Cyclopeptide or its pharmaceutically acceptable salt, methods of preparation and pharmaceutical composition

 

(57) Abstract:

Usage: in medicine. The inventive cyclopeptide I:

< / BR>
where R1is hydrogen or acyl; R2- hydroxy - or alloctype; R3- hydroxysulfonic group; R4- carbarnoyl, provided that R1can't be Palmitoyl, when R2is hydroxy, R3- hydroxysulfonic group, or their pharmaceutically acceptable salts, methods for their production: (a) by the removal of R1b) obtain compounds I where R1- acyl, by acylation of I, where R1- N; C) obtain I where R1ar(lower)alkanoyl by the release of amino groups and g) obtaining the compounds I where R1- pyridylthio(lower)alkanoyl by interaction of I, where R1halogen(lower) alkanoyl with pyridinethione; d) I, where R2- acyloxy by acylation of I, where R2the hydroxy - group; a pharmaceutical composition having antimicrobial activity comprising as active ingredient I in an effective amount. 7 C. and 1 C.p. f-crystals, 10 PL.

The invention relates to new polypeptide compound and its pharmaceutical acceptable salts.

More specifically the invention ivairovei activity in particular fungicidal activity, the method of its preparation, to pharmaceutical compositions comprising this compound, and to a method of treating or preventing infectious diseases in humans and animals.

Accordingly one purpose of the invention is the provision of a polypeptide compound and its pharmaceutically acceptable salts, which possess high activity against pathogens in humans and animals.

Another aim of the invention is the provision of a method of preparation of polypeptide compounds and salts thereof.

An additional objective of the invention is to provide pharmaceutical compositions comprising as an active ingredient specified polypeptide compound or its farmacevtichesky acceptable salt.

Another aim of the invention is the provision of a method for the treatment or prevention of infectious diseases caused by pathogenic microorganisms, which includes the appointment of a specified polypeptide connections to people or animals.

The target polypeptide compound of the invention is novel and can be represented by the following General formula:

,

gir>3is a hydrogen atom or hydroxysulfonic-group and

R4is a hydrogen atom or carnemolla group,

provided that:

a) R2- alloctype, when R3- the hydrogen atom and

b) R1is not palmitoleic group, when R2the hydroxy - group,

R3- hydroxysulfonic and

R4is carbamoyl group.

The polypeptide compounds (1) can be prepared using methods that are illustrated below:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
In these formulas:

R3and R4such as indicated above,

R1ais an acyl group, excluding the Palmitoyl,

R1ar(lower)alkanoyl), which has higher alkoxy and protected amino group,

R1cis ar(lower)alkanoyl, which has higher alkoxy -, amino-group,

R1dis halogen(lower)alkanoyl,

R1e- pyridylthio(lower)alkanoyl, which may have higher alkyl,

R1fis icalneu group

R2a/- acyloxy-group and

R5is an acyl group.

Starting material (II) or its salt, is a new e of the starting compounds (IV) are new and can be obtained in accordance with the methods 1-4.

A suitable pharmaceutically acceptable salt of the target compound (I) are conventional non-toxic mono - or di - salts and include a metal salt such as a salt of an alkali metal (for example sodium, potassium, and others) and salt, alkaline earth metal (e.g. calcium, magnesium and others) and ammonium salt, and a salt of organic bases such as trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine, N, N - dibenziletilendiaminom and others); additive salt of an organic acid, for example formate, acetate, triptorelin, maleate, tartrate, methanesulfonate, bansilalpet, toluensulfonate and others), salt with aminosilanes (such as arginine, asparticularly acid, glutamic acid, and others), etc.

It is assumed that the term "lower" means a content of 1 to 6 carbon atoms, unless otherwise specified; the term "highest" means the content of 7 to 20 carbon atoms, unless otherwise indicated.

Suitable "acyl group" may be aliphatic acyl, aromatic acyl, heterocyclic acyl, arylaliphatic acyl and geterotsiklicheskikh-aliphatic acyl, - made from carboxylic acid, carboxylic acid, carbamino acid, sulfonic acid, etc.

Suitable primality, hexanoyl, pivaloyl, etc.), which may have one or more (preferably 1 to 3) suitable substituents, such as halogen (for example fluorine, chlorine, bromine, iodine); aryl (e.g. phenyl, naphthyl, anthracene and others), which may have one or more (preferably 1-3) suitable substituents such as hydroxy, higher alkoxy group (explained below), the above-mentioned aryl or so on ; protected amino group, preferably acylamino group, since the lower alkoxycarbonyl (e.g., methoxycarbonylamino, ethoxycarbonylethyl, propoxycarbonyl, butoxycarbonylamino, tert-butoxycarbonylamino, ventilatsioonile, hexyloxyphenyl and others) and the like; di(lower)alkylamino group (for example, dimethylamino-, -methylethylamine, diethylamine-, N-propylamino, diphenhydamine, digoxigenin etc ); lower alkoxyimino group (for example, methoxyimino, amoxiillin, propoxyimino, butachimie, tert-butoxysilane, petrochemie, hexylamine and others); ar(lower)alkoxyimino group, such as phenyl(lower) alkoxyimino (for example, benzylamino, venetiancasino, benzhydrylamine and others), which may have one or more (preferably 1-3) suitable Salina pyridylthio-, which may have one or more (preferably 1-3) suitable substituents, such higher alkyl (for example heptyl, octyl, 2-ethylhexyl, Ionel, decyl, 3,7-dimethyloctyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, 3-methyl-10-ethyldecyl, hexadecyl, heptadecyl, octadecyl, yandell, icosyl and others) and the like; heterocyclic group (for example, thienyl, imidazolyl, pyrazolyl, furyl, tetrazolyl, thiazolyl, thiadiazolyl and others), which may have one or more (preferably 1-3) suitable substituents, such amino-mentioned protected amino group, mentioned higher alkyl, etc; and the like;

the highest alkanoyl (for example heptenyl, octanoyl, nonanoyl, decanoyl, undecanoyl, lauroyl, tridecanol, myristyl, pentadecanol, Palmitoyl, 10, 12-dimethylethylene, heptadecanoyl, Palmitoyl, stearoyl, nonadecanoic, emosanal and others);

lowest alkanoyl (such as acryloyl, thetailor, crotonoyl, 3-patanol, 5-hexenol and others), which may have one or more (preferably 1-3) suitable substituents, such as the above-mentioned aryl which may have one or more (preferably 1-3) suitable substituents, such higher alkoxy-group /explained nor is catranis, 4,10-heptadecadiene and others);

lowest alkoxycarbonyl, (for example methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxybenzoyl, hexyloxybenzoyl and others);

the highest alkoxycarbonyl (such as heptyloxybiphenyl, octyloxybiphenyl, 2-ethylhexylcarbonate, nonlexically, decyloxybenzoic, 3,7-dimethylethoxysilane, undecalactone, dodecyloxybenzoyl, treeselectionmodel, tetradecyltrimethyl, pentadecylcatechol, 3-methyl-10-amidocarbonyl, hexadecacarbonyl, heptadecadiene, octadecylsilane, nondisjunctional, casinosecure and others);

aryloxyalkyl (such as phenoxycarbonyl, naphthalocyanines and others);

acilglycerol (such as phenylglyoxylic, afterpotential and others);

ar(lower)alkoxycarbonyl, which may have one or more suitable substituents, such as phenyl(lower)-alkoxycarbonyl, which may have nitro or lower alkoxy group (for example, benzyloxycarbonyl, ventilatsioonil, p-nitrobenzenesulfonyl, p-methoxybenzenesulfonyl and others);

lower Acesulfame (for example methylsulphonyl, ethylsulfonyl, propylsulfonyl and others), which may have one or more suitable substituents (preferably 1-3), such as lower alkyl as explained below, higher alkoxy-group, which are explained in the following or similar;

ar(lower)alkylsulfonyl, such as phenyl(lower)alkylsulfonyl (for example bansilalpet, penetrameter, Benzylalcohol and others), etc.;

aroyl (for example benzoyl, Naftoli, internalkernel and others), which may have one or more (preferably 1-5) suitable substituents, such as the above-mentioned halogen; lower alkyl (e.g. methyl, ethyl, propyl, butyl, tert-butyl, pentyl, hexyl, and others); the above alkyl; lower alkoxy group (e.g. methoxy, ethoxy-, propoxy-, butoxy, tert-butoxy, pentyloxy, hexyloxy and others ); which may have one or more (preferably 1-10) suitable substituents, like mentioned lower alkoxygroup, halogen, aryl or etc.; higher alkoxy group (for example, heptyloxy, octyloxy, 2-ethylhexyloxy, nonyloxy, decyloxy, 3,7-dimethyloctane, undecyloxy, dodecyloxy, tridecylamine, tetradecenoic, pentadecylic, 3-methyl-10-ethyldimethylamine, hexadecylamine, heptadecenoic, octadecylamine, nonadecanoic, tosyloxy and others), which may have one or not is a (e.g. 3-heptyloxy, 7 octenoate, 2,6-oxydianiline, 5-nonyloxy, 1 desenlace, 3,7-dimethyl-2,6-octadienal, 3,7-dimethyl-6-octenoate, 8-undecyloxy, 3,6,8-dodecadienol, 5-tridecanoate, 7 tetradecanoate, 1,8-pentadecanedioic, 15-hexadecenoic, 11 heptadecenoic, 7 octadecanoyloxy, 10-nonadecanone, 18 kosenlose and others); carboxy; the above-mentioned aryl which may have one or more suitable substituents (preferably 1-3), like mentioned higher alkoxy-group; aryloxy (for example, phenoxy, naphthyloxy, anthranilate and others), which may have one or more (preferably 1-3) suitable substituents, like mentioned lower alkoxy or higher alkoxy-ruppy; or etc.

In the above-mentioned "acyl group" may be preferred lower alkanoyl; halogen(low alkanoyl; ar(lower)alkanoyl, which may have one or more (preferably 1-3) groups: hydroxy, lower alkoxy, higher alkoxy group, aryl, amino, protected amino group, di(lower)alkyl-amino, lower alkoxyimino or ar(lower)alkoxyimino group which may have one or more (preferably 1-3)higher alkoxy groups;

heterocyclic thio(lower)alkanoyl, which can amatory may have one or more (preferably 1-3) groups: lower alkoxyimino, higher alkyl, amino or protected amino group;

ar(lower)alkoxyimino(lower) alkanoyl, which may have one or more (preferably 1-3) higher alkoxygroup;

the highest alkanoyl;

ar(nisi)alkanoyl, which may have one or more (preferably 1-3) higher alkoxy groups;

the highest alkanoyl; lower alkoxycarbonyl group; the highest alkoxycarbonyl; aryloxyalkyl;

arylsulfonyl, which may have one or more (preferably 1-3) lower alkyl or higher amoxil groups;

aroyl, which may have one or more (preferably 1-5) of atoms of halogen, lower Akilov, the highest Akilov, carboxy group, lower alkoxy group which may have one or more (preferably 1-10) of atoms of halogen, lower alkoxy(lower)alkoxy group, ar(lower)alkoxy, higher alkoxy groups which may have one or more (preferably 1-17) halogen atoms, the higher alkenylamine groups, aryl which may have one or more (preferably 1-3) higher alkoxy - or aryloxy group which may have one or more (preferably 1-3) lower alkoxy or higher alkoxy groups;

among which the most preferred gr)alkanoyl, each of which may have 1-3 hydroxy groups, lower alkoxy, higher alkoxy, phenyl, amino, lower alkoxycarbonyl-, di(lower)alkylamino-, lower alkoxyimino-, or phenyl(lower)alkoxyimino group which may have 1-3 higher alkoxy groups;

pyridylthio(lower)alkanoyl, which may have 1-3 higher alkyl groups;

imidazolyl(lower)alkanoyl or thiazolyl(lower)alkanoyl, each of which may have 1-3 lower alkoxyimino, higher alkyl, amino or lower alkoxycarbonyl groups;

phenyl(lower)alkoxyimino(lower)alkanoyl, which may have 1-3 higher alkoxy groups;

the highest alkanoyl;

phenyl(lower)alkanoyl, which may have 1-3 higher alkoxy groups;

the highest alkanoyl; lower alkoxycarbonyl, higher alkoxycarbonyl; phenoxycarbonyl;

phenylsulfonyl or naphthylmethyl, each of which may have 1-3 tertiary alkyl or tertiary alkoxy groups;

benzoyl, naphtol or anthracenediones, each of which may have 1 to 5 halogen atoms, lower Akilov, the highest Akilov, carboxy, lower alkoxy groups which may have from 6 to 10 atoms of halogen, lower alkoxy(lower)alkoxy group which may have a 12-17 halogen atoms, higher Almaty 1-3 lower alkoxy or higher alkoxy-group;

the most preferred may be the group (C1-C4)alkanoyl; halogen(C1-C4)alkanoyl;

phenyl(C1-C4)alkanoyl, which may have 1-3 hydroxy groups, (C1-C4)alkoxy, (CV7-C16)alkoxy, phenyl, amino, (C1-C4)alkoxycarbonyl-, di(C1-C4)alkylamino, (C1-C4)alkoxyimino-, or phenyl(C1-C4)alkoxyimino group which may have a (C7-C16)alkoxy group;

naphthyl(C1-C4)alkanoyl, which may have 1-3 (C1-C4)alkoxycarbonyl-group;

1-(C7-C16)alkylpyridinium (C1-C4)alkanoyl;

imidazolyl(C1-C4)alkanoyl, which may have 1-3 (C7-C16)alkyl or (C1-C4) alkoxycarbonyl-group;

thiazolyl(C1-C4)alkanoyl, which may have 1-3 (C1-C4)alkoxyimino - or amino-groups;

phenyl(C1-C4)alkoxyimino(C1-C4) alkanoyl, which may have 1-3 (C7-C16)alkoxy group;

(C7-C17)alkyl;

phenyl(C1-C4)alkanoyl, which may have 1-3 (C7-C16)alkoxy group;

(C7-C18)al is Lionel, which may have a (C1-C4)alkyl or (C7-C16)alkoxy-;

naphthylmethyl, which can have a (C7-C16)alkoxy-;

benzoyl which may have 1 to 5 halogen atoms, (C3-C6)-alkyl, (C7-C16)alkyl, carboxy, (C1-C6)alkoxy which may have from 6 to 10 atoms of halogen, (C1-C4)alkoxy-(C1-C4)alkoxy, phenyl(C3-C6)alkoxy, (C7-C16)alkoxy which may have a 12-17 halogen atoms, phenyl which may have 1-3 (C7-C16)alkoxy group or phenoxy group which may have 1-3 C3-C6alkoxy or (C7-C16)alkoxy group;

naphtol, which may have 1-3 (C3-C6)alkoxy groups, (C7-C16)alkoxy or (C7-C16)alkenylacyl-group;

anthracenediones;

and the most preferable one may be acetyl, 2-bromoacetyl, 2-(4-definily)acetyl, 2-(4-octyloxyphenyl)acetyl, 3-(4-octyloxyphenyl)propionyl, 2-amino-2-(4-octyloxyphenyl)acetyl, 2-(tert-butoxycarbonylamino)-2-(4-octyloxyphenyl)acetyl, 2-amino-3-(4-octyloxyphenyl)propionyl, 2-(tert-butoxycarbonylamino)-3-(4-octyloxyphenyl)propionyl, 2-dimethylamino-3-(4-octyloxyphenyl)propionyl, 2-(Neil)acetyl, 2-(4-octyloxybenzophenone)-2-(4-hydroxyphenyl)acetyl, 2-(4-octyloxybenzophenone)-2-phenylacetyl, 2-(4-oxyacetylene)acetyl, 2-(1-octyl-4-pyridinio)diacetyl, 2-methoxyimino-2-(2-aminothiazol-4-yl)acetyl, 2-(tert-butoxycarbonylamino)-3-(1-octyl-4-imidazolyl)propionyl, 3-(4-octyloxyphenyl)acryloyl, 3,7,11-trimethyl-2,6,10-dodecatrien, tert-butoxycarbonyl, octyloxybiphenyl, phenoxycarbonyl, p-tamilselvan, 4-octyloxybenzophenone, 6-octyloxy-2-naphthylmethyl, 4-(tert-butyl)benzoyl, 4-octylbenzoic, 2,3,5,6-titrator-4-(2,2,3,3,4,4,5,5-octafluoropentyl)benzoyl, 4-(2-butoxyethoxy)benzoyl, 4-(4-phenylmethoxy)benzoyl, 4-octyloxybenzoic, 2-carboxy-4-octyloxybenzoic, 3-methoxy-4-octyloxybenzoic, 4-(2,2,3,3,4,4,5,5,6,6,7,7,8,8-pentadecafluorooctanoic)-2,3,5,6 - tetracarbonyl, 4-(4-activational)benzoyl, 4-(4-octyloxyphenyl)benzoyl, 6-butoxy-2-naphtol, 6-hexyl-hydroxy-2-naphtol, 6-octyloxy-2-naphtol, 6-(2-ethylhexyloxy)-2-naphtol, 6-decyloxy-2-naphtol, 6-(3,7-dimethyloctyl)-2-naphtol, 6-dodecyloxy-2-naphtol, 6-(3,7-dimethyl-6-octenoate)-2-naphtol, 6-(3,7-dimethyl-6-octadecanoyloxy)-2-naphtol, and 2-anticarbon, 4-(4-heptyloxybiphenyl)-benzoyl and 4-(4-hexyloxyphenyl)benzoyl.

Suitable acyl group, excluding palmoil" can the right functional group "ar(lower)alkanoyl" in "ar(lower)alkanoyl, which has higher alkoxy group and a protected amino group, and "ar(lower)alkanoyl, which has higher alkoxy group and a protected amino group may be the same as shown in the example for the "acyl group" and suitable examples of the Deputy (deputies) of "higher alkoxy" and "protected amino group" may be the same as those listed as examples of "acyl group".

Suitable "halogen(lower)alcoolica group" may be the same as shown in the example for the "acyl group".

Suitable "pyridylthio(lower)alkanoyl" pyridylthio(lower)alkanoyl, which may have higher alkyl" can be the same as shown in the example for the "acyl group", and suitable examples of the substituent of "higher alkyl" can be the same as those listed as examples of "acyl group".

Suitable "acyloxy group" may include hydroxysulfonic, phosphonooxy etc.

The target compound (1), marked thus, especially preferred is the following connection /1h/.

,

in which R1is a hydrogen atom or acyl group, provided that R1is not Palmitoyl.

Among the compounds (V) are new the following substances

.

(V-I) or its reactive derivative at the carboxy group or its salt

.

(V-2) or its reactive derivative at carboxypropyl, or its salt

in which R6is lower alkoxy, higher alkoxy group, or the highest alkenylamine group, R7is a group-COOH or SO3H, R8complies with 1-4 halogen atoms, R9- higher alkoxy group which has one or more halogen atoms, a lower alkoxy group which has one or more halogen atoms.

Substance (V-1) and (V-2) can be obtained in the following ways:

Method B

.

(VI) or its salt (VII) or its salt (V-1) or its salt

The method C

.

(VIII) or its salt (IX) or its salt (Y-2) or its Vlaamse lower alkyl, higher alkyl or higher alkenyl, R11is lower alkyl which has one or more halogen atoms, or tertiary alkyl which has one or more halogen atoms, and each X and Y is tsepliaeva group.

In the above definitions, appropriate groups of lower alkoxy, higher alkoxy", "upper alkenylacyl", "halogen atom", the "lower alkyl" and "higher alkyl" can be such as described above, as an example.

Suitable "higher alkenylamine group" may include 3-heptenyl, 7-octenyl, 2,6-octadiene, 5-nonanol, 1-decenyl, 3,7-dimethyl-6-octenal, 3,7-dimethyl-2,6-octadienal, 8-undecenyl, 3,6,8-dodecatrien, 5-tridecanol, 7-tetradecene, 1,8-pentadecatriene, 15-hexadecanyl, 11-heptadecanol, 7-octadecenyl, 10-nonadecane, 18-ecosoil, etc., in which the preferred groups can be (C7-C16)alkenyl.

As for the radical R9, the "lower alkoxy group" is one or more (preferably 1-10) of atoms of halogen and "higher alkoxy group has one or more (preferably 1-17, more preferably 12-17) halogen atoms.

As for the radical R11, "lower alkyl" has one or more (preferably 1 to 10, is preferably 12-17) halogen atoms.

As for R6preferred "lower alkoxy group" may be (C4-C6)alkoxy.

Suitable "tsepliaeva group" may include the above-mentioned halogen atom, a lower alkanoyloxy group (such as acetoxy and others ), sulfonyloxy (for example, mesilate, tosyloxy and others), etc.

With regard to suitable salt or reactive derivative at the carboxy group of the compounds (Y-1) and (Y-2), it can be the same as specified in example for compound (V) below.

The reaction in method B and C can be carried out according to methods which are disclosed below in the preparative part of the application, or similar methods.

In the compound (V) there are other new substances, which differ from the compounds (Y-1) and (Y-2), and they can be prepared, for example, using the methods disclosed in the preparative part.

Suitable "peridition" in method 4 may include 1,2-dihydropyridin-2-tion, 1,4-dihydropyridines-4-tion, etc., and specified "peridition" may have referred to "higher alkyl".

The methods of preparation of the target compounds (1) or its salt in the invention are explained in detail below.

Method 1

The target compound (1a) or its salt is dust.

This reaction is carried out in accordance with a conventional method such as hydrolysis, reduction, interaction with the enzyme or the like.

The hydrolysis is preferably carried out in the presence of a base or acid, including Lewicowy acid. Suitable base may include an inorganic base and organic base, such as alkali metal (e.g. sodium, potassium, and others), alkaline earth metal (e.g. magnesium, calcium, and others ), their hydroxides, carbonates or bicarbonates, trialkylamine (for example trimethylamine, triethylamine, etc. ), picoline, 1,4-diazabicyclo-(2,2,2)octane, 1,5-diazabicyclo(4,3,0)but-5-ene, 1,8-diazabicyclo-(5,4,0)undec-7-ene, or etc.

Suitable acid may include an organic acid (e.g. formic, acetic, propionic, trichloroacetic, triperoxonane and others) and inorganic acid (e.g. hydrochloric, Hydrobromic acid, sulfuric, hydrogen chloride, hydrogen bromide, and others). When elimination using a Lewis acid such as troglodytella acid (e.g. trichloroacetic, triperoxonane and others) or the like, the reaction is preferably conducted in the presence of agents-acceptors cations uh, naprimer (for example methanol, ethanol and other), methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which has no adverse effect on the reaction. The solvent can also be used in a liquid base or acid. The reaction temperature is not critical and the reaction is usually carried out under conditions of cooling or heating.

The recovery method that is applicable for the elimination reaction may include chemical reduction and catalytic reduction.

Suitable reducing agents which may be used in chemical reduction are a combination of metals (such as tin, zinc, iron and others) or compound of the metal (e.g. chromium chloride, chromium acetate, and others) and organic or inorganic acid (e.g. formic, acetic, propionic, triperoxonane, para-toluensulfonate, hydrochloric, Hydrobromic acid and others).

Suitable catalysts that can be used in catalytic reduction are conventional catalysts such as platinum catalysts (for example in the form of a plate, spongy platinum, platinum mobile, colloidal platinum oxide is, XID palladium, palladium on charcoal, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, and others), Nickel catalysts (e.g restored Nickel, Nickel oxide, Raney Nickel, etc.), cobalt catalysts (e.g recovered cobalt, Raney cobalt and others ) iron catalysts (e.g. reduced iron, Raney iron, and others), copper catalysts (e.g recovered copper, Raney copper, copper of Ullman and others), etc.

The restoration carried out in a conventional solvent which does not exert any harmful effects on the course of the reaction such as water, methanol, ethanol, propanol, N,N-dimethylformamide or mixtures thereof. In addition, in the case, when the above-mentioned acids used in chemical reduction are liquids, they can also be used as solvents. Hereinafter used in the catalytic reduction of a suitable solvent, may be mentioned solvent and other conventional solvent such as diethyl ether, dioxane, tetrahydrofuran, etc. or a mixture thereof.

The temperature of this reaction recovery is not critical and the reaction can be carried out while cooling or heating the Oli enzyme which are suitable for the reaction of elimination of the N-acyl group.

Suitable example of this enzyme may include an enzyme produced by some microorganisms Actinoplanes, for example, Actinoplanes utahensis ADS 12301, Actinoplanes missouriensis NRRL 12053, etc; etc.

Typically, this elimination reaction is carried out in a solvent such as phosphate buffer, the buffer is Tris-HCl, or any other solvent which does not exert adverse influence on the reaction. The reaction temperature is not critical, and the elimination can be carried out at a temperature from room temperature up to high.

Method 2.

The target compound (1b) or its salt can be prepared by bringing the compound (1) or its salt in the reaction of acylation.

The acylation reaction of this method can be carried out by reacting the compound (1a) or its salt with the above-mentioned "allermuir agent, for example with compound (V) or its reactive derivative or a carboxy group, or its salt.

Suitable reactive derivative at the carboxy group of compound (V) may include an acid halide, acid anhydride, activated AMI is to be an acid chloride; azide acid; a mixed acid anhydride with an acid such as substituted poorna acid (for example dialkylphosphinate acid, phenylphosphine acid, diphenylphosphoryl acid, dibenzylamine acid, halogenated phosphoric acid, and others ), dialkylphosphorous acid, sulfurous acid, tisera acid, sulfuric acid, sulfonic acid (e.g. methanesulfonate acid and others), aliphatic carboxylic acid (e.g. acetic, propionic, butyric, somalina, trimethylhexane acid, pentane acid, isopentane acid, 2-ethylmalonate acid, trichloroacetic acid, and others); or aromatic carboxylic acid (e.g. benzoic acid and others); or symmetrical anhydride of the acid; amide, activated imidazole, 4-substituted imidazole, dimethylpyrazole, triazole, tetrazole or 1-hydroxy-1H-benzotriazole; or an activated ester (such as complex cinematology ether complex methoxymethyl ether, dimethylaminomethylene /(CH3)2= CH-/ ester, vinyl ester, propargilovyh, p-nitrophenyloctyl, 2,4-dinitrophenoxy, trichloranisole, pentachlorphenol, methylphenylamine, phenylazophenyl ether complex penaltiesfor, slo is Il, pyridyloxy ester, piperidinyl ether complex tiefer 8-quinoline and others), or an ester with N-hydroxidealuminum (for example N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridine, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole and others), etc., These reactive derivatives can be optionally selected from those listed in accordance with the type of compound (V).

Suitable salts of the compounds (V) and its reactive derivative can be those that are given as an example for compound (1).

This reaction is usually carried out in a conventional solvent such as water, alcohol (for example methanol, ethanol, and others) acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine or any other organic solvent which does not exert any harmful effects on the course of the reaction. These traditional solvents can also be used in mixture with water.

In this reaction, when the compound (1) is used in the form of the free acid or in the form of its salts, then preferably the interaction is carried out in the presence of a conventional condensing Agay is monocyclohexyl)carbodiimide; N,N-diethylcarbamoyl, N,N-diisopropylcarbodiimide; N-ethyl-N-(3-dimethylaminopropyl)carbodiimide, N,N-carbonylic-(2-methylimidazole); pentamethylene-N-cyclohexylamine; dioiketes-N-cyclohexylamine; ethoxyacetylene; 1-alkoxy-1-chlorethylene; trialkylphosphine; tiliaefolia; isopropylmyristate; phosphorus oxychloride (chlorine phosphoryl); trichloride phosphorus; thionyl chloride; oxacillin; lower alkylsulfonic (for example, ethylchloride, isopropylcarbamate and others); triarylphosphine; salt of 2-ethyl-7-hydroxybenzotriazole; salt intramolecular 2-ethyl-5-(m-sulfenyl) isoxazoline hydroxide; 1-(p-chlorobenzenesulfonate)-6-chloro-1H-benzotriazol; the so-called reagent of Vilsmeier obtained by the interaction of N, N-dimethylformamide with chloride tiomila, phosgene, trichloromethylcarbonate, phosphorus oxychloride, methanesulfonamido and others; or etc.

This reaction can also be carried out in the presence of inorganic or organic bases such as carbonate, alkali metal bicarbonate, alkali metal, three (lower)-alkylamino, pyridine, di(lower)alkylenediamine (for example 4-dimethylaminopyridine and others ), N-(lower)alkalifying, N, N-(lower)alkylbenzenes etc.

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Method 3:

The target connection /Id/ or its salt can be prepared by involving connections /Ic/ or its salt to elimination reaction aminoamide group.

Suitable salts of the compounds /Ic/ and /Id/ can be those as indicated for example for compound (I).

This elimination reaction can be carried out in accordance with the traditional method, as explained in process 1.

Method 4.

Target connection /If/ or its salt can be prepared by reaction of compounds /Iee/ or its salt with the compound (III or its salt.

Suitable salt of the compound /If/ can be the same as specified in example for compound (1).

Suitable salt of the compound (III) may be the same additive salt of the acid, as indicated as an example for compound (I).

This interaction can be carried out in a solvent, such as water, phosphate buffer, acetone, chloroform, acetonitrile, nitrobenzol, methylene chloride, ethylene dichloride, formamide, N, N-dimethylformamide, methanol, ethanol, diethyl ether, tetrahydrofuran, dimethylsulfoxide or any other organic solvent which does not okazyvaetsa-hydrophilic can be used in a mixture with water. When the compound (III) is a liquid, it can also be used as solvent.

Preferably the reaction is carried out in the presence of a base, for example, inorganic bases such as hydroxide of alkali metal carbonate, alkali metal bicarbonate, alkali metal organic bases, such as trialkylamine, etc.

The reaction temperature is not critical, and the interaction can be carried out under cooling, at room temperature, when heated or boiled.

This interaction is preferably carried out in the presence of alkali metal halide (e.g. sodium iodide, potassium iodide, and others), thiocyanate of an alkali metal (such as thiocynate sodium, potassium thiocyanate, etc. or etc.

Method 5.

The target connection /Ig/ or its salt can be obtained by inclusion of the compound (IV) whether its salts in the reaction of acylation.

Suitable salts of the compounds /Ig/, and (IV) can be the same as those listed as examples for the substance (I).

Suitable "allermuir agent" in Method 5 may be acid compound corresponding to the acyl group to be introduced, the Naya acid and its derivatives (for example, complexes of sulfur trioxide and pyridine, sulfur trioxide and three(lower)alkylamine (e.g. trimethylamine, triethylamine, etc.), chlorosulfonic acid, etc. or etc.

This reaction can be conducted in the traditional way.

The method of obtaining the starting compound (II) or salts thereof are explained below in the description.

Method A.

The compound (II) or its salt according to this invention can be obtained by fermentation in a nutrient medium strains belonging to the genus of Coleophora and producing the compound (II) or its salt, for example the type of Coleophora F-11899.

The microorganism.

Features of the microorganism used for the production of compound (II) or its salt, as discussed below.

The strain F-11899 was originally extracted from a soil sample collected in the town of Iwaki, district, Fukushima, Japan. This organism grew quite limited in various cultural environments and formed colonies from dark gray to brownish-gray color. Anamorph (conidiomata) produced on the segment of the sheet, sterilized by steam, and is attached to the LCA plate Miura, /I/ or on agar plate made of corn flour, although agar environment which the cultural and physiological characteristics, summarised in table. 1.

Culture on agar potato dextrose grew quickly, reaching 3.5 to 4.0 cm in diameter after 2 weeks at 25oC. the Surface of the colony was flat, much is omitted, partly wrinkled and brownish-gray. The center of the colony was yellowish-gray (to brownish-gray in color and was covered serialname the hyphae. The reverse side was dark gray. Colonies on malt extract agar grew more limited. Colonies on malt extract agar grew more limited, reaching about 2.5-3.0 cm in diameter under the same conditions. The surface was flat, slightly lowered and olive-brown. The center of the colony was yellowish-gray and covered serialname the hyphae. The reverse side was a brownish-gray.

Morphological characteristics were determined on the basis of cultures in sterilized sheet attached to the LCA plate Miura. Clonidime were formed only on the segment of the sheet. They were the jug-shaped, surface, single, had a shape from discoid to ambulatornoi, flattened at the base, unilocular, thin-walled, black; had a diameter of 90-160 (-200) µm and a height of 40-70 microns. Pores were often single, round, Central and Patrick "jug". They were hyaline, simple or rarely branched, divided by partitions and smooth. Conidiogenous cells were enterolactone, fieldname, deterministic, was shaped from pear-shaped to ampoule-shaped, hyaline, smooth, size 5-8x4-6 ám collarette. Collarette were a bell (to a cylindrical shape with dimensions of 14-h-5 μm. Conidia were hyaline, cylindrical, thin-walled, without septa, smooth, with sizes 14-16(-18)x2-3 μm.

The strain F-11899 grew in a temperature range from 0 to 31oC, and the optimal temperature from 23 to 27oC on agar potato dextrose.

Given the characteristics of the strain F-11899 belongs to a group of Coelomycetes /1-4/. Thus, we named this strain Coelomycetes strain F-11899".

Named thus culture Coelomycetes strain F-11899, was deposited on October 26, 1989 Research Institute of fermentation, the Agency of industrial science and technology (1 to 3, Higashi 1-Chom, , Tsukuba, etc. Ibaraki 305, Japan) under number FEEM BP-2635.

However, after that, we studied an additional classification of the strain F-11899, and found that this strain reminds Toleafoa empetri (Rotw" globose or flattened at the base, shipped without papillata.

After discussing these characteristics, classified this strain in more detail and renamed it to "Coleophora, type F11899".

In this regard, we have taken steps to change the name "Coelomycetes strain F11899 on Coleophora, type F11899, September 21, 1990 at the Research Institute of fermentation, the Agency of industrial science and technology.

Production of compound (II) or its salt.

In this invention the compound (II) or its salt obtained when the strain belonging to the genus of Coleophora, produces the compound (II) or its salt in a nutrient medium containing a source of assimilable carbon and nitrogen under aerobic conditions (such as shake culture, submerged culture, and others).

The preferred sources of carbon in the nutrient medium are carbohydrates such as glucose, sucrose, starch, fructose or glycerol, or etc.

The preferred sources of nitrogen are yeast extract, peptone, gluten meal, crushed cotton seeds, soy flour, syrup from corn stalk, dried yeast, wheat germ, and others, as well as inorganic and organic nitrogen compounds such as ammonium salts (napta preferred sources of carbon and nitrogen are used in combination, there is no need for their use in pure form, as materials with a lesser degree of purification, which contain traces of growth factors and considerable quantities of mineral nutrients, also suitable for use.

If desired, they can be added to the medium mineral compounds, such as carbonates of sodium or calcium, phosphate, sodium or potassium, chlorides of sodium or potassium iodide, sodium or potassium, salt, magnesium, copper, zinc or cobalt, or etc.

If necessary, especially when the cultural environment intensively foam, you can add anti-foam agent, such as liquid paraffin, fatty oil, vegetable oil, mineral oil, or silicone, or etc.

As in the case of the preferred methods used for the production of other biologically active substances in large quantities for the production of compound (II) or its salt in large quantities are preferred submerged aerobic cultivation conditions.

For production in small quantities are used culture with shaking or surface in flasks or bottles.

In addition, when the cultivation is carried out in large takach, preferred the button to avoid latent period in the production process of the compound (II) or its salt. Accordingly, it is advisable to get a vegetative inoculum of the organism by inoculation of a relatively small quantity of culture medium with spores or mycelium organism and cultivation specified inoculated environment, and then to transfer the cultured vegetative inoculum in large containers. The environment in which is formed the vegetative inoculum is almost the same as the environment used for the production of compound (II) or its salt, or different from that environment.

Mixing and aeration of the culture mixture can be carried out in a variety of ways. Agitation may be provided by a propeller or similar mechanical peremeshivaemogo equipment by rotating or shaking the fermenter, using different transfer equipment, or by passing sterile air through the medium. Aeration can be carried out by passing sterile air through the fermentation mixture.

Typically, fermentation is carried out at a temperature between about 10 and 40oC, preferably 20 - 30oC, over a period of about 50 to 150 hours, which may vary in accordance with USLOVIE is directed to the extraction of compound (II) or its salt using various techniques, traditionally used for extraction and purification of biologically active substances. for example, extraction with appropriate solvent or a mixture of several solvents, chromatographytandem or recrystallization from an appropriate solvent or mixture of several solvents, or etc.

In accordance with the invention, in General, the compound (II) or its salt found in the cultured mycelium, teak and in the culture broth. Respectively, then the compound (II) or its salt are removed from the whole broth by extraction with a suitable organic solvent, such as acetone or ethyl acetate, or mixtures of these solvents, or etc.

The extract is treated in the traditional way, to obtain the compound (II) or its salt, for example the extract is concentrated by evaporation or distillation to a smaller volume and the resulting residue containing the active material, i.e. the compound (II) or its salt, is cleaned by conventional cleaning methods, for example, chromatography or recrystallization from a suitable solvent or mixture of such solvents.

When the target substance is released in the form of a salt soy methods.

Biological properties of the polypeptide compound (I) of the present invention

In order to demonstrate the usefulness of the polypeptide compound (I) sets out some of the biological data representative substances.

Test 1. Antimicrobial activity.

Antimicrobial activity of the substance of example 2 disclosed below (in the following it is referred to as substance FR 131535), was measured by the method of microrasbora broth in multitrack with 96 cells using primary dextrose medium and nitrogen from yeast. To 50 μl of the sample solution with serial twofold dilution add 50 μl of the suspension of microorganisms in saline to obtain a final concentration of 1 to 105forming a colony units per 1 ml Culture Candida was cultured at 37oC for 22 h After cultivation was determined by the growth of microorganisms in each cell, measuring the turbidity. The results are presented as values IC50in which the concentration turbidity was half the value of the turbidity in the cell without the sample. The results are presented below.

The body - IC50< / BR>
Candida albicans FR578 - 0,31

Candida trophy is 1535 identified in mice IPC (females, age 4 weeks) by a single intravenous injection. When the Doge 500 mg/kg did not observe any symptoms of toxicity.

Test 3. Antimicrobial activity of 2.

Antimicrobial activity of the substance of example 12, the disclosed below (in the following referred to as substance FR 139687), defined outside the body through a twofold dilution method on agar plate, as described below.

One loop of culture, which is done during the night, for each test microorganism in the broth Sabouraud containing 2% Glucose (105/ml of viable cells) was shaken on the basis of dextrose agar with nitrogen from yeast (Y WDA) containing a given concentration of a substance FR139687 and minimum inhibitory concentration MIC) was expressed in units of μg/ml after cultivation at 30oC for 24 h

The body - MIC, mcg/ml

Candida albicans YU-1200 - 0,05

In table. 2 and 3 shows the results of the tests described compounds. In table. 2 - antimicrobial activity, in table.3 - effect against infections caused by Candida Albicans.

From the test result it is clear that the polypeptide compound (I) has antimicrobial activity (especially proteome pharmaceutical drug, for example, in solid, semisolid, or liquid form. This product contains the polypeptide compound (I) or its pharmaceutically acceptable salt, as an active ingredient in a mixture with an organic or inorganic carrier or medium for medicines for rectal, pulmonary (nasal or buccal injection), nasal, ocular, external (topical), oral or parenteral (including subcutaneous, intravenous and intramuscular) the appointment or injection.

Capsules containing 100 mg of the compound of example 2

Ingredient - Qty mg capsule

Connection - 100

Lactose - 146

Magnesium stearate - 4

Capsule (n 1) - 250

Connection with neutral components are crushed into powder, mixed and placed in a dry gelatin capsules.

Tablets

Ingredient - Qty mg capsule

Connection example 2 - 150

Pregelatinized corn starch - 60

Polyvinylpyrrolidone - 36

Magnesium stearate - 4

The connection is finely pulverized and mixed with a powdered inert ingredients according to the recipe, and then pressed into tablets using standard hardware.

The active ingredient may be compounded, for example, the MOU of rastrac, aerosols, powders for injection, solutions, emulsions, suspensions, and any other form suitable for use. And, if necessary, also can be used auxiliary, stabilizing, thickening and coloring agents and perfumes. The polypeptide compound (I) or its pharmaceutically acceptable salt are included in the pharmaceutical composition in amounts sufficient to provide antimicrobial action in the course of the disease or morbid condition.

To apply the composition to the people it is preferable to use intravenous, intramuscular, pulmonary, or oral or by injection. While the dosage of therapeutically effective amount of the polypeptide of the substance (I) is changed and, in addition, depends on the age and condition of each individual patient, be extracted, in the case of intravenous destination daily dose of the polypeptide of the substance (I) is 0.01 - 20 mg per 1 kg of weight of the person; in the case of intramuscular administration, a daily dose of substance (I) is 0.1 - 20 mg per 1 kg of weight of the person and in the case of oral daily destination Doha is 0.5 - 50 mg of the compound (I) per 1 kg of weight of the person. This number is normally set for Leche is ustrali of the invention in more detail.

Preparative example 1. The methanol /50 ml/ -5oC was added chloride thionyl /8,73 ml and the resulting mixture was stirred for 10 minutes and then cooling systems ice was added 5 g of D-2-/p-hydroxyphenyl/glycine. The resulting mixture was stirred for 12 hours at room temperature. The reaction mixture is evaporated under reduced pressure with the formation of methyl ester hydrochloride, d-2-/p-hydroxyphenyl/-glycine /6.3 g/.

IR /Nuol/: 3380, 1720, 1580, 1250 cm-1< / BR>
NMR /DMCO-d6, /: 3,70 /3H, singlet/, 5,11 /1H, singlet/, 6,83 /2H, doublet, J=8.6 Hz/, 7,28 /2H, doublet, J=8.6 Hz/, 8,91 /2H, singlet/, to 9.93 /1H, singlet/.

Preparative example 2. To a solution of methyl ester hydrochloride, D-2-/p-hydroxyphenylglycine /6.3 g/ triethylamine /8,71 ml/ tetrahydrofuran /100 ml) was added di-tert-butyl dicarbonate /6,82 g/. The mixture was stirred for 2 hours at room temperature. The reaction mixture was added to diethyl ether /1 l/ and undissolved material was filtered, then the filtrate is evaporated under reduced pressure with the formation of methyl ester of N-/tert-butoxycarbonyl/-D-2-/p-hydroxyphenyl/glycine/6,83 g/.

IR /Nuol/: 3420, 3350, 1720, 1660 cm-1.

NMR /DMCO-d6, /: 1,38 /9H, singlet/, 3,59 /3H, SYN">

Preparative example 3. To a suspension of methyl ester of N-/tert-butoxycarbonyl/-D-2-/p-hydroxyphenyl/glycine /6.7 g/ potassium bicarbonate /1.84 g/ N, N-dimethylformamide /34 ml) was added bromide octyl /4,176/ ml. The mixture was stirred for 6 hours at 60oC. the Reaction mixture was added to a mixture of water with ethyl acetate. The organic layer was separated and dried over magnesium sulfate. The magnesium sulfate was filtered and the filtrate evaporated under reduced pressure with the formation of N-/tert-butoxycarbonyl-D-2/p-octyloxyphenyl/glycine, methyl ester /of 6.96 g/.

IR/Nuol/: 1710, 1490, 1240, 1160 cm-1.

NMR /DMCO-d6, /: 0,859 /3H, triplet, J=6.2 Hz/, of 1.17 and 1.33 /10H, multiplet/, 1,38 /9H, singlet/, 1,60-1,80 /2H, multiplet/, 3,59 /3H, singlet/, 3,93 /3H, singlet/ 3,93 /2H, triplet, J=6.3 Hz/, 5,11 /1H, doublet, J=7.9 Hz/, 6,87 /2H, doublet, J=8.7 Hz/, 7,27 /2H, doublet, J=8.7 Hz/, 7,68 /1H, doublet, J=7.9 Hz/.

Preparative example 4. To aqueous solution of sodium hydroxide /8,77 ml) was added methyl ether N-/tert-butoxycarbonyl/-D-2/p-octyloxyphenyl/glycine /6,9 g/ and the mixture was stirred for 1.5 hours at room temperature. The reaction mixture was added to a mixture of water with ethyl acetate and was added 1N. hydrochloric acid to establish a pH of the mixture is equal to 3. The organic layer is about is the t with the formation of N-/tert-butoxycarbonyl/-D-2/p-octyloxyphenyl/glycine /3,9 g/.

NMR /DMCO-d6, /: 0,860 /3H, triplet, J=6,8 Hz/, of 1.17 and 1.33 /10H, multiplet/, 1,38 /9H, singlet/, 1,60 - 1,80 /2H, multiplet/, 3,93 /2H, triplet, J=6 Hz/, 5,10 /1H, doublet, J=8,2 Hz/, 6,87 /2H, doublet, J=8.7 Hz/, 7,28 /2H, doublet, J=8.7 Hz/, 7,46 /1H, doublet, J=1,82 Hz/.

Preparative example 5. To a solution of N-/tert-butoxycarbonyl/-D-2-/p-octyloxyphenyl/glycine /1 g/ acetonitrile /10 ml) and pyridine /0,213 ml/ acetonitrile /10 ml) was added N, N-disuccinimidyl carbonate /0,675 g/. The resulting mixture was stirred 12 hours at room temperature. The reaction mixture was added to a mixture of water with ethyl acetate. The organic layer is evaporated and dried over magnesium sulfate. The magnesium sulfate was filtered and the filtrate evaporated under reduced pressure to obtain operations ether N-/tert-butoxycarbonyl/-D-2/p-octyloxyphenyl/glycine. /0,92 g/.

IR/Nuol/: 3350, 1810, 1730, 1680 cm-1.

NMR /DMCO-d6, /: 0,862 /3H, triplet, J=6,7 Hz/, of 1.17 and 1.33 /10H, multiplet/, 1,40 /9H, singlet/, 1,60-1,80 /2H, multiplet/, 2,77 /4H, singlet/, 3,97 /2H, triplet, J=6,5 Hz/, 5,54 /1H, doublet, J=8,1 Hz/, 6,91 /2H, doublet, J=8.7 Hz/, 7,39 /2H, doublet, J=8.7 Hz/, 8,05 /1H, doublet, J=8,1 Hz/.

Preparative example 6. Methyl ester of N-/tert-butoxycarbonyl/-I-tyrosine was obtained according to the same method as described in preparative example 2.

59 /3H, the singlet/, 4,05 /1H, multiplet/, 6,65 /2H, doublet, J=8,4 Hz/, 7,00 /2H, doublet, J=8,4 Hz/, 7,21 /1H, doublet, J=8.0 Hz/, which 9.22 /1H, singlet/.

Preparative example 7. Methyl ester of O4-octyl-N/tert-butoxycarbonyl/-I-tyrosine was obtained according to a method similar to that described in preparative example 3.

IR /Nuol/: 3350, 1735, 1685, 1250, 1170 cm-1.

NMR /MDCO-d6, /: 0,859 /3H, triplet, J=6,7/, 1,20-1,30 /10H, multiplet/, 1,68 /2H, quintet, J=7,3 Hz/, 2,82 /2H, multiplet/, 3,60 /3H, singlet/, 3,91 /2H, triplet, J=7,3 Hz/, 4,08 /1H, multiplet/, for 6.81 /2H, doublet, J=6,8 Hz/, 7,12 /2H, doublet, J=8.6 Hz/, 7,25 /1H, doublet, J=8.0 Hz/.

Preparative example 8. O4-octyl-N/tert-butoxycarbonyl/-I-tyrosine was obtained according to a method similar to that described in preparative example 4.

IR /Nuol/: 3400-2900 /wide/, 1700, 1240, 1160 cm-1.

NMR /DMCO-d6, / 0,859 /3H, triplet, J=6,8 Hz/, 1,20-1,30 /10H, multiplet/, 1,32 /9H, singlet/, 1,68 /2H, Quintet, J=7,0 Hz/, 2,67-2,95 /1H, multiplet/, 3,90 /2H, triplet, J=7,0 Hz/, 4,01 /1H, multiplet/, for 6.81 /2H, doublet, J=8.6 Hz/, 7,02 /1H, doublet, J=8,3 Hz/, 7,13 /2H, doublet, J=8.6 Hz/.

Preparative example 9. Operations ether 04-octyl-N/tert-butoxycarbonyl/-1-tyrosine was obtained according to a method similar to that described in preparative example 5.

the multiplet/, 1,32 /9H, singlet/, 1,68 /2H, quintet, 1=7,0 Hz/, 2,82 /4H, singlet/, 2,80 - 3,20 /1H, multiplet/, 3,92 /2H, triplet, 1=7,0 Hz/, of 4.44 /1H, multiplet/, for 6.81 /2H, doublet, 1=8,5 Hz/, 7,22 /2H, doublet, 1=8,5 Hz/, 7,60 /1H, doublet, 1=8,3 Hz/.

Preparative example 10. /1/ the Sowing medium /160 ml/, containing 4% sucrose, 2 flour cottonseed, 1% of dried yeast, 1% peptone, KH2PO4/2%/, 0,2% CaCO3and tween 80 /manufactured Nakarai Camels Ltd./ poured into each of two Erlenmeyers flasks with a capacity of 500 ml and sterilized for 30 min at 121oC. Full loop of culture on the sloped agar varieties Coloephoma G-11899 was inoculable in each of the environments and were cultured in shaking for 4 days at 25oC.

Productional environment /20 l/ containing 3% pine code /3/, manufactured by Matsutani Kemikl Ltd./, 1% glucose, 1% wheat embryos, 0.5% of the flour cottonseed, 2% KH2PO4of 1.5% Na2HPO40.01% of ZnSO47H2O and 0.05% Adekanola /anti-foam agent manufactured by Asahi Denka To. Ltd./ poured into a 30-liter fermenter and sterilizable for 30 min at 121oC.

The resulting seed culture broth /320 ml/ inoculable in production medium and cultured at 25oC is atom kulturarena broth /20 l/ added equal volume of acetone. After optional stirring at room temperature broth was filtered. The filtrate was concentrated in vacuo to remove acetone. The aqueous filtrate /10 l/ washed two equal volumes of ethyl acetate and was extracted twice with n-butanol /10 l/. The combined n-butanolic layer was concentrated in vacuum and the residue was applied to column /300 ml/ silica gel 60/ obtained from E. Merck/ after etogo was carried out by elution with a mixture of organic solvents consisting of dichloromethane and methanol. Fractions with anti-candidas activity was suirable in the range of a solvent mixture of 3: 1 to 1:1. Active fractions were combined and concentrated in vacuum to dryness. The residue was dissolved in 50% aqueous methanol /15 ml and passed through a column /250 ml/ ML of SMC THIS /produced by Yamamura Kemikl lab./. The column was washed with 50% aqueous methanol and was suirable 80% aqueous methanol. The eluate was concentrated and optionally purified by the method of distribution chromatography on a centrifuge /CDS/ using system n-butanol: methanol:water /4:1:5/ as the upper stationary phase and the lower mobile phase in sequential mode. Combined fractions containing the target compound /the main component of the/the ol:acetic acid:water /6:1:1/. Active fractions were combined and concentrated in vacuum to dryness and dissolved in a small volume of 50% aqueous methanol. The solution was passed through a column /3.5 ml/ ML of SMC Cel. This column was washed with 50% aqueous methanol and was suirable the same solvent. The eluate was concentrated to dryness, dissolved in a small volume of water and have established a pH equal to 7.0 with the help of 0.01 N. NaOH. The solution was dried by freezing to the formation of white powder Ukhanova connection in the form of its sodium salt /which is hereinafter referred to as substance FR 901379 //II mg/.

The compound obtained FR 901379 has the following physico-chemical properties.

Appearance: white powder. Nature is neutral connection. The melting point: 215 - 221oC /colour / div./. Specific rotation: (a)2D3= -20,3 /C: 0.5, AND H2O/.

Calculated, %: C 51,17; H 6,77; N 9,36; S 2,68.

C51H81N8SO21Na.

Found, %: C 49,61; H 7,58; N 7,65; S 2,14/%/.;

mol/m : HPFAB-M 1219, 5078 /calculated for C51H82N8SO21+ 2Na - H: 1219, 5032/;

solubility: soluble: methanol, water, partly soluble: eteltetet; acetone; insoluble: chloroform, n-hexane;

Color reaction: positive: reaction with steam is the action of Dragendorf, the reaction of Ehrlich.

Thin-layer chromatography /TCX/ are given in table. 4.

UV spectrum: methanemaxol(E1%1Cm) : 207 /169/; 276 /13,5/, 225 /sh/, 283 /sh/ nm.

methanemaxol+0,01-NaOH(E1%1Cm) : 209 /232/; 244 /59,5/, 284 /13,5/, 294 /sh/ nm.

IR-spectrum:KBmACA.3350, 2920, 2840, 1660, 1625, 1530, 1510, 1435, 1270, 1240, 1070, 1045, 800, 755, 710 cm-1.

Range1H-NMR /CD3OD, 400 MHz / : 7,30 /1H, doublet, J=2 Hz/, 7,03 /1H, doublet, J= Hz/, 7,03 /1H, doublet, J-Hz/, 7,03 /1H, double doublet, J=8 and 2 Hz/, 6,85 /1H, doublet, J=8 Hz/, 5,23 /1H. doublet, J=3 Hz/, 5,06 /1H, doublet, J= 4 Hz/, 4,93 /1H, doublet, J=3 Hz/, 4,59 - 4,51 /3H, multiplet/, 4,47 - 4,34 /5H, multiplet/, 4,29 /1H, double doublet, J=6 and 2 Hz/, 4,17 /1H, multiplet/, 4,07 /1H, multiplet/, 3,95 - 3,89 /2H, multiplet/, 3,76 /1H, broad doublet, J=11 Hz/, 3,36 /1H, multiplet/, 2,75 /1H, double doublet, J=16 and 4 Hz/, 2,50 /1H, multiplet/, 2,47 /1H, double doublet, J=16 and 9 Hz/, 2,38 /1H, multiplet/, 2,21 /2H, multiplet/, 2,03 - 1,93 /3H, multiplet/, 1,57 /2H, multiplet/, 1,45 - 1,20 /24H, multiplet/, 1,19 /3H, doublet, J=6 Hz/, 1,08 /3H, doublet, J=6 Hz/, 0,90 /3H, triplet, J=7 Hz/.

From the analysis above, the physical and chemical properties, and additional research to identify the chemical structure was icanseeyou FR 901379 was removed by the reaction with the enzyme. Further, the elimination process is explained in more detail.

/1/ the Fermentation of Actinoplanes utahensis. =Enzyme used for the elimination of the N-icalneu group connection FR 901379, is produced by some microorganisms Actinoplanaceal, preferably, the microorganism Actinoplanes utahensis IFO-13244.

Stem culture of Actinoplanes Utahen IFO-13244 prepared and maintained on an agar slant. Full loop of culture on the sloped agar was inoculable in the sowing medium containing 1% starch, 1% glucose flour cottonseed, 0.5% peptone, 0.5% of soybean flour, and 0.1% CaCO3. Inoculated vegetative medium is incubated in a wide-mouthed Erlenmeyer the flask with a capacity of 225 ml at 30oC for 22 hours on a rotary shaking.

This incubated vegetative medium used for direct inoculation of production medium containing 2% sucrose, 1% powder of groundnuts, 0,12% K2HPO4, 0,05% KH2PO4and 0.025% MgSO47H2O. Inoculated production medium was fermentatively in the fermenter with a capacity of 30 l, 30oC for 80 hours of Fermentation medium was stirred conventional agitators at a speed of 250 rpm./min and aeronavali rate of 20 l/min Vegetative mycelium were collected from fermenter the mining N-acyl groups of the compounds of FR901379 as the source of enzyme.

/2/ terms of elimination

Connection FR901379 was dissolved in 0.25 M phosphate buffer /pH 6,5/ with a concentration of 0.9 mg/ml In 36 liters of solution was added to 2 kg per wet weight of washed mycelium Actinoplanes utahen IFO-13244. The reaction eliminowania was carried out at 37oC for 23 hours reducing the number of connections FR901379 and increase decelerating connection FR901379 /hereinafter in connection FR13303/ was measured by liquid chromatography high pressure /HPIC/ with speakers with a reversible phase. 30 g of compound FR901379 in the reaction mixture formed of 22.2 g of compound FR133303.

/3/ Selection of connection FR133303.

Described the reaction mixture was filtered using a filtration media. Mycelial residue on the filter is discarded. Thus obtained filtrate was passed through a column of activated angle /2 l/. the column was washed with 6 l of water and was suirable 12 l of 50% aqueous acetone. The eluate is evaporated in vacuo to remove acetone and then passed through a column /4 l/ s UMC GEI ODS-AM 120-50 /Yamamura Kemikl labs./ This column was rinsed with water and suirable 2% aqueous acetonitrile containing 50 M NaH2PO4. Over the course of the elution was monitored by analytical method HPIC using 4H2PO4at flow rate 1 ml/min with detection of the connection FR133303 in the ultraviolet region at a wavelength of 210 nm. The fractions containing FR133303, were combined and passed through a column of activated carbon /400 ml/. The column was washed with water and suirable 50% aqueous acetone. The eluate was concentrated in vacuo to remove acetone and liofilizirovanny with the receipt of 16.4 g FR133303 in the form of a white powder. Connection FR133303 had the following physicochemical properties:

Appearance: powder. Melting point: 150-160oC /colour / div./

Specific rotation: (a)2D4- 31,17oA /C:1,0, H2O/. Molecular formula: C35H51N8SO20Na.

Calculated, %: C 43,84; H Are 5.36; N Of 11.69; S 3,34.

C35H51N8SO2Na.

Found,%: C 41,14; H 5,74; N 10,88; S 3,10.

The solubility. Soluble in water; limited soluble in methanol; insoluble in n-hexane.

Color reaction: positive with iodine, the reaction with cerium sulfate, the Ninhydrin reaction. Negative: the reaction of MOLISA.

Thin-layer chromatography /TIC/ table. 5.

UV spectrum: 201 /340/, 273 /18/, 224 /sh/, 281 /sh/ nm.

(E1%1Cm) 207 /414/, 243 /122/, 292 /34/.

An NMR spectrum WITH13/ D2O, 100 MHz/ : 178,3 /singlet/, 175,9 /singlet/, 174,3 /singlet/, 174,2 /singlet/, 174,0 /singlet/, 171,8 /singlet/, is 171.3 /singlet/, 150,9 /singlet/, 141,5 /singlet/, RUR 134.4 /singlet/, 128,2 /doublet/, 124,5 /doublet/, to 120.3 /doublet/, 78,1 /doublet/, 77,0 /doublet/, 76,9 /doublet/, 76,6 /doublet/, 72,9 /doublet/, 72,8 /doublet/, 71,2 /doublet/ and 69.3 /doublet/, 69,2 /doublet/, 63,7 /doublet/, 60,1 /doublet/, 58,3 /doublet/, 54,7 /triplet/, 41,8 /triplet/, 39,7 /doublet/, 39,5 /triplet/, 33,5 /triplet/, 21,4 /quintet/, 13,3 /quintet/.

Was identified following the link structure FR133303:

.

Example 2. /1/ Solution of 4-hydroxybenzoic acid /19,2 g/ 10% NaOH /120 ml/ bury to 480 ml of dimethyl sulfoxide for 30 min, during which the temperature of the reaction mixture was controlled in the range of 30 - 40oC. After addition the solution was cooled to 17 - 20oC. To the solution for 30 min was bury 1-bromooctane /28,95 g/ and morals in the icy water /1200 ml and acidified with 40 ml conc. of hydrochloric acid. After intensive stirring for 1 h the resulting solid was removed by filtration and was dissolved in 60 ml of acetonitrile. The resulting solution was heated under reflux for 30 min and was stood overnight at room temperature with the formation of 4-octyloxybenzoic acid /13.8 g/ in the form of crystals /so pl. 96oC.

Calculated, %: C 71,97; H 8,86.

C15H22O3< / BR>
Found, %: C 71,30; H 8,89.

To a solution of 4-octyloxybenzoic acid /13.8 g/ diethyl ether /552 ml) was added 2,4,5-trichlorophenol /10,87 g/ and N,N-dicyclohexylcarbodiimide /11,37 g/. The resulting solution was stirred in nitrogen atmosphere for 18 hours at room temperature. The precipitate was removed by filtration and the filtrate was concentrated in vacuum. The residue was dissolved in petroleum ether and stood in a bath of ice water. The resulting crystals /15.2 g/ was filtered and dissolved in warm n-hexane /150 ml/. After maturation over night at room temperature, the resulting crystals were removed by filtration. The filtrate was concentrated to a oil which was purified by the method of column chromatography on silica gel using a mixture of the analysis for C21H23O3Cl3: Cl 24,75 found: Cl 24,05/.

To a solution of compound FR133303 /2,04 g/ in N,N-dimethylformamide /60 ml) was added 2,4,5-trichlorophenyl-4-octyloxybenzoate /2,04 g/ and 4-dimethylaminopyridine /0,283 g/. The resulting solution was stirred in the atmosphere for 15 hours To the solution was added 4-dimethylaminopyridine /0.20 g/ and the resulting mixture was stirred for another 24 h the Reaction mixture was stirred in water /600 ml/ and set pH equal to 6.0. The mixture is washed twice with equal volumes of ethyl acetate and concentrated to a volume of 30 ml. of the Concentrate is passed through a column /150 ml/ s DEAE-Cobra /Cl-form, manufactured by Toso/. The column was washed with 50% aqueous methanol and showed 50% aqueous methanol containing aqueous 1M solution of sodium chloride. The process was suirable controlled using the same system HPIC that described in example 1/3/ except that the concentration of acetonitrile in the solvent was 40%. The fractions containing the target compound were combined and evaporated in vacuo to remove methanol. In order to remove the salt solution was absorbed on a column /1 l/ s UMC GEI ODS-AM 120 - 50. The column was washed with water and suirable 30% aqueous acetonitrile. Eluent evaporated in vacuum to remove the acetone is powder.

Connection FR131535 had the following physicochemical properties:

Appearance: white powder. Melting point: 170 - 189oC /colour / div./

Specific rotation: (a)2D0- 14.4VoC /C: 10, H2O/; molecular formula: C50H71N8SO22Na.

Calculated, %: C 46,22; H 6,44; N 8,62; S 2,46; Na 1.77 In.

C50H71N8SO22Na 6H2O.

Found, %: C 46,80; H 7,13; N 8,78; S 1,96; Na Is 1.81.

Solubility: soluble in methanol, water; sparingly soluble in acetone; insoluble in n-hexane.

Color reaction: positive: reaction with iodine, the reaction with sodium sulfate.

Thin-layer chromatography /TCl/ table.6.

The infrared spectrum,KBmACA.: 3330, 2900, 2850, 1620, 1500, 1430, 1270, 1250, 1170, 1110, 1080, 1040, 960, 940, 880, 840, 800, 750, 710 cm-1.

An NMR spectrum-H1: /CD3OD, 200 MHz/: 7,78 /2H, doublet, J = 8 Hz/, 7,31 /1H, doublet, J = 2 Hz/, 7,03 /2H, double doublet, J = 2 Hz and 8 Hz/, of 6.96 /2H, doublet, J = 6 Hz/, 6,87 /1H, doublet, J = 8 Hz/, 5,33 /1H, doublet, J = 3 Hz/, 5,08 /1H, doublet, J = 4 Hz/, 4,99 /1H, doublet, J = 3 Hz/, 4,80 - 3,20 /17H, multiplet/, 2,83 /1H, multiplet/, 2,65 - 2,30 /4H, multiplet/, 2,22 - 1,90 /2H, multiplet/, 1,79 /2H, multiplet/, 1,56 - 1,25 /10H, multiplet/, 1,19 /3H, doublet, J = 5 Hz/, 1,06 /3H, doublet, J ith:

.

In table.7 shows the structure of the compounds of examples 3 to 11.

Example 3. To a solution of compound FR 133303 /1 g/ and operations ether N-/tert. -butoxycarbonyl/-D-2-/p-octyloxyphenyl/glycine /0,596 g/ in N,N-dimethylformamide /3 ml) was added 4-dimethylaminopyridine /0,165 g/. The mixture was stirred for 12 hours at room temperature. The reaction mixture was added to water /30 ml/ and then the pH of the solution was set equal to 6. The aqueous solution was washed with ethyl acetate and subjected to ion-exchange chromatography on DEAE-Toyopearl /Cl-/ /60 ml/ and suirable 50% methanol in 1M aqueous solution of sodium chloride. The fractions containing the target compound were combined and evaporated under reduced pressure to remove methanol. the pH of the aqueous solution was set equal to 4.5 with 1 N. hydrochloric acid and subjected to column chromatography on Diaion HP-20 /trade name, manufactured by Mitsubishi of Kemikl industries/ /130 ml/ and suirable 80% aqueous methanol. The fractions containing the compound were combined and evaporated under reduced pressure to remove methanol. The remainder liofilizirovanny to obtain the desired acylated compounds /hereinafter in connection FR138260/ /0,77 g/.

IR /Nuol/: 3300, 1660, 1500, 1240, 1045, 800, 7 /9H, the singlet/, 1,6 - 1,8 /2H, multiplet/, 1,9 - 2,1 /3H, multiplet/, 2,50 /3H, multiplet/, 2,75 /1H, double doublet, J = 16 Hz and 4 Hz/, 3,35 /1H, multiplet/, 3,7 - 3,8 /1H, multiplet/, 3,93 /2H, triplet, J = 6.2 Hz/, 3,9 - 4,2 /5H, multiplet/, 4,3 - 4,5 /5H, multiplet/, 4,5 - 4,7 /3H, multiplet/, equal to 4.97 /1H, doublet, J = 3 Hz/, of 5.05 /1H, doublet, J = 4 Hz/, 5,11 /1H, singlet/, 5,30 /1H, doublet, J = 3 Hz/, 6,85 /1H, doublet, J = 8 Hz/, 6,86 /2H, doublet, J = 8.6 Hz/, 7,02 /1H, doublet, J = 8,3 Hz/, 7,26 /2H, doublet, J = 8.6 Hz/, 7,31 /1H, singlet/.

FAB-mass spectrum: e/z = 1343 /M + Na/.

Example 4. Connection FR138260 obtained in example 3 /0.25 g/, was added to triperoxonane acid /1.25 ml/ and was stirred for 10 min. the Reaction mixture was added to water /30 ml/ and then set pH 45 with saturated aqueous sodium bicarbonate solution. The aqueous solution was subjected to column chromatography on Diaion HP-20 /100 ml and was suirable 80% aqueous solution of methanol. The fractions containing the target compound were combined and evaporated under reduced pressure to remove methanol. The remainder liofilizirovanny with obtaining the target compound /hereinafter in connection FR138727/ /15 mg/.

NMR /CD3OD, /: 0,90 /3H, triplet, J = 6,8 Hz/, 1,05 /3H, doublet, J = 6,8 Hz/, 1,17 -1,33 /13H, multiplet/, 1,6 - 1,8 /2H, multiplet/, 1,9 - 2,1 /3H, multiplet/, 2,50 /1H, multiplet/, 2,75 /1H, double/1H, doublet, J = 3 Hz/, 5,06 /1H, singlet/, 5,20 /1H, doublet, J = 3 Hz/, 5,40 /1H, doublet, J = 3 Hz/, 6,85 /1H, doublet, J = 8,3 Hz/, 6,95 /2H, doublet, J = 8,5 Hz/, 7,02 /1H, doublet, J = 8,3 Hz/, 7,30 /1H, doublet, J = 8,5 Hz/, 7,44 /1H, singlet/.

FAB-Mass spectrum: e/z = 1259 /M + K/.

Example 5. Connection FR138364 was obtained by the reaction of compounds of FR133303 operations with ether O4-octyl-N/tert-butoxycarbonyl/-1-tyrosine in accordance with the method similar to that described in example 3.

IR /Nuol/: 3300, 1660, 1620, 1240, 1050 cm-1.

NMR /CD3OD, /: 0,904 /3H, triplet, J = 6,8 Hz/, 1,06 /3H, doublet, J = 7,8 Hz/, 1,17 /3H, doublet, J = 6,7 Hz/, 1,20 - 1,30 /10H, multiplet/, 1,35 /9H, singlet/, 1,74 /2H, quintet, J = 6,5 Hz/, 1,9 - 2,1 /3H, multiplet/, 2,45 /3H, multiplet/, was 2.76 /1H, double doublet, J = 16 Hz and 4 Hz/, 3,0 - 3,1 /2H, multiplet/, 3,37 /1H, multiplet/, of 3.77 /1H, doublet, J = 11 Hz/, 3,92 /2H, triplet, J = 6,8 Hz/, 3,9 - 4,2 /7H, multiplet/, 4,3 - 4,5 /5H, multiplet/, 4,5 - 4,6 /3H, multiplet/, 4,94 /1H, doublet, J = 3 Hz/, of 5.05 /1H, doublet, J = 3.8 Hz/, 5,31 /1H, doublet, J = 3 Hz/, 6,79 /2H, doublet, J = 8,5 Hz/, 6,85 /1H, doublet, J = 8,3 Hz/, 7,03 /1H, double doublet, J = 8,3 Hz and 2 Hz/, 7,12 /2H, doublet, J = 8,5 Hz/, 7,31 /1H, doublet, J = 2 Hz/.

FAB-Mass spectrum: e/z = 1357 /M + Na/.

Example 6. A solution of compound FR133303 /0.5 g/ in a mixture of water /5ml/ and tetrahydrofuran (THF /5 ml/ brought to pH 7 with saturated aqueous solution is remedial at room temperature, maintaining pH at a value of 7 with saturated aqueous sodium bicarbonate solution. The reaction mixture was added to water and set the pH to the value 6. The aqueous solution was washed with ethyl acetate and subjected to ion-exchange chromatography on DEAE-Toyopearl /Cl-/ 30 ml/ and suirable 50% methanol in IM aqueous solution of sodium chloride. The fractions containing the whole compound were combined and evaporated under reduced pressure to remove methanol. the pH of the aqueous solution was set at a value of 4.5 with IH hydrochloric acid and then subjected to column chromatography on Diaion HP-20 /100 ml and after elution was performed using 80% aqueous methanol. The fractions containing the target compound were combined and evaporated under reduced pressure to remove methanol. The remainder liofilizirovanny with obtaining the target compound in acylated form /next connection ER138261/ /0.145 g/.

The IR spectrum Nuol/: 3300, 1660, 1620, 1240, 1050 cm -1.

NMR/ CD3OD, /: 1,06 / 3H, doublet, J=6.8 G/, 1,18 /3H, doublet, 1=6,0/, 1,40 /9H, singlet/, 1,9-2,1/ 3H, multiplet/, 2,44 /3H, multiplet/, 2,82 /1H, double doublet, J= 16 Hz and 4 Hz/, 3,37 /1H, multiplet/, 3,75 /1H, doublet, J = 11 Hz/, 3,89-4 /2H, multiplet/, 4,10 /1H, multiplet/, 4,15 /1H, multiplet/, 4,29 /1H, double doublet, J = 6 Goblet, J = 3 Hz/, 6,85 /1H, doublet, J = 8,3 Hz/, 7,03 /1H, double doublet, J = 8,3 Hz and 2 Hz/, 7,30 /1H, doublet, J = 2 Hz/, 7,50 /1H, doublet, J = 8,2 Hz/.

FAB-mass spectrum of E/z = 1081 /M + Na/.

Example 7 Compound FR 138363 was obtained by the reaction of compounds FR 133303 with acetyl chloride according to the method described in example 6.

IR-spectrum /Nuol/: 3300, 1620, 1250, 1040 cm-1.

NMR CD3OD, /: 1,06 /3H, doublet, J= 6,8 Hz/, 1,20 /3H, doublet, J= 6 Hz/, 1,78-2,05 /3H, multiplet/, 1,96 /3H, singlet/, 2,21-2,54 /3H, multiplet/, 2,95 /1H, multiplet/, 3,35-3,42 /1H, multiplet/, to 3.58 was 4.42 /11H, multiplet/, 4,50-of 5.05 /5H, multiplet/, 5,23 /1H, multiplet/, 6,88 /1H, doublet, J = 8,3 Hz, 7,05 /1H, double doublet, J = 8,3 Hz/, 7,35 /1H, doublet, J = 2 Hz/.

FAB-mass specip /M + Na/ 5 1023.

Example 8. Connection FR 138728 was obtained by the reaction of compounds FR 133303 c 2-bromoacetyl chloride according to the method similar to the method described in example 6.

IR Nuol/: 3300, 1660, 1620, 1500, 1220, 1040 cm-1.

NMR CD3OD, /: 1,06 /3H, doublet, J = 6,9 Hz/, 1,17 /3H, doublet, J= 6,1 Hz/, 1,9-2,1 /3H multiplet/, 2,50 /3H, multiplet/, 2,80 /1H, double doublet, J= 16 Hz and 4 Hz/, 3,37 /1H, multiplet/, 3,6-4,0 /5H, multiplet/, 4,16 /1H, multiplet/, 4,29 /1H, double doublet, J= 6 Hz and 2 Hz/, 4,36 is 4.45 5H, multiplet/, 4,5-4,7 /3H, multiplet/, equal to 4.97 /1H, doublet, J = 3 Hz/, 5,04 /1H, double doublet, J = 8.6 Hz and 4 Hz/, 5,25 t, J = 8.6 Hz/.

FAB-mass spectrum: e/z 1103 /M + Na/.

Example 9. Connection FR138538 was obtained by the reaction of FR133303 with benzoyl chloride according to the method described in example 6.

IR /Nuol/: 3300, 1640, 1240 cm-1.

NMR /CD3OD, /: 1,05 /3H, doublet, J = 6,8 Hz/, 1,18 /3H, doublet, J = 6 Hz/, 1,89-2,12 /3H, multiplet/, 2,31-2,53 /3H, multiplet/, 2,75 /1H, double doublet, J= 12 Hz and 4 Hz/, 3,38 /1H, multiplet/, 3,76 /1H, doublet, J = 11 Hz/, a 3.87-3,98 /1H, multiplet/, was 4.02-4,18 /2H, multiplet/, 4,22-4,32 /4H, multiplet/, 4,37-4,40 /3H, multiplet/, 4,49-4,62 /3H, multiplet/, 4,98 /1H, multiplet/, 5,02 /1H, multiplet/, lower than the 5.37 /1H, doublet, J = 3 Hz/, 6,85 /1H, doublet, J = 8,3 Hz/,? 7.04 baby mortality /1H, double doublet, J = 8,3 Hz and 2 Hz/, 7,11-7,50 /6H, multiplet/.

FAB-mass spectrum: e/z = 1101 /M + Na/.

Example 10. Connection FR138539 was obtained by the reaction of compounds of FR133303 2-/2-aminothiazol-4-yl/-2-methoxyethoxy acid according to the method described in example 6.

IR-spectrum /Nuol/: 3300, 1650, 1620, 1520, 1260, 1040 cm-1.

NMR-spectrum /CD3OD, /: 1,05 /3H, doublet, J=6,8 Hz/, 1,21 /3H, doublet, J= 5,9 Hz/, 1,89-2,21 /3H, multiplet/, 2,29-2,61 /3H, multiplet/, 2,78-2,89 /1H, multiplet/, 3,32-3,42 /1H, multiplet/, 3,76-3,82 /1H, multiplet/, 3,91-4,01 /2H, multiplet/, 3,95 /3H, singlet/, 4,13 /1H, multiplet/, 4,16 /1H, multiplet/, 4,24-4,27 /1H, multiplet/, 4,32-4,43 /5H, multiplet/, 4,46-4,62 /1H, double doublet, J=81 Hz/, 7,31 /1H, doublet, J=2 Hz/, 7,51 /1H, doublet, J=7 Hz/.

FAB-mass spectrum: e/z = 1143 /M+/.

Example 11. Connection FR138365 was obtained by the reaction of compounds FR 133303 chloride tosilos according to the method described in example 6.

IR-spectrum /Nuol/: 3300, 1650, 1620, 1260, 1060 cm-1.

NMR-spectrum /CD3OD, /: 0,75 /3H, doublet, J=6,8 Hz/, 1,07 /3H, doublet, J=6.0 Hz/, 1,61-1,79 /1H, multiplet/, 1,91-2,05 /3H, multiplet/, 2,30-2,59 /3H, multiplet/, 3,36 /1H, multiplet/, 3,68 /1H, doublet, J=11 Hz/, 3,81-4,07 /4H, multiplet/, 4,22 /1H, multiplet/, 4,32-4,40 /5H,multiplet/, 4,42-4,60 /3H, multiplet/, 4,47 /1H, multiplet/, 5,0 /1H, multiplet/, 5,42 /1H, doublet, J=3 Hz/, 6,85 /1H, doublet, J=8,3 Hz/, 7,03 /1H, double doublet, J= 8,3 Hz and 2 Hz/, 7,29-7,33 /3H, multiplet/, 7,55 /1H, doublet, J= 8,3 Hz/.

FAB-mass spectrum: e/z = 1135 /M+Na/.

Preparative example 11. To a solution of 6-hydroxy-2-naphthoic acid /1 g/ in a mixture of 10% aqueous sodium hydroxide solution /4,25/ ml and dimethyl sulfoxide /17 ml) was added bromide octyl /0,918 ml/. The mixture was stirred for 6 hours at 60oC.

The resulting reaction mixture was added to a mixture of water and ethyl acetate and established a pH value of 4 with conc.of hydrochloric acid. The organic layer was separated and dried over magnesium sulfate. The sulphate mailody /0,91 g/.

IR-spectrum /Nuol/: 1607, 1620, 1210 cm-1.

NMR-spectrum /DMCO-d6, /: 0,86 /3H, triplet, J=6,7 Hz/, 1,2-1,6/1OH, multiplet/, 1,78 /2H, multiplet/, 4,1 /2H, triplet/, J=6,7 Hz/, 7,19 /1H, double doublet, J=2.3 and 8.8 Hz Hz/, of 7.36 /1H, doublet, J=2.3 Hz/, 7,83 /1H, doublet, J=8,8 Hz/, 7,97 /2H, doublet, J=8,8 Hz/, charged 8.52 /1H, the singlet/.

Preparative example 12. Hydrochloride of 1-ethyl-3-/3-dimethylaminopropyl/carbodiimide /0,703 g/ was added to a solution of 6-octyloxy-2-naphthoic acid /0.85 grams/ 1-hydroxy-1H-benzotriazole /0,382 g/ ethyl acetate /26 ml/. The resulting mixture was stirred for 2 hours at room temperature.

The resulting reaction mixture was added to water and the separated organic layer was further washed with water and aqueous sodium chloride solution. Then the organic layer was dried over magnesium sulfate. The magnesium sulfate was filtered and the filtrate evaporated under reduced pressure to obtain 1-/6-octyloxy-2-naphtol/-1H-benzotriazole-3-oxide/0.74 g/.

IR-spectrum /Nuol/: 1770, 1740, 1620, 1190, 1020, 740 cm-1.

NMR-spectrum /CDCl3, /: 0,90 /3H, triplet, J=6,8 Hz/, 1,2-1,6 /10H, multiplet/, 1,89 /2H, multiplet/, 4,14 /2H, triplet, J=6,8 Hz/, 7,1-7,3 /2H, multiplet/, 7,4-7,6 /3H, multiplet/, 7,8-8,0 /2H, multiplet/, 8,1-8,2 /2H, multiplet/, 8,80 /1H, singlet/,

In table. presents the Lil/-IH-benzotriazole-3-oxide /0,271 g/ N, N-dimethylformamide /a 1.5 ml) was added 4-dimethylaminopyridine /0,0828 g/. The resulting mixture was stirred for 12 hours at room temperature.

The reaction mixture was added water and set a pH of 6. The aqueous solution was washed with ethyl acetate and subjected to ion exchange treatment with DEAE-Toyoperl /Cl-/ /30ml/ and suirable 50% solution of methanol in IM sodium chloride solution. The fractions containing the target compound were combined and evaporated under reduced pressure to remove methanol. the pH of the aqueous solution was set equal to 4.5 using IH hydrochloric acid and subjected to ion-exchange treatment on the chromatographic column with Diamonon HP-20 /65 ml/, carrying out elution with 80% aqueous methanol. The fractions containing the target compound were combined and evaporated under reduced pressure to remove methanol. The residue was difinitively with obtaining the target compound in acylated form /next connection FR139687 /0,214 g/.

IR-spectrum /Nuol/: 3300, 1620, 1500 cm-1.

NMR-spectrum /DMCO-d6+D2O, /: 0,86 /3H, triplet, J=6,8 Hz/, 0,97/3H, doublet, J= 6,8 Hz/, 1,06 /3H, doublet, J=6,8 Hz, 1.2 to 1.5 /10H, multiplet/, 1,6-2,0 /5H, multiplet/, 2,2-2,2-2,5 /3H, multiplet/, 2,4-2,6 /1H, multiplet/, 3,18 (1H, multiplet/, the em J=8,3 Hz/, 6,93 /1H, doublet, J=8,3 Hz/, 7,13 /1H, singlet/, 7,25 /1H, doublet, J=8,3 Hz/, 7,39 /1H, singlet/, 7,8-8,0 /3H, multiplet/, 8,44 /1H, singlet/.

FAB-mass spectrum: e/z=1264 /M+ Na/.

The following connections /preparative examples 13-16/ polycaste according to the method described in example 5.

Preparative example 13. N-/t-butoxycarbonyl/-L-2-a/2-naphthyl/glycine.

IR-spectrum /Nuol/: 3350, 1800, 1770, 1730, 1680, 1500, 1200 cm-1.

Preparative example 14. Succinimido 2-/4-biphenylyl/acetate

IR-spectrum /Nuol/ : 1800, 1770, 1720, 1200 cm-1.

NMR-spectrum /DMCO-d6, / : 2,82 /4H, singlet/, 4,17 /2H, singlet/, 7,30-7,50 /5H, multiplet/, 7,45 /2H, doublet, J=8,1 Hz/, to 7.67 /2H, doublet, J=8,1 Hz/.

Preparative example 15. Succinimido 4-tert-butylbenzoate.

IR-spectrum /Nuol/ : 1760, 1730, 1200, 1070, 990 cm-1.

NMR /DMCO-d6, / : 1,33 /9H, singlet/, 2,89 /4H, singlet/, 7,68 /2H, doublet, J=8,5 Hz/, 8,03 /2H, doublet, J=8,5 Hz/.

Preparative example 16. Succinimido 4-/4-phenylbutane/benzoate.

IR-spectrum /Nuol/ : 1730, 1600, 1240, 1170, 1070 cm-1.

NMR-spectrum /DMCO-d6, / : 1,75 /4H, multiplet/, 2,65 /2H, multiplet/, 4,14 /2H, multiplet/, 7,15 /2H, doublet, J=8,9 Hz/, 7,13-7,35 /5H, multiplet, 8,03 /2H, doublet, J=8,9 Hz/.

Preparative example 17. To 3,7-dimethyl>. The reaction mixture was added to a mixture of water with n-hexane. The organic layer was separated and dried over magnesium sulfate. The magnesium sulfate was filtered and the filtrate evaporated under reduced pressure with the formation of 3,7-methyl dimethyloctyl /4,40 g/.

IR-spectrum /net/ : 2900, 1450 cm-1.

NMR-spectrum /CDCl3, / : 0,87 /6H, doublet, J=6,6 Hz/, 0,89 /3H, doublet, J= 6,4 Hz/, 1,1-1,3 /6H, multiplet/, 1,5-1,9 /4H, multiplet/, 3,3-3,5 /2H, multiplet/.

The following connections /preparative examples 18-23/ received according to the manner similar to that described in preparative example 1.

Preparative example 18. 4-/4-/Octyloxy/phenoxy/benzoic acid.

IR-spectrum /Nuol/: 1680, 1600, 1240, 840 cm-1.

NMR-spectrum /DVCO-d6, / : 0,87 /3H, triplet, J=6,7 Hz/, 1,1 - 1,6 /10H, multiplet/, 1,71 /2H, multiplet/, 3,96 /2H, triplet, J=6,4 Hz/, 6,9-7,1 /6H, multiplet/, 7,92 /2H, doublet, J=8.7 Hz/, 12,8 /1H, broad singlet/.

Preparative example 19. 6-/Butoxy/-2-naphthoic acid.

IR-spectrum /Nuol/ : 1660, 1610, 1205 cm-1.

NMR-spectrum /DVCO-d6, / : 0,96 /3H, triplet, J=7,29 Hz/, 1,48 /2H, quintet-triplet, J= 7,29 Hz and 7 Hz/, 1,78 /2H, triple triplet, J=7 Hz and 6,45 Hz/, 4,12 /2H, triplet, J=6,45 Hz/, 7,24 /1H, double doublet, J=9,0 Hz and 2.3 Hz/, 7,40 /1H, doublet, J=2 the emer 20. 6 Dellucci-2-naphthoic acid.

IR-spectrum /Nuol/: 1670, 1620, 1210 cm-1.

NMR-spectrum /DMCO-d6, /: 0,85 /3H, triplet, J= 6,7 Hz/, 1,2-1,6 /14H, multiplet/, 1,78 /2H, multiplet/, 4,11 /2H, triplet, J=6,4 Hz/, of 7.23 /1H, double doublet, J=a 8.9 Hz and 2.4 Hz/, 7,39 /1H, doublet, J=2,4 Hz/, 7,86 /1H, doublet, J= 8.7 Hz/, 7,93 /1H, doublet, J=8.7 Hz/, 8,01 /1H, doublet, a 8.9 Hz/, 8,5 /1H, singlet/.

Preparative example 21. 6 Hexyloxy-2-naphthoic acid.

IR-spectrum /Nuol/: 1660, 1620, 1290, 1210 cm-1.

NMR-spectrum /DMCO-d6, /: 0,89 /3H, triplet, J=6,8 Hz/, 1,2-1,6 /6H, multiplet/, 1,78 /2H, quintet, J=6,5 Hz/, 4,11 /2H, triplet, J=6,5 Hz/, of 7.23 /1H, double doublet, J=9.0 Hz and 2.4 Hz/, 7,39 /1H, doublet, J=2,4 Hz/, 7,86 /1H, doublet, J=8.7 Hz/, 7,94 /1H, doublet, J=8.7 Hz/, 8,01 /1H, doublet, J=9,0 Hz/, charged 8.52 /1H,singlet/.

Preparative example 22. 6 Dodecyloxy-2-naphthoic acid

IR-spectrum /Nuol/: 1670, 1620, 1210 cm-1.

NMR-spectrum /DMCO-d6, /: 0,86 /3H, triplet, J=6,7 Hz/, 1,20 - 1,60 /18H, multiplet/, 1,78 /2H, multiplet/, 4,11 /2H, triplet, J=6,5 Hz/, 7,22 /1H, double doublet, J= 9 Hz and 2.4 Hz/, 7,39 /1H, doublet, J=2,4 Hz/, a 7.85 /1H, doublet, J=8.7 Hz/, 7,93 /1H, doublet, J=8.7 Hz/, 8,00 /1H, doublet, J=9,0 Hz/, 8,51 /1H, Singlet/, 12,90 /1H, singlet/.

Preparative example 23. 6-/3,7-Dimethyloctane/-2-naphthoic acid.

IR-spectrum /Nuol/: 1660, 1610, 1290, 12, ultiple/, 4,15 /2H, triplet, J= 6,7 Hz/, 7,22 /1H, double doublet, J=9.0 Hz and 2.4 Hz/, 7,41 /1H, doublet, J=2,4 Hz/, 7,86 /1H, doublet, J=8.6 Hz/, 7,93 /1H, doublet, J=8 Hz/, 8,01 /1H, doublet, J=9,0 Hz/, charged 8.52 /1H, singlet/.

The following connections /preparative examples 24-31/ received according to the manner similar to that described in preparative example 12.

Preparative example 24. 1-/4-(4-Octyloxy)phenoxy/benzoyl-1H - benzotriazole-3-oxide

IR /Nuol/: 1770, 1730, 1600, 1500, 1230, 980 cm-1.

Preparative example 25. 1-/6-Butoxy-2-naphtol/-1H-benzotriazole-3-oxide.

IR-spectrum /Nuol/: 1760, 1610, 1260, 1180, 1020 cm-1.

Preparative example 26. 1-/6-Decyloxy-2-naphtol/-1h-benzotriazole-3-oxide.

IR-spectrum /Nuol/: 1780, 1620, 1190, 1000 cm-1.

Preparative example 27. 1-/6-Hexyloxy-2-naphtol/-1H-benzothiazol-3-oxide.

IR-spectrum /Nuol/: 1780, 1610, 1190 cm-1.

NMR-spectrum /DMCO-d6, /: 0,89 /3H, triplet, J=6,7 Hz/, 1,2-1,6 /6H, multiplet/, 1,79 /2H, multiplet/, 4,12 /2H, triplet, J=6,5 Hz/, 7,24 /1H, double doublet, J=9.0 Hz and 2.4 Hz/, 7,39 /1H, doublet, J=2.3 Hz/, 7,41 /1H, triplet, J= 8 Hz/, 7,54 /1H, triplet, J=8 Hz/, 7,72 /1H, doublet, J=8 Hz/, 7,88 /1H, doublet, J=8.7 Hz/, of 7.90 /1H, doublet, J=8.7 Hz/, 7,97 /1H, doublet, J=8 Hz/, 8,02 /1H, doublet, J=9,0 Hz/, 8,51 /1H, singlet/.

Preparative approx .

NMR-spectrum /DMCO-d6, / : 0,85 /3H, triplet, J=6,7 Hz/, 1,2-1,3 /18H, multiplet/, 1,78 /2H, multiplet/, 4,11 /2H, triplet, J=6,5 Hz/, 7,22 /1H, double doublet, J=9.0 Hz and 2.4 Hz/, 7,39 /1H, doublet, J=2,4 Hz/, 7,40 /1H, triplet, J= 8 Hz/, 7,55 /1H, triplet, J=8 Hz/, 7,73 /1H, doublet, J=8 Hz/, a 7.85 /1H, doublet, J=8.7 Hz/, 7,93 /1H, doublet, J=8.7 Hz/, 7,99 /1H, doublet, J=8 Hz/, 8,00 /1H, doublet, J=8 Hz/, 8,51 /1H, singlet/.

Preparative example 29. 1-/6-(3,7-Dimethyloctyl)-2-naphtol/1H-benzotriazole-3-oxide

IR-spectrum /Nuol/: 1780, 1620, 1190 cm-1.

Preparative example 30. 1-/(2E, 6E)-3,7,11-Trimethyl-2,6,10 - dodecatrien/-1H-benzotriazole-3-oxide.

IR-spectrum /pure substance/: 2900, 1780, 1620, 1420, 1070 cm-1< / BR>
Preparative example 31. 3,7-Dimethyl-6-chenil bromide was obtained according to a method similar to that described in preparative example 17.

IR-spectrum /pure substance/: 2900, 1440, 1380 cm-1.

NMR-spectrum /DMCO - d6, /: 0,86 /3H, doublet, 1=6.3 Hz/, 1,0-1,5 /2H, multiplet/, 1,57 /3H, singlet/, 1,65 /3H, singlet/, 1,7-2,1 /5H, multiplet/, 3,4-3,7 /2H, multiplet/, 5,08 /1H, multiplet/.

Preparative example 32. To a suspension of sodium hydride /2,04 g/ in N,N - dimethylformamide /50 ml) was added 4-hydroxypyridine /5g/ at room temperature. Added bromide octyl /remaining 9.08 ml/. The mixture was stirred during the 00 ml/. The organic layer was separated and dried over magnesium sulfate. The magnesium sulfate was filtered and the filtrate evaporated under reduced pressure to obtain 1-octyl-4-pyridone /14,7 g/.

NMR-spectrum /DMCO-d6, /: 0,86 /3H, triplet, J=6 Hz,/, 1,1-1,4 /10H, multiplet/, 1,4-1,8 /2H, multiplet/ 3,81 /2H, triplet, J=7 Hz/, 6,05 /2H, doublet, J=8 Hz/, 7,63 /2H, doublet, J=8 Hz/.

Preparative example 33. To a solution of 1-octyl-4-pyridone /10,9 g/ pyridine /100 ml was added pentasulfide phosphorus /8.65 g/ at room temperature. The mixture was stirred for 3 hours at 80oC. the Reaction mixture was added to a mixture of water /200 ml with methylene chloride /200 ml/. The organic layer was separated and dried over magnesium sulfate. The magnesium sulfate was filtered and the filtrate evaporated under reduced pressure with the formation of 1-octyl-1,4-dihydropyridines-4-thione /5,27 g/.

IR-spectrum /pure substance/: 2910, 2850, 1620, 1460, 1110 cm-1.

NMR-spectrum /DMCO-d6, /: 0,86 /3H, triplet, J=6 Hz,/, 1,1-1,4 /10H, multiplet/, 1,5-1,9 /2H, multiplet/, 3,95 /2H, triplet, J=7 Hz/, 7,13 /2H, doublet, J=7 Hz/, 7,60 /2H, doublet, J=7 Hz/.

The following connections / preparative examples 34-36/ received according to the manner similar to that described in preparative example 1.

Preparative example 34. Methyl is-range /DMCO-d6, /: 3,23 /3H, singlet/, 3,60 /3H, singlet/, 4,73 /1H, singlet/, 6,72 /2H, doublet, J=8,9 Hz/, 7,15 /2H, doublet, J=8,9 Hz/.

E1 Mass spectrum /e/z/=196 /M+.

Preparative example 35. The hydrochloride of the methyl ester of D-tyrosine.

IR-spectrum /Nuol/: 3300, 1740, 1220 cm-1.

NMR-spectrum /DMCO-d6, /: 3,02 /2H, multiplet/, 3,67 /3H, singlet), 4,16 /1H, triplet, J=6,7 Hz/, 6,72 /2H, doublet, J=8,4 Hz/, 7,01 /2H, doublet, J=8,4 Hz/, 8,58 /2H, singlet/, for 9.47 /1H, singlet/.

Preparative example 36. Methyl /4-hydroxyphenyl/glyoxylate, being.

IR-spectrum /Nuol/: 3380, 1730, 1700, 1600, 1580, 1220 cm-1.

NMR-spectrum /DMCO-d6, /: 3,91 /3H, singlet/, 6,94 /2H, doublet, J=8,8 Hz/, 7,83 /2H, doublet, J=8,8 Hz/, 10,9 /1H, singlet/.

Preparatively example 37. Methyl ester of N - /tertbutoxycarbonyl/D-tyrosine was obtained according to a method similar to that described in preparative example 2.

IR-spectrum /Nuol/: 3360, 1700, 1680, 1290, 1270, 1250 cm-1< / BR>
NMR-spectrum /DMCO-d6, /: 1,33 /9H, singlet/, 2,73 /2H, multiplet/, 3,59 /3H, singlet/, 4,05 /1H, multiplet/, 6,65 /2H, doublet, J=8,4 Hz/, 7,00 /2H, doublet, J=8,4 Hz/, of 7.23 /1H, doublet, J=7.9 Hz/, 9,23 /1H, singlet/.

Preparative example 38. To a solution of methyl ester hydrochloride 1-tyrosine /1 g/ water /1.5 ml/ added sodium bicarbonate /0,363 g/ when aldehyde /0,637 ml/ and cyanoborohydride sodium /of 0.182 g/ -5oC. the Mixture was stirred for 2 hours at -5oC. the resulting insoluble material was filtered and the filtrate was extracted with ethyl acetate. The organic layer was separated and dried over magnesium sulfate. The magnesium sulfate was filtered and the filtrate evaporated under reduced pressure to obtain methyl ester of N,N-dimethyl-1-tyrosine /0.21 g/.

IR-spectrum /Nuol/: 1730, 1260, 1010 cm-1.

NMR-spectrum /DMCO-d6, /: 2,24 /6H, singlet/, 2,72 /2H, multiplet/, 3,34 /1H, multiplet/, 3,53 /3H, singlet/, 6,64 /2H, doublet, J=8,4 Hz/, 6,97 /2H, doublet, J=8,4 Hz/, 9,18 /1H, singlet/.

The following connections /preparative examples 39-44/ received according to the manner similar to that described in preparative example 3.

Preparative example 39. Methyl 2-/4-octyloxyphenyl/acetate.

IR-spectrum /pure substance/: 2910, 2850, 1730, 1240 cm-1.

NMR-spectrum /DMCO-d6, /: 0,86 /3H, triplet, J=6.3 Hz/, 1,2-1,5 /10H, multiplet/, 1,6-1,9 /2H, multiplet/, to 3.58 /2H, singlet/, 3,59 /3H, singlet/, 3,92 /2H, triplet, J=6,4 Hz/, 6,85 /2H, doublet, J=8.7 Hz/, 7,15 /2H, doublet, J=8.7 Hz/.

Preparative example 40. Ethyl 3-/4-octylphenyl/propionate.

IR-spectrum /pure substance/: 2920, 2850, 1730, 1240 cm-1.

NMR /DMCO-d6, /: 0,86 /3H, triplet, J=6,7 0 /2H, triplet, J=6,4 Hz/, 4,03 /2H, quintet, J=7,1 Hz/, for 6.81 /2H, doublet, J=8.6 Hz/, 7,11 /2H, doublet, J=6,8 Hz/.

Preparative example 41. Methyl 2-/4-octyloxyphenyl/-2-methoxyacetate.

IR-spectrum /pure substance/: 2910, 2850, 1740, 1600, 1240, 1100 cm-1.

NMR-spectrum /DMCO= d6, /: 0,86 /3H, triplet, J=6,8 Hz/, 1,2-1,5 /1OH, multiplet/, 1,6-1,8 /2H, multiplet/, 3,26 /3H, singlet/, 3,62 /3H, singlet/, 3,94 /2H, triplet, J=6,4 Hz/ of 4.83 /1H, singlet/, 6,91 /2H, doublet, J= 7,8 Hz/, 7,27 /2H, doublet, J=8.7 Hz/.

EI-mass spectrum /e/z/ = 308 /M+/.

Preparative example 42. Methyl ester of O4octyl-N/tert-butoxycarbonyl/-D-tyrosine

IR /Nuol/: 3350, 1730, 1680, 1510, 1240, 1160 cm-1< / BR>
NMR-spectrum /DMCO-d6/: 0,86 /3H, triplet, J=6,7 Hz/, 1,2-1,3 /1OH, multiplet/, 1,68 /2H, multiplet/, 2,82 /2H, multiplet/, 3,60 /3H, singlet/, 3,91 /2H, triplet, J=7,3 Hz/, 4,08 /1H, multiplet/, for 6.81 /2H, doublet, J=6,8 Hz/, 7,12 /2H, doublet, J=6,8 Hz/, 7,25 /1H, doublet, J=8 Hz/.

Preparative example 43. Methyl ester of O4-oxyl-N, N-dimethyl-1-tyrosine.

IR-spectrum /pure substance/: 2930, 2860, 1730, 1250, cm-1.

NMR-spectrum /DMCO-d6, /: 0,86 /3H, triplet, J=6,6 Hz/, 1,26 /1OH, multiplet/, 1,68 /2H, multiplet/, 2,80 /2H, multiplet/, to 3.33 /6H, singlet/, 3,37 /1H, multiplet/, 3,53 /3H, singlet/, 3,89 /2H,triplet, J=6,4 Hz/, 6,79 /2H, doublet, J=6,8 Hz/, 7,08 /2H, is East of the substance/: 2930, 2850, 1730, 1670, 1600, 1260, 1210, 1160 cm-1.

NMR-spectrum /DMCO-d6, /: 0,86 /3H, triplet, J=6.3 Hz/, 1,2-1,5 /1OH, multiplet/, 1,6-1,9 /2H, multiplet/, 3,93 /3H, singlet/, 4,1 /2H, triplet, J=6,5 Hz/, 7,12 /2H, doublet, J=8,9 Hz/, 7,92 /2H, doublet, J=8,9 Hz/.

The following connections /preparative examples 45-51/ received according to the manner similar to that described in preparative example 4.

Preparative example 45. 4-/2-Butoxyethoxy/benzoic acid.

IR-spectrum /Nuol/: 1670, 1610, 1260 cm-1.

NMR-spectrum /DMCO-d6, /: 0,87 /3H, triplet, J=7,2 Hz/, 1,2-1,6 /4H, multiplet/, 3,45 /2H, triplet, J=6,4 Hz/, 3,70 /2H, triplet, J=4.4 Hz/, 4,16 /2H, triplet, J=4.4 Hz/, 7,02 /2H, doublet, J=8,9 Hz/, 7,88 /2H, doublet, J=8,9 Hz/, 12,63 /1H, singlet/.

Preparative example 46. 2-/4-Kilometer/acetic acid.

IR-spectrum /Nuol/: 1680, 1250, 820, 780 cm-1.

NMR-spectrum /DMCO-d6, /: 0,86 /3H, triplet, J=6,8 Hz/, 1,1-1,5 /1OH, multiplet/, 1,6-1,8 /2H, multiplet/, 3,47 /2H, singlet/, 3,92 /2H, triplet, J=6,4 Hz/, 6,84 /2H, doublet, J=8.6 Hz/, 7,14 /2H, doublet, J=6,8 Hz/.

Preparative example 47. 3-/4-Octyloxyphenyl/propionic acid.

IR-spectrum /Nuol/: 1680, 1500, 1200 cm-1.

NMR /DMCO-d6, /: 0,86 /3H, triplet, J=6.3 Hz/, 1,1-1,5 /1OH, multiplet/, 1,6-1,8 /2H, multiplet/, 2,47 /2H, triplet, J=6,4 shall idoxifene/-2-metacercaria acid.

IR-spectrum /Nuol/: 1760, 1720, 1600, 1500, 1240, 1180, 1100, 830 cm-1.

NMR /DMCO-d6, /: 0,86 /3H, triplet, J=6,7 Hz/, 1,2-1,5 /10H, multiplet/, 2,6-2,8 /2H, multiplet/, 3,26 /3H, singlet/, 3,94 /2H, triplet, J= 6,4 Hz/, 4,67 /1H, singlet/, 6,90 /2H, doublet, J=8.6 Hz/, 7,27 /2H, doublet, J=8.6 Hz/.

Preparative example 49. O4-Octyl-N/tert-butoxycarbonyl/-D-tyrosine

IR-spectrum /Nuol/: 3400-2900, 1700, 1500, 1240, 1160 cm-1< / BR>
NMR-spectrum /DMCO-d6, /: 0,859 /3H, triplet, J=6,8 Hz/, 1,20-1,30 /10H, multiplet/, 1,32 /9H, singlet/, 1,68 /2H, multiplet/, 2,67-2,95 /1H, multiplet/, 3,90 /2H, triplet, J=7 Hz/, 4,01 /1H, multiplet/, for 6.81 /2H, doublet, 7,02 /1H, doublet, J=8,3 Hz/, 7,13 /2H, doublet, J=8.6 Hz/.

Preparative example 50. O4-Octyl-N, N-dimethyl-1-tyrosine.

IR-spectrum /pure substance/: 2940, 2860, 2600, 1620, 1240 cm-1< / BR>
NMR /DMCO-d6, /: 0,86 /3H, triplet, J=6,6 Hz/, 1,26 /10H, multiplet/, 1,68 /2H, multiplet/, 2,67 /6H, singlet/, 2,8-3,6 /3H, multiplet/, 3,91 /2H, triplet, J=6,4 Hz/, 6,85 /2H, doublet, J=8,5 Hz/, 7,16 /2H, doublet, J= 8,5 Hz/.

Preparative example 51. O4-/Octyloxyphenyl/Glyoxylic acid.

IR-spectrum /pure substance/: 1730, 1670, 1600, 1260, 1160 cm-1.

NMR /DMCO-d6, /: 0,86 /3H, triplet, J = 6,8 Hz/, 1,2-1,5 /10H, multiplet/, 1,65-1,85 /2H, multiplet/, 4.09 to /2H, triplet, J = 6,5 Hz/, 7,12 /2H, doublet, J = 8,9 Hz/,C N-/tert-butoxycarbonyl/-1-histidine, methyl ester according to the method similar to that described in preparative examples 3 and 4.

NMR /DMCO-d6, /: 0,85 /3H, triplet, J = 6.3 Hz/, 1,23 /10H, multiplet/, 1,35 /9H, singlet/, 2,83 /2H, multiplet/, 3,90 /2H, triplet, J = 1.7 Hz/, 4,0-4,2 /1H, multiplet/, 6,35 /1H, singlet/, 7,02 /1H, doublet, J = 1=8 Hz/, 7,75 /1H, singlet/.

The following connections /preparative examples 53-60/ received according to the manner similar to that described in preparative example 11.

Preparative example 53. 4-Octyloxyphenyl acid

IR-spectrum /pure substance/: 2930, 2860, 2500, 1700, 1600, 1260 cm-1.

NMR /DMCO-d6, /: 0,86 /3H, triplet, J = 6,8 Hz/, 1,2-1,5 /10H, multiplet/, 1,5-1,8 /2H, multiplet/, 4,05 /2H, triplet, J = 6.2 Hz/, 7,03 /1H, doublet, J = 2,6 Hz/, 7,06 /1H, double doublet, J = 8,4 Hz and 2.6 Hz/, 7,72 /1H, doublet, J = 8,4 Hz/.

Preparative example 54. 3-Methoxy-4-octyloxybenzoic acid.

IR-spectrum /Nuol/: 2600, 1680, 1600, 1270, 1230 cm-1.

NMR-spectrum /DMCO-d6, /: 0,86 /3H, triplet, J = 6,8 Hz/, 1,2-1,5 /10H, multiplet/, 1,6-1,8 /2H, multiplet/, 3,80 /3H, singlet/, 4,01 /2H, triplet, J = 6,5 Hz/, 7,03 /1H, doublet, J = 8,5 Hz/, 7,44 /1H, doublet, J = 1.9 Hz/, 7,54 /1H, double doublet, J=8,5 Hz and 1.9 Hz/.

Preparative example 55. 4-/4-Octyloxyphenyl/benzoic acid.

IR-spectrum /Nuol/: 167 ultiple/, 4,01 /3H, triplet, J = 6,4 Hz/,? 7.04 baby mortality /2H, doublet, J = 8,8 Hz/, 7,68 /2H, doublet, J = 8,8 Hz/, 7,75 /2H, doublet, J = 8,5 Hz/, 7,99 /2H, doublet, J = 8,5 Hz/.

Preparative example 56. 6-/2-Ethylhexyloxy/-2-naftalina acid.

IR-spectrum /Nuol/: 1660, 1610, 1280, 1200 cm-1.

NMR-spectrum /DMCO-d6, /: 0,88 /3H, triplet, J = 7,3 Hz/, 0,92 /3H, triplet, J = 7 Hz,/, 1,2-1,6 /8H, multiplet/, 1,7-1,9 /1H, multiplet/, 4,01 /2H, doublet, J = 5.7 Hz/, of 7.23 /1H, double doublet, J = a 8.9 Hz and 2.4 Hz/, 7,42 /1H, doublet, J = 2,4 Hz/, 7,86 /1H, doublet, J = 8.7 Hz/, 7,94 /1H, doublet, J = 8.7 Hz/, 8,01 /1H, doublet, J = 8,9 Hz/, 8,51 /1H, singlet/, 12,9 /1H, singlet/.

Preparative example 57. 6-/3,7-Dimethyl-6-octenoate/naphthoic acid.

IR-spectrum /Nuol/: 1660, 1610, 1290, 1200 cm-1.

NMR-spectrum /DMCO-d6, /: 0,95 /3H, doublet, J = 6,1 Hz/, 1,1-1,5 /2H, multiplet/, 1,57 /3H, singlet/, 1,64 /3H, singlet/, 1,6-2,1 /5H, multiplet/, 4,15 /2H, triplet, J = 6,7 Hz/, 5,10 /1H, triplet, J = 7,1 Hz/, 7,22 /1H, double doublet, J = 8,9 Hz and 2.3 Hz/, 7,42 /1H, doublet, J = 2.3 Hz/, 7,86 /1H, doublet, J = 8.6 Hz/, 7,94 /1H, doublet, J = 8.6 Hz/, 8,01 /1H, doublet, J = 8,9 Hz/, charged 8.52 /1H, singlet/, 12,89 /1H, singlet/.

Preparative example 58. 6-/3,7-Dimethyl-2,6-octadienal/ naphthoic acid.

IR-spectrum /Nuol/: 1660, 1620, 1210 cm-1.

NMR-spectrum /DMCO-d6, /: 1,57 /3H, singlet/, 1,60 /3H, singlet/, 1,76 /3H, Singhs and 2.4 Hz/, 7,41 /1H, doublet, J = 2,4 Hz/, a 7.85 /1H, doublet, J = 8.7 Hz/, 7,94 /1H, doublet, J = 8.7 Hz/, 8,01 /1H, doublet, J = 8,9 Hz/, charged 8.52 /1H, singlet/, 12,88 /1H, singlet/.

Preparative example 59. /2E/-3-/-Octyloxyphenyl/acrylic acid.

IR-spectrum /Nuol/: 1660, 1600, 1240 cm-1.

NMR-spectrum /DMCO-d6, /: 0,86 /3H, triplet, J = 6,7 Hz/, 1,2-1,5 /10H, multiplet/, 1,6-1,8 /2H, multiplet/, 4,00 /2H, triplet, J = 6,4 Hz/, 6,36 /1H, doublet, J = 16 Hz/, 6,95 /2H, doublet, J = 8.7 Hz/, 7,54 /1H, doublet, J = 16 Hz/, to 7.61 /2H, doublet, J = 8.7 Hz/, 12,20 /1H, a broad singlet/.

Preparative example 60.

6-Octyloxy-2-naphthalene sulfonate sodium.

IR-spectrum /Nuol/: 1230, 1180, 860, 820 cm-1.

NMR-spectrum /DVCO-d6, /: 0,86 /3H, triplet, J=6 Hz,/, 1,1 - 1,6 /10H, multiplet/, 4,06 /2H, triplet, J=5 Hz/, 7,08 /1H, doublet, J=9 Hz/, 7,21 /1H, singlet/, 7,79 /1H, doublet, J=9 Hz/, 8,00 /1H, singlet/.

Preparative example 61. To a solution of chloride of tonila /0,692 ml/. and N, N-dimethylformamide /0,022 ml) was added 6-octyl-2-naphthalenesulfonate sodium /1 g/ cooling system with ice and stirred for 1.5 hours at 95oC. the Reaction mixture was evaporated under reduced pressure to obtain 6-octyloxy-2-naphthylmethyl chloride solution /1 g/.

IR-spectrum /Nuol/: 1610, 1260, 1160 cm-1< / BR>
NMR-spectrum /CDCI3, /:0,90 /3H, triplet, J=6.2 G is 0 Hz and 2.2 Hz/, 7,84 - 7,97 /3H, multiplet/, 8,49 /1H, singlet/.

The following connections /preparative examples 62 - 71/ received according to the manner similar to that described in preparative example 12.

preparative example 62. 1-/4-Octylbenzoic/-1H-benzotriazole-3-oxide.

IR-spectrum /pure substance/: 2930, 2850, 1780, 1610, 1240, 990 cm-1.

Preparative example 63. 1-/4-/4-Octyloxyphenyl/benzoyl/1H-benzotriazole-3-oxide.

IR-spectrum /Nuol/: 1770, 1600, 980 cm-1.

Preparative example 64. 1-/6-2-Ethylhexyloxy/-2-naphtol/-1H, benzotriazole-3-oxide.

IR-spectrum /Nuol/: 1770, 1620, 1270, 1180 cm-1.

NMR /CDCI3, /: 0,93 /3H, triplet, J=7,1 Hz/, 0,98 /3H, triplet, J=7,4 Hz/, 1,3 - 1,7 /8H, multiplet/, 1,7 - 2,0 /1H, multiplet, 4,03 /2H, doublet, J=5.7 Hz/, 7,22 /1H, doublet, J=2.2 Hz/, 7,29 /1H, double doublet, J=8,9 Hz, 2.2 Hz/, 7,4 - 7,7 /3H, multiplet/, 7,87 /1H, doublet, J=9.5 Hz/, 7,92 /1H, doublet, J=9.5 Hz/, 8,1 - 8,2 /2H, multiplet/, 8,80 /1H, singlet/.

Preparative example 65. 1-/6-/3,7-Dimethyl-6-octenoate/2-2-naphtol/-1H-benzotriazole-3-oxide.

IR-spectrum /pure substance/: 2900, 1770, 1620, 1180 cm-1.

Preparative example 66, 1-/6//E/-3.7-Dimethyl-2,6-octadienal/-2-naphtol/-1H-benzotriazole-3-oxide.

IR-spectrum /Nuol/: 1770, 1620, 1270, 1180 cm-1-1.

preparative example 68, 1-/2-/4-Octyloxyphenyl/acetyl/-1H-benzotriazole-3-oxide

IR-spectrum /Nuol/: 1730, 1460, 1420, 1250, 1130 cm-1.

Preparative example 69, 1-/3-/4-Octyloxyphenyl/propionyl/-1H-benzotriazole-3-oxide.

IR-spectrum /Nuol/: 1730, 1420, 1340, 1240, 950 cm-1.

Preparative example 70, 1-//E/-3-/4-Octyloxyphenyl/acryloyl/-1H-benzotriazole-3-oxide

IR-spectrum /Nuol/: 1770, 1600, 1260, 1080 cm-1.

Preparative example 71, 1-/04-Octyl-N, N-dimethyl-1-tyrosyl/-1H-benzotriazole-3-oxide.

IR-spectrum /pure substance/: 2930, 2850, 1800, 1610 cm-1.

Preparative example 72. To a suspension of lithium aluminum hydride /4,05 g/ tetrahydrofuran /475 ml/ bury a solution of 4-octyloxybenzoic /25 g/ in tetrahydrofuran /25 ml/ 55 - 60oC. the Reaction mixture was stirred at reflux for 1 h and was added sodium fluoride /35,84 g/ and water /to 11.52 ml/ cooling system with ice. The resulting mixture was stirred for 30 min and filtered. The filtrate is evaporated in vacuum to obtain 4-octyloxybenzoate alcohol /25,1 g/ in the form of crystals.

IR-spectrum /Nuol/: 3200, 1605, 1510 cm-1.

NMR-spectrum /DMCO-d7 Hz/, 5,03 /1H, triplet, J=5.7 Hz/, 6,85 /2H, doublet, J=8.6 Hz/, 7,20 /2H, doublet, J=8.6 Hz/.

Preparative example 73. To a suspension of 4-octyloxybenzoic alcohol /25 g/ N-hydroxyphthalimide /17,15 g/ and triphenylphosphine /27,74 g/ tetrahydrofuran /250 ml/ bury diethylazodicarboxylate /18,4 g/ cooling system with ice. The reaction mixture was stirred for 2 hours at room temperature and evaporated in vacuum. The residue was purified by chromatography on silica gel to obtain N-/4-octyloxybenzoate/phtalimide /33,45 g/ in the form of crystals.

IR-spectrum /Nuol/: 1780, 1725, 1605, 1580, 1505 cm-1.

NMR /DMCO-d6, /: 0,86 /3H, multiplet/, 1,26 /10H, multiplet/, 1,70 /2H, multiplet/, 3,95 /2H, triplet, J=6,5 Hz/, 5,08 /2H, singlet, 6,93 /2H, doublet, J=8.6 Hz/, 7,40 /2H, doublet, J=8.6 Hz/, a 7.85 /4H, singlet/.

Preparative example 74. To a solution of N-/4-octyloxybenzoate/phtalimide /4,13 g/ tetrahydrofuran /16 ml/ at room temperature was added hydrazine hydrate /of 0.53 ml/. after stirring the mixture at the same temperature for 1 h the precipitate was filtered. To the filtrate was added water /6 ml/ 4-hydroxyphenylglycine acid /1.5 g/ at room temperature. the pH of the mixture was set equal to 4 to 4.5 with aqueous solution of sodium bicarbonate for 2 hours, Diwali brine and dried over magnesium sulfate. The organic solvent is evaporated in vacuum to obtain 2-/4-hydroxyphenyl/2-/4-octyloxybenzophenone/acetic acid /3,4 g/.

IR-spectrum /Nuol/: 3400, 1715, 1605, 1590, 1505 cm-1.

NMR /DMCO-d6, /: 0,86 /3H, multiplet/, 1,25 /10H, multiplet/, 1,69 /2H, multiplet/, 3,94 /2H, triplet, J=6,4 Hz/, 5,07 /2H, singlet/, 6,82 /2H, doublet, J=8.7 Hz/, 6,90 /2H, doublet, J=6,8 Hz/, 7,29 /2H, doublet, J=6,8 Hz/, 7,35 /2H, doublet, J=8.7 Hz/.

The following connections /preparative examples 75 and 76 were obtained according to the method similar to that described in preparative example 74.

Preparative example 75, 2-Phenyl-2-/4-octyloxybenzophenone/acetic acid.

IR-spectrum /Nuol/: 1720, 1610, 1585, 1515 cm-1< / BR>
Range-NMR /DMCO-d6, /: 0,86 /3H, triplet, J=6,7 Hz/, 1,26 /10H, multiplet/, 1,69/2H, multiplet/, 3,94 /2H, triplet, J=6,5 Hz/, 5,13 /2H, singlet/, 6,91 /2H, doublet, J=8.6 Hz/, 7,22-7,49 /7H, multiplet/.

Preparative example 76, 2-/4-Octyloxybenzophenone/acetic acid.

IR-spectrum /Nuol/: 1700, 1670, 1600 cm-1.

NMR-spectrum /DMCO-d6, /: 0,86 /3H, triplet, J=6.2 Hz/, 1,26 /10H, multiplet/, 1,70-/2H, multiplet/, 3,95 /2H, triplet, J=6,5 Hz/, 5,13 /2H, singlet/, 6,91 /2H, doublet, J=8.6 Hz/, 7,29 /2H, doublet, J=8.6 Hz/, 7,56 /1H, singlet/.

Preparative example 77. the hydrofuran /18 ml/ and at room temperature was set pH, equal to 3.5-4, using 1H hydrochloric acid and the hydrochloride methoxyamine /of 0.337 g/. The resulting mixture was stirred for 2 hours at room temperature, maintaining a pH of 3.5-4 using 1H hydrochloric acid. The reaction mixture was added ethyl acetate. The organic layer was separated and dried over magnesium sulfate. The magnesium sulfate was filtered and the filtrate evaporated under reduced pressure to obtain 2-/4-octylphenyl/-2-methoxyethoxy acid /0,57 g/.

IR-spectrum /Nuol/: 1700, 1600, 1250, 1030 cm-1.

NMR-spectrum /DMCO-d6, /: 0,86 /3H, triplet, J=6.3 Hz/, 1,2-1,5 /10H, multiplet/, 1,6-1,8 /2H, multiplet/, 3,89 /3H, singlet/, 3,99 /2H, triplet/, J= 6,4 Hz/, 7,00 /2H, doublet, J=8,9 Hz/, 7,45 /2H, doublet, J=8,9 Hz/, 14,05 /1H, singlet/.

Preparative example 78. In a mixture of 2,3,4,5,6 - pentafluorobenzoic acid /1 g/ and 2,2,3,3,4,4,5,5,-octafluoropentyl /1.18 g/ N, N-dimethylformamide /5 ml) was added 62% sodium hydride /0.39 g/ at room temperature. The mixture was stirred at the same temperature for 1 h and added to it a mixture of water with ethyl acetate. Otdeleniya the organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuum. The residue was purified by chromatography on silica gel to obtain 4-/2,2,3,3,4,4,5,5-octave

NMR-spectrum /DMCO-d6, /: 4,96 /2H, triplet, J= 14,2 Hz/, 7,10 /1H, triple triplet, J=5,6 and 50.2 Hz/.

Preparative example 79. 4-/2,2,3,3,4,5,5,5,6,6,7,7,8,8,8-pentadecafluorooctanoic/ -2,3,5,6-tetrafluorobenzoic acid.

IR /Nuol/: 3400, 1640, 1560 cm-1.

NMR-spectrum /DMCO-d6/: 4,95 /2H, triplet, J=14 Hz/.

The following connections /preparative examples 80-90/ received according to the manner similar to that described in preparative example 5.

Preparative example 80. Succinimido 2-/4-hydroxyphenyl/-2-/4-octyloxybenzophenone/acetate.

IR-spectrum /Nuol/: 1800, 1770, 1700, 1600 cm-1.

Preparative example 81. Succinimido 2-phenyl-2-/4-octyloxybenzophenone/acetate

IR-spectrum /Nuol/: 1780, 1730, 1605 cm-1.

NMR /DMCO-d6, /: 0,86 /3H, multiplet/, 1,26 /10H, multiplet/, 1,69 /2H, multiplet/, 2,90 /4H, multiplet/, 3,94 /2H, triplet, J=6,4 Hz/, 5,30 /2H, singlet/, 6,91 /2H, doublet, J=8.6 Hz/, 7,25-7,56 /7H, multiplet/.

Preparative example 82. Succinimido 2-/4-Octyloxybenzophenone/acetate.

IR-spectrum /Nuol/: 1760, 1725, 1600, 1580 cm-1.

NMR-spectrum /DMCO-d6, /: 0,86 /3H, triplet, J=6,7 Hz/, 1,26 /10H, multiplet/, 1,70 /2H, multiplet/, 2,85 /4H, singlet, 3,96 /2H, multiplet/, 5,28 /2H, singlet/, 6,91 /2H, take the acetyloxy/2,3,5,6-tetrafluorobenzoate.

IR-spectrum /Nuol/: 3500, 1770, 1740, 1640 cm-1< / BR>
NMR-spectrum /DMCO-d6, /: 2,90 /4H, singlet/, 5,23 /2H, triplet, J=13,8 Hz/, 7,11 /1H, triple triplet, J=50,2 and 5.6 Hz/.

Preparative example 84. Succinimido 4-/2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluorooctanoic/ -2,3,5,6-tetrafluorobenzoate.

IR /Nuol/: 1735, 1620, 1600 cm-1.

NMR-spectrum /DMCO-d6, /: 2,90 /4H, singlet/, 5,12 /2H,triplet, J=13,8 Hz/.

Preparative example 85. Succinimido 3-methoxy-4-octyloxybenzoate.

IR-spectrum /Nuol/: 1760, 1730, 1600, 1280, 1200, 880 cm-1.

NMR-spectrum /DMCO-d6, /: 0,86 /3H, triplet, J=6,7 Hz/, 1,2-1,5 /10H, multiplet/, 1,6-1,9 /2H, multiplet/, 2,88 /4H, singlet/, 3,84 /3H, singlet/, 4.09 to /2H, triplet, J=6,5 Hz/, 7,19 /1H, doublet, J=8.6 Hz/, 7,49 /1H, doublet, J=2.0 Hz/, 7,73 /1H, double doublet, J=8.6 and 2 Hz/.

Preparative example 86. Succinimido 4-/2-butoxyethoxy/benzoate.

IR-spectrum /Nuol/: 1730, 1600, 1250, 1060 cm-1.

NMR-spectrum /DMCO-d6, /: 0,87 /3H, triplet, J = 7,2 Hz/, 1,2 - 1,6 /4H, multiplet/, 2,89 /4H, singlet/, 3.46 in /2H, triplet, J=6.3 Hz/, to 3.73 /2H, triplet, J= 4.4 Hz/, 4,25 /2H, triplet, J= 4.4 Hz/, 7,18 /2H, doublet, J=9,0 Hz/, 8,04 /2H, doublet, J = 9 Hz/.

Preparative example 87. Succinimido 2-/4-Octyloxyphenyl/2-methoxyacetate.

IR-spectrum /Nuol/: 1810, 1740, 1610, 1250, 1210, 1100 cmyears/, 3,35 /3H, singlet/, 3,97 /2H, triplet, J = 6,4 Hz/, 5,35 /1H, singlet/, of 6.96 /2H, doublet, J = 8.7 Hz/, 7,38 /2H, doublet, J = 8.7 Hz/.

Preparative example 88. O4Octyl-N /tert-butoxycarbonyl/-D-tyrosine, operations ether.

IR-spectrum /Nuol/: 3370, 1780, 1730, 1700, 1250, 1200 cm-1.

Preparative example 89. Succinimido 2-/4-octyloxyphenyl/-2-methoxyimino.

IR-spectrum /Nuol/: 1800, 1780, 1730, 1600, 1250, 1180, 1130 cm-1.

NMR-spectrum /DMCO-d6, /: 0,86 /3H, triplet, J = 6,6 Hz/, 1,2-1,5 /10H, multiplet/, 1,6-1,8 /2H, multiplet/, 2,89 /4H, singlet/, 4,01 /3H, singlet/, 4,03 /2H, triplet, J = 6,4 Hz/, 7,08 /2H, doublet, J = 8,9 Hz/, 7,68 /2H, doublet, J = 8,9 Hz/.

Preparative example 90. NOctyl-N /tert-butoxycarbonyl/-1-histidine, operations ether.

IR-spectrum /pure substance/: 1810, 1780, 1730, 1500, 1360, 1200, 1160 cm-1.

Preparative example 91. 4-Octyloxyphenyl anhydride was obtained from 4-octyloxyphenyl acid according to the method similar to that described in preparative example 5.

IR-spectrum /pure substance/: 2910, 2850, 1840, 1760, 1640, 1610, 1290, 1260 cm-1.

NMR-spectrum /DMCO-d6, /: 0,86 /3H, triplet, J = 6,8 Hz/, 1,2-1,5 /10H, multiplet/, 1,6-1,9 /2H, multiplet/, 4,19 /2H, triplet, J= 6,5 Hz/, 7,47 /1H, double doublet, J = 8.4 and 2.2 Hz,/, 7, was obtained by the same method, as the drug 5.

IR Spectr /pure/: 2960, 2850, 1780, 1740, 1260, 1230 cm-1.

NMR-spectrum /in deuterium chloroform/, million share: 0,89 /3H, triplet, J = 6,7 Hz/, 1,2-1,4 /10H, multiplet/, 1,6-1,8 /2H, multiplet/ 2,84 /4H, singlet/ 4,32 /2H, triplet, J = 6,7 Hz/.

Preparative example 93. To a solution of antiferromag ether /1,53 g/ 6 ml of chloroform added at 0oC chlorosulfonic acid. The mixture is stirred at room temperature for 30 min, then poured into a mixture of water and tetrahydrofuran.

The separated organic layer was washed with aqueous solution of sodium chloride, dried over magnesium sulfate and then the solvent is evaporated in vacuum. The residue is subjected to chromatographicaliy on a column of silica gel to obtain 1.25 g of 4-octyloxyphenyl chloride.

IR-spectrum /pure/: 1600, 1580, 1500, 1380, 1180 cm-1< / BR>
NMR-spectrum /in deuterium chloroform/ million D.: 0,89 /3H, triplet, J = 6,6 Hz/, 1,20-1,50 /10H multiplet/ 1,80 /2H, multiplet/, 4,06 /2H, triplet, J = 6,4 Hz/, 7,03 / 2H, doublet, J = 9 Hz/, of 7.96 /2H, doublet, J = 9,0 Hz/.

In table. 8 presents the structure of the compounds of examples 13-53.

Example 13. FR139835 was obtained by the reaction of compounds of FR133303 N-octyloxybenzophenone according to the method, analogic is 2">

Example 14. Connection FR139537 was obtained by the reaction of compounds of FR133303 with succinimido 4-tert-butylbenzoate according to the manner similar to that described in example 3.

IR-spectrum /Nuol/: 3300, 1620 cm-1.

NMR-spectrum /D2O, /: 1,05 /3H, doublet, J = 6,9 Hz/, 1,15 /3H, doublet, J = 5,9 Hz/, 1,33 /9H, singlet/, 2,0 - 2,3 /3H, multiplet/, 2,4 - 2,6 /3H, multiplet/, 2,7 - 2,9 /1H, multiplet/, 3,4 - 3,6 /1H, multiplet/, 3,8 - 4,9 /12H, multiplet/, 5,07 /2H, multiplet/, 5,40 /1H, doublet, J = 3 Hz/, 7,06 /1H, doublet, J = 8,2 Hz/, 7,08 /1H, double doublet, J = 8,2 Hz and 2 Hz/, 7,27 /1H, doublet, J = 2 Hz/, 7,60 /1H, doublet, J = 8.6 Hz/, 7,75 /1H, doublet, J = 8.6 Hz/.

Example 15. Connection FR141145 was obtained by the reaction of compounds of FR133303 with succinimido 4-/2-butoxyethoxy/benzoate according to the manner similar to that described in example 3.

IR-spectrum /Nuol/: 3300, 1620 cm-1.

NMR-spectrum /DMCO-d6/: 0,88 /3H, triplet, J = 7,3 Hz/, 0,93 /3H, doublet, J = 6,7 Hz/, 1,04 /3H, doublet, J = 5.7 Hz/, 1,2 - 1,6 /4H, multiplet/, 1,7 - 2,0 /3H, multiplet/, 2,1 - 2,65 /4H, multiplet/, 3,16 /1H, multiplet/, 3,7 - 4,5 /20H, multiplet/, 4,78 /1H, doublet, J = 3 Hz/, 4,86 /1H, doublet, J = 3.8 Hz/, 5,02 /1H, doublet, J = 3 Hz/, 6,74 /1H, doublet, J = 8,2 Hz/, 6,79 /1H, doublet, J = 8,2 Hz/, 7,00 /2H, doublet, J = 8,9 Hz/, 7,06 /1H, singlet/, 7,87 /2H, doublet, J = 8,9 Hz/.

FAB-mass spectrum of e/z = 1201 /M + Na/.

Example 16. Shanalogic.com described in example 3.

IR-spectrum /Nuol/: 3300, 1620 cm-1.

FAB-mass spectrum of e/z = 1233 /M + Na/.

Example 17. Connection FR140215 obtained by the reaction of compounds of FR133303 4-octyloxyphenyl anhydride according to the method similar to that described in example 3.

IR-spectrum /Nuol/: 3300, 1620 cm-1.

FAB-mass spectrum of e/z = 1257 /M + Na/.

Example 18. Connection FR140216 was obtained by the reaction of compounds FR 133303 with succinimido 3-methoxy-4-octylbenzoic according to the manner similar to that described in example 3.

IR-spectrum /Nuol/: 3300, 1620 cm-1.

FAB-mass spectrum of e/z = 1243 /M + Na/.

Example 19. Connection FR140727 was obtained by the reaction of compounds FR 133303 with succinimido 4-/2,2,3,3,4,4,5,5-octafluoropentyl/-2,3,5,6-tetracosanoate according to the manner similar to that described in example 3.

IR-spectrum /Nuol/: 3300, 1630 cm-1.

FAB-mass spectrum of e/z = 1387 /M + Na/.

Example 20. Connection FR143301 was obtained by the reaction of compounds FR 133303 with succinimido 4-/2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluorooctanoic/- 2,3,5,6-tetracosanoate according to the manner similar to that described in example 3.

IR-spectrum /Nuol/: 3300, 1630 cm-1.

FAB-mass spectrum of e/z = 1534 /M + Na/.

Example 21. Connection FR140495 Palau in example 3.

IR-spectrum /Nuol/: 3300, 1620 cm-1.

NMR-spectrum /CD3OD, /: 1,0 - 1,1 /6H, multiplet/, 1,9 - 2,2 /3H, multiplet/, 2,3 - 2,6 /3H, multiplet/, 2,7 - 2,85 /1H, multiplet/, 3,35 /1H, multiplet/, to 3.58 /2H, singlet/, 3,65 - 4,7 /13H, multiplet/, 4,93 /1H, doublet, J = 3 Hz/, 5,04 /1H, doublet, J = 3.8 Hz/, 5,25 /1H, doublet, J 3 Hz/, 6,85 /1H, doublet, J = 8,3 Hz/, 7,01 /1H, double doublet, J = 8,3 Hz and 2 Hz/, 7,3 - 7,6 /10H, multiplet/.

Example 22. Connection FR139503 was obtained by the reaction of compounds of FR133303 with succinimido 2-/4-octyloxyphenyl/-2-methoxyacetate according to the manner similar to that described in example 3.

IR-spectrum /Nuol/: 3330, 1620 cm-1.

FAB-mass spectrum of e/z = 1257 /M+Na/.

Example 23. Connection AC was obtained by the reaction of compounds FR 133303 operations with ether O4-octyl-N/tert-butoxycarbonyl/-D-tyrosine according to the manner similar to that described in example 3.

IR-spectrum /Nuol/: 3300, 1620 cm-1.

NMR-spectrum /CD3OD, /: 0,90 /3H, triplet, J=6,8 Hz/, 1,06 /3H, doublet, J=6,8 Hz/, 1,17 /3H, doublet, J=6,7 Hz/, 1,2-1,3 /10H, multiplet/, 1,35 /9H, singlet/, 1,74 /2H, multiplet/, 1,9-2,1 /3H, multiplet/, 2,45 /3H, multiplet/, was 2.76 /1H, multiplet/, 3,0-3,1 /1H, multiplet/, 3,37 /1H, multiplet/, 3,7-4,6 /18H, multiplet/, 4,94 /1H, doublet, J=3 Hz/, 5,01 /1H, doublet, J=3.8 Hz/, 5,25 /1H, doublet, J=3 Hz/, 6,79 /2H, doublet, J=8,>Example 24. Connection FR139501 was obtained by the reaction of compounds of FR133303 N-/tert-butoxycarbonyl/-1-2-/2-naphthyl/-glycine operations ether according to the method similar to that described in example 3.

IR-spectrum /Nuol/: 3300, 1620 cm-1.

Example 25. Connection FR139502 obtained by the reaction of compounds of FR133303 with N-octyl-N/tert-butoxycarbonyl/-1-his-tag operations ether according to the method similar to that described in example 3.

IR-spectrum /Nuol/: 3300, 1620 cm-1.

FAB mass spectrum of e/z = 1330 /M+Na/.

Example 26. Connection FR139959 was obtained by the reaction of compounds of FR133303 with succinimido-2-/4-octyloxyphenyl/-2-methoxykynuramine according to the manner similar to that described in example 3.

IR-spectrum /Nuol/: 3300, 1620 cm-1.

NMR-spectrum /CD3OD, /: 0,91 /3H, triplet, J=6,7 Hz/, 1,06 /3H, doublet, J=6,8 Hz/, 1,25 /3H, doublet, J=6.3 Hz/, 1,25-1,6 /10H, multiplet/, 1,65-1,9 /2H, multiplet/, 1,9-2,2 /3H, multiplet/, 2,3-2,65 /3H, multiplet/, of 1.75 to 1.9 /1H, multiplet/, 3,3-3,5 /1H, multiplet/, 3,95 /3H, the singlet/, 3,7-4,75 /1H, multiplet/, 5,03 /1H, doublet, J=3.0 Hz/, 5,11 /1H, doublet, J= 3,7 Hz/, 5,46 /1H, doublet, J=2.7 Hz/, 6,86 /1H, doublet, J=8,2 Hz/, 6,89 /2H, doublet, J= 8,9 Hz/, 7,01 /1H, double doublet, J=8,2 Hz and 2 Hz/, 7,31 /1H, doublet, J=2 Hz/, 7,54 /2H, doublet, J=8,9 Hz/.

IR-spectrum /Nuol/: 3250, 1650, 1620 cm-1.

FAB mass spectrum of e/z = 1363 /M+Na/.

Example 28. Connection FR141580 was obtained by the reaction of compounds of FR133303 with succinimido 2-phenyl-2-/4-octyloxybenzophenone/acetate according to the method similar to that described in example 3.

IR-spectrum /Nuol/: 3300, 1646 cm-1.

FAB mass spectrum of e/z = 1346 /M+Na/.

Example 29. Connection FR141579 obtained by the reaction of compounds of FR133303 with succinimido 2-/4-octyloxybenzophenone/acetate according to the method similar to that described in example 3.

IR-spectrum /Nuol/: 3250, 1650 cm-1.

FAB mass spectrum of e/z = 1270 /M+Na/.

Example 30. Connection FR141146 was obtained by the reaction of compounds of FR133303 1/2E, 6E/-3,7,11-trimethyl-2,6,10-dodecatrien/-1H - benzotriazole-3-oxide according to a method similar to that described in example 12.

IR-spectrum /Nuol/: 3300, 1620, 1040 cm-1.

NMR /CD3OD, /: 1,06 /3H, doublet, J=6,8 Hz/, 1,19 /3H, doublet, J=5,9 Hz/, 1,60 /3H, singlet/, 1,62 /3H, singlet/, 1,66 /3H, singlet/, 1,9-2,2 /11H, multiplet/, 2,05 /3H, singlet/, 2,3-2,6 /3H, multiplet/, 2,7-2,9 /1H, multiplet/, 3,35 /1H, multiplet/, 3,7-5,0 /14H, multiplet/, 5,08 /4H, multiplet/, 5,27 /1H, doublet, J=2,8 Hz/, 5,77 /1H, singlet/, 6,86 /1H, doublet, J= 8,3 reaction compounds FR 133303 1/4-octylbenzoic/-1H-benzotriazole-3-oxide according to the method, similar to that described in example 12.

IR-spectrum /Nuol/ : 3300, 1620, 1040 cm-1.

NMR-spectrum /CD3OD, / : 0,86 /3H, triplet, J=6,8 Hz/, 1,06 /3H, doublet, J= 6,8 Hz/, 1,21 /3H, doublet, J=5.8 Hz/, 1,25-1,45 (10H, multiplet/, 1,55-1,75 /2H, multiplet/, 1,9-2,25 /3H, multiplet/, 2,35-2,6 /3H, multiplet/, 2,65 /2H, triplet, J=7.5 Hz,/, 2,81 /1H, multiplet/, 3,32 /1H multiplet/, 3,7-4,8 /14H, multiplet/, 4,98 /1H, doublet, J=3 Hz/, 5,09 /1H, doublet, J=3,9 Hz/, 5,31 /1H, doublet, J= 3 Hz/, 6,86 /1H, doublet, J=8,3 Hz/, 7,03 /1H, double doubles, J=8,3 and 2 Hz/, 7,24 /2H, doublet, J=8,2 Hz/, 7,33 /1H, doublet, J=2 Hz, 7,74 /2H, doublet, J=8,2 Hz/.

FAB-mass spectrum of e/z=1197 /M+Na/.

Example 32. Connection FR140217 was obtained by the reaction of compounds FR 1333303 1-/4-/4-octyloxy/phenoxy/benzoyl/1H-benzotriazole-3-oxyl according to the method similar to that described in example 3.

IR-spectrum /Nuol/ : 3300, 1620 cm-1.

FAB mass spectrum of e/z=1305 /M+Na/.

Example 33. Connection FR142472 was obtained by the reaction of compounds of FR133303 c 1-/4-/4-/4-octyloxyphenyl/benzoyl/-1H-benzotriazole-3 - oxide according to a method similar to that described in example 12.

IR-spectrum /Nuol/ : 3300, 1620 cm-1.

NMR-spectrum /CD3OD, / : to 0.88 (3H, triplet, J=6,7 Hz/, 1,06 /3H, doublet, J= 6,8 Hz/, 1,23 /3H, doublet, J=6,1 Hz/, between 1.3-1.6 (10H, multiplet/, 1,8-1,9 /2H, multiplet/, 1,9-2,3 /3H/, 5,10 /1H, doublet, J=3,7 Hz/, 5,35 /1H, doublet, J=2.7 Hz/, 6,87 /1H, doublet, J=8,3 Hz/, 6,99 /2H, doublet, J=8,8 Hz/,? 7.04 baby mortality /1H, double doublet, J= 8.3 and 1.9 Hz/, 7,33 /1H, doublet, J=1.9 Hz/, 7,58 /2H, doublet, J=8,8 Hz, 7,62 /2H, doublet, J=8,4 Hz/, 7,87 /2H, doublet, J=8,4 Hz/.

FAB mass spectrum of e/z=1289 /M+Na/.

Example 34. Connection FR140496 was obtained by the reaction of compounds FR 13303 with 1-6/6 tucuxi-2-naphtol/-1H-benzotriazole-3-oxide according to a method similar to that described in example 12.

IR-spectrum /Nuol/ : 3300, 1620 cm-1.

FAB-mass spectrum of e/z=1207 /M+Na/.

Example 35. Connection FR140497 was obtained according to the reaction between the compound FR133303 and 1/6th hexyloxy-2-naphtol/-1H-benzotriazole-3-oxide according to a method similar to that described in example 12.

IR-spectrum /Nuol/, 3300, 1620 cm-1.

Range-NMR /DMCO-d6, / : 0,89 /3H, triplet, J=6,6 Hz/, 0,97 /3H, doublet, J= 6,9 Hz/, 1,08 /3H, doublet, J=5,9 Hz/, 1,2-1,6 /6H, multiplet/, 1,7-2,1 /5H, multiplet/, 2,1-2,5 /3H, multiplet/, 2,5 - 2,7 /1H, multiplet/, 3,19 /1H, multiplet/, to 3.73 /2H, multiplet/, 3,8-4,5 /12H, multiplet/, 4,80 /1H, doublet, J= 3 Hz/, 4,88 /1H, doublet, J=3.8 Hz/, 5,08 /1H, doublet, J= 3 Hz/, 6,74 /1H, doublet, J=8,2 Hz/, 6,80 /1H, double doublet, J= 8,2 Hz and 2 Hz/, 7,08 /1H, J=2 Hz/, 7,26 /1H, double doublet, J=a 8.9 Hz and 2.4 Hz/, 7,39 /1H, doublet, J=2,4 Hz/, a 7.85 /1H, doublet, J=8.7 Hz/, 7,89 /1H, doublet, J=8.7 Hz/, 7,93 /1H, doublet, J=8 and connection FR133303 1-/6-/2-ethylhexyloxy/-2-naphtol/-1H-benzotriazole-3 - oxide according to the method, similar to that described in example 12.

IR-spectrum /Nuol/ : 3250, 1620 cm-1.

NMR /CD3OD, / : 0,93 /3H, triplet, J=7,4 Hz/, 0,98 /3H, triplet, J=7,4 Hz/, 1,06 /3H, doublet, J=6,8 Hz/, 1,24 /3H, doublet, J=6 Hz/, 1,3-1,7 /8H, multiplet/, 1,7-1,9 /1H, multiplet/, 1,9-2,3 /3H, multiplet/, 2,3-2,7 /3H, multiplet/, 2,8-3,0 /1H, multiplet/, 3,39 /1H, multiplet/, 3.7 to 4.7 (16H, multiplet/, 5,0 /1H, doublet, J=4.4 Hz/, 5,11 /1H, doublet, J=3,7 Hz/, lower than the 5.37 /1H, doublet, J 2.6 Hz/, 6,87 /1H, doublet, J=8,3 Hz/,? 7.04 baby mortality /1H, double doublet, J=8,3 and 2 Hz/, 7,17 /1H, double doublet, J=8,9 and 1.9 Hz/, 7,22 /1H, doublet, H=2 Hz/, 7,33 /1H, doublet, J=1.9 Hz/, 7,7-7,9 /3H, multiplet/, 8,29 /1H, singlet/,

FAB mass spectrum of e/z = 1263 /M+Na/.

Example 37. Connection FR140728, obtained by the reaction of compounds FR 133303 1/6 decyloxy-2-naftol/-1H-benzotriazole-3-oxide according to a method similar to that described in example 12.

IR-spectrum /Nuol/: 3300, 1620 cm-1.

NMR-spectrum /DMCO-d6+ D2O, /: 0,86 /3H, triplet, J=6,6 Hz/, 0,97 /3H, doublet, J= 6,7 Hz/, 1,07 /3H, doublet, J=5,9 Hz/, 1,2-1,6 /14H, multiplet/, 1,7-2,1 /5H, multiplet/, 2,1-2,5 /3H, multiplet/, 2,5-2,7 /1H, multiplet/, 3,19 /1H, multiplet/, 3,45 /1H, multiplet/, to 3.73 /2H, multiplet/, 3.9 to 4.5 /12H, multiplet/, 4,79 /1H, doublet, J=3 Hz/, 4,87 /1H, doublet, J= 3.8 Hz/, 5,07 /1H, doublet, J=3 Hz/, 6,74 /1H, doublet, J=8,2 Hz/, 6,79 /1H, double doublet, J=8.1 and 2 Hz/, 7,06 /1H, doublet, J=2 Hz/ 7.2V is C/, 8,45 /1H, singlet/.

FAB mass=range e/z = 1291 /M+Na/.

Example 38. Connection FR142172 was obtained by the reaction of the compound FR 133303 with 1-36/3,7-dimethyloctane/-2-naftol/-1H-benzotriazole-3-oxide according to a method similar to that described in example 12.

IR-spectrum /Nuol/: 3300, 1610 cm-1< / BR>
NMR-spectrum /DMCO-d6+ D2O, /: 0,85 /6H, doublet, J=6,6 Hz/, 0,95 /3H, doublet, J-5,9 Hz/, 0,97 /3H, doublet, J=6,7 Hz/, 1,08 /3H, doublet, J=5,9 Hz/, 1,1-1,4 /6H, multiplet/, 1,4-2,1 /7H, multiplet/, 2,1-2,5 /3H, multiplet/, 2,5-2,7 /1H, multiplet/, 3,19 /1H, multiplet/, 3,74 /2H, multiplet/, 3,9-4,6 /12H, multiplet/, 4,81 /1H, doublet, J=3 Hz/, 4,87 /1H, doublet, J=3.8 Hz/, 5,07 /1H, doublet, J=3 Hz/, 6,74 /1H, doublet, J=8,2 Hz/, 6,83 /1H, double doublet, J= 8.1 and 2 Hz/, 7,06 /1H, doublet, J=2 Hz/, of 7.23 /1H, double doublet, J=8,9 and 2.4 Hz/, 7,40 /1H, doublet, J=2,4 Hz/, a 7.85 /1H, doublet, J= 8.7 Hz/, 7,89 /1H, doublet, J=8.7 Hz/, 7,93 /1H, doublet, J=8,9 Hz/, 8,45 /1H, singlet/

FAB mass spectrum of e/z = 1291 /M+Na/.

Example 39. Connection FR143326 was obtained by the reaction of compounds of FR133303 1-/6-/3,7-dimethyl-6-octenoate/2 naphtol/-1H-benzotriazole-3-oxide according to a method similar to that described in example 12.

IR-spectrum /Nuol/: 3300, 1620, 1260, 1040 cm-1.

NMR-spectrum /CD3OD, /: 1,0/3H, doublet, J=6.2 Hz/, 1,06 /3H, doublet, J= 6,8 Hz/, 1,25 /3H, doublet, J=5,9 Hz/, 1,2-1,6 /2H, multiplet/, 1,61 /3H, miltiple/, 5,00 /1H, doublet, J=5,1 Hz/, 5,08-5,2 /2H, multiplet/, lower than the 5.37 /1H, doublet, J=2,5 Hz/, 6,87 /1H, doublet, J=8,3 Hz/,? 7.04 baby mortality /1H, doublet, J=8,3 Hz/, 7,15 /1H, doublet, J=8,9 Hz/, 7,21 /1H, singlet/, 7,33 /1H, singlet/, 7,71 /1H, doublet, J=8.7 Hz/, to 7.77-a 7.85 /2H, multiplet/, 8,28 /1H, singlet/.

Example 40. Connection FR142390 was obtained by the reaction of compounds FR 133303 1-/6-//E/-3,7-dimethyl-2,6-octonionic/-2-naphtol/- 1H-benzotriazole-3-oxide according to a method similar to that described in example 12.

IR-spectrum /Nuol/: 3300, 1620 cm-1.

NMR-spectrum /DMCO-d6D2O, /: 0,97 /3H, doublet, J=6,7 Hz/, 1,07 /3H, doublet, J= 6 Hz/, 1,57 /3H, singlet/, 1,61 /3H, singlet/, 1,76 /3H, singlet/, 1,8-2,5 /9H, multiplet/, 2,5-2,7 /1H, multiplet/, 3,19 /1H, multiplet/, 3,45 /1H, multiplet/, to 3.73 /2H, multiplet/, 3,9-4,6 /11H, multiplet/, 4,70 /2H, doublet, J=5.6 Hz/, 4,80 /1H, doublet, J=3 Hz/, 4,87 /1H, doublet, J= 3.8 Hz/, 5,07 /2H, multiplet/, 5,51 /1H, triplet, J=6,5 Hz/, 6,74 /1H, doublet, J= 8,3 Hz/, 6,83 1H, double doublet, J=8,3 Hz/ 2 Hz/, 7,07 /1H, doublet, J=2 Hz/, 7,24 /1H, double doublet, J=8,9 and 2.4 Hz/, 7,40 1H, doublet, J= 2,4 Hz/, 7,8-8,0 /3H, multiplet/, 8,45 /1H, singlet/.

FAB mass spectrum of e/z = 1287 /M+Na/.

Example 41. Connection FR140729 was obtained by the reaction of compounds FR 133303 1-/5-dodecyloxy-2-naphtol/-1H-benzotriazole-3-oxide according to a method similar to that described in example 12.

IR-spectrum /new 1,07 /3H, doublet, J=5,9 Hz/, 1,2-1,6 /18H, multiplet/, 1,7-2,1 /5H, multiplet/, 2,1-2,5 /3H, multiplet/, 2,5-2,7 /1H, multiplet/, 3,19 /1H, multiplet/, 3,45 /1H, multiplet/, to 3.73 /2H, multiplet/, 3,9-4,5 /12H, multiplet/, 4,79 /1H, doublet, J = 3 Hz/, 4,87 /1H, doublet, J = 3.8 Hz/, 5,07 /1H, doublet, J = 3 Hz/, 6,74 /1H, doublet, J = 8,1 Hz/, 6,78 /1H, double doublet, J = 8.1 and 2 Hz/, 7,06 /1H, doublet, J = 2 Hz/, of 7.23 /1H, double doublet, J = 8,9 and 2.4 Hz/, 7,38 /1H, doublet, J = 2,4 Hz/, a 7.85 /1H, doublet, J = 8.7 Hz/, 7,89 /1H, doublet, J = 8.7 Hz/, 7,93 /1H, doublet, J = 8,9 Hz/, 8,44 /1H, singlet/.

FAB mass spectrum of e/z = 1320 /M+Na/

Example 42. Connection FR140730 was obtained by the reaction of compounds FP 133303 1-/2-anticarbon/-1H-benzotriazole-3-oxide according to a method similar to that described in example 12.

IR-spectrum /Nuol/: 3300, 1620 cm-1.

FAB mass spectrum of e/z = 1185 /M+Na/.

Example 43. Connection FR143020 was obtained by the reaction of compounds FP 133303 1-/2-octyloxyphenyl/acetyl/-1H-benzotriazole-3-oxide according to a method similar to that described in example 12.

IR-spectrum /Nuol/: 3300, 1620 cm-1.

NMR-spectrum /CD3OD, /: 0,87 /3H, triplet, J = 6,8 Hz/, 1,0-1,2 /6H, multiplet/, 1,2-1,6 /10H, multiplet/, 1,6-1,85 /2H, multiplet/, 1,85-2,1 /3H, multiplet/, 2,3-2,6 /3H, multiplet/, 2,7-2,85 /1H, multiplet/, 3,32 /1H, multiplet/, 3.46 in /2H, singlet/, 3.7 to 4.7 /16H, multiplet/, 5,04 /1H, doublet, J =="ptx2">

FAB mass spectrum = 1227 /M+Na/

Example 44. Connection FR143021 was obtained by the reaction of compounds FR 133303 1-/3-/4-octyloxyphenyl/propionyl/-1H-benzotriazole-3-oxide according to a method similar to that described in example 12.

IR-spectrum /Nuol/: 3300, 1620 cm-1< / BR>
FAB mass spectrum of e/z= 1241 /M+Na/

Example 45. Connection FR141315 was obtained by the reaction of compounds FR 133303 1-//E/-3-/4-octyloxyphenyl/acryloyl/-1H-benzotriazole-3 - oxide according to a method similar to that described in example 12.

IR-spectrum /Nuol/: 3300, 1620 cm-1< / BR>
NMR-spectrum /DMCO-d6+D2O, /: 0,86 /3H, triplet, J = 6,7 Hz/, 0,97 /3H, doublet, J = 6,7 Hz/, 1,04 /3H, doublet, J = 5.4 Hz/, 1,2-1,5 /10H, multiplet/, 1,6-2,0 /5H, multiplet/, 2,1-2,5 /3H, multiplet/, 2,5-2,6 /1H, multiplet/, 3,17 /1H, multiplet/, 3,3-4,5 /15H, multiplet/, 4,79 /1H, doublet, J = 3 Hz/, 4,86 /1H, doublet, J = 3.8 Hz/, 5,01 /1H, doublet, J = 3 Hz/, 6,57 /1H, doublet, J = 15,8 Hz/, 6,74 /1H, doublet, J = 8,2 Hz/, 6,82 /1H, doublet, J = 8,2 Hz/, 6,97 /2H, doublet, J = 8,8 Hz/, 7,09 /1H, singlet/, 7,34 /1H, doublet, J = 15,8 Hz/, 7,52 /2H, doublet, J = 8,8 Hz/.

FAB mass spectrum of e/z= 1239 /M+Na/

Example 46. Connection FR140105 was obtained by the reaction of compounds FR 0 133303 1/O4-octyl-N,N-dimethyl-1-tyrosine/-1H-benzotriazole-3 - oxide according to a method similar to that described in example 12.

IR-spectrum /Nuol/: 3300, 1620 cm

Example 47. Connection FR141564 was obtained by the reaction of compounds FR 133303 4-octyloxybenzophenone chloride according to the method similar to that described in example 6.

IR-spectrum /Nuol/: 3300, 1620 cm-1< / BR>
NMR-spectrum /DMCO-d6+D2O, /: 0,87 /3H, triplet, J = 6,7 Hz/, 0,97 /3H, doublet, J = 6,8 Hz/, 1,04 /3H, doublet, J = 5.7 Hz/, 1,1-1,5 /10H, multiplet/, 1,6-2,1 /5H, multiplet/, 2,45 /3H, multiplet/, 2,5-2,7 /1H, multiplet/, 3,19 /1H, multiplet/, 3,7-4,5 /16H, multiplet/, 4,80 /1H, doublet, J = 3 Hz/, 4,88 /1H, doublet, J = 4 Hz/, 5,08 /1H, doublet, J = 3 Hz/, 6,74 /1H, doublet, J = 8,2 Hz/, 6,82 /1H, doublet, J = 8,2 Hz/, 6,84 /2H, doublet, J = 8.7 Hz/, 7,07 /1H, singlet/, 7,51 /2H, doublet, J = 8.7 Hz/.

FAB mass spectrum of e/z = 1249 /M+Na/.

Example 48. Connection FR143170 was obtained by the reaction of compounds of FR133303 with 6-octyloxy-2-naphthylmethyl chloride according to the method similar to that described in example 6.

IR-spectrum /Nuol/: 3300, 1620 cm-1< / BR>
NMR-spectrum /CD3OD /: 0,29 /3H, doublet, J = 6 G is 3,37 /1H, multiplet/, 3,55 - 4,65 /17H, multiplet/, equal to 4.97 /1H, multiplet/, 5,54 /1H, multiplet/, 6,84 /1H, doublet, J = 8,3 Hz/, 7,01 /1H, double doublet, J = 8,4 Hz and 2 Hz/, 7,15 - 7,3 /3H, multiplet/, 7,75 - 8,0 /3H, multiplet/, 8,35 /1H, singlet/.

FAB-mass spectrum: e/z = 1299 /M + Na/

Example 49. To a solution of compound FR138364 obtained in example 5 /0.25 g/ acetonitrile /5 ml, was added p-toluensulfonate /0,132 g/ and the resulting mixture was stirred for 8 hours at room temperature. The reaction mixture was added water and the water layer was set pH 4.5 with saturated aqueous sodium bicarbonate solution. The aqueous solution was subjected to column chromatography on Diaion HP-20, spend elution with 80% aqueous methanol. The fractions containing the target compound were combined and evaporated under reduced pressure to remove methanol. The remainder liofilizirovanny getting connection FR138912 /0.15 g/.

IR-spectrum /Nuol/: 3300, 1620 cm-1.

FAB-mass spectrum: e/z = 1272 /M + K/.

Example 50. The mixture of compounds FR138728 obtained in example 8 /0.15 g/ 1-oxtel-1,4-dihydropyridin-4-thione /0,0341 g/ in N,N-dimethylformamide was stirred for 1.5 hours while cooling with ice. In the reaction mixture were sprayed diethyl ether /50 ml/. The precipitate was filtered and su is m 4.5. The aqueous solution was subjected to column chromatography on Diaion HP-20 /50 ml/ conduct elution with 80% aqueous solution. Fractions containing the target compound were combined and evaporated under reduced pressure to remove methanol. The remainder liofilizirovanny getting connection FR138960 /0.15 g/.

IR-spectrum /Nuol/: 3300, 1620 cm-1< / BR>
FAB-mass spectrum: e/z = 1222 /free M + Na/.

The following compounds /Examples 51 - 53/ received according to the manner similar to that described in example 3.

Example 51. Connection FR138727

Range-NMR /CD3OD /: 0,90 /3H, triplet, J = 6,8 Hz/, 1,05 /3H, doublet, J = 6,8 Hz/, of 1.17 and 1.33 /13H, multiplet/, 1,6 - 1,8 /2H, multiplet/, 1,9 - 2,1 /3H, multiplet/, 1,9 - 2,1 /3H, multiplet/, 2,50 /1H, multiplet/, 2,75 /1H, double doublet, J = 16 Hz and 4 Hz/, 3,40 /1H, multiplet/, 3,7 - 3,8 /1H, multiplet/, 3,98 /2H, triplet, J = 6.2 Hz/, 3,9 - 4,2 /5H, multiplet/, 4,3 - 4,5 /5H, multiplet/, 4,5 - 4,7 /5H, multiplet/, equal to 4.97 /1H, doublet, J = 3 Hz/, 5,06 /1H, singlet/, 5,20 /1H, doublet, J = 3 Hz/, 5,40 /1H, doublet, J = 3 Hz/, 6,85 /1H, doublet, J = 8,3 Hz/, 6,95 /2H, doublet, J = 8,5 Hz/, 7,02 /1H, doublet, J = 8,3 Hz/, 7,30 /1H, doublet, J = 8,5 Hz/, 7,44 /1H, singlet/.

Example 52. Connection FR139912.

IR-spectrum /Nuol/: 3300, 1620 cm-1< / BR>
Example 53. Connection FR138960.

IR-spectrum /Nuol/: 3300, 1620 cm

Getting 94. Succinimido 4-/4-heptyloxybiphenyl/benzoate.

IR-spectrum /Nujol/: 1760, 1740, 1600 cm-1< / BR>
NMR-spectrum /CDCl3, /: 0,87 /3H, T., J = 6,8 Hz/, 1,2 - 1,7 /8H, m/, 1,7 - 1,9 /2H, m,/, 2,92 /4H, S./, 4,01 /2H, m,/, J = 6,5 Hz/, 7,00 /2H, d, /, J = 8,8 Hz/, 7,58 /2H, d,/, J = 8,8 Hz/, 7,69 /2H, d, J = 8,5 Hz/, 8,17 /2H, D., J = 8,5 Hz/.

Getting 95. Succinimido 4-/4-hexyloxyphenol/benzoate.

IR-spectrum /Nujol/: 1760, 1720, 1600 cm-1< / BR>
NMR /CDCl3, /: 0,92 /3H, T., J = 6,8 Hz/, 1,2 - 1,5 /6H, m/, 1,7 - 1,9 /2H, m,/, 2,90 /4H, S./, 3,96 /2H, T., J = 6,5 Hz/, 6,9 - 7,1 /6H, m/, 8,07 /2H, d, J = 9 Hz/.

In table.4 shows the structure of the compounds of examples 54 and 55.

The following connections /examples 54 and 55/ was obtained by the method similar to the method of example 3.

Example 54. FR 144274

IR-spectrum /Nujol/: 3300, 1620 cm-1.

Calculated, %: C 48,53; H 6,29; N 8,23; S 2,35.

C55H73N8SO22Na .

The claimed connection

.

To a solution of starting compound (0.5 g) in N,N-dimethylformamide (10 ml) in the presence of molecular sieves added acetic anhydride (0,119 ml) and then with cooling with ice, add triethylamine (0,175 ml). The mixture is stirred for 5 hours while cooling with ice. The reaction mixture is treated with ethyl acetate (50 ml). The precipitate exchange column chromatography on DOWEX-50Wx4 (Dow chemical) and elute with water. The fractions containing the inventive compound are combined and subjected to column chromatography on ODS (YMC-gel ODS-AM S-50) (Yamamura chemical) and elute 40% aqueous solution of methanol. The fractions containing the inventive compound evaporated under reduced pressure to remove methanol. The remainder lyophilizer and get the claimed compound (104 mg).

NMR (CD3OD, ): of 0.90 (t, 3H, J = 6,7 Hz) of 1.07 (d, 3H, J = 6.8 Hz), of 1.20 (d, 3H, J = 6,1 Hz), 1.3 to 1.6 (m, 10H), 1.7 to 1.9 (m, 2H), 1,9 - 2,2 (m, 3H), to 2.29 (s, 3H), 2,2 - 2,6 (m, 3H), 2,7 - 2,9 (m, 1H), 3,39 (m, 1H), 3.7 to 4.7 (m, 16H), to 4.98 (s, 1H), 5,10 (d, 1H, J = 3.5 Hz), 5,32 (d, 1H, J = 2,8 Hz), 6,93 (d, 2H, J = 8,9 Hz), to 7.09 (d, 1H, J = 8,3 Hz), 7,19 (dd, 1H, J = 8,3; and 1.7 Hz), 2,60 (d, 1H, J = 1.7 Hz), 7,80 (d, 2H, J = 8,9 Hz).

1R (Nujol): 3300, 1740, 1600, 1040 cm-1< / BR>
FAB-MS e/z = 1255 (M + Na).

Calculated, %: C 46,56; H 6,38; N 8,35;

C52H73N5NaO33< / BR>
where R1is a hydrogen atom or acyl group;

R2- hydroxy - or alloctype;

R3- hydrogen, hydroxychloroquine;

R4is hydrogen, carbarnoyl, provided that R1is not a, which, when R2the hydroxy - group, and R3- hydroxysulfonic,

or its pharmaceutically acceptable salt.

2. The method of producing cyclopeptide General formula Ia

< / BR>
the carbarnoyl,

or its pharmaceutically acceptable salts, characterized in that compounds of General formula II

< / BR>
where R1- Palmitoyl;

R2the hydroxy - group;

R3- hydrogen, hydroxychloroquine;

R4is hydrogen, carbarnoyl,

or its pharmaceutically acceptable salt, otscheplaut group, R1.

3. The method of producing cyclopeptide General formula IB

< / BR>
where R1a- acyl group;

R2the hydroxy - group;

R3- hydrogen, hydroxychloroquine;

R4is hydrogen, carbarnoyl,

or its pharmaceutically acceptable salts, characterized in that the compound of General formula Ia

< / BR>
where R2the hydroxy - group;

R3- hydrogen, hydroxychloroquine;

R4is hydrogen, carbarnoyl,

or its pharmaceutically acceptable salt is subjected to acylation.

4. The method of producing cyclopeptide General formula Ib

< / BR>
where R1aar(lower)alkanoyl, which has higher alkoxy and amino;

R2the hydroxy - group;

R3- hydrogen, hydroxychloroquine;

R4is hydrogen, carbarnoyl,

or its pharmaceutically acceptable salt, ExC is related values;

R1bar(lower)alkanoyl, which has higher alkoxy and protected amino groups,

or its pharmaceutically acceptable salt otscheplaut aminosidine group, R1b.

5. The method of producing cyclopeptide General formula Id

< / BR>
where R1e- pyridylthio(lower)alkanoyl, which is higher alkyl;

R2the hydroxy - group;

R3- hydrogen, hydroxychloroquine;

R4is hydrogen, carbarnoyl,

or its pharmaceutically acceptable salts, characterized in that the compound of General formula Ie

< / BR>
where each of R2, R3and R4has the specified values;

R1d- halogen(lower)alkanoyl,

or its pharmaceutically acceptable salt is administered in cooperation with pyridine, which contains higher alkyl, or its salt.

6. The method of producing cyclopeptide General formula If

< / BR>
where R1f- acyl group;

R2- alloctype;

R3- hydrogen, hydroxychloroquine;

R4- hydrogen, carbamoyl,

or its pharmaceutically acceptable salts, characterized in that the compound of General formula IV

< / BR>
where each of R3and R4have indicated the key acceptable salt is subjected to acylation.

7. Pharmaceutical composition having antimicrobial activity, containing the active ingredient and a carrier, wherein the ingredient is a compound of General formula I on p. 1 or its pharmaceutically acceptable salt in an effective amount.

8. Connection on p. 1 having antimicrobial activity.

Priority signs and items:

18.06.90 on PP.1 and 2, compound I, where R1- H, acyl, R2- OH;

31.10.90 on p. 4;

24.01.91 on p. 6.

 

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EFFECT: improved stability and bioaccessibility properties.

48 cl, 4 tbl

FIELD: chemico-pharmaceutical industry.

SUBSTANCE: the present innovation deals with new stabilized pharmaceutical composition in its lyophilized form including the compound of formula I

as an active ingredient and lactose disaccharide as a stabilizing agent. The present pharmaceutical compositions are of high stability at storage. As for active ingredient it is not destroyed in the course of time.

EFFECT: higher efficiency.

10 cl, 15 ex, 6 tbl

FIELD: organic chemistry, amino acids.

SUBSTANCE: invention proposes agonists of somatostatin of the formula (I): X-A1-cyclo-(D-Cys-A3-A4-Lys-A6-A7)-A8-Y or its pharmaceutically acceptable salt wherein X represents hydrogen atom (H); A1 represents L-Cpa, L-Phe, L-Trp or L-Nal; A3 represents L-3-Pal or L-4-Pal; A4 represents D-Trp; A6 represents -NH-(CHR1)n-CO- wherein n = 2, 3 or 4; A7 represents L- or D-Cys; A8 represents D- or L-isomer of amino acid taken among the group consisting of Nal, Phe, Cpa and Trp; Y represents NH2; R1 represents hydrogen atom (H), and Cys in A3 is bound by disulfide bong in A wherein this disulfide bond is formed by thiol groups of each Cys residue.

EFFECT: valuable biological properties of compounds.

9 cl, 2 ex

FIELD: organic chemistry, polypeptides.

SUBSTANCE: invention relates to new antagonists of urotensin-II. Invention represents group of cyclic polypeptides of the general formula: (R1)a-AA1-cyclo-[AA2-AA3-AA4-AA5-AA6-Cys]-AA7-R2 wherein AA1 means L-isomer of aromatic amino acid; AA2 means L- or D-isomer of Cys; AA3 means L-isomer of aromatic amino acid; AA4 means L- or D-isomer of Trp; AA5 means L- or D-isomer of Lys, N-Me-Lys or Orn; AA6 means L- or D-isomer of Val, Thr, Leu, Ile, Tle, Nle or aromatic amino acid; AA7 means L- or D-isomer of Val, Thr, Leu, Ile, Tle, Abu, Nle or aromatic amino acid; R1 means hydrogen atom (H), lower alkyl, lower alkanoyl or lower acyl; a = 1 or 2; R2 means hydroxyl; group (OH), OR3, N(R3)2 or NHR3 wherein R3 means H, lower alkyl or arylalkyl. These cyclic polypeptides are used as antagonists of urotensin-II.

EFFECT: valuable biological properties of compounds.

24 cl, 1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: preparation belongs to decapeptides considered to be an analog of receptor-binding fragment of TGFα from 22 to 31 amino acids in which the eighth amino acid residue Lys is substituted with Ser residue. The analog is bindable to wide range of cytotoxic agents and operate as vector in directed delivery of antitumor agents to tumor cells. The preparation also comprises decapeptide conjugate with a cytotoxic agent showing selective action with respect to tumors and capable of reducing tumor cells resistivity to cytotoxic agents. Conjugated parts are bound by a bond scissile with respect to acid hydrolysis. Another embodiment of the invention is related to pharmaceutical composition containing effective quantity of conjugate and carrier applicable as intravenous injections.

EFFECT: enhanced effectiveness of treatment; high antitumor action selectivity.

6 cl, 2 dwg, 2 tbl

FIELD: molecular pharmacology, in particular human endostatin preparation and method for production thereof.

SUBSTANCE: claimed preparation is isolated after cell incubation E.coli BL21 (DE3) in cultural medium up to dense level of 0.4-0.6 OD6-00. Cell contains plasmide vector pBSH-ED15 or pBSH-ED16 having size of 6675 n.p. and gene of canamicine resistance gene; vector contains replicative sites pUS ori and M13 and gene encoding lac-repressor controlled by T7-promoter, and finished product has purity of 99 % and apyretic properties. Claimed preparation is obtained by expression of endostatin gene using plasmide DNA containing in E.coli cells; product refolding and purification, wherein expression is carried out in E.coli BL21 (DE3) cells, transformed by recombinant plasmide DNA pBSH-ED15 or pBSH-ED16. Cells are cultivated in cultural medium up to dense level of 0.4-0.6 OD6-00, then 0.1-0.3 mM of isopropyltiogalactoside is added into medium and cultivation is carried out for 2-3 h up to product accumulation. Further cells is exposed with ultrasound for 50-70 s at 0°C in presence of 0.1 % sodium deoxycholate. Bodies are dissolved in presence of 1 % sodium N-lauryl sarcosine. Suspension is multiply washed and centrifuged at 5000 g. In refolding process oxidation with air oxygen is carried out for 35 h, and target product is purified using chromatography depending on used incorporated plasmide.

EFFECT: apyretic product of high purity.

6 cl, 9 ex, 7 dwg

FIELD: molecular biopharmacology.

SUBSTANCE: method for production of stress protein (heat shock protein) preparations includes such protein gene expression in E.coli cells followed by isolation, refolding and purification. Gene expression is carried out in structure of vector cDNA containing T7 promoter, kanamycin resistance gene, replicative pUC ori origin, and gene encoding lac-inductor. Vector DNA is cultured in structure of E.coli cells BL21 in nutrient medium with addition of kanamycin (100 mug/ml) and glucose (0.2 %) up to turbidity level of 0.5-0.6 OD600. Then 0.02mM isopropyl beta-D-thiogalactoside is added into medium and culturing is carried out for 1-3 h to accumulate finish product. Target product is purified by anion exchange chromatography. In said method vector DNA encoding proteins: HSP 100-200; HSP 100; HSP 90; Lon; HSP 70; HSP 60; TF 55; HSP 40; FKBPl cyclophylin; HSP 2-30; ClpP; GrpE; HSP 10, etc. of any gene are used. Invention also related to stress protein (heat shock protein) preparation obtained by abovementioned method. Protein represents recombinant HSP protein having molecular weight of about 70 kDa, which is isolated after incubation of E.coli cells in growth medium LB for 12 h at 37°C with addition of kanamycin (100 mug/ml) and glucose (0.2 %) up to turbidity level of 0.5-0.6 OD600, wherein transformed cell contains pBSH2-HSP70 plasmide DNA, carrying cDNA of heat shock protein gene, whish has size of 5118 n.p. and represents pBSH2 promoter containing T7 promoter, kanamycin resistance gene, replicative pUC ori origin, and gene encoding lac-inductor. Finished protein product has purity of at least 98 %.

EFFECT: stress proteins of high activity and high purity.

8 cl, 5 ex, 5 dwg

FIELD: biochemistry.

SUBSTANCE: method relates to new cyclopeptides of general formula cyclo(R1-Arg-Ile-Lys-Pro-His-R2) selected from group containing: P11: cyclo(DPhe-Pro-Gln-Ile-Met-Arg-Ile-Lys-Pro-His-Gln-Gly-Gln-His-Ile-Gly-Glu) (SEQ ID NO:5), P16: cyclo(Arg-Ile-Lys-Pro-His-Gln-Gly (SEQ ID NO:8), P17: cyclo(Pro-Arg-Ile-Lys-Pro-His-Gln-Gly) (SEQ ID NO:9), P19: cyclo(Gln-Ile-Met-Arg-Ile-Lys-Pro-His-Gln-Gly-Gln-His-Ile-Gly-Glu) (SEQ ID NO:10), P20: cyclo(Dphe-Pro-Gln-Ile-Met-Arg-Ile-Lys-Pro-His-Gln-Gly-Gln-His-Ile-Gly) (SEQ ID NO:11), P23: cyclo(DPhe-Pro-Arg-Ile-Lys-Pro-His-Gln) (SEQ ID NO:13), P24: cyclo(Gly-Arg-Ile-Lys-Pro-His) (SEQ ID NO:25), as well as P11, P20 and P23 with DPhe substituted by DTyr. Cyclopeptides are useful in systems for angiogenesis inhibition. System includes substrate with cyclopeptides attached by organic spacer arm optionally containing group cleavable by any fermentation system.

EFFECT: angiogenesis inhibiting cyclopeptides.

23 cl, 4 dwg, 2 tbl, 2 ex

FIELD: organic chemistry, amino acids.

SUBSTANCE: invention proposes agonists of somatostatin of the formula (I): X-A1-cyclo-(D-Cys-A3-A4-Lys-A6-A7)-A8-Y or its pharmaceutically acceptable salt wherein X represents hydrogen atom (H); A1 represents L-Cpa, L-Phe, L-Trp or L-Nal; A3 represents L-3-Pal or L-4-Pal; A4 represents D-Trp; A6 represents -NH-(CHR1)n-CO- wherein n = 2, 3 or 4; A7 represents L- or D-Cys; A8 represents D- or L-isomer of amino acid taken among the group consisting of Nal, Phe, Cpa and Trp; Y represents NH2; R1 represents hydrogen atom (H), and Cys in A3 is bound by disulfide bong in A wherein this disulfide bond is formed by thiol groups of each Cys residue.

EFFECT: valuable biological properties of compounds.

9 cl, 2 ex

FIELD: organic chemistry, polypeptides.

SUBSTANCE: invention relates to new antagonists of urotensin-II. Invention represents group of cyclic polypeptides of the general formula: (R1)a-AA1-cyclo-[AA2-AA3-AA4-AA5-AA6-Cys]-AA7-R2 wherein AA1 means L-isomer of aromatic amino acid; AA2 means L- or D-isomer of Cys; AA3 means L-isomer of aromatic amino acid; AA4 means L- or D-isomer of Trp; AA5 means L- or D-isomer of Lys, N-Me-Lys or Orn; AA6 means L- or D-isomer of Val, Thr, Leu, Ile, Tle, Nle or aromatic amino acid; AA7 means L- or D-isomer of Val, Thr, Leu, Ile, Tle, Abu, Nle or aromatic amino acid; R1 means hydrogen atom (H), lower alkyl, lower alkanoyl or lower acyl; a = 1 or 2; R2 means hydroxyl; group (OH), OR3, N(R3)2 or NHR3 wherein R3 means H, lower alkyl or arylalkyl. These cyclic polypeptides are used as antagonists of urotensin-II.

EFFECT: valuable biological properties of compounds.

24 cl, 1 tbl, 2 ex

FIELD: medicine, hormones, chemistry of peptides.

SUBSTANCE: invention describes compound of the formula: cyclo-[{4-NH2-C2H4-NH-CO-O-)-Pro}-Phg-D-Trp-Lys-Tyr-(4-Bzl)-Phe] being not obligatory in protected form, or its pharmaceutically acceptable salt of complex. Compound possesses the inhibitory activity on release of the growth hormone and insulin.

EFFECT: valuable medicinal properties of peptide.

9 cl, 2 ex

FIELD: chemical technology.

SUBSTANCE: invention relates to variants of a method for synthesis of a mixture (E)- and (Z)-isomers of ISATX247. By one variant acetyl-ciclosporin is heated with the first compound chosen from group consisting of triarylphosphine, trialkylphosphine, arylalkylphosphine and triarylarsine for preparing an intermediate substance that is stirred with the second compound chosen from group consisting of acetaldehyde, formaldehyde, deuterium-labeled formaldehyde, 2-chlorobenaldehyde and benzaldehyde. Mixture of (E)- and (Z)-isomers of acetyl-1,3-diene is prepared that is treated with a base and mixture of (E)- and (Z)-isomers of ISATX247 is prepared. Other variant for preparing mixture of (E)- and (Z)-isomers of ISATX247 represents interaction of acetyl-ciclosporin A aldehyde that is prepared by oxidation of acetyl-ciclosporin A, with phospholide by Wittig reaction followed by treatment of the prepared mixture with a base. Also, invention relates to a method for synthesis of mixture of (E)- and (Z)-isomers of ISATX247 enriched with E-isomers or Z-isomer, and to a method for synthesis of the preliminary assigned isomeric mixture of (E)- and (Z)-isomers of ISATX247 by mixing materials enriched with (E)- and (Z)-isomers.

EFFECT: improved method of synthesis.

77 cl, 7 tbl, 16 dwg, 39 ex

FIELD: chemistry.

SUBSTANCE: invention concerns biochemistry, particularly biologically active peptides with stress-protection effect, which can be applied in medicine and pharmaceutics. The invention extends the range of safe substances stress resistance of an organism to include cyclopeptides I and II featuring the following aminoacid sequence: Cyclo(Gly1-Lys2-Val3-Leu4-Lys5-Lys6-Arg7-Arg8)n, where n = 2-3.

EFFECT: extension of the range of safe substances enhancing stress resistance of an organism.

5 tbl, 5 ex

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