A derivative of the antibiotic and 40926, the methods of its production and pharmaceutical composition

 

(57) Abstract:

The present invention relates to new derivatives of antibiotic And 40926 General formula 1, which have carboxyl, (C1-C4) alkoxycarbonyl, aminocarbonyl, (C1-C4) alkylaminocarbonyl, di (C1-C4) alkylaminocarbonyl or hydroxymethylene Deputy to the N-acidaminophilum fragment and hydroxyl or polyamines Deputy in position 63 of the molecule. Compounds according to the invention exhibit high activity in vitro against enterococci and staphylococci resistant to glycopeptides. Synthesis of derivatives And 40926 are using amidation reactions, recovery of the amino group. 3 S. and 19 C.p. f-crystals, 5 PL.

The present invention describes derivatives of antibiotic A 40926 formula (I):

< / BR>
where

R1represents hydrogen or a protective group of amino group;

R2is a (C9-C12) alkyl;

M represents hydrogen, D - mannopyranosyl or 6-O-acetyl --D - mannopyranosyl;

Y represents a carboxy, (C1-C4) alkoxycarbonyl, aminocarbonyl, (C1-C4) alkylaminocarbonyl, di(C1-C4-C4) alkylamino and di (C1-C4) alkylamino or hydroxymethyl;

X represents a hydroxy or amine residue formula

-NR3-alk1-(NR4-alk2)p- (NR5-alk3)q-W,

where

R3represents hydrogen or (C1-C4) alkyl;

alk1, alk2and alk3each independently represents a linear or branched alkylen with 2-10 carbon atoms;

p and q are integers which are independently of each other can have values 0 or 1;

R4and R5independently represent hydrogen, (C1-C4) alkyl, or R3and R4together represent a (C2-C4) alkalinity fragment connecting the two nitrogen atom, provided that p is 1; or R4and R5together represent a (C2-C4) alkalinity fragment connecting the two nitrogen atom, provided that p and q is 1; W represents hydrogen, (C1-C4) alkyl, amino, (C1-C4) - alkylamino, di (C1-C4) alkylamino, amino group, substituted by one or two amino-(C2-C4) alkyl substituents or one or two (C1-C4) alkylamino-(C2-C4 is Linyi substituents, or, if p and q are 0, together with the group-NR3-alk1this radical may also represent a piperazine derivatives or 4-methylpiperazine,

provided that when X is hydroxy, Y is hydroxymethyl,

Z represents hydrogen or a group of the formula

< / BR>
where

Arepresents the anion of a mineral or organic acid, or, when there is carboxylate group in the remaining part of the antibiotic, this radical can also be an internal anion derived from this carboxylate group;

as well as pharmaceutically-acceptable salts of these derivatives, which are products of the merger.

The numbers in brackets in the above formula (I) and in the following formulas indicate the usual numbering of the corresponding carbon atoms in the molecular structure of the antibiotic A-40926 and its derivatives.

Antibiotic A 40926 is a glycopeptides antibiotic complex, isolated from the culture of Actinomadura called Actinomadura sp. ADS 39727 in culture medium containing assimilated sources of carbon, nitrogen and inorganic salts (see EP-177882). According to the procedure described in Viseu is of factor A, factor B, factor B0factor B1factor PA and factor PB, cultural liquid, after filtration or after pre-treatment were subjected to affinity chromatography on a stationary D-alanyl-D-alanine.

Identified to date, the factors of antibiotic A 40926 can be described by the formula (II) below, where R'1represents hydrogen, X' is hydroxy, Y' is carboxy, R'2is a (C9-C12) alkyl group, and M' represents-D-mannopyranosyl or 6-O-acetyl --D-/ mannopyranosyl group.

< / BR>
Specifically, the factor A, antibiotic A 40926 is a compound of the above formula (II), where R'1- hydrogen. X' is hydroxy, Y' is carboxy, R'2is a n-decyl, and M' represents-D - mannopyranosyl. According to the latest studies, the substance is identified as a factor Boantibiotic A 40926 in the abovementioned patent EP-177882 actually consists of two close components. Factor Boantibiotic A 40926 in fact is the main component of factor B and corresponds to the compound of the above formula (II), where R'1is hydrogen, X' is hydroxy, Y' is carboxy, R'2is a 9-methyldecyl and M' presi differs from factor B0only the fact that R'2is a n-undecyl (see E. Riva and others, "Chromatographia, vol 24, S. 295, 1987).

Factor PA and factor PB antibiotic A 40926 differ from those of factor A and B that mandonna group they substituted at the 6-O-acetyl--D-mannopyranosyl group.

Factors PA and PB of antibiotic A 40926 at least under certain fermentation conditions are the main antibiotic products of the microorganism, producing A 40926.

The factors A and B, antibiotic A 40926 are mostly products of transformation factors PA and PB of antibiotic A 40926, respectively, and are often already present in the culture media.

All sugar fragments connected with the core of antibiotic A 40926 via O-glycosidic linkages.

Found that the factor PA and antibiotic A 40926 can be transformed into A factor of antibiotic A 40926, and factor PB antibiotic A 40926 can be transformed in factor B, antibiotic A 40926 in an alkaline environment, where the removal of acetyl groups mannaseo fragment without bias acyl group on aminopyrrolidine fragment.

As a result, if the culture medium or an antibiotic A 40926, containing an extract or concentrate, leave on for some who can get antibiotic A 40926, rich the factor A and factor B, antibiotic A 40926.

Factor A, antibiotic A 40926 can be obtained from compound A 40926 by chromatographic separation using the method described in EP-177882. Net factor B0that in the above-described conditions (according to the patent EP-177882) is about 90% factor, A, can be obtained by further purification of factor B, for example, several times after chromatography with reversed phase.

The latest research (L. Serelli and others, Rapid Communications in Mass Spectrometry, vol. 6, S. 109, 1992) showed that the antibiotic complex A 40926 there are also some secondary factors that identify with acronyms A1RS-1, RS-2 and RS-3, respectively. These secondary factors were separated by HPLC and structure of these factors was determined using gas chromatography / mass spectrometric analysis of metanalyses complex of A-40926. All of the above secondary factors had structures corresponding to the structures of the main factors A, B0and B1except that the residues of fatty acids were associated with aminoglutethimide fragment. In particular, with reference to formula (II), the radicals R'1, X' and Y' have the above significance, and R'2

Despite the fact that the drugs antibiotic complex A 40926, obtained using the conditions described in EP 177882, strongly dominated by the factors, where R'2is a (C10-C11) alkyl, you can change the conditions of fermentation in order to increase the content of minor components, in which R'2represents a C9or C12alkyl.

In the ordinary course of purification of the antibiotic complex A 40926 factors PA and PB is usually converted to factors A and B.

In addition, it was found that it is possible to transform the antibiotic complex A 40926, individual factors or a mixture of these factors in any proportion in the corresponding N-acylaminopenicillins complex AB, N-acylaminopenicillins factor of a N-acylaminopenicillins factor B and mannosylation antibiotic A 40926 by controlled acid hydrolysis of one of the sugar portions of the source material (see EP-A-240609 and EP-A-228015).

Preferred hydrolysis conditions to obtain the N-acylaminopenicillins involve the use of a mixture of dimethyl sulfoxide/concentrated hydrochloric acid in line from 8:2 to 9.5:0.5 to at a temperature of from 40 to 80o1and M' are hydrogen atoms, X' is hydroxy, Y' is carboxy, and R'2is a (C9-C12) alkyl.

Complete removal of all sugar fragments of antibiotic A 40926 gives the aglycone. This hydrolysis process described in EP-A-240609.

Antibiotic complex A 40926, its factors, the corresponding N-acylaminopenicillin, mannosylation, aglycon and mixtures thereof in any proportion are most active against gram-positive bacteria and Neisseriae.

In the application for international patent N PCT/EP92/00374 the claimed priority, according to EP ser. N 91104857, ether derivatives of antibiotic A 40926 (esterified in position 6B, i.e., the carboxyl group present on the N-acetylaminofluorene fragment) and described N-acylaminopenicillin this antibiotic, e.g. the compounds of formula (II), where X' is HE, Y' is a (C1-C4) alkoxycarbonyl, and R'1, R'2and M' have the same meanings as the radicals R1, R2and M described above.

These ether derivative obtained by the interaction of the amine substrate A 40926 having a protective group at the N15(in the present description, the term "N15" refers to the nitrogen atom in the amino group in the N15or demagnetising derivative of this substance (i.e., N-acylaminopenicillin) alkanol in an acidic environment, or derived A 40926 with a protective group at the N15or demagnetising analogue, with alkylhalogenide (preferably bromide, chloride or iodide), possibly in the presence of acceptor halogenation acid, in particular, with an excess of the selected alkanol in the presence of concentrated mineral acid at a temperature of from 0oC to room.

These ether derivatives of antibiotic A 40926 obtained by the aforementioned method, are used as starting materials to obtain a derivative of formula (1) antibiotic A 40926.

Controlled esterification used to obtain the ether derivatives of antibiotic A 40926 and ether derivatives demagnetising antibiotic A 40926, which are the starting materials for producing compounds according to the invention includes the reaction of esterification, in which the substrate is A 40926 connect with an excess of the selected alkanol in the presence of concentrated mineral acid at a temperature of from 0oC to room over a period of time, the duration of which depends on steric complexity of g in position 15 predecessor A 40926 with the in order to avoid undesirable side reactions. This can be done by known methods, for example by the methods described in such references as T. C. green, "Protective Groups in Organic Synthesis", published by "Joe Willy & sons, new York, 1981 and M. Makami "Protectig Groups in Organic Chemistry", publishing house "Plenum Press, new York, 1973. These protecting groups must be stable under the conditions of reaction processes, they should not interfere with the flow of the main reaction and must be of such nature that will allow you to easily delete these groups at the end of the main reaction.

Among the suitable aminosidine groups groups such as tert-butoxycarbonyl (BOC), carbobenzoxy (CBz) and arylalkyl. Benzylidene with possibly substituted by benzylchloride in the presence of a base proceeds smoothly with quantitative yield and leads exclusively to the formation of the corresponding N15-benzyl derivative without concomitant formation of benzyl ether carboxylic groups.

Selective protection of the amino group in position 15 can be accomplished through interaction with benzylbromide in the presence of acceptor galoidovodorodov (i.e., tertiary amine) without concomitant esterification of the two carboxylating groups, but first it is necessary to evaluate the chemical activity of the other groups present in the molecule.

The source of the ether compound of the formula (II), where M' represents-D-mannopyranosyl or 6-O-acetyl --D - mannopyranosyl, and Y' represents a (C1-C4) alkoxycarbonyl, can be converted into the corresponding compound in which M' is hydrogen, by selective acid hydrolysis. As described in EP-A-240609, for carrying out hydrolysis to obtain demagnetising derivatives of antibiotic A 40926 (e.g., N-acylaminopenicillin) it is preferable to use a mixture of dimethyl sulfoxide with concentrated hydrochloric acid in a ratio of 8:2 (o/o) up to 9.5:0.5 to (o/o) at a temperature of from 40 to 80oC.

Accordingly demandside derivatives of esters of A 40926 can be obtained in a mixture with the corresponding aglycone and divide by preparative HPLC.

Conditions for hydrolysis can be changed to obtain different ratios of the reaction products. For example, if the source material to use A 40926, esterified in position 6Bto increase the ratio of solvent/hydrochloric acid to 78:1, to maintain the temperature of the reactions is svodnik A 40926, esterified in position 6Bunwanted aglycone A 40926 would be roughly a 1.4:1.0 in.

The progress of the reaction is controlled using HPLC by using one of the known methods. Based on the results of these analyses specialist can assess the course of the reaction and to decide when to stop the reaction and start spraying the reaction mixture by known methods, including, for example, solvent extraction, precipitation nerastvorim components, subsequent separation and purification using chromatography.

Ether derivatives used as starting materials for preparing compounds of formula (I) may represent individual compounds corresponding to each of several factors predecessor antibiotic complex A 40926, or a mixture of two or more components in any proportion, corresponding to the different factors predecessor A 40926. The compounds of the ether derivatives can be obtained with the use of a complex of A 40926, or a mixture of factors predecessor complex A 40926 in the process of obtaining ester in 6B, or through special conditions of selection/refinement of essential product (change the 40926), or by mixing in the desired proportions pure essential products allocated by chromatography with reversed phase or obtained using pure factors of A 40926 as precursors.

In the present description and the claims, the term "alkyl", taken alone or in combination with other substituents, includes hydrocarbon group with straight and branched chain; more specifically, the term "(C1-C4) alkyl" refers to aliphatic hydrocarbons with straight or branched chain, containing from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 1,1-dimethylethyl, and 2-methylpropyl.

In this text the terms "alk1", "alk2", "alk3mean alkylen straight or branched chain, containing 2-10 carbon atoms, such as, for example:

-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-CH2-CH2-CH-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-,

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
The terms "(C2-C4) alkyl fragments and(C2-C4alkylene fragments" in this text represent aliphatic fragments with a straight or branched chain containing 2-4 carbon atoms. Examples of such fragments are contained in the above list.

The expression(C1-C4) alkoxycarbonyl includes alkoxycarbonyl group with straight and branched chain, such as, for example, methoxycarbonyl, etoxycarbonyl, propylenecarbonate, isopropoxycarbonyl, butoxycarbonyl, isobutoxide and tert-butoxycarbonyl.

Below are some examples of amine residues

-NR3-alk1-(NR4-alk2)p- (NR5-alk3)q-W

according to the above definition:

-NH-(CH2)2-NH2< / BR>
-NH-(CH2)3-NH2< / BR>
-NH-(CH2)4-NH2< / BR>
-NH-(CH2)5-NH2< / BR>
-NH-(CH2)2-N(CH3)2< / BR>
-NH-(CH2)3-N(CH3)2< / BR>
-NH-(CH2)2-N(C2H5)2< / BR>
-NH-(CH2)7-N(CH)2< / BR>
-NH-(CH2)3-N(C4H9)2< / BR>
-N(CH3)-(CH2)2-NH2< / BR>
-N(CH3)-(CH2)3-NH2< / BR>
-N(CH3)-(CH2)2-N(CH3)2< / BR>
-N(CH3)-(CH2)3-N(CH3)2< / BR>
-NH-(CH2)n-CH3< / BR>
n= 0, 1, 2, 3, 4 or 5

< / BR>
n= 0, 1, 2, 3, 4 or 5

m = 0, 1, 2, or 3

< / BR>
-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>
-NH-(CH2)2-NH-(CH2)4-NH- (CH2)2-NH2< / BR>
-NH-(CH2)3-NH-(CH2)3-NH- (CH2)3-NH2< / BR>
-NH-(CH2)3-NH-(CH2)4-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)3-NH-(CH2)9-NH- (CH2)3-NH2< / BR>
-NH-(CH2)3-NH-(CH2)<(CH2)3-[NH(CH2)3]3-NH2< / BR>
-NH-(CH2)2-N[(CH2)2NH2]2< / BR>
-NH-(CH2)3-N[(CH2)2NH2]2< / BR>
-NH-(CH2)2-N[(CH2)3NH2]2< / BR>
-NH-(CH2)2-N[(CH2)4NH2]2< / BR>
-NH-(CH2)3-N[(CH2)3NH2]2< / BR>
-NH-(CH2)4-N[(CH2)2NH2]2< / BR>
-NH-(CH2)4-N[(CH2)3NH2]2< / BR>
-NH-(CH2)2- N[(CH2)2N(CH3)2]2< / BR>
-NH-(CH2)2- N[(CH2)3N(CH3)2]2< / BR>
-NH-(CH2)3- N[(CH2)2N(CH3)2]2< / BR>
-NH-(CH2)3- N[(CH2)3N(CH3)2]2< / BR>
-NH-(CH2)2- N[(CH2)2N(C2H5)2]2< / BR>
-N(CH3)(CH2)2- N[(CH2)2NH2]2< / BR>
< / BR>
n = 0, 1, 2, or 3

-NH-(CH2)n-NHCH3< / BR>
n = 2, 3 or 4

-NH-(CH2)n-NHiC3H7< / BR>
n = 2, 3 or 4

< / BR>
n = 1, 2 or 3

< / BR>
n = 1, 2 or 3

-NH(CH3)-(CH2)n-NHCH3< / BR>
n = 2, 3 or 4

-N(CH2)n-NHC2H5< / BR>the battle (C2-C4) alkalinity fragment that connects two volumes of nitrogen, saturated heterocyclic fragment formed in combination with the parts alk1(or alk2) and two adjacent nitrogen atoms, preferably, is a pieperazinove ring.

For example, when R3and R4(or R4and R5together represent a (C2-C4) alkalinity fragment connecting the two nitrogen atom, or when both p and q is O, W, together with a fragment-NR3-alk1- represents piperazine derivatives or 4-methylpiperazine, the amine residue of the formula

-NR3-alk1-(NR4-alk2)p- (NR5-alk3)q-W

identifies the following groups:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
The present invention encompasses the individual compounds of the formula (I) obtained from individual factors, the precursor of the antibiotic complex A 40926, as well as mixtures of compounds of formula (I) obtained from the complex A 40926 or from a mixture of two or more factors in any proportion. Accordingly, variants of proportional relationships of the components of mixtures of compounds of formula (I), the relevant factors at A 40926, receive as a result of use of the complex A 40926, or by mixing separate factors source esters of the formula (II) in the desired proportions prior to their conversion to compounds of formula (I), or by mixing pure individual factors of the compounds according to the invention of formula (I) in the right proportions.

Preferred compounds according to the invention are the compounds of formula (I), where

R1represents hydrogen or a protective group of the amine fragment;

R2is a (C9-C12) alkyl;

M represents hydrogen, D-mannopyranosyl or 6-O-acetyl-D-mannopyranosyl;

Y represents carboxy, (C1-C4) alkoxycarbonyl, aminocarbonyl, (C1-C4) alkylaminocarbonyl, di (C1-C4) alkylaminocarbonyl, where the alkyl part may have a Deputy, selected from hydroxy, amino (C1-C4) alkylamino and di (C1-C4) alkylamino or hydroxymethyl;

X represents a hydroxy or amine residue formula

-NR3-alk1-(NR4-alk2)p- (NR5-alk3)q-W

where

R3, R4and R5represents hydrogen;

alk1, alk2and alk3each independent is AMI, are independently of one another zero or 1;

W represents hydrogen, (C1-C4)alkyl, amino, (C1-C4)alkylamino, di(C1-C4) alkylamino, amino group, substituted by one or two amino-(C2-C4)alkyl fragments or one or two (C1-C4)alkylamino-(C2-C4)alkyl fragments, or when both p and q equal to 0, together with the fragment-NR3-alk1this radical can represent the piperazine derivatives or 4-methyl-piperazine derivatives,

provided that when X is hydroxy, Y is hydroxymethyl;

Z represents hydrogen or a group of the formula:

< / BR>
where

Arepresents the anion of a mineral or organic acid or, when present carboxylate group in the remaining part of the antibiotic, this radical can be an internal anion derived from a specified carboxylate group;

and pharmaceutically acceptable salts of these compounds.

Another preferred group of compounds according to the invention include those derivatives of formula (I), where R2is a (C10-C11)alkyl, M represents-D - mannopyranosyl">

The following preferred group of compounds according to the invention includes those compounds of formula (1) where:

R1represents hydrogen or a protective group of amino group, preferably hydrogen;

R2is a 7-metrotel, n-nonyl, 8-methylnon, n-decyl, 9-methyldecyl, n-undecyl, or n-dodecyl, preferably, n-decyl, 9-methyldecyl, or n-undecyl, preferably 9-methyldecyl; M represents hydrogen or D - mannopyranosyl, preferably D - mannopyranosyl;

Y represents carboxy, (C1-C4) alkoxycarbonyl, aminocarbonyl, (C1-C4) alkylaminocarbonyl, di (C1-C4) alkylaminocarbonyl, where the alkyl part may have a Deputy, selected from hydroxy, amino (C1-C4) alkylamino or di (C1-C4) alkylamino or hydroxymethyl, preferably, carboxy, methoxycarbonyl, aminocarbonyl, methylaminomethyl, dimethylaminoethyl, (dimethylamino) ethylaminomethyl or hydroxymethyl;

X is an amine residue-NR3-alk1- (NH-alk2)p-(NH-alk3)q-W, where R3is hydrogen;

alk1, alk2and alk3independently represents a linear alkylene with 2-4 atoms Ino, di(C1-C4)-alkylamino, amino group, substituted by one or two amino-(C2-C4)-alkyl fragments, or, when p and q equal to 0, together with the fragment-NR3-alk1this radical can represent the piperazine derivatives or 4-methylpiperazine; it is best to X represented an amine residue selected from:

-NH-(CH2)3-N(CH3)2,

-NH-(CH2)3-[NH(CH2)3]2-NH2,

-NH-(CH2)3-N[(CH2)3NH2]2,

< / BR>
Z represents hydrogen;

and pharmaceutically acceptable salts of these compounds.

The compounds of formula (1), where Y is a (C1-C4-alkoxycarbonyl, R1, R2, M and Z have the above meanings and X represents an amine residue of the formula:

-NR3-alk1-(NR4-alk2)p- (NR5-alk3)q-W

where

R3, R4, R5, alk1, alk2, alk3, p, q and W have the meanings given in the beginning of the description, get by amidation of the corresponding derivatives of formula (II) above, where R'1, R'2and M' have the same meaning as R1, R2and M, X' represents hydroxy, and Y' is the major way some examples of these compounds are described in the aforementioned application for international patent N PCT/EP92/00374.

The amidation process involves the condensation of these starting materials of the formula (II) corresponding amine of formula (III):

OTHER3-alk1-(NR4-alk2)p- (NR5-alk3)q-W (III),

where

R3, R4, R5, alk1, alk2, alk3, p, and q and W have the above meanings, in the presence of a condensing agent, or through education "activated ester" specified source C63carboxylic acids of formula (II) in an inert organic solvent.

For the amidation reaction using the inert organic aprotic solvents, which do not have adverse effects on the course of the reaction and at least partially dissolve the starting materials.

Examples of such inert organic solvents include organic amides, ethers of glycols and polyols, phosphoramide and sulfoxidov. Preferred organic solvents are, for example, dimethylformamide, dimethoxyethane, hexamethylphosphoramide, dimethylsulfoxide and mixtures thereof.

The condensing agent in the process according to the invention of apeptico.

Examples of condensing agents diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC) in the presence of hydroxybenzotriazole (HBT), benzothiazolinone-Tris-(dimethylamino) fosfodiesterasa, benzothiazolinone-Tris-(pyrrolidino)phosphonium - hexaphosphate and (C1-C4) alkyl, phenyl or heterocyclic phosphorazidate, such as diphenylphosphonate, diethylphosphoramidite, di-(4-nitrophenyl)phosphorazidate, dimorpholino-phosphorazidate and diphenylphosphinylchloride. The preferred condensing agents are diphenylphosphonate, i.e. diphenylethers phosphoric acid (DPPA), benzothiazolinone-Tris(dimethylamino)phosphonium-hexaphosphate (BOP), benzotriazole-Tris-(pyrrolidino)phosphonium-hexaphosphate (Py BOP).

Of the last two condensing agents Py BOP is the most preferred because the resulting by-product of pyrrolidin has a lower toxicity than dimethylamine.

In the amidation process according to the invention, the amine reagent is generally used in a molar excess, although in some cases the reaction can be performed, obtaining good output, and when using amine reagent in equimolar ratio or in low mole is m, if the amine reagent fairly inexpensive or readily available, use 2 - to 10-fold excess of amine (III), although preferred is 3-to 4-fold excess.

For amidation of the above starting material of formula (II) with the amine (III) in the presence of a condensing agent, it is necessary that the amine reagent was capable of forming a salt with a carboxyl group (X'-hydroxy) source material. In the case when the amine reactant is not strong enough for the formation of such salts in the reaction medium, it is necessary to add a salt-forming base (e.g. tertiary aliphatic or heterocyclic amine, such as triethylamine, N-methylpyrrolidine or N-methylpiperazine, which cannot form an amide bond with a carboxyl group), a salt-forming base is added in at least equimolar amount relative to the original material.

The use of amine reagent in diskomalaria excessive amount of with the addition of salt-forming base is most appropriate in cases where the amine reagent is very expensive or hard to get.

Examples of the above-mentioned salt-forming bases tertiary organic alifa.

The condensing agent is generally used in equimolar amounts or in low molar excess, for example, from 1.1 to 1.7 times, preferably 1.2 to 1.5 times compared to the original compound A 40926. In particular, it is noted that when using starting materials of the formula (II), where Y' represents a (C1-C4) alkoxycarbonyl, and Py-BOP as a condensing agent in a large excess (e.g., in 3-fold molar excess) and with a large excess of amine reagent (e.g., 6 - to 10-fold molar excess), the final amide products of formula (I) where Z represents:

< / BR>
where

Ahas the above value,

get almost quantitative yields.

Amine reagent can be introduced in the reaction medium in the form of the corresponding acid salt such as hydrochloride. In this case, the amine reagent add at least double the molar ratio, and a strong base capable of releasing amine salt, add 2 - 4-fold molar excess. In this case, the appropriate basis is usually a tertiary aliphatic or heterocyclic amine, which is not able to form amide bond with a carboxyl group in contrast to dry place using the specified radix is the preferred method, especially in cases when the salt is more stable than the corresponding free amine.

The reaction temperature may be different depending on the type of starting materials and the conditions of the reaction. In General, it is preferable to conduct the reaction at temperatures from 0 to 30oC.

The time of reaction may also be different and depends on the type of the condensing agent and other parameters of the reaction. Usually the condensation reaction is completed within a period of from one hour to 24 to 48 hours.

In any case, the course of the reaction is controlled by thin-layer chromatography or preferably HPLC using any known method.

Based on the results of the chromatographic analysis specialist can evaluate the course of the reaction and to decide when to stop the reaction and start the processing of the reaction mixture by any known method, for example, such a method may include extraction with solvents, precipitation by adding precipitators, etc., with subsequent separation and purification, e.g., using column chromatography.

Usually when using condensing agents such as those, kotorgo sometimes it is desirable to use the original esters, with a suitable protective group, in particular in those cases when these esters obtained on the previous stage reaction in which the ester is obtained from the predecessor of antibiotic A 40926. Moreover, there may be other cases when the conditions of the amidation reaction require or at least suggest the protection of the amino group in the N15the original ether of the formula (II).

In these cases, the introduction of the protective group at position N15amino produce one of the known methods described in the references mentioned in the present description in connection with the protection of the predecessor of the A 40926 to obtain esters of the formula (II), where Y' represents a (C1-C4) alkoxycarbonyl.

N-protective group must be stable under the reaction conditions, they should not have an adverse effect on the course of the amidation reaction, they must have such properties that will make it easy to remove these groups from the reaction medium at the end of the reaction, without causing changes in the newly formed amide bond and the General structure of the compounds, e.g. sugar fragments.

Examples of the N-protective groups, which can be used to protect any other amino groups, which should not come in the amidation reaction are carbamate-forming reagents characterized by the following oxycarbonyl groups: 1,1-dimethylphenylcarbinol, tert-butyloxycarbonyl, vinyloxycarbonyl, cinnamoylcocaine, benzyloxycarbonyl, p-nitrobenzenesulfonyl, 3,4-dimethoxy-6-nitrobenzisoxazole, 2,4-dichlorobenzenesulfonyl, 5-benzyloxycarbonyl, 9-internalservererror, diphenylmethylsilane, isonicotinoilhidrazone, diphenylmethylsilane, S-benzyloxycarbonyl etc.

Typically, these protective groups can be removed after completion of the amidation reaction by handling strong organic acids such as triperoxonane acid (TGA), or dilute mineral acids. To avoid the risk of hydrolysis of the sugar fragments attached to the core molecule antibiotic, you can also remove some of the protective groups in various conditions, such as catalytic hydrogenation using, for example, palladium on carbon as catalyst. Otherwise you can delete aminosidine group from among the above groups by controlled acidification, for example, at low those who cut intermediate education "activated ester" of starting compound of the formula (II), this "activated ester" is usually formed in place or, alternatively, the ether is first allocated, and then interact with the amine of formula (III). The amino group in position N15starting material of formula (II), first introducing the protective group, to avoid any interaction between the reagent that activates the formation of ether, and the amino group in the N15. Protection of the amino group can provide any of the known methods described above.

Education "activated esters" of carboxylic acids in General is described in Fisher and Fisher, "Reagent for organic syntjesis" ed. "John Willy & sons", pages 129-130 (1967).

Examples of these reagents, forming an activated ester, which can be used in the process according to the invention cited in P. Swizer and other "Helv. Chim. Acta", 1955, 38, 69-70 and include those of the ether derivatives of the formula (II), where X' represents CH2CN, CH2COOC2H5CH2(COOC2H5)2CH2COCH3,

CH2CH2N(C2H5)2< / BR>
which can be obtained from starting materials of the formula (II), where R'1represents a suitable protective group, and X' submitted the SUB>2
,

ClCH2COCH3,

ClCH2CH2N(C2H5)2< / BR>
accordingly, in the presence of acid acceptor in a solvent.

The preferred reagent of this type is chloroacetonitrile.

In this case, chloroacetonitrile, dimethylformamide (DMF) or dimetilsulfoksid (DMSO) is used as the preferred solvent.

Usually for education "activated esters" inert organic aprotic solvents, which do not have an undesirable effect on the course of the reaction and is capable of at least partially dissolving the carboxylic acid, which is the source material.

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

More preferred solvents are acetonitrile, dimethylsulfoxide, dimethylformamide. The production of activated ester is usually carried out in the presence of a base, which is not stupe is of use in 2 - 6-fold molar proportions to the original material, and preferably it is used in approximately three-fold molar excess. The preferred base is triethylamine.

The reagent, forming an "activated ester" is used in a large excess relative to the starting material of formula (II) containing carboxylic acid in the C63. Usually this reagent is used in 5-35 molar ratio, preferably 20-30 fold molar excess. The reaction is carried out at a temperature of from 10 to 60oC, preferably at 15-30oC. As usual, the time of reaction depends on other parameters of the reaction and can vary from 3 to 48 hours.

The progress of reaction is monitored by HPLC or thin-layer chromatography to determine the time of completion of the reaction and begin recovery of the desired intermediate. Intermediate "activated ester" can be used directly in the same reaction medium, where he was received, however, usually produce precipitation with the use of precipitators or by extraction with solvents, after which the "activated ester" is used in the next steps without further clear the chromatography with reversed phase.

Then the obtained intermediate "activated ester" interact with the amine derivative of formula (III) (in molar excess) in the presence of an organic polar solvent at a temperature of from 5 to 60oC, preferably from 10 to 30oC.

In this case, the organic polar solvent may be a polar proton or aprotic solvent.

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

Preferred organic polar aprotic solvents are N,N-dimethylformamide (DMF), hexamethylphosphoramide (HMPA), or mixtures thereof, 1,3-dimethyl-3,4,5,6-tetrahydro - 2-(1H)-pyrimidine (DMPU), dimethylsulfoxide (DMSO) or dimethoxyethane (DME).

Reaction of the activated ester with the amine of formula (III) can be carried out at a temperature of from 5 to 60oC, but preferably at temperatures from 10 to 30oC, preferably at 20-25oC, and the preferred molar ratio between the intermediate activated ester and the amine (III) is the ratio of from 1:5 to 1:30, more is or HPLC.

If the amine reagent is a polyamine of the formula (III), one or more of the amine groups of the compounds that do not participate in the formation of the amide bond can be protected. In these cases, suitable protective group should be selected from the groups listed for the position of N15.

Accordingly, the obtained amide derivatives containing a protective group at the N63then treated to remove these protective group, removing the protective groups are produced in the same conditions as those described above in relation to the removal of the protective groups in position 15.

The compounds of formula (I), where Y is hydroxymethyl, R1, R2, M, X and Z have the meanings given in the beginning of the description, can be obtained by restoring the corresponding derivatives of formula (I), where R2, M, X and Z have the above meanings, Y is a (C1-C4) alkoxycarbonyl, and R1represents a suitable protective group for the amino group in the N15using alkali metal borohydride, preferably, wireimage from the group: sodium borohydride, potassium borohydride and cyanoborohydride sodium, at a temperature from 0 to 40oC in water or water-Speer is ptx2">

Using this method is necessary for obtaining the compounds of formula (I), where Y is hydroxymethyl, X is hydroxy, R1, R2and M have the meanings given in the beginning of the description, and Z is hydrogen. In this case the source material, which is subjected to recovery under these conditions, is a compound of formula (II), where Y' represents a (C1-C4) alkoxycarbonyl, X' is hydroxy, R'2and M' have the same values as R2and M, respectively, and R'1represents a suitable protective group for the amino group in the N15. The receipt of the initial compounds described in the Application for international patent N PCT/EP92/00374 and conducted in accordance with the General method of obtaining the original ether of the formula (II) as described above.

Usually Vodopyanova environment used in reduction reactions, mentioned above, is a mixture of water and a water-soluble or partially miscible with water lower alkanol, and the ratio of water/low alkanol ranges from 40/60 to 90/10 (o/o), preferably from 60/40 to 68/32 (o/o), preferably 65/35 (o/o).

Although in some cases the reaction occurs when smaller quantities of water, e.g. in the mixture is canal below, than 40/60.

Preferred lower alkanols are (C1-C4)alkyl alcohols with linear or branched chain, among which the most preferred n-butanol, ethanol and methanol.

Sometimes in some cases, add a small amount of a polar co-solvent to completely dissolve the starting material in the reaction, e.g. , N, N-dimethylformamide, 1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidone (DMPU), dimethyl sulfoxide. Sometimes add various amounts of diethyl ether, to avoid foaming.

Most preferred among borhydride alkali metal is sodium borohydride. The amount of alkali metal borohydride may be different depending on the type of solvent and reaction temperature, but it is recommended to use the alkali metal borohydride in a large excess relative to the stoichiometric requirements, so that the pH of the reaction mixture was neutral or alkaline, preferably pH 7 to 10. In General, the molar ratio between the alkali metal borohydride and a starting material for antibiotic ranges from 50 to 300.

The reaction temperature may be substantially war is boditi reaction at a temperature from 0 to 40oC, preferably at room temperature.

The time of reaction may also be different depending on other parameters of the reaction, however, the reaction time should be carefully controlled. The reaction usually completes in approximately 1-4 hours. If we continue the reaction for more than 4 hours, you can place undesirable side reactions that lead to the rupture of peptide bonds in the core of the molecule.

In any case, over the course of the reaction is observed using thin-layer chromatography, preferably HPLC, using known methods. Based on the results of chromatographic analyses any expert can evaluate the course of the reaction and decide when it should stop and start spraying the reaction mass is one of the known methods, which includes, for example, extraction with solvents, precipitation by adding precipitators, etc. and, if necessary, separation and purification of column chromatography.

After completion of the reaction the excess of borohydride of an alkali metal is removed by adding the appropriate amount of acid, e.g., (C1-C4) alkyl organic acid, (C1-C6) alkyl-sulfate the 4
) alkilany alcohol.

In another embodiment, the compounds of formula (I), where Y is hydroxymethyl, R1, R2and M have the values listed in the beginning of the description, X represents an amine residue

-NR3-alk1-(NR4-alk2)p)- (NR5-alk3)q-W

where

R3, R4, R5, alk1, alk2, alk3, p, q and W have the values listed in the beginning of the description, and Z represents hydrogen, get through amidation, which was described above, interacting the corresponding compound of formula (I), where Y is hydroxymethyl, X is hydroxy, R1, R2and M have the above meanings and Z represents hydrogen, with an amine of formula (III), as described above.

In this case, the amidation reaction can be conducted using an appropriate condensing agent or through intermediate formation "activated ester", as described above for preparing compounds of formula (I), where Y is a (C1-C4) alkoxycarbonyl.

In General, the amidation derivatives of formula (I), where Y is hydroxymethyl, X is hydroxy and Z is hydrogen, using Py BOP in kachestva Py BOP is used in a large molar excess in relation to the original carboxylic acid. When the amidation reaction is carried out by formation of the activated ester" of the compounds of formula (I), where X is hydroxy, Y is hydroxymethyl, and Z is hydrogen, preferably introduced one of the above protective groups in position N15amino specified connection.

Next, the process for obtaining compounds of formula (I), where Y is a (C1-C4) alkoxycarbonyl or hydroxymethyl, R1, R2, M and Z have the values listed in the beginning of the description, X represents the balance:

-NR3-alk1-(NR4-alk2)p- (NR5-alk3)q-W

where

R3, R4, R5each independently represents hydrogen or (C1-C4)alkyl, alk1, alk2, alk3and W have the values listed in the beginning of the description, p is 1 and q is 1 or 0, is that derivative, amide N63having a protective group at the N15(in the present description, the term "N63" refers to the nitrogen atom in carboxyamide group, which is linked to the carbon atom in the molecule A 40926 at number 63) of the formula (I), where Y, R2, M and Z have the above meanings and X represents an amine residue of the formula:

-NR3-alk1-(NR5,

where

R

where

R3, R4, R5, alk1and alk2have the above values,

with amine reagent of formula (IV) or (IVa), respectively;

r-alk2-(NR5-alk3)g-W (IV) and r-alk3-W (IVa),

where

R5, alk2, alk3and W have the above values, q is 0 or 1, r represents a halogen, methanesulfonyl or tosyl, in the presence of an acid acceptor in an inert solvent. Derivative amide N63with a protective group at the N15receive in accordance with the General method of preparing compounds of formula (I) according to the invention. Removing the protective group at the N15the amino group is produced in the above way.

In this case, the alkylation is desirable or necessary to apply in order to introduce a protective group into the amino group (group) in addition to N15-amino amide derivative of N63formula (I) and/or amine reagent (IV) or (IVa), which are not involved in the alkylation reaction. The protective group of the amides of N63you can delete the above method.

Protective groups which can be used in all the above reactions are already listed above. However, special attention should be given to removal of the protective group and the attachment is removed under the influence of acid, the stage of removal of the protective group is very important because it is relatively quick replacement of the corresponding acylglucuronide fragment 56 during processing, for example, dry triperoxonane acid (TFA). In any case, these adverse reactions can be easily minimized. For example, when the protective group using tert-butyloxycarbonyl (t-BOC), you can use the following method: processing of dry TFA for one minute at room temperature or for 10-30 minutes at a temperature of from 0 to 5oC followed by rapid deposition of the reaction product of diethyl ether or a mixture of methanol/diethyl ether at 0-5oC. on the Contrary, in respect of compounds of formula (I) where Y represents carboxy or methoxycarbonyl, it is seen that the fragment acylaminopyrazoles acid 56 is significantly more stable to TFA. In fact, the formation of traces corresponding diglucuronide of pseudoalleles was observed only after 1 hour the course of the reaction. However, in this case the removal of the protective group is t-BOC is carried out for 30 minutes

Another suitable method of removing the protective group is t-BOC without a significant impact on other parts of the molecule is about what shiiteled.

The compounds of formula (I), where R1, R2, M, X and Z have the values listed in the beginning of the description, and Y represents carboxy, obtained from corresponding compounds of formula (I), where Y is a (C1-C4) alkoxycarbonyl, preferably methoxycarbonyl, and all the other radicals have the abovementioned meanings, by treatment with an aqueous solution of hydroxides of alkali metals (e.g. NaOH or KOH) at a temperature of from 0 to 30oC (higher temperatures invalid, as may occur epimerization at the carbon atom at the 3-position of the molecule), in an inert organic solvent, for example di-(lower alkyl) ether of ethylene glycol or tetrahydrofuran.

The compounds of formula (I), where R1, R2, M, X and Z have the values listed in the beginning of the description, and Y represents aminocarbonyl, (C1-C4) alkylaminocarbonyl, di (C1-C4) alkylaminocarbonyl, where the alkyl part may have a Deputy, selected from hydroxy, amino, (C1-C4) alkylamino and di (C1-C4) alkylamino, can be obtained in the following way:

i) deriving, where the radical Y and a fragment of COX in C63represent the same group (C1-C41-C4) alkylamino and di (C1-C4) alkylamino;

(a) Amidation of the antibiotic complex A 40926, it demagnetising derived or factor (formula (II), X' = hydroxy, Y' = carboxy, R'1, R'2and M' have the same values as R1, R2and (M) a large excess of the appropriate amine of formula (III), where the radicals R3, R4, R5, alk1, alk2, alk3, p, q and W have meanings that are compatible with the above carboxamide residues Y and COX. This amidation reaction is carried out in the same conditions as described above.

ii) deriving, where the radical Y and a fragment of COX in C63represent different carboxamide balances, the value of Y is chosen from aminocarbonyl, (C1-C4) alkylaminocarbonyl, di(C1-C4) alkylaminocarbonyl, and the alkyl part may have a Deputy chosen from amino, hydroxy, (C1-C4) alkylamino and di (C1-C4) alkylamino, and X represents an amine residue, described at the beginning of this description;

Method A: the Amidation of the corresponding compounds of formula (I), where R1, R2, M and Z have the values listed in the beginning of the description, X SUB>-W, where all the radicals have the meanings specified in the beginning of the description, and Y is carboxy by reaction with the appropriate amine to form the above carboxamide residue Y in the presence of a condensing agent (e.g., Py BOP or DPPA) under the above described conditions;

Method (B): (a) the original connection (the same as in Method A) introducing a protective group at position N15amino group (for example, the group is t-BOC or CBz); (b) receive an "activated ester" carboxyl group in position 6b(for example, by interacting with chloroacetonitrile); (c) interact fragment "activated ester" specified connection with the corresponding amine to obtain the above carboxamide residue Y in the above conditions, (d) optionally removing the protective group at the N15the above method (e.g., acidolysis or hydrogenolysis).

The compounds of formula (I), where M represents hydrogen, receive the above method using the corresponding parent molecules of formula (II), where M' represents hydrogen.

In addition, an alternative method of obtaining the compounds of formula (I), where M represents hydrogen, consists in transforming SOEDINENIYa, where M represents a hydrogen by selective acid hydrolysis in accordance with the conditions described in EP-A-240609.

As described above, the compounds of formula (I) may consist of individual compounds corresponding to individual factors predecessor of antibiotic A 40926 or mixtures thereof in various proportions. Because in many cases the biological activity of the mixtures is similar to the biological activity of individual factors, it makes no sense to separate the individual components after obtaining a mixture. However, in cases where the needs clean the factors of the formula (I) can be separated from mixtures using column chromatography with reversed phase according to the method described in EP 177882. In another embodiment, it can be obtained using the raw materials of formula (II) containing individual compounds corresponding to individual factors antibiotic complex A 40926.

According to the General method and conditions of course of reactions described here can be used predecessor complex A 40926, containing one of the individual factors (e.g., factor B0in predominant proportion to the other components in the mixture (e.g., 60% according to HPLC). Accordingly, the compounds of formula (I), posobiacemu division, they consist of mixtures, the predominant component of which corresponds to the factor, who prevailed in the specified precursor complex of the A 40926.

A method of producing a complex of A-40926 saturated with factors A and/or B0or PA and/or PB, is described, for example, in EP-A-259781.

Compounds according to the invention that have alkaline properties, can form salts with organic and inorganic acids in the usual way.

Examples of suitable salts of the compounds according to the invention include salts obtained by standard reactions with organic and inorganic acids, such as, for example, hydrochloric, Hydrobromic, sulfuric, phosphoric, acetic, triperoxonane, trichloroacetic, succinic, citric, ascorbic, lactic, maleic, fumaric, palmitic, cholic, Panova, mucus, glutamic, camphoric, glutaric, glycolic, ftalievogo, tartaric, lauric, stearic, salicylic, methansulfonate, benzolsulfonat, sorbic, picric, benzoic, cinnamic, etc. acids.

The compounds of formula (I), where X represents hydroxy, and Y is hydroxymethyl, and compounds, where Y is carboxy, also have acidic group, the tions, which may form a salt with the compounds according to the invention, containing acid groups, are: hydroxides of alkaline or alkaline earth metals such as sodium, potassium, calcium, magnesium, barium hydroxide, ammonia, and aliphatic, acyclic or aromatic organic amines, such as methylamine, dimethylamine, triethylamine, ethanolamine, and picoline.

The conversion of the compounds according to the invention into the corresponding salts and the reverse process, i.e. the conversion of the corresponding salts of the compounds according to the invention is carried out by conventional means and are within the scope of the present invention.

For example, the compound of formula (I) can be converted into the corresponding salts with acids or bases by dissolution or suspension of the compounds of formula (I) in an aqueous solvent and an additive selected acid or base in a small molar excess. The resulting solution or suspension is then lyophilizer to restore the desired salt.

When the final salt is insoluble in the solvent, at which instant the connection according to the invention, this salt can be recovered by filtration from the solution of the compounds according to the invention after the addition stagione the tion according to the invention can be obtained from the corresponding salt, dissolved in an aqueous solvent, which is then neutralized to release the connection. Then the connection is restored, for example, by extraction with an organic solvent or converted into another salt by adding the selected acid or base and carrying out the above processing.

In those cases, when conducting the neutralization, it is necessary desalination, which is performed by conventional methods. For example, using column chromatography on Polydextrose resins with a given porosity (such as Sephadex LH 20) or milanesiana silica gel. After elution of unwanted salt aqueous solution, the desired product elwira linear gradient or stepwise gradient of a mixture of water with a polar or nonpolar organic solvent, such a mixture as acetonitrile - water in a ratio of from 50:50 to 100% acetonitrile.

It is known that the formation of salts when using any pharmaceutically-acceptable acids and bases or pharmaceutically-unacceptable acids and bases can be used as a purification method. After the formation and allocation of the salt of the compounds of formula (I) can be converted to the corresponding connection is not in the form of a salt or partway, all that refers to the biological activity of the compounds of formula (I), can be attributed also to the pharmaceutically-acceptable salts of these compounds.

In the following table. 1 presents a series of representatives of the compounds of the present invention.

Derivatives of antibiotic A 40926 are active mainly against gram-positive bacteria.

In particular, the compounds according to the invention exhibit high activity against resistant to glycopeptides enterococci and staphylococci.

Antimicrobial activity of derivatives of formula (I) antibiotic A 40926, expressed as minimum inhibitory concentration (MIC) against selected strains of gram-positive bacteria was associated with antimicrobial activity teicoplanin and antibiotic complex A 40926. To use this method of dilution microcultural environment in broth Mueller Hinton in the presence of 0.01% (m/o) bovine serum albumin (fraction Sigma), the final inoculum was about 105colony forming units/ml, and the minimum inhibitory concentration (MIC) was at the lowest level (µg/ml) that talked about the lack of visible growth after 18-24 hours incubation at 37oC.

In the following table. 3 presents data on the activity in vitro of some representative compounds of the present invention in comparison with teicoplanin and vancomycin, indicating that the compounds according to the invention are active in vitro against strains of enterococci with high resistance to glycopeptides in conventional therapy.

In the following table. 4 shows the results of experimental use of some representative compounds of the invention against streptococcal sepsis mice.

The experiments were carried out according to the methodology described and the work of the Century Arioli and others, "Journal of Antibiotics" 29. 511 (1976)

The above data show that despite the fact that the compounds according to the invention is generally less active against Neisseria gonorrheae than predecessor A 40926, these compounds have a higher activity against Susceptible crops and Enterococci compared with other compounds. In particular, these compounds are:

a) show significantly higher activity in vitro than teicoplanin and A 40926, against staphylococci, which are intermediates of glycopeptides or possessing resistance to glycopeptides;

b) active in vitro against enterococci, obladaushiy exhibit some resistance to A 40926 (MIC 64 µg/ml);

c) show greater efficacy in vivo than teicoplanin and A 40926, streptococcal sepsis mice.

Thanks to this antimicrobial activity of the compounds according to the invention can be effectively used as active ingredients of antimicrobials used for the treatment of humans and in veterinary practice for the prevention and treatment of infectious diseases caused by pathogenic bacteria, in particular, for the treatment of infectious diseases caused by enterococci, streptococci and staphylococci, which have low sensitivity to glycopeptides antibiotics.

Compounds of the present invention may be administered orally, topically or parenterally, parenteral administration is preferred.

Depending on the method of administration of the compounds according to the invention consists in the composition of drugs in various doses. Preparations for oral administration can be produced in the form of capsules, tablets, liquid solutions or suspensions. According to the usual practice of capsules and tablets may contain, besides the active ingredient, conventional carriers, such as diluents, for example lactose, calcium phosphate, sorbitol, etc., lubricating fedelatin, sorbitol, tragakant, acacia, flavors and acceptable splitting and wetting agents. Liquid preparations, usually in the form of aqueous or oil solutions or suspensions can contain the usual additives, such as suspendresume agents.

For topical use the compounds according to the invention is introduced into the formulations, suitable for absorption through the mucous membranes of the nasal or bronchial tissues, these drugs are usually manufactured in the form of liquid aerosol or inhalation of drugs, pills, or drugs designed to lubricate the throat.

For the treatment of diseases of the eye or ear medication can have a liquid or semi-liquid form. For the local application of drugs made in hydrophobic or hydrophilic bases, such as ointments, creams, lotions or powders.

For rectal use of compounds according to the invention is administered in the form of suppositories containing conventional media, such as, for example, coconut oil, wax, spermaceti or glycols and their derivatives.

Compositions for injection may be in the form of suspensions, solutions or emulsions in oily or aqueous carriers can contain additional agents, such as suspendida, stabil the Rosca, before the injection is mixed with a suitable carrier, for example water.

The amount of the active ingredient, be inserted depends on various factors such as weight and condition of the patient, the type and frequency of administration, the type of the pathogen.

Compounds according to the invention is usually effective in doses of from about 1 to about 40 mg of active ingredient per 1 kg of body weight of the patient. Depending on the characteristics specific to the connection type of infection and the condition of the patient effective dose is administered once a day or divide it into 2-4 servings per day. Preferred compositions are prepared as separate doses by 30-500 mg per dose.

Example 1

Obtaining source material (MA) (compounds of formula (II), where Y' represents - COOCH3X' represents - OH, R'1is - H, R'2is (C9-C12) alkyl corresponding to the factors of the complex A 40926, M' is D - mannopyranosyl and Z is - H).

Antibiotic complex A 40926 (150 mg, 0,0866 mmol) obtained by the method described in EP-A-177882, dissolved in methanol (30 ml) and concentrated sulfuric acid to bring the pH to 2. The mixture is stirred at room temperature is additive diethyl ether, the precipitate is collected, washed thoroughly with diethyl ether and dried. Output: 150 ml (99%).

Example 2

Getting connection 1 (RA) (the compounds of formula (I), where Y is - CH2OH, X is - OH, R1is - H, R2is (C9-C12) alkyl corresponding to the factors of the complex A 40926, M represents-D - mannopyranosyl, and Z is - H).

Step a: obtaining N15-(t-BOC)-MA

Under stirring a solution of 1.8 g of the compound from example 1 (MA) and 1 g of sodium bicarbonate in 50 ml of a mixture of dioxane/water 1/1, add a solution of 0.25 g of di-tert-butyl-dicarbonate in 5 ml of dioxane with 5oC, the additive is produced by drop within 15 minutes After 1 hour at room temperature the pH of the reaction mixture was adjusted to 4 with 1N HCL. Then add 150 ml of water and the resulting mixture is extracted with n-butanol (2 x 100 ml). The organic layer is separated, washed with 100 ml of water and then concentrated to small volume (about 25 ml) at 40oC under reduced pressure. Sediment deposited after the addition of diethyl ether (100 ml) is collected and dried under vacuum at room temperature overnight to obtain 1.6 g of the desired compound N15-(t-BOC)-MA, sufficiently pure for use in the next step.

Atapwd add 30 ml of a mixture n-butanol/diethyl ether 1/1, then add 0.9 g sodium borohydride. For 30 min at room temperature to produce additive reductant (portions) and then the reaction mixture was stirred at room temperature for 1 hour. After that the reaction mixture is cooled to 5oC and add 1.5 ml of glacial acetic acid and then 50 ml of water. The resulting mixture was extracted with n-butanol (100 ml) and the organic layer is treated as described above to obtain 0.8 g of the desired compound N15-(t-BOC)-RA, sufficiently pure for use in subsequent final stage.

Step c: a Solution of 0.5 connection N15-(t-BOC)-RA, obtained in stage B above in 5 ml of dry triperoxonane acid (TFA) was stirred at room temperature for 1 minute (or alternatively, at 0-5oC for 20-30 min, then poured into 10 ml of methanol/diethyl ether 1/4 at 0-5oC. the Desired compound RA collected by filtration to obtain (after washing with diethyl ether, and drying at room temperature under vacuum over night) of 0.35 g of product. Sample 0.15 g of pure compound RA obtained by column chromatography with reversed phase milanesiana silica gel, combining all fractions 2 (MA-A-1/B0) and compound 6 (MA-A-1). (compound of formula (I) where Y represents-COOCH3X represents - NH-(CH2)3- N(CH3)2, R1is - H, R2is a 9-methyldecyl (MA-A-1/B0) or (C9-C12)-alkyl corresponding to the factors of the complex A 40926 (MA-A-1), M represents L-D-mannopyranosyl, and Z is - H).

Method A.

Step a: obtaining N15-(t-BOC)-MA-A-1.

When moving into a solution of 1.3 g of N15-(t-BOC)-MA - in 30 ml of dimethyl sulfoxide (obtained in step a in example 2 above) was added 0.2 ml of 3,3-dimethylamino-1-Propylamine and 0.3 ml of diphenylphosphinite (DPPA). After 4 hours stirring at room temperature was added 0.15 ml of DPPA and continued stirring at room temperature for 20 hours. A solid residue, precipitated after addition of 170 ml of diethyl ether, collected to obtain 1.3 g of the desired compound N15-(t-BOC)-MA-A-1.

Step b: the Product of the above reaction was dissolved in 10 ml TFA. The resulting solution was stirred at room temperature for 20 min, then added to 90 ml of diethyl ether. The precipitation was collected, washed twice with 50 ml diethyl ether, and then dried at room temperature under Vacu is the philosophy with reversed-phase column with silanation silica gel (connecting fractions, containing pure desired factor) to obtain 0.15 g, pure MA-A-1/B0.

Method B.

Under stirring a solution of 1.8 g (about 1 mmol) of the compound from example 1 (MA) in 30 ml of dimethylformamide was added to 0.14 ml (about 1.15 mmol) 3,3-dimethylamino-1-Propylamine and 600 mg (about 1.2 mol) Rover, additive produced at room temperature. After stirring at 20-25oC for 3 hours was added 150 ml of diethyl ether. The precipitation was collected and purified column chromatography with reversed phase (combining all fractions containing pure individual factors), receiving of 1.15 g of compound MA-A-I.

Example 4

Obtain compound 7 (Py MA-A-I). (Compound of formula (I) where Y represents - COOCH3X is-NH-(CH2)3- N(CH3)2, R1is - H, R2is a (C9-C12) alkyl corresponding to the factors of the complex A 40926, M represents-D - mannopyranosyl and Z is P(NC4H8)3CH3COO-D - mannopyranosyl and Z is - H).

How A

Step a: obtaining N15-(t-BOC)-RA-A-1.

Using the method according to example 3, method A, step a, from 2 g of N15-(t-BOC)-RA (example 2, step b) was obtained 1.7 g of the desired the data connection N15-(t-BOC)-RA-1 got to 0.22 g of pure compound RA-A-1.

Factor RA-A-1/B0received, using the specified method, except that purification by chromatography with reversed phase produced for only those fractions that contained pure desired individual factor (combining these fractions).

Method B.

Under stirring a solution of 50 g (about 27 mmol) of the compound from example 2 (RA) in 200 ml of dimethylformamide was added 11 ml (90 mmol) of 3,3-(N,N-dimethylamino)-1-Propylamine and 18 g (35 mmol) Py BOP, additive produced at room temperature. After stirring for 15 minutes was added 1 liter of ethyl acetate and precipitated sludge (about 63 g) was collected and subjected to purification column chromatography with reversed phase (combining all fractions containing pure individual factors) with 25 g of compound RA-A-1.

Example 6

Getting connection 4 (MA-A-2/B0) (Compound of formula (I), where Y is - COOCH3X is - NH-(CH2)3-[NH-(CH2)3]2-NH2, R1is - H, R2is a 9-methyldecyl, M is an L-D-mannopyranosyl and Z is - H).

Step a: obtaining N15-(t-BOC)-MA, cyanomethylene e is 10 ml of dimethyl sulfoxide (DMSO) was stirred at room temperature for 4 hours. Then add 90 ml of ethyl acetate and precipitated precipitate is collected, obtaining 2.8 g of the crude desired compound N15-(t-BOC)-MA, cinematology ether.

Step b: obtaining N15-(t-BOC)-MA-A-2.

The above cinematology ester (crude) was dissolved in 30 ml of DMSO. In the resulting solution was added to 2.8 ml of N,N'-bis(3-aminopropyl)-1,3-propandiamine and stirred the reaction mixture at room temperature for 4 hours. Then add 200 ml of ethyl acetate and the precipitated solid precipitate is collected, obtaining 3 g of the crude desired compound N15-(t-BOC)-MA-A-2.

Stage c: the Above crude compound is treated with TFA as described above in example 3, method A, step b, to obtain (after column chromatography with reversed phase (connecting only the fractions containing the pure desired individual factor)) 0.45 g of pure compound MA-A-2/Bo.

Example 7

Getting connection 5 (MA-A-3/B0). (Compound of formula (I), where Y is COOH3X is - NH-(CH2)3-N[(CH2)3-NH2]2, R1is - H, R2is a 9-methyldecyl, M represents-D-mannopyranosyl and Z is - H).

Step a: obtaining N',N"-di(t-BOC) is artny patent N WO 90/11300.

Step b: condensation MA with N',N"-di(t-BOC)-Tris (3-aminopropyl)amine.

A solution of 18 g (about 10 mmol) of the compound from example 1 (MA), 14 g (about 36 mmol) protected amine, 3 ml (22 mmol) of TEA and 6 ml (about 28 mmol) of DPPA 150 DMSO was stirred at room temperature for 2 hours, then add 500 ml of ethyl acetate. Precipitated precipitated solid is collected (about 22 g) and used in the next step without further purification.

Stage: removal of protective groups t-BOC:

The crude reaction product of step b dissolved in 150 ml of dry TFA, pre-cooled to 0oC and the resulting solution was stirred at 0-5oC for 20 minutes. Then add 150 ml of methanol and 300 ml of diethyl ether. The precipitation is collected, washed several times with diethyl ether, and then purified column chromatography with reversed phase (connecting only the fractions containing the pure desired individual factor) to obtain 9 g of the compounds MA-a-3/B0.

Example 8

Obtaining the compound (9) (RA-A-2). (The compounds of formula (I), where Y is - CH2OH, X is - NH-(CH2)3- [NH(CH2)3]2-NH2, R1is - H, R2is a (C9-C12) ALK is Step a: obtaining N15-(t-BOC)-RA, cyanomethylene ether.

A solution of 8 g (4 mmol) of the compound from example 2, step b (N15-(tBOC)-RA), 0.75 ml (about 5.5 mol) TEA and 8 ml of chloroacetonitrile in 40 ml of DMSO was stirred at room temperature for 5 hours. Then add 200 ml of ethyl acetate and the precipitated solid precipitate is collected, receiving 8,2 desired crude cyanomethylene ether. Stages b and c: Condensation with N', N"-bis-(3-aminopropyl)-1,3 - propandiamine and acidosis protective group is t-BOC:

Untreated cinematology broadcasts from the stage and dissolved in 80 ml DMCO and add 9 g of N,N'-bis-(3-aminopropyl)-1,3-propandiamine. After stirring at room temperature for 20 hours add ethyl acetate. Precipitated solid precipitate is collected and re-dissolved in 70 ml dry ice TFA. The resulting solution was stirred at 0oC for 10 minutes, then add 230 ml of chilled diethyl ether. Precipitated solid precipitate is collected and quickly re-dissolved in 200 ml of water. the pH of the solution was adjusted to 5.5 with 1N NaOH and purified by chromatography with reversed phase (combining all fractions containing pure individual factors), receiving 1,3 pure desired compound RA-A-2.

Example 9

The connection 10 (RA-A-3). (UB>, R1is H, R2is a (C9- C12) alkyl corresponding to the factors of the complex A 40926, M represents-D - mannopyranosyl and Z is - H).

Under stirring a solution of 9 g (about 5 mmol) in 100 ml DMSO was added 7 g (18 mmol) of N',N"-di(-tBOC)-Tris-(3-aminopropyl)amine (example 7, step a), 1.5 ml of TEA and 3 ml of DPPA at 10oC. After stirring at 10oC for 1 hour and at room temperature for 4 hours was added 400 ml of ethyl acetate. Precipitated solid residue (12 g) was re-dissolved in 80 ml ice-cold TFA and the resulting solution was stirred at 0-5oC for 10 minutes. Then added a mixture of methanol/diethyl ether 1/1 (about 300 ml), previously cooled to 10oC. the Solid precipitate was collected and quickly re-dissolved in 200 ml of water. the pH of the resulting solution is brought to 4 with 1N NaOH and spent clearing chromatography with reversed phase (combining all fractions containing pure individual factors) to obtain 1.8 g of the pure desired compound RA-A-3.

Example 10

Obtaining the compound (II) (A-A-1). (Compound of formula (I), where Y is - COOH, X is - NH-(CH2)3-N(CH3)2, R1is - H, R2is a (C9-).

Under stirring suspension of 5 g (about 2.5 mmol) of compound 6 (MA-A-1) obtained as described in example 3, method B, in 60 ml of tetrahydrofuran (THF) was added 10 ml of water and 20 ml of 1H NaOH at room temperature. After 30 min the pH of the resulting solution is brought to 7 with 1N HCl was added 150 ml of n-butanol and concentrated mixture to a small volume (about 20 ml) at 40oC under reduced pressure. A solid residue, precipitated after the addition of diethyl ether (200 ml) collected (5,2 g) and purified by chromatography with reversed phase (combining all fractions containing pure individual factors), having 2,1 desired compound A-A-1.

Example 11

The formation of compounds 12 (Py A-A-1) (Compound of formula (I), where Y is - COOX is - NH-(CH2)3- N(CH3)2, R1is - H, R2is a (C9-C12) alkyl corresponding to the factors of the complex A 40926, M represents-D - mannopyranosyl and Z is P(NC4H8)3).

Compound 12 (Py A-A-1) is produced from compound 7 (Py MA-A-1) of example 4 by the method described in example 10 to obtain the compound (II) (A-A-1) from compound 6 (MA-a-1), output is 35%.

Example 12

The connection 13 (A-A-3/SUB>]2, R1is - H, R2is a 9-methyldecyl, M represents-D-mannopyranosyl and Z is - H).

Compound 13 (A-A-3/B0) is produced from compound (MA-A-3/B0from example 7 by the method described in example 10 to obtain the compound (II) (A-A-1) from compound 6 (MA-A-1), the output is 41%.

Example 13

The connection 14 (ABA-A-1). (Compound of formula (I), where Y is - CONHCH3X is - NH-(CH2)3- N(CH3)2, R1is - H, R2is a (C9-C12) alkyl corresponding to the factors of the complex A 40926, M represents-D - mannopyranosyl and Z is - H).

Step a: obtaining N15-(t-BOC)-A-A-1, 6b-cinematology ether.

Under stirring into a solution of 22 g (about 11 mmol) of compound II (A-A-1) of example 10 and 3 g of NaHCO3in 220 ml of a mixture water/1/1 dioxane was added a solution of 5 g of di-tert-butyl-dicarbonate in 20 ml of dry dioxane, additive produced by drop at room temperature for 10 minutes After stirring for 2 hours at room temperature was added 200 ml of water, then the pH of the resulting solution was brought to 3 with 1N HCl and was extracted with a solution of 300 ml of n-butanol. The organic layer was separated and conc is the additives diethyl ether (250 ml) was collected (about 20 g of the crude N15-(t-BOC)- A-A-1) and re-dissolved in 150 ml of DMSO. After addition of 3 ml of TFA and 20 ml of chloroacetonitrile the resulting solution was stirred at room temperature for 5 hours, then added 500 ml of ethyl acetate. Precipitated solid precipitate (about 18, cyanomethylene ether) was sufficiently pure for use in the next step.

Step b: Interaction obtained above 6b-cyanomelana ester with methylamine and removing the protective group is t-BOC.

A solution of 5 g of the above product in 75 ml 250 (m/o) of methylamine in ethanol was stirred at room temperature for 3 hours, then added 300 ml of diethyl ether. Precipitated solid precipitate (about 5.1 g) was collected and re-dissolved in 35 ml of TFA at 0oC. the resulting solution was stirred at 0oC for 15 min, then was added 50 ml of a mixture methanol/diethyl ether 1/1 to precipitation of 4.5 g of the crude product, which was purified column chromatography with reversed phase (combining all fractions containing pure individual factors) to obtain 1.7 g of the desired compound 14 (ABA-A-1).

Example 14

The connection 15 (ADA-A-1). (Compound of formula (I), where Y is - CONH-(CH2)3-N(CH3)2X is-Kil, corresponding to the complex factors of A 40926, M represents-D - mannopyranosyl and Z is - H).

A solution of 7 g (4 mmol) of the antibiotic complex A 40929, 2.5 ml (20 mmol) of 3,3-dimethylamino-1-Propylamine and 5.2 g (about 10 mmol) Py BOP in 70 ml of DMF was stirred at room temperature for 1 hour, then added 400 ml of ethyl acetate. Precipitated solid precipitate was collected and purified by chromatography with reversed phase (combining all fractions containing pure individual factors) to give 2.1 g of the desired compound 15 (ADA-A-1).

Example 15

The connection 16 (Py Ra-A-A-1). (Compound of formula (I), where Y is - CH2OH, X is - NH-(CH2)3- N(CH3)2, R1is - H, R2is (C9-C12)alkyl corresponding to the factors of the complex A 40926, M represents-D - mannopyranosyl and Z is P(NC4H8)3CH3COO< / BR>
R1is - H, R2is a (C9-C12)alkyl corresponding to the factors of the complex A 40926, M is a-D - mannopyranosyl and Z is - H).

Under stirring solution of 5 g of compound from example 1 (MA) in 60 ml of a mixture of DMF/DMSO 5/1, was added 0.3 ml of N-methyl-piperazine and 1.7 g Py BOP, Dubai solid precipitate was collected and purified column chromatography with reversed phase (combining all fractions, containing pure individual components) with 1.9 grams of the desired compound MA-A-4.

Example 17

Obtain compound 24 (RA-A-4). (Compound of formula (I), where Y is - CH2OH, X is a:

< / BR>
R1is - H, R2is a (C9-C12)alkyl corresponding to the factors of the complex A 40926, M represents-D-mannopyranosyl and Z is - H).

Applying the method described in example 16 above and in the same conditions, from 5 g RA obtained 2.7 g of the pure desired compound RA-A-4.

Column chromatography with reversed phase

Pure samples of the above compounds were obtained using column chromatography with reversed phase milanesiana silica gel (0,063 - 0.2 mm; Merck). The crude product (e.g., 0.5 g) was dissolved in minimum amount of a mixture of acetonitrile/water 1/1, then the pH of the solution was brought to 7 by using 1H NaOH and diluted solution of water before the formation of a turbid solution. Then added a few drops of acetonitrile with vigorous stirring. As soon as the solution became transparent, it was placed on a column silanizing silica gel (100 g) in water. Elution was performed with a linear gradient from 10 to 60% acetonitrile in 0.1 n were subjected to HPLC analysis. The fractions containing pure compound of formula (I), was chosen and, in those cases where the desired compound were the compounds of formula (I), where R2was a (C9-C12)-alkyl, the corresponding fractions of the complex A 40926, all fractions containing pure factors were combined and the solvents evaporated at 40oC under reduced pressure in the presence of n-butanol in order to avoid foaming.

In those cases, when the process for obtaining compounds of formula (I) of the antibiotic complex A 40926 was used to obtain the predecessor and the desired compound was individual factor amide compounds of formula (I), where R2matches one of the values that characterize the individual factors of the complex A 40926 (e.g., R2= 9-methyldecyl), then combined and subjected to the above processing, only those fractions, which according to HPLC contained the desired pure factor.

The identity and structure of each individual factor of the compounds according to the invention was determined by conducting HPLC analysis of each reaction product. Accordingly, a preliminary identification of the desired factor produced by comparing the HPLC fingerprints of compound A 40926 with prints n is 109, 1992) (in this work, the factor B0complex A 40926 called factor B).

HPLC analysis was performed on a column Hibar" (125 4 mm; Merck), pre-planted reagent "Li-Chrospher RP-8" (5 μm), using a liquid chromatograph Varian Model 5500 equipped with a variable UV detector. The chromatogram was recorded at 254 nm. Elution was performed with a linear step gradient from 20 to 60% acetonitrile in 0.2% aqueous ammonium formate for 30 min at a flow rate of 1.5 ml/min

Because in General all the complex compounds according to the invention give a typical HPLC fingerprints similar to the fingerprint of the corresponding precursor compound A 40926, individual factors of the compounds according to the invention, corresponding to the factors of the precursor complex of the A 40926, can be easily identified by correlation of the two spectrograms HPLC. Erwerbende fraction chromatograms with reversed phase, which includes the pure factors can be separated and processed as described above. To confirm the identity (C9-C12) alkyl chains, a sample of each fraction can evaporate as described above to obtain a product which can be subjected to gas-chromatography/mass-spectral. 5 shows the values of the retention time (tR) net factor of each of the compounds of formula (I) according to the invention, where R2is a 9-methyldecyl, i.e., corresponding to a factor B0complex A 40926 (these values were used during purification using chromatography with reversed phase).

In table. 5 shows also the values of tRfactor B0predecessor complex A 40926 and the corresponding essential source material (MA) obtained in the above-described conditions.

Illustrated below are the most significant chemical shift (Delta MMD) of some representative compounds.

Connection 1 (RA):

0,85, 1,13, 1,42, 1,98 (acyl chain); and 3.72 (CH2OH), 4,05-6,22 (peptidic CH's); to 6.43-charged 8.52 (aromatic protons and peptidic NH's).

Compound 2 (MA-A-1/B0):

0,83, 1,14, 1,38, 1,99 (acyl chain); 1,83, 2,83 (CH2- lateral chain), 2,73 (N(CH3)2); 4,11 - 6,10 (peptidic CH's); 6,48 - 9,50 (aromatic protons and peptidic NH's).

Connection 3 (RA-A-1/B0):

0,84, 1,14, 1,38, 1,92 (acyl chain); 1,72, 2,75 (CH2- side chain); 2,53 (N(CH3)2); 3,69 (CH2-OH); 4.09 to - 6,11 (peptidic CH's); 6,41 - 9,18 (aromatic protons and peptidic NH)

Compound 4 (MA-A-2/B0):

0,84, 1,1 P CLASS="ptx2">

Compound 5 (MA-A-3/B0):

0,85, 1,13, 1,42, represented 2.02 (acyl chain); 1,73, 2,82 (alkylamine chain); 2,42 (-N-CH3); 3,63 (COOCH3); 3,10 - 3,80 (sugar); 4,10 - 6,10 (peptidic CH's); 6,41 - charged 8.52 (aromatic protons and peptidic NH's).

Compound 7 (Py MA-A-1);

0,84, 1,13, 1,42, 2,01 (acyl chain); 1,83, 2,16 (dimethylpropyl-amide); 2,32 (HN-CH3); 1,70, 3,23 (pyrrolidin); 3,10 - 3,80 (sugar); 4,10 - 6,20 (peptidic CH's); 6,38 - 8,40 (aromatic protons and peptidic NH's).

Compound 9 (RA-A-2):

0,84, 1,13, 1,39, 1,98 (acyl chain); 1,88, 2,91 (alkylamine chain); 2,41 (HN-CH3); 3,10 - 3,80 (sugar); 4,10 - 6,10 (peptidic CH's); 6,38 - 8,49 (aromatic protons and peptidic NH's).

Compound 10 (RA-A-3):

0,84, 1,13, 1,39, 1,98 (acyl chain); 1,73, 2,82 (alkylamine chain); 2,47 (HN-CH3); 3,10 - 3,80 (sugar); 4,10 - 6,10 (peptidic CH's); 6,37 - 8,70 (aromatic protons and peptidic NH's); 9,2 was 1.04 (phenolic OH).

Compound 11 (A-A-1):

0,84, 1,13, 1,39, 2,00 (acyl chain); 1,74 - 2,79 (alkylamine chain); 2,37 (NH-CH3); 3,10 - 3,80 (sugar); 4,10 - 6,10 (peptidic CH's); 6,39 - 8,50 (aromatic protons and peptidic NH's).

Compound 12 (Py A-A-1):

0,84, 1,13, 1,42, represented 2.02 (acyl chain); 1,87, 2,73, 3,00 (dimethylpropylene); 2,48 (NH-CH3); 1,71, 3,30 (pyrrolidin); 3,10 - 3,80 (sugar); 4,10 - 6,25 (peptidic CH's); 6,38 - 8,55 (aromatic protons and peptidic NH's).

Compound 14 (ABA-A-1):

0,84, 1,13, 1,42, 1,96 (acyl chain); 2,35 [(CH-NH-)-CH3); 1,78, 2,70 (alkylamine chain); 3,10 - 3,80 (sugar); 4,10 - 6,10 (peptidic CH's); 6,37 - 8,50 (aromatic protons and peptidic NH's).

Compound 15 (ADA-A-1):

0,82, 1,13, 1,40, 1,98 (acyl chain); 2,50 (NH-CH3); 1,72, 1,85, 2,73, 3,00 (alkylamine chain); 3,10 - 3,80 (sugar); 4,10 - 6,10 (peptidic CH's); 6,40 - 8,55 (aromatic protons and peptidic NH's).

Compound 16 (Py RA-A-1): 0,84, 1,13, 1,41, 2,00 (acyl chain); 2,33 (NH-CH3); 1,82, 2,16 (dimethylpropylene); 1,71, 3,23 (pyrrolidin); 3,10 - 3,80 (sugar); 4,10 - 6,20 (peptidic CH), 6,38 - 8,40 (aromatic protons and peptidic NH's).

Compound 24 (RA-A-4):

0,84, 1,13 1,40, 1,97 (acyl chain); 2,10 (piperazine CH3); 2,38 (NH-CH3); 3,10 - 3,80 (sugar); 4,05 - 6,07 (peptidic CH's); 6,38 - 8,49 (aromatic protons and peptidic NH's).

Compound 25 (MA-A-4):

0,84, 1,13 1,40, 2,00 (acyl chain); 2,13 (piperazine CH3); 2,43 (NH-CH3); 3,10 - 3,80 (sugar); 3,63 (COOCH3); 4,05 - 6,09 (peptidic CH's); 6,38 - 8,49 (aromatic. protons and peptidic NH's).

31P-NMR spectra were taken at 161,98 MHz (compound 12) or 202,46 MHz (compounds 7 and 16) in DMSO-d6(the solution) with 85% H3PO4as NR is A Py-A-1) (31P): one signal at Delta 23,50 MMD

Compound 16 (Py PA-A-1) (31P): one signal at Delta 24,11 MMD

The composition for parenteral administration.

The composition is prepared by dissolving 100 mg of compound 3 (table. 1) in sterile water for injection (5 ml), brought to pH 4.5 to 5.5. Forms for parenteral administration of the compounds of the 5, 6, 8, 10, 13, 21 25, 26 and 31 is prepared in a similar manner using the same amount of the active substance and the carrier.

Ointment for local application

The connection 33 to 200 mg

Polyethylene glycol 4000 - 3-6 g

The polyethylene glycol 400 - 6.2 g,

1. A derivative of the antibiotic And 40926 General formula I

< / BR>
R1hydrogen, or a protective group of amino group;

R2- C9-C12alkyl;

M is hydrogen, -D-mannopyranosyl;

Y is carboxy, - C1-C4alkoxycarbonyl, aminocarbonyl, hydroxymethyl;

X - hydroxy - or amino residue of the formula

NR3-alK1-(NR4- alK2)p-(NR5- alK3)q-W,

where R3is hydrogen or C1-C4alkyl; alK1, alK2and alK3each independently represents a linear or branched alkylen2-C10; p and q are each 0 or 1;

lcyl, amino, C1-C4-alkylamino, di(C1-C4)-alkylamino, amino group, substituted by one or two amino(C2-C4)-alkyl groups, and if p and q equal to 0, then W, together with a fragment-NR3- alK1- represents piperazine derivatives - or 4-methylpiperazine provided that when X is hydroxy, Y is hydroxymethyl, Z is hydrogen or a group of the formula

< / BR>
where Athe anion of a mineral or organic acid, or their pharmaceutically acceptable salts connection.

2. A derivative of the antibiotic And 40926 under item 1, wherein R1is hydrogen or a protective group for the amino group, R2- C9-C12alkyl, M is hydrogen, -D-mannopyranosyl, Y is carboxy, aminocarbonyl or hydroxymethyl, X is a hydroxy - or amine residue formula

NR3-alK1-(NR4- alK2)p-(NR5- alK3)q-W,

where R3, R4and R5-hydrogens, alK1, alK2and alK3each independently represent a linear or branched alkylen2-C4p and q = 0 or 1, W is hydrogen, C1-C4alkyl, amino, C1-C4alkylamino, di(C1-C4)-alkylamino, amino group, substituted by one or two amino(C2-
< / BR>
where a-the anion of a mineral or organic acid or its pharmaceutically acceptable salt accession.

3. A derivative of the antibiotic And 40926 under item 1, wherein R2- C10-C11-alkyl, M - a-D-mannopyranosyl, R1X, Y and Z has a value under item 1 or its pharmaceutically acceptable salt accession.

4. A derivative of the antibiotic And 40926 under item 1, wherein R1is hydrogen or a protective group of amino group, R2- 9-methyldecyl, M is hydrogen or-D-mannopyranosyl, Y is carboxy, aminocarbonyl, hydroxymethyl, X is an amine residue of the formula

NR3-alK1-(NH-alK2)p-(NH-alK3)q-W,

where R3is hydrogen, alK1, alK2and alK3each independently a linear alkylene2-C4, p and q are each independently 0 or 1, W is amino, WITH1-C4alkylamino, di1-C4alkylamino, amino group, substituted by one or two amino (C2-C4)alkyl groups, or, when both p and q equal to 0, then W, together with a fragment-NR3-alK1- represents the piperazine derivatives - or 4-methylpiperazine, Z is hydrogen or pharmaceutical is the, what R1is hydrogen, R2- 9-methyldecyl, M-D-mannopyranosyl, Y is carboxy, aminocarbonyl, hydroxymethyl, X is an amine residue selected from-NH-(CH2)3-N(CH3)2-NH(CH2)3-[N-(CH2)3]-NH2, -NH-(CH2)3-N[(CH2)3NH2]2or Z is hydrogen, or its pharmaceutically acceptable salt accession.

6. A derivative of the antibiotic And 40926 under item 5, wherein R2-9-methyldecyl.

7. A derivative of the antibiotic And 40926 under item 5, wherein R2-9-methyldecyl, and R2, M, Y, X, and Z have values under item 5 or its pharmaceutically acceptable salt accession.

8. A derivative of the antibiotic And 40926 under item 5, wherein Y is hydroxymethyl, X is-NH-(CH2)3-N(CH3)2, R1R2, M, Z and a have the meanings specified in paragraph 5, or its pharmaceutically acceptable salt accession.

9. A derivative of the antibiotic And 40926 General formula I:

< / BR>
R1is hydrogen or a protective group of amino group;

R2- C10-C11alkyl;

M is hydrogen, -D-mannopyranosyl;

Y is hydroxymethyl;

X is hydroxy or amine residue-NR3-alK1-(NR4- alK2)p-(NR5- alK2-C10;

p and q are independently 0 or 1;

R4and R5independently hydrogen, C1-C4alkyl;

W is hydrogen, C1-C4alkyl, amino, C1-C4alkylamino, di(C1-C4)alkylamino, amino group, substituted by one or two amino (C2-C4) alkyl groups, provided that when X is hydroxy, Y is hydroxymethyl,

or its pharmaceutically acceptable salt accession.

10. The method of obtaining the derivative of the antibiotic And 40926 General formula I on p. 1, where R1, R2, M, Y, R3, p, q, R4, R5, W, Z, andhave the values listed in paragraph 1, or its pharmaceutically acceptable salt accession, characterized in that

a) in the case when X is an amine residue-NR3-alK1-(NR4- alK2)p-(NR5- alK3)q-W, a compound of General formula II

< / BR>
where R'1, R'2M' have the meanings indicated for R1, R2and M;

Y'-C1-C4alkoxycarbonyl;

X' is hydroxy,

subjected to amidation reaction with amine reagent of General formula III

-OTHER3-alK1-(NR4- alK2)p-(NR5- alK3)q-W,

where R3, R4, R5, alKand by the formation of the activated ester in63-carboxylic acids and

i do not necessarily derived formula I, where Y'-C1-C4alkoxycarbonyl, and R1- protective group of amino group, and all other radicals have the above meanings, is subjected to the repair using a borohydride of an alkali metal and possibly a protective group of the amino group is removed to obtain compound I, where Y is hydroxymethyl and R1is hydrogen;

ii) optional derived formula I, where Y1-C4alkoxycarbonyl or hydroxymethyl and R1- protective group for the N15amino group, R2, M, Z have the above meanings, X is an amine residue-NR3-alK1-OTHER4where R3and R4each independently hydrogen or C1-C4-alkyl, alK1have the above meanings; or is a residue-NR3-alK1- alK2-OTHER5where R3, R4and R5each independently hydrogen or (C1-C4) alkyl, alK1and alK2have the above values, alkylate with amine reagent of the General formula IV or A:

r-alK2-(NR5-alK3)q-W, IY

r-alK2-W, W

where R5, alK2, alK3and W have the above values,

q = 0 or 1;

r is a protective group at the N15remove;

iii) optionally derived formula I, where Y1-C4alkoxycarbonyl and all the other radicals have the above values, treated with an aqueous alkali metal hydroxide to obtain the corresponding compound I, where Y is carboxy;

d) in cases when the target compound is a derivative of the formula I, where R1, R2, M, Z have the values listed in the beginning of this paragraph, and Y and COX are different carboxamide residues, and Y - aminocarbonyl, X - amine residue-NR3-alK1-(NR4-alK2)p-(NR5-alK3)-W, where R3, R4, R5, alK1, alK2, alK3, p, g, and W have the above values, the derived formula I, where R1, R2, M and Z have the above meanings, and X is an amine residue-NR3-alK1-(NR4-alK2)p-(NR5-alK3)q-W, where R3, R4, R5, alK1, alK2, alK3, p, g, and W have the above meanings and Y is carboxy, subjected to amidation appropriate amine to form the above carboxamide residue Y in the presence of a condensing agent.

11. The method according to p. 10, characterized in that alapaha, choose from diphenylphosphide at a temperature of 0 - 20oC .

12. The method according to p. 10, wherein the amidation on the steps a), d (i) is carried out by converting the carboxylic source derivative of the formula II into the corresponding activated ester, preferably containing a protective group at the N15amino group, with the subsequent interaction of this activated ester with a molar excess of amine of formula III in the presence of a polar organic solvent at a temperature 5 - 60oC, preferably 10 - 30oC.

13. The method according to p. 12, wherein the activated ester is cinematology ether at a molar ratio of the ester to amine of formula III is 1 : 5 to 1 : 30.

14. The method according to p. 13, characterized in that cinematology ether is produced by the interaction of the original carboxylic acid of the formula II containing a protective group at the N15amino group, with 20 - to 30-fold excess of chloroacetonitrile in the presence of an inert organic solvent and the substrate that does not react at a temperature of 10 - 30oC.

15. The method according to p. 10, characterized in that stage a) molar ratio of alkali metal borohydride to the compound of formula II is jut from dimethylformamide or dimethyl sulfoxide.

17. The method according to p. 12, wherein the polar organic solvent selected from lower alkanols, dimethylformamide, dimethyl sulfoxide.

18. The method according to p. 15, wherein the borohydride of an alkali metal selected from sodium borohydride, and the solvent is a mixture of water and water-soluble lower alkanol.

19. The method according to p. 10, characterized in that the protective group at the N15is tert. butoxycarbonyl group, which at the end of the amidation reaction are removed.

20. The method of obtaining the derivative of the antibiotic under item 9., characterized in that (a) to obtain compound I, where Y is hydroxymethyl, X is hydroxy, R1, R2and M have the meanings specified in paragraph 9, the compounds of formula II

< / BR>
X is hydroxy;

Y' -C1-C4-alkoxycarbonyl;

R11the corresponding protective group of amino group,

restore the alkali metal borohydride, preferably sodium borohydride, at a temperature 0 - 40oC in aqueous-alcoholic medium with the subsequent removal of the protective group.

21. Pharmaceutical komposizia having antibacterial activity comprising an effective amount of the active ingredient, pharmac is it a connection on p. 1.

22. Connection PP.1 to 9, with antibakterialnye properties.

Priority points:

29.07.91 - PP.1 - 22, except for values of R2- C9-C12-alkyl, Y is carboxy, aminocarbonyl, Z is a group W together with a fragment NR3-alK1-piperazine derivatives or 4-methylpiperazine, when p and q are 0;

12.06.92 - PP.1 - 22.

 

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