64 (ethyl acetate).

94) Benzyl 2(S)-(2(S)-isobutyl-4-methyl-3-oxopiperidin-1 carbonyloxy)-3 - phenylpropionate.

Rf: 0,73 (ethyl acetate).

95) Benzyl 2(S)-(6(S)-3(S)-morpholinosydnonimine-2-oxo-1,4-diazabicyclo-[4.3.0]- nonan-4-carbonyloxy)-3-phenylpropionate.

Rf: 0,78 (chloroform methanol, 10 1, V/V).

Preparation 34.

To a solution of benzyl 2(S)-[N-methyl-N-(2-ventilatsioonile)-aminocarbonyl] -3 - phenylpropionate (1.0 g) in acetic acid (10 ml) was added in portions Zinkova is add more zinc dust (0.2 g). The reaction mixture was stirred at the same temperature and filtered, then the filtrate is evaporated in vacuum. The residue is dissolved in ethyl acetate (30 ml) and 0.5 G. hydrochloric acid (30 ml). The organic layer is extracted with 1 N. solution Paon (20 ml x 3). Coupled aqueous extract is acidified to pH 2 using 1 N. hydrochloric acid, and then extracted with chloroform (50 ml x 3). The resulting extract is washed with brine and dried over magnesium sulfate. After evaporation of the solvent receive benzyl ester 2(S)-[N-methyl-N-(2-carboxyethyl) aminocarbonyl]-3-phenylpropionic acid (543 mg) in the form of butter.

Rf: 0,11 (chloroform, methanol, acetic acid, 16 1 1, V/V).

Preparation 35.

To a mixture of benzyl ester 2(S)-[N-methyl-N-(2-carboxyethyl)-aminocarbonyl] -3-phenylpropionic acid (460 mg) and isobutylamine (143 ml) in anhydrous methylene chloride (10 ml) was added in portions hydrochloride N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide (274 mg) at 0, 5oC. After stirring at the same temperature for 3 h the solvent is evaporated in vacuum and the obtained residue was dissolved in ethyl acetate (30 ml). The solution is successively washed with 0.5 G. hydrochloric acid (30 ml), water (30 ml), ECCE magnesium. After evaporation of the solvent receive benzyl ester 2(S)-[N-methyl-N-(2-isobutylamino)-ethyl)-aminocarbonyl] -3 - phenylpropionic acid (440 mg) as oil.

Rf: 0,59 (ethyl acetate).

Preparation 36.

In accordance with the method of preparation 35 receive the following connections:

1) Benzyl 2(S)-[N-{ 2-(N-methyl-N-phenylcarbamoyl)-ethyl} - N-methylaminorex]-3-phenylpropionate (510 mg) obtained from a mixture of benzyl 2(S)-[N-methyl-N-(2-carboxyethyl)-aminocarbonyl] -3-phenylpropionate (460 mg) and N-methylaniline (154 mg).

Rf: 0,74 (ethyl acetate).

2) Benzyl 2(S)-[N-{2-(N-methyl-N-isobutylamino)-ethyl}- N-methylaminoethanol] -3-phenylpropionate (586 mg) obtained from benzyl 2(S)-[N-methyl-N-(2-carboxyethyl)-aminocarbonyl] -3-phenylpropionate (846 mg) and N-methyl-N-isobutylamine (230 mg).

Rf: 0,70 (ethyl acetate).

3) Benzyl 2(S)-[N-[2-{N-methyl-N-(2-picolyl)-carbarnoyl}-ethyl]- N-methylaminorex] -3-phenylpropionate (941 mg) obtained from benzyl 2(S)-[N-methyl-N-(2-carboxyethyl)-aminocarbonyl] -3-phenylpropionate (771 mg) and N-methyl-N-(2-picolyl) amine (257 mg).

Rf: of 0.26 (ethyl acetate).

4) Benzyl 2(S)-[N-(2-cyclopentanecarbonyl)-N-methylaminorex] -3 - f is a (578 mg) and cyclopentylamine (154 mg).

Rf: 0,33 (ethyl acetate).

5) Benzyl 2(S)-[N - {2-(2-methoxyethanol)-ethyl}-N-methylaminorex] -3 - phenylpropionate (517 mg) obtained from a mixture of benzyl 2(S)-[N-methyl-N-(2-carboxyethyl)-aminocarbonyl] -3-phenylpropionate (578 mg) and 2-methoxyethylamine (136 mg).

Rf: of 0.60 (ethyl acetate).

6) Benzyl 2(S)-[N-(2-morpholinoethyl)-N-methylaminorex] -3 - phenylpropionate (721 mg) obtained from a mixture of benzyl 2(S)-[N-methyl-N-(2-carboxyethyl)-aminocarbonyl] -3-phenylpropionate (787 mg) and 4-aminomorpholine (251 mg).

Rf: 0,09 (ethyl acetate).

Preparation 37.

To a solution containing benzyl ester 2(S)-3-oxopiperidine)-3-phenylpropionic acid (477 mg) in methylene chloride (10 ml), added bichromate pyridinium (0,99 g), and then the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was passed through a column Florisil (trade name), manufactured by Floridin Co. (60 to 100 mesh), using as eluent first simple diethyl ether, and then methylene chloride. After evaporation under reduced pressure to obtain benzyl ester 2(S)-(3-oxopiperidine)-3-phenylpropionic acid (278 mg).

Rf: 0,55 (n-hexane ethyl acetate, 1 1, V/V).

Preparation 39.

To a solution of benzyl 2(S)-[N-(3-isobutyryl)-N-methylaminorex]-3 - phenylpropionate (120 mg) in ice methylene chloride (3 ml) was added portions of m-chloro-nabintou acid (117 mg). After completing the introduction of the specified acid, cooling the solution was removed and the reaction mixture stirred for 4 h Then diluted with ethyl acetate (20 ml) and successively washed with 10 aqueous solution of sodium bisulfate (20 ml x 2), water (20 ml), saturated aqueous sodium bicarbonate (20 ml x 2), water (20 ml) and saline solution. After drying over magnesium sulfate and evaporation of the solvent receive benzyl ester 2(S)-[N-(3-isobutylphenyl)-N-methylaminorex] -3 - phenylpropionic acid (145 mg) as oil.

Rf: 0,14 (n-hexane ethyl acetate, 1 1, V/V).

Preparation 40.

Benzyl 2(S)-[N-(2-isopropylaminoethyl)-N-methylaminorex] -3 - phenylpropionate get on the methods of preparation 39.

Rf: of 0.58 (ethyl acetate n-hexane, 2 1, V/V).

Preparation 41.

To a solution of benzyl 2(S)-(3-thiazolidinethione)-3-phenylpropionate (371 mg) the offer is stirred at the same temperature for 30 minutes Then it added to 10 aqueous solution of sodium sulfite and methylene chloride, and this mixture is divided. The separated aqueous layer was extracted (2 times) methylene chloride. Connected the extract is washed successively with saturated solutions of sodium bicarbonate and sodium chloride, dried over magnesium sulfate and concentrate under reduced pressure. The resulting crystals are washed with n-hexane to yield benzyl ester 2(S)-(1-oxo-thiazolidin-3-carbonyloxy)-3-phenylpropionic acid (350 mg).

So pl. 84 85oC.

Rf: to 0.29 (ethyl acetate).

Preparation 42.

Benzyl 2(S)-(1-associationvoice)-3-phenylpropionate get on the methods of preparation 41.

So pl. 100 101oC.

Rf: to 0.24 (ethyl acetate).

Preparation 43.

To a solution of benzyl 2(S)-(thiazolidinedione)-3-phenylpropionate (371 mg) in methylene chloride (7 ml) was added 80 chlormadinone acid (431 mg). The resulting mixture was stirred at ambient temperature for 2 days. Then enter 10 solution of sodium sulfite and methylene chloride and the resulting mixture is separated. The aqueous layer was extracted with methylene chloride. Connected alternately extract prom the of over magnesium sulfate and evaporation under reduced pressure to obtain benzyl 2(S)-(1,1-dioxothiazolidine-3-carbonyloxy)-3-phenylpropionate (330 mg).

So pl. 110,5 111,5oC.

Rf: 0.84 (chloroform methanol, 9 1, V/V).

Preparation 44.

Benzyl 2(S)-(1,1-vocationalguidance)-3-phenylpropionate get on the methods of preparation 43.

So pl. 77 78oC.

Rf: 0,46 (ethyl acetate n-hexane, 1 1, V/V).

Preparation 45.

A solution of benzyl 2(S)-morpholinoethoxy-3-phenylpropionate (300 mg) in methanol (20 ml) hydronaut 10 palladium on coal (30 mg) under hydrogen pressure of 3 ATM for 1 hour the Solution is filtered and concentrated in vacuo to yield 2(S)-morpholinoethoxy-3-phenylpropionic acid (220 mg) in the form of oil,

Rf: 0,59 (chloroform, methanol, acetic acid, 8 1 1, V/V).

Preparation 46.

A solution of benzyl (S)-[N-(2-morpholinoethyl)-N-methylaminorex] -3 - phenylpropionate (726 mg) in a mixture of methanol (150 ml) with water (10 ml) hydronaut 10 palladium mobile (80 mg) under hydrogen pressure of 3 ATM for 1 h After filtering and evaporating the solution in vacuo get 2(S)-[N-(2-morpholinoethyl)-N-methylaminorex] -3 - phenylpropionate acid (573 mg).

So pl. 120 124oC.

Rf: 0,67 (chloroform, methanol, acetic acid, 8 1 1, R/is the current connection.

1) 2(S)-(N,N-diethylaminoethoxy)-3-phenylpropionate acid.

Rf: 0,71 (chloroform, methanol, acetic acid, 8 1 1, V/V).

2) 2(S)-(2-methoxymethylethoxy)-3-phenylpropionate acid.

Rf: 0,55 (chloroform, methanol, acetic acid, 8 1 1, V/V).

3) 2(S)-(N-methoxycarbonylmethyl-N-methylaminorex)-3 - phenylpropionate acid.

Rf: of 0.60 (chloroform, methanol, acetic acid, 8 1 1, V/V).

4) 2(S)-[N-(2-oxyethyl)-N-methylaminorex] -3 - phenylpropionate acid.

Rf: 0,38 (chloroform, methanol, acetic acid, 16 1 1, V/V).

5) 2(S)-(N'-acetyl-N'-methyl-N-methylhydrosiloxane)-3 - phenylpropionate acid.

Rf: of 0.64 (chloroform, methanol, acetic acid, 16 1 1, V/V).

6) 2(S)-(2(S)-ethoxycarbonylpyrimidine-1 carbonyloxy)- 3-phenylpropionate acid.

Rf: of 0.50 (chloroform, methanol, acetic acid, 16 1 1, V/V).

7) 2(S)-(N-n-butyl-N-ethylenedicarboxylic)-3-phenylpropionate acid.

Rf: 0,49 (chloroform, methanol, acetic acid, 16 1 1, V/V).

8) 2(S)-(N-methyl-N-phenylenecarbonyl)-3 - phenylpropionate acid

Rf: 0,52 (chloroform metanoia acid.

Rf: of 0.50 (chloroform, methanol, acetic acid, 16 1 1, V/V).

10) 2(S)-(N-n-butyl-N-methylaminorex)-3-phenylpropionate acid.

Rf: 0,52 (chloroform, methanol, acetic acid, 16 1 1, V/V).

11) 2(S)-(N-methyl-N-phenylenecarbonyl)-3-phenylpropionate acid.

Rf: 0,52 (chloroform, methanol, acetic acid, 16 1 1, V/V).

12) 2(S)-(2(S)-ximetilpropan-1 carbonyloxy)-3-phenylpropionate acid.

Rf: 0,31 (chloroform, methanol, acetic acid, 16 1 1, V/V).

13) 2(S)-hexamethylenediisocyanate-3-phenylpropionate acid.

Rf: 0,52 (chloroform, methanol, acetic acid, 16 1 1, V/V).

14) 2(S)-(2(R)-ximetilpropan-1 carbonyloxy)-3-phenylpropionate acid.

Rf: to 0.28 (chloroform: methanol: acetic acid, 16 1 1, V/V).

15) 2(S)-[N-(1(R)-morpholinoethyl)-N-methylaminorex] -3 - phenylpropionate acid.

Rf: 0,26 (methanol chloroform, 10 V/V); to 0.75 (chloroform, methanol, acetic acid, 8 1 1, V/V).

16) 2(S)-[N-(2-dimethylaminocarbonylmethyl)-N-methylaminorex] -3 - phenylpropionate acid.

So pl. 138 144oC.

Rf: 0,63 (chlorotriisopropylsilane acid.

Rf: 0,16 (methanol chloroform, 10 V/V); of 0.53 (chloroform, methanol, acetic acid, 8 1 1, V/V).

18) 2(S)-(N-dimethylaminocarbonylmethyl)-N-(methylaminorex)-3 - phenylpropionate acid.

Rf: of 0.51 (chloroform, methanol, acetic acid, 8 1 1, V/V).

19) 2(S)-[N-(n-butylaminoethyl)-N-methylaminorex]-3 - phenylpropionate acid.

Rf: of 0.53 (chloroform, methanol, acetic acid, 8 1 1, V/V).

20) 2(S)-[N-(4-pilleriinikeolen)-N-methylaminorex]--3 - phenylpropionate acid.

Rf: 0,08 (chloroform, methanol, acetic acid, 8 1 1, V/V).

21) 2(S)-[N-(N-methyl-N-penicillincephalexin)- N-methylaminorex]-3-phenylpropionate acid.

Rf: 0,66 (chloroform, methanol, acetic acid, 8 1 1, V/V).

22) 2(S)-(2(R)-dimethylaminocarbonylmethyl-1 carbonyloxy)-3 - diphenylpropionic acid.

Rf: 0,38 (chloroform, methanol, acetic acid, 8 1 1, V/V).

23) 2(S)-6(S)-2-oxo-1,4-diazabicyclo-[4,3,0] -nonan-4-carbonyloxy)-3 - phenylpropionate acid.

Rf: of 0.44 (chloroform, methanol, acetic acid, 16 1 1, V/V).

24) 2(S)-(4-methyl-3-oxopiperidin-1 carbonyloxy)-3-phenylpro is B>f
: 0,30 (chloroform, methanol, acetic acid, 16 1 1, V/V).

26) 2(S)-(N-isobutoxyethanol-N-methylaminomethyl-oxy)-3 - phenylpropionate acid.

Rf: to 0.29 (chloroform methanol, 10 1, V/V).

27) 2(S)-(N-methylene-N-ventilatsiooniinseneride-3 - phenylpropionate acid.

Rf: 0,31 (chloroform methanol, 10 1, V/V).

28) 2(S)-[N-methyl-N-(5-methyl-2-oxohexyl)-aminocarbonyl]-3 - phenylpropionate acid.

Rf: 0,18 (chloroform methanol, 10 1, V/V).

29) 2(S)-[N-methyl-N-(2-hydroxy-5-methylhexan)-aminocarbonyl]-3 - phenylpropionate acid.

Rf: 0,19 (chloroform methanol, 10 1, V/V).

30) [2(S)-[N-methyl-N-(2-oxopropanenitrile)-aminocarbonyl]-3 - phenylpropionate acid.

Rf: to 0.24 (chloroform methanol, 10 1, V/V).

31) 2(S)-[N-{2-(ethoxycarbonylmethylene}- N-methylaminorex]-3-phenylpropionate acid.

Rf: of 0.14 (chloroform methanol, 10 1, V/V).

32) 2(S)-(2(S)-methoxypiperidine-1 carbonyloxy)-3-phenylpropionate acid.

Rf: or 0.57 (chloroform, methanol, acetic acid, 16 1 1, V/V).

33) 2(S)-[N-{2-(2-morpholinosydnonimine)-this is acid 16 1 1, V/V).

34) 2(S)-[N-{2-(2-picolylamine)ethyl}- N-methylaminorex] --3-phenylpropionate acid.

Rf: 0,31 (chloroform, methanol, acetic acid, 16 1 1, V/V).

35) 2(S)-[N-[2-[N-{2-(2-pyridyl-N-methylaminomethyl]-ethyl]- N-methylaminorex]-3-phenylpropionate acid.

Rf: 0,31 (chloroform, methanol, acetic acid, 16 1 1, V/V).

36) 2(S)-[N-{2-(3-picolylamine)-ethyl}-N-methylaminorex] -3 - phenylpropionate acid.

Rf: 0,16 (chloroform, methanol, acetic acid, 16 1 1, V/V).

37) 2(S)-[N-[2-{N-(2-pyridyl)-N-methylaminomethyl}-ethyl]- N-methylaminorex]-3-phenylpropionate acid.

Rf: 0,34 (chloroform, methanol, acetic acid, 16 1 1, V/V).

38) 2(S)-[N-(2-isopropylaminocarbonyl)-N-methylaminorex]-3 - phenylpropionate acid.

Rf: 0,40 (chloroform, methanol, acetic acid, 16 1 1, V/V).

39) 2(S)-[N-{2-(4-methylpiperazin-1-carbonyl)-ethyl}- N-methylaminorex]-3-phenylpropionate acid.

Rf: 0,12 (chloroform, methanol, acetic acid, 16 1 1, V/V).

40) 2(S)-(2-isopropylcarbodiimide-1 carbonyloxy)-3-phenylpropionate acid.

is drinkability]-3 - phenylpropionate acid.

Rf: of 0.51 (chloroform, methanol, acetic acid, 16 1 1, V/V).

42) 2(S)-[N'-(N,N'-dimethylcarbamoyl)-N,N'-dimethyldithiocarbamate] -3 - phenylpropionate acid.

Rf: 0,63 (chloroform, methanol, acetic acid, 16 1 1, V/V).

43) 2(S)-[N'-(morpholinomethyl)-N, N'-dimethyldithiocarbamate]-3 - phenylpropionate acid.

Rf: 0,08 (chloroform methanol, 10 1, V/V).

44) 2(S)-[N'-(isopropylcarbamate)-N,N'-dimethyldithiocarbamate]-3 - phenylpropionate acid.

Rf: of 0.53 (chloroform, methanol, acetic acid, 16 1 1, V/V).

45) 2(S)-[N'-(benzylcarbamoyl)-N,N'-dimethyldithiocarbamate]-3 - phenylpropionate acid.

Rf: 0,40 (ethyl acetate, benzene, acetic acid, 20 20 1, V/V).

46) 2(S)-(N'-isobutoxide-N, N'-dimethyldithiocarbamate)-3 - phenylpropionate acid.

Rf: 0,34 (ethyl acetate, benzene, acetic acid, 20 20 1, V/V).

47) 2(S)-[N-(2-oxyethyl)-N-ethylenedicarboxylic]-3-phenylpropionate acid.

Rf: 0,32 (chloroform, methanol, acetic acid, 16 1 1, V/V).

48) 2(S)-[N-methyl-N-[2-{ N-(morpholinoethyl)-N-methylamino} -ethyl] - aminocarbonyl]-3-phenylpropionate acid.

So pl. 104 109oC.

Rf: 0,43 (chloroform, methanol, acetic acid, 16 1 1, V/V).

50) 2(S)-N-methyl-N-[2-(N-isovaleryl-N-methylamino)-ethyl]- aminocarbonyl-3-phenylpropionate acid.

So pl. 108 110oC.

Rf: 0,54 (chloroform, methanol, acetic acid, 16 1 1, V/V).

51) 2(S)-[N-methyl-N-[4-{N-(morpholinoethyl)-N-methylamino}-butyl]- aminocarbonyl}-3-phenylpropionate acid.

52) 2(S)-[N-{ 2-(N-methyl-N-phenylcarbamoyl)ethyl} -N-methyl-aminocarbonyl]-3 - phenylpropionate acid.

Rf: of 0.25 (chloroform, methanol, acetic acid, 16 1 1, V/V).

53) 2(S)-[N-{2-(N-methyl-N-isobutylamino)-ethyl}-N - methylaminorex]-3-phenylpropionate acid.

Rf: 0,35 (chloroform, methanol, acetic acid, 15 1 1, V/V).

54) 2(S)-[N-(4-morpholinoethyl)-N-methylaminorex]-3 - phenylpropionate acid.

Rf: a 0.27 (chloroform, methanol, acetic acid, 16 1 1, V/V).

55) 2(S)-(3-oxopiperidine)-3-phenylpropionate acid.

Rf: 0,52 (chloroform, methanol, acetic acid, 16 1 1, V/V).

56) 2(S)-[N-methyl-N-(2-isobutylbarbituric)-aminocarbonyl]-3 - phenylpropionate acid.

Rf: of 0.44 (chloroform, methanol, acetic acid, 16 1 1, V/V).

58) 2(S)-[N-(4-isopropylcarbamate)-N-methylaminorex]-3 - phenylpropionate acid.

Rf: 0,30 (chloroform, methanol, acetic acid, 16 1 1, V/V).

59) 2(S)-[N-methyl-N-[3-{N-(morpholinoethyl)-N-methylamino}- propyl]-aminocarbonyl]-3-phenylpropionate acid.

Rf: of 0.21 (chloroform methanol acetic acid, 10 1 1, V/V).

60) 2(S)-[N-methyl-N-(3-morpholinomethyl)-aminocarbonyl] -3 - phenylpropionate acid.

Rf: 0,18 (chloroform methanol, 10 1, V/V).

61) 2(S)-[N-methyl-N-{3-(N-isopropyl-N-methylcarbamoyl)-propyl}- aminocarbonyl]-3-phenylpropionate acid.

Rf: 0,19 (chloroform methanol, 10 1, V/V).

62) 2(S)-[N-methyl-N-{2-(P-tert-butoxycarbonyl-N-methylamino)-ethyl}- aminocarbonyl]-3-phenylpropionate acid.

Rf: 0,52 (chloroform, methanol, acetic acid, 16 1 1, V/V).

63) 2(S)-[N-[2-{N-methyl-N-(2-picolyl)carbarnoyl}ethyl]-N - methylaminorex]-3-phenylpropionate acid.

Rf: 0,19 (chloroform, methanol, acetic acid, 16 1 1, V/V).

64) 2(S)-[N-(2-cyclopentanecarbonyl)-N-methylaminorex] -3 - phenyl who-[N-{2-(2-methoxyethanol)-ethyl]-N-methylamino-carbonyloxy] -3 - phenylpropionate acid.

Rf:of 0.21 (chloroform, methanol, acetic acid, 16 1 1, V/V).

66) 2(S)-[N-(2-morpholinoethyl)-N-methylaminorex]-3 - phenylpropionate acid.

Rf: 0,16 (chloroform, methanol, acetic acid, 16 1 1, V/V).

67) 2(S)-[N-methyl-N-[5-{N-(morpholinoethyl)-N-methylamino}-pentyl]- aminocarbonyl]-3-phenylpropionate acid.

Rf: 0,33 (chloroform methanol, 10 1, V/V).

68) 2(S)-[N-methyl-N-(3-isopropylcarbamate)-aminocarbonyl] -3 - phenylpropionate acid.

Rf: 0,16 (chloroform methanol, 10 1, V/V).

69) 2(S)-[N-methyl-N-(3-oxo-5-etylhexyl)-aminocarbonyl]-3 - phenylpropionate acid.

Rf: to 0.17 (chloroform methanol, 10 1, V/V).

70) 2(S)-(2-acetylpyrrolidine-1 carbonyloxy)-3-phenylpropionate acid.

Rf: 0,41 (chloroform, methanol, acetic acid, 16 1 1, V/V).

71) 2(S)-(2-butylphenoxyacetyl-1 carbonyloxy)-3-phenylpropionate acid.

Rf: 0,52 (chloroform, methanol, acetic acid, 16 1 1, V/V).

72) 2(S)-(2-isobutylpyrazine-1 carbonyloxy)-3-phenylpropionate acid.

Rf: 0,49 (chloroform, methanol, acetic acid, 16 1 1, V/V).

74) 2(S)-(2-cyclohexylcarbodiimide-1 carbonyloxy)-3 - phenylpropionate acid.

Rf: 0,55 (chloroform, methanol, acetic acid, 16 1 1, V/V).

75) 2(S)-(2-acetylpyrrolidine-1 carbonyloxy)-3-phenylpropionate acid.

Rf: 0,22 (chloroform, methanol, acetic acid, 16 1 1, V/V).

76) 2(S)-(2-isobutylbarbituric-1 carbonyloxy)-3-phenylpropionate acid.

Rf: 0,36 (chloroform, methanol, acetic acid, 16 1 1, V/V).

77) 2(S)-(2-methoxyacetanilide-1 carbonyloxy)-3-phenylpropionate acid.

Rf: 0,32 (chloroform, methanol, acetic acid, 16 1 1, V/V).

78) 2(S)-[2-(4-dimethylaminostyryl)-pyrazolidine-1 carbonyloxy] -3 - phenylpropionate acid.

Rf: to 0.17 (chloroform, methanol, acetic acid, 16 1 1, V/V).

79) 2(S)-(2-benzylaminocarbonyl-1 carbonyloxy)-3-phenylpropionate acid.

Rf: 0,32 (chloroform, methanol, acetic acid, 16 1 1, V/V).

80) 2(S)-(2-methylcarbamoylmethyl)-1-carbonyloxy)-3-phenylpropionate acid.

Rf: to 0.48 (chloroform, methanol, acetic acid, 16 1 1, V/V).

81) 2(S)-(2-morpholinoethyl, 16 1 1, V/V).

82) 2(S)-[2-(N-tert-butoxycarbonyl-1-leucyl)pyrazolidine-1 carbonyloxy] -3 - phenylpropionate acid.

Rf: 0,40 (chloroform, methanol, acetic acid, 16 1 1, V/V).

83) 2(S)-2-(N-acetyl-L-leucyl)pyrazolidine-1 carbonyloxy] -3-phenylpropionate acid.

Rf: 0,22 (chloroform, methanol, acetic acid, 16 1 1, V/V).

84) 2(S)-[2-(N-tert-butoxycarbonyl-Nim-tosyl-L-histidyl)- pyrazolidine-1 carbonyloxy]-3-phenylpropionate acid.

Rf: 0,16 (chloroform, methanol, acetic acid, 16 1 1, V/V).

85) 2(S)-(4-methylpiperazin-1 carbonyloxy)-3-phenylpropionate acid.

Rf: 0,18 (chloroform methanol, 9 1, V/V).

86) 2(S)-(4-methylcarbamoylmethyl-1 carbonyloxy)-3-phenylpropionate acid.

Rf: 0,11 (chloroform, methanol, acetic acid, 16 1 1, V/V).

87) 2(S)-[4-(tert-butoxycarbonylmethyl)-piperazine-1-carbonyloxy] -3 - phenylpropionate acid.

Rfof 0.24 (chloroform methanol, 9 1, V/V).

88) 2(S)-[4-(morpholinomethyl)piperazine-1-carbonyloxy]-3-phenylpropionate acid.

Rf: 0,13 (chloroform, methanol, acetic acid, 16 1 1, V/V).

89) 2(S)-(3-oxopyrrolo 16 1 1, about/about).

90) 2(S)-(2-oxazolidinone-3-carbonyloxy)-3-phenylpropionate acid.

Rf: 0,15 (chloroform, methanol, acetic acid, 16 1 1, V/V).

91) 2(S)-(2(R)-methyl-3-(R-dimethylcyclopropanecarboxylic-oxy)-3 - phenylpropionate acid.

Rf: 0,40 (chloroform, methanol, acetic acid, 30 1 1, V/V).

92) 2(S)-(2(S)-isobutyl-4-methyl-3-oxopiperidin-1 carbonyloxy)-3 - phenylpropionate acid.

Rf: to 0.45 (chloroform, methanol, acetic acid, 30 1 1, V/V).

93) 2(S)-(6(S)-3(S)-morpholinosydnonimine-2-oxo-1,4 - diazabicyclo-[4.3.0]-nonan-4-carbonyloxy)-3-phenylpropionate acid.

Rf: to 0.10 (chloroform methanol, 10 1, V/V).

Preparation 48.

To a solution of benzyl ester 2(S)-[N-(2-dimorpholinyldiethyl)-N-methylaminorex]-3 - phenylpropionic acid (418 mg) in methanol (5 ml), cooled to 0oC, add 1 N. aqueous solution of NaOH (1,33 ml). The mixture was stirred at ambient temperature for 1 h After evaporation of the methanol aqueous solution with alkali residues washed with chloroform (5 ml x 2). Then the aqueous solution is acidified to pH 25 hydrochloric acid and extracted with ethyl acetate (10 ml x 2). The extract was washed with water (10 ml) reduced pressure get 2(S)-N-(2-dimorpholinyldiethyl)-N-methylaminorex] -3 - phenylpropionate acid (315 mg).

Rf: 0,56 (chloroform, methanol, acetic acid, 16 1 1, V/V).

Preparation 49.

To a solution of benzyl ester 2(S)-[N-(2-isopropylaminoethyl)-N-methylaminorex] -3 - phenylpropionic acid (623 mg) in ethanol (10 ml) was added 1 n potassium hydroxide at ambient temperature and the reaction mixture was stirred at the same temperature for 1 h the Solution is evaporated in vacuo and the residue partitioned between water (20 ml) and diethyl ether (20 ml). The aqueous layer was separated and acidified to pH 2 10 solution of hydrochloric acid, followed by extraction of the resulting product is chloroform (20 ml x 2). The extract was washed with water (30 ml) and dried over magnesium sulfate. After evaporation of the solvent to obtain 2(S)-[N-(2-isopropylaminoethyl)-N-methylaminorex]-3 - phenylpropionate acid (485 mg).

Rf: 0.84 (chloroform, methanol, acetic acid, 8 1 1, V/V).

Preparation 50.

In accordance with the method of preparation 48 or 49 received the following connections:

1) 2(S)-[N-{2-(2-thiazolidinethione)ethyl}-N-methyl-aminocarbonyl] -3 - phenylpropionate acid.

Rf: 0,56 (chloroform, methanol, acetic acid, 16 1 1, V/V).

2) 2(S)-[N-{ 2-(1,2,3,6-tetr (chloroform methanol acetic acid, 16 1 1, V/V).

3) 2(S)-[N-(3-isobutyryl)-N-methylaminomethyl-oxy] -3 - phenylpropionate acid.

Rf: 0,38 (chloroform, methanol, acetic acid, 16 1 1, V/V).

4) 2(S)-[N-(3-isobutylphenyl)-N-methylaminorex]-3 - phenylpropionate acid.

Rf: to 0.24 (chloroform, methanol, acetic acid, 16 1 1, V/V).

5) 2(S)-[N-(2-isopropylaminoethyl)-N-methylaminorex] -3-phenylpropionate acid.

Rf: of 0.58 (chloroform, methanol, acetic acid, 8 1 1, V/V).

6) 2(S)-(1,2,3,6-tetrahydropyridine-1-carbonyloxy)-3-phenylpropionate acid.

Rf: 0,37 (chloroform, methanol, acetic acid, 16 1 1, V/V).

7) 2(S)-(3-thiazolidinethione)-3-phenylpropionate acid.

Rf: of 0.44 (chloroform, methanol, acetic acid, 16 1 1, V/V).

8) 2(S)-n-(1-oxothiazolidine-3-carbonyloxy)-3-phenylpropionate acid.

So pl. 148,5 of 149.5oC.

Rf: to 0.17 (chloroform, methanol, acetic acid, 16 1 1, V/V).

9) 2(S)-(1,1-dioxothiazolidine-3-carbonyloxy)-3-phenylpropionate acid.

Rf:0,19 (ethyl acetate).

10) 2(S)-timorgaleevich-3-phenylpropionate acid.

So pl. 162 163oC.

Rf: 0,19 (chloroform, methanol, acetic acid, 16 1 1, V/V).

12) 2(S)-(1,1-vocationalguidance)-3-phenyl-propionic acid.

So pl. 92,5 93,5oC.

Preparation 51.

1) To a solution of N-tert-butoxycarbonyl-1-cyclohexylamine (7073 g) in dry tetrahydrofuran (200 ml), cooled to -78oC, was added dropwise a solution containing isopentylamine obtained from methyl isopentyl (46.4 g) and magnesium (7.47 g) dissolved in dry tetrahydrofuran (500 ml). After completing the addition of the specified solution, the reaction mixture is heated to ambient temperature for 2 h, and then poured into a saturated aqueous solution of ammonium chloride (500 ml). The resulting mixture was extracted with simple ether (500 ml x 2), and after connection of the extract dried over magnesium sulfate and evaporation receive oil (10.1 g). The residue purified column chromatography on silica gel (1 kg) (as eluent used 10 ethyl acetate in hexane) to yield 2(S)-tert-butoxycarbonylamino-1-cyclohexyl-3-(S)hydroxy-6-methyl-heptane (3.03 g).

Rf: 0,67 (benzene, ethyl acetate, 4 1, V/V).

[]2D023,46o(the Noah acid (10 ml) stirred at 0oC within 30 minutes After evaporation of the solvent the residue is dissolved in ethyl acetate (20 ml). The solution was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and after evaporation in vacuo get 2(S)-amino-1-cyclohexyl-3(S)-hydroxy-6-formed (412 mg) as oil.

Rf: 0,63 (chloroform, methanol, acetic acid, 8 1 1, V/V).

3) To a solution of N-tert-butoxycarbonyl-NN-methyl-Nim-tosyl-L-histidyl)- amino-1-cyclohexyl-3-(S)-hydroxy-6-methylheptane (1,61 g) as amorphous powder.

So pl. 55 58oC.

Rf0,56 (benzene, ethyl acetate, acetic acid, 20 20 1, V/V).

4) Solution of 2(S)-(N-tert-butoxycarbonyl-N]2D59,5 (1,0, 50 water-methanol).

2) The crude salt (51.9 g) is dissolved in isopropyl alcohol (986 ml) at reflux. The solution is filtered and the filter, add water (52 ml). After cooling, the formed precipitate is collected by filtration and after drying receive refined salt L-tartaric acid 2(S)-amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane them (46.7 g).

So pl. 119 122oC.

[]2D510,5 (1,0, 50 water is 6-methylheptane them (46.7 g) and methylene chloride (374 ml), add 25 ammonia water (140 ml) and water (47 ml). The separated organic layer washed with water (140 ml) and after evaporation of the solvent to obtain 2(S)-amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (28,1 g).

Example 1. To a solution containing 2(S)-morpholinoethoxy-3-phenylpropionate acid (86 g) and 2(S)-(NN-methyl-Nim-tosyl-L-histidyl)-amino-1-cyclohexyl-3(S)- hydroxy-6-formed (150 mg) in dry methylene chloride (20 ml), cooled to 0oC, add the hydrochloride of N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide (60 mg). The reaction mixture was stirred at the same temperature for 6 hours After evaporation of the solvent the residue is dissolved in ethyl acetate (30 ml). The resulting solution was sequentially washed with 5 hydrochloric acid, 1 M sodium bicarbonate solution and water, dried over magnesium sulfate and concentrate under reduced pressure. Then the residue is dissolved in N, N-dimethylformamide (20 ml) and the resulting solution was added pyridine hydrochloride (326 mg) at ambient temperature. The reaction mixture was stirred at the same temperature for 2 hours After evaporation of the solvent the residue is dissolved in ethyl acetate (30 ml). The resulting solution was successively washed with water, 1 M solution of bicarb who participate thin-layer chromatography on silica gel (chloroform methanol, 8 1, V/V) to yield 2(S)-[N-2(S-morpholinoethoxy-3-phenyl-propionyl)- N-methyl-L-histidyl]amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (of 98.2 mg) as amorphous powder.

So pl. 91 95oC.

Rf: 0,61 (chloroform methanol, 6 1, V/V).

Example 2. To a solution containing 2(S)-N-(2-morpholinoethyl)-N-methylaminorex-3-phenylpropionate acid (449 mg) and 2(S)-(NN-methyl-Nim-tosyl-L-histidyl)- amino-1-cyclohexyl-3(S)-hydroxy-6-formed (300 mg) in dry methylene chloride (30 ml), cooled to 0oC, add the hydrochloride of N-ethyl-N-(3-dimethylaminopropyl)-carbodiimide (140 mg). The reaction mixture is stirred at 5oC during the night. After evaporation of the solvent the residue is dissolved in ethyl acetate (30 ml). The resulting solution was sequentially washed with 5 hydrochloric acid, 1 M sodium bicarbonate solution and water, then dried over magnesium sulfate and concentrate under reduced pressure. Then the residue is dissolved in N,N-dimethylformamide (20 ml) and the resulting solution was added pyridine hydrochloride (650 mg) at ambient temperature. The reaction mixture was stirred at the same temperature for 2 hours After evaporation of the solvent OS the DOI, dried over magnesium sulfate and concentrate under reduced pressure. After cleaning sediment thin-layer chromatography on silica gel (chloroform methanol, 6 1, V/V). get 2(S)-[N-[2(S)-[N-(2-morpholinoethyl)-N-methylamino-carbonyloxy-3 - phenylpropionyl] -N-methyl-L-histidyl] -amino-1-cyclo-hexyl-3(S)-hydroxy-6 - formed (221 mg) as amorphous powder.

Rf: to 0.48 (chloroform methanol, 6 1, V/V).

Example 3. To a solution containing 2(S)-[N-methyl-N-[2-{N-(morpholinoethyl)-N-methylamino] -ethyl] - aminocarbonyl-3-phenylpropionate acid (222 mg) in dry methylene chloride (10 ml), cooled to 0oC, add chloride of oxalyl (0,051 ml) and three drops of N,N-dimethylformamide. The reaction mixture was stirred at the same temperature for 1 h After evaporation of the solvent the residue is dissolved in methylene chloride (5 ml) and the resulting solution added to a mixture of 2(S)-NN-methyl-Nim-tosyl-L-histidyl)amino-1-cyclohexyl-3(S)- hydroxy-6-methylheptane (300 mg) and triethylamine (57 mg) in methylene chloride (10 ml) at 0oC. the resulting mixture was stirred at the same temperature for 3 hours After evaporation of the solvent the residue is dissolved in ethyl acetate (30 ml) and the resulting solution was then magnesium and concentrated in vacuo. The residue is purified by thin-layer chromatography in silica gel (chloroform methanol, 9 1, V/V) to yield 2(S)-[N-[2(S)-[N-methyl-N-[2-{N-(morpholinoethyl)-N-methylamino}- ethyl] -aminocarbonyl] -3-phenylpropionyl] -N-methyl-L-histidyl]- amino-1-cyclohexyl-3(S) - hydroxy-6-formed (297 mg) as amorphous powder.

So pl. 69 74oC.

Rf: to 0.45 (chloroform methanol, 10 1, V/V).

Example 4. To a solution containing 2(S)-[N-methyl-N-{2-(N-isobutyryl-N-methylamino)-ethyl} - aminocarbonyl]-3-phenyl-propionic acid (217 mg) in dry methylene chloride (20 ml), cooled to 0oC, add chloride of oxalyl (0,054 ml) and three drops of N,N-dimethylformamide. The reaction mixture was stirred at the same temperature for 1 h After evaporation of the solvent the residue is dissolved in dry methylene chloride (5 ml) and the resulting solution was added to a solution containing 2(S)-(NN-methyl-Nim-tosyl-L-histidyl)amino-1-cyclohexyl-3-(S)- hydroxy-6-formed (300 ml) and triethylamine (63 mg) in methylene chloride (10 ml) at 0oC. the Mixture is stirred at the same temperature for 3 hours After evaporation of the solvent the residue is dissolved in ethyl acetate (30 ml), and then the resulting solution was washed polycentric under reduced pressure. Then the residue is dissolved in N, N-dimethylformamide (15 ml) and the resulting solution was added pyridine hydrochloride (650 mg) at ambient temperature. The reaction mixture was stirred at the same temperature for 2 hours After evaporation of the solvent the residue is dissolved in ethyl acetate (30 ml) and the resulting solution was successively washed with 1 M sodium bicarbonate solution and water. Then dried and concentrated in vacuo. The residue purified by thin-layer chromatography on silica gel (chloroform methanol, 9 1, V/V) to yield 2(S)-[N-[2(S)-[N-methyl-N-{ 2-(N-isobutyryl-N-methylamino)-ethyl} - aminocarbonyl]-3-phenylpropionyl N-methyl-L-histidyl] - amino-1-cyclohexyl-3(S)-hydroxy-6-formed (295 mg) as amorphous powder.

So pl. 68 72oC.

Rf: 0,46 (chloroform methanol, 10 1, V/V).

Example 5. In accordance with the methods of examples 1 to 4 obtained the following compounds:

1) 2(S)-[N-{ 2(S)-(N, N-diethylaminoethoxy)-3-phenylpropionyl} - N-methyl-L-histidyl]-amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 75 79oC.

Rf: 0,61 (chloroform methanol, 6 1, V/V).

2) 2(S)-[N-{ 2(S)-(2-methoxymethylethoxy). 0 84oC.

Rf: to 0.45 (chloroform methanol, 6 1, V/V).

3) 2(S)-[N-{2(S)-(N-methoxycarbonylmethyl-N-methylamino-carbonyloxy)-3 - phenylpropionyl} -N-methyl-L-histidyl] -amino-1-cyclo-hexyl-3(S)-hydroxy-6 - formed.

So pl. 84 87oC.

Rf: 0,55 (chloroform methanol, 6 1, V/V).

4) 2(S)-[N-{ 2(S)-{ N-(2-oxyethyl)-N-methylaminomethyl-oxy} -3 - phenylpropionyl] -N-methyl-L-histidyl] -amino-1-cyclohexyl-3(S)-hydroxy-5 are formed.

So pl. 82 86oC.

Rf: or 0.57 (chloroform methanol, 6 1, V/V).

5) 2(S)-[N-{ 2(S)-(N-acetyl-N-methyl-N-methylhydrazino-carbonyloxy)-3 - phenylpropionyl}-N-methyl-L-histidyl]-amino-1-cyclohexyl-3(S)-hydroxy-6 - formed.

So pl. 82 92oC.

Rf: to 0.68 (chloroform methanol, 6 1, V/V).

6) 2(S)-[N-{2(S)-(2(S)-ethoxycarbonylpyrimidine-1 carbonyloxy)-3 - phenylpropionyl} -N-methyl-L-histidyl] -amino-cyclohexyl-3(S)-hydroxy-6 - formed.

So pl. 71 76oC.

Rf: 0,31 (chloroform methanol, 10 1, V/V).

7) 2(S)-[N-{ 2(S)-(N-n-butyl-N-ethylenedicarboxylic)-3-phenylpropionyl} -N - methyl-1-histidyl]-amino-1-cyclohexyl-3(S)-hydroxy-) 2(S)-[N-{ 2(S)-(N-methyl-N-penicillinallergic)-3-phenyl-propionyl} N-methyl-L-histidyl]-amino-1-cyclohexyl-3(S)-hydroxy-6-methyl-heptane.

So pl. 66 69oC.

Rf: 0,30 (chloroform methanol, 10 1, V/V).

9) 2(S)-[N-{ 2(S)-(2(R)-ethoxycarbonylpyrimidine-1 carbonyloxy)-3 - phenylpropionyl] -N-methyl-L-histidyl] -amino-1-cyclohexyl-3(S)-hydroxy-6 - formed.

So pl. 73 79oC.

Rf0,41 (chloroform methanol, 10 1, V/V).

10) 2(S)-[N-{2(S)-(N-n-butyl-N-methylaminomethyl-oxy)-3-phenylpropionyl] N-methyl-L-histidyl]-amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 67 71oC.

Rf: 0,40 (chloroform methanol, 10 1, V/V).

11) 2(S)-[N-{2(S)-(N-methyl-N-phenylenecarbonyl-oxy)-3-phenylpropionyl}

N-methyl-L-histidyl]-amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 83 87oC.

Rf: 0.83 (chloroform methanol, 10 1, V/V).

12) 2(S)-[N-{ 2((S)-(2(S)-ximetilpropan-1 carbonyloxy)-3 - phenylpropionyl-N-methyl-L-histidyl] -amino-1-cyclohexyl-3(S)-hydroxy-6 - formed.

So pl. 94 101oC.

Rf: to 0.29 (chloroform /SUP>-methyl-L-histidyl]-amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 71 77oC.

Rf: 0,36 (chloroform methanol, 10 1, V/V).

14) 2(S)-[N-2(S)-(2(R)-ximetilpropan-1 carbonyloxy)-3 - phenylpropionyl]-N-methyl-L-histidyl]-amino-1-cyclohexyl-3(S)-hydroxy-6 - formed.

So pl. 93 99oC.

Rf: 0,30 (chloroform methanol, 10 1, V/V).

15) 2(S)-[N-(S)-{ N-(1(R)-morpholinoethyl)-N - methylaminorex} -3-phenylpropionyl] -N-methyl-L-histidyl] - amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 92 97oC.

Rf: 0,42 (chloroform methanol, 6 1, V/V).

16) 2(S)-[N-[2(S)-{ N-(2-dimethylaminocarbonylmethyl)- N-methylaminorex} -3-phenylpropionyl]-N-methyl-L-histidyl]- amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 55 60oC.

Rf: to 0.39 (chloroform methanol, 6 1, V/V).

17) 2(S)-[N-{2(S)-(N-morpholinosydnonimine-N-methylaminomethyl-oxy]- 3(S)-hydroxy-6-formed.

So pl. 91 94oC.

Rf: 0,49 (chloroform methanol, 6 1, V/V).

18) 2(S)-[N-{ 2(S)-(N-dimethylaminocarbonylmethyl-N-methylaminopropane is. 9 83oC.

Rf: 0,40 (chloroform methanol, 6 1, V/V).

19) 2(S)-[Na-[2(S)-{ N-n-butylaminoethyl)-N - methylaminorex}-3-phenylpropionyl]-Na-methyl-L-histidyl]- amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 77 81oC.

Rf: 0,55 (chloroform methanol, 6 1, V/V).

20) 2(S)-[Na-[2(S)-{N-(4-pilleriinikeolen)-N - methylaminorex]-3-phenylpropionyl]-Na-methyl-1-histidyl - amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 80 89oC.

Rf: 0,36 (chloroform methanol, 6 1, V/V).

21) 2(S)-[Na-[2(S)-{ N-(N-methyl-N-penicillinaseand-methyl)-N - methylaminorex} -3-phenylpropionyl] -Na-methyl-L-histidyl]- amino-1-cyclohexyl-(3(S)-hydroxy-6-formed.

So pl. 72 80oC.

Rf: 0,42 (chloroform methanol, 6 1, V/V).

22) 2(S)-[Na-[2(S)-(2(R)-dimethylaminocarbonylmethyl-1 carbonyloxy)-3-phenylpropionyl} -Na-methyl-L-histidyl]- amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 100 102oC.

Rf: 0,70 (chloroform methanol, 6 1, V/V).

23) 2(S)-[Na-{ 2(S)-(6(S)-2-oxo-1,4-diazabicyclo-[4.3.0]-nonan-4 - carbonyloxy)-3-phenylpropionyl} -Na-met (methanol chloroform, 10 about/about).

24) 2(S)-[Na-{2(S)-(4-methyl-3-oxopiperidin-1 carbonyloxy)-3 - phenylpropionyl}-Na-methyl-L-histidyl]amino-1-cyclohexyl-3(S)- hydroxy-6-formed.

So pl. 81 85oC.

Rf: 0,38 (chloroform methanol, 10 1, V/V).

25) 2(S)-[Na-{ 2(S)-(3-oxopiperidin-1 carbonyloxy)-3 - phenylpropionyl} -N-methyl-L-histidyl]-amino-1-cyclohexyl-3(S)- hydroxy-6-formed.

So pl. 108 112oC.

Rf: to 0.48 (chloroform methanol, 10 1, V/V).

26) 2(S)-[Na-{ 2(S)-(N-isobutoxyethanol-N - methylaminorex)-3-phenylpropionyl} -Na-methyl-L-histidyl]- amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 58 60oC.

Rf: of 0.62 (chloroform methanol, 10 1, V/V).

27) 2(S)-[Na-{ 2(S)-(N-methyl-N-ventilatsiooniinseneride)-3-phenylpropionyl} -Na-methyl-1-histidyl] amino-1 - cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 54 57oC.

Rf: of 0.64 (chloroform methanol, 10 1, V/V).

28) 2(S)-[Na-[2(S)-{N-methyl-N-(5-methyl-2-oxohexyl)- aminocarbonyl} -3-phenylpropionyl-Na-methyl-L-histidyl]- amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 65 67oC.

Rf: 0,38 (chloropropionyl] -Na-methyl-L-histidyl] - amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 76 78oC.

Rf: to 0.24 (chloroform methanol, 10 1, V/V).

30) 2(S)-[Na-[2(S)-{ N-methyl-N-(2-oxopropanenitrile)- aminocarbonyl} -3-phenylpropionyl] -Na-methyl-L-histidyl] - amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 65 68oC.

Rf: 0,78 (chloroform methanol, 10 1, V/V).

31) 2(S)-[Na-[2(S)-[N-{ 2-(ethoxycarbonylmethylene)- ethyl}-N-methylaminorex]-3-phenylpropionyl-Na-methyl-L - histidyl]-amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 72 75oC.

Rf: of 0.44 (chloroform methanol, 10 1, V/V).

32) 2(S)-[Na-[2(S)-(2(S)-methoxypiperidine-1 carbonyloxy)-3 - phenylpropionyl}-Na-methyl-L-histidine-1-cyclohexyl-3(S)- hydroxy-6-formed.

So pl. 72 77oC.

Rf: of 0.44 (chloroform methanol, 9 1, V/V).

33) 2(S)-[Na-[2(S)-[N-{ 2-(2-morpholinosydnonimine)-ethyl}-N - methylaminorex] -3-phenylpropionyl] -Na-methyl-L-histidyl]- amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 60 64oC.

Rf: of 0.26 (chloroform methanol, 9 1, V/V).

34) 2(S)-[N

So pl. 64 67oC.

Rf: 0,40 (chloroform methanol, 9 1, V/V).

35) 2(S)-[Na-[2(S)-[N-{ 2-{N-{2-[(2-pyridyl)ethyl-N - methylaminomethyl] -ethyl]-N-methylaminorex]-3-phenylpropionyl]- Na-methyl-1-histidyl]-amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 55 58oC.

Rf: to 0.17 (chloroform methanol, 9 1, V/V).

36) 2(S)-[Na-[2(S)-[N-{ 2-(3-picolylamine)-ethyl}-N - methylaminorex] -3-phenylpropionyl] -N-methyl-L-histidyl] amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 67 71oC.

Rf: of 0.44 (chloroform methanol, 9 1, V/V).

37) 2(S)-[Na-[2(S)-[N-[2-{N-(2-pyridyl)-N-methylamino-carbonyl]- ethyl]-N-methylaminorex] -3-phenylpropionyl] -Na-methyl-1]- histidyl]-amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 73 77oC.

Rf: a 0.27 (chloroform methanol, 9 1, V/V).

38) 2(S)-[Na-[2(S)-{ N-(2-isopropylaminocarbonyl)-N - methylaminorex} -3-phenylpropionyl] -Na-methyl-L-histidyl] - amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

Rf: 0,49 (chloroform methanol, 9 1, V/V).

39) 2(S)-[Na-[2(S)-[N-{ 2-(4-methylpiperazin-1-CT and-6 are formed.

So pl. 65 71oC.

Rf: to 0.17 (chloroform methanol: 9 1, V/V).

40) 2(S)-[Na-[2(S)-{N-(2-dimorpholinyldiethyl)-N - methylaminorex} -3-phenylpropionyl] -Na-methyl-L-histidyl] - amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 66 72oC.

Rf: to 0.45 (chloroform methanol, 9 1, V/V).

41) 2(S)-[Na-[2(S)-[N-{2-(2-thiazolidinethione)-ethyl}-N - methylaminorex] -3-phenylpropionyl] -Na-methyl-L-histidyl]- amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 100 106oC.

Rf: to 0.45 (chloroform methanol, 9 1, V/V).

42) 2(S)-[Na-[2(S)-[N-{ 2-(1,2,3,6-tetrahydropyridine-1-carbonyl)- ethyl} -N-methylaminorex] -3-phenylpropionyl]-N-methyl-L-histidyl]- amino-1-cyclohexyl-3(S) - hydroxy-6-formed.

So pl. 67 73oC.

Rf: to 0.48 (chloroform methanol, 9 1, V/V).

43) 2(S)-[Na-{ 2(S)-(2-isopropylcarbodiimide-1 carbonyloxy)-3-phenylpropionyl} -Na-methyl-L-histidine-1 - cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 86 89oC.

Rf: 0,46 (chloroform methanol, 9 1, V/V).

44) 2(S)-[Na-[2(S)-{ N'-(methylcarbamoyl)-N,N'- dimethyldithiocarbamate] -3-phenylpropionyl] -N Rf: of 0.50 (chloroform methanol, 10 1, V/V).

45) 2(S)-[Na-[2(S)-{ N'-(N, N-dimethylcarbamoyl)-N,N'- dimethyldithiocarbamate} -3-phenylpropionyl]-Na-methyl-L - histidyl]-amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 75 79oC.

Rf: 0,54 (chloroform methanol, 6 1, V/V).

46) 2(S)-[Na-[2(S)-{N'-(morpholinomethyl)-N,N'- (dimethyldithiocarbamate}-3-phenylpropionyl}-N-methyl-L-histidyl]- amino-1-cyclohexyl-3(S)-hydroxy-6-metrogate.

So pl. 86 92oC.

Rf: 0,42 (chloroform methanol, 10 1, V/V).

47) 2(S)-[Na-[2(S)-{ N-(isopropylcarbamate)-N, N'- dimethyldithiocarbamate} -3-phenylpropionyl] -N-methyl-L-histidyl] - amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 94 99oC.

Rf: 0,54 (chloroform methanol, 6 1, V/V).

48) 2(S)-[N-[2(S)-{ N'-(benzylcarbamoyl)-N,N'- dimethyldithiocarbamate} -3-phenylpropionyl] -N-methyl-histidyl] - amino-1-cyclohexyl-3(S)-hydroxy-6-metrogate.

So pl. 99 104oC.

Rf: 0,31 (chloroform methanol, 6 1, V/V).

49) 2(S)-[N-[2(S)-{ (N-isobutoxide-N, N - dimethyldithiocarbamate)-3-phenylpropionyl-N-methyl-L-histidyl] - amino-1-cyclohexyl-3(S is carbonyloxy)-3 - phenylpropionyl]-N-methyl-L-histidyl]-amino-1-cyclohexyl-3(S)-hydroxy-6 - formed.

So pl. 80 84oC.

Rf: of 0.53 (chloroform methanol, 6 1, V/V).

51) 2(S)-[N-[2(S)-[N-methyl-N-{ 2(N-isovaleryl-N-methylamino)-ethyl] - aminocarbonyl] -3-phenylpropionyl-N-methyl-L-histidyl] -amino-1 - cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 68 72oC.

Rf: of 0.44 (chloroform methanol, 10 1, V/V).

52) 2(S)-[N-[2(S)-[N-methyl-N-[4-{ N-(morpholinoethyl)-N-methylamino}- butyl] -aminocarbonyl] -3-phenylpropionyl-N-methyl-L-histidyl]- amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 64 67oC.

Rf: 0,35 (chloroform methanol, 10 1, V/V).

53) 2(S)-[N-[2(S)-{ N-{2-(N-methyl-N-phenylcarbamoyl)-ethyl}-N - methylaminorex] -3-phenylpropionyl] -N-methyl-L-histidyl] - amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 67 71oC.

Rf: to 0.47 (chloroform methanol, 9 1, V/V).

54) 2(S)-[N-[2(S)-[N-{2-(N-methyl-N-isobutylamino)-ethyl}-N-methyl-L - histidyl]-amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 73 79oC.

Rf: of 0.50 (chloroform methanol, 9 1, V/V).

55) 2(S)-[N-[2(S)-{ N-(4-morpholinoethyl)-N - methylaminorex} -3-8oC.

Rf: to 0.48 (chloroform methanol, 9 1, V/V).

56) 2(S)-[N-{ 2(S)-(3-oxopiperidine)-3-phenylpropionyl]-N-[2(S)-{N-methyl-N-(2-isobutylbarbituric)- aminocarbonyl] -3-phenylpropionyl] -N-methyl-L-histidyl] -amino-1 - cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 78 83oC.

Rf: 0,54 (chloroform methanol, 9 1, V/V).

58) 2(S)-[N-[2(S)-[N-{4-(N-methyl-N-isopropylcarbamate)-butyl]-N - methylaminorex] -3-phenylpropionyl] -N-methyl-L-histidyl] - amino-1-cyclohexyl-3(S)-hydroxy-6-methyl-heptane.

So pl. 64 71oC.

Rf: 0,46 (chloroform methanol, 9 1, V/V).

59) 2(S)-[N-[2(S)-{ N-(4-isopropylcarbamate)-N - methylaminorex} -3-phenylpropionyl]-N-methyl-L-histidyl]- amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 74 80oC.

Rf: 0,41 (chloroform methanol, 9 1, V/V).

60) 2(S)-[N-[2(S)-[N-methyl-N-[3-{ N-(morpholinoethyl)-N-methylamino}- propyl] -aminocarbonyl] -3-phenylpropionyl]-N-methyl-L-histidyl]- amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 62 66oC.

Rf: 0,51 (chlorolabe} -3-phenylpropionyl]-N-methyl-L-histidyl]-amino-1 - cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 60 63oC.

Rf: to 0.39 (chloroform methanol, 10 1, V/V).

62) 2(S)-[N-[2(S)-[N-methyl-N-{3-N-isopropyl-N-methylcarbamoyl)-propyl}- aminocarbonyl]-3-phenylpropionyl]-N-methyl-L-histidyl]-amino-1 - cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 70 72oC.

Rf: 0,41 (chloroform methanol, 10 1, V/V).

63) 2(S)-[N-[2(S)-[N-methyl-N-{ 2-(N-tertbutoxycarbonyl-N-methylamino)- ethyl} -aminocarbonyl] -3-phenylpropionyl]-N-methyl-L-histidyl]- amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 61 65oC.

Rf: of 0.50 (chloroform methanol, 10 1, V/V).

2(S)-[N-[2(S)-[N-[2-{ N-methyl-N-(2-picolyl)-carbarnoyl} -ethyl] -N - methylaminorex] -3-phenylpropionyl] -N-methyl-L-histidyl]- amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 65 69oC.

Rf: to 0.48 (chloroform methanol, 9 1, V/V).

65) 2(S)-[N-[2(S)-{ N-(2-cyclopentanecarbonyl-N - methylaminorex] -3-phenylpropionyl-N-methyl-L-histidyl] - amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 86 92oC.

-methyl-L-histidyl]- amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 58 74oC.

Rf: 0,40 (chloroform methanol, 9 1, V/V).

67) 2(S)-[N-[2(S)-{ N-(2-morpholinoethyl)-N - methylaminorex} -3-phenylpropionyl] -N-methyl-L-histidyl] - amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 92 98oC.

Rf: to 0.39 (chloroform methanol, 9 1, V/V).

68) 2(S)-[N-[2(S)-{ N-(3-isobutylphenyl)-N-methylaminorex} -3 - phenylpropionyl] -N-methyl-L-histidyl] -amino-1-cyclohexyl-3(S)-hydroxy-6 - formed.

So pl. 62 68oC.

Rf: of 0.53 (chloroform methanol, 9 1, V/V).

69) 2(S)-[N-[2(S)-{ N-(3-isobutylphenyl)-N - methylaminorex} -3-phenylpropionyl] -N-methylhistidine] -amino-1 - cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 77 82oC.

Rf: or 0.57 (chloroform methanol, 9 1, V/V).

70) 2(S)-[N-[2(S)-[N-methyl-N-[5-{ N-(morpholinoethyl)-N-methylamino}- pentyl-aminocarbonyl] -3-phenylpropionyl]-N-methyl-L-histidyl]- amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 58 61oC.

Rf: 0,33 (chloroform meth-3-phenylpropionyl]-N-methyl-L-histidine-1 - cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 62 66oC.

Rf: 0,38 (chloroform methanol, 10 1, V/V).

72) 2(S)-[N-[2(S)-{N-methyl-N-(3-oxo-5-etylhexyl)-aminocarbonyl} -3 - phenylpropionyl]-N-methyl-L-histidyl]-amino-1-cyclohexyl-3(S)- hydroxy-6-formed.

So pl. 62 72oC.

Rf: 0,32 (chloroform methanol, 10 1, V/V).

73) 2(S)-[N-[2(S)-{N-(2-isopropylaminoethyl)-N-methylaminorex]-3 - phenylpropionyl] -N-methyl-L-histidyl] -amino-1-cyclohexyl-3(S)-hydroxy-6 - formed.

So pl. 70 74oC.

Rf: 0,46 (chloroform methanol, 10 1, V/V).

74) 2(S)-[N-[2(S)-{N-(2-isopropylaminoethyl)-N - methylaminorex] -3-phenylpropionyl]-N-methyl-L-histidyl]- amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 68 71oC.

Rf: 0,42 (chloroform methanol, 10 1, V/V).

75) 2(S)-[N-[2(S)-(2-acetylpyrrolidine-1 carbonyloxy)-3 - phenylpropionyl}-N-methyl-L-histidyl]-amino-1-cyclohexyl-3(S)- hydroxy-6-formed.

So pl. 80 84oC.

Rf: to 0.39 (chloroform methanol, 9 1, V/V).

2(S)-[N

So pl. 73 77oC.

Rf: of 0.58 (chloroform methanol, 9 1, V/V).

77) 2(S)-[N-{2(S)-(2-isobutylpyrazine-1 carbonyloxy)-3 - phenylpropionyl}-N-methyl-L-histidyl]-amino-1-cyclohexyl-3(S)-hydroxy-6 - formed.

So pl. 73 81oC.

Rf: 0,36 (chloroform methanol, 9 1, V/V).

78) 2(S)-[N-{2(S)-(2-benzoylpiperidine-1 carbonyloxy)-3 - phenylpropionyl} -N-methyl-L-histidyl] -amino-1-cyclohexyl-3(S)-hydroxy-6 - formed.

So pl. 77 82oC.

Rf: 0,49 (chloroform methanol, 9 1, V/V).

79) 2(S)-[N-{ 2(S)-(2-cyclohexylcarbodiimide-1 carbonyloxy)-3-phenylpropionyl} -N-methyl-L-histidyl] -amino-1 - cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 70 76oC.

Rf: 0,38 (chloroform methanol, 9 1, V/V).

80) 2(S)-[N-{ 2(S)-(2-acetylpyrrolidine-1 carbonyloxy-3 - phenylpropionyl}-N-methyl-L-histidyl]-amino-1-cyclohexyl-3(S)-hydroxy-6 - formed.

So pl. 77 82oC.

Rf: 0,30 (chloroform methanol, 9 1, V/V).

81) 2(S)-[N-{2(S)-(2-isobutylpyrazine)-1-carbonyloxy)-3 - phenylpropionyl}-N-m3 (chloroform methanol, 9 1, V/V).

82) 2(S)-[N-{ 2(S)-(2-methoxyacetanilide-1 carbonyloxy)-3 - phenylpropionyl} -N-methyl-L-histidyl] -amino-1-cyclohexyl-2(S)-hydroxy-6 - formed.

So pl. 80 85oC.

Rf: 0,34 (chloroform methanol, 9 1, V/V).

83) 2(S)-[N-{2(S)-{2-(4-dimethylaminostyryl)-pyrazolidine-1 carbonyloxy} -3-phenylpropionyl]-N-methyl-L-histidyl]-amino-1 - cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 58 63oC.

Rf: 0,05 (chloroform methanol, 9 1, V/V).

84) 2(S)-[N-{ 2(S)-(2-benzylaminocarbonyl-1 carbonyloxy]-3-phenylpropionyl] -N-methyl-L-histidyl] -amino-1 - cyclohexyl-3(S)-hydroxy-6-formed.

Rf: 0,35 (chloroform methanol, 9 1, V/V).

85) 2(S)-[N-{2(S)-(methylcarbamoylmethyl-1 carbonyloxy)-3 - phenylpropionyl} -N-methyl-L-histidyl] -amino-1-cyclohexyl-3(S)- hydroxy-6-formed.

So pl. 80 83oC.

Rf: 0,40 (chloroform methanol, 9 1, V/V).

86) 2(S)-[N-{2(S)-(2-morpholinobenzenediazonium-1 carbonyloxy)-3-phenylpropionyl} -N-methyl-L-histidyl] -amino-1 - cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 79 87
-methyl-L-histidyl]-amino-1 - cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 83 89oC.

Rf: to 0.39 (chloroform methanol, 9 1, V/V).

88) 2(S)-[N-[2(S)-{2-(N-acetyl-L-leucyl)-pyrazolidine-1 carbonyloxy}-3 - phenylpropionyl] -N-methyl-L-histidine-1-cyclohexyl-3(S)-hydroxy-6 - formed.

So pl. 85 93oC.

Rf: of 0.26 (chloroform methanol, 9 1, V/V).

89) 2(S)-[N-[2(S)-{ 2-(N-tert-butoxycarbonyloxyimino)- pyrazolidine] -1-carbonyloxy-3-phenylpropionyl] -N-methyl-L-histidyl]- amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 74 81oC.

Rf: of 0.21 (chloroform methanol, 9 1, V/V).

90) 2(S)-[N-{2(S)-(4-methylpiperazin-1 carbonyloxy)-3-phenylpropionyl]- N-methyl-L-histidyl]-amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 82 86oC.

Rf: 0,19 (chloroform methanol, 9 1, V/V).

91) 2(S)-[N-{ 2(S)-(4-methylcarbamoylmethyl-1 carbonyloxy)-3 - phenylpropionyl}-N-methyl-L-histidyl]-amino-1-cyclohexyl-3(S)-hydroxy-6 - formed.

So pl. 107 112oC.

Rf: 0,37 (chloroform methanol, 9 1, V/V).

92) is delamina-1 - cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 84 89oC.

Rf: 0,19 (chloroform methanol, 9 1, V/V).

93) 2(S)-[N-[2(S)-{ 4-(morpholinomethyl)-piperazine-1-carbonyloxy}-3 - phenylpropionyl]-N-methyl-L-histidyl]-amino-1-cyclohexyl-3(S)-hydroxy-6 - formed.

So pl. 81 88oC.

Rf: to 0.24 (chloroform methanol, 9 1, V/V).

94) 2(S)-[N-{2(S)-(3-oxopyrrolidin-1 carbonyloxy)-3-phenylpropionyl}- N-methyl-L-histidyl]-amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 80 84oC.

Rf: 0,40 (chloroform methanol, 89 1, V/V).

95) 2 (S)-[N-{2(S)-(2-oxazolidinone-3-carbonyloxy)-3-phenylpropionyl}- N-methyl-L-histidyl]-amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 82 89oC.

Rf: of 0.25 (chloroform methanol, 9 1, V/V).

2(S)-[N-{ 2(S)-(1,2,3,6-tetrahydropyridine-1-carbonyloxy)-3 - phenylpropionyl]-N-methyl-L-histidyl]-amino-1-cyclohexyl-3(S) - hydroxy-6 - formed.

So pl. 69 74oC.

Rf: 0,38 (chloroform methanol, 9 1, V/V).

97) 2(S)-[N-{2(S)-(thiazolidinedione)-3-phenylpropionyl}-N-{2(S)-(1-oxothiazolidine-3-carbonyloxy-3-Fenster]-amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

100) 2(S)-[N-{ 2(S)-(timorgaleevich)-3-phenylpropionyl} -N- methyl-L-histidyl]-amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 78 82oC.

Rf: 0,36 (chloroform methanol, 9 1, V/V).

101) 2(S)-[N-{ 2(S)-(1-associationvoice)-3-phenylpropionyl} -N- methyl-L-histidyl]-amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 90 96oC.

Rf: 0,93 (chloroform methanol, 9 1, V/V).

102) 2(S)-[N-{ 2(S)-(1,1-vocationalguidance)-3-phenylpropionyl} N-methyl-L-histidyl]-amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 99 103oC.

Rf: 0,31 (chloroform methanol, 9 1, V/V).

103) 2(S)-[N-{2(S)-(2(R)-methyl-3(R)- dimethylcyclopropanecarboxylate)-3-phenylpropionyl}-N-{2(S)-(2(S)-isobutyl-4-methyl-3-oxopiperidin-1 carbonyloxy)-3-phenylpropionyl} -N-methyl-L-histidyl] -amino-1 - cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 88 92oC.

Rf: of 0.50 (chloroform methanol, 10 1, V/V).

105) 2(S)-[N-{2(S)-(6(S)-3(S)-morpholinosydnonimine-2-oxo-1,4 - diazabicyclo-[4.3.0] -nonan-4-carbonyloxy)-3-phenyl-Christ. oC.

Rf: 0,37 (chloroform methanol, 10 1, V/V).

Example 6.

1) To a solution containing N-tert-butoxycarbonyl-L-histidyl (365 mg) and 2(S)-amino-1-cyclohexyl-3(S)-hydroxy-6-formed (294 mg) in dry N,N-dimethylformamide (20 ml), cooled to 0oC, add a solution diphenylphosphinite (390 mg) in dry N,N-dimethylformamide (5 ml) and triethylamine (144 mg). The resulting mixture is stirred over night at ambient temperature. After evaporation of the solvent the residue is dissolved in ethyl acetate (30 ml) and the resulting solution was successively washed with 10 citric acid solution, saturated sodium bicarbonate solution and water. Then dried over magnesium sulfate and concentrate under reduced pressure. The residue is purified column chromatography on silica gel (eluent used chloroform) to yield 2(S)-(N-tert-butoxycarbonyl-L-histidyl)-amino-1-cyclohexyl-3(S)-hydroxy-6 - methylheptane (384 mg) as amorphous powder.

So pl. 96 100oC.

Rf: to 0.47 (chloroform, methanol, acetic acid, 9 1 1, V/V).

2) a Solution containing 2(S)-(N-tert-butoxycarbonylmethyl)-amino-1-cyclohexyl-3(S)-hydroxy-6 - formed (383 mg) in triperoxonane acid (10 ml), peremeci the ATA (20 ml). The solution was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo to obtain 2(S)-(L-histidyl)-amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (275 mg) as amorphous powder.

So pl. 126 130oC.

Rf: 0,11 (chloroform, methanol, acetic acid, 8 1 1, V/V).

3) To a mixture of 2(S)-morpholinoethoxy-3-phenylpropionic acid (120 mg) and 2(S)-(L-histidyl)-amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (142 mg) in dry N,N-dimethylformamide (20 ml), cooled to 0oC, add a solution diphenylphosphinite (108 mg) in dry N,N-dimethylformamide (5 ml) and triethylamine (40 mg). The resulting mixture was stirred for 16 h at ambient temperature. After evaporation of the solvent the residue is dissolved in ethyl acetate (30 ml). The solution is successively washed with 1 M sodium bicarbonate solution and water, dried and evaporated under reduced pressure. The residue is purified by thin-layer chromatography on silica gel (chloroform methanol, 6 1 V/V) to yield 2(S)-[N-(2 morpholinoethoxy-3-phenylpropionyl)-L-histidine-1 - cyclohexyl-3(S)-hydroxy-6-methylheptane (177 mg) as amorphous powder.

Rf: 0,63 (chloroform methanol, 6 1R>
1) 2(S)-[N-{ 2(S)-(N, N-diethylaminoethoxy)-3-phenylpropionyl} -L - histidyl]-amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 73 77oC.

Rf: 0,49 (chloroform methanol, 6 1, V/V).

2) 2(S)-[N-{2(S)-{N-(2-morpholinoethyl)-N-methylaminomethyl-hydroxy-3 - phenylpropionyl] -1-histidyl]-amino-1-cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 82 86oC.

Rf: 0,49 (chloroform methanol, 9 1, V/V).

3) 2(S)-[N-{ 2(S)-{N'-(morpholinomethyl)-N,N'- dimethyldithiocarbamate} -3-phenylpropionyl] -L-histidyl] amino-1 - cyclohexyl-3(S)-hydroxy-6-formed.

So pl. 76 80oC.

Rf: to 0.48 (chloroform methanol, 10 1, V/V).

Example 8.

A solution containing 2(S)-[N-[(2(S)-[N-methyl-N-2-(N-tert-butoxycarbonyl-N-methylamino)- ethyl} -aminocarbonyl]-3-phenylpropionyl]-N-methyl-L-histidyl] - amino-1-cyclohexyl-3(S)-hydroxy-6-formed (114 mg) in triperoxonane acid (10 ml) stirred at 0oC for 1 h After evaporation of the solvent, the obtained residue is dissolved in ethyl acetate (20 ml) and the solution successively washed with 1 M sodium bicarbonate solution and water, and then dried over which enecarboxylate]-3 - phenylpropionyl]-N-methyl-L-histidyl]-amino-1-cyclohexyl-3(S)-hydroxy-6 - formed (88 mg) as amorphous powder.

So pl. 65 68oC.

Rf: 0,20 (chloroform methanol, 6 1, V/V).

Example 9.

1) To a solution containing 2(S)-(N-tert-butoxycarbonyl-N-methyl-L-histidyl)-amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (46 g).

Rf: 0,16 (chloroform, methanol, acetic acid, 8 1 1, V/V).

2) To a solution containing 2(S)-(N-methyl-L-histidyl)-amino-1-cyclohexyl-3(S)-hydroxy-6-formed (900 mg) and triethylamine (494 mg) in methylene chloride (20 ml), add chloride of trityl (696 mg) at a temperature of 0oC. the resulting mixture was stirred at the same temperature for 1 h After evaporation of the solvent the residue is dissolved in ethyl acetate (30 ml) and the resulting solution was sequentially washed with 1 M sodium bicarbonate solution and water, and then dried over magnesium sulfate. After evaporation of the solvent to obtain 2(S)-(NN-methyl-Nim-triethyl-L-histidyl)-amino-1-cyclohexyl-3(S)- hydroxy-6-formed (1,46 g) as amorphous powder.

Rf: 0,43 (chloroform methanol, 10 1, V/V).

3) To a solution containing 2(S)-[N-methyl-[2-{N-methylene (20 ml), cooled to 0oC, add oxalicacid (0,22 ml) and three drops of N,N-dimethylformamide. The reaction mixture was stirred at the same temperature for 1 h and then added to a solution of 2(S)-(NN-methyl-Nim-triethyl-L-histidyl)-amino-1-cyclohexyl-3(S)- hydroxy-6-methylheptane (1.40 g) and N-methylmorpholine (502 mg) in methylene chloride (20 ml) at 0oC. the Reaction mixture was stirred at the same temperature for 1 h After evaporation of the solvent the residue is dissolved in ethyl acetate (30 ml). The solution is washed successively with 5 hydrochloric acid, 1 M sodium bicarbonate solution and water and dried over magnesium sulfate. After evaporation of the solvent to obtain 2(S)-[N-[2(S)-[N-methyl-N-[2-{ N-(morpholinoethyl)-N-methylamino} - ethyl] -aminocarbonyl] -3-phenylpropionyl]-NN-methyl-Nim- trityl-1 histidine-1-cyclohexyl-3(S)-hydroxy-6-formed (of 2.21 g) as amorphous powder.

Rf: 0,80 (chloroform methanol, 10 1, V/V).

4) 2(S)-[N-[2(S)-[N-methyl-N-[2-{ N-(morpholinoethyl)-N-methylamino} - ethyl] -aminocarbonyl]-3-phenylpropionyl]-NN-methyl-Nim- trityl-L-histidyl] -amino-1-cyclohexyl-3(S)-hydroxy-6-formed (1,00 g) dissolved in 50 solution of acetic key environment resulting triphenylcarbinol filtered and the filtrate evaporated under reduced pressure. The residue is dissolved in ethyl acetate (50 ml). The resulting solution was sequentially washed with 1 M sodium bicarbonate solution and water, dried over magnesium sulfate and concentrated in vacuo. The residue is purified by chromatography on a column of silica gel (5 ethanol in chloroform is used as eluent) to yield 2(S)-[N-2(S)-[N-methyl-N-[2-{N-(morpholinoethyl)-N-methylamino} - ethyl]-aminocarbonyl]-3-phenylpropionyl]-N-methyl-L-histidyl]-amino-1 - cyclohexyl-3(S)-hydroxy-6-methyl-heptane (700 mg) as amorphous powder.

Rf: to 0.45 (chloroform methanol, 10 1, V/V).

Example 10.

To a solution containing 2(S)-[N-[2((S)-{N-(2-morpholinoethyl)-N - methylaminorex} -3-phenylpropionyl]-N-methyl-L-histidyl]- amino-1-cyclohexyl-3(S)-hydroxy-6-formed (4,55 g) in ethanol (50 ml), cooled to 0oC, was added 4 n hydrogen chloride in dioxane solution (1.9 ml). Then the reaction mixture was stirred at the same temperature for 10 min and the solvent evaporated under reduced pressure. The residue is crystallized from ethanol (5 ml) in a mixture with ethyl acetate (150 ml) to yield 2(S)-[N-[2(S)-{ N-(2-morpholinoethyl)-N - methylenedioxy] -3-phenylpropionyl] -N2D051,93o(c 1.0, the Meon)

Example 11.

In accordance with the method of example 10, the following connections:

1) 2(S)-[N-[2((S)- [N-methyl-N-{ 2-(N-isobutyryl-N-methylamino)-ethyl} - aminocarbonyl] -3-phenylpropionyl-N-methyl-L-histidyl]-amino-1 - cyclohexyl-3(S)-hydroxy-6-methylheptane monochlorohydrin.

So pl. 118 122oC.

2) 2(S)-[N-[2(S)-[N-methyl-N] -2-{ N-(morpholinoethyl)-N-methylamino}- ethyl]-aminocarbonyl]-3-phenylpropionyl]-N-methyl-L-histidyl]- amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane monochlorohydrin.

So pl. 108 116oC.

1. Amino acid derivatives of the formula

< / BR>
where R1lower alkyl, optionally substituted Deputy selected from the group consisting of acyl, hydroxyl, lower alkoxy, phenyl, lower alkylthio and groups of the formula

< / BR>
where R5hydrogen or acetyl;

R6hydrogen or lower alkyl, phenyl or amino, optionally substituted by substituent(s) selected from the group consisting of lower alkyl and acyl;

R2hydrogen or lower alkyl, or R1and R2taken with the nitrogen atom to which they are attached, form morpholino, Timo solidin-3-yl, its 1-oxide or 1,1-dioxide, oxazolidin-3-yl, perpetratin-1-yl, 1,4-dihydropyridines-1-yl, 1,2,3,6-tetrahydropyridine-1-yl, 1,2,3,4-tetrahydroisoquinoline-2-yl, 1,2,3,4-tetrahydroquinolin-1-yl, hexamethyleneimino or 1,4-diazabicyclo-(4.3.0)nonan-4-yl, each of which may be substituted by substituent(s) selected from the group consisting of lower alkyl, hydroxy(lower)alkyl, lower alkoxy(lower)of alkyl, acyl(lower)alkyl, oxo, or acyl;

R3hydrogen or lower alkyl;

R4lower alkyl;

and its pharmaceutically acceptable salts.

2. Connection on p. 1, wherein R1lower alkyl, optionally substituted Deputy selected from the group consisting of hydroxyl, lower alkoxy, phenyl, lower alkylthio, groups of the formula

< / BR>
where R9and R10each hydrogen, phenyl, cyclo(lower)alkyl, thiazolyl, pyridyl, morpholino or lower alkyl, optionally substituted Deputy selected from the group consisting of lower alkoxycarbonyl, lower alkoxy, phenyl, thiazolyl, pyridyl, morpholino, or R9and R10taken together with the nitrogen atom to which they are attached, form morpholino, dimorpholino, its 1-oxide or 1,1-dioxide, pyrrolidin-1-yl, eraserheads-1-yl, 1,4-dihydropyridines-1-yl, 1,2,3,6-tetrahydropyridine-1-yl, 1,2,3,4-tetrahydroisoquinoline-2-yl, 1,2,3,4-tetrahydroquinolin-1-yl, hexamethyleneimino or 1,4-diazabicyclo(4.3.0)nonan-4-yl, each of which may be substituted by lower alkyl;

R11phenyl, cyclo(lower)alkyl, lower alkyl, optionally substituted Deputy selected from the group consisting of lower alkoxy and mono - or di(lower)alkylamino, or lower alkoxy, optionally substituted Deputy selected from the group consisting of lower alkanoyl and phenyl, and groups of the formula

< / BR>
where R5hydrogen or a group of the formula

< / BR>
where R9, R10and R11each has a specified value;

R6hydrogen or lower alkyl, phenyl or amino, optionally substituted by substituent(s) selected from the group consisting of lower alkyl and a group of the formula

< / BR>
where R9, R10and R11each has a specified value;

R2hydrogen or lower alkyl;

or R1and R2taken together with the nitrogen atom to which they are attached, form morpholino, thiomorpholine, its 1-oxide or 1,1-dioxide, pyrrolidin-1-yl, pyrazolin-1-yl, piperidino, piperazine-1-yl, pyrrolin-1-yl, thiazolidin-3-yl, 1-oxide or 1,1 hydroisoquinoline-2-yl, 1,2,3,4-tetrahydroquinolin-1-yl, hexamethyleneimino or 1,4-diazabicyclo(4.3.0)nonan-4-yl, each of which may be substituted by substituent(s) selected from the group consisting of lower alkyl, hydroxy(lower)alkyl, lower alkoxy(lower)alkyl, morpholinoethyl(lower)alkyl, thiomorpholine(lower)alkyl, piperazinylcarbonyl(lower)alkyl, 4-methyl-1-piperazinylcarbonyl(lower)alkyl, 1,2,3,6-tetrahydro-1-pyridylcarbonyl(lower)alkyl, oxo, aminosidine or unprotected amino acid residue and a group of the formula

;

R11-CO - or-SO2-,;

where R9, R10and R11have the specified values.

3. Connection on p. 2, wherein R1lower alkyl, optionally substituted Deputy selected from the group consisting of hydroxyl, lower alkoxy, phenyl, lower alkylthio, groups of the formula

< / BR>
R11-CO - or-SO2-

and groups of the formula

4. Connection on p. 3, wherein R1lower alkyl substituted by a group of the formula

< / BR>
where R9and R10each hydrogen or lower alkyl or R9and R10taken together with the nitrogen atom to which they are attached, form morpholino.

5. The connection is ylamino-carbonyloxy}- 3-phenylpropionyl] methyl-L-histidyl)amino-1-cyclohexyl-3(S)-hydroxy-6-formed or its hydrochloride.

6. Connection on p. 3, wherein R1lower alkyl substituted by a group of the formula

< / BR>
where R5hydrogen

or a group of the formula

< / BR>
where R9and R10taken together with the hydrogen atom, to which they are attached, form morpholino;

R11lower alkyl;

R6hydrogen or lower alkyl.

7. Connection on p. 6, characterized in that it consists of 2(S)-[[N-[2(S)-[N-methyl-N-[2-{N-(morpholinoethyl)- N-methylamino}ethyl]aminocarbonyl] -3-phenylpropionyl)-N-methyl-L-histidyl] amino-1-cyclohexyl-3(S)-hydroxy-6-formed or its hydrochloride.

8. Connection on p. 6, characterized in that it consists of 2(S)-[N-[2(S)-[N-methyl-N-{ 2-(N-isobutyryl-N - methylamino)-ethyl}aminocarbonyl] -3-phenylpropionyl] --N- methyl-L-histidyl)-amino-1-cyclohexyl-3(S)-hydroxy-6-formed or its hydrochloride.

9. The pharmaceutical composition inhibiting the action of renin, characterized in that it contains an effective amount of the compounds under item 1 as an active ingredient in combination with pharmaceutically acceptable, essentially nontoxic carrier or excipients.

10. Connection on p. 1>amino group, optionally substituted Deputy, selected from the group consisting of lower alkyl, or lower alkanoyl, or lower alkyl, optionally substituted Deputy selected from the group consisting of hydroxyl, lower alkoxy and phenyl, R2is hydrogen or lower alkyl, or R1and R2taken together with the nitrogen atom to which they are attached, form morpholino, thiomorpholine, pyrrolidin-1-yl, pyrazolin-1-yl, piperidino, piperazine-1-yl, pyrrolin-1-yl, 1,4-dihydropyridines-1-yl, 1,2,3,6-tetrahydropyridine-1-yl, 1,2,3,4-tetrahydroisoquinoline-2-yl, 1,2,3,4-tetrahydroquinolin-1-yl or hexamethyleneimino, each of which can be substituted by the Deputy selected from the group consisting of lower alkyl, hydroxy(lower)alkyl, R3hydrogen or lower alkyl, R4lower alkyl;

30.10.87 when R1amino group, a substituted lower alkyl and Deputy selected from gruppu containing acyl Il lower alkyl, substituted acyl, R2hydrogen or lower alkyl or R1and R2taken together with the nitrogen atom to which they are attached, form morpholino, thiomorpholine, pyrrolidin-1-yl, piperidino, piperazine-1-yl, pyrrolin-1-yl, 1,4-dihydropyridines-1-yl, 1,2,3,6-tetrahydropyridine-1-yl, 1,2,3, is substituted by the Deputy, selected from the group consisting of lower alkoxy(lower)alkyl, oxo, or acyl; pyrazolidine-1-yl, thiazolidin-3-yl, oxazolidin-3-yl, perpetratin-1-yl or 1,4-diazabicyclo-[4.3.0]nonan-4-yl, each of which can be selected from the group consisting of lower alkyl, hydroxy(Nissen)alkyl, lower alkoxy(lower)alkyl, oxo, or acyl, R3hydrogen or lower alkyl, R4lower alkyl;

07.03.88 when R1lower alkyl substituted by a group of the formula

< / BR>
where R5acyl and R6hydrogen or lower alkyl, R2is hydrogen or lower alkyl, R3hydrogen or lower alkyl, R4is lower alkyl.

 

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< / BR>
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to their pharmaceutically acceptable additive salts, and stereochemical isomeric forms, where a1AND2AND3AND4is a bivalent radical having the formula

-CH CH-CH CH- (a-1),

-N CH-CH CH- (a-2)

-CH N-CH CH- (a-3)

-CH CH-N CH- (a-4),

-CH CH-CH N- (a-5),

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-CH N-CH N- (a-7), where one or two hydrogen atoms in said radicals (a-1) to(a-7) can be independently substituted by a halogen atom, a C1-C6-alkyl, C1-C6-alkyloxy, hydroxy, or trifluoromethyl; R represents hydrogen or C1-C4-alkyl; R1represents hydrogen, C1-C6-alkyl or hydroxy WITH1-C6-alkyl;

m is 1 or 2;

represents a C1-C4-alcander; B is an R2CH2, O, SO or SO2where R2is hydrogen or C1-4-alkyl;

n is 0, 1 or 2;

L represents hydrogen; C1-2-alkyl; C3-6-cycloalkyl; C3-C6alkenyl, optionally substituted by aryl; C1-C6-alkylsulphonyl; C1-C6-алкилоксикBR>
-Alк-Y-R4(o-2);

-Alк-Z1-C X-2-R5(o-3); or

-CH2-CHOH-CH2-O-R6(o-4); where R3represents cyano, aryl or Het; R4represents hydrogen, aryl, Het, or1-C6-alkyl, optionally substituted aryl or Het; R5represents hydrogen, aryl, Het or1-C6-alkyl, optionally substituted aryl or Het; R6represents aryl or naphthalenyl; Y represents O, S, NR7where R7is hydrogen, C1-C6-alkyl or C1-C6-alkylcarboxylic;

Z1and Z2each independently represents O, S, NR8or a simple link, where R8is hydrogen or C1-C6-alkyl; X represents O, S or NR9where R9is hydrogen, C1-C6-alkyl or cyano; Alк each independently is a C1-C6-Alcantara; each Het represents: (i) optionally substituted heterocyclic ring with 5 or 6 members containing 1, 2, 3 or 4 heteroatoms selected from oxygen, sulfur and nitrogen, provided that there is not more than 2 oxygen atoms and/or sulfur; (ii) optionally substituted heterocyclic ring with 5 or 6 members which of substituted five - or six-membered ring through 2 carbon atoms or 1 nitrogen atom; and that in the rest of the condensed ring contains only carbon atoms; (iii) optionally substituted heterocyclic ring with 5 or 6 members, which contains 1 or 2 heteroatoms selected from oxygen atoms, sulfur and nitrogen, and optionally substituted five - or six-membered ring through 2 carbon atoms or 1 carbon atoms and 1 nitrogen atom; and which in the rest of the condensed ring contains 1 or 2 heteroatoms selected from oxygen atoms, sulfur and nitrogen; and, if Het is a monocyclic ring system, it is not necessary to have up to 4 substituents; and if Het is a bicyclic ring system, it may not necessarily be up to 6 substituents, which are selected from halogen, amino, mono - and di(C1-C6-alkyl)amino, aryl WITH1-C6-amino, nitro, cyano, aminocarbonyl,1-C6-alkyl, C1-C6alkyloxy,1-C6-alkylthio,1-C6-allyloxycarbonyl,1-6-alkyloxy-FROM1-6-alkyl, C1-6-allyloxycarbonyl1-6-alkyl, hydroxy, mercapto, hydroxy1-C6-alkyl, C1-C6-alkylcarboxylic aryl, Rilc1-C6-alkylamino is whether 3 substituents, each of which is independently selected from halogen, hydroxy, nitro, cyano, trifloromethyl,1-C6-alkyl, C1-C6-alkyloxy,1-C6-alkylthio, mercapto, amino, mono - and di-(C1-C6-alkyl)amino, carboxyl,1-6-allyloxycarbonyl, and C1-C6-alkylcarboxylic

The invention relates to new derivatives of pyrazole and their pharmaceutically acceptable salts

The invention relates to medicine, specifically to antisecretory and antiulcer drug
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