MXPA00007709A

MXPA00007709A - Antibacterial agents

Info

Publication number: MXPA00007709A
Application number: MXPA/A/2000/007709A
Authority: MX
Inventors: Raymond Paul Beckett; Mark Whittaker; Michael George Hunter; John Martin Clements; Stephen John Davies; Lisa Marie Pratt; Zoe Marie Spavold; Steven Launchbury
Original assignee: Raymond Paul Beckett; British Biotech Pharmaceuticals Limited; John Martin Clements; Stephen John Davies; Michael George Hunter; Steven Launchbury; Lisa Marie Pratt; Zoe Marie Spavold; Mark Whittaker
Priority date: 1998-02-07
Filing date: 2000-08-07
Publication date: 2001-07-31

Abstract

Compounds of formula (I) are antibacterials:wherein R1 represents hydrogen, or C1-C6 alkyl or C1-C6 alkyl substituted by one or more halogen atoms;R2 represents a group R10-(X)n-(ALK)M- wherein R10 represents hydrogen, or a C1-C6 alkyl, C2-C6 alkenyl,C2-C6 alkynyl, cycloalkyl, aryl, or heterocyclyl group, any of which may be unsubstituted or substituted by (C1-C6) alkyl, (C1-C6) alkoxy, hydroxy, mercapto, (C1-C6) alkylthio, amino, halo (including fluoro, chloro, bromo and iodo), trifluoromethyl, cyano, nitro, -COOH, -CONH2, -COORA, -NHCORA, -CONHRA, -NHRA, -NRARB, or -CONRARB wherein RA and RB are independently a (C1-C6) alkyl group, and ALK represents a straight or branched divalent C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene radical, and may be interrupted by one or more non-adjacent -NH-, -O- or -S- linkages, X represents -NH-, -O- or -S-, and m and n are independently 0 or 1;and A represents a group as defined in the specification.

Description

ANTIBACTBRIAN AGENTS DESCRIPTION OF THE INVENTION The invention relates to the use of derivatives of N-formylhydroxylamine as antibacterial agents, with a novel class of such compounds and with pharmaceutical and veterinary compositions comprising such compounds.

BACKGROUND OF THE INVENTION In general, bacterial pathogens are classified as gram-positive or gram-negative. Many antibacterial agents (including antibiotics) are specific against one or another gram class of pathogens. Effective antibacterial agents against both Gram-positive and Gram-negative pathogens are therefore generally considered to have broad-spectrum activity. Many classes of antibacterial agents are known, including penicillins and cephalosporins, tetracyclines, sulfonamides, monolactams, fluoroquinolones and quinolones, aminoglycosides, glycopeptides, macrolides, polymyxins, lincosamides, trimethoprim and chloramphenicol. The fundame-ntalee mechanisms of these antibacterial classes vary. REF: 121977 Bacterial resistance to many known antibacterials is a growing problem. Accordingly, there is a continuing need in the art for alternative antibacterial agents, especially those which have mechanisms of action fundamentally different from the known classes. Among gram-positive pathogens such as Staphylococci, Streptococci, Mycobacteria and Enterococci, resistant strains have been / have emerged which make them particularly difficult to eradicate. Examples of such strains are Staphylococcus aureus, methicillin-resistant (MRSA), methicillin-resistant coagulase-negative Staphylococci (MRCNS), penicillin-resistant Streptococcus pneumoniae and multiple-resistant Enterococus faecium. Pathogenic bacteria are often resistant to aminoglycosides, beta-lactams (penicillins and cephalosporins) and some types of chloramphenicol antibiotics. This resistance involves the enzymatic inactivation of the antibiotic by hydrolysis or by the formation of inactive derivatives. The family of β-lactam antibiotics (penicillin and cephalosporin) are characterized by the presence of a β-lactam ring structure. Resistance to this family of antibiotics in clinical isolates is mainly due to the production of a "penicillinase" (ß-lactamase) enzyme by resistant bacteria. = - '* "" - - which hydrolyse the β-lactam ring and therefore eliminate its antibacterial activity. Recently, the germination of vancomycin-resistant strains of enterococci (oodford N. 1998 Glycopeptide-resistant enterococci: a decade of experience, Journal of Medical Microbiology, 4.7 (10): 8_9-62) has been mentioned. Vancomycin-resistant enterococci are particularly dangerous insofar as they are frequent causes of hospital-based infections and are inherently resistant to most antibiotics. Vancomycin works by binding the D-Ala-D-Ala terminal residues of the glycan peptide precursor to the cell wall. The high level of resistance to vancomycin is known as VanA and is conferred by genes located in a transposable element which alters the terminal residues to D-Ala-D-lac and therefore reduces the affinity for vancomycin. In view of the rapid germination of bacteria resistant to multiple drugs, the development of antibacterial agents with novel modes of action that are effective against the increasing number of resistant bacteria, particularly enterococci resistant to vancomycin and bacteria resistant to ß-lactam antibiotics , such as methicillin-resistant Staphylococcus aureus, are of utmost importance.

BRIEF DESCRIPTION OF THE INVENTION This invention is based on the finding that certain N-formylhydroxylamine derivatives have antibacterial activity, which generates a new class of antibacterial agents available. The inventors have found that the compounds with which this invention relates are antibacterial with respect to the range of gram-positive and gram-negative organisms. In addition, there is evidence that some compounds are antibacterial with respect to bacteria which are resistant to commonly used antibiotics such as vancomycin and ß-lactam antibiotics, for example methicillin-resistant Staphylococcus aureus. Although it may be of interest to establish the mechanism of action of the compounds with which the invention relates, it is their ability to inhibit bacterial growth which makes them useful. However, it is currently considered that its antibacterial activity is due, at least in part, to the intracellular inhibition of the bacterial polypeptide deformylase enzyme (PDF). Bacterial polypeptide deformylases (PDF) (EC 3.5.1.31) are a conserved family of metalloenzymes (Reviewed: Meinnel T, Lazennec C, Villoing S, Blanquet S, 1997, Journal of Molecular Biology 267, 749-761) which are essential for bacterial viability, its function is to remove the formyl group from the N-terminal methionine residue of proteins synthesized in ribosome in eubacteria. Mazel et al. (EMBO J. 13 (4): 914-923, 1994) have recently cloned and characterized a PDF of E. coli. Since PDF is essential for the growth of bacteria and there is no eukaryotic counterpart for PDF, Mazel et al. (ibid), Rajagopalan et al. (J. Am. Chem. Soc. 119: 12 18-12 19, 1997) and Becker et al., (J. Biol. Chem. 273 (19): 11413-11416, 1998) each have proposed that PDF is an excellent antibacterial goal. Previously certain N-formylhydroxylamine derivatives have been claimed in the patent publications included below, although very few examples of such compounds have been specifically developed and described: EP-B-0236872 (Roche) WO 92/09563 (Glycomed) WO 92/04735 (Syntex) WO 95/19965 (Glycomed) WO 95/22966 (Sanofi Winthrop) WO 95/3709 (Roche) WO 96/23791 (Syntex ) WO 96/16027 (Syntex / Agouron) WO 97/03783 (British Biotech) WO 97/18207 (DuPont Merck) WO 98/38179 (Glaxo Wellcome) WO 98/47863 (Labs Jaquse Logeais) The pharmaceutical utility ascribed to the N-formyl hydroxylamine derivatives in these publications is the ability to inhibit matrix metalloproteinases (MMP) and in some cases the release of tumor necrosis factor (TNF), and therefore the treatment of diseases or conditions mediated by these enzymes, such as cancer and rheumatoid arthritis. What the prior art does not describe or imply is that the N-formyl hydroxylamine derivatives have antibacterial activity. In addition to these, US-A-4, 738, 803 (Roques et al.) Also discloses N-formyl hydroxylamine derivatives, however, these compounds are described as enkephalinase inhibitors and are proposed for use as antidepressants and agents hypotensive In addition, WO 97/38705 (Bristol-Myers Squibb) discloses certain N-formylhydroxylamine derivatives as inhibitors of enkephalinase and angiotensin-converting enzyme. This prior art does not disclose or imply that the N-formylhydroxylamine derivatives also have antibacterial activity.

DETAILED DESCRIPTION OF THE INVENTION According to the first aspect of the first invention, there is provided the use of a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof, in the preparation of an antibacterial composition: wherein: R 1 represents hydrogen or C-C6 alkyl or C 1 -C 8 alkyl substituted by one or more halogen atoms, - R 2 represents a group R 10 - (X) "- (ALK). wherein R10 represents hydrogen or an alkyl group of Cj-Cj, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, aryl or heterocyclyl, any of which may be unsubstituted or substituted by C2-C6 alkyl, alkoxy of CJ-CJ, hydroxy, mercapto, amino alkylthio, halo (including fluoro, chloro, bromo, and iodo), trifluoromethyl, cyano, nitro, -COOH, -C0NH2, -C00RA, -NHC0RA, -CONHRA, -NHR. -NRARB, or -C0NRARB wherein RA and RB are independently an alkyl group of C_-C3, and ALK represents a divalent linear or branched alkylene radical of Cj-Cg, C2-C6 alkenylene or C2-C6 alkynylene, and which may be interrupted by one or more adjacent bonds of -NH-, - O- or -S-, X represents -NH-, -O- or -S-, and m and n are independently 0 6 1; and A represents (i) a group of formula (IA), (IB), (IC) or (ID) (IA) (IB) (ID) (IC) where : R3 represents hydrogen and R4 represents the side chain of a natural or unnatural alpha amino acid, or R3 and R4, when taken together with the nitrogen and carbon atoms to which they are respectively attached, form an optionally substituted saturated heterocyclic ring of to 8 atoms, ring which is optionally fused to a carbocyclic ring or second heterocyclic ring, R5 and Rβ, independently represent hydrogen or optionally substituted alkyl, cycloalkyl, aryl, arylalkyl of C ^ Cj, heterocyclic or Cj-heterocyclic alkyl, or R5 and R6, when taken together with the nitrogen atom to which they are attached, form an optionally substituted saturated heterocyclic ring of 3 to 8 atoms , ring which is optionally fused to a carbocylic ring or second heterocyclic ring, and R7 represents hydrogen, alkyl of or an acyl group. In another aspect, the invention provides a method for the treatment of bacterial infections in human and non-human mammals, which comprises administering to a subject suffering from such infection an effective antibacterial dose of a compound of formula (I) as defined above. In a further aspect of the invention, there is provided a method for the treatment of bacterial contamination by applying an antibacterial effective amount of a compound of formula (I) as defined above at the site of contamination. The compounds of formula (I) as defined above can be used as components of antibacterial cleaning or disinfecting materials. According to a preferred embodiment, the various aspects of the invention can be applied against bacteria resistant to vancomycin, quinolone and "β-lactam" and the infections they produce. Regarding the hypothesis that the compounds (I) act by inhibiting intracellular PDF, the most potent antibacterial effect can be obtained by using the compounds which efficiently pass through the bacterial cell wall. Therefore, compounds which are highly active as inhibitors of PDF in vitro and which penetrate bacterial cells are preferred for use according to the invention. It is expected that the antibacterial potency of compounds which are potent inhibitors of the PDF enzyme in vitro, but which are poorly penetrating in cells, may improve their use in the form of a precursor, ie, a structurally modified analogue which is converts the parent molecule of formula (I), for example by enzymatic action, after it has passed through the bacterial cell wall.

The invention also provides novel compounds of formula (I) above or pharmaceutically or veterinarily acceptable salts thereof, wherein: Rx represents hydrogen, Ci-Cj alkyl or Cj-Cj alkyl substituted with one or more halogen atoms; R2 represents a group R10- (ALK) m- wherein R10 represents hydrogen or an alkyl group of C ^ Cj, C2-C6 alkenyl, C2-C6 alkynyl, a cycloalkyl, aryl or heterocyclyl, any of which may be unsubstituted or substituted by C ^ Cj alkyl, C ^ Cj alkoxy, hydroxy, mercapto, amino alkylthio, halo (including fluoro, chloro, bromo, and iodo), trifluoromethyl, nitro, -COOH, -C0NH2, -COOR \ -NHC0R \ -C0NHRA, -NHR \ -NRARB, or -C0NRARB, where RA and RB are independently an alkyl group of Cj-C6. ALK represents a linear or branched divalent radical of alkylene of Cj-C3, alkenylene of C2-C6, alkynylene of C2-C6, and can be interrupted by one or more non-adjacent bonds of -NH-, -O- or -S- , and m represents 0 or 1; A represents a group of formula (IA), (IB), (IC) or (ID) above wherein: R3 represents hydrogen and R4 represents the side chain of a natural or unnatural alpha amino acid, or R3 and R4, when taken together with the nitrogen and carbon atoms to which they are attached respectively, form a ring optionally substituted saturated heterocyclic of 5 to 8 atoms, ring which is optionally fused to a carbocyclic ring or second heterocyclic ring, R5 and R6, independently represent hydrogen or optionally substituted alkyl, cycloalkyl, arylalkyl of Cj-Cf, non-aromatic heterocyclic or heterocyclic (C ^ Cs alkyl), or R5 and R6, when taken together with the nitrogen atom to which they are attached, form an optionally substituted saturated heterocyclic ring of 3 to 8 atoms, which ring is optionally fused to a ring carbocyclic or a second heterocyclic ring, and R7 represents hydrogen, Cj-C alkyl; or an acyl group. WITH THE CONDITION THAT (i) when A is a group of formula (IA) or (IB) and R2 is C2-C5 alkyl, then R4 is not the side chain of a natural alpha amino acid or the side chain of an alpha natural amino acid in which any functional substituent is protected, any amino group is acylated and any carboxyl group is stapled; (ii) when A is a group of formula (IA) or (IB) then R4 is not a bicyclicarylmethyl group; and (iii) when A is a group of formula (IA) and R2 is cyclopropylmethyl, cyclobutylmethyl or cyclopentylmethyl and one of R5 and R6 is hydrogen, then R4 is not terbutyl.

As used herein, the term "Cj-C8 alkyl" means a straight or branched chain alkyl portion having from 1 to 6 carbon atoms, which includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and n-hexyl. As used herein, the term "alkylene radical of divalent Cj-Cj" means a saturated hydrocarbon chain of 1 to 6 carbon atoms and two unfilled valencies. As used herein, the term "C2-C6 alkenyl" means a straight or branched chain alkenyl portion having from 2 to 6 carbon atoms having at least one stereo E or Z double bond, when applicable. The term includes, for example, vinyl, allyl, 1-and 2-butenyl and 2-methyl-2-propenyl. As used herein, the term "divalent C2-C6 alkenylene radical" means a hydrocarbon chain having from 2 to 6 carbon atoms, at least one double bond and two unfilled valencies. As used herein, the term "C2-C6 alkynyl" refers to a straight chain or branched chain of hydrocarbon groups having from 2 to 6 carbon atoms and further having a triple bond. This term may include, for example, ethinyl, 1-propinyl, 1- and 2-butinyl, 2-methyl- propinyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl. As used herein, the term "divalent C2-C6 alkynylene radical" means a hydrocarbon chain having from 2 to 6 carbon atoms, at least one triple bond and two unfilled valencies. As used herein, the term "cycloalkyl" means a saturated alicyclic portion having 3-8 carbon atoms and including, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. As used herein, the term "cycloalkenyl" means an unsaturated alicyclic portion having 3-8 carbon atoms and including, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. In the case of cycloalkenyl rings of 5-8 carbon atoms, the ring may contain one or more double bonds. As used herein, the term "aryl" refers to a mono-, bi- or tricyclic carbocyclic aromatic group and to the groups consisting of two monocyclic carbocyclic aromatic groups covalently linked. Illustrative of such groups are phenyl, biphenyl and naphthyl. As used herein, the term "heteroaryl" refers to an aromatic ring of 5 or 6 members containing one or more heteroatoms, and optionally fused to a benzyl pyridyl ring; and to groups consisting of 2 aromatic rings of 5 or 6 members covalently linked, each with one or more heteroatoms; and to groups consisting of a monocyclic carbocyclic aromatic group covalently bound to 5 or 6 membered aromatic rings containing one or more heteroatoms; Illustrative of these groups are thienyl, furyl, pyrrolyl, imidazolyl, benzimidazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, 4- ([1, 2, 3] -thiadiazolyl-4-yl) phenyl and 5-isoxazol-3-ylthienyl.

As used herein, the term "heterocyclyl" or "heterocyclic" does not include "heteroaryl" as defined above, and in particular means a 5-7 membered aromatic or nonaromatic heterocyclic ring containing one or more heteroatoms selected from S, N and 0, and optionally fused to a benzene ring, including, for example, pyrrolyl, furyl, thienyl, piperidinyl, imidazolyl, oxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrimidinyl, morpholinyl , piperazinyl, indolyl, benzimidazolyl, maleimido, succinimido, phthalimido and 1,3-dioxo-l, 3-dihydro-isoindol-2-yl groups.

As used herein, the term "acyl" means a group R20C (0) -, wherein R20 is Cj-Cs alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, phenyl, heterocyclic, phenylalkyl -C6, heterocyclylalkyl of CJ-CJ, cycloalkyl (C3-C7) alkyl of C_-C6, phenylalkenyl of C2-Cß, heterocyclylalkenyl of C2-C6, cycloalkyl (C3-C7) alkenyl of C2-C6, any of which groups R20 may be substituted. As used herein, the term "bicyclic acylmethyl" means: (i) a methyl group substituted by a monocyclic or heteroaryl aryl group which in turn is substituted by a monocyclic aryl or heteroaryl group, or (ii) a methyl group substituted by a monocyclic or heteroaryl aryl group to which a second monocyclic or heteroaryl aryl group is fused; and which includes substituted bicyclicrilmethyl. Examples of such bicycliccarylmethyl groups include naphthyl, indolyl, quinolyl and isoquinolyl. Unless otherwise specified in the context in which it is presented, the term "substituted" as applied to any portion herein means substituted with up to four substituents, each independently of which may be Cj-alkyl. Cj, benzyl, C1-C6 alkoxy, phenoxy, hydroxy, mercapto, C ^ Cj alkylthio, amino, halo (including fluoro, chloro, bromo and iodo), trifluoromethyl, nitro, -COOH, -CONH2, -CORA, -COOR, -NHC0RA, -CONHRA, -NHRA, -NRARB, or -CONRARB wherein RA and RB are independently a C1-C6 alkyl group. In the case where "substituted" means benzyl, the phenyl ring thereof may itself be substituted with any of the foregoing, except benzyl. As used herein, the terms "side chain of a natural alpha-amino acid" and "side chain of an unnatural alpha amino acid" means the group R * respectively in a natural and unnatural amino acid, of formula NH 2 -CH ( Rx) -COOH). Examples of natural alpha amino acid side chains include those 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, tt-aminoadipic acid, a-amino-n-butyric acid, 3,4-dihydroxyphenylalanine, homoserin, o-methylserine, ornithine, pipecolic acid and tyrosine. In natural chains of natural alpha amino acids which contain functional substituents, for example amino, carboxyl, hydroxy, mercapto, guanidyl, imidazolyl or indolyl groups such as in arginine, lysine, glutamic acid, aspartic acid, tryptophan, histidine, serine, threonine, tyrosine and cysteine, such functional substituents may optionally be protected. Likewise, in the side chains of non-natural alpha amino acids which contain functional substituents, for example amino, carboxyl, hydroxy, mercapto, guanidyl, imidazolyl or indolyl groups, such functional substituents may optionally be protected. The term "protected", when used in relation to a functional substituent on a side chain or a natural or unnatural alpha amino acid, means a derivative of such a substituent which is substantially non-functional. The manual of T. W. Greene and P. G. Wuts "Protective Groups in Organic Synthesis" is used extensively. Second Edition, Wiley, New York, 1991 where the subject is reviewed. For example, the carboxyl groups can be esterified (for example as an alkyl ester of Cj ^ -C, the amino groups can be converted to amides (for example as an NHCOCi-C-alkylamide or carbamates (for example an NHC carbamate (= 0) 0C alkyl of Cj-Cg or of NHC (= 0) 0CH2Ph), the hydroxyl groups can be converted to ethers (for example an alkyl of CJ-CJ or a 0 (alkyl of Cj-C phenylether) or esters (for example a 0C (= 0) C 1 -C 6 alkyl ester), and thiol groups which can be converted to thioethers (for example tert-butyl or benzyl thioether) or thioesters (for example a SC (= 0) alkyl thioester of Cx-Cß).

There are several real or potential chiral centers in the compounds according to the invention due to the presence of asymmetric carbon atoms. The presence of several asymmetric carbon atoms gives rise to numerous diastereoisomers with R or S stereochemistry at each chiral center. The invention includes all of the diastereoisomers and mixtures thereof. At present, the preferred stereoconfiguration of the carbon atom exhibiting the group R2 is R; that of the atom that presents the group R4 (when it is asymmetric) is S; and that of the carbon atom having the group Ra (when it is asymmetric) is R. In the compounds of formula (I) as defined above for use according to the invention, and in the novel compounds of the invention of the formula (II) as defined in the above (but subject to the conditions in which): Rj can be, for example, hydrogen, methyl or trifluoromethyl. Hydrogen is currently what is preferred. R2 may be, for example: optionally substituted Cj-Cj alkyl, C3-Cß alkenyl, C3-C6 alkynyl or cycloalkyl; phenylalkyl of Cj-Cj-, C3-C6 phenylalkenyl or C3-C6- phenylalkyl, optionally substituted on the phenyl ring; cycloalkyl (C, -C6 alkyl) -, cycloalkyl (C3-Cß alkenyl) - or cycloalkyl (C3-C6 alkynyl) - optionally substituted on the cycloalkyl ring; heterocyclyl (C 1 -C 8 alkyl), heterocyclyl (C 3 -C 6 alkenyl) - or heterocyclyl (C 3 -C 4 alkynyl) - optionally substituted on the heterocyclic ring; or CH3 (CH2) pO (CH2), - or CH3 (CH2) pS (CH2) q-, where p is 0, 1, 2 or 3 and q is 1.2, or 3. Specific examples of R2 groups include methyl , ethyl, n- and iso-propyl, n- and iso-butyl, n-pentyl, iso-pentyl, 3-methyl-but-l-yl, n-hexyl, n-heptyl, n-acetyl, n-octyl , methylsulfanylethyl, ethylsulfanylmethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-ethoxymethyl, 3-hydroxypropyl, allyl, 3-phenylprop-3-en-1-yl, prop-2-yn-1-yl, 3-phenylpro-2 -in-l-yl, 3- (2-chlorophenyl) prop-2-yn-l-yl, but-2-yn-l-yl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, furan-2-methylmethyl, furan-3-methyl, te rahydrofuran-2-ylmethyl, tetrahydrofuran-2-ylmethyl, piperidinylmethyl, phenylpropyl, 4-chlorophenylpropyl, 4-methylphenylpropyl, 4-methoxyphenylpropyl, benzyl, 4-chlorobenzyl, 4-methylbenzyl and 4-methoxybenzyl. The groups currently preferred in R2 are n-propyl, n-butyl, n-pentyl, benzyl and cyclopentylmethyl. In the case of R3, hydrogen is currently preferred.

R4 can be, for example, the characterizing group of a natural a-amino acid, for example benzyl or 4-methoxyphenylmethyl, in which any functional group can be protected, any amino group can be acylated and any carboxy group present can be amidated; or a group - [Alk] nR, is an alkylene group of C1-C or alkenylene of C2-C6, optionally interrupted by one or more atoms of -0- or -S-, or groups -N (R12) - [in where R12 is a hydrogen atom or an alkyl group of Cj-C, n is 0 or 1 and R9 is hydrogen or an optionally substituted phenyl group, aryl, heterocyclyl, cycloalkyl or cycloalkenyl (only when n is 1) R9 may additionally be hydroxy, mercapto, C-C6 alkylthio, amino, halo, trifluoromethyl, nitro, -COOH, -C0NH2, -C00RA, -NHC0RA, -C0NHRA, -NHR-NRARB, or -C0NRARB wherein RA and RB are independently alkyl group of or a benzyl group substituted on the phenyl ring by a group of formula -0CH2C0Rβ wherein RB is hydroxyl, amino, Ci-C3 alkoxy, C ^ Cj phenylalkoxy, C ^ alkylamino, di (C3- alkyl) C6) amino, phenylalkylamino of C ^ Cs, - or a heterocyclic C1-C6 alkyl group, whether unsubstituted or mono- or di-substituted on the heterocyclic ring with halo, nitro, carbo xi, Cj-C ^ cyano alkoxy, Cj-C3 alkanoyl, trifluoromethylalkyl of Cj-Cj, hydroxy, formyl, amino, dialkyl amino alkylamino, mercapto, Cx-C6 hydroxyalkyl alkylthio, O-alkyl (Ci-) phenylmethyl mercaptoalkyl, - or a group -CR "R_RC in which: each of Ra, Rb and Rc is independently hydrogen, C [-Cg] alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenylalkyl of Cj-Cg, C3-C8 cycloalkyl; or R. is hydrogen and R "and Rb are independently phenyl or heteroaryl such as pyridyl; or R_ is hydrogen, Cj-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 phenylalkyl or C3-C3 cycloalkyl, and R, and Rb together with the carbon atom to which they are attached , form a 3- to 8-membered cycloalkyl or a 5-6 membered heterocyclic ring; or Ra, Rb and Rc together with the carbon atom to which they are attached, form a tricyclic ring (for example adamantyl); or Ra and Rb are each independently Cj-Cg alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-Ce phenylalkyl or a group as defined for R = below, other than hydrogen, or R, and Rb, together with the carbon atom to which they are attached, form a cycloalkyl or heterocyclic ring, and R. is hydrogen, -OH, -SH, halogen, -CN, -C02H, perfluoroalkyl of dC ,, -CH2OH, - C02 alkyl of Cj-C8, -O alkyl of d-Cg, -O alkenyl of C2-C6, -S alkyl of Cj-Cg, -SO Cj-Cg alkyl, -S02 d-Cg alkyl, -S-C2-C al alkenyl, -C2-C6-alkenyl, -S02 -C2-C6 alkenyl or a -QW group, where Q represents a bond - 0-, -S-, -SO- or -S02- and W represents a phenyl, phenylalkyl, cycloalkyl group of C3-CB, cycloalkylalkyl of C3-C ", cycloalkenyl of C4-C8, cycloalkenylalkyl of C4-Cß, heteroaryl or heteroarylalkyl, group W which is optionally substituted by one or more substituents that are independently selected from hydroxyl, halogen, -CN, -C02H, -C02 d-Cg alkyl, -C0NH2, -CONH Cx-C6 alkyl, -CONH (Cj-Cg alkyl, -CHO, -CH20H, perfluoroalkyl of C ^ -C ,, -0 alkyl of d-Cg, -S alkyl of Cj-Cg, -SO alkyl of -S02 alkyl of Cj-Cg, - N02, -NH2, -NH alkyl of Cj-Cg, -N (alkyl of Cj-Cg); ,, -NHCO alkyl of Cj-Cg, alkyl of Cj-Cg, alkenyl of C2-C6, alkynyl of C2-C6 , C3-Cß cycloalkyl, C4-Ca cycloalkenyl, phenyl or benzyl Examples of particular R4 groups include methyl, ethyl, ben cyl, 4-chlorobenzyl, 4-hydroxybenzyl, phenyl, cyclohexyl, cyclohexylmethyl, pyridin-3-ylmethyl, tert-butoxymethyl, naphthylmethyl, iso-butyl, sec-butyl, tert-butyl, 1-benzylthio-1-methylethyl, 1- methylthio-l-methylethyl, 1-mercapto-1-methylethyl, 1-methoxy-1-methylethyl, 1-hydroxy-1-methylethyl, 1-fluoro-1-methylethyl, hydroxymethyl, 2-hydroxyethyl, 2-carboxyethyl, 2- methylcarbamoylethyl, 2-carbamoylethyl and 4- aminobutyl. Presently preferred R4 groups include terbutyl, isobutyl, benzyl and methyl. R3 and R4 when taken together with the nitrogen and carbon atoms to which they are respectively attached can form an optionally substituted saturated heterocyclic ring of 5 to 8 atoms. For example, R3 and R "can form a bridge between the nitrogen and carbon atoms to which they are attached, the bridge is represented by the divalent radical - (CH2) 3.6-, or - (CH2) r- 0 - (CH2 ), -, or - (CH1), - S- (CH1, -, where r and s are each independently 1, 2 or 3, with the proviso that r + s = 2, 3, 4 or 5 Rs and R6 may independently be, for example, hydrogen, methyl, ethyl, tertbutyl, cyclopentyl, cyclohexyl, 1,3,3-tetramethylbutyl, benzyl or 2-hydroxyethyl; or R5 and R6, when taken together with Nitrogen atom to which they are attached, can form a saturated 5- to 8-membered monocyclic N-heterocyclic ring, which is attached via the N atom and which optionally contains -N (RX1) - where R "is hydrogen or Cj-Cg alkyl, benzyl, acyl or an amino protecting group, 0, S, SO or S02 as a ring member and / or is optionally substituted by one or more C atoms by hydroxy, C1-C6 alkyl , hid C1-C €-hydroxyalkyl, C1-C6 alkoxy, oxo, ketalized oxo, amino, mono (d-Cg alkyl) amino, di (d-Cg alkyl) amino, carboxy, d-Cg alkoxycarbonyl, hydroxymethyl, d-Cg alkoxymethyl, carbamoyl, mono (Cj-Cg alkyl) carbamoyl, di (Cj-Cg alkyl) carbamoyl or hydroxyimino. Examples of such rings are substituted or unsubstituted 1-pyrrolidinyl, piperidin-1-yl, 1-pi? Erazinyl, hexahydro-1-pyridazinyl, morph olin-4-yl, tetrahydro-1,4-thiazin-4-yl , - 1-tecrahydro-1, -thiazin-1-yl, tetrahydro-1,4-thiazin-4-yl, hexahydroazipine or octahydroazocine-1-oxide. The substituted examples of the above are 2- (methylcarbamoyl) -1-pyrrolidinyl, 2- (hydroxymethyl) -1-pyrrole-idinyl, 4-hydroxypiperidino, 2- (methylcarbamoyl) piperidino, 4-hydroxyiminopiperidino, 4-methoxypiperidino, 4-methylpiperidin -l-yl, 4-benzylpiperidin-1-yl, 4-acetylpiperidin-1-yl, 4-methyl-l-piperazinyl, 4-phenyl-1-piperazinyl, 1,4-dioxa-8-azaspiro [4, 5 ] decan-8-yl, hexahydro-3- (methylcarbamoyl) -2-pyridazinyl and hexahydro-1- (benzyloxycarbonyl) -2-pyridazinyl, decahydroisoquinolin-2-yl and 1,2,3,4-tetrahydroisoquinolin-2-yl . When A is a group of the formula (IA), it is currently preferred that R5 is methyl or hydrogen and that R6 is methyl.

R7 can be, for example hydrogen, or a group R20C (O) - wherein R20 is an alkyl group of Cj-Cg such as methyl or ethyl.

Specific examples of compounds useful as antibacterial agents according to the invention include those of the specific examples herein. Preferred novel compounds of the invention include: (lS-dimethylcarbamoyl-ethyl) -amide of 2R (or S) - [(formyl-hydroxy-amino) -methyl] -hexanoic acid (SS-dimethyl carbamoyl -2,2-dimethylpropyl) ) 2R (or?) - [(formy 1-hydroxy-amino) -met i 1] -3-cyclopentylpropionic acid amide and its pharmaceutically and veterinarily acceptable salts. The compounds with which the invention relates can be prepared by deprotecting a protected N-formyl-N-hydroxyamino O compound of formula (II): in which R1 # R2 and A are as defined in the general formula (I) and R25 is a protective group of hydroxy removable to leave a hydroxy group by hydrogenolysis or by hydrolysis. Benzyl is a preferred Rs group for removal by hydrogenolysis and terbutyl and tetrahydropyranyl are preferred groups for removal by acid hydrolysis. The compounds of formula (II) wherein A is a group of formula (IA), (IB), (IC) or (ID) can be prepared by causing an acid of the formula (III) or an activated derivative thereof react with an amine of the formula (IVA), (IVB), (IVC) or (IVD) respectively (IVD) (IVC) wherein R.sup.lf R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are as defined in general formula (I) except that the group -OH in (IVB) and any substituent in R.sup.lf R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R7 which are potentially reactive in the coupling reaction, themselves must be protected from such a reaction and R5 is as defined in relation to formula (II) above and optionally remove protective groups from the -OH group in (IVB) and R1; R2, R3, The compounds of formula (III) can be prepared by N-formylation, for example using acetic anhydride and formic acid, or 1-formylbenzotriazole of compounds of formula (V) wherein R1 (R2 and R25 are as defined in relation to formula (II) and X is either a chiral auxiliary group or an OR26 group, wherein R26 is hydrogen or a hydroxy protecting group. that X is an OR26 group or a chiral auxiliary group of the hydroxy or auxiliary protecting group, is removed after the formylation step to provide the compound of formula (V). Suitable chiral auxiliaries include substituted oxazolidinones which can be removed by hydrolysis in the presence of base. In an alternative procedure, the compounds of general formula (II) can be prepared by N-formylation, for example using acetic anhydride and formic acid or 1-formylbenzotriazole, of compounds of formula (VI) wherein R1 (R2 and R25 and A are as defined in relation to formula (II).) Compounds of formula (VI), wherein A is a group of formulas (IA), (IB), (IC) or (ID) can be prepared by causing an acid of the general formula (VII) or an activated derivative thereof wherein R1 # R2 and R25 are as defined in relation to formula (II), react with an amine of the formula (IVA), (IVB), (IVC) or (IVD) respectively as defined in the foregoing. Alternatively, the compounds of the general formula (VI) can be prepared by reduction of an oxime of the general formula (VIII).

Reducing agents include certain metal hydrides (eg sodium cyanoborohydride in acetic acid, triethylsilane or borane / pyridine) and hydrogen in the presence of a suitable catalyst. In an alternative procedure, the compounds of general formula (II), wherein Rx and R2 are as defined in general formula (I), R2S is a hydroxy protecting group as defined above and A is a group of formula (IA), wherein R3, R4 and R5 are as defined in the general formula (IA) and R6 is hydrogen, can be prepared by a Ugi reaction of 4 carboxylic acid components of the general formula (III) as defined above, an amine of the formula (IX), an aldehyde of the formula (X) and an isonitrile of the formula (XI) R3-NH2 (IX) R -CHO (X) R5 CN (XI) wherein R3, R4 and R5 are as defined in the foregoing. A compound of the general formula (V) can be prepared by reduction of an oxime of the general formula (XI) wherein R1 # R2 and R25 are as defined in the above and X is either a group OR26 as defined above or a chiral auxiliary. Reducing agents include certain metal hydrides (e.g., sodium cyanoborohydride in acetic acid. triethylsilane or borane / pyridine) and hydrogen in the presence of a suitable catalyst. After reduction, when the group X is a chiral auxiliary, it can optionally be converted to an OR26 group. A compound of general formula (XI) can be prepared by reaction of a β-ketocarbonyl compound of the general formula (XII) wherein R1 # R2 and X are as defined above, with a protected hydroxylamine 0. The β-ketocarbonyl compounds (XII) can be prepared in racemic form by formulation or acylation of a carbonyl compound of the general formula (XIII) wherein R2 and X are as defined in the foregoing, with a compound of the general formula (XIV) wherein R1 is as defined above and Z is a leaving group such as halogen or alkoxy, in the presence of a base. Another method for the preparation of a compound of the general formula (V) is by the addition of Michael of a hydroxylamine derivative to α, β-unsaturated carbonyl compounds of the general formula (XV) where Rlf R2 and X are as defined above. After the Michael addition reaction, when the group X is a chiral auxiliary, an OR26 group can optionally be converted.

The carbonyl, β-unsaturated compounds (XV) can be prepared by standard methods. The salts of the compounds of the invention include physiologically acceptable acid addition salts, for example hydrochlorides, hydrobromides, sulfates, methanesulfonates, p-toluenesulfonates, phosphates, acetates, citrates, succinates, lactates, tartrates, fumarates and maleates. The salts can also be formed with bases, for example sodium, potassium, magnesium and calcium salts. The compositions with which the invention relates can be prepared for administration by any route consistent with the pharmacokinetic properties of the active ingredient or ingredients. Orally administrable compositions may be in the form of tablets, capsules, powders, granules, dragees, liquid or gel preparations, such as oral, topical or sterile parenteral solutions or suspensions. Tablets and capsules for oral administration may be in the form of a unit dose presentation, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; filling materials, for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; lubricants for tableting, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch or acceptable wetting agents such as sodium lauryl sulfate. The tablets can be coated according to methods well known in normal pharmaceutical practice. The oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspension improving agents, for example, sorbitol, syrup, methyl cellulose, glucose syrup, hydrogenated edible fats and gelatin, emulsifying agents for example lecithin, sorbitan monooleate or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerin, propylene glycol or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired, conventional flavoring or color imparting agents. For topical application to the skin, the active ingredients can be constituted in a cream, lotion or ointment. The cream or ointment formulations which can be used for the medicament are conventional formulations well known in the art, for example as described in Standard pharmaceutical textbooks such as the British Pharmacopoeia. The active ingredient or ingredients can also be administered parenterally in a sterile medium. Depending on the vehicle and the concentration used, the medication can be suspended or dissolved in the vehicle. Advantageously, adjuvants such as a local anesthetic, a preservative and buffering agents can also be dissolved in the vehicle. Intravenous infusion is another route of administration for the compounds used according to the invention. Safe and effective dosages for different classes of patients and for different disease states will be determined by clinical trial as required in the art. It will be understood that the specific dose level for any particular patient will depend on various factors including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, combination with other medications and the severity of the particular disease that is undergoing therapy. The finding that these compounds with inhibitory activity of PDF can inhibit or inhabit bacterial growth, allows a novel approach to identify new antibacterial agents through analysis tests of compounds to determine activity as inhibitors of PDF ia vi tro, followed by confirmation of their antibacterial capacity using bacterial growth inhibition studies. This finding also makes available (i) the use of compounds with PDF inhibitory activity as antibacterial agents, and (ii) a method for the treatment of bacterial infection or contamination by applying or administering a compound which inhibits the activity of bacterial PDF.

According to a further aspect of the invention therefore, there is provided a method for the identification of antibacterial compounds, comprising tests of compounds analysis to determine their ability to inhibit PDF in vi tro, select those compounds which show such capacity and try these to determine their ability to inhibit bacterial growth. The ability to inhibit bacterial growth can be carried out using classical inhibition studies of bacterial growth in plaque or in broth culture, such as those performed in the biological examples herein. A suitable inhibition analysis of PDF in vi tro may comprise mixing together PDF, a PDF substrate, preferably, labeled with a detectable marker, and a test compound, and determining, after an appropriate duration of time, whether the presence of the Test compound inhibits or does not inhibit the ability of PDF to deformulate the substrate.

In a preferred embodiment, the separated substrate is detected with a fluorogenic label such as fluorescamine.

By removing the formyl group from the N-terminal methionine of the PDF substrate, the free amino group reacts with fluorescain which generates a fluorescent product. An alternative analysis involves determining whether a protein expressed by bacteria that expresses endogenous PDF (or that is expressed recombinantly), when grown in the presence of the test compound, provides a suitable substrate for N-terminal sequencing or provides a smaller amount of substrate , that the expressed protein of the same bacteria grows in the absence of the test compound. Such a method can be based on those used in the biological Examples herein. The person skilled in the art will be able to develop, without inventive ability, alternative methods for the analysis of the test compound to determine its ability to inhibit bacterial PDF. The natural antibiotic actinonin (see, for example J.C.S Perkin I, 1975, 819) is a hydroxamic acid derivative of structure (A): In addition to actinonin, several structural analogs of actinonin have also been shown to have antibacterial activity (see, for example, 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 Transactiosn 1 (9): 857-860, 1975). Until now, the mechanism underlying the antibacterial activity of actinonin is not known. The present inventors have found that actinonin inhibits the activity of bacterial PDF. The methylstatin group of compounds share many structural similarities with actinonin. Both are peptide molecules with metal functional hydroxamic acid linking groups (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; Tamaki et al., J. Antibiotics 47 (12): 1481-1492). The matlistatinas and their close structural analogs are characterized by the presence in the molecule of a divalent piperazin-1,6-diyl group, i.e.

In view of its close structural similarity to actinonin, the observation that actinonin inhibits PDF implies that matlistatin compounds can also inhibit PDF. According to a further aspect of the present invention, there is provided the use of a compound which inhibits the activity of bacterial PDF, in the preparation of an antibacterial composition or agent, with the proviso that (i) the compound is not formula (XI) RCO-CH (W) -NH-CO-CH (Y) -CH 2 -CO-NH-OH (XI) where, (a) R is a cyclic amino group, W is hydrogen, methyl, isopropyl, isobutyl or benzyl, and Y is hydrogen, d-Cg alkyl, phenyl, benzyl, 4-chlorophenylmethyl, 4-nitrophenylmethyl or 4-aminophenylmethyl; or (b) R is 2-pyridylamino or 2-thiazolylamino, W is isopropyl and Y is n-pentyl; or (c) R is diethylamino, W is methyl or isopropyl, and Y is n-pentyl; or (ii) the compound is not one that contains a divalent piperazin-1,6-diyl group, ie, a group of formula (XII): In accordance with a further aspect of the invention, there is provided a method for treating an infection or bacterial contamination by administration to a patient suffering from such infection or contamination, or applying to the site of such infection or contamination an antibacterial effective amount of a compound the which inhibits the activity of the bacterial PDF enzyme, with the proviso that the compound is not one provided in the exclusions in the immediately preceding paragraph. These exclusions eliminate actinonin and its antibacterial active analogues as described 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 the matlistatin compounds described 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 embodiments of the invention. L-ter-leucine-N-methylamide and L-ter-leucine-N, N-dimethylamide and other amino acid derivatives are prepared according to the methods established in the literature. The following abbreviations have been used throughout: DMF N, N-dimethylformamide EDC N-ethyl-N1 - (3-dimethylaminopropyl) -carbodiimide hydrochloride HOAt l-hydroxy-7-azabenzotriazole HOBt 1-hydroxybenzotriazole CLAP Liquid chromatography high resolution LREM Low resolution mass spectrometry CCD Thin layer chromatography The * H and 13 C NMR spectra were recorded using a Bruker AC 250E spectrometer at 250.1 and 62.9 MHz, respectively. Mass spectra are obtained using a Perkin Elmer Sciex API 165 spectrometer using both positive and negative ion modes. The infrared spectra are recorded on a Perkin Elmer PE 1600 FTIR spectrometer.

Example 1 (2, 2-dimethyl-lS-methyl-carbamoyl-propyl) -amide of 2R (or S) - [(formyl-hydroxy-amino) -methyl] -hexanoic acid The title compound is prepared according to the route indicated in Scheme 1 and as described in detail in the following: Scheme 1 Reagents and conditions: A, piperidine, HCHO, EtOH, 80 ° C, or /; B. H2N0Bzl, 80 ° C or / n, -C, HCOOH, Ac20; d. Pentafluorophenol, EDC, CH2C12; E. H-ter-LeuNHMe, DMF, 35 ° C; F. H2, 10% Pd / C, EtOAc / EtOH.

STAGE A: 2-butylacrylic acid Butylmalonic acid (25 g, 156 mmol) is dissolved in 250 ml of ethanol and a solution of 37% formaldehyde (15.45 ml, 156 mmol) is added followed by piperidine (47 ml, 624 mmol). The mixture is stirred overnight at 80 ° C under a reflux condenser. The solvents are removed under reduced pressure and the residue is diluted with 1 M hydrochloric acid and extracted with dichloromethane (3 x 30 ml). The combined organic extracts are washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give the desired product as a yellow oil (25 g, with residual solvent). -RN: d (CDC13), 10.04 (1H, broad 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) and 0.91 (3H, t, J = 7.2 Hz).

STAGE B: 2RS- (benzyloxyamomethyl) -hexanoic acid A mixture of 2-butylacrylic acid (3.43 g, 27. 1 mmole) and O-benzylhydroxylamine (5 g, 40.65 mmole) is heated at 80 ° C overnight. The mixture is cooled to room temperature, diluted with 40 ml of ethyl acetate and washed with 1M hydrochloric acid (3 x 20 ml), saturated sodium hydrogen carbonate solution (2 x 20 ml) and brine. (2 x 20 ml), dried over anhydrous magnesium sulfate, filtered and evaporated to leave the title compound as a white solid (2.62 g, 39%). "H-NMR: d (CDC13), 8.05 (1H s broad), 7.35 (5H, m), 5.00 (2H, m), 3.28 (2H, m), 2.98 1H, m), 1.31 (6H, m) and 0.88 (3H, t, J = 5.0 Hz).

STAGE C: 2RS- [(benzyloxy-dimylamino) -methyl] -hexanoic acid 2RS (benzyloxymethyl) -hexanoic acid (2.62 g, 10.51 mols) 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 is diluted with 40 ml of ethyl acetate, washed with water (40 ml), 20 ml of a saturated sodium hydrogen carbonate solution and 20 ml of brine, dried over anhydrous magnesium sulfate, filtered and evaporated. to leave the desired product as a yellow oil (2.9 g, 99%). -RMN: d (CDC13, rotamers), 8.21 (0.5H, S), 8.14 (0.5H, s), 7.37 (5H, m), 4.98 (2H, m), 3.86 (1H, m), 3. 27 (0.5H, dd, J = 6.0, 14.0 Hz), 2.93 (0.5H, m), 2.77 (1H, m), 1.50 (2H, m), 1.30 (4H, m) and 0.88 (3H, m) .

STAGE D: e s t e r p t t f f o f f e r i f e n t i i c t o r t 2 R S - [(benzyloxyformylamino) -methyl] -hexanoic 2RS- [(Benzyloxy-dimylamino) -methyl] hexanoic acid (30.72 g, 110 mmol) and pentafluorophenol (26.31 g, 143 mmol) are dissolved in 150 ml of dichloromethane, and the solution is stirred and cooled in an ice bath during the EDC addition (25.3 g, 131 mmol). The reaction mixture is allowed to warm to room temperature and is stirred overnight. The solution is washed successively with 1 M hydrochloric acid (2 x 50 ml), 0.5 M sodium carbonate (2 x 50 ml) and 50 ml of brine, dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated under reduced pressure and the residue is purified by flash chromatography (silica gel, dichloromethane) to give the title compound as a colorless oil (15.0 g, 31%). -RN: d (CDC13 rotamers), 8.17 (1H, broad s), 7.37 (5H, m), 4.95 -4.70 (2H broad), 4.10 - 3.75 (2 H, broad m), 3.10 (1H, broad s) ), 1.88 - 1.55 (2H, m), 3.39 (4H, m) and 0.92 (3H, t, J = 7.0 Hz).

STAGE E: 2R (or S) - [(benzyloxyformylamino) -methyl] -hexanoic acid (2, 2-dimethyl-1-methylcarbamoylpropyl) -amide The pentafluorophenyl acid ester dissolves 2RS- [(benzyloxy-dimylamino) -methyl] -hexanoic acid (5 g, 11 mmol) and ter-leucine N-methylamide (1.62 g, 11 mmol) in 60 mL of DMF, and the mixture is stirred overnight at 35 ° C. . The solvent is stir under reduced pressure and the residue is redissolved 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. The two diastereoisomeric products are separated by flash chromatography (silica gel, gradient elution with 30% to 0% hexane in ethyl acetate). Diastereomer A (upper Rf):? -RMN: d (CDC13, rotamers), 8.12, 7.87 (1H, s 2amplio), 7.27 (5H, m), 6.26 (1H, d, J = 8.7 Hz), 5.78 (1H , s broad), 4.91 - 4.60 (2H, broad m), 4.15 (1H, d, J = 9.2 Hz), 3.75 (2H, broad m), 2.79 (3H, d, J = 4.8 Hz), 2.56 (1H , m), 1.60 - 1.35 (2H, broad m), 1.24 (4H, m), 0.96 (9H, s) and 0.86 (3H, t, J = 6.7 Hz), Diastereomer B (lower R £): 1H- NMR: d (CDC13, rotamers), 8.16, 7.88 (1H, s 2amplio), 7.27 (5H, m), 6.28 (1H, d, J = 8.9 Hz), 5.70 - 5.44 (1H, broad s), 4.98 - 4.61 (2H, broad m), 4.14 (1H, d, J = 9.2 Hz), 3.78 - 3.62 (2H, broad m), 2.85 - 2.60 (3H, broad), 2.47 (1H, m), 1.72 - 1.25 ( 6H, broad m), 0.98 (9H, s) and 0.88 (3H, t, J = 6.7 Hz).

STAGE F: 2R (or S) -t (formylhydroxyamino) -methyl] -hexanoic acid (2, 2-dimethyl-lS-methylcaramoylpropyl) -amide.

Dissolves (2- (benzyloxyformylamino) -methyl] -hexanoic acid (2, -dimethyl-l-methylcarbamoylpropyl) -amide (diastereomer A) (1.0 g, 2.5 mmol) in a mixture of 20 ml of ethyl acetate and 1 ml of ethanol, and the solution is placed under an argon atmosphere. Palladium 10% is added to carbon and a stream of fine vapor and hydrogen gas is bubbled through the suspension. After 40 minutes, the CCD analysis shows that all the initial material has been consumed leaving more polar, positive ferric chloride species. The system is purged with argon before removing the catalyst by filtration. The filtrate is evaporated to dryness to leave the title compound as a whitish foam (810 mg, which includes a residual solvent). lH-R N: d ((CD3) 2SO, rotamers), 9.81, 9.41 (1H, s 2amplio), 7.82-7.60 (3H, m), 4.04 (1H, d, J = 9.3 Hz), 3.50 - 3.02 ( 2H, m), 3.87 - 2.60 (1H, m), 2.41 (3H, d, J = 4.5 Hz), 1.39 - 0.93 6H, m), 0.75 (9H, s) and 0.67 (3H, t, J = 5.7 Hz). "C-NMR: d ((CD3) 2SO), 172.5, 170.2, 157.5, 59.9, 42.8, 33.3, 29.0, 28.4, 28.2, 26.4, 24.8, 21.7 and 13.3 IR (KBr disk), vms; t 3309, 2959, 2873, 1646 and 1540 cm "1. [2- (Benzyloxyfumylamino) -methyl] -hexanoic acid (2, 2-dimethyl-l-methylcarbamoyl-propyl) -amide (diastereomer B) (1.0 g, 2.5 mmol) is similarly deprotected to provide the diastereomer B of the compound of the title (740 mg, 97%). -RMN: d ((CD3) 2S0, rotamers), 9.75, 9.30 (1H, s 2 broad), 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 (6H, m), 0.72 (9H, s) and 0.67 (3H, t, J = 6.7 Hz). "C-NMR: d ((CD3) 2SO), rotamers), 172.6, 170.4, 161.7, 157.0, 59.8, 34.0, 29.4, 28.6, 26.7, 25.2, 22.1 and 14.1 IR (KBr disk), vm" 3312, 2959, 1640, 1541, 1369 and 1240 crn "1.

Example 2 (2, 2-dimethyl-lS-tert-butylcarbamoylpropyl) -amide of 2R (or S) - [(formylhydroxyamino) -methyl] -hexanoic acid The title compounds are prepared by analogy with Example 1, using L-ter-leucine-N-tert-butylamide in place of L-ter-leucine-N-methylamide in Step E. Diastereoisomers are not separable by flash chromatography (silica gel, ethyl acetate) in Step E and converted to a mixture of the desired N-formylhydroxylamine derivatives by hydrogenolysis. White solid. "C-NMR: d ((CD3) 2SO), rotamers), 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, 20.3 and 13.9. IR (KBr disk), vax 3311, 2964, 1639, 1548, 1456, 1394, 1364 and 1226 Cir.1.

Example 3 2R (or S) - [(formylhydroxyamino) -methyl] -hexanoic acid (lS-methyl-2-morpholin-4-yl-2-oxoethyl) -amide A solution of the pentafluorophenyl ester of 2RS- [(benzyloxyformylamino) -methyl] -hexanoic acid (Example 1, Step D) (445 mg, 1 mmol) in 5 ml of DMF is added to L-alanine-N-morpholinoamide (158 mg, 1 mmol) in a boiling tube and stirred at 35 ° C overnight. The DMF is removed in vacuo and the residue redissolved in 2 ml of dichloromethane and it is passed through a purification cartridge (Isolute-NH2), eluting with 4 ml of dichloromethane in order to remove the pentafluorophenol. The dichloromethane is removed under reduced pressure and the residue redissolved in 2 ml of formic acid and 2 ml of ethyl acetate. The solution is then treated with 200 mg of 10% palladium in carbon and stirred at room temperature for 2 hours. The catalyst is removed by filtration through Celite, washed with methanol and the solvents are removed in vacuo. The compounds are purified by reverse phase CLAP (gradient elution, acetonitrile 10-90% / water). Diastereomer A: "H-NMR: d (CD3OD), 8.03 (0.5H, s), 7.84 (0.5H, 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,), 1.34 (7H, m), and 0.92 (3H, m). LRMS: -ve ion 328 [M-H]. Diastereomer B: 'H-NMR: d (CD3OD), 3.66 (8H, m), 3.41 (1H, dd, J = 9.98, 13.1Hz), 3.23 (1H, m), 2.90 (0.5H, m), 2.71 (0.5H, m), 1.62 (2H, m), 1.33 (7H, m) and 0.92 (3H, t, J = 6.7 Hz), LRMS: -ve ion 328 [MH]. The compounds of Examples 4 to 12 are prepared by analogy with Example 3 using the appropriate amine component in place of L-alanine-N-morpholinoamide. When both diastereoisomers are prepared, the diastereomer A is the one that elutes faster and the more potent against PDF in vi tro. In some cases, only the diastereomer that runs faster towards the final product is taken.

Example 4 (2S -dimethylcarbamoylethyl) -amide of 2R (or S) [(formylhydroxyamino) -methyl] -hexanoic acid Diastereomer A: -RMN: d (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 (0.5H, m), 2.74 (0.5H, m), 1.57 (2H, m), 1.33 (7H, m) and 0.92 (3H, m). LREM: + ve ion 288 [M + H], -ve ion 286 [M-H]. Diastereomer B: "H-NMR: d (CD3OD), 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 (0.5H, m), 2.72 (0.5H, m), 1.53 (2H, m), 1.33 (7H, m) and 0.93 (3H, t, J = 6.7 Hz). LREM: + ve ion 310 [M + Na], -ve ion 286 [MH].

Example 5 2R (or S) [(formylhydroxyamino) -methyl] -hexanoic acid (lS-hydroxymethyl-3-methyl-butyl) -amide.

Diastereoisomer A: -RMN: d (CD3OD), 4.07 (1H, m), 3.55 (1H, m), 3.45 (2H, m), 3.20 (1H, m), 2.85 (0.5H, m), 2.80 (0.5 H, m), 1. 60 (3H, m), 1.35 (6H, m) and 0.93 (9H, m). LREM: + ve ion 289 [M + H], -ve ion 287 [M-H]. Diastereomer B: 'H-NMR: d (CD30D), 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 (6H, m) and 0.93 (9H, m). LREM: + ve ion 311 [M + Na], 289 [M + H], -ve ion 287 [M-H].

Example 6 2R (or S) - [(f ormylhydroxyamino) -methyl] -hexanoic acid (lS-hydroxymethyl-2-p-ethylhexyl) -amide Diastereoisomer A: -RMN: d (CD30D), 7.24 (5H, m), 4.15 (1H, m), 3.54 (2H, d, J = 5.4Hz), 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), and 0.91 (3H, t, J = 6.7 Hz). LREM: + ve ion 345 [M + Na], 323 [M + H], -ve ion 321 [M-H]. Diastereoisomer B: LREM: + ve ion 345 [M + Na], 323 [M + H], -ve ion 321 [M-H].

Example 7 [2, 2-dimethyl-lS-? Iridin-2-yl-carbamoyl) -propyl] -amide of 2R (or S) - [(formylhydroxy-amino) -methyl] -hexanoic acid Diastereoisomer A: colorless oil 'H-NMR: d (CD3OD), 8.34 (1H, m), 8.06 (1H, m), 7.90 (1H, m), 7.33 (1H, m), 4.45 (1H, s), 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 (9H, s) and 0.85 (3H, m). LREM: + ve ion 379 [M + H], -ve ion 377 [M-H]. Diastereoisomer B: colorless oil. ^ -RMN: d (CD30D), 8.33 (1H, m), 8.20 (0.5H, m), 7.93 (1H, m), 7.41 (0.5H, 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 (0.5H, m), 2.87 (0.5H, m), 1. 62 (2H, m), 1.36 (4H, m), 1.11 (9H, s) and 0.93 (3H, m). LREM: + ve ion 393 [M + Na], 379 [M + H], -ve ion 377 [M-H].

Example 8 2R (or S) - [(formylhydroxyamino) -methyl] -hexanoic acid (lS-dimethylcarbamoyl-2-methylpropyl) -amide.

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

Example 9 2R (or S) - [(formylhydroxyamino) -methyl] -hexanoic acid (lS-dimethylcarbamoyl-2-phenylethyl) -amide Diastereoisomer A: colorless oil. LRMS: + ve ion 386 [M + Na] -ve ion 362 [M-H]. Diastereoisomer B: colorless oil. LRMS: + ve ion 386 [M + Na] -ve ion 362 [M-H].

Example 10 2R (or S) [(formylhydroxyamino) -methyl] -hexanoic acid (lS-dimethylcarbamoyl-3-methylbutyl) -amide Diastereoisomer A: colorless oil. LRMS: + ve ion 352 [M + Na] -ve ion 328 [M-H].

Example 11 2R (or S) - [(formylhydroxyamino) -methyl] -hexanoic acid [3-methyl-lS-pyrrolidin-1-carbonyl) -butyl] -amide Diastereomer A: colorless oil. LRMS: -ve ion 354 [M-H].

Example 12 Dimethylamide of acid 1-. { 2R (or S) - [(formylhydroxyamino) methyl] -hexanoyl} -pyrrolidin-2S-carboxylic acid Diastereoisomer A: colorless oil. LRMS: + ve ion 336 [M + Na], -ve ion 312 [M-H]. Diastereoisomer B: colorless oil. LRMS: + ve ion 336 [M + Na], -ve ion 312 [M-H].

Example 13 (2S (or S) - [(formylhydroxyamino) -methyl] -hexanoic acid (lS-dimethylcarbamoyl-2, 2-dimethylpropyl) -amide.

Method I A synthesis route for the title compound is indicated in Scheme 2 and is described in detail below.

Scheme 2 Stage C [~ Stage E A. HCOOt, NaOEt; B. HCl.NHOBzl, NaOAc, aqueous EtOH; C. NaOH, MeOH; D. H-TleNMe2, EDC, HOAt, DMF; E. NaCNBH3, AcOH and then separating diastereoisomers, - F. HCOBt, THF; G. H2, Pd / C, MeOH.

Stage A: 2RS-formyl-heptanoic acid ethyl ester Metallic sodium (4.38 g, 0.191 mmol) is cut into small pieces and placed in a two-necked round bottom flask, oven dried, under an argon atmosphere. 100 ml of anhydrous diethyl ether are added and the suspension is stirred and cooled to 0 ° C. The flask is placed with a reflux condenser before the dropwise addition of ethanol (1.03 ml, 17.3 mmol). A mixture of ethyl formate (15.41 g, 0.208 mmol) and ethyl caproate (25 g, 0.173 mol) are then added dropwise by means of a dropping funnel over a period of about 20 minutes. The resulting orange suspension (the metallic sodium is still visible) is allowed to warm to room temperature and stir overnight. The resulting orange thick suspension (no visible metallic sodium) is cooled to 0 ° C and diluted with 100 ml of ice-cold water. The mixture is transferred to a separatory funnel and the aqueous phase is removed, washed with diethyl ether, cooled to 0 ° C and acidified with 200 ml of 1 M hydrochloric acid. The emulsion is extracted with ethyl acetate and the The organic layer is separated, washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to provide a yellow oil containing mainly 11.09 g of the title which is used without further purification in stage B.

Stage B: 2RS- (benzyloxyimino-methyl) -heptanoic acid ethyl ester The crude Claisen product from the Step (11.0 g, 63.9 mmol) is dissolved in 100 ml of ethanol and 10 ml of water, and cooled to 0 ° C during the addition of sodium acetate (6.2 g, 76.6 mmol) and O-benzylhydroxylamine hydrochloride (12.23 g, 76.6 mmol). The mixture is allowed to warm to room temperature and stir overnight. The resulting suspension is filtered and the filtrate is concentrated under reduced pressure. The residual yellow paste is divided between ethyl acetate and water. The organic layer is washed with 1 M hydrochloric acid and brine, dried over anhydrous magnesium sulfate, filtered and evaporated to a yellow oil. The desired product is obtained by flash chromatography (silica gel, gradient elution with 10% to 25% ethyl acetate in hexane) Yield 9.19 g (52%). 1 H-NMR: d (CDC13), mixture of syn- and anti-isomers), 7.46 (0.6H, d, J = 8.0 Hz), 7 38-7.28 (5H, m), 6.79 (0.4H, d, J = 7.1 Hz), 5.11 (0.8H, s), 5.08 (1.2H, s), 4.16 (1.2H, c, J = 7.0 Hz), 4.13 (0.6H, c, J = 7.0 Hz), 3.91 (0.4H, c, J = 7.2 Hz), 3.21 (0.6H , td, J = 8.0 and 6.1 Hz), 1.90-1.48 (2H, m), 1.37-1.20 (7H, m), 0.87 (3H, t, J = 7.0 Hz).

Stage C: 2RS- (benzyloxyimino-methyl) -heptanoic acid The ethyl ester of 2RS- (benzyloxyiminomethyl) -heptanoic acid (7.0 g, 25.24 mmoles) is dissolved in 125 ml of methanol and the solution is cooled to 0 ° C. 1 M sodium hydroxide (26 ml, 26 mmol) is added in portions over 2 minutes to provide a light yellow emulsion. Additional methanol is added until a clear solution is obtained. The solution is allowed to stir for 90 minutes at 0 ° C and then for 5 hours at room temperature, after which the CCD analysis suggests that all of the initial material has been consumed. The solvent is removed under reduced pressure and the residue is partitioned between water and ethyl acetate. The aqueous layer is cooled to 0 ° C and acidified with 1 M hydrochloric acid. The emulsion which is formed in this manner is extracted twice with ethyl acetate. The combined organic extracts are washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to provide the title compound as a yellow oil (5.15 g, 82%) which is used without further purification in step D. 1 H-NMR: d (CDC13, mixture of syn) - and anti, -isomers), 8.00 (1H, s, broad), 7.46 (0.6H, d, J = 7.9 Hz), 7.36-7.24 (5H, m), 6.80 (0.4H, d, J = 7.0 Hz), 5.13 (0.8 H, s), 5.09 (1.2H , s), 3.194 (0.4H, c, J = 7.1 Hz), 3.27 (0.6H, td, 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 3: 2RS- (benzyloxyimino-methyl) -heptanoic acid (2S-dimethylcarbamoyl-2, 2-dimethylpropyl) -amide 2- (Benzyloxyimino-methyl) heptanoic acid (5.16 g, 20.7 mmol), ter-leucine N, N-dimethylamide (3.60 g, 22.77 mmol) and EDC (4.7 g, 24.84 mmol) are stirred together in 75 ml of DMF and cooled to 0 ° C. HOAt (250 mg, cat.) Is added, and the bright yellow mixture is allowed to warm to room temperature and stir overnight. The solvent is removed under reduced pressure and the residual oil is partitioned between ethyl acetate and 1 M hydrochloric acid. The organic layer is washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The title compound is obtained as a colorless oil by flash chromatography (silica gel, gradient elution with 33% to 66% ethyl acetate in hexane). Yield, 6.84 g (85%). 'H-NMR: d (CDC13, mixture of syn) - and anti, -isomers), 7.45 (0.6H, 2d), 7.40-7.26 (5H, m), 6.72 (0.4H, 2d), 6.58 (1H, m), 5.20-4.69 (3H, m), 3.82 (0.4H, m), 3.16-3.10 (3H, m), 3.05 (0.6H, m), 2.99-2.92 (3H, m), 1.90- 1. 54 (2H, m), 1.39-1.17 (4H, m), 0.97 (2.7H, s), 0.96 (1.8H, s), 0.94 (2.7H, s), 0.92 (1.8H, s) and 0.92- 0.82 (3H, m).

Step E: 2R (or S) - (benzyloxyamino-methyl) -heptanoic acid (lS-dimethylcarbamoyl-2, 2-dimethylpropyl) amide To a solution of 2 RS- (benzyloxyimino-methyl) -heptanoic acid (2S-dimethyl-carbamoyl-2, 2-dimethylpropyl) amide in 40 ml of acetic acid is added sodium cyanoborohydride (2.02 g, 32.0 mmol) in one portion. . During the course of one hour, the reagent dissolves slowly with moderate effervescence to provide a colorless solution which is allowed to stir overnight. The solvent is removed by evaporation under reduced pressure and separated by azeotroping with toluene. The remaining oil is divided between diethyl ether and 1 M sodium carbonate (CAUTION, some gas is produced). The organic layer is washed with 70 ml of brine, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The two diastereoisomers of the title compound are purified and separated by flash chromatography (silica gel, gradient elution with 50% to 100% ethyl acetate in hexane). Diastereomer A (faster elution): colorless oil (2.27 g, 45%). __- NMR: d (CDC13), 7.43-7.28 (5H, m), 6.76 (1H, broad d, J = 9.4 Hz), 5.69 (1H, broad s), 4.93 (1H, 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 (9H, s) and 0.86 (3H, t, J = 6.8 Hz). Diastereomer B (slower elution): colorless oil (1.44 g, 46%). -RMN: d (CDC13), 7.40-7.27 (5H, m), 6.70 (1H, broad d, J = 9.0 Hz), 5.99 (1H, broad 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 (6H, m) , 1.00 (9H, s) and 0.88 (3H, broad t, J = 6.7 Hz).

Step F: 2R (or S) - [(benzyloxyformylamino) -methyl] -heptanoic acid (lS-dimethylcarbamoyl-2, 2-dimethyl-propyl) amide The 1 S-d ime tyl 1 -amino and 2- (2-dimethylpropyl) amide of 2- (benzyloxyamino-methyl) -heptanoic acid (diastereomer A) (2.02 g, 5.13 mmoles) is dissolved in 50 ml of anhydrous THF and placed under an argon atmosphere. N-formyl-benzotriazole (A.R. Katritzky et al., Synthesis 1995, 503) (0.83 g, 5.65 mmol) is added and the mixture is allowed to stir at room temperature for 4 hours. The solvent is evaporated under reduced pressure and the residual oil is partitioned between dichloromethane and 1 M sodium hydroxide. The organic layer is washed with more sodium hydroxide and brine, dried over anhydrous magnesium sulfate, filtered and concentrated dryness under reduced pressure. The title compound is obtained as a white crystalline solid by flash chromatography (silica gel, elution with 33% ethyl acetate in hexane). Yield 1.60 g (74%). __- NMR: d (CDC13 rotamers), 8.00 (1H, broad m), 7.47-7.29 (5H, m), 6.25 (1H, broad d, J = 9.3 Hz), 5.08-4.74 (2H, broad m), 4.87 (1H, d, J = 9.4 Hz), 3.89-3.52 (2H, broad m), 3.13 (3H, s), 2.94 (3H, s), 2.54 (1H, m), 1.67-1.11 (6H, m ), 0.95 (9H, s) and 0.85 (3H, broad t, J = 6.9 Hz). The 2- (benzyloxyamomethyl) -heptanoic acid (lS-dimethylcarbamoyl-2, 2-dimethylpropyl) amide (diastereomer B) is prepared in a similar manner from the diastereomer which elutes more slowly in step E. Yield, 0.38 g (41 %). "H-NMR: d (CDC13, rotamers), 8.00 (1H, broad m), 7.47-7.28 (5H, broad m), 6.29 (1H, broad d, J = 9.3 Hz), 5.01-4.63 (2H, m broad), 4.88 (1H, d, J = 9.3 Hz), 3.82-3.51 (1.5H, broad m), 3.20-2.78 (6.5H, broad m), 2.50 (1H, broad m), 1.76-1.17 (6H , broad m), 0.97 (9H, s) and 0.85 (3H, broad t, J = 6.7 Hz).

Step G: 2R (or S) - [(formylhydroxyamino) -methyl] -hexanoic acid (lS-dimethylcarbamoyl-2, 2-dimethylpropyl) -amide. 2- [(benzyloxyformylamino) -methyl] - (2-dimethylcarbamoyl-2, 2-dimethylpropyl) -amide is dissolved heptane (1.43 g, 3.41 mmol) in 50 ml of methanol and placed under an argon atmosphere. A suspension of 10% palladium on carbon (100 mg, cat.) In 2 ml of ethyl acetate is added and the mixture is stirred vigorously while bubbling hydrogen gas through the solution. After 10 minutes the mixture is placed under a hydrogen atmosphere and allowed to stir for 3 hours, after which the CCD analysis indicates that all of the initial material has been consumed. The system is purged with argon and the catalyst is removed by filtration. The filtrate is concentrated under reduced pressure to provide the title compound as a colorless hygroscopic foam (1.11 g, 99%). 'H-NMR: d (CDC13, rotamers), 8.41 (0.35H, s), 7.83 (0.65H, broad s), 6.80 (0.35H, broad d, J = 8.9 Hz), 6.62 (0.65H, broad d , J = 9.4 Hz), 4.91 (0.65H, broad d, J = 9.4 Hz), 4.88 (0.35H, broad d, J = 8.9 Hz), 4.04 (1H, dd, J = 14.7 and 7.4 Hz), 3.82 (0.65, dd, J = 14.0 and 9.7 Hz), 3.56 (0.35H, dd, J = 14.7 and 3.3 Hz), 3.48 (0.65H, dd, J = 14.0 and 4.0 Hz), 3.16 (1.05H, s) , 3.15 (1.95H, S), 2.98 (1.05H, S), 2.96 (1.95H, s), 2.90-2.74 (0.65H, broad m), 2.74-2.61 (0.35H, broad m) 1.73-1.17 ( 6H, broad m), 0.99 (3.15H, s). 0.95 (5.85H, s) and 0.87 (3H, broad t, J = 6.7 Hz). "C-NMR: d (CDC13), 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. C, 26.3, 20.8, 20.2, 14.0 and 13.7 LREM: -ve ion 328 [MH]. (2- S (dimethylcarbamoyl-2, 2-dimethylpropyl) -amide of 2- [(formylhydroxyamino) -methyl] -hexanoic acid (diastereomer B) is prepared in a similar manner from diastereomer B in Step E-RMN: d (CDC13 , rotamers), 9.37 (0.5H, s), 8.40 (0.5H, s), 7.75 (0.5H, broad s), 6.62 (0.5H, broad s), 6.41 (0.5H, broad d, J = 7.1 Hz ), 4.87 (0.5H, broad d, J = 6.6 Hz), 4.66 (0.5H, broad d, J = 7.6 Hz), 3.84-3.39 (2H, m), 3.21 (1.5H, broad s), 3.14 ( 1.5H, broad s), 2.98 (3H, broad s), 2.91-2.54 (1H, m), 1.79-1.23 (6H, m), and 1.08-0.83 (12H, m). "C-NMR: d (CDC13, rotamers), 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, 26.6, 26.5, 22.6, 22.5 and 13.9 LREM: + ve ion 352 [M + Na], -ve ion 328 [MH].

Method II An alternative asymmetric synthesis route for the compound of Example 13 is set forth in Scheme 3 and is described in detail in the following.

Scheme 3 Reagents and conditions: A. piperidine, HCHO, EtOH, 80C, o / n; B. tBuCOCl, Et3N subsequently 3-lithium-4-benzyl-5,5-dimethyl-oxazolidin -one, -C. HNOBzl, room temperature, o / n and then pTsOH, EtOAc; D. LiOH, aqueous THF, 0 ° C; E. H-TleNM2, HOBt, EDC, DMF, - F. HCOBt, THF; G. H2, Pd / C, EtOH.

Stage A: 2-butylacrylic acid To a solution of n-butylmalonic acid (17.2 g, 107 mmol) in 200 ml of ethanol is added piperidine (12.76 ml, 129 mmol) and 37% aqueous formaldehyde (40.3 ml, 538 mmol). The solution is heated to 80 ° C, during which time a precipitate appears and then it is gradually dissolved again for 1 hour. The reaction mixture is stirred at 80 ° C overnight and then cooled to room temperature. The solvents are removed under reduced pressure and the residue is dissolved in 200 ml of ethyl acetate, washed successively with 1 N hydrochloric acid and brine, dried over magnesium sulfate and filtered. The filtrate is concentrated to provide the title compound as a clear oil (13.37 g, 97%). ^ -RMN: d (CDC13), 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).

Step B: 4S-benzyl-3- (2-butyl-acryloyl) -5,5-dimethyl-oxazolidin-2 -one Dissolve 2-butylacrylic acid (21.5 g, 168 mmoles) in 500 ml of dry THF and cooled to -78 ° C under an argon atmosphere. Triethylamine (30 ml, 218 immoles) is added and pivaloyl chloride (21 ml, 168 mmol) at a rate such that the temperature remains below -60 ° C. The mixture is stirred at -78 ° C for 30 minutes, heated at room temperature for 2 hours and finally cooled again to -78 ° C. In a separate flask, 4S-benzyl-5,5-dimethyl-oxazolidin-2-one is dissolved in 500 ml of dry THF and cooled to -78 ° C under an argon atmosphere. N-Butyllithium (2.4 M solution in hexanes, 83 ml, 200 mmol) is added slowly and the mixture is stirred for 30 minutes at room temperature. The resulting anion is transferred via a cannula into the original reaction vessel. The mixture is allowed to warm to room temperature and is stirred overnight at room temperature. The reaction is suspended with 200 ml of 1 M potassium hydrogen carbonate and the solvents are removed under reduced pressure. The residue is partitioned between ethyl acetate and water. The organic layer is washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to provide an orange oil. The CCD analysis shows the presence of a chiral auxiliary that has not reacted in addition to the required product. A 30 g portion of the material is dissolved in dichloromethane and washed through a pad of silica to provide 25.3 g of the pure title compound as a yellow oil. * H-NMR: d (CDC13), 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). Some chiral auxiliary is recovered by washing the silica pad with methanol.

Step C: (salt of p-toluenesulfonic acid) of 4S-benzyl-3- [2- (benzyloxyamino-methyl) -hexanoyl] -5,5-dimethyl-oxazolidin-2-one 4S-Benzyl-3- (2-butylacryloyl) -5,5-dimethyl-oxazolidin-2-one (19.8 g, 62.8 mmol) is mixed with 0-benzylhydroxylamine (15.4 g, 126 mmol) and stirred overnight. room temperature. The mixture is dissolved in ethyl acetate and the solution is 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 25.3 g of a light yellow oil which is shown by NMR and analysis by CLAP containing 4S-benzyl-3- [2- (benzyloxyamino-methyl) -hexanoyl] -5,5-dimethyl. -oxazolidin-2-one (ca 82%) together with traces of the initial material. The product is combined with another batch (26.9 g, 76% d.e.) and dissolved in 200 ml of ethyl acetate. P-Toluenesulfonic acid (22.7 g, 119 mmol) is added and the mixture is cooled to 0 ° C. The title compound is obtained as a white crystalline solid by seeding and scraping. Performance: . 2 g, (34%, single diastereomer). A second crop is also obtained (14.7 g, 20% diastereomer alone). * H-NMR: d (CDC13), 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-benzyloxyamino-methyl) -hexanoic acid The salt of 4S-benzyl-3- [2R- (benzyloxyamino-methyl) -hexanoyl] -5,5-dimethyl-olidin-2-one (25.2 g, 40.2 mmol) is divided between ethyl acetate and sodium carbonate 1 M. The organic phase is dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residual oil is dissolved in 150 ml of THF and 50 ml of water, and cooled to 0 ° C and treated with lithium hydroxide (1.86 g, 44.2 mmol). The solution is stirred for 30 minutes at 0 ° C, and then overnight at room temperature. The reaction is acidified to pH 4 with 1 M citric acid and the solvents are removed. The residue is partitioned between dichloromethane and 1 M sodium carbonate. The basic aqueous layer is acidified to pH 4 with 1 M citric acid and extracted three times with ethyl acetate. The combined organic layers are dried over anhydrous magnesium sulfate, filtered and concentrated provide the title compound as a colorless oil (7.4 g, 73%). 'H-NMR: d (CDC13), 8.42 (2H, broad s), 7.34-7.25 (5H, m), 4.76-4.66 (2H, m), 3.20-3.01 (2H, m), 2.73 (1H, m ), 1.70-1.44 (2H, m), 1.34-1.22 (4H, m) and 0.92-0.86 (3H, m).

Step E.- (2S- (benzyloxyamino-methyl) -hexanoic acid (lS-dimethylcarbamoyl-2, 2-dimethyl-l-propyl) -amide) The 2R-benzyloxyamino-methyl) -hexanoic acid (7.98 g, 3.18 mmol) is dissolved in 150 ml of DMF and the solution is cooled to 0 ° C. EDC (6.1 g, 31.8 mmol) and HOBt (430 mg, 3.2 mmol) are added and the mixture is stirred for 15 minutes. Ter-Leucine-N, N-dimethylamide (5.53 g, 34 mmol) is added and the reaction is allowed to warm to room temperature and stir overnight. The solvent is removed under reduced pressure and the residue is dissolved in ethyl acetate, washed successively with 1 M hydrochloric acid, saturated sodium hydrogen carbonate and brine, dried and filtered. The solvent is removed to leave the title compound as a yellow oil (8.7 g, 69%) which is used in Step F without further purification. "? -RMN: d (CDC13), 7.35-7.28 (5H, m), 6.77 (1H, broad d, J = 9.2 Hz), 5.69 (1H, broad 8), 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 (6H, m), 0.99 ( 9H, s) and 0.86 (3H, t, J = 6.8 Hz).

Step F: 2R- [(benzyloxyformylamino) -methyl] -hexanoic acid (lS-dimethylcarbamoyl-2,2-dimethyl-l-propyl) amide Dissolve 2R- (benzyloxyamino-methyl) -hexanoic acid (2S-dimethylcarbamoyl-2, 2-dimethyl-1-propyl) -amide (7.8 g, 19.9 mmol) in 100 ml of dry THF and treat with 1-formyl. -benzotriazole (3.08 g, 21.0 mmol). The reaction is stirred overnight at room temperature. The solvent is removed under reduced pressure and the residue is dissolved in ethyl acetate, washed with a 2M sodium hydroxide solution and brine. The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The product crystallizes from ether-hexane (4.83 g, 57% in two crops). -RMN: d (CDC13, rotamers), 8.12 (0.6H, broad s), 7.89 (0.4H, broad s), 7.37 (5H, s), 6.25 (1H, d, J = 9.3 Hz), 4.96 (0.6 H, s broad), 4.86 (1H, d, J = 9.4 Hz), 4.80 (0.4 H, broad s), 3.74 (2H, s broad), 3.13 (3H, S), 2.94 (3H, s), 2.53 (1H, m), 1387-1.21 (6H, m), 0.95 (9H, s) and 0.85 (3H, t, J = 6.9 Hz). Note: A small sample is crystallized from ether-hexane to provide crystals suitable for X-ray crystallography. The stereochemistry is demonstrated as set forth herein.

Step G: 2R- [(formylhydroxyamino) -methyl] -hexanoic acid (lS-dimethylcarbamoyl-2, 2-dimethyl-l-propyl) amide Dissolve 2R- [(benzyloxymorphinylamino) -methyl] -hexanoic acid (2S-dimethylcarbamoyl-2, 2-dimethyl-1-propy-U-amide (4.72 g, 11.3 mmol) in 80 mL of ethanol and place under an argon atmosphere A suspension of 940 mg of 10% palladium on carbon in 2 ml of ethyl acetate is added and the mixture is vigorously agitated as hydrogen gas is bubbled through the system., the suspension is placed under a hydrogen balloon and stirred overnight at room temperature. The flask is purged with argon before removing the filtration catalyst. The filtrate is concentrated under reduced pressure to provide the title compound as a colorless foam which crystallizes upon standing (3.65 g, 98%). 1 H-NMR: d (CDC 13, rotamers), 9.32 (0.4 H, broad s), 8.41 (0.4 H, s), 7.88 (0.6 H, broad s), 7.27 (0.6 H, s), 6.75 (0.4 H, d wide, J = 8.8 Hz), 6.58 (0.6H, broad d, J = 9.3 Hz), 4.89 (1H, m), 4.04 (0.4H, m), 3.82 (0.6H, m), 3.53 (1H, m), 3.16 (1.2H, s), 3.15 (1.8H, s), 2.98 (1.2H, s), 2.96 (1.8H, s), 2.79 (= .6, m), 2.65 (0.4H, m ), 1.78-1.58 (6H, m), 0.99 (3.6H, s), 0.95 (5.4H, s) and 0.87, 3H, t, J = 6.7Hz). 13 C-NMR: d (CDC13, rotamers), 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, 23.0 and 14.3. LREM: + ve ion 352 [M + Na], -ve ion 328 [M-H].

Compounds of Examples 14 to 27 are prepared by analogy with Example 13, method I, substituting the appropriate ester for ethyl caproate in step A. When both diastereoisomers are prepared, diastereomer A is the one that elutes faster and usually It is the most powerful against PDF in vi tro. In some cases only the diastereomer that runs faster (stage E) is taken to the final product.

Example 14 2R (or S) - [(formyl-hydroxy-amino) -methyl] -3-cyclopentyl-propionic acid (lS-dimethyl-carbamoyl-2, 2-dimethyl-propyl) -amide.

Diastereoisomer A - colorless glass. 'H-NMR; d (CDC13, rotamers), 9.33 (0.4H, broad s), 8.94 (0.6H, s broad), 8.40 (0.4H, s), 7.82 (0.6H, s), 6.82 (0.4H, d) broad, J = 8.6 Hz), 6.62 (0.6H, broad d, J = 9.3 Hz), 4'.90 (1H, m), 4.06 (0.4H, broad dd, J = 14.7, 7.3 Hz), 3.81 ( 0.6H, broad dd, J = 14.0, 9.7 Hz), 3.50 (1 H, m), 3.16 (1.2H, s), 3.14 (1.8H, s), 2.97 (1.2H, s), 2.95 (1.8H , s), 2. 80 (11H, m), 1.87-1.32 (9H, m), 1.16-0.95 (2H, m), 0.99 (3.6H, s), and 0.95 (5.4H, s). "C-NMR; d (CDC13, rotamers), 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. LREM: + ve ion 378 [M + Na], -ve ion 354 [M-H].

Diastereoisomer B. Colorless glass: 1 H-NMR; d (CDC13, rotamers), 9.30 (0.6H, broad s), 8.41 (0.6H, s), 7.75 (0.4H, s), 6.52 (0.4H, broad d, J = 8.7 Hz), 6.41 (0.6H , broad d, J = 7.3 Hz), 4.85 (0.4H, broad d, J = 9.5 Hz), 4.63 (0.6H, broad d, J = 7.5 Hz). 3.85-3.40 (2H, m), 3.25-2.95 (6H, 3 s broad), 2.78 (1H, 2 m wide), 1.90-1.40 (8H, m), 1.30 (1H, m), 1.20-1.00 (2H , m) and 1.05-0.95 (9H, 2s). 13C-NMR; d (CDClj, rotamers), 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. LREM: + ve ion 378 [M + Na], -ve ion 354 [M-H].

Example 15 (lS-dimethylcarbamoyl-2, 2-dimethyl-propyl) -amide of 2R (or S) - [(Formyl-hydroxy-amino) -methyl] -heptanoic acid Diastereoisomer A. Dark orange oil. jH-NMR; d (CDClj, rotamers), 8.32 (0.33H, s), 7.76 (0.67H, broad s), 6.78 (0.33H, broad d, J = 9.1 Hz), 6.68 (0.67H, broad d, J = 9.1 Hz ), 4.87-4.79 (1H, m), 3.96 (0.33H, broad dd, J = 14.6, 7.6 Hz), 3.14 (0.67H, broad 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, broad m), 0.92 (3H, s), 0.88 (6H, s) and 0.79 (3H, m). 13C-NMR; d (CDClj, rotamers), 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, 25.8, 25.5 , 21.4 and 12.9. LREM: + ve ion 344 [M + H], -ve ion 342 [M-H].

Diastereoisomer B. Dark orange oil. 'H-NMR; d (CDClj, rotamers), 8.36 (0.5H, s), 7.74 (0.5H, s), 6.69 (0.5H, broad s), 6.57 (0.5H, broad d, J = 7.6 Hz), 4.89 (0.5H, broad s), 4.70 (0.5H, d, J = 7.8 Hz), 3.76-3.40 (2H, m), 3.21 (1.5H, S), 3.16 (1.5H, s), 2.98 (3H, s), 2.81 (1H, broad s), 2.72-2.60 (1H, m), 1.67 (2H, broad s), 1.42-1.22 (6H, m), 1.02 (4.5H, s), 0.99 (4.5H, s), 0.90 (1.5H, s) and 0. 87 (1.5H, s). 13C-NMR; d (CDC13, rotamers), 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, 36.3, 35.6, 34.9, 32.1, 32.0, 30.1, 29.9, 27.4, 27.4, 27. 0, 26.9, 22.9 and 14.3. LREM: + ve ion 344 [M + H], -ve ion 342 [M-H].

Example 16 (lS-dimethylcarbamoyl-2, 2-dimethyl-propyl) -amide of 2R (or S) - [(Formyl-hydroxy-amino) -methyl] -pentanoic acid Diastereoisomer A. White hydroscopic foam.

-I-NMR; d (CDC13, rotamers), 8.40 (0.33H, s), 7.83 (0.67H, broad s), 6.88 (0.33H, broad d, J = 8.6 Hz), 6.69 (0.67H, broad d, J = 9.2 Hz ), 4.90 (1H, t), 4.06 (0.33H, broad dd, J = 14.5, 7.4 Hz), 3.82 (0.67H, broad 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, broad m), 0.98 (3H, s), 0.94 (6H, s) and 0.90 (3H, t, J = 7.3 Hz), "C-NMR; d (CDC13, rotamers), 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. LREM: tve ion 338 [M + Na], -ve ion 314 [M-H].

Example 17 (SS-dimethylcarbamoyl -2, 2-dimethyl-propyl) -amide of 2R (or S) - [Formyl-hydroxy-amino) -methyl] -4-methyl-pentanoic acid Diastereoisomer A. White hydroscopic solid. -RMN; d (CDC13, rotamers), 8.41 (0.4H, s), 7.83 (0.6H, s), 6. 65 (0.4H, d, J = 8.6 Hz), 6.55 (0.6H, d, J = 9.0 Hz), 4. 91-4.83 (1H, m), 4.03-3.95 (0.4H, m), 3.84-3.74 (0.6H, 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 (0.6H, m), 2.76-2.71 (0.4H, m), 1.69- 1.34 (1.8H, m), 1.29-1.20 (1.2H, m), 1.0 (3.6 H, s), 0.95 (5.4H, s) and 0.93-0.88 (6H, m). 13C-NMR; d (CDC13, rotamers), 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. LREM: + ve ion 352 [M + Na], -ve ion 328 [M-H].

Example 18 (lS-dimethyl-carbamoyl-2, 2-dimethyl-propyl) -amide of 3-Cyclohexyl-2R (or S) - [(formyl-hydroxy-amino) -methyl] -propionic acid White solid. __- RMN, d (CDC13, rotamers), 8.38 (0.25H, s), 7.82 (0.75H, s), 6.93 (0.25H, d, J = 8.9 Hz), 6. 74 (0.75H, d, J = 8.9 Hz), 4.90 (1H, d, J = 9.4 Hz), 4.02 (0.25H, dd, J = 9.7, 14.1 Hz), 3.78 (0.75H, 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 (6H, m), 1.20 (5H, m), 0.98 (9H, s) and 0.87 (2H, m). 13C-NMR; d (CDC13, rotamers), 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. LREM: + ve ion 370 [M + H], 368 [M-H].

Example 19 (2S-dimethyl-carbamoyl-2, 2-dimethyl-propyl) -amide of 2R (or S) -cyclopentyl-3- (formyl-hydroxy-amino) -propionic acid Diastereoisomer A. Whitish foam. ^ -RMN; d (CD30D, rotamers), 8.22 (0.33H, s), 7.79 (0.66H, s), 4.89 (1H, s), 3.87 (1H, m), 3.50 (1H, m), 3.19 (3H, s, ), 2.93 (3H, s), 2.82 (0.66H, m), 2.65 (0.33H, m), 1.89 (2H, m), 1.56 (5H, m), 1.24 (2H, m) and 0.98 (9H, s). 13C-NMR; d (CD30D, rotamers), 176.0, 56.7, 53.2, 51.1, 42.7, 39.2, 36.5, 36.4, 32.0, 27.4, 26.4 and 26.2. IR (reflection disk) vmax 3318, 2953, 1663, 1628, 1529, 1367, 1229, 1142, 1087, 877 cm'1. LREM: tve ion 364 [M + Na], -ve ion 340 [M-H].

Example 20 2R (or S) - [(Formyl-hydroxy-amino) -methyl] -octanoic acid (2S-dimethyl-carbamoyl-2, 2-dimethyl-propyl) -amide.

Diastereoisomer A. 'H-NMR; d (CDC13, rotamers), .40 (0.4H, s), 7.83 (0.6H, s), 6.88 (0.4H, d, J = 8.9 Hz), 6. 68 (0.6H, d, J = 9.2 Hz), 4.90 (1H, m), 4.05 (0.4H, m), 3.81 (0.6H, m), 3.50 (1H, m), 3.16 (1.2H, s) , 3.15 (1.8H, s), 2.97 (1.2H, s), 2.96 (1.8H, s), 2.86 (0.6H, m), 2.69 (0.4H, m), 1.59-1.25 (10H, m), 1.14-0.95 (9H, m) and 0.89-0.77 (3H, m). "C-NMR; d (CDC13, rotamers), 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, 22.4 and 14.0 LREM: + ve ion 380 [M + Na], 358 [M + H], -ve ion 356 [MH].

Example 21 2R (or S) - [(Formyl-hydroxy-amino) -methyl] -nonanoic acid (2S-dimethyl-carbamoyl-2, 2-dimethyl-propyl) -amide.

Diastereoisomer A: Brown solid. "H-NMR; d (CDC13, rotamers), 9.30 (0.4H, s), 8.41 (0.6H, s), 7.83 (0.4H, s), 6.66 (0.4H, d, J = 8.g Hz) , 6.52 (0.6H, d, J = 9.7 Hz), 4.92-4.84 (1H, m), 4.06-3.97 (0.4H, m), 3.87-3.77 (0.6H, m), 3.63-3.45 (1H, m ), 3.16 (1.2H, s), 3.14 (1.8H, s), 2.98 (1.2H, S), 2.96 (1.8H, s), 2.86-2.74 (0.6H, m), 2.66-2.63 (0.4H) , m), 1.95-1.25 (12H, m), 1.00-0.95 (gH, m), and 0.90-0.84 (3H, M). "C-NMR; d (CDC13, rotamers), 175.5, 172.8, 171.4, 162.2, 156.1, 55.1, 54.5, 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. LREM: + ve ion 394 [M + Na], 372 [M + H], -ve ion 370 [M-H].

Example 22 2R (or S) - [(Formyl-hydroxy-amino) -methyl] -decanoic acid (2S-dimethyl-carbamoyl-2, 2-dimethyl-propyl) -amide.

Diastereoisomer A: Colorless oil. LREM: tve ion 408 [M + Na], 386 [M + H], -ve ion 384 [M-H].

Example 23 2R (or S) - [(Formyl-hydroxy-amino) -methyl] -5-methyl-hexanoic acid (2S-dimethyl-carbamoyl-2, 2-dimethyl-propyl) -amide.

Diastereoisomer A: Colorless oil. 'H-NMR; d (CDC13, rotamers), 9.31 (0.4H, s), 8.40 (0.4H, s), 8.17 (0.6H, s), 6.77 (0.4H, d, J = 7.5 Hz), 6.60 (0.6H, s) , J = 8.0 Hz), 4.89 (1H, m), 4.04 (0.4H, m), 3.83 (0.6H, m), 3.52 (1H, m), 3.16 (1.2H, s), 3.15 (1.8H, s), 2.98 (1.2H, s), 2.96 (1.8H, s), 2.70 (1H, m), 1.58-1.14 (5H, m), 1.00-0.95 (9H, m) and 0.87-0.84 (6H, m). 13C-NMR; d (CDC13, rotamers), 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. LREM: tve ion 366 [M + Na], 344 [M + H], -ve ion 342 [MH].

Example 24 2R (or S) - [(Formyl-hydroxy-amino) -methyl] -propanoic acid (2S-dimethyl-carbamoyl-2, 2-dimethyl-propyl) -amide.

Diastereoisomer A: 'H-NMR; d (CDC13, rotamers), 8. 41 (0.55H, s), 7.81 (0.45H, s), 6.67 (0.45H, d, J = 8.4 Hz), 6.51 (0.45H, d, J = 7.2 Hz), 4.88 (0.45H, d, J = 9.4 HZ), 4.66 (0.55H, d, J = 7.7 Hz), 3.76 (1H, m), 3.55 (0.55H, dd, J = 14.3, 9.8 Hz), 3.44 (0.45H, dd, J = 14.2 , 5.3 Hz), 3.21 (1.65H, s), 3.14 (1.35H, s), 2.99 (1.65H, s), 2.97 (1.35H, s), 2.81 (1H, m), 1.21 (1.65H, d , J = 6.7 Hz), 1.19 (1.35H, d, J = 6.8 Hz), 1.01 (4.95H, s) and 0.98 (4.05H, s). LREM: + ve ion 310 [M + Na], -ve ion 286 [M-H].

Diastereoisomer B: -RMN; d (CDC13, rotamers), 9.47 (0.4H, broad s), 8.41 (0.4H, s), 7.86 (0.6H, s), 6.96 (0.4H, broad s), 6.74 (0.6H, d, J = 7.3Hz), 4.91 (1H, m), 3.9g (0.4H, dd, J = 14.2, 7.6 Hz), 3.83 (0.6H, dd, J = 13.8, gO Hz), 3.50 (1H, m), 3.16 (1.2H, s), 3.15 (1.8H, s), 2.g7 (3H, s), 2.90 (1H, m), 1.21 (1.2H, d, J = 6.8 Hz), 1.15 (1.8H, d , J = 6.5Hz), 0.99 (3.6H, s) and 0.95 (5.4H, s). LREM: + ve ion 310 [M + Na], -ve ion 286 [M-H].

Example 25 2R (or S) - [(Formyl-hydroxy-amino) -methyl] -3-methylbutyric acid (2S-dimethyl-carbamoyl-2, 2-dimethyl-propyl) -amide.

Diastereoisomer A: -RMN; d (CDC13, rotamers), 9.33 (0.4H, S), 8.38 (0.4H, s), 7.81 (0.6H, s), 6.86 (0.4H, broad s), 6.58 (0.6H, d, J = 8.6 Hz), 4.90 (1H, m), 4.06 (0.4H, dd, J = 14.7, 7.3 Hz), 3.91 (0.6H, dd, J = 13.8, 10.6 Hz), 3.17 (1.2H, s), 3.15 ( 1.8H, s), 2.98 (1.2H, s), 2.96 (1.8H, s), 2.62 (0.6H, m), 2.48 (0.4H, m), 1.90 (1H, m), 1.09-0.86 (15H, m). LREM.- + ve ion 338 (M + Na), -ve ion 314 (M-H).

Example 26 2R (or S) - [(Formyl-hydroxy-amino) -methyl] -3-phenyl-propionylpropionic acid (lS-dimethyl-carbamoyl-2, 2-dimethyl-propyl) -amide.

Diastereoisomer A. Colorless glass. 1 H-NMR; d (CDC13, rotamers), 9.33 (0.3H, broad s), 8.95 (0.7H, broad s), 8.43 (0.3H, broad s), 7.83 (0.7H, broad s), 7.27-7.10 (5H, m ), 6.65 (0.3H, broad s), 6.45 (0.7H, broad d, J = 8.2 Hz), 4.80-4.70 (1H, m), 4.22-4.10 (0.3H, m), 3.89 (0.7H, dd) , J = 13.7, 9.6 Hz), 3.63-3.47 (1H, m), 3.20-2.69 (3H, m), 3.04 (3H, broad s), 2.86 (3H, broad s), and 0.87 (9H, broad s) ). 13C-NMR; 6 (CDC13, rotamers), 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. LREM: + ve ion 386. (M + Na), -ve ion 362 (M-H).

Example 27 (2S- ((S) - [(Formyl-hydroxy-amino) -methyl] -3- (4-methoxy-phenyl) -propionic acid (lS-dimethyl-carbamoyl-2, 2-dimethyl-propyl) -amide.

Diastereoisomer A: LREM: tve ion 416 (M + Na), 394 (M + H), -ve ion 392 (M-H).

The compounds of examples 28 to 31 are prepared by analogy with example 13, method II, substituting the amide or benzyl ester of the appropriate amino acid for ter-leucine, N, N-dimethylamide in step E.

Example 28 Acid 2 S -. { 2R- [formyl-hydroxy-amino) -met-il] hexanoi lamino} -3 - phenylpropionic White foam ^ -RMN; d (CD3OD, rotamers), 8.11 (0.35H, s), 7.80 (0.65H, s), 7.31-7.16 (5H, m), 4.68 (1H, dd, J = 8.7, 5.5 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 (6H, m) and 0.90-0.85 (3H, m). 13C-NMR; d (CD30D, rotamers), 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, 23.7 and 14. 2 IR (Reflection disk) vnax 2932, 2359, 1727, 1660, 1551, 1454, 1381, 1221, 882, 701 crn "1. LREM: + ve ion 359 [M + Na], -ve ion 335 (MH) .

Example 29 2S-acid. { 2R- [formyl-hydroxy-amino) -methyl] hexanoyl amino} -3, 3 -dimet ilbut í rico White foam -RMN; 6 (CD30D, rotamers.), 8.25 (0.3H, s), 7.82 (0.7H, s), 4.31 (1H, s), 3.83-3.29 (2H, m), 3.10-2.89 (1H, m), 1.54 -1.33 (6H, m), 1.03 (3H, s), 1.01 (6H, s) and 0.92-0.87 (3H, m). "C-NMR; d (CD3OD, rotamers), 174.9, 172.9, 61.0, 52.4, 44.2, 44.0, 33.6, 30.1, 29.1, 26.2, 22.6, and 13.1 IR (Reflection disc) vm, _ 2959, 2359, 1644 , 1537, 1371, 1218, 881 and 704 crn "1. LREM: + ve ion 325 (M + Na), -ve ion 301 (M-H).

The emplo 30 . { 1- [2- (2S-hydroxymethyl-pyrrolidin-1-carbamoyl] -2,2-dimethyl-propyl] -amide of 2S- [2R- (formyl-hydroxy-amino) -methyl] -hexanoic acid Colorless oil lH-NMR; d (CD3OD, rotamers), 8.26 (0.4H, s), 7.84 (0.6H, s), 4.62 (0.4H, d, J = 8.2 Hz), 4.39 (0.6H, d, J = 8.4 Hz), 4.12 (1H, m), 3.91-3.37 (6H, broad m), 2.93 (0.6H, m), 2.78 (0.4H, m), 1.93 (5H, m), 1.45 (2H, m), 1.39 (3H, m), 0.97 (3H, broad s), 0.95 (3H, broad s), and 0.89 (3H, t, J = 6.7 Hz). "C-NMR; d (CDC13, rotamers), 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, 14.7 and 13.3, LREM: + ve ion 394 (M + Na), 372 (M + H), -ve ion 370 (MH).

Example 31 . { 1- [(2-Hydroxy-ethyl) methyl -carbamoyl] -2, 2 -dimethyl-propyl} -amide of 2S- [2R- (formyl-hydroxy-amino) -methyl] -hexanoic acid White foam -RMN; d (CD3OD, rotamers), 8.25 (0.25H, s), 8.03 (0.125H, s), 7.82 (0.625H, s), 4.88 (1H, m), 3.83-3.54 (4H, broad m), 3.41 ( 2H, m), 3.25 (2H, s), 2.96 (2H, sym), 1.49 (2H, m), 1.23 (4H, m), 1.00 (6H, s), 0.99 (3H, s), and 0.88 ( 3H, m). 13C-NMR; d (CD3OD, rotamers), 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, 24.1 and 14.7. LREM: + ve ion 382 [M + Na], -ve ion 358 [M-H].

Compounds of Examples 32 to 59 are prepared by analogy with Example 7, method II, substituting the appropriate amine or the amino acid amide / benzyl ester for ter-leucine, N, N-dimethylamide in stage E. In some cases, HOAt is used in stage E and hydrogenolitic deprotection is carried out (stage G) under catalytic transfer conditions (cyclohexane, palladium in carbon, in ethanol) ).

Example 32 (lR-dimethylcarbamoyl-2, 2-dimethyl-propyl) -amide of 2R- [(formyl-hydroxy-amino) -methyl] -hexanoic acid Colorless oil LREM: + ve ion 330 [M + H], -ve ion 328 [M-H].

Example 33 2R- [(formyl-hydroxy-amino) -methyl] -hexanoic acid (lS-dimethylcarbamoyl-2S-methyl-butyl) -amide White foam LREM: + ve ion 352 [M + Na], -ve ion 328 [M-H].

Example 34 2R- [(formyl-hydroxy-amino) -methyl] -hexanoic acid (S-dimethylcarbamoyl-2-methoxy-2-methyl-propyl) -amide racemic form of ß-hydroxymethylvaline. Diastereoisomer A. Colorless oil. LREM: + ve ion 368 [M + Na], 346 [M + H], -ve ion 344 [M-H]. Diastereoisomer B. LREM: tve ion 368 [M + Na], 346 [M + H], -ve ion 344 [M-H]. Example 35 (2S -dimet ilcarbamoyl-2-hydroxy-2-methyl-propyl) -amide of 2R- [(formyl-hydroxy-amino) -methyl] -hexanoic acid Colorless oil LREM: + ve ion 354 [M + Na], -ve ion 330 [M-H].

Example 36 [2- (4-chloro-phenyl) -lS-dimethyl-carbamoyl-ethyl] -amide of 2R- [(formyl-hydroxy-amino) -methyl] -hexanoic acid Colorless oil LREM: + ve ion 330 (M + H), -ve ion 328 (M-H).

Example 37 2R- [(formyl-hydroxy-ammo) -methyl] -hexanoic acid [lS-dimethylcarbamoyl-2- (4-hydroxy-phenyl) -ethyl] -amide Colorless oil LREM: + ve ion 402 (M + Na), 380 (M + H) Example 38 2R- [(formyl-hydroxy-amino) -methyl] -hexanoic acid (2S -dimethylcarbamoyl-2-naphthalen-2-yl-ethyl) -amide Colorless oil LREM: + ve ion 414 (M + H), -ve ion 412 (M-H) Example 39 2R- [(formyl-hydroxy-amino) -methyl] -hexanoic acid (2-cyclohexyl-is-dimethyl-carbamoyl-ethyl) -amide White foam LREM: + ve ion 392 (M + Na), 370 (M + H).

Example 40 2R- [(formyl-hydroxy-amino) -methyl] -hexanoic acid (lS-dimethylcarbamoyl-phenyl-methyl) -amide Colorless oil LREM: + ve ion 350 (M + H), 348 (M-H) Example 41 Dimethylamide of acid 2-. { 2R- [(formyl-hydroxy-amino) -methyl] -hexanoyl} -1,2,3,4-tetrahydro-isoquinoline-3S-carboxylic acid LREM: + ve ion 398 (M + Na), 376 (M + H), -ve ion 374 (M-H).

Example 42 2R- [(formyl-hydroxy-amino) -methyl] -hexanoic acid (4-amino-lS-dimethylcarbamoyl-butyl) -amide Colorless oil LREM: + ve ion 345 (M + H), -ve ion 343 (M-H) Example 43 (2S- [(formyl-hydroxy-amino) -methyl] -hexanoic acid] -dimethylcarbamoyl-2-hydroxy-ethyl) -amide Colorless oil LREM: + ve ion 326 (M + Na), -ve ion 302 (M-H).

Example 44 N-Hydroxy-N- [2R- (4-methyl-piperazin-1-carbonyl) -hexyl] -formamide LREM: + ve ion 272 [M + H].

Example 45 N-Hydroxy-N- [2R- (morpholin-4-carbonyl) -hexyl] formamide LREM: tve ion 281 (M + Na), 259 (M + H), -ve ion 257 (M-H).

Example 46 N-Hydroxy-N- [2R- (2S-hydroxymethyl-pyrrolidin-1-carbonyl) -hexyl] -formamide LREM: -ve ion 271 (M-H) Example 47 2R- [(formyl-hydroxy-amino) -methyl] -hexanoic acid (2S-hydroxymethyl-2, 2-dimethyl-propyl) -amide LREM: tve ion 289 (M + H), -ve ion 287 (M-H) Example 48 2R- [(formyl-hydroxy-amino) -methyl] -hexanoic acid (2S-methoxymethyl-2, 2-dimethyl-propyl) -amide LREM: + ve ion 303 (M + H), -ve ion 301 (M-H).

Example 49 [ÍS- (4-benzyl-piperidin-1-carbonyl) -2, 2-dimethyl-propyl) -amide of 2R- [(formyl-hydroxy-amino) -methyl] -hexanoic acid LREM: -ve ion 458 (M-H).

Example 50 [ÍS- (benzyl-phenethyl-carbamoyl) -2, 2-dimethyl-propyl] -amide of 2R- [(formyl-hydroxy-amino) -methyl] -hexanoic acid LREM: + ve ion 496 (M + H), -ve ion 494 (M-H).

Example 51 [2, 2 - [(formyl-hydroxy-amino) -methyl] -hexanoic acid [2, 2-dimethyl-lS- (pyrrolidin-1-carbonyl) -propyl] -amide] LREM: + ve ion 356 (M + H), -ve ion 354 (M-H).

Example 52 2R- [(formyl-hydroxy-amino) -methyl] -hexanoic acid [2, 2-dimethyl-lS- (marfolin-4-carbonyl) -propyl] -amide] LREM: + ve ion 372 (M + H), -ve ion 370 (M-H).

Example 53 2R- [(formyl-hydroxy-amino) -methyl] hexanoic acid [2, 2-dimethyl-lS- (4-methyl-piperazin-1-carbonyl) -propyl] -amide] LREM: + ve ion 385 (M + H), -ve ion 383 (M-H).

Example 54 2R- [(formyl-hydroxy-amino) -methyl] hexanoic acid [2, 2-dimethyl-lS- (4-methyl-piperidin-1-carbonyl) propyl] -amide LREM: + ve ion 384 (M + H), -ve ion 382 (M-H). Example 55 2R- [(formyl-hydroxy-amino) -methyl] -hexanoic acid (2S-cyclohexylcarbamoyl-2, 2-dimethyl-propyl) -amide LREM: + ve ion 398 (M + H), -ve ion 396 (M-H) Example 56 [ÍS- (4-acetyl-piperidin-1-carbonyl) -2, 2-dimethyl-propyl] -amide of 2R- [(formyl-hydroxy-amino) -methyl] -hexanoic acid LREM: + ve ion 412 (M + H), -ve ion 410 (M-H) Example 57 1- (2S-. {2R- [(formyl-hydroxy-amino) -methyl] -hexanoylamino} -3,3-dimethyl-butyryl) iperidine-4-carboxylic acid methyl ester LREM: tve ion 442 (M + H), -ve ion 440 (M-H).

Example 58 2R- [(formyl-hydroxy-amino) -methyl] hexanoic acid [2, 2-dimethyl-bis- (octahydro-quinoline-1-carbonyl) propyl] -amide LREM: + ve ion 424 (M + H), -ve ion 422 (M-H) Example 59 [ÍS- (3, 4-dihydro-2H-quinol in-1-carbonyl) -2,2-dimethyl-propyl) -amide of 2R- [(formyl-hydroxy-amino) -methyl] -hexanoic acid LREM: -ve ion 416 (M-H).

Example 60 2S-. { 3-ethylsulfanylmethyl-2R- [(formyl-hydroxy-amino) methyl] propionyl amino} -3, 3, N, N-tetramethylbutyramide A synthesis route of the title compound is indicated in scheme 4 and is described in detail below.

Scheme 4 Reagents and conditions: A. 3-lithium-4-benzyl-oxazolidin-2-one, THF, -78 ° C; B. LIN (SlMe3) 2, THF, -78 ° C then AcCl; C. H2N0Bzl HCl, NaOAc, aqueous ethanol; D. NaCNBH3, AcOH, room temperature; E. HCOBI, THF; F. LiOH, aqueous THF, 0 ° C; G. H-Tle-NMe2, HOAl, EDC, DMF; H. H2, Pd / C, MeOH and then the diastereoisomers (CLAP) are separated.

Stage A: 2-ethylsulfanylmethyl-acrylic acid A mixture of malonic acid (5.2 g, 50 mmol), paraformaldehyde (3.3 g, 110 mmol), dicyclohexylamine (9. g5 mL, 50 mmol) and ethanethiol (4.06 mL, 55 mmol) in dioxane (120 mL) is heated to 70 ° C for 2 hours. The solvents are removed under reduced pressure, the residue is redissolved in ethyl acetate and the solution is extracted with saturated aqueous sodium hydrogen carbonate (4 x 20 ml). The combined aqueous layers are washed with 20 ml of ethyl acetate and then acidified with 1M hydrochloric acid. The resulting suspension is extracted into dichloromethane and the solution is dried over anhydrous magnesium sulfate, filtered and evaporated to give the title compound as a white solid (3.76 g, 52%). lH-NMR; d (CDC13), .8g (1H, broad 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, t, J = 5.2 Hz).

Step B: 4S-benzyl-3- (2-ethylsulfanylmethyl-acryloyl) -5,5-imethyl-oxazolidin-2 -one Dissolve 2-ethylsulfanylmethyl-acrylic acid (3.76 g, 25.8 mmol) in dry THF (75 ml) and cooled to -78 ° C under an argon atmosphere. Triethylamine (4.6 ml, 33.5 mmol) and pivaloyl chloride (3.17 ml, 25.8 mmol) are added to a speed such that the temperature remains below -60 ° C. The mixture is 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, 4S-benzyl-5,5-dimethyl-oxazolidin-2-one is dissolved in dry THF (75 ml) and cooled to -78 ° C under an argon atmosphere. N-Butyllithium (2.4M solution in hexanes, 12.9 ml, 30.9 mmol) is added slowly and the mixture is stirred for 30 minutes at room temperature. The resulting anion is transferred via a cannula to the original reaction vessel. The mixture is allowed to warm to room temperature and is stirred overnight at room temperature. The reaction is suspended with 20 ml of saturated sodium hydrogen carbonate and the solvents are removed under reduced pressure. The residue is partitioned between ethyl acetate and water. The organic layer is washed successively with saturated sodium hydrogen carbonate, 1M hydrochloric acid and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash chromatography (silica gel, 20% ethyl acetate in hexane) to give the title compound as a yellow oil (6.5 g, 76%). -RMN; d (CDC13), 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). LREM: tve ion 356 (M + Na), 334 (M + H).

Step C: 4S-benzyl-3- [2R-tert-butoxyamino-methyl) -3-ethylsulfanylmethyl-propionyl] -5,5-dimethyl-oxazolidin-2 -one Dissolve 4S-benzyl-3- (2-ethylsulfanylmethyl-acryloyl) -5,5-dimethyl-oxazolidin-2-one (2.1 g, 6.3 mmol) in ethanol (10 mL) and add 0-tert-butyl hydrochloride. -hydroxylamine (0.95 g, 7.56 mmol), followed by triethylamine (ll ml, 7.87 mmol). The mixture is stirred at 30 ° C overnight. The solvents are removed under reduced pressure and the residue is dissolved in ethyl acetate. The organic solution is washed successively with 1M hydrochloric acid, saturated sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to provide the title compound as a light yellow oil (2.42 g, 91%, single diastereomer by CLAP). "H-NMR; d (CDC13), 7.30 (5H, m), 5.09 (1H, broad 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 (9H, s). LREM: + ve ion 423 (M + H). - ng - Stage D: 2R-tert-butoxyamino-methyl) -3-ethylsulfanylmethyl-propionic acid A solution of 4S-benzyl-3- [2R-tert-butoxyamino-methyl) -3-ethylsulfanylmethyl-propionyl] -5,5-dimethyl-oxazolidin-2-one (2.42 g, 5.72 mmol) in THF (40 ml) it is cooled to 0 ° C, and a solution of lithium hydroxide (288 mg, 6.86 mmol) in 10 ml of water is added. The mixture is allowed to warm to room temperature and then stirred for 5 hours. The solvent is removed under reduced pressure and the residue is partitioned between water and ethyl acetate. The aqueous layer is removed and the ethyl acetate layer is washed successively with water and saturated sodium hydrogen carbonate. The combined aqueous layers are washed with 20 ml of ethyl acetate before acidifying with 1M hydrochloric acid. The resulting emulsion is extracted with dichloromethane (3 x 20 ml) and the combined organic layers are dried over anhydrous magnesium sulfate, filtered and evaporated to give the title compound as a colorless oil (0.68 g, 50%). -RMN; d (CDC13), 8.03 (2H, broad s), 3.21 (2H, d, J = 6.1 Hz), 2.8g (2H, m), 2.75 (1H, m), 2.57 (2H, dd, J = 7.4, 14.8 Hz), 1.26 (3H, t, J = 7.4 Hz) and 1.18 (9H, s). LREM: + ve ion 236 [M + H], -ve ion 234 [M-H].

Step E: a solution of 2S- [2R- (tert-butoxy-amino-methyl) -3-ethyl-sulfanylmethyl-propionyl amino} -3, 3, N, N-tetramethylbutyramide 2R-tert-Butoxyamino-methyl) -3-ethylsulfanylmethyl-propionic acid (340 mg, 1.44 mol) is dissolved in DMF (10 ml) and tert-leucine-N, N-dimethylamide (272 mg, 1.73 mmol) is added. , HOAt (19.6 mg, 0.14 mmol) and EDC (331 mg, 1.73 mmol). The reaction is stirred overnight at room temperature. The solvent is removed under reduced pressure and the residue is dissolved in dichloromethane. The organic solution is washed successively with 1M hydrochloric acid, 1M sodium carbonate and brine, dried over anhydrous magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to provide the required product as a colorless oil (440 mg, 82%). 'H-NMR; d (CDC13), 6.87 (1H, d, J = 9.0 Hz), 5.11 (1H, broad 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 (9H, s) and 1.01 (9H, s). LREM: tve ion 398 [M + Na], 376 [M + l].

Stage F: 2S-. { 2R- [(tert-Butoxy-formyl-amino) -methyl] -3-ethylsulfanylmethyl-propionyl amino} -3, 3, N, N-tetramethylbutyramide A solution of 2S- [R- (tert-butoxy-amino-methyl) -3-ethylsulfanylmethyl-propionyl amino} -3, 3, N, N-tetramethylbutyramide (220 mg, 0.58 mmol) in dichloromethane (5 ml) is cooled to 0 ° C and treated with 0.1 ml of formic acetic anhydride. The reaction is stirred at room temperature for 4 hours the solvent is evaporated under reduced pressure. The residue is purified by flash chromatography (silica gel, 50% ethyl acetate in hexanes as eluent) to give the title compound as a colorless oil (120 mg, 52%). "H-NMR; d (CDC13, rotamers), 8.31 (1H, broad s), 6.56 (1H, d, J = 9.1 Hz), 4. g4 (0.33H, d, J = g.4 Hz), 4.88 (0.67H, d, J = g.2 Hz), 4.08 (0.67H, broad m), 3.83 (1.34H, broad m), 3.13 (3H, s), 2.g5 (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 (9H, s), 1.25 (3H, t, J = 7.2 Hz ) and 0.g9 (9H, s). LREM: tve ion 426 [M + Na], 404 [M + H].

Stage G: 2S-. { 3-ethylsulfanylmethyl-2R- [(formyl-hydroxy-amino) -methyljpropionyl amino} -3,3, N, N-tetramethylbutyramide A solution of 2S-. { 2R- [(tert-Butoxy-formyl-amino) -methyl] -3-ethylsulfanylmethylpropionyl amino} -3, 3, N, N-tetramethylbutyramide (120 mg, 0.3 mmol) in 1 ml of deuteriochloroform is treated with TFA (4 ml) and allowed to Rest at 4 ° C during the night. The solvents are removed under reduced pressure and the residual TFA is removed by azeotropic distillation with toluene. The residue is purified by preparative CLAP to give the title compound as a colorless oil (40 mg, 38%, 7: 2 mixture of diastereomers by CLAP). 'H-NMR; d (CDC13, rotamers), 8.40 (0.33H, S), 7.87 (0.67H, s), 7.24 (0.33H, d, J = 9.3 Hz), 6.98 (0.67H, d, J = 9.3 Hz), 4 .gi (0.67H, d, J = 9.3 Hz), 4.90 (0.33H, d, J = 9.3 Hz), 4.07 (0.33H, dd, J = 7.5, 14.5 Hz), 3.86 (0.67H, dd, J = 8.8, 14.2 Hz), 3.75 (0.67H, m), 3.68 (0.33H, 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), 0.9g (3H, s) and 0.96 (6H, s). 13C-NMR; d (CDC13, rotamers), 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 LREM: + ve ion 370 [M + Na], 348 [M + H], -ve ion 346 [MH].

The compound of Example 61 is prepared similarly using piperidine in place of ethanethiol in step A.

Example 61 2 - . 2 - . { 2 - [(formyl-hydroxy-amino) -methyl] -3-piperidin-1-yl-propionyl amino} -3, 3, N, N-tetramethyl-butyramide White solid (4: 1 mixture of diastereomers by CLAP). -RMN; d (CDC1-, rotamers), 8.29 (1H, s), 7.95 (1H, broad 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 (3H, s), 2.96 (3H, s), 2.89 (1H, m), 2.69 (1H, m), 2.52 (5H, m), 1.65 (4H, m), 1.49 (2H, m) and 0.9g (gH, s). "C-NMR; d (CDC13) 172.2, 171.3, 60.4, 55.0, 54. gi 48.6, 42.4, 38.8, 36.2, 36.1, 27.0, 25.6 and 24.3 LREM: + ve ion 371 [M + H], -ve ion 369 [MH].

The compounds of Examples 62 to 65 are prepared by analogy to Example 7, Method II, substituting 0-tert-butylhydroxylamine for O-benzylhydroxylamine in Step B and the amine or amino acid amide / benzyl ester appropriate for terleucine N, N-dimethylamide in Step E. The final deprotection is carried out by acidolysis with TFA (see Example 60, above).

Example 62 (2-R- [(formyl-hydroxy-amino) -methyl] -hexanoic acid-2-dimethyl-carbamoyl-2-methyl-2-methyl-sulfanyl-propyl) -amide Colorless oil 'H-NMR; d (CDCI3, rotamers), 8.4 (0.5H, S), 7.85 (0.5H, s), 7.11 (0.5H, d, J = 9.1 Hz), 6.93 (0.5H, d, J = 9.1 Hz), 5.15 (1H, d, J = 9.4 Hz), 3.90 (0.5H, m), 3.73 (0.5H, m), 3.64 (0.5H, d, J = 14.3 Hz), 3.48 (0.5H, dd, J = 14.0, 3.9 Hz), 3.22 (3H, s), 2.97 (3H, s), 2.83 (0.5H, m), 2.70 (0.5H, m), 2.07 (1.5H, s), 2.04 (1.5H, s), 1.58 (1H, m), 1.36 (4H, m), 1.32 (3H, s) ), 1.28 (3H, s) and 0. 86 (3H, t, J = 6.6 Hz). "C-NMR; d (CDC13, rotamers), 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. LREM: tve ion 362 [M + H], -ve ion 360 [M-H].

Example 63 2R- [(formyl-hydroxy-amino) -methyl] -hexanoic acid (2-benzylsulfanyl-IR-dimethyl-cylcarbamoyl-2-methyl-propyl) -amide White foam 'H-NMR; d (CDC13, rotamers), 8.37 (0.33H, s), 7.81 (0.66H, s), 7.31 (5H, m), 7.06 (0.33H, d, J = 8.8 Hz), 6.8g (0.66H, d, J = 9.3 Hz), 5.20 (1H, d, J = 9.3 Hz), 3.94 (0.33H, dd, J = 8.3, 14.6 Hz), 3.78 (2.66H, m), 3.61 (0.33H, dd, J = 3.5, 14.4 Hz), 3.42 (0.66H, dd, J = 5.1, 14.9 Hz), 3.21 (3H, s), 3.03 (3H, s), 2.82 (0.66H, m), 2.69 (0.33H, m), 1.61 (1H, m) , 1.42 (1H, m), 1.37 (3H, s), 1.32 (3H, s), 1.26 (4H, m) and 0.86 (3H, t, J = 6.6 Hz). 13C-NMR; d (CDClj, rotamers), 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. LREM: + ve ion 460 [M + Na], 438 [M + H], -ve ion 436 [M-H].

Example 64 2R- [(formyl-hydroxy-amino) -methyl] -hexanoic acid [2-benzylsulfanyl-2-methyl-lR- (morpholin-4-carbonyl) -propyl] -amide] White foam 1 H-NMR; d (CDC13, rotamers), 8.44 (0.5H, s), 8.37 (0.5H, s), 7.30 (5H, m), 6.88 (0.5H, d, J = 8.3 Hz), 6.78 (0.5H, 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 (0.5H, m), 2.64 (0.5H, 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-, d (CDC13, rotamers), 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, 22.9 and 14.3. LREM: + ve ion 502 [M + Na], 480 [M + H], -ve ion 478 [M-H].

Example 65 2 - [(formyl-hydroxy-amino) -methyl] -hexanoic acid [2-benzylsulfanyl-2-methyl-lR (or S) - (4-methyl-piperidin-1-carbonyl) -propyl] -amide] Diastereoisomer A. White solid. LREM: tve ion 514 [M + Na], 492 [M + H],.-Ve ion 490 [M-H].

Diastereoisomer B. Colorless rubber. LREM: tve ion 514 [M + Na], 492 [M + H], -ve ion 490 [M-H].

The compounds of Examples 66 to 68 are prepared by analogy to Example 7, Method II, substituting the appropriate malonic acid for butylmalonic acid in Step A, O-tert-butylhydroxylamine for O-benzylhydroxylamine in Step C. The stereoselectivity in Michael's addition is variable. The final deprotection is carried out by acidolysis with TFA (see Example 60, above).

Example 66 2R- [(formyl-hydroxy-amino) -methyl] -pent-4-enoic acid (S-dimethylcarbamoyl-2, 2-dimethyl-propyl) -amide Single diastereoisomer. 1H-NMR, d (CDC13, rotamers), 8.40 (0.25H, s), 7.84 (0.75H, s), 7.05 (0.35H, d, J = 9.0 Hz), 6.74 (0.65H, d, J = 9.3 Hz), 5.70 (1H, m), 5.03-5.24 (2H, m), 4.88 (1H, dd, J = 9.4, 6.7Hz), 3.98 (0.5H, m), 3.81 (0.5H, m), 3.55 (1H, m), 3.14 (3H, s), 2.97 (1.3H, s), 2.g6 (1.7H, s), 2.75-2.g2 (1H, m), 2.16-2.50 (2H, m), 0.98 (4.5H, s) and 0.94 (4.5H, s). LREM: + ve ion 336 [M + Na] -ve ion 312 [M-H].

Example 67 (2S-dimethylcarbamoyl-2, 2-dimethyl-propyl) -amide of 2R- [(formyl-hydroxy-amino) -methyl] -hex-5-enoic acid Diastereoisomer A: Colorless oil. 'H-NMR; £ (CDC13, rotamers), 8.42 (0.45H, s), 7.84 (0.55H, s), 6.7E (0.45H, d, J = 8.4Hz), 6.60 (0.55H, d, J = 9.3Hz), 5.74 (1H, m), 5.03 (2H, m), 4.88 (1H, m), 4.14 (0.4H, m), 3.81 (0.6H, m), 3.55 (1H, m), 3.16 (1H, s) , 3.15 (2H, s), 2.98 (1H, s), 2.97 (2H, s), 2.85 (0.7H, m), 2.68 (0.3H, m), 2.07 (2H, m), 1.73 (1.6H, m), 1.50 (0.4H, m), 0.99 (4H, s) and 0.95 (5H, s). LREM: + ve ion 350 [M + Na], -ve ion 326 [M-H].

Diastereoisomer B: Colorless oil. 'H-NMR, -d (CDClj, rotamers), 8.41 (0.5H, s), 7.75 (0.5H, s), 6.58 (0.5H, d, J = 9.1 Hz), 6.36 (0.5H, d, J = 9.1 Hz), 5.75 (1H, m 5.01 (2H, m), 4.86 (0.5H, d, J = 9.5Hz), 4.64 (0.5H, d, J = 7.5Hz), 3.42-3.82 (2H, m ), 3.22 (1.5H, s), 3.07 (1.5H, s), 2.9g (3H, s), 2.87 (0.5H, m), 2.66 (0.5H, m), 2.13 (2H, m 1.81 (1H , m), 1.49 (1H, m), 1.02 (4.5H, s) and 1.00 (4.5H, s). LREM: + ve ion 350 [M + Na], -ve ion 326 [MH].

Example 68 2R- [(formyl-hydroxy-amino) -methyl] -hex-4-ynyl (lS-dimethylcarbamoyl-2, 2-dimethyl-propyl) -amide Diastereoisomer A: Colorless oil. -RMN; d (CDC13, rotamers), 8.39 (0.4H, s), 7.87 (0.6H, s), 7.20 (0.4H, d, J = 8.4Hz), 6.94 (0.6H, d, J = 9.3Hz), 4.90 (1H, m), 3.66-4.14 (2H, m), 3.16 (2H, s), 3.14 ( 2H, s), 2.96 (lH, s), 2.88 (1H, m), 2.41 (2H, m), 1.77 (3H, m), 1.00 (3.5H, s) and 0.96 (5.5H, s). LREM: + ve ion 348 [M + Na], -ve ion 324 [M-H].

Diastereoisomer B: Colorless oil. lH-NMR; d (CDClj, rotamers), 8.37 (0.5H, s), 7.81 (0.5H, s), 6.87 (1H, m), 4.91 (0.5H, d, J = 9.4 Hz), 4.79 (0.5H, d, J = 8.2 Hz), L3.76 (1.5H, m), 3.63 (0.5H, m), 3.19 (1.5H, s), 3.14 (1.5H, s), 2.98 (3H, s), 2.85 (1H , s), 2.41 (2H, m), 1.77 (3H, m), 1.03 (4.5H, S) and 1.01 (4.5H, s). LREM: + ve ion 348 [M + Na], -ve ion 324 [M-H].

Example 69 (l-dimethylcarbamoyl-2, 2-dimethyl-propyl) -amide of 2R- [IR (or S) - (formyl-hydroxy-amino) -ethyl] -hexanoic acid The title compound is prepared according to the route indicated in scheme 5 and as described in detail in the following: Scheme 5 Reagents and conditions: A. (CHO) n, EtSH, dicyclohexylamine, dioxane, 70 ° C, 2h; B. 'BuCOCl, Et 3 N then 3-lithium-4-benzyl-5,5-dimethyl-oxazolidin-2-one; C. HCl.H2NOBu, EtjN, o / n; D. LiOH, aqueous THF, 0 ° C; E. H-t-LeuNMe2, HOAt, EDC, DMF; H. HCOAc, CH2C12; G. TFA, CDC13.

Stage A.: -benzyl-3-hexanoyl-oxazolidin-2-one Dissolve S-benzyl-oxazolidin-2-one (14.5 g, 81.7 m mol) in dry THF (75 ml) under an argon atmosphere. The solution is cooled in an ice bath before the slow addition of n-butyllithium (1.6M in hexanes, 56 ml, 89.2 mmol). The lithium salt crystallized from the solution as a solid mass is then allowed to warm to room temperature overnight. The resulting orange solution is again cooled in an ice bath during the addition of a cold solution of hexanoyl chloride (10.4 ml., 74.3 mmol) in dry THF (50 ml). The mixture is allowed to warm to room temperature and then stirred for 3 hours. The reaction is suspended with 5 ml of a 1M sodium carbonate solution and the solvent is removed under reduced pressure. The residue is divided between 100 ml of 1M sodium carbonate and 150 ml of ethyl acetate. The organic layer is removed and the aqueous layer is extracted with more ethyl acetate. The combined organic layers are successively washed with water, 1M sodium carbonate and brine, dried over anhydrous magnesium sulfate and filtered. The filtrate is concentrated to provide an orange oil. Purification by flash chromatography afforded the title compound as a yellow oil (10.21 g, 50%). "H-NMR; d (CDC13), 7. 38-7.24 (3H, m), 7.24-7.16 (2H, m), 4.68 (1H, m), 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, broad t, J = 6. g Hz).

Step B: l- (4S-benzyl-2-oxo-oxazolidin-3-yl) -2R-butyl-butan-1,3-dione 4-Benzyl-3-hexanoyl-oxazolidin-2-one (10.2 g, 37.1 mmol) is dissolved in THF (150 mL) under an argon atmosphere and cooled to -78 ° C. Lithium hexamethyldisilazide (1M in THF, 41 ml, 41 mmol) is added via cannula for a few minutes, and the resulting green solution is stirred at -78 ° C for 2 hours. Acetyl chloride (3.3 ml, 46.3 mmol) is added slowly and the reaction mixture is stirred for 3.5 hours. A solution of citric acid (3.0 g, 14 mmol) in water (15 ml) is added rapidly to suspend the reaction. The solvent is removed under reduced pressure and the residue is partitioned between ethyl acetate and water, washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate is concentrated to provide the title compound as a yellow oil (12.11 g, containing residual solvent) which is used without further purification in step C.-RMN; d (CDC13), 7.37-7.21 (5H, m), 4.68 (1H, m), 4.53 (1H, dd, J = g.6, 3.7 Hz), 4.23-4.13 (2H, m), 3.43 (1H, dd, J = 13.5, 3.3 Hz), 2.75 (1H, dd, J = 13.5, g.9 Hz), 2.33 (3H, s), 2.03 (1H, m), 1.77 (1H, m), 1.46-1.26 (4H, m) and 0.98-0.86 (3H, m).

Step C: 1- (4S-benzyl-2-oxo-oxazolidin-3-yl) -2R-butyl-butan-1,3-dione 3- (O-benzyl oxime) To a solution of 1- (4S-benzyl-2-oxo-oxazolidin-3-yl) -2R-butyl-butan-1,3-dione (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 O-benzylhydroxylamine hydrochloride (7.31 g, 45.78 mmol). The resulting suspension is allowed to stir at room temperature overnight. The product (7.3 g, 45%, single oxime isomer) crietalizes directly from the reaction and is filtered, washed with aqueous ethanol (1: 1) and dried under vacuum. Additional material (5.31 g, 33%, mixture of oxime isomers) is obtained as a yellow oil from the mother liquors by acid-base extraction followed by column chromatography. "? -RMN; d (CDC13, major oxime isomer), 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, broad 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 0.9 1 (3H, broad t, J = 6.9 Hz).

Step D: 4S-benzyl-3- [2R- (IR (or S) -bezyloxyamino-ethyl) -hexanoyl] -oxazolidin-2-one The oxime mixture from Step C (5.31 g, 12.5 mmol) is dissolved in 30 ml of acetic acid and cooled in an ice-water bath before the addition of sodium cyanoborohydride (0.8 g, 12.5 mmol) in a portion. The effervescence subsides after a few minutes and an additional portion of borohydride (0.8 g) is added. The reaction is allowed to warm to room temperature and is stirred overnight. The acetic acid is removed under reduced pressure and the residue is azeotroped with toluene. The resulting oil is dissolved in ethyl acetate, washed with water, 1M sodium carbonate and brine, dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated to leave a light yellow oil which is purified by flash chromatography (silica gel, 10% to 25% ethyl acetate in hexane as eluent). Yield, 3.43 g, 64%. 'H-NMR; d (CDC13, a-diastereomer mixture), 7.36-7.17 (10H, m), 5.80 (0.45H, broad e), 5.55 (0.55H, broad d, J = 8.9 Hz), 4.72-4.59 (3H, m ), 4.20-4.05. { 2H, m), 3.97 (0.45H, m), 3.82 (0.55H, 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).

Step E: N- [2R- (4S-benzyl-2-oxo-oxazolidin-3-carbonyl) -IR (or S) -methyl-hexyl] N-benzyloxy-formamide Dissolve 4S-benzyl-3- [2R- (IR (or S) -benzyloxy-amino-ethyl) -hexanoyl] -oxazolidin-2-one (3.08 g, 7.3 mmol) in dry THF and treat with N-formylbenzotriazole (1.60 g, 10.9 mmol). The reaction is stirred for 4 hours at room temperature. The solvent is removed under reduced pressure and the remaining oil is partitioned between dichloromethane (40 ml) and a 1M sodium hydroxide solution (30 ml). The organic layer is removed, washed with more sodium hydroxide and then with brine, dried over anhydrous magnesium sulfate, filtered and evaporated. Purification by flash chromatography (silica gel, 20% to 50% ethyl acetate in hexane) gives the title compound as a light yellow solid (2.50 g, 76%). 41-NMR; d (CDC13, a-diastereoisomer and rotamer mixture), 8.22 (1H, broad m), 7.54-7.13 (10H, m), 5.22-3.g2 (7H, broad m), 3.30 (1H, m), 2.48 (1H, broad m), 1.85-1.13 (9H, broad m) and 0.93-0.83 (3H, m).

Stage F: 2R- [IR (or S) - (benzyloxy-formyl-amino) -ethyl] -hexanoic acid Dissolve N- [2R- (4S-benzyl-2-oxo-oxazolidin-3-carbonyl) -lR (or S) -methyl-hexyl] N-benzyloxy-formamide (1.50 g, 3.31 mmol) in THF (25 ml ) and water (5 ml), and the solution is cooled in an ice bath. A solution of hydrogen peroxide (27%, w / w, 13.26 mmol) is added followed immediately by lithium hydroxide (167 mg, 3.98 mmol). The reaction is allowed to warm to room temperature and is stirred for an additional 3 hours. The solution is cooled again before the addition of sodium nitrite (0.92 g, 13.3 mmol). After 10 minutes, most of the solvent is removed under reduced pressure to leave a white paste which is divided between 25 ml of ethyl acetate and 30 ml of 1M sodium carbonate. The organic layer is washed with more sodium carbonate solution and the combined aqueous extracts are washed with ethyl acetate. The aqueous layer is cooled and acidified with 1M hydrochloric acid and extracted twice with ethyl acetate. The combined organic layers are washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give the title compound as a yellow oil (839 mg, 86%). __- RMN; d (CDC13, mixture of a-diastereoisomers and rotamers), 8.40-7.64 (2H, broad m), 7.48-7.27 (5H, m), 5.23-4.80 (2H, m), 4.16 (1H, broad m) , 2.79 (1H, m), 1.67-1.47 (2H, m), 1.47-1.18 (7H, m) and 0.95-0.82 (3H, m).

Step G: 2R- [IR (or S) - (benzyloxy-formyl-amino) -ethyl] -hexanoic acid (lS-dimethylcarbamoyl-2, 2-dimethyl-propyl) -amide.

The 2R- [IR (or S) - (benzyloxy-formyl-amino) -ethyl] -hexanoic acid (839 mg, 2.86 mmol), ter-leucine N, N-dimethylamide (498 mg, 3.15 mmol) are dissolved together and EDC (658 mg, 3.43 mmol) in DMF (15 ml) and a catalytic amount, 60 mg, of HOAt is added. The solution is left stirring for several days at room temperature. The solvent is removed under reduced pressure and the remaining oil is partitioned between ethyl acetate and 75 ml of 1M hydrochloric acid. The organic layer is washed successively with 1M hydrochloric acid, 1M sodium carbonate and brine, dried over anhydrous magnesium sulfate, filtered and evaporated to leave a yellow foam (1.08 g, 82%). "H-NMR; d (CDC13, mixture of diastereoisomer and rotamers), 8.13 (1H, broad m), 7.52-7.31 (5H, m), 6.28 (1H, broad m), 5.36-4.67 (3H, broad m ), 4.09 (1H, broad m), 3.14 (3H, s), 2.95 (1.2H, s), 2.93 (1.8H, s), 2.48 (1H, broad m), 1.61-1.04 (9H, m), 0.99 (3.6H, s), 0.95 (5.4H, s) and 0.8g-0.75 (3H, m).

Step H: 2R- [IR (or S) - (formyl-hydroxy-amino) -ethyl) -hexanoic acid (2S-dimethylcarbamoyl-2, 2-dimethyl-propyl) -amide (2R- [IR (or S) - (benzyloxy-formyl-amino) -ethyl] -hexanoic acid (lS-dimethylcarbamoyl-2, 2-dimethyl-propyl) -amide (200 mg, 0.46 mmol) is dissolved in methanol (15 ml) and placed under an argon atmosphere. A suspension of 20 mg palladium 10% in carbon, in ethyl acetate, is added and the mixture is stirred under a hydrogen atmosphere for 3 hours. The catalyst is removed by filtration and the filtrate is evaporated to give a colorless oil. (163 mg, quant.). The two diastereoisomeric products are separated by preparative CLAP.

Diastereoisomer A (27 mg): -RMN; d (CDC13, mainly a rotamer), 8.67 (O.gH, broad s), 8.33 (0.1H, broad s), 7.92 (1H, s), 6.74 (0.1H, broad m), 6.54 (0.9H, d , J = 9.4 Hz), 4.93 (0.9H, d, J = 9.4 Hz), 4.64 (0.1H, broad m), 3.89 (1H, cd, J = 6.6, 2.6 Hz), 3.16 (3H, S), 2.96 (3H, s), 2.62-2.48 (1H, m), 1.52-1.06 (6H, m), 1.35 (3H, d, J = 6.6 Hz), 1.00 (9H, s) and 0.82 (3H, t, J = 6.9Hz). 13C-NMR; d (CDClj), 173.0, 171.3, 57.2, 54.4. 50.4, 38.4, 35.6, 29.9, 29.1, 26.6, 22.5, 17.2 and 13.9. LREM: tve ion 366 [M + Na], -ve ion 342 [M-H].

Diastereoisomer B (42 mg): 'H-NMR; d (CDC13, mixture of rotamers), 9.15 (0.6H, s), 8.60 (0.4H, s broad), 8.42 (0.6H, e), 7.84 (0.4H, s), 6.83 (0.6H, d, J = 9.2 Hz), 6.55 (0.4H, d, J = g.4Hz), 4.gi (0.6H, d, J = 9.2 Hz), 4.89 (0.4H, d, J = 9.4 Hz), 4.69 (0.6H, cd, J = 7.0, 4.3 Hz), 3.92 (0.4H, dc, J = 9.1, 6.8 Hz), 3.15 (3H, s), 2.97 (1.8H, s), 2.95 (1.2H, s), 2.59 (0.4H, td , J = 9.8, 4.3 Hz), 2.39 (0.6H, td, J = 7.4, 4.3 Hz), 1.92-1.07 (6H, m), 1.37 (1.2H, d, J = 6.8 Hz), 1.31 (1.8H , d, J = 7.0 Hz), 1.01 (5.4H, s), 0.96 (3.6H, s), 0.85 (1.8H, t, J = 7.2 Hz) and 0.83 (1.2H, t, J = 7.2 Hz) . 13C-NMR; 6 (CDC13, mixture of rotamers), 175.7, 173.2, 171.3, 170.7, 56.7, 55.0, 54.4, 53.2, 50.8, 49., 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. LREM: + ve ion 366 [M + Na], -ve ion 342 [M-H].

Example 70 N-cyclohexyl -2 -. { 2 - [(formyl-hydroxy-amino) -methyl] -3-f-enyl-propionyl amino} - 3, 3-dimethyl-butyramide Concentrated solutions of 1M ammonia in methanol (1 mL, 1 mmol) and 1 M trimethylacetaldehyde in methanol (1 mL, 1 mmol) are mixed in a boiling tube and allowed to stand for 1 hour. A 1M solution of cyclohexyl isocyanide in methanol (1 ml, 1 mmol) is added followed by 0.5M [2-benzyl-oxy-formyl-amino] -methyl] hexanoic acid in methanol (2 ml, 1 mmol). The reaction mixture is allowed to stir at room temperature for 2 days. The solvent is removed using Savant Speedvac equipment and the reaction mixture is pre-crystallized from ethyl acetate-hexane to provide 2-. { 2- [(becyloxy-formyl-amino) -methyl] -3-phenyl-propionylamino} -N-cyclohexyl-3,3-dimethyl-butyramide as a white solid (93 mg, 18%), which is deprotected by catalytic transfer hydrogenolysis (gaseous hydrogen, 10% palladium on carbon, methanol-ethyl acetate) to provide the title compound (75 mg, 99%). White solid. LREM: + ve ion 440 [M + Na], 418 [M + H], -ve ion 416 [M-H].

The compounds of Examples 71 to 77 are prepared in a similar manner using the Ugi4 component of the condensation reaction, as described above. All products are obtained with > 85% purity, determined by CLAP.

Example 71 Cyclohexylamide of acid 2-. { 2- [(formyl-hydroxy-amino-methyl] -3-phenyl-propionyl amino} -3,3-dimethylhexanoic acid White solid (90 mg). -RMN; d (CD30D), 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, broad m), 1.44-1.05 (9H, broad m) and 0.8g (9H, s). LREM: tve ion 468 [M + Na], 446 [M + H], -ve ion 444 [M-H].

Example 72 2- Phenylmetilamide. { 2- [(formyl-hydroxy-amino) -methyl] -3-phenyl-propionyl amino} -3, 3-dimethylhexanoic White solid (77 mg). 'H-NMR; d (CD3OD), 7.82 (1H, s), 7.35-7.1 1 (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 (9H,). LREM: tve ion 476 [M + Na], 454 [M + H].

Example 73 2- Tert-butylamide. { 2- [(formyl-hydroxy-amino) -methyl] -3-phenyl-propionyl amino} -3, 3-dimethyl-butyric White solid (47 mg). 'H-NMR; d (CD3OD), 7.82 (1H, s), 7.45 (1H, m), 7.30-7.0g (5H, m), 4.12 (1H, d, J = 7.2 Hz), 3.8g (1H, m), 3.41 (1H, m), 3.15 (1H, m), 2.g7-2.68 (2H, m), 1.28 (gH, s) and 0.g2 (gH, s). LREM: + ve ion 414 [M + Na], 3 2 [M + H], -ve ion 3? [M-H] Example 74 (1, 1, 3, 3-tetramethyl) -butyramide of 2- acid. { 2- [(formyl-hydroxy-amino) -methyl] -3-phenyl-propionylamino} -3,3-dimethylhexanoic White solid (65 mg). -RMN; d (CD3OD), 7.7g (1H, s), 7.42-7.21 (1H, m), 7.20-7.10 (5H, m), 4.23 (1H, d, J = g, 1 Hz), 3.86 (1H, m ), 3.51 (1H, m), 3.23 (1H, m), 3.00-2.56 (2H, m), 1.50-1.15 (12H, m) and 1.02-0.83 (18H, m). LREM: + ve ion 498 [M + Na], 476 [M + H], -ve ion 474 [M-H].

Example 75 N- (cyclohexyl-hexylcarbamoyl-methyl) -2- [(formyl-hydroxy-amino) -methyl] -3-phenyl-propionamide White solid (98 mg). 'H-NMR; d (CD30D), 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, broad m) and 1. 45-0.83 (11H, broad m). LREM: tve ion 466 [M + Na], 444 [M + H], -ve ion 442 [M-H].

Example 76 N- (cyclohexyl-f-enylmethylcarbamoyl-metyl) -2- [(formyl-hydroxy-amino) -methyl] -3-f-enyl-propionamide White solid (34 mg). ? -RMN; d (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, broad m) and 0.75-0.51 (2H, broad m). LREM: + ve ion 474 [M + Na], -ve ion 450 [M-H].

Example 78 N- [cyclohexyl- (1,1,3, 3-tetramethyl-butylcarbamoyl) -methyl] -2- [(formyl-hydroxyamino) -methyl] -3-phenyl-propionamide White solid (51 mg). "H-NMR; d (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 (10H, m) and 1.08-0.83 (10H, m). LREM: + ve ion 496 [M + Na], 474 [M + H], -ve ion 472 [M-H].

Biological Example A Demonstration of antibacterial effect of compound 1 (example 1) and example 13 of compound 2 (example 2). to) . The minimal individual concentrations (MIC) of the inhibitors against E. coli strain DH5a (genotype, - F-f80d / acZ? M15? (LacZYA-argF) U16g deoR recAl endAl hedR17 (rk7 mk +) phoA supE44? "Thi-1 gyrA96 relAl) obtained from Gibco BRL Life Technologies, Enterobacter cloacae (American Type Culture Collection, No. 13047), Klebsiella pneumoniae (American Type Culture Collection, No. 13883) or Staphylococcus capitis (American Type Culture Collection, No. 35661), are determined as follows. The concentrated solutions of the test compound (compounds 1 and 2 from examples 1 and 2, respectively (both isomer A)) and three standard laboratory antibiotics, carbenicillin (Sigma, catalog number C3416), kanamycin (Sigma, catalog number K4000) and chloramphenicol (Sigma, catalog number C1919) are prepared by dissolving each compound in dimethyl sulfoxide at 10 mM. For the determination of the minimum inhibitory concentration, serial double dilutions are prepared and presented in 2xYT broth (tiptona 16 g / 1, yeast extract 10 g / 1, sodium chloride 5 g / 1 obtained from BIO 101 Inc., 1070 Joshua Way, Vista CA92083, USA), to provide 0.05 ml of compound containing medium, per well. The inocula are prepared from cultures grown overnight in 2xYT broth at 37 ° C. The cell densities are adjusted to absorbance at 660 nm (Ag60) = 0.1; the standardized preparations by optical density are diluted 1: 1000 broth 2xYT; and each well is inoculated with 0.05 ml of the diluted bacteria. The microtiter plates are incubated at 37 ° C for 18 hours in a humidified incubator. The MIC (μM) and the lowest drug concentration that inhibits visible growth are recorded.

Table 1 b) The minimum inhibitory concentrations (MIC) of the inhibitors against Mycrobacterium ranae (American Type Culture Collection, number 110), Pseudomonas aeruginosa (American Type Culture Collection, number 9027), Klebsiella pneumoniae (American) were determined as follows.

Type Culture Collection, number 10031), phíelico £ >acter pylori (American Type Culture Collection, number 43504), clinical isolates of Streptococcus pneumoniae resistance to aminoglycoside and erythromycin, and methicillin-resistant Staphylococcus aureus (MR) (American Type Culture Collection, number 33591). Concentrated solutions of test compounds 1 and 2 (isomer A for each) and three standard laboratory antibiotics, gentamicin (G), ampicillin (A) and erythromycin (E) are prepared by dissolving each compound at 10 mg / ml in dimethyl sulfoxide. The methods used were those used for part a), except that the medium for Mycobacterium ranae was used with brain heart infusion broth (GIBCO) and incubated at 37 ° C for 48 hours, using Staphylococcus aureus ( MR), Krebsiella pneumoniae and Pseudomonas aeruginosa with nutrient broth (DIFCO) and incubated at 37 ° C for 20 hours, Heli cobacter pylori is used with Columbia-based agar (OXOID) containing 7% sheep blood and incubated at 35 ° C. ° C for 72 hours, and Streptococcus pneumoniae with Tryptic Soy Broth (DIFCO) containing 7% bovine serum is used and incubated at 37 ° C for 48 hours. MIC (μg / ml) is recorded as the lowest drug concentration that inhibits visible growth.

The control of positive vehicle (DMSO 1% without test agent) causes the growth of all microorganisms. A negative blank control (absence of microorganisms; + test agent) shows that there is no growth of microorganisms.

Table 2 nd not determined.

In another experiment, the minimum inhibitory concentrations of compounds 1 and the product of Example 13 (compound 3) were determined against a range of Gram-positive and Gram-negative bacteria using the broth microdilution method, according to the standard tested by the National Committee for Clinical Laboratory Standards (Methids for dilution antimicrobial susceptibility tests for bacteria that aerobically-Fourth Edition ISBN l-56238-309-4).

Activity against Gram positive bacteria Activity against Gram negative bacteria The activities of compound 3 and the product of example 14 (compound 4) against a clinical isolate of multiresistant Enterococcus faecalis, determined by the method used for the immediately preceding results, is established in the following table and compared with the results obtained by the same method for known antibacterial agents.

Activity against clinical isolates of multiresistant Enterococcus feacalis Biological Example B i) Cloning of the Escheri chia coli PDF gene The PDF gene of E. coli is cloned into pET24a (+) (designated pTE24-PDF) and used to transform BL21 DE3 cells from Novagen Inc. (Madison, Wisconsin). Clones are selected at 37 ° C on YT agar plates (8 g / 1 tipone, 5 g / yeast extract, 5 g / 1 NaCl, 15 g / 1 agar) supplemented with 30 μg / ml kanamycin. ii) PDF expression An overnight culture of 20 ml of BL21 DE3 cells harboring pET24-PDF is used to infect 500 ml of 2xYT broth (16 g / 1 of tiptona, 10 g / 1 of wash extract, 5 g / 1 of NaCl ) containing 30 μg / ml kanamycin in a 2 liter baffled flask and grown at 37 ° C with agitation to a D0g00 of 0.6. Culture is then induced by adjusting the medium to 1.0 mM isopropyl β-D thiogalactopyranoside (IPTG). The induction is allowed to proceed for 3 hours at 37 ° C, the cells are harvested by centrifugation and the cell pellet is washed with 250 ml of phosphate buffered saline (PBS) and the pellet is stored at -70 ° C. iii) Preparation of the soluble protein fraction The cells of a 1 liter of expression are resuspended in 2 x 25 ml of ice-cold phosphate-buffered saline. The cell suspension is subjected to sonication on ice a MSE Soniprep 150 equipment to which a medium probe is placed at an amplitude of 20-25 micrometers in pulses of 60 x 20 seconds. The resulting suspeneion is then clarified by centrifugation at 20,000 x g for 15 minutes. The supernatant is then used for further purification of the enzyme. iv) PDF Purification The E. coli lysate from a culture of 1 1 in phosphate buffered saline (PBS) is adjusted with 2M ammonium sulfate. A 15 ml phenyl sepharose column is equilibrated with PBS / 2M ammonium sulfate at 4 ° C. The lysate is loaded onto the column and washed with equilibrium buffer. The column is eluted by reducing the concentration of ammonium sulfate from 2M to 0M with 10 column volumes. Fractions of 5 ml are collected and analyzed by SDS-PAGE. The fractions that have the most part of PDF 20 kDa are accumulated. The accumulated fractions are concentrated using a membrane with a limit of 3 kDa to a volume of 5 ml. The fraction is then loaded onto a Superdex 75 column (size exclusion chromatography) equilibrated in PBS. The concentrated PDF concentration is eluted at 1 ml / min, at 4 ° C and fractions of 5 ml are collected and analyzed by SDS-PAGE. The purest fractions are stored and accumulated at -70 ° C. v) PDF in vitro test The assay is performed on a single 6-well plate with a final volume of 100 μl, which contains: - 20 μl PDF (4 μg / ml) - 20 μl Hepes lOOmM pH 7.0 + 1M KCl + Brij 0.05% - 10 μl serial dilution of the test compound in DMSO 20% - 50 μl formyl-Met-Ala- Ser (8 mM) The assay is incubated at 37 ° C for 30 minutes. The free amino group of the deformylated product (Met-Ala-Ser) is detected using fluorescamine by the following additions: - 50 μl of 0.2M borate, pH 9.5 - 50 μl of fluorescamine (150 μg / ml in dry dioxane).

Fluorescence is quantified in an SLT Fluostar plate reader using an excitation wavelength of 390 nM and an emission wavelength of 485 nM. The standard control reactions are without reaction inhibitor which provides an amount of zero inhibition and without enzyme and reaction inhibitor ein, which provides the amount of 100% inhibition. The data are analyzed by conversion of the fluorescence units to% inhibition and the inhibitor concentration is plotted against% inhibition. The data are fitted to a sinoidal function: y = A + ((BA) / (1+ ((C / x) D))), where A represents zero inhibition, B represents 100% inhibition and C represents the IC50 , D represents the slope. The IC 50 represents the concentration of inhibitor (nM) necessary to decrease the activity of the enzyme by 50%. It is found that the compounds of the invention inhibit bacterial PDF in vi tro. In addition, it is also found that actinonin (Sigma, catalog number A-6671) also inhibits bacterial PDF in vitro.

Biological Example C Demonstration of compound 2 that inhibits PDF in vivo 1. Blocking the trans formylation reaction of tRNAi -Met confers resistance to compound 2 (diastereomer / shallow A) Trimethoprim specifically inhibits dihydrofolate reductase, thereby decreasing the accumulations of tetrahydrofolate derivatives (THF), including formyl tetrahydrofolate (fTHF), the methionyl-tRNA formyl transferase substrate (EC 2.1.2.9). If all the essential metabolites whose biosynthesis involves THF derivatives, for example pantothenate, methionine, glycine, purine nucleotides and thymidine are exogenously supplied in the form of precursor compounds in a rich medium supplemented with thymidine, then the bacteria grow in a rich medium. Thymidine (0.3 mM) and trimethoprim (100 μg / ml) can synthesize all the chemical compounds of normal cells, except f-Met-tRNAi (Baumstark, et al., J. Bacteriol 129: 457-471, 1977). Unformed Met-tRNAi is used which results in the formation of polypeptides lacking a formyl group in its N-terminal part, independent of the action of deformylase. As predicted by the inventors, DH5a cells grow in LB medium (tiptone 10 g / 1, yeast extract 5 g / 1, NaCl 10 g / 1, pH 7.5) supplemented with trimethoprim and thymidine, and found to be resistant to compound 2 (diastereomer TO) . The demonstration that cells undergoing normal formulation process on expressed proteins are inhibited by compound 2A, while non-formylated proteins, as produced in cells, grow under these conditions, and are not inhibited by compound 2A , demonstrates that compound 2A is likely to work by inhibiting the deformylation reaction carried out by PDF.

Table 3 Treatment of bacteria with compound 2A leads to accumulation of blocked proteins in the N-terminal part If the compounds of the invention actually inhibit PDF in vivo, then a consequence of treatment of bacteriae with compound 2 (example 2, diastereomer A) will be the accumulation of N-formyl methionine in the N-terminal part of the newly synthesized proteins. Such proteins will be blocked in the N-terminal part and will be unable to be used as a substrate for N-terminal sequencing by Edman degradation chemistry. To test hypothesis, a desired protein is expressed in the presence or absence of the test compound. The protein is isolated, purified and then subjected to protein sequencing by Edman degradation using techniques known to those skilled in the art. Bacterial cells transformed with an expression vector allow expression of the small regulatory safety of human calpain and grow to an OD 600 of 0.6 and then subjected to IPTG to induce the expression of the heterologous protein in the presence of 200 μM of compound 2A in presence of 240 μM carbenicillin or, in the presence of control vehicle for 2.5 hours. The protein extracts are separated by SDS-PAGE, the eubunit of calpain elutes and the protein sequence is determined by Edman degradation chemistry using an ABI automated protein sequencer. Sequences equal amounts of protein. The inventors found that the yield of compound 2A of treated protein is reduced significantly at 85% compared to the vehicle and controls treated with carbecillin. Small regulatory subunits of calpain are cloned from messenger RNA obtained from a gastric tumor biopsy using the Invitrogen Micro Fats Track mRNA isolation kit "R version 2.2 (catalog number K1520-02) .The DNA copy of this mRNA is synthesized using a Promega Riboclone cDNA synthesis system "" M-MLV-RT (H-), Notl (Promega, catalog number C1660) according to the manufacturer's instructions Two oligonucleotide primers are synthesized for use in the reaction in polymerase chain (PCR) by Applied Biosystems, Inc., Custo, Services, based on the sequence of the published small subunit of calpain (EMBL, accession number X04106) The HindIII / Xhol calpain fragment is then cloned into the directed expression vector with HindIII and Xhol pET24d (+) from Novagen Inc., (Madison, WI, USA) using standard procedures.The ligation mixture is used to transform competent DH5a cells (Life Technologi is, Inc., Grand Ieland, NY, USACat # 18265-017). Lae colonye are selected by growth overnight at 37 ° C on YT plates plus 30 μg / ml kanamycin. Plasmid DNA is prepared as used in the Promega Plus SV miniprep kit and clones with the calpain insert are identified using standard procedures. The sequence is confirmed of DNA using the cycle sequencing of Applied Biosystems PE as described above. The E. coli gene cloned in pET24d (+) (designated pET24-CANS) is used to transform BL21 DE3 cells from Novagen Inc., (Madison, Wisconsin). The clones are selected at 37 ° C on YT agar plates (8 g / 1 of tiptona, 5 g / 1 of yeast extract, 5 g / 1 of NaCl, 5 g / 1 of agar) supplemented with 30 μg / ml of kanamycin. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.

Claims

1. The use of a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof, in the preparation of an antibacterial composition: characterized in that: R represents hydrogen or Ci-Cg alkyl or alkyl substituted by one or more halogen atoms; R2 represents a group R10- (X) "- (ALK)" wherein R10 represents hydrogen or a C1-C6 alkyl group, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, aryl or heterocyclyl, any of which which may be unsubstituted or substituted by C2-C6 alkyl, Cj-Cg alkoxy, hydroxy, mercapto, Cj-Cg alkylthio, amino, halo (including fluoro, chloro, bromo and iodo), trifluoromethyl, cyano, nitro , -COOH, -C0NH2, -COORA, -NHC0R- -CONHRA, -NHRA, -NRARB, or -CONRARB wherein Rs and RB are independently an alkyl group of and ALK represents a linear or branched divalent radical of C2-C6 alkenylene alkylene or C2-C6 alkynylene, and which may be interrupted by one or more adjacent bonds of -NH-, -0- or -S-, X represents -NH-, -0- or -S-, and m and n are independently 0 or 1; and A represents (i) a group of formula (IA), (IB), (IC) or (ID) (IA) (IB) (ID) (IC) where: R3 represents hydrogen and R4 represents the side chain of a natural or unnatural alpha amino acid, or R3 and R4, when taken together with the nitrogen atoms and carbon to which they are attached respectively, form an optionally substituted saturated heterocyclic ring of 5 to 8 atoms, ring which is optionally fused to a carbocyclic ring or second heterocyclic ring, Rs and R6, independently represent hydrogen 0 Cj-Cg alkyl optionally substituted, cycloalkyl, aryl, arylalkyl of Cj-Cg, heterocyclic or heterocyclic Cj-Cg alkyl, or R5 and R6, when taken together with the nitrogen atom to which they are attached, form a ring optionally substituted saturated heterocyclic of 3 to 8 atoms, ring which is optionally fused to a carbocylic ring or second heterocyclic ring, and R7 represents hydrogen, alkyl of or an acyl group.

2. A method for the treatment of bacterial infections in human and non-human mammals, characterized in that it comprises administering to a subject suffering from such infection, an effective antibacterial dose of a compound of formula (I), according to claim 1.

3. The use in accordance with the claim 1 or a method according to claim 2, characterized in that the compound of formula (I): R x represents hydrogen or C 1 -C alkyl; R2 represents a group R10- (X) "- (ALK) - where ' R10 represents hydrogen or an alkyl group of C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, aryl or heterocyclyl, any of which may be unsubstituted or substituted by C2-C3 alkyl, C6 alkoxy, hydroxy , mercapto, C1-C6 alkylthio, amino, halo (including fluoro, chloro, bromo, and iodo), trifluoromethyl, cyano, nitro, -COOH, -CONH2, -COORA, -NHCORA, -CONHRA, -NHR -NRARB or - CONR - RB where RA and RB are independently an Ci-Cg alkyl group, and ALK represents a divalent linear or branched radical of C 1 -C 6 alkylene, C 2 -C 6 alkenylene or C 2 -C 6 alkynylene, and which may be interrupted by one or more adjacent bonds of -NH-, -O- or -S-, X represents -NH-, -O- or -S-, and n is 0 or 1; and R3 represents hydrogen or C3-Cg alkyl, and R4 represents the side chain of a natural or unnatural alpha amino acid, and R5 and R6 independently represent hydrogen or alkyl of or Rs and R6, when taken together with the nitrogen atom to which they are attached, they form an optionally substituted saturated heterocyclic ring of 3 to 8 atoms, and R7 represents hydrogen or an acyl group.

4. a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof characterized in that R x represents hydrogen, C 1 -C 6 alkyl or Ci-Cg alkyl substituted with one or more halogen atoms; R2 represents a group R10- (ALK) m- wherein R10 represents hydrogen or an alkyl group of Cj-Cg, C2-C6 alkenyl, C2-C3 alkynyl, a cycloalkyl, aryl or heterocyclyl, any of which may be unsubstituted or substituted by alkoxy of Cj-Cg, hydroxy, mercapto, alkylthio of Cj-Cg, amino, halo (including fluoro, chloro, bromo and iodo), trifluoromethyl, nitro, -COOH, -CONH2, -COOR \ -NHCORA, -CONHR \ -NHRA, -NRARB, or -CONRARB, where Rs and RB are independently an alkyl group of Cj-Cg. ALK represents a linear or branched divalent radical of alkenylene of C2-C6 alkenylene, C2-C6 alkynylene, and can be interrupted by one or more non-adjacent bonds of -NH-, -0- or -S-, and m represents 0 or 1; A represents (i) a group of formula (IA), (IB), (IC) or (ID) (IA) (IB) (ID) (IC) where- R3 represents hydrogen and R4 represents the side chain of a natural or unnatural alpha amino acid, or R3 and R4, when taken together with the nitrogen and carbon atoms to which they are attached respectively , form an optionally substituted saturated heterocyclic ring of to 8 atoms, ring which is optionally fused to a carbocyclic ring or second heterocyclic ring, R5 and R6, independently represent hydrogen or Cj-Cg alkyl. optionally substituted, cycloalkyl, aryl, C3-Cg arylalkyl, heterocyclic or heterocyclic alkyl, or R5 and R6, when taken together with the nitrogen atom to which they are attached, form an optionally substituted saturated heterocyclic ring of 3 to 8 atoms , ring which is optionally fused to a carbocylic ring or second heterocyclic ring, and R7 represents hydrogen, C1-C1 alkyl or an acyl group. WITH THE CONDITION THAT (i) when A is a group of formula (IA) or (IB) and R2 is C2-C5 alkyl, then R4 is not the side chain of a natural alpha amino acid or the side chain of an alpha natural amino acid in which any functional substituent is protected, any amino group is acylated and any carboxyl group is esterified; (ii) when A is a group of formula (IA) or (IB) then R4 is not a bicyclicarylmethyl group; and (iii) when A is a group of formula (IA) and R 2 is cyclopropylmethyl, cyclobutylmethyl or cyclopentylmethyl and one of Rs and Rβ is hydrogen, then R4 is not terbutyl. (iv) when R ^ is hydrogen and A is a group of formula (IA) wherein -NRsRg is a 2-carboxylpyrrolidino group, R4 is methyl and R3 is hydrogen, then R2 is not hydrogen; (v) R2 is a linear saturated or unsaturated C13-C24 hydrocarbon chain, optionally substituted by alkyl of hydroxy, methoxy, amino, halo (including fluoro, chloro, bromo and iodo), -COOH, -CONH2, -COORA, -NHCORA, -CONHRA, -NHRA, -NRARB, or -CONRARB where RA and RB are independently methyl; and (vi) when R1 is hydrogen and A is a group of formula (ID), wherein Rs is methyl and R6 is hydrogen, then R2 is not benzyl.

5. The compound according to claim 4, characterized in that: Rj represents hydrogen or alkyl of R 2 represents a group R 1 0 - (ALK) - wherein R 10 represents hydrogen or an alkyl group of C 1 -C 1, C 2 -C 6 alkenyl, alkynyl of C2-C6, a cycloalkyl, aryl or heteroaryl, any of which may be unsubstituted or substituted by alkyl of Cj-C8 alkoxy, hydroxy, mercapto, Cth-Cg alkylthio, amino, halo (including fluoro, chloro, bromine and iodine), trifluoromethyl, nitro, -COOH, -CONH2, -COORA, -NHCOR \ -CONHRA, -NHRA, -NRARB, or - CONRARB, wherein RA and RE are independently an alkyl group of ALK represents a linear or branched divalent radical of alkenylene of C2-C6 alkenylene, C2-C6 alkynylene, and may be interrupted by one or more non-adjacent bonds of -NH -, -0- or -S-; R3 represents hydrogen or C3-Cg alkyl, and R4 represents the side chain of a natural or unnatural alpha amino acid, and ¡and E1 independently represent hydrogen or Ci-Cg alkyl, or Rs and R6, when taken together with the nitrogen atom to which they are attached form an optionally substituted saturated heterocyclic ring of 3 to 8 atoms, and R7 represents hydrogen or an acyl group; WITH THE CONDITION THAT (a) when A is a group of formula (IA) then: (i) R, is not the side chain of a natural alpha amino acid or the side chain of a natural alpha amino acid in which any functional substituent is protected, any amino group is acylated and any carboxyl group is esterified; R4 is not a fused bicyclicrilmethyl group, and (iii) R4 is not terbutyl when R2 is cycloalkyl (Cj-C6 alkyl); and (IV) R2 is not a linear saturated or unsaturated C13-C24 hydrocarbon chain optionally substituted by alkyl of d-C8, hydroxy, methoxy, amino, halo (including fluoro, chloro, bromo, and iodo), -COOH, -CONH2, -COORA, -NHCOR -CONHRA, -NHRA, -NRARB, or -CONRARB wherein RA and RB are independently methyl; and (b) when Ri is hydrogen and A is a group of formula (ID), wherein Rs is methyl and R6 is hydrogen, then R2 is not benzyl.

6. The use according to claim 1, the method according to claim 2 or the compound according to claim 4, characterized in that, in the compound of formula (I), R is hydrogen.

7. The use in accordance with the claim 1, the method according to claim 2, or the compound according to claim 4, characterized in that in the compound of formula (I), R 2 is: C 1 -C 6 alkyl, optionally substituted, C 3 -C 6 alkenyl, C3-C6 alkynyl or cycloalkyl; phenyl (C, -C6 alkyl) -, phenyl (C3-C6 alkenyl) - or phenyl (C3-C3 alkenyl) - optionally substituted on the phenyl ring; cycloalkyl (C 1 -C alkyl), cycloalkyl (C 3 -C 8 alkenyl) - or cycloalkyl (C 3 -C 6 alkynyl), optionally substituted on the cycloalkyl ring; heterocyclyl (C 1 - alkyl, heterocyclyl (C 3 - alkenyl) C6) - or heterocyclyl (C3-C6 alkynyl) - optionally substituted on the heterocyclyl ring; or CH3 (CH2) pO (CH2) q- or CH3 (CH2) pS (CH2) q-, where p is 0.1 , 2 or 3 and q is 1, 2 6 3.

8. The use according to claim 1, the method according to claim 2, or the compound according to claim 4, characterized in that, in the compound of formula (I), R 2 is methyl, ethyl, n- and iso -propyl, n- and iso-butyl, n-pentyl, iso-pentyl, 3-methyl-but-l-yl, n-hexyl, n-heptyl, n-acetyl, n-octyl, methylsulfonylethyl, ethylsulfanylmethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-ethoxymethyl, 3-hydroxypropyl, allyl, 3-phenylprop-3-en-1-yl, prop-2-yn-l-yl, 3-f enylpro-2-in-l -yl, 3- (2-chloro-enyl) prop-2-yn-l-yl, but-2-yn-l-yl, cyclopentyl, cyclohexyl, cyclopentelmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, furan- 2-ylmethyl, furan-3-methyl, tetrahydrofuran-2-ylmethyl, tetrahydrofuran-2-ylmethyl, piperidinylmethyl, f-enylpropyl, 4- chlorophenylpropyl, 4-methylphenylpropyl, 4-methoxyphenylpropyl, benzyl, 4-chlorobenzyl, 4-methylbenzyl and 4-methoxybenzyl.

9. The use according to claim 1, the method according to claim 2, or the compound according to claim 4, characterized in that, in the compound of the formula (I), R2 is n-butyl, benzyl or cyclopentylmethyl .

10. The use in accordance with the claim 1, the method according to claim 2, or the compound according to claim 4, characterized in that, in the compound of formula (I), R 3 is hydrogen.

11. The use according to claim 1, the method according to claim 2, or the compound according to claim 4, characterized in that, in the compound of formula (I), R4 is: the defining group of an amino acid natural, for example benzyl, or 4-methoxyphenylmethyl, in which any functional group may be protected, any amino group may be acylated and any carboxyl group present may be amidated; or a group - [Alk] _R9 wherein Alk is an alkylene group of Ci-C8 or alkenylene of C2-C6, optionally interrupted by one or more atoms of -0- or -S-, or groups -N (R12) - in where R12 is a hydrogen atom or a Ci-C8 alkyl group, n is 0 or 1 and R9 is hydrogen or an optionally substituted phenyl group, aryl, heterocyclyl, cycloalkyl or cycloalkenyl or (only when n is 1) R9 may additionally be hydroxy, mercapto, Ci-Cg alkylthio, amino, halo, trifluoromethyl, nitro, -COOH, -C0NH2, -C00RA, -NHC0RA, -C0NHRA, -NHRA, -NRARB, or -C0NRARB wherein RA and RB are independently an alkyl group of Cj-Cg, - or a benzyl group substituted on the phenyl ring by a group of formula -0CH2C0Rβ wherein R8 is hydroxyl, amino, Cj-Cg alkoxy, C3-Cg phenylalkoxy, C1-C6 alkylamino, di (amino alkyl, Ci-Cg phenylalkylamino, - or a heterocyclic Cj-Cg alkyl group, whether unsubstituted or mono- or di-substituted on the heterocyclic ring with halo, nitro, carboxy, C1-Cβ alkoxy, cyano, Cj-Cg alkanoyl, trifluoromethylalkyl of Cj-Cg, hydroxy, formyl, ammo, C 1 -C 8 alkylamino , dialkyl (Ci-Cg) amino, mercapto, hydroxyalkyl alkylthio of C-C6 mercaptoalkyl or alkyl (Cj-Cg) phenylmethyl; or a group -CR, RbRc in which: each of Ra, Rb and Rc is independently hydrogen, C2-C3 alkenyl alkyl, C2-C6 alkynyl, phenylalkyl of Cj-Cg, C3-Cβ cycloalkyl; or R. is hydrogen and R, and Rb are independently phenyl or heteroaryl such as pyridyl; or Rc is hydrogen, d-Cg alkyl, alkenyl C2-C6, C2-C6 alkynyl, phenylalkyl of Cj-Cg or C3-Cβ cycloalkyl, and R, and Rb together with the carbon atom to which they are attached, form a 3- to 8-membered cycloalkyl or a heterocyclic ring from 5 to 6 members; or R. < and o together with the carbon atom to which they are attached, form a tricyclic ring (for example adamantyl), - or R and _ > are each independently Cx-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenylalkyl Cj-Cg or a group as defined for R. below, other than hydrogen, or R, and R ", together with the carbon atom to which they are attached, form a cycloalkyl or heterocyclic ring, and 0 is hydrogen, -OH , -SH, halogen, -CN, -C02H, perfluoroalkyl of -CH2OH, -C02 alkyl of Cj-C8, -O alkyl of d-Cg, -O alken that of C2-C6, -S alkyl of -8, - SO alkyl of -S02-S-alkenyl alkyl of C2-C6, -SO alkenyl of C2-C6, -S02 alkenyl of C2-C6 or a group -QW, wherein Q represents a bond -O-, -S-, -S0- or -S02- and W represents a phenyl group, phenylalkyl, C3-Cß cycloalkyl, C3-C8 cycloalkylalkyl, C4-Cß cycloalkenyl, C4-C8 cycloalkenylalkyl, heteroaryl or heteroarylalkyl, group W which is optionally substituted by one or more substituents that are independently selected from hydroxyl, halogen, - CN, -C02H, -C02 C3-Cg alkyl, -C0NH2, -CONH alkyl of CÍ-CJ, -CONH (C1-C alkyl,) 2, -CHO, -CH20H, perfluoroalkyl of CJ-CÍ, -0 alkyl of -S alkyl of -SO alkyl of Ci-Cg, -S02 alkyl of Cj-C ,, -N0_, -NH2, -NH alkyl of Cj-Cg, -N (alkyl of -NHCO alkyl alkyl of Cj- Cg, C2-C6 alkenyl, C2-C6 alkynyl, C3'-Ca cycloalkyl, C4-Cβ cycloalkenyl, phenyl or benzyl.

12. The use according to claim 1, the method according to claim 2 or the compound according to claim 4, characterized in that, in the compound of formula (I) R 4 is methyl, ethyl, benzyl, 4-chlorobenzyl, 4-hydroxybenzyl, phenyl, cyclohexyl, cyclohexylmethyl, pyridin-3-ylmethyl, tert-butoxymethyl, naphthylmethyl, isobutyl, sec-butyl, tertbutyl, 1-benzylthio-1-methylethyl, 1-methylthio-1-methylethyl, 1- mercapto-1-methylethyl, 1-methoxy-1-methylethyl, 1-hydroxy-1-methylethyl, 1-fluoro-1-methylethyl, 2-hydroxyethyl, 2-carboxyethyl, 2-methylcarbamoyl, 2-carbamoylethyl or 4-aminobutyl.

13. The use according to claim 1, the method according to claim 2 or the compound according to claim 4, characterized in that, in the compound of formula (I), R 4 is tert-butyl, iso-butyl, benzyl or methyl.

14. The use according to claim 1, the method according to claim 2 or the compound according to claim 4, characterized in that, in the compound of formula (I), R3 and R4, when taken together with the atoms of nitrogen and carbon to which they are respectively attached can form an optionally substituted saturated heterocyclic ring of 5 to 8 atoms.

15. The use according to claim 1, the method according to claim 2 or the compound according to claim 4, characterized in that, in the compound of formula (I), R3 and R4 form a bridge between the nitrogen atoms and carbon to which they are attached, the bridge is represented by the divalent radical - (CH2) 3.6, or - (CH2) r- or - (CH2) "-, or - (CH2) rS- (CH2)" -, where r and s are each independently 1, 2 or 3, with the proviso that r + s = 2, 3, 4 or 5.

16. The use according to claim 1, the method according to claim 2 or the compound according to claim 4, characterized in that, in the compound of formula (I), R5 and R6 are independently hydrogen, methyl, ethyl, tert-butyl, cyclopentyl, cyclohexyl, 1,1,3,3-tetramethylbutyl, benzyl, or 2-hydroxyethyl.

17. The use according to claim 1, the method according to claim 2 or the compound according to claim 4, characterized in that, in the compound of formula (I), R5 and R6, when taken together with the atom of nitrogen to which they are attached, form a 5 to 8 membered monocyclic n-heterocyclic ring, saturated, which is attached via the N atom and which optionally contains -N (R31) - wherein Rlx is hydrogen or akyl of Cj-Cg, benzyl, acyl or an amino protecting group, O, S, SO, or S02 as a ring member, and / or is optionally substituted on one or more C atoms by hydroxy, alkyl, alkoxy, oxo, ketalized oxo, amino, mono (Cj-Cg alkyl) amino, di (amino alkyl, carboxy, hydroxymethyl alkoxycarbonyl, C1-Cg alkoxymethyl, carbamoyl, mono (Cj-Cg alkyl) carbamoyl, di (alkyl) of Cj-Cg) carbamoyl or hydroxyimino.

18. The use according to claim 1, the method according to claim 2 or the compound according to claim 4, characterized in that, in the compound of formula (I), R5 and Rg, when taken together with the atom of nitrogen to which they are attached, form a substituted or unsubstituted ring of 1-pyrrolidinyl, piperidin-1-yl, 1-piperazinyl, hexahydro-1-pyridazinyl, morpholin-4-yl, tetrahydro-1,4-thiazin-4 -yl, tetrahydro-1,4-thiazin-4-yl-1-oxide, tet rahydro-1,1-dioxide, 1,4-tiaz-4-i-1, t-iia-iin idin-3-i 1, hexahydroazipine or octahydroazocine.

19. The use according to claim 1, the method according to claim 2 or the compound according to claim 4, characterized in that, in the compound of formula (I), Rs and R6, when taken together with the atom of nitrogen to which they are attached, form a substituted or unsubstituted ring of 1-pyrrolidinyl, piperidin-1-yl, 1-piperazinyl, hexahydro-1-pyridazinyl, morpholin-4-yl, tetrahydro-1,4-thiazin-4 -yl, tetrahydro-1,4-thiazin-4-yl, 1,1-tetrahydro-1,4-thiazin-4-yl, hexahydroazipine or octahydroazocine dioxide; the substituted examples of the above are 2- (methylcarbamoyl) -1-pyrrolidinyl, 2- (hydroxymethyl) -1-pyrrolidinyl, 4-hydroxypiperidino, 2- (methylcarbamoyl) piperidino, 4-hydroxyiminopiperidino, 4-methoxypiperidino, 4-methylpiperidin-1-yl, 4-benzylpiperidin-1-yl, 4-acetylpiperidin-1-yl, 4-methyl-1-piperazinyl, 4-phenyl-1 -piperazinol, 1,4-dioxa-8-azaspiro [4.5] decan-8-yl, hexahydro-3- (methylcarbamoyl) -2-pyridazinyl, and hexahydro-1- (benzyloxycarbonyl) -2-pyridazinyl, decahydroisoquinoline- 2-yl, or 1, 2, 3, 4-tetrahydroisoquinolin-2-yl.

20. The use according to claim 1, the method according to claim 2 or the compound according to claim 4, characterized in that, in the compound of formula (I), R7 is hydrogen or a group R20C (O) - wherein R20 is a C1-C6 alkyl group such as methyl or ethyl.

21. The use according to claim 1, the method according to claim 2 or the compound according to claim 4, characterized in that, in the compound of formula (I), R20 is methyl or ethyl.

22. The use according to claim 1, the method according to claim 2 or the compound according to claim 4, characterized in that, in the compound of formula (I), A represents a group of formula (IA), Rt represents hydrogen, R2 represents n-butyl, benzyl or cyclopentylmethyl, R3 is hydrogen, R4 is tert-butyl, isobutyl, benzyl or methyl, R5 is hydrogen or methyl and R6 represents methyl.

23. The use according to claim 1, the method according to claim 2 or the compound according to claim 4, characterized in that, in the compound of formula (I), A represents a group of formula (IB), R1 represents hydrogen, R 2 represents n-butyl, benzyl, or cyclopentylmethyl, R 3 is hydrogen, and R 4 is tert-butyl, iso-butyl, benzyl or methyl.

24. The 2R (or S) - [(formyl-hydroxy-amino) -methyl] -hexanoic acid (lS-dimethylcarbamoyl-ethyl) -amide, or a pharmaceutically or veterinarily acceptable salt thereof.

25. 2R (or S) - [(formyl-hydroxy-amino) -methyl] -3-cyclopentyl-propioic acid (lS-dimethyl-carbamoyl-2, 2-dimethyl-propyl) -amide, or a pharmaceutically or veterinarily salt acceptable of it.

26. A compound according to claim 4, characterized in that it is described in any of Examples 1-3, 5-13, or 15-78, or a pharmaceutically or veterinarily acceptable salt thereof.

27. A pharmaceutical or veterinary antibacterial composition, characterized in that it comprises a compound according to any of claims 4 to 26, together with a pharmaceutically or veterinarily acceptable carrier or excipient.

28. A method for the identification of antibacterial compounds, characterized in that it comprises: (i) analyzing test compounds to determine activity as inhibitors of PDF in vi, (ii) analyzing those compounds which show inhibitory activity for PDF in order to determine capacity to inhibit bacterial growth.

29. The use of a compound, characterized in that it inhibits the activity of bacterial PDF, in the preparation of an antibacterial composition or agent, with the proviso that (i) the compound is not of formula (XI) RCO-CH (W) -NH-CO (Y) -CH-CH 2 -CO-NH-OH (XI) wherein, (a) R is an aminocyclic group, W is hydrogen, methyl, isopropyl, isobutyl or benzyl, and Y is hydrogen, C1-C3 alkyl, phenyl, benzyl, 4-chlorophenylmethyl, 4-nitrophenylmethyl or 4-aminophenylmethyl; or (b) R is 2-pyridylamino or 2-thiazolylamino, W is isopropyl and Y is n-pentyl; or (c) R is diethylamino, W is methyl or isopropyl, and Y is n-pentyl; or (ii) the compound is not one that contains a divalent piperazin-1,6-diyl group.

30. A method for treating an infection or bacterial contamination by administering to a patient suffering from such infection or contamination, or by applying to the site of such infection or contamination, an antibacterial effective amount of a compound which inhibits the activity of the bacterial PDF enzyme , with the proviso that: (i) the compound is not of formula (XI) RCO-CH (W) -NH-COCH (Y) -CH 2 -CO-NH-OH (XI) wherein, (a) R is an aminocyclic group, W is hydrogen, methyl, isopropyl, isobutyl or benzyl, and Y is hydrogen, C-C3 alkyl? phenyl, benzyl, 4-chlorophenylmethyl, 4-nitrophenylmethyl or 4-aminophenylmethyl; or (b) R is 2-pyridylamino or 2-thiazolylamino, W is isopropyl and Y is n-pentyl; or (c) R is diethylamino, W is methyl or isopropyl, and Y is n-pentyl, or (ii) the compound is not one that contains a divalent piperazin-1,6-diyl group.