Derivatives of the peptides or their pharmaceutically acceptable salts, method of production thereof, pharmaceutical composition, method of treatment of diseases, by the intermediary of which is tachykinin

 

(57) Abstract:

Purpose: in medicine in the treatment of diseases, by the intermediary of which is tachykinin. The essence of the invention: derivatives of dipeptides of General formula I:

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where R1is phenyl, unsubstituted or substituted by halogen or lower alkoxy; benzofuran; pyridyl or indolyl; R2is hydrogen or lower alkyl; R3- lower alkyl, unsubstituted or substituted 1-3 times with halogen; amino; lower alkanesulfonyl; carboxy (lower) alkoxy; unsubstituted or esterified halogen, lower alkoxy, nitro; R4is lower alkyl; R5the phenyl (lower) alkyl; R7is hydrogen; lower alkyl; halogen; A hydroxy - or didehydrothymidine; Y is a bond, lower alkylene, lower albaniles or their pharmaceutically acceptable salts. Reagent I: AN(R2)CH(CH2C6H5R3R7) CONR4R5. Reagent II: R1-Y-COOH. In the resulting product to remove the ester group R3or restore the nitrogroup radical R3. The pharmaceutical composition comprises a pharmaceutically acceptable carrier and as an active agent, compound I in an amount of 0.1-1000 mg per unit dose; the method of treatment of diseases, posledni is 1-1000 mg per day. 9 table.

The present invention relates to new peptide compounds to their pharmaceutically acceptable salts. More specifically, it relates to new peptide compounds and their pharmaceutically acceptable salts, which have such a pharmacological activity, as thekennady antagonism, especially the antagonism to substance P antagonism to neirokinina A, antagonism the neirokinina B, etc., to methods for their preparation, to pharmaceutical compositions containing them and to their use as medicines.

One of the purposes of the present invention is to provide a new and useful peptide compounds and their pharmaceutically acceptable salts, which have such a pharmacological activity, as thekennady antagonism, especially the antagonism to substance P antagonism to neirokinina A, antagonism the neirokinina B, etc.

Another objective of the present invention is to develop methods of obtaining these peptide compounds and their salts.

The next objective of the present invention is to provide pharmaceutical compositions containing as active ingredient the above peptide compounds and their pharmaceutically acceptable salts.

E is or its pharmaceutically acceptable salt as an antagonist tachykinin, especially antagonist neirokinina A or antagonist neirokinina B, useful for the treatment or prevention of diseases caused by tachykinins, for example, respiratory diseases such as asthma, bronchitis, rhinitis, cough, as an expectorant, etc. ophthalmologically diseases such as conjunctivitis, vernal conjunctivitis, etc., skin diseases such as contact dermatitis, superficial dermatitis, urticaria and other eczematoid dermatitis, etc., inflammatory diseases such as rheumatoid arthritis, osteoarthritis, etc., of pains of different origin (for example, migraine, headache, dental pain, pain in cancer, back pain, etc) and similar in humans and animals.

The target compounds of the present invention can be represented by the following General formula (I):

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in which R1represents phenyl which may have 1 to 3 substituents selected from halogen and lower alkoxy; benzofuran; pyridyl or a group of the formula

< / BR>
in which R6represents hydrogen or lower alkyl;

R2represents hydrogen or lower alkyl;

R3represents lower alkyl which may have 1 to 3 Halogens;

halogen;

lower alkoxy or nitro;

R4is lower alkyl;

R5represents phenyl (lower) alkyl;

R7represents hydrogen; lower alkyl or halogen;

A represents hydroxyproline or dedehydration;

Y is the concatenation of the lower alkylene or lower Alcanena;

or are their pharmaceutically acceptable salts.

According to the present invention of a new peptide compound (I) can be obtained according to the methods shown in the following diagrams:

method 1:

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method 2:

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method 3:

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method 4:

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method 5:

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method 6:

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method 7:

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< / BR>
< / BR>
method 8:

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method 9:

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method 10:

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< / BR>
method 11:

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method 12:

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< / BR>
way 13:

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< / BR>
where R1, R2, R3, R4, R5, R7, A, X and Y each has the previously indicated meaning;

R3ais protected carboxy (lower) alkoxy;

R3bis carboxy (lower) alkoxy;

R4ais a protected hydroxy (lower) alkyl;

R4
R6bis protected carboxy (lower) alkyl;

R6c/is carboxy (lower) alkyl;

R6dis carbarnoyl (lower) alkyl which may have suitable(e) the Deputy(s);

R6eis a protected amino group;

R9is lower alkyl;

Aandis an amino acid residue containing thio;

Abis an amino acid residue containing sulfinil or sulfonyl;

Acis an amino acid residue containing amino, hydroxyl and/or carboxyl;

Adis an amino acid residue containing a protected amino group, protected hydroxyl and/or protected carboxyl;

Aeis an amino acid residue containing sulfonyloxy, which may have a suitable Deputy;

Agis an amino acid residue containing amino;

Afis an amino acid residue containing azido;

Ahis an amino acid residue containing a protected hydroxyl;

Aiis an amino acid residue containing a lower alkylthio;

L is an acidic residue;

MA and Mb each of assespretty methodologies described in the preparations and examples described later, or in the usual way.

In the present description amino acids, peptides, protective groups, condensing agents, etc. are indicated by abbreviations in accordance with JUPAC-JUB (Commission on biological nomenclature), which is usually used in the field of biology.

In addition, unless otherwise indicated, amino acids and their residues, when they are shown these cuts are having the L-configuration compounds and residues.

Suitable pharmaceutically acceptable salts of the source and target connections is a convenient non-toxic salt, and includes salt accession acid, such as salt of organic acid (for example, acetate, triptorelin, maleate, tartrate, methanesulfonate, bansilalpet, format, toluensulfonate and so on), salt of an inorganic acid (e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.,) or the salt of the amino acid (e.g. arginine, asparginase acid, glutamic acid, etc.,), or a metal salt such as a salt of an alkali metal (e.g. sodium salt, potassium salt, etc.,), and salts of alkaline earth metals (e.g. calcium salt, magnesium salt etc ), Ammon is salt, picolina salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc) or similar.

In the above and subsequent description of the present application, suitable examples and illustrations of the various definitions that are included in the scope of the present invention will be explained in more detail.

The term "lower" means the average of 1-6, preferably 1-4, carbon atoms, unless otherwise indicated.

Suitable "lower alkyl" may include alkyl straight or branched chain such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, hexyl, etc., most preferred is methyl.

Suitable "lower alkylene is alkylene having 1-6 carbon atoms, and may include methylene, ethylene, trimethylene, propylene, tetramethylene, metallisation, hexamethylene, etc., among which preferred is methylene, ethylene or trimethylene.

Suitable "lower Alcanena is albaniles having 2-6 carbon atoms, and may include vinile, propylen, etc., among which preferred is vinile.

Suitable "amino acid residue except Dr. Thr" means a divalent OST is anin (Ala), -alanine (bAIa), D - or L-valine (Val), D - or L-leucine (Leu), D - or L-threonine (Thr), D - or L-cysteine (ys), D - or L-isoleucine (Ile), D - or L-serine (Ser), D - or L-methionine (Met), D - or L-phenylalanine (Phe), L-tryptophan (Trp), D - or L-tyrosine (Tyr), D - or L-Proline (Pro), D - or L-dedehydration (DPro), such as 3,4-dedehydration (D) (3,4 Pro), D - or L-hydroxyproline (Pro(HE)) such as 3-hydroxyproline (Pro(3OH) and 4-hydroxyproline (Pro(40H)), D - or L-azetidine-2-carboxylic acid (Azt), D - or L-thioproline (TWG), D - or L-aminopropan (Pro(NH2)) such as 3-aminopropyl (Pro(3NH2)) and 4-aminopropyl (Pro(4NH2)), D - or L-pyroglutamyl acid (pGlu), D - or L-2-aminoadamantane acid, Aib, D - or L-glutamic acid (Glu), D - or L-aspartic acid (Asp), D - or L-glutamic acid (Gln), D - or L-asparagine (Asn), D - or L-lysine (Lys), D - or L-arginine (Arg), D - or L-histidine (His), D - or L-ornithine (Orn), D - or L-oxypiperidine acid, such as 5-oxopiperidine-2-carboxylic acid, D - or L-mercaptopropyl (Pro(SH)), such as 3-mercaptopropyl (Pro(3SH)) and 4-mercaptopropyl (Pro(4SH)), the side chains of which are amino, hydroxy, tirinya or carboxyl group which may be substituted by suitable substituents.

These suitable substituents may include acyl such as carbarnoyl, lower alkanoyl (for example, oxycarbonyl (for example, benzyloxycarbonyl and so on), lower alkylsulfonyl (for example, methylaminoethanol and so on ), the lower alkoxyalkyl (for example, methoxyethyl, ethoxyethyl and so on), arylsulfonyl (for example, phenylsulfonyl, tamilselvan and so on), galour(lower)alkoxycarbonyl (for example, o-chlorobenzylidene and etc.), carboxy(lower)alkanoyl (for example, carboxyethyl, carboxypropyl and so on), glycyl, b-alanyl, N-lower alkoxycarbonylmethyl (for example, N-tert.-butoxycarbonylmethyl etc.) and N-lower alkoxycarbonyl-b-alanyl (for example, N-tert.-butoxycarbonyl-b-alanyl, etc.,), N, N-di(lower)alkylamino(lower)alkanoyl (for example, N,N-dimethylaminoacetyl, N,N-diethylaminoethyl, N,N-dimethylaminopropanol, N,N-diethylaminopropyl and so on ), carboxylic, morpholinoethyl, amino(lower)alkanoyl (for example, aminoacetyl, aminopropionic and so on), N-ar(lower)alkoxycarbonyl(lower)alkanoyl (for example, N-benzyloxycarbonylamino and so on), threonyl, N-lower alkoxycarbonylmethyl (for example, N-tert. -butoxycarbonylmethyl and so on), N-lower alcoholtramadol (for example, N-acetylation and so on), N-lower alkoxycarbonyl(lower)alkyl-N-lower alkoxycarbonyl(lower)alkanoyl (for example, N-tert. -butoxycarbonylmethyl-N-tert.-butoxycarbonylamino is-O-benzyl-α-glutamyl, etc), g-glutamyl, N-ar(lower)alkoxycarbonyl-O-ar (lower)alkyl-g-glutamyl (for example, N-benzyloxycarbonyl-O-benzyl-g-glutamyl and so on), lower alkyl (e.g. methyl, ethyl, tert.-butyl, etc.,), carboxy(lower)alkyl (e.g. carboxymethyl, etc.,), morpholino, glycinamide, threonine amide, N'-glutamine N-lower alkylamide (for example, N'-glutamine-N-tert. -butylamide and so on), di(lower)alkylamino (e.g., dimethylamino, etc.,), ar(lower)alkyl (e.g. benzyl, phenethyl, etc.,), trihalo(lower)alkyl (e.g., 2,2,2-trichloroethyl and so on), low alkoxycarbonyl(lower)alkyl (e.g., methoxycarbonylmethyl, ethoxycarbonylmethyl, tert.-butoxycarbonylmethyl and so on), or useful protecting group used in this technical field. When this amino acid contains thio, she may be his sulfoxide or sulfona.

Suitable "carboxy(lower)alkyl" may include carboxymethyl, carboxyethyl, carboxypropyl etc.

Suitable "protected carboxy(lower)alkyl" means the above-mentioned carboxy(lower)alkyl, in which the carboxyl group is protected by conventional protecting group, such as cloneelement carboxyl group. Preferred examples of the ester fragment of the new ether, complex tert.-butyl ether, etc.,), etc.

Suitable "carbarnoyl(lower)alkyl, which may be suitable(e) the Deputy(s), may include carbarnoyl(lower)alkyl (e.g., carbamoylmethyl, carbamoylethyl, carbamoylmethyl and so on ), carbarnoyl(lower)alkyl having suitable(s), the substituent(s) such as lower allylcarbamate(lower)alkyl (e.g., methylcarbamoylmethyl, ethylcarboxylate and so on), amino(lower)allylcarbamate(lower)alkyl (e.g., aminoethylaminomethyl, aminoethylaminomethyl and so on), lower alkylamino(lower)alkyl/carbarnoyl(lower)alkyl (e.g., dimethylaminocarbonylmethyl, diethylaminocarbonylmethyl and so on), etc.

Suitable "lower alkyl which may have suitable(s), the substituent(s)" may include traditional groups, which are used in this technical field, such as lower alkyl, carboxy(lower)alkyl, protected carboxy(lower)alkyl, carbarnoyl(lower)alkyl which may have suitable(e) the Deputy(s), each of which is confirmed by the example above, lower alkylamino(lower)alkyl (e.g., dimethylaminomethyl, dimethylaminoethyl and etc.), hydroxy(lower)alkyl (e.g., oximeter, oxyethyl, etc), protected hydroxy(lower)ALK is silt and so on), etc.

Suitable "amino acid residue containing thio" means a bivalent residue derived from amino acids, containing thio, and may include Tpr, Met, etc.

"Suitable amino acid residue containing sulfinil or sulfonyl" means the divalent residue derived from amino acids, containing sulfinil or sulfonyl, and may include TWG(O), Met(O), TWG(O2), Met(O2etc.

"Suitable amino acid residue containing amino, hydroxy and/or carboxy" may include bivalent residue of the amino acids, such as RHS(N), Ser, Thr, Tyr, etc.

Suitable "amino acid residue containing a protected amino group, protected hydroxyl and/or protected carboxy" means the aforementioned group in which the amino, hydroxyl and/or carboxyl protected by the traditional group, usually used in this technical field, such as carbarnoyl, lower alkylsulfonyl (for example, mesyl, ethylsulfonyl and so on), arylsulfonyl (for example, phenylsulfonyl, tamilselvan and so on), low alkoxycarbonyl(lower)alkyl (e.g., methoxycarbonylmethyl, ethoxycarbonylmethyl and so on), etc.

Suitable "amino acid residue containing sulfo, containing sulfonyloxy, which has a suitable Deputy, in which "sulfonyloxy, which has a suitable Deputy" may include lower alkylsulfonate (for example, methylsulfonylamino, ethylsulfonyl and etc.), halogen(lower)alkylsulfonate (for example, tripterocalyx and so on ), arylsulfonate (for example, phenylsulfonyl, tolilsulfonil and so on), etc.

Suitable "amino acid residue containing azido" may include bivalent residue of the amino acids, such as Pro(4N3), etc.

Suitable "amino acid residue containing amino" may include bivalent residue of the amino acids, such as Pro(4NH2), etc.

Suitable "amino acid residue containing a protected hydroxyl" means the aforementioned group in which the hydroxyl is protected by the traditional group, as mentioned above.

Suitable "alkaline metal" may include sodium, potassium, etc.

Suitable "acid residue" may include halogen (e.g. fluorine, chlorine, bromine, iodine), acyloxy (for example, tosyloxy, mesilate and so on), etc.

Suitable "amino acid residue containing alkylthio" means the divalent residue and the>Suitable "carboxy(lower)alkoxy" may include carboxymethyl, carboxymethoxy, carboxypropanoyl etc.

Suitable "protected carboxy(lower)alkoxy" means the above-mentioned carboxy(lower)alkoxy, in which the carboxyl group is protected by conventional protecting group, such as cloneelement carboxyl group. A preferred example of the ester fragment may include lower alkilany ester (e.g. methyl ester, complex ethyl ester, complex propyl ether complex tert.-butyl ether, and so on), etc.

In particular, preferred options R1, R2, R3, R4, R5, R7A and Y are given below.

R1phenyl which may have one or more, preferably one to three, halogen or lower alkoxy (for example, phenyl, differenl, acid, etc), benzofuran; pyridyl or a group of the formula

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where R6is hydrogen or lower alkyl (for example, stands and so on);

R2is hydrogen or lower alkyl (for example, stands and so on);

R3represents lower alkyl which may have one or more, preferably one to three, halogen (e.g. the Boxing(lower)alkoxy (e.g., carboxymethoxy etc.); esterified carboxy(lower) alkoxy (e.g., ethoxycarbonylmethoxy and etc.); halogen (e.g. fluorine, chlorine, etc); lower alkoxy (e.g. methoxy, etc.,) or nitro;

R4is lower alkyl (for example, stands and so on);

R5is phenyl(lower)alkyl (e.g. benzyl, etc.,);

R7is hydrogen; lower alkyl (e.g., stands, etc.,) or halogen (e.g. chlorine and so on);

A represents hydroxyproline (for example, 4-hydroxyproline, etc.,) or dedehydration (for example, 3,4-dedehydration and so on);

Y is a bond, lower alkylene (for example, ethylene, etc.,) or lower Alcanena (for example, vinylene and so on).

Preferred options R1, R2, R3, R4, R5, R7A and Y are as follows:

R1is phenyl which may have one to three halogen (for example, phenyl, differenl and so on), benzofuran or a group of the formula

< / BR>
where R6is hydrogen or lower alkyl (for example, stands and so on);

R2is hydrogen;

R3is lower alkyl which may have halogen (e.g., methyl, trifluoromethyl and etc.); amino; lower alkanol; issim alkoxycarbonyl(lower)alkoxy (e.g., ethoxycarbonylmethoxy and etc.); halogen (e.g. fluorine, etc); lower alkoxy (e.g. methoxy, etc.,) or nitro;

R4is lower alkyl (for example, stands and so on);

R5is phenyl(lower)alkyl (e.g. benzyl, etc.,);

R7is hydrogen; lower alkyl (for example, stands and so on);

A is a hydroxiproline (for example, 4-hydroxyproline, etc.,) or delegitimation (for example, 3,4-dedehydration and so on);

Y is a bond or lower Alcanena (for example, vinylene and so on).

Ways to obtain the target compound (I) is explained in more detail below.

Method 1.

The target compound (I) or its salt can be obtained by the reaction of compound (II) or its reactive derivative at the amino group or its salt with the compound (III) or its reactive derivative at the carboxy group or its salt.

Suitable reactive derivative at the amino group of compound (II) may include Schiff's base type imino or its tautomeric isomer raminosoa type obtained by the reaction of compound (II) with a carbonyl compound such as aldehyde, ketone or so on silil the ilil)ndimethylacetamide, mono(trimethylsilyl)acetamide", she bis(trimethylsilyl)-urea or similar derivative, obtained by the reaction of compound (II) with phosphorus trichloride or phosgene, etc.

Suitable salts of the compound (II) and its reactive derivative can be referred to those given as examples for the compound (I).

Suitable reactive derivative at a carboxyl group of compound (III) may include galoyanized acid, acid anhydride, activated amide, an activated ester, etc.

Suitable examples of the reactive derivatives may be an acid chloride of the acid, acid azide, mixed acid anhydride with an acid such as substituted phosphoric acid (e.g., dialkylphosphorous acid, phenylphosphine acid, diphenylphosphoryl acid, dibenzylamine acid, halogenated phosphoric acid, etc.,), dialkylphosphorous acid, sulfurous acid, tisera acid, sulfuric acid, sulfonic acid (e.g., methanesulfonate acid and etc.), aliphatic carboxylic acid (e.g. acetic acid, propionic acid, butyric acid, somalina acid, Pavlova acid, pentane acid, isopentane acid,sauna acid, etc.,); a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole or activated ester (for example, cinematology ether, methoxymethyl ether, dimethylaminomethylene ether) (), vinyl ether, propargilovyh ether, p-nitrophenyloctyl ether, 2,4-dinitrophenoxy ether, trichloranisole ether, pentachlorphenol ether, methylphenylene ether, phenylazophenyl ether, phenylthio ether, p-nitrophenylthio ether, p-crazily ether, carboxymethoxy tiefer, paranjoy ether, pyridyloxy ether, piperidinyl ether, 8-hinolinovy tiefer etc.) or an ester of N-oxycontintear (for example, N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, N-oxysuccinimide, N-oxyproline, 1-hydroxy-1H-benzotriazole and so on), etc., These reactive derivatives may not necessarily be selected from among them depending on the type of used compound (III).

Suitable salts of the compound (III) and its reactive derivative can be a basic salt such as a salt of an alkali metal (e.g. sodium salt, potassium salt, etc.,), alkali earth metal salt (e.g. calcium salt, magnesium salt, etc.,), ammonium salt, salt with organic base (nanoway salt, N,N'-dibenzylethylenediamine salt and so on), etc., and salt accession acid as described for compound (I).

The reaction is usually carried out in a conventional solvent such as water, alcohol (e.g. methanol, ethanol, etc.,), acetone, dioxane, acetonitrile, chloroform, methylene chloride, telengard, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which has no adverse effect on the reaction. Such conventional solvents can also be used in mixture with water.

In this reaction, when the compound (III) used in the form of the free acid or its salt, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinobutyrophenone, N-cyclohexyl-N'-(4-diethylaminoethoxy)carbodiimide, N,N'-diethylcarbamoyl, N,N'-diisopropylcarbodiimide, N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide, N,N'-carbonyl-bis-(2-Mei); pentamethylene-N-cyclohexylamine, diphenylmethan-N-cyclohexylamine, ethoxyacetylene, 1-alkoxy-1-chlorethylene, trialkylphosphites, etiloleat, isopropylpalmitate, phosphorus oxychloride (phosphorylchloride), trichloride fo propylchloride and so on), triphenylphosphine, 2-ethyl-7-oxybenzenesulfonate salt, 2-ethyl-5-(m-sulfophenyl)isoxazoline hydroxide intramolecular salt, benzotriazol-1-yl-oxy-Tria(dimethylamino)phosphonium hexaflurophosphate, 1-(p-chlorobenzenesulfonate)-6-chloro-1H-benzotriazol, the so-called reagent Vilsmeier, obtained by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, trichloromelamine, phosphorus oxychloride, etc. etc.

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

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

Method 2.

The target compound (I-b) or its salt can be obtained by the interaction of the compound (I-a) or its salt with the compound (IV).

This reaction is carried out in the presence of a base, such as lithium alkali (for example, n-utility and etc.), alkali metal hydride (e.g. sodium hydride, potassium hydride, etc.,), three(lower)alkylamine (for example, trimethylamine, triethylamine, etc.), pyridine or its derivatives t in the environment of the solvent, such as dioxane, dimethylsulfoxide, dimethylformamide, diethylformamide, dimethylacetamide, benzene, tetrahydrofuran or any other solvent which has no adverse effect on the reaction. In the case of using a liquid Foundation, it can also be used as solvent.

If necessary, this reaction may be used catalyst phase transfer (for example, cetyltrimethylammoniumbromide and so on).

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

The present reaction includes, within its scope, the case when a hydroxyl group in A reacts during the reaction or at the stage after processing this way.

Method 3:

The target compound (1-d) or its salt can be obtained when exposed to the compound (1) or its salt to remove the protecting carboxyl group.

In this elimination reaction can be applied to all the traditional methods used in the reactions of elimination protecting carboxyl groups, such as hydrolysis, repairing, removing, using a Lewis acid, etc. When zadanie Lewis acid. The hydrolysis is preferably carried out in the presence of a base or acid.

Suitable base may include, for example, inorganic base such as alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.,), hydroxide of alkaline earth metal (e.g. magnesium hydroxide, calcium hydroxide, etc.,), a carbonate of an alkali metal (e.g. sodium carbonate, potassium carbonate, etc.,), carbonate of alkaline earth metal (e.g. magnesium carbonate, calcium carbonate, etc.,), bicarbonate of an alkali metal (e.g. sodium bicarbonate, potassium bicarbonate, etc.,), acetate of an alkali metal (for example, sodium acetate, potassium acetate, etc.,), phosphate, alkaline earth metal (e.g. magnesium phosphate, calcium phosphate, etc.,), a phosphate of an alkali metal (for example, disodium hydrogen phosphate, Dikili phosphate, etc) or etc., and organic base, such as trialkylamine (for example, trimethylamine, triethylamine, etc.,), picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo(4.3.O)non-6-he, 1,4-diazabicyclo(2.2.2)octane, 1,5-diazabicyclo(5.4. O)undecen-5 - or similar. Hydrolysis with the use of reason is often carried out in water or a hydrophilic organic solvent, or mixtures thereof.

Rodionova acid, etc.,) and inorganic acid (for example, hydrochloric acid, Hydrobromic acid, sulfuric acid, etc.,).

This hydrolysis is usually carried out in an organic solvent, water or mixtures thereof.

The reaction temperature is not critical and it can conveniently be selected depending on the type of protecting carboxyl groups and removal method.

Remove using a Lewis acid is carried out at the interaction of the compound (1-c) or its salt with a Lewis acid, such as triploid boron (for example, trichloride boron, boron TRIFLUORIDE, etc.,), tetraploid titanium (for example, titanium tetrachloride, tetrabromide titanium, etc.,), tetraploid tin (for example, tin tetrachloride, tetrabromide tin, etc.,), a halide of aluminum compounds (e.g., aluminum chloride, aluminum bromide, etc.,), troglodytella acid (e.g., trichloroacetic acid, triperoxonane acid, etc.,) or similar. This reaction removal is preferably carried out in the presence of absorbing a cation of an agent (e.g. anisole, phenol, etc.,), and its usually carried out in a solvent such as nitroalkane (for example, nitromethane, nitroethane, etc.,), AcceleRAID (for example, methylene chloride, telengard and so on), diethyl ether, carbon disulfide, or any other dissolve the x mixture.

Reductive elimination can be applied preferably for removal of such protecting groups as halo(lower)alkyl (e.g., 2-Iodate, 2,2,2-trichlorethyl and so on), ester, ar(lower)alkyl (e.g. benzyl, etc.,), ester or the like.

The repair method is applicable for the elimination reaction may include, for example, recovery using a combination of metal (e.g. zinc, zinc amalgam, etc., or salts of compounds of chromium (e.g., chloride, divalent chromium acetate divalent chromium, etc., and organic or inorganic acid (e.g. acetic acid, propionic acid, hydrochloric acid, etc.,) and conventional catalytic reduction in the presence of traditional metal catalyst (e.g. palladium on charcoal, Raney Nickel, etc.,).

The reaction temperature is not critical and generally the reaction is carried out under cooling, at room temperature or when heated.

The present elimination reaction includes in its scope the case when during the reaction is removed protecting the amino group, the hydroxyl and/or carboxyl group in A or in subsequent stages of processing in this way.

<-d) or its reactive derivative at the carboxy group or its salt.

Lidiruyushey agent used in the present amidation may include amine, which may be suitable(e) the substituent(s) such as lower alkyl (e.g. methyl, ethyl, etc.,), amino(lower)alkyl (e.g., aminomethyl, aminoethyl and so on), lower alkylamino(lower)alkyl (e.g., dimethylaminomethyl, dimethylaminoethyl, etc.,) and the like.

Suitable reactive derivative at a carboxyl group of compound (1-d) may relate to such, as confirmed by the examples of compound (III) in method 1.

This reaction can be performed essentially by the same method as the method 1 and, consequently, the way of reaction and reaction conditions (e.g. reaction derivatives, solvents, reaction temperature and so on) this reaction can relate to that explained for the method 1.

Method 5.

The target compound (1-g) or its salt can be obtained by oxidation of compound (1-f) or salts thereof.

The oxidizing agent for use in this reaction may include inorganic percolate or its salt (for example, periodic acid, nadseroy acid or the sodium or potassium salt of this acid, etc.,), organic percolate or its salt (for example, perennou, cryptocercus acid or their sodium and potassium salts, etc.,), ozone, hydrogen peroxide, urea-hydrogen peroxide, N-halosaccion (for example, N-bromosuccinimide, N-chlorosuccinimide and so on), permanganate (e.g. potassium permanganate, etc.,), or any other oxidizing agent that can oxidize sulfonyloxy group to sulfonyloxy group.

This reaction can also be carried out in the presence of metal joining V or VI of the Periodic table of elements, such as tungsten acid, molybdenum acid, vanadium acid, etc. or their alkali or alkaline earth salts.

This oxidation reaction is usually carried out in a conventional solvent which does not exert adverse influence on the reaction, such as water, acetic acid, chloroform, methylene chloride, acetone, methanol, ethanol or mixtures thereof.

The reaction temperature is not critical and preferably the reaction is carried out under cooling or at room temperature.

Method 6.

The target compound (I-i) or its salt can be obtained with the introduction of the compound (I-h) or its reactive derivative at the amino, hydroxyl and/or carboxyl group or its salt group, protecting the both 1 and therefore, the reaction method and reaction conditions (e.g. solvent, reaction temperature, etc.,) for this reaction are for those that are explained in method 1.

The present reaction includes in its scope a case where the amino group, R1reacts during the reaction or at the stage of further processing of this method.

Method 7-(i).

The target compound (I) or its salt can be obtained by the reaction of the compound (I-j) or its salt with the compound (V).

The reaction is usually carried out in a conventional solvent such as dimethyl sulfoxide, or any other solvent which does not exert adverse influence on the reaction.

The reaction temperature is not critical and the reaction is usually carried out at low heat or heated.

Method 7-(ii).

The target compound (I) or its salt can be obtained by hydrogenation of the compound (VI) or its salt. The reaction is usually carried out in the presence of triphenylphosphine, palladium on coal or similar.

The reaction is usually carried out in a conventional solvent such as alcohol (e.g. methanol, ethanol, etc), or any other solvent which does not exert any harmful influence on reachieve.

Method 8.

The target compound (I-h) or its salt can be obtained by introducing the compound (I-i) or its salt to elimination reaction of the group protecting the amino, hydroxyl and/or carboxyl.

This reaction can be conducted in essentially the same way as method 3, and therefore, the method of reaction and reaction conditions (e.g., bases, acids, reducing agents, catalysts, solvents, reaction temperature, etc.,) this reaction belongs to him, as explained in method 3.

The present elimination reaction includes in its scope the case when removing protecting carboxyl-group in R1during the reaction or at the stage of further processing of this method.

Method 9.

The target compound (I-l) or its salt can be obtained by the reaction of the compound (I-k) or its salt with a compound (VI).

The reaction is usually carried out in a conventional solvent such as N,N-dimethylformamide or any other solvent which does not exert adverse influence on the reaction.

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

Method 10.

Target loadedimage the amino group.

This reaction can be carried out essentially in the same way as method 3, and therefore, the method of reaction and reaction conditions (e.g. solvent, reaction temperature, etc.,) this reaction is referred as explained in method 3.

Method 11.

The target compound (I-a) or its salt can be obtained by introducing the compound (I-n) or its salt to elimination reaction for protecting the hydroxyl group.

This reaction can be performed essentially the same way as method 3, and therefore, the method of reaction and reaction conditions (e.g., bases, acids, reducing agents, catalysts, solvents, reaction temperature, etc.,) this reaction is referred as explained in method 3.

Method 12.

The target compound (I-q) and its salt can be obtained by introducing the compound (I-p) or its salt to elimination reaction protects carboxyl group.

This reaction is carried out essentially in the same way as method 3, and therefore, the method of reaction and reaction conditions (e.g., bases, acids, reducing agents, catalysts, solvents, reaction temperature, etc.,) this reaction is referred to as those of CTO when reconnecting (I-r) or its salt.

This reaction can be carried out essentially in the same way as method 3, and therefore, the method of reaction and reaction conditions (e.g., bases, acids, reducing agents, catalysts, solvents, reaction temperature, etc.,) this reaction are referred to as those explained in method 3.

Compounds obtained by the above methods can be isolated and purified by traditional methods, such as spraying, recrystallization, column chromatography, pereosazhdeniya or etc.

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

The target compound (I) and its pharmaceutically acceptable salt possess pharmacological activities such as antagonism tachykinin, especially the antagonism of substance P antagonism neirokinina A or antagonism neirokinina B, and, therefore, are useful for the treatment or prevention of diseases caused by tachykinins, for example, respiratory diseases such as asthma, bronchitis, rhinitis, cough, expectoration, etc., ophtalmological dermatitis, superficial dermatitis, urticaria, eczematoid dermatitis, etc., inflammatory diseases such as rheumatoid arthritis, osteoarthritis, etc., of pains of different origin (for example, migraine, headache, dental pain, pain with cancer, back pain, etc.,) and the like.

In addition, it is expected that the target compound (I) of the present invention will be useful for the treatment and prevention of ophthalmologic diseases such as glaucoma, uveitis, etc., gastrointestinal diseases such as ulcers, ulcerative colitis, irritable bowel syndrome, food allergies, etc., vascular diseases such as hypertension, stenocardia, cardiac failure, thrombosis, etc., inflammatory diseases such as NARIC etc. epilepsy; spastic paralysis; pollakiuria; dementia; Alzheimer's disease; schizophrenia, horei of Huntington; carcinoid syndrome, etc. and are useful as immunosuppressants.

For therapeutic purposes, the compounds (I) and their pharmaceutically acceptable salts can be used in the form of pharmaceutical preparations containing one of these compounds as an active ingredient in a mixture with a pharmaceutically acceptable esentiale or external use. The pharmaceutical preparations can be in the form of capsules, tablets, pills, granules, solutions, suspensions, emulsions, etc., If desired, they can be included in these preparations additional substances, stabilizing agents, wetting and emulsifying agents, buffers and other commonly used additives.

Although the dosage of the compounds (I) largely depends on the age and condition of the patient, the average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound (1) can be effective for the treatment of asthma and the like. In total amount between 0.1 mg/body and about 100 mg/body can be entered per day.

To illustrate the usefulness of the target compound (I) below is data of pharmacological tests of some representatives of the compounds (I).

Compound:

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(I) receptor Binding of 3H-substance P.

Test method.

(a) Preparation of crude pulmonary membrane. Male Guinea pigs breed Hartley put to death by beheading. Remove the trachea and lungs and homogenized in buffer (0.25 M sucrose, 50 mm Tris-Hcl, pH 7.5, 0.1 mm of EDTA) using Polytron (Kinematics). Centrifugeuse balls. The beads re-suspended in buffer (5 mm Tris-Hcl, pH 7.5), homogenized in a Teflon homogenizer and centrifuged (14000 x g, 20 min), and receiving the balls, referred to as crude membrane fractions. The resulting beads stored at -70oC until use.

(b) Binding of 3H-substance P for the preparation of membranes. Frozen crude membrane fraction was thawed and re-suspended in medium 1 (50 mm Tris-Hcl, pH 7.5, 5 mm MnCl2, 0,02% BSA, 2 μg/ml of hemostatis, 4 μg/ml leupeptin, 40 μg/ml bacitracin). Incubated 1 nm 3H-substance P with 100 μl of the membrane preparation in medium 1 at 4oC for 30 minutes with a final volume of 500 ál. At the end of the incubation period, the reaction mixture was rapidly filtered through Whatman CF/B glass filter (pretreated with 0.1% polyethylenimine for 3 hours before use) in terms of aspiration. The filters are then washed 4 times with 5 ml of buffer (50 mm Tris-Hcl, pH 7.5). Count the radioactivity in 5 ml Aquasol-2 acquired scintillation counter Packard (Packard RI-CARB 34530).

Test results:

The test compound (0.1 ág/ml) Inhibition (%)

(1) 96

(2) 100

(3) 91

(4) 80

(5) 94

(6) 89

(7) 93

The following examples are aeademie in addition to the abbreviations accepted IUPAC-YB (IUPAC-IUB):

Ac acetyl

Aib 2-aminoadamantane acid

Azt, azetidin-2-carboxylic acid

Boc tert.-butoxycarbonyl

The BSA bestemmelsessted

Buttert.-butyl

Bz benzoyl

Bzl benzyl

Bzl(O-F) o-terbisil

Bzl(M-F) m-terbisil

DMAP dimethylaminopyridine

DMF dimethylformamide

DMSO dimethyl sulfoxide

Et ethyl

NOT N-hydroxybenzotriazole

IPE isopropyl ether

Me methyl

MS-mesyl

NMM N-methylmorpholine

HCl/DOX hydrogen chloride in 1,4-dioxane

Priisopropyl

Py(2) 2-pyridyl

Su, succinimido

TEA triethylamine

FA triperoxonane acid

F tetrahydrofuran

The TWG tiopronin

Ts tosyl

WSC 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide

Z benzyloxycarbonyl

di di

Used the original connection and the target compounds obtained in the following examples, are given in tables 1 and 2, in which formula first given in table 1, and the last formula of the compounds, respectively, are given in table 2.

Example of getting 1. To a suspended mixture of starting compound (5 g) in a mixed solvent of 35 ml of water and 35 ml of acetone added TEA (4,47 ml) under cooling liver stirred at the same temperature for one hour and another hour at room temperature, and at this time add 1 g of di-tert.-butylboronic. After removal of acetone, water is added, and the aqueous solution washed with ether. Then the aqueous layer was acidified to pH 2 by adding 6 n hydrochloric acid, and extracted with ethyl acetate. The extract was washed with aqueous solution of sodium chloride and dried over magnesium sulfate. After evaporation the residue is recrystallized from a mixed solvent: diisopropyl ether and n-hexane and filtered to obtain the target compound (6,58 g).

Melting point 116oC.

NC(nujol): 3370, 1715, 1690, 1620, 1520 cm-1.

NMR (DMCO-d6, ): 1,30 (N, C) 2,90 (1H) 3.14 (1H)(ABX. JABof 13.7 Hz, JACa 4.4 Hz, JBCof 10.7 Hz), 4,17 (1H, m), 7,18 (1H, d, J 8.6 Hz), 7,47 (1H, d, J8 Hz), the 7.65 (1H, d, J 8 Hz).

Example of getting a 2. Target connections get the same way obtain 1 (see tab.3)

Example of getting a 3. To a cooled with ice to a solution of starting compound (2 g) N-methylbenzylamine (0,77 ml) and HOBT (0,81 g) in methylene chloride (50 ml) is added WSCHCI (1,15 g). The resulting solution was stirred at this temperature for one hour and overnight at room temperature. After evaporation, the reaction mixture was extracted with ethyl acetate and water bicarb the donkey evaporation of this solution obtain the target compound (2,88 g).

The melting point of 86-88oC.

IR (nujol): 3370, 1685, 1640, 1520 cm-1.

NMR (DMCO-d6d): 1,12 (s) and 1.31 (s, N), 2,77, and only 2.91 (3H, s), 4,4-4,8 (3H, m) and 7.1 to 7.4 (6N, m), between 7.4 and 7.7 (4H, m), 2,8-3,1 (2H, m).

Example 4.

By way of example, receive 3 receive connection table. 4.

Example of getting a 5. To a solution of starting compound (1.54 g) in THF (30 ml) is added sodium hydride (60% in oil, 176 mg) and 0.5 ml under the conditions. The resulting mixture was stirred at 60oC for one hour. After concentration, the product is extracted with ethyl acetate, and the organic layer washed successively with water and aqueous sodium chloride solution, dried over magnesium sulfate. After evaporation of this solution obtain the target compound (1.78 g) as oil.

IR (l3): 3320, 1705, 1640, 1510, 1450, 1365, 1250, 1170 cm-1.

NMR (DMCO-d6d): 1,2-1,4 (N, m), 2,7-2,9 (5H, m), 3,70 (s) and 3,72 (s) (3H), 4,3-4,6 (3H, m), 6,7-6,9 (2H, m), 7,0-7,4 (8H, m).

Example of getting a 6. It chilled with ice to a solution of starting compound (2,05 g) in 20 ml of methylene chloride added 4n-HCl/DBX (19 ml). The resulting solution was stirred at this temperature for 5 minutes. Then the cooling bath removed, and the resulting solution was stirred at room the play by filtration and dried over sodium hydroxide in vacuo to obtain 1.68 g of the target compound.

Melting point 159oC.

IR (nujol): 1650, 1605, 1580, 1495, 1335 cm-1.

NMR (DMCO-d6d): 2,73 (3H, s), 3,1-3,3 (2H, m), 4,1-4,8 (3H, m), 7,1-7,2 (2H, m), 7,2-7,4 (3H, m), 7,37 (2H, d, J 8 Hz) and 7.69 (d, J 8 Hz), 8,51 (2H, Shir. C).

Example of getting a 7. According to the method of example 6 receive connection table.5.

Example of getting 8. To an ice-cold solution of starting compound (1.65 g) Boc-(2S, 4R)-Pro(N)-HE (1,02 g) and NOT (0,60 g) in a mixture solvent of methylene chloride (45 ml) and dimethylformamide (10 ml) was added WSC (0,80 ml). The resulting solution was stirred at the same temperature for one hour and then overnight at room temperature. After evaporation, the reaction mixture was extracted with ethyl acetate and the organic layer washed sequentially with an aqueous solution of sodium bicarbonate, water, 0.5 n hydrochloric acid, water and aqueous sodium chloride solution, dried over magnesium sulfate and evaporated in vacuum to obtain the target compound (2.35 g) in the form of butter.

IR (l3): 1700, 1685, 1665, 1645, 1635, 1555, 1540 cm-1.

NMR (DMCO-d6d): 1,1-1,3 (m) and of 1.65 (s, N), 1,5 -1,8 (1H, m), 1,8-2,1 (1H, m), 2,9 (3H, s), of 2.7-3.1 (2H, m), 3.1 to 3.4 (1H, m), 3,4-3,5 (1H, m), 4,1-4,3 (2H, m), a 4.3 to 4.5 (2H, m), 4,7-5,1 (2H, m), of 7.0 to 7.7 (N, m), 8,39 (1H, d, J 8 Hz).

Example of receipt 9. the oru parent compound (2.5 g) in methanol (70 ml) is added 10% palladium on coal (0.5 g) and the resulting mixture hydronaut at atmospheric pressure and room temperature for 1.5 hours. After filtration and concentration of the mixture and get targeted connection of 2.27 g) as an amorphous solid product.

IR (l3): 3370, 1705, 1640, 1520, 1365, 1290, 1250, 1170 cm-1.

NMR (DMCO-d6d): 1.1 to 1.4 (N, m), 2,5-2,9 (5H, m), 4,3-4,6 (3H, m), 4,91 (2H, s), 6,4-6,5 (2H, m), 6,74 (1H, d, J 8 Hz), 6.89 in (1H, d, J 8 Hz), 7.0 and 7.2 and 7,2-7,4 (6N, m).

Example of getting 11. To a cooled with ice to a solution of starting compound (1.75 g) in 35 ml of pyridine added methanesulfonamide (0,39 ml). The resulting solution is stirred for one hour at the same temperature. After concentration, the product is extracted with ethyl acetate, and the organic layer washed successively with water, diluted aqueous sodium bicarbonate solution, water, 0.5 n hydrochloric acid and sodium chloride solution and dried over anhydrous magnesium sulfate. After evaporation of the extract to obtain 2.14 g of the target compound as an amorphous solid product.

IR (l3): 1710-1690, 1635, 1510, 1400, 1335, 1250 cm-1.

NMR (DMCO-d6d): 1.26 in (C) and 1.34 (C) (N), 2,7-2,9 (5H, m), with 2.93 (3H, s), 4,4-4,7 (3H, m), of 7.0 to 7.4 (10H, m), 9,62 (1H, s).

Example 12. By way of examples of the preparation 6 and 8 receive the target compounds are shown in table.7.

Example of receipt 13. The solution is XI sodium (0,80 g). Then to this mixture add 2,02 g ethylbromoacetate, and the resulting mixture is stirred for two hours at room temperature. After adding 1 ml of acetic acid and concentration the residue is added ethyl acetate and water. Selected aqueous layer was extracted again with ethyl acetate and the organic layers combined, washed sequentially with an aqueous solution of sodium bicarbonate, 0.5 n hydrochloric acid and aqueous sodium chloride solution and then dried over magnesium sulfate. After concentration of this solution get the crude product (3,83 g) which is purified on a column of silica gel, elwira mixed solvent by methylthiofentanyl (97:3 to 94:6) to obtain 3.13 g of the target compound as an amorphous solid product.

IR (CH2Cl2): 3600, 3400, 1750, 1680, 1640 cm-1.

NMR (CDCl3d): of 1.30 (3H, t), 1,45 (N, s), 1.8-to 2.2 (2H, m), 2,71, and only 2.91 (3H, s), 2,9-3,1 (3H, m), 3,3-3,55 (2H, m), 4.26 deaths (2H, q), 4.0 to 4.5 (4H, m), 4,55-4,6 (3H, m), 5,1-5,2 (1H, m), 6,7-6,8 (2H, m), 7,0-7,2 (4H, m), 7,25 of 7.3 (3H, m).

Example of getting a 14. To a cooled with ice to a solution of starting compound (1.1 g) in 11 ml of methylene chloride added 4n-Hcl/DOX (8.1 ml). The resulting solution was stirred at this temperature for 5 minutes and then at room temperature in thecandle obtain the target compound (0.88 g).

IR (nujol): 3250, 1670, 1645, 1580, 1555 cm1.

NMR (DMCO-d6d): 1,6-1,9 (1H, m), 2,2-2,4 (1H, m), 2,79 (C) 2,89 (3H), 2,9-3,4 (4H, m), 4,2-4,6 (4H, m), 4,9-5,2 (1H, m), 5,5-5,6 (1H, m), of 7.0 to 7.7 (10H, m), 9,23 (1H, d, J 8 Hz).

Example of receipt 15. By way of example, obtaining 14 receives the target compounds are shown in table.8.

Example of 16. By way of example, obtain 1 get the target connection.

IR (l3): 3470, 1725, 1715, 1500 cm-1.

NMR (DMCO-d6d): 1,33 (N, C) 2,17 (6N, (C), 2,65 -3,0 (2H, m), 3.95 to a 4.1 (1H, m), 6,9-7,05 (4H, m), 12,46 (1H, Shir.C).

Example of receipt 17. Method for producing 3 get the target connection.

IR (net): 3450, 3320, 1710, 1640, 1365 cm-1.

NMR (DMCO-d6d): 1,2-1,4 (N, m), 2,1-2,2 (6N, m), 2,65-2,95 (5H, m), 4,3-4,7 (3H, m), 6.75 in-7,4 (N, m).

Example obtain 18. By way of example, get 6 get the target connection.

Melting point 96-104oC.

IR (nujol): 3440, 1650, 1610, 1490, 1450, 1280 cm-1.

NMR (DMCO-d6d): 2,1-2,25 (6N, m), 2,62 (C) 2,69 (3H, s), 2,85 is 3.2 (2H, m), 4.0 to 4.1 and 4,35 with 4.65 (3H, m), of 6.9 to 7.4 (8H, m), 8,49 (3H, Shir. C).

Example obtain 19. By way of example, get 8 get the target connection.

IR (l3): 3450-3300, 1690-1650, 1645-1625, 1450, 1155 cm-1.

An example of obtaining 20. By way of example, obtaining 14 except that instead of 4n-Hcl/DOX using THF, get the target connection.

IR (l3): 3450-3200, 1680, 1640, 1565, 1455 cm-1.

NMR (DMCO-d6d): 1.7 to 1.9 (1H, m), of 2.1-2.4 (7H, m), 2,65 is 3.15 (5H, m), 3,25-3,5 (2H, m), 4,2-5,1 and 5.55-5,65 (6N, m), 6,8-7,4 (8H, m), 9,1-9,3 (1H, m), 8,65 (1H, Shir. C), and 10.0 (1H, Shir.S.).

Example of getting a 21. To a suspended mixture of starting compound (18 g) in 90 ml of water was added 1 n aqueous sodium hydroxide solution (65.8 ml). This solution is heated to 37oC and pH set to 8 by adding 1 n hydrochloric acid. Then to the solution add uranyl cobalt (II) chloride (90 mg) and acylase (brand Acylase Amano 15000) (900 mg). The reaction mixture was stirred at 37oC during the night, and at this time the pH of support to 7.5 by adding 1 n aqueous sodium hydroxide solution. Remains collected by filtration, washed with water and dried to obtain the target compound (4,75 g).

Melting point 192oC.

IR (nujol): 3400, 1605, 1584, 1512, 888, 840 cm-1.

NMR (D2O + NaOD, d): 2,65-3,15 (2H, m), 3,49 (1H, DV.D. J 7,38 Hz, 5,72 Hz), 7,12 (1H, DV.d, J 8,24 Hz, 1.70 GHz), was 7.36 (1H, d, J 1.6 Hz), 7,42 (1H, d J by 8.22 Hz).

Example of getting a 22. To a cooled l is osphere nitrogen. The resulting mixture was stirred at room temperature overnight. To the mixture, water is added and the THF evaporated. Add ether and water, and the aqueous layer is evaporated. The organic layer is washed again with water. These aqueous layers are combined and acidified with 6 n hydrochloric acid to pH 2 separated oil is extracted with ethyl acetate. The extract obtained was washed with an aqueous solution of nitriloside, dried over magnesium sulfate and evaporated to obtain the target compound in the form of oil (4,20 g).

IR (l3): 2600, 1700 cm-1.

NMR (CDCl3d): of 1.34 and 1.41 (N, C), 2,22 (6N, s), 2.69 and was 2.76 (3H, s), 2,9-3,3 (2H, m),4,64 (LW.D. J 10,9 Hz and 4.5 Hz, 4,82 (LW.D. J of 10.7 Hz and 5.2 Hz)} (1H), 6,9-7,1 (3H, m), 8,83 (1H, s).

An example of retrieving 23. By way of example, obtain 1 get the target connection.

Melting point 119,0-to 121.6oC.

IR (nujol): 3370, 1718, 1690, 1526, 818 cm-1.

NMR (DMCO-d6d): 1,26, 1,31 (N, C), 2,70 is 3.15 (2H, m), 4,00-4,10 (1H, ), 7,10-7,30, 7,45-7,60 (4H, m) 12,70 (1H, Shir.C).

Example of getting 24. To a cooled with ice to a solution of starting compound (5 g) in 50 ml of methylene chloride add to 2.29 ml of tea and 2.03 ml of pivaloate. The resulting mixture was stirred for 35 minutes at this temperature, and then to the solution was added 1 After concentration the residue is added water and ethyl acetate, and separate the organic layer is washed successively with an aqueous solution of sodium bicarbonate, water, 0.5 n hydrochloric acid and aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. After concentration of the crystalline residue (7,10 g) was washed with diisopropyl ether, filtered and dried to obtain the target compound (5.29 g).

Melting point 103-106oC.

IR (nujol): 3390, 1690, 1638, 814, 730, 710 cm-1.

NMR (DMCO-d6d): 1,21, 1,32 (N, C), 2,90, to 2.94 (3H, s), 2,70 was 3.05 (2H, m), 4,40-of 4.75 (3H, m), 7,05-7,65 (N, m).

An example of obtaining 25. By way of example, get 3 get the target connection.

Melting point 126-127oC.

IR (nujol): 1680, 1645 cm-1.

NMR (CDCl3d): 1,05, 1,19, 1,22 and 1,37 (N, C) to 2.18, 2.20 2,22 (6N, (C), 2,83, 2,85, and 2,89 (6N, (C), 2,9-of 3.25 (2H, m), 4,36-of 4.75 (2H, m), of 4.95-5.03 and 5,30-of 5.45 (1H, m), 6,85 of 7.3 (8H, m).

Example of receipt 26. To a cooled with ice to a solution of starting compound (2 g) in 7.5 ml of ethyl acetate added to the solution (15 ml), 4 n hydrochloric acid in ethyl acetate. This solution was stirred at the same temperature for 35 minutes and concentrate. To the residue add methylene chloride and aqueous sodium bicarbonate solution, the organic SLC cooled with ice to a solution of Boc-(2S,4R)-Pro(N)-HE 1.06 g in 15 ml of methylene chloride in a different reaction vessel add tea (0.7 ml) and pivaloate (0,62 ml), and the resulting mixture is stirred for 15 minutes at this temperature. To this solution was added previously obtained solution (solution 1) and the resulting solution is stirred for one hour while cooling with ice, and then left overnight at room temperature. To the solution was added N, N-dimethyl-1,3-propandiamine (0,23 ml) and the resulting mixture for one hour stirred at room temperature. After concentration the residue is added ethyl acetate and water, and the organic layer washed sequentially with an aqueous solution of sodium bicarbonate, water, 0.5 n hydrochloric acid, water and an aqueous solution of nitriloside, then dried over magnesium sulfate. After evaporation of the solution obtain the target compound (2,43 g) as an amorphous solid product.

IR (l3): 3400-3260, 2960, 2930, 1625 cm-1.

NMR (DMCO-d6d): 1,19, 1,38 (N, C), 1,50 is 2.10 (2H, m), 2,70-3,10 (5H, m), 3,15-3,50 (2H, m), 4,05-of 5.05 (6N, m), 7,00-the 7.65 (8H, m), 8,25-to 8.40 (1H, m).

Mass spectrum: M+: 550.

Example of getting 27. The target connection get by way of the first half of the sample receiving 26.

Melting point 219-221oC.

IR (nujol): 2750, 1650, 1550 cm-1.

NMR (DMCO-d6d): to 2.15 (3H, s), are 2.19 (3H, s), 2,5 (6N, m), 2,85-3 to 9.5 (2H, Shir.).

Example of getting 28. The target connection get by way of the second half of the sample receiving 26.

IR (l3): 3450, 1690, 1660 (shoulder), 1640 cm-1.

NMR (DMCO-d6d): 1,09, 1,21, 1,27, 1,28, 1,37 and 1.38 (N, ), 1,2-1,4, 1,4-1,6, 2,0-2,2 (2H, m), 1.99 and 2,13 (6N, (C), 2,6-2,8 (4H, m), and 3.0 (3H, m), 3,2 is-3.45 (3H, m), of 4.1 to 4.7 (4H, m) 5,0 (1H, m), of 5.4 to 5.6 (1H, m), of 6.8 to 7.3 (8H, m).

Example get 29. To a cooled with ice to a solution of starting compound (2.20 g) in 7.5 ml of ethyl acetate added to the solution (15 ml), 4 n hydrochloric acid in ethyl acetate. This solution is stirred at this temperature for two hours. After concentration the residue is crystallized from ether to obtain 1,59 g of target compound.

Melting point 168-175oC.

IR (nujol): 3270, 1640 cm-1.

NMR (DMCO-d6d): 1,60-1,90, 2,10-2,40 (2H, m), 2,80, with 2.93 (3H, s), 2,70 is 3.40 (4H, m), 4,05-of 4.75 (4H, m), 4,85-5,10 (1H, m), 5,50-the ceiling of 5.60 (1H, m), 7,00-the 7.65 (8H, m), 8,30-8,80, 9,60-10,15 (2H, Shir. C), 9,17 (1H, d J 8,08 Hz).

Example 1. To a cooled with ice to a solution of 1-methylindol-3-carboxylic acid (0,23 g), starting compound (0,63 g), methylene chloride (12 ml) and HOBT (0,18) added WSC (0,24 ml). The resulting solution was stirred at this temperature for one hour and then at room temperature overnight. PEFC is dnim solution of sodium bicarbonate, water, 0.5 n hydrochloric acid, water and an aqueous solution of nitriloside, dried over magnesium sulfate. After evaporation the residue is purified on a chromatographic column (100 g), elwira solvent mixture chloroform/methanol (50: 1). The fractions containing the target compound is collected and evaporated. Then the residue is crystallized from ethyl acetate, filtered and dried to obtain the target compound (0.50 g).

Melting point 183-184oC.

IR (nujol): 3270, 1680, 1655, 1580, 1570, 1530 cm-1.

NMR (DMCO-d6d): 1.7 to 1.9 (1H, m), 1,9-2,1 (1H, m), 2,72 (C) 2,85 (s) (3H), 2,9-3,3 (2H, m), 3,66 (1H, d J 5 Hz), of 3.8-4.1 (1H, m), 3,85 (3H, s), 4,30 (C) and 4,43 (C) and 4.6 -4,8 (m) (4H), 4,9-5,2 (2H, m), of 7.0 to 7.7 (N, m), 7,88 (1H, s), 8,07 (1H, d, J 8 Hz), 8,4-8,7 (1H, m).

Example 2. According to the method of example 1 to obtain the target compounds are shown in table.9.

Example 3. To a suspended mixture of starting compound (1 g) in 25 ml of methylene chloride added pyridine (0.65 g) and cinnamoroll (0,343 g) under cooling with ice. To the resulting mixture add 5 ml of tetrahydrofuran, and the resulting solution was stirred at this temperature for one and a half hours and then two hours at room temperature. After concentrating the resulting product is extracted with ethyl acetate, and organic and solution nitriloside, then dried with magnesium sulfate. After concentration the residue is crystallized mixed solvent of ethyl acetate/diisopropyl ether/ether, filtered and washed with diisopropyl ether to obtain the target compound (1.13 g).

Melting point 91-94oC.

IR (nujol): 3350 (shoulder), 3290, 1665, 1645, 1610, 1585, 1530 cm1.

Example 4. To a cooled with ice to a solution of starting compound (1,61 g) and BSA (1.89 g) in methylene chloride (35 ml) was added indole-3-carbonylchloride (0,70 g). The resulting solution was stirred at this temperature for two hours. After evaporation the residue is added a mixture of THF (20 ml) and water (5 ml). The resulting mixture was stirred at room temperature for 20 minutes. The solution is washed with water, dilute sodium bicarbonate solution, 0.5 n hydrochloric acid and the solution nitriloside and dried over magnesium sulfate. After concentration, the residue is introduced into a column of silica gel (42 g) and elute first with chloroform and then a mixture of chloroform/methanol (100:1.5 to 100:2 gradient elution) to obtain the target compound (1.89 g).

IR (nujol): 3250, 1750, 1630, 1510 cm-1.

NMR (DMCO-d6d): of 1.20 (3H, t, J 7 Hz), a 1.7-2.1 (2H, m), 2,65 to 3.0 (5H, m), up 3.6-3.7 and 3.8 to 4.0 (2H, m), is 4.15 (2H, square is R. C).

Example 5. The target connection receive by way of example, receiving 15 and example 1.

IR (nujol): 3340, 1600, 1530 cm-1.

NMR (DMCO-d6d): 1,7 (C), 2,83 (C), (3H), 2,9 -3,2 (2H, m), 3,86 (3H, s), 4,3-4,8 (4H, m), 4,8-5,1 (1H, m), 5,3-5,4 (1H, m), 5,6-5,7 (1H, m), 6,0-6,1 (1H, m), 6,9 to-7.6 (N, m), to 7.99 (1H, Shir.C), 8,16 (1H, d, J 8 Hz), 8,5-8,7 (1H, m).

Example 6. To a cooled with ice to a solution of starting compound (727 mg) in 15 ml of ethanol is added a solution of 1 n sodium hydroxide (to 2.57 ml). The resulting solution was stirred at room temperature for 3 hours. After evaporation of the alcohol, water is added, and the resulting solution lyophilized to obtain the target compound (660 ml) in powder form.

IR (nujol): 3200, 1610, 1515 cm-1.

NMR (DMCO-d6d): 1,9-2,1 (1H, m), 2,7-3,0 (including singlets 2,72 and 2,85) (5H, m), 3,55-3,65 and of 3.7-3.9 (2H, m), 4,13 (2N, C) and 4.2 (1H, m), 4,4-4,6 (including singlet of 4.44), and 4.68 (1H, m), 4,89 (1H, m), of 5.24 (1H, s), compared to 6.6-7.4 (11N, m), 7,49 (1H, D. J 7 Hz), and 7.8 (1H, Shir. C). of 9.02 (1H, d, J 7 Hz), 8,31 (1H, m).

Example 7. The original compound (0.6 g) is dissolved in 40 ml of methanol and hydronaut over 10% palladium on coal (0.06 g) at atmospheric pressure for one hour. The catalyst is filtered off and the filtrate concentrated to obtain the target compound (0,61 g ) as amorphous TV is d): 1.7 to 1.9 (1H, m), 1,9-2,1 (1H, m), 2,6-2,9 (5H, m), up 3.6-3.7 (1H, m), 3,85 (3H, s), 3,8-4,0 (1H, m), a 4.3 to 4.5 (3H, m), 4,65-5,1 (5H, m), 6,4-6,5, 6,7-7,1, 7,1-7,3 and 7.4-7.5 (M, m), 7,8-8,0 (1H, m), with 8.0 and 8.1 (1H, m), 8,3 an 8.4 (1H, m).

Example 8. The original compound (0.6 g) dissolved in 6 ml of tetrahydrofuran. To the resulting solution was added 4n-Hcl/DOX (0,28 ml) under cooling with ice. This solution is stirred for 10 minutes and concentrated. The residue is triturated with ether and filtered, then dried (40oC, 6 hours) to obtain the target compound (0,58 g).

Melting point 173oC C decomposition.

IR (nujol): 3500-3100, 1630, 1530, 1510, 1250 cm-1.

NMR (DMCO-d6d): 1.7 to 1.9 (1H, m), 1,9-2,1 (1H, m), 2,7-3,2 (5H, m), up 3.6-3.7 (1H, m), 3,8-4,2 (4H, m), of 7.0 and 7.6 (N, m), to $ 7.91 (1H, s), of 8.06 (1H, d, J 7 Hz), to 8.3 and 8.6 (1H, m), 4,2-5,1 (6N, m), 10,3 (3H, s).

Example 9. The target connection receive according to the method of example 1.

The melting temperature of more than 105oC (with decomposition).

IR (nujol): 3430-3280, 1645-1630, 1605, 1530, 1415 cm-1.

NMR (DMCO-d6d): 1,75-of 1.95 (1H, m), of 2.0-2.2 (7H, m), 2,70-2,78 (3H, s), 2,8-3,05 (2H, m), 3.6 and 4.0 (2H, m), 3,85 (3H, s), 4,25-of 5.05 (6N, m), 6.75 in-7,5 (11N, m), 7,8 and 8.1 (2H, m), 8,3-8,5 (1H, m).

Example 10. The target connection receive according to the method of example 1.

IR (l3): 3300, 1660, 1650, 1460-1420 cm-1.

NMR (DMCO-d

The melting point of more than 145oC (with decomposition).

IR (nujol): 3270, 1690, 1660, 1580, 1565 cm-1.

NMR (DMCO-d6d): 1,9-of 2.25 (8H, m), 2,6-3,1 (5H, m), 3,6-3,9 (2H, m), 4,25-5,15 (6N, m) of 5.7 to 8.0 and 8.4 and 9.3 (15 NM, m).

Example 12. To a cooled with ice to a solution of 1-methylindol-3-carboxylic acid (0.25 g) in methylene chloride (10 ml) are added sequentially TEA (0,22 ml) and pivaloate (0,19 ml). The resulting solution was stirred for 25 minutes at the same temperature (solution 1).

The original connection (0,70 g) is distributed between methylene chloride and aqueous sodium bicarbonate solution. The organic layer is isolated and dried over magnesium sulfate, and concentrated to a volume of 5 Il.

This solution is added to solution 1 obtained previously, and the resulting solution is stirred overnight, and during this time the temperature is gradually increased to room temperature. To the solution was added N, N-dimethyl-1,3-propandiamine (0,044 ml) and the resulting mixture is stirred for 40 minutes. After concentration, the residue is extracted with ethyl acetate. The organic layer is successively washed with aqueous sodium bicarbonate solution, water, 0.5 n hydrochloric acid and saturated aqueous solution of nitriloside, then su is alance silica gel, elwira mixed solvent of chloroform/methanol (concentration of methanol from 0.5% to 5%) to obtain the target compound as an amorphous solid product (0,72 g).

IR (nujol): 3330, 1640-1630, 1530, 740 cm-1.

NMR (DMCO-d6d): 1,60-2,10 (2H, m), 2,60-3,10 (5H, m), 3,86 (3H, s), 3,55-4,00 (2H, m), 4,20-5,10 (6N, m), 6,95-7,60, 7,80-8,55 (14N, m).

Mass spectrum: M+: 607.

Example 13. Cooled with ice a solution of starting compound (1.25 g) in 6.8 ml of methylene chloride is treated FA (5,1 ml) for 40 minutes. After concentrating add methylene chloride and sodium bicarbonate solution, the organic layer is isolated and washed with a solution of nitriloside, then dried over anhydrous magnesium sulfate. This solution is concentrated to a volume of 16 ml (solution 1).

To a cooled with ice to a solution of 1-methylindol-3-carboxylic acid (350 ml) in methylene chloride (15 ml) is added TEA (202 mg) and pivaloate (241 mg). This solution is stirred for 20 minutes at the same temperature, and then to this solution was added previously obtained solution (solution 1).

The resulting solution was stirred for 2 hours at room temperature. After concentrating add ethyl acetate and water and separate the organic layer, probivautsa over magnesium sulfate. After concentration the crude product was then purified through column chromatography with silica gel (24 g) elwira mixed solvent of chloroform/methanol (methanol from 2% to 2.5%) to obtain the pure product (0.95 g), which crystallized by adding ethyl acetate. The crystals are collected by filtration, washed with diisopropyl ether and dried to obtain the target compound (0,72 g).

Melting point 204-205oC.

IR (nujol): 3410, 1640, 1590, 1525 cm-1.

NMR (DMCO-d6d): 1,6-2,2 (2H, m), 2,08 and 2.14 (6N, (C), by 2.55 to 2.9 (4H, m), of 3.0-3.4 (4H, m), 3,6-of 4.05 (5H, m), 4,3-4,6 (3H, m), 4.95 points-of 5.15 (2H, m), of 5.4 to 5.6 (1H, m), 6,85 of 7.3 (10H, m), and 7.5 (1H, m), 7,9-8-15 (2H, m).

Example 14. To a cooled with ice to a solution of 3-(3,4-acid)propionic acid (0.28 g) and HOBT (0.18 g) in methylene chloride (10 ml) add WSCHCl (0.26 g). The resulting solution was stirred for 2.5 hours at the same temperature (solution 1).

To a cooled with ice to a solution of starting compound (0,70 g) in methylene chloride (10 ml) is added TEA (0,20 ml). This solution is stirred for 1.5 hours at the same temperature. This solution is added to solution 1 obtained previously at the same temperature, and the resulting solution is stirred over night at room temperate aqueous solution of sodium bicarbonate, water, 0.5 n hydrochloric acid and a saturated solution of nitriloside, dried over magnesium sulfate. After concentration added to the residue diisopropyl ether, and the resulting residue is collected by filtration, dried, resulting in a gain of the target compound as an amorphous solid product (0,53 g).

IR (l3): 3300, 2940, 1630, 1512 cm-1.

NMR (DMCO-d6d): 1,65-of 2.45 (2H, m), 2.06 to, 2,13, 2,18 (6N, (C), 2,55-3,20 (6N, m), 2,74, 2,78, of 2.81 (3H, s) and 3.15 (3H, s), 3,15-are 3.90 (2H, m,), 3,67, 3,69, 3,70, 3,72, 3,73 ( 6N, (C), 4,15-5,15 (6N, m), 6,55-7,40 (11H, m), 8,25-8,40, 8,60 -8,80 (1H, m).

Mass spectrum: M+: 601.

Example 15. To obtain compositions in the form of capsules powder of the following composition was inkapsulirovanne conventional method:

The compound of example 1 1 mg

Lactose 39 mg

Example 16. Composition in the form of a suspension prepared from the following ingredients:

The compound of example 1 mg

Dimethyl sulfoxide 100 ml

1. Derivatives of the peptides of formula 1

< / BR>
where R1phenyl which may have one to three substituent selected from halogen and lower alkoxy; benzofuran, pyridyl or a group of the formula

< / BR>
where R6hydrogen or lower alkyl;

R2hydrogen or lower alkyl;

R3- ness monoethylamine carboxy (lower) alkoxy; halogen; lower alkoxy or nitro;

R4lower alkyl;

R5phenyl(lower)alkyl;

R7hydrogen, lower alkyl or halogen;

And hydroxyproline or dedehydration;

Y link, lower alkylene or lower albaniles,

or their pharmaceutically acceptable salts.

2. Connection on p. 1, wherein R1phenyl which may have one or two halogen or one or two lower alkoxy, benzofuran, pyridyl, indolyl or 1-lower acylinder;

R3lower alkyl, triploid(lower)alkyl, amino, lower alkanesulfonyl, carboxy(lower)alkoxy, lower alkoxycarbonyl(lower)alkoxy, halogen, lower alkoxy or nitro;

R3phenyl(lower)alkyl;

And hydroxyproline or dedehydration.

3. Connection on p. 2, wherein R1phenyl, differenl, acid, benzofuran, pyridyl, indolyl or 1-methylindolin;

R2hydrogen or methyl;

R3is methyl, trifluoromethyl, amino, methanesulfonamido, carboxymethoxy, ethoxycarbonylmethoxy, fluorine, chlorine, methoxy or nitro;

R4methyl;

R5benzyl;

R7hydrogen, methyl or chlorine; Y is a bond, ethylene or vinile.

4. Connection on p. 3, Olde di di. Bzl is benzyl,

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
5. The method of obtaining derivatives of the peptides of formula I

< / BR>
where R1, R2, R3, R4, R5, R7And each has the specified values, or their pharmaceutically acceptable salts, characterized in that the compound of formula II

< / BR>
where R2, R3, R4, R5, R7and As everyone has previously mentioned values,

or its reactive derivative at the amino group or its salt is subjected to reaction with the compound of the formula III

R - COOH,

where R' and everyone has these values,

or its reactive derivative at carboxypropyl, or its salt, and, if necessary, (i) remove the ester group of the radical R3or (ii) restore the nitrogroup radical R3and the target product is isolated in free form or in the form of pharmaceutically acceptable salts.

6. Pharmaceutical composition for the treatment of diseases, by the intermediary of which is tachykinin comprising an effective amount of an active agent and a pharmaceutically acceptable carrier or excipient, characterized in that as the active agent, it is ery has the specified values, or its pharmaceutically acceptable salt in an amount of 0.1 - 1000 mg per unit dose.

7. A method of treating diseases, by the intermediary of which is tachykinin, characterized in that the patient is to receive the connection of the mentioned formula I, or its pharmaceutically acceptable salt in an amount of 0.1 to 1000 mg per day.

 

Same patents:

The invention relates to new derivatives of dipeptides with pharmacological activity, and the way they are received, and may find application in medicine

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to applying compounds of the formula (I) for preparing an antibacterial composition and veterinary composition eliciting with the enhanced activity.

EFFECT: valuable properties of agents.

4 cl, 3 tbl, 78 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to macrocyclic peptides of the general formula (I): wherein W means nitrogen atom (N); R21 means hydrogen atom (H), (C1-C6)-alkoxy-, hydroxy-group or N-(C1-C6-alkyl)2; R22 means hydrogen atom (H), (C1-C6)-alkyl, CF3, (C1-C6)-alkoxy-group, (C2-C7)-alkoxyalkyl, C6-aryl or Het wherein het means five- or six-membered saturated or unsaturated heterocycle comprising two heteroatoms taken among nitrogen, oxygen or sulfur atom and wherein indicated Het is substituted with radical R24 wherein R23 means hydrogen atom (H), -NH-C(O)-R26, OR26, -NHC(O)-NH-R26, -NHC(O)-OR26 wherein R26 means hydrogen atom, (C1-C6)-alkyl; R3 means hydroxy-group or group of the formula -NH-R31 wherein R31 means -C(O)-R32, -C(O)-NHR32 or -C(O)-OR32 wherein R32 means (C1-C6)-alkyl or (C3-C6)-cycloalkyl; D means a saturated or unsaturated alkylene chain comprising of 5-10 carbon atoms and comprising optionally one-three heteroatoms taken independently of one another among oxygen (O), sulfur (S) atom, or N-R41 wherein R41 means hydrogen atom (H), -C(O)-R42 wherein R42 means (C1-C6)-alkyl, C6-aryl; R4 means hydrogen atom (H) or one-three substitutes at any carbon atom in chain D wherein substitutes are taken independently of one another from group comprising (C1-C6)-alkyl, hydroxyl; A means carboxylic acid or its alkyl esters or their derivatives. Invention relates to pharmaceutical compositions containing indicated compounds and eliciting activity with respect to hepatitis C virus and these peptides inhibit activity of NS3-protease specifically but don't elicit significant inhibitory activity with respect to other serine proteases.

EFFECT: valuable biochemical and medicinal properties of peptides.

106 cl, 9 tbl, 61 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I):

wherein r = 1, 2 or 3; s = 0; t = 0; R1 is taken among group including R11-CO and R12-SO2- wherein R11 is taken among group including (C6-C14)-aryl, (C1-C8)-alkyloxy-group wherein all given group are unsubstituted or substituted with a single or some similar or different substitutes R40; R12 means (C6-C14)-aryl wherein indicated group is unsubstituted or substituted with a single or some similar or different substituted R40; R2 means R21(R22)CH-, R23-Het-(CH2)k-, R23(R24)N-(CH2)m-D-(CH2)n- or R25(R26)N-CO-(CH2)p-D-(CH2)q- wherein D means bivalent residue -C(R31)(R32)-, bivalent (C6-C14)-arylene residue or bivalent residue obtained from aromatic group Het comprising 5 or 6 atoms in cycle among them 1 or 2 are similar or different cyclic heteroatoms taken among group including nitrogen and sulfur atoms; numbers k, m, n, p and q = 0, 1, 2; R21 and R22 that are independent of one another can be similar or different and taken among group including hydrogen atom, (C1-C12)-alkyl, (C6-C14)-aryl and so on; R23 means hydrogen atom, R27-SO2- or R28-CO-; R24, R25 and R26 mean hydrogen atom; R27 is taken among group including (C1-C8)-alkyl, (C6-C14)-aryl and so on; R28 is taken among group including R27, (C1-C8)-alkyloxy-group; R31 and R32 mean hydrogen atom; R40 is taken among group including halogen atom, hydroxy-, (C1-C8)-alkyloxy-group, (C1-C8)-alkyl, (C6-C14)-aryl and so on; R91, R92, R93 and R96 means hydrogen atom; R95 means amidino-group; R97 means R99-(C1-C8)-alkyl; R99 is taken among group including hydroxycarbonyl- and (C1-C8)-alkyloxycarbonyl-; Het means saturated, partially unsaturated or aromatic monocyclic structure comprising from 3 to 6 atoms in cycle among them 1 or 2 are similar or different heteroatoms taken among group comprising nitrogen and sulfur atoms; in all its stereoisomeric forms and also their mixtures in any ratios, and its physiologically acceptable salts. Invention proposes a method for preparing compound of the formula (I). Also, invention proposes a pharmaceutical preparation eliciting inhibitory activity with respect to factor VIIA and containing at least one compound of the formula (I) and/or its physiologically acceptable salts and pharmaceutically acceptable carrier. Invention provides preparing compounds of the formula (I) eliciting power anti-thrombosis effect and useful for treatment and prophylaxis of thrombosis-embolic diseases.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 70 ex

FIELD: organic chemistry and drugs.

SUBSTANCE: New class of compounds of general formula 1, where R has formula 2 or 3; other residues are as described in claim of invention is disclosed. Said compounds are interleikyn-1β converting enzyme (ICE) inhibitors and have specific structural and physicochemical properties. Invention also relates to pharmaceutical composition containing said compounds. Compounds and composition of present invention are particularly useful in ICE activity inhibition and thereby can be used as drug for treating of diseases mediated by IL-1, apoptosis, IGIF and IFN-γ, as well as inflammations, autoimmune diseases, bone-destructive disorder, infections, disorder associated with cell proliferation, degenerative and necrotic disorders. Uses of claimed compounds and compositions as well as methods for production of N-acylamino compounds also are disclosed.

EFFECT: effective interleikyn-1beta converting enzyme inhibitors.

64 cl, 35 ex, 35 tbl, 21 dwg

FIELD: medicine, gastroenterology.

SUBSTANCE: traditional eradication therapy should be supplemented with licopid at the dosage of 10 mg per os once daily before breakfast for 10 d. The present innovation prevents transfer of microorganisms into inactive form, accelerates restoration of mucosal epithelial layer in gastroduodenal area, provides complete eradication of microorganisms, that in its turn, favors to prevent disease exacerbation and restoration of gastroduodenal functions.

EFFECT: higher efficiency of therapy.

3 dwg, 2 ex

FIELD: biotechnology, biochemistry.

SUBSTANCE: invention relates to producing the biologically active complex eliciting antioxidant and immunomodulating activity and used in medicine, cosmetics, veterinary science and food industry. The biologically active complex preparing by enzymatic hydrolysis of muscle tissue represents complex of biologically active compounds involving carnosine and anserine in the amount 85-97 wt.-% of the native content of these components in poultry muscle tissue, 1-7 weight parts of amino acids, 0.5-12 weight parts of oligopeptides of molecular mass 10 kDa, not above, and 0.1-15 weight parts of cyclic and polycyclic phenolic compounds as measured for 1 weight part of carnosine and anserine in the complex. This complex is prepared by enzymatic hydrolysis of milled and homogenized water muscle tissue in preferable dilution homogenate with water in the range 0.2-0.6 and with using proteolytic enzymes in the amount 2-5 wt.-% of the protein content and working at pH 4.5-8.5 and at enhanced temperature being preferably at 45-65°C. Product is isolated as extract or powder prepared in drying the extract. Invention provides enhancing effectiveness of the claimed complex.

EFFECT: improved method for preparing, valuable properties of complex.

7 cl, 6 tbl, 6 ex

FIELD: medicine, cardiology, gastroenterology.

SUBSTANCE: invention relates to a method for treatment of ulcer-erosion injures in gastroduodenal region in patients with arterial hypertension. Method involves detection of immune disturbances and carrying out the combined immunomodulating therapy and hypotensive therapy. Immunocorrecting complex consists of licopide, cortexinum, vetoronum TK in arterial hypertension of I-II degree and comprises superlymph additionally in arterial hypertension of III degree. Method provides attaining optimal results in treatment for relatively short time due to adequate immunocorrection in such patients.

EFFECT: improved method for treatment.

5 cl, 6 tbl, 2 ex

FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to new inhibitors of thrombin of the formula (I)

,

method for their preparing, intermediate compounds used for their preparing of the formula (II)

and a pharmaceutical composition comprising compounds of the formula (I). Invention provides enhancing effectiveness in inhibition of thrombin.

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

23 cl, 61 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a combined medicinal agent used in treatment of arterial hypertension. The proposed agent comprises the combination of enalapril maleate and hydrochlorothiazide as an active component, and also sodium hydrocarbonate, starch, lactose, iron oxide and stearate as accessory substances. The proposed agent is stable in storage and releases the active component easily.

EFFECT: improved and valuable properties of agent.

8 cl, 1 tbl, 5 ex

FIELD: veterinary science, pharmacy.

SUBSTANCE: invention proposes a composition for antioxidant protection of cells, tissues and a whole body against hyperproduction of free radicals in acute inflammation, chemical thermal and radiation damages. The composition comprises peroxyredoxin Prx VI and, additionally, lipoic acid and pharmaceutically acceptable additives. The composition comprises peroxyredoxin Prx VI and dihydrolipoic acid taken in the effective amount in the ratio peroxyredoxin Prx VI to dihydrolipoic acid in the range (w/w) from 1:1 to 50:1 wherein peroxyredoxin Prx VI can represents human recombinant peroxyredoxin Prx VI. Also, invention relates to a method for enhancing antioxidant protection of mammals involving delivery of indicated pharmaceutical composition is carried out into intercellular space of tissue, organ or a whole body of mammal. The delivery can be carried out by passive or active diffusion in application or spraying, by parenteral or endolumbal administration by injection, by parenteral administration, infusion, inhalation, drainage, by sublingual, vaginal or rectal administration, by nasal or ophthalmic drops. Except for, the delivery can be carried out with using other therapeutic agent, in particular, interferon simultaneously. Invention provides prophylaxis of secondary alternative damages, recovery of epithelial tissue, protection of biomacromolecules against effect of irradiation.

EFFECT: valuable medicinal properties of composition.

6 cl, 9 tbl, 11 dwg, 45 ex

FIELD: chemistry of peptides, microbiology, biotechnology.

SUBSTANCE: L-alanyl-L-glutamine is prepared by incubation of a mixture containing a microorganism able to produce L-alanyl-L-glutamine from L-alanine ester and L-glutamine, L-alanine ester and L-glutamine, and isolation of the end product. Using the invention allows simplifying the process for preparing L-alanyl-L-glutamine. Invention can be used in pharmacy and food processing industry.

EFFECT: improved preparing method of dipeptide.

3 cl, 3 tbl, 1 ex

FIELD: organic chemistry of natural compounds.

SUBSTANCE: invention relates to novel compounds, namely, to N'-{N-[3-oxo-lupan-28-oyl]-9-aminononanoyl}-3-amino-3-phenylpropionic acid and its salts of the formula (I) given in the invention description. This compound shows antiviral activity, in particular, anti-HIV activity, and immunostimulating activity. Compounds of the formula (I) are nontoxic and can be obtained from betulin isolated from birch bark as available raw with the high yield.

EFFECT: valuable medicinal properties of compound.

4 tbl, 9 ex

Perindopril // 2339645

FIELD: chemistry.

SUBSTANCE: formula (I) is obtained from protected precursor compound of the formula (II) , where R is carboxy protective group. Method involves protection removal from COOR carboxylic group linked to heterocyclic ring in the formula (II), thus obtaining respective free acid. Protection removal is performed in the presence of an alkali forming pharmaceutically acceptable salt with the indicated free acid and, if necessary, is followed by hydration of pharmaceutically acceptable perindopril salt.

EFFECT: improved method of perindopril obtainment.

15 cl, 1 dwg, 1 tbl, 7 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: present invention refers to bioactive compounds of formula (Ic) , pharmaceutical compositions and application at cancer treatment, where R2-R7, X2, R, Q, G, J, L and M represent values estimated in invention formula and description.

EFFECT: production of compounds which can be used for anticancer medical product.

55 cl, 19 ex

FIELD: chemistry.

SUBSTANCE: desired dipeptides are synthesised by reaction of methyl ether N - (9-aminononanoyl)-3-amino-3-phenylpropionic acid and betulonic (3-oxo-lup-20 (29)-en-28) and dihydrobetulonic (3-oxo-lupan-28) acid chloranhydrides.

EFFECT: lupane triterpene dipeptides develop antiviral antiproliferative and immunopotentiating activity.

9 ex

FIELD: medicine.

SUBSTANCE: application describes ACE inhibitor complexes of Perindopril Erbumine with cyclodextrins, polyvinylpyrrolidone or hydroxypropyl cellulose, methods for making thereof, pharmaceutical compositions.

EFFECT: application for treatment of cardiovascular diseases.

19 cl, 23 dwg, 13 ex

FIELD: pharmacology.

SUBSTANCE: there is produced synthetic derivative of phthalyl-glycyl-agginyl-piperidide peptide expressing anticoagulant activity estimated by inhibiting amidolytic thrombin activity in system in vitro and double prolongation of rats' blood plasma coagulation as compared with the control values in tests activated partial thromboplastin and thrombin time tests and having formula 1, including pharmaceutically acceptable salts.

EFFECT: new synthetic peptide derivative expressing anticoagulant activity.

1 dwg, 2 tbl, 4 ex

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