WO2014191789A1

WO2014191789A1 - New cationic amino acids, pharmaceutical compositions containing the same and their use for the treatment of bacterial infections

Info

Publication number: WO2014191789A1
Application number: PCT/IB2013/001772
Authority: WO
Original assignee: Universite Pierre Et Marie Curie (Paris 6); Centre National De La Recherche Scientifique; KAROYAN, Philippe; MOUMNE, Roba; BOULLET, Héloise
Priority date: 2013-05-27
Filing date: 2013-05-27
Publication date: 2014-12-04
Also published as: WO2014191392A1

Abstract

The present invention relates to new cationic amino acids pharmaceutical compositions containing the same and their use for the treatment of bacterial infections.

Description

NEW CATIONIC AMINO ACIDS, PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME AND THEIR USE FOR THE TREATMENT OF

BACTERIAL INFECTIONS

Increasing bacterial resistance and the lack of new anti-infective agents have become major public health problems (Citro, G.; Perrotti, D.; Cucco, C; D'Agnano, I.; Sacchi, A.; Zupi, G; Calabretta, B. PNAS 1992, 89, 7031-7035). Only four new infectious agents have been developed over the last 20 years, i.e. linezolid, daptomycin, tigecycline and telavancin (Luo, D.; Saltzman, W. M. Nat Biotech 2000, 18, 33-37). In addition, the emergence of hospital bacterial Gram (+) strains (Staphylococcus aureus) and Gram (-) (Escherichia coli and Klebsiella pneumoniae) methicillin-resistant or with a plasmid carrying the gene NDM-1 (conferring resistance to most antibiotics, including fluoroquinolones, aminoglycosides, all beta-lactams including carbapenems, which are the drugs of last resort) are indicators of the urgency to launch research programs to discover new anti- infectious agents (Frankel, A. D.; Pabo, C. O. Cell 1988, 55, 1189-1193; Green, M.; Loewenstein, P. M. Cell 1988, 55, 1179- 1188; Joliot, A.; Pernelle, C; Deagostini-Bazin, H.; Prochiantz, A. PNAS 1991, 88, 1864- 1868; Vives, E.; Brodin, P.; Lebleu, B. J. Biol. Chem. 1997, 272, 16010-16017 ; Derossi, D.; Calvet, S.; Trembleau, A.; Brunissen, A.; Chassaing, G; Prochiantz, A. J. Biol. Chem. 1996, 271, 18188-18193; Elmquist, A.; Lindgren, M.; Bartfai, T.; Langel, U. Exp. Cell Res. 2001, 269, 237-244; Elliott, G; O'Hare, P. Cell 1997, 88, 223-233).

However, despite all these warning signs, the pharmaceutical industry is reluctant to date to launch programs in this sense for many reasons, all related to the economics of such a challenge: the discovery of a new drug requires fifteen years of research with an estimated $ 1 billion cost and no guarantee of success. In the case of antibiotics, the discovery of new anti- infective agents is correlated to the rapid appearance of resistant strains, not allowing a return on investment for the company (Bloquel, C; Fabre, E.; Bureau, M. F.; Scherman, D. J. Gene Med. 2004, 6, SI 1-S23 ; Ryser, H. J.; Hancock, R. Science 1965, 150, 501-503).

The discovery of anti- infective agents presenting an original mechanism of action liable to prevent the appearance of resistant bacterial strains after the treatment outcomes would be an interesting solution for the pharmaceutical industry. Like the majority of antibiotics the mechanism of action of which is related to the inhibition of enzymes involved in the biosynthesis of the bacterial cell wall, the cationic antimicrobial peptides (CAPs) kill bacteria by interacting with the cytoplasmic membrane and destroying it (Zasloff, M.; Nature 2002, 415, 389-395). This mode of action makes it unlikely the appearance of resistant bacterial strain and is therefore a promising line of research. CAPs have been identified in all the animal kingdom and 1200 are listed in the databases of peptides (Morris, M.; Vidal, P.; Chaloin, L.; Heitz, F.; Divita, G. Nucl. Acids Res. 1997, 25, 2730- 2736 ; Morris, M. C; Depollier, J.; Mery, J.; Heitz, F.; Divita, G. Nat Biotech 2001, 19, 1173- 1176). These are generally amphiphilic peptides of 20-50 residues. The large size of these peptides (responsible for adverse immune reactions and difficult to use on an industrial scale because of the prohibitive cost of production) their pharmacokinetic profile and proteolytic instability are major obstacles to the use of these CAPs as medicaments (Dietz, G. P.; Bahr, M. Mol. Cell Neurosci. 2004, 27, 85-131).

The development of stable small CAPs candidates could help remove these locks.

In 1996, the screening of a combinatorial hexapeptide rich in tryptophan and arginine residues library helped highlight the importance of these two amino acids in the bactericidal activity of CAP. Although the role of these residues is not fully understood, it appears that the cationic nature of arginine and its ability to form hydrogen bonds are paramount. Hydrophobic properties and the quadrupole moment of tryptophan are also major elements explaining the properties of these small peptides in their ability to interact with membranes. These peptides consist of natural amino acids and are unstable against proteolytic degradation.

Haug B. E. et al (Synthetic Antimicrobial Peptidomimetics with Therapeutic Potential, J. Med. Chem., 2008, 51, 4306-4314) disclose synthetic antimicrobial peptidomimetics (SAMPs) having activity against Gram-negative and Gram-positive bacterial strains.

However, these compounds also present instability against proteolytic degradation due to the natural amino acid structure.

The appearance of biofilms, bacterial contamination and the development of marine bio films on submerged structures are recurring and very expensive problems. However, the use of antibacterial compounds that are harmful to the ecosystem is now banned.

The micro-organisms living in an aqueous medium can be observed in two forms: planktonic (suspended in their natural surroundings) or in a biofilm. Biofilm is the result of adhesion, development and cooperation within a community of micro-organisms. A biofilm is composed of nutrients, living or dead microorganisms and extracellular matrix. Through the flow channels in its matrix, the biofilm can carry oxygen and nutrients to the upper layers of micro-organisms, to remove the waste towards the outside and to protect the microorganisms from external attacks. The extracellular matrix is composed of water (95%) and extracellular polymeric substances (EPS) comprising polysaccharides (40-95%), proteins (1-60%), nucleic acids (1 to 10%>) and lipids (1-40%). In the case of submerged marine surfaces, the biofilm is often a point of attachment for macroscopic organisms such as algae, shellfish and some invertebrates.

The biofilm is formed in several steps: formation of a primary film, adhesion of microorganisms, growth and secretion of EPSs, and finally the formation of biofilm.

The formation of said primary film starts from the introduction of a surface in the marine environment. It modifies the physicochemical properties of said surface and facilitates the future adhesion of microorganisms. Simultaneously with the formation of this film, there is a transport of microorganisms to the surface either passively (current or diffusion) or in an active way, thanks to the presence of flagella or pili on some strains of bacteria. The grip of microorganisms on the surface is in two stages: the reversible adsorption involving weak interactions (hydrogen bonds, Van der Waals force...). Then, the so-called irreversible adhesion stage involving biological phenomena, such as the expression of genes involved in adhesion, production of biopolymers or communication between cells.

Cells will create strong interactions with the surface (dipole-dipole, polymeric bridges...), but also with each other via the EPSs, reinforcing their adhesion. After adhesion, micro-organisms multiply, form microcolonies, followed by the consequent maturation and structuration of the biofilm. The biofilm begins to structure in the shape of columns or fungi comprising microorganisms within the extracellular matrix, said matrix comprising circulation channels.

It has been observed that these channels provide more nutrients to the outer layers of the biofilm: in the most hidden layers, there are fewer bacteria and they grow less rapidly due to the depletion of nutrients. When nutrients are lacking or when the biofilm reaches full maturity, sessile bacteria return to the planktonic state, a new cycle of surface colonization and biofilm development begins. This cycle of biofilm formation occurs with all types of bacteria (Gram-positive and Gram-negative).

The recurring problem in the control of marine biofilms is the complexity and biodiversity of micro-organisms in the marine world (between 3500 and 4500 species of phytoplankton), which does not allow the use of targeted active ingredients. On the other hand, polluting paints based on tin, lead or copper are commonly used. An alternative to these paints is the grafting of materials comprising natural biocides such as PMAs. If these later are promising, their size (high production costs) and their instability over time are severe drawbacks. In another aspect, nosocomial infections are a major public health problem and 80% of these opportunistic infections are the result of biofilms. Biofilms on the surface of medical devices carry the bacteria that cause hospital-acquired infections and serve as a reservoir for plasmids tha carry genes of antibiotic resistance. It is possible to limit the development of biofilms by grafting for example antibiotics on medical equipment, but this approach does not avoid the emergence of resistant strains.

Therapeutic requirements and the desire to understand the mechanisms that govern cellular function led, in recent years, to the development of many strategies based on the intracellular import of proteins, DNA and other bioactive compounds. However, the hydrophobic nature of the membrane and the absence of cellular carriers that are specific to these compounds render difficult the import into the cell.

Several solutions have been proposed to allow the crossing of this barrier. Among these, the use of a natural way of entering into the cell: endocytosis. This process allows the cell to import the hydrophilic compounds it needs to operate. By targeting a receptor (eg transferrin) with a specific ligand, it has been possible to import potential bioactive compounds, such as oligonucleotides. Although it provides access to the intracellular medium, low release of the contents of the endosome into the cytosol and degradation of its contents by the cell during the fusion with lysosome highly limits the use of endocytosis.

Liposomes have also been proposed for the intracellular delivery of bioactive compounds, but their induced cytotoxicity and the fact that they are internalized by endocytosis limit their scope.

Other techniques exist, but they are subject to use restrictions. For instance, viral transfection, although promising, has drawbacks because of the induced immune response to the used viral capsid.

Finally, techniques such as electroporation or microinjection are widely used in the laboratory but require the use of special equipment, and are only used in vivo in special cases.

Discovery fifteen years ago of peptides with the ability to cross and to make cross the cell membrane to the compounds of interest, has emerged as a noninvasive alternative to these techniques. The first reference to this type of compound was made in 1965. It was revealed at the time that proteins were more efficiently internalized into cells when they were previously mixed with lysine polymers of high molecular weight. But it will take more than twenty years, and the highlighted cell penetration properties of proteins Tat and Antennapedia, respectively from HIV-1 and Drosophila, to make this field of investigation fully taken into account. Given their properties, these proteins were quickly subjected to structure-activity studies having shown, in each of them, the presence of a short sequence responsible for this surprising ability (the Tat peptide (49-58) and penetratin or pAntp). Since then, several protein domains (PVEC, VP22), chimeric peptides (Transportan, MPG, Pep-1) and peptides with artificial sequence (MAP, (Arg)₉) with similar properties were conceived and described. Several terms are used to name these peptides: Cell-Penetrating Peptides (CPP), sequences of the membrane translocation of the protein transduction domains, Trojans peptides or most commonly peptides vectors.

Behind these different names is a single definition: peptides whose sequence does not exceed 35 amino acid residues, soluble in water, with limited toxicity and able to effectively cross the membrane together with a hydrophilic cargo, which is usually covalently bond. Several types of covalent bonds have been used for this purpose, some of which can be cleaved under specific physiological conditions: disulfide bridges, oxime or hydrazone linkages, amide bonds and thioether bonds.

The potential of these compounds has been from the beginning, and although they have not yet reached the stage of therapeutic use, they have been widely used for the transport of active compounds in the cell (cargo).

One of the aims of the invention is to provide synthetic compounds bearing beta- amino acids presenting an improved stability toward plasma degradation for the treatment of bacterial infections.

Another aim of the invention is to provide new synthetic compounds bearing beta- amino acids.

Still another aim of the invention is to provide pharmaceutical compositions comprising new synthetic compounds bearing beta-amino acids.

Still another aim of the invention is to provide cosmetic compositions comprising new synthetic compounds bearing beta-amino acids.

Still another aim of the invention is to provide new synthetic compounds bearing beta- amino acids for their use in anti-bio film surface treatment.

Still another aim of the invention is to provide new synthetic compounds bearing beta- amino acids for their use in the preparation of vector peptides.

The present invention relates to a compound having the following formula (I):

wherein:

- n and m = 0 or 1 provided that n and m = 0 together are excluded;

- Ri represents the lateral chain of ornithine or arginine;

- R₂ represents H, a protecting group of the amino function, or an amino acid selected from the group consisting of:

wherein R4 re resents H, a protecting group of the amino function, H₂N(C=NH) or

wherein A, B, C, D and E represent independently from each other H,

an alkyl group or a aryl group;

wherein R4 is as defined above and F, G, H, I and J represent independently from each other: H, an alkyl group, an aryl group or CF₃.

- X represents O or NH, and R₃ represents H, an alkyl, an alkylaryl group such as a substituted benzyl group with A, B, C, D and E defined above or a substituted ethylbenzene group with A, B, C, D and E defined above;

- X and R₃ represent together an amino acid selected from the group consisting of:

wherein Y represents O or NH, and R₆ represents H or an alkyl, an alkylaryl group such as a substituted benzyl group with A, B, C, D and E defined above or a substituted ethylbenzene group with A, B, C, D and E defined above; or

wherein Y represents O or NH, and ¾ represents a H, an alk l group, a substituted benzyl group with A, B, C, D and E defined above; or

wherein F, G, H, I and J represent independently from each other: H, an alkyl group, an aryl group or CF₃, Y represents O or NH, and Re represents a H, or an alkyl, an alkylaryl group such as a substituted benzyl group with A, B, C, D and E defined above or a substituted ethylbenzene group with A, B, C, D and E defined above; provided that:

when R₂ represents an amino acid selected from the group as defined above, then X represents O or NH, and R₃ represents an alkyl or a substituted benzyl group with F, G, H, I and J defined above; and

when R₂ represents H, Fmoc, then X and R₃ represent together an amino acid selected from the group defined above;

for its use as a drug for the treatment of microbial infections, in particular bacterial infections.

The peptides of the invention have antimicrobial activity and are defined as antimicrobial peptides. The expression "antimicrobial peptides" refers to an agent that kills microorganisms or inhibits their growth.

Said microorganisms can be bacteria, fungi, viruses or yeast.

Advantageously, said antimicrobial peptides are antibacterial peptides.

The Inventors have unexpectedly found that the simultaneous introduction of two lateral chains of ornithine or arginine giving thus two positive charges instead of one, allows to reduce the number of residues that must be present in the molecule and thus the size of the peptides to synthesize, while keeping the antibiotic activity and at the same time increasing the stability toward proteolytic degradation of said peptides given thus peptides, liable to be active.

The reduction of the size of the peptides also provides compounds liable to escape from the immune system and thus to prevent immune reactions.

A further advantage of the invention is the use of beta amino acid instead of alpha amino acid allowing to incorporate directly said beta amino acid into peptides without encountering the problems due to the steric hindrance of the quaternary centre bearing both Ri .

"Ri represents the lateral chain of ornithine and arginine" means that both Ri represent the lateral chain of ornithine or both Ri represent the lateral chain of arginine, or one Ri represents the lateral chain of ornithine and the other one represents the lateral chain of arginine.

A basic group such as the nitrogen of the ornithine or arginine moiety or an amino group present on the molecule can be under a salt form, the salt being any pharmaceutically acceptable salt obtained by reaction of an inorganic acid, an organic acid or a halogenoalkyl on an amino group to give a quaternary ammonium.

Examples of inorganic acids allowing to obtain pharmaceutically acceptable salts include, without being limited to them: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, formic acid, monohydrogenocarbonic acid, phosphoric acid, monohydrogenophosphoric acid, dihydrogenophosphoric acid, perchloric acid, sulfuric acid, monohydrogenosulfuric acid.

Examples of organic acid allowing to obtain pharmaceutically acceptable salts include, without being limited to them, acetic acid, lactic acid, propionic acid, butyric acid, isobutyric acid, palmitic acid, malic acid, glutamic acid, hydroxymalic acid, malonic acid, benzoic acid, succinic acid, glycolic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, salicylic acid, benzenesulfonic acid, /?-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, hydroxynaphthoic acid, trifluoroacetic acid.

In particular, compounds of the invention are under the form of trifluoroacteic salts.

As an example, see Berge et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19.

The expression "protecting group of the amino function" refers for example, but without being limited to them, to Fmoc, Z and Boc groups.

Other protecting groups as well as the protection process and their cleavage can be found in: "Greene's Protective Groups in Organic Synthesis, 4th Edition, Peter G. M. Wuts, Theodora W. Green, 2006, Wiley editions).

It must be noted that the amino function of ornithine and arginine can also be protected by said protecting group.

The expression "alkyl group" refers to a linear alkyl group or a branched alkyl group or a cycloalkyl group.

Said alkyl group can be from Ci to C₁₅, advantageously from Ci to C₇.

By linear alkyl group from Ci to C₇ is meant a group such as methyl, ethyl, propyl, butyl, pentyl, hexyl or heptyl.

By branched alkyl group is meant an alkyl group as defined above bearing substituents selected from the list of linear alkyl groups defined above, said linear alkyl group being also liable to be branched.

The definition of alkyl group and of linear and branched alkyl applies to the entire specification.

By cycloalkyl group from C₃ to C₇ is meant a group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Such groups can also be substituted by a linear or branched alkyl group as defined above.

The definition of cycloalkyl group applies also to the entire specification.

The term "aryl group" refers to any functional group or substituent derived from a simple aromatic ring or heteroaromatic group.

The "aryl group" can be substituted by one or more groups chosen independently among an halogen, a linear or branched (Ci-C₇)-alkyl, a (C₃-C₇)-cycloalkyl, CN, CF₃, OH, OR_x, NH₂, NHPv_x, NPv_xR_y, R_x and R_y being a linear or branched (Ci-C₇)-alkyl, a (C₃-C₇)- cycloalkyl, an aryl substituted or not, CH₂-aryl, CO-(Ci-C₇)-alkyl or cycloalkyl, CO-aryl, C0₂H, C0₂-(Ci-C₇)-alkyl or cycloalkyl. The term "heteroaromatic" refers to a compound having the characteristics of an aromatic compound whilst having at least one non-carbon atom in the ring.

The heteroaromatic can be substituted by one or more groups chosen independently among those defined for aryl.

The expression "alkylarylgroup" refers to a group constituted of an alkyl such as defined above linked to an aryl group such as defined above.

Advantageously, when R₃ or 5 represents an alkyl, said alkyl is a C₁-C₇ alkyl, more advantageously a methyl group.

The definition for A, B, C, D, E, F, G, H, I and J applies to the entire specification.

The expression "bacterial infections" refers to any infection caused by bacteria, in particular a pathogenic bacteria.

The amino-acid defined in R₂ and X-R₃ or the beta-amino-acid can be independently from each other R or S.

Advantageously, the amino-acid is S defined in R₂ and X-R₃.

The group also named in all the specification C₁₀H₇CO.

The group is also named in all the specification C22H25CO.

In an advantageous embodiment, the present invention relates to a compound having the following formula (I):

wherein:

- n and m = 0 or 1 provided that n and m = 0 together are excluded;

- Ri represents the lateral chain of ornithine or arginine;

- R₂ represents H, a protecting group of the amino function, or an amino acid selected from the group consisting of: 

- X represents O or NH, and R₃ represents H or an alkyl, an alkylaryl group such as a substituted benzyl group with A, B, C, D and E defined above or a substituted ethylbenzene group with A, B, C, D and E defined above; or

wherein Y represents O or NH, and R₆ represents H or an alkyl, an alkylaryl group such as a substituted benzyl group with A, B, C, D and E defined above, or a substituted ethylbenzene group with A, B, C, D and E defined above; or

wherein Y represents O or NH, and R6 represents a H, C1-C15 alkyl or a substituted benzyl group with A, B, C, D and E defined above; or

wherein

F, G, H, I and J represent independently from each other: H, an alkyl group, an aryl group or CF₃, Y represents O or NH, and Re represents a H, or an alkyl or a substituted benzyl group with A, B, C, D and E defined above;

provided that:

- when R₂ represents an amino acid selected from the group as defined above, then X represents O or NH, and R₃ represents an alkyl or a substituted benzyl group with F, G, H, I and J defined above and provided that the following compounds are excluded:

and - when R₂ represents H or a protective group of the amino function, then X and R₃ represent together an amino acid selected from the group defined above;

In an advantageous embodiment, the present invention relates to a compound for its use as a drug for the treatment of microbial infections, as defined above, wherein said antimicrobial peptide has an activity directed against Gram-positive and Gram-negative bacteria.

The term "Gram-positive bacteria" refers to the two bacterial phyla defined in the Bergey's manual of systematic bacteriology (2^nd edition, G. M. Garrity (ed.), Springer, 2005), Actinobacteria, and Firmicutes, and include the well known genera Staphylococcus, Streptococcus; Enterococcus, Listeria and Bacillus,

The term "Gram-negative bacteria" refers to 22 bacterial phyla defined in the Bergey's manual of systematic bacteriology (2^nd edition, G. M. Garrity, Springer, 2005), Aquificae, Thermotogae, Thermodesulfobacteria, Deinococcus-Thermus, Chrysiogenetes, Chloroflexi, Thermomicrobia, Nitrospira, Deferribacteres, Cyanobacteria, Chlorobia, Proteobacteria, Planctomycetes, Chlamydiae, Spirochaetes, Fibrobacteres, Acidobacteres, Bacteroidetes, Fusobacteria, Verrucomicrobia, Dictyoglomi, and Gemmatimonadetes.

Proteobacteria, in particular, include a large number of human pathogens such as the Enterobacteriaceae, Pseudomonadaceae, Vibrionaceae, Moraxellaceae, Neisseriaceae and Pasteur ellaceae families.

In an advantageous embodiment, the present invention relates to a compound for its use as a drug for the treatment of microbial infections, as defined above, wherein said Gram- positive bacteria are selected from the group consisting of: Staphylococcus aureus, in particular S. aureus ATCC25923 or S. aureus 1199B, or Enterococcus faecalis, in particular ATCC29212.

The term "Staphylococcus aureus" refers to a pathogen responsible of numerous infections such as furuncles and carbuncles (a collection of furuncles), staphylococcal scalded skin syndrome (SSSS), septic arthritis, staphylococcal endocarditis (infection of the heart valves) and pneumonia.

The term "Enterococcus faecalis " refers to a pathogen responsible of endocarditis and bacteremia, urinary tract infections (UTI), meningitis, and other infections in humans. In an advantageous embodiment, the present invention relates to a compound for its use as a drug for the treatment of microbial infections as defined above, wherein said Gram- negative bacteria are selected from the group consisting of: Escherichia coli, in particular ATCC25922, Pseudomonas aeruginosa, in particular ATCC27853 or Acinetobacter baumannii, in particular ATCC 19606.

The term "Escherichia coli" refers to Enterotoxigenic E. coli (ETEC), Enteropathogenic E. coli (EPEC), Enteroinvasiveji. coli (EIEC), Enterohemorrhagic _E. coli (EHEC), Enteroaggregative__E. coli (EAEC), Uropathogenic E. coli (UPEC), or E. coli responsive of Neonatal meningitis.

The term "Pseudomonas aeruginosa " refers to a pathogen responsible of pneumonia, Septic shock, urinary tract infection, gastrointestinal infection and skin and soft tissue infections.

The term "Acinetobacter baumannii" refers to a pathogen responsible of pulmonary infections, septicaemia, and burn and wound infections.

In an advantageous embodiment, the present invention relates to a compound for its use as a drug for the treatment of microbial infections as defined above, having the following general formula (II):

R R.

(Π)

wherein R_{l s} R₂, R₃ and X are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (II) for its use as a drug for the treatment of microbial infections, as defined above, having the following general formula (Ha):

wherein R_{l s} R₃, R4 and X are as defined above. In an advantageous embodiment, the present invention relates to a compound of formula (Ila) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, C₁₀H₇CO, C₂₂H₂₅CO, or Fmoc, X represents O or NH and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Ila) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Ila) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents O and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Ila) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents NH and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Ila) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Ila) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents C₁₀H₇CO, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Ila) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents C₂₂H₂₅CO, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Ila) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents O and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Ila) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents C₁₀H₇CO, X represents O and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Ila) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents C₂₂H₂₅CO, X represents O and R₃ represents CH₃ or a benzyl group. In an advantageous embodiment, the present invention relates to a compound of formula (Ila) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents NH and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Ila) for its use as a drug as a drug for the treatment of microbial infections, as defined above, having the following general formula (II-a-1):

(IIa-1)

wherein R₃, R₄ and X are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (IIa-1) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, C₁₀H₇CO, C₂₂H₂₅CO, or Fmoc, X represents O or NH and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IIa-1) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IIa-1) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents C₁₀H₇CO, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IIa-1) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents C₂₂H₂₅CO, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group. In an advantageous embodiment, the present invention relates to a compound of formula (IIa-1) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents O and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IIa-1) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents NH and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IIa-1) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IIa-1) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents C₂₂H₂₅CO, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IIa-1) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents O and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IIa-1) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents C₁₀H₇CO, X represents O and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IIa-1) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents C₂₂H₂₅CO, X represents O and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IIa-1) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents NH and R₃ represents CH₃ or a benzyl group. In an advantageous embodiment, the present invention relates to a compound of formula (IIa-1) for its use as a drug for the treatment of microbial infections, as defined above, having one of the following formulae:

In an advantageous embodiment, the present invention relates to a compound of formula (IIa-1) for its use as a drug for the treatment of microbial infections, as defined above, having one of the following formulae:

In an advantageous embodiment, the present invention relates to a compound of formula (Ila) for its use as a drug for the treatment of microbial infections, as defined above, having the following general formula (IIa-2):

wherein R₃, R4 and X are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (IIa-2) for its use as a drug for the treatment of microbial infections, as defined above, wherein R4 represents H or Fmoc, X represents O or NH and R₃ represents H, C1-C7 alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IIa-2) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IIa-2) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents O and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IIa-2) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents NH and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IIa-2) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IIa-2) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents O and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IIa-2) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents NH and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IIa-2) for its use as a drug for the treatment of microbial infections, as defined above, having one of the following formulae:

In an advantageous embodiment, the present invention relates to a compound of formula (I) for its use as a drug for the treatment of microbial infections, as defined above, having the following general formula II- 1):

wherein R_{l s} R₂, R₃ and X are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (I) for its use as a drug for the treatment of microbial infections, as defined above, having the following general formula (Π-2):

wherein Ri, R₂, R₃ and X are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (II) for its use as a drug for the treatment of microbial infections, as defined above, having the following general formula (III):

(III) wherein R_{l s} R₃ R₄, and X are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (III) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H or Fmoc, X represents O or NH and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (III) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (III) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents O and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (III) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents NH and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (III) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (III) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents O and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (III) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents C₁₀H₇CO, X represents O and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (III) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents NH and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (III) for its use as a drug for the treatment of microbial infections, as defined above, having the following general formula (Ilia):

wherein R₃, R₄ and X are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (Ilia) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, C₁₀H₇CO or Fmoc, X represents O or NH and R₃ represents H, Ci- C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Ilia) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Ilia) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents O and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Ilia) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents NH and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Ilia) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Ilia) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents C₁₀H₇CO, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Ilia) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents O and R₃ represents CH₃ or a benzyl group. In an advantageous embodiment, the present invention relates to a compound of formula (Ilia) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents C₁₀H₇CO, X represents O and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Ilia) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents NH and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (III) for its use as a drug for the treatment of microbial infections, as defined above, having the following general formula (Illb):

wherein R₃, R₄ and X are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (Illb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H or Fmoc, X represents O or NH and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Illb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Illb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents O and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Illb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents NH and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Illb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R4 represents Fmoc, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Illb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R4 represents Fmoc, X represents O and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Illb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R4 represents Fmoc, X represents NH and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (II) for its use as a drug for the treatment of microbial infections, as defined above, having the following general formula IV):

wherein R_{l s} R₃ R4, and X are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (IV) for its use as a drug for the treatment of microbial infections, as defined above, wherein R4 represents H or Fmoc, X represents O or NH and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IV) for its use as a drug for the treatment of microbial infections, as defined above, wherein R4 represents H, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IV) for its use as a drug for the treatment of microbial infections, as defined above, wherein R4 represents H, X represents O and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IV) for its use as a drug for the treatment of microbial infections, as defined above, wherein R4 represents H, X represents NH and R₃ represents CH₃ or a benzyl group. In an advantageous embodiment, the present invention relates to a compound of formula (IV) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IV) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents O and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IV) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents NH and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IV) for its use as a drug for the treatment of microbial infections, as defined above, having the following general formula IVa):

wherein R₃, R₄ and X are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (IVa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H or Fmoc, X represents O or NH and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IVa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IVa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents O and R₃ represents CH₃ or a benzyl group. In an advantageous embodiment, the present invention relates to a compound of formula (IVa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents NH and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IVa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IVa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents O and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IVa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents NH and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IV) for its use as a drug for the treatment of microbial infections, as defined above, having the following general formula IVb):

wherein R₃, R₄ and X are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (IVb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H or Fmoc, X represents O or NH and R₃ represents H, C₁-C₇ alkyl or a benzyl group. In an advantageous embodiment, the present invention relates to a compound of formula (IVb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R4 represents H, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IVb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R4 represents H, X represents O and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IVb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R4 represents H, X represents NH and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IVb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R4 represents Fmoc, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IVb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R4 represents Fmoc, X represents O and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IVb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R4 represents Fmoc, X represents NH and R₃ represents CH₃ or a benzyl group, wherein R_{l s} R₃ R4, and X are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (II) for its use as a drug for the treatment of microbial infections, as defined above, having the following gen ral formula (V):

In an advantageous embodiment, the present invention relates to a compound of formula (V) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H or Fmoc, X represents O or NH and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (V) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (V) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents O and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (V) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents NH and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (V) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (V) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents O and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (V) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents NH and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (V) for its use as a drug for the treatment of microbial infections, as defined above, having the following general formula (V

wherein R₃, R₄ and X are as defined above. In an advantageous embodiment, the present invention relates to a compound of formula (Va) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H or Fmoc, X represents O or NH and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Va) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Va) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents O and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Va) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents NH and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Va) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Va) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents O and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Va) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents NH and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (V) for its use as a drug for the treatment of microbial infections, as defined above, having the following general formula (Vb):

wherein R₃, R₄ and X are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (Vb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H or Fmoc, X represents O or NH and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Vb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Vb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents O and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Vb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents NH and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Vb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Vb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents O and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Vb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents NH and R₃ represents CH₃ or a benzyl group. In an advantageous embodiment, the present invention relates to a compound of formula (II) for its use as a drug for the treatment of microbial infections, as defined above, having the following general formula VI):

wherein R_{l s} R₃ R₄, and X are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (VI) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H or Fmoc, X represents O or NH and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (VI) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (VI) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents O and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (VI) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents NH and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (VI) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (VI) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents O and R₃ represents CH₃ or a benzyl group. In an advantageous embodiment, the present invention relates to a compound of formula (VI) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents NH and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (VI) for its use as a drug for the treatment of microbial infections, as defined above, having the following general formula Via):

wherein R₃, R₄ and X are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (Via) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H or Fmoc, X represents O or NH and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Via) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Via) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents O and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Via) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents NH and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Via) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Via) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents O and R₃ represents CH₃ or a benzyl group. In an advantageous embodiment, the present invention relates to a compound of formula (Via) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents NH and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (VI) for its use as a drug for the treatment of microbial infections, as defined above, having the following general formula VIb):

wherein R₃, R₄ and X are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (VIb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H or Fmoc, X represents O or NH and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (VIb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (VIb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents O and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (VIb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents NH and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (VIb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (VIb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents O and R₃ represents CH₃ or a benzyl group. In an advantageous embodiment, the present invention relates to a compound of formula (VIb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents NH and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (II) for its use as a drug for the treatment of microbial infections, as defined above, having the followin general formula (VII):

wherein R_{l s} R₃ R₄, and X are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (VII) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H or Fmoc, X represents O or NH and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (VII) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (VII) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents O and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (VII) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents NH and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (VII) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group. In an advantageous embodiment, the present invention relates to a compound of formula (VII) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents O and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (VII) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents NH and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (VII) for its use as a drug for the treatment of microbial infections, as defined above, having the following general formula Vila):

wherein R₃, R₄ and X are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (Vila) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H or Fmoc, X represents O or NH and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Vila) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Vila) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents O and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Vila) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents NH and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Vila) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Vila) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents O and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Vila) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents NH and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (VII) for its use as a drug for the treatment of microbial infections, as defined above, having the followin general formula (Vllb):

wherein R₃, R₄ and X are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (Vllb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H or Fmoc, X represents O or NH and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Vllb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Vllb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents O and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Vllb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents NH and R₃ represents CH₃ or a benzyl group. In an advantageous embodiment, the present invention relates to a compound of formula (Vllb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R4 represents Fmoc, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Vllb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R4 represents Fmoc, X represents O and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Vllb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R4 represents Fmoc, X represents NH and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (II) for its use as a drug for the treatment of microbial infections, as defined above, having the followin general formula (VIII):

^H (VIII)

wherein R_{l s} R₃ R4, F to J and X are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (VIII) for its use as a drug for the treatment of microbial infections, as defined above, wherein R4 represents H or Fmoc, X represents O or NH and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (VIII) for its use as a drug for the treatment of microbial infections, as defined above, wherein R4 represents H, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (VIII) for its use as a drug for the treatment of microbial infections, as defined above, wherein R4 represents H, X represents O and R₃ represents CH₃ or a benzyl group. In an advantageous embodiment, the present invention relates to a compound of formula (VIII) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents NH and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (VIII) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (VIII) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents O and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (VIII) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents NH and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (VIII) for its use as a drug for the treatment of microbial infections, as defined above, having the following general formula (Villa):

^H (Villa)

wherein R₃, R₄, F to J and X are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (Villa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H or Fmoc, X represents O or NH and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Villa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group. In an advantageous embodiment, the present invention relates to a compound of formula (Villa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents O and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Villa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents NH and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Villa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Villa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents O and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Villa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents NH and R₃ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (VIII) for its use as a drug for the treatment of microbial infections, as defined above, having the followin general formula (Vlllb):

(Vlllb)

wherein R₃, R₄, F to J and X are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (Vlllb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H or Fmoc, X represents O or NH and R₃ represents H, C₁-C₇ alkyl or a benzyl group. In an advantageous embodiment, the present invention relates to a compound of formula (Vlllb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Vlllb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents O and R₃ represents CH₃ or a benzyl group, and in particular F, G, I, J represent a hydrogen atom and H represents tBu or CF₃.

In an advantageous embodiment, the present invention relates to a compound of formula (Vlllb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents H, X represents NH and R₃ represents CH₃ or a benzyl group, and in particular F, G, I, J represent a hydrogen atom and H represents tBu or CF₃.

In an advantageous embodiment, the present invention relates to a compound of formula (Vlllb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents O and R₃ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Vlllb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents O and R₃ represents CH₃ or a benzyl group, and in particular F, G, I, J represent a hydrogen atom and H represents tBu or CF₃.

In an advantageous embodiment, the present invention relates to a compound of formula (Vlllb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₄ represents Fmoc, X represents NH and R₃ represents CH₃ or a benzyl group, and in particular F, G, I, J represent a hydrogen atom and H represents tBu or CF₃.

In an advantageous embodiment, the present invention relates to a compound of formula (I) for its use as a drug for the treatment of microbial infections, as defined above, having the following general formula (IX):

wherein R_{l s} R₂, Re and Y are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (IX) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H or Fmoc, X represents O or NH and ¾ represents H, C₁-C7 alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IX) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents O and 5 represents H, C₁-C7 alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IX) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents O and 5 represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IX) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents NH and 5 represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IX) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents O and 5 represents H, C₁-C7 alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IX) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents O and 5 represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IX) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents NH and 5 represents CH₃ or a benzyl group. In an advantageous embodiment, the present invention relates to a compound of formula (IX) for its use as a drug for the treatment of microbial infections, as defined above, having the following general formula IXa):

wherein R₂, Re and Y are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (IXa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H or Fmoc, X represents O or NH and Re represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IXa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents O and Re represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IXa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents O and Re represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IXa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents NH and Re represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IXa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents O and Re represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IXa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents O and Re represents CH₃ or a benzyl group. In an advantageous embodiment, the present invention relates to a compound of formula (IXa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents NH and Re represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IX) for its use as a drug for the treatment of microbial infections, as defined above, having the following general formula IXb):

wherein R₂, 5 and Y are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (IXb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H or Fmoc, X represents O or NH and R6 represents H, C₁-C7 alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IXb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents O and 5 represents H, C₁-C7 alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IXb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents O and 5 represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IXb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents NH and 5 represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IXb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents O and Re represents H, C₁-C7 alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IXb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents O and Re represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IXb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents NH and R6 represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (IXb) for its use as a drug for the treatment of microbial infections, as defined above, having one of the following formulae:

In an advantageous embodiment, the present invention relates to a compound of formula (I) for its use as a drug for the treatment of microbial infections, as defined above, having the following general formula (X):

wherein R_{l s} R₂, Re and Y are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (IX) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents NH and 5 represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (X) for its use as a drug for the treatment of microbial infections, as defined above, having the following general formula (Xa):

wherein R₂, Re and Y are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (Xa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H or Fmoc, X represents O or NH and Re represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Xa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents O and Re represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Xa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents O and Re represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Xa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents NH and Re represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Xa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents O and Re represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Xa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents O and Re represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Xa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents NH and Re represents CH₃ or a benzyl group. In an advantageous embodiment, the present invention relates to a compound of formula (X) for its use as a drug for the treatment of microbial infections, as defined above, having the following general formula Xb):

wherein R₂, Re and Y are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (Xb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H or Fmoc, X represents O or NH and Re represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Xb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents O and Re represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Xb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents O and Re represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Xb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents NH and Re represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Xb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents O and Re represents H, C₁-C₇ alkyl or a benzyl group. In an advantageous embodiment, the present invention relates to a compound of formula (Xb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents O and Re represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Xb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents NH and Re represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (I) for its use as a drug for the treatment of microbial infections, as defined above, having the following general formula (XI):

wherein R_{l s} R₂, Re and Y are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (XI) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H or Fmoc, X represents O or NH and Re represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XI) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents O and Re represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XI) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents O and Re represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XI) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents NH and Re represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XI) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents O and Re represents H, C₁-C₇ alkyl or a benzyl group. In an advantageous embodiment, the present invention relates to a compound of formula (XI) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents O and Re represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XI) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents NH and Re represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XI) for its use as a drug for the treatment of microbial infections, as defined above, having the following general formula (XIa):

wherein R₂, 5 and Y are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (XIa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H or Fmoc, X represents O or NH and ¾ represents H, C₁-C7 alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XIa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents O and 5 represents H, C₁-C7 alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XIa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents O and 5 represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XIa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents NH and 5 represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XIa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents O and 5 represents H, C₁-C7 alkyl or a benzyl group. In an advantageous embodiment, the present invention relates to a compound of formula (XIa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents O and Re represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XIa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents NH and Re represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XI) for its use as a drug for the treatment of microbial infections, as defined above, having the following general formula (Xlb):

wherein R₂, 5 and Y are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (Xlb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H or Fmoc, X represents O or NH and ¾ represents H, C₁-C7 alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Xlb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents O and 5 represents H, C₁-C7 alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Xlb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents O and 5 represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Xlb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents NH and 5 represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Xlb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents O and 5 represents H, C₁-C7 alkyl or a benzyl group. In an advantageous embodiment, the present invention relates to a compound of formula (Xlb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents O and Re represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Xlb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents NH and Re represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (I) for its use as a drug for the treatment of microbial infections, as defined above, having the following general formula XII):

wherein R_{l s} R₂, Re and Y are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (XII) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H or Fmoc, X represents O or NH and Re represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XII) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents O and Re represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XII) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents O and Re represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XII) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents NH and Re represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XII) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents O and ¾ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XII) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents O and 5 represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XII) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents NH and R6 represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XII) for its use as a drug for the treatment of microbial infections, as defined above, having the following general formula Xlla):

wherein R₂, 5 and Y are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (Xlla) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H or Fmoc, X represents O or NH and 5 represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Xlla) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents O and 5 represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Xlla) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents O and 5 represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Xlla) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents NH and 5 represents CH₃ or a benzyl group. In an advantageous embodiment, the present invention relates to a compound of formula (Xlla) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents O and Re represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Xlla) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents O and 5 represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Xlla) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents NH and R6 represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XII) for its use as a drug for the treatment of microbial infections, as defined above, having the following general formula Xllb):

wherein R₂, 5 and Y are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (Xllb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H or Fmoc, X represents O or NH and 5 represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Xllb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents O and 5 represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Xllb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents O and 5 represents CH₃ or a benzyl group. In an advantageous embodiment, the present invention relates to a compound of formula (Xllb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents NH and ¾ represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Xllb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents O and ¾ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Xllb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents O and R6 represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Xllb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents NH and 5 represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (I) for its use as a drug for the treatment of microbial infections, as defined above, having the following neral formula (XIII):

wherein R_{l s} R₂, 5 and Y are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (XIII) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H or Fmoc, X represents O or NH and 5 represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XIII) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents O and 5 represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XIII) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents O and 5 represents CH₃ or a benzyl group. In an advantageous embodiment, the present invention relates to a compound of formula (XIII) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents NH and Re represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XIII) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents O and Re represents H, C₁-C7 alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XIII) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents O and R6 represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XIII) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents NH and 5 represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XIII) for its use as a drug for the treatment of microbial infections, as defined above, having the following general formula (Xllla):

(Xllla) wherein R₂, 5 and Y are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (Xllla) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H or Fmoc, X represents O or NH and 5 represents H, C₁-C7 alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Xllla) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents O and 5 represents H, C₁-C7 alkyl or a benzyl group. In an advantageous embodiment, the present invention relates to a compound of formula (Xllla) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents O and Re represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Xllla) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents NH and Re represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Xllla) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents O and R6 represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Xllla) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents O and 5 represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Xllla) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents NH and 5 represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XIII) for its use as a drug for the treatment of microbial infections, as defined above, having the following general formula (Xlllb):

(Xlllb)

wherein R₂, 5 and Y are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (Xlllb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H or Fmoc, X represents O or NH and 5 represents H, C₁-C₇ alkyl or a benzyl group. In an advantageous embodiment, the present invention relates to a compound of formula (Xlllb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents O and Re represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Xlllb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents O and Re represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Xlllb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents NH and R6 represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Xlllb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents O and 5 represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Xlllb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents O and 5 represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (Xlllb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents NH and 5 represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (I) for its use as a drug for the treatment of microbial infections, as define above, having the following general formu

wherein R_{l s} R₂, 5 and Y are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (XIV) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H or Fmoc, X represents O or NH and ¾ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XIV) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents O and R6 represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XIV) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents O and Re represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XIV) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents NH and 5 represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XIV) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents O and 5 represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XIV) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents O and 5 represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XIV) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents NH and 5 represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XIV) for its use as a drug for the treatment of microbial infections, as defined above, having the following general formula (XI Va):

(XlVa) wherein R₂, 5 and Y are as defined above. In an advantageous embodiment, the present invention relates to a compound of formula (XIV a) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H or Fmoc, X represents O or NH and Re represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XlVa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents O and 5 represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XIV a) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents O and R6 represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XIV a) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents NH and 5 represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XIV a) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents O and 5 represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XIV a) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents O and 5 represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XIV a) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents NH and 5 represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XIV) for its use as a drug for the treatment of microbial infections, as defined above, having the following general formula (XI Vb):

wherein R₂, Re and Y are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (XlVb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H or Fmoc, X represents O or NH and Re represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XlVb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents O and R6 represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XlVb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents O and 5 represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XlVb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents NH and 5 represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XlVb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents O and 5 represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XlVb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents O and 5 represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XlVb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents NH and Re represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (I) for its use as a drug for the treatment of microbial infections, as defined above, having the following general formula (XV):

wherein R_{l s} R₂, 5 and Y are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (XV) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H or Fmoc, X represents O or NH and ¾ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XV) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents O and 5 represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XV) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents O and 5 represents CH₃ or a benzyl group, and in particular F, G, I, J represent a hydrogen atom and H represents tBu or CF₃.

In an advantageous embodiment, the present invention relates to a compound of formula (XV) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents NH and R₆ represents CH₃ or a benzyl group, and in particular F, G, I, J represent a hydrogen atom and H represents tBu or CF₃.

In an advantageous embodiment, the present invention relates to a compound of formula (XV) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents O and 5 represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XV) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents O and ¾ represents CH₃ or a benzyl group, and in particular F, G, I, J represent a hydrogen atom and H represents tBu or CF₃.

In an advantageous embodiment, the present invention relates to a compound of formula (XV) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents NH and R6 represents CH₃ or a benzyl group, and in particular F, G, I, J represent a hydrogen atom and H represents tBu or CF₃.

In an advantageous embodiment, the present invention relates to a compound of formula (XV) for its use as a drug for the treatment of microbial infections, as defined above, having the following neral formula (XVa):

wherein R₂, Re and Y are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (XVa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H or Fmoc, X represents O or NH and ¾ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XVa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents O and 5 represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XVa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents O and 5 represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XVa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents NH and 5 represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XVa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents O and 5 represents H, C₁-C₇ alkyl or a benzyl group. In an advantageous embodiment, the present invention relates to a compound of formula (XVa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents O and Re represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XVa) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents NH and Re represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XV) for its use as a drug for the treatment of microbial infections, as defined above, having the following general formula (XVb):

wherein R₂, 5 and Y are as defined above.

In an advantageous embodiment, the present invention relates to a compound of formula (XVb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H or Fmoc, X represents O or NH and ¾ represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XVb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents O and 5 represents H, C₁-C₇ alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XVb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents O and 5 represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XVb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents H, X represents NH and 5 represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XVb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents O and Re represents H, C1-C7 alkyl or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XVb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents O and Re represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound of formula (XVb) for its use as a drug for the treatment of microbial infections, as defined above, wherein R₂ represents Fmoc, X represents NH and R6 represents CH₃ or a benzyl group.

In an advantageous embodiment, the present invention relates to a compound for its use as a drug for the treatment of microbial infections, having one of the formula (I) to (XV), as defined above, wherein said compound is liable to be administered by oral route at a unit dose comprised from 100 mg to 1,500 mg, in particular from 100 mg to 1,000 mg, in particular from 100 to 500 mg.

Said pharmaceutical composition can be administered 2 or 3 times per day.

In an advantageous embodiment, the present invention relates to a compound for its use as a drug for the treatment of microbial infections, having one of the formula (I) to (XV), under a form liable to be administrable by intraveinous route at a dose comprised from 0,1 mg to 1000 mg, in particular from 10 mg to 1,000 mg, in particular from 10 to 500 mg, in particular from 10 to 100 mg.

Said pharmaceutical composition can be administered 2 or 3 times per day.

In an advantageous embodiment, the present invention relates to a compound, for its use as a drug for the treatment of microbial infections, having one of the formula (I) to (XV), as defined above, administrable by oral route at a dose comprised from about 10 mg/kg to about 200 mg/kg.

In an advantageous embodiment, the present invention relates to a compound, for its use as a drug for the treatment of microbial infections, having one of the formula (I) to (XV), as defined above, administrable by intraveinous route at a dose comprised from about 5 μg/kg to about 50 mg/kg.

In another aspect, the present invention relates to a compound of formula (I) to (XV) such as defined above, for its use in anti-bio film surface treatment.

In an advantageous embodiment, the present invention relates to a compound of formula (I) to (XV) such as defined above, for its use in anti-biofilm treatment of the surface of submerged structures, in particular submerged marine structures. In an advantageous embodiment, the present invention relates to a compound of formula (I) to (XV) such as defined above, for its use in anti-biofilm treatment of the surface of medical devices.

In an advantageous embodiment, said compound of formula (I) to (XV) such as defined above is grafted onto the surface to treat. Grafting can be performed by a method known by the one skilled in the art.

In another aspect, the present invention relates to a compound of formula (I) to (XV) such as defined above, for its use in drug vectorization.

The present invention also relates to a compound of formula (I) to (XV) such as defined above, for its use in the preparation of a vector peptide.

In another aspect, the present invention relates to a compound of formula (I) to (XV) such as defined above, having one of the following formulae:

70

In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) to (XV) such as defined above, in association with a pharmaceutically acceptable vehicle.

and provided that the following compounds are excluded:

The expression "pharmaceutically acceptable vehicle" denotes in particular cellulose, starch, benzyl alcohol, polyethylene glycol, gelatin, lactose, polysorbate, magnesium or calcium stearate, xanthan gum, guar, alginate, colloidal silica.

The compositions according to the invention can be used by oral, parenteral, topic, or rectal route or in aerosols.

As solid compositions for oral administration, tablets, pills, gelatin capsules, powders or granules can be used. In these compositions, the active ingredient according to the invention is mixed with one or more inert diluents or adjuvants, such as saccharose, lactose or starch. These compositions can comprise substances other than the diluents, for example a lubricant such as magnesium stearate or a coating intended for controlled release.

As liquid compositions for oral administration, pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water or paraffin oil can be used. These compositions can also comprise substances other than the diluents, for example wetting products, sweeteners or flavourings.

The compositions for parenteral administration can be sterile solutions or emulsions. As solvent or vehicle, water, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate can be used. These compositions can also contain adjuvants, in particular wetting agents, isotoning agents, emulsifiers, dispersants and stabilizers.

The sterilization can be carried out in several ways, for example using a bacteriological filter, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the moment of use in sterile water or any other injectable sterile medium.

The compositions for topical administration can be for example creams, ointments, lotions or aerosols.

The compositions for rectal administration are suppositories or rectal capsules, which, in addition to the active ingredient, contain excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

The compositions can also be aerosols.

For use in the form of liquid aerosols, the compositions can be stable sterile solutions or solid compositions dissolved at the moment of use in pyrogen-free sterile water, in serum or any other pharmaceutically acceptable vehicle. For use in the form of dry aerosols intended to be directly inhaled, the active ingredient is finely divided and combined with a diluent or hydrosoluble solid vehicle, for example dextran, mannitol or lactose. In an advantageous embodiment, the present invention relates to a pharmaceutical composition as defined above, comprising one of the following compounds:

In an advantageous embodiment, the present invention relates to a pharmaceutical composition as defined above, comprising one of the following compounds:

In another aspect, the present invention relates to a pharmaceutical composition comprising:

- at least one compound of formula (I) to (XV) as defined above, and

- at least one antibiotic compound, in particular from the family of the fluoroquinolones, such as ciprofloxacin, norfloxacin, pefloxacin, enofloxacin, ofloxacin, levofloxacin and moxifloxacin, in combination with a pharmaceutically acceptable vehicle.

- at least one compound of formula (I) to (XV) as defined above, and

- at least one antibiotic compound, in particular from the family of the fluoroquinolones, such as ciprofloxacin, norfloxacin, pefloxacin, enofloxacin, ofloxacin, levofloxacin and moxifloxacin, in combination with a pharmaceutically acceptable vehicle, and provided that the following compounds are excluded:

In an advantageous embodiment, the present invention relates to a pharmaceutical composition comprising at least one compound of formula (I) to (XV) and at least one antibiotic compound, as defined above,

wherein the weight proportion of said compound is comprised from 15% to 85% and the weight proportion of said antibiotic compound is comprised from 15% to 85%.

The pharmaceutical composition of the invention as defined above comprises approximately 350 to approximately 2,000 mg, preferably approximately 1,000 to approximately 1,500 mg, of compound of formula (I) according to the invention in 1 to 4 administrations per day and approximately 350 to approximately 2,000 mg, preferably approximately 1,000 to approximately 1,500 mg, of antibiotic compound, in particular of the family of the fluoroquinolones, such as ciprofloxacin in 1 to 4 administrations per day, preferably in 2 administrations per day.

In another aspect, the present invention relates to products comprising:

- at least one compound of formula (I) to (XV), as defined above, and - at least one antibiotic compound, in particular from the family of the fluoroquinolones, such as ciprofloxacin, norfloxacin, pefloxacin, enofloxacin, ofloxacin, levofloxacin and moxifloxacin,

as a combination for the simultaneous, separate use or successive administration for the treatment of bacterial infections.

In another aspect, the present invention relates to products comprising:

- at least one compound of formula (I) to (XV), as defined above, and

- at least one antibiotic compound, in particular from the family of the fluoroquinolones, such as ciprofloxacin, norfloxacin, pefloxacin, enofloxacin, ofloxacin, levofloxacin and moxifloxacin,

provided that the following compounds are excluded:

In another aspect, the present invention relates to a cosmetic composition comprising a compound of formula (I) to (XV) such as defined above, in association with a cosmetically acceptable vehicle.

The expression "cosmetically acceptable vehicle" denotes in particular a vehicle suitable for use in contact with human and animal cells, in particular cells of the epidermis, without toxicity, irritation, allergic response and the like.

Said cosmetic compositions are for example solutions, such as lotions, liquid or semi- liquid emulsions, such as milks, or emulsions of soft consistency such as creams or gels, obtained by dispersion of a fatty phase in an aqueous phase, or conversely liquid, semi-soft or liquid suspensions, ointments, powders or aerosols.

For use in the form of liquid aerosols, the compositions can be stable sterile solutions or solid compositions dissolved at the moment of use in pyrogen-free sterile water, in serum or any other pharmaceutically acceptable vehicle.

In an advantageous embodiment, said cosmetic composition is a toothpaste or a hair lotion.

All these compositions are adapted and prepared according to conventional methods known to those skilled in the art.

Among cosmetically acceptable vehicles can be mentioned surfactants, dyes, fragrances, preservatives, emulsifiers, emulsion stabilizers, emollients, moisturizers, natural or synthetic waxes, thickeners and / or gelling agents, humectants, liquid carriers such as water, fatty substances such as natural or synthetic oils designed to form the fatty phase milks or creams, and mixtures thereof. In an advantageous embodiment, the present invention relates to a cosmetic composition as defined above, comprising one of the following compounds:

In an advantageous embodiment, the present invention relates to a cosmetic composition as defined above, comprising one of the following compounds:

EXAMPLES:

I) CHEMICAL SYNTHESIS PART

EXAMPLE 1: Synthesis of p²-bis ornithine

Methyl 2,4-dicyano-2-(2-cyanoethyl)butanoate

Methyl 2-cyanoacetate [10 g (100 mmol)] was first mixed with acrylonitrile [11.66 g (220 mmol)]. Then, triethylamine [5.05 g (50 mmol)] was added, followed by lithium perchlorate [5.32 g (50 mmol)]. The reaction was stirred continuously and allowed to react overnight. After confirming completion of the reaction by TLC, the product was extracted with ethyl acetate. The organic layer was washed with 5% citric acid solution and brine, dried over magnesium sulfate, filtered and evaporated. The product precipitated overnight, and the crystals were filtered with a minimum AcOEt as yellow pale powder. (12.6 g, 61 mmol, 61% yield)

R_f (1:1, cyclohexane:ethyl acetate)

1H NMR (250 MHz, CDC1₃) δ 3.93 (s, 3H, C0₂C¾), 2.72 - 2.45 (m, 4H, 2xCH₂CH2C≡N), 2.37 (ddd, J= 15.5, 8.6, 6.8, 2H, CH2C≡N), 2.20 (ddd, J= 14.2, 8.6, 6.1, 2H, CH2C≡N). C-NMR (300 MHz, CDC1₃):6 166.55 (C, C=0), 1 17.21 (2C, 2xC≡N), 1 16.10 (C, C≡N), 54.30 (CH3, C0₂CH₃), 47.60 (C, CCH2CH2C≡N), 32.07 (2CH2, 2xCH2CH2C≡N), 13.60 (2CH2, 2xCH2C≡N)

MS-ESI+: calcd for Ci₀Hi iN₃O₂205.09, found228.07 [M+Na]⁺ Methyl 2-cvano-4-(Boc)amine-2-(3-(Boc)amine propyDpentanoate

oc

Methyl 2,4-dicyano-2-(2-cyanoethyl)butanoate [1 g (4.9mmol)] was dissolved in methanol [25 rriL]. Boc₂0 [2.35 g (10.78mmol)] and Pt0₂ [0.22 g (0.98mmol)] were added and the reaction mixture was stirred at rt for 3 days under 5 bar H₂ pressure. Afterward, the reaction mixture was filtered through a celite pad to remove the Pt0₂ before evaporation to dryness. The crude compound was purified by flash chromatography (Cy/AE 100/0— 7/3). (0.5 g, 1.23mmol, 25% yield)

Rf (1: 1, cyclohexanerethyl acetate) = 0.56

1H-NMR (300 MHz, CDC1₃): δ (ppm) 4.56 (bs, 2H, 2xNH), 3.82 (s, 3H, C0₂C¾), 3.22 - 3.10 (m, 4H, 2xC¾NHBoc), 2.00 - 1.44 (m, 8H, 2xCH2C¾CH₂NHBoc), 1.57 - 1.37 (s, 18H, 2xC(CH₃)₃).

¹³C NMR (63 MHz, CDC1₃) δ 169.22 (C, C=0 ester), 155.89 (2C, 2xC=Ocarbamate), 1 18.78 (2C, 2xC≡N), 79.28 (2C, 2xC(CH₃)₃), 53.43 (CH₃, C0₂CH₃), 49.22 (C, CCH₂CH₂CH₂NHBoc), 39.75 (2CH₂, 2xCH₂NHBoc), 34.54 (2CH₂, 2xCH₂CH₂CH₂NHBoc), 28.34 (6CH3, 2xC(CH₃)₃), 26.18 (2CH₂, 2xCH₂CH₂NHBoc).

MS-ESI+: calcd for C20H35N3O6 413.25, found 436.24[M+Na]⁺

H-B²bisOrn(Boc)?OMe (HB313)

oc Methyl 2-cyano-4-(Boc)amine-2-(3-(Boc)amine propyl)pentanoate [2.35 g (4.9mmol)] was dissolved in methanol [lOOmL]. Raney nickel was added and the mixture was hydrogenated at rt for 3 days under 5 bar H₂ pressure. Afterward, the reaction mixture was filtered through a celite pad to remove the Raney nickel before evaporation to dryness. The product was used in the following step without any further purification. (2.0 g, 4.8 mmol, 98% yield)

R_f (1:1, cyclohexanerethyl acetate)

1H NMR (300 MHz, MeOD) δ 3.67 (s, 3H, C0₂C¾), 3.01 (t, J = 6.7, 4H, 2xC¾NHBoc), 2.75 (s, 2H, C¾NH₂), 1.61 - 1.53 (m, 4H, 2xC¾CH₂CH₂NHBoc), 1.51 - 1.31 (m, 23H, 2xC¾CH₂NHBoc and 2xC(C¾)₃).

¹³C NMR (75 MHz, MeOD) δ 177.91 (C, C=0 ester), 158.60 (2C, 2xC=Ocarbamate), 79.94 (2C, 2xC(CH₃)₃), 52.35 (CH₃, C0₂CH₃), 51.47 (2CH₂, 2xCCH₂CH₂CH₂NHBoc), 45.85 (CH₂, CH₂NH₂), 41.61 (2CH₂, 2xCH₂NHBoc), 31.17 (2CH₂, 2xCH₂CH₂CH₂NHBoc), 28.82 (6CH₃, 2xC(CH₃)₃), 25.40 (2CH₂, 2xCH₂CH₂NHBoc).

MS-ESI+: calcd for C20H39N3O6 417.2839, found 418.2915 [M+H]⁺

FmocB²bisOrn(Boc)₇OH

Boc

Methyl 2-cyano-4-(Boc)amine-2-(3-(Boc)amine propyl)pentanoate [2.3 g (5.6mmol)] was dissolved in methanol [125mL]. A solution of sodium hydroxide in water (2M) (12.5 mL, 25 mmol) and Raney nickel were added and the mixture was stirred at room temperature for 7 days under 5 bar H₂ pressure. The reaction mixture was filtered through a celite pad to remove Raney nickel before evaporation to dryness. The crude mixture was dissolved in a 5:5 mixture of tetrahydroiuran and water. Then, FmocOSu [2.3 g (6.8 mmol)] and potassium carbonate [1.7 g (12.2 mmol)] were added. The solution was left to react at rt for 1 night. After TLC plates confirmed completion of the reaction, THF was evaporated. The resulting solution was acidified to pH=2 by adding 1 M hydrochloric acid dropwise at 0°C. The product was extracted with ethyl acetate, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude compound was purified by flash chromatography (Cy/AE 100/0 —

75/25).(2.5 g, 3.9 mmol, 71% yield) R_f (7:3:0.1, cyclohexane:ethylacetate:acetic acid) = 0.27

1H NMR (250 MHz, CDC1₃) δ 7.75 (d, J = 7.2, 2H, CH(Ar)), 7.59 (d, J = 7.2, 2H,CH(Ar)), 7.45 - 7.22 (m, 4H, 4xCH(Ar)), 5.53 (bs, 1H, NH), 4.95 (bs, 1H, NH), 4.40 (d, J = 6.5, 2H, CH₂(Fmoc)), 4.20 (t, J = 6.5, 1H, CH(fluorene)), 3.47 - 3.32 (m, 2H, C¾NHFmoc)), 3.07 (m, 4H, 2xC¾NHBoc), 1.67 - 1.20 (m, 26H, 2xC¾C¾CH₂NHBoc and 2xC(C¾)₃).

¹³C NMR (63 MHz, CDC1₃) δ 176.45 (C, C=0 acid), 157.20, 156.36 (3C, 3xC=Ocarbamate), 143.88 (2C,CCHC(Ar)), 141.31 (2C,CCCCH(Ar)), 127.72, 127.09, 125.10, 120.00 (8CH, CH(Ar)), 79.29 (2C, 2xC(CH₃)₃), 66.95 (CH₂, CH₂(Fmoc)), 49.83 (CH₂, CH₂NHFmoc), 47.22 (CH, CH(fluorene)), 40.72 (2CH₂, 2xCH₂NHBoc), 30.59 (2CH₂, 2xCH₂CH₂CH₂NHBoc), 28.41 (6CH₃, 2xC(CH₃)3), 24.25 (2CH₂, 2xCH₂CH₂NHBoc).

MS-ESI+: calcd for C34H47N3O8 625.3255, found 648.3261 [M+Na]⁺

FmocB²bisOrn(Alloc)₇OH

AIIoc hb477fl

R_f (7:3:0.1, cyclohexane:ethylacetate: acetic acid) = 0.20

1H NMR (300 MHz, CDC1₃) δ 7.75 (d, J = 7.5, 2H, CH(Ar)), 7.58 (d, J = 7.3, 2H, CH(Ar)), 7.43 - 7.28 (m, 4H, 4xCH(Ar)), 5.98 - 5.74 (m, 2H, 2xCH=CH₂), 5.38 (bs, 1H, NH), 5.36 - 5.07 (m, 4H, 2xCH=CH₂), 4.66 - 4.32 (m, 4H, 2xCH₂CH=CH₂), 4.20 (t, J = 7.0, 1H), 3.44 - 3.30 (m, 2H, C¾NHFmoc), 3.25 - 3.05 (m, 4H, C¾NHFmoc), 1.72 - 1.34 (m, 8H, 2xC¾C¾CH₂NHBoc).

¹³C NMR (75 MHz, CDC1₃) δ 179.07 (C, C=0 acid), 157.30 (C, C=0 (Fmoc)), 156.63 (2C, 2xC=0 (Alloc)), 143.75 (2C,CCHC(Ar)), 141.16 (2C,CCCCH(Ar)), 132.80 (2CH, 2xCH=CH₂), 127.62, 126.96, 124.99, 119.90 (8CH, CH(Ar)), 117.50 (2CH₂, 2xCH=CH₂), 66.95 (CH₂, CH₂(Fmoc)), 65.42 (2CH₂, 2xCH₂CH=CH₂), 49.80 (C, CCH₂CH₂CH₂NHBoc), 47.03 (CH, CH(fluorene)), 43.1 1 (CH₂, CH₂NHFmoc), 40.92 (2CH₂, 2xCH₂NHBoc), 30.19 (2CH₂, 2xCH₂CH₂CH₂NHBoc), 23.91 (2CH₂, 2xCH₂CH₂NHBoc).

MS-ESI+: calcd for C32H39N3O8 593.2737, found 616.2626 [M+Na]⁺ FmocB²bisOrn(Boc)?NH(CH?)^CH^

HB339F1

FFmmoocc ²²bbiissOOrrnn((BBoocc))₂₂OOHH [[330000 mmgg ((00..4488mmmmooll))]] wwaass ddiissssoollvveedd iinn DDCCMM [[88mmLL]].. DDCCCC [[110099 mmgg ((00..5533mmmmooll))]],, HHOOBBtt [[7722 mmgg ((00..5533mmmmooll))]],, DDMMAAPP [[55 mmgg ((00..0055mmmmooll))]] aanndd tteettrraaddeeccyyllaammiinnee[[ll 1133 mmgg ((00..5533 mmmmooll))]] wweerree aaddddeedd.. TThhee mmiixxttuurree wwaass ssttiirrrreedd ffoorr 44 hhoouurrss.. TThhee oorrggaanniicc llaayyeerr wwaass wwaasshheedd wwiitthh NNaaCCll,, ddrriieedd oovveerr mmaaggnneessiiuumm ssuullffaattee,, ffiilltteerreedd aanndd eevvaappoorraatteedd.. TThhee ccrruuddee ccoommppoouunndd wwaass ppuurriiffiieedd bbyy ffllaasshh cchhrroommaattooggrraapphhyy ((CCyy//AAEE 110000//00—— »»5500//5500)) ttoo aaffffoorrdd aa yyeelllloowwiisshhooiill ((339900 mmgg,, 00..4477 mmmmooll,, 9999%% yyiieelldd))..

RR_ff ((55::55,, ccyycclloohheexxaanneerreetthhyyll aacceettaattee)) == 00..7766

1H1H NNMMRR ((330000 MMHHzz,, CCDDCC11₃₃)) δδ 77..6677 ((dd,, JJ == 77..44,, 22HH,, 22xxCCHH((AArr)))),, 77..5511 ((dd,, JJ == 77..44,, 22HH,, 22xxCCHH((AArr)))),, 77..3366 -- 77..1177 ((mm,, 44HH,, 44xxCCHH((AArr)))),, 66..0055 ((bbss,, 11HH,, NNHH)),, 55..4477 ((bbss,, 11HΗ,, NNHH)),, 44..8800 ((bbss,, 22HΗ,, 22xxNNHHBBoocc)),, 44..3300 ((dd,, JJ == 66..55,, 22HΗ,, CCHH₂₂((FFmmoocc)))),, 44..1111 ((tt,, JJ == 66..55,, 11HH,, CCHH((fflluuoorreennee)))),, 33..2288 ((mm,, 22HΗ,, C CH¾₂NNHHFFmmoocc)),, 33..1133 ((mm,, 22HH,, NNHHCCH¾₂CCHH₂₂)),, 33..0000 ((mm,, 44HH,, 22xxCCH¾₂NNHHBBoocc)),, 11..5500 -- 11..1100 ((mm,, 5500HH,, CCHH2₂CCHH2₂CCHH2₂CCHH2₂CCHH2₂CCHH2₂CCHH2₂CCHH2₂CCHH2₂CCHH2₂CCHH2₂CCHH3₃ aanndd 22xxCCHH₂₂CCHH₂₂CCHH₂₂NNHHBBoocc aanndd 22xxCC((CCHH₃₃))₃₃)),, 00..8800 ((tt,, JJ== 66..66,, 33HΗ,, CCHH₃₃))..

¹ ¹³³CC NNMMRR ((7755 MMHHzz,, CCDDCC11₃₃))66 117755..6677 ((CC,, CC==00 aammiiddee)),, 115577..6655 ((CC,, CC==00 FFmmoocc)),, 115566..6666 ((22CC,, 22xxCC==OOBBoocc)),, 114444..1177 ((22CC,,CCCCHHCC((AArr)))),, 114411..5588 ((22CC,,CCCCCCCCHH((AArr)))),, 112277..9900,, 112277..2255,, 112255..2288,, 112200..1122 ((88CCHH,, 88xxCCHH((AArr)))),, 7788..9988 ((22CC,, 22xxCC((CCHH₃₃))₃₃)),, 6666..7700,, 4499..2299,, 4466..8888 ((CCHH,, CCHH((ffiiuuoorreennee)))),, 4444..2222,, 4400..3322,, 3399..4444,, 3399..3377,, 3311..5511,, 3300..3355,, 2299..2288,, 2299..2233,, 2299..1188,, 2299..1144,, 2288..9944,, 2288..8899,, 2277..9977 ((66CCHH₃₃,, 22xxCC((CCHH₃₃))₃₃)),, 2266..6622,, 2266..5511,, 2222..2233,, 1133..6622 ((CCHH₃₃,, CCHH₂₂CCHH₃₃))..

MMSS--EESSII++:: ccaallccdd ffoorr CC4488HH7766NN44OO77 882200..55771144,, ffoouunndd 884433..55660066 [[MM++NNaa]]⁺⁺

hb443Fl Fmocp²bisOrn(Boc)₂NH(CH₂)i₃CH₃ [130 mg (0.12 mmol)] was dissolved in THF (2mL) and octanethiol [0.21 mL (1.2 mmol)] and DBU [0.54 μΐ, (0.0036 mmol)] were added. Before THF evaporation, the mixture was stirred for 15 minutes. The crude compound was purified by flash chromatography (DCM/MeOH/NEt₃ 100/0/0→ 90/10/0.1)to afford a colourless oil(58 mg, 0.1 mmol, 81% yield).

1H NMR (300 MHz, CDC1₃) δ 8.45 (s, 1H, NH), 4.77 (s, 2H, 2xNHBoc), 3.15 (dd, J = 12.7, 6.6, 2H, NHC¾CH₂), 3.03 (m, 4H, 2xCH₂NHBoc), 2.80 (s, 2H, C¾NH₂), 1.73 (s, 2H, NH), 1.55 (m, 2Η, CH₂), 1.45 (m, 26Η, 2xC(CH₃)₃and 2xCH₂CH₂NHBoc and 2CH₂), 1.21 (s, 22Η, CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃ and 2xCH₂CH₂CH₂NHBoc), 0.83 (t, J = 6.5, 3H, CH₂C¾).

¹³C NMR (75 MHz, CDC1₃) δ 176.16(C, C=0 amide), 156.01 (2C, 2xC=OBoc), 78.89 (2C, 2xC(CH₃)₃), 47.23 (C, CCH₂CH₂CH₂NHBoc), 45.64 (CH₂, CH₂NH₂), 40.80 (2CH₂, 2xCH₂NHBoc), 38.95 (CH₂, NHCH₂CH₂), 31.81, 31.66 (3CH₂, CH₂CH₂CH₃ and2xCH₂CH₂CH₂NHBoc), 29.59, 29.55, 29.52, 29.49, 29.25, 29.20 (9CH₂,OT₂CH₂OT₂OT₂OT₂OT₂OT₂CH₂CH₂CH₂CH₂CH₂CH₃, 28.33 (6CH₃, 2xC(CH₃)₃), 27.01(CH₂, NHCH₂CH₂CH₂), 24.46 (CH₂, H₂CH₃), 22.58 (2CH₂, 2xCH₂CH₂NHBoc), 14.03 (CH₃, CH₂CH₃).

MS-ESI+: calcd for C33H66N4O5 598.5033, found 599.5112 [M+H]⁺

FmocB²bisOrn(Boc)₇NHBn

HB414

Fmoc ²bisOrn(Boc)₂OH [300 mg (0.48 mmol)] was dissolved in DCM [20mL]. DCC [100 mg (0.48 mmol)], HOBt [64 mg (0.48 mmol)], DMAP [5 mg (0.05 mmol)] and benzylamine [56 mg (0.53 mmol)] were added. The mixture was stirred for 16 hours. The product was extracted with ethyl acetate and the organic layer was washed with NH₄CI three times, dried over magnesium sulfate, filtered and evaporated. The crude compound was purified by flash chromatography (Cy/AE 100/0— 50/50) to afford a colorless oil (251 mg, 0.35 mmol, 73% yield). R_f (7:3, cyclohexanerethyl acetate) = 0.50

1H NMR (300 MHz, CDC1₃)6 7.77 (d, J = 7.5, 2H, 2xCH(Ar)), 7.60 (d, J = 7.4, 2H, 2xCH(Ar)), 7.33 (m, J = 8.2, 6.3, 9H, 9xCH(Ar)), 6.49 (bs, 1H, NH), 5.48 (bs, 1H, NH), 4.79 (bs, 2H, 2NHBoc), 4.40 (m, 4H, C¾Ph and CH₂ (Fmoc)), 4.18 (m, 1H, CH(fluorene)), 3.38 (m, 2H, C¾NHFmoc), 3.14 - 2.98 (m, 4H, 2xC¾NHBoc), 1.69 - 1.31 (m, 24H, 2xC¾C¾CH₂NHBoc and 2xC(C¾)₃).

¹³C NMR (75 MHz, CDC1₃)6 175.80 (C, C=0 amide), 157.67 (C, C=0 Fmoc), 156.65 (2C, 2xC=0 Boc), 144.21 (2C,CCHC(Ar)), 141.64 (2C,CCCCH(Ar)), 138.59 (C, C(Ar)), 129.01, 128.00, 127.95, 127.80, 127.31, 125.31, 120.18 (13CH, 13xCH(Ar)), 79.07 (2C, 2xC(CH₃)₃), 66.72 (CH₂, CH₂(Fmoc)), 49.50 (C, CCH₂CH₂CH₂NHBoc), 46.93 (CH, CH(fluorene)), 43.40 (CH₂, CH₂Ph), 40.31 (CH₂, CH₂NHFmoc), 33.60 (2CH₂, 2xCH₂NHBoc), 30.31 (2CH₂, 2xCH₂CH₂CH₂NHBoc), 28.01 (6CH₃, 2xC(CH₃)3), 23.74 (2CH₂, 2xCH₂CH₂NHBoc).

H-B²bisOrn(Boc)₇NHBn

HB426F1

Fmoc ²bisOrn(Boc)₂NHBn[251 mg (0.35 mmol)] was dissolved in THF (6mL) and octanethiol [0.6mL (3.5 mmol)] and DBU [1.5μί (0.01 mmol)] were added. Before THF evaporation, the mixture was stirred for 15 minutes. The crude compound was purified by flash chromatography (DCM/MeOH/NEt₃ 100/0/0→ 90/10/0.1) to afford a colorless oil(150 mg, 0.3 mmol, 87% yield).

1H NMR (300 MHz, CDC1₃)6 7.35 - 7.20 (m, 5H), 4.82 (bs, 2H), 4.41 (m, 2H), 3.11 - 2.98 (m, 4H), 2.87 (s, 2H), 1.73 - 1.01 (m, 26H).

¹³C NMR (75 MHz, CDC1₃)6 176.82 (C, C=0 amide), 156.47 (2C, 2xC=0 Boc), 139.25 (C, C(Ar)), 128.65, 127.51, 127.17 (5CH, 5xCH(Ar)), 78.72 (2C, 2xC(CH₃)₃), 47.00 (C, CCH₂CH₂CH₂NHBoc), 44.99 (CH₂, CH₂NH₂), 42.54 (CH₂, CH₂Ph), 40.39 (2CH₂, 2xCH₂NHBoc), 31.17 (2CH₂, 2xCH₂CH₂CH₂NHBoc), 27.90 (6CH₃, 2xC(CH₃)₃), 23.92 (2CH₂, 2xCH₂CH₂NHBoc). H-B²bisOrn(Boc)?OBn

Fmoc ²bisOrn(Boc)₂OH was dissolved in CH₃CN then Cs2C03 and BnBr were added. The mixture was stirred and heated in MW at 60°C (P=150W) for 10 min four times. CH3CN was evaporated and the compound was extracted with ethyl acetate and washed with 5% NaHC0₃ solution, 5% citric acid solution and brine, dried over magnesium sulfate, filtered and evaporated. The crude compound was purified by flash chromatography (DCM/MeOH/NEt3 100/0/0. l→95/5/0.1) to afford a colorless oil(80 mg, O. l lmmol, 28% yield).

R_f (5:5, cyclohexanerethyl acetate) = 0.43

1H NMR (300 MHz, MeOD)6 7.43 - 7.30 (m, 5H, 5xCH(Ar)), 5.14 (s, 2H, C¾Ph), 2.98 (t, J = 6.8, 4H, 2xCH₂NHBoc), 2.81 (s, 2H, C¾NH₂), 1.59 (dd, J = 9.3, 7.5, 4H, 2xC¾CH₂CH₂NHBoc), 1.43 (s, 18H, 2xC(C¾)₃), 1.40 - 1.26 (m, 4H, 2xC¾CH₂NHBoc).

¹³C NMR (75 MHz, MeOD) δ 177.03 (C, C=0 ester), 158.63 (2C, 2xC=Ocarbamate), 137.66 (C, C(Ar)), 129.77, 129.58, 129.45 (5CH, 5xCH(Ar)), 80.01 (C, 2xC(CH₃)₃), 67.66 (CH₂, CH₂Ph), 51.45 (CH₂, CH₂NH₂), 45.64 (C, CCH₂CH₂CH₂NHBoc), 41.68 (CH₂, 2xCH₂NHBoc), 31.30 (CH₂, 2xCH₂CH₂CH₂NHBoc), 28.96 (6CH₃, 2xC(CH₃)₃), 25.46 (CH₂, 2xCH₂CH₂NHBoc).

MS-ESI+: calcd for CzehUsNsOe 493.3152, found 494.3225 [M+H]⁺

Example 2: Synthesis of β -bis-ornithine

1-benzyl 3-tert-butyl 2,2-bis(2-cyanoethyl)malonate :

Benzyl teri-butylmalonate [10 g (100 mmol)] was mixed with acrylonitrile [25 g (100 mmol)]. Triethylamine [6.7mL (50 mmol)] was added, followed by lithium perchlorate [5.32 g (50 mmol)]. The reaction was stirred continuously and allowed to react overnight. After confirming completion of the reaction by TLC, the product was extracted with ethyl acetate. The organic layer was washed with 5% citric acid solution and brine, dried over magnesium sulfate, filtered and evaporated. The crude compound was purified by flash chromatography (Cy/AE 100/0→ 8/2) to afford a yellow oil. (31.5 g, 88 mmol, 88% yield)

R_f (8:2, cyclohexanerethyl acetate) = 0.37

1H NMR (250 MHz, CDC1₃)6 7.37 (m, 5H, CH2C6H5), 5.21 (s, 2H, (CH2, C¾Ph)), 2.32 (m, 8H, 2xCH₂CH₂C≡N), 1.35 (s, 9H, C(CH₃)₃).

¹³C NMR (63 MHz, CDC1₃)6 168.38, 167.06 (2C, C=0), 133.73 (C, Ph), 128.14, 128.08, 127.97, 127.75, 126.85, 126.16 (5CH, Ph), 1 17.78 (2C, 2xC≡N), 83.19 (C, C(CH₃)₃), 67.14 (CH2, OfcPh), 55.36 (C, CCH₂CH₂C≡N), 28.74 (2CH₂, 2xCH₂CH₂C≡N), 26.84 (3CHs, C(CH₃)3), 12.14 (2CH₂, 2xCH₂C≡N).

MS-ESI+: calcd for C₂₀H₂₄N₂O₄356.1736, found 379.1628 [M+Na]⁺ 2-(tert-butoxycarbonyl)-4-cvano-2-(2-cvanoethyl)butanoic acid :

1-benzyl 3-tert-butyl 2,2-bis(2-cyanoethyl)malonate[12 g (35 mmol)] was dissolved in MeOH. Then, ammonium formate [1 1 g (175 mmol)] and Pd/C [1.2 g (3.50 mmol)] were added and the reaction mixture was stirred for 3 hours. Afterward, the reaction mixture was filtered through a celite pad to remove the Pd/C before evaporation to dryness. The product was extracted with dichloromethane. The organic layer was washed with 10% citric acid solution and brine, dried over magnesium sulfate, filtered and evaporated. The product was used in following synthesis without any further purification. (7.6 g, 29mmol, 81%> yield)

R_f (8:2:0.1, cyclohexane:ethylacetate: acetic acid) = 0.1

1H NMR (250 MHz, CDC1₃)6 2.48 (m, 4H, 2xC¾CH₂C≡N), 2.24 (m, 4H, 2xCH₂C¾C≡N), 1.51 (s, 9H, C(CH₃)₃).

¹³C NMR (63 MHz, CDC1₃)6173.07 (C, C=0 acid), 168.27 (C, C=0 ester), 1 18.49 (2C, 2xC≡N), 84.75 (C, C(CH₃)₃), 56.23 (C, CCH₂CH₂C≡N), 29.95 (2CH₂, 2xCH₂CH₂C≡N), 27.82 (3CH3, C(CH₃)₃), 13.14 (2CH₂, 2xCH₂C≡N).

MS-ESI+: calcd for Ci3Hi₈N₂0₄266.1267, found 289.1 159 [M+Na]⁺ 1-tert-butyl 4-methyl 2,2-bisf2-cyanoethyl)succinate :

2-(tert-butoxycarbonyl)-4-cyano-2-(2-cyanoethyl)butanoicacid [9.0 g (34 mmol)] was dissolved under Argon in dichloromethane. Ghosez reagent [9.0 mL (68 mmol)] was added. The reaction mixture was stirred for 2h under Argon before the solvent was concentrated in vacuo. Acetonitrile (170 mL), DIEA [1 1.9 mL (68mmol)] and trimethylsilyldiazomethane [34mL (68mmol)] were added under argon at 0°C. The reaction mixture was stirred under argon at 0°C for 16h. Afterwards, the solvents were evaporated in vacuo. The crude product was extracted with ethyl acetate and washed with 10% citric acid, saturated NaHC0₃ and brine. Finally, the organic phase was dried over MgSC^, filtered, and evaporated to dryness. DMF (180mL), MeOH (90mL) and Ag₂0 [39.4 g (170mmol)] were added to the crude compound. The reaction mixture was stirred at reflux during 10 minutes. Afterward, the reaction mixture was filtered through celite and MeOH was evaporated. The product was extracted with diethyl ether. The organic layer was washed three times with NH₄C1 saturated solution, dried over magnesium sulfate, filtered and evaporated. The crude compound was purified by flash chromatography (Cy/AE 100/0— 6/4) to afford a yellow oil (2 g, 6.8 mmol,

20% yield).

R_f (5:5, cyclohexanerethyl acetate) = 0.68

1H NMR (300 MHz, CDC1₃)6 3.71 (s, 3H, C0₂C¾), 2.61 (s, 2H, G¾C0₂Me), 2.37 - 2.27 (m, 4H, 2CH₂CH₂C≡N), 2.07 - 1.91 (m, 4H, 2CH₂C≡N), 1.48 (s, 9H, C(CH₃)₃).

¹³C NMR (75 MHz, CDC1₃)6171.36, 170.12 (2C, 2xC=0), 118.75 (2C, 2xC≡N), 82.54 (C, C(CH₃)₃), 51.62 (CH₃, C0₂CH₃), 46.57 (CH₂, CH₂C0₂Me), 37.35 (C, CCH₂CH₂C≡N), 30.62 (2CH₂, 2xCH₂CH₂C≡N), 27.47 (3CH₃, C(CH₃)₃), 12.27 (2CH₂, 2xCH₂C≡N).

MS-ESI+: calcd for C14H18N4O3294.I58O, found 317.4718 [M+Na]⁺

2,2-bisf2-cyanoethyl)-4-methoxy-4-oxobutanoic acid :

1-tert-butyl 4-methyl 2,2-bis(2-cyanoethyl)succinate[1.3 g (4.4 mmol)] was dissolved in dichloromethane [40 mL]. Triisopropylsilane [0.9mL (4.4 mmol)] then TFA [40 mL]were added and the reaction mixture was stirred 1 hour before evaporation to dryness. The crude compound was purified by flash chromatography (Cy/AE/ Acetic acid 100/0/0.1 — 50/50/0. l)to afford a colorless oil(0.9 g, 3.8mmol, 90% yield).

R_f (5:5:0.1, cyclohexane:ethylacetate: acetic acid) = 0.34

1H NMR (300 MHz, CDC1₃)6 3.66 (s, 3H, C0₂C¾), 2.65 (s, 2H, CH2C0₂Me), 2.49 - 2.30 (m, 4H, 2xCH₂CH₂C≡N), 2.16 - 1.98 (m, 4H, 2xCH₂C≡N).

¹³C NMR (75 MHz, CDC1₃)6 177.90 (C, C=0 acid), 170.45 (C, C=0 ester), 118.73 (2C, 2xC≡N), 52.39 (CHs, C0₂CH₃), 46.33 (C, CCH₂CH₂C≡N), 36.96 (CH₂, CH₂C0₂Me), 30.84 (2CH₂, 2xCH₂CH₂C≡N), 12.75 (2CH₂, 2xCH₂C≡N).

MS-ESI+: calcd for CiiHi₄N₂O₄238.10, found 261.0845 [M+Na]⁺ methyl 3-((tert-butoxycarbonyl)amino)-5-cvano-3-(2-cvanoethyl)Dentanoate :

(ref : A methodology for the synthesis of beta aminoacids, J. Chem Soc, Perkin Trans. I, 2000, 1461-1466)

2,2-bis(2-cyanoethyl)-4-methoxy-4-oxobutanoic acid [0.450 g (1.9mmol)] was dissolved in dry acetone [15 mL]. The solution was cooled at 0°C and NEt₃[0.3 mL (2.3mmol)] and ClC0₂Et [0.2 mL (2.1mmol)] were added. The reaction mixture was stirred for one hour and a half. To the mixture was added NaN₃ in H₂0 and stirred at 0°C for for 2 hours. The solvent was evaporated. The residue was then extracted with toluene three times. The organic layer was dried over MgS0₄, filtered. The volume was reduced by evaporation until 20 mL of toluene. i-BuOH was added and the reaction was gently allowed to reflux for an additional 16h. The solvent was evaporated to dryness. The crude compound was purified by flash chromatography (Cy/AE 100/0 — 7/3) to afford a white powder (0.2 g, 0.67mmol, 35 % yield).

R_f (5:5, cyclohexanerethyl acetate) = 0.44

1H NMR (300 MHz, CDC1₃)65.17 (bl, 1H, NHBoc), 3.72 (s, 3H, C0₂C¾), 2.60 (s, 2H, CH₂C0₂Me), 2.45 - 2.22 (m, 6H, 0.75 CH₂CH₂C≡N), 2.12 - 1.99 (m, 2H, CH₂CH₂C≡N), 1.40 (s, 9H, C(CH₃)₃).

¹³C NMR (75 MHz, CDC1₃)6 170.38 (C, C=0 ester), 154.24 (C, COcarbamate), 1 19.19 (2C, C≡N), 80.46 (C, C(CH₃)₃), 55.29 (C, CCH₂CH₂C≡N), 52.33 (CHs, C0₂CH₃), 39.49 (CH₂, CH₂C0₂Me), 31.81 (2CH₂, 2xCH₂CH₂C≡N), 28.27 (3CHs, C(CH₃)3), Π .95 (2CH₂, 2xCH₂C≡N).

MS-ESI+: calcd for C15H23N3O4 309.1689, found 332.1581 [M+Na]⁺ methyl 3,6-bis((tert-butoxycarbonyl)amino)-3-(3-((tert-butoxycarbonyl)amino) propyDhexanoate :

methyl 3-((tert-butoxycarbonyl)amino)-5-cyano-3-(2-cyanoethyl)pentanoate [0.145 g (0.47 mmol)] was dissolved in a 5 : 1 mixture of methanol and chloroform. Pt0₂ [0.016 g (0.07 mmol)] was added and the reaction mixture was hydrogenated at room temperature for 3 days under 5 bar H₂ pressure. Afterward, the reaction mixture was filtered through celite to remove the Pt0₂ before evaporation to dryness. The crude product was dissolved in a 1 : 1 mixture of THF and H₂0 and Boc₂0 was added. The reaction mixture was stirred for one night. THF was evaporated and afterward the product was extracted with dichloromethane. The organic layer was washed with NaCl saturated solution, dried over magnesium sulfate, filtered and evaporated. The crude compound was purified by flash chromatography (Cy/AE 7/3) to afford a colorless oil (0.150 g, 0.29mmol, 62 % yield).

R_f (5:5, cyclohexanerethyl acetate)

1H NMR (300 MHz, CDC1₃)6 3.64 (s, 3H, C0₂C¾), 3.11 - 3.02 (m, 4H, 2xC¾NHBoc), 2.61 (s, 2H, C¾C0₂Me), 1.77 - 1.56 (m, 4H, 2xC¾CH₂CH₂NHBoc), 1.48 - 1.34 (m, 32H, 2xC¾CH₂NHBoc and 3xC(C¾)₃). ^1JC NMR (75 MHz, CDC1₃)6 171.65 (C, C=0 ester), 156.01 (2C, 2xC=Ocarbamate), 154.48 (C, C=Ocarbamate), 79.06 (3C, 3xC(CH₃)₃), 56.12 (C, CCH₂CH₂CH₂NHBoc), 51.64 (CHs, C0₂CH₃), 40.48 (2CH₂, 2xCH₂NHBoc), 40.29 (CH₂, CH₂C0₂Me), 33.25 (2CH₂, 2xCH₂CH₂CH₂NHBoc), 28.39 (9CHs, 3xC(CH₃)3), 23.80 (2CH₂, 2xCH₂CH₂NHBoc).

MS-ESI+: calcd for C25H47N3O8 517.6560, found 540.3255 [M+Na]⁺

3,6-bisfftert-butoxycarbonyl)amino)-3-f3-fftert-butoxycarbonyl)amino)propyl)hexanoic acid :

Methyl-3,6-bis((tert-butoxycarbonyl)amino)-3-(3-((tert- butoxycarbonyl)amino)propyl)hexanoate [0.130 g (0.25 mmol)] was dissolved in a 1 : 1 mixture of THF and H₂0. LiOH [0.012 g (0.5 mmol)] was added and the reaction mixture was stirred at rt for 5 days. The product was used in following synthesis without any further purification. (0.120 g, 0.24 mmol, 98% yield).

R_f (5:5, cyclohexane: ethyl acetate) = 0.20

1H NMR (300 MHz, MeOD) δ 3.01 (t, J = 6.6, 4H, 2xC¾NHBoc), 2.62 (s, 2H, (CH₂, CH2C0₂H)), 1.73 (m, 4H, 2xC¾CH₂CH₂NHBoc), 1.42 (m, 32H, 2xC¾CH₂NHBoc and 3xC(CH₃)₃).

¹³C NMR (75 MHz, MeOD) δ 158.63 (3C, 3xC=Ocarbamate), 79.96 (3C, 3xC(CH₃)₃), 57.18 (C, CCH₂CH₂CH₂NHBoc), 41.70 (3CH₂, CH₂C0₂H and 2xCH₂NHBoc), 34.31 (2CH₂, 2xCH₂CH₂CH₂NHBoc), 28.95 (9CHs, 3xC(CH₃)₃), 25.04 (2CH₂, 2xCH₂CH₂NHBoc).

MS-ESI+: calcd for C24H45N3O8 503.6294, found 526.3099[M+Na]⁺

Example 3 : Synthesis of dipeptides

General procedure 1 for coupling of protected-hydrophobic amino acids and H-B²-bis- OrnfBoc OMe in solution

The protected-hydrophobic amino acid (1 mmol) was dissolved in DMF. HBTU (1 mmol) and DIE A (1 mmol) were added. The protected hydrophobic amino acid (1 mmol) was preactivated for 5 minutes before H-p²-bis-Orn(Boc)₂R (R= OMe, OBn, NHBn or NH(CH₂)i₃CH₃) was added. The reaction mixture was stirred at room temperature for one night before it was diluted with diethylether and washed with saturated NH₄C1 three times. The organic phase was dried over MgSC^, filtered, and evaporated to dryness. The crude compound was purified by flash chromatography to afford the pure protected dipeptide. Then, the Boc-protected β-peptidomimetic was deprotected by dissolving it in DCM (-0.4 M) and adding an equivalent volume of TFA:TIS: water (95:2.5:2.5). The mixture was stirred at rt for 2 h before it was evaporated to dryness. When Fmoc protection is used, a secondary deprotection can be made with piperidine/DCM (20/80). The mixture was stirred at rt for 2 h before it was evaporated to dryness. The crude product was purified by preparative RP- HPLC. The purity of the pure β-peptidomimetics was checked by analytical RP-HPLC before the residue was lyophilized. All compounds possessed purity above 95%.

General procedure 2 in order to obtain B²-bis-arginine containing peptides from the deprotectedB²-bis-ornithine containing peptides in solution

The synthesis was conducted in accordance to the last general procedure 1 with the exception of after the deprotections, the deprotected amines were reacted with l,3-Di-Boc-2- (trifluoromethylsulfonyl)guanidineand NEt₃ in THF for one night. The solvent was evaporated and the Boc groups were removed with a solution ofTFA:TIS: water (95:2.5:2.5). The mixture was stirred at rt for 2 h before it was evaporated to dryness. The crude product was purified by preparative RP-HPLC. The purity of the pure β-peptidomimetics was checked by analytical RP-HPLC before the residue was lyophilized. All compounds possessed purity above 95%.

General procedure 3 in order to obtain protected-N terminal dipeptide

The synthesis was conducted in accordance to the last general procedure 1 with the exception of before deprotections, the compound was dissolved in THF (0.4 M) and octanethiol and DBU were added. Before THF evaporation, the mixture was stirred for 15 minutes. The crude compound was purified by flash chromatography to afford free N terminal dipeptide. Finally, the desired acid was activated with HBTU, DIEA in DMF and stirred with the obtained compound for 3 hours. The crude compound was purified by flash chromatography to afford protected-N terminal dipeptide. The Boc groups were removed with a solution ofTFA:TIS:water (95:2.5:2.5). The mixture was stirred at rt for 2 h before evaporation to dryness. The crude product was puri ied by preparative RP-HPLC. The purity of the pure β- peptidomimetics was checked by analytical RP-HPLC before the residue was lyophilized. All compounds possessed purity above 95%.

General procedure 4 for coupling of protected- B²-bis-Orn(Boc)20Me H- hydrophobic amino acids in SPPS

HMBA-AM resin (100-200 mesh) (leq) was initially washed five times with DMF, DCM and DMF, then allowed to swell in DMF for 30 min. Fmoc-Tbt-OH (4eq) was dissolved in dry DCM. The solution was cooled to 0 °C before DIC (4eq) was added. The reaction was stirred for 20 min before the solvent was removed in vacuo. The resulting symmetrical anhydride was redissolved in DMF before adding directly to the resin. A solution of DMAP (O. leq) in DMF was added and the resin shaken for 1 h before washing with DMF, DCM and DMF. Fmoc removal was performed by using 20% (v:v) piperidine in DMF3 times for 5 min. The resin was washed five times with DMF. Stepwise couplings were accomplished with 2 equivalents of protected- PbisOrn(Boc)₂OH, 2 equivalents of HATU and 4 equivalents of DIEA. Coupling reaction with Fmocp²bisOrn(Boc)₂OH was allowed to proceed for 16h twice at 50°C and coupling reaction with Bocp³bisOrn(Boc)₂OH was allowed to proceed for 2h at room temperature.All protected amino acids and reagents were dissolved in DMF at 0.15 M. After desired time, the solution was removed by filtration and the resin was washed with DMF five times. Reaction completion was checked by Kaisertest. If necessary, Fmoc removal was performed by using 20% (v:v) piperidine in DMF3 times for 5 min. The resin was washed five times with DMF and DCM.Boc removal was performed by using TFA/TIS/H₂0 (95/2.5/2.5) twice. The deprotected amines were reacted with l ,3-Di-Boc-2-(trifluoromethylsulfonyl)guanidine (6eq)in DCM for one night. The resin was filtrated and the Boc groups were removed with a solution of TFA:TIS:water (95:2.5:2.5). The mixture was stirred at rt for 2 h. The solution was removed and the resin was cleaved using MeOH/DMF/DIEA (5/5/1) for 16 hours at 50°C. The solution was filtrated and solvents were evaporated. The crude product was purified by preparative RP-HPLC. The purity of the pure β-peptidomimetics was checked by analytical RP-HPLC before the residue was lyophilized. All compounds possessed purity above 95%.

1H NMR (300 MHz, MeOD) δ 7.59 (d, J = 7.8, 1H, CH(Ar)), 7.39 (d, J = 7.8, 1H, CH(Ar)), 7.20 (s, 1H, CH(Ar)), 7.14 (t, J= 6.9, 1H, CH(Ar)), 7.06 (t, J= 7.5, 1H, CH(Ar)), 3.91 - 3.81 (m, 1H, CHNH₂), 3.70 (s, 3H, C0₂C¾), 3.50 (d, J = 14.2, 1H, 0.5 C¾CCO₂Me), 3.40 (d, J = 14.2, 1H, 0.5 CH₂CCO₂Me), 3.15 (dd, J = 14.2, 6.0, 1H, CH₂-indole), 3.08 (dd, J = 14.2, 7.5, 1H, C¾-indole), 2.94 - 2.78 (m, 4H, 2xC¾NH₂), 2.70 (dd, J = 16.3, 5.0, 1H), 2.57 (dd, J= 16.3, 7.8, 1H), 1.73 - 1.47 (m, 8H, 2xC¾C¾CH₂NH₂).

MALDI-TOF: calcd for C22H35N5O3417.27, found 418.28[M+H]⁺

HPLC (Water/ACN (0.1% TFA); 5 to 100 % ACN in 30 minutes): tr= 7.12 min

MALDI-TOF: [M+H]⁺calcd 417.3, found 418.1

HPLC (Water/ACN (0.1% TFA); 5 to 35 % ACN in 30 minutes): tr= 11.76 min

Exact Mass: 372,3100 HB220

1H NMR (300 MHz, MeOD) δ 3.73 (s, 3H, C0₂C¾), 3.67 (s, 1H, 0.5xC¾CCO₂Me), 3.34 (s, 1H, 0.5xC¾CCO₂Me), 3.15 (dd, J = 12.8, 7.8, 1H, 0.5xC¾NH₂), 3.02 (dd, J = 12.8, 4.5, 1H, 0.5xC¾NH₂), 2.90 (d, J = 4.8, 4H, 2xCH₂C¾NH₂), 2.75 - 2.64 (m, 1H, CHCH₂NH₂), 1.75 - 1.48 (m, 10H, 2xC¾C¾CH₂NH₂ and CH3CH2CH2CH2CH2CH2), 1.32 (d, J= 3.3, 8H, CH₃C¾C¾C¾C¾), 0.91 (t, J= 6.7, 3H, C¾CH₂). MALDI-TOF

HPLC (Water/ACN (0.1% TFA); 5 to 100 % ACN in 30 minutes): tr= 8.53 min

1H NMR (300 MHz, MeOD) δ 8.36 (s, 1H, NH(Trp)), 7.30 (d, J= 1.6, 1H, CH(Ar)), 7.16 (d, J = 1.6, 1H, CH(Ar)), 4.05 (dd, J = 10.5, 5.2, 1H, CHNH₂), 3.65 (d, J = 14.2, lH,0.5xCH₂NHC=O), 3.59 (s, 3H, C0₂CH₃), 3.47 (dd, J= 14.3, 10.5, 3H), 3.38 (dd, J= 14.3, 5.2, 2H), 2.85 (dd, J = 7.8, 4.7, 4H), 2.91 - 2.77 (m, 4H, 2xC¾NH₂), 2.44 (d, J = 14.2, 1H, 0.5xC¾NHC=O), 1.78 - 1.35 (m, 38H, 2xC¾C¾CH₂NH₂ and 3xC(C¾)s).

MALDI-TOF: calcd 571.45, found 572.60[M+H]"

HPLC (Water/ACN (0.1% TFA); 30 to 50 % ACN in 30 minutes): tr= 12.73 min

1H NMR (300 MHz, MeOD) δ 8.35 (s, 1H, NH(Trp)), 7.31 (d, J= 1.5, 1H, CH(Ar)), 7.14 (d, J= 1.5, 1H, CH(Ar)), 4.39 (t, J= 7.2, 1H, CHCH₂-indole), 3.65 (s, 3H, C0₂C¾), 3.52 (d, J = 14.2, 1H, 0.5xC¾NHC=O), 3.47 (dd, J = 1 1.1, 7.2, 2H, C¾-indole), 3.13 - 3.01 (m, 4H, 2xC¾NHC(NH)NH₂), 2.82 (d, J = 14.2, 1H, 0.5xC¾NHC=O), 1.64 - 1.26 (m, 35H, 2xC¾C¾CH₂NHC(NH)NH₂ and 3xC(C¾)s).

MALDI-TOF: calcd for C36H₆3Nii0₃697.5, found 698.4 [M+H]⁺, 720.4 [M+Na]⁺, 736.3 [M+K]⁺, 681.3 [M+H-NH₃]⁺

HPLC (Water/ACN (0.1% TFA); 30 to 50 % ACN in 30 minutes): tr= 14.08 min

1H NMR (300 MHz, MeOD) δ 8.38 (s, 1H, NH(Trp)), 7.27 (d, J= 1.6, 1H, CH(Ar)), 7.15 (d, J= 1.6, 1H, CH(Ar)), 4.03 (t, J= 7.9, 1H, CHCH₂-indole), 3.57 (s, 3H, C0₂C¾), 3.56 (d, J = 14.2, 1H, 0.5 CH₂NHC=O), 3.43 (d, J= 8.6, 2H, , C¾-indole), 3.10 - 3.00 (m, J= 11.6, 5.1, 4H, 2xCH₂NHC(NH)NH₂), 2.26 (d, J = 14.2, 1H, 0.5xC¾NHC=O), 1.66 - 1.15 (m, 35H, 2xC¾C¾CH₂NHC(NH)NH₂ and 3xC(C¾)s).

MALDI-TOF: calcd for C35H61N5O3655.5, found 656.4 [M+H]⁺, 678.4 [M+Na]⁺,694.4 [M+K]⁺,639.4 [M+H-NH₃]⁺

HPLC (Water/ACN (0.1% TFA); 30 to 50 % ACN in 30 minutes): tr= 16.11 min

1H NMR (300 MHz, MeOD)6 7.63 (d, J = 7.9, 1H, CH(Ar)), 7.40 (d, J = 7.9, 1H, CH(Ar)), 7.23 (s, 1H, CH(Ar)), 7.15 (t, J = 7.4, 1H), 7.07 (t, J = 7.4, 1H), 4.30 (t, J = 7.5, 1H, CHCH₂- indole), 3.67 (s, 3H, C0₂C¾), 3.49 (d, J = 14.3, 1H, 0.5xC¾NHC=O), 3.41 - 3.19 (m, 3H, C¾-indole and 0.5xC¾NHC=O), 2.78-2.73 (m, 4H, 2xC¾NH₂), 1.71 - 1.15 (m, 8H, 2xC¾C¾CH₂NH₂).

MALDI-TOF: calcd for C21H33N5O3403.3, found 404.5 [M+H]⁺, 426.5 [M+Na]⁺, 442.5 [M+K]⁺

HPLC (Water/ACN (0.1% TFA); 10 to 40 % ACN in 30 minutes): tr= 7.15 min

1H NMR (300 MHz, MeOD) δ 7.59 (d, J = 7.8, 1H, CH(Ar)), 7.36 (d, J = 7.8, 1H, CH(Ar)), 7.16 (s, 1H, CH(Ar)), 7.12 (dt, J = 7.8, 1.1, 1H, CH(Ar)), 7.03 (dt, J = 7.8, 1.1, 1H, CH(Ar)),4.64 (t, J = 7.2, 1H, CHCH₂-indole), 3.66 (s, 3H, C0₂C¾), 3.50 (d, J = 14.6, 2H, 0.5 C¾NHC=O), 3.34 (d, J= 14.6, 2H, 0.5xC¾NHC=O), 3.37 - 3.27 (m, 1H, C¾-indole), 3.19 (dd, J= 14.7, 7.2, 1H, C¾-indole), 2.97 (m, 4H, 2xC¾NHC(NH)NH₂), 1.58 - 1.12 (m, 8H, 2xC¾C¾CH₂NHC(NH)NH₂).

MALDI-TOF: calcd for C36H₆3Nii0₃529.3, found 530.6 [M+H]⁺, 552.6 [M+Na]⁺, 513.6 [M+H-NH₃]⁺

HPLC (Water/ACN (0.1% TFA); 10 to 40 % ACN in 30 minutes):tr= 12.75 min

1H NMR (300 MHz, MeOD) δ 8.30 (bs, 1H, NH), 7.24 (s, 1H, CH(Ar)), 7.11 (s, 1H, CH(Ar)), 4.28 - 4.22 (m, 1H, CHCH₂CH₂CH₂NH₂), 4.07 (t, J= 8.1, 1H, CHNH₂), 3.45 - 3.39 (m, 2H, C¾CHNH₂), 3.39 (s, 3H, C0₂Me), 2.85 (d, J = 5.8, C¾NH₂), 1.83 - 1.56 (m, 4H, CH₂CH₂CH₂NH₂), 1.53 (s, 9H, C(CH₃)₃), 1.50 (s, 9H, C(CH₃)₃), 1.37 (s, 9H, C(CH₃)₃).

MALDI-TOF: calcd for C₂9H₄₈N₄O₃500,4 found 501.3 [M+H]⁺, 523.3 [M+Na]⁺,539.3 [M+K]⁺

HPLC (Water/ACN (0.1% TFA); 40 to 70 % ACN in 30 minutes): tr= 9.01 min

1H NMR (300 MHz, MeOD) δ 7.81 (d, J = 7.5, 2H, 2xCH(Ar)), 7.64 - 7.56 (m, 2H, 2xCH(Ar)), 7.43 - 7.22 (m, 6H, 6xCH(Ar)), 7.14 (d, J = 1.5, 1H, CH(indole)), 4.48 - 4.39 (m, 1H, CH-Fmoc), 4.25 - 4.14 (m, 3H, CHNHFmoc and C¾-Fmoc), 3.64 - 3.56 (m, 4H, 0.5xC¾NHC=O and C0₂C¾), 3.43 (dd, J = 14.4, 9.0, 1H, 0.5xC¾-indole), 3.26 (dd, J = 14.7, 9.0, 1H, 0.5xC¾-indole), 2.87 (d, J = 14.1, 1H, 0.5xC¾NHC=O), 2.83 - 2.74 (m, 4H, 2xC¾NH₂), 1.75 - 1.18 (m, 43H, 2xC¾C¾CH₂NHC(NH)NH₂ and 3xC(C¾)s).

MALDI-TOF: calcd for C₄8H67N50₅793.5, found 794.5 [M+H]⁺, 816.4 [M+Na]⁺,832.4 [M+K]⁺

HPLC (Water/ACN (0.1% TFA); 50 to 100 % ACN in 30 minutes): tr= 11.88 min

1H NMR (300 MHz, MeOD)6 8.36 (s, 1H, NH(indole)), 7.32 - 7.29 (m, 5H, CH(Ar)), 7.28 (s, 1H, CH(indole)), 7.15 (s, 1H, CH(indole)), 5.03 (d, J= 12.0, 1H, 0.5xCH₂Ph), 5.01 (d, J = 12.0, 1H, 0.5xC¾Ph),4.03 (t, J= 6.1, 1H, CHNH₂), 3.60 (d, J= 14.2, 1H, 0.5xCH₂NHC=O), 3.45 - 3.38 (m, 2H, C¾-indole), 3.00 - 2.95 (m, 4H, 2xC¾NHC(NH)NH₂), 2.33 (d,J = 14.2, 1H, 0.5xC¾NHC=O), 1.59 - 1.20 (m, 35H, 2xC¾C¾CH₂NHC(NH)NH₂ and 3xC(C¾)s).

MALDI-TOF: calcd for C₄8H67N50₅731.5, found 732.4 [M+H]⁺, 770.3 [M+K]⁺,716.31 [M+H-NH₃]⁺

HPLC (Water/ACN (0.1% TFA); 20 to 90 % ACN in 30 minutes): tr= 15.43 min

Exact Mass: 697,51 15 HB438

MALDI-TOF: calcd for CseHesNnOs 697.5, found 698.5 [M+H]⁺, 720.4 [M+Na]⁺, 736.4 [M+K]⁺

HPLC (Water/ACN (0.1% TFA); 40 to 90 % ACN in 30 minutes): tr= 9.90 min

1H NMR (300 MHz, MeOD) δ 7.27 (d, J = 1.7, 1H, CH(Ar, indole)), 7.11 (d, J = 1.7, 1H, CH(Ar, indole)), 4.67 (dd, J= 8.8, 6.7, 1H, CHNH₂), 3.44 - 3.30 (m, 2H, C¾-indole), 3.28 - 3.17 (m, 4H, 2xC¾NHC(NH)NH₂), 2.67 (d, J= 15.8, 1H, C¾CONH), 2.56 (d, J= 15.8, 1H, C¾CONH), 1.81 - 1.60 (m, 8H, 2xCH₂CH₂CH₂NHC(NH)NH₂), 1.51 (s, 9H, C(C¾)s), 1.49(s, 9H, C(CH₃)₃),1.37 (s, 9H, C(CH₃)₃)

MALDI-TOF: calcd for CssHeiNgOz 655.5, found 656.5 [M+H]⁺, 678.5 [M+Na]⁺, 694.5 [M+K]⁺

HPLC (Water/ACN (0.1% TFA); 30 to 100 % ACN in 30 minutes): tr= 12.81 min

1H NMR (300 MHz, MeOD) δ 7.33 - 7.17 (m, 6H,6xCH(Ar)), 7.14 (s, 1H, CH(Ar)), 4.26 (s, 2H, C¾Ph), 4.06 (dd, J = 9.3, 6.0, 1H, CHNH₂), 3.57 - 3.38 (m, 3H, 0.5x C¾NHC=0 and C¾-indole), 3.20 - 2.98 (m, 4H, 2xC¾NHC(NH)NH₂), 2.37 (d, J = 14.0, 1H, 0.5x CH₂NHC=0), 1.61 - 1.27 (m, 35H, 2xC¾C¾CH₂NHC(NH)NH₂ and 3xC(C¾)s).

MALDI-TOF: calcd for C₄iH₆6Ni₀O₂730.54, found 731.63[M+H]⁺

HPLC (Water/ACN (0.1% TFA); 40 to 100 % ACN in 30 minutes): tr= 13.11 min

1H NMR (300 MHz, MeOD)6 8.06 (s, 1H, CH(Ar)), 7.91 (d, J = 8.1, 2H, 2xCH(Ar)), 7.86 (d, J= 7.8, 1H, CH(Ar)), 7.75 (d, J= 8.5, 1H, CH(Ar)), 7.64 - 7.53 (m, 2H, CH(Ar)), 7.41 (s, 1H, CH(Ar, indole)), 7.18 (s, 1H, CH(Ar, indole)), 4.57 (t, J = 7.5, 1H, CHNH), 3.69 (d, J = 14.2, 1H, 0.5x C¾NHC=0), 3.56 (dd, J = 14.7, 6.5, 1H, 0.5xC¾-indole), 3.59 (s, 3H, C0₂CH₃), 3.48 (dd, J = 14.7, 6.6, 1H, 0.5xCH₂-indole), 3.01 (d, J = 14.1, 1H, 0.5xC¾NHC=O), 2.92 - 2.77 (m, 4H, 2xC¾NH₂), 1.79 - 1.44 (m, 26H, 2xCH₂CH₂CH₂NH₂ and 2xC(CH₃)₃), 1.30 (s, 9H, C(CH₃)₃).

MALDI-TOF: calcd for C44H₆3N50₄725.49, found 726.42 [M+H]⁺, 748.4 [M+Na]⁺, 764.4 [M+K]⁺

HPLC (Water/ACN (0.1% TFA); 5 to 100 % ACN in 30 minutes): tr= 22.20min

1H NMR (300 MHz, MeOD)6 7.80 (d, J = 7.5, 2H, 2xCH(Ar)), 7.60 (d, J = 7.4, 2H, 2xCH(Ar)), 7.45 - 7.23 (m, 5H, 5xCH(Ar)), 7.13 (s, 1H, CH(indole)), 4.37 - 4.14 (m, 4H, CH-Fmoc and CHNHFmoc and C¾-Fmoc), 3.58 (s, 3H, C0₂CH₃), 3.56 (d, J =14.3, 0.5xC¾NHC=O), 3.40 (dd, 1H, J =14.7, 9.0, 0.5xC¾_indole), 3.25 (dd, 1H, J =14.7, 5.4, 0.5xC¾-indole), 3.09 - 2.95 (m, 4H, 2xC¾NHC(NH)NH₂), 2.71 (d, J = 14.3, 1H, 0.5xC¾NHC=O), 1.74 - 1.15 (m, 35H , 2xC¾C¾CH₂NH C(NH)NH₂ and 3xC(C¾)₃).

MALDI-TOF: calcd for C50H71N9O5877.56, found 878.45 [M+H]⁺, 916.3 [M+K]⁺

HPLC (Water/ACN (0.1% TFA); 5 to 100 % ACN in 30 minutes):tr= 25.04min

1H NMR (300 MHz, MeOD) 7.79 (s, 1H, CH(Ar)), 7.71 (d, J = 8.1, 2H, 2xCH(Ar)), 7.59 (s, 1H, CH(Ar)), 7.49 (d, J = 8.1, 2H, 2xCH(Ar)), 7.36 (s, 1H, CH(Ar, indole)), 7.14 (s, 1H, CH(Ar, indole)), 4.38 (dd, J = 9.9, 4.1, 1H, CHNH), 3.65 (d, J = 14.4, 1H, 0.5xC¾NHC=O), 3.61 - 3.50 (m, 4H, 0.5xC¾-indole and C0₂CH₃), 3.39 (dd, J = 14.7, 4.1, 2H, 0.5xC¾- indole), 2.65 (d, J = 14.4, 1H, 0.5xC¾NHC=O), 2.61 - 2.35 (m, 4H, 2xC¾NH₂), 1.63 - 1.23 (m, 53H, 2xCH₂CH₂CH₂NH₂ and 5xC(CH₃)₃).

MALDI-TOF: calcd for C55H81N5O4 875.63, found 876.63 [M+H]⁺, 898.6 [M+Na]⁺, 914.6 [M+K]⁺

HPLC (Water/ACN (0.1% TFA); 45 to 100 % ACN in 30 minutes): tr= 21.89 min

1H NMR (300 MHz, MeOD) δ 7.24 (s, 1H, CH(Ar, indole)), 7.11 (s, 1H, CH(Ar), indole), 4.25 (t, J = 5.6, 1H, CHNH₂), 4.08 (t, J = 8.1, 1H, CHC0₂Me), 3.42 (d, J = 8.4, 2H, G¾- indole), 3.39 (s, 3H, C0₂G¾), 3.17 - 3.07 (m, 2H, G¾NHC(NH)NH₂), 1.80 - 1.65 (m, 1H, 0.5 CH₂CHCO₂CH₃), 1.62 - 1.44 (m, 21H, CH₂CH₂CHC0₂CH₃ and0.5 xCH₂NHC(NH)NH₂and 2xC(CH₃)₃), 1.37 (s, 9H, C(CH₃)₃).

MALDI-TOF: calcd for CsoHsoNeOs 542.39, found 543.25[M+H]⁺, 565.2 [M+Na]⁺

HPLC (Water/ACN (0.1% TFA); 5 to 100 % ACN in 30 minutes): tr= 18.83 min

MALDI-TOF: calcd for C48H₈8Nio0₂ 836.7, found 837.6 [M+H]⁺, 859.6 [M+Na]⁺

BIOLOGICAL PART:

Example 1: Antimicrobial activity of the compounds of the Invention

The Minimal Inhibitory Concentration (MIC in μg/mL) of the compounds of the invention has been determined over six bacterial strains (three Gram positive: S. aureus ATCC25923 ATCC25923, S. aureus 1199B and E. faecalis ATCC29212; and three Gram negative strains: E. coli ATCC25922 , P. aeruginosa ATCC27853 and A. baumannii ATCC 19606) according to Synthetic Antimicrobial Peptidomimetics with Therapeutic Potential (Bengt Erik Haug, Wenche Stensen, Manar Kalaaji, 0ystein Rekdal, and John S. Svendsen, J. Med. Chem. 2008, 51, 4306-4314).

Results are presented in Table 1 :

P. A.

S. aureus E. faecalis E. coli

S. aureus aeruginosa baumannii ATCC25923 ATCC29212ATCC25922

1199B ATCC27853ATCC19606

RTbtPv-NH₂ ⁽¹⁾ 8 16 32 64 32 >64

HB331 32 32 32 - 32 32 HB 331 ⁽¹⁾ 16 32 32 16 64 32

HB 490p2 ⁽¹⁾ 8 ; 8 16; 8 16 ; 16 >64 ; 64 >64 ; 64 >64 ; 64

HB 320 >64 >64 >64 >64 >64 >64

HB 321 >64 >64 >64 >64 >64 >64

HB 318 ⁽¹⁾ 8->64 16->64 16->64 >64->64 16⁽³⁾ >64 >64->64

HB309p2 2 4 8 16 32-16 64

HB309p3 2 2 2-4 4-8 8 >64-

HB 438 8 8 8 32 >64 64

HB 483p2 2;2 2;2 4;4 8 ; 8 8 ; 8 >64 ; >64

HB 449 32 64 >64 64 >64 >64

HB 358 1-2 2-2 2-2 4-2 8 ->16 8 - 16

HB 437 4;2 4 8 8 >64 8

HB 332 ⁽¹⁾ 2-2 4-2 2-2 16-8 >16->16 4-8

HB 494 ⁽¹⁾ 4;2 2;2 2;4 8 ; 16 32 ; 16 32; 64

HB 506 ⁽¹⁾ 8 ; 16 16; 8 8 ; 16 >64 ; >64 >64 ; >64 64; 64

HB491p2 ⁽¹⁾ 8;4 2;4 2;4 >64 ; >64 >64 ; >64 8;4

Table 1

RTbtR-NH₂ represents the following structure:

¹ Aussedat, B. Dupont, E. Sagan, S. Juliot, A. Lavielle, S. Chassaing, G. Burlina, F. (2008) Chem. Comm., 1398.

The antibacterial activities of the peptides were investigated by measurement of the Minimal Inhibitory Concentration (MIC) over six species of bacteria, three gram positive strains, Staphylococcus aureus ATCC25923, Enterrococcus faecalis ATCC29212, and the methicillin resistant Staphylococcus aureus SA-1199B, and three Gram negative bacterial strains, Escherichia coli ATCC25922, Pseudomonas aeruginosa ATCC29853 and Acinetobacter baumannii ATCC 19606. (table 1) The tripeptide Arg-Tbt-Arg-OMe reported by Svendsen was used as a positive control. The dipeptide Tbt-Arg-OMe was also prepared as a negative control.

Most of the tested peptides have good antimicrobial activities comparable to or more potent than that of the positive control. The broad spectrum of activity is a hallmark of natural host-defence peptides, and is due to their non-specific mode of action. For example, no significant difference is observed between the compound derived from the β²'²- (HB308P2) and β ³'³-bis fiArg (HB483P2). Similarly the additional guanidine group on the β -amine has little influence on the potency of the compound (compare HB309P2 versus HB321). The importance of the guanidine groups for the bactericidal activity was confirmed by the

2 2 2 2 2 2 synthesis of peptide in which the β ' -bis hArg was replaced by theD β ' -bis hOrn (Tbt- β ' - bis hOrn-OMe). This peptide shows no antimicrobial activity. The superior potency of arginine vs lysine in membrane active peptides is in agreement with the literature and is believed to be due to the stronger ability of the guanidine group to form hydrogen bond with the phospholipid of the membrane additionally to the electrostatic interactions. Similarly to confirm the importance of the iBu group on the tryptophan moiety, peptide Guanidine-Trp- β ²'²-bis fiArg-OMe and peptide Trp- β ²'²-bis hOrn-OMe were also prepared. None of these compounds present any activity. This lack of activity is probably related to their poor lipophilicity evaluated by the lower retention time of these two compounds in RP-HPLC compared to the Tbt derivatives. The sequence of the dipeptide seems to have an influence on the bacterial activity since the reverse peptide is slightly less potent that peptide HB321. Since these two peptides have the same net charge and the same hydrophobicity as can be judged by there identical retention time on a reversed-phase HPLC, this difference might be related to the different spatial disposition of the cationic groups in the two series of compounds, giving a poorer amphiphilicity to peptide. Indeed AMPs usually adopt facially amphiphilic conformations in which cationic hydrophilic and hydrophobic side chains segregate onto distinctly opposing regions of the molecular surface. The importance of this overall topology and not the precise sequence, secondary structure or chirality of the peptides has been highlighted as the key feature for their cell-killing activity.

Example 2: Cytotoxicity study against two types of human cells, Jurkat and SHSYS5

To be therapeutically useful the new AMP must be selective to bacteria over mammalian cells. To evaluate their selectivity, the cytotoxicity of the compounds of the invention against two types of human cells, Jurkat and SHSYS5, were evaluated (Delaroche D. et al, Anal. Chem. (2007), 79(5): 1932-8).

Significant cytolytic activities occur only at concentrations much higher than the antibacterial MIC values, indicating selectivity for bacterial cells over mammalian cells.

Results are presented on table 2

Table 2

Compd. = Compound

Inc. = Incubation HB265 corresponds to the following structure:

HB 265

In conclusion, new polycationic tools have been synthesized for the design of membrane active peptides, the β ²'²-bis hArginine and the β ³'³-bis hArginine and their utility in the design of short AMP active with a broad spectrum of activity and good selectivity against bacteria vs human cells has been exemplified.

Example 3: Synthesis of Cell-Penetrating Peptides (CPP)

The synthesis of CPPs of the following formula:

is performed according to the following general procedure.

General procedure

Peptides were synthesized manually on solid support using a Fmoc-rink amide resin (substitution level = 0.52 mmol/g resin, 100-200 mesh) at a 0.05 mmol scale. The resin was swollen in DCM 15 min prior to use. Fmoc removal was performed by using 20% (v:v) piperidine in NMP third times for 5 min. The resin was washed five times with NMP. For Fmoc ²bisOrn(Alloc)₂-OH or Fmocp²bisOrn(Alloc)₂-OH, stepwise couplings were accomplished with 2 equivalents of amino acids, 2 equivalents of HATU and 4 equivalents of DIEA. Coupling reaction was allowed to proceed for 16h at 50°C. For other stepwise couplings, 10 equivalents of Fmoc-amino acids or biotin(0₂), 9 equivalents of HBTU and HOBt and 25 equivalents of DIEA were used. Each coupling reaction was allowed to proceed for 0.5 h at room temperature. All reagents were dissolved in l-methy-2-pyrrolidone (NMP) at 0.15 M. Then, the solution was removed by filtration and the resin was washed with NMP five times. Reaction completion was checked by Kaiser test for primary amines. In case of positive test, the same amino acid was condensed again until getting a negative test. Cycles of deprotection/washing/coup ling/washing were repeated until the desired sequence was achieved. Cleavage of peptides was accomplished by treatment of the resin with 3 mL of TFA/ triisopropylsilane/H20 (95/2.5/2.5 v:v:v) for 3h at room temperature. The TFA solution was collected, followed by rinsing the resin three times with neat TFA. All washings were combined and evaporated. The peptide was triturated with cold diethylether, collected by centrifugation, and the pellet was washed three times with cold diethylether. The pellet was then dried for 3 hours under vacuum, redissolved in deionized water and lyophilized. The peptide dissolved in deionized water containing 0.1% of TFA (v:v) was purified by reversed phase HPLC using a C18 column with an acetonitrile/water gradient containing 0.1% TFA.

Example 4: Study of the internalization of Cell-Penetrating Peptides (CPP)

The internalization of the CPPs obtained in example 3 is studied according to the MALDI- TOF based method described by Aubry et al. (Biochimica et Biophysica Acta 1798 (2010) 2182-2189).

Claims

1. Compound having the following formula (I):

- n and m = 0 or 1 provided that n and m = 0 together are excluded;

- Ri represents the lateral chain of ornithine or arginine;

- R₂ represents H, a protecting group of the amino function, or an amino acid selected from the roup consisting of:

wherein A, B, C, D and E represent independently from each other

H, an alkyl group or a aryl group;

- X represents O or NH, and R₃ represents H, an alkyl, an alkylaryl group such as a substituted benzyl group with A, B, C, D and E defined above or a substituted ethylbenzene group with A, B, C, D and E defined above; or

wherein Y represents O or NH, and Re represents H, an alkyl, an alkylaryl group such as a substituted benzyl group with A, B, C, D and E defined above or a substituted ethylbenzene group with A, B, C, D and E defined above; or an alkylaryl group such as a substituted benzyl group with A, B, C, D and E defined above, or a substituted ethylbenzene group with A, B, C, D and E defined above; or

wherein Y represents O or NH, and ¾ represents a H, C1-C15 alkyl or a substituted benzyl group with A, B, C, D and E defined above; or

or wherein

F, G, H, I and J represent independently from each other: H, an alkyl group, an aryl group or CF₃, Y represents O or NH, and 5 represents a H, or an alkyl, a substituted benzyl group with A, B, C, D and E defined above;

provided that:

2. Compound for its use as a drug for the treatment of microbial infections according to claim 1, wherein said antimicrobial peptide has an activity directed against Gram- positive and Gram-negative bacteria, in particular said Gram-positive bacteria are selected from the group consisting of: Staphylococcus aureus, in particular S. aureus ATCC25923 or S. aureus 1199B, or Enterococcus faecalis, in particular ATCC29212, and said Gram-negative bacteria are selected from the group consisting of: Escherichia coli, in particular ATCC25922, Pseudomonas aeruginosa, in particular ATCC27853 or Acinetobacter baumannii, in particular ATCC 19606.

3. Compound for its use as a drug for the treatment of microbial infections according to claim 1 or 2, having the following general formula (II):

R R.

(Π)

wherein R_{l s} R₂, R₃ and X are as defined above.

Compound for its use as a drug for the treatment of microbial infections according claim 3, having the following general formula (Ha):

wherein R_{l s} R₃, R4 and X are as defined above.

5. Compound for its use as a drug for the treatment of microbial infections according to claim 4, having the following general formula (IIa-1):

wherein R₃, R4 and X are as defined above.

Compound for its use as a drug for the treatment of microbial infections according claim 5, having one of the following formulae:

7. Compound for its use as a drug for the treatment of microbial infections according to claim 4, having the following general formula (IIa-2):

wherein R₃, R₄ and X are as defined above.

8. Compound for its use as a drug for the treatment of microbial infections according to claim 7, having one of the following formulae:

HB309p3,

HB358,

Compound for its use as a drug for the treatment of microbial infections according claim 1 or 2, having the followin general formula (IX):

wherein R_{l s} R₂, R6 and Y are as defined above.

10. Compound for its use as a drug for the treatment of microbial infections according to claim 9, having the followin general formula (IXa):

11. Compound for its use as a drug for the treatment of microbial infections according to claim 10, having the following general formula (IXb):

12. Compound for its use as a drug for the treatment of microbial infections according to claim 1 1, having one of the following formulae:

13. Compound for its use as a drug for the treatment of microbial infections according to anyone of claims 1 to 12, administrable by oral route at a dose comprised from about 10 mg/kg to about 200 mg/kg.

14. Compound for its use as a drug for the treatment of microbial infections according to anyone of claims 1 to 12, administrable by intraveinous route at a dose comprised from about 5 μg/kg to about 50 mg/kg.

15. Compound such as defined in claims 1 to 12, having one of the following formulae:

16. Pharmaceutical composition comprising a compound of formula (I) such as defined in claims 1 to 12, in association with a pharmaceutically acceptable vehicle.

17. Pharmaceutical composition according to claim 19, comprising a compound defined in claim 6, 8 or 12.

18. Pharmaceutical composition comprising:

- at least one compound as defined in anyone of claims 1 to 12, and

19. Products comprising:

- at least one compound as defined in anyone of claims 1 to 12, and