Amide derivatives teicoplanin or their pharmaceutically suitable acid salt additive, the method of obtaining teicoplanin derivatives and pharmaceutical composition

 

(57) Abstract:

Usage: as pharmaceutical compounds against gram-positive and gram-negative bacteria. The inventive product is C63amide derivatives teicoplanin, which is obtained by reaction of the complex, preferably of atmoephere teicoplanin with the corresponding di - or polyallylamine. 3 S. and 18 C. p. F.-ly, 8 PL.

The invention relates to substituted alkylamino teicoplanin having the formula:

< / BR>
where R is hydrogen or a protective group of the amine functional group;

Y connection formulas

-NR1-Ala1-[X - Ala2]p-[T-Ala3]p-[T-Ala3]q-W,

where R1hydrogen or (C1-C4) alkyl;

Ala2, Ala2and Ala3each independently from each other alkylen with a linear or branched chain with 2 to 10 carbon atoms;

p is an integer of 1 to 50, including the boundary values;

q is an integer of 0 to 12, including the boundary values;

X group-NR2or oxygen atom, where R2represents hydrogen, (C1-C4)alkyl, a group ALK1NR3R4where ALK4is alkylen straight or branched zeplyaet a hydrogen, (C1-C4)alkyl, or 5-6-membered cycloalkyl; or R1and R2taken together, represent a (C2-C4)alkylene link between the two nitrogen atom, provided that in this case p is 1;

T the group-NR5or oxygen atom, where R5represents hydrogen, (C1-C4)alkyl; a group ALK5NR6R7where ALK5is alkylen straight or branched chain with 2 to 4 C atom, R6represents hydrogen or (C1-C4)alkyl and R7represents hydrogen, (C1-C4)alkyl, or 5-6-membered cycloalkyl; or R2and R5together form a (C2-C4)Akilova link connecting the two nitrogen atom, provided that in this case both p and q are equal to 1;

W oxygraph, NR8N9where R8represents H or (C1-C6)alkyl and R9represents H1-C6)alkyl, 5-6-membered cycloalkyl, COOR10where R10is a (C1-C6)-aryloxy-(C1-C4)alkyl group and NR11R12R13Anwhere R11, R12and R13each independently from each other represent shodney acid, provided that when X represents NR2, p 1 and q 0, then W is not actigraphy;

A H or-N-[(C9-C12)aliphatic acyl]-β-D-2-deoxy-2-aminopropanoic;

B is hydrogen or N-acetyl-beta-D-2-deoxy-2 - aminopropanoic;

M is hydrogen or alpha-D-mannopyranosyl,

and their acid-additive pharmaceutically suitable salts, provided that B represents hydrogen only when A and M are both hydrogen atom.

Teicoplanin is the international nonproprietary name (INN) antibiotic substances, which were formerly known as takamiya, which is obtained by cultivating the strain Actinoplanes teichomyceticus vov. sp. ADS 31121 in the environment of cultivation, containing assimilated sources of carbon, nitrogen and inorganic salts (see U.S. patent N 4239751).

According to the procedure described in the mentioned patent, the antibiotic complex, is described in ibid, antibiotic complex containing Takaisin A1, A2and A3extracted from the separate fermentation broth by extraction with a suitable water-insoluble organic solvent and precipitation of the extracting solvent according to conventional% is separated from the others by chromatography in Sephadex columnIt is known (see patent England N 2121401) that the antibiotic Takaisin A2is actually a mixture of five closely related to each other together get the main components.

As shown by recent structural studies, it is possible to introduce the key components 1, 2, 3, 4 and 5 teicoplanin A2(previously called Takamiya A2) the above formula I, in which R represents hydrogen, Y oxygraph, A N[(C6-C11-)-aliphatic acyl]-β-D-2-deoxy-2-amino-glyukopiranozil, B N-acetyl-beta-D-2-dexi-2-amino-glyukopiranozil and M alpha-D-mannopyranosyl.

In particular, in teicoplanin A2component 1 Deputy [(C10-C11)-aliphatic acyl] is a Z-4 decanoyl, teicoplanin A2component 2 8-methyl-nonanoic, teicoplanin A2component 3 decanoyl, teicoplanin A2component 4 - 8-methyldecyl, teicoplanin A2component 5 9-methyldecyl.

It is known (see European patent application N 306645) obtaining teicoplanin compounds in which the group of aliphatic acid beta-D-2-deoxy-2-aminopropionitrile link are 6-methyl-occasionaly group (compound A or RS3) ReadLine patterns of non-core components teicoplanin". 17th international Symposium on chromatography. Vienna. 25-30 September 1988) two other teicoplanin connection (RS1 and RS2).

These compounds differ in that group, aliphatic acyl beta-D-2-deoxy-2-aminopropionitrile link are respectively methyl-undecanol (RS1) and dodecanol (RS2). All groups of sugar, in case of their presence, associated with nuclei teicoplanin O-glycosidic bonds.

Also found that you can convert teicoplanin, its net factor or a mixture of any of these factors in any proportion in the components of one antibiotic products by selective hydrolysis of one or two sugar units. They are called antibiotic L 17054 and antibiotic L 17046 (see European patent N 119575 and N 119574, respectively).

Preferred hydrolysis conditions for the receipt of antibiotic L 17054 are the following: 0,5 N. hydrochloric acid, temperature 70 90oC and the duration of the process is usually 15 to 90 minutes

Antibiotic L 17054 represented by the above formula I in which Y represents oxygraph, R and A is hydrogen, B is N-acetyl-beta-D-2-deoxy-2-aminoglutaramic, M alpha-D-mannopyranosyl in which sugar chains tie the receipt of antibiotic L 17046 are the following: 1 3 N. hydrochloric acid, the temperature of 50 90oC, the duration of the process is usually 30 to 60 minutes

Antibiotic L 17046 represented by the above formula I in which Y represents oxygraph, R, A and M are hydrogen atoms, B - N-acetyl-beta-D-2-deoxy-2-amino-glyukopiranozil, where the sugar level is associated with a peptide core through O-glycosidic bonds.

Known (see European patent application N 301247) de-mannosilirovanii derivatives, i.e. compounds of the above formula I in which A and B have values different from hydrogen, M represents hydrogen, and Y oxygraph.

In the full electoral cleavage all sugar units teicoplanin compounds obtained Aglyamova molecule, which is called antibiotic L 17392 or diglycolamine, and it is represented above by formula I in which Y represents oxygraph, R, A, B, and M each independently from each other hydrogen atom (see the electoral process of hydrolysis in European patent application N 146053).

The substance having the same structural formula, is called the factor B, antibiotic A 41030 (see European patent application N 0090578).

This substance is obtained by Mick the coming environment, extraction, purification and separation of components of antibiotic A 41030, antibiotic complex, consisting of at least seven factors, including factor B, antibiotic A 41030.

All of the mentioned compounds, namely teicoplanin, complex teicoplanin A2component 1 teicoplanin A2component 2 teicoplanin A2component 3 teicoplanin A2component 4 teicoplanin A2component 5 teicoplanin A2connection A or RS3, compound B or RS4, RS1, RS2, antibiotic L17054, antibiotic L 17046, antibiotic L 17392, derived de-mannosylation (see European patent application N 301247) and their mixtures in any proportion, are the original products suitable for obtaining the appropriate alkylamine derivatives according to this invention.

In the description of this patent application the term "teicoplanin connection" or "teicoplanin source material" is used to show any of the above starting materials, namely teicoplanin obtained according to the U.S. patent N 4239751, any further purification, the complex teicoplanin A2the compound of the above formula I, in which R represents hydrogen or N protecting group is dared or N-acetyl-beta-D-2-deoxy-2-aminopropanoic, M is hydrogen or alpha-D-mannopyranosyl, provided that B can be hydrogen only when A and M simultaneously represent hydrogen; their salt or a mixture in any proportion.

The term alkyl, either as such or in combination with other substituents, includes hydrocarbon group with a straight or branched chain, in particular "(C1-C6)alkyl" represents a hydrocarbon chain, straight or branched chain with the content of 1-6 carbon atoms, for example methyl, ethyl, propyl, 1-mutilative, 1-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 1-hexyl, 2-hexyl, 8-hexyl, 3,3 dimethyl-1-butyl, 4-methyl-4-pentyl and 3-methyl-1 - pentyl; similarly, (C1-C4)alkyl" represents a straight or branched hydrocarbon chain with the content of 1-4 carbon atoms, for example alkyl with the content of 1-4 carbon atoms, examples of which are listed above.

The term "ALK1", "Ala2", "Ala3" you mean independently linear or branched Allenova chain with 2 to 10 carbon atoms, for example

-CH2-CH2-,

-CH2-CH2-CH2-,

-CH2-CH2-CH2-CH2-,

< / BR>
-CH2-CH2SUB>-CH2-CH2-CH2- CH2-CH2-,

-CH2-CH2-CH2-CH2-CH2-CH2- CH2-CH2-,

-CH2-CH2-CH2-CH2-CH2- CH2-CH2-CH2-CH2-,

-CH2-CH2-CH2-CH2-CH2- CH2-CH2-CH2-CH2-CH2-,

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
Similarly, "Ala4and Ala5" are independently linear or branched alkylenes chain with 2 to 4 carbon atoms, such as Allenova chain with 2 to 4 carbon atoms, examples of which are given above.

The preferred compounds are the compounds of formula I,

where R is hydrogen or a group protecting the amine functional group;

Y connection formulas

-NR1-Ala1-[X-Ala2]p-[T-Ala]q-W,

where R1hydrogen or (C1-C4)alkyl;

Ala1, Ala2and Ala3each independently of one another linear or branched Allenova chain with 2 to 4 carbon atoms;

p is an integer of 1 to 12;

q is an integer of 0 to 12;

X group-NR2or oxygen atom, where R2represents hydrogen, (C1-C3
represents hydrogen or (C1-C4)alkyl and R4is hydrogen, (C1-C4)alkyl, or 5-6-membered cycloalkyl; or R1and R2taken together form a (C2-C4) alkylene link between the two nitrogen atom, provided that in this case p is 1;

T the group-NR5or oxygen atom, where R5represents hydrogen, (C1-C4)alkyl, a group ALK5NR6R7in which ALK5is a linear or branched alkylene contents 2 4 C atom, R6represents hydrogen or (C1-C4)alkyl, and R7hydrogen, (C1-C4)alkyl, or 5-6-membered cycloalkyl; or R2and R5taken together form a (C2-C4) alkylene link between the two nitrogen atom, provided that in this case both p and q are equal to 1;

W oxygraph, NR8R9where R8represents H or (C1-C6)alkyl and R9H, (C1-C6)alkyl, 5-6-membered cycloalkyl, COOR10where R10is a (C1-C6)alkoxy-(C1-C4)alkyl, and a group of the formula NR11R12R13Anin which R11, R12and R13each independently Armaceuticals suitable acid; provided that when X represents NR2, p 1 and q 0, then W has a value other than actigraphy;

H or-N[(C9-C12)aliphatic acyl]-β-D-2-deoxy-2-aminopropanoic;

B is hydrogen or N-acetyl-beta-D-2-deoxy-2-aminopropanoic;

M is hydrogen or alpha-D-mannopyranosyl,

and their pharmaceutically suitable acid additive salt, with the additional condition that B represents hydrogen only when a and M simultaneously represent hydrogen. Preferably, when X and/or T represents a-NR2- and/or-NR5- Ala4and Ala5represents a C2-C3linear carbon chain.

As described above, p is an integer in the range from 1 to 50, including the boundary values, and q is an integer from 0 to 12, including the boundary values. Preferably, when X and/or T represents a-NR2- and/or-NR5- then p and q is 1 to 12, and at the same time, when X and T represent oxygen atoms, then p and q have values such that p + q is in the range from 12 to 50.

The term "C5-C6"cycloalkyl" as it is used in the description of the present invention, comprises a group cyclopentyl actualname compounds are also compounds of formula I, in which X represents a group-NR2-, where R2is a hydrogen atom, (C1-C4)alkyl or Ala4NR3R4.

Another group of preferred compounds are the compounds of formula I in which p is 1 and X represents-NR2-, where R2together with R1form (C2-C3)alkylene link between the nitrogen atom. In this case, particularly preferred such compounds, in which ALK1represents a group-CH2CH2-. In addition, a preferred group of compounds are those compounds in which ALK1represents a group-CH2CH2-. The following preferred group of compounds includes compounds of formula I in which p is 1, q is 1 and X and T are a-NR2and-NR3-, respectively, in which R2and R3together form a (C2-C3)alkylene link between the nitrogen atoms.

In this case, particularly preferred such compounds, in which ALK2represents a group-CH2-CH2-.

Other preferred compounds are represented by formula I, in which X and T represent oxygen atoms, p + q zostaw>1-C4)alkyl and R9hydrogen, (C1-C4)alkyl, cyclopentyl or cyclohexyl.

Other preferred compounds are such compounds in which R8represents NR8R9where R8defined above and R9represents COOR10where R10is (C1-C6) acyloxy-(C1-C4)alkyl group.

IN(C1-C6)acyloxy-(C1-C4)alkyl" group (C1-C4the alkyl represents a methylene link, optionally substituted (C1-C3linear or branched alkyl chain, for example

-COOCH2OCOCH3,

< / BR>
< / BR>
and others.

According to the General definitions above, typical examples of the group

-NR1-Ala1-[X-Ala]p-[T-Ala3]q-W

following are the

-NH(CH2)2-NH(CH2)2-NH2< / BR>
-NH(CH2)2-NH(CH2)3-NH2< / BR>
-NH(CH2)2-NH(CH2)4-NH2< / BR>
-NH(CH2)4-NH(CH2)2-NH2< / BR>
-NH(CH2)3-NH(CH2)4-NH2< / BR>
-NH(CH2)2-NH(CH2)3-NH(CH2)2-NH2< / BR>
-NB>-NH(CH2)3- NH2< / BR>
-NH(CH2)2-NH(CH2)3-NH(CH2)4- NH2< / BR>
-NH(CH2)4-NH(CH2)3-NH(CH2)4-NH2< / BR>
-NH(CH2)3NH(CH2)9-NH(CH2)3NH2< / BR>
-NH(CH2)3NH(CH2)10-NH(CH2)3NH2< / BR>
-NH[(CH2)2NH]2-(CH2)2-NH2< / BR>
-NH[(CH2)3NH]2-(CH2)3-NH2< / BR>
-NH[(CH2)4NH]5-(CH2)4-NH2< / BR>
-NH[(CH2)5NH]3-(CH2)5-NH2< / BR>
< / BR>
< / BR>
-NH(CH2)2-NH(CH2)2-NHCH3< / BR>
-NH(CH2)2-NH(CH2)2-NHC2H5< / BR>
-NH(CH2)2-NH(CH2)4-NH(nC4H9)

< / BR>
< / BR>
< / BR>
-NH(CH2)3-N[(CH2)3NH2]2< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
-NH(CH2)3NH(CH2)4NHCOOCH(CH3) OCOCH3< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
-NH-CH(CH3)CH2-[OCH2CH2]42OCH2CH(CH3)NH2< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
The connection is such antibacterial agents, active against gram-positive bacteria, especially against gram-negative bacteria, especially against Escherichia coli and Pseudomonas aeruginosa.

Known (see European patent application N 218099 and International patent application N WO 88/06600) various C63amide derivatives teicoplanin complex, its individual components and the aglycone and pseudoglioma.

Connections matching the invention, obtained by amidation of the corresponding derivatives of the formula I in which Y represents OH (i.e. the corresponding carboxylic acids).

Substances used as feedstock to produce compounds corresponding to this invention, can be either products as such or mixtures of one or more products.

Because the raw materials for producing compounds conforming to the invention can be used in both forms, the resulting products can, in turn, to be a separate compounds as such or in mixtures of two or more compounds of the above formula I. These compounds compounds are also covered by the invention and can be used as such due to their biological activities or in negotia, suitable for individual components of finite mixtures of amide derivatives teicoplanin known (see European patent application N 218099 and International patent application N 88/06600).

The amidation procedure described in these two publications, can also be used to produce compounds corresponding to this invention. These procedures include a condensation of the original carboxylic acids mentioned above, with an excess of the appropriate amine of formula II

OTHER1-Ala1-[X-Ala2]p-[T-Ala3]q-W,

where R1, Ala1, Ala2, Ala3X, T, p, q and W have the same meanings as above,

in an inert organic solvent in the presence of a condensing agent.

Inert organic solvents used for the amidation reaction are aprotic organic solvents which do not adversely affect the course of the reaction and is capable of at least partially solubilisate source teicoplanin product.

Examples of inert organic solvents are organic amides, complex alkalemia esters, ethers, glycols and polyhydric alcohols, phosphoramide imitacion, hexamethylphosphoramide, dimethylsulfoxide and mixtures thereof.

The condensing agent used in this invention, suitable for the formation of amide bonds in organic compounds, in particular in the synthesis of the peptide.

Typical examples of condensing agents are (C1-C4)alkyl, phenyl, or heterocyclic phosphorazidate, such as diphenylphosphonate, diethylphosphoramidite, di(4-nitrophenyl)phosphorazidate, dysmorphological and diphenylphosphinylchloride. The preferred condensing agent is diphenylphosphonate, i.e. azide complex of diphenyl ether phosphoric acid (DPPA). When carrying out the amidation process, as specified in this description, the amine reagent is generally used in molar excess amounts.

Usually, when the amine reagent is inexpensive or quite easily obtained with a reagent used 2 6-fold molar excess, but preferred 3-4-fold molar excess.

For amidation requires that Amin was capable of forming a salt with the carboxyl functional group teicoplanin the original product. When Amin is not subject to the second mixture to enter the salt-forming base is not less than ravnomyerno number of number of source teicoplanin.

Use a small molar excess of amine reactant with the introduction of salt-forming base is quite suitable manner when the amine reactant is quite expensive and difficult to get a product.

Examples of salt-forming bases are tertiary organic or heterocyclic amines, such as triethylamine, tromethamine, N-methyl pirrolidone or picoline, and others.

The condensing agent is usually used in slight molar excess, amounting to, for example, 1.2 to 1.7-fold amount, preferably the 1.5-fold amount of teicoplanin source connection.

In addition, amine reagent can be easily introduced into the reaction medium in the form of a suitable acid additive salts, such as hydrochloride. In this case, using a double molar ratio and preferably 2 to 4-fold molar excess of a strong base capable of free amine form of its salts. Along with this, in this case, the suitable base is a tertiary organic aliphatic or heterocyclic amine, such as described above. In fact, at least in some cases, the use of the amine salt, which is interesting, especially when this salt is more stable than the corresponding free amine.

The reaction temperature usually varies within wide limits depending on the type of starting material and the reaction conditions. Usually it is desirable to carry out the reaction at temperatures in the range 0-20oC.

In addition, the reaction time also varies widely depending on other parameters of the reaction. Usually the condensation reaction is completed within about 24 to 48 hours

In any case, the course of the reaction is controlled by thin-layer (TLC) chromatography or liquid chromatography high resolution (HPLC) according to existing methods.

Based on the results of these analyses specialist in this area to assess the progress of the reaction and to decide when to stop the reaction and when to begin treatment of the reaction mass according to known techniques, which include, for example, extraction with solvents, precipitation by entering nerastvorimaya, etc. in combination with other well-known operations of separation and purification, for example by using columnar chromatography.

If the amine reactant contains other functional groups, which is imayutsya through already known protective groups.

According to the following preferred aspect of the invention: compounds of formula I in which Y represents the above group can be obtained by reaction of the "activated complex ether carboxylic acids of the same formula I in which Y is OH, and N15-amine functional group is preferably protected with an appropriate amine of formula II.

N15-amine functional group may be protected by known methods (see, for example, kN. T. W. Greene. "Protective groups in organic synthesis". John Wiley and Sons. New York. 1981; M. Mc. Omie. "Protective groups in organic chemistry". Plenum Press. New York. 1973).

The protective group must be stable in the reaction should not have an adverse impact on the amidation reaction and should be easily cleaved and removed from the reaction medium after the reaction without changing the newly formed amide bond and the General structure of the compounds, such as components of sugar.

Typical examples of the N-protective groups which can be successfully used in the method of the present invention to protect the N15-primary amine functional group source teicoplanin, and when it is needed, and who embody the following oxycarbonyl groups: I, I dimethylphenylcarbinol, tert-butyloxycarbonyl, vinyloxycarbonyl, cinnamoylcocaine, benzyloxycarbonyl, para-nitrobenzenesulfonyl, 3,4-dimethoxy-6-nitrobenzisoxazole, 2,4-dichlorobenzenesulfonyl, 5-benzyloxycarbonyl, 9-internalservererror, diphenylmethylsilane, isonicotinamide, diphenylmethylsilane, isonicotinamide, S-benzyloxycarbonyl and others. Other suitable N-zameshayushei agents are aldehydes or ketones or their derivatives, which are capable of forming Schiff bases with amine group that must be protected.

Preferred examples of such agents, forming a Schiff base, are benzaldehyde and particularly preferred is 2-oxybenzaldehyde (salicylic aldehyde).

A simple method of protection in some cases is the formation of benzylidene derived, which can be obtained by reaction of the amine with benzaldehyde in a lower alcohol, such as ethanol, preferably at room temperature. After stopping the reaction with the selected teicoplanin source material benzylidene protective group can be removed already known the th media as a catalyst.

However, in this case, you should pay attention to the presence of groups that can be modified by catalytic hydrogenation. A typical consequence of the catalytic hydrogenation of an amino-protected derivative of the formula I, in which And represent the above group, in which the acyl is (Z)-4-decenal(or its containing mixture), is the fact that at least partially decanoate connection turns into a corresponding Technologie connection.

As should be clear to experts in this field, the selection of specific protective group depends on the characteristics of a specific amide derivative, which is desirable. In fact, this amide functional group end of the connection must be stable under the conditions of removal of the protective group (or groups).

As the conditions for the removal of various functional groups known to the person skilled in the art can choose a suitable protective group.

Getting "activated esters" is known (see Fieser and Fieser. Reagents for organic synthesis. John Wiley and Sons Inc. S. 129 130, 1967).

Examples of reagents that form these activated complex EF is Schwyzer and other Helv. Chim. Acta 1955 , 69-70, and include the following compounds: ClCH2CN, BrCH2COOC2H5, BrCH(COOC2H5)2, CICH2COCH3, , ClCH2CH2N(C2H5)2.

The preferred reagent of this type is chloroacetonitrile. In this case, itself chloroacetonitrile or dimethylformamide (DMF) can be used as a preferred solvent.

Usually inert organic solvents used to get "activated esters" are aprotic organic solvents which do not adversely affect the course of the reaction and is capable of at least partially to solubilisate original carboxylate.

Examples of these inert organic solvents are organic amides, alkalemia ethers, ethers of glycols and polyols, phosphoramide, sulfoxidov and aromatic compounds. Preferred examples of inert organic solvents are dimethylformamide, dimethoxyethane, hexamethylphosphoramide, dimethyl sulfoxide, benzene, toluene, and mixtures thereof.

More preferably, the solvent is selected from among the following: acetatee Foundation, which does not affect the course of the reaction, such as trialkylamine, such as triethylamine, sodium carbonate or sodium bicarbonate or potassium. Typically, the base used in the 2-6-molar proportions to the original carboxylic acid teicoplanin, preferably it is approximately 3-fold molar excess. The preferred base is triethylamine.

The reagent, forming an "activated ester" is used in large excess relative to the carboxylic acid source teicoplanin. It is typically used in 5-35-molar ratio, preferably about 20-30-fold molar excess. The reaction temperature is 10 to 60oC, preferably 15 to 30oC. Typically, the duration of the reaction depends on other specific parameters of the reaction and is usually 3: 48 PM

In this case, the course of the reaction can be traced by thin layer (TLC) chromatography and liquid chromatography high resolution (HPLC) to determine when the reaction can be considered as completed and when may be the procedure of retrieving the desired intermediate product. Intermediate product "activated ester" can use is Sardinia nerastvorim or by solvent extraction and is used as such without further purification in the next reaction step. However, if desirable, it can be purified by columnar chromatography, such as chromatography with evaporative column or a chromatography column with a reversible phase.

The obtained intermediate product "activated ester" then reacted with a molar excess of amine derivative of the formula II

OTHER1-[Ala1]p-[T-Ala3]q-W II

in the presence of an organic polar solvent at a temperature 5 - 60oC, preferably 10 to 30oC.

Organic polar solvent in this case can be proton polar solvent or aprotic solvent.

Preferred examples of the organic proton polar solvents are low (C2-C4)alkanols, such as ethanol, n-propanol, ISO-propanol, I-butanol, etc. or mixtures thereof, preferably used in the dry form.

Preferred examples of the organic polar aprotic solvent is N,N-dimethylformamide (DMF), hexamethylphosphoramide (HMPA), or mixtures thereof, 1,3-dimethyl-3,4,5,6-tetrahydro-2(IH)-pyrimidone (DMPU), dimethylsulfoxide (DMSO) or dimethoxyethane (DME).

The reaction of the "activated complex ester" SEL which is temperature 10 30oC, most preferably 20 to 25oC, while the preferred molar ratio between the intermediate activated complex ester and amine II, as defined above, is (1 5) (1 to 30), more preferably (1 10) (1 20). The course of the reaction can be adjusted as accepted by TLC or HPLC.

Amide derivative obtained by the amidation reaction, is removed from the reaction solution according to the conventional procedures, for example by evaporation of the solvent or by entering herstories. The removal of the amine protecting group is usually carried out on the crude product isolated from the reaction medium amidation.

Examples of processes for the removal of these protective groups from teicoplanin derivatives are known (see, for example, International patent application N WO 88/06600).

If the procedures of the catalytic hydrogenation reaction is usually carried out in the presence of a diluted aqueous solution of a strong acid, preferably an inorganic acid, an organic solvent, is mixed with a dilute aqueous solution of a strong acid. The filtrate from the reaction medium is then processed to extract either additive or toxic treatments are carried out in the case, when the amine protecting group is one which can be removed by treatment with diluted inorganic acid, such as Schiff base or a carbonyl group C-C alkoxy, in conditions which do not cause cleavage of the sugar units, such as low temperature, short reaction time.

The following procedure for obtaining compounds of formula I according to the invention consists in the reaction of N15-protected derivative of N63amide of the formula I in which Y represents-NR1Ala, XH or NR1-Ala1-[X-Ala2]p-TH reagent of the formula r-[ALK]p-[T-Ala3]q-W or r-[Ala3]qW, respectively, where R1, Ala1, Ala2, Ala3, X and T have the same values as above, r represents halogeno, methanesulfonyl or tosyl, in the presence of an acid acceptor in an inert solvent. In these cases, p is preferably 1 or 2, q has a value other than zero, is preferably 1 or 2, X and T are preferably NH or oxygen, most preferably oxygen. N15-protected derivative of N63amide above, obtained according to the General description of the JV the uly I, in which W represents-NR8R9-, where R8defined above, R9is a group COOR10and R10(C1-C6) acyloxy-(C1-C4) alkyl, you need to N15-protected derivative of N63amide, in which W represents-other8-, where R8defined above, interacted with alpha-acyloxy-alkyl-para-nitrophenylarsonic in the presence of anhydrous carbonate of an alkali metal such as sodium carbonate.

Alpha-acyloxy-alkyl-para-nitrophenylarsonic can be obtained in a known manner (see J. Med. Chem. 31, S. 318 322. 1988). Some amides, corresponding to the invention, such as amides complex teicoplanin A2that is a separate component, or any mixture of two or more of its components, can be used as a starting material to obtain unitary antibiotic products by selective hydrolysis of one or two sugar molecules with the existence of procedures thus, as already described in the European patent N 119575 and N 119574. An alternative method of preparing compounds of the formula I in which A represents hydrogen, B Is N-acetyl-beta-D-2-deoxy-2 - aminopropanoic, M alpha-D-mannopyranosyl,/SUB>-C12)- aliphatic acyl]-β-D-2 - deoxy-2-aminopropanoic, B N-acetyl-beta-D-2-deoxy-2-aminopropanoic, M alpha-D-mannopyranosyl (i.e. carboxamide derivatives of complex teicoplanin A2or a separate component)(see European patent application N 146822).

This method consists in contacting the above material with a concentrated aqueous solution of an organic acid at about room temperature, preferably with an aqueous solution triperoxonane acid concentration of 75 to 95 at a temperature of 10 50oC.

An alternative method of preparing compounds of the formula I, in which both A and M represent hydrogen atom, B - N-acetyl-beta-D-2-deoxy-2-aminopropanoic is the compounds of formula I in which A represents N[(C9-C12aliphatic acyl]-β-D-2-deoxy-2 - aminopropanoic, B - N-acetyl-beta-D-2-deoxy-2-aminopropanoic, M alpha-D-mannopyranosyl, undergoes hydrolysis (see European patent application N 175100).

This method consists in contacting the above starting material with a strong acid in the presence of a polar aprotic organic restorationhardware.

In the latter case, as the source materials may also be used amide compounds of formula I in which A represents hydrogen, B is N-acetyl-beta-D-2-deoxy-2 - aminopropanoic, M alpha-D-mannopyranosyl, which are obtained by hydrolysis of concentrated aqueous solution triperoxonane acid, as described above.

To extract the acid additive salts the pH value of the reaction solution obtained by cleavage of the amino-protecting group, typically adjusted to a value of 4 to 7 by entering a water base, for example an aqueous solution of hydrate of sodium oxide, and after evaporation of the solvent under reduced pressure, the obtained solid product is recovered in the form of an acid additive salt formed from a strong acid, which is introduced during the removal phase protection. This product can be further purified by using common methods, for example by columnar chromatography, precipitation from solution by entering nerastvorimaya, preparative chromatography and other methods. An acid additive salt may be converted into the corresponding free base of formula I by suspending or dissolving an acid additive salt in water Estonia. This product is then extracted, for example, by extraction with an organic solvent and / or converted into another acid additive salt by adding the selected acid and implementation of a process as described above.

Sometimes after the above described operations may be necessary routine demineralization of the extracted product.

For example, can be used with success columnar chromatography using Polydextrose resin with controlled porosity (such as Sephadex LH20) or silanizing silica gel. After elution of unwanted salts in an aqueous solution of the desired product eluted by a linear ingredient or a stepwise gradient of a mixture of water with polar or aprotic organic solvent, such as acetonitrile/water containing from about 5 to 100 acetonitrile, and then it is extracted by solvent evaporation or lyophilization.

The compound of formula I in free base form may be transformed into the corresponding acid additive salt by suspending or dissolving forms of the free base in an aqueous solvent and enter a small molar excess of the selected acid. Received s cases, instead of lyophilization can extract the final salt by precipitation by entering herstories, mix with water.

When the final salt is insoluble in an organic solvent, in which the soluble form of the free base, it can be removed by filtration from the organic solution mesolevel form after entering the stoichiometric amount of a small molar excess of the selected acid.

Typical and suitable acid additive salts of compounds of formula I include salts formed by standard reactions with both organic and inorganic acids such as hydrochloric acid, Hydrobromic, sulfuric, phosphoric, acetic, triperoxonane, trichloroacetic, succinic, citric, ascorbic, lactic, maleic, fumaric, palmitic, cholic, Mamonova, Tlisova, camphoric, glutaric, glycolic, phthalic, tartaric, lauric, stearic, salicylic, methansulfonate, benzolsulfonat, sorbic, picric, benzoic, cinnamic acid and other acids.

The preferred acid additive salts of compounds conforming to the invention are pharmaceutically suitable acid additive salt.

The term "pharmaceutically suitable acid additive salts" refers to salts formulations meet the requirements of pharmaceutical practice. Examples of acids suitable for pharmaceutical acid additive salts" listed above.

Connections matching the invention, shaped as free bases and their acid additive salts, are useful antimicrobial agents, effective against both gram-positive and anti-gram-negative bacteria.

However, the connection corresponding to this invention exhibit extremely high activity against gram-negative bacteria, especially against Pseudomonas aeruginosa.

In fact, currently they are the most active derivative of the number teicoplanin of antibiotics against microorganisms of this type. This activity is especially characteristic of those compounds conforming to the invention, which have dglucosaminidase the kernel, but it is also characteristic of compounds conforming to the invention, which have teicoplanin the kernel.

Antibacterial activity of compounds corresponding to this invention can be demonstrated in terms of in vitro by standard double test dilution in microtitre device using nutrient broth Difco Todd-Hewitt (S is litura nutrient broth diluted sufficiently, to end inoculum was approximately 104forming colonies units/ml (CFU/ml). Minimum inhibitory concentration (MIC) is considered as the lowest concentration that does not show visible growth after incubation for 18 to 24 hours at a temperature of 37oC.

The results of antibacterial tests of typical compounds corresponding to this invention, are summarized in table. 1.

In table. 2 illustrates the activity of compounds 22, 23, 25, 26, 27 and 29 against some resistant to many antibiotics in clinical isolates of Pseudomonas aeruginosa.

The activity of compounds conforming to the invention, against Pseudomonas aeruginosa is greater than the activity teicoplanin and closest analog connections (see European patent application N 218099 and International patent application N WO 88/06600) where the value of MIC (μg/ml) against the same microorganism is never less than 32.

The activity of compounds corresponding to this invention, against Pseudomonas aeruginosa is particularly important in view of the importance of communicable infection, caused by this strain.

Clinical infectious diseases infection with P. aeruginosa include local infection, such as wounds (especially burns), urinary canal, respiratory tract, local infection in patients with low resistance and leading to the formation of metastatic lesion in various organs.

The prognosis for patients who develop septic infection with Pseudomonas small, and in some publications reported a very high mortality rate (sometimes 100) (see, for example, "Genetics and Biochemistry of Pseudomonas". P. H. Clarke and M. H. Richmond (Chapter 2), John Wiley and Sons. 1975).

In addition, teicoplanin connections matching the invention, which is different from diglycolamine and pseudoalleles teicoplanin, show significantly higher activity in the in vivo during oral input into the organism compared with the known amide derivatives teicoplanin. ED50(mg/kg) typical compounds conforming to the invention, under conditions of in vivo tests conducted on mice, catechesi infected with Strep. pyogenes, obtained according to known procedure (see V. Arioli and other Journal of Antibiotics. 1976), are given below in table. 3.

It was found that the connection 50 when tested in conditions in vivo is especially effective in the treatment of mice septicisle infected with E. coli after you enter (the dose of 40 mg/kg, 7/8 survive./processing) intravenously and after entering subcutaneously (ED5038 mg/kg).

In view of the above antimicrobial activity of the compounds corresponding to this invention, can be used as active ingredients antimic diseases, caused by pathogenic bacteria, which are sensitive to the specified active ingredients.

With this treatment, these compounds can be used as such or in the form of mixtures in any proportions.

Compounds corresponding to this invention, may be introduced into the body orally, locally or parenteral, preferably parenteral input method. Depending on the input method in the body these compounds may be prepared in the form of various dosage forms. Preparations for oral input can be in the form of capsules, tablets, liquid solutions or suspensions. As is well known, capsules and tablets can contain along with the active ingredient conventional excipient, such as diluents, for example lactose, calcium phosphate, sorbitol, etc., lubricants such as magnesium stearate, talc, polyethylene glycol, binding agents such as polyvinylpyrrolidone, gelatin, sorbitol, tragakant, Arabian gum, flavouring substances and suitable dezintegriruetsja and wetting agents. Liquid preparations, usually in the form of aqueous or oil solutions or suspensions can contain the usual additives, such as suspendiruemye agents. For local use s on the skin, the mucous membranes of the nose and throat or bronchial tissues and may take the form of creams, ointments, liquid, sprayable solutions or inhalers, cakes or medications applied with a brush in his throat.

Another advantage of the compounds corresponding to this invention, is their much higher solubility in water at a wider range of pH values and therefore the existing problems for the pharmaceutical compositions are eliminated.

For the treatment of eyes or ears this drug may have a liquid or semi-liquid form, prepared in hydrophobic or hydrophilic bases, such as ointments, creams, lotions, preparations for application by brush or powders.

To enter through the rectum connections matching the invention, are introduced in the form of candles in a mixture with conventional carriers, such as oil kako, paraffin, spermaceti or glycols and their derivatives.

Compositions for injection can have such forms as suspensions, solutions or emulsions in oil or water carriers, and they can include forming composition agents, such as suspendiruemye, stabilizing and/or dispersing agents.

As a possible variant, the active Jakim as sterilized water.

The amount of the main active ingredient, which must be introduced into the body depends on various factors such as the size and condition of the object being treated, the method and the input frequency of the drug and causing disease agent.

Compounds corresponding to this invention, usually, effective at the dose of their input in the range of about from 0.5 to 30 mg of active ingredient per kg of body weight, preferably in divided doses taken 2 to 4 times a day. Particularly desirable compositions are those which contain about 20 to 300 mg per single dose.

Examples. The experimental part.

In the following examples, the source material may be a complex teicoplanin A (TGA), a separate component, or any mixture of two or more of these components.

A typical complex mixture of mainly consist of five components corresponding to the above formula I, in which groups of aliphatic acyl beta-D-2-deoxy-2-aminopropionitrile radical represented by the symbol A, have respectively the following values: Z-(4-)-decanoyl (AC1); 8-methylnonanoic (AC2); decanoyl (AC3); 8-methyldecyl (AC4) and 9-methyldecyl Ozil (Man), and Y is OH.

This mixture is identified as an acronym TGAC1-5.

In the case when the source material is one of the components of this mixture, it is identified as: TGnAC1, TGAC2, TGAC3, TGAC4or TGAC5depending on the specific aliphatic acyl rest of specified aminopropionitrile radical.

When using mixtures of one or more components of the marking is the same as in the same system for the complex. For example, the Acronym TGAC2-5shows that this mixture of components 2 to 5, in which component 1 is no longer present. This mixture is obtained when the catalytic hydrogenation saturates the double bond of the component 1, which converts this component in the component 3. The acronym TGAC2,3means that it is a mixture of components 2, 3 and Acronym TGAC4,5shows that this mixture of components 4 and 5.

Antibiotic L17392 (i.e. the aglycone teicoplanin) is presented as an Acronym DTG, while pseudoglioma L17054 and L17046 represented respectively as TGA3-1 and TGA3-2, and dmannose pseudogene (European patent application N 301247) is represented as DM-TGAC.

The final products in the Pref is La beta-D-2-deoxy-2-aminopropionitrile radical (A/AC) is identified using conventional notation AC1AC2AC3AC4AC5as explained above. When the result is a mixture of two or more components, it is denoted by the same system as above.

Examples 1 to 30.

When the desired N63-carboxyamide mixtures TGAC2-5are the following procedures.

A. Obtaining a complex of N15-benzyloxycarbonyl(CBZ)teicoplanin A2and its components 1 5.

A solution of 4.5 ml of benzylchloride in 10 ml of dry acetone is introduced dropwise at room temperature in a mixed solution of 45 g (about 24 mmol) of complex teicoplanin A (or its individual component 1 5) and 6 ml (44 mmol) of triethylamine (TEA) in 300 ml of dimethylformamide (DMF). After about 60 min being 600 ml simple ethyl ether and the resulting precipitate (about 59 g) is removed by filtration and re-dissolved in 2.5 l of a mixture of acetone-water (1 1, V/V). The resulting solution was concentrated at 35oC under reduced pressure to a volume of approximately 1.6 l, then it is extracted with 1.6 l simple ethyl ether which is separated and removed.

The pH of the aqueous layer is brought to 4.8 by glacial acetic acid and he extraparams about 200 ml at 45oC under reduced pressure. When you enter ethyl acetate (about 800 ml) is separated solid product recovered by filtration, washed with simple ethyl ether (about 500 ml) and dried at room temperature under vacuum over night, the result of 45.7 g (approximately 96) clean the end of the connection.

C. Obtaining cyanomethylation of ester N15-CBZ-Teicoplanin-A2complex and its individual components.

In the mixed solution of 45 g (about 22 mmol) of N15-CBZ-teicoplanin A2complex (or individual component) in 450 ml of DMF is injected at room temperature of 5.25 l (approximately 37 mmol) TEA and 60 ml of chloroacetonitrile. After 20 h the reaction mixture was poured into 4.5 l of ethyl acetate and the precipitate (about 50 g) is removed by filtration and re-dissolved in 900 ml of a mixture of methanol water (1 1, V/V). The pH of the resulting solution is brought to 5.5 by means of glacial acetic acid are then introduced 1,1 l-butanol. The largest part of the methanol is evaporated at 35oC under reduced pressure, and the resulting mixture (about 1.5 l) and-butanol and water, from which separated the organic layer, washed with 500 ml of water and concentrated at 4 the STV, which is extracted, washed with 500 ml of a simple ethyl ether and dried at 35oC in vacuum overnight, the result is a 44.2 g (yield approximately 98) clean the end of the connection.

C. Obtaining N63-carboxamido complex N15-CBZ-teicoplanin A2and its components 1 5.

A solution of 16 g (approximately 8 mmol) of N15-CBZ - teicoplanin A2complex (or individual component 1 5), cyanomethylation of ester and a large excess (50 100 mmol) of the appropriate amine reagent in 160 ml of DMF or DMSO is stirred at room temperature for 60 to 120 min, and then injected 160 ml of absolute ethanol, and then 1.5 l of ethyl acetate. Separated solid product is removed by filtration and washed with 500 ml of a simple ethyl ether, then dried at room temperature in air, the result is a powder (usually output > 85), which is sufficiently pure product (as shown by liquid chromatography HPLC, purity > 90) for subsequent hydrogenation.

D. Obtaining N63-carboxamido complex teicoplanin A2and its components 2 5.

The product obtained to hydrogenperoxide at room temperature and pressure in the presence of 5 Pd/C (5 g). Once the reaction is finished (as indicated by HPLC), the catalyst is removed by filtration through a layer of celite (BDH 545). The pH of pure filtrate is brought to 6.5 by 11 N. NaOH and put 500 ml of n-butanol. The resulting mixture was concentrated at 40oC under reduced pressure to a volume of about 150 ml, and then injected 350 ml simple ethyl ether and the precipitate is removed by filtration. When the reaction in the substrate containing the derivative, the corresponding component 1 complex teicoplanin A2corresponding to the final product does not contain carboxyamide component 1, because it is almost entirely converted into carboxylic component 3.

E. Cleaning products by chromatography in a column with the reversible phase.

The crude products obtained as described above (10 g) dissolved in a mixture (300 ml) of acetonitrile and water (1 1, V/V). Then you enter the water until, until it forms a cloudy solution (in any case is not entered more than 700 ml of water), enter from the top of a column filled with 500 g silanizing silica gel (0,06 0,2 min; Merck Co.), obtained in the same solvent mixture (i.e. CH3CH and H2O in the ratio, calculated on the basis of kolichestvennie. The column is eluted with a linear gradient from 10 to 80 acetonitrile in water with pre bringing the pH to 2.2 by glacial acetic acid for 15 h at a speed of 400 ml/h, collecting 25 ml fractions, which are controlled by HLPC. The fractions containing the desired pure product, are combined and injected enough-butanol to obtain after concentration at 45oC in vacuum muddy dry butanole solution. When you enter three simple volumes of ethyl ether is separated solid product that is extracted, washed with simple ether and dried at room temperature under vacuum over night, the result is a pure target compound.

Thus obtained compounds corresponding to this invention, in the form of free bases (HS), when a group of base present in the molecule, is a free amino group in position 15 complex teicoplanin A2or when additional amino group, put together with the amide Deputy, is not a sufficient basis for the formation of acid additive salts with acetic acid. In other words, they are extracted in the form of acetates. Obtaining respective ASS="ptx2">

1 mmol of amide complex teicoplanin A2(or individual component) or in free base form or in the form of acetate, dissolved in 10 ml of DMF. Then introduced with simultaneous stirring at 5oC 10-cent molar excess of 10 N. HCl (0,11 ml for one amine functional group, which must be converted into a salt and 0.22 ml for two amine functional groups, and so on), and then introduced 40 ml of a simple ethyl ester. The resulting precipitate is then recovered by filtration, washed simple with ethyl ether and dried at room temperature under vacuum overnight (yield > 95).

When the desired N63carboxamide component 1 complex teicoplanin A2(TG AC1) (or a mixture of TGAC1-5), are the following procedures.

And'. Obtaining a complex of N15-tert-butyloxycarbonyl (t-BOC)-teicoplanin A2and its components 1 5.

A solution of 10 g (about 5 mmol) of complex teicoplanin A2or a separate component 1 5, 1.2 ml (8.5 mmol) of triethylamine (TEA) and 2.4 g (approximately 8 mmol) of tert-butyl-2,4-4,5-trichlorovinylsilane in 100 ml of dimethylformamide is stirred at room temperature for 24 hours C is stragies 600 ml of a mixture n-butanol ethyl acetate (35 to 65, about/about). The organic layer is separated, washed with water (2 x 100 ml), then concentrated to a volume of about 100 ml at 45oC under reduced pressure. When you enter ethyl acetate (about 400 ml) is separated solid product recovered by filtration, washed with simple ethyl ether (about 200 ml) and dried at room temperature under vacuum over night and the result is 10.3 g (approximately 98) clean the end of the connection.

B'. Obtaining complex ester complex t-tert-BOC-teicoplanin A2and its individual component 1 5.

Carrying out the procedure in the same manner as described above (see paragraph (B) obtain the target compound (yield approximately 98) of the complex t-BOC-teicoplanin A2.

C'. Obtaining N63-carboxamido complex N63-t-BOC-teicoplanin A2and its individual component 1 5.

Carrying out the procedure in the same manner as described above (see paragraph (C), but using dimethyl sulfoxide (DMSO instead of DMF as a preferable solvent, get the ultimate connection of cyanomethylene of ester N15-BOC-teicoplanin A2complex with the same output (typically > 85) and with the same degree of frequency as p is a high component.

The product (N63carboxamid complex N15-t-BOC-teicoplanin A2or a separate component) is dissolved in 40 ml of dry triperoxonane acid (TFA) in 10oC. once formed a clear solution (about 2 min) (in any case not more than 5 min after entering TFA), the reaction mixture is diluted with 40 ml of methanol while cooling with 10oC. When entering 420 ml simple ethyl ester is separated precipitate, which is removed by filtration and washed with simple ethyl ether (5 x 200 ml).

Cleaning products is easily accomplished by dissolving the crude material (5 g) in a mixture (150 ml) of acetonitrile and water (1 1, V/V), adjusting the pH of the resulting solution to 6 by 1 N. NaOH and subsequent dilution with water and subsequent chromatographic procedure as described above (see paragraph (E).

When the desired N63-carboxamide diglycolamine (TPA), are the following procedures.

A". Obtaining N15- tert-butyloxycarbonyl(t-BOC)diglycolamine.

In a mixed solution of 45 g (about 37 mmol) of antibiotic L17392 (delicatelooking) in 600 ml of DMF enter 19.3 g (65 mmol) of tert-butyl-2,4,5-trichlorophenylhydrazine 24 h, then it is poured into 1.5 liters of water. The pH of the resulting solution is brought to 3 by 1 N. hydrochloric acid, then it is extracted 3 l of a mixture of ethyl acetate and n-butanol (2 1, V/V). The organic layer is separated, washed with 1 l of water, then concentrated at 40oC in vacuum to a volume of approximately 300 ml When entering 700 ml simple ethyl ester is separated solid product recovered by filtration, washed with 200 ml of a simple ethyl ether and dried at room temperature under vacuum over night, the result is 44 grams (92) net final connection.

B". Getting cyanomethylation of ester N15-t-BOC-diglycolamine.

A solution of 44 g (about 33 mmol) of N15-t-BOC-diglycolamine, 4,7 ml (34 mmol) TEA and 44 ml of chloroacetonitrile in 440 ml of DMF is stirred at room temperature for 20 h, after which you enter 1 l of ethyl acetate and the precipitate is removed by filtration. He again dissolved (approximately g) in 1.5 liters of methanol-water (1 2, V/V) and the pH of the resulting solution is brought to 5.6 by means of glacial acetic acid.

After entering 2 l of n-butanol largest part of the methanol is evaporated at 30oC in vacuum and volume of approximately 300 ml When you enter 700 ml of ethyl acetate, a solid precipitate, which is removed by filtration, washed with 500 ml of a simple ethyl ether, then dried at room temperature under vacuum over night, the result is 42.5 g (96) net final connection.

C". Obtaining N63carboxamido N15-t-BOC-diglycolamine.

In the mixed solution of 14 g (about 10 mmol) of N105-t-BOC-diglycolamine and a large excess (100 to 150 mmol) of the appropriate amine reagent in 200 ml MG administered to 8.9 ml (150 mmol) of glacial acetic acid at room temperature. The molar amount of glacial acetic acid depends on the structure of amine reagent. In fact, for 1 mmol of amine required 0.5 mmol of glacial acetic acid, when the amine contains no additional major functional groups, 1 mmol of glacial acetic acid, when the amine contains one additional basic functional group, 2 mmol, when the amine contains two additional basic functional group, and so on, Although the presence of acetic acid is not necessary for condensation, sometimes it is necessary to correct the lateral epimerization molecules in C3position, which can speed the condensation reaction in most cases.

After 3 to 6 h (reaction, except in certain cases completed within 3 hours) introduces 600 ml of ethyl acetate and the precipitate recovered by filtration, washed with 200 ml of a simple ethyl ether and dried at room temperature in a vacuum, the result is a product, sufficiently pure for the next step in removal protection (output > 75).

D". Obtaining N63carboxamido diglycolamine.

A solution of 1 mmol of the product obtained as described above, which has a total HPLC titre > 85 and contains acetate amine reagent as the main impurity, 25 to 30 ml of anhydrous triperoxonane acid (TFA) was stirred at room temperature for 20 min, then the solvent is evaporated at 25oC under reduced pressure. The oily residue is re-dissolved in 50 ml of a mixture of water, acetonitrile (6 4, V/V) and the resulting solution is diluted with water prior to the deposition. The pH of the resulting suspension is brought to 3.0 by 1 N. hydrochloric acid (if necessary) and the resulting solution is introduced from above into the column containing 100 g silanizing silica gel (0,06 0,2 min, Merck Co.) water.

E". Cleaning products by columnar chromatography with skim milk is by elution with a linear gradient from 10 acetonitrile in water up to 50 acetonitrile in 0.01 N. hydrochloric acid for 15 h at a flow rate of 200 ml/h and collect fractions of 10 ml. Fractions containing pure product, merge, and add a sufficient amount of n-butanol to obtain after concentration of the mixture cloudy dry butanole solution (30 100 ml). When you enter three simple volumes of ethyl ether is separated solid product, which is extracted by filtration, washed with simple ethyl ether and dried at room temperature in vacuum for 2 to 3 days, the result is the ultimate pure amides diglycolamine in the form of clorhidrato.

Appropriate triptoreline obtained by the implementation provided above chromatographic purification procedure, but with a linear elution gradient 10 to 60 acetonitrile in water and maintaining the pH of eluent equal to 2.5 by entering triperoxonane acid.

Using the appropriate reagents TGAC, its individual components, DTG or DMTAC and amines of the formula

-OTHER1-Ala1-[X-Ala2]p- [T-Ala3]q-W

in the above-described conditions are compounds that are listed in the table. 4.

Example 31. The connection 31 of the formula I

< / BR>
Rastvornogo as described above, and 2 ml of 1,3-dimethyl-1,3-propandiamine in 20 ml of DMF is stirred at room temperature for 2 h, after which injected 20 ml of absolute ethanol, and then 200 ml of ethyl acetate. Separated solid product recovered by filtration, washed with 50 ml of a simple ethyl ether and dried in vacuum at room temperature overnight and the result of 1.95 g of pure complex N15-CBZ-teicoplanin A2-1-methyl-3-(methylamino)propyl-amide.

In the mixed solution of 1.37 g (of 0.65 mmol) of the above compound in 100 ml of dry material is injected at room temperature 1 g (9.4 mmol) of anhydrous sodium bicarbonate and 2.5 g (10.1 mmol) of 2-pamatinformacija. The reaction mixture was stirred at 45oC for three days, then cooled to 10oC and poured into 100 ml of water. The methanol is evaporated at 30oC under reduced pressure and the aqueous phase is extracted with 300 ml of a mixture of n-BuOH/EtOAc (1/2 V/V). The organic layer is separated and concentrated at 40oC under reduced pressure to small volume (about 20 ml). When you enter 180 ml simple ethyl ester precipitated solid product (1.12 g of N15-CBZ predecessor specified in the connection name) izvlekaete the CLASS="ptx2">

Example 32. The connection 32 of the formula I

(R=H, A/AC=H, B=H, M=H,

)

Carrying out the procedure in the same manner as described in example 31, but using a solution of 2 g of complex cyanomethylene ether N15-CBZ-diglycolamine get the connection 32.

Example 33. The connection 33 of the formula I

(R=H, A/AC=AC2-5B=AcGlu, M=Man,

Y=-H(CH2)3NH(CH2)4HCOOCH(CH3)OCOCH3< / BR>
mixed with

YNH(CH2)4NH (CH2)3NHCOOCH(CH3)OCOCH3).

In the mixed solution of 2 g (0.9 mmol) of N15-CBZ-derived compound 5 obtained as described, the example1, in 50 ml of dry dimethylformamide, enter 1.2 g (11 mmol) of anhydrous sodium carbonate and 2.7 g (10 mmol) of alpha-acetoxy-ethyl-para-nitrophenylphosphate at room temperature. After 3 h the reaction mixture was poured into 500 ml of ethyl acetate and the precipitated solid product is extracted, washed with 100 ml of ethyl acetate and hydrogenperoxide, as described above in example 1, and the result of 0.57 g of the final compound 33.

Example 34. The connection 34 of the formula I

(R=H, A/AC=H, B=H, M=H,

Y=NH(CH2)3NH(CH2)4NHCOOCH(CH3)OCOCH3< / BR>
in a system with

Y=NH(CH215-CBZ-derived compounds 23, receive 0,6 connection 34.

Examples 35-36. The connection 35 of the formula I

(R=H, A/AC=AC2-5B=AcGlu, M=Man,

)

and the connection 36 of the formula I

(R=H, A/AC=AC2-5B=AcGlu, M=Man,

)

In the mixed suspension of 5.3 g (about 2.5 mmole) of N15-CBZ-teicoplanin AND2in 560 ml of methanol injected with 1-methyl-3(methylamino)propyl-amide, obtained as described above in example 31), 17 ml of the appropriate chloroethoxy-exitloop reagent of the formula ClCH2CH2(OCH2CH2)2OH and ClCH2CH2OCH2CH2OH, respectively, and 1.86 g (13.5 mmol) of potassium carbonate at room temperature. After stirring at 45oC for 3 h, the reaction mixture is cooled to 15oC and its pH value is brought to 6 by 1 N. HCl.

The methanol is evaporated at 30oC under reduced pressure and the residual acid product hydrogenperoxide as described in example 1, and the result is of 1.9 g of compound 35 or 0.97 g of compound 36.

Examples 37-41. Getting amide derivatives TCAS-1.

A solution of 4 g (about 2 mmol) of suitable amide derivative of the complex teicoplanin A2or the comp is peremeshivaete at room temperature for 2 h, after that, the solvent evaporated and the residual oily product re-dissolved in 200 ml of H2O. After adjusting the pH to 8 and the solution so obtained is introduced into a column filled with 400 g silanizing silica gel in H2O. chromatography Is carried out as described above in example 1, and the result is a final desired connection.

Examples 42-45. Deriving TGA3-2 amide.

A suspension of 4 g (about 2 mmol) of the corresponding amide derivative teicoplanin compounds obtained as described above and below in the table. 6, 80 mm 1,2-dimethoxyethane (DMA), stirred at room temperature for 2 days with simultaneous transmission of bubbles HCl, after which the insoluble solid is removed by filtration. In the purification by column chromatography as described above (example 1), we obtain the final desired compound.

Examples 46 to 55.

A"'. General procedure (using diphenylphosphoryl).

To the stirred solution of 6 mmol teicoplanin A2or individual component (or a mixture of its components in any proportion) or N15-tert-butyloxycarbonyl (t-BOC)Deluca described below) and 10 mmol of diphenylphosphinite (DPPA) at a temperature of 0 to 5oC. After stirring at room temperature during the night is administered with 240 ml of ethyl acetate and the precipitated solid product is extracted and purified in a chromatography column with a reversible phase, as described previously (method E), resulting in net TGAC amides or N15-t-BOC-deglycosylated (RE-TPA-amides).

In the case of amides VOS-TPA or amides containing BOC-protective group on the amide link, the BOC-protective group is removed by dissolving 1 mmol of these compounds in 30 ml of anhydrous triperoxonane acid at room temperature and implementation procedures in the same way as described earlier (such as the D ' to obtain the N63-carboxamido DTG).

B"'. The intermediate amines of compounds 46 55.

1. Diamine-O, O'-bis(2-aminopropyl)polyethylene glycol 1900 (Jeffamine TM 2001) was obtained from Fluka Chemie AG (intermediate amine compound 46).

2. For intermediate interaction of amine compounds 47 52 was previously received common intermediate di-(3-BOC-aminopropyl)amine of the formula

BOC-NH-(CH2)3-NH-(CH2)3-NH-BOC

the following way. A solution of 142 g of 2-(tert-butoxycarbonyloxyimino-2-phenyl-clonetree (BOC-ON, Aldrich-C is)amine (Fluka Chemie AG) in 400 ml of TNG. After 16 h at room temperature the solvent is evaporated and the residual oily product is dissolved in 1 l of ethyl acetate. The resulting solution was washed with 1 N. NaOH (200 ml) and then water (2 x 300 ml), then it is mixed with 0.01 to N. HCl (2 x 500 ml). The pH value of the aqueous phase is brought to 8 by 1 N. NaOH and it is extracted with 500 ml of n-butanol. The organic layer is separated, washed with 250 ml of water and then concentrated to a final volume of about 70 ml per exposure during the night when 6oC crystals are formed, which are extracted by filtering and the result is a 75 g of pure final compounds as free base.

1H NMR: 2,93, 2,44 1,47 (CH2), 1,38 (N-BOC) 6,68 (NH).

3. N',N"-di-t-BOC-Tris(3-aminopropyl)amine (for derivatives 47 and 50).

In the mixed solution of 45 g of the above di-t-BOC intermediate triad in 500 ml of absolute ethanol is injected 21 ml of 3-bromo-propionitrile and 25 g of potassium carbonate at room temperature. The reaction mixture was stirred over night, then it is filtered and concentrated to a final volume of about 100 ml, after which it is diluted with 800 ml of water. The resulting solution (pH 8) and extracted with ethyl acetate (2 x 800). Organic Koei exposure for the 6oC during the night separated crystalline solid product is removed by filtration and the result is 34 g of di-(3-t-BOC-aminopropyl)amino-1-propionitrile.

1H NMR: 2,94, 2,63, 2,54, 2,37, 1,47, (CH2, 1,36 (N-BOC), 6.73 X (H).

This product is dissolved in 200 ml of ethanol solution containing 5 g of NaOH. In the resulting solution is introduced 4 g of Nickel Rinoa as active catalyst (Aldrich-Chemie) and suspension hydrogenperoxide at a pressure of 2.5 ATM. within 10 hours, the Catalyst was filtered and the solvent evaporated. Oily residual product is dissolved in 500 ml ethyl acetate and the resulting solution washed with water (2 x 100 ml), after which the organic solvent is evaporated and the result is approximately 34 g of the final desired compound.

1H NMR: 2,93, 2,54, 2,32, 1,49 (CH2), 1,41 (N-BOC); 6,77 (NH).

4. 2-(3-aminopropyl)-3-(3,3-dimethylaminopropyl)-amino-1-Propylamine (derived 51).

In the mixed solution of 19 g of the hydrochloride 3,3 - dimethyl-amino-1-propylchloride in 400 ml of absolute ethanol is injected at room temperature, 20 g of di-t-BOC intermediate analogue and 28 g of potassium carbonate, and then enter 3 g of potassium iodide. The reaction mixture was agriroducts re-dissolved in 400 ml of water and the resulting solution is extracted with 600 ml of ethyl acetate. The organic layer is separated, washed with water (2 x 200 ml) and the solvent is then evaporated and the resulting residual oily product (8.7 g), di-t-BOC derivative of the end connections, enough pure for the next step.

1H NMR: 2,91 2,42, 2,31, 2,16, 1,47 (CH2), 1,36 (N-BOC), 2,09 (NCH3).

A solution of this product in 30 ml of methylene chloride is treated with 30 ml of dry triperoxonane acid at room temperature for 2 h, then the solvents evaporated. Oily residual product is dissolved in 40 ml of absolute ethanol and dry HCl is passed in the form of bubbles at room temperature until, until complete precipitation of the product. After filtering is obtained 3.8 g of the final compound in the form of Tetra-hydrochloride.

1H NMR: 3,2 2.91 IN (6-CH2); 2,13 1,90 (3-CH2); 2,73 (NCH3).

For concentrations from RE-DTG uses the free base is obtained by dissolving Tetra-hydrochloride (10 mmol) in 1 N. NaOH (40 ml), followed by evaporation to dryness the resulting solution. The residual product is then suspended in methylene chloride (100 ml) and the insoluble substance is filtered. Dissolve the S="ptx2">

5. 3-(3-aminopropyl)-3-(2,2-diethylaminoethyl)-amino-1-Propylamine (derived 52).

Carrying out the procedure in exactly the same way as described above but using the hydrochloride of 2,2-diethylamino-1-ethylchloride (21 g) for the reaction with di-t-BOC intermediate triamine (20 g) first obtained 11 g of di-t-BOC derivative of the final connection. Then the protective groups are removed by similar processing triperoxonane acid in a solution of methylene chloride. In the end the free base (oil), as described above, from which to obtain the target compound (8.2 g).

1H NMR: 2,6 2,3 (8-CH2), 1,42 (2-CH2), 0,92 (2-CH3).

The progress of these reactions and the homogeneity of the final polyamines tested method TLC on pre-coated silica gel 60 F254(Merck Co.) the plates using a mixture of methylene chloride methanol (9 1, V/V) containing 1 ammonium hydroxide as the mobile phase. Spots appear with iodine.

6. 4-(3,3-dimethylaminopropyl)piperazine (derived 53).

In the mixed solution of 15.8 g of 3,3-dimethylamino-1-propylchloride in 300 ml of absolute ethanol is injected 9 ml of 1-benzylpiperazine and 14 g of potassium carbonate. The reaction mixture was stirred p is illtreats. The solvent is evaporated and the residual oily product is dissolved in 300 ml of water. The resulting solution is extracted with methylene chloride (2 x 200 ml). The organic layer is separated, washed with 200 ml of water and then the solvent evaporated. Oily residual product (9 g) was dissolved in 300 ml of 95-aqueous ethanol and hydrogenperoxide (25oC, 1 ATM.) over 3 g 10 Pd/C. for 6 hours absorbed approximately 1 l H2. The catalyst was filtered and dry HCl is passed in the form of bubbles in the clear filtrate. Separated solid product that is extracted, washed with absolute ethanol and dried in vacuum at room temperature overnight, and the result is 7 grams of pure final compounds in the form of a three-hydrochloride.

1H NMR: 2,79, 2,53, 2,30 (CH2piperazine), 2,79, 2,23, 2,15 (CH2dimethylaminopropyl), 2,10 (NCH3).

The free base is obtained by dissolving this trichloride (6 g) in 2 N. NaOH (30 ml) followed by extraction with methylene chloride (170 ml) and evaporation of the organic solvent. The resulting residual oily product is used without further purification in the process of obtaining a connection 53.

7. N, N'-Bis(3-aminopropyl)disiniame and obtained according to a known method (see Israck M. J. Rosenfield S. S. Modest, E. J. J. Med. Chem. 1964, 7, 710) by mono - and di-cyanoethylidene the corresponding alpha, omega-alkylenediamines followed by catalytic regeneration of NITRILES usually mild conditions.

For the compounds obtained according to the procedure A"' (46 of 55), you should contact table. 6.

HPLC analysis is performed using the pump model Varian 5000 LC, equipped with injector Rheodyne model 7125 and UV detector at 254 nm.

Columns: the first column (1.9 cm) Hibor hichro Cart. 25 4 (Merck) with the first filler Zichrozorb RP-8 (20 to 30 μm) and subsequent column Hibar RT 250-4 (Merck) with the first filler Lichrosorb RP-8 (10 μm)

Elements: A, 0,2 water HCOONH4. (B, CH3CH.

Flow rate: 2 l/min

Injection: 20 μl.

Elution: linear gradient 20 60 B and a for 30 minutes retention Time in the column of some typical compounds are shown in table. 7.

Acid-base titration. The products are dissolved in MCS (methylcellosolve) H2O (4 1, V/V), then enter the excess of 0.01 M HCl in the same solvent mixture and the resulting solution tarouca of 0.01 N. NaOH. The equivalent weight of some typical compounds are shown in table. 8.

1H NMR: spectrum1H NMR of prana tetramethylsilane (TMS) as internal standard (Delta 0,00 hours/million).

In table. 7 shows the retention time (tR) defined as described above, for some typical compounds of the invention.

The following are the data values 1H NMR of some typical compounds recorded in DMSO-D6using tetramethylsilane as internal standard (Delta of 0.001 h/million).

Compound 2. 3,61, 2,95 (CH2side chain); 0,83, 1,18, 1,46, 2,02 (acyl chain); 4,18 5,62 (peptidic CH's); 1,89 (acetylglucosamine); 6,18 to 8.45 (aromatic protons and peptidic NH's).

Connection 4. 3,45, 2,82, 2,63, 2,08, 1,66 (CH2side chain); 0,87, 1,23, 1,45, 2,01 (acyl chain); 1,83 (acetylglucosamine); 4,15 5,71 (peptidic CH's); 6,26 8,56 (aromatic protons and peptidic NH's).

Connection 6. 3,52, 2,73, 2,581,91, 1,56 (CH2side chain); 0,84, 1,15, 1,46, 2,02 (acyl chain); 1,82 (acetylglucosamine); 3,42 (mannose); 4,15 5,69 (peptidic CH's); 6,29 8,53 (aromatic protons and peptidic NH's).

The connection 7. 3,68 3,12, 2,98, 2,05 (CH2side chain): 0,84, 1,16, 1,44, 2,01 (acyl chain); 1,89 (acetylglucosamine), 3,42 (mannose), 4,13 5,58 (peptidic CH's); 6,21 8,53 (aromatic and peptide NH).

Compound 8. 3,68, 2,92, 1,98 (CH2side chain); 0,82, 1,25, 1,43, 2,01 (acyl chain); 1,87 (acetylglucosamine); 4,17 5,65 (peptidic CH's); 6,26 to 8.57 (aromatizes the ü); 1,86 (acetylglucosamine); 4,16 5,62 (peptidic CH's); 6,18 8,58 (aromatic protons and peptidic NH's).

The connection 11. 3,71 2,93, 1,98, 1,73 (CH-lateral chain); 0,83, 1,23, 1,47, 2,02 (acyl chain); 1,89 (acetylglucosamine); 4,13 5,58 (peptidic CH's); 6,21 8,62 (aromatic protons and peptidic NH's).

The connection 15. 3,52, 3,13 (CH2piperazine); 3,42 2,07 (CH2side chain); 0,83, 1,16, 1,45, 2,02 (acyl chain); 1,88 (acetylglucosamine); 4,16 5,32 (peptidic CH's); 6,18 8,53 (aromatic protons and peptidic NH's).

Connection 21. 3,52, 3.04 FROM, 2,81 (CH2); 4,15 5,62 (peptidic CH's); 6,18 to 8.62 (aromatic protons, peptidic NH's).

Connection 22. 3,17, 2,93, 2,83, 1,87, 1,80 (CH2side chain); 4,15 5,61 (peptidic CH's); 6,18 8,53 (aromatic protons and peptidic NH's).

Connection 23. 3,42, 2,98 2,71, 1,72 1,61 (CH2the spermidine); 5,15 5,63 (peptidic CH's); to 6.19 8,43 (aromatic protons and peptidic NH's).

The connection 24. 3,38, 3,12, 2,98 (CH2N); 1,89 (CH2); 4,17 - 5,58 (peptidic CH's); 6,18 8,48 (aromatic protons, peptidic NH's).

Connection 25. 3,34, 3,08, 2,84, 1,78 (CH2side chain); 4,16 - 5,58 (peptidic CH's); 8,31 8,48 (aromatic protons and peptidic NH's).

The connection 26. 3,36 2,98, 2,87 (CH2N); OF 1.78, 1.77 IN (CH2); 4,15 5,62 (peptidic CH's); 6,18 8,42 (aromatic protons, peptidic NH's).

Coedie NH).

The connection 29. 3,48 3,12, 2,64 (CH2N); 4,18 5,61 (peptidic CH's); 6,21 8,70 (aromatic protons and peptidic NH's).

Connection 30. 3,49, 3,11, 2,95, 2,85, 1,85 (CH2side chain); 4,18 of 5.81 (peptide CHN); 6,21 8,56 (aromatic protons, peptidic NH's).

The connection 31. 3,01 (CH3)3; 2,95, 2,21, 1,68 (CH2side chain); 2,28, to 2.06 (NCH3); 0,83, 1,21, 1,46 (acyl chain); 1,86 (acetylglucosamine); 3,48 (Mendoza); 4,17 of 5.82 (peptidic CH's); 6,14 8,62 (aromatic protons and peptidic NH's).

Connection 34. 3,03 2,81, 1,82, 1,62, 1,43 (CH2-side chain); 2,01 (CH3-CH); 1,23 (CH3); 4,13 5,62 (peptidic CH's); to 6.19 - of 8.47 (aromatic protons and peptidic NH's).

The connection 35. THE 5.25 (CH2-O); 4,51 (CH2OH); TO 2.06 (NCH3); 0,81, 1,23, 1,45, 2,02 (acyl chain); 1,87 (acetylglucosamine); 4,12 5,69 (peptidic CH's); 6,14 8,48 (aromatic protons and peptidic NH's).

The connection 36. 5,22 (CH2O); 3,72, 3,82 (CH2side chain); 1,93 (NCH2); 0,83, 1,14, 1,43, 2,01 (acyl chain); 1,87 (acetylglucosamine); 4,18 5,72 (peptidic CH's); of 6.31 8,45 (aromatic protons and peptidic NH's).

Connection 44. 3,68, 3,34, 2,95, 1,99, 1,84 (Spermine); 1,87 (acetylglucosamine); 4,18 5,61 (peptidic CH's); to 6.19 8,56 (aromatic protons and peptidic NH's).

Connection 39. 3,71, 3,372,98, 1,98, 1,82 (spermine); 1,86 (acetylic,41, 3,23, 3,16, 2,94 (CH2side chain); 1,121,23, (CH3side chain); 0,81, 1,151,46, 2,00 (acyl chain); 1,86 (acetylglucosamine); 4,16 5,59 (peptidic CH's); 6,23 8,01 (aromatic protons, peptidic NH's).

Connection 47. 3,45, 3,09, 2,35, 1,84 (CH2side chain); 0,82, 1,14, 1,46, 2,03 (acyl chain); 1,68 (acetylglucosamine); 4,12 5,62 (peptidic CH's); 6,23 8,43 (aromatic protons, peptidic NH's).

Connection 50. 3,43, 3,24, 2,85, 1,84 (CH2side chain); 4,12 - 5,62 (peptidic CH's); 6,12 8,51 (aromatic protons; peptide NH).

Connection 51. 3,45, 3,39, 3,05, 2,91, 2,12, 1,98 (CH2side chain); 2,74 (NCH3); 4,13 5,59 (peptidic CH's); 6,18 8,61 (aromatic protons, peptidic NH's).

The connection 52. 3,48, 3,12, 1,89 (CH3-side chain); 1,18 (2CH3-ethyl); 4,12 5,61 (peptidic CH's); 6,20 charged 8.52 (aromatic protons, peptidic NH's).

Connection 53. 3,42, 3,39, 3,30, 1,98 (CH2-p p, CH2-propyl); 2,75 (NCH3); 4,05 5,63 (peptidic CH's); 6,32 - charged 8.52 (aromatic protons, peptidic NH's).

Connection 55. 3,32, 2,98, 2,76, 1,86, 1,52, 1,24 (CH2side chain), 4,13, 5,62 (peptidic CH's), of 6.31 8,42 (aromatic protons, peptidic NH's).

Connection 54. 3,37, 3,34, 3,07, 2,86, 2,78, 1,75, 1,59, 1,26, (CH2-lateral chain), 4,14 5,61 (peptidic CH), 6,21 to 8.34 (aromatic protons, peptidic NH's).

Example pharmacycodeine General formula I

where R is hydrogen or a protective group of the amine function;

Y is a radical-NR1-alK1-[X-alK2]p- [T-alK3]q-W, where R1hydrogen, C1C4- alkyl, alK1alK3each independently from each other, a normal or branched C2C10-alkylen, 1 p, 42 integer q 0 2 integer, X is a group-NR2or oxygen, R2hydrogen, C1C4- alkyl, a group alK4NR3R4where alK4normal or branched alkylen C2C4, R3hydrogen, C1C4-alkyl, R4hydrogen, C1C2-alkyl, or R1and R2taken together form a C2C4-alkylene linking the two nitrogen atom, provided that p is 1; T is oxygen, a group NR5where R5hydrogen, C1C4-alkyl, or R2and R5together form a C2C4-alkylene linking the two nitrogen atom, provided that p q 1, W oxygraph, NR8R9where R8hydrogen, C1C6-alkyl, R9hydrogen, C1- C6-alkyl, COOR10where R10C1- C6-acyloxy - C1C4-alkyl or a group of N+R11R12R13An- anion formed from the pharmaceutically premaxillary;

A hydrogen or N[(C9-C12)]aliphatic acyl] -β-D-2-deoxy-2-aminopropanoic;

B is hydrogen, N-acetyl-beta-D-2-deoxy-2-aminopropanoic;

M is hydrogen or alpha-mannopyranosyl,

or their pharmaceutically suitable acid additive salts, provided that B is hydrogen in the case where A and M are simultaneously hydrogen.

2. Connection on p. 1, characterized in that the radicals (C9- C12)-aliphatic acyl included in A, have one of the following values: (Z)-4-decanoyl, 8-methylnonanoic, decanoyl, 8-methyldecyl, 9-methyldecyl, 6-methyloctanoic, nonanoyl, 10-methylundecanal and dodecanoyl.

3. Connection on p. 1, wherein X and/or T represents a-NR2- and/or-NR5-; alK1, alK2, alK3represent a (C2-C10linear chain, p 1 5 integer, q 0 12 integer.

4. Connection on p. 1, characterized in that X and T is oxygen, and p and q are such that p+q 2 42.

5. Connection on p. 1, wherein X is the group-NR2-, where R2hydrogen, C1C4-alkyl or alK4NR3R4where alK4R3and R4have the values listed in paragraph 1.

6. Connection on p. 1, characterized in that s nitrogen.

7. Connection on p. 1, wherein p 1, q 1, X and T is-NR2- , and-NR5respectively, where R2and R5together form a C2C3-alkylene linking the nitrogen atoms.

8. Connection on p. 6 or 7, characterized in that Allenova group represents a group-CH2-CH2-.

9. Connection on p. 1, characterized in that X and T is oxygen, W is oxygraph or-NR8R9-, where R8hydrogen or C1- C4-alkyl, R9hydrogen, C1C4-alkyl.

10. Connection on p. 1, characterized in that W NR8R9where R8has the specified value, R9-COOR10where R10- acyloxy-C1C4is an alkyl group.

11. Connection on p. 10, wherein group C1- C4-alkyl-C1C6-acyloxy-C1- C4-alkyl chain is a methylene, possibly substituted C1C3- linear or branched alkyl chain.

12. The method of obtaining the amide derivatives teicoplanin, characterized in that conduct amidation of the corresponding derived carboxymethylamino formula I on p. 1, where A, B and M have the above meanings and Y is OH, an amine of General formula II is out values, specified in paragraph 1.

13. The method according to p. 12, wherein the amidation is carried out in an inert organic solution in the presence of a condensing agent selected from C1C4-alkyl, -phenyl or heterocyclic of phosphorazidate, at 0, 20oC.

14. The method according to p. 12, wherein the amidation is carried out by conversion of the carboxyl of the original product in the corresponding activated ester this product preferably with protection N15-amine functional group and the activated ester is reacted with a molar excess of an amine of General formula II under item 12 in the presence of an organic polar solvent at 5 60oWith, preferably 10 to 30oC.

15. The method according to p. 14, characterized in that the activated ester is cinematology ester and its molar ratio to amine of 1:5 to 30.

16. The method according to p. 15, characterized in that cinematology ester obtained by the reaction of carboxylic acid as the source of the product, preferably with protection N15-amine functional group with about 20 to 30 - fold molar excess of chloroacetonitrile in the presence of inert CLASS="ptx2">

17. The method according to PP.12 to 16, characterized in that the conduct additional step of removal of the protective group for the N15.

18. The method of obtaining compounds of formula I where A is hydrogen, B Is N-acetyl-beta-D-2-deoxy-2-aminopropanoic, M alpha-D-mannopyranosyl, wherein conducting the hydrolysis of the corresponding amide compounds of formula I, where A N[(C9C12)aliphatic acyl]-β-D-2-deoxy-2-imiglucerase, B - N-acetyl-beta-D-2-deoxy-2-aminopropanoic, M alpha-D-mannopyranosyl, by means of concentrated aqueous organic acid at about room temperature, preferably by means of a water triperoxonane acid concentration of 85 to 95% at 10 50oC.

19. The method of obtaining compounds of formula I, where both A and M are hydrogen, B is acetyl-beta-D-2-deoxy-2-aminopropanoic, wherein spend the interaction of the corresponding amide compounds of formula I, where A - N[(C9C12)aliphatic acyl]-β-D-2-deoxy-2-aminopropanoic, B - N-acetyl-beta-2-deoxy-2-aminopropanoic, M alpha-D-mannopyranosyl, with a strong acid in the presence of a polar aprotic organic solvent selected from ethers, ketones, or mixtures thereof, Kay I on p. 1, which have antibacterial activity.

21. Pharmaceutical composition, characterized in that as the active ingredient contains a compound I on p. 1.

 

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FIELD: organic chemistry, biochemistry.

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FIELD: chemistry.

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Organic compounds // 2394038

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20 cl, 2 tbl, 3 ex, 2 dwg

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19 cl, 17 dwg, 2 tbl, 17 ex

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48 cl, 7 dwg, 7 tbl, 15 ex

FIELD: chemistry.

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FIELD: chemistry.

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2 cl, 1 tbl, 5 ex

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13 cl, 14 dwg, 3 tbl, 15 ex

FIELD: organic chemistry, chemical technology, antibiotics.

SUBSTANCE: invention relates to a method for preparing fumarate salt of compound of the formula (II) wherein R1 represents hydrogen atom or lower alkyl group; R2 represents lower alkyl group. Method involves interaction of compound of the formula (I) wherein R1 represents hydrogen atom or lower alkyl group with chloroformate. Then all carbamate groups are removed followed by alkylation of nitrogen atom at 3'-position of desosamine ring to obtain compound of the formula (II) and conversion of this compound to fumarate salt. Interaction of compound of the formula (I) with chloroformate is carried out in the presence of cyclic ether or carboxylic acid ester. Carbamate groups are removed in the presence of sodium hydrocarbonate. Crystallization and re-crystallization of compound of the formula (II) fumarate salt is carried out from alcohol-containing solvent, in particular, from isopropyl alcohol. Method provides increasing yield and enhancing purity of the end product.

EFFECT: improved preparing and purifying method.

28 cl, 11 ex

FIELD: production of macrolide road-spectrum antibiotic tylosine.

SUBSTANCE: claimed method includes tylosine deposition from organic tylosine base concentrate with organic solvent (hexane). Deposition is carried out by addition of organic tylosine base concentrate to hexane at velocity of 3-5 ml/min per 50 ml of concentrate.

EFFECT: method for production of tylosine base in granulated form with homogeneous composition.

2 cl, 6 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to new acid-additive nitrate salts of compounds taken among salbutamol, cetirizine, loratidine, terfenadine, emedastine, ketotifen, nedocromil, ambroxol, dextrometorphan, dextrorphan, isoniazide, erythromycin and pyrazinamide. Indicated salts can be used for treatment of pathology of respiratory system and elicit an anti-allergic, anti-asthmatic effect and can be used in ophthalmology also. Indicated salts have less adverse effect on cardiovascular and/or gastroenteric systems as compared with their non-salt analogues. Also, invention proposes pharmaceutical compositions for preparing medicinal agents for treatment of pathology of respiratory system and comprising above indicated salts or nitrate salts of metronidazol or aciclovir.

EFFECT: improved and valuable properties of compounds.

6 cl, 5 tbl, 19 ex

FIELD: antibiotics, chemical technology.

SUBSTANCE: invention relates to a method for preparing erythromycin oxime in homogenous conditions by oximylation of erythromycin A with hydroxylamine hydrochloride in dry methanol using triethylamine as a base. Method provides enhancing yield and quality of product.

EFFECT: improved method for preparing.

3 ex

FIELD: organic chemistry, antibiotics, chemical technology.

SUBSTANCE: invention relates to a novel crystalline form E of erythromycin derivative fumarate salt represented by the formula (I)

and to a method for its preparing. Indicated crystalline form E shows strong roentgen diffraction peaks at diffraction angles (2θ) 5.6° and 10.4° that was established by roentgen diffractometry with Cu-Kα-radiation. Also, invention proposes crystalline form D of erythromycin derivative fumarate salt represented by the formula (I) showing average particles size 90 mcm or above and/or the content of residual solvent 1500 ppm or less. Method for preparing indicated crystalline form D involve suspending indicated crystalline form E in mixture ethyl acetate and water in the ratio = (99:1)-(97:3) at temperature from -20°C to 20°C. Invention provides reducing the content of residual solvent and elimination of difficulties in making tablets.

EFFECT: improved preparing methods.

14 cl, 1 tbl, 5 dwg, 6 ex

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