Antibacterial agents

FIELD: organic chemistry, medicine.

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

EFFECT: valuable properties of agents.

4 cl, 3 tbl, 78 ex

 

The present invention relates to the use of derivatives of N-formylhydrazine as antibacterial agents, to a new class of these compounds, and to pharmaceutical and veterinary compositions containing these compounds.

The level of technology.

Generally, pathogenic bacteria are classified as either gram-positive or gram-negative. Many antimicrobial agents (including antibiotics) show a specific effect against one or another gram-positive or gram-negative pathogen. Thus, the antimicrobial agents that are effective against gram-positive, and against gram-negative pathogens, usually referred to as agents with a broad spectrum of activity

There are many classes of antibacterial agents, including penicillins and cephalosporins, tetracyclines, sulfonamides, carbapenems, fluoroquinolones and quinolones, aminoglycosides, glycopeptides, macrolides, polymyxins, lincosamides, trimethoprim and chloramphenicol. The basic mechanisms of action of these classes of antibacterial agents are different.

A growing problem is the resistance of bacteria to a lot of known antibacterial agents. Accordingly there is a continuing need in the creation of al the alternative antibakterialnyh agents, especially such whose mechanism of action differs significantly from the mechanism of action of known classes.

Among gram-positive pathogens, such as Susceptible, Streptococci, Mycobacteria and Enterococci, resistant strains are prone to evolution/reproduction, which makes it particularly difficult to destroy them. Examples of such strains are methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant coagulase-negative Susceptible (MRCNS)resistant to penicillin Streptococcus pneumoniae and resistant to many antibiotic Enterococcus faecium.

Pathogenic bacteria are often resistant to these types of antibiotics like aminoglycosides, β-lactams (penicillins and cephalosporins) and chloramphenicol. Sustainability includes enzymatic inactivation of antibiotics by hydrolysis or transfer to inactive derivatives.

The family β-lactam antibiotics (penicillins and cephalosporins) is characterized by the presence in their structure β-lactam ring. Resistance to this family of antibiotics in clinical cultures most often caused by the production of resistant bacterial enzyme "penitsillinazy"(β-lactamase, which hydrolyzes ring b-lactam, thus eliminating antibacterial activity.

Recently created a tense situation with vancomycin-resistant enterococci (Woodford N. 1998 Resistant to glycopeptides enterococci: a decade of experiment. Journal of Medical Microbiology. 47(10):849-62). Vancomycin-resistant enterococci are particularly dangerous because they often cause infections that require treatment in a hospital, and they are characterized by resistance to many antibiotics. Vancomycin works by binding to terminal D-ALa-D-ALa residues peptidoglycan predecessors of the cell wall. Increased resistance to vancomycin known as VanA, and it occurs due to genes, localized on the inner element, which replaces the end rests on the D-Ala-D-lac, reducing, thus, the affinity for vancomycin.

In light of the rapid emergence of resistant to many drugs of bacteria is extremely important is the search for antibacterial agents that are effective against the increasing number of resistant bacteria, particularly vancomycin-resistant enterococci and bacteria resistant β-lactam antibiotics, such as methicillin-resistant Staphylococcus aureus.

Brief description of the invention

The invention is based on the discovery of the fact that certain derivatives of N-formylhydrazine have antibacterial activity and are available new class of antibacterial agents. It was found that compounds, which are nastojashemu the invention, possess antibacterial activity against several gram-positive and gram-negative organisms. Moreover, it is obvious that some compounds exhibit antibacterial activity against bacteria that are resistant to commonly used antibiotics, such as vancomycin and β-lactam antibiotics, such as methicillin-resistant Staphylococcus aureus.

If this is of interest the establishment of the mechanism of action of compounds that are related to the present invention, i.e. their ability to inhibit the growth of bacteria, which causes the usefulness of these compounds. However at the moment it is believed that their antibacterial activity is provided, at least partially, due to intracellular inhibition of the enzyme polypeptide deformylase (PDF).

Bacterial polypeptide deformylase (PDF) (EC 3.5.1.31), represent a conservative family metallothionen (Review: Meinnel T, Lazennec, Villoing S, Blanquet S, 1997, Journal of Molecular Biology 267, 749-761), which determines the viability of the bacteria, their function is the removal of the formyl group from N-terminal methioninamide balance synthesized on ribosomes proteins of eubacteria. Mazel et al. (EMBO J. 13(4):914-923, 1994) have recently cloned and characterized E. coliPDF. Because PDF is necessary claresta bacteria and there is no eukaryotic analogue PDF, each of Mazel et al. (ibid). Ms. Rajagopalan et al. (J. Am. Chem. Soc. 119:12418-12419, 1997) and Bicker et al., (J. Biol Chem. 273(19):11413-11416, 1998) suggested that (PDF) is a great antibacterial target.

Some derivatives of N-formylhydrazine were previously announced in a number of patent publications, which are listed below, however obtained and described only a small number of specific compounds.

EP-B-0236872 (Roche)

WO 92/09563 (Glycomed)

WO 92/04735 (Syntex)

WO 95/19965 (Glycomed)

WO 95/22966 (Sanofi Winthrop)

WO 95/33709 (Roche)

WO 96/23791 (Syntex)

WO 96/16027 (Syntex/Agouron)

WO 97/03783 (British Biotech)

WO 97/18207 (DuPont Merck)

WO 98/38179 (GlaxoWellcome)

WO 98/47863 (Labs Jaques Logeais)

The pharmaceutical use of these derivatives of N-formylhydrazine listed in the publications is determined by their ability to inhibit matrix metalloproteinases (MMP) and, in some cases, release of tumor necrosis factor (TNF) and, hence, to treat such disease or condition generated by these enzymes as cancer or rheumatoid arthritis. However, in the prior art not disclosed and is not meant antibacterial activity of derivatives of N-formylhydrazine.

In addition to the above sources of information US-A-4738803 (Roques et al.) also discloses derivatives of N-formylhydrazine, however, these derivatives are described as inhibitors of enkephalinase and before ageny for use as antidepressants and anti-hypertensive agents. Also WO 97/38705 (Bristol-Myers Squibb) reveals some derivatives of N-formylhydrazine as inhibitors of enkephalinase and enzymes involved in the conversion of angiotensin. This source information is not disclosed and is not implied any antibacterial activity of derivatives of N-formylhydrazine.

Detailed description of the invention.

According to the first aspect of the present invention provides the use of compounds of formula (I) or its pharmaceutically or veterinary acceptable salts for the preparation of an antibacterial composition:

where R1represents hydrogen or C1-C6alkyl or C1-C6alkyl, substituted by one or more halogen atoms;

R2represents a group R10(X)n-(ALA)m-where

R10represents hydrogen or C1-C6alkyl, C2-C6alkenylphenol, C2-C6alkylamino, cycloalkyl, aryl, or heterocyclic group, each of which may be unsubstituted or substituted (C1-C6)alkyl, (C1-C6) alkoxy, hydroxy, mercapto, (C1-C6) alkylthio, amino, halogen (including fluorine, chlorine, bromine and iodine), trifluoromethyl, cyano, nitro, -COOH, -CONH2, -COORA, NHCORA-CONHRA-NR A, NRARBor CONRARBwhere RAand RBindependently represent a (C1-C6) alkyl group, and ALK represents a linear or branched divalent C1-C6alkalinity, C2-C6alkenylamine, or C2-C6alkynylaryl radical, which can be terminated on one or more nesoedinimoe-NH-, -O - or-S - linkages,

X represents-NH-, -O - or-S-,

and m and n independently represent 0 or 1;

and a represents (i) a group of the formula (IA), (IB), (IC) or (ID)

where R3represents hydrogen and R4represents a side chain of a natural or unnatural alpha-amino acids or R3and R4taken together with the nitrogen atoms and the carbon to which they are respectively attached, form an optionally substituted saturated heterocyclic ring of 5 to 8 atoms, which is optionally condensed with a carbocyclic or second heterocyclic ring,

R5and R6independently represent hydrogen or optionally substituted C1-C8alkyl, cycloalkyl, aryl, aryl(C1-C6alkyl), heterocyclyl or heterocyclyl(C1-C6alkyl), or R5and R6taken together with the nitrogen atom to which they are attached, clicks the form optionally substituted saturated heterocyclic ring of 3 to 8 atoms, the ring, which is optionally condensed with a carbocyclic or second heterocyclic ring, and

R7represents hydrogen, C1-C6the alkyl or acyl group.

In accordance with another aspect of the invention provides a method of treating bacterial infections in humans and other mammals which comprises administration to a patient suffering from such infection, antibacterial effective amount of the compounds of formula (I)as defined above.

In accordance with another aspect of the present invention provides a method of treating bacterial infections by applying an antibacterial effective amount of the compounds of formula (I)as defined above, to the site of infection.

The compounds of formula (I)as defined above, can be used as components of purifying antibacterial or disinfectant.

According to a preferred embodiment of the invention in its various aspects can be used against bacteria resistant to vancomycin, chinolone, and "β-lactams", as well as infections that they cause.

Based on the hypothesis that the compounds of formula (I) act as inhibitors of intracellular PDF, greatest antibacterial effect can be achieved in the case of using compounds that effectively pronica the t through the cell wall of bacteria. Thus, compounds that are highly active as inhibitors of PDF in vitro and which penetrate into the cells of bacteria, preferred for use in accordance with the invention. It can be expected that the antibacterial efficacy of compounds that are potential inhibitors of PDF enzymes in vitro, but not penetrate into the cell, can be improved by using them in proletarienne the form of, for example, in the form of their structurally modified analogue, which goes back to the original molecule of formula (I), for example, under the action of the enzyme after penetration through the cell wall of bacteria.

The invention also includes the new compounds of formula (I)above or their pharmaceutically or veterinary acceptable salt,

where R1represents hydrogen, C1-C6alkyl or C1-C6alkyl, substituted by one or more halogen atoms ;

R2represents a group R10-(ALA)m-where

R10represents hydrogen or C1-C6alkyl, C2-C6alkenylphenol, C2-C6alkylamino, cycloalkyl, aryl or heterocyclic group, each of which may be unsubstituted or substituted (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy, mercapto, (C1-C6)alkisti is, amino, halogen (including fluorine, chlorine, bromine and iodine), trifluoromethyl, nitro, -COOH, -NH2, -RA, -NHCORA, -CONHRA-The otherA-The otherARBor-CONRARBwhere RAand RBindependently represent a (C1-C6)alkyl group,

ALK represents a linear or branched divalent C1-C6alkilinity,2-C6alkenylamine, C2-C6alkynylaryl radical, and it can be broken one or more non-adjacent-NH-, -O - or-S - linkages, and

m represents 0 or 1;

A represents a group of formula (IA), (IB), (IC) or (ID)above, where:

R3represents hydrogen and R4represents a side chain of a natural or unnatural alpha-amino acids or R3and R4taken together with the nitrogen atoms and the carbon to which they are respectively attached, form an optionally substituted saturated heterocyclic ring of 5 to 8 atoms, which is optionally condensed with a carbocyclic or second heterocyclic ring,

R5and R6independently represent hydrogen or optionally substituted C1-C6alkyl, cycloalkyl, aryl(C1-C6alkyl), non-aromatic heterocyclyl, or heterocyclyl(C1-C6alkyl), or R5and R6/sub> taken together with the nitrogen atom to which they are attached, form an optionally substituted saturated heterocyclic ring of 3 to 8 atoms, which is optionally condensed with a carbocyclic or second heterocyclic ring, and

R8represents hydrogen, C1-C6the alkyl or acyl group.

Provided that (i) when a represents a group of formula (IA) or (IB) and R2represents a C2-C5alkyl, then R4not a side chain of a natural alpha-amino acid or side chain of a natural alpha-amino acid in which any functional substituents are protected, any amino group acylated, and any carboxyl group tarifitsirovannyim;

(ii) when a represents a group of formula (IA) or (IB), then R4is not bicyclogermacrene group; and

(iii) when a represents a group of formula (IA) and R2is cyclopropylmethyl, cyclobutylmethyl or cyclopentylmethyl and one of R5and R6represents hydrogen, then R4is not tert.-bootrom.

As used here, the term "(C1-C6)alkyl" denotes a linear or branched chain alkyl residue containing from 1 to 6 carbon atoms, including for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, image is Teal, sec-butyl, t-butyl, n-pentyl and n-hexyl.

The term "divalent (C1-C6)alkalinity radical" denotes a saturated hydrocarbon chain containing from 1 to 6 carbon atoms and two free valence.

The term "(C2-C6)alkenyl" denotes a linear or branched chain alkenylphenol residue containing from 2 to 6 carbon atoms and containing at least one double bond of either E or Z configuration, where possible. The term includes, for example, vinyl, allyl, 1 - and 2-butenyl and 2-methyl-2-propenyl.

The term "divalent (C2-C6)alkenylamine radical" means a hydrocarbon chain containing from 2 to 6 carbon atoms, at least one double bond, and two unsaturated valence.

The term "C2-C6quinil" refers to a linear or branched chain hydrocarbon groups containing from two to six carbon atoms and having in addition one triple bond. This term would include for example, ethinyl, 1-PROPYNYL, 1 - and 2-butynyl, 2-methyl-2-PROPYNYL, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl.

The term "divalent (C2-C6)alkynylaryl radical" means a hydrocarbon chain containing from 2 to 6 carbon atoms, at least one triple bond, and two free valence.

The term "cycloalkyl" about the means a saturated alicyclic residue, containing from 3-8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

The term "cycloalkenyl" refers to unsaturated alicyclic residue containing from 3-8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctanol. If cycloalkenyl ring of 5-8 carbon atoms of the ring may contain more than one double bond.

The term "aryl" refers to mono-, bi - or tricyclic carbocyclic aromatic group and to groups consisting of two covalently linked monocyclic carbocyclic aromatic groups. An illustration of such groups are phenyl, biphenyl and naphthyl.

The term "heteroaryl" refers to 5 - or 6-membered aromatic ring containing one or more heteroatoms and optionally condensed with benzyl or pyridinium ring; and to groups consisting of two covalently linked 5 - or 6 - membered aromatic rings, each of which contains one or more heteroatoms; and to groups consisting of a monocyclic carbocyclic aromatic group, covalently linked 5 - or 6-membered aromatic rings containing one or more heteroatoms. An illustration of such groups are thienyl, furyl, pyrrolyl, and imazalil, benzimidazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazole. triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, 4-([1,2,3]-thiadiazole-4-yl)phenyl and 5-isoxazol-3-Eltanin.

Quality the term "heterocyclic" or "heterocyclyl" includes "heteroaryl", as defined above, and, in particular, represents a 5-7 membered aromatic or non-aromatic heterocyclic ring containing one or more heteroatoms selected from S, N and O and optionally condensed with a benzene ring, including, for example, groups such as pyrrolyl, furyl, thienyl, piperidinyl, imidazolyl, oxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrimidinyl, morpholinyl, piperazinil, indolyl, benzimidazolyl, maleinimide, succinimido, phthalimido and 1,3-dioxo-1,3-dihydro-isoindole-2-yl.

The term "acyl" denotes a group R20C(O)-, where R20is a (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C7)cycloalkyl, phenyl, heterocyclyl, phenyl(C1-C6)alkyl, heterocyclyl(C1-C6)alkyl, (C3-C7)cycloalkyl(C1-C6)alkyl, phenyl(C2-C6)alkenyl, heterocyclyl(C2-C6)alkenyl, (C3-C7)cycloalkyl (C2-C6)alkenyl, each of the groups R20may be substituted.

The term "bicycloalkyl" means (i) methyl group, a substituted monocyclic aryl or heteroaryl group, which is in turn substituted monocyclic aryl or heteroaryl group, or (ii) methyl group, a substituted monocyclic aryl and heteroaryl group which is condensed with a second monocyclic aryl or heteroaryl group; and includes both unsubstituted and substituted bicycloalkyl. Examples of such bicyclogermacrene groups include naphthyl, indolyl, chinosol and ethanolic.

If not specifically mentioned in the context where it is used, the term "substituted" in respect of any balance in this description denotes a substituted up to four substituents, each of which independently may be (C1-C6)alkyl, benzyl, (C1-C6)alkoxy, phenoxy, hydroxy, mercapto, (C1-C6)alkylthio, amino, halogen (including fluorine, chlorine, bromine and iodine), trifluoromethyl, nitro, -COOH, -CONH2, -CORA, -COORA, -NHCORA, -CONHRA-The otherA, -NRARBor-CONRARBwhere RAand RBindependently represent a (C1-C6)alkyl group. In the case when the "substituted" is benzyl, its phenyl ring itself may be substituted for either the Deputy is except benzyl.

The term "side chain of a natural alpha-amino acid and a side chain unnatural alpha-amino acid" refers to the group RXaccordingly, natural and non-natural amino acids of formula NH2-CH(RX)-COOH.

Examples of side chains of natural alphalinolenic include the side chains of alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, histidine, 5-hydroxylysine, 4-hydroxyproline, isoleucine, leucine, lysine, methionine, phenylalanine, Proline, serine, threonine, tryptophan, tyrosine, valine, and-aminoadipic acid, a-amino-n-butyric acid, 3,4-dihydroxyphenylalanine, homoserine and methylsilyne, ornithine, pipecolinic acid and tyrosine.

In side chains of prirodno alpha-amino acids that contain functional substituents, such as, for example, amino, carboxyl, hydroxy, mercapto, guanidyl, imidazolyl or indolyl in arginine, lysine, glutamic acid, aspartic acid, tryptophan, histidine, serine, threonine, tyrosine and cysteine, such functional substituents can be optionally protected.

Similarly, the side chains unnatural alpha-amino acids that contain functional substituents, for example, such groups as amino, carboxyl, hydroxy, mercapto, guanidyl, imidazolyl, or indolyl, such functioning of the social substituents can be optionally protected.

The term "reserved"when used in relation to functional substituent in the side chain of a natural or unnatural alpha-amino acids, denotes the derivative of this Vice, which is essentially functionally disabled. Widely known reference T. W. Greene and P. G. Wuts "Protective Groups in Organic Synthesis" Second Edition. Wiley, New York, 1991, covers this subject. For example, the carboxyl group can be tarifitsirovana (such as C1-C6alkalemia ester), the amino group can be converted to amides (for example, as NHCOC1-C6alkylamide) or carbamates (for example as NHC(=O)OC1-C6alkyl or NHC(=O)OCH2Ph carbamate), a hydroxyl group can be converted to ethers (for example, OC1-C6alkalemia or O(C1-C6alkyl) phenyl ethers or esters (for example, SC(=O)C1-C6alkilany ester ) and tirinya group can be converted into a simple thioethers (for example tert.-butyl or benzyldimethyl) or complex thioethers (for example SC(=O)C1-C6alkalemia the thioethers).

In the compounds according to the invention there are several actual or potential chiral centers, because they contain asymmetric carbon atoms. The presence of several asymmetric carbon atoms leads to an increase in the number of diasterous the ' with R or S stereochemistry of each chiral center. The invention includes all of these diastereoisomers and mixtures thereof. Usually the most preferred stereoconfiguration carbon atom carrying the group R2is the R configuration; and the carbon atom carrying the group R4(when there is asymmetry)has the S configuration; and the carbon atom carrying the group R1(when there is asymmetry), has the configuration R.

In the compounds of formula (I)as defined above, for use according to the invention, the new compounds according to the invention of the formula (II), as defined above, ( including these conditions):

R1may be, for example, hydrogen, stands, or trifluoromethyl. Hydrogen is usually the most preferred.

R2may be, for example:

optionally substituted C1-C6the alkyl, C3-C6alkenyl,3-C6the quinil or cycloalkyl; phenyl (C1-C6by alkyl)-, phenyl (C3-C6alkenyl)- or phenyl(C3-C6the quinil)-, optionally substituted in the phenyl ring; cycloalkyl(C1-C6by alkyl)-, cycloalkyl(C3-C6alkenyl)or cycloalkyl(C3-C6the quinil)-, optionally substituted in cycloalkene ring; heterocyclyl(C1-C6by alkyl)-, heterocyclyl(C3-C6alkenyl)or heterocyclyl (C3-C6the quinil), h is necessarily substituted in the heterocyclic ring; or

CH3(CH2)pO(CH2)qor CH3(CH2)S(CH2)q-where R has the values 0,1, 2 or 3 and q is 1, 2 or 3.

Specific examples of R2groups include methyl, ethyl, n - and isopropyl, n - and isobutyl, n-pentyl, isopentyl, 3-methyl-but-1-yl, n-hexyl, n-heptyl, n-acetyl, n-octyl, methylsulfonylmethyl, ethylsulfanyl, 2-methoxyethyl, 2-ethoxyethyl, 2-ethoxyethyl, 3-hydroxypropyl, allyl, 3-phenylprop-3-EN-1-yl, prop-2-in-1-yl, 3-phenylprop-2-in-1-yl, 3-(2-chlorophenyl)prop-2-in-1-yl, but-2-in-1-yl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclopentylmethyl, cyclopentylpropionyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylmethyl, furan-2-ylmethyl, furan-3-methyl, tetrahydrofuran-2-ylmethyl, tetrahydrofuran-2-ylmethyl, piperidinomethyl, phenylpropyl. 4-chlorpheniramine, 4-methylphenylethyl, 4-methoxypropyl, benzyl, 4-Chlorobenzyl, 4-methylbenzyl, and 4-methoxybenzyl.

The most preferred groups R2are n-propyl, n-butyl, n-pentyl, benzyl and cyclopentylmethyl.

For R3the most preferred example is hydrogen.

R4may be, for example, a characteristic group of natural a-amino acids, such as benzyl or 4-methoxyphenylethylamine, in which any functional group may be protected, any amino group may be allerban any presence is adequate carboxyl group can be liderovna; or

group -[ALK]nR9where ALK is a (C1-C6)alkylenes or (C2-C6)alkynylamino group, optionally broken by one or more-O - or-S - atoms or-N(R12)- groups [where R12represents a hydrogen atom or a (C1-C6) alkyl group], n is 0 or 1, and R9represents hydrogen or optionally substituted phenyl, aryl, heterocyclic, cycloalkyl or cycloalkenyl group or (only when n has a value of 1) R9may additionally represent a hydroxy, mercapto, (C1-C6) alkylthio, amino, halogen, trifluoromethyl, nitro, -COOH, -CONH2, -COORA, -NHCORA, -CONHRA-The otherA, -NRARBor-CONRARBwhere RAand Rinindependently represent a (C1-C6)alkyl group; or

benzyl group substituted in the phenyl ring by a group of the formula-OCH2COR8where R8is hydroxyl, amino, (C1-C6)alkoxy, phenyl(C1-C6)alkoxy, (C1-C6)alkylamino, di((C1-C6)alkyl)amino, phenyl(C1-C6) alkylamino; or

heterocyclyl(C1-C6)alkyl group unsubstituted, or mono - or disubstituted in the heterocyclic ring with halogen, who and Jethro, carboxy, (C1-C6)alkoxy, cyano, (C1-C6)alkanoyl, trifluoromethyl (C1-C6)alkyl, hydroxy, formyl, amino, (C1-C6)alkylamino, di-(C1-C6)alkylamino, mercapto, (C1-C6)alkylthio, hydroxy(C1-C6)alkyl, mercapto(C1-C6)alkyl or (C1-C6)alkyltrimethyl; or

group-CRaRbRcwhere:

each of Ra, Rband Rcindependently represent hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)quinil, phenyl(C1-C6)alkyl, (C3-C8) cycloalkyl; or

Rcis hydrogen and Raand Rbindependently represent phenyl or heteroaryl, such as pyridyl; or

Rcis hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)quinil, phenyl(C1-C6)alkyl, or (C3-C8)cycloalkyl, and Raand Rbtogether with the carbon atom to which they are attached, form a 3-8-membered cycloalkyl or 5-6-membered heterocyclic ring; or

RaRband Rctogether with the carbon atom to which they are attached form a tricyclic ring (such as substituted); or

Raand Rbeach independently represent the a(C 1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)quinil, phenyl(C1-C6)alkyl, or a group as defined for Rcbelow other than hydrogen, or Raand Rbtogether with the carbon atom to which they are attached, form cycloalkyl or heterocyclic ring, and Rcrepresents hydrogen, -OH, -SH, halogen, -CN, -CO2N, (C1-C4)perfluoroalkyl, -CH2HE IS the CO2(C1-C6)alkyl, -O(C1-C6)alkyl, -O(C2-C6)alkenyl, -S(C1-C6)alkyl, -SO(C1-C6)alkyl, -SO2(C1-C6)alkyl, -S(C2-C6)alkenyl, -SO(C2-C6)alkenyl, -SO2(C2-C6)alkenyl or a group-Q-W, where Q is a bond or-O-, -S-, -SO - or-SO2and W represents a phenyl, phenylalkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkenyl, (C4-C8)cycloalkenyl, (C4-C8)cycloalkenyl, heteroaryl or heteroallyl group, with the specified group W may be optionally substituted by one or more substituents, independently selected from hydroxyl, halogen, -CN, -CO2H, -CO2(C1-C6)alkyl, -CONH2, -NH(C1-C6)alkyl, -N(C1-C6the alkyl)2, -Cho, -CH2IT, (C1-C4)PERFLUORO is Lila, -O(C1-C6)alkyl, -S(C1-C6)alkyl, -SO(C1-C6)alkyl, -SO2(C1-C6)alkyl, -NR2, -NH2, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)2-N(C1-C6)alkyl, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)quinil, (C3-C8)cycloalkyl, (C4-C8)cycloalkenyl, phenyl or benzyl.

Examples of the individual group values of R4include methyl, ethyl, benzyl, 4-Chlorobenzyl, 4-hydroxybenzyl, phenyl, cyclohexyl, cyclohexylmethyl, pyridine-3-ylmethyl, tert.-butoxymethyl, naphthylmethyl, isobutyl, sec-butyl, tert.-butyl, 1-benzylthio-1-methylethyl, 1-methylthio-1-methylethyl, 1-mercapto-1-methylethyl, 1-methoxy-1-methylethyl, 1-hydroxy-1-methylethyl, 1-fluoro-1-methylethyl, hydroxymethyl, 2-hydroxyethyl, 2-carboxyethyl, 2-methylcarbamoylmethyl, 2-carbamoylethyl, and 4-aminobutyl. Particularly preferred meanings of the group R4include tert.-butyl, isobutyl, benzyl and methyl.

R3and R4taken together with the nitrogen atoms and the carbon to which they are respectively attached may form an optionally substituted saturated heterocyclic ring of 5 to 8 atoms. For example, R3and R4can form a bridge between the nitrogen atoms and the carbon to which they are attached, and specified on the represents the divalent radical -(CH 2)3-6or -(CH2)r-O-CH2)sor -(CH2)r-S-(CH2)s-, where r and s each independently have values of 1, 2 or 3, provided that r+s=2,3,4, or 5.

R5and R6can independently represent, for example, hydrogen, methyl, ethyl, tert.-butyl, cyclopentyl, cyclohexyl, 1,1,3,3-TETRAMETHYLBUTYL, benzyl or 2-hydroxyethyl; or R5and R6taken together with the nitrogen atom to which they are attached, may form a saturated 5-8 membered monocyclic N-heterocyclic ring which is attached via the N atom and which optionally contains a-N(R11)-, where R11is hydrogen or C1-C6alkyl, benzyl, acyl, or amino-protective group, O, S, SO or SO2as part of a ring and/or optionally substituted by one or more atoms with hydroxy, C1-C6of alkyl, hydroxy(C1-C6the alkyl)-, C1-C6alkoxy, oxo, katalizirovannogo oxo, amino, mono(C1-C6alkyl)amino, di(C1-C6alkyl)amino, carboxy, C1-C6alkoxycarbonyl, hydroxymethyl, C1-C6alkoxymethyl, carbamoyl, mono(C1-C6alkyl)carbamoyl, di(C1-C6alkyl)carbamoyl or hydroxyimino.

Examples of such rings are substituted or unsubstituted 1-pyrrolidinyl, piperidine-1-yl, 1-Pipa is azinil, hexahydro-1-pyridazinyl, morpholine-4-yl, tetrahydro-1,4-thiazin-4-yl, tetrahydro-1,4-thiazin-4-yl 1-oxide, tetrahydro-1,4-thiazin-4-yl 1,1-dioxide, hexahydroazepin or octahydrate.

Examples of the above substituted rings are 2-(methylcarbamoyl)-1-pyrrolidinyl, 2-(hydroxymethyl)-1-pyrrolidinyl, 4-hydroxypiperidine, 2-(methylcarbamoyl)piperidino, 4-hydroxylaminopurine, 4-methoxypiperidine, 4-methylpiperidin-1-yl, 4-benzylpiperidine-1-yl, 4-acetylpiperidine-1-yl, 4-methyl-1-piperazinil, 4-phenyl-1-piperazinil, 1,4-dioxa-8 azaspiro[4,5] Decan-8-yl, hexahydro-3-(methylcarbamoyl)-2-pyridazinyl, hexahydro-1-(benzyloxycarbonyl)-2-pyridazinyl, decahydroquinoline-2-yl, and 1,2,3 .4-tetrahydroisoquinoline-2-yl.

When a represents a group of formula (IA), particularly preferably, R5was stands or hydrogen and R6was the stands.

R7can represent, for example, hydrogen, or the group R20C(O)-, where R20is a (C1-C6)alkyl group such as methyl or ethyl.

Specific examples of compounds used as antibacterial agents in accordance with the invention include those that are included in the experimental part of the description. Preferred new compounds according to the invention include

2R(or S)-[(Formyl-hydroxy-amino)-methyl]-hexanoic sour the s (1S-dimethylcarbamoyl-ethyl)-amide and

2R(or S)-[(Formyl-hydroxy-amino)-methyl]-3-cyclopentyl-propionic acid (1S-dimethyl-carbarnoyl-2,2-dimethyl-propyl)-amide

and their pharmaceutically and veterinarni acceptable salt.

Compounds relating to the invention, can be obtained by removing the protection of O-protected N-formyl-N-hydroxyamino the compounds of formula (II):

in which R1, R2, and a have the meanings as defined in General formula (I) and R25is a protective group of hydroxyl, removed to free hydroxy group by hydrogenolysis or hydrolysis. Benzyl group is preferred group R25removal using hydrogenolysis and tert.-bucilina and tetrahydropyranyl groups are preferred for removal using acid hydrolysis.

The compounds of formula (II), where a represents a group of formula (IA), (IB), (IC) or (ID)can be obtained by introducing an acid of formula (III) or activated derivative, in interaction with the amine of formula (IVA), (IVB), (IVC) or (IVD), respectively

where R1, R2, R3, R4, R5, R6and R7have the meanings defined in General formula (I) except for the-Oh groups in (IVB), and any substituents in R1, R23, R4, R5, R6and R7which are potentially reactive in the condensation reactions, may themselves be protected from such reaction, and R25has the values defined in accordance with formula (II)above, and optionally removing the protective groups,-Oh groups in (IVB) and R1, R2, R3, R4, R5, R6and R7.

The compounds of formula (III) can be obtained by N-formirovaniya, for example, with acetic anhydride and formic acid, or 1-formylbenzoate, compounds of formula (V)

where R1, R2and R25such as defined in accordance with formula (II) and X is either chiral auxiliary substance, or a group OR26where R26is hydrogen or a protective group of hydroxyl. In the case when X is a group OR26or chiral auxiliary substance, the protective group of the hydroxyl or auxiliary chiral substance is removed after carrying out stage formirovaniya with obtaining the compounds of formula (V). Suitable chiral auxiliary substances include substituted oxazolidinone, which can be removed by hydrolysis in the presence of a base.

In an alternative process, compounds of General formula (II) can be obtained PU is eat N-formirovaniya, for example, with acetic anhydride and formic acid, or 1-formylbenzoate, compounds of formula (VI)

where R1, R2, R25and As such, as defined in the formula (II). The compounds of formula (VI), where a represents a group of formula (IA), (IB), (IC) or (ID) can be obtained by introducing an acid of General formula (VII) or its activated derivative

where R1, R2and R25such as defined in the formula (II), in cooperation with the amine of formula (IVA), (IVB), (IVC) or (IVD), respectively, as defined above.

Alternative compounds of General formula (VI) can be obtained by reduction of the oxime of General formula (VIII).

Reducing agents include certain metal hydrides (for example, cyanoborohydride sodium acetic acid, triethylsilane or borane/pyridine) and hydrogen in the presence of a suitable catalyst.

In an alternative process, compounds of General formula (II), where R1and R2such as defined in the General formula (I), R25represents a protective group of hydroxyl, as defined above, and a is a group of formula (IA), where R3, R4, R5have the meanings defined in General formula (IA) and R6represents hydrogen, which may be obtained using the 4-component Ugi reaction of carboxylic acids of General formula (III) as defined above, amine of formula (IX), the aldehyde of formula (X) and isonitrile formula (XI).

R3-NH2(IX)

R4-CHO (X)

R5-CN (XI)

where R3, R4and R5such as defined above.

The compound of General formula (V) can be obtained by recovery of the oxime of General formula (XI)

where R1, R2and R25have the meanings as defined above, and X represents either a group or SIG25as defined above, or a chiral auxiliary substance. Reducing agents include certain metal hydrides (for example, cyanoborohydride sodium acetic acid, triethylsilane or borane/pyridine) and hydrogen in the presence of a suitable catalyst. After recovering, when X is a chiral auxiliary substance, it does not need to be transferred to OR26group.

The compound of General formula (XI) can be obtained by reaction β-Methocarbamol compounds of General formula (XII)

where R1, R2and X have the meanings as defined above, with O-protected hydroxylamine.

β-Methocarbamol compounds (XII) can be obtained in the form of racemates by formirovaniya or acylation of carbonyl compounds of General formula (XIII)

where R2and X have the meanings as defined above, a compound of General formula (XIV)

where R1that matter, as defined above, and Z represents a leaving group such as halogen or alkoxy, in the presence of a base.

Another way to get soedineniya General formula (V) is joining the derivative of hydroxylamine Michael α,β-unsaturated carbonyl compounds of General formula (XV)

where R1, R2and X have the meanings as defined above. After the reaction joining Michael in the case when the group X is a chiral auxiliary substance, it does not need to be transferred to OR26group. (α,β-Unsaturated carbonyl compound (XV) can be obtained using standard methods.

Salts of the compounds according to the invention include physiologically acceptable acid additive salts, such as chlorhidrate, bromhidrosis, sulphates, methanesulfonate, p-toluensulfonate, phosphates, acetates, citrates, succinate, lactates, tartratami, fumarate and maleate. You can also form salts with bases, such as sodium, potassium, magnesium and calcium salts.

The composition of the invention for any route of administration can be obtained in the accordance with the pharmacokinetic properties of the active (main) ingredient(s).

Introduce oral compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel formulations, such as orally, topically applied, or sterile parenteral solutions or suspensions. Tablets and capsules for oral administration may be in the form of a single dose and may contain conventional excipients such as binding agents, for example, syrups, Arabian gum, gelatin, sorbitol, tragakant or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize starch, calcium phosphate, sorbitol or glycine; grease for tablets, for example magnesium stearate, talc, polyethylene glycol or silicon dioxide; disintegrating agents such as potato starch, or priemlemaya wetting agents such as sodium lauryl sulfate. Tablets may be coated according to methods well known in normal pharmaceutical practice. Liquid orally administered compositions can be, for example, in the form of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or they can be in the form of dry matter, ready for dilution with water or other suitable diluent before use. Such liquid compositions may contain conventional additives such as suspendresume agents, for example sorbitol, syrup, methylcellulose, syrup glitch is SHL, gelatin, hydrogenated edible fats, emulsifying agents, for example, lethicin, monooleate sorbitan or Arabian gum; non-aqueous diluents, (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, optionally, conventional perfumes and dyes.

For local application on the skin of the active(s) ingredient(s) can be added to creams, lotions or ointments. Formulations of creams or ointments that can be used for the production of medicines, are conventional formulations well known in the art and described, for example, in the standard pharmacopoeial reference books, such as the British Pharmacopoeia.

Active(s) ingredient(s) can be introduced parenterally in a sterile environment. Depending on the solvent and the concentration of the drug can be either suspended in it, or dissolved. Mainly in the diluent can be dissolved with an adjuvant, such as local anesthetics, preservatives or buffer agents. Another way of introducing the compounds of the present invention is an intravenous infusion.

Safe and effective dosage for the different the types of patients and different levels of development of disease will be determined during clinical trials in accordance with accepted standards in this area. It should be clear that the specific dose for each individual patient will depend on many factors, including the specific activity of the applied compound, the age, weight, General health, sex, diet, time of administration, route of administration, rate of excretion, combination of drugs, the rigidity of therapy.

The discovery of the fact that compounds with PDF inhibitory activity can inhibit or prevent the growth of bacteria, opens a new approach to identify new antibacterially agents by screening test compounds for activity as inhibitors of PDF in vitro with subsequent confirmation of their antibacterial ability by studying the inhibition of bacterial growth. This discovery also makes available (i) the use of compounds with PDF inhibitory activity as antibacterial agents, and (ii) a method of treating bacterial infections or infections by application or administration of a compound that inhibits the activity of bacterial PDF.

Thus, according to further aspect of the invention provides a method for the identification of antibacterial compounds, including screening test compounds for their ability to inhibit PDF in vitro, the selection of those compounds which have specified the FPIC of the institutional capacity and testing their ability to inhibit the growth of bacteria. The ability to inhibit the growth of bacteria can be demonstrated by the classic studies of inhibition of bacterial growth using cultures in liquid or on solid nutrient medium, such as presented here in this biological experiment.

Suitable screening inhibition PDF in vitro may be mixed with one another PDF, the PDF of the substrate, preferably labeled detektivami marker, and the test compound, followed by determination through a suitable period of time, inhibited or not in the presence of test compounds ability PDF deformirovaly substrate.

In the preferred embodiment of the invention the split substrate detects using fluorogenic marker, such as fluorescein. After removal of the formyl group from N-terminal methionine in the substrate PDF free amino group reacts with fluorescamine, generating a fluorescent product.

Alternative screening includes an assessment of whether the protein expressed by bacteria, which Express endogenous (or recombinante expressed) PDF, in the case when the bacteria are grown in the presence of test compounds, a suitable substrate for N-terminal sequencing, or it provides a smaller amount of the substrate than the protein expressed is th the same bacteria, grown in the absence of the test compound. This method can be based on the material that is used in the biological experiment description.

The person skilled in the art can, without leaving the scope of the invention to develop alternative methods of screening test compounds with respect to their ability to inhibit bacterial PDF.

Natural antibiotic actionin (see, for example J..S Perkin I, 1975, 819) is a derivative of hydroxamic acid structure (A):

In addition actionin antibacterial activity was determined for various structural analogues (see, e.g. Broughton et al. (Devlin et al. Journal of the Chemical Society. Perkin Transactions 1 (9):830-841, 1975; Broughton et al. Journal of the Chemical Society. Perkin Transactions 1 (9):857-860, 1975).

However, it is still not established the mechanism of action underlying the antibacterial activity actionin. The authors of the present invention found that actionin inhibits the activity of bacterial PDF.

Mutlinational group of compounds refers to the number of structures similar to actionism. They are all peptide molecules with functional hydroxamic acid group linking the metal. (Ogita et al., J. Antibiotics. 45(11):1723-1732; Tanzawa et al., J. Antibiotics. 45(11): 1733-1737; Haruyama et ai., J. Antibiotics. 47(12): 1473-1480; Tamaki et al. J. Antibiotics. 47(12): 1481-1492). Malistaire and nl is Skye structural analogs are characterized by the presence in the molecule of divalent piperazine-1,6-deeley group, ie:

Because they are close in structure to actionin, the observation that actionin inhibits PDF, implies that matatalino compounds can also inhibit PDF.

According to further aspect of the present invention provides use of a compound that inhibits the activity of bacterial PDF, for the preparation of an antibacterial composition or agent, provided

(i) that the compound is not a compound of the formula (XI)

RCO-CH(W)-NH-CO-CH(Y)-CH2-CO-NH-OH (XI)

where (a) R represents a cyclic amino group, W represents hydrogen, methyl, isopropyl, isobutyl or benzyl, and Y is hydrogen, C1-C6alkyl, phenyl, benzyl, 4-chloroformate, 4-nitrophenolate or 4-aminophenethyl; or

(b) R is a 2-pyridylamino or 2-thiazolylazo, W is isopropyl and Y is n-Pentium; or

(c) R represents diethylamino, W is the stands or isopropyl and Y is n-Pentium;

or (ii) that the compound is not a compound containing divalent piperazine-1,6-dialnow group, i.e. a group of the formula (XII):

According to another aspect of the invention provides a method of treating bacterial infections or infections by introducing the patient, tradeasia from such infection or contamination, or drawing on the site such infection or infection, antibacterial effective amount of a compound that inhibits the activity of bacterial PDF enzyme, provided that the compound does not apply to compounds that are included in the conditions listed in the previous paragraph.

These conditions exclude actionin and its antibacterial active analogs disclosed in Devlin et al., Journal of the Chemical Society. Perkin Transactions 1 (9):830-841, 1975 and Broughton et al. Journal of the Chemical Society. Perkin Transactions 1 (9):857-860,1975, and matatalino compounds disclosed in Ogita et al., J. Antibiotics. 45(11): 1723-1732; Tanzawa et al., J. Antibiotics. 45(11): 1733-1737; Haruyama et al., J. Antibiotics. 47(12): 1473-1480 and Tamaki et al., J.Antibiotics. 47(12):1481-1492.

The following examples illustrate the implementation of the invention. L-tert.-leucine-N-methylamide and L-tert-leucine-N.N-dimethylamide and other derivatives of amino acids receive in accordance with the methods known from the prior art. We used the following abbreviations:

DMF - N,N-Dimethylformamide, DMF

EDC - N-Ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride

HOAt is 1-Hydroxy-7-Aza-benzotriazol

HOBt is 1-Hydroxybenzotriazole

HPLC - high performance liquid chromatography

LRMS - Mass spectrometry low resolution

TLC - Thin layer chromatography

1H and1The NMR spectra were recorded with a spectrometer Bruker AC 250E when 250.1 and 62.9 MHz sootvetstvenno is; s - singlet, d - doublet, m = multiplet, t - triplet, q - Quartet.

Mass spectra were obtained on a spectrometer Perkin Elmer Sciex API 165 using both positive and negative ion modes.

Infrared spectra were recorded on a spectrometer Perkin Elmer PE 1600 FTIR.

Example 1

2R (or S)-[(Formyl-hydroxy-amino)-methyl]-hexanoic acid-(2,2-dimethyl-1S-methyl-carbarnoyl-propyl)-amide

A named connection receive in accordance with scheme 1 and as described in detail below:

Reagents and conditions:

A. piperidine, NSNO, EtOH, 80°C, o/n;

C. H2NOBzl, 80°o/n;

C. HCOOH, Ac2O;

D. Pentafluorophenol, EDC, CH2Cl2;

That is, N-tert.-LeuNHMe, DMF, 35°C;

F. H2, 10% Pd/C, EtOAc/EtOH.

STAGE A: 2-Butyl-acrylic acid

Butylmalonic acid (25 g, 156 mmol) dissolved in ethanol (250 ml) and add 37% formaldehyde solution (15,45 ml, 156 mmol)and then piperidine (47 ml, 624 mmol). The mixture is stirred over night at 80°With a reflux condenser. The solvents are removed under reduced pressure and the residue diluted with 1 M hydrochloric acid and extracted with dichloromethane (I ml). The combined organic extracts washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to obtain the desired product in the form of altago oil (25 g, residual solvent).1H-NMR: δ (Dl3), 10.04 (1H, broadened s), 6.22 (1H, s), 5.57 (1H, d, J=1.3 Hz), 2.30 (2H, t, J=6.9 Hz), 1.38 (4H, m), 0.91 (3H, t, J=7.2 Hz).

STAGE: 2RS-(Benzyloxy-amino-methyl)-hexanoic acid

A mixture of 2-butyl-acrylic acid (3,43 g, 27,1 mmol) and 0-benzylhydroxylamine (5 g, 40,65 mmol) is heated at 80°C during the night. The mixture is cooled to room temperature, diluted with ethyl acetate (40 ml), and washed with 1 M hydrochloric acid (3h20 ml), saturated sodium bicarbonate solution (2x20 ml) and brine (2x20 ml), dried over anhydrous magnesium sulfate, filtered and evaporated to obtain these compounds in the form of a white solid (2.62 g, 39%).1H-NMR: δ (CDCl3). 8.05 (1H, broadened s), 7.35 (5H, m), 5.00 (2H, m), 3.28 (2H, m), 2.98 (1H, m), 1.31 (6N, m) and 0.88 (3H, t, J=5.0 Hz).

Stage C: 2RS-[(Benzyloxy-formyl-amino)-methyl]-hexanoic acid

2RS-(Benzylamino-methyl)-hexanoic acid (2,62 g, 10,51 mmol) is dissolved in formic acid (4 ml, 105 mmol) and acetic anhydride (1.9 ml, 21,02 mmol) and stirred overnight at room temperature. The solution was diluted with ethyl acetate (40 ml), washed with water (2x20 ml), saturated sodium bicarbonate solution (20 ml) and brine (20 ml), dried over anhydrous magnesium sulfate, filtered and evaporated to give the desired product as a yellow oil (2.9 g, 99%).1H-NMR: δ (CDCl3R is tamera), 8.21 (S, s), 8.14 (D, s), 7.37 (5H, m), 4.98 (2H, m), 3.86 (1H, m), 3.27 (N, DD, J=6.0, 14.0 Hz), 2.93 (N, m), 2.77 (1H, m). 1.50 (2H, m), 1.30 (4H, m) and 0.88 (3H, m).

STAGE D: 2RS-[(Benzyloxy-formyl-amino)-methyl]-hexanoic acid pentafluorophenyl ester

2RS-[(Benzyloxy-formylamino]-hexanoic acid (30,72 g, 110 mmol) and pentafluorophenol (26,31 g, 143 mmol) dissolved in dichloromethane (150 ml) and the solution is stirred and cooled in a bath with ice during the addition of EDC (25,3 g, 131 mmol). The reaction mixture is allowed to warm to room temperature and stirred over night. The solution is washed successively 1 M hydrochloric acid (g ml), 0.5 M sodium carbonate (g ml) and brine (50 ml), dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated under reduced pressure and the residue purified by flash chromatography (silica gel, dichloromethane)to obtain the titled compound as a colourless oil (15.0 g, 31%).1H-NMR: δ (CDCl3, rotamer), 8.17 (1H, broadened s), 7.37 (5H, m), 4.95-4.70 (2H, broadened m), 4.10-3.75 (2H, broadened m), 3.10 (1H, broadened s), 1.88-1.55 (2H, m), 1.39 (4H, m) and 0.92 (3H,T,J=7.0 Hz).

STAGE E: 2R (or S)-[(Benzyloxy-formyl-amino)-methyl]-hexanoic acid (2,2-dimethyl-1-methylcarbamoylmethyl)-amide

2RS-[(Benzyloxy-formyl-amino)-methyl]-hexanoic acid pentafluorophenyl ester (5 g, 11 mmol) and tert.-leucine N-methylamide (1,62 g, 11 mmol) dissolved in DMF (60 ml) and the ect is stirred overnight at 35° C. the Solvent is removed under reduced pressure and the residue pererastayut in dichloromethane. The solution is washed successively with 0.5 M sodium carbonate, 1.0 M hydrochloric acid and brine, dried over anhydrous magnesium sulfate and filtered. Two diastereoisomeric product is separated by flash chromatography (silica gel, gradient elution from 30% to 0%hexane in ethyl acetate). Diastereoisomer A (higher R-value):1H-NMR: δ (CDCl3, rotamer), 8.12, 7.87 (1H, 2 broadened s), 7.27 (5H, m), 6.26 (1H, d, J=8.7 Hz), 5.78 (1H, broadened s), 4.91-4.60 (2H, broadened m), 4.15 (1H, d, J=2 Hz), 3.75 (2H, broadened m), 2.79 (3H, d, J=4.8 Hz), 2.56 (1H, m), 1.60-1.35 (2H, broadened m), 1.24 (4H, m), 0.96 (D,) and 0.86 (3H, t, J=6.7 Hz). Diastereoisomer In (a lower value of Rf):1H-NMR: δ (CDCl3, rotamer), 8.16, 7.88(1H, 2 broadened singlet), 7.27 (5H, m), 6.28 (1H, d, J=8.9 Hz), 5.70-5.44(1H, broadened s), 4.98-4.61(2H, broadened m), 4.14 HE, d, J=9.2 Hz), 3.78-62 (2H, broadened m), 2.85-2.60 (3H, broadened m), 2.47(1H, m), 1.72-1.25 (6N, extended m), 0.98 (S, s) and 0.88 (3H,T,J=6.7 Hz).

STAGE F: 2R (or S)-[(Formyl-hydroxy-amino)-methyl]-hexanoic acid (2,2-dimethyl-1S-methylcarbamoyl)-amide.

2-[(Benzyloxy-formylamino)-methyl]-hexanoic acid-(2,2-dimethyl-1-methylcarbamoylmethyl)-amide (diastereoisomer A) (1.0 g, 2.5 mmol) dissolved in a mixture of ethyl acetate (20 ml) and ethanol (1 ml) and the solution placed in an atmosphere of argon. Add 10% palladium on what and where thin bubbled a stream of hydrogen through the suspension. After 40 minutes, TLC analysis showed that all the original product has been consumed, remained more positive polar particles of ferric chloride. System purge with argon before removing the catalyst by filtration. The filtrate is evaporated to dryness to obtain these compounds in the form of not very white foam (810 mg, including residual solvent).1H-NMR: δ ((CD3)2SO, rotamer), 9.81, 9.41 (1H, 2 broadened singlet), 7.82-7.60 (3H, m), 4.04 (1H, d, J=9.3 Hz). 3.50-3.02 (2H, m). 2.87-2.60 (1H, m), 2.41 (3H, d, J=4.5 Hz), 1.39-0.93 6N, m), 0.75 (N,) and 0.67 (3H, t, J=5.7 Hz).13C-NMR: δ ((CD3)2WITH), 172.5, 170.2. 157.5, 59.9, 42.8, 33.3. 29.0, 28.4, 28.2, 26.4, 24.8, and 21.7 13.3. IR (KBR, table), vmax3309, 2959, 2873, 1646 and 1540 cm1.

2-[(Benzyloxy-formyl-amino)-methyl]-hexanoic acid-(2,2-dimethyl-1-methylcarbamoylmethyl)-amide (diastereoisomer) (1.0 g, 2.5 mmol) was subjected to unprotect getting diastereoisomer At the named compound (740 mg, 97%).1H-NMR: δ ((CD3)2SO, rotamer), 9.75, 9.30 (1H, 2 broadened singlet), 7.81-7.42 (3H, m), 4.04 (1H, d, J=9.5 Hz), 3.53-3.02 (2H, m), 2.80-2.55 (1H, m), 2.41 (3H, d, J=4.5 Hz), 1.33-0.82 (6N, m), 0.72 (N,) and 0.67 (3H, t, J=6.7 Hz).13C-NMR: δ ((CD3)2SO), 172.6, 170.4, 161.7, 157.0, 59.8, 34.0, 29.4, 28.6, 26.7, 25.2, and 14.1 22.1. IR (KBR PL.), vmax, 3312, 2959, 1640, 1541, 1369 and 1240 cm1.

Example 2

2R (or S)-[(Formyl-hydroxy-amino)-methyl]-hexanoic acid (2,2-dimethyl-15-the pet.-butylcarbamoyl)-amide

A named connection receive similarly to the method of example 1, using L-tert.-leucine-N-tert.-butylamide instead of L-tert.-leucine-N-methylamide on Stage that Diastereoisomer, not shared by flash chromatography (silica gel, ethyl acetate) at Stage E, turn in the mixture the desired derivatives of N-formyl hydroxylamine by hydrogenolysis. Get a white solid.13C-NMR: δ ((CD3)2SO), 172.8, 172.5, 170.1, 169.6, 161.6, 156.9, 59.9, 59.7, 51.9, 51.7, 50.2, 49.6, 48.3, 43.2, 43.1, 42.7, 34.2, 34.0, 29.6, 29.3, 29.2, 28.8, 28.6. 26.7, 22.2, 22.1, and 20.3 13.9. IR (KBr), vmax, 3311, 2964, 1639, 1548, 1456, 1394, 1364 and 1226 cm-1.

Example 3

2R (or S)-[(Formyl-hydroxy-amino)-methyl]-hexanoic acid (1S-methyl-2-morpholine-4-yl-2-oxoethyl)-amide

The solution 2RS-[(benzyloxy-formylamino)-methyl]-hexanoic acid pentafluorophenyl ester (Example 1, step D) (445 mg, 1 mmol) in DMF (5 ml) is added to L-alanine-N-morpholinothio (158 mg, 1 mmol) in a test tube and stirred at 35°With during the night. DMF is removed under vacuum, the residue is again dissolved in dichloromethane (2 ml) and passed through a purifying coal briquette (cartridge) (Icolute-NH;), elwira dichloromethane (4 ml) to remove pentafluorophenol. Dichloromethane is removed under reduced pressure and the residue again dissolved in formic acid (2 ml) and ethyl acetate (2 ml). Then plants the PRS is treated with 10% palladium on coal (200 mg) and stirred at room temperature for 2 hours. The catalyst was removed by filtration through celite, well washed with methanol and the solvent is removed under vacuum. Compounds purified by HPLC with reversed phase (gradient elution, 10-90% acetonitrile/water). Diastereoisomer:1H-NMR; δ (CO3OD), 8.03 (D, s), 7.84 (D, s), 4.75 (1H, m), 3.65 (8H, m), 3.39 (1H, m), 3.24(1H, DD, J=4.0, 13.2 Hz), 2.84 (1H, m), 1.57 (2H, m), 1.34 (7H, m), 0.92 (3H, m). LRMS: -ve ion 328 [M-H]. Diastereoisomer In:1H-NMR; δ (CD3OD), 3.66 (8H, m), 3.41 (1H, DD, J=9.98, Hz), 3.23 (1H, m), 2.90 (M, m), 2.71 (N, m), 1.62(2H, m), 1.33(7H, m), 0.92 (3H, t, J=6.7 Hz). LRMS: -ve ion 328 [M-N].

Compounds according to examples 4 to 12 get by, similar to that described in example 3, using a suitable amine or amino-instead of L-alanine-N-morphodynamics. In the case when you get both diastereoisomer, diastereoisomer And eluted faster and it is more active against PDF in vitro. In some cases, only the product resulting faster, were subjected to further transformations to the end of the connection.

Example 4

2R (or S)-[(Formyl-hydroxy-amino)-methyl]-hexanoic acid (1S-dimethylcarbamoyl)-amide

Diastereoisomer:1H-NMR; δ (CD3OD), 4.72 (1H, m), 3.53 (1H. DD, J=8.9, 13.0 Hz), 3.23 (1H, m). 3.14 (3H, s), 2.95 (3H, s). 2.83 (N, m). 2.74 (N. m), 1.57 (2H, m), 1.33 (7H, m) and 0.92 (3H, m). LRMS; +ve ion 288 [M+H], -ve ion 286 [M-N].

Diastereoisomer In:1H-NMR; δ (C 3OD), 4.74 (1H, m), 3.41 (1H, DD, J=9.9. 13.0 Hz), 3.25 (1H, DD, J=4.0, 13.1 Hz), 3.15 (3H, s), 2.97 (3H, s), 2.89 (N, m), 2.72 (0.5 H, m), 1.53 (2H, m), 1.33 (7H, m) and 0.93 (3H, t, J=6.7 Hz). LRMS: +ve ion 310 [M+Na], -ve ion 286 [M-N].

Example 5

2R (or S)-[(Formyl-hydroxy-amino)-methyl]-hexanoic acid (1S-hydroxymethyl-3-methyl-butyl)-amide

Diastereoisomer:1H-NMR; δ (CD3OD), 4.07 (1H, m), 3.55 (1H, m), 3.45 (2H, m), 3.20 (1H, m), 2.85 (N, m), 2.80 (N, m), 1.60 (3H, m), 1.35 (6N, m) and 0.93 (N, m). LRMS: +ve ion 289 [M+H], -ve ion 287 [M-H]. Diastereoisomer In:1H-NMR; δ (CO3OD), 4.07 (1H, m), 3.59 (1H, m), 3.45 (2H, m), 3.24 (1H, m), 2.70 (1H, m), 1.62 (3H, m), 1.35 (6N, m) and 0.93 (N, m). LRMS: +ve ion 311 [M+H], 289 [M+H], -ve ion 287 [M-N].

Example 6

2R (or S)-[(Formylhydrazine)-methyl]-hexanoic acid (1S-hydroxymethyl-2-phenylethyl)-amide

Diastereoisomer:1H-NMR; δ (CO3D), 7.24 (5H, m), 4.15 (1H, m), 3.54 (2H, d, J=5.4 Hz), 3.38 (1H, DD, J=7.8, 13.1 Hz), 3.14 (1H, DD, J=4.7, 13.2 Hz), 2.95 (1H, DD, J=7.3, 13.7 Hz), 2.68 (2H, m), 1.58 (2H, m), 1.32 (4H,m), 0.91 (3H, t, J=6.7 Hz). LRMS: +ve ion 345 [M+Na], 323 [M+H], -ve ion 321 [M-H]. Diastereoisomer IN: LRMS: +ve ion 345 [M+Na], 323 [M+H], -ve ion 321 [M-N].

Example 7

2R (S)-[(Formyl-hydroxy-amino)-methyl]-exanovaa acid [2,2-dimethyl-pyridin-2-yl-carbarnoyl)-propyl]-amide

Diastereoisomer And: colorless oil.1H-NMR; δ (CO3D), 8.34 (1H, m), 8.06 (1H, m), 7.90 (1H, m), 7.33 (1H, m), 4.45 HE), 3.55 (1H, DD, J=8.3, 13.2 Hz), 3.25 (1H, m), 3.05 (1H, m), 1.61 (2H, m), 1.32 (4H,m), 1.11 (D,) and 0.85 (3H, m). LRMS:+ve ion 379 [M+H], -ve ion 377 [M-N].

Diastereoisomer In: colorless oil.1H-NMR; δ (CO3D), 8.33 (1H, m), 8.20 (D, m), 7.93 (1H, m), 7.41 (D, m), 7.28 (1H, m), 4.48 (1H, s), 3.52 (1H, DD. J=8.8, 13.1 Hz), 3.23 (1H, DD, J=3.9, 13.1 Hz), 3.05 (M, m), 2.87 (N, m), 1.62 (2H, m), 1.36 (4H, m), 1.11 (D,) and 0.93 (3H, m). LRMS: +ve ion 393 [M+Na], 379 [M+H], -ve ion 377 [M-N].

Example 8

2R (or S)-[(Formyl-hydroxy-amino)-methyl]-hexanoic acid (1S-dimethylcarbamoyl-2-methylpropyl)amide

Diastereoisomer And: colorless oil. LRMS: +ve ion 338 [M+Na], -ve ion 319 [M-N].

Example 9

2R (or S)-[(Formyl-hydroxy-amino)-methyl]-hexanoic acid (1S-dimethylcarbamoyl-2-phenylethyl)amide

Diastereoisomer And: colorless oil. LRMS: +ve ion 386 [M+Na], -ve ion 362 [M-H] Diastereoisomer In: colorless oil LRMS: +ve ion 386 [M+Na], -ve ion 362 [M-H]

Example 10

2R (or S)-[(Formylhydrazine)-methyl]-hexanoic acid (1S-dimethylcarbamoyl-3-methyl-butyl)amide

Diastereoisomer And: colorless oil. LRMS: +ve ion 352 [M+Na], -ve ion 328 [M-N].

Example 11

2R (or S)-[(Formyl-hydroxy-amino)-methyl]-hexanoic acid [3-methyl-lS-pyrrolidin-1-carbonyl)-butyl]amide

Diastereoisomer And: colorless oil. LRMS:-ve ion 354 [M-H].

Example 12

1-{2 (or S)-[(Formyl-hydroxy-amino)-methyl]-hexanoyl}-pyrrolidine-2S-carboxylic acid dimethylamide

Diastereoisomer And: colorless oil. LRMS: +ve ion 336 [M+Na], -ve ion 312 [M-H]. Diastereoisomer In: colorless oil. LRMS:+ve ion 336 [M+Na], -ve ion 312 [M-N].

Example 13

2R (or S)-[(Formyl-hydroxy-amino)-methyl]-hexanoic acid-1S-dimethylcarbamoyl-2,2-dimethylpropyl)-amide

The method I

The way of synthesis of these compounds are presented in scheme 2 and described in detail below.

A. HCOOEt, NaOEt;

B. HCl, NHOBzl, NaOAc, water EtOH;

C. NaOH, CH3OH;

D. H-TleN (CH3)2; EDC, HOAt, DMF;

E. NaCNBH3, AcOH then split diastereoisomers;

F. HCOBt, THF;

G. H2Pd/C, CH3OH.

Stage A: 2RS-Formyl-heptane acid ethyl ester

Sodium metal (of 4.38 g, 0,191 mmol) cut into small pieces and placed in dvuhgolosy kiln dried round bottom flask under a layer of argon. Add anhydrous diethyl ether (100 ml), the suspension is stirred and cooled to 0°C. To the flask was attached a reflux before adding dropwise ethanol (of 1.03 ml, 17.3 mmol). Then added dropwise via an addition funnel a mixture of ethylformate (15,41 g, 0,208 mmol) and ethylcaproic (25 g, 0,173 mmol) for about 20 minutes. The resulting suspension orange (sodium metal can still be seen) allowed to warm to room te is temperature and stirred over night. The resulting thick orange suspension (sodium metal is not visible) is cooled to 0°and diluted with ice water (100 ml). The mixture is transferred into a separating funnel, the aqueous phase is removed, washed with diethyl ether, cooled to 0°and acidified with 1 M hydrochloric acid (200 ml). The emulsion is extracted with ethyl acetate and the organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure with the formation of a yellow oil containing mainly a named connection (11,09 g), which is used without further purification in Stage C.

Stage: 2RS-(Benzylamino-methyl)-heptane acid ethyl ester

The solid product of Clausena from the Stage And (11,0 g, and 63.9 mmol) dissolved in ethanol (100 ml) and water (10 ml) and cooled to 0°while adding sodium acetate (6.2 g, to 76.6 mmol) and 0-benzylhydroxylamine of hydrochloride (12,23 g, to 76.6 mmol). Mixture is allowed to warm to room temperature and stirred over night. The resulting suspension is filtered and the filtrate concentrated under reduced pressure. The remaining pasta yellow is distributed between ethyl acetate and water. The organic layer was washed with 1 M hydrochloric acid and brine, dried over anhydrous magnesium sulfate, filtered and evaporated before the formation of a yellow oil. The desired product is obtained is by flash chromatography (silica gel, gradient elution from 10 to 25%ethyl acetate in hexane. Output 9,19 g (52%).1H-NMR: δ (Dl3a mixture of SYN - and anti-isomers), 7.46 (M, d, J=8.0 Hz), 7.38-7.28 (5H, m), 6.79 (D, d, J = 7.1 Hz), 5.11 (S, s), 5.08 (S, s), 4.16 (M, kV, J=7.0 Hz), 4.13 (M, kV, J=7.0 Hz), 3.91 (S, kV, J=7.2 Hz), 3.21 (D, TD, J=8.0 and Hz), 1.90-1.48 (2H, m), 1.37-1.20 (7H, m), 0.87 (3H, t, J=7.0 Hz).

Stage C: 2RS-(Benzylamino-methyl)-heptane acid 2RS-(Benzylamino-methyl)-heptane acid ethyl ester (7.0 g, 25,24 mmol) dissolved in methanol (125 ml) and the solution cooled to 0°C. 1 M sodium Hydroxide (26 ml, 26 mmol) is added by portions over 2 minutes, which leads to the formation of a pale yellow emulsion. Enter the additional amount of methanol until it forms a clear solution. The solution is stirred for 90 minutes at 0°C, followed by 5 hours at room temperature until TLC analysis shows that the entire original product came in reaction. The solvent is removed under reduced pressure and the residue partitioned between water and ethyl acetate. The aqueous layer was cooled to 0°and acidified with 1 M hydrochloric acid. Thus obtained emulsion extracted twice with ethyl acetate. The combined organic extracts washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to get the named compound as a yellow oil (5,15 g, 82%), to the / establishment, which is used without further purification in Stage D. 1H-NMR: δ (CDCl3the mixture of SYN - and anti - isomers), 8.00 (1H, broadened s), 7.46 (M, d, J=7.9 Hz), 7.36-7.24 (5H, m), 6.80 (M, d, J=7.0 Hz), 5.13 (S, s), 5.09 (S, s), 3.94 (M, q, J=7.1 Hz), 3.27 (M, etc. J=6.4 and 8.0 Hz), 1.94-1.58 (2H, m), 1.48-1.24 (4H, m) and 0.94-0.84 (3H, m).

Stage D: 2RS-(Benzylamino-methyl)-heptane acid (1S-dimethylcarbamoyl-2,2-dimethylpropyl)amide

2-(Benzoyloxymethyl)-heptane acid (5,16 g of 20.7 mmol), tert.-leucine N.N-dimethylamide (of 3.60 g, 22,77 mmol) and EDC (4,g, 24.84 mmol) are stirred together in DMF (75 ml) and cooled to 0°C. Add HOAt (250 mg, cat.) and the resulting bright yellow mixture is allowed to warm to room temperature and stirred over night. The solvent is removed under reduced pressure and the remaining oil is distributed between ethyl acetate and 1 M hydrochloric acid. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The named compound obtained as colorless oil by flash chromatography (silica gel, gradient elution from 33 to 66%ethyl acetate in hexane). Exit at 6.84 g (85%).1H-NMR: δ (CDCl3the mixture of SYN - and anti - isomers), 7.45 (D, 2D), 7.40-7.26 (5H, m), 6.72 (D, 2D), 6.58 (1H, m), 5.20-4.69 (3H, m), 3.82 (N, m), 3.16-3.10 (3H, m), 3.05 (N. m). 2-99-2 .92 (3H, m), 1.90-1.54 (2H, m), 1.39-1.17 (4H, m), 0.97 (S, s), 0.96 (N. s), 0.94 (S, s), 0.92 (N,) and 0.92-0.82 (3H, m).

Stage E: 2R (or S)-(Benzoyloxymethyl)-heptane acid (1S-dimethylcarbamoyl-2,2-dimethylpropyl)amide

To a solution of 2RS-(benzylamino-methyl)-heptane acid (1S-dimethyl-carbarnoyl-2,2-dimethyl-propyl) amide (5.0 g, 12,84 mmol) in acetic acid (40 ml) is added in one portion sodium cyanoborohydride (2,02 g, 32,0 mol). The reagent dissolves slowly over 1 hour with a small gas with the formation of a colourless solution, which is left to mix overnight. The solvent is removed by evaporation under reduced pressure and distillation as azeotrope with toluene. The remaining oil is partitioned between diethyl ether and 1 M sodium carbonate (Note - there is a certain amount of gas). The organic layer was washed with brine (70 ml), dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. Two diastereoisomer these compounds are purified and separated using flash chromatography (silica gel, gradient elution from 50% to 100%ethyl acetate in hexane). Diastereoisomer And faster elution): colorless oil (2.27 g, 45%).1H-NMR: δ (CDCl3), 7.43-7.28 (5H, m), 6.76 (1 H, broadened d, J=9.4 Hz), 5.69 (1 H, broadened s), 4.93 (1 H, d, J=9.4 Hz), 4.72 (2H, s), 3.15 (3H, s), 3.18-3.00 (2H, m), 2.96 (3H, s). 2.49 (1H, m), 1.66-1.49(2H, m), 1.46-1.19 (4H, m), 0.99 (D,) and 0.86 (3H, t, J=6.8 Hz).

Diastereoisomer In (slower elution): colorless oil (1.44 g, 46%).1H-NMR: δ (CDCl3, 7.40-7.27 (5H, m), 6.70 (1H, broadened the th d, J=9.0 Hz), 5.99 (1H, broadened s), 4.85 (1H, d, J=9.0 Hz), 4.71 (2H, d, J=1.6 Hz), 3.16 (3H, s), 3.06-2.97 (2H, m), 2.95 (3H, s), 2.57 (1H, m), 1.74-1.21 (6N, m), 1.00 (S, s) and 0.88 (3H, broadened t, J=6.7 Hz).

Stage F: 2R (or S)-[(Benzyloxy-formyl-amino)-methyl]-heptane acid (1S-dimethylcarbamoyl-2,2-dimethyl-propyl)amide

2-(Benzylamino-methyl)-heptane acid (1S-dimethylcarbamoyl-2,2-dimethyl-propyl) amide (diastereoisomer A) (2,02 g, 5,13 mmol) dissolved in anhydrous THF (50 ml) and placed under a layer of argon. Add N-formyl-benzotriazol (A.R.Katrizky et al., Synthesis 1995, 503) (0,83 g, the 5.65 mmol) and the mixture is stirred at room temperature for 4 hours. The solvent is evaporated under reduced pressure and the remaining oil is partitioned between dichloromethane and 1 M sodium hydroxide. The organic layer is washed again with sodium hydroxide and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. A named connection receive in the form of a white crystalline solid using flash chromatography (silica gel, elution with 33% ethyl acetate in hexane). Yield 1.60 g (74%).1H-NMR: δ (CDCl3), rotamer), 8.00 (1H, broadened m), 7.47-7.29 (5H, m), 6.25 (1 H, broadened d, J=9.3 Hz), 5.08-4.74 (2H, broadened m), 4.87 (1H, d, J=9.4 Hz), 3.89-3.52 (2H, broadened m), 3.13 (3H, s), 2.94 (3H, s), 2.54 (1H, m), 1.67-1.11 (6N, m), 0.95 (N,) and 0.85 (3H, broadened t, J=6.9 Hz).

2-(Benzylamino-methyl)-HepB is anovas acid (1S-dimethylcarbamoyl-2,2-dimethyl-propyl)amide(diastereoisomer) get similar from more slowly aliremove of diastereoisomer Stage E. The yield of 0.38 g (41%).1H-NMR: δ (Dl3, rotamer), 8.00 (1H, broadened m), 7.47-7.28 (5H, broadened m), 6.29 (1H, broadened d, J=9.3 Hz), 5.01-4.63 (2H, broadened m), 4.88 (1H, d, J=9.3 Hz), 3.82-3.51 (M, broadened m), 3.20-2.78 (M, broadened m), 2.50 (1H, broadened m), 1.76-1.17 (6N, broadened m), 0.97 (D, ) and 0.85 (3H, broadened t, J=6.7 Hz).

Stage G: 2R (or S)-[(Formyl-hydroxy-amino)-methyl]-hexanoic acid-(1S-dimethyl carbarnoyl-2,2-dimethyl-propyl)-amide

2-[(Benzyloxy-formyl-amino)-methyl]-heptane acid (1S-dimethylcarbamoyl-2,2-dimethyl-propyl)amide (diastereoisomer A) (1,43 g, 3,41 mol) is dissolved in methanol (50 ml) and placed under a layer of argon. Add a suspension of 10% palladium on coal (100 mg, cat.) in ethylacetate (2 ml) and the mixture is vigorously stirred while bubbling through a solution of hydrogen. After 10 minutes the mixture is placed in an atmosphere of hydrogen and allowed to mix for 3 hours, up until TLC analysis shows that all the source material entered into the reaction. The system is saturated with argon and the catalyst removed by filtration. The filtrate is concentrated under reduced pressure with the formation of these compounds in the form of a colorless hygroscopic foam (1,11 g, 99%).1H-NMR: δ (CDCl3, rotamer), 8.41 (S, s), 7.83 (D, broadened s), 6.80 (D, broadened D. J=8.9 Hz), 6.62 (D, broadened d, J=9.4 Hz), 4.91 (D, broadened d, J=9.4 Hz), 4.88 (M, broadened d, J=8.9 Hz), 4.04 (1H, DD, J=14.7 and 74 Hz), 3.82 (0.65, DD, J=14.0 and 9.7 Hz), 3.56 (N, DD, J=14.7 and 3.3 Hz), 3.48 (N, DD, J=14.0 and 4.0 Hz), 3.16 (N. C). 3.15 (M, s), 2.98 (M, s), 2.96 (IN with). 2.90-2.74 (M, broadened m). 2.74-2.61 (M, broadened m), 1.73-1.17 (6N, broadened m), 0.99 (IN with). 0.95 (N,) and 0.87 (3H, broadened t, J =6.7 Hz).13C-NMR; δ (CDCl3,, 174.6, 171.2. 162.2, 157.2, 60.1, 54.5, 54.3, 52.3, 48.4, 44.8, 44.3, 35.6, 35.4, 29.6, 29.0, 26.3, 20.8, 20.2, and 14.0 13.7. LRMS: +ve ion 352 (M+Na), -ve ion 328 (M-H).

2-[(Formyl-hydroxy-amino)-methyl]-hexanophenone-(1S-dimethylcarbamoyl-2,2-dimethyl-propyl)-amide (diastereoisomer) get likewise diastereoisomer In Stage E

1H-NMR; δ (Dl3, rotamer), 9.37 (S, s), 8.40 (S, s), 7.75 (D, broadened s), 6.62 (D, broadened s), 6.41 (D, broadened d, J=7.1 Hz), 4.87 (D, broadened d, J=6.6 Hz). 4.66 (M, broadened d, J=7.6 Hz), 3.84-3.39 (2H, m), 3.21 (M, broadened s), 3.14 (1,5H, broadened s), 2.98 (3H, broadened s), 2.91-2.54 (1H, m), 1.79-1.23 (6N, m) and 1.08-0.83 (N, m).13C-NMR; δ (CDCl3, rotamer), 174.9, 173.3, 56.3, 54.8, 51.6, 50.3, 45.5, 45.1, 38.6, 38.4, 36.2, 36.0, 35.3, 34.4, 29.5, 29.4, 29.3, 29.2, 26.6, 26.5, 22.6, 22.5, and 13.9. LRMS: +ve ion 352 [M+Na], -ve ion 328 [M-N].

Method II

Alternative asymmetric way of synthesis of compounds according to Example 13 is shown in figure 3 and described below

Reagents and conditions:

A. piperdine, HCHO, EtOH, 80%, o/n;

B. tert.-BuCOCl, Et3N, then 3-lithium 4-benzyl-5,5-dimethyloxazolidine-2-he;

C. H2NOBzl, bedroom tepmerature, o/n, then TsOH, EtOAc;

D. LiOH, water, THF, 0°C;

E. H-TleN(Me2)2; HOBt, EDC, DMF;

F. HCOBt, THF;

G. H2Pd/C, EtOH.

Stage A: 2-Butyl-acrylic acid

To a solution of n-butylmalonic acid (17,2 g, 107 mmol) in ethanol (200 ml) is added piperidine (12,76 ml, 129 mmol) and 37% aqueous formaldehyde solution (40,3 ml, 538 mmol). The solution is heated to 80°and at this time, a precipitate gradually dissolved within 1 hour. The reaction mixture was stirred at 80°C overnight, then cooled to room temperature. The solvents are removed under reduced pressure and the residue is dissolved in ethyl acetate (200 ml), washed sequentially 1 M hydrochloric acid and brine, dried over anhydrous magnesium sulfate and filtered. The filtrate is concentrated with the formation of these compounds in the form of a clear oil (13,37 g, 97%).1H-NMR; δ (CDCl3), 6.29 (1H, s). 5.65 (1H, s). 2.34-2.28 (2H, m), 1.54-1.26 (4H, m) and 0.94 (3H, t, J=7.1 Hz).

Stage b: 45-Benzyl-3-(2-butylacrylate)-5,5-dimethyl-oxazolidin-2-he

2-Butylacrylate acid (21,5 g, 168 mmol) dissolved in dry THF (500 ml) and cooled to -78°under a layer of argon. Add triethylamine (30 ml, 218 mmol) and pivaloyl chloride (21 ml, 168 mmol) at such a speed that the temperature remained below -60°C. the Mixture was stirred at -78°C for 30 minutes, warmed to room temperature for 2 hours and finally cooled again to -78° C.

In a separate flask dissolve 4S-benzyl-5,5-dimethyl-oxazolidin-2-he in dry THF (500 ml) and cooled to -78°under a layer of argon. n-Utility (2.4 M solution in hexane, 83 ml, 200 mmol) is added slowly and the mixture is stirred for 30 minutes at room temperature. The resulting anion is moved through the tube in the original reaction vessel. Mixture is allowed to warm to room temperature and stirred over night at room temperature. The reaction is quenched with 1 M potassium bicarbonate (200 ml) and the solvents removed under reduced pressure. The residue is distributed between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure with the formation of an orange oil. TLC analysis showed the presence of unreacted chiral auxiliary substances in addition to the desired product. A portion of the product (30 g) is dissolved in dichloromethane and passed through a layer of silica gel to obtain the titled compound in pure form, which is a yellow oil (25,3 g).1H-NMR: δ (CDCl3), 7.31-7.19 (5H, m), 5.41 (2H,s), 4.51 (1H, DD, J=9.7, 4.2 Hz), 3.32 (1H, DD, J=14.2, 4.2 Hz), 2.82 (1H, DD, J=14.2, 9.7 Hz), 2.40-2.34 (2H, m), 1.48-1.32 (4H, m), 1.43 (3H, s), 1.27 (3H, s) and 0.91 (3H, t, J=7.1 Hz). A number of auxiliary chiral substance is isolated by washing silicagel what I methanol.

Stage C: 4S - Benzyl-3-[2-(benzylamino-methyl)-hexanoyl]-5,5-dimethyl-oxazolidin-2-it (salt n-toluensulfonate acid)

4S-Benzyl-3-(2-butyl-acryloyl)-5,5-dimethyl-oxazolidin-2-he (to 19.8 g of 62.8 mmol) is mixed with 0-benzylhydroxylamine (15,4 g, 126 mmol) and stirred overnight at room temperature. The mixture is dissolved in ethyl acetate and the solution washed with 1 M hydrochloric acid, 1 M sodium carbonate and brine, dried over anhydrous magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to a pale yellow oil (25,3 g), which, as shown by the data of NMR and HPLC, contains 4S-Benzyl-3-[2-(benzylamino-methyl)-hexanoyl]-5,5-dimethyl-oxazolidin-2-he (CA. 82% cu) along with traces of the original substance. The product is combined with another sample (26,9 g, 76% cu) and dissolved in ethyl acetate (200 ml). Add p-toluensulfonate (22,7 g, 119 mmol) and the mixture cooled to 0°C. a Named connection receive in the form of a white crystalline solid by persecution and solidification (34%, only diastereoisomer). A second sample (14,7 g, 20%, only diastereoisomer) was also obtained.1H-NMR; δ (Dl3, 7.89 (2H, d, J=8.2 Hz), 7.37-7.12 (10H, m), 7.02 (2H, d, J=6.9 Hz), 5.28-5.19 (2H, m), 4.55 (1H, m), 4.23 (1H, m), 3.93 (1H, m), 3.58 (1H, m), 2.58 (1H, m), 2.35 (3H, s), 1.67-1.51 (2H,m), 1.29-1.16 (4H, m), 1.25 (3H, s), 1.11 (3H, s) and 0.80-0.75 (3H, m).

Stage D: 2R-Benzylacetone the o-methyl)-hexanoic acid 4S-Benzyl-3-[2R-(benzylamino-methyl)-hexanoyl]-5,5-dimethyl-oxazolidin-2-about salt of p-toluenesulfonic acid (25,2 g, 40,2 mmol) is distributed between ethyl acetate and 1 M sodium carbonate. The organic phase is dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The remaining oil is dissolved in THF (150 ml) and water (50 ml), cooled to 0°and treated with lithium hydroxide (1.86 g, a 44.2 mmol). The solution is stirred for 30 minutes at 0°C, then overnight at room temperature. The reaction mass is acidified to pH 4 with 1 M citric acid and the solvents removed. The residue is partitioned between dichloromethane and 1 M sodium carbonate. The alkaline aqueous layer is acidified to pH 4 with 1 M citric acid and extracted three times with ethyl acetate. The combined organic layers dried over anhydrous magnesium sulfate, filtered and concentrated to obtain these compounds in the form of a colorless oil (7.4 g, 73%).1H-NMR; δ (CDCl3). 8.42 (2H, broadened s), 7.34-7.25 (5H. m), 4.76-4.66 (2H, m), 3.20-3.01 (2H, m), 2.73 (1 H, m), 1.70-1.44 (2H, m), 1.34-1.22 (4H, m) and 0.92-0.86 (3H, m).

Stage E: 2R-(Benzylamino-methyl)-hexanoic acid (1S-dimethylcarbamoyl-2,2-dimethyl-1-propyl)amide

2R-Benzylamino-methyl)-hexanoic acid (7.98 g, of 31.8 mmol) dissolved in DMF (150 ml) and the solution cooled to 0°C. Add EDC (6,1 g of 31.8 mmol) and HOBt (430 mg, 3.2 mmol) and the mixture is stirred for 15 minutes. Then add tert.-leucine-m, M-dimethylamide (5.53 g, 34 the mole), mixture is allowed to warm to room temperature and stirred over night. The solvent is removed under reduced pressure and the residue is dissolved in ethyl acetate, washed sequentially 1 M hydrochloric acid, saturated sodium bicarbonate solution and brine, dried and filtered. The solvent is removed to obtain the named compound as a yellow oil (8.7 g, 69%), which is used without further purification in Stage F.1H-NMR; δ (Dl3), 7.35-7.28 (5H, m), 6.77 (1H, broadened d, J=9.2 Hz), 5.69 (1H, broadened with). 4.93 (1H, d, J=9.4 Hz), 4.72 (2H, s), 3.15 (3H, s), 3.10-3.00 (2H, m), 2.95 (3H, s), 2.49 (1H, m), 1.64-1.21 (6N, m), 0.99 (D,) and 0.86 (3H, t, J=6.8 Hz)

Stage F: 2R-[(Benzyloxy-formyl-amino)-methyl]-hexanoic acid (1S-dimethylcarbamoyl-2,2-dimethyl-1-propyl)amide

2R-(Benzylamino-methyl)-hexanoic acid (1S-dimethylcarbamoyl-2,2-dimethyl-1-propyl)amide (7.8 g, to 19.9 mmol) dissolved in dry THF (100 ml) and treated with 1-formyl-benzotriazole (is 3.08 g, 21,0 mmol). The reaction mass is stirred over night at room temperature. The solvent is removed under reduced pressure and the residue is dissolved in ethyl acetate, washed with 2 M sodium hydroxide solution and brine. The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The product is crystallized from ethyl ether-hexane (4.83 g, 57% two samples). 1H-NMR; δ (CDCl3, rotamer), 8.12 (D, broadened s), 7.89 (D, broadened s), 7.37 (5H. s), 6.25 (1 H, d, J=9.3 Hz), 4.96 (D, broadened s), 4.86 (1H, d, J=9.4 Hz). 4.80 (M, broadened s), 3.74 (2H, broadened s), 3.13 (3H, s), 2.94 (3H. C). 2.53 (1H, m), 1.38-1.21 (6N, m), 0.95 (D,) and 0.85 (3H, t, J=6.9 Hz). Note: a Small amount of sample is crystallized from ethyl ether-hexane to obtain crystals suitable for x-ray analysis. The stereochemistry shown in the description, confirmed.

Stage G: 2R-[(Formyl-hydroxy-amino)-methyl]-hexanoic acid (1S-dimethylcarbamoyl-2,2-dimethyl-1-propyl)amide

2R-[(Benzyloxy-formyl-amino)-methyl]-hexanoic acid (1S-dimethylcarbamoyl-2,2-dimethyl-1-propyl)amide (4.72 in g, 11.3 mmol) is dissolved in ethanol (80 ml) and placed under a layer of argon. Add a suspension of 10% palladium on coal (940 mg) in ethyl acetate (2 ml) and the mixture vigorously stirred as hydrogen is bubbled through the system. After 30 minutes, the suspension is placed under the current balloon of hydrogen and stirred overnight at room temperature. The flask was saturated with argon before to remove the catalyst by filtration. The filtrate is concentrated under reduced pressure to obtain the above compound as a colourless foam, which crystallized upon standing (3.65 g, 98%).1H-NMR; δ (CDCl3, rotamer), 9.32 (S, broadened s), 8.41 (S, s), 7.88 (D, broadened s) 7.27 (D, s), 6.75 (D, broadened d, J=8.8 Hz), 6.58 (D, broadened d, J=9.3 Hz), 4.89 (1H, m), 4.04 (N, m), 3.82 (N, m), 3.53 (1H, m), 3.16 (M, s), 3.15 (M, s), 2.98 (M, s), 2.96 (M, s), 2.79 (0.6, m), 2.65 (N, m), 1.78-1.58 (6N, m), 0.99 (S, s), 0.95 (D,) and 0.87, 3H, t, J=6.7 Hz).13C-NMR; δ (CDCl3; rotamer), 175.8, 173.3, 172.0, 55.4, 54.9, 52.2, 48.8, 46.3, 38.9, 38.8, 36.3, 36.1, 30.3, 30.2, 29.7, 26.9, and 23.0 14.3. LRMS: +ve ion 352 [M+Na], -ve ion 328 [M-H]. Compounds according to examples 14 to 27 obtained by, similar to that described in example 13, the Method I when replacing the corresponding ether ether of ethylcaproic on Stage A. If you get both diastereoisomer, diastereoisomer And eluted faster and usually it is more potent against PDF in vitro. In some cases, only more quickly out diastereoisomer (stage E) is transferred to the final product.

Example 14

2R (or S)-[(Formylhydrazine)-methyl]-3-cyclopentyl-propionic acid (1S-dimethyl-carbarnoyl-2,2-dimethyl-propyl)-amide

Diastereoisomer A. Colorless glassy substance.1H-NMR; δ (CDCl3, rotamer), 9.33 (S, broadened s), 8.94 (S, broadened s), 8.40 (S, s), 7.82 (D, s), 6.82 (D, broadened d, J=8.6 Hz), 6.62 (D, broadened d, J=9.3 Hz), 4.90 (1H, m), 4.06 (M, broadened DD, J=14.7, 7.3 Hz), 3.81 (S, broadened DD. J=14.0, 9.7 Hz), 3.50 (1H, m), 3.16 (M, s), 3.14 (M, s), 2.97 (N. s), 2.95 (M, s), 2.80 (1H, m), 1.87-1.32 (M, m), 1.16-0.95 (2H, m), 0.99 (D,) and 0.95 (N, C).13C-NMR; δ (Dl3rotamer), 172.9, 171.3, 55.0, 54.5, 52.0, 48.6, 45.4, 44.2, 38.5, 38.4, 37.9, 37.6, 36.4, 36.3, 35.8, 35.6, 35.5, 32.7, 32.6, 26.5, 26.4, and 25.1. LRMS: +ve ion 378 [M+Na], -ve ion 354 [M-H].

Diastereoisomer Century Colorless glassy substance.1H-NMR; δ (CDCl3, rotamer), 9.30 (S, broadened s), 8.41 (S, s), 7.75 (D, s), 6.52 (D, broadened d, J=8.7 Hz), 6.41 (D, broadened d, J=7.3 Hz), 4.85 (M, broadened d, J=9.5 Hz), 4.63′(N, broadened d, J=7.5 Hz), 3.85-3.40 (2H, m), 3.25-2.95 (6N,3 broadened singlet), 2.78 (1H, 2 broadened multiplet), 1.90-1.40 (8H, m), 1.30 (1H, m), 1.20-1.00 (2H, m) and 1.05-0.95 (M, 2C).13C-NMR; δ (CDCl3), rotamer), 174.9, 173.3, 172.8, 56.5, 54.7, 51.5, 50.5, 44.7, 44.6, 38.6, 38.4, 38.0, 37.8, 36.2, 36.0, 35.7, 35.5, 35.3. 34.3, 33.0, 32.9, 32.4, 32.3, 30.9, 26.6, 26.5, 25.1, 25.0 and 24.9. LRMS: +ve ion 378 [M+Na], -ve ion 354 [M-H].

Example 15

2R (or S)-[(Formyl-hydroxy-amino)-methyl]-heptane acid-(1S-dimethylcarbamoyl-2.2-dimethyl-propyl)-amide

Diastereoisomer A. Dark orange oil.1H-NMR; δ (Dl3, rotamer), 8.32 (S, s), 7.76 (D, broadened s), 6.78 (D, broadened d, J=9.1 Hz), 6.68 (D, broadened d, J=9.1 Hz), 4.87-4.79 (1H,m), 3.96 (M, broadened DD, J=14.6, 7.6 Hz), 3.74 (S, broadened DD, J=13.9, 9.7 Hz), 3.51-3.36 (1H, m), 3.09 (1H, s), 3.08 (2H, s), 2.90 (1H, s), 2.89 (2H, s), 2.86-2.55 (1H, m), 1.53-1.19 (8H, broadened m), 0.92 (3H, s), 0.88 (6N,) and 0.79 (3H, m).13C-NMR; δ (Dl3, rotamer), 174.3, 172.0, 170.5, 170.4, 54.0, 53.5, 53.4, 50.8, 49.7, 47.4, 44.9, 43.8, 37.5. 37.4, 34.8, 34.7, 34.6, 30.6, 29.2, 29.1, 25.8, 25.5, and 21.4 12.9. LRMS: +ve ion 344 M+H], -ve ion 342 [M-N].

Diaster the isomer Century Dark orange oil.1H-NMR; δ (CDCl3, rotamer), 8.36 (S, s), 7.74 (D, s), 6.69 (D, broadened s), 6.57 {N, broadened d, J=7.6 Hz), 4.89 (D, broadened s), 4.70 (M, d, J=7.8 Hz), 3.76-3.40 (2H, m), 3.21 (N. s), 3.16 (M, s), 2.98 (3H. s), 2.81 (1H, broadened s), 2.72-2.60 (1 H, m), 1.67 (2H, broadened s), 1.42-1.22 (6N, m), 1.02 (S, s), 0.99 (S, s), 0.90 (N,) and 0.87 (N, C).13C-NMR; δ (CDCl3, rotamer), 175.2, 173.8, 173.1, 56.5, 55.1, 52.3, 51.1, 50.6, 45.8, 45.5, 39.0, 38.9, 36.6. 26,3, 35.6, 34.9, 32.1, 32.0, 30.1, 29.9, 27.4, 27.4, 27.0, 26.9, and 22.9 14.3. LRMS: +ve ion 344 [M+H], -ve ion 342 [M-N].

Example 16

2R (or S)-[(Formyl-hydroxy-amino)-methyl]-pentanol acid-(1S-dimethylcarbamoyl-2,2-dimethyl-propyl)-amide

Diastereoisomer A. White hygroscopic foam.1H-NMR; δ (CDCl3, rotamer), 8.40 (S, s), 7.83 (D, broadened s), 6.88 (D, broadened d, J=8.6 Hz), 6.69 (D, broadened D. J 9.2 Hz), 4.90 (1H, t). 4.06 (N, broadened DD, J 14.5, 7.4 Hz), 3.82 (S, broadened DD, J=13.7, 9.8 Hz), 3.57-3.44 (1H, m), 3.16 (1H, s), 3.15 (2H, s), 2.98 (1H, s), 2.96 (2H, s), 2.87-2.63 (1H, m), 1.64-1.26 (4H, broadened m), 0.98 (3H, s), 0.94 (6N, (C) and 0.90 (3H, t, J=7.3 Hz).13C-NMR; δ (Dl3, rotamer), 175.8, 173.2, 172.0, 55.4, 54.9, 52.2, 48.7, 46.2, 45.0, 38.9, 38.9, 36.3, 36.1, 36.1, 32.7, 32.6, 27.0, 26.9, 20.9, 20.8 and 14.4. LRMS: +ve ion 338 [M+Na], -ve ion 314 [M-N].

Example 17

2R (or S)-[(Formyl-hydroxy-amino)-methyl]-4-methyl-pentanol acid-(1S-dimethyl-carbarnoyl-2,2-dimethylpropyl)-amide

Diastereoisomer A. Bel is e hygroscopic solid. 1H-NMR; δ (CDCl3, rotamer), 8.41 (S, s), 7.83 (D, s), 6.65 (D, d, J=8.6 Hz), 6.55 (D, d, J=9.0 Hz), 4.91-4.83 (1H, m), 4.03-3.95 (M, m), 3.84-3.74 (M, m), 3.62-3.43 (1H. m), 3.16 (1H, s), 3.13 (2H, s), 2.98 (1H, s), 2.96 (2H, s), 2.89-2.79 (M, m). 2.76-2.71 (N. m), 1.69-1.34 (M, m), 1.29-1.20 (M, m), 1.0 (N, s), 0.95 (N. C) and 0.93-0.88 (6N, m).13C-NMR; δ (CDCl3, rotamer), 175.8, 173.3, 172.0, 171.7, 55.5, 55.0, 52.4, 49.1, 44.3, 43.2, 39.5, 39.4, 38.9, 38.8, 36.3, 36.1, 27.0. 26.9, 26.3, 26.0, 23.1, 23.0, and 22.8. LRMS: +ve ion 352 [M+Na], -ve ion 328 [M-N].

Example 18

3-Cyclohexyl-2R (or S)-[(Formylhydrazine)-methyl]-propionic acid(1S-dimethylcarbamoyl-2,2-dimethyl-propyl)-amide

White solid.1H-NMR; δ (CDCl3, rotamer), 8.38 (S, s), 7.82 (D, s), 6.93 (D, d, J=8.9 Hz), 6.74 (D, d, J=8.9 Hz), 4.90 (1H, d, J=9.4 Hz), 4.02 (N, DD, J=9.7, HZ), 3.78 (N, DD, J=9.7, 14.1 Hz), 3.46 (1H,m), 3.15 (3H. s), 2.96 (3H, s), 2.92 (1H, m), 1.65 (6N, m), 1.20 (5H, m). 0.98 (N,) and 0.87 (2H, m).13C-NMR; δ (CDCl3, rotamer), 176.4, 174.2, 172.4, 56.0, 55.6, 53.4, 49.9, 44.0, 43.3, 39.6, 39.4, 38.7, 38.5, 36.9, 36.7, 36.6, 34.8, 34.5, 27.5, 27.4 and 27.2. LRMS: +ve ion 370 [M+H], 368 [M-N].

Example 19

2R (or S)-Cyclopentyl-3-(Formyl-hydroxy-amino)-propionic acid (1S-dimethylcarbamoyl-2,2-dimethyl-propyl)-amide

Diastereoisomer A. Foam off-white color.1H-NMR; δ (CD3OD, rotamer), 8.22 (S, s), 7.79 (D, s), 4.89 HE, s), 3.87 (1H, m), 3.50 (1H, m), 3.19 (3H, s,), 2.93 (3H, s), 2.82 (N, m), 2.65 (N, m), 1.89 (2H, m), 1.56 (5H, m), .24 (2H, m) and 0.98 (N, C).13C-NMR; δ (CD3OD, rotamer), 176.0, 56.7, 53.2, 51.1, 42.7, 39.2, 36.5, 36.4, 32.0, 27.4, 26.4, 26.2. IR (reflective table.) vmax3318, 2953, 1663, 1628, 1529, 1367, 1229, 1142, 1087, 877 cm1. LRMS: +ve ion 364 [M+Na], -ve ion 340 [M-N].

Example 20

2R (or S)-[(Formyl-hydroxy-amino)-methyl]-octanoic acid (1S-dimethylcarbamoyl-2,2-dimethyl-propyl)-amide

Diastereoisomer A.1H-NMR; δ (CDCl3), rotamer), 8.40 (S, s), 7.83 (N. s), 6.88 (D, d, J=8.9 Hz), 6.68 (D, d, J=9.2 Hz), 4.90 (1H, m), 4.05 (M, m). 3.81 (N, m), 3.50 (1H, m), 3.16 (M, s), 3.15 (M, s), 2.97 (N. s), 2.96 (M, s), 2.86 (N, m), 2.69 (N, m), 1.59-1.25 (10H. m), 1.14-0.95 (N. m) and 0.89-0.77 (3H. m).13C-NMR; δ (Dl3, rotamer), 175.2, 172.9, 171.6, 171.4, 54.9, 54.5, 54.3, 52.0, 48.4, 46.1. 45.7, 45.1, 44.7, 39.7, 38.5, 38.4, 35.8, 35.6, 35.6, 31.7, 31.5, 30.2, 30.1, 29.1, 29.1, 27.0, 26.4, and 22.4 14.0. LRMS: +ve ion 380 [M+Na], 358 [M+H], -ve ion 356 [M-N].

Example 21

2R (or S)-[(Formyl-hydroxy-amino)-methyl]-nonanol acid (1S-dimethylcarbamoyl-2,2-dimethyl-propyl)-amide

Diastereoisomer: solid brown color.1H-NMR; δ (Dl3, rotamer), 9.30 (S, s), 8.41 (S, s), 7.83 (D, s), 6.66 (D, d, J=8.9 Hz), 6.52 (D, d, J=9.7 Hz), 4.92-4.84 (1 H, m), 4.06-3.97 (M, m), 3.87-3.77 (M, m), 3.63-3.45 (1H. m), 3.16(M,s), 3.14(M,s), 2.98 (M, s), 2.96 (M, s), 2.86-2.74 (M, m), 2.66-2.63 (M, m), 1.95-1.25 (N, m), 1.00-0.95 (N. m), 0.90-0.84 (3H, m).13C-NMR; δ (Dl3,rotamer), 175.5, 172.8, 171.4, 162.2, 156.1, 55.1. 4.5, 51.3, 50.8, 48.4, 46.3, 44.9, 38.4, 38.4, 35.8, 35.7, 33.9, 31.7, 30.3, 30.2, 29.4, 29.0, 27.1, 26.5, 26.5, 24.9. 22.6 and 14.0. LRMS: +ve ion 394 [M+Na], 372 [M+H], -ve ion 370 [M-N].

Example 22

2R (or S)-[(Formyl-hydroxy-amino)-methyl]-decanoas acid (1S-dimethylcarbamoyl-2,2-dimethyl-propyl)-amide

Diastereoisomer And: colorless oil. LRMS: +ve ion 408 [M+Na], 386 [M+H], -ve ion 384 [M-N].

Example 23

2R (or S)-[(Formyl-hydroxy-amino)-methyl]-5-methylhexanoic acid (1S-dimethylcarbamoyl-2,2-dimethyl-propyl)-amide

Diastereoisomer And: colorless oil.1H-NMR; δ (CDCl3, rotamer), 9.31 (S, s), 8.40 (S, s), 8.17 (S, s), 6.77 (D, d, J=7.5 Hz), 6.60 (M, d, J=8.0 Hz). 4.89 (1H, m), 4.04 (N, m), 3.83 (N, m), 3.52 (1H. m), 3.16 (M, s), 3.15 (N. s), 2.98 (M, s), 2.96 (M, s), 2.70 (1H, m), 1.58-1.14 (5H, m), 1.00-0.95 (N, m) and 0.87-0.84 (6N, m).13C-NMR; δ (CDCl3, rotamer), 172.9, 171.5, 162.2. 156.3, 55.1, 54.6, 51.4, 48.5, 46.4, 45.0, 38.5, 38.4, 36.2, 35.9, 35.6, 29.7, 28.1, 28.0, 27.9, 26.7, 26.6, 26.5 and 22.4. LRMS:+ve ion 366 [M+Na], 344 [M+H], -ve ion 342 [M-N].

Example 24

2R (or S)-[formyl-hydroski-amino)methyl]propanoic acid (1S-dimethylcarbamoyl-2,2-dimethyl-propyl)-amide

Diastereoisomer:1H-NMR; δ (CDCl3), rotamer), 8.41 (S, s), 7.81 (D, s), 6.67 (D, d, J=8.4 Hz), 6.51 (D, d, J=7.2 Hz), 4.88 (M, d, J=9.4 Hz), 4.66 (M, d, J=7.7 Hz), 3.76 (1H, m), 3.55 (N, DD, J=14.3, 9.8 Hz). 3.44 (N, DD, J=14.2, 5.3 Hz), 3.21 (M, s), 3.14 (M, s), 2.99 (S, s), 2.97 (N, C), .81 (1H, m), 1.21 (M, d, J=6.7 Hz), 1.19 (D, D. J=6.8 Hz), 1.01 (D,) and 0.98 (IN with). LRMS: +ve ion 310 [M+Na], -ve ion 286 [M-N].

Diastereoisomer In:1H-NMR; δ (CDCl3, rotamer), 9.47 (S, broadened s), 8.41 (S, s), 7.86 (D, s), 6.96 (D, broadened s), 6.74 (D, d, J=Hz), 4.91 (1H, m), 3.99 (N. DD, J=14.2, 7.6 Hz), 3.83 (N, DD, J=13.8, 9.0 Hz), 3.50 (1H, m), 3.16 (M, s), 3.15 (M, s), 2.97 (3H, s), 2.90 (1H, m), 1.21 (M, d, J=6.8 Hz), 1.15 (N. d, J=6.5 Hz), 0.99 (D,) and 0.95 (IN with). LRMS: +ve ion 310 [M+Na], -ve ion 286 [M-N].

Example 25

2R (or S)-[(Formyl-hydroxy-amino)-methyl]-3-methylbutanoic acid (1S-dimethyl-carbarnoyl-2,2-dimethyl-propyl)-amide

Diastereoisomer:1H-NMR; δ (CDCl3, rotamer), 9.33 (S, s), 8.38 (S, s), 7.81 (D, s), 6.86 (D, broadened s), 6.58 (N. d, J=8.6 Hz), 4.90 (1H, m), 4.06 (N, DD, J=14.7, 7.3 Hz), 3.91 (N, DD, J=13.8, 10.6 Hz), 3.17 (M, s), 3.15 (M, s), 2.98 (M, s), 2.96 (M, s), 2.62 (N, m), 2.48 (N, m), 1.90 (1H, m), 1.09-0.86 (15 NM, m). LRMS: +ve ion 338 (M+Na), -ve ion 314 (M-N).

Example 26

2R(or S)-[(Formyl-hydroxy-amino)-methyl]-3-phenyl-propenylboronic acid-(1S-dimethylcarbamoyl-2,2-dimethylpropyl)-amide

Diastereoisomer A. Colorless glassy substance.1H-NMR; δ (Dl3, rotamer), 9.33 (S, broadened s), 8.95 (S, broadened s), 8.43 (D, broadened s), 7.83 (D, broadened s), 7.27-7.10 (5H, m), 6.65 (0,3H, broadened s), 6.45 (D, broadened d, J=8.2 Hz), 4.80-4.70 (1 H, m), 4.22-4.10 (M, m), 3.89 (N, DD, J=13.7, 9.6 Hz), 3.633.47 (1H, m), 3.20-2.69 (3H. m), 3.04 (3H, broadened s), 2.86 (3H, broadened s), and 0.87 (N, broadened s).13C-NMR; δ (Dl3, rotamer), 137.9, 137.7, 128.8, 128.5, 126.6, 54.9, 54.5, 51.3, 48.3, 47.3, 46.6, 38.3. 38.2. 36.2, 36.1, 35.8, 35.7, 35.6, 35.5 and 26.4. LRMS: +ve ion 386 (M+Na), -ve ion 362 (M-H).

Example 27

2R (or S)-[(Formyl-hydroxy-amino)-methyl]-3-(4-methoxyphenyl)-propionic acid-(1S-dimethylcarbamoyl-2,2-dimethyl-propyl)-amide

Diastereoisomer: LRMS: +ve ion 416 (M+Na), 394 (M+H), -ve ion 392 (M-H)

Compounds according to examples 28 to 31 are obtained by, similar to that described in example 13, Method II, replacing the corresponding amidon or benzyl ester of the amino acid tert.-leucine N.N-dimethylamide on Stage E.

Example 28

2S-{2R-[Formyl-hydroxy-amino)-methyl]-hexanamine}-3-phenylpropionate acid

The white foam.1H-NMR; δ (CD3OD, rotamer), 8.11 (N, s), 7.80 (D, s), 7.31-7.16 (5H, m), 4.68 (1H, DD, J=8.7, Hz), 3.58 (1H, m), 3.39 (1H, m), 3.19 (1H, m), 2.98 (1H, m), 2.76 (1H, m), 1.55-1.26 (6N, m) and 0.90-0.85 (3H, m).13C-NMR; (CD3OD, rotamer), 176.1, 175.7, 174.7, 174.5, 138.6, 138.5, 130.3, 129.5, 129.4, 127.7, 55.0, 53.3, 49.8, 45.4, 38.4, 38.3, 31.0, 30.8, 30.1, and 23.7 14.2. IR (reflective table.) vmax2932, 2359, 1727, 1660, 1551, 1454, 1381, 1221, 882, sm -1. LRMS: +ve ion 359 [M+Na], -ve ion 335 (M-H).

Example 29 2S-{2R-[Formyl-hydroxy-amino)-methyl]-hexanamine}-3,3-dimethylbutanoate acid

White pen is. 1H-NMR; δ (CD3OD, rotamer), 8.25 (S, s), 7.82 (D, s), 4.31 (1H,s), 3.83-3.29 (2H, m), 3.10-2.89 (1H, m), 1.54-1.33 (6N. m), 1.03 (3H,s), 1.01 (6N,) and 0.92-0.87 (3H, m).13C-NMR; δ (CD3OD, rotamer), 174.9, 172.9, 61.0, 52.4, 44.2, 44.0, 33.6, 30.1, 29.1, 26.2, and 22.6 13.1. IR (reflective table.)vmax2959, 2359, 1644, 1537, 1371, 1218, 881 and 704 cm-1. LRMS: +ve ion 325 (M+Na), -ve ion 301 (M-N).

Example 30

2S-[2R-(Formyl-hydroxy-amino)-methyl]-hexanoic acid {1-[(2S-hydroxymethyl-pyrrolidin-1-carbarnoyl]-2,2-dimethyl-propyl}-amide

A colorless oil.1H-NMR; δ (CD3OD, rotamer), 8.26 (S, s), 7.84 (D, s), 4.62 (M, d, J=8.2 Hz), 4.39 (M, d, J=8.4 Hz), 4.12 (1H,m), 3.91-3.37 (6N, broadened m), 2.93 (N, m), 2.78 (N, m), 1.93 (5H,m), 1.45 (2H,m), 1.39 (3H,m), 0.97 (3H, extended s), 0.95 (3H, broadened s), and 0.89 (3H, t, J=6.7 Hz).13C-NMR; δ (Dl3, rotamer), 174.8, 172.9, 65.3, 65.1, 59.6, 59.5, 55.9, 55.7, 51.9, 47.8, 44.7, 44.0, 31.5, 30.5, 29.3, 28.7, 28.1, 27.3, 23.8, 22.0, 21.2. 18.7, 18.3, 17.6, and 14.7 13.3. LRMS: +ve ion 394 (M+Na), 372 (M+H), -ve ion 370 (M-H).

Example 31

2S-[2R-(Formyl-hydroxy-amino)-methyl]-hexanoic acid {1-[(2-hydroxy-ethyl)methylcarbamoyl]-2,2-dimethyl-propyl}-amide

The white foam.1H-NMR; δ (CD3OD, rotamer), 8.25 (S, s), 8.03 (D, s), 7.82 (D, s), 4.88 (1H, m), 3.83-3.54 (4H, broadened m), 3.41 (2H, m), 3.25 (2H, s), 2.96 (2H, m), 1.49 (2H, m), 1.23 (4H, m), 1.00 (6N, s), 0.99 (3H, s), 0.88 (3H. m).13C-NMR; δ (CD3OD, rotamer), 173.6, 164.4, 61.1, 61.0, 56.9, 56.5, 54.2, 53.9,52.2, 41.8, 38.9, 36.9, 36.3, 35.3, 31.6, 30.8, 27.5, and 24.1 14.7. LRMS: +ve ion 382 [M+Na], -ve ion 358 [M-N].

Connection examples with 32 59 get by, similar to that described in example 7, Method II, replacing the corresponding amine or amide/benzyl ester of the amino acid tert.-leucine - N.N-dimethylamide on Stage E. In some cases the use of HOAt in Stage E and carry out the removal of protection by hydrogenolysis (stage G) in terms of catalytic transfer (cyclohexen, palladium on coal in ethanol)

Example 32

2R-[(Formyl-hydroxy-amino)-methyl]-hexanoic acid-(1R-dimethylcarbamoyl-2,2-dimethylpropyl)-amide

A colorless oil. LRMS: +ve ion 330 [M+H], -ve ion 328 [M-N].

Example 33

2R-[(Formyl-hydroxy-amino)-methyl]-hexanoic acid (1S-dimethylcarbamoyl-28-methyl - butyl)-amide

The white foam. LRMS: +ve ion 352 [M+Na], -ve ion 328 [M-N].

Example 34

2R-[(Formyl-hydroxy-amino)-methyl]-hexanoic acid (1S-

dimethylcarbamoyl-2-methoxy-2-methylpropyl)-amide

Of racemic p-hydroxymethylamino. Diastereoisomer A. Colourless oil. LRMS: +ve ion 368 [M+Na], 346 [M+H], -ve ion 344 [M-H]. Diastereoisomer Century LRMS: +ve ion 368 [M+Na], 346 [M+H], -ve ion 344 [M-N].

Example 35

2R-[(Formyl-hydroxy-amino)-methyl]-hexanoic acid (1S-dimethylcarbamoyl-2-hydroxy-2-methylpropyl)-amide

A colorless oil. LRMS: +ve ion 354 [M+Na], -ve ion 330 [M-N].

Example 36

2R-[(Formyl-hydroxy-amino)-methyl]-hexanoic acid [2-(4-chlorophenyl)-1S-dimethylcarbamoyl]-amide

A colorless oil. LRMS: +ve ion 330 (M+H), -ve ion 328 (M-H).

Example 37

2R-[(Formyl-hydroxy-amino)-methyl]-hexanoic acid [1S-dimethylcarbamoyl-2-(4-hydroxyphenyl)-ethyl]-amide

A colorless oil. LRMS: +ve ion 402 (M+Na), 380 (M+H).

Example 38

2R-[(Formyl-hydroxy-amino)-methyl]-hexanoic acid (1S-dimethylcarbamoyl-2-naphthalen-2-yl-ethyl)-amide

A colorless oil. LRMS: +ve ion 414 (M+H), -ve ion 412 (M-H)-

Example 39

2R-[(Formyl-hydroxy-amino)-methyl]-hexanoic acid (2-cyclohexyl-1S-dimethylcarbamoyl-ethyl)-amide

The white foam. LRMS: +ve ion 392 (M+Na), 370 (M+N)

Example 40

2R-[(Formyl-hydroxy-amino)-methyl]-hexanoic acid (1S-dimethylcarbamoyl-methyl)-amide

A colorless oil. LRMS: +ve ion 350(M+H), -ve ion 348 (M-H).

Example 41

2-{2R-[(Formyl-hydroxy-amino)-methyl]-hexanoyl}-1,2,3,4-tetrahydro-isoquinoline-3S-carboxylic acid dimethylamide

LRMS: +ve ion 398 (M+Na), 376 (M+H), -ve ion 374 (M-H).

Example 42

2R-[(Formyl-hydroxy-amino)-methyl]-hexanoic acid (4-Amin is-1S-dimethylcarbamoyl-butyl)-amide

A colorless oil. LRMS: +ve ion 345 (M+H), -ve ion 343 (M-H).

Example 43

2R-[(Formyl-hydroxy-amino)-methyl]-hexanoic acid (1S-dimethylcarbamoyl-2-hydroxy-ethyl)-amide

A colorless oil. LRMS: +ve ion 326 (M+Na), -ve ion 302 (M-N).

Example 44

N-Hydroxy-N-[2R-(4-methylpiperazin-1-carbonyl)-hexyl]-formamide

LRMS: +ve ion 272 [M+H].

Example 45

N-Hydroxy-N-[2R-(morpholine-4-carbonyl)-hexyl]-formamide

LRMS: +ve ion 281 (M+Na), 259 (M+H), -ve ion 257 (M-N).

Example 46

N-Hydroxy-N-[2R-(2S-hydroxymethyl-pyrrolidin-1-carbonyl)-hexyl]-formamide

LRMS: -ve ion 271 (M-N).

Example 47

2R-[(Formyl-hydroxy-amino)-methyl]-hexanoic acid (1S-hydroxymethyl-2,2-dimethylpropyl)-amide

LRMS: +ve ion 289 (M+H), -ve ion 287 (M-N).

Example 48

2R-[(Formyl-hydroxy-amino)-methyl]-hexanoic acid (1S-methoxymethyl-2,2-dimethylpropyl)-amide

LRMS: +ve ion 303 (M+H), -ve ion 301 (M-N).

Example 49

2R-[(Formyl-hydroxy-amino)-methyl]-hexanoic acid [1S-(4-benzyl-piperidine-1-carbonyl)-2,2-dimethylpropyl]-amide

LRMS: -ve ion 458 (M-H).

Example 50

2R-[(Formyl-hydroxy-amino)-methyl]-hexanoic acid [1S-(Ben the Il-phenylethanol)-2,2-dimethylpropyl]-amide

LRMS: +ve ion 496 (M+H), -ve ion 494 (M-H).

Example 51

2S-[(Formyl-hydroxy-amino)-methyl]-hexanoic acid [2,2-dimethyl-1S-(pyrrolidin-1-carbonyl)-propyl]-amide

LRMS: +ve ion 356 (M+H), -ve ion 354 (M-H).

Example 52

2R-[(Formyl-hydroxy-amino)-methyl]-hexanoic acid [2,2-dimethyl-1S-(morpholine-4-carbonyl)-propyl]-amide

LRMS: +ve ion 372 (M+H), -ve ion 370 (M-H).

Example 53

2R-[(Formyl-hydroxy-amino)-methyl]-hexanoic acid [2,2-dimethyl-1S-(4-methylpiperazin-1-carbonyl)-propyl]-amide

LRMS: +ve ion 385 (M+H), -ve ion 383 (M-N).

Example 54

2R-[(Formyl-hydroxy-amino)-methyl]-hexanoic acid [2,2-dimethyl-1S-(4-methylpiperidin-1-carbonyl)-propyl]-amide

LRMS: +ve ion 384 (M+H), -ve ion 382 (M-H).

Example 55

2R-[(Formyl-hydroxy-amino)-methyl]-hexanoic acid (1S-cyclohexylcarbonyl-2,2-dimethylpropyl)-amide

LRMS: +ve ion 398 (M+H), -ve ion 396 (M-H).

Example 56

2R-[(Formyl-hydroxy-amino)-methyl]-hexanoic acid [1S-(4-acetyl-piperidine-1-carbonyl)-2,2-dimethylpropyl]-amide

LRMS: +ve ion 412 (M+H), -ve ion 410 (M-H).

Example 57

1-(2S{2R-[(Formyl-hydroxy-amino)-methyl]-hexanamine}-3,3-dimethyl-butyryl)-piperidine-4-carboxylic acid which thou methyl ether

LRMS: +ve ion 442 (M+H), -ve ion 440 (M-H).

Example 58

2R-[(Formyl-hydroxy-amino)-methyl]-hexanoic acid [2,2-dimethyl-1S-(octahedrally-1-carbonyl)-propyl]-amide

LRMS: +ve ion 424 (M+H), -ve ion 422 (M-H).

Example 59

2R-[(Formyl-hydroxy-amino)-methyl]-hexanoic acid [1S-(3,4-dihydro-2H-quinoline-1-carbonyl)-2,2-dimethylpropyl]-amide

LRMS: -ve ion 416 (M-H).

Example 60

2S-{3-Ethylsulfanyl-2R-[(formylhydrazine)-methyl]propionamide}-3,3,N,N-tetramethylbutylamine

The way of synthesis of these compounds are presented in scheme 4 and described in detail below.

Reagents and conditions;

A. 3-lithium 4-benzyl-oxazolidin-2-he, THF, -78°C;

C. LiN(SiCH3)2, THF, -78°With, then l;

C. HCl, H2NOBzl, NaOA, water Etalon;

D. NaCNBH3The asón, room temperature;

E. HCOBt, THF;

F. LiOH, water, THF, 0°C;

G. H-Tle-N(CH3)2,HOAt, EDC, DMF;

N. H2Pd/C, methanol, and then split diastereoisomers (HPLC).

Stage A: 2-Ethylsulfanyl-acrylic acid

A mixture of malonic acid (5.2 g, 50 mmol), paraformaldehyde (3.3 g, 110 mmol), dicyclohexylamine, 9,95 ml, 50 mmol) and ethanthiol (4,06 ml, 55 mmol) in dioxane (120 ml) is heated at 70°in ECENA 2 hours. The solvents are removed under reduced pressure, the residue pererastayut in ethyl acetate and the solution extracted with saturated aqueous sodium bicarbonate solution (4x20 ml). The combined aqueous layers washed with ethyl acetate (20 ml), then acidified with 1 M hydrochloric acid. The resulting suspension is extracted with dichloromethane and the solution is dried over anhydrous magnesium sulfate, filtered and evaporated to obtain the titled compound as a white solid (3,76 g, 52%).1H-NMR; δ (CDCl3), 9.89 (1H, broadened s), 6.35 (1H, s), 5.77 (1H, s), 3.39 (2H, s), 2.49 (2H, DD, J=7.4, 14.5 Hz) and 1.25 (3H, so J=5.2 Hz).

Stage b: 4S-Benzyl-3-(2-ethylsulfanyl-acryloyl)-5,5-dimethyl-oxazolidin-2-it 2-Ethylsulfanyl-acrylic acid (3,76 g for 25.8 mmol) dissolved in dry THF (75 ml) and cooled to -78°under a layer of argon. The triethylamine (4.6 ml of 33.5 mmol) and pivaloate (3,17 ml of 25.8 mmol) is added in such a rate that the temperature remained below -60°C. the Mixture was stirred at -78°C for 30 minutes, warmed to room temperature for 2 hours and finally cooled again to -78°C.

In a separate flask dissolve 4S-benzyl-5,5-dimethyl-oxazolidin-2-he in dry THF (75 ml) and cooled to -78°under a layer of argon. n-Utility (2.4m solution in hexane, 12.9 ml of 30.9 mmol) is added slowly and the mixture is stirred for 30 minutes at room themes is the temperature value. The resulting anion is transported through a tube in the original reaction vessel. Mixture is allowed to warm to room temperature and stirred over night at room temperature. The reaction is quenched with saturated sodium bicarbonate solution (20 ml) and the solvents removed under reduced pressure. The residue is distributed between ethyl acetate and water. The organic layer is washed sequentially with saturated sodium bicarbonate solution, 1 M hydrochloric acid and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified using flash chromatography (silica gel, 20% ethyl acetate in hexane)to obtain the titled compound as a yellow oil (6.5 g, 76%).1H-NMR; δ (CDCl3), 7.29 (5H, m), 5.58 (1H, s), 5.49 (1H. s), 4.54 (1H, DD, J=3.9, 9.7 Hz), 3.52 (2H, DD, J=15.8, 3.1 Hz). 3.38 (1H, DD, J=3.9, 14.5 Hz), 2.84 (1H, DD, J=4.6, 14.3 Hz), 2.52 (2H, DD, J=7.2, 14.6 Hz), 1.42 (3H, s). 1.29 (3H, s) and 1.22 (3H, t, J=7.5 Hz). LRMS: +ve ion 356 (M+Na), 334 (M+H).

Stage C: 4S-Benzyl-3- [ 2 R-t. botoxonline-methyl) -3-ethylsulfanyl-propionyl]-5,5-dimethyl-oxazolidin-2-he

4S-Benzyl-3-(2-ethylsulfanyl-acryloyl)-5,5-dimethyl-oxazolidin-2-he (2.1 g, 6.3 mmol) was dissolved in ethanol (10 ml) and add 0-tert.-butylhydrazine hydrochloride (0.95 g, 7.56 mmol)and then triethylamine (1.1 ml, 7.87 mmol). The mixture was stirred at 30°With during the night. Dissolve Italy removed under reduced pressure and the residue is dissolved in ethyl acetate. The organic solution is washed successively 1 M hydrochloric acid, saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to obtain the titled compound as pale yellow oil (2,42 g, 91%; the only diastereoisomer by HPLC).1H-NMR; δ (Dl3), 7.30 (5H, m), 5.09 (1H, broadened s), 4.54 (1H, DD, J=3.5, 9.9 Hz), 4.33 (1H, m), 3.19 (2H, m), 3.08 (1H, DD, J=5.4, 11.8 Hz), 2.80 (3H, m), 2.56 (2H, DD, J=7.4, 14.7 HZ), 1.41 (3H, s), 1.36 (3H, s), 1.23 (3H, t, J=7.3 Hz) and 1.13 (N. C). LRMS: +ve ion 423 (M+H).

Stage D: (2R-tert.-botoxonline-methyl)-3-arilsulfonilglitsinov acid

A solution of 4S-Benzyl-3-[2R-tert.-botoxonline-methyl)-3-arilsulfonilglitsiny]-5,5-dimethyl-oxazolidin-2-he (2,42 g, 5,72 mmol) in THF (40 ml) cooled to 0°and add a solution of lithium hydroxide (288 mg, 6,86 mmol) in water (10 ml). Mixture is allowed to warm to room temperature, after which it is stirred for 5 hours. The solvent is removed under reduced pressure and the residue partitioned between water and ethyl acetate. The aqueous layer was removed and the ethyl acetate layer is washed successively with water and saturated sodium bicarbonate solution. The combined aqueous layers washed with ethyl acetate (20 ml)and then acidified with 1 M hydrochloric acid. The resulting emulsion is extracted with dichloromethane (3h20 ml) the combined organic layers dried over anhydrous magnesium sulfate, filtered and evaporated to obtain the titled compound as a colourless oil (0.68 g, 50%).1H-NMR; δ (CDCl3), 8.03 (2H, broadened s), 3.21 (2H, d, J=6.1 Hz), 2.89 (2H, m), 2.75 (1H, m), 2.57 (2H, DD, J=7.4, 14.8 Hz), 1.26 (ZN, t, J=7.4 Hz) and 1.18 (IN with). LRMS: +ve ion 236 [M+H], -ve ion 234 M-N].

Stage E: a Solution of 2S-[2R-(tert.-butoxymethyl)-3-arilsulfonilglitsiny-amino}-3,3,N,N-tetramethylbutylamine 2R-tert.-botoxonline-methyl)-3-ethylsulfanyl-propionic acid (340 mg, 1.44 mol) is dissolved in DMF (10 ml) and added dropwise tert.-leucine-N,N-dimethylamide (272 mg, at 1.73 mmol), HOAt (19.6 mg, 0.14 mmol) and EDC (331 mg, at 1.73 mmol). The reaction mass is stirred over night at room temperature. The solvent is removed under reduced pressure and the residue is dissolved in dichloromethane. The organic solution is washed successively 1 M hydrochloric acid, 1 M sodium carbonate solution and brine, dried over anhydrous magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to δ (CDCl3), 6.87 (1H, d, J=9.0 Hz), 5.11 (1H, broadened s), 4.93 (1H, d, J=9.3 Hz), 3.15 (3H, s), 3.11 (1H, m), 2.95 (3H. s), 2.79 (3H, m), 2.54 (3H, s), 1.22 (3H, t, J=7.6 Hz), 1.18 (D,) and 1.01 (IN with). LRMS: +ve ion 398 [M+Na], 376[M+1].

Stage F: 2S-{2R-[(tert.-Butoxy-formyl-amino)-methyl]-3-metilsulfonilmetane}-3,3,N,N-tetramethylbutylamine.

A solution of 2S-[2R-(tert.-butoxy-amino-methyl)-3-ethylsulfanyl-propionicum is but}-3,3,N,N-tetramethylbutylamine (220 mg, of 0.58 mmol) in dichloromethane (5 ml) cooled to 0°and process mixed formic-acetic anhydride (0.1 ml). The reaction mass was stirred at room temperature for 4 hours, then the solvent is evaporated under reduced pressure. The residue is purified using flash chromatography (silica gel, 50% ethyl acetate in hexane as eluent)to obtain the titled compound as a colourless oil (120 mg, 52%).1H-NMR; δ (Dl3rotamer), 8.31 (1H, broadened s), 6.56 (1H, d, J=9.1 Hz), 4.94 (M, d, J=9.4 Hz), 4.88 (M, d, J=9.2 Hz), 4.08 (M, broadened m), 3.83 (S, broadened m), 3.13 (3H, s), 2.95 (3H. s), 2.80 (2H, m). 2.61 (1H, DD, J=6.8, 14.0 Hz), 2.49 (2H, DD, J=7.4, 14.7 Hz), 1.29 (S, s), 1.25 (3H, t, J=7.2 Hz) and 0.99 (IN with). LRMS: +ve ion 426 [M+Na], 404 [M+H].

Stage G: 2S{3-Ethylsulfanyl-2R-[(formyl-hydroxy-amino)-methyl]propionyl amino}-3,3,N,N-tetramethylbutylamine

A solution of 2S-{2R-[(tert.-butoxy-formyl-amino)-methyl]-3-metilsulfonilmetane}-3,3,N,N-tetramethylbutylamine (120 mg, 0.3 mmol) in deuterium chloroform (1 ml) is treated triperoxonane acid (4 ml) and allowed to stand at 4°With during the night. The solvents are removed under reduced pressure and the remaining triperoxonane acid is removed by azeotropic distillation with toluene. The residue is purified using preparative HPLC to obtain the titled compound as a colourless oil (40 m is, 38%; 7:2 mixture of diastereoisomers using HPLC).1H-NMR; δ (CDCl3. rotamer), 8.40 (S, s), 7.87 (D, s), 7.24 (M, d, J=9.3 Hz), 6.98 (M, d, J=9.3 Hz), 4.91 (N. d, J=9.3 Hz), 4.90 (M, d, J=9.3 Hz), 4.07 (N, DD, J=7.5, 14.5 Hz), 3.86 (N, DD, J=8.8, 14.2 Hz), 3.75 (N, m), 3.68 (N, m), 3.16 (1H, s), 3.15 (2H, s), 3.05 (1H, m), 2.96 (3H, s), 2.77 (1H, m). 2.66 (1H, m), 2.52 (2H, DD, J=7.4, 14.8 Hz), 1.22 (3H, t, J=7.3 Hz), 0.99 (3H, s) and 0.96 (6N, C).13C-NMR; δ (CDCl3, rotamer), 173.3, 171.6, 171.2, 55.2, 54.8, 51.1, 48.5, 45.2, 44.4, 38.5, 38.4, 35.9, 35.8, 35.7, 31.7, 31.4, 26.7, 26.6, 26.5, and 14.6. LRMS: +ve ion 370 [M+Na], 348 [M+H], -ve ion 346 [M-H]. Connection example 61 receive similar when using piperidine instead of ethanthiol at the Stage of A.

Example 61

2-{2-[(Formyl-hydroxy-amino)-methyl]:-3-piperidine-1-yl-propionamide}-3,3,N,N-tetramethylene butyric acid

White solid (4:1 mixture of diastereoisomers using HPLC).1H-NMR; δ (CDCl3, rotamer), 8.29 (1H, s), 7.95 (1H, broadened s), 4.87 (1H, d, J=9.1 Hz), 4.02 (1H, DD, J=5.0. 14.6 Hz), 3.56 (1H, DD, J=8.2, 14.6 Hz). 3.14 (ZN, s), 2.96 (ZN, s), 2.89 (1H. m), 2.69 (1H, m), 2.52 (5H, m). 1.65 (4H, m), 1.49 (2H, m) and 0.99 (N, C).13C-NMR; δ (CDCl3), 172.2, 171.3, 60.4, 55.0, 54.9, 48.6, 42.4, 38.8, 36.2, 36.1, 27.0, and 25.6 24.3. LRMS: +ve ion 371 [M+H], -ve ion 369 [M-N].

Connection examples 62 through 65 are obtained by, similar to that described in example 7, Method II, replacing O-tert.-butylhydroxyanisole 0-benzylhydroxylamine on Stage and In the corresponding amines by Ilumina/benzyl ether amino acid tert.-leucine N,N-dimethylamide on Stage E. Final removal of the protectors by acidolysis using triperoxonane acid (see example 60 above).

Example 62

2R-[(Formyl-hydroxy-amino)-methyl]-hexanoic acid (1R-dimethylcarbamoyl-2-methyl-2-methylsulfinylpropyl)-amide

A colorless oil.1H-NMR; δ (CDCl3, rotamer), 8.4 (S, s), 7.85 (D, s), 7.11 (M, d, J=9.1 Hz), 6.93 (D, d, J=9.1 Hz), 5.15 (1H, d, J=9.4 Hz). 3.90 (N. m), 3.73 (N, m), 3.64 (M, d, J=14.3 Hz), 3.48 (N, DD, J=14.0. 3.9 Hz). 3.22 (3H, s), 2.97 (3H, s), 2.83 (N, m), 2.70 (M, m), 2.07 (S, s), 2.04 (S, s), 1.58 (1 H, m), 1.36 (4H, m), 1.32 (3H, s), 1.28 (3H, s) and 0.86 (3H, t, J=6.6 Hz).13C-NMR; δ (CDCl3), rotamer), 175.4,173.5, 170.8, 63.6, 53.2. 53.1, 52.5,,49.5, 47.5, 46.1, 44.9, 41.6, 37.5, 36.5, 36.4, 35.4, 30.2, 29.8, 28.0, 14.3, 12.0 and 11.9. LRMS: +ve ion 362 [M+H], -ve ion 360 [M-N].

Example 63

2R-[(Formyl-hydroxy-amino)-methyl]-hexanoic acid (2-benzylmethyl-1R-dimethylcarbamoyl-2-methyl-propyl)-amide

The white foam.1H-NMR; δ (CDCl3, rotamer), 8.37 (S, s), 7.81 (D, s), 7.31 (5H, m), 7.06 (M, d, J=8.8 Hz). 6.89 (M, d, J=9.3 Hz), 5.20 (1H, d, J=9.3 Hz), 3.94 (N, DD, J=8.3, 14.6 Hz), 3.78 (N, m), 3.61 (N, DD, J=3.5, 14.4 Hz), 3.42 (N, DD, J=5.1, 14.9 Hz), 3.21 (3H, s), 3.03 (3H, s), 2.82 (N, m), 2.69 (N, m), 1.61 (1 H, m), 1.42 (1 H, m), 1.37 (3H, s), 1.32 (3H, s), 1.26 (4H, m) and 0.86 (3H, t, J=6.6 Hz).13C-NMR; δ (CDCl3,rotamer), 175.3, 173.5, 171.0, 138.1, 137.4, 129.5, 129.3, 129.1, 129.0, 128.9, 127.6, 127.4, 55.9, 53.7, 52.5, 51.2, 49.6, 49.5, 46.1, 44.9, 39.0, 38.6, 36.6, 36.4, 33.9 33.7, 30.3, 30.1, 29.7, 26.7, 26.1, 25.7, 25.5, 24.2, 22-9 and 14.3. LRMS: +ve ion 460 [M+Na], 438 [M+H], -ve ion 436 [M-N].

Example 64

2R-[(Formyl-hydroxy-amino)-methyl]-hexanoic acid [2-benzylmethyl-2-methyl-1R-(morpholine-4-carbonyl)-propyl]-amide

The white foam.1H-NMR; δ (CDCl3, rotamer), 8.44 (S, s), 8.37 (IN with). 7.30 (5H. m), 6.88 (D, d, J=8.3 Hz), 6.78 (D, d, J=9.2 Hz), 5.12 (1H, d, J=9.5 Hz), 3.91 (1H, DD, J=8.2, 14.6 Hz), 3.78 (10H, m), 3.45 (1H, DD, J=4.5, 14.2 Hz), 2.80 (N, m), 2.64 (N, m), 1.61 (1H, m), 1.41 (1H, m,), 1.36 (3H, s), 1.33 (3H, s), 1.29 (4H, m) and 0.87 (3H, t, J=6.8 Hz).13C-NMR; δ (CDCl3, rotamer), 175.5, 173.4, 169.4, 137.8, 129.5, 129.3, 129.1, 129.0, 127.8, 127.5, 67.1, 67.0, 53.3, 53.2, 51.99, 49.6, 49.5, 49.2, 47.9, 46.5, 45.0, 43.2. 43.0, 34.0, 30.3, 30.2, 29.7, 26.8, 26.5, 25.9, 25.8, and 22.9 14.3. LRMS: +ve ion 502 [M+Na], 480 [M+H], -ve ion 478 [M-N].

Example 65

2-[(Formyl-hydroxy-amino)-methyl]-hexanoic acid [2-benzylmethyl-2-methyl-1R(or S)-(4-methylpiperidin-1-carbonyl)-propyl]-amide

Diastereoisomer A. White solid. LRMS: +ve ion 514[M+Na], 492[M+H], -ve ion 490[M-H].

Diastereoisomer Century Colorless resin. LRMS: +ve ion 514 [M+Na], 492 [M+H], -ve ion 490[M-H].

Connection examples 66 to 68 is obtained by, similar to that described in example 7, Method II, replacing the corresponding malonic acid butylmalonic acid at the Stage A, O-tert-butylhydroxyanisole O-Benzylhydroxylamine on Stage With. Stereoselectivity in the reactions proceed by Micah the ale varied. The final removal of the protection is held by acidolysis using triperoxonane acid (see example 60 above).

Example 66

2R-[(Formyl-hydroxy-amino)-methyl]-Penta-4-ene acid (1S-dimethylcarbamoyl-2,2-dimethylpropyl)-amide

The only diastereoisomer.1H-NMR; δ (CDCl3, rotamer), 8.40 (S, s), 7.84 (D, s), 7.05 (N. d, J=9.0 Hz), 6.74 (D, d, J=9.3Iu), 5.70 (1H, m), 5.03-5.24 (2H, m), 4.88 (1H, DD, J=9.4, 6.7 Hz), 3.98 (N, m). 3.81 (N, m), 3.55 (1H, m), 3.14 (3H, s). 2.97 (N, s), 2.96 (M, s), 2.75-2.92 (1H, m), 2.16-2.50 (2H, m), 0.98 (N,) and 0.94 (IN with). LRMS: +ve ion 336 [M+Na], -ve ion 312 [M-N].

Example 67

2R-[(Formyl-hydroxy-amino)-methyl]-Gex-5-ene acid (1S-dimethylcarbamoyl-2,2-dimethylpropyl)-amide

Diastereoisomer And: colorless oil.1H-NMR; δ (CDCl3, rotamer), 8.42 (S, s), 7.84 (D, s), 6.78 (D, d, J=8.4 Hz), 6.60 (M, d, J=9.3 Hz), 5.74 (1H, m), 5.03 (2H, m), 4.88 (1H, m), 4.14 (N, m), 3.81 (N, m), 3.55 (1H, m), 3.16 (1H, s), 3.15 (2H, s), 2.98 (1H, s), 2.97 (2H, s), 2.85 (N, m), 2.68 (M, m), 2.07 (2H. m), 1.73 (N, m), 1.50 (M, m), 0.99 (4H, s) and 0.95 (5H, s). LRMS: +ve ion 350 [M+Na], -ve ion 326 [M-H]. Diastereoisomer In: colorless oil.1H-NMR; δ (CDCl3, rotamer), 8.41 (S, s), 7.75 (D, s), 6.58 (D, d, J=Hz), 6.36 (D, d, J=9.1 Hz), 5.75 (1H, m), 5.01 (2H, m), 4.86 (M, d, J=9.5Iu), 4.64 (M, d, J=7.5In), 3.42-3.82 (2H, m), 3.22 (M, s), 3.07 (M, s), 2.99 (3H, s), 2.87 (N, m), 2.66 (N, m), 2.13 (2H, m), 1.81 (1H, m), 1.49 (1H, m), 1.02 (D,) and 1.00 (IN with). LRMS: +ve IO is 350 [M+Na], -ve ion 326 [M-N].

Example 68

2R-[(Formyl-hydroxy-amino)-methyl]-Gex-4-invoi acid (1S-dimethylcarbamoyl-2,2-dimethylpropyl)-amide

Diastereoisomer And: colorless oil.1H-NMR; δ (CDCl3, rotamer), 8.39 (N. s), 7.87 (D, s), 7.20 (M, d, J=8.4 Hz), 6.94 (D, d, J=9.3 Hz), 4.90 (1H, m), 3.66-4.14 (2H, m), 3.16 (2H, s), 3.14 (2H, s), 2.96 (3H, s), 2.88 (1H, m). 2.41 (2H, m). 1.77 (3H, m), 1.00 (D,) and 0.96 (IN with). LRMS: +ve ion 348 [M+Na], -ve ion 324 [M-N].

Diastereoisomer In: colorless oil.1H-HMP; δ (Dl3, rotamer), 8.37 (S, s), 7.81 (D, s), 6.87 (1H, m), 4.91 (M, d, J=9.4 Hz), 4.79 (M, d, J=8.2 Hz). 3.76 (N, m), 3.63 (N, m), 3.19 (M, s), 3.14 (M, s), 2.98 (3H, s), 2.85 (1H, s), 2.41 (2H, m), 1.77 (3H, m), 1.03 (D,) and 1.01 (IN with). LRMS: +ve ion 348 [M+Na], -ve ion 324 [M-N].

Example 69

2R-[1R (or S)-(Formyl-hydroxy-amino)-ethyl]-hexanoic acid (1S-dimethylcarbamoyl-2,2-dimethyl-propyl)-amide

A named connection receive according to the synthesis pathway presented in figure 5 and described in detail below:

Scheme 5

Reagents and conditions:

A. (CHO)n, EtSH, dicyclohexylamine, dioxane, 70°C, 2 hours;

C. Tert.-BuCOCl, triethylamine, then 3-lithium 4-benzyl-5,5-dimethyloxazolidine-2-he;

C. HCl, H2NO-tert.-Bu, triethylamine, o/n;

D. LiOH, water, THF, 0°C;

E. H-tert.-LeuN(Me2)2, HOAt, ED, DMF;

F. HCOAc, CH2CL2;

G. t is everysunday acid, the chloroform.

Stage A: 4-Benzyl-3-hexanoyl-oxazolidin-2-he 4S-Benzyl-oxazolidin-2-he (14.5 g, to 81.7 mmol) dissolved in dry THF (75 ml) in an argon atmosphere. The solution is cooled in a bath with ice before slow addition of n-utility (1.6 M in hexane, 56 ml of 89.2 mmol). From the solution crystallized salt of lithium in the form of a solid mass, and he was allowed to warm to room temperature over night. Received the orange suspension is again cooled in a bath with ice while adding the cooled solution hexanolactone (10.4 ml of 74.3 mmol) in dry THF (50 ml). The mixture is left to warm to room temperature and then stirred for 3 hours. The reaction is quenched with 1 M sodium carbonate solution (5 ml) and the solvent is removed under reduced pressure. The residue is partitioned between 1 M sodium carbonate solution (100 ml) and ethyl acetate (150 ml). The organic layer removed and the aqueous layer was extracted with additional ethyl acetate. The combined organic layers are washed successively with water, 1 M sodium carbonate solution and brine, dried over anhydrous magnesium sulfate and filtered. The filtrate is concentrated to obtain orange oil. Purification using flash chromatography results in the named compound as a yellow oil (10.21 g, 50%).1H-NMR; δ (CDCl3), 7.38-7.24 (3H, m). 7.24-7.16 (2H, m), 4.68 (1H, is), 4.24-4.12 (2H, m), 3.30 (1H, DD, J=13.4, 3.2 Hz), 3.02-2.86 (2H. m), 2.77 (1H, DD, J=13.4, 9.6 Hz), 1.77-1.63 (2H, m), 1.44-1.30 (4H, m) and 0.92 (3H, broadened t, J=6.9 Hz).

Stage b: 1-(4S-Benzyl-2-oxo-oxazolidin-3-yl)-2R-butyl-butane-1,3-dione 4-Benzyl-3-hexanoyl-oxazolidin-2-he (10.2 g, 37,1 mmol) dissolved in THF (150 ml) in an argon atmosphere and cooled to -78°C. Hexamethyldisilazide lithium (1 M in THF, 41 ml, 41 mmol) is injected through the tube for several minutes and the resulting green solution was stirred at -78°in for 2 hours. Added slowly acetyl chloride (3.3 ml, with 46.3 mmol) and the reaction mixture was stirred for 3.5 hours. Quickly add a solution of citric acid (3.0 g, 14 mmol) in water (15 ml) and quenched the reaction. The solvent is removed under reduced pressure and the residue distributed between ethyl acetate and water, washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate is concentrated to obtain the titled compound as a yellow oil (12,11 g contains residual solvent), which is used without further purification in Stage C.1H-NMR; δ (Dl3,), 7.37-7.21 (5H, m), 4.68 (1H, m), 4.53 (1H, DD, J=9.6, 3.7 Hz), 4.23-4.13 (2H, m), 3.43 (1H, DD, J=13.5, 3.3 Hz), 2.75 (1 H, DD, J=13.5, 9.9 Hz), 2.33 (3H, s), 2.03 (1H, m), 1.77 (1 H, m), 1.46-1.26 (4H, m) and 0.98-0.86 (3H, m).

Stage C: 1-(4S-Benzyl-2-oxo-oxazolidin-3-yl)-2K-butalbital-1,3-dione 3-(0-benzyloxy)

To a solution of 1-(4S-benzyl-2-oxo-oxazo the one-3-yl)-2R-butyl-butane-1,3-she (12, 11 g, 38,15 mmol) in water (10 ml) and ethanol (90 ml) is added sodium acetate (3.75 g, 45,78 mmol) and 0-benzylhydroxylamine hydrochloride (7,31 g, 45,78 mmol). The resulting slurry is mixed at room temperature over night. Product (7,3 g, 45%, single isomer of the oxime) is crystallized directly from the reaction mixture and was filtered, washed with water-ethanol (1:1) and dried under vacuum. Additional product (5.31g, 33%, mixture of isomers of oxime) are obtained in the form of a yellow oil of the manifold using an acid-base extraction, and then column chromatography.1H-NMR; δ (Dl3the main isomer oxime), 7.34-7.20 (8H, m), 7.12-7.07 (2H. m), 5.14-5.02 (2H, m), 4.53 (1H, m), 4.13 (1H, DD, J=9.4, 4.0 Hz), 4.04 (1H, broadened t, J=8.4 Hz), 3.91 (1H, DD, J=9.0, 2.7 Hz), 3.16 (1H, DD, J=13.4, 2.9 Hz), 2.09 (3H, s), 1.97 (1H, m), 1.75 (1H, DD, J=13.4, 10.8 Hz), 1.67(1H,m), 1.45-1.22 (4H, m) and 0.91 (3H, broadened t, J=6.9 Hz).

Stage D: 4S-Benzyl-3-[2R-(1R(or S)-benzylamino-ethyl)-hexanoyl]-oxazolidin-2-he

The mixture Asimov obtained in Stage (5.31g, 12.5 mmol) is dissolved in acetic acid (30 ml) and cooled in a water bath with ice, and then add Lamborghini sodium (0.8 g, 12.5 mmol) in one portion. After a few minutes stops the rapid evolution of gas, then enter the additional portion of laborgerate (0.8 g). The reaction mass is allowed to warm to room temperature and stirred over their night. Acetic acid is removed under reduced pressure and the residue is distilled in the form of an azeotrope with toluene. The oil obtained is dissolved in ethyl acetate, washed with water, 1 M sodium carbonate and brine, dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated to obtain a pale yellow oil, which was purified by flash chromatography (silica gel, 10 to 25%ethyl acetate in hexane as eluent). The output of 3.43 g (64%).1H-NMR; δ (Dl3the mixture of diastereoisomers), 7.36-7.17 (10H, m), 5.80 (M, broadened s), 5.55 (D, broadened d, J=8.9 Hz), 4.72-4.59 (MN, m), 4.20-4.05 (2H. m), 3.97 (N, m), 3.82 (N, m), 3.47-3.22 (2H, m), 2.45 (1H, m), 1.90-1.48 (2H, m).1.40-1.14 (7H, m) and 0.95-0.84 (3H, m).

Stage E: M-[2R-(4S-Benzyl-2-oxo-oxazolidin-3-carbonyl)-1R (or S)-methyl-hexyl]-N-benzyloxycarbonyl

4S-Benzyl-3-[2R-(1 R (or S)-benzylamino-ethyl)-hexanoyl]-oxazolidin - 2-he is 3.08 g, 7,3 mmol) dissolved in dry THF and treated with N-formylbenzoate (1.60 g, 10.9 mmol). The reaction mass is stirred for 4 hours at room temperature. The solvent is removed under reduced pressure and the remaining oil partitioned between dichloromethane (40 ml) and 1 M sodium hydroxide solution (30 ml). The organic layer is removed, washed with an additional quantity of sodium hydroxide solution, then brine, dried over anhydrous magnesium sulfate, filtered and evaporated. Cleaning with the lash chromatography (silica gel, from 20 to 50%ethyl acetate in hexane gives the titled compound as a pale yellow solid (2.50 g, 76%.1H-NMR; δ (Dl3the mixture of diastereoisomers and rotamers), 8.22 (1H, broadened m), 7.54-7.13 (10H, m), 5.22-3.92 (7H, broadened, m),3.30 (1H,m),2.48 (1H, broadened, m), 1.85-1.13 (M, broadened m) and 0.93-0.83 (3H, m).

Stage F: 2R-[1R (or S)-(Benzyloxy-formyl-amino)-ethyl]-hexanoic acid N-[2R-(4S-Benzyl-2-oxo-oxazolidin-3-carbonyl)-1R (or S)-methyl-hexyl]-N-benzyloxy-formamid (1.50 g, and 3.31 mmol) dissolved in THF (25 ml) and water (5 ml) and the solution is cooled in a water bath with ice. Add a solution of hydrogen peroxide (27% vol./vol.), 13,26 mmol), and then immediately add lithium hydroxide (167 mg, 3,98 mmol). The reaction mixture is allowed to warm to room temperature and stirred for additional 3 hours. The solution is cooled again before adding sodium nitrite (0,92 g, 13.3 mmol). After 10 minutes, a large part of the solvent is removed under reduced pressure to obtain a white paste, which is distributed between ethyl acetate (25 ml) and 1 M sodium carbonate (30 ml). The organic layer was washed with an additional quantity of sodium carbonate solution and the combined aqueous extracts washed with ethyl acetate. The aqueous layer was cooled and acidified with 1 M hydrochloric acid and extracted twice with ethyl acetate. The combined organic layers washed with brine is m, dried over anhydrous magnesium sulfate, filtered and evaporated to obtain the titled compound in the form of oil green (839 mg, 86%).1H-NMR; δ (CDCl3the mixture of diastereoisomers and rotamers), 8.40-7.64 (2H, broadened m), 7.48-7.27 (5H, m), 5.23-4.80 (2H, m), 4.16 (1H, broadened m). 2.79 (1H, m), 1.67-1.47 (2H, m), 1.47-1.18 (7H, m) and 0.95-0.82 (3H, m).

Stage G: 2R-[1R (or S)-(Benzyloxy-formyl-amino)-ethyl]-hexanoic acid (1S-dimethylcarbamoyl-2,2-dimethylpropyl)-amide 2R-[1R (or S)-(Benzyloxy-formyl-amino)-ethyl]-hexanoic acid (839 mg, of 2.86 mmol), tert.-leucine N.N-dimethylamide (498 mg, 3,15 mmol) and EDC (658 mg, of 3.43 mmol) are dissolved together in DMF (15 ml) and add a catalytic amount HOAt (60 mg). The mixed solution is kept for several days at room temperature. The solvent is removed under reduced pressure and the remaining oil is distributed between ethyl acetate and 1 M hydrochloric acid (75 ml). The organic layers are washed successively 1 M hydrochloric acid, 1 M sodium carbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and evaporated to obtain a yellow foam (1.08 g, 82%).1H-NMR; δ (Dl3the mixture of diastereoisomers and rotamers), 8.13 (1H, broadened m), 7.52-7.31 (5H, m), 6.28 (1H, broadened m), 5.36-4.67 (3H, broadened m), 4.09 (1H, broadened m), 3.14 (3H, s), 2.95 (M, s), 2.93 (M, s), 2.48 (1H, broadened m), 1.61-1.04 (N, m), 0.99 (S, s), 0.95 N, C) and 0.89-0.75 (3H, m).

Stage H: 2R-[1R (or S)-(Formyl-hydroxy-amino)-ethyl]-hexanoic acid (1S-dimethylcarbamoyl-2,2-dimethylpropyl)-amide

2R-[1R (or S)-(Benzyloxy-formyl-amino)-ethyl]-hexanoic acid (tS-dimethylcarbamoyl-2,2-dimethylpropyl)-amide (200 mg, 0.46 mmol) dissolved in methanol (15 ml) and placed under a layer of argon. Add a suspension of 10% palladium on coal (20 mg) in ethyl acetate and the mixture is stirred in hydrogen atmosphere for 3 hours. The catalyst is removed by filtration and the filtrate evaporated to obtain a colorless oil (163 mg, quantitative);

Two diastereoisomeric product separated by preparative HPLC. Diastereoisomer And (mg):1H-NMR; δ (CDCl3basically one of rotamer), 8.67 (D, broadened s), 7.92 (1H, s), 6.74 (0.1 N, broadened m), 6.54 (D, d, J=9.4 Hz), 4.93 (M, d, J=9.4 Hz), 4.64 (0.1 N, broadened m), 3.89 (1H, DD, J=6.6, 2.6 Hz), 3.16 (3H, s), 2.96 (3H, s), 2.62-2.48 (1H, m), 1.52-1.06 (6N. m), 1.35 (3H, d, J=6.6 Hz), 1.00 (D,) and 0.82 (3H. t, J=6.9 Hz).13C-NMR; δ (CDCl3), 173.0, 171.3, 57.2, 54.4, 50.4, 38.4, 35.6, 29.9, 29.1, 26.6, 22.5, and 17.2 13.9. LRMS: +ve ion 366 [M+Na], -ve ion 342 [M-H]. Diastereoisomer In (mg):1H-NMR; δ (Dl3, mixture of rotamers), 9.15 (S, s), 8.60 (D, broadened s), 8.42 (S, s), 7.84 (D, s), 6.83 (D, d, J=9.2 Hz), 6.55 (D, d, J=9.4 Hz), 4.91 (M, d, J=9.2 Hz), 4.89 (M, d, J=9.4 Hz), 4.69 (M, arcs, J=7.0, 4.3 Hz), 3.92 (N. DQC, J=9.1, 6.8 Hz), 3.15 (3H, s), 2.97 (S, s), 2.95 (M, s), 2.59 (D, TD, J=9.8, 4.3 Hz), 2.39 (D, TD, J=7.4, 4.3 Hz), 1.92-1.07 (6N, is), 1.37 (M, d, J=6.8 Hz), 1.31 (M, d, J=7.0 Hz), 1.01 (S, s), 0.96 (N. s), 0.85 (N, t, J=7.2 Hz) and 0.83 (N, t, J=7.2 Hz).13C-NMR; δ (Dl3, mixture of rotamers), 175.7, 173.2, 171.3, 170.7, 56.7, 55.0, 54.4, 53.2, 50.8,49.9, 38.3, 35.7, 35.6, 35.5, 35.4, 30.3, 29.5, 29.3, 26.5, 26.4, 22.5, 22.4, 16.0, 15.4 and 13.8. LRMS: +ve ion 366 [M+Na], -ve ion 342 [M-N].

Example 70

N-Cyclohexyl-2-{2-[(formyl-hydroxy-amino)-methyl]-3-phenyl-propionamido}-3,3-dimethylamide butyric acid

The starting solutions of 1 M ammonia in methanol (1 ml, 1 mmol) and 1 M trimethylacetaldehyde in methanol (1 ml, 1 mmol) are mixed in a test tube and left to stand for 1 hour. Add a 1 M solution of cyclohexyldiamine in methanol (1 ml, 1 mmol), and then 0.5 M 2RS-[(benzyloxycarbonylamino)-methyl]-hexanoic acid in methanol (2 ml, 1 mmol). The reaction mixture was stirred at room temperature for 2 days. The solvent is removed using a centrifuge Savant and the reaction mixture is crystallized from ethyl acetate-hexane to obtain 2-{2-[(benzyloxy-formyl-amino)-methyl]-3-phenyl-propionamido}-N-cyclohexyl-3,3-dimethylamide butyric acid as a white solid (93 mg, 18%), which was charged through a catalytic exchange hydrogenolysis (hydrogen, 10% palladium on coal, methanol-ethyl acetate), which allowed to obtain the titled compound (75 mg, 99%). White solid. LRMS: +ve ion 440 [M+Na], 418 [M+H], -ve ion 416 [is-N].

Connection examples 71 through 77 concurrently using the Ugi 4-component reaction of condensation, as described above. All products are obtained with a purity of >85%, as shown by the HPLC data.

Example 71

2-{2-[(Formyl-hydroxy-amino)-methyl]-3-phenyl-propionamido}-3,3-dimethylhexanoic acid cyclohexylamin

White solid (90 mg).1H-NMR; δ (CD3OD), 7.82 (1H, s), 7.29-7.08 (5H, m), 4.20 (1H, d, J=5.0 Hz), 3.89 (1H, m), 3.19 (1H, m), 2.95-2.67 (2H, m). 1.88-1.58 (5H. broadened m), 1.44-1.05 (M, broadened m) and 0.89 (IN with). LRMS: +Wein 468 [M+Na], 446 [M+H], -ve ion 444 [M-N].

Example 72

2-{2-[(Formyl-hydroxy-amino)-methyl]-3-phenyl-propionamido}-3,3-dimethylhexanoic acid feniletilamin

White solid (77 mg).1H-NMR; δ (CD3OD), 7.82 (1H, s), 7.35-7.11 (10H, m), 4.38-4.19 (3H, m), 3.85 (1H, m), 3.52 (1H, m), 2.97-2.63 (3H, m), 1.37-1.11 (4H, m) and 0.93-0.78 (N, m). LRMS: +ve ion 476 [M+Na], 454 [M+H].

Example 73

2-{2-[(Formyl-hydroxy-amino)-methyl}-3-phenylpropionylamino}-3,3-dimethylbutanoate acid tert.-butylamide

White solid (47 mg).1H-NMR; δ (CD3D), 7.82 (1H, s), 7.45 (1H. m), 7.30-7.09 (5H, m), 4.12 (1H, d, J=7.2 Hz), 3.89 (1H, m), 3.41 (1H. m), 3.15 (1H. m), 2.97-2.68 (2H, m), 1.28 (M,) and 0.92 (IN with). LRMS: +ve ion 414 [M+Na], 392 [M+H], -ve ion 390 [M-H].

Example 74

2{2-[(Formyl-hydroxy-amino)-methyl]-3-phenyl-PR is pinellino}-3,3-dimethylhexanoic acid (1,1,3,3-tetramethyl)-butyramide.

White solid (65 mg).1H-NMR; δ (CD3D), 7.79 (1H, s), 7.42-7.21 (1H, m), 7.20-7.10 (5H, m), 4.23 (1H, d, J=9.1 Hz), 3.86 (1H, m), 3.51 (1H, m), 3.23 (1H, m), 3.00-2.56 (2H, m), 1.50-1.15 (N, m) and 1.02-0.83 (N,m). LRMS: +ve ion 498 [M+Na], 476 [M+H ], -ve ion 474 [M-N]

Example 75

N-(Cyclohexyl-cyclohexylcarbonyl-methyl)-2-[(formyl-hydroxy-amino)-methyl]-3-phenylpropionamide

White solid (98 mg).1H-NMR; δ (CD3D), 7.38-7.08 (5H, m), 4.01 (1H. m), 3.81 (1H, m), 3.68-3.35 (2H, m), 3.15 (1H, m), 2.98-2.65 (2H, m), 1.88-1.49 (10H, broadened m) and 1.45-0.83 (11 H, broadened m). LRMS: +ve ion 466 [M+Na], 444 [M+H], -ve ion 442 [M-N].

Example 76

N-(Cyclohexyl-formethylcarbamoyl-methyl)-2-[(formyl-hydroxy-amino)-methyl]-3-phenylpropionamide

White solid (34 mg).1H-NMR; δ (CD3OD), 7.35-7.10 (10H, m), 4.44-4.23 (2H, m). 4.05 (1H, m), 3.87-3.35 (2H, m), 3.09 (1H, m), 2.85-2.72 (2H. m), 1.65-1.46 (4H, m), 1.38-0.93 (5H, broadened m) and 0.75-0.51 (2H, broadened m). LRMS: +ve ion 474 [M+Na], -ve ion 450 [M-N].

Example 78

N-[Cyclohexyl-(1,1,3,3-tetramethyl-butylcarbamoyl)-methyl]-2-[(formyl-hydroxy-amino)-methyl]-3-phenylpropionamide

White solid (51 mg).1H-NMR; δ (CD3OD), 7.80 (1H. s), 7.36-7.10 (5H, m), 4.05 (1H, m), 3.85 (1H, m), 3.49 (1H, m), 3.15 (1H, m), 2.91 (1H, m), 2.68 (1H, m), 1.90 (1H, m), 1.80-1.48 (7H, m), 1.40-1.12 (YOON, m) and 1.08-0.83 (10H, m). LRMS: +ve ion 496 [M+Na] 474 [M+H], -ve ion 472 [M-N].

Biological Example A.

Demonstration of antibacterial effect of the compound 1 (Example 1) and compound 2 (Example 13).

a).

The minimum inhibiting concentration (MIC) of inhibitors against E. coli strain DH5a (Genotype F-f80d/acZDM15D(lacZYA-argF)U169 deoR recA1 endA1 hsdR17(r

-
k
m
+
k
)phoA supE441-thi-1 gyrA96 relA1), obtained from GibcoBRL Life Technologies, Enterobacter cloacae (American collection number of standard culture 13047), Klebsiella pneumoniae (American collection number of standard culture 13883) or Staphylococcus capitzs (American collection number of standard culture 35661) was determined as follows. Initial solutions of the test compounds (Compounds 1 and 2 of Examples 1 and 13, respectively (both isomers (A)) and three standard laboratory antibiotics carbenicillin (Sigma, catalogue number S), kanamycin (Sigma, catalogue number C) and chloramphenicol (Sigma, catalogue number In 1919) were prepared by dissolving each compound in dimethyl sulfoxide at a concentration of 10 mm. To determine the minimum inhibitory concentration were prepared twofold serial dilution in culture medium 2xYT(Tipton (typtone) 16 g/l, yeast extract 10 g/l, sodium chloride 5 g/l, obtained from BIO 101Inc, 1070 Joshua Way, Vista, CA92083, USA) with a 0.05 ml containing the connection environment to the hole. The inoculum was obtained from cultures grown overnight in 2xYT medium at 37°C. cell Density was brought to the absorption at 660 nm (A660)=0,l, standardized optical density of the compositions were diluted 1:1000 nutrient medium 2xYT, and each well was inoculable 0.05 ml of the diluted bacteria. The microtiter plates were incubated at 37°C for 18 hours in a humid incubator. MIC (mm) was defined as the minimum concentration of drug at which inhibited visible growth.

b).

The minimum inhibiting concentration (MIC) of inhibitors against Mycobacterium ranae (American collection number of standard culture 110), Pseudomonas aeruginosa (American collection number of standard culture 9027), Klebsiella pneumoniae (American collection number of standard culture 10031), Helicobacter pylori (the American collection number of standard culture 43504), clinical crops that are resistant to aminoglycosides and eritromicina Streptococcus pneumoniae and methicillin-resistant (MR) Staphylococus aureus (American collection number of standard culture 33591) were determined in the following way, the Original solutions of the tested compounds is s 1 and 2 (both isomers And three standard laboratory antibiotic gentamicin (G), ampicillin (a) and erythromycin (E), were obtained by dissolving each compound in dimethyl sulfoxide at a concentration of 10 mm. Use the same methods as for a), except that, as a medium for Mycobacterium ranae used nutrient medium Brain Heart Infasion (GIBCO), and incubated them at 37°C for 48 hours for Staphylococcus aureus (MR), Klebsiella pneumoniae and Pseudomonas aeruginosa were used nutrient medium Nutrient (DIFCO) incubated them at 37°C for 20 hours, for Helicobacter pylori used the medium based on Columbia agar (OXOID)containing 7% sheep blood, and incubated them at 37°C for 72 hours, for Streptococcus pneumoniae used tryptanol soy nutrient medium (DIFCO)containing 7% calf serum, and incubated them at 37°C for 48 hours. MIC (mm) was defined as the minimum concentration of drug at which inhibited visible growth.

When positive control organisms (1% DMSO without test compounds was due to the growth of all microorganisms.

When empty negative control (absence of microorganisms + test compound) was not the growth of microorganisms.

In another experiment the minimum inhibiting concentration of the compound 1 and the product from Example 13 (compound 3) against gram-positive and gram-negative bacter the th was determined using the Method of microrasbora nutrient medium (Broth Microdilution Method according to the approved standard methods National Committee for Clinical Laboratory Standards (Methids for dilution antimicrobial susceptibility tests for bacteria that grow aerobically - Fourth Edition ISBN 1-56238-309-4).

Activity against gram-positive bacteria.

Activity against gram-negative bacteria.

Activity of compounds 3 and the product from Example 14 (compound 4) against clinical cultures of Enterococcus faecalis resistant to many antibiotics, which were estimated using the method used for the above results are summarized in the following table and compared with the results obtained by the same method known antibacterial agents:

Biological Example

i) Cloning of the gene PDF Escherichia coli.

Gene PDF E. coli cloned in RETA(+) (labeled pet24 - PDF) and used to transform cells BL21 DE3) from Novagen Inc. (Madison, Wisconsin). Clones were selected at 37°on tablets with YT agar (Tipton 8 g/l, yeast extract 5 g/l, NaCl 5 g/l, agar 15 g/l) supplemented with kanamycin.

and) Expression PDF

20 ml overnight culture of cells BL21 DE3 containing pet24 - PDF was used to infect 500 ml of culture medium 2xYT (Tipton 16 g/l, yeast extract 10 g/l, NaCl 5 g/l)containing 30 μg/ml kanamycin in a 2-liter flask with a septum, and were grown at 37°under stirring until OD6000,6. Then the culture was induced by adding to the medium to a concentration of 1.0 mm isopropyl-b-D-thiogalactopyranoside (IPTG). Induction was continued for 3 hours at 37°C, cells were collected by centrifugation, the cell sediment was washed with 250 ml of saline phosphate buffer (PBS) and kept at -70°C.

iii) Obtaining a soluble protein fraction.

Cells from 1 l of gene-expression solution re-suspended in I ml ice-cold saline phosphate buffer. A cell suspension in ice was treated with ultrasound using a MSE Soniprep 150, calibrated in the image of the environment, when the amplitude of 20-25 microns in h pulses per second. The resulting slurry is then cleared by centrifugation at 20000 xg for 15 minutes. Then the supernatant was used for further purification of the enzyme.

iv) Purification of the PDF.

The E. coli lysate from 1 l of culture in saline phosphate buffer (PBS) was added to 2 M ammonium sulphate. 15 ml fenilefrina column was equilibrated PBS/2M ammonium sulfate at 4°C. the Lysate was loaded onto a column and washed equilibrating buffer. The column was washed with decreasing concentrations of ammonium sulfate from 2 M to 0 M with a volume of buffer equal to 10 column volumes. Collected fractions of 5 ml and analyzed using SDS-PAGE. The fractions containing the greater part of 20 kDa PDF, United. The combined fractions were concentrated using a membrane with a capacity of 3 kDa to volume of 5 ml and Then the fraction was loaded on the Alonso Superdex 75 (pressure chromatography on size of molecules), balanced PBS. Concentrated combined fractions PDF was suirable at 1 ml/min at 4°collected fractions (5 ml) and analyzed them by SDS-PAGE. The most pure fractions were pooled and stored at -70°C.

(v) Research PDF in vitro.

The study was performed in a single 96-well-plate in a final volume of 100 μl containing:

- 20 ál PDF (4 µg/ml)

to 20 μl of 100 mm Hepes pH 7.0 + 1 M KCl + 0,05% Brij

to 10 μl of a serial dilution of test compound in 20% DMSO

50 ál formyl-Met-Ala-Ser (8 mm)

Tablet incubated at 37°C for 30 minutes. Free amino deformirovannogo product (Met-Ala-Ser) was determined using fluorescamine by adding the following components:

50 ál of 0.2 M borate pH of 9.5

50 ál of fluorescamine (150 μg/ml in dry dioxane)

Quantification of fluorescence was performed on the instrument SLT Fluostar plate reader at excitation wavelength of 390 nm and radiating a wavelength of 485 nm. Standard control reactions were reactions without inhibitor, which gave the graph a zero ingibirovaniya, and the reaction without enzyme and without inhibitor, which gave the schedule 100% inhibition. Data were analyzed by transferring units of fluorescence in % inhibition and built a graph of % inhibition concentration of the inhibitor. Data were optimised in the sigmoid f is NCLI: y=A+((B-A)/1+(C/x) D))), where a is a zero inhibition, represents 100% inhibition and represents the IC50D represents the angle of inclination. IC50represents the concentration of inhibitor (nm), which is required for reduction of enzyme activity by 50%. It was found that the compounds according to the invention inhibit bacterial PDF in vitro. Additionally, it was found that actionin (Sigma, cat. No. and-6671) inhibits bacterial PDF in vitro.

Biological Example C.

The demonstration that compound 2 inhibits PDF in vivo.

1. Stop reaction pereformyrovanye mPHKi-Met leads to stability with respect to the connection 2 (diastereoisomer/isomer A).

Trimethoprim-specific inhibits dihydrofolate-reductase, thereby reducing inventories derivatives tetrahydrofolate (THF), including formyltetrahydrofolate (fTHF), substrate methionyl-tRNA-formyltransferase (EU 2.1.2.9). If all significant metabolites biosynthesis which includes derivatives of THF, for example Pantothenate, methionine, glycine, purine nucleotides and thymidine, are supplied from outside in the form of compounds, the precursors in an enriched environment with the addition of thymidine, the bacteria are grown in an enriched environment with thymidine (0.03 mm) and trimethoprim (100 μg/ml), can synthesize all the chemical components of normal cells, with the exception of fMet-TPHKi (Bumstark et al., J.Bacteriol. 129^457-471, 1977). Instead, it uses reformirovannaya Met-TRNC, which leads to the formation of polypeptides that do not contain formyl group at the N-end, regardless of the actions of deformylase. As predicted by the inventors, it was found that DH5a cells grown in LB medium (Tipton 10 g/l, yeast extract 5 g/l, NaCl 10 g/l, pH 7.5) with the addition of trimethoprim and thymidine, resistant to connection 2 (diastereoisomer A). The demonstration that the growth of cells that expressed proteins undergo the normal process of determenirovana, is inhibited by compound 2A, whereas neformirovanie proteins that are produced by cells grown in these conditions, is not inhibited by compound 2A, shows that the compound 2A, probably acts by inhibiting reaction determenirovana, which is carried PDF.

Table 3
Growing conditionsMinimum inhibitory concentration, µm
LB15
LB trimethoprim (Umcg/ml), thymidine (0,3mm)>200

2. Treatment of bacterial compound 2A leads to the accumulation of proteins with blocked N-end.

If the compounds according to the invention indeed inhibit PDF in vivo, the implication is the processing of bacteria compound 2 (Example 2, the diastereoisomer A) is the accumulation of newly synthesized proteins with N-formylmethionine at N-end. Such proteins will be blocked by the N-end, and cannot be used as a substrate for sequencing by N-terminal chemical degradation on Admino.

To test this assumption required protein Express in the presence or in the absence of the test compound. Protein produce, purify and then is sequenced, exposing its degradation by Admino, using techniques known to a person skilled in the technical field.

Bacterial cells transformed by the expression vector, which allows to Express the small regulatory subunit of the human calpain, were grown to OD values600equal to 0.6, and then exposed IPTG to induce expression of the heterologous protein in the presence of 200 μm of compounds 2A, in the presence of 240 μm of carbenicillin or in the presence of the control vector for 2.5 hours. Protein extracts were separated using SDS-PAGE, was suirable kalainov subunit was determined by protein sequencing by chemical degradation on Adminu using ABI automated protein sequencing machine. Sequenced the same amount of protein. The inventors have discovered that the protein yield after treatment with compound 2 which was significantly reduced by 85% compared with control vector and carbenicillin.

Kalainov small regulatory subunit cloned from messenger RNA derived from the tumor biopsy of stomach, by using a set of selection mRNA InVitrogen Micro Fast Track™series 2.2 (catalogue number C-02). DNA copy of the RNA was synthesized using a cDNA synthesis system Promega Riboclone™ M-MLV RT(H-), Noti (Promega, catalog number With 1660), in accordance with the manufacturer's instructions. Two oligonucleotide primers for use in polymerase chain reactions (PCR) were synthesized by Applied Biosystems, Inc., Custom Services based on the published sequence of small chelpanovoy subunit (EMBL access number H).

The fragment calpain Hindlll/Xhol then cloned into the cut Hindlll and Xhol expression vector pET24d(+) from Novagen Inc., (Madison, WI, USA)using standard techniques. Used ligious mixture to transform competent DH5a cells (Life Technologies, Inc, Grand Island, NY, USACat# 18265-017). Colonies were selected by growing overnight at 37°on YT tablets 30 µg/ml kanamycin. The DNA plasmid was obtained using a set of Promega Plus SV miniprep, and clones with chelpanovoy insert identified using standard techniques. The DNA sequence was confirmed using cycle sequencing PE Applied Biosystems, as described above.

Gene E. coli cloned into pET24d(+) (labeled pet24 - CANS), use the Ali to transform BL21 DE3 cells from Novagen Inc, (Madison, Wisconsin). Clones were selected at 37°C on agar plates (Tipton 8 g/l, yeast extract 5 g/l, NaCl 5 g/l, agar 15 g/l) supplemented with 30 μg/ml kanamycin.

1. The use of the compounds of formula (I) or its pharmaceutically or veterinary acceptable salts to obtain an antibacterial composition:

where R1hydrogen or C1-C6alkyl;

R2group -(ALA)m-R, where R is alkyl With1-C6or cycloalkyl; ALK is a linear or branched bivalent1-C6alkylene; m = 0 or 1;

And

R4represents a side chain of a natural or unnatural alpha-amino acids

R5and R6independently represent hydrogen or optionally substituted C1-C8alkyl, cycloalkyl, aryl, aryl(C1-C6alkyl), heterocyclyl or heterocyclyl (C1-C6alkyl).

2. Application under item 1, wherein the compound of formula I is a 2R(or S)-[formyl-hydroxyamino)-methyl]-hexanoic acid (1S-dimethylcarbamoyl)-amide or pharmaceutically or veterinary acceptable salt.

3. The use according to claim 1, wherein the compound of formula I is a 2R(or S)-[(formyl-hydroxyamino)-methyl]-3 cyclopentylpropionic acid (1S-DIMET carbamoyl-2,2-dimethylpropyl)-amide or pharmaceutically or veterinary acceptable salt.

4. Antibacterial pharmaceutical or veterinary composition comprising a compound of formula I with the values of the substituents described in claim 1, together with pharmaceutically or veterinary acceptable excipient or carrier.

According to claim 1 of the claims in part of the signs of R5and R6is hydrogen or C1-C6-alkyl installed priority from 07.02.1998 according to the first application GB 98025497.

For other signs to claim 1 of the formula and PP. 2-4 set the priority from 05.02.1999 according to international application PCT/GB 99/00386.



 

Same patents:

FIELD: medicine, pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to compositions used for treatment and/or prophylaxis of chlamydium infections caused by C. pheumoniae. Pharmaceutical composition used for treatment and/or prophylaxis of chlamydium infection caused by C. pneumoniae comprises the taken phenolic compound, or extract, or fraction, or incomplete fraction comprising the taken phenolic compound or corresponding synthetic compound, or mixture of indicated compounds obtained from plants. An anti-chlamydium effect of phenolic compound or extract, or fraction, or incomplete fraction obtained from plants and comprising indicated compound or corresponding synthetic compound on C. pneumoniae represents the definite percent of inhibition for formation of inclusions. The composition useful for health eliciting an anti-chlamydium effect with respect to C. pneumoniae comprises the taken phenolic compound or extract, or fraction, or incomplete fraction containing indicated compound or corresponding synthetic compound, or mixture of indicated compounds obtained from plants. An anti-chlamydium effect of phenolic compound or extract, or fraction, or incomplete fraction comprising indicated compound or corresponding synthetic compound obtained from plants on C. pneumoniae represents the definite percent for inhibition in formation of inclusions. Also, invention relates to applying the composition useful for health in preparing foodstuffs or as supplements for nutrition for every day. Also, invention relates to applying phenolic compound or extract, or fraction, or incomplete fraction comprising indicated compound or corresponding synthetic compound or mixture of indicated compounds obtained from plants in manufacturing a medicinal agent used for treatment and/or prophylaxis of chlamydium infections caused by C. pneumoniae. An anti-chlamydium effect of phenolic compound or extract, or fraction, or incomplete fraction comprising indicated compound or corresponding synthetic compound obtained from plants on C. pneumoniae represents the definite percent in inhibition in formation of inclusions. Compositions promote to effective prophylaxis and treatment of chlamydium infections caused by C. pneumoniae.

EFFECT: valuable medicinal properties of compounds.

21 cl, 1 dwg, 1 tbl, 6 ex

FIELD: biotechnology, vaccines.

SUBSTANCE: vaccine comprises bacterial mass of Pasteurella multocida of serovariants A, B and D, Haemophilus pleuropneumonia of serogroups 1 and 2, and streptococcus of serogroups C and R, and also lysate-anigens of salmonellae Salmonella cholerae - suis, strain № 370 and Salmonella typhimurium № 415 mixed in the definite concentration. Vaccine elicits the high immunogenicity and provides the protection of pigs against infectious pneumonia of bacterial etiology and salmonellosis.

EFFECT: valuable veterinary properties of vaccine.

3 cl, 1 tbl, 5 ex

FIELD: veterinary science.

SUBSTANCE: the method deals with injecting oxylate once daily for 3 d at the dosage of 1 ml/30 kg body weight at repeated therapy course in 5 d at the background of antibioticotherapy. The method enables to normalize biochemical and morphological blood values and increase average daily body weight gain in sick animals.

EFFECT: higher efficiency of therapy.

2 ex, 2 tbl

FIELD: organic synthesis.

SUBSTANCE: invention provides substituted 7-acylaminocephalosporins of formula I:

(I), where W denotes CH or B; V denotes NO; R1 hydrogen or С14-alkyl; R3 hydrogen or ester residue; and R2 one of the following groups: , , , , in which X, R5, R6, R'6, R7, and Hal have meanings indicated in claims, in free state, in the form of salts and/or solvates, or, if such forms are stable, in the form of internal salt, quaternary salt, or their hydrates, possessing antimicrobial activity. Invention also discloses a method for preparing such compounds and a pharmaceutical connected containing them.

EFFECT: increased choice of antimicrobial preparations.

13 cl, 10 tbl, 225 ex

FIELD: pharmaceutics.

SUBSTANCE: composition is constituted by effective amount of thymol obtained from plant Trychyspermum ammi, mint oil combination of mint oil containing required amounts of monoterpenes and isolated from Mentha spicata and Mentha arvensis, and typical additives. Invention also relates to preparation of the composition by mixing above ingredients and to method of treating patients by administering therapeutically effective amount of the composition.

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19 cl, 12 tbl, 11 ex

FIELD: pharmacology, fluorinated quinolone-based drug, in particular ofloxacine for injections.

SUBSTANCE: claimed composition contains therapeutically acceptable amount of ofloxacine and trilon-B, sodium chloride, water for injections as additives.

EFFECT: high therapeutic effectiveness; non-crystallized active agent for a long-time storage.

1 ex

FIELD: biotechnology, medicine, infectious diseases, medicinal microbiology.

SUBSTANCE: invention relates to a composition designated for treatment and prophylaxis of infections caused by Neisseria microorganism that comprises the following components: (a) protein with amino acid sequence similar by 65% and above with the natural Neisseria protein of a single species (the first group of amino acid sequences is given in the text) and/or its fragment consisting of 10 and more amino acids and eliciting antigen properties; (b) the second protein with amino acid sequence similar by 65% and above with the natural Neisseria protein of another species (the second group of amino acid sequences with even numbers is given in the text), and/or its fragment consisting of 10 or more amino acids and eliciting antigen properties; in particular, the second protein represents NspA. The composition comprises additionally adjuvant. The composition is used both a medicinal agent and for manufacturing the medicinal agent. Applying the invention provides enhancing the effectiveness of prophylaxis or treatment due to the universal effect of the composition (vaccine). Invention can be used in medicine for treatment of infections.

EFFECT: valuable medicinal properties of composition.

8 cl, 137 dwg, 5 tbl, 12 ex

The invention relates to crystalline polyhydroxylated 8-cyan-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid of formula (VI)

The invention relates to pharmaceutical compositions cefuroxime aksetila in the form of particles

The invention relates to a new five-membered heterocyclic compounds of General formula I:

in which W denotes R1-A-C(R13); Y represents a carbonyl group; Z represents N(Rabout); And denotes phenylene; E denotes R10CO; means (C1-C6-alkylene, which may be unsubstituted or substituted (C1-C6)-alkyl; R0indicates if necessary substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl; Rrepresents H or (C1-C6)-alkyl; R1denotes X-NH-C(=NH)-(CH2)p; p = 0; X denotes hydrogen, -HE, (C1-C6-alkoxycarbonyl or, if necessary, substituted in the aryl residue phenoxycarbonyl or benzyloxycarbonyl; R2, R2a, R2bdenote hydrogen; R3means R11NH - or-CO-R5-R6-R7; R4denotes a divalent(C1-C4)-alkalinity residue; R5denotes a bivalent residue of a natural or unnatural amino acid with a lipophilic side chain, selected from grupy residues, if necessary, replaced byin the aryl residue, and, if necessary, substituted (C6-C12)-aryl residues; R6represents a simple bond; R7denotes Het; R10denotes hydroxyl or (C1-C6)-alkoxygroup; R11means R12-NH-C(O) R12-NH-C(S) or R14a-O-C(O) R12means (C6-C14)-aryl-(C1-C6)-alkyl, if necessary substituted in the aryl residue; R13means (C1-C6)-alkyl; R14aindicates if necessary substituted heteroaryl, heteroaryl-(C1-C6)-alkyl, if necessary substituted in the heteroaryl residue, or R15; R15means R16or R16-(C1-C6)-alkyl; R16mean residue 3-12-membered monocyclic or 6 to 24-membered bicyclic, or 6-24-membered tricyclic ring; Het means a 5-7 membered monocyclic residue of a heterocycle bound over the nitrogen atom in the ring, containing, if necessary, another heteroatom from the group consisting of N, O or S; g and h denote 0 or 1, in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts, the

The invention relates to substituted derivatives of imidazolidine formula 1

where W denotes the R1-A-C(R13or

where the ring system may be substituted by 1, 2 or 3 identical or different substituents R13and where L denotes C(R13and ml and m2 independently of one another denote 0, 1, 2, 3 or 4, and the sum of m l + m2 is 3 or 4; Y represents a carbonyl group; A represents a direct bond or a bivalent residue of a phenylene, A denotes a divalent (C1-C6)-alkalinity balance, and (C1-C6)-alkilinity the residue is unsubstituted or substituted by one or more identical or different residues from the series (WITH1-C8)-alkyl and (C3-C10-cycloalkyl-(C1-C6)-alkyl, F denotes R10CO., HCO, or R8O-CH2; R is H or (C1-C8)-alkyl, (C3-C12-cycloalkyl-(C1-C8)-alkyl or, if necessary, substituted (C6-C14)-aryl, and all residues R are independently from each other may be the continuously or repeatedly substituted by fluorine, or the rest of the X-NH-C(=NH) -R20, X - N, R2- N or (C1-C8) -alkyl; R3- N, (C1-C10) -alkyl, which optionally can be substituted one or more times by fluorine, optionally substituted (C6-C14)-aryl, optionally substituted heteroaryl, (C6-C12-bicycloalkyl, R11NH, COOR21, CONHR4or CONHR15; R4- (C1-C10)-alkyl, which is unsubstituted or substituted once or many times, equal or different residues from the series hydroxycarbonyl, aminocarbonyl, mono - or di-((C1-C10)-alkyl)-aminocarbonyl, (C1-C8-alkoxycarbonyl, R5, R6-CO, R5denotes optionally substituted (C6-C14)-aryl, R6denotes the residue of a natural or unnatural amino acid, R8- N or (C1-C10)-alkyl, and R8independently from each other may be the same or different, R10hydroxy, (C1-C10)-alkoxy, (C1-C8-alkylsulphonyl hydroxy-(C1-C6)-alkoxy, (C1-C8)-alkoxycarbonyl-(C1-C6)-alkoxy, amino, mono - or di-((C1-C10)-alkyl)-amino, or R8R8N-CO-(C1-C means R12a-O-CO-or R12a-S(OH)2, R12ameans (C1-C10)-alkyl, optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C4)-alkyl, or R15, R13- N or (C1-C6)-alkyl, which may optionally be substituted one or more times by fluorine, R15means R16-(C1-C6)-alkyl, or R16; R16denotes a 6-membered to 24-membered bicyclic or tricyclic residue, R20denotes a direct bond or (C1-C6-alkylen; R21- N or (C1-C8)-alkyl, R30represents one of the residues R32(R)N-CO-N(R)-R31or R32(R)N-CS-N(R)-R31; R32-CO-N(R)-R31or R12AO-CO-N(R)-R31and R30cannot mean R32-CO-N(R)-R31,ifat the same time W denotes R1-A-C(R13), And denotes a direct bond and R1andR13- N, R31denotes the divalent residue of R33-R34-R35-R36and R36linked to the nitrogen atom in the ring of imidazolidine in formula 1, R32means (C1-C8)-alkyl, which, when neobloc substituted (C6-C14)-aryl, optionally substituted in the aryl (C6-C14)-aryl-(C1-C8)-alkyl or optionally substituted heteroaryl, R33denotes a direct bond, R34denotes a bivalent residue of a number (C1-C8-alkylene, optionally substituted (C6-C14)-Allen; R35denotes a direct bond or a bivalent residue (C1-C8)-alkylene; R36denotes a direct bond, e and h represent independently from each other 0 or 1; in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts, process for the preparation of compounds I; pharmaceutical drug that has the ability to inhibit the adhesion and/or migration of leucocytes and/or VLA-4 receptor

The invention relates to medicine, infectious diseases and can be used for the treatment of brucellosis

The invention relates to medicine, infectious diseases and can be used for the treatment of brucellosis

The invention relates to the field of medicine and relates to new N-pinakamaraming tryptophanase of dipeptides of the formula

C6H5-(CH2)n-CO-NH-(CH2)m-CO-X-Trp-R,

where n=1-5;

m=1-3;

X=L or D-configuration;

R=OH, OCH3OC2H5, NH2, NHCH3,

as well as pharmaceutical compositions containing them

Thrombin inhibitors // 2221808
The invention relates to compounds of formula I, the values of the radicals defined in the claims and their pharmaceutically acceptable salts

The invention relates to means for inhibiting the adhesion or migration of cells, or inhibition of VLA-4 receptor, representing the heterocycles of General formula (I), where W means R1-A-C (R13), Y represents carbonyl, Z denotes N(R0), And means a divalent residue of phenylene, divalent (C1-C6)-alkalinity balance, means the divalent (C1-C6)-alkalinity residue which may be substituted (C1-C8)-alkyl, D is C(R2) (R3), E mean R10CO., R and R0independently of one another denote hydrogen, if necessary substituted (C6-C14)-aryl, if necessary substituted heteroaryl, if necessary substituted in the aryl residue (C6-C14)-aryl-(C1-C6)-alkyl or, if necessary, substituted in the heteroaryl residue heteroaryl-(C1-C6)-alkyl, R1means hydrogen, Gets the remainder R28N (R21)-C(O)-, R2means hydrogen, R3means CONHR4, R11NH, R4means (C1-C28)-alkyl, which optionally may be single - or multi-substituted by identical or different residues selected from the range hydroxy (C6-C14)-aryl, R10means hydroxyl or (C1-C6)-alkoxy, R11means R12CO., R12means R15-O-, R13means (C1-C6)-alkyl, R15means R16-(C1-C6)-alkyl, R16means 7-12-membered bicyclic or tricyclic residue, a saturated or partially unsaturated and which may be substituted by one or more identical or different (C1-C4)-alkyl residues, R21means hydrogen, R28means R21, Het denotes a mono - or polycyclic, 4-14-membered, aromatic or non-aromatic cycle, which may contain 1, 2, 3 or 4 nitrogen atom, b, C, d and f independently of one another denote 0 or 1, but at the same time may not mean zero, e, g and h independently of one another denote 0, 1, 2, 3, 4, 5 or 6, in all their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts

The invention relates to a simple, effective method of obtaining the N2-(1(S)-carboxy-3-phenylpropyl)-L-lysyl-L-Proline (2), which includes the first stage of implementation of the alkaline hydrolysis of N2-(1(S)-alkoxycarbonyl-3-phenylpropyl)-N6-TRIFLUOROACETYL-L-lysyl-L-Proline (1) in a mixed solution consisting of water and a hydrophilic organic solvent using an inorganic base n number of molar equivalents (n3) per mole of the above compound (1), the second stage of neutralization of the hydrolysis product with the use of inorganic acid in an amount of (n-1) to n molar equivalents (n3) and remove inorganic salts, obtained at deposition from a solvent system suitable for reducing the solubility of the inorganic salt, and the third stage is crystallization of the compound (2) present in the mixture after removal of inorganic salts from the solvent at its isoelectric point and thereby removing the compound (2) in the form of crystals, salts containing salt of organic acid - derived triperoxonane acid remains dissolved in the mother

The invention relates to compounds of formula (1), where X and Y Is N or O; R1substituted alkyl, substituted arylalkyl or cycloalkyl; R2and R3Is h or alkyl; And a Is-C(O)-, -OC(O)-, -S(O)2-; R4- alkyl, cycloalkyl or (C5-C12)aryl; compounds of the formula (2), where X and Y are O, S or N; R1- alkyl, optionally substituted arylalkyl; R2and R3Is h or alkyl;- C(O)-; R6- Deputy, including the condensed heterocyclic rings; and compounds of the formula (3), where X and Y are O, S or N; R1- alkyl, alkylsilane, (C5-C12)arylalkyl, (C5-C12)aryl; R2and R3Is h or alkyl; R2' and R3' - N; R11, R12and E together form a mono - or bicyclic ring which may contain heteroatoms

FIELD: medicine, operative gynecology.

SUBSTANCE: at final stage of laparoscopic operation for 5-7 min one should introduce 16 U lidase in 1 ml 2%-lidocaine solution into uterine mesentery from both sides, and then, by not removing a needle - a half of single dose of antimicrobial preparation in 1 ml 2%-lidocaine solution, then in postoperational period - an antimicrobial preparation applied during laparoscopy lymphotropically under mucosa of lateral vaginal arch from both sides for 5-7 d once daily and one antimicrobial preparation - intravenously for 5-7 d, moreover, as antimicrobial preparations one should apply gentamicin, metrogyl and other preparations permitted for intravenous application. The present innovation stimulates lymphatic drainage in area of inflammation and activates interstitial humoral transport of antimicrobial preparations that, in its turn, favors complete sanitation of inflammation foci and prophylaxis of disease relapses.

EFFECT: higher efficiency of therapy.

1 cl, 1 ex

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