New depsipeptides and methods of their obtainment

FIELD: chemistry.

SUBSTANCE: invention concerns new depsipeptide compounds, as well as pharmaceutical compositions of these compounds and application of the compounds as antibacterial compounds.

EFFECT: methods of obtaining the new depsipeptide compounds and intermediary products applied in obtaining these compounds.

31 cl, 3 tbl, 25 ex

 

Cross-reference to related applications

This application claims the priority of application of the United States No. 60/310313, filed August 6, 2001, which is hereby incorporated here in its entirety by reference.

The technical field to which the invention relates.

The present invention relates to a new depsipeptide compounds. The invention also relates to pharmaceutical compositions based on these compounds and to methods of using these compounds as antibacterial agents. The invention also relates to methods of producing these new depsipeptide compounds and intermediate products used to produce these compounds.

Prior art

The rapid increase in cases of gram-positive infections, including caused by resistant bacteria, re-awakened interest in the development of new classes of antibiotics. A class of compounds that has shown itself as a potential antibiotic agents are cyclic depsipeptide. A notable member of the cyclic depsipeptides are lipopetides A-21978C described, for example, in United States patents RE 32333; RE 32445; RE 32311; RE 32310; 4482487; 4537717 and 5912226 and in international patent applications WO 01/44272; WO 01/44274 and WO 01/44271. In addition, the class A54145 compounds described in patents United W is the ATA 4994270; 5039789 and 5028590, also, as shown, has antibiotic activity.

Daptomycin, also known as LY 146032, includes n-technology a side chain that is connected with the N-terminal tryptophan chain of three amino acids, connected with a cyclic peptide of 10 amino acids. Daptomycin has a strong antibacterial activity in vitro and in vivo against clinically significant gram-positive bacteria that cause serious and life-threatening diseases. These bacteria include resistant pathogens such as vancomycin-resistant enterococci (VRE), methicillin-resistant Staphylococcus aureus (MRSA), are susceptible to the intermediate product glycopeptide Staphylococcus aureus (GISA), vancomycin-resistant Staphylococcus aureus (to the VRSA), negative against coagulase staphylococci (CNS) and are resistant to penicillin Streptococcus pneumoniae (PRSP), for which there are very few therapeutic alternatives. See, for example, Tally et al., 1999, Exp. Opin. Invest. Drugs 8:1223-1238.

Despite the prospects that are associated with existing antibacterial agents, there remains a need for new antibiotics. Many pathogens re-exhibited with commonly used antibiotics. This exposure led to the selection of variants of antibacterial strains resistant to broad spectrum antibiotics. Loss of strength and effectiveness of the antibiotic is defined by the occurrence of mechanisms of resistance, leads to the ineffectiveness of the antibiotic and, therefore, can lead to some life-threatening infections that are resistant to treatment. Once on the market new antibiotics, pathogens may develop resistance or transition resistance to these new drugs, effectively creating the need for the flow of new antibacterial agents for combating the emerging strains. In addition, compounds that exhibit bactericidal activity, have advantages compared to currently available bacteriostatic compounds. Thus, we should expect that new antibacterial agents will be suitable for impact not only on the "natural" pathogens, but also pathogens transition resistance and resistant pathogens, because the pathogen has never been exposed with a new antibacterial agent. New antibacterial agents may have different effectiveness against different types of pathogens.

A brief statement of the substance of the invention

In the present invention proposed new compounds that possess antibacterial activity against a broad spectrum of bacteria, including drug-resistant bacteria, and methods for producing such compounds.

In the present invention offer the I in one aspect, the compounds of formula

and their salts;

where

(a) R is a 2-butyl, isopropyl or 2-(2'-aminopentyl);

(b) each of R1and R6independently represents hydrido or methyl;

(c) R2represents methyl or-CH2CH2CH2R8;

(d) R3represents methyl or-CH2CH2CH2CH2R9;

(e) R4represents hydrido or methoxy;

(f) R5represents hydroxy or carboxamido;

(g) each of R7, R8and R9independently represents an amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbarnoyl, sulfonamide, thioacetamide, touraid, minamino or postonline;

(h) provided that

(1) when R2represents-CH2CH2CH2R8, R7is different from the

where R10represents amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbarnoyl, sulfonamide, thioacetamide, minamino or postonline;

(2) when R2represents methyl, R7is different from the

where each of R11and R12represents hydrido, C6-C18the unsubstituted alkanoyl, C8-Csub> 18the unsubstituted alkenyl, C8-C18unsubstituted alkyl or C8-C18selected substituted alkyl; or alternatively R11and R12together represent a C8-C18alkylidenes.

In another aspect, the present invention relates to pharmaceutical compositions containing the compounds of formula I, and methods of use thereof.

In an additional aspect, the present invention relates to a method of preparing compounds of formula I.

In another aspect the present invention relates to compounds useful as intermediates for preparing compounds of formula I.

Detailed description of the invention

Definition

The term "activating group" refers to a group, which when joined to a carbonyl group activates the carbonyl group to influence her nucleophilic amine, which leads to loss of the activating group and the formation of amide linkages. Examples of activating groups are aryloxy, acyloxy, imidazolyl

Preferred activating groups are alloctype. The most preferred activating group is Pantothenate.

The term "acyl" denotes a carbonyl radical attached to an alkyl, alkenyl, quinil, cycloalkyl, heterocyclyl is, aryl or heteroaryl group, and examples include without limitation such radicals, such as acetyl and benzoyl. The term acyl is divided into (1) "the unsubstituted alkanoyl", which is defined as a carbonyl radical attached to an unsubstituted alkyl group, and (2) "the unsubstituted alkanoyl", which is defined as a carbonyl radical attached to the unsubstituted alkenylphenol group.

The term "acylamino" denotes a nitrogen radical, attached to the acyl group.

The term "acyloxy" denotes an oxygen radical attached to the acyl group.

The term "alkenyl" is defined as linear or branched radicals having two to about twenty carbon atoms, preferably three to about ten carbon atoms, and containing at least one carbon-carbon double bond. One or more hydrogen atoms may also be replaced by a Deputy selected from acyl, acylamino, acyloxy, alkenyl, alkoxy, alkyl, quinil, amino, aryl, aryloxy, carbamoyl, carbalkoxy, carboxy, carboxamido, carboxamido, cyano, disubstituted amino, formyl, guanidino, halogen, heteroaryl, heterocyclyl, hydroxy, minamino, monosubstituted amino, nitro, oxo, fastonline, sulfinil, sulfonamide, sulfonyl, thio, thioacetamide, toridori ureido. Double(s) link(s) unsaturated hydrocarbon chain can be either CIS or TRANS configuration. Examples alkenyl groups include, without limitation tylenil or phenylethylene. The term of alkenyl subdivided into "unsubstituted of alkenyl", which is defined as alkenylphenol group that does not have a Deputy.

The term "alkoxy" denotes an oxygen radical, substituted alkyl, cycloalkyl or heterocyclyl group. Examples include without limitation, methoxy, tert-butoxy, benzyloxy, cyclohexyloxy.

The term "alkyl" is defined as a linear or branched radical having from one to about twenty carbon atoms, unless otherwise specified. The term "lower alkyl" is defined as an alkyl group containing 1-4 carbon atoms. One or more hydrogen atoms can be replaced by substituents selected from acyl, acylamino, acyloxy, alkenyl, alkoxy, alkyl, quinil, amino, aryl, aryloxy, carbamoyl, carbalkoxy, carboxy, carboxamido, carboxamido, cyano, disubstituted amino, formyl, guanidino, halogen, heteroaryl, heterocyclyl, hydroxy, minamino, monosubstituted amino, nitro, oxo, fastonline, sulfinil, sulfonamide, sulfonyl, thio, thioacetamide, touraid or ureido. Examples of alkyl groups include without limitation methyl, butyl, tert-BU the sludge, isopropyl, trifluoromethyl, nonyl, undecyl, octyl, dodecyl, methoxymethyl, 2-(2'-aminopentyl), 3-indolylmethane, benzyl and carboxymethyl. The term alkyl is divided into (1) "unsubstituted alkyl", which is defined as an alkyl group which has substituents, (2) "substituted alkyl", which denotes an alkyl radical in which one or more hydrogen atoms replaced by a Deputy selected from acyl, acylamino, acyloxy, alkenyl, alkoxy, alkyl, quinil, amino, aryl, aryloxy, carbamoyl, carbalkoxy, carboxy, carboxamido, carboxamido, cyano, disubstituted amino, formyl, guanidino, halogen, heteroaryl, heterocyclyl, hydroxy, minamino, monosubstituted amino, nitro, oxo, fastonline, sulfinil, sulfonamide, sulfonyl, thio, thioacetamide, touraid or ureido, and (3) "selected substituted alkyl", which denotes an alkyl radical, in which (a) one proton is replaced by a group selected from hydroxy, carboxy, C1-C8alkoxy or (b) from one to three protons are replaced by halogen.

The term "alkylidene" is defined as the carboxylic radical of the formula

where Rxand Rx1independently selected from hydrido or C7-C17unsubstituted alkyl, where the total number of carbon atoms, Rxand Rx1does not exceed 17.

Those who min "quinil" denotes linear or branched radicals, containing from two to about ten carbon atoms and containing at least one carbon-carbon triple bond. One or more hydrogen atoms may also be replaced by a substituent selected from acyl, acylamino, acyloxy, alkenyl, alkoxy, alkyl, quinil, amino, aryl, aryloxy, carbamoyl, carbalkoxy, carboxy, carboxamido, carboxamido, cyano, disubstituted amino, formyl, guanidino, halogen, heteroaryl, heterocyclyl, hydroxy, minamino, monosubstituted amino, nitro, oxo, fastonline, sulfinil, sulfonamide, sulfonyl, thio, thioacetamide, touraid or ureido. Example alkenylphenol group includes without limitation PROPYNYL.

The term "amino" is defined as NH2the radical.

The term "amino acid residue" refers to a compound of the formula

where Raarepresents the side chain of amino acids.

The term "side chain of amino acid" refers to any side chain (R group) existing in nature or synthetic amino acids. For example, 3-indoleacetic could also be called the side chain of tryptophan.

The term "2-(2'-AMINOPHENYL)" refers to a radical of the formula

The term "aminosidine group" refers to any chemical compound that can be used is about, to prevent chemical reaction of the amino group of the molecule, while in another portion of the molecule is a chemical change. Specialists in the art will know of many aminosidine group, and examples can be found in "Protective Groups in Organic Synthesis" by Theodora W. Greene, John Wiley and Sons, New York, 1981. Examples aminosidine groups include phthalimido, trichloroacetyl, STA-base, benzyloxycarbonyl, tert-butoxycarbonyl, tert-aryloxyalkyl, isobornylacitate, adamantanecarbonyl, chlorobenzenesulfonyl, nitrobenzisoxazole and the like. Preferred aminosidine groups are urethane aminosidine groups", which are defined as aminosidine group, which upon binding to the amino group to form a carbamate. Preferred aminocarnitine protective groups are allyloxycarbonyl (alloc), carbobenzoxy (CBZ) and tert-butoxycarbonyl protective group.

The term "aryl" or "aryl ring" denotes an aromatic radical in single or condensed carbocyclic ring system containing from five to fourteen ring members. In a preferred implementation, the ring system contains from six to ten members of the ring. One or more hydrogen atoms may also be replaced by a Deputy selected from acyl, the acyl is Mino, acyloxy, alkenyl, alkoxy, alkyl, quinil, amino, aryl, aryloxy, azido, carbamoyl, carbalkoxy, carboxy, carboxamido, carboxamido, cyano, disubstituted amino, formyl, guanidino, halogen, heteroaryl, heterocyclyl, hydroxy, minamino, monosubstituted amino, nitro, oxo, fastonline, sulfinil, sulfonamide, sulfonyl, thio, thioacetamide, touraid or ureido. Examples of aryl groups include, without limitation phenyl, naphthyl, biphenyl, terphenyl.

The term "aryloxy" means containing oxy-containing radicals, substituted aryl or heteroaryl group. Examples include, without limitation, phenoxy.

The term "carbarnoyl" denotes a nitrogen radical of the formula

where Rx2selected from hydrido, alkyl, aryl, cycloalkyl, heteroaryl or heterocyclyl, and Rx3selected from alkyl, aryl, cycloalkyl, heteroaryl or heterocyclyl.

The term "carbalkoxy" is defined as a carbonyl radical attached to the alkoxy or alloctype.

The term "carboxy" refers to a radical COOH.

The term "carboxamido" refers to a radical CONH2.

The term "carboxamido" denotes a carbonyl radical attached to a monosubstituted or disubstituted amino group.

The termα-carboximetilna side chain" refers to carbon, R is dical formula

where Rx4is defined as the side chain of amino acids.

The term "carboxymethyl" refers to a radical, CH2CO2H.

The term "cycloalkyl" or "cycloalkyl ring" means a saturated or partially unsaturated carbocyclic ring in single or condensed carbocyclic ring system containing from three to twelve ring members. In the preferred implementation of cycloalkyl represents a ring system containing from three to seven members in the ring. One or more hydrogen atoms may also be replaced by a Deputy selected from acyl, acylamino, acyloxy, alkenyl, alkoxy, alkyl, quinil, amino, aryl, aryloxy, carbamoyl, carbalkoxy, carboxy, carboxamido, carboxamido, cyano, disubstituted amino, formyl, guanidino, halogen, heteroaryl, heterocyclyl, hydroxy, minamino, monosubstituted amino, nitro, oxo, fastonline, sulfinil, sulfonamide, sulfonyl, thio, thioacetamide, touraid or ureido. Examples cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclohexyl and cycloheptyl.

The term "disubstituted amino" refers to aminoacyl containing two substituting groups, independently selected from alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl. Preference is sustained fashion disubstituted by aminosalicylate are "lower disubstituted amino" radicals, where the substituting group are lower alkilani. Also preferred disubstituted by aminosalicylate are aminosalicylic in which one Deputy is a lower alkyl group, and the other Deputy is a side chain α-carboxymethylate.

Group "Fmoc" represents 9-fluorenylmethoxycarbonyl group.

The term "guanidino" denotes a nitrogen radical of the formula

where each of Rx5, Rx7and Rx8independently selected from hydrido, alkyl, aryl, cycloalkyl, heteroaryl or heterocyclyl group; and Rx6selected from alkyl, aryl, cycloalkyl, heteroaryl or heterocyclyl group. The term "halogen" refers to a radical of bromine, chlorine, fluorine or iodine.

"Heteroaryl" or "heteroaryl ring" means an aromatic radical which contains from one to four heteroatoms or heterogroup selected from O, N, S, or SO, in single or condensed heterocyclic ring system containing from five to fifteen ring members. In the preferred implementation of the heteroaryl ring system contains from six to ten ring members. One or more hydrogen atoms may also be replaced by a Deputy selected from acyl, acylamino, acyloxy, alkenyl, Alcock and, of alkyl, quinil, amino, aryl, aryloxy, carbamoyl, carbalkoxy, carboxy, carboxamido, carboxamido, cyano, disubstituted amino, formyl, guanidino, halogen, heteroaryl, heterocyclyl, hydroxy, minamino, monosubstituted amino, nitro, oxo, fastonline, sulfinil, sulfonamide, sulfonyl, thio, thioacetamide, touraid or ureido. Examples of heteroaryl groups include, without limitation pyridinoline, thiazolidine, thiadiazolidine, athinodorou, pyrazolidine, oxazolidine, oxadiazoline, triazolyl and pyrrolidino group.

The term "heterocyclyl", "heterocyclic" or "heterocyclyl ring" means a saturated or partially unsaturated ring containing from one to four heteroatoms or heterogroup selected from O, N, NH, N(lower alkyl), S, SO or SO2in single or condensed heterocyclic ring system containing from three to twelve ring members. In the preferred implementation heterocyclyl represents a ring system containing from three to seven ring members. One or more hydrogen atoms may also be replaced by a Deputy selected from acyl, acylamino, acyloxy, alkenyl, alkoxy, alkyl, quinil, amino, aryl, aryloxy, carbamoyl, carbalkoxy, carboxy, carboxamido, carboxamido, cyano, disa is EDINOGO amino, of formyl, guanidino, halogen, heteroaryl, heterocyclyl, hydroxy, minamino, monosubstituted amino, nitro, oxo, fastonline, sulfinil, sulfonamide, sulfonyl, thio, thioacetamide, touraid or ureido. Examples of heterocyclic groups include, without limitation, morpholinyl, piperidinyl and pyrrolidinyl.

The term "hydrido" denotes a single hydrogen atom (H).

The term "minamino" denotes a nitrogen radical of the formula:

where Rx9and Rx11independently selected from hydrido, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl group; and Rx10selected from alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl group.

The term "modifying agent" is defined as (a) nucleophilic acceptor or (b) an aldehyde or ketone which reacts with the amine under the conditions of recovery with the formation of the alkylated amine.

The term "monosubstituted amino" means aminoacyl containing peridogram and substituting group selected from alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl. Preferred monosubstituted by aminosalicylate are "lower monosubstituted amino" radicals, where the substituting group is a lower alkyl group. More preferred monosubstituted of aminor what calami are aminosalicylic, containing side chain α-carboxymethylate.

The term "nucleophilic acceptor" refers to a compound which is susceptible to nucleophilic attack of a primary or secondary amine. Examples of nucleophilic acceptors include, without limitation isocyanates, isothiocyanates, activated esters, acid anhydrides, sulphonylchloride activated sulfonamides, activated heterocycles, activated heteroaryl, chloroformiate, cyanoformate, thioethers, phosphorylchloride, phosphoramidate, imidate and lactones.

The term "postonline" denotes a nitrogen radical of the formula:

where Rx12selected from hydrido, alkyl, aryl, cycloalkyl, heteroaryl or heterocyclyl; where each of Rx13and Rx14independently selected from alkyl, alkoxy, aryl, aryloxy, cycloalkyl, heteroaryl and heterocyclyl.

The term "sulfinil" denotes a tetravalent radical of sulfur, substituted Deputy oxo and second Deputy selected from the group comprising alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group.

The term sulfonamide denotes aminoacyl formula:

where Rx15selected from hydrido, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl group; and Rx16you are the wounds of alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl group.

The term "sulfonyl" refers to a radical of hexavalent sulfur, substituted with two oxo substituents, and the third substituent is selected from alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.

The term "thio" refers to a radical containing a replacement group, independently selected from hydrido, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl attached to the divalent sulfur atom, such as methylthio, phenylthio.

The term "thioacetamide" means aminoacyl formula

where Rx17selected from hydrido, alkyl, aryl, cycloalkyl, heteroaryl or heterocyclyl group; and where Rx18selected from alkyl, aryl, cycloalkyl, heteroaryl or heterocyclyl group.

The term "touraid" refers to a sulfur radical of the formula:

where each of Rx19and Rx20independently selected from hydrido, alkyl, aryl, cycloalkyl, heteroaryl or heterocyclyl group; and Rx21selected from alkyl, aryl, cycloalkyl, heteroaryl or heterocyclyl group.

Triticina group is triphenylmethyl group.

The term "ureido" denotes a nitrogen radical of the formula

where each of Rx21and Rx22independently selected from hydrido, alkyl, aryl, cycloalkyl, heteroaryl or heterocyclyl group; and Rx23selected from alkyl, aryl, cycloalkyl, heteroaryl or heterocyclyl group.

Salts of the compounds according to the invention include additive salt and acid additive salts of the bases. In the preferred implementation of the salt is a pharmaceutically acceptable salt of the compounds of formula I. the Term "pharmaceutically acceptable salts" embraces salts and is used to denote salts of alkali metals and denote the additive salts of free acids or free bases. The nature of salt is not the limiting factor in the case, if it is pharmaceutically acceptable. Suitable pharmaceutically acceptable additive, acid salts of the compounds according to the invention can be derived from inorganic acids or organic acids. Examples of such inorganic acids include, without limitation, hydrochloric, Hydrobromic, yodiewonderdog, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from the classes of aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic and organic sulfonic acids, examples of which which include, without limitation formic, acetic, propionic, succinic, glycolic, gluconic, maleic, ambalavao (Paveway) acid, methanesulfonate, econsultation, 2-hydroxyethanesulfonic, Pantothenic acid, benzosulfimide, toluensulfonate, sulfanilic, mailovou acid, cyclohexanesulfonic, stearic, alginic, β-hydroxybutiric, malonic, galactogogue and galacturonic acid. Suitable pharmaceutically acceptable additive salts of the bases of the compounds according to the invention include, but are not limited to, metal salts, derivatives of aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts, derivatives of N,N'-dibenziletilendiaminom, chloroprocaine, choline, diethanolamine, Ethylenediamine, N-methylglucamine, lysine and procaine. All of these salts may be obtained using conventional methods from the corresponding compounds according to the invention by processing, for example, the compounds according to the invention with a suitable acid or base. Compounds according to the invention can contain one or more asymmetric carbon atoms and thus can exist as optical isomers, as well as their racemic or narramissic mixtures. Compounds according to the invention can be used in the present invention in the form of a single isomer or as a mixture of stereochemical from hernych forms. Diastereoisomer, i.e. not imposed stereochemical isomers, can be separated by conventional means such as chromatography, distillation, crystallization or sublimation. The optical isomers can be obtained by separation of racemic mixtures by conventional means, for example, through education diastereoisomeric salts in the processing of optically active acid or base. Examples of suitable acids include, without limitation wine, diatsetilvinny, dibenzoyltartaric, detailview and camphorsulfonate. The mixture of diastereomers can be separated by crystallization, followed by the separation of the optically active bases from optically active salts. An alternative method of separation of optical isomers involves the use of chiral chromatography column optimally chosen to maximize the separation of enantiomers. Another method involves synthesis of covalent diastereoisomeric molecules by reacting compounds according to the invention with an optically pure acid in an activated form or an optically pure isocyanate. Synthesized diastereoisomer can be separated by conventional methods such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to obtain enantiomerically pure compounds. Optically active compounds of p. the invention can also be obtained by using optically active starting materials. These isomers can be in the form of the free acid, free base, complex, ester or salt.

The invention also relates to selected compounds. Dedicated connection refers to a connection that is at least 10%, preferably at least 20%, more preferably at least 50% and most preferably at least 80% of the compound present in the mixture. In a preferred implementation, the compound, its pharmaceutically acceptable salt or pharmaceutical composition comprising the compound, are defined (i.e. statistically significant) antimicrobial activity in the study using conventional biological methods, such as described here.

Depsipeptide compounds

In one aspect the invention relates to a compound of formula I

and its salts;

where (a) R is a 2-butyl, isopropyl or 2-(2'-aminopentyl);

(b) each of R1and R6independently represents hydrido or methyl;

(c) R2represents methyl or-CH2CH2CH2R8;

(d) R3represents methyl or-CH2CH2CH2CH2R9;

(e) R4represents hydrido or methoxy;

(f) R5represents a hydroxy or carboxy is Mino;

(g) each of R7, R8and R9independently represents an amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbarnoyl, sulfonamide, thioacetamide, touraid, minamino or postonline;

(h) provided that,

(1) when R2represents-CH2CH2CH2R8, R7is different from the

where R10represents amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbarnoyl, sulfonamide, thioacetamide, touraid, minamino, fastonline;

(2) when R2represents methyl, R7is different from the

where each of R11and R12represents hydrido, C6-C18the unsubstituted alkanoyl, C8-C18the unsubstituted alkenyl, C8-C18unsubstituted alkyl or C8-C18selected substituted alkyl; or alternatively R11and R12together represent a C8-C18alkylidenes.

Preferably, R7represents a

where each of Raa, Raa2and Raa3independently represents a side chain of amino acids, where R13represents amino, monosubstituted amino, disubstituted and the Ino, acylamino, ureido, guanidino, carbarnoyl, sulfonamide, thioacetamide, touraid, minamino or postonline.

In one implementation of the invention, R represents a 2-(2'-aminopentyl); each of R1and R4represents hydrido; R2represents-CH2CH2CH2R8; each of R3and R6represents methyl; and R5represents hydroxyl. In this implementation serves the compound of formula II.

In another implementation of the invention, R represents isopropyl or 2-butyl; each of R1and R2represents methyl; R3represents - CH2CH2CH2CH2R9; each of R4represents methoxy, and R5represents carboxamido. In this implementation serves the compound of formula III.

where R14represents hydrido or methyl.

Table I presents typical compounds of formula II.

Table I

The compounds of formula II

where R7**represents amino, monosubstituted amino, disamis the config amino, acylamino, ureido, guanidino, carbarnoyl, sulfonamide, thioacetamide, touraid, minamino or fastonline and each of Raa4, Raa5and Raa6independently represents a side chain of amino acids.

Table II presents the typical compounds of formula III.

Table II

The compounds of formula III

where R7**represents amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbarnoyl, sulfonamide, thioacetamide, touraid, minamino or fastonline and each of Raa4, Raa5and Raa6independently represents a side chain of amino acids.

Intermediate products

The present invention also provides compounds of formula IV, which are particularly suitable as intermediates for producing compounds of formula I.

and their salts;

where

(a) R is a 2-butyl, isopropyl or 2-(2'-aminopentyl);

(b) each of R1and R6independently represents hydrido or methyl;

4represents hydrido or methoxy;

(d) R5represents hydroxy or carboxamido;

(e) R15represents hydrido,

where R18represents amino or hydroxy; R19represents hydrido or hydroxy; and R20represents carboxamido or carboxymethyl

(f) R16represents methyl or-CH2CH2CH2R21;

(g) R17represents methyl or-CH2CH2CH2CH2R22;

where each of R21and R22independently represents an amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbarnoyl, sulfonamide, thioacetamide, touraid, minamino or postonline.

In a preferred implementation of the invention, each of R21and R22is an-other23where R23represents aminosidine group. In a more preferred implementation of the invention R23is a urethane aminosidine group selected from allyloxycarbonyl, carbobenzoxy and tert-butoxycarbonyl. In the most preferred implementation of R23is allyloxycarbonyl.

In a more preferred implementation of the present invention proposed elapsed is cnie products of formula V, VI, VII, VIII, IX and X, which are particularly suitable as intermediates for producing compounds of formula I.

where R6and R14are already defined.

where R6and R14are already defined.

where R6and R14are already defined.

Pharmaceutical compositions and their uses

In the present invention proposed pharmaceutical composition or compositions comprising the compounds of formula I or their salts.

Compounds of the present invention, preferably, the compounds of formula I, or their pharmaceutically acceptable salts can be included in the composition for oral, intravenous, intramuscular, subcutaneous or parenteral administration for therapeutic or prophylactic treatment of diseases, particularly bacterial infections. For oral or parenteral administration of the compounds of the present invention can be mixed with commonly used pharmaceutical carriers and excipients and can be applied in the form of tablets, capsules, elixirs, suspensions, syrups, about the patches and the like. Compositions comprising a compound of this invention should contain from about 0.1 to about 99% by weight of active compound, and more usually from about 10 to about 30%.

Described here pharmaceuticals receives in accordance with standard procedures and injected in doses that are selected to reduce, prevent, or destroy the infection (see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA and Goodman and Gliman''s The Pharmaceutical Basis of Therapeutics, Pergamon Press, New York, NY, the contents of which are incorporated herein by reference for a General description of how the introduction of various antimicrobial agents for treatment of humans). Compositions of the present invention, preferably, the compounds of formula I, can be delivered using delivery systems with controlled (e.g., capsules) or supported (e.g., biodegradable matrices) release. Typical delivery systems with delayed release for drug delivery that are suitable for administration of the compositions of the invention, preferably of the formula I, are described in U.S. patent No. 4452775 (the owner of the patent Kent), 5239660 (Leonard), 3854480 (Zaffaroni).

Pharmaceutically acceptable kompoziciia of the present invention contain one or more compounds according to the invention, preferably, the compounds of formula I, in combination the one or more non-toxic pharmaceutically acceptable carriers and/or diluents, and/or adjuvants and/or excipients, collectively referred to here as the substance of the "carrier", and, if desired, other active ingredients. The composition may contain conventional carriers and excipients, such as corn starch or gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid. The composition may contain croscarmellose sodium, microcrystalline cellulose, corn starch, sodium salt glycolate starch and alginic acid.

Binding agents that can be included in the tablets are gum, methylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone (Povidone), hypromellose, sucrose, starch and ethylcellulose.

Lubricating agents which can be used include magnesium stearate or other metallic stearates, stearic acid, silicone fluid, talc, waxes, oils and colloidal silicon dioxide.

Can also be used flavoring agents such as peppermint, oil of simalube, cherry flavoring or the like. It may also be desirable to add a coloring agent to obtain a more aesthetic in appearance dosage forms or for assistance in identifying the product.

For oral administration, particularly suitable is s solid formulations such as tablets and capsules. Can also be applied to drugs with a supported release or drugs covered for absorption in the intestine. For use in Pediatrics and geriatrics are particularly suitable suspensions, syrups and chewable tablets. For oral administration the pharmaceutical compositions may be in the form of, for example, tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of standard dosage forms containing a therapeutically effective amount of the active ingredient. Examples of such dosage forms are tablets and capsules. For therapeutic purposes, the tablets and capsules may contain, in addition to the active ingredient, conventional carriers such as binding agents, for example, Arabian gum, gelatin, polyvinylpyrrolidone, sorbitol or tragakant; fillers, for example, calcium phosphate, glycine, lactose, maize starch, sorbitol, or sucrose; and lubricating agents, e.g. magnesium stearate, polyethylene glycol, silicon dioxide or talc; loosening agents, for example, potato starch, flavouring or colouring agents, or acceptable moisturizing agents. Oral liquid preparations are usually in the form of aqueous or oily solutions, suspensions, emulsions, syrups or e is of Kirov, and may contain conventional additives such as suspendresume agents, emulsifying agents, non-aqueous agents, preservatives, coloring agents and flavoring agents. Examples of additives for liquid preparations include gum, almond oil, ethyl alcohol, fractionated coconut oil, gelatin, glucose syrup, glycerin, hydrogenated edible fats, lecithin, methylcellulose, methyl or propyl para-hydroxybenzoate, propylene glycol, sorbitol or sorbic acid.

For intravenous (IV) use of the compound of the present invention can be dissolved or suspended in any of the commonly used intravenous fluids and introduced by infusion. Intravenous fluids include, without limitation, saline solution or ringer's solution. Intravenous administration can be carried out using, without limitation syringe, minipump or intravenous system.

Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile solutions or suspensions for injection. These solutions or suspensions can be obtained from sterile powders or granules having one or more carriers mentioned for use in the formulations for oral administration. The compounds may be dissolved in polyethylene glycol, PR is pillarlike, ethanol, corn oil, benzyl alcohol, sodium chloride and/or various buffers.

For intramuscular preparations, a sterile composition of the present invention or a suitable soluble salt form of the compounds, for example, cleaners containing hydrochloride salt, can be dissolved and put in a pharmaceutical diluent such as water for injection (WFI), physiological saline or 5% glucose. A suitable insoluble form of connection can be obtained and put into suspension in water, or in pharmaceutically acceptable oil-based, for example, ester of fatty acid with a long chain, such as etiloleat.

The dose intravenous, intramuscular or parenteral composition of the present invention can be introduced in the form of a bolus or by slow infusion. The bolus is a standard dosage form, which is injected in less than 30 minutes. In the preferred implementation of the bolus is administered in less than 15 or less than 10 minutes. In a more preferred implementation of the bolus is administered less than 5 minutes. In a more preferred implementation of the bolus is administered within one minute or less. Infusion is a dose that is administered for 30 minutes or more. In the preferred implementation of the infusion lasts for one hour or more. Another is sushestvennee infusion is essentially constant.

For topical use the compounds of the present invention, preferably, the compounds of formula I can also be obtained in forms suitable for application to the skin or on the mucous membranes of the nose and throat, and can be in the form of creams, ointments, liquid sprays or formulations for inhalation, cakes or lubrication for the throat. Such local compositions may additionally include chemical compounds such as dimethyl sulfoxide (DMSO), to facilitate penetration of the active ingredient through the surface. For application to the eyes or ears of the compounds of the present invention, preferably, the compounds of formula I may be presented in liquid or semi-liquid form, made on the hydrophobic or hydrophilic base, in the form of ointments, creams, lotions, lubrication or powders.

For rectal injection of the compounds of the present invention, preferably the compounds of formula I, can be introduced in the form of suppositories, based on mixtures of commonly used carriers such as cocoa butter, wax or other glycerides.

Alternatively, compounds of the present invention, preferably, the compounds of formula I may be in powder form for distribution in a suitable pharmaceutically acceptable carrier during use. In another implementation of the standard drug is a form of connection may be a solution of the compound or preferably, its salts in a suitable diluent in sterile sealed ampoule or syringe of sterile. The concentration of compounds in the standard dosage form may vary, for example, from about 1 percent to about 50 percent, depending on the compound and its solubility and the desired doctor dose. If the compositions contain unit doses, each unit dose preferably contains 1-500 mg of active substance. For the treatment of adult the dose applied, preferably, ranges from 5 mg to 10 g per day, depending on the route and frequency of administration.

In another aspect of the present invention, a method for inhibiting the growth of microorganisms, preferably bacteria, comprising contacting these organisms with a compound of the present invention under conditions that provide a contact connection with the specified body and with the specified microorganism. Such conditions are known to the specialist in the art and illustrated in the examples. This method comprises contacting the microbial cells with a therapeutically effective amount of the compound(s) according to the invention, preferably, the compound(s) of formula I, in vivo or in vitro.

In accordance with this aspect of the invention, new compositions described herein are placed in formats whitesky acceptable carrier and they are delivered to a subject, recipient (preferably, person) in accordance with known methods of drug delivery. Typically, in the methods according to the invention for delivery of the compositions according to the invention in vivo apply known in the art methods of delivery agent, essentially, with only one change, namely, that in the exercise of these known in the art methods as drug use compounds of the present invention, preferably, compounds of the formula I. furthermore, the uses of the claimed compositions for treatment of cells in culture, for example, to destroy or reduce the level of bacterial contamination of cell cultures, using known in the art methods for handling cell cultures antibacterial(mi) agent(Tami) essentially with only one change of method lies in the fact that in the implementation of those known in the field of methods of use of compounds of the present invention, preferably, the compounds of formula I.

In one implementation of the present invention, a method for treatment of infections, in particular caused by gram-positive bacteria, the subject with a therapeutically effective amount of the compounds according to the invention. Examples of methods for the delivery of the antibacterial agent is described in U.S. patent No. 541567 and patent application number PCT EP94/02552 (publication WO 95/05384), the full contents of these documents are incorporated herein as references. Used here, the phrase "therapeutically effective amount" means an amount of compound according to the present invention which prevents, alleviates symptoms or stops the growth of bacterial infection. The term "treatment" is defined as the introduction to the subject therapeutically effective amounts of compounds according to the invention, as to prevent infection and to control or destroy the infection. Described here, the term "subject" is defined as a mammal, a plant, or cell culture. In the preferred implementation of the subject is the person or another sick animal that needs antibiotic treatment.

The method includes introducing to a subject an effective dose of the compounds of the present invention. Effective dose is usually from about 0.1 to about 100 mg/kg of the compounds according to the invention or its pharmaceutically acceptable salt. The preferred dose is from about 0.1 to about 50 mg/kg of the compounds according to the invention or its pharmaceutically acceptable salt. A more preferred dose is from about 1 to 25 mg/kg of the compounds according to the invention or its pharmaceutically acceptable salt. Effective the I dose for cell culture is usually from about 0.1 to 1000 μg/ml, more preferably from 0.1 to 200 μg/ml

Compositions containing the compounds according to the invention, can be entered as a single daily dose or in divided doses per day. For treatment may require the introduction for extended periods of time, for example, within a few days, or two to four weeks. The number input on the dose or the total input quantity should depend on such factors as the nature and severity of the infection, the age and General health of the patient, the tolerance of the patient to the connection and the microorganism or microorganisms involved in the infection. The way the introduction of patient daptomycin, another member of depsipeptide class of compounds described in U.S. patent serial No. 09/406568, filed September 24, 1999, which claims the priority of provisional application U.S. No. 60/101828, filed September 25, 1998, and 60/125750, filed on March 24, 1999, the contents of which are incorporated herein by reference.

Compounds of the present invention can also be injected to the patient or animal feeding or with food. When introduced as part of the total food intake, the number of used connections can be less than 1% of the mass of products and, preferably, not more than 0.5% by weight. Food for the animals may be conventional products to to the which can be added to the connection, or it can be added to a previously prepared mixture.

The present invention also suggests ways of introducing the compounds of formula I or pharmaceutical composition needs it to the subject in amounts that are effective to reduce or eliminate the bacterial infection. The compound may be administered orally, parenterally, via inhalation, topically, rectally, intranasally, cheek, vaginally or via an implantable reservoir, the outer pump or catheter. The connection can be adapted for ophthalmic or aerosol application. Compounds of the present invention can be introduced into an aerosol for the treatment of pneumonia or other lung infections. The preferred tool for aerosol delivery is anhydrous inhaler or dry powder inhaler. The compounds of formula I or pharmaceutical composition may also be injected or introduced directly into the abscess, the ventricle or the joint. Parenteral administration includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, abdominal, intrathecal, intrahepatic, in the injury area, and intracranial injection or infusion. In the preferred implementation of the compounds of the present invention are administered intravenously, subcutaneously or PE is administered orally. In a preferred implementation for the introduction of the compounds of formula I in a cell culture connection may be included in a nutrient medium.

The method according to the present invention can be applied to treatment of a subject having a bacterial infection, in which the infection is caused or complicated by any type of bacteria, in particular gram-positive bacteria. In one implementation, the connection of the present invention or pharmaceutical composition is administered to the patient in accordance with the methods of the invention. In a preferred implementation, the bacterial infection may be caused or complicated by gram-positive bacteria. Data gram positive bacteria include, but are not limited to, sensitive and methicillin methicillin-resistant staphylococci (including Staphylococcus aureus, S. epidermidis, S. haemolyticus, S. hominis, S. saprophyticus, and coagulase-negative staphylococci), susceptible to the intermediate product glycopeptide S. aureus (GISA), vancomycin-resistant Staphylococcus aureus (to the VRSA), susceptible to penicillin and resistant to penicillin streptococci (including Streptococcus pneumoniae, S. pyogenes, S. agalactiae, S. avium, S. bovis, S. lactis, S. sangius and Streptococcus group C Streptococcus group G and streptococci Streptococci Group C Streptococci Group G and viridans streptococci, enterococci (including susceptible to vancomycin and resistant to fancomic is well strains, such Enterococcus faecalis and E. Faecium), Clostridium difficile, C. clostridiiforme, C. innocuum, C. perfringens, C. ramosum, Haemophilus influenzae, Listeria monocytogenes, Corynebacterium jeikeium, Bifidobacterium spp., Eubacterium aerofaciens, E. lentum, Lactobacillus acidophilus, L. casei, L. plantarum, Lactococcus spp., Leuconostoc spp., Pediococcus, Peptostreptococcus anaerobius, P. asaccarolyticus, P. magnus, P. micros, P. prevotii, P. productus, Propionibacterium acnes, Actinomyces spp., Moraxella spp. (including M. catarrhalis) and Escherichia spp. (including E. coli).

In the preferred implementation of the antibacterial activity of the compounds of formula I in terms of classical "resistant" strains comparable to those in respect of "susceptible" strains in vitro experiments. In another preferred implementation of the minimum inhibitory concentration (MIC) of the compounds in accordance with this invention in relation to susceptible strains is usually the same or lower than that of vancomycin. Thus, in a preferred implementation of the connection according to this invention or pharmaceutical composition is administered in accordance with the methods of the present invention to a patient who has a bacterial infection that is resistant to other compounds, including vancomycin or daptomycin. In addition, unlike glycopeptides antibiotics depsipeptide compounds such as described in the present invention, showing a rapid, dose-dependent bactericidal activity against gram is organizmov. Thus, in the preferred implementation of the connection in accordance with the present invention or pharmaceutical composition is administered in accordance with the methods of the present invention to a patient in need of fast-acting therapy with antibiotics.

The method according to the present invention can be applied to any bacterial infections of any organ or tissue of the body. In a preferred implementation, the bacterial infection is caused by gram bacteria. These organs or tissue include, without limitation, skeletal muscle, skin, blood, kidneys, heart, lungs and bones. The method of the invention can be applied to treat without limitation, infections of skin and soft tissues, bacteriemic diseases and infections of the urinary tract. The method according to the invention can be applied for the treatment of transmissible contact by respiratory infections, including, without limitation, inflammation of the middle ear, sinusitis, chronic bronchitis, and pneumonia, including pneumonia caused by drug-resistant S. Pneumoniae or H. Influenzae. The method according to the invention can also be applied for the treatment of mixed infections that include different types of gram-positive bacteria, or that include both gram-positive and gram-negative bacteria. These types of infections include intraperitoneal infection and obstetric/gin the substance abuse infection. The method of the invention can also be applied for treatment of infections, including, without limitation, endocarditis, nephritis, septic arthritis, intraperitoneal sepsis, infections of bones and joints, and osteomyelitis. In the preferred implementation of any of the above diseases can be treated using compounds in accordance with this invention or pharmaceutical compositions.

The method according to the present invention can also be used in practice along with the simultaneous introduction of one or more other antimicrobial agents, such as antibacterial agents (antibiotics or antifungal agents. In one aspect, the method can be applied in practice by introducing more than one connection in accordance with this invention. In another implementation of the method can be applied in practice by introducing a compound in accordance with this invention with lipopeptides connection, such as daptomycin or lipopeptide compounds described, for example, in international patent applications WO 01/44272; WO 01/44274 and WO 01/44271.

Antibacterial agents and their classes that can be entered together with the connection according to the invention, include, without limitation, penicillins and related drugs, carbapenems, cephalosporins and related drugs, aminoglycosides, bacitracin, gramicidin, mupirocin, chloramphenicol, thiamphenicol, fusidate sodium, lincomycin, clindamycin, macrolides, novobiocin, polymyxins, rifamycins, spectinomycin, tetracyclines, vancomycin, teicoplanin, streptogramins, protivopolojnye agents including sulfonamides, trimethoprim and its combinations, as well as pyrimethamine, synthetic antibacterial agents, including nitrofurans, Mandela methenamine and hippurate methenamine, nitroimidazoles, quinolones, fluoroquinolones, isoniazid, ethambutol, pyrazinamide, para-aminosalicylic acid (PAS), cycloserine, capreomycin, ethionamide, protionamide, Thiacetazone, viomycin, evernimicin, glikopeptid glycylcycline, ketolide the oxazolidinone; imipenem, amikacin, netilmicin, fosfomicin, gentamicin, cefriaxone, sarazin, LY 333328, CL 331002, HMR 3647, Zyvox®, Synercid®, aztreonam and metronidazole, epiroprim, OCA-983, GV-143253, sanfetrinem sodium, CS-834, biapenem, A-99058.1, A-165600, A-179796, KA 159, dynemicin AND DX8739, DU 6681; celapram, ER 35786, cefoselis, superintellectual, HGP-31, cefpirome, HMR-3647, EN-59863, mersacidin, KP 736, rifalazil; AM 1732, MEN 10700, lenaine, BO 2502A, NE-1530, PR 39, K130, OPC 20000, OPC 2045, Venedik, PD 138312, PD 140248, CP 111905, sulopenem, recipientemail, RO-65-5788, ciclacillin, Sch-40832, SEP-132613, Mikkonen A, SB-275833, SR-15402, SUN A0026, TOC 39, carumonam, cefozopran, capitaladequacy and T 3811.

Antifungal agents that can be introduced together with the connection is receiving according to the invention, include, without limitation, caspofungin, voriconazole, sertaconazole, IB-367, FK-463, LY-303366, Sch-56592, sitafloxacin, DB-289, a polyene, such as amphotericin, nystatin, pimaricin; azoles, such as fluconazole, Itraconazole and ketoconazole; allylamine, such as naftifine and terbinafine; and antimetabolites, such as flucytosine. Other antifungal agents include, without limitation described Fostel et al., Drug Descovery Today 5:25-32 (2000), incorporated herein by reference. Fostel et al. open antifungal compounds, including marinecandy, Mer-WF3010, fusionzone, airtricity/LL 15G256, saldarini, zipentry, anoxybacillus, aureobasidin and carefully.

Connection in accordance with this invention can be entered in this way up until the bacterial infection is destroyed or weakened. In one implementation, the compound of formula I is administered for a period of time from 2 days to 6 months. In a preferred implementation, the compound of formula I is administered for 7 to 56 days. In a more preferred implementation, the compound of formula I is administered for 7 to 28 days. In a more preferred implementation, the compound of formula I is administered for 7 to 14 days. The compound of the formula I can be entered for a longer or shorter period of time, if so desired.

Getting new depsipeptides

1. Semi-synthetic method

Method of producing compounds of the formula I, in which at least one of R2and R3different from methyl and each of R8and R9independently represents NH2.

The way A

For compounds of formula I in which at least one of R2and R3different from methyl and each of R8and R9independently represents NH2the method in accordance with one aspect of the invention involves the following stages:

(a) obtaining a depsipeptide derivative of the formula XI

where R, R1, R4, R5, R6, R18, R19and R20described above; R25represents an alkyl group; R26represents methyl or-CH2CH2CH2NH2; and R27represents methyl or-CH2CH2CH2CH2NH2; or its salt(b) protect and defend free(Oh) amino group(s) of compounds of formula XI with a protective group to obtain protected depsipeptide compounds;

(c) treatment of protected depsipeptide compound obtained in stage (b), desacelerou agent for connection with an end aminoguanidinium;

(d) removal of the tryptophan amino acid residue of the connection end aminoguanidinium obtained in stage (c), to obtain de the tryptophan compounds;

(e) removal of the terminal amino acid residue of descriptionwho compounds obtained in stage (d), to obtain tendipedidae connection;

(f) removing terminal amino acid residue of tendipedidae compounds obtained in stage (e), to obtain depsipeptide compounds;

(g) processing towards basic compounds from step (f) modifying agent; and

(h) removing the protective group of the protected compounds of formula I to obtain the compounds of formula Ia.

Procedure A is illustrated in scheme I.

Semi-synthetic method in accordance with one aspect of the invention includes obtaining the compounds of formula XI (stage a)). The compounds of formula XI can be obtained using the methods described in U.S. patents RE 32333; RE 32455; RE 32311; 4482487; 4537717; 4800157; 4874843; 4885243; 5912226; 4994270; 5039789 and 5028590; international patent applications numbers registration WO01/44272, WO01/44274, WO01/44271, WO01/53330 and WO02/059322, each of which is incorporated herein by reference.

In a preferred implementation, the compound of formula XI is one in which each of R1and R4represents hydrido; each of R3and R6represents methyl; R5represents a hydroxyl; R 25is a 7-methylnon, 9-methyldecyl, 9-methylundecyl, nonyl, decyl or mixtures thereof, and R26represents - CH2CH2CH2NH2.

In another preferred implementation, the compound of formula XI is one in which R represents isopropyl or 2-butyl; each of R1and R2represents methyl; R4represents methoxy; R5represents carboxamido; R25is an 8-methylnonanoic, n-decanol or 8-methyldecyl; and R27represents-CH2CH2CH2CH2NH2.

The free amine compound of formula XI is treated with a protective group to obtain protected depsipeptide compound of the formula XII (stage (b)), where R, R1, R4, R5, R6, R18, R19, R20and R25described above; R28represents methyl or-CH2CH2CH2HP; R29represents methyl or-CH2CH2CH2CH2NHP; where P is aminosidine group, or its salt.

Examples aminosidine groups and ways of protection of amines with these groups can be found in Protective Groups in Organic Synthesis by Theodora W.Greene, (New York: John Wiley and Sons, Inc.), 1981, hereinafter referred to as "Greene", incorporated herein by reference. Preferred aminosidine groups are urethane am nosadini group. Preferred amino groups are allyloxycarbonyl (alloc), carbobenzoxy (CBZ) and tert-butoxycarbonyl protective group. The most preferred aminosidine urethane group is allyloxycarbonyl. Methods of protection Amin daptomycin, A54145 and related lipopetides can be found in the patents of the United States RE 32310; RE 32311; 4482487; 4524135; 4537717; 5039789 and 5028590; international patent applications numbers registration WO01/44272, WO01/44274 and WO01/44271.

Protected depsipeptide compound is then treated desacelerou agent with the formation of compounds with terminal amino acid of the formula XIII (stage (c)). Desetilirovania agents suitable for the invention are enzymatic destileria agents. The enzyme that is suitable for disallowance the compounds of formula XII, is produced by a particular microorganism of the family Actinoplanaceae. Some of these known species and many of this family include Actinoplanes philippinensis, Actinoplanes armeniacus, Actinoplanes utahensis, Actinoplanes missouriensis, Spirillospora albida, Streptosporiangium roseum, Streptosporangium vulgare, Streptosporangium roseum var hollandensi, Streptosporangium album, Streptosporangium viridialbum, Amorphosporangium auranticolor, Ampullariella regularis, Ampullariella campanulata, Ampullariella lobata, Ampullariella digitata, Pilimelia terevasa, Pimelia anulata, Planomonspora parontospora, Planomonspora venezuelensis, Planobispora longispora, Planobispora rosea, Dactylosporangium aurantiacum and Dactylosporangium thailandende. All natural and artificial variants and utenti, obtained from Actinoplanacea and which produce the enzyme can be used in this invention.

Preferred sources detailimage enzyme are Actinoplanes utahensi: NRRL 12052; Actinoplanes missouriensis NRRL 12053; Actinoplanes sp.: NRRL 8122; Actinoplanes sp.: NRRL 12065; Streptosporsngium roseum var hollandensis: NRRL 12064; Actinoplanes utahenis ATCC 14539 and Actinoplanes missouriensis ATCC 14538. The preferred source detailimage enzyme is a kind of Actinoplanes utahensi. The most preferred source detailimage enzyme is a recombinant Streptomyces lividans, which expresses desacelerado enzyme Actinoplanes utahensis, as described in J. Ind. Environ. Biotechnol. 2000, 24(3) 173-180. This enzyme is also known as echinocandin B deacylase or ECB deacylase.

Suitable methods of enzymatic diallylamine compounds of formula XII can be found in U.S. patent 4524135; 4537717; 4482487; RE 32310; RE 32311, 5039789 and 5028590; international patent applications numbers registration WO01/44272, WO01/44274 and WO01/44271, each of which is incorporated herein by reference.

The removal of the tryptophan amino acid residue of the connection terminal amino acid of the formula XIII leads to the formation of compounds of formula XIV (stage (d)). Ways to remove tryptophan amino acid residue known to specialists in this field of technology. The preferred method of removal of the tryptophan amino acid residue line which meets the conditions of degradation on Admino.

Degradation by Admino is a well-substantiated response, known to experts in the art (see, for example, P. Edman, 1950, Acta Chem. Scan. 4:283-93 and P. Edman, 1956, Acta Chem Scan 10:761-768). In this reaction end-NH2the group interacts with isothiocyanato education timesaving derived peptide. After treatment with acid or base timesaving peptide undergoes a cyclization reaction to obtain thiohydantoin and shortened peptide (see scheme II).

where each of R30, R31and R32represents the amino acid side chain; and R33represents an aryl or alkyl group.

Degradation by Admino can be performed in a variety of conditions. At the first stage of the sequence of degradation on Adminu isothiocyanate interacts with the amine at a neutral or moderately alkaline (pH<9,5) conditions in solvents such as tetrahydrofuran, N,N'-dimethylformamide, dichloromethane, dioxane or ethanol. Can be applied to many isothioscyanates (see K. K. Han et al. Biochemie 1977, 59:557-576).

Subsequent cyclization and cleavage can be carried out in various conditions. Usually applied anhydrous triperoxonane acid, heptapteridae acid (see, for example, W.F. Brandt et al., 1976, Z. Physiol. Chem. 357:1505-1508) or concentrated with anou acid (see, for example, G. E. Tarr, 1977, Methods in Enzymology, 47:335-337). Can also be applied to moderately alkaline conditions, such as triethylamine or N,N-dimethylalanine/acetic acid (pH˜9) (see G.C. Barrett et al., 1985, Tetrahedron Letters 26(36):4375-4378). As an overview for this reaction see K.K. Han, 1985, Int. J. Biochem 17(4):429-445.

In the preferred implementation timesaving peptide (compound of formula (XVIII), formed by the interaction thioisocyanate with the compound of the formula XIII is treated under acidic conditions to obtain the compounds of formula XIV. In a more preferred implementation of the invention the compound of formula XVIII is treated triperoxonane acid to obtain the compounds of formula XIV (scheme III).

where each of R, R1, R4, R5, R6, R18, R19, R20, R28, R29and R33above.

In the preferred implementation of R33represents phenyl, n-decyl, nonyl or octyl. In a more preferred implementation of R33is a n-decyl.

Remove terminal amino acid residue of the compounds of formula XIV leads to the formation distibuting the compounds of formula XV (stage (e)). Ways to remove terminal amino acid residue known to specialists in this field of technology. The preferred method of removal of the terminal amino acid is on the balance corresponds to the conditions degradation by Admino (see above).

In the preferred implementation timesaving peptide (compound of formula XIX), formed by the interaction thioisocyanate with the compound of the formula XIV is treated under acidic conditions to obtain distibuting the compounds of formula XV. In a preferred implementation of the invention the compound of formula XIX is treated triperoxonane acid to obtain the compounds of formula XV (scheme IV).

Scheme IV

where each of R, R1, R4, R5, R6, R18, R19, R20, R28and R29described above; and R34represents alkyl or aryl.

Remove terminal amino acid residue of the compounds of formula XV leads to the formation of depsipeptide basic compounds of formula XVI (stage (f)). Ways to remove terminal amino acid residue known to specialists in this field of technology. The preferred method of removal of the terminal amino acid residue corresponds to the conditions degradation by Admino (see above).

In the preferred implementation timesaving peptide (compound of formula XX), formed by the interaction thioisocyanate with the compound of the formula XV is treated under acidic conditions to obtain towards basic compounds of formula XVI. In a preferred implementation of the invention the compound of formula XX is srabatyvayut triperoxonane acid to obtain the compounds of formula XVI (scheme IV (A).

where each of R, R1, R4, R5, R6, R18, R19, R20, R28and R29described above; and R35represents alkyl or aryl.

Processing towards basic compounds of formula XVI modifying agent leads to the formation of the protected compounds of formula I (compounds of formula XVII, stage (f)). The interaction of the amine with the modifying agents, as defined here, is well known to specialists in this field of technology. For example, treatment of compounds of formula XVI isocyanate gives the compounds of formula XVII, in which R7represents ureido. Similarly, treatment of compounds of formula XVI activated complex ether, lactone or acid chloride of the acid gives the compounds of formula XVII, in which R7represents acylamino. Treatment of compounds of formula XVI sulphonylchloride or active sulfonamide gives compound of formula XVII, in which R7represents sulfonamide. Treatment of compounds of formula XVI activated heterocycle gives compound of formula XVII, in which R7represents a heterocyclic amino. Treatment of compounds of formula XVI activated heteroaryl gives compound of formula XVII, in which R7represents a heteroaryl amino. Education is denied the compounds of formula XVI carbonate, chloroformiate or cyanoformate gives the compounds of formula XVII, in which R7is a carbamate. Treatment of compounds of formula XVI tieferen gives the compounds of formula XVII, in which R7represents thioacetamide. Treatment of compounds of formula XVI phosphorylchloride or phosphoramidate gives the compounds of formula XVII, in which R7represents postonline. Treatment of compounds of formula XVI imitator gives the compounds of formula XVII, in which R7represents minamino. Treatment of compounds of formula XVI thioisocyanate gives the compounds of formula XVII, in which R7represents touraid. Treatment of compounds of formula XVI aldehyde or ketone in reducing conditions gives compounds of formula XVII, in which R7represents a monosubstituted amino or disubstituted by an amino group. Treatment of compounds of formula XVI imitator gives the compounds of formula XVII, in which R7represents minamino. Treatment of compounds of formula XVI guanidinium agent such as

gives the compounds of formula XVII, in which R7represents guanidino.

Specialists in the art should be understood that, if the modifying agent contains substituents that are incompatible with the reaction conditions under which about azueta compound of formula XVII, these deputies must be protected before use in the reaction. Suitable protective groups and methods for their preparation can be found in Greene (see above).

Interaction of amines of complex molecules, such as daptomycin and related depsipeptide can be found in the patents of the United States 4399067; 4482487; and 4537717; 5039789; and 5028590; and International patent applications numbers registration WO01/44272, WO01/44274 and WO01/44271.

In the preferred implementation of the reaction of the modifying agent is an activated ester. In a more preferred implementation of the reaction of the modifying agent is a

where each of Raa1, Raa2and Raa3represents a side chain of an amino acid or a protected form the side chain of amino acids; R36represents amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbarnoyl, sulfonamide, thioacetamide, touraid, minamino or postonline; × represents an activating group. In even more preferred implementation × represents alloctype. In a more preferred implementation × represents Pantothenate.

Compounds of formula XXI, XXII and XXIII can be obtained from the corresponding peptide or amino acid processing AK is everyime agents, such as anhydrides, chloroformiate, pentafluorophenol/dicyclohexylcarbodiimide, N',N'-carbonyldiimidazole, hydroxybenzotriazole or N-hydroxysuccinimide. The peptides can be obtained using any standard procedure for peptides. As an overview of some of the procedures of formation of peptides see Vogel''s Textbook of Practical Organic Chemistry, 5thEd., eds. B.S. Furniss, A.J. Hannaford; P.W.G. Smith; A.R. Tatchell (New York: John Wiley and Sons, Inc.), 1089, p. 750-763 and Introduction to Organic Chemistry, 2ndEd. by A. Streitwieser, Jr. and C.H. Heathcock (New York: MacMillan Publishing Co., Inc.), p. 954-962. Other methods that are suitable for obtaining the peptides of the present invention include solid-phase synthesis. Specific examples of such methods are described in detail in the examples (see below).

The removal of the protective group of the protected compounds of formula I (compounds of formula (XVII) leads to the formation of compounds of formula Ia (stage h), in which R1, R4, R5, R6and R7described above; R2arepresents methyl or-CH2CH2CH2NH2and R3arepresents methyl or-CH2CH2CH2CH2NH2. Remove aminosidine group may be made by those methods described in Greene (see above). Specialists in the art will understand that the choice aminosidine group used in the first stage of the method, determines the reagents and methods used in ishemia to delete this aminosidine group.

When the modifying agent contains one or more protective group (s)specified protective group (s) should also be removed. The choice of protective group (s)that apply to the Deputy (deputies) of the modifying agent, determines the reagents and methods used to remove the specified protective group (s). When the protective group (s)that apply to the Deputy (deputies) of the modifying agent, and the protective group used in stage (b)are compatible, the protective group can be removed in one stage. However, when the protective group (s) are incompatible, removal of all protective groups may require several stages.

The method of obtaining compounds of formula I where at least one of R2and R3different from methyl and each of R8and R9different from the NH2.

Method B

For compounds of formula I in which at least one of R2and R3different from methyl and each of R8and R9different from the NH2the method in accordance with another aspect of the invention includes additional stages:

(i) treatment of compounds of formula I with a free amine from step (h) method with A modifying agent to obtain compounds of formula I.

Treatment of compounds of formula I in free amine of the formula Ia and modifying entom well known to experts in the art and described for stage (g) of method A (see above).

Description of the interaction of free amines of complex molecules, such as daptomycin and related depsipeptide can be found in U.S. patent 4399067, 4482487; and 4537717; and international patent applications WO01/44272, WO01/44274 and WO01/44271.

Specialists in the art it is clear that if R7or the modifying agent from step (i) contains substituents that are incompatible with the reaction conditions, in which is formed a compound of formula I, the substituents must be protected prior to stage (i). Suitable protective groups and methods for their preparation can be found in Greene (see above).

When R7and the modifying agent, stage (i) contain a protective group (s)specified protective group (s) can be removed. The choice of protective group (s) Deputy (deputies) R7and the modifying agent should determine the reagents and methods used to remove the specified protective group (s). When the protective group (s)used at the Deputy (deputies) R7and the modifying agent are compatible, the protective group can be removed in one stage. However, when the protective group (s) are incompatible, removal of all protective groups may require several stages.

The method C

An alternative method for preparing compounds of the formula I, in which less than the least one of R2and R3different from methyl and each of R8and R9different from the NH2includes the following stages:

(a) obtaining a depsipeptide derivative of the formula XI

where R, R1, R4, R5, R6, R18, R19, R20, R25, R26and R27described above;

(b) processing of free amino groups (groups of) compounds of the formula XI modifying agent with getting blocked depsipeptide compounds, where specified, the modifying agent is selected so that a well-educated blocked depsipeptide compound stable at stages (c), (d), (e), (f) and (g);

(c) treatment blocked depsipeptide compound obtained in stage (b), desacelerou agent with obtaining connection with limit aminoguanidinium;

(d) destruction of tryptophan amino acid residue of the connection end aminoguanidinium obtained in stage (c), with descriptionwho connection;

(e) removing the terminal amino acid residue of descriptionwho compounds obtained in stage (d), with tendipedidae connection;

(f) removing the terminal amino acid residue of tendipedidae compounds obtained in stage (e), with depsipeptide compounds;

(g) processing depsipeptides the basic compound from step (f) modifying agent.

Method C is illustrated by the scheme V

Treatment of compounds of formula XII modifying agent leads to the formation of the protected compounds of formula I (compounds of formula XXIV, stage (b)), where R37represents methyl or-CH2CH2CH2R8; and R38represents methyl or-CH2CH2CH2CH2R9; attached so that at least one of R37and R38must be different from methyl, and R8and R9must differ from the amino. Education-protected compounds of the formula I is carried out as described previously for the stage (g) of method A (see above).

Disallowance connection XXIV leads to the formation of end amino compounds XXV. Suitable agents for disallowance compounds of formula XXVI are enzymatic destileria agents (see above).

The removal of the tryptophan amino acid residue of the connection end aminoguanidinium formula XXV leads to the formation of compounds of formula XXVI (stage (d)). Ways to remove tryptophan amino acid residue known to specialists in this field of technology. The preferred method of removal of the tryptophan amino acid residue corresponds to the conditions degrade the AI on Adminu (see above).

Remove terminal amino acid residue of the compounds of formula XXVI leads to the formation distibuting the compounds of formula XXVII (stage (e)). Ways to remove terminal amino acid residue known to specialists in this field of technology. The preferred method of removal of the terminal amino acid residue corresponds to the conditions degradation by Admino (see above).

Remove terminal amino acid residue of the compounds of formula XXVII leads to the formation of depsipeptide basic compounds of formula XXVIII (stage (f)). Ways to remove terminal amino acid residue known to specialists in this field of technology. The preferred method of removal of the terminal amino acid residue corresponds to the conditions degradation by Admino (see above).

Processing depsipeptide compound of the formula XXVIII modifying agent well-known to experts in the art and described for stage (g) of method A (see above).

Specialists in the art it is clear that, if the modifying agent contains substituents that are incompatible with the reaction conditions, in which is formed a compound of formula I, these substituents must be protected before the interaction of the compounds of formula XXVIII. Suitable protective groups and methods for their preparation can be found in Greene (see above).

the hen is desirable, the protective group can be removed. When the protective traveler group (the group) are(is) compatible, protective groups can be removed in one stage. However, when the protective traveler group (the group) are(is) incompatible, removal of all protective groups may require several stages.

Method D

The compounds of formula I and the compounds of formula Ia, in which R7represents a

where each of R18, R19and R20described previously, and R39represents amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbarnoyl, sulfonamide, thioacetamide, touraid, minamino or postonline; can be obtained from compound XIII as described in scheme VI, or through connection XXV, as described in scheme VII.

Method E

Similarly, the compounds of formula I and the compounds of formula Ia, in which R7represents a

where each of R18, R19and R20described previously, and R39represents amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbarnoyl, sulfonamide, thioacetamide, touraid, minamino or postonline; can be by the researchers from compound XIV, as described in scheme VIII, or through connection XXVI, as described in scheme IX.

Method F

Similarly, the compounds of formula I and the compounds of formula Ia, in which R7represents a

where each of R18and R19described previously, and R39represents amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbarnoyl, sulfonamide, thioacetamide, touraid, minamino or postonline; can be obtained from compound XV, as described in scheme X, or through connection XXVII, as described in scheme XI.

2. Synthetic method

Solid-phase synthesis of depsipeptide compounds

In an alternate implementation of the invention depsipeptide compounds of formula I can be synthesized on a solid support (scheme XII, the scheme of scheme XIII and XV).

In stage 1 N-protected O-allyl ester β-methylglucamine acid or protected O-allyl ester of glutamic acid attached to the resin with the connection 101, where R6described above. In this reaction can be applied resin or solid base, such as, but not about rancevas this, Wang, HMPA, Safety Catch, Rink Acid, 2-horticulturally resin, Fritillaria resin, 4-methyltrichlorosilane resin, 4-methoxytryptamine resin or resin PAM.

To unprotect a connection 101 with the subsequent connection of the free amino-protected serine or protected asparagine network connection 102, where R40represents-OP2or CONHP3; and each of P, P1, P2and P3independently represents a protective group. This method of joining peptide, i.e. removing protection from the alpha-amino group and subsequent coupling with a protected amino acid repeat to attach to the resin the desired number of amino acids. In scheme XII was connected in a total of seven amino acids with obtaining connection 103, where A3represents; A4represents,

where P4represents a protective group, and R4described above; A5represents,

where R44represents methyl or-CH2CH2CH2CH2NP5,

where P5represents aminosidine group; A6represents,

where P6represents a protective group; and A7representswhere R45represents methyl or-CH2CH2CH2NP7where P7represents aminosidine group. The second peptide attached to the resin in a similar manner, as shown in scheme XIII.

In stage 1 to the resin added N-substituted glycine or sarcosine getting connection 104, where R1described above, and P8is aminosidine group. The choice of resin used in stage 1 depends on the nature of amino acids attached at the stages 2-6. If the side chains of the amino acids contain a protective group, the resin should be selected so that the protective group remained intact in the separation of the resin from the peptide on stage 7. Resins which can be split while maintaining the protective groups of the peptides include, but are not limited to, Safety Catch, Rink Acid, 2-horticulturally resin, titillating resin, 4-methyltricyclo resin, 4-methoxymethanol resin or resin PAM.

Unprotect the protected amino compound 104 is accompanied by the connection of the free amino

getting connection 105, where R41represents amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbarnoyl, sulfonamide, thioacetamide, touraid, minamino or postonline.

the hen R 41represents amino, this method of peptide binding, i.e. removing protection from the alpha-amino group and subsequent coupling with substituted amino acid is repeated until the desired number is attached to the resin of amino acids. In scheme XIII was connected to five amino acids with obtaining connection 108, where A8represents,

where R46represents hydrido, a side chain of an amino acid or a side chain-protected amino acids;

A9represents,

where R47represents hydrido, a side chain of an amino acid or a side chain-protected amino acids;

A10represents,

where R48represents hydrido, a side chain of an amino acid or a side chain protected amino acids, and R49represents amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbarnoyl, sulfonamide, thioacetamide, touraid, minamino or postonline.

The connection 108 is connected with

getting connection 111, where P9represents a protective group, and R42is a 2-butyl, isopropyl or

where R43is the Oh group, able to transform into an amino group. For example, R43can be azido, protected amino, phthalimido or nitro.

Peptide 111 then separated from the resin with obtaining connection 112.

Connection peptide fragments 103 and 112 depicted in scheme XIV

Peptide fragments 103 and 112 are connected to a receipt associated with the resin peptide 113. Removing the protective group P9and O-allyl complex with ether followed by crystallization gives associated with resin depsipeptide 114. Removal depsipeptide from the resin, followed by removal of the protecting any remaining protective groups gives the compounds of formula I (scheme XVI).

When the desired compounds of formula I, in which no ekzoticheskih amino acids, instead of the connection 108 may be used in connection 105 (scheme XV). Connection 105 is connected with the connection 110 with the connection 115; after separation from the resin get a connection 116; after connecting to the connection 103 receives the connection 117; then remove the protection and cyclist with getting associated with the resin depsipeptide (118) and otscheplaut from the resin as described previously in schemes XIII and XIV (see above).

When the desired compounds of formula I, in which there is one ekzoticheskaya amino acid, instead of the connection 108 may be used to connect the tion 106 (scheme XVII). The connection 106 is connected with the connection 110 with the connection 119; after separation from the resin get the connection 120; after connecting to the connection 103 receives the connection 121; then remove the protection and cyclist with getting associated with the resin depsipeptide (122) and otscheplaut from the resin as described previously in schemes XIII and XIV (see above).

When the desired compounds of formula I, in which there are two ekzoticheskie amino acids, instead of the connection 108 may be used in connection 107 (scheme XVIII). Connection 107 is connected with the connection 110 with the connection 123; after separation from the resin get a connection 124; after connecting to the connection 103 receives the connection 125; then remove the protection and cyclist with getting associated with the resin depsipeptide (126) and otscheplaut from the resin as described previously in schemes XIII and XIV (see above).

After the above schemes of synthesis (scheme XII-XII) it is clear that the amino group of amino acids, and the functional group of the side chain of the amino acids must be orthogonal protected before you attach them to increasing peptide chain. Suitable protective groups can be any aminosidine group suitable for peptide synthesis. Such a pair of protective groups are well known. See, e.g., "Synthesis Notes" in kata is og Novabiochem and Peptide Synthesis Handbook (1999), pages S1-S93 and cited in its reference.

Specialists in the art should also be clear that the choice of protective groups for functional groups of the side chain amino acids should lead or not to lead to the elimination of the protective group at the same time with the final cleavage of the peptide from the resin, which should give functional natural acid or its protected derivative, respectively. When the protective group is not hatshepsuts simultaneously with the removal of depsipeptide from resin, may require additional removal of protection.

3. Biosynthetic method

Compounds of the present invention can also be obtained by recombinant methods. In this way a modified primoonline patalenitsa of daptomycin injected into a cell capable of producing the compound of formula I, and the cell is cultivated with the formation of compounds of formula I. primoonline patalenitsa of daptomycin, and the modifications of these synthetases were reported (see International patent application with the registration number 02/059322).

In order for this invention to be understood more fully, the following examples. These examples are intended for illustrative purposes and should not be interpreted as limiting the scope of invention in any way.

Example 1: Synthesis of n is btitney resin compounds I:

Commercially available Nα-(9-fluorenylmethoxycarbonyl)-L-threonine (2 ml of 0.5 molar solution in N-methylpyrrolidine), 1,3-diisopropylcarbodiimide (2 ml of 0.5 molar solution in N-methylpyrrolidine) and 1-hydroxybenzotriazole (2 ml of 0.5 molar solution in N-methylpyrrolidine) was added to a commercially available glycine 2-chlorotrityl resin (334 mg). The mixture was stirred for one hour, filtered and several balls were tested for the presence of free amine using standard test Kaiser (see E. Kaiser, et al (1970) Anal. Biochem., 34, 595; and Advanced Chemtech Handbook of Combinatorial, Organic and Peptide Chemistry 2003-2004 page 208). Test Kaiser gave a blue color, so that the above conditions of accession were reproduced. After filtering, the carrier product resin was washed with N-methylpyrrolidine (3 × 6 ml), methanol (3 × 6 ml) and again with N-methylpyrrolidine (3 × 6 ml) to obtain compound 2.

Compound 2 was dissolved in 20% piperidine in N-methylpyrrolidone (6 ml) for 30 minutes. The resin was filtered and re-suspended in 20% piperidine in N-methylpyrrolidone (6 ml) and was shaken for 30 minutes. The reaction mixture was filtered, after which the solid was washed with N-methylpyrrolidine (3 × 6 ml), methanol (3 × 6 ml) and again with N-methylpyrrolidine (3 × 6 is l) to obtain compound 3.

Commercially available βtert-butyl ether Nα-(9-fluorenylmethoxycarbonyl)-L-aspartic acid (2 ml of 0.5 molar solution in N-methylpyrrolidine), 1,3-diisopropylcarbodiimide (2 ml of 0.5 molar solution in N-methylpyrrolidine) and 1-hydroxybenzotriazole (2 ml of 0.5 molar solution in N-methylpyrrolidine) was added to compound 3. The mixture was stirred for one hour, filtered and the accession repeated. The reaction mixture was filtered and then the solid was washed with N-methylpyrrolidine (3 × 6 ml), methanol (3 × 6 ml) and again with N-methylpyrrolidine (3 × 6 ml) to obtain the connection.

Compound 4 was dissolved in 20% piperidine in N-methylpyrrolidone (6 ml) for 30 minutes. The resin was filtered and re-suspended in 20% piperidine in N-methylpyrrolidone (6 ml) and was shaken for 30 minutes. The reaction mixture was filtered and then washed with N-methylpyrrolidine (3 × 6 ml), methanol (3 × 6 ml) and again with N-methylpyrrolidine (3 × 6 ml) to obtain compound 5.

Commercially available Nα-(9-fluorenylmethoxycarbonyl)-L-asparagine δ-N-trityl (2 ml of 0.5 molar solution in N-methylpyrrolidine), 1,3-diisopropylcarbodiimide (2 ml of 0.5 molar solution in N-methylpyrrolidine) and 1-hydroxybenzotriazole (2 ml of 0.5 solarnog the solution in N-methylpyrrolidine) was added to the resin 5. The reaction mixture was stirred for one hour, filtered and the accession repeated. The reaction mixture was filtered and then the solid was washed with N-methylpyrrolidine (3 × 6 ml), methanol (3 × 6 ml) and again with N-methylpyrrolidine (3 × 6 ml) to obtain compound 6.

Compound 6 was dissolved in 20% piperidine in N-methylpyrrolidone (6 ml) for 30 minutes. The resin was filtered and re-suspended in 20% piperidine in N-methylpyrrolidone (6 ml) and was shaken for 30 minutes. The reaction mixture was filtered and then the solid was washed with N-methylpyrrolidine (3 × 6 ml), methanol (3 × 6 ml) and again with N-methylpyrrolidine (3 × 6 ml) to obtain compound 7.

Commercially available Nα-(9-fluorenylmethoxycarbonyl)-L-tryptophan (2 ml of 0.5 molar solution in N-methylpyrrolidine), 1,3-diisopropylcarbodiimide (2 ml of 0.5 molar solution in N-methylpyrrolidine) and 1-hydroxybenzotriazole (2 ml of 0.5 molar solution in N-methylpyrrolidine) was added to the resin. The reaction mixture was stirred for one hour, then filtered and the accession repeated. The reaction mixture was filtered and then the solid was washed with N-methylpyrrolidine (3 × 6 ml), methanol (3 × 6 ml) and again with N-methylpyrrolidine (3 × 6 ml) to obtain compound 8.

Compound 8 was dissolved in 20% piperidine in N-methylpyrrolidone (6 ml) for 30 minutes. The resin was filtered and re-suspended in 20% piperidine in N-methylpyrrolidone (6 ml) and was shaken for 30 minutes. The reaction mixture was filtered and then the solid was washed with N-methylpyrrolidine (3 × 6 ml), methanol (3 × 6 ml) and again with N-methylpyrrolidine (3 × 6 ml) to obtain the peptide compounds of resin 1.

Example 2: Synthesis of peptide resin compound (9):

To a suspension of commercially available 4-hydroxymethylene resin (Wang resin) (5 g, 0.4 mmol/g) in dichloromethane (60 ml) was added 1,3-diisopropylcarbodiimide (0,940 ml), 4-dimethylaminopyridine (24 mg N-methylpyrrolidine (1 ml)and commercially available α-allyl ether Nα-(9-fluorenylmethoxycarbonyl)-L-glutamic acid (2,46 g N methylpyrrolidine (9 ml)). The reaction mixture was stirred for 16 hours, filtered and the solid washed with N-methylpyrrolidinone and dichloromethane and dried to obtain compound 10.

Compound 10 (526 mg) was dissolved in 20% piperidine in N-methylpyrrolidone (6 ml) for 30 minutes. The resin was filtered and re-suspended in 20% piperidine in N-methylpyrrolidone (6 ml) and was shaken for 30 minutes. The reaction mixture was filtered click the solid was washed with N-methylpyrrolidine (3 × 6 ml), methanol (3 × 6 ml) and again with N-methylpyrrolidine (3 × 6 ml) to obtain compound 11.

Commercially available tert-butyl ether Nα-(9-fluorenylmethoxycarbonyl)-L-serine (2 ml of 0.5 molar solution in N-methylpyrrolidine), 1,3-diisopropylcarbodiimide (2 ml of 0.5 molar solution in N-methylpyrrolidine) and 1-hydroxybenzotriazole (2 ml of 0.5 molar solution in N-methylpyrrolidine) was added to the resin 11. The reaction mixture was stirred for one hour, then filtered and the accession repeated. The reaction mixture was filtered and then the solid was washed with N-methylpyrrolidine (3 × 6 ml), methanol (3 × 6 ml) and again with N-methylpyrrolidine (3 × 6 ml) to give compound 12.

Compound 12 was dissolved in 20% piperidine in N-methylpyrrolidone (6 ml) for 30 minutes. The resin was filtered and re-suspended in 20% piperidine in N-methylpyrrolidone (6 ml) and was shaken for 30 minutes. The reaction mixture was filtered and then the solid was washed with N-methylpyrrolidine (3 × 6 ml), methanol (3 × 6 ml) and again with N-methylpyrrolidine (3 × 6 ml) to give compound 13.

Commercially available Nα-(9-fluorenylmethoxycarbonyl)-L-glycine (2 ml of 0.5 molar solution in N-methylpyrrolidine), 1,3-diisopropylcarbodiimide the d (2 ml of 0.5 molar solution in N-methylpyrrolidine) and 1-hydroxybenzotriazole (2 ml of 0.5 molar solution in N-methylpyrrolidine) was added to the resin 13. The reaction mixture was stirred for one hour, then filtered and the accession repeated. The reaction mixture was filtered and then the solid was washed with N-methylpyrrolidine (3 × 6 ml), methanol (3 × 6 ml) and again with N-methylpyrrolidine (3 × 6 ml) to give compound 14.

Compound 14 was dissolved in 20% piperidine in N-methylpyrrolidone (6 ml) for 30 minutes. The resin was filtered and re-suspended in 20% piperidine in N-methylpyrrolidone (6 ml) and was shaken for 30 minutes. The reaction mixture was filtered and then the solid was washed with N-methylpyrrolidine (3 × 6 ml), methanol (3 × 6 ml) and again with N-methylpyrrolidine (3 × 6 ml) to give compound 15.

Commercially available βtert-butyl ether Nα-(9-fluorenylmethoxycarbonyl)-L-aspartic acid (2 ml of 0.5 molar solution in N-methylpyrrolidine), 1,3-diisopropylcarbodiimide (2 ml of 0.5 molar solution in N-methylpyrrolidine) and 1-hydroxybenzotriazole (2 ml of 0.5 molar solution in N-methylpyrrolidine) was added to the resin 15. The reaction mixture was stirred for one hour, then filtered and the accession repeated. The reaction mixture was filtered and then the solid was washed with N-methylpyrrolidine (3 × 6 ml), methanol (3 × 6 ml) and again with N-methylpyrrolidine is (3 × 6 ml) to give compound 16.

Compound 16 was dissolved in 20% piperidine in N-methylpyrrolidone (6 ml) for 30 minutes. The resin was filtered and re-suspended in 20% piperidine in N-methylpyrrolidone (6 ml) and was shaken for 30 minutes. The reaction mixture was filtered and then the solid was washed with N-methylpyrrolidine (3 × 6 ml), methanol (3 × 6 ml) and again with N-methylpyrrolidine (3 × 6 ml) to give compound 17.

Commercially available Nα-(9-fluorenylmethoxycarbonyl)-L-alanine (2 ml of 0.5 molar solution in N-methylpyrrolidine), 1,3-diisopropylcarbodiimide (2 ml of 0.5 molar solution in N-methylpyrrolidine) and 1-hydroxybenzotriazole (2 ml of 0.5 molar solution in N-methylpyrrolidine) was added to the resin 17. The reaction mixture was stirred for one hour, then filtered and the accession repeated. The reaction mixture was filtered, and then the solid was washed with N-methylpyrrolidine (3 × 6 ml), methanol (3 × 6 ml) and again with N-methylpyrrolidine (3 × 6 ml) to give compound 18.

Compound 18 was dissolved in 20% piperidine in N-methylpyrrolidone (6 ml) for 30 minutes. The resin was filtered and re-suspended in 20% piperidine in N-methylpyrrolidone (6 ml) and was shaken for 30 minutes. The reaction mixture is filtered and then the solid was washed with N-methylpyrrolidine (3 × 6 ml), methanol (3 × 6 ml) and again with N-methylpyrrolidine (3 × 6 ml) to give compound 19.

Commercially available βtert-butyl ether Nα-(9-fluorenylmethoxycarbonyl)-L-aspartic acid (2 ml of 0.5 molar solution in N-methylpyrrolidine), 1,3-diisopropylcarbodiimide (2 ml of 0.5 molar solution in N-methylpyrrolidine) and 1-hydroxybenzotriazole (2 ml of 0.5 molar solution in N-methylpyrrolidine) was added to the resin 19. The reaction mixture was stirred for one hour, filtered and the accession repeated. The reaction mixture was filtered and then the solid was washed with N-methylpyrrolidine (3 × 6 ml), methanol (3 × 6 ml) and again with N-methylpyrrolidine (3 × 6 ml) to obtain compound 20.

Compound 20 was dissolved in 20% piperidine in N-methylpyrrolidone (6 ml) for 30 minutes. The resin was filtered and re-suspended in 20% piperidine in N-methylpyrrolidone (6 ml) and was shaken for 30 minutes. The reaction mixture was filtered and then the solid was washed with N-methylpyrrolidine (3 × 6 ml), methanol (3 × 6 ml) and again with N-methylpyrrolidine (3 × 6 ml) to obtain compound 21.

Commercially available Nα-(9-fluorenylmethoxycarbonyl)-Nδ-(tert-butoxycarbonyl)-L-ornithine (2 ml of 0.5 molar rastvorov N methylpyrrolidine), 1,3-diisopropylcarbodiimide (2 ml of 0.5 molar solution in N-methylpyrrolidine) and 1-hydroxybenzotriazole (2 ml of 0.5 molar solution in N-methylpyrrolidine) was added to the resin 21. The reaction mixture was stirred for one hour, then filtered and the accession repeated. The reaction mixture was filtered and then the solid was washed with N-methylpyrrolidine (3 × 6 ml), methanol (3 × 6 ml) and again with N-methylpyrrolidine (3 × 6 ml) to give compound 22.

Compound 22 was dissolved in 20% piperidine in N-methylpyrrolidone (6 ml) for 30 minutes. The resin was filtered and re-suspended in 20% piperidine in N-methylpyrrolidone (6 ml) and was shaken for 30 minutes. The reaction mixture was filtered and then the solid was washed with N-methylpyrrolidine (3 × 6 ml), methanol (3 × 6 ml) and again with N-methylpyrrolidine (3 × 6 ml) to obtain compound (9).

Example 3: Synthesis of peptide resin compound 23:

The peptide resin 1 (2 g) was added to a solution of pentafluorophenyl ester decanoas acid 24 (440 mg, obtaining connection 24 see example 6, reaction 1) in dichloromethane. The mixture was stirred for 17 hours, filtered and using test Kaiser (see above), it was determined that the reaction was incomplete. Dekanovu acid (517 mg), 1-hydroxybenzotriazol is (446 mg) and 1,3-diisopropylcarbodiimide (438 μl) was dissolved in N-methylpyrrolidine (8 ml) and was stirred for one hour. Then to the mixture was added to the resin and stirred for 8 hours, filtered and washed with N-methylpyrrolidine (3 × 6 ml), methanol (3 × 6 ml) and again with N-methylpyrrolidine (3 × 6 ml). Using test Kaiser was found that the reaction proceeded completely with getting associated with the resin lipopeptide 23.

Example 4: Synthesis of compound 29:

L-2-N-(Allyloxycarbonyl)-4-(2-azidophenyl)-4-oxomethane acid 25 (636 mg, see example 15 (see below)), 4-dimethylaminopyridine (25 mg) and N-methyl-2-chloropyridine iodide (511 mg) was thoroughly washed with a stream of argon and then suspended in dichloromethane (10 ml). Was added triethylamine (560 μl) and the reaction mixture was stirred to obtain a homogeneous solution. To the solution was added lipopeptide resin 23 (667 mg) and the vessel was again purged with argon and was stirred for 17 hours. Took a 20 mg sample of the resin to verify completion of the reaction (20 mg resin in dichloromethane (0.6 ml), was treated with 2,2,2-triptoreline (0.2 ml) and acetic acid (0.2 ml) and was stirred for 3 hours. The reaction mixture was filtered and the solvent evaporated to obtain a residue. Analysis by liquid chromatography/mass spectrometry showed that the reaction has not gone completely. Adherence was assessed as incomplete, and therefore, the resin was dried PR is the reduced pressure in the course of 5 days, and the above connection was repeated for another 17 hours. The reaction mixture was filtered and the solid was thoroughly washed with dichloromethane. The solid is then suspended in dichloromethane (6 ml), 2,2,2-triptoreline (2 ml), acetic acid (2 ml) and was stirred for 5 hours. The reaction mixture was filtered and evaporation of the filtrate gave the crude desired peptide 26 (44 mg). The crude product was purified HPLC with reversed phase (C18 10 μm column Jupiter 250 × 21,2 mm) with elution with a gradient mixture of 20% acetonitrile and 0.5% formic acid: 80% water and 0.5% formic acid to 80% acetonitrile and 0.5% formic acid: 20% water and 0.5% formic acid for 25 minutes. Containing the product fractions were liofilizovane with obtaining the pure product 26 a (10.6 mg).

To a solution of compound 26 (10,6 mg) in N-methylpyrrolidine (0.7 ml) was added hydroxybenzotriazole (5 mg), 1,3-diisopropylcarbodiimide (6 ml) and the peptide resin 9 (12.3 mg) and then stirred for 22 hours. The resin was filtered and completeness of accession was evaluated using a test Kaiser that gave associated with resin lipopeptide 27.

The dried resin 27 was placed in an argon atmosphere and treated with a solution of tetrakis-(triphenylphosphine)palladium(0) (19 mg) in dichloromethane (1,47 ml), acetic acid (74 μl) and N-methylmorpholin is (37 μl). The mixture was stirred for 4 hours at ambient temperature, filtered and the solid was washed twice with N-methylmorpholine, twice with methanol and once again two times N-methylmorpholine. To the resin was added 1-hydroxybenzotriazole (0.5 ml of a 0.5 molar solution in N-methylmorpholine) and 1,3-diisopropylcarbodiimide (0.5 ml of a 0.5 molar solution in N-methylmorpholine). The reaction mixture was stirred for 17 hours, filtered and thoroughly washed with N-methylmorpholine obtaining associated with resin cyklinowanie of depsipeptide 28.

The dried resin 28 suspended in dichloromethane (4 ml), triperoxonane acid (6 ml), acondition (250 μl) and triisopropylsilane (250 μl) and the reaction mixture was stirred for 3 hours at ambient temperature. The resin was filtered and the combined filtrates were evaporated under reduced pressure. The crude product is then subjected distribution between diethyl ether (6 ml) and water (3 ml). The aqueous layer was liofilizovane with obtaining a crude product. The crude product was purified HPLC with reversed phase (C18 10 μm column Jupiter 250 × 21,2 mm) with elution with a gradient mixture of 20% acetonitrile and 0.5% formic acid: 80% water and 0.5% formic acid to 80% acetonitrile and 0.5% formic acid: 20% water and 0.5% formic acid for 25 minutes. Containing the product f the shares were consolidated and were liofilizovane with obtaining the pure product 29 (1.0 mg).

Example 5: Synthesis of compound 33:

Commercially available Nα-(9-fluorenylmethoxycarbonyl)-L-isoleucine (95 mg), 4-dimethylaminopyridine (6 mg) and N-methyl-2-chloropyridine iodide (69 mg) was thoroughly washed with a stream of argon and then suspended in dichloromethane (2.7 ml). Was added triethylamine (76 μl) and the reaction mixture was stirred to obtain a homogeneous solution. To the solution was added lipopeptide resin 23 (200 mg) and the vessel was again purged with argon and then stirred for 14 hours. The resulting resin was then filtered and washed with dichloromethane. The solid is suspended in dichloromethane (6 ml), 2,2,2-triptoreline (2 ml) and acetic acid (2 ml) and was stirred for 3 hours. The resin was filtered and evaporation of the filtrate gave the desired peptide 30 (54 mg) as a white solid.

1-Hydroxybenzotriazole (26 mg), 1,3-diisopropylcarbodiimide (30 ml) and the peptide resin 9 (64 mg) was added to a solution of depsipeptide 30 (54 mg) in N-methylmorpholine (3.8 ml) and the resulting mixture was stirred for 22 hours. The resin was filtered and using test Kaiser adherence was assessed as complete obtaining associated with the resin depsipeptide 31.

The dried resin 31 was placed in the atmosphere arg is on and treated with a solution of tetrakis-(triphenylphosphine)palladium(0) (48 mg) in dichloromethane (7,63 ml)), acetic acid (0,38 ml) and N-methylmorpholine (0,19 ml). The mixture was stirred for 4 hours at ambient temperature, filtered and the solid was washed twice with N-methylmorpholine, twice with methanol and once again two times N-methylmorpholine. The solid resin was suspended in 20% piperidine in N-methylmorpholine (7 ml) for 105 minutes, filtered and the solid is thoroughly washed with N-methylmorpholine. To the resin was added 1-hydroxybenzotriazole (0.3 ml of a 0.5 molar solution in N-methylmorpholine) and 1,3-diisopropylcarbodiimide (0.3 ml of a 0.5 molar solution in N-methylmorpholine). The reaction mixture was stirred for 17 hours, filtered and the precipitate thoroughly washed with N-methylmorpholine obtaining associated with resin cyklinowanie of depsipeptide 32.

The dried resin 32 suspended in dichloromethane (4 ml), triperoxonane acid (6 ml), acondition (250 μl) and triisopropylsilane (250 ml) and was stirred for 3 hours at ambient temperature. The reaction mixture was filtered and washed with dichloromethane (2 × 2 ml) and the combined filtrates were evaporated under reduced pressure. The crude product is then subjected distribution between diethyl ether (6 ml) and water (3 ml). The aqueous layer was separated and was liofilizovane obtaining crude product 33 (21,5 mg). The crude product is then purified VE is X with reversed phase (C18 10 μm column Jupiter 250 × of 21.2 mm) with elution with a gradient mixture of 20% acetonitrile and 0.5% formic acid: 80% water and 0.5% formic acid to 80% acetonitrile and 0.5% formic acid: 20% water and 0.5% formic acid for 25 minutes. Containing the product fractions were combined and liofilizovane with obtaining the pure product 33 (1.8 mg).

Example 6: Synthesis of compound 34:

To a solution of commercially available decanoas acid (13,78 g)in tetrahydrofuran (40 ml) was added 1,3-diisopropylcarbodiimide (13,76 ml). After 5 minutes the solution was added pentafluorophenol (16,20 g) in tetrahydrofuran (40 ml) and the reaction mixture was stirred for 72 hours. The resulting mixture was filtered; the residue was washed with tetrahydrofuran (40 ml) and tertrahydrofuran ring filtrates were combined. The solvent is evaporated and the residue was purified on silica gel using a mixture of 9:1 hexane:ethyl acetate as eluent to give the desired product 24 in the form of oil (23,49 g).

A solution of commercially available Boc-L-3-benzothiadiazine 35 (1.0 g) in anhydrous methanol (20 ml) was cooled to 0°in a bath with ice. Was added dropwise thionyl chloride (1.63 g) and the reaction mixture was allowed to warm to ambient temperature for 16 hours. Evaporation of the solvent gave the crude product, which was subjected to the distribution between ethyl acetate and aqueous potassium bicarbonate. The organic layer is washed with aqueous potassium bicarbonate and saturated sodium chloride, dried with anhydrous sodium sulfate and evaporated to obtain the product 36 (0.66 g).

To a solution of methyl ester benzothiadiazine 36 (0.66 g) in tetrahydrofuran (10 ml) solution was added technolotechnology ether 24 (1.04 g) in tetrahydrofuran (10 ml). The resulting solution was stirred for 24 hours. The reaction mixture was poured into ethyl acetate and washed successively 1 N. hydrochloric acid, 10% aqueous potassium carbonate and saturated sodium chloride. The combined organic layer was then dried with anhydrous sodium sulfate and evaporated to obtain the product 37 (1.40 g), which was used as a raw agent in the following reaction.

The monohydrate of lithium hydroxide (0,59 g) was added to a solution of compound 37 (1.40 g), methanol (15 ml) and water (3 ml) and the reaction mixture was stirred for one hour. The methanol was removed by evaporation and the aqueous solution was acidified to pH 1 with 1 N. hydrochloric acid and was extracted with ethyl acetate. The organic layers were combined and dried with anhydrous sodium sulfate and evaporated to obtain the product 38.

1,3-Diisopropylcarbodiimide (121 mg) was added to the mortar joint is 38 (200 mg) and pentafluorophenol (108 mg) in tetrahydrofuran (5 ml) and the reaction mixture was stirred for one hour. The resulting mixture was filtered, the solvent evaporated and the residue was purified on silica gel. The application of a mixture of 9:1 hexane:ethyl acetate as eluent gave the pollution with greater mobility, and a mixture of 4:1 hexane:ethyl acetate as eluent gave the product 34 (80 mg).

Example 7: Synthesis of compound 39:

Compound 39 was obtained from commercially available compounds 40 under the above conditions as follows: Compound 39 was converted into the corresponding methyl ester under the conditions described in example 6, reaction 2. Methyl ether was etilirovany under the conditions described in example 6, reaction 3. Acylated compound was then saponifiable under the reaction conditions described in example 6, reaction 4. Saponification substance is then turned in the connection 39 with the conditions described in example 6, reaction 5.

Example 8: Synthesis of compound 41:

Commercially available compound 42 was converted into compound 43 under the conditions described in example 6, reaction 2.

Decanolide (0.51 ml) was added to a solution of methyl ester of the amino acid 43 (440 mg) and triethylamine (0,43 ml), cooled to 0°in a bath with ice. The reaction mixture was allowed to warm to ambient temperature for three cha is impressive. The reaction mixture was then poured into ethyl acetate and then washed with water and saturated sodium chloride. The organic layers were then dried with anhydrous sodium sulfate and evaporated to obtain the product 44.

Compound 44 was converted into compound 41 under the conditions described below. Compound 44 was saponifiable under the reaction conditions described in example 6, reaction 4. Saponification substance is then turned in the connection 41 under the conditions described in example 6, reaction 5.

Example 9: Synthesis of compound 45:

Compound 45 was obtained from commercially available compounds 46 under the above conditions as follows: Compound 46 was converted into the corresponding methyl ester under the conditions described in example 6, reaction 2. Methyl ether was etilirovany under the conditions described in example 8, the reaction of 2. Acylated compound was then saponifiable under the reaction conditions described in example 6, reaction 4. Saponification substance is then turned in the connection 45 under the conditions described in example 6, reaction 5.

Example 10: Synthesis of compound 47:

Commercially available compound 48 was treated under the conditions described above in example 6, reaction 3, to obtain the compound 4. Treatment of compound 49 as described in example 6, reaction 5, gave compound 47.

Example 11: Synthesis of compound 50:

Commercially available compound 51 was treated under the conditions described above in example 6, reaction 3, with the only modification involving the use of solvent is N,N'-dimethylformamide instead of the solvent of tetrahydrofuran, to obtain the connection 52. Treatment of compound 52 as described above in example 6, reaction 5, with the only modification involving the use of solvent is N,N'-dimethylformamide instead of the solvent tetrahydrofuran (THF) gave compound 50.

Example 12: Synthesis of compound 53:

A solution of commercially available ethylindole-2-carboxylate 54 (2 g), codekana (2.25 ml) and potassium carbonate (2,92 g) in anhydrous dimethylformamide (30 ml) was stirred for 24 hours. The reaction mixture was poured into ethyl acetate (200 ml) and washed with water (300 ml). The organic layer was then dried with anhydrous magnesium sulfate and evaporated to obtain the product 55 (2,604 g).

The lithium hydroxide/water (1.65 g) in water (16 ml) was added to a solution of compound 55 (2.6 g) in tetrahydrofuran (16 ml) and was stirred for 4 days. Added ethyl acetate (20 ml) and water (10 ml), the pH of the aqueous layer was brought on the 1 and was extracted with ethyl acetate (3 × 5 ml). The organic layers were combined, dried and evaporated to obtain an oil. The hydrolysis was incomplete, and therefore the oil was dissolved in methanol/water 2:1 was added potassium hydroxide (0.88 g). The reaction mixture was stirred for 15 hours. Added ethyl acetate (20 ml) and water (10 ml), the layers were separated, the pH of the aqueous layer was brought to 1 and was extracted with ethyl acetate (3 × 5 ml). The organic layers were combined, dried and evaporated to obtain the crude product in the form of oil, which was purified on silica gel using a mixture of 10:1 hexane:ethyl acetate as eluent to obtain the product 56 (0.35 g).

1,3-Diisopropylcarbodiimide (206 mg) was added to a solution of compound 56 (340 mg) and pentafluorophenol (227 mg) in dichloromethane (5 ml) and the reaction mixture was stirred for 15 hours. The mixture was suppressed hexane, filtered and the solvent evaporated. Purification of the residue on silica gel using a mixture of 20:1 hexane:ethyl acetate as eluent gave the product 53 (490 mg).

Example 13: Synthesis of compound 57:

To a commercially available solution of methyl ester of tryptophan 58 (2,54 g) and triethylamine (2.9 ml) in dichloromethane (10 ml) was added 4-dimethylaminopyridine (0.12 g) and acetic anhydride (1,03 ml). After 18 hours the reaction mixture is extinguished 1 N. hydrochloric what Isletas (10 ml) and the aqueous layer was extracted with ethyl acetate (3 × 10 ml). The combined organic layers were washed with saturated sodium bicarbonate and saturated sodium chloride, then dried with anhydrous sodium sulfate and evaporated to obtain crude product. Purification on silica gel using a mixture of 2:1 hexane:ethyl acetate gave the product 59 (1,99 g).

Connection 59 alkilirovanie under the conditions described above in example 8, the reaction of 2 with the replacement of potassium hydroxide to potassium carbonate to obtain the connection 60.

Hydrolysis of compound 60 using the procedure described in example 6, reaction of 4 gave compound 61.

Compound 61 was made in connection 57 using conditions described in example 6, reaction 4.

Example 14: Synthesis of compound 62:

Commercially available methyl ester of tryptophan 58 made in connection 63 by means of the conditions described in example 8, the reaction of 2.

Compound 63 was converted into compound 64 using conditions described in example 12, reaction 1, with the use of methyliodide instead of codekana.

The connection 64 hydrolyzed using conditions described in example 13, the reaction of 3 with connection 65.

Compound 65 was made in connection 62 using conditions described in example 13, the reaction of 4.

Example 15: Synthesis of compound 25:

To a suspension of commercially available L-2-amino-4-(2-AMINOPHENYL)-4-oxomalonate acid A (3,93 g) and triethylamine (5,79 ml) in tetrahydrofuran (181 ml) was added water in an amount sufficient to obtain a homogeneous solution. The solution is then cooled to 0°in a bath with ice and was added dropwise diallylmalonate (3,36 ml). The reaction mixture was allowed to warm to ambient temperature for 16 hours and then concentrated to one third of the original volume. The mixture was poured into dichloromethane (350 ml), washed with 1 N. hydrochloric acid (3 × 100 ml) and saturated sodium chloride (1 × 100 ml). The combined aqueous layers was extracted again with ethyl acetate (4 × 100 ml) and the combined organic fraction was dried with anhydrous sodium sulfate. Evaporation of the solvent gave the product B in the form of a yellow solid (5,14 g).

To a solution of compound B (of 5.00 g) in water (130 ml) and concentrated hydrochloric acid (43 ml) at -2°C was added dropwise a solution of sodium nitrite (1,30 g) in water (3 ml), so that the temperature remained below 0°C. the Reaction mixture is displaced is ivali at -4° With over 135 minutes and the solution was added sodium azide (3,34 g) in water (3 ml). The reaction mixture was allowed to warm to ambient temperature for 16 hours. The mixture was then poured into water (130 ml) and the aqueous phase was extracted with dichloromethane (4 × 80 ml). The combined organic layer was then dried with anhydrous sodium sulfate. Evaporation of the solvent gave the product 25 as an orange foam (5,14 g).

Example 16: Synthesis of compound 77:

To a suspension of commercially available 2-hortatives resin C (1 g) and commercially available 2-N-(9-fluorenylmethoxycarbonyl)-4-N - (tert-butoxycarbonyl)-L-2,4-diaminoalkanes acid in dichloromethane D (10 ml) was added diisopropylethylamine (1.65 ml). The mixture was stirred for 3 hours, filtered and the solid washed with dichloromethane (10 ml), then dried to obtain compound E.

Compound E was dissolved in 20% piperidine in N-methylpyrrolidone (20 ml) for 60 minutes. The reaction mixture was filtered, after which the solid was washed with N-methylpyrrolidinone (20 ml) to obtain compound F.

Diisopropylethylamine (0.5 ml) was added to a solution of commercially available Nα-(9-fluorenylmethoxycarbonyl)-L-tryptophan (1,23 g), TBTU (0,92 g) and N,N-dimethylformamide (10 ml)and the resulting mixture was stirred for 10 minutes. Then the solution was added to the resin F was stirred for one hour, filtered and the solid washed with N-methylpyrrolidinone (10 ml) to obtain compound G.

Compound G was dissolved in 20% piperidine in N-methylpyrrolidone (20 ml) for 60 minutes. The reaction mixture was filtered, after which the solid was washed with N-methylpyrrolidinone (20 ml) to obtain compound H.

Diisopropylethylamine (0.5 ml) was added to a solution of commercially available decanoas acid (0.50 g), TBTU (0,92 g) and N,N-dimethylformamide (15 ml) and the resulting mixture was stirred for 10 minutes. Then the solution was added to the resin H, was stirred for one hour, filtered and the solid washed with N-methylpyrrolidinone (10 ml) to obtain compound I.

The connection I was treated with a mixture of dichloromethane:2,2,2-triptoreline:acetic acid (3:1:1) and the resulting mixture was stirred for 3 hours. The reaction mixture is then filtered and the filtrate was evaporated to obtain compound J in the form of a white solid (180 mg).

Compound J was made in connection 77 using conditions described in example 6, reaction 4.

Example 17: Synthesis of protected Alloc of daptomycin:

compound 67:

To a solution of daptomycin 66 (10 g) in anhydrous N,N'-dimethylformamide (40 ml) at 0°With added allyl-1-benzothiazolinone (13.5 g). The reaction mixture was allowed to warm to room temperature and was stirred for 18 hours. The mixture was diluted with water (200 ml), then were applied to the resin Bondesil 40 μm C8 (400 g), which was pre-washed with methanol (1 l) and water (1 l). The resin was washed with water (1 l)and the product was suirable methanol (1 liter). Evaporation of the methanol gave compound 67 as a yellow solid (1 g).

Example 18: the connection 68:

The preparation of the enzyme deacylase received from recombinant Streptomyces lividans, which expresses the enzyme deacylase Actinoplanes utahensis. The enzyme in aqueous ethylene glycol (10 ml) was added to a solution of compound 67 (15 g in water, 1.9 l) at pH 8. The reaction mixture was stirred at room temperature for 18 hours and the pH was brought to 8 with 1 M sodium hydroxide. The reaction mixture was poured into a resin Bondesil 40 μm C8 (400 g), which was pre-washed with methanol (1 l) and water (1 l). The product was suirable 20% acetonitrile in water (1 l) and was liofilizovane getting connection 68 in the form of a yellow solid (9.1 g).

Example. 19: Degradation by Admino removal tryptophan preparation of compound 70:

To suspend and connection 68 (9.1 g) in anhydrous N,N'-dimethylformamide (15 ml) was added n-dutilisation (1.2 ml). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into a resin Bondesil 40 μm C8 (400 g), which was pre-washed with methanol (1 l) and water (1 l). The product was suirable methanol (800 ml) after being washed with water (800 ml) and then with 20% acetonitrile in water (800 ml). Evaporation of the methanol gave compound 69 as a yellow solid (7.3 km).

Compound 69 (7,3 g) was stirred at room temperature in 25% triperoxonane acid in anhydrous dichloromethane (30 ml) for 2 hours before evaporation to dryness. The residue was dissolved in water (50 ml) and poured on the resin Bondesil 40 μm C8 (400 g), which was pre-washed with methanol (1 l) and water (1 l). The product was suirable gradient from 20 to 40% acetonitrile in water and liofilizovane getting connection 70 in the form of a yellow solid (1,05 g).

Example. 20: Degradation by Admino to remove aspartic drug desparaging connection 72:

To a suspension of compound 70 (0,57 g) in anhydrous N,N'-dimethylformamide (5 ml) was added n-dutilisation (0.16 ml). The reaction mixture was stirred at room temperature for 18 hours before evaporation to dryness. The residue is triturated with diethyl ether (5 ml) to give compound 71 in the form of a yellow solid is th substances (0.54 g).

Compound 71 (0.54 g) was stirred in 50% triperoxonane acid in anhydrous dichloromethane (4 ml) for 2 hours before evaporation to dryness. The residue was dissolved in water (25 ml) and poured on the resin Bondesil 40 μm C8 (50 g), which was pre-washed with methanol (100 ml) and water (100 ml). The product was suirable 20% acetonitrile in water after being washed with water (100 ml). Eluent evaporated to dryness to obtain compound 72 as a yellow solid (0.40 g).

Example. 21: Degradation by Admino removal of the drug aspartic acid basic compound 74:

To a suspension of compound 72 (1.0 mmol) in anhydrous N,N'-dimethylformamide (5 ml) was added phenylisothiocyanate (1.0 mmol). The reaction mixture was stirred at ambient temperature for 18 hours and then evaporated to dryness. The residue is triturated with diethyl ether (5 ml) to give the product 73.

Compound 73 was stirred in dichloromethane (2 ml) and triperoxonane acid (2 ml) for 2 hours before evaporation to dryness to obtain the product as a salt triperoxonane acid 74.

Example 22: connection 76:

Compound 50 (397 mg) was added to a solution of decelerating descriptionwho daptomycin is and 70 (500 mg) and diisopropylethylamine (2-3 drops) in N,N'-dimethylformamide (5 ml). The reaction was monitored by analytical HPLC with reversed phase (elution with a gradient mixture of from 5% to 95% acetonitrile and 0.1% formic acid in water and 0.1% formic acid using luna C18 5 μm (150 × 3 mm) and complete consumption of compound 70 was observed after stirring for 16 hours. The solvent was removed by evaporation and the crude product 75 (631 mg) was then applied to the next stage.

Tetrakis-(triphenylphosphine)palladium(0) (631 mg) was added to a solution of compound 75 (631 mg), N-methylmorpholine (631 μl) in dioxane (10 ml) and 1 N. hydrochloric acid (of 6.31 ml). After stirring for 16 hours the reaction mixture was filtered and purified HPLC with reversed phase using column C18 10 μm Jupiter 250 × 21,2 mm, elution with a gradient mixture of acetonitrile:water:formic acid is from 30:70:0.1 to 90:10:0.1 V for 25 minutes. Evaporation containing the product fractions gave the product 76 (44 mg).

Example 23: Obtaining connection 79:

Compound 77 (1.2 mmol, see example 16 (see above)) was added to a solution of decelerating description-desparaging of daptomycin 72 (1.0 mmol) and diisopropylethylamine (2-3 drops) in anhydrous dimethylformamide (5 ml). The reaction mixture was stirred at ambient temperature before spending the entire source of the substance is about data analytical HPLC with reversed phase (elution with a gradient mixture of from 5% to 95% acetonitrile - of 0.1% formic acid in water and 0.1% formic acid using luna C18 5 μm 150 × 3 mm). The mixture was evaporated to dryness and the residue triturated with ether (5 ml) to give the desired product 78.

To a solution of compound 78 (1 mmol) in 0.5 M hydrochloric acid (1 ml) and dioxane (3 ml) was added N-methylmorpholine (0.1 ml) and tetrakis-(triphenylphosphine)palladium(0) (100 mg). The reaction mixture was stirred in an argon atmosphere for 24 hours, filtered and concentrated to obtain the crude intermediate. The residue was dissolved in anhydrous dichloromethane (4 ml). Added triisopropylsilane (0.1 ml) and triperoxonane acid (1 ml) and the reaction mixture was stirred for 2 hours before evaporation to dryness. The residue was purified preparative HPLC using C8 column 10 µm Jupiter 250 × 21,2 mm, elution with a gradient of 30-80% acetonitrile in water with 0.1% formic acid as eluent. Evaporation of the solvent containing the product fractions gave the desired product in 79.

Example 24

Biological activity

Compounds according to formula I were tested for antimicrobial activity with a set of organisms in accordance with standard procedures described by the National Committee for clinical laboratory standards (NCCLS document M7-A5, Vol. 20, No. 2, 2000), except that all testing p is bodily at 37° C. Compounds were dissolved in 100% dimethyl sulfoxide and diluted to a final reaction concentration of 0.1 μg/ml-100 μg/ml) in the environment of microbial growth. In all cases the final concentration of DMSO in the incubation with the cells was less than or equal to 1%. For the calculation of the minimum inhibitory concentration (MIC) in the wells for micrometrology containing 5x104bacterial cells in a final volume of 100 μl medium (broth Mueller-Hinton with the addition of 50 mg/l of Ca2+) was added 2-fold dilution of the compounds. Using a commercially available tablet reader measured the optical density (OD) of bacterial cells, which is a measure of the growth and proliferation of bacteria. MIC was defined as the lowest concentration of compounds inhibitory to the growth of the test organism. The MIC values (μg/ml) typical compounds of the present invention are listed in table III.

Table III

The biological activity of the compounds of formula I

SA399 is a methicillin-resistant Staphylococcus aureus.

SA42 is a Staphylococcus aureus wild-type.

EF14 represents Enterococcus faecium wild-type.

EF201 represents Enterococcus faecalis wild-type.

Where "+++" indicates that the compound has an MIC (μg/ml 1 μg/ml or below or ED501 mg/kg and below;

"++" indicates that the compound has an MIC (μg/ml) or ED50more than 1 μg/ml or 1 mg/kg, respectively, but less than or equal to 10 µg/ml or 10 mg/kg for ED50, respectively; and

"+" indicates that the compound has an MIC (µg/ml) higher than 10 µg/ml or ED50above 10 mg/kg

Example 25

Activity in vivo

Test protection of mice is an industry standard for measuring the effectiveness of test compounds in vivo [examples of this model, see J. J. Clement, et al., Antimicrobial Agents and Chemotherapy, 38 (5), 1071-1078, (1994)]. As illustrated below, this test is used to demonstrate the effectiveness of compounds of the present invention against bacteria in vivo.

Antibacterial activity in vivo detected by infection of female mice CD-1 (Charles River Lab, MA) weighing 19-23 g intraperitoneally methicillin-resistant the inoculum of S. aureus (MRSA). The inoculum is obtained from methicillin-resistant S. aureus (ATCC 43300). The inoculum of MRSA cultured in broth Mueller-Hinton (MH) at 37°C for 18 hours. The optical density at 600 nm (OD600) determine dilution 1:10 night culture. Bacteria (8 × 108SOME) are added to 20 ml of phosphate buffered saline (Sigma P-0261)containing 5% hog gastric mucin (Sigma M-2378). All animals injected with 0.5 ml of inoculum equivalent to 2 × 107cfu/mouse, what is with the Oh dose, causing 100% mortality of animals without treatment.

The test compound dissolved in 10.0 ml of 50 mm phosphate buffer to obtain a solution of 1 mg/ml (pH 7.0). The solution is serially diluted with carrier 4 times (1.5 ml to 6.0 ml) to obtain the solutions of 0.25, 0,063 and 0,016 mg/ml. All solutions are filtered using a filter for syringe 2 m Nalgene. Immediately after bacterial inoculation group 1 animals subcutaneously (s/C) is injected buffer (without test compound), and groups 2 through 5 receive the test compound p in a dose of 10.0 and 2.5, 0.63 and 0.16 mg/kg, respectively. Group 6 animals receives the test compound p in a dose of 10 mg/kg (or highest therapeutic dose of this compound) only for tracking acute toxicity. Data repeat injections again for the respective groups after 4 hours after inoculation. The volume of injection each time is 10 ml per kilogram of body weight. 50% protective dose (PD50) calculated based on the number of surviving mice 7 days after inoculation.

All publications and patent applications cited herein, incorporated herein by reference, as if each publication or patent application was specifically and individually indicated that it is included as a reference. Although the above invention has been described in some detail in the form of illustrations and examples to facilitate under the tion, in the light of the indications of this invention to a person skilled in the technical field should be obvious that it can be made certain changes and modifications without going beyond the spirit and scope of the attached claims.

1. The compound of the formula

or its pharmaceutically acceptable salt,

where R represents 2-butyl, isopropyl or 2-(2'-aminopentyl);

each of R1and R6independently represents hydrogen or methyl;

R2represents-CH2CH2CH2R8where R8represents amino or carbarnoyl;

R3represents methyl;

R4represents hydrogen;

R5represents hydroxy;

R7selected from the group consisting of

or R7represents a

where

Raa1represents CH2

Raa2represents CH2CONH2;

R13represents an amino group, cheoreography formula

where

Rx19and Rx20each independently represents hydrogen; Rx21is a (C1-C10)alkyl or (C6-C10)aryl.

2. The compound according to claim 1, where R represents a 2-(2'-aminopentyl); each of R1and R4represents hydrogen; R2represents - CH2CH2CH2R8; each of R3and R6represents methyl and R5represents hydroxyl.

3. The compound according to claim 1, where R is a 2-butyl or isopropyl; each of R1and R3represents methyl; R2represents-CH2CH2CH2NH2; R4represents hydrogen and R5represents hydroxy.

4. The compound according to claim 2 or 3, where R7selected from the group consisting of

5. Joint who according to claim 1, where R7represents a

where

Raa1represents CH2COOH;

Raa2represents CH2CONH2;

R13represents an amino group, cheoreography formula

where

Rx19and Rx20each independently represents hydrogen; Rx21is a (C1-C10)alkyl or (C6-C10)aryl.

6. The compound according to claim 5, where R represents a 2-(2'-aminopentyl); each of R1and R4represents hydrogen; R2represents - CH2CH2CH2R8; each of R3and R6represents methyl and R5represents hydroxyl.

7. The compound according to claim 5, where R is a 2-butyl or isopropyl; each of R1and R3represents methyl; and R2represents-CH2CH2CH2R8where R8represents amino or carbarnoyl; R4represents hydrogen and R5represents hydroxyl.

8. The compound of formula IV

or its pharmaceutically acceptable salt, where

(a) R is a 2-butyl, isopropyl or 2-(2'-aminopentyl);

(b) each of R1 and R6independently represents hydrogen or methyl;

(c) R4represents hydrogen;

(d) R5represents hydroxy;

(e) R15represents hydrogen,

or

where R18represents amino or hydroxy; R19represents hydrogen and R20represents carboxamido;

(f) R16represents methyl or-CH2CH2CH2R21;

(d) R17represents methyl;

where R21independently represents an amino or carbarnoyl.

9. The connection of claim 8, where R21represents an amino group.

10. The compound of claim 8 where the compound of formula I is a

where each of R6and R14represents independently hydrogen or methyl.

11. Pharmaceutical composition having antibacterial activity comprising a therapeutically effective amount of the compounds of formula I according to claim 1.

12. The composition according to claim 11, where R represents a 2-(2'-aminopentyl); each of R1and R4represents hydrogen; R2represents-CH2CH 2CH2R8; each of R3and R6represents methyl and R5represents hydroxyl.

13. The composition according to claim 11, where R is a 2-butyl or isopropyl; each of R1represents hydrogen and R2represents - CH2CH2CH2R8; each of R3represents methyl; R4represents hydrogen and R5represents hydroxyl.

14. The composition according to claim 11, comprising a compound of formula I according to claim 1 where R7represents a

where

RAa1represents CH2COOH;

RAa2represents CH2CONH2;

R13represents an amino group, cheoreography.

15. The use of compounds according to claim 1 for the preparation of medicines for treatment of bacterial infections.

16. The method of obtaining the compounds of formula I

or its salt,

where R represents 2-butyl, isopropyl or 2-(2'-aminopentyl);

each of R1and R6independently represents hydrogen or methyl;

R2represents-CH2CH2CH2R8where R8represents amino or carbarnoyl;

R3represents methyl;

R4represents hydrogen;

R5represents hydroxy;

R7selected from the group consisting of

or R7represents a

where RAa1represents CH2COOH;

RAa2represents CH2CONH2;

R13represents an amino group, cheoreography formula

where Rx19and RX20each independently represents hydrogen; RX21is a (C1-C10)alkyl or (C6-C10)aryl,

including the removal of aminosidine group of the compounds of formula XVII

or its pharmaceutically acceptable salt,

where R28represents-CH2CH2CH2NHP; R29represents methyl and R represents aminosidine group.

17. The method according to clause 16, in addition VK is uchumi treatment of compounds of formula XVI

or its pharmaceutically acceptable salt, a modifying agent to obtain compounds of formula XVII, or its salts.

18. The method according to 17, further including the removal of the terminal amino acid residue of the compounds of formula XV

or its pharmaceutically acceptable salt,

where R18represents hydroxy; R19represents hydrogen;

obtaining the compounds of formula XVI, or its pharmaceutically acceptable salt.

19. The method according to p, additionally including the removal of the terminal amino acid residue of the compounds of formula XIV

or its pharmaceutically acceptable salt,

where R20represents carboxamido;

obtaining the compounds of formula XV or its salts.

20. The method according to claim 19, further including the removal of the tryptophan amino acid residue from the compounds of formula XIII

or its pharmaceutically acceptable salt with obtaining the compounds of formula XIV or its salts.

21. The method according to claim 20, further comprising disallowance the compounds of formula XII

or its pharmaceutically acceptable salt

where R25represents an alkyl group,

obtaining the compounds of formula XIII or its pharmaceutically acceptable salt.

22. The method according to item 21, further including the protection of the free(data) amino(PP) compounds of the formula XI

or its pharmaceutically acceptable salt,

where R26represents methyl or-CH2CH2CH2NH2; a R27represents methyl;

obtaining the compounds of formula XII or its pharmaceutically acceptable salt.

23. The method of obtaining the compounds of formula I

or its pharmaceutically acceptable salt,

where R represents 2-butyl, isopropyl or 2-(2'-aminopentyl);

each of R1and R6independently represents hydrogen or methyl;

R2represents-CH2CH2CH2R8where R8represents amino or carbarnoyl;

R3represents methyl;

R4represents hydrogen;

R5represents hydroxy;

R7selected from the group consisting of

or R7represents a

where Raa1represents CH2COOH;

RAa2represents CH2CONH2;

R13represents an amino group, cheoreography formula

RX19and RX20each independently represents hydrogen; RX21is a (C1-C10)alkyl or (C6-C10) aryl,

includes treatment of compounds of formula Ia

or its pharmaceutically acceptable salt,

where R2Arepresents-CH2CH2CH2NH2; and R3Arepresents methyl; modifying agent.

24. The method of obtaining the compounds of formula I

or its pharmaceutically acceptable salt,

where R represents 2-butyl, isopropyl or 2-(2'-aminopentyl);

each of R1and R6independently represents hydrogen or methyl;

R2represents-CH2CH2CH2R 8where R8represents amino or carbarnoyl;

R3represents methyl;

R4represents hydrogen;

R5represents hydroxy;

R7selected from the group consisting of

or R7represents a

where Raa1represents CH2COOH;

RAa2represents CH2CONH2;

R13represents an amino group, cheoreography formula

where RX9and RX20each independently represents hydrogen; RX21is a (C1-C10)alkyl or (C6-C10)aryl,

includes treatment of compounds of formula XXVIII

or its pharmaceutically acceptable salt,

where R37represents-CH2CH2CH2R8and R38represents IU the sludge, the modifying agent.

25. The method according to paragraph 24, further including the removal of the terminal amino acid residue of the compounds of formula XXVII

or its pharmaceutically acceptable salt,

where R18represents hydroxy and R19represents hydrogen,

obtaining the compounds of formula XXVIII or its pharmaceutically acceptable salt.

26. The method according to p. 25, further including the removal of the terminal amino acid residue of the compounds of formula XXVI

or its pharmaceutically acceptable salt,

where R20represents carboxamido,

obtaining the compounds of formula XVII, or its pharmaceutically acceptable salt.

27. The method according to p, additionally including the removal of the tryptophan amino acid residue from the compounds of formula XXV

or its pharmaceutically acceptable salt with obtaining the compounds of formula XVII, or its pharmaceutically acceptable salt.

28. The method according to item 27, further comprising diallylamine the compounds of formula XXIV

or its pharmaceutically acceptable salt,

where R25represents an alkyl group, with the receipt with the unity of formula XXV or its pharmaceutically acceptable salt.

29. The method according to p, further comprising processing free(data) amino(PP) compounds of the formula XI

or its pharmaceutically acceptable salt,

where R26represents methyl or-CH2CH2CH2NH2and R27represents methyl, the modifying agent to obtain compounds of formula XXV or its pharmaceutically acceptable salt.

30. The method of obtaining the compounds of formula XXXII

or its pharmaceutically acceptable salt,

where (a) R is a 2-butyl, isopropyl or 2-(2'-aminopentyl);

(b) each of R1and R6independently represents hydrogen or methyl;

(c) R4represents hydrogen;

(d) R5represents hydroxy or carboxamido;

(e) R18represents amino or hydroxy;

(f) R19represents hydrogen;

(g) R20represents carboxamido;

(h) R28represents-CH2CH2CH2NHP;

(i) R29represents methyl;

(j) P is aminosidine group;

(l) provided that,

(1) when R2represents-CH2CH2CH2R8, 7is different from the

where R10represents amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbarnoyl, sulfonamide, thioacetamide, minamino or postonline;

(2) when R2represents methyl, R7is different from the

where each of R11and R12represents hydrogen, C6-C18the unsubstituted alkanoyl, C8-C18the unsubstituted alkenyl, C8-C18unsubstituted alkyl or C8-C18selected substituted alkyl; or alternatively R11and R12together represent a8-C18alkylidene;

includes treatment of compounds of formula XIV

or its pharmaceutically acceptable salt, a modifying agent.

31. The method of obtaining the compounds of formula XXXIV

or its pharmaceutically acceptable salt;

where R represents 2-butyl, isopropyl or 2-(2'-aminopentyl);

each of R1and R6independently represents hydrogen or methyl;

R4represents hydrogen;

R5represents hydroxy or carbox is amino;

R18represents amino or hydroxy;

R19represents hydrogen;

R20represents carboxamido;

R28represents-CH2CH2CH2NHP;

R29represents methyl;

R represents aminosidine group;

R39independently represents an amino, touraid;

(k) provided that, (1) when R2represents-CH2CH2CH2R8, R7is different from the

where R10represents amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbarnoyl, sulfonamide, thioacetamide, minamino or postonline;

(2) when R2represents methyl, R7is different from the

where each of R11and R12represents hydrogen, C6-C18the unsubstituted alkanoyl, C8-C18the unsubstituted alkenyl, C8-C18unsubstituted alkyl or C8-C18selected substituted alkyl; or alternatively R11and R12together represent a C8-C18alkylidene,

includes treatment of compounds of formula XV

or its pharmaceutically acceptable salt, a modifying agent.



 

Same patents:

The invention relates to the field of medicine

FIELD: chemistry.

SUBSTANCE: method of obtaining dodecapeptide of the formula I: H-Asp-His-Leu-Asp-Lys-Gln-Thr-Gln-Thr-Pro-Lys-Thr-OH and tripeptide of the formula II: X-Asp(Y)-His-Leu-OH is the intermediate compound in its synthesis. Solid-phase synthesis of dodecapeptide I is realised by sequential growth of the peptide chain, beginning with the C-end dipeptidilpolymertill the obtaining of C-end nonapeptidilpolimer, which is condensed with the protected N-end tripeptide of the formula II: X-Asp (Y)-His-Leu-OH where X, Y are protected groups and the obtained dodecapeptidilpolymer is processed with an unblocking agent for removing the protective groups and the polymeric matrix and in 1 stage the end product is given out by means of HELC.

EFFECT: increasing the output of the end product and simplification of the process.

3 cl, 2 ex

FIELD: medicine; pharmacology.

SUBSTANCE: essence of the invention includes an agent for external application which structure includes a peptide from the allopherones group, allostatin-1 and auxiliary substances. The offered agent is applied to treatment of diseases of a skin and mucosa caused by a virus of herpes, a virus of papilloma, and also cosmetic defects of a skin.

EFFECT: scope expansion.

4 cl, 1 dwg, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention concerns biologically active compounds with inhibition effect on binding antigen with II class MHC molecules, particularly with II class MHC molecule HLA-DR2. Also, the invention proposes pharmaceutical compositions containing such compounds, and their application in obtaining medications for treatment or prevention of diseases connected to T-cell proliferation, such as autoimmune diseases and disorders of inhibition of binding II class MHC molecule HLA-DR2.

EFFECT: obtaining pharmaceutical composition for treatment or prevention of diseases connected with T-cell proliferation.

17 cl, 4 tbl, 6 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to methods of self-specific T-cell vaccine production. Self-specific T-cell vaccine for disseminated sclerosis treatment includes attenuated T-cells which are reactive relative to one or several epitopes, yet SEQ ID NOS: 1-6 contain these epitopes. Invention is intended for treatment of autoimmune diseases, such as disseminated sclerosis or rheumatoid arthritis using self-specific T-cell vaccines. Besides, invention provides diagnostics of diseases associated with T-cells. Advantage of this invention implies that it can be applied for production of T-call vaccines with heterogenous gene VR-Dp-JR to take into consideration clonal shift if self-reactive T-cells.

EFFECT: method has improved efficiency.

10 cl, 7 ex, 2 dwg

FIELD: medicine, biotechnology.

SUBSTANCE: invention proposes variants of antibodies showing specificity to peptide domain located by both side of hinged site R76S77 in pro-BNP(1-108). Indicated antibodies recognize specifically also circulating pro-BNP(1-108) in human serum or plasma samples but they don't recognize practically peptides BNP(1-76) or BNP(77-108). Also, invention describes variants of peptides used in preparing antibodies. Amino acid sequence is given in the invention description. Also, invention discloses methods for preparing indicated antibodies and among of them by using indicated peptides. Also, invention describes methods for preparing antibody-secreting hybridoma, and hybridoma is disclosed prepared by indicated method. Also, invention describes a monoclonal antibody secreted by hybridoma 3D4 and deposited at number CNCM I-3073. Also, invention discloses variants for diagnosis of cardiac insufficiency in vitro and by using antibodies proposed by the invention. Also, invention describes a set used for detecting pro-BNP(1-108) in a biological sample. Using this invention simplifies detection of pro-BNP(1-108) circulating in human serum or plasma samples and provides specific detection of pro-BNP(1-108) that can be used in early diagnosis of human cardiac insufficiency.

EFFECT: valuable medicinal properties of antibodies.

24 cl, 16 dwg, 5 tbl, 20 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to an improved chelate conjugates of the formula: wherein each R1, R2 and R3 represents independently R group; Y represents -(A)n-X-Z wherein X represents -NH-, -CO2-, -N(C=O)-; Z represents a biological group for directed delivery that is chosen from 3-20-membered peptide, substrate for enzyme, enzyme inhibitor or synthetic compound binding with receptor; -(A)n represent linker wherein each A represents independently -CR2-, -NRCO-, -CONR-, -CR2OCR2 or polyalkylene glycol group; n represents a whole number from 2 to 10; each R group represents independently hydrogen atom (H) or (C1-C10)-alkyl, or two R groups in common with atoms to which they are added form (C3-C6)-carbocyclic saturated ring. Complexes with radioactive metals are useful as radioactive pharmaceutical preparation, especially, with 99mTc.

EFFECT: valuable medicinal properties of conjugates.

30 cl, 3 tbl, 4 dwg, 30 ex

FIELD: medicine, oncology, immunology.

SUBSTANCE: invention relates to antibodies directed on EGF-receptor (HER1) for designation to human, in particularly, for therapeutic using in tumors. Antibodies represent modified antibodies wherein their modification results to reduced tendency to induce immune response after their administration in human. In particular, invention relates to modification of anti-EGER antibody 425 in its different forms and their fragments that results to preparing variants of Mab 425 that are essentially not immunogenic or less immunogenic as compared with any their unmodified equivalent in using in vivo. The advantage of invention involves reducing immunogenicity of antibody.

EFFECT: improved and valuable properties of antibodies.

10 cl, 5 tbl, 1 ex

FIELD: medicine, polypeptides.

SUBSTANCE: invention relates to fusion polypeptides with enhanced pharmacokinetic properties. Fusion polypeptides comprising enhancing peptide sequences associated with the core polypeptide possess with the enhanced pharmacokinetic properties, such as prolonged half-time period. Also, invention relates to methods for enhancing pharmacokinetic properties of any core polypeptide by binding the enhancer peptide sequences with the core polypeptide. Proposed core polypeptides can comprise any pharmacologically useful peptide that can be used, for example, the therapeutic or prophylactic agent. The advantage of invention involves the enhancing of pharmacokinetic properties of polypeptides.

EFFECT: enhanced pharmacokinetic properties of polypeptides.

52 cl, 18 dwg, 14 tbl, 11 ex

FIELD: biotechnology, medicine, oncology.

SUBSTANCE: invention relates to peptides found by selection of phage peptide library by a feature for selective binding with target-cells. These peptides are able to accumulate in lung adenocarcinoma cells and show the following amino acid sequences: RNVPPIFNDVYWIAF, SVAILPRSFSPFXVG, PFARAPVEHHDVVGL. New tumor-targeted peptides allow carrying out the purposeful delivery of preparation of different designation to lung adenocarcinoma cells. Invention can be used in medicine in treatment and diagnosis of lung adenocarcinoma and its metastasis.

EFFECT: valuable medicinal properties of peptides.

2 dwg, 2 ex

FIELD: chemistry of peptides, medicine.

SUBSTANCE: invention relates to preparing new peptides possessing immunomodulating, anti-proliferative, anti-tumor and antiviral activity. Invention proposes new peptides comprising up to 30 amino acid residues of the general structural formula: X1-Trp-Gly-Gln-X2 wherein X1 is taken among the following group: -His-Gly-Val-Ser-Gly-, -His-Gly-Gly-Gly-, -His-Val-Gly-Gly-, -His-Gly-Gly-Gly-Gly-, and -Gln-Gly-Gly-Gly-Gly, or absent; X2 is taken among the following group: -His-Gly-Thr-His-Gly, -Gly-Gly-Thr-His-Gly, -Pro-His-Val-Gly-Gly, -Pro-His-Gly-Gly-Gly, -Pro-His-Gly-Gly-Gly-Trp-Gly, -Gly-Gly-Gly-Thr-His-Ser, or absent.

EFFECT: valuable medicinal properties of peptides.

8 cl, 5 tbl, 5 dwg, 6 ex

FIELD: chemistry.

SUBSTANCE: invention concerns crystalline azithromycin L-malate monohydrate of formula (I) with high stability, solubility and non-hygroscopicity. Also invention concerns pharmaceutical composition for microbe infection treatment, based on compound of the formula (I), and method of obtaining compound of the formula (I), involving: a) interaction of azithromycin with malic acid in aqueous organic solvent, or b) recrystallisation of water-free azithromycin L-malate from aqueous organic solvent.

EFFECT: obtaining crystalline azithromycin L-malate monohydrate of formula (I) with high stability, solubility and non-hygroscopicity.

15 cl, 7 tbl, 7 dwg, 18 ex

FIELD: chemistry.

SUBSTANCE: compounds of the invention have chemokine antagonistic properties and can be applied in treatment of immunoinflammatory diseases, such as atherosclerosis, allergy diseases. In general formula (I) R1 is hydrogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxyl, cyclopropylmethoxy group, (C1-C4)-alkylthio group; R2 is halogen atom, (C1-C8)-alkyl, perfluoro-(C1-C4)-alkyl, (C3-C10)-cycloalkyl, phenyl, (C1-C8)-alkoxyl, values of the other radicals are indicated in the claim of the invention.

EFFECT: improved properties.

14 cl, 7 tbl, 20 dwg, 17 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula (I) and their pharmaceutically acceptable salts. Claimed compounds have antibacterial effect. In formula (I) , X is ; R1 is i) hydrogen, ii) (CH2)nNR5R6, iv) NRCO2R, v) (C1-6alkyl)CN, CN, (CH2)pOH; Y is NR*, O or S(O)p; is phenyl or 5-6-member heteroaryl with N or S as heteroatoms; R3 is NR(C=X2)R12, NR*R12, or -(O)n-5-6-member heteroaryl with 1-3 heteroatoms selected out of N, O, which can be linked over either carbon atom or heteroatom; the indicated 5-6-member heteroaryl can be optionally substituted by 1-3 groups of R7; R4, R4a, R4b and R4c are independently i) hydrogen, ii) halogen; other radicals are defined in the claim.

EFFECT: pharmaceutical composition containing effective volume of the claimed compound.

13 cl, 1 dwg, 194 ex

FIELD: medicine; veterinary science.

SUBSTANCE: strains Streptococcus pyogenes No 289 and Pseudomonas aeruginosa No 5292, 4762, 5271, 5211, and 5002 are grown up separately, inactivated and added with adjuvant. Thereafter produced monovaccines are mixed in equal ratio. Herewith used are daily culture of strain Streptococcus pyogenes No 289 containing 106x0.5 million micr.kl., strain Pseudomonas aeruginosa No 5292 with titre in "РТГА" 1:512, strains Pseudomonas aeruginosa No 4762 and No 5271 - with titre in "РП" 1:16, strains Pseudomonas aeruginosa No 5211 and No 5002 with titre in "РП" 1:16.

EFFECT: prevention of losses in reproduction of fur-bearing animals within farms with unfavourable streptococcal and pseudomonas infection conditions.

3 ex

FIELD: medicine.

SUBSTANCE: during acute period of purulent meningitis (BPM) additionally, Wobenzyme is prescribed in daily dose 1 tablet per 6 kg of body weight 3 times a day within 10 days simultaneously with antibacterial therapy. Treatment of meningococcal and pneumococcal meningitis is ensured with prescribed benzylpenicillin in daily dosage 300 thousand units/kg. Haemophilic meningitis is treated by prescribed Ceftriaxone in daily dose 100 mg/kg.

EFFECT: higher efficiency of BPM specific therapy due to Wobenzyme ability to improve antibiotic penetration through blood-brain barrier and transport to inflammatory tissue and autointoxication reduction.

3 cl, 2 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention concerns peptide compounds representing an amino acid sequence X1KEFX2RIVX3RIKX4FLRX5LVX6, where X1 is N-end segment which is IG; X2 is K or E; X3 is Q or E; X4 is D or R; X5 is N or E; X6 is C-end segment, which is a sequence selected out of PRTE or RPLR; where N-end segment is acetylated and/or C-end segment is amidated; with affinity to toxins, particularly to bacterial toxins, such as lipopolysaccharide or lipoteichoic acid. These compounds can inhibit or neutralise toxins. Invention also concerns pharmaceutical compositions and application of the claimed compounds in prevention or treatment of diseases or states caused by fungi or bacterial infection.

EFFECT: obtaining compounds for prevention or treatment of diseases or states caused by fungi or bacterial infection.

12 cl, 4 tbl, 4 ex

FIELD: medicine; biotechnologies.

SUBSTANCE: vaccine drug includes deactivated Escherichia coli bacteria of strain No 389 (078) and auxiliary substances. Additionally the drug includes aminoethylethyleneimine and liposome-forming mix as auxiliary substance at the following component rate in fluid form, wt %: aminoethylethyleneimine - 0.5-3; liposome-forming mix - 7.3-15; suspension of deactivated Escherichia coli bacteria of serotype 078 - 82.0-91.5.

EFFECT: harmless for fowl, enhanced antigenic and immunogenic activity.

3 cl, 4 tbl, 6 ex

FIELD: medicine; veterinary.

SUBSTANCE: medicine includes metal iodine and potassium iodide, prolongator and water. 1,2-propylene glycol is used as prolongator, and additionally vitamin A (retinol acetate), vitamin E (alpha-tocopherol acetate), vitamin B1 (thiamine hydrochloride), vitamin B2 (riboflavin), vitamin B6 (pyridoxine hydrochloride), vitamin B12 (cyanocobalamin), iron carbonate, magnium phosphate, manganese sulfate, copper sulfate, zinc sulfate, cobalt chloride, sodium chloride, amber acid, glucose, rectified ethyl alcohol (96%) are applied. Medicine components are taken at the following rate, g/100 ml of distilled water: metal iodine, chemically pure 0.112-0.187; potassium iodide, R 0.337-0.562; vitamin E (alpha-tocopherol acetate) 0.060-0.100; vitamin A (retinol acetate) 3.750-6.250 thousand mass units; vitamin B1 (thiamine hydrochloride) 0.052-0.087; vitamin B2 (riboflavin) 0.037-0.062; vitamin B6 (pyridoxine hydrochloride) 0.034-0.056; vitamin B12 (cyanocobalamin) 0.026-0.044; iron carbonate, R 0.337-0.562; magnium phosphate, R 0.337-0.562; manganese sulfate, R 0.172-0.287; copper sulfate, R 0.090-0.150; zinc sulfate, R 0.315-0.525; cobalt chloride, R 0.071-0.119; sodium chloride, R 0.589-0.981; amber acid, primary standard 0.225-0.375; glucose, AR 0.172-0.287; rectified ethyl alcohol (96%) 0.300-0.500 ml; 1,2- propylene glycol 0.900-1.500 ml. Method involves medicine administration with fodder in dosage of 1.00-1.50 mg per 1 kg of fish weight once per day for 5-7 days.

EFFECT: correction of needs for bioactive substances, prevention of avitaminosis, achievement of high antioxidant organism protection level, prevention of accumulation of non-saturated fatty acid peroxides harmful to fish.

2 cl, 3 tbl, 3 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention is used for treatment of bacteriemic infections, it is prepared as composition in the form of dry powder, adapted for delution by water with reception of the suspension important pH in a range from approximately 5.0 to approximately 5.5 at initial delution and which in addition contains the stabilizer pH which represents sodium-carboxymethyl cellulose. Besides, the invention concerns application sodium-carboxymethyl cellulose for reduction of degree of degradation clavunalate and for stabilisation pH the received suspension.

EFFECT: stability improvement in preparation.

7 cl, 1 dwg, 1 tbl

FIELD: medicine.

SUBSTANCE: method is implemented as follows: bacterial-enzymatic probiotic "Balance-narine-f" is introduced locally and orally in combination with inhalation of negative air ions.

EFFECT: allows for decrease of complications and higher efficiency of treatment.

1 tbl, 3 ex

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