MXPA06000525A - Compositions of lipopeptide antibiotic derivatives and methods of use thereof - Google Patents

Abstract

The present invention provides derivatives of lipopeptide antibiotics that display antimicrobial activity against microorganisms, methods and compounds for synthesizing such antimicrobial derivatives and analogues, and methods of using the compounds in a variety of contexts, including in the treatment and prevention of microbial infections.

Description

COMPOSITIONS OF DERIVATIVES OF IPIPEPTIDE ANTIBIOTICS AND METHODS OF USE OF THE SAME FIELD OF THE INVENTION The present invention is generally concerned with the treatment of infectious diseases and more specifically with methods and compounds for the preparation of compositions of lipopeptide antibiotic derivatives that they comprise derivatives of lipopeptide antibiotics and therapeutic uses thereof.

BACKGROUND OF THE INVENTION In addition to an immune response to the healthy host, therapeutic regimens employing antibiotics now represent the primary course of treatment for most infectious diseases in developed countries. An important class of effective antibiotics against Gra-positive bacteria are lipopeptide antibiotics. In general, lipopeptide antibiotics have either a cyclic peptide core or a cyclic depsipeptide core acylated with a lipophilic fragment. The lipophilic fragment (e.g., an unsaturated fatty acid) may vary in length and this length may affect the activity of a particular lipopeptide.

However, due to the widespread use of antibiotics, drug resistance to these and other antibiotics is becoming an increasingly common problem throughout the world to control several previously treatable infectious diseases. For example, infections due to drug-resistant Gram-positive organisms, such as those due to vancomycin-resistant Enterococci (VRE) and methicillin-resistant Staphylococcus aureus (M SA), are emerging. In addition, the main cause of nosocomial infections (that is, those who suffer in hospitals) is now due to cocci Gra-positive and bacteria that have resistance to multiple antibiotics is increasingly common. Given the rampant rise of strains of microorganisms that are resistant to current antibiotic therapies, there is a continuing need for the development of new antibiotics and antibiotics with new mechanisms of action. The present invention satisfies such needs and further provides other related advantages.

BRIEF DESCRIPTION OF THE INVENTION Briefly, the present invention provides lipopeptide derivatives, in particular ampicillin or aspartocin derivatives and compositions of such lipopeptides for use in the treatment or prevention, for example primary infection sites, secondary infections arising from a condition of primary disease or infections associated with foreign bodies. In one aspect, the present invention provides lipopeptide antibiotics based on ampomycin or based on aspartocin, wherein the antibiotic comprises a "core" of cyclic peptide and a lipophilic substituent. The cyclic peptide core includes one or more amino acids having a side chain with an amino group and derivatives thereof, which is commonly at the 9-position of the macrocyclic peptide of the nucleus. In one embodiment, the amino acid at position 9 of the macrocyclic peptide of the nucleus is a Dab9. The core of the macrocyclic peptide also includes at least one amino terminal exocyclic amino acid, which is commonly Asp or Asn. In another embodiment, the amino terminal exocyclic amino acid is located between the cyclic portion of a core peptide and a lipophilic substituent. In another aspect, the invention provides an antimicrobial compound and pharmaceutically acceptable salts thereof characterized by structure (IIa) R2-L-R-R3, wherein R is a cyclic core peptide of ampomycin or aspartocin; R1 is OH or NH2 at the amino acid position 1 of the cyclic peptide of the R-core; L is selected from at least one amino acid, at least one substituted amino acid, -R'C (= 0) -, -R'OC (= 0) (NR ') ~ and -0-PhC (= 0) -; R2 is selected from -C (= 0) R5, -C (= 0) ORs, -C (= 0) NHR4, -C (= 0) NR4R4, C (= S) NHR4, -C (= S) ) NR4R4, -C (= NR) NHR4 and -C (= NR4) NRR4; R3 is selected from -OR5, -SR5, NR5R5, -CN, -N02, -N3, -C (= 0) R5, -C (= 0) 0R5, -C (= 0) NR5R5, -C ( = S) NR? R5, -C (= NR5) NR5R5, -C (= 0) H, -R5C (= 0), -S02R ?, -S (= 0) R5, P (= 0) (OR5) 2, -P (= 0) (OR5), -C02H, -SO3H, -PO3H, halogen, trihalomethyl, (C? -C25) alkyl, substituted (C_-C25) alkyl, heteroalkyl (C-C25), heteroalkyl ( C? -C25) substituted, aryl (C3-C0), aryl (C5-C10) substituted, arylaryl (C5-C15) / arylaryl (C5-C? 5) substituted, biaryl (C5-C15), biaryl (C5- C 5) substituted, heteroaryl of 5 to 10 members, substituted heteroaryl of 5 to 10 members, arylalkyl (CS ~ C26), arylalkyl (C6-C2S) substituted, heteroarylalkyl of 6 to 26 members, heteroarylalkyl substituted of 6 to 26 members , at least one amino acid, at least one substituted amino acid; R 4 is independently selected from (C 7 -C 0) alkyl, arylalkyl (C 17 -C 26), and heteroarylalkyl of 17 to 26 members, an aliphatic or hydroxyaliphatic saturated or single or multiple unsaturated, branched or straight chain portion having a chain length of 7 to 25 carbon atoms, a primary or secondary amine, at least one amino acid and at least one substituted amino acid; R 5 is independently selected from hydrogen (C 1 -C 10) alkyl, aryl (C 5 -C 0), 5- to 10-membered heteroaryl, arylalkyl (C 6 -C 2 S) and heteroarylalkyl from 6 to 26 members, an aliphatic or hydroxyaliphatic moiety saturated or individually unsaturated or multiple unsaturated straight or branched chain having a chain length of 5 to 25 carbon atoms, a primary or secondary amine, at least one amino acid, at least one substituted amino acid and any combination of these and R 'is independently one or more of the same or different substituents as defined R3 or R5. In certain embodiments, the present disclosure provides any of the compounds mentioned above wherein R 1 is OH or R 1 is NH 2. In further embodiments, any of the compounds mentioned above has R2 which is -C (= 0) OR5 or -C (= 0) R5 or which is -C (= 0) NR4, -C (= S) NHR4 or -C (= NR4) HR4. In other embodiments, any of the compounds mentioned above are provided wherein R3 is at least one amino acid selected from glycine, β-alanine, sarcosine, lysine, or any combination thereof or is at least one amino acid selected from of Gly, β-alanine, GABA, 5-aminopentanoic acid, 6-aminohexanoic acid, Lys, gDab, Sar, Orn, Dap, hLys or any combination thereof. In related embodiments, the amino acid R3 includes two amino acids selected from glycine-lysine or sarcosine-lysine. In certain embodiments, any of the compounds mentioned above are provided wherein R3 further comprises at least one protecting group. In some embodiments, any of the compounds mentioned above wherein L is at least one amino acid or at least one substituted amino acid selected from p-aminophenylacetyl, (p-aminophenylpropanoyl) p wherein n is 1 or 2, .m -aminophenylacetyl, (m-aminophenylpropanoyl) n where n is 1 or 2, o-aminophenylacetyl, (o-aminophenylpropanoyl) __ where n is 1 or 2, GABA, p-aminobenzoic acid (PABA), m-aminobenzoic acid, o-aminobenzoic acid, p-hydrazinobenzoic acid, m-hydrazinobenzoic acid, o-hydrazinobenzoic acid, p-amino-trans-cinnamyl, m-amino-trans-cinnamyl, o-amino-trans-cinnamyl, L-BBTA or any combination of these. In certain embodiments, R2 and R3 are optionally substituted with a saturated straight-chain aliphatic or hydroxyaliphatic portion having a chain length of 10 to 15 carbon atoms. In some embodiments, certain compounds are provided, such as compound 91 of Table 6D, compound 33 or 332 of Table 16, compound 86 of Table 6D, compound 87 or 280 of Table 7 or compound 89 of Table 8. In a further aspect, the invention provides an antimicrobial compound and pharmaceutically acceptable salts thereof characterized by the structure (lia) R2-LR-R3 wherein R is a cyclic peptide of amphomycin nucleus or aspartocin; R1 is OH or NH2 at the amino acid position 1 of the cyclic peptide of the R-core; L is selected from at least one amino acid, at least one substituted amino acid, -R'C (= 0) -, -R'OC (= 0) (NR ') -; R2 is selected from -OR5, -SR5, NR5R5, -C (= 0) 0R5, -C (= 0) R5, -C (= 0) NHR4, -C (= 0) NR4R4, -C (= S) NHR4, ~ C (= S) NR4R4, -C (= NR4) NHR4, -C (= NR) NRR4, -R5C (= 0), S02R5, -S (= 0) R5, -P (= 0 ) (OR5) 2, P (= 0) (0R5), -C02H, -S03H, -P03H, halogen and trihalomethyl; R3 is selected from hydrogen; R4 is independently selected from (C7-C10) alkyl, arylalkyl (C_7-C2S), and heteroarylalkyl from 17 to 26 members, a saturated or individually unsaturated or multiple unsaturated, branched or straight chain aliphatic or hydroxyaliphatic portion having a chain length of 7 to 25 carbon atoms, a primary or secondary amine, at least one amino acid and at least one substituted amino acid; R5 is independently selected from hydrogen, (C1-C10) alkyl, (C5-C6) aryl, 5- to 10-membered heteroaryl, (C6-C2S) arylalkyl, and 6 to 26-membered heteroarylalkyl, an aliphatic portion or hydroxyaliphatic saturated or individually unsaturated or multiple unsaturated straight or branched chain having a chain length of 5 to 25 carbon atoms, a primary or secondary amine, at least one amino acid, at least one substituted amino acid and any combination of these and R 'is independently one or more of the same or different substituents as defined for R2 or R5. In certain embodiments, the present disclosure provides any of the compounds mentioned above wherein R 1 is OH or R 1 is NH 2. In further embodiments, any of the above compounds has R2 which is -C (= 0) R5, -C (= 0) NHR4, -C (= S) NHR4, -C (= NR) NHR4. In other embodiments, any of the aforementioned compounds are provided wherein R 5 is a heteroarylalkyl of 10 to 20 members or a straight chain saturated aliphatic or hydroxyaliphatic portion having a chain length of 5 to 17 carbon atoms or R 4 is a aliphatic or saturated hydroxyaliphatic portion of straight chain having a chain length of 8 to 16 carbon atoms. In some embodiments, L is at least one amino acid or at least one substituted amino acid, such as glycine, sarcosine, phenylglycine, phenylalanine, O-methyl aspartic acid, Ot-butyl aspartic acid, p-aminobenzoic acid (PABA), acid m-aminobenzoic acid, p-hydrazino-benzoic acid, p-aminophenylpropanoic acid, (p-amino-phenylpropanoic acid) n where n is 1 or 2, L-BBTA, m-phenylacetic acid, p-amino-phenylacetic acid (Apa ), p-amino-trans-cinnamic acid, o-aminobenzoic acid, o-diaminobenzoic acid, p, p-diaminobenzoic acid, o-p-diaminobenzoic acid,? u, p-diaminobenzoic acid, m, m- acid diaminobenzoic acid, o-amino-phenylacetic acid, m-amino-phenylacetic acid, p-amino-phenylacetic acid (Apa), aminothiazole acetic acid or any combination thereof. In yet other embodiments, any of the compounds mentioned above are provided wherein R3 is at least one amino acid selected from Gly, β-alanine, GABA 5-aminopentanoic acid, 6-aminohexanoic acid, Lys, gDab, Sar, Orn , Dap or hLys. In still other embodiments, R3 further comprises at least one protecting group. In still other embodiments, any of the compounds mentioned above include compound 103, 105, 106, 107, 112, 115, 116, 118, 311, 313, 314, 315, 316, 317, 344, 345, 346, 358, 359 or 360 of Table 3; the compound 104, 108, 109, 110, 111, 113, 122, 119, 281, 193, 294, 296, 297, 300, 301, 303, 310, 312 or 361 of Table 6D; compound 117 of Table 6C; compound 21, 85, 282, 283, 284, 285 or 123 of Table 7; compound 120 of Table 8; compound 305, 320, 319, 337, 374, 337, 305, 320 or 319 of Table 14; compound 286, 321, 304, 254, 307, 295 or 291 of Table 4; or compound 288, 306, 290, 362, 289, 292, 287 or 302 of Table 6A. In still another aspect, the invention provides an antimicrobial compound and pharmaceutically acceptable salts thereof characterized by the structure (IVa) R2-L-R-L-R3 wherein R is a cyclic peptide of amphiphilic nucleus or aspartocin; R1 is OH or NH2 at the amino acid position 1 of the core R cyclic peptide; L is independently selected from at least one amino acid, at least one substituted amino acid, -C (= 0) -, -R'C (= 0) -, -S02, -C (= S), -P (= 0), -OP (= 0), -OC (= 0), -R'OC (= 0) (NR '), -NHC (= 0) -, -0-PhC (= 0) - and NR' C (= 0) -, with the proviso that L in Dab9 is -C (= 0) -; R2 is selected from -OR4, -SR4, NR4R4, -CN, -N02, -N3, -C (= 0) OR4, -C (= 0) R4, -C (= 0) NR4R4, -C (= S) ) NR4R4, -C (= NR4) NR4R4, -C (= 0) H, -R4C (= 0), -S02R4, -S (= 0) R4, -P (= 0) (OR4) 2, -P (= 0) (0R4), -C02H, -S03H, -PO3H, halogen, trihalomethyl, alkyl (C __-C25), substituted (C? -C25) alkyl, heteroalkyl (Cx-C25), heteroalkyl (C _.- C25 ) substituted, aryl (C5-C__0), substituted (C5-C_0) aryl, arylaryl (C5-C15), arylaryl (C5-C15) substituted, biaryl (C5-C5), biaryl (C5-C15) substituted, 5 to 10 membered heteroaryl, 5 to 10 membered substituted heteroaryl, (C6-C2s) arylalkyl, substituted (C6-C26) arylalkyl, 6 to 26 membered heteroarylalkyl, 6 to 26 membered heteroarylalkyl, at least one amino acid and at least one substituted amino acid; R3 is selected from -C (= 0) 0R4, -C (= 0) NR4R4, -C (= S) NRR4, -C (= NR) NR4R4, -C (= 0) H, -R4C (= 0), -C02H, substituted (Cx-Css) alkyl, substituted heteroalkyl (C-C25), substituted (C5-C10) aryl, substituted (C5-C15) arylaryl, substituted (C5-C15) biaryl, substituted heteroaryl from 5 to 10 members, substituted (C6-C26) arylalkyl, substituted heteroarylalkyl of 6 to 26 members, at least one amino acid and at least one substituted amino acid, with the proviso that R3 contains at least one of -C ( = 0) -, -C (= S) - or -C (= NR4) -; R 4 is independently selected from hydrogen, (C 1 -C 6) alkyl, (C 5 -C 10) aryl, 5 to 10 membered heteroaryl, (C 6 -C 26) arylalkyl, and 6 to 26 membered heteroarylalkyl, a saturated aliphatic or hydroxyaliphatic moiety or individually unsaturated or multiple unsaturated straight or branched chain having a chain length of 5 to 25 carbon atoms, a primary or secondary amine, at least one amino acid, at least one substituted amino acid and any combination thereof and R 'is independently one or more of the same or different substituents as defined for R2, R3 or R4. In certain embodiments, the present disclosure provides any of the compounds mentioned above, wherein R 1 is OH or R 1 is NH 2. In further embodiments, any of the compounds mentioned above have R3 which is -C (= 0) - or -C (= S) -. In other embodiments, any of the compounds mentioned above include compound 210, 373, 223, 237, 235 or 81 of Table 12. In certain embodiments, R3 is at least one amino acid or substituted amino acid selected from Gly, β -alanine, GABA, 5-aminopentanoic acid, 6-aminohexanoic acid, Lys, gDab, Sar, Orn, Dap and hLys. In still other embodiments, R3 further comprises at least one protecting group. In still another aspect, the invention provides an antimicrobial compound and pharmaceutically acceptable salts thereof such as compound 3 of Table 1; compound 4 of Table 10; compound 60 of Table 13; compound 128 of Table 16; compound 147 of Table 1; compound 199 of Table 10; compound 253 of Table 4 or compound 278 of Table 4. In another aspect, any of the compounds mentioned above may be structurally pure or may be in the form of a composition comprising a mixture of one or more structurally different compounds. In certain embodiments, the compounds of the invention may be in the form of a free acid or base or in the form of a salt, such as a pharmaceutically acceptable salt. In still other embodiments, the core cyclic peptide is a β-isomer, anhydrous isomer or a dianhydro isomer. In a further aspect, the present invention provides pharmaceutical compositions comprising any of the aforementioned compounds. In some modalities, the compositions comprise one or more compounds of the invention and a pharmaceutically or physiologically acceptable carrier, excipient or diluent. The exact nature of the carrier, excipient or diluent will depend on the intended use for the composition and can range from being appropriate or acceptable for environmental or industrial uses, to being appropriate or acceptable for veterinary uses, to being acceptable or appropriate for human use (ie , pharmaceutically acceptable). In yet another aspect, the present invention provides methods for synthesizing the compounds of the invention. In one embodiment, the compounds of the invention can be prepared from an ampicillin-based lipopeptide antibiotic or from original aspartocin-based isolate from culture by reacting the original antibiotic with an appropriately protected reagent, such as an amino acid appropriately. protected, under appropriate conditions to attach the reactant to the amino-terminal amino group of an exocyclic amino acid or a β-nitrogen of a macrocyclic Dab 9 residue. In certain embodiments, the protective fields can be removed or removed to produce compounds of the invention having a specific amino terminal substituent with or without a linker, a specific Dab9 substituent with or without a linker or any combination thereof. In some embodiments, such original antibiotics are mixtures of compounds that differ from each other with respect to the structures of their macrocyclic peptide cores or lipophilic substituents. In certain embodiments, the resulting amino terminal or derivative of Dab9 derived from the invention is obtained as a mixture of compounds, the structures and relative amounts of which are determined by the structures and relative amounts of the compounds comprising the original antibiotic mixture. . In certain other embodiments, the component compounds comprising the original antibiotic mixture are separated and isolated from each other before derivatization of an amino terminal amino acid or a macrocyclic Dab 9 residue. Alternatively, separation and isolation can be carried out on the resulting product of the amino terminal amino acid or Dab9 derivatization reaction, either before or after removal of any protecting groups, to produce a structurally pure amino terminal amino acid or Dab9 derivatives of the invention and any termination thereof. In another related aspect, the structure of a fatty acid moiety in the amino terminus of an original antibiotic is unknown. In certain embodiments, the lipophilic fatty acid moiety is removed and replaced with a lipophilic substituent, amino acid substituent and combinations thereof, optionally attached via a linker group L, having a structure specified to provide an amino terminal amino acid or Dab9 derivative. of the invention having precisely defined substituents with or without linkers. In one embodiment, the original antibiotic mixture is protected in the ß-amino group of the macrocyclic and delipidated Dab9 residue to produce a delipidated intermediate and then this delipidated intermediate is reacted with a desired lipophilic substituent under acylation conditions to produce a synthetic antibiotic. which has a precisely defined lipophilic portion. In another embodiment, this synthetic antibiotic can be derivatized according to the methods described above to produce Dab9 derivatives of the invention. The synthetic routes described above produce protected intermediates and these intermediates constitute another aspect of the present invention (as described above and containing a protecting group). In other aspects, the present invention provides methods for inhibiting the growth of microbes, such as Gram-positive bacteria. The method generally involves contacting a microbe with one or more compounds of the invention (or an acceptable salt thereof) in an amount effective to inhibit the growth of the microbe. The method can be carried out to obtain a microbiostatic effect, where the growth of the microbe is inhibited or to obtain a microbiocidal effect, where the microbe is exterminated. In a related aspect, the present invention provides methods for the treatment or prevention of microbial infections, such as infections caused by Gram-positive bacteria, in a subject such as human, plant or animal. In certain embodiments, the methods involve administering to a subject one or more compounds or compositions of the invention in an amount effective to treat or prevent infection. The compounds or compositions can be administered systemically or applied topically, depending on the nature of the invention. In certain embodiments, compounds and compositions of the invention are used to treat or prevent skin infections and infections of the skin structure (in which complicated infections are included) or pneumonia.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 is an illustration of exemplary ß-isomers of the lipopeptide antibiotic compounds derived from the invention. Figure 2 is an illustration of exemplary anhydrous and dianhydro isomers of the lipopeptide antibiotic compounds derived from the invention.

Figure 3 is an illustration (Scheme I) of two general synthetic methods for making lipopeptide antibiotic compounds derived from the invention. Figures 4A-4I show kill curves for various lipopeptide derivatives against Enterococcus faecalis. Figures 5A-5K show kill curves for various lipopeptide derivatives against Staphylococcus aureus.

DETAILED DESCRIPTION OF THE INVENTION As described above, the present invention provides compositions and methods for using and manufacturing antimicrobial lipopeptide derivatives to treat or prevent infectious diseases. Accordingly, the invention is generally concerned with the surprising discovery that certain lipopeptide antibiotics can be chemically modified to maximize their antimicrobial activity in vivo and in vi tro. In particular, these lipopeptide antibiotics are useful for the treatment or prevention of infections involving Gram-positive bacteria, such as Enterococci, Streptococci and Staphylococci, which may arise in a variety of facilities (eg nosocomial infections, acne and infections associated with intravascular penetration, such as in the use of hypodermic needles, catheters and other medical devices). Next, lipopeptide derivatives suitable for use in the present invention are discussed in more detail, also as representative compositions and therapeutic uses. Before summarizing the invention in more detail, it may be useful for an understanding thereof to summarize definitions of certain terms to be used subsequently herein. As used herein "amino acids" refers to a natural amino acid (those which occur stably in nature), a substituted natural amino acid, an unnatural amino acid, a substituted non-natural amino acid or any combination thereof. The designations for natural amino acids are here summarized as either the Standard Code of one or three letters. Natural polar amino acids include Asparagine (Asp or N) and Glutamine (Glu or Q); also as basic amino acids such as Arginine (Arg or R), Lysine (Lys or K), histidine (His or H) and derivatives thereof and amino acids such as aspartic acid (Asp or D) and glutamic acid (Glu or E) and derivatives thereof. Natural hydrophobic amino acids include tryptophan (Trp or), phenylalanine (Phe or F), isoleucine (lie or I), leucine (Leu or L), methionine (Met or M), valine (Val or V) and derivatives thereof; also as other non-polar amino acids such as glycine (Gly or G), alanine (Ala or A), proline (Pro or P) and derivatives thereof. Natural amino acids of intermediate polarity include serine (Ser or s) threonine (Thr or T), tyrosine (Tyr or Y), cysteine (Cys or C) and derivatives thereof. Unless otherwise specified, any amino acid described herein may be in the D or L configuration. A capital letter indicates an L-enantiomeric amino acid; a lower case letter indicates an amino acid D-enantiomer. Other exemplary amino acids include cinnamic acids (such as amino-cinnamic acids, amino-trans-cinnamic acids, amino-cis-cinnamic acids, o-amino-cinnamic acids, m-amino-cinnamic acids, p-amino-cinnamic acids, acid or amino-trans-cinnamic acid, n-amino-trans-cinnamic acid, p-amino-trans-cinnamic acid, o-amino-cis-cinnamic acid, m-amino-cis-cinnamic acid, p-amino-cis-acid cinnamic), phenylglycine (Phg), 2,3-diaminobutyric acid (Dab), 2,4-diaminobutyric acid (gDab), 2,3-diaminopropionic acid (Dap), ß-metilasparato (MeAsp), cyclohexylalanine (ß-Cha), norleucine (or), norvaline (Lv), isonipecotic acid (Ina), pipecolic acid (homoproline) (Pip or hPro), phenylacetic acids (such as aminofenilacéticos acids, diaminofenilacéticos acids, triaminofenilacéticos acids, o-aminophenylacetic acid m-aminophenylacetic p-aminophenylacetic acid (Apa), acid o, o-diaminofenilacético acid O / in-diaminofenilacético acid o, o-diaminofenilacético, 127.127-diaminofenilacético acid, m acid, p-diaminofenilacético, or acid, or, .m-triaminofenilacético acid o, o, p-triaminofenilacético acid o, m, p-triaminofenilacético, í_7 acid, 0.7., p-triaminofenilacético acid or / i77 /? 3-triaminofenilacético acid 0,0,277-triaminofenilacético), fenilpropanoicos acids (such as aminofenilpropanoicos acids, diaminofenilpropanoicos acids, triaminofenilpropanoicos acids, acid or amino-phenylpropanoic-acid 277-amino-phenylpropanoic, p-amino-phenyl propanoic acid o, o-diamino-phenyl propanoic acid 0.272-diamino-phenylpropanoic acid or p-diamino-phenylpropanoic, m, zn-diamino-phenylpropanoic, 277 acid, p-diamino-phenylpropanoic acid, acid or 0.272 triamine phenylpropanoic acid o, o, p-triamino-phenylpropanoic acid o, m, p-triamino-phenylpropanoic acid jn / m / p-triamino-phenylpropanoic acid 0177177 triamine phenylpropanoic acid or, or, m-triamino-phenylpropanoic acid), 2-aminobutyric acid (Abu), sarcosine (Sar or N-methyl glycine), 6-aminohexanoic acid (Ahx), para-fluoro-phenylalanine (pF-Phe),? -amino-butyric acid (GABA), benzoic acids (such as aminobenzoic, diaminobenzoic, triaminobenzoic, o-amino-benzoic acid, m-amino-benzoic acid) , p-aminobenzoic acid (PABA), o, o-diaminobenzoic acid, o, m-diamino-benzoic acid, o, p-diamino-benzoic acid, 277,227-diamino-benzoic acid, m, p-diamino-benzoic acid, 0,0,277-triamino-benzoic acid, or, or, or, p-triamino-benzoic acid, s, 277, p-triamino-benzoic acid, 277,277 acid, p-triamino-benzoic acid, 0,272,277-triamino-benzoic acid, or acid, 0,277-triamino-benzoic acid), hydrazinobenzoic acids (such as dihydrazinobenzoic acids, trihydrazinobenzoic acids, o-hydrazino-benzoic acid, m-hydrazino-benzoic acid, p-hydrazino-benzoic acid, o, o-dihydrazino-benzoic acid, 0,227- dihydrazino-benzoic, or, p-dihydrazino-benzoic, 277,277-dihydrazino-benzoic, 277, p-dihydrazino-benzoic, 0,0,277-trihydrazino-benzoic, or, or, p-trihydrazino-benzoic , or, 277, p-trihydrazino-benzoic, m, ii-p-trihydrazino-benzoic, 0,277,272-trihydrazino-benzoic, or, 0,271-trihydrazino-benzoic), homophenylalanine (homoPhe or hPhe), ß-cyano alanine (ß- cyano- Ala), methyl or ethylarylesters of tyrosine (Tyr (Me) or Tyr (Et) , respectively), aminoisobutyric acid (Aib, which is also known as 01, α-dimethylglycine), S-methylcysteine (MeCys), N, N '~ dimethyl-arginine ((Me) 2Arg), hydroxyproline (Hyp), citrulline (Cit), N, N, N-trimethyllisine or N, N, N- (CH3) 3-lysine or ?,?,? - trimetillysine ((Me) 3Lys), homolysine (homoLys or hLys), 5-aminopentanoic acid or aminovaleric acid (5-Ava), (S) -3-benzo [b] thiophen-3-yl acid -Aminopropanoic acid (L-BBTA), pyroglutamic acid (pGlu), aminothiazoleacetic acids, 2-amino-thiazol-4-yl-acetic acids, aminoheptanoic acids, aminooctanoic acids, aminononanoic acids, aminodecanoic acids, aminoundecanoic acids, aminododecanoic acids, acid 7-aminohepta oico, 8-aminooctanoic acid, 9-nonanoic acid, 10-aminodecanoic acid, 11-aminoundecanoic acid, 12-aminododecanoic acid, 3- or 4-mercaptoproline derivatives, N5-acetyl-N5-hydroxy-N-ornithine , aN-hydroxyamino acids and the like. An antimicrobial lipopeptide analogue or derivative thereof can include any or a combination of the amino acids indicated above or any or a combination of the above-mentioned optionally substituted amino acids. As used herein, the term "ATCC" refers to the American Type Culture Collection, Manassas, VA 20108 (see also -www.atcc.org) and "NRRL" refers to the American Research Service Culture Collection, Microbial Genomics and Bioprocessing Research Unit, National Center for Agriculture Utilization Research, Peoria, IL 61604 (see also nrrl.ncaur.usda.gov). In the present description any concentration range, percentage range, ratio range or range of integers is understood to include the value of any integer within the quoted range and where appropriate, fractions thereof (such as a tenth and one thousandth of an integer), unless indicated otherwise. As used herein, the term "about" or "consisting essentially of" means + 15%. The use of the alternative (for example, "or") must be understood to mean either one, both or any combination of the alternatives. Furthermore, it should be understood that the individual components or groups of compounds derived from the various combinations of the structures and their subsequent ones described herein are disclosed by the present application to the same extent as if each compound or group of compounds was individually summarized. . Thus, the selection of particular structures or particular substituents is within the scope of the present invention. As used herein, the term "alkyl" refers to a saturated or unsaturated, branched, straight-chain or monovalent cyclic hydrocarbon group derived from the removal of a hydrogen atom from a single carbon atom of a alkane, alkene or original alkyne. Typical alkyl groups include methyl; ethyl esters such as ethanyl, ethenyl, ethynyl; propyl such as propan-1-yl, propan-2-yl, cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), cycloprop-1-en-1-yl; cycloprop-2-en-l-yl, prop-1-yn-l-yl, prop-2-yn-l-yl, etc.; butyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl, but-l-en-1-yl , but-l-en-2-yl, 2-methyl-prop-l-en-l-yl, but-2-en-l-yl, but-2-en-2-yl, buta-1, 3 -dien-l-yl, buta-1, 3-dien-2-yl, cyclobut-1-en-l-yl, cyclobut-l-en-3-yl, cyclobuta-1,3-dien-1-yl , but-1-in-l-yl, but-l-in-3-yl, but-3-yn-l-yl, etc., and the like. The term "alkyl" is specifically designed to include straight or branched chain hydrocarbons having from 1 to 25 carbon atoms, more preferably 5 to 20 and more preferably 10 to 18. Alkyls may have any degree or level of saturation, this is, groups that have exclusively individual carbon-carbon bonds, groups that have one or more carbon-carbon double bonds, groups that have one or more triple carbon-carbon bonds, and groups that have mixtures of single, double, and triple carbon-carbon bonds . Where a specific saturation level is proposed, the expressions "alkalyl", "alkenyl" and "alkynyl" are used. The term "lower alkyl" refers to alkyl groups comprising from 1 to 8 carbon atoms. The alkyl group may be substituted or unsubstituted. The term "alkanyl" refers to a branched, straight-chain or cyclic saturated alkyl group. Typical alkanyl groups include meta-ilo; ethanyl; propanyls such as propan-1-yl, propan-2-yl (isopropyl), cyclopropan-1-yl, etc .; butanyls such as butan-1-yl, butan-2-yl (sec-butyl9, 2-methyl-propan-l-yl (isobutyl), 2-methyl-propan-2-yl (t-butyl), cyclobutan-1) -yl, etc., and the like The term "alkenyl" refers to a branched chain, straight chain, unsaturated cyclic alkyl group or combinations thereof having at least one carbon-carbon double bond derived from the removal of a hydrogen atom of a single carbon atom of an original alkene The group can be either in a cis or trans conformation around the double bonds (s) Typical alkenyl groups include ethenyl; propenyls such as prop-1-en-l-yl, prop-l-en-2-yl, prop-2-en-1-yl (allyl), pro-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-l-yl; butenyls such as but-1-en-l-yl, but-l-en-2-yl, 2-methyl-prop-l-en-l-yl, but-2-en-l-yl, but-2 -in-l-yl, but-2-en-2-yl, buta-1,3-dien-l-yl, buta-1,3-dien-2-yl, cyclobut-1-en-l-yl , cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl and the like. The alkenyl group may be substituted or unsubstituted. The term "alkynyl" refers to a branched, straight chain or cyclic unsaturated alkyl group or having at least one carbon-carbon triple bond derived from the removal of a hydrogen atom from a single carbon atom of an original alkyne. Typical alkynyl groups include ethynyl, -propynyls such as prop-1-yn-l-yl, prop-2-yn-l-yl, etc .; butynyls such as but-1-yn-l-yl, but-l-in-3-yl, but-3-yn-l-yl, etc., and the like. The term "alkyldiyl" refers to a saturated or unsaturated, branched-chain, straight-chain or divalent cyclic hydrocarbon group derived by the removal of one hydrogen atom from each of two different carbon atoms of an original alkane, alkene or alkyne or by the removal of two hydrogen atoms from a single carbon atom of an original alkane, alkene or alkyne. The two monovalent radical centers or each valence of the divalent radical center can form bonds with the same or different atoms. Typical alkyldiyl groups include methanediyl; etildyls such as ethan-1, 1-diyl, ethane-1,2-diyl, ethene-1,1-diyl, ethen-1,2-diyl; propyl diols such as propan-1,1-diyl, propan-1,2-diyl, propan-2,2-diyl, propan-1,3-diyl, cyclopropan-1,1-diyl, cyclopropan-1,2-diyl , prop-l-en-1, 1-diyl, prop-1-enl, 2-diyl, prop-2-en-l, 2-diyl, prop-1-in 1,3-diyl, cycloprop-l- en-1, 2-diyl, cycloprop-2-en-1,2-diyl, cycloprop-2-en-1, 1-diyl, prop-1-yl-1,3-diyl, etc .; butyldyls such as butan-1, 1-diyl, butan-1,2-diyl, butan-1,3-diyl, butan-1,4-diyl, butan-2, 2-diyl, 2-methyl-propan-1 , 1-diyl, 2-methy1-propan-1,2-diyl, cyclobutan-1, 1-diyl, cyclobutan-1, 2-diyl, cyclobutan-1,3-diyl, but-l-en-1,1 -diyl, but-l-en-l, 2-diyl, but-l-en-1, 3-diyl, but-l-en-1,4-diyl, 2-methyl-prop-1-en-1 , 1-diyl, 2-methanilidene-propan-1,1-diyl, buta-1,3-dien-l, 1-diyl, buta-1,3-dien-l, 2-diyl, buta-1, 3 -dien-1, 3-diyl, buta-1,3-dien-l, 4-diyl, cyclobut-1-en-1,2-diyl, cyclobut-1-en-1,3-diyl, cyclobut-2 -in-l, 2-diyl, cyclobuta-l, 3-dien-l, 2-diyl, cyclobuta-1,3-dien-l, 3-diyl, but-l-yl-1,3-diyl, but -l-in-1, 4-diyl, buta-1,3-di-1,4-diyl, etc., and the like. Where specific levels of saturation are proposed, the nomenclature is used alkyldiyl, alkenyldiyl or alkynyldiyl. In preferred embodiments, the alkyldiyl group is (C? -C4) -alkyldiyl. Also preferred are acyclic saturated alkyldiyl groups in which the radical centers are in the terminal carbons, for example methane di (methane); ethane-1,2-diyl (ethane); propan-1,3-diyl (propane); butan-1,4-diyl (butane) and the like (also referred to as alkylenes defined infra). The term "alkylene" refers to a straight chain alkyldiyl group having two terminal monovalent radical centers derived from the removal of a hydrogen atom from each of the two terminal carbon atoms of straight chain alkane, alkene or original alkyne. Typical alkyl groups include methane; ethylenes such as ethane, ethene and ethyne; propylenes such as propane, prop [l] ene, propa [1,2] diene, prop [1] ino, etc .; butylenes such as butane, but [1] ene, but [2] ene, buta [1, 3] diene, but [1] ino, but [2] ino, but [1, 3] diine, etc., and similar.

Where specific saturation levels are proposed, the nomenclature alkane, alkene or alkyne is used. In preferred embodiments, the alkylene group is alkylene (C? -Cs) or (C _.- C4). Also preferred are straight chain saturated alkane groups, for example, methane, ethane, propane, butane and the like. The term "heteroalkyl, heteroalkanyl, heteroalkenyl, heteroalkynyl, heteroalkyldiyl and heteroalkylene" refer to alkyl, alkanyl, alkenyl, alkynyl, alkyldiyl and alkylene groups respectively, in which one or more of the carbon atoms (and any associated hydrogen atoms) ) are each independently replaced with the same or different heteroatoms or heteroatom groups. Heteroatoms or heteroatom groups that may be included in these groups include -O-, -S-, -Se-, -OO-, -SS-, -OS-, -OSO-, -O-NR'-, -NR ' -, -NR '-NR'-, = NN =, -N = N-, -N = N-NR'-PH-, -P (02) -, -0-P (= 0) 2-, - SH2-, -S (= 0) 2-. -SNH2-, and the like and combinations thereof, wherein -NR '-S (= 0) 2- are included, wherein each R' is independently selected from hydrogen, alkyl, alkanyl, alkenyl, alkynyl, aryl , arylalkyl, heteroaryl and heteroarylalkyl as defined herein. The term "aryl" refers to a monovalent aromatic hydrocarbon group derived from the removal of a hydrogen atom from a single carbon atom of an original aromatic ring system. Typical aryl groups include groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, creisen, coronen, fluoranthene, fluorene, hexacene, hexafen, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene , octalene, ovalene, penta-2, 4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, piceno, pleyadene, pyrene, pyrantrene, rubiceno, triphenylene, trinaphthalene and the like. In preferred embodiments, the aryl group is aryl (C __-Ci4), aryls (C5-C10) are even more preferred. Particularly preferred aryls are cyclopentadienyl, phenyl and naphthyl. The aryl group may be substituted or unsubstituted. The term "arylalkyl" refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, commonly a terminal carbon atom or sp3 carbon atom is replaced with an aryl group. Typical arylalkyl groups include benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthyletan-1-yl, 2-naphthylene-1-yl, naphthobenzyl, 2-naphthophenyletan-1-yl and the like. Where specific alkyl portions are proposed, the arylalkanyl, arylalkenyl or arylalkynyl nomenclature is used. In preferred embodiments, the arylalkyl group is arylalkyl (C6-C20), for example, the alkanyl, alkenyl or alkynyl portion of the arylalkyl group is (C_-C6) and the aryl portion is (C5-C14). In particularly preferred embodiments, the arylalkyl group is (C6-C3), for example, the alkanyl, alkenyl or alkynyl portion of the arylalkyl group is (C-C3) and the aryl portion. The term "heteroaryl" refers to a group monovalent heteroaromatic derivative by the removal of a hydrogen atom from a single atom of an original heteroaromatic ring system, in which it may be a monocyclic or fused ring (that is, rings that share an adjacent pair of atoms). Typical heteroaryl groups include groups derived from acridine, carbazole, β-carboline, chroman, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolicin, isobenzofuran, isochromen, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole , oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, sunflower, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole , xanthene and the like. In preferred embodiments, the heteroaryl group is a 5-14 membered heteroaryl, 5-10 membered heteroaryl is particularly preferred. The most preferred heteroaryl groups are those derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine. The heteroaryl group may be substituted or unsubstituted. The term "heteroarylalkyl" refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, commonly a terminal carbon atom or sp3 carbon atom is replaced with a heteroaryl group. Where specific alkyl portions are proposed, the heteroarylalkane, heteroarylalkenyl, or heteroaryl alkynyl nomenclature is used. In preferred embodiments, the heteroarylalkyl group is a heteroarylalkyl of 6-20 members, for example, the alkanyl, alkenyl or alkynyl portion of the heteroarylalkyl is a 1-6 membered portion and the heteroaryl portion is a 5-14 membered heteroaryl. In particularly preferred embodiments, the heteroarylalkyl is a 6-13 membered heteroarylalkyl, for example the alkanyl, alkenyl or alkynyl portion is 1-3 members and the heteroaryl portion is a 5-10 membered heteroaryl. The term "acyl" refers to the group C (= 0) -R ", wherein R" is preferably selected from hydrogen, hydroxy, alkyl, haloalkyl, cycloalkyl, aryl optionally substituted with one or more alkyl, haloalkyl, alkoxy, halo and substituted amino, heteroaryl (linked via a ring carbon) optionally substituted with one or more alkyl, haloalkyl, alkoxy, halo and substituted amino and heteroalicyclic groups (linked via a ring carbon) optionally substituted with one or more alkyl, haloalkyl, alkoxy, halo and amino substituted groups. Acyl groups include aldehydes, ketones, acids, acid halides, esters and amides. Preferred acyl groups are carboxy groups, for example acids and esters. The esters include amino acid ester derivatives. The acyl group can be attached to the fundamental chain of the compound either at one end or the other of the acyl group, that is, via C or R ". Where the acyl group is attached via R", then C will carry another substituent, such as hydrogen, alkyl and the like. The term "substituted" refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent (s). Typical substituents include -X, -R13, -O-, = 0, -OR, SR13, -S-, = S, -NR13R13, = NR13, CX3, -CF3, -CN, -OCN, -SCN, -NO , N02, = N2, -N3, -S (= 0) 20-, -S (= 0) 20H, -S (= 0) 2R13, -0S (= 0) 20-, -0S (= 0) 20H , -0S (= 0) 2R13, -P (= 0) (0") 2, -P (= 0) (OH) (O"), -0P (= 0) 2 (0_), -C (= 0) R13, -C (= S) R13, -C (= 0) 0R13, -C (= 0) 0"_ -C (= S) 0R13, -NR13-C (= 0) -N (R13) 2, -NR13-C (= S) -N (R13) 2 and -C (= NR13) NR13R13, wherein each X independently a halogen; each R13 is independently hydrogen, halogen, alkyl, aryl, arylalkyl, arylaryl, arylheteroalkyl, heteroaryl, heteroarylalkyl- NR14R14, -C (= 0) R14 and -S (= 0) 2R14 and each R14 is independently hydrogen, alkyl, alkanyl, alkynyl, aryl, arylalkyl, arylheteroalkyl, arylaryl, heteroaryl or heteroarylalkyl. Substituents containing aryl, whether or not they have one or more substitutions, can be attached in a conformation for (p-), meta (m-) or ortho (or-) or any combination thereof. The term . "Pharmaceutically acceptable salt" refers to a salt of a compound of the invention which is pharmaceutically acceptable and which possesses the desired pharmacological activity of the parent compound. Such salts include the following: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid , mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [ 2.2.2] -oct-2-en-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylac acid Ethical, tertiary butyl acetic acid, lauryl sulphonic acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like or (2) salts formed when an acidic proton present in the original compound is replaced by an ion of metal, for ele an alkali metal ion, an alkaline earth metal ion or an aluminum ion or coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. In another aspect, any of the compounds mentioned above may have a central peptide that is aspartocin derivative. Aspartocin that occurs stably in nature varies from ampomycin which occurs stably in nature only in the acyl tail region. In general, the compounds of the present invention can have the acyl glue that is stably present in nature or a different (non-natural) acyl glue can be attached to the central peptide of ampomycin or aspartocin. The lipopeptide compounds derived from the present disclosure having a central peptide of aspartocin are manufactured by similar or identical methods used to make derivatives of the central peptide of amphomycin and vary only in the source of the starting material, which is derived from a Streptsmyces species. different (for ele, Streptomyces canus produces ampomycin and Streptomyces griseus produces aspartocin). As used herein, any general description of the synthesis of "ampomycin-based" lipopeptide derivatives of the invention should be understood to be replaceable interchangeably with "aspartocin-based" without altering the scope of the invention, not to be indicated otherwise. The following substituents are also designated herein by the following abbreviations, which include cyclohexyl (cHex or cHexyl), picolinic acid (Pia), 2-pyrazinecarboxylic acid (Pea), acetyl (Ac), succinic acid (Suc) . In the nomenclature of compounds listed in the eles, the substituent listed opposite "ampomycin" (or "aspartocin") indicates a substituent, such as an acyl tail or an amino acid, is attached to the terminal amino group of the central peptide, so much so that the substituent listed after "ampomicin-9-" indicates a substituent attached at the Dab9 position of the peptide core. further, the short form Cn (for example, C_0 / C__2, C15) refers to a compound comprising a chain of linear carbon atoms, such as an acyl tail, with n carbon atoms. In the example of an acyl tail, the designation Cn can also describe an acyl tail by means of the following exemplary structural formula: C__ = CH3- (CH2) -C (= 0) -, in which i = n-2 . In a specific example, a designation C_5 for an acyl tail refers to the following structural formula: CH3- (CH2)? 3-C (= 0) -. As indicated above, lowercase italic letters "o", "277", or "p" in the name of a compound refer to ortho, 277eta, and para substitution positions, respectively. Ph, as used herein, refers to a phenyl ring and -OSu refers to a compound activated by succinimide, such as an amino acid (eg, Ala-OSu), which can be produced with a reaction as is described herein (see, for example, Example 1) or may be purchased commercially (such as from Bachem California Inc., Torrance, CA).

LIPOPEPTIDE ANTIBIOTICS AND DERIVATIVES THEREOF As indicated above, the present invention provides lipopeptide antibiotic derivatives, pharmaceutically acceptable salts thereof and use thereof. The lipopeptide antibiotic derivatives of the present invention include a "central cyclic peptide" (also referred to as "central macrocyclic peptide" herein) and an amino-terminal lipophilic substituent. The "central cyclic peptide" refers to the portion of cyclic peptide or cyclic depsipeptide of a lipophilic antibiotic that remains after the amino-terminal lipophilic substituent has been separated, which may include one or more hexocychic amino acids. The lipopeptide antibiotic derivatives of the present invention may have a lipophilic substituent attached to the central cyclic peptide (1) directly (eg, as a lipophilic amido or amino substituent), (2) by means of one or more intermediate or exocyclic amino acids. (3) by a "linker" (L) either directly to the central cyclic peptide or by means of one or more intermediate exocyclic amino acids, as described herein. In a preferred embodiment, a "central cyclic peptide" is derived from A1437, aspartocin or ampicillin and more preferably from aspartocin or ampomycin. Common amphotericin lipopeptide antibiotics include ampomycin (glumamycin) (Heinemann et al., 1953, Antibiot, Chemother, 3: 1239-1242, Fujino et al., 1965, Bull, Chem. Soc. Jap. 38: 515, Bodansz. U et al., 1973, J. Am. Chem. Soc. 95: 2352; Shibata et al., U.S. Patent No. 3,160,561); aspartocin (Shay et al., U.S. Patent No. 3,057,779, Shay et al., 1960, Antibiotics Ann. 194: Hausman et al., 1964, Antimicrob.Ag.Chemother., 352; Hausman et al., 1969, &J; Antibiotics 22: 207; Martin et al., 1960, J. Am. Chem. Soc. 2079); crystallomycin (Gauze et al., 1957, Antibiotiki 2: 9-14); antibiotic 1437 (Hammann et al., EP 0 629 636 Bl; Hammann et al., U.S. Patent No. 6, 194, 353; Lattrell et al., U.S. Patent No. 5,629,288); friulimycin (Vertesy et al., 2000, "Antibiotics 53: 816), tsushimycin (Shoji et al., 1968, J. Antibiotics 21: 439; Nishimura et al., US Patent No. 3,781,420) and zaomycin (Hinuma, 1954). , J. "Antibiotics 7 (4): 134-136; Kuroya, 1960, Antibiotics Ann., 194; Kuroya, JP 8150). Amphodian-type lipopeptide antibiotics exhibit their antibiotic activity against Gram-positive bacteria, such as for example Streptococci, Staphylococci and Enterococci and consist of a "nucleus" of macrocyclic peptide acylated at its terminal amino group with a lipophilic fatty acid. Examples of other lipopeptide antibiotics useful in combination with the compounds of the invention or useful for derivatization with the methods of the present invention include aspartomycin (Umezawa et al., U.S. Patent No. 3,639,582; Naganawa et al., 1968, J Antibiot 21, 55, Naganawa et al., 1970, "Antiidot 23, 423), brevistin (Shoji et al., 1916, J. Antibiot 29, 380), cerexin A (Shoji et al., 1916 , J. Antibiotics, 29, 1268), cerexin B (Shoji et al., 1976, J. "Antibiotics, 29, 1275), daptomycin (Debono et al., 1976, J. Antibiotics, 41, 1093), antibiotic A -30912 (Hoehn et al., U.S. Patent No. 5,039,789), antibiotic A-54145 (Fukada et al., U.S. Patent No. 5,039,789; Boeck et al., 1990, J. Antijbio ics, 43, 587 ) and antibiotic A-21978C (Debono et al., 1988, J. Antibiotics, 41, 1093). As used herein, the term "ampomycin lipopeptide antibiotic" or "aspartocin lipopeptide antibiotic" refers to an antibiotic comprising a macrocyclic peptide core that includes an amino acid having a side chain with a primary amino group , such as a Dab residue and a lipophilic substituent, such as a fatty acid portion. A macrocyclic peptide of amphomycin or aspartocin core includes at least one exocyclic amino acid, which is in general an Asn or an Asp. The exocyclic amino acid (s) may be sandwiched between the cyclic peptide and the lipophilic substituent or between the cyclic peptide and a linker having a lipophilic substituent attached. In certain aspects of the invention, R refers to an ampicillin or aspartocin core cyclic peptide, which is illustrated as follows: In the anterior core cyclic peptide portion, the dotted line emanating from the exocyclic amino acid indicates the point of attachment of for example, an L linker, one or more additional exocyclic amino acids, a lipophilic substituent or any combination thereof. The broken line emanating from the Dab9 residue indicates the point of attachment of for example, a linker L, one or more additional exocyclic amino acids, a lipophilic substituent or any combination thereof, as described herein. Alternatively, the cyclic peptide portion of the above nucleus is illustrated equivalently and interchangeably as follows (wherein the terminal amino group of the cyclic peptide of the nucleus is now on the right side of the illustration): In certain embodiments, R_ of the core cyclic peptide portion will be -OH (that is, the exocyclic amino acid is Asp) and such a compound can be determined by its name in the IUPAC (CRC Handbook of Chemistry and Physics, CRC Press, Inc. ., Boca Raton, FL, Weast, RC, (ed.) And references therein) as follows: 3-amino-N- [16- (1-amino-ethyl) -31- (1-carboxy-ethyl) acid ) -22, 28- is (carboxymethyl) -13-isopropyl-4-methyl-2,6,12,15,18,21,24,27,30,33-decaoxo-1,5,11,14,17 , 20,23,26,29, 32-decaaza-tricyclo [32.4.0. O7'11] octatriacont-3-yl] succinámico. The tricyclic macrocyclic nucleus of this peptide is named "2, 6,12, 15, 18, 21,24, 27, 30, 33-decaoxo-I, 5, 11, 14, 17, 20, 23, 26, 29, 32-decaaza-tricyclo [32.4.0, O7'11] -octatriacontane "in which the term Pro11 represents a ring, Pip3 represents another ring and the cyclic lactam nucleus of the cyclic peptide represents the third ring of 31 members. The positions of each of the nitrogen atoms of the tricyclic nucleus are in positions 1, 5, II, 14, 17, 20, 23, 26, 29 and 32. The positions of each of the carbonyls of the tricyclic nucleus are in positions 2, 6, 12, 15, 18, 21, 24, 27, 30 and 33 The nitrogens and carbonyls, each taken together, represent the amine bonds of the cyclic peptide core. The carbons at positions 3, 7, 13, 16, 19, 22, 25, 28, 31 and 34 are the carbon atoms of the amino acids that make up the cyclic peptide of the nucleus. The carbon atom in position 4 is the β-carbon of the side chain of Dab2, which forms the cyclic lactam by cyclizing the carboxy terminus of the lipopeptide. The ß-methyl side chain of Dab2 is in position 4 and is referred to as "4-methyl". The nitrogen or a.-nitrogen of Dab2 is referred to as a "3-a ino" substituent in position 3. The portion "N- [" portion and "] -succinnamic" represents the amino acid Asp1 (that is, when R_ is -OH), which may be the substitution point of, for example, acyl tails (that is, in Asp1). The β-Asp4 side chain is designated as "1-carboxyethyl" at position 31 of the tricyclic core. The side chains of Asp5 and Asp7 are designated as "bis-carboxymethyl" at positions 28 and 22 of the tricyclic core, respectively. The side chain of Val10 is referred to as the "isopropyl" at position 13 of the tricyclic core. Finally, the side chain Dab9 is designated as "1-aminoethyl" at position 16 of the tricyclic core, which may be the substitution point for Dab9 substituents. It should be understood that the name would be identical for a cyclic lipopeptide of the nucleus where R_ is NH 2 (that is, when the exocyclic amino acid is Asn), except that "succinamic acid" would be replaced by "succinamide". By way of example, the compound C15-ampomicin-9- (ß-Ala), would be named "3- (pentadecanoyl) amino-N- [16- [1- (3-a-n-propionylane) -ethyl]] -31- (1-carboxy-ethyl) -22,28-jbis- (carboxymethyl) -13-isopropyl-4-methyl-2,6,12,15,18,21,24,27,30,33-decaoxo -1,5,11,14,17,20,23,26,29,32-decaaza-tricyclo [32.4.0. O7'11] octatriacont-3-yl] -succinámico ", where two substituents, the group C15 tail acyl (referred to as "pentadecanoyl") and the Dab9 ß-Ala group (referred to as ["1- (3-amino-propionylamino) -ethyl"]), are highlighted in bold for clarity.

In one embodiment, a lipopeptide antibiotic based on ampomycin is characterized by the following structure I: wherein: R1 is OH or NH2 and each of R2 and R3 are independently selected from hydrogen, -OR4, -SR4, NR4R4, -CN, -N02, - 3 / -C (= 0) 0R4 -C (= 0) R4 -C (= NR) NRR -C (= 0) H, -R4-C (= 0) -S02R4 -S (= 0) R4, -P (= 0) (OR4) 2, -P (= 0) (OR4), -C02H, -S03H, -P03H, halogen, trihalomethyl, alkyl (C! -C25), alkyl (C __-C25) substituted, heteroalkyl (C? -C25), heteroalkyl (_-C25) substituted, aryl (C5-C10), aryl (C5-C10) substituted, arylaryl (C5-C_5), arylaryl (C5-C_5) substituted, biaryl (C5) -C__5), substituted biaryl (C5-C__5), 5- to 10-membered heteroaryl, substituted 5- to 10-membered heteroaryl, (C6-C26) arylalkyl, substituted (C6-C2S) arylalkyl, heteroarylalkyl of 6 to 26 members, heteroarylalkyl replaced from 6 to 26 members, amino acids or substituted amino acids. Some exemplary and independently selected substitutions include -OR4, -SR4, NRR4, -CN, -N02, -N3, -C (= 0) OR4, -C (= 0) R4, -C (= 0) NRR4, -C (= S) NRR4, -C (= NR4) NRR4, -C (= 0) H, -R4 ~ C (= 0), -S02R4, -S (= 0) R4, -P (= 0) (0R4 ) 2, -P (= 0) (0R4), -C02H, -S03H, -P03H, halogen, trihalomethyl; wherein each R4 is independently selected from hydrogen, alkyl (C? -C_0), aryl (C5-C15), heteroaryl from 5 to 10 members, arylalkyl (C6-C16), and heteroarylalkyl from 6 to 16 members, an aliphatic moiety or hydroxy-aliphatic saturated or individually or multiple unsaturated straight chain or branched chain having a chain length of 6 to 25 carbon atoms, a primary or secondary amine, at least one amino acid, at least one substituted amino acid and any combinations of the same; with the proviso that both R2 and R3 can not be hydrogen. In certain embodiments, intermediaries of the structure (I) are provided wherein R__ is OH or NH2; R2 is hydrogen and R3 has a protecting group, such as protected amino acids Gly, Sar, β-Alanine, Gly-Lys or Sar-Lys. In another embodiment, a lipopeptide antibiotic based on ampomycin is characterized by the following structure II: wherein: Ri is OH or NH2; L is selected from at least one amino acid or substituted amino acid, -C (= 0) -, -R'C (= 0) -, -S02, -C (= S) -, -P (= 0) -, -OP (= 0) -, -OC (= 0) -, -R'OC (= 0) (NR'R ") -, -NHC (= 0) -, -OPhC (= 0) -, or - NR'C (= 0) - and each of R2 and R3 are independently selected from hydrogen, -OR, -SR, NRR, -CN, -N02, -N3, -C (= 0) OR4, - C (= 0) R4, -C (= 0) NR4R4, -C (= S) NRR4, -C (= NR4) NR4R4, -C (= 0) H, -R4-C (= 0), -S02R4 , -S (= 0) R4, -P (= 0) (0R4) 2, -P (= 0) (0R4), -C02H, -S03H, -P03H, halogen, trihalomethyl, alkyl (C __-C5), substituted (C? -C25) alkyl, heteroalkyl (C_-C25), heteroalkyl (C_-C5) substituted, aryl (C5-C? o), aryl (C5-C? 0) substituted, arylaryl (C5-C15), substituted aryl (C5-C5), biaryl (C5-C5), biaryl (C5-C15) substituted, heteroaryl 5-10 members, substituted heteroaryl 5-10 members, arylalkyl (C6-C26) / arylalkyl (C3) -C26) substituted, heteroarylalkyl of 6 to 26 members, heteroarylalkyl substituted of 6 to 26 members, at least one amino acid or at least one ami substituted noacid. Some exemplary and independently selected substitutions include -OR4, -SR4, NR4R4, -CN, -N02, -N3, -C (= 0) 0R4, -C (= 0) R4, -C (= 0) NR4R4, -C (= S) NRR4, -C (= NR4) NR4R4, -C (= 0) H, -R4-C (= 0), - S02R4, -S (= 0) R4, -P (= 0) (OR4 ) 2, -P (= 0) (0R4), -C02H, -S03H, -PO3H, halogen and trihalomethyl; wherein each R4 is independently selected from hydrogen, (C_-C10) alkyl, (C5-C5) aryl, 5- to 10-membered heteroaryl, (C6-C6) arylalkyl, and 6 to 16-membered heteroarylalkyl, an aliphatic or hydroxyaliphatic portion saturated or single or multiple unsaturated straight chain or branched chain having a chain length of 6 to 25 carbon atoms, a primary or secondary amine, at least one amino acid, at least one amino acid substituted and any combinations thereof; and each of R 'and R "are independently one or more of the same or different substituents defined by R2, R3 or R4, with the proviso that R2 and R3 can not both be hydrogen.In a preferred embodiment, the structure (II), wherein: R1 is OH or NH2; L is selected from at least one amino acid, at least one substituted amino acid, -R'C (= 0) -, -R'OC (= 0 ) (NR ') and -0-PhC (= 0) -, where R' is independently one or more of the same or different substituents as defined for R3 or R5 as described herein; R2 is independently selected from -C (= 0) R5, -C (= 0) 0R5, -C (= 0) NHR4, -C (= 0) NRR4, -C (= S) NR4R4, -C (= S) NHR4, -C (= S) NR4R4, -C (= NR4) NHR4 and -C (= NR4) NR4R; R3 is independently selected from OR5, SR5, NR5R5, -CN, -N02, -N3,, -C (= 0) R5 , -C (= 0) OR5, -C (= 0) NR5R5, -C (= S) NR? R5, -C (= NR4) NR5R5, -C (= 0) H, -R5-C (= 0 ), -S02R5, -S (= 0) R5, -P (= 0) (0R5) 2, -P (= 0) (0R5), -C02H, -S03H, -P03H, halogen, trihalomethyl, alkyl (C_ .-C25), alquil or (C? -C25) substituted, heteroalkyl (C? -C25), heteroalkyl (C? -C25) substituted, aryl (C5-C10), aryl (C5-C10) substituted, arylaryl (C5-C? 5), arylaryl (C5-C_5) substituted, biaryl (C5-C15), biaryl (C5-C15) substituted, heteroaryl of 5 to 10 members, substituted heteroaryl of 5 to 10 members, arylalkyl (C6-C26), arylalkyl (C3-C26) substituted, heteroarylalkyl of 6 to 26 members, substituted heteroarylalkyl of 6 to 26 members, at least one amino acid and at least one substituted amino acid and wherein each R4 is independently selected from (C7-C_o) alkyl, arylalkyl (C? 7) -C2e) and heteroarylalkyl of 17 to 26 members, a saturated or single or multiple unsaturated straight or branched chain aliphatic or hydroxyaliphatic portion having a chain length of 7 to 25 carbon atoms, a primary or secondary amine, at least an amino acid and at least one substituted amino acid and wherein each R5 is independently selected from Oxygen, alkyl (C __-C__), aryl (C5-C 0), heteroaryl of 5 to 10 members, arylalkyl (C 6 -C 2 S) and heteroarylalkyl of 6 to 26 members, a saturated or single or multiple unsaturated aliphatic or hydroxyaliphatic moiety straight or branched chain having a chain length of 5 to 25 carbon atoms, a primary or secondary amine, at least one amino acid, at least one substituted amino acid and any combination thereof. In certain embodiments, R2 is -C (= 0) R5 or -C (= 0) 0R5, or which is -C (= 0) NHR4, -C (= S) NHR4 or -C (= NR4) NHR. In still other embodiments, R3 is at least one amino acid selected from glycine, β-alanine, sarcosine, lysine or any combination thereof or is at least one amino acid selected from Lys, gDab, Sar, Orn, Dap, hLys, or any combination thereof. In related embodiments the amino acid R3 includes two amino acids, such as glycine-glycine or sarcosine-glycine. Preferably, R3 is the amino acid glycine or β-alanine. In some embodiments, R2 and R3 are optionally substituted by a straight or branched chain saturated or single or multiple unsaturated aliphatic or hydroxyaliphatic chain portion having a chain length of 10 to 15 carbon atoms. In particular embodiments where structure (II) is preferred intermediates, any of the above compounds are provided wherein R3 further comprises at least one protecting group, as described herein. In some embodiments, L of structure (II) is at least one amino acid or at least one substituted amino acid. For example, amino acids or substituted amino acids can be p-aminophenylacetyl, (p-aminophenylpropanoyl) __ where n is 1 or 2, m-aminophenylacetyl, (227-aminophenylpropanoyl) __ where n is 1 or 2, o-aminophenylacetyl, (o-aminophenylpropanoyl) __ where n is 1 or 2, GABA, p-aminobenzoic acid (PABA), m-aminobenzoic acid, o-aminobenzoic acid, p-hydrazinobenzoic acid, zn-hydrazinobenzoic acid, o-hydrazinobenzoic acid, p-amino-trans-cinnamyl, 227-amino-trans-cinnamyl, o-amino-trans-cinnamyl, L-BBTA or any combination thereof. Preferably, L is p-aminophenylacetyl, PABA, 227-aminobenzoic acid, o-aminobenzoic acid, p-amino-trans-cinnamyl, 277-amino-trans-cinnamyl, o-amino-trans-cinnamyl, or any combination thereof . In certain preferred embodiments, the present disclosure provides certain antimicrobial lipopeptide compounds useful, for example, in the treatment or prevention of microbial infections. Exemplary derivatives of structure (II) compounds include compounds 93, 331, 332, 86, 87, 280 or 89. In a preferred embodiment, the invention provides compound 280. In yet another embodiment, a lipopeptide antibiotic based on Amphotericin is characterized by the following structure II: wherein: R1 is OH or NH2; L is selected from at least one amino acid, at least one substituted amino acid, R'C (= 0) - and R'0C (= 0) (NR ') -, wherein R' is independently one or more of the same or different substituents as defined for R2 or R5; R2 is selected from OR5, SR5, NR5R5, -C (= 0) 0R5, -C (= 0) R5, -C (= 0) NHR4, -C (= 0) NRR4, -C (= S) NHR4, -C (= S) NRR4, -C (= NR) NHR4, -C (= NR) NR4R4 '-R5-C (= 0), -S02R5, -S (= 0) R5, ~ P (= 0) (0R5) 2, -P (= 0) (0R5), -C02H, -S03H, -P03H, halogen and trihalomethyl; R3 is hydrogen, wherein each R4 is independently selected from (C7-C10) alkyl, arylalkyl (C_7-C2_) and heteroarylalkyl from 17 to 26 members, an aliphatic or hydroxyaliphatic saturated or single or multiple unsaturated straight or branched chain portion having a chain length of 7 to 25 carbon atoms, a primary or secondary amine, at least one amino acid and at least one substituted amino acid wherein each R5 is independently selected from hydrogen, alkyl (C_-C_0), aryl (C5-C? 0), heteroaryl of 5 to members, arylalkyl (C6-C6) and heteroarylalkyl of 6 to 26 members, an aliphatic or hydroxyaliphatic saturated or single or multiple unsaturated straight or branched chain portion having a chain length of 5 to 25 carbon atoms, a primary or secondary amine, at least one amino acid, at least one amino acid replaced and any combination thereof. In certain embodiments, R2 is -C (= 0) R5, -C (= 0) NHR4, -C (= S) NHR4 or -C (= NR) NHR4. In other embodiments, R 5 is a 10 to 20 membered heteroarylalkyl or straight chain or branched chain saturated aliphatic or hydroxyaliphatic portion having a chain length of 5 to 17 carbon atoms. In still other embodiments, R 4 is a straight chain saturated aliphatic or hydroxyaliphatic portion having a chain length of 8 to 16 carbon atoms. In some embodiments, L is at least one amino acid or substituted amino acid, such as glycine, sarcosine, phenylglycine, phenylalanine, methyl-O-aspartic acid, Ot-butyl aspartic acid, p-aminobenzoic acid (PABA), 227-aminobenzoic acid , p-hydrazino-benzoic acid, p-aminophenylpropanoic acid, (p-amino-phenylpropanoic acid) n where n is 1 or 2, L-BBTA, 227-phenylacetic acid, p-amino-phenylacetic acid (Apa), acid p-amino-trans-cinnamic acid, o-aminobenzoic acid, o-o-diaminobenzoic acid, 0,227-diaminobenzoic acid, o-p-diaminobenzoic acid, 272 acid, p-diaminobenzoic acid, 227,277-diaminobenzoic acid, o-amino-phenylacetic acid , 177-amino-phenylacetic acid, p-amino-phenylacetic acid (Apa), aminothiazole acetic acid or any combination thereof. Preferably, L is 227-aminobenzoic acid, o-aminobenzoic acid, 277,227-diaminobenzoic acid, aminothiazole acetic acid, or PABA, more preferably L is PABA. In still other embodiments, R3 is an amino acid of Gly, β-alanine, GABA, 5-aminopentanoic acid, 6-aminohexanoic acid, Lys, gDab, Sar, Orn, Dap or hLys. Alternatively, when intermediates of derivatives of structure (II) are provided, R3 further comprises at least one protecting group. In preferred embodiments, the antimicrobial compounds of the invention are capable of treating or preventing a microbial infection, such as that caused by a Gram-positive bacterium. Exemplary compounds include compounds 21, 85, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 122, 123, 254 , 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 300, 301, 302, 303, 304, 305, 306, 307 , 310, 311, 312, 313, 314, 315, 316, 317, 320, 321, 337, 344, 345, 346, 358, 359, 360, 361, 362 and 374. In certain preferred embodiments, the lipopeptide derivatives of the present invention include compound 85 or 108 or 119. In another embodiment, a lipopeptide antibiotic based on ampomycin is characterized by the following structure III: wherein: R1 is OH or NH2; L is selected from at least one amino acid or substituted amino acid, -C (= 0) -, -R'C (= 0) -, -S02, -C (= S) -, -P (= 0) -, -0P (= 0) -, -0C (= 0) -, -R'0C (= 0) (NR'R ") -, -NHC (= 0) -, -0PhC (= 0) -, or - NR'C (= 0) - and each of R and R 'are independently selected from hydrogen, -OR4, -SR4, NR4R4, -CN, -N02, -N3, -C (= 0) 0R4, - C (= 0) R4, -C (= 0) NR4R4, -C (= S) NR4R4, -C (= NR4) NR4R4, -C (= 0) H, -R4-C (= 0) • S02R -S (= 0) R4 -P (= 0) (0R) 2, -P (= 0) (0R4), -C02H, -S03H, -P03H, halogen, trihalomethyl, alkyl (C __-C25), substituted (C_C 5) alkyl, heteroalkyl (C_-C25), substituted hetero (C_-C25), aryl (C5-C10), aryl (C3-C_0) substituted, arylaryl (C5-C15), arylaryl (C5-C_5) substituted, biaryl (C5-C) ?), Substituted (C5-C15) biaryl, 5- to 10-membered heteroaryl, substituted 5-10 membered heteroaryl, (C6-C26) arylalkyl, substituted (C6-C2e) arylalkyl, heteroarylalkyl of 6 to 26 membered, heteroarylalkyl replaced from 6 to 26 members, natural amino acids, non-natural amino acids and natural and non-natural amino acids substituted. Some exemplary and independently selected substitutions include -OR4, -SR4, NR4R4, -CN, -N02, -N3, -C (= 0) 0R4, -C (= 0) R4, -C (= 0) NR4R4, -C (= S) NR4R4, -C (= NR4) NR4R4, -C (= 0) H, -R4-C (= 0), -S02R4, -S (= 0) R4, -P (= 0) (OR4 ) 2, -P (= 0) (0R4), -C02H, -S03H, -P03H, halogen and trihalomethyl; wherein each R4 is independently selected from hydrogen, (C1-C10) alkyl, (C5-Cio) aryl, 5- to 10-membered heteroaryl, (C3-C6) arylalkyl, and 6 to 16-membered heteroarylalkyl, an aliphatic moiety or hydroxyaliphatic saturated or single or multiple unsaturated straight or branched chain having a chain length of 6 to 25 carbon atoms, a primary or secondary amine, at least one amino acid, at least one substituted amino acid and any combination of the same and each R 'and R "are independently one or more of the same or different substituents defined for R2, R3 or R4, with the proviso that R2 and R3 can not both be hydrogen.

In certain embodiments, intermediaries of structure (III) wherein R1 is OH or NH2; L is an amino acid that is selected from Gly and Sar; R2 is hydrogen and R3 is an amino acid with a protecting group such as Lys. In another embodiment, a lipopeptide antibiotic based on ampomycin is characterized by the following structure IV: wherein: Ri is OH or NH2; L is selected from at least one amino acid or substituted amino acid, -C (= 0) -, -R'C (= 0) -, -0C (= 0) -, -S02, - -C (= S ) -, -P (= 0) -, -0P (= 0) -, -R'OC (= 0) (NR'R ") -, -NHC (= 0) -, -OPhC (= 0) - , or -NR'C (= 0) - and each of R2 and R3 are independently selected from hydrogen, -OR4, -SR4, NR4R4, -CN, -N02, -N3, -C (= 0) OR4, -C (= 0) R4, -C (= 0) NR4R4, -C (= S) NR4R4, -C (= NR4) NR4R4, -C (= 0) H, -R4-C (= 0) , -S02R4, -S (= 0) R4, -P (= 0) (OR) 2, -P (= 0) (OR4), -C02H, -S03H, -P03H, halogen, trihalomethyl, alkyl (C? -C25), substituted (C? -C25) alkyl, heteroalkyl (C? -C25), heteroalkyl (C? -C25) substituted, aryl (C5-C10), aryl (C5-C_0) substituted, arylaryl (C5-C) 5), arylaryl (C5-C5) substituted, biaryl (C5-C5), biaryl (C5-C5) substituted, heteroaryl 5-10 members, substituted heteroaryl 5-10 members, arylalkyl ( C6-C26), substituted (C6-C26) arylalkyl, heteroarylalkyl of 6 to 26 members, substituted heteroarylalkyl of 6 to 26 members, at least one amino acid or amino acid substituted. Some exemplary and independently selected substitutions include -OR4, -SR4, NR4R4, -CN, -N02, -N3, -C (= 0) OR4, -C (= 0) R4, -C (= 0) NR4R4, -C (= S) NR4R4, -C (= NR4) NR4R4, -C (= 0) H, -RC (= 0), -S02R4, -S (= 0) R4, -P (= 0) (0R4) 2 , -P (= 0) (0R4), -C02H, -S03H, -P03H, halogen and trihalomethyl; wherein each R4 is independently selected from hydrogen, (C1-C10) alkyl, (C5-C10) aryl, 5- to 10-membered heteroaryl, arylalkyl (C6-C? s), and heteroarylalkyl from 6 to 16 members, a portion aliphatic or hydroxyaliphatic saturated or single or multiple unsaturated straight or branched chain having a chain length of 6 to 25 carbon atoms, a primary or secondary amine, at least one amino acid or substituted amino acid and any combination thereof, - and each of R 'are independently one or more of the same or different substitutions defined for R2, R3 or R4; with the proviso that R2 and R3 can not both be hydrogen. In a preferred embodiment, a lipopeptide antibiotic based on ampicillin or based on aspartocin of structure (IV) is provided, wherein R1 is OH or NH2; L is independently selected from at least one amino acid, at least one substituted amino acid, -C (= 0) -, -R'C (= 0) -, -S02, -C (= S) -, -P ( = 0) -, -OP (= 0), -0C (= 0) -, -R'0C (= 0) (NR ') -, -NHC (= 0) -, -0PhC (= 0) - and -NR'C (= 0) -, with the proviso that L in Dab9 is -C (= 0) -, where R 'is independently one or more of the same or different substituents as defined for R2, R3 or R4; R2 is selected from -OR4, -SR4, NR4R4, -CN, -N02, -N3, -C (= 0) 0R4, -C (= 0) R4, -C (= 0) NR4R4, -C (= S) ) NR4R4, -C (= NR4) NR4R4, -C (= 0) H, -RC (= 0), -S02R4, -S (= 0) R4, -P (= 0) (0R4) 2, -P (= 0) (0R4), -C02H, -S03H, -P03H, halogen, trihalomethyl, alkyl (C? ~ C25), alkyl (_-C25) substituted, heteroalkyl (C? -C5), heteroalkyl (C? -C25) substituted, aryl (C5-C0), aryl (C5-C? 0) substituted, arylaryl (C5-C15), arylaryl (C5-C? 5) substituted, biaryl (C5-C5), biaryl (C5- C 5) substituted, 5 to 10 membered heteroaryl, 5 to 10 membered substituted heteroaryl, (C 6 -C 26) arylalkyl, substituted (C 3 -C 2) arylalkyl, 6 to 26 membered heteroarylalkyl, 6 to 26 membered heteroarylalkyl , at least one amino acid or at least one amino acid substituted; R3 is selected from -C (= 0) 0R4, -C (= 0) NR4R4, -C (= S) NR4R4, -C (= NR4) NR4R4, -C (= 0) H, -R4-C (= 0), -C02H, alkyl (C? -C25) substituted, substituted heteroalkyl (C? -C25), substituted (C5-Co) aryl, substituted (C5-C15) arylaryl, biaryl (C5-C_5) substituted, substituted heteroaryl of 5 to 10 members, arylalkyl (C_-C26) substituted, heteroarylalkyl substituted of 6 to 26 members, at least one amino acid and at least one substituted amino acid, with the proviso that R3 contain at least one of -C (= 0), -C (= S) or -C (= NR4); wherein each R4 is independently selected from hydrogen, alkyl (L-CIO), aryl (C5-C? 0), heteroaryl to 10 members, arylalkyl (C6-C2S) and heteroarylalkyl of 6 to 26 members, an aliphatic or hydroxyaliphatic portion saturated or single or multiple unsaturated straight or branched chain having a chain length of 5 to 25 carbon atoms, a primary or secondary amine, at least one amino acid, at least one substituted amino acid and any combination thereof.

In certain embodiments, the present disclosure provides lipopeptide derivative compounds of structure (IV) wherein R 1 is OH or NH 2. In further embodiments, R3 is -C (= 0) - or -C (= S). In other preferred embodiments, compounds with antimicrobial activity are provided. Exemplary compounds include 81, 210, 223, 235, 237 or 373. In certain embodiments, R3 is at least one amino acid or substituted amino acid that is selected from Gly, β-alanine, GABA, 5-aminopentanoic acid, 6-amino acid, -aminohexanoic, Lys, gDab, Sar, Orn, Dap and hLys. In particular embodiments wherein structure (IV) intermediates are preferred, any of the compounds mentioned above are provided, wherein at least one of L or R3 further comprises at least one protecting group, as described herein. In other embodiments, antimicrobial lipopeptide derivative compounds and pharmaceutically acceptable salts thereof are provided, such as compounds 3, 4, 60, 128, 147, 199, 253 or 278. Either of these derivatives or those described herein may be further formulated with a pharmaceutically acceptable carrier, excipient or diluent. In certain embodiments, the lipopeptide derivative compounds of the present disclosure may be structurally pure or may be in the form of a composition comprising a mixture of one or more structurally different compounds. In certain embodiments, the compounds of the invention may be in the form of a free acid or base or in the form of a salt, such as a pharmaceutically acceptable salt. In still other embodiments, the central cyclic peptide is a β-isomer, anhydrous isomer or a dianhydro isomer. For convenience, the cyclic peptide derivatives of the amphomycin nucleus can be abbreviated in the following ways: (la) R2-R-R3; (Ila) R2-L-R-R3; (Illa) R2-R-L-R3 and (IVa) R2-L-R-L-R3; wherein R is an amphiphilic core cyclic peptide (which includes a hexoclicic amino acid in position 1, wherein R1 is attached), R2 and R3 can be any substituents described herein, in which, for example, hydrogen is included , alkyl (C! -C25), substituted (C-C25) alkyl, heteroalkyl (C? -C25), heteroalkyl (C? -C25) substituted, aryl (C5-C? 0), aryl (C5-C? 0) ) substituted, arylaryl (C5-C5), arylaryl (C5-C15) substituted, biaryl (C5-C5), biaryl (C5-C15) substituted, heteroaryl from 5 to 10 members, substituted heteroaryl from 5 to 10 members, arylalkyl (C6 ~ C2S), substituted arylalkyl (C3-C26), heteroarylalkyl of 6 to 26 members, substituted heteroarylalkyl of 6 to 26 members, amino acids and substituted amino acids or the like, with the proviso that R2 and R3 are not both hydrogen. Optionally, R2 and R3 can be attached to the core cyclic peptide by means of a linker portion L as described herein, in which any kind of chemical functionality that can form a covalent bond with nitrogen known by those of skill is included. of the technique. Exemplary linker groups L may include an amide, imide, sulfonamide, sulfonimide, amidine, carbonate, carbamate, thiourea, urea and the like. In certain embodiments, L is selected from one or more amino acids, one or more substituted amino acids, -C (= 0) -, S02-, -C (= S) -, -P (= 0) -, -OP (= 0) -, -0C (= 0) -, R'OC (= 0) (NR'R ") -, -NHC (= 0) -, -OPhC (= 0) - and NR'C (= 0) and each R 'is independently one or more of the same or different substituents defined herein for R2, R3 or R4 As is known in the art, lipopeptide antibiotics (eg ampomycin, aspartocin) isolated from cultures commonly comprise mixtures of compounds that differ with respect to the structures of their macrocyclic nuclei (defined below) or their lipophilic substituents (eg, fatty acid moieties) The various different compounds comprising the mixture can be separated from each other and isolated either as submixes or as structurally pure compounds, as described herein As used herein, reference to a "lipopeptide antibiotic" is intended to include, inter alia, mixtures produced naturally by the producer strain, also any sub-mixtures or structurally pure compounds isolated or derived therefrom. In addition, the cyclic peptides of the core can be modified to include β-isomers, anhydrous isomers and dianhydro isomers. For example, the Asp-Gly pair (at positions 5,6 and 7,8, respectively) of a cyclic peptide of amphomycin nucleus or aspartocin can be modified from a linkage a. to a link ß. In the modification, the fundamental chain of the continuous peptide changes from the acid to the β-acid of the aspartate residue. The resulting β isomers may contain one or more of the following three possible structural modifications, without taking into account possible changes in stereochemistry: (a) 5, 6-ß-7, 8-Q !, (b) 5.6-CÜ with 7 , 8-ß or (c) 5,6-ß with 7,8-ß. Each of these β-isomers of cyclic peptide of amphomycin nucleus or aspartocin have the same molecular weight as a whole cyclic peptide of α-ampicillin core. Similarly, the Asp-Gly pair (in positions 5,6 and 7,8, respectively) of an ampicillin cyclic peptide can be modified in such a way that one molecule of water is lost to give an anhydrous isomer or dianhydro isomer.

Two possible mono-anhydrous isomers can be formed by the loss of a molecule of water. If both positions are modified, a dianhydro isomer can be formed by the loss of two water molecules. It should be understood that combinations of β-isomers and anhydrous isomers are also possible, as are modifications to the stereochemistry of the individual aspartate residues. Hence, as used herein, reference to a "lipopeptide antibiotic" is intended to include any such modified structures or combinations thereof as well. Ampicillin core cyclic peptide isomers are illustrated in Figure 1. Anhydrous and dianhydro isomers of ampicillin core cyclic peptide are illustrated in Figure 2. The term "structurally pure" refers to a composition of compounds in the which a substantial percentage, for example of the order of 95% to 100% and preferably ranges from about 95%, 96%, 97%, 98%, 99% or more, of the individual molecules comprising the composition each contain the same number and type of atoms appended to each other in the same order and with the same links. As used herein, "structurally pure" is not intended to distinguish different geometric isomers or different optical isomers from each other. For example, as used herein, a mixture of cis- and trans-but-2, 3-ene is considered to be structurally pure, since it is a racemic mixture. When compositions are proposed to include a substantial percentage of a single geometric isomer or optical isomer, the "geometrically pure" and "optically or enantiomerically pure" nomenclature respectively are used respectively. The phrase "structurally pure" also does not intend to discriminate between different tautomeric forms or ionization states of a molecule or other forms of a molecule that result as a consequence of equilibrium phenomena or other reversible interconversions. Thus, a composition of for example an organic acid is structurally pure although some of the carboxyl groups may be in the protonated state (-COOH) and others may be in the deprotonated state (-C00"). Also, a composition comprising a mixture of tautomers of keto and enol, unless otherwise specified herein, is considered structurally pure In some embodiments, the compounds of the invention are lipopeptide derivatives of original amphiphilic lipopeptide-type antibiotics produced from cultures. Examples of such original amphiphilic lipopeptide antibiotics include ampomycin (glumamycin), aspartocin, crystallomycin, friulimycin, tsushimycin and zaomycin Those of ordinary skill in the art will recognize that in these embodiments, the structures of the exocyclic amino acid (s) ( s) and the lipophilic substituent R2 in the formulas (I) to (IV) will be largely determined by the producer strain and culture conditions. Those of ordinary skill in the art will also recognize that in these embodiments, the original amphiphilic lipopeptide antibiotics may comprise mixtures of compounds that differ from each other with respect to the structure of the exocyclic amino acid or lipophilic substituent R2. As will be discussed in more detail hereinbelow with regard to the synthesis of the compounds of the invention, the desired compounds of the invention can be obtained by appropriate selection of the original amphiphilic lipopeptide antibiotic used as the starting material. For example, although preparations of aspartocin, ampicillin, zaomycin, and tsushimycin isolated from cultures present mixtures of compounds, it is believed that they all share the same macrocyclic amphicroid-like nucleus: the ampicillin-type cyclic peptide core R in which R1 is -OH . Likewise, in friulimycin preparations, it is believed that the components of the mixture share the same core of cyclic ampicillin-like peptide: the ampicillin-type cyclic peptide core R in which R1 is -NH2. A) Yes, it is believed that the compounds comprising these respective antibiotic mixtures differ from each other only with respect to the structures of their lipophilic substituent (ie, fatty acid portions). Alternatively, antibiotic A1437 comprises a mixture of compounds that are believed to differ from each other with respect to the structures of their macrocyclic ampicillin-like nuclei and fatty acid portions (see, e.g., U.S. Patent No. 6,194,383). All of these original amphiphilic lipopeptide antibiotics can be used as starting materials to produce the desired lipopeptide antibiotic (e.g., having a specific lipophilic substituent or Dab9 substitution) of the invention. Structurally pure lipopeptide derivatives of the invention can be obtained by separating and isolating the component compounds of the original amphiphilic based lipopeptide antibiotic starting material prior to the derivation of the macrocyclic peptide from the core or alternatively, separating the component compounds from the mixture resulting from the derivation, as will be described in more detail below. In addition, in many instances, the exact structures of the fatty acid portions of such original amphiphilic lipopeptide antibiotics are unknown. Compounds of the invention having a fatty acid moiety of a specified structure can be obtained by delipidating the original amphiphilic lipopeptide antibiotic starting material and reacting the delipidated intermediary with a fatty acid or other substituent (e.g. lipophilic substituent) having a specified structure. The resulting product can optionally be derived, for example, at the Dab9 residue, which would produce a Dab9 derivative of the invention having a lipophilic substituent specified at the amino terminus. Alternatively, a Dab9 derivative of the invention, prepared by derivatizing an original amphiphilic lipopeptide antibiotic, can be delipidated and the delipidated intermediate derived from Dab9 can be reacted with a fatty acid or other specified structure substituent. Fatty acids suitable for use in the production of an appropriate fatty acid moiety or for attaching an appropriate fatty acid moiety to the macrocyclic peptide of the nucleus are well known in the art (see, for example, Rummp Chemie Lexicon, Prof. Falbe and Prof. Regitz, 9th edition, Georg Thieme Verlag Stuttgart, New York; and Hawley, 3rd Edition, Van Nostrand Reinhold Company, New York, each of which is incorporated herein by reference). In one embodiment, a fatty acid is selected that produces a compound of the invention and that has a fatty acid moiety that is identical to a fatty acid moiety of a known amphiphilic lipopeptide antibiotic. Such fatty acids are well known to those of ordinary skill in the art. Illustrative examples are provided, for example, in US Patent No. 6,194,383 (see especially columns 5-8), which is incorporated herein by reference. However, the fatty acid does not need to correspond to a fatty acid of a known amphiphilic lipopeptide antibiotic. Suitable fatty acids may include unbranched and saturated fatty acids (for example, caproic, enanthic, caprylic, pelargonic, capric, undecanoic, lauric, tridecanoic, myristic, pentadecanoic, palmitic, margaric, stearic, nonadecanoic, arachidic, behenic, limnoceric, pentacosenoic and the like); branched and saturated (eg, isobutyric, isovaleric, isopalmitic and the like and corresponding acids in the ante-iso configuration and may contain methoxy or hydroxy substitutions); monoenoic (e.g., obtusyl, caproleic, lauroleic, lindric, myristoleic, fisetheric, tsuzuic, palmitoleic, petroselinic, oleic, vaccenic, gadoleic, gondoic, ketoleic, erucic, nervonic, and the like); polyenoic (for example, linoleic,? -linoleic, arachidonic, stearidonic and the like and polyenes interrupted by methylene, polyenes interrupted by polyethylene, conjugated fatty acids and halogenated fatty acids). See also U.S. Patent No. 6,194,383 which is incorporated herein by reference. In certain preferred embodiments, the fatty acid is a fatty acid portion or a hydroxy fatty acid portion with a chain length of 6 to 25 carbon atoms and more preferably 10-20 carbon atoms. The fatty acid or hydroxy fatty acid may be linear or branched, saturated or single or multiple unsaturated and combinations thereof. In one embodiment, the fatty acid is a fatty or individually unsaturated acid comprising 10 or 18 carbon atoms, which is either linear or individually branched, preferably in the iso or ante-iso configuration. In another embodiment, the fatty acid is a saturated or individually unsaturated hydroxy fatty acid comprising 10 or 18 carbon atoms that is either linear or individually branched, preferably in the iso or ante-iso configuration. In a specific embodiment, the hydroxy fatty acid is hydroxylated at the 2,3-position or at the end of the chain. In certain aspects, as shown for example in compounds having structures (I) - (III), R2 (for example, a lipophilic substituent) can be directly linked to the amino-terminal amino group of Asp or Asn and a substituent R3 can being directly linked to the ß-amino group of Dab9, wherein R2 and R3 are independently selected from hydrogen, (C _, -C25) alkyl, substituted (C? -C25) alkyl, heteroalkyl (C-C2S), heteroalkyl (C? -C25) substituted, aryl (C5-C10), aryl (C5-C10) substituted, arylaryl (C5-C5), arylaryl (C5-C15) substituted, biaryl (C5 ~ C_5), biaryl (C5-CX5) substituted, 5- to 10-membered heteroaryl, substituted 5-10 membered heteroaryl, arylalkyl (C6-Ce), substituted arylalkyl (C6-C26), heteroarylalkyl of 6 to 26 members, substituted heteroarylalkyl of 6 to 26 members, natural amino acids, non-natural amino acids and natural and non-natural amino acids substituted; wherein R2 and R3 can not both be hydrogen. Some exemplary substitutions R independently selected include -OR4, -SR4, NR4R4, -CN, -N02, -N3, -C (= 0) 0R4, -C (= 0) R4, -C (= 0) NR4R4, -C (= S) NR4R4, -C (= NR4) NR4R4, -C (= 0) H, -R4-C (= 0), -S02R4, -S (= 0) R4, -P (= 0) (OR4 ) 2, -P (= 0) (0R4), -C02H, -S03H, -PO3H, halogen and trihalomethyl; wherein each R4 is independently selected from hydrogen, alkyl (L-CIO), aryl (C5-C? 0), heteroaryl from 5 to 10 members, arylalkyl (C6-C? S) and heteroarylalkyl from 6 to 16 members , an aliphatic or hydroxyaliphatic saturated or single or multiple unsaturated straight or branched chain portion having a chain length of 6 to 25 carbon atoms, a primary or secondary amine, at least one amino acid, at least one substituted amino acid and any combination of them.

In the compounds of structures (I) to (IV), R1 can be -OH or -NH2, which means that the amino-terminal exocyclic amino acid is an Asp residue or an Asn residue, respectively. If the amino-terminal exocyclic amino acid is Asp or Asn, it will depend on the choice of the original ampomycin-based lipopeptide antibiotic used as a starting material in the synthesis of the lipopeptide derivatives of the invention or derivatives of the invention with specified lipophilic substituents and / or Dab9 substituents, as will be apparent to those of ordinary skill in the art. For example, lipopeptide derivatives in which the amino-terminal exocyclic amino acid is Asp can be prepared from ampomycin, aspartocin, tsushimycin or the Asp fraction of antibiotic A1437. Lipopeptide derivatives of the invention in which the amino-terminal exocyclic amino acid is Asn can be prepared from friulimycin or from the Asn fraction of antibiotic A1437. The Asp and Asn fractions of the antibiotic A1437 can be isolated from a preparation of the cultivated antibiotic A1437 according to the methods described in for example, US patent 6,194,383, which is incorporated herein by reference. In certain aspects, the antimicrobial compounds derived from structural formulas (I) to (IV) may have a substituent R3 including hydrogen, -OR4, -SR4, NRR4, -CN, -N02, -N3, -C (= 0) OR4, -C (= 0) R4, -C (= 0) NRR4, -C (= S) NR4R4, -C (= NR4) NR4R4, -C (= 0) H, -R4-C (= 0) , -S02R4, -S (= 0) R4, P (= 0) (0R) 2, -P (= 0) (0R4), -C02H, -S03H, -P03H, halogen, trihalomethyl, alkyl (C? - C25), substituted (C-C25) alkyl, heteroalkyl (C-C2S), heteroalkyl (C? -25) substituted, aryl (C5-C10), aryl (C5-C10) substituted, arylaryl (C5-C15), arylaryl (C5-C15) substituted, (C5-C5) biaryl, substituted (C5-C5) biaryl, 5- to 10-membered heteroaryl, 5-10 membered substituted heteroaryl, arylalkyl (CS-C2S), arylalkyl (C6-) C26) substituted, heteroarylalkyl of 6 to 26 members, substituted heteroarylalkyl of 6 to 26 members, natural amino acids, non-natural amino acids and natural and substituted non-natural amino acids. Some exemplary and independently selected substitutions include -OR4, -SR4, NR4R4, -CN, -N02, -N3, -C (= 0) 0R4, -C (= 0) R4, -C (= 0) NR4R4, -C (= S) NR4R4, -C (= NR4) NR4R4, -C (= 0) H, -RC (= 0), -S02R4, -S (= 0) R4, -P (= 0) (0R4) 2 , -P (= 0) (0R4), -C02H, -S03H, -P03H, halogen and trihalomethyl; wherein each R4 is independently selected from hydrogen, alkyl (L-CIO), aryl (C5-Cio) / heteroaryl from 5 to 10 members, arylalkyl (C6-C6) and heteroarylalkyl from 6 to 16 members, an aliphatic moiety or hydroxyaliphatic saturated or single or multiple unsaturated straight or branched chain having a chain length of 6 to 25 carbon atoms, a primary or secondary amine, at least one amino acid, at least one substituted amino acid and any combination of the same, a primary amine group, a secondary amine group, one or more amino acids and one or more substituted amino acids. In a preferred embodiment, the ß-amino group of Dab9 is directly attached to a substituent R 3 to form a primary or secondary amine having the formula -NHR 3, wherein R 3 is hydrogen, (C 1 -C 25) alkyl, .-C25) substituted, -heteroalkyl (C? -C25), heteroalkyl (C? -C25) substituted, aryl (C5-C? 0), aryl (C5-C? 0) substituted, arylaryl (C5-C5), arylaryl (C5-C5) substituted, biaryl (C5-C5), biaryl (C5-C5) substituted, heteroaryl of 5-10 members, substituted heteroaryl of 5-10 members, arylalkyl (C6-C2e) , substituted (C6-C26) arylalkyl, heteroarylalkyl of 6 to 26 members, substituted heteroarylalkyl of 6 to 26 members, natural amino acids, non-natural amino acids and substituted natural and non-natural amino acids and any combination thereof. In another preferred embodiment, the primary or secondary amine group may be spaced from the macrocyclic Dab 9 residue by means of an optional linking moiety, as described and shown herein, for example in structures of compounds (I) and (IV). The present invention is based in part on the surprising discovery that amphotericin-based lipopeptide antibiotics derived at the amino-terminal exocyclic amino acid, at the Dab9 residue or at both positions, retain substantially the same antimicrobial properties of the lipopeptide antibiotics. original ampicillin type of which are derivatives, but may have altered solubility properties. For example, this may lead to lipopeptide antibiotic derivatives based on ampicillin having improved therapeutic properties or effects as compared to the original amphiphilic lipopeptide antibiotics from which they are derived. Without wishing to be bound by theory the optional linker portion for attaching either or both of R2 and R3 to the core macrocyclic peptide it may be preferred to introduce a sufficient number of atoms to separate the added substituent from the core cyclic peptide in the range of about 1A to about 10A. Commonly, a linking group is a portion which, when taken together with the amino-terminal amino-amino atom of the amino-terminal amino or the nitrogen-nitrogen atom of Dab9 to which the linking group is bonded, produces a bond that is stable to the physiological conditions under which the compounds of the invention will be used. Examples of suitable linkages include amide, imide, sulfonamide, sulfonimide, amidine, carbonate, carbamate, thiourea, urea and the like. Thus, examples of appropriate linking groups include one or more amino acids, one or more substituted amino acids, a combination of one or more amino acids with one or more substituted amino acids and groups -C (= 0) -, -S (= 0) 2-, -C (= NH) -, -NHC (= 0) -, -NHC (= S) -, -NHC (= 0) NH-, -NHC (= S) NH- and -C (= 0 ) 0-. The person of ordinary skill in the art will recognize that the exact number of atoms necessary to obtain a particularly desired spacing between the substituents R2 or R3 and the core cyclic peptide will depend, among other things, on the types of atoms (e.g. , O, S, C, etc.) and links (eg, single, double, triple, etc.) that comprise the linking portion and therefore, will be able to select additional substituents, if necessary, to produce an appropriate spacing . For example, additional spacer substituents, which may be present or absent, may include virtually any combination of carbon atoms or heteroatoms suitable for spacing. In certain embodiments, the linker L may further comprise a spacer portion that is hydrophilic or hydrophobic, long or short, rigid, semi-rigid or flexible. For example, suitable groups that may comprise the spacer include -CH2-, -CH = CH-, -C = C-, -O-, -S-, -NH-, -NH-NH-, -N = N- , -C (= 0) -, -S (= 0) 2-, -S (= 0) 2-0-, -C (AH) - and the similar ones. Other spacers suitable for spacing are known in the art and include alkyl, heteroalkyl, acyclic heteroatomic bridges, aryl, arylaryl, arylalkyl, heteroaryl, heteroaryl-heteroaryl, substituted heteroaryl-heteroaryl, heteroarylalkyl, heteroaryl-heteroalkyl and the like. Thus, the spacers can include single, double, triple bonds or aromatic carbon-carbon bonds, nitrogen-nitrogen bonds, carbon-nitrogen bonds, carbon-oxygen bonds or carbon-sulfur bonds and can therefore include functionalities such as carbonyls, ethers, thioesters , carboxamides, sulfonamides, ureas, urethanes, hydrazines and the like. These and other groups, which will be apparent to those of ordinary skill in the art, can be used in a multitude of combinations to create appropriate spacers or combined linkers-spacers. In addition, the spacers may optionally be substituted with one or more of the same or different substituents as described herein. The choice of an appropriate linker or separator is within the capabilities of those of ordinary skill in the art. For exampleWhere a rigid linker or separator is desired, it may be a rigid polyunsaturated alkyl or an aryl, diaryl, heteroaryl and the like. When a flexible linker or separator is desired, it may be a flexible peptide, such as Gly-Gly-Gly or a flexible saturated alkanyl or heteroalkanyl. Hydrophilic binders or separators can be, for example, polyalcohols or polyethers, such as polyalkylene glycols. Hydrophobic linkers or separators can be, for example, alkyls or aryls. In certain preferred embodiments of derivatives of structural formulas (I) - (IV), the substituent R2 or R3 may be one or more amino acids which is linked via its terminal carboxyl group to the amino-terminal amino group of the exocyclic amino acid or to the group β- amino of the macrocyclic Dab9 residue, respectively, to form an amide bond. Such amino acids may include α-, β- and α-amino acids. The amino acids may optionally include side chain portions, such as a side chain portion of one of the 20 genetically encoded amino acids or an analogue thereof. In certain preferred embodiments, the substituent is an amino acid selected from glycine, proline, pipecolic acid, sarcosine, phenylalanine, phenylglycine, asparagine, tyrosine, tryptophan, leucine, alanine, isoleucine, valine, glutamine, threonine, β-alanine, acid 2, 4-diaminobutyric acid, 2, 3-diaminopropionic acid, ß-methylaspartate, cyclohexylalanine, isonipecotic acid, ornithine and 6-aminohexanoic acid. In other preferred embodiments, more than one amino acid substituent is added, such as glycine-leucine, glycine-lysine, glycine-glycine, glycine-leucine, proline-glycine, (β-alanine) - (6-aminohexanoic acid), (β -alanine) -noritin, (ß-alanine) -lysine, glycine-alanine, (6-aminohexanoic acid) -glycine, glycine- (6-aminohexanoic acid), glycine-glycine-glycine, lysine-glycine-glycine, glycine- glycine-lysine, glycine-lysine-lysine, lysine-lysine-lysine, lysine-lysine-glycine, glycine-valine, proline-lysine, glycine-ornithine, glycine- (2,3-diaminobutyric acid), glycine- (acid 2) , 3-diaminopropionic), glycine-homolysine, sarcosine- (6-aminohexanoic acid), sarcosine-lysine. Any chiral centers in the amino acid can be either in the R- or S-configuration. Examples of appropriate amino acids include the 20 amino acids genetically encoded; the various amino acids listed in Handbook and Biochemistry and Molecular Biology, 1989, CRC Press Inc., Boca Raton, FL on pages 4-60 and amino acids c, β-unsaturated enlisted in Fasman, 1989, supra, on page 69 Other suitable amino acids will be apparent to those of ordinary skill in the art.

METHODS OF SYNTHESIS The compounds of the invention can be synthesized by means of different synthetic routes using commercially available starting materials or starting materials prepared by conventional synthetic or biosynthetic methods. Two general synthetic methods are illustrated in Figure 3. In Reaction Scheme (I), R and R1 are as previously defined in structural formulas (I) - (IV). According to 1 Reaction Scheme (I), an original amphiphilic lipopeptide antibiotic (or mixtures of antibiotics) 10 is coupled with an appropriately protected reagent 12, which in the specific illustrated example is Fmoc-protected glycine, to produce the protected intermediate Dab9 (or mixture of intermediates) 14. The protected reagent can be any of the substituents described herein, in which 'lipophilic substituents, other organic substituents, one or more amino acids (natural, non-natural, substituted, etc.) and the like. Reaction conditions for the coupling of primary amines, such as antibiotic (or mixture of antibiotics), with carboxylic acids, such as reagent 12, to produce amide bonds are known to those skilled in the art and can be found in any compendium of standard scientific methods or literature related to the synthesis of peptides and proteins. See, for example, March, J., Advanced Organic Chemistry; Reactions, Mechanisms and Structure, 4th edition, 1992; Larock, Comprehensive Organic Transformations, VCH, New York, 1999; Bodanzky, Principies of Peptide Synthesis, Springer Verlag, 1984; Bodanzsky, Practice of peptide Synthesis, Springer Verlag, 1984; Lloyd-Williams et al. , Chemical Approaches to the Synthesis of Peptides and Proteins, CRC Press, 1997 (see especially pages 105-114) and Atherton and Sheppard, Solid Phase Peptide Synthesis; A Practical Approach, IRL Press, 1989). Alternative reactive groups can be used, such as isocyanate (which would produce a urea) and others exemplified herein, in methods known in the art. Then, the protected intermediary 14 is - deprotected to produce the Dab9 derivative (or mixture of derivatives) 16. While the method is illustrated using a Fmoc protecting group, the person having ordinary skill in the art will recognize that other protecting groups can be used. In addition, in some instances, reagent 12 may include additional functionalities or functionalities that may require protection. Suitable groups to protect a wide variety of different functionalities, also as conditions for their removal, are well known and will be apparent to those of ordinary skill in the art. Specific guidelines for selectively protecting a wide variety of functionalities can be found, for example in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd edition, 1999 ("Greene and Wuts"). Preferred protecting groups are those that can be easily separated. Preferred groups to protect primary amines are tert-butyloxycarbonyl ("Z"), 9-fluorenylmethoxycarbonyl ("Fmoc") and benzyloxycarbonyl ("Z"). If the original amphiphiline-type lipopeptide antibiotic 10 is a mixture of individual components, it should be recognized by those skilled in the art that a mixture of derivative 16 results as a result and can be isolated individually, partially or completely or purified to produce a number of independent derivatives 16 as various groups R1, as described herein. Representative derivatives 16 that were prepared by this method are shown in Table 16 and Examples 367, 378, 369, 370, 371 and 372. The original amphiphiline-type lipopeptide antibiotic 10 can be obtained by isolation from a culture of known microorganisms that produce the antibiotic. The microorganisms for producing ampomycin-like lipopeptide antibiotics are well known, as are the conditions for isolation and optionally further purifying the resulting antibiotics. For example, strains to produce ampomycin (glumamycin) include Streptoznyces cannus (ATCC No. 12237; see also Heinemann et 1. , 1953, Ant ± biot. Chemother. 3: 1239-1272) and Streptomyces zao27tyce icus (ATCC No. 13876, see also US Patent No. 3,160,561 to Shibata et al.). Strains for producing aspartocin include Streptomyces griseus subsp. Spiralis (ATCC No. 13733, see also US Patent No. 3,057,779 for Shay et al.) And Streptomyces violaceus (Rossi-Doria) Waksman (ATCC No. 13734; see also US Pat. 3,057,779). Strains to produce crystalomycin include Streptcmyces violaceoniger variety crystallomycini (Gauze et al., 1957, Antibiotiki 2 (6): 9-14). Strains to produce antibiotic A1437 include Actinoplanes sp. (DSM No. 7358; see also US Patent 6,194,383 to Hammann et al.). Strains to produce friulimycin include Actinoplanes friulensis (HAG No. 010964). Strains for producing tsushimycin include Streptomyces pseudogriseolus Okami and Umezawa (ATCC pseudogriseolus No. 21139 and No. 21140, see also US Patent No. 3,781,420 for Nishimura et al.) And Streptomyces pseudogriseolus subspecies glucofermentans Nishimura and Otsuka (ATCC No. 21141; also US Patent No. 3,781,420 to Nishimura et al.). Strains to produce zaomycin include Streptomyces zaomyceticus Hinuma (NRRL No. B-2038). The conditions for culture and isolation of the various lipopeptide antibiotics are described herein and are found in the above patents and references cited above, as well as the various references mentioned previously in connection with these various antibiotics. The following description is an exemplary method for making lipopeptide compounds based on ampomycin using fermentation in a bioreactor. A lipopeptide based on ampomycin can be produced by fermentation in a 700 liter stainless steel bioreactor. The biochemical synthesis of ampomycin is carried out by inoculating a compound medium of 1.0% dextrose, 0.5% molasses, 1.0% Bacto Peptone and 0.1% CaC03 in 100 ml of tap water, with spore scrapings and mycelial an inclined fermentor tube from Streptomyces griseus ssp. spiralis (NRRL B-3290; BSP-M707). The inoculated medium is incubated at a temperature of about 28 ° C on a rotary shaker at about 180 rotations per minute (RPM) for about 48 hours providing a substantial and uniform vegetative culture. This seed growth (10 ml) is transferred to 400 ml of the same medium in a two-liter flask, which is incubated under the same conditions and then added to 9.6 liters of the same medium in a 16-liter fermenter to give the seed of third stage after 48 hours, 200 rpm, air flow of 5 liters per minute. This final seeding stage is used to inoculate 500 liters of medium containing 1 g / CaCO3, 10 g / L of Grandma molasses (without sulfur), 10 g / L of Difco Bacto peptone and 20 g / L of Baker Dextrose adjusted to a pH of 7.1 before sterilization. The fermentation is carried out with agitation speed of 200 rpm, air flow of 125 liters per minute and 28 ° C with the addition of antifoam, Mazu DF204, as required. The fermentation broth is cultivated after 114 hours. After fermentation, the following exemplary processes to obtain a crude preparation of the lipopeptide based on ampomycin can be used. The cells and other solids from the fermentation broth can be separated by centrifugation and the supernatant (470 liters) is adjusted to a pH of 3.3 with HCl and allowed to stand at 14 ° C for 2 hours. The precipitate that forms is separated by centrifugation and discarded. The decant is adjusted to a pH of 7.0 and ammonium sulfate is added to precipitate the crude antibiotic complex. The precipitate is sedimented by centrifugation, dissolved in water, adjusted to a pH of 7.0 and then freeze-dried to give a pH of 7.0., 058 grams of solid containing 5-7% of the lipopeptide complex based on ampomycin. To further purify the lipopeptide based on ampomycin, an exemplary chelate procedure can be used as follows. The dark-colored crude preparation, 68.3 grams, containing 5-7% of the lipopeptide complex based on ampomycin is dissolved in 500 ml of distilled water and stirred as it is adjusted to a pH of 7.0 to maximize the solubility in water . Some insoluble material can be formed, which is separated by centrifugation and then the remaining decantate is adjusted to a pH of 3.5. The lipopeptide complex based on ampomycin is extracted by two sequential extractions with 1-butanol (500 ml, 300 ml) and 600 ml of water are added to the combined butanol phases. The resulting two-phase system is stirred and adjusted to a pH of 8.0 with 1 N NaOH to provide the lipopeptide complex based on ampomycin as a sodium salt in the aqueous phase. Calcium chloride (2,642 grams) is added to the separated aqueous phase and the lipopeptide based on ampomycin is extracted to 1-butanol as chelate by two sequential extractions. (500 ml, 250 ml). To separate the calcium, the 1-butanol phases are combined, mixed with 900 ml of water, adjusted to a pH of 3.0, separated from the aqueous phase and washed with 150 ml of water. The 1-butanol phase containing the lipopeptide complex based on ampomycin is combined with 500 ml of water and adjusted to a pH of 7.0. To separate some residual elements, the aqueous phase containing the antibiotic complex is adjusted to a pH of 3.0 and mixed with 500 ml of 1-butanol. The 1-butanol phase is separated, washed with 150 ml of water (pH 2-3), combined with 500 ml of water and then the mixture is adjusted to a pH of 7.0. The aqueous phase containing the lipopeptide complex based on ampomycin as a partial salt of sodium is evaporated under vacuum to remove the residual 1-butanol and freeze-dried to obtain 3.6 grams of a white powder. HPLC analysis of the purified complex is used to determine the purity of the ampomycin-based lipopeptide by 215 nm area% with complex peaks between 9.4 and 10.6 minutes (preferably it is from about 85% to about 95% pure, more preferably about 90% to about 95% pure). The HPLC system used can be a Prodigy® 5μ ODS (2) column with an 8-minute gradient of 10% to 75% acetonitrile at a pH of 7.2 with 0.05M phosphate buffer. As discussed previously, in most instances, the antibiotic-based lipopeptide antibiotic or antibiotic mixture 10, isolated from cultures are mixtures of compounds that differ with respect to the R1 structures and the cyclic peptide core R. for example, ampomycin is a mixture of compounds in which R1 is a mixture of fatty acids C_2 and C? 3 iso and ante-iso. Aspartocin is a mixture of compounds in which R1 is a mixture of fatty acids of C_3 and CX iso and ante-iso. Tsushimycin is a mixture of compounds in which R1 is a mixture of Ci4 and C5 iso and ante-iso fatty acids. In ampomycin, aspartocin and tsushimycin, the cyclic peptide of the nucleus is connected to R1 by an amino acid of exocyclic aspartic acid. Friulimycin is a mixture of compounds in which R1 is a mixture of C13 and C15 iso and ante-iso fatty acids. In friulimycin, the cyclic peptide of the nucleus is connected to R1 by an exocyclic asparagine amino acid. The antibiotic A1347 is a complex mixture of 11 compounds, wherein R1 is a mixture of C_3 C14 fatty acids, and C15 iso and ante-iso and the exocyclic amino acid may be either aspartic acid or asparagine. In most instances, the culture conditions useful for producing one or more compounds of the mixtures in higher or lower yields are known (see, for example, J. "Biotechnology 1: 283-292, 1988). Such methods can be used in conjunction with the invention to provide mixtures of Dab9 derivatives having fatty acid moieties of defined molar proportions. He . lipopeptide antibiotic type ampomycin (or mixtures of antibiotics) 10 isolated from cultures can be used directly in the Reaction Scheme (I) without prior separation and isolation of the various components of the mixtures or they can be first separated, either with with respect to the fatty acids or in the case of the antibiotic A1347, with respect to the exocyclic amino acid (for example, aspartic acid or asparagine), to structurally pure compounds or sub-fractions or sub-mixtures. Methods for separating individual components or sub-mixtures of antibiotic preparations are well known in the art. Specific appropriate methods are provided, for example in U.S. Patent No. 6,194,383 (see especially columns 10-12) and in the Examples section infra. In some instances, the structures of the fatty acid portions of the ampicillin-based lipopeptide antibiotic (or mixtures of antibiotics) may be unknown. In certain instances, it may be desirable to have compounds derived from the invention with substituents specified at the amino terminus, such as a fatty acid portion or macrocyclic Dab 9 position. In other instances, it may be desirable to have derivatives that are structurally pure, geometrically pure or optically pure with respect to for example the lipophilic substituent. Thus, instead of isolating compounds from a cultured antibiotic preparation, it may be more convenient or desirable to replace the natural fatty acid portion of the cultured antibiotic (or mixture of antibiotics) with a specific substituent, which may be an acid portion. particular fatty or any other portion that is capable of covalently linking to the N-terminus as described herein. As illustrated in the Reaction Scheme (I), this can be obtained by several synthesis strategies. According to a first strategy, the antibiotic-like lipopeptide antibiotic (or mixture of antibiotics) is first protected in the ß-amino group of the macrocyclic Dab9 residue to produce the protected intermediate (or mixture of intermediates) 18. Again, in so much so that the illustrated protective group is Fmoc, those of ordinary skill in the art will appreciate that other commonly known amine protecting groups can be used. Then, the protected intermediate (or mixture of intermediates) 18 is delipidated or deacylated to produce the protected ampicillin-like macrocyclic core 20. Then, the protected core 20 is coupled with a reactive group 22, which is exemplified as a carboxylic acid, another once using standard chemistries, to produce the protected amphiphilic lipopeptide antibiotic 24. It should be recognized by those skilled in the art that any reactive group that is capable of reacting with the N term could be used to produce other lipopeptide antibiotics 24, as described herein. In the exemplified carboxylic acid 22, Rx combined with its -C (= 0) -carbonyl could represent either R2 of structures (I) or (II), or R2-L of structures (II) or (IV). Briefly, this carboxylic acid can be activated and purified by the following exemplary procedure (see Example 1 below). The carboxylic acid can be dissolved in anhydrous dimethylformamide (DMF) under an inert atmosphere, dihydroxysuccinimide added and then cooled in an ice bath. Then, dicyclohexylcarbodiimide is added in two equal portions to the reaction mixture separated by 10 minutes, after which the mixture was stirred while being stirred on ice, allowed to warm to room temperature and then stirred for at least 2 hours) . Then the resulting crude product can be concentrated in vacuo and purified by recrystallization using isopropanol and hexane, which gives a good yield and a relatively clean activated ester. The addition of the activated carboxylic acid to a protected core macrocyclic peptide can be carried out by the following exemplary procedure (see also Examples). Protected ampicillin-based core peptide 20 (e.g., ampomycin-9-Fmoc) is dissolved in water and then diluted with dimethylformamide. A solution of baking soda is added slowly and the mixture is then cooled in an ice bath. A predisposed solution of acyl activated ester 22 in DMF is added to the reaction mixture while it is still on ice, then the reaction mixture is allowed to stir for at least 6 hours at room temperature. Dipyridine is added and the reaction mixture is stirred for an additional hour. The reaction is filtered, the insolubles washed with additional dimethylformamide and the concentrated filtrate in vacuo until it is dry. Flash chromatography using a gradient system of methanol in chloroform (or methanol in ethyl acetate) provides an ampicillin coupled to the desired acyl tail in good overall yield and purity. Then, the protected antibiotic 24 can be deprotected to produce the compound 26, reacted with the reagent 12 to produce the protected Dab9 derivative 28, which, following deprotection, produces the Dab9 derivative 30. The addition of a substituent The macrocyclic Dab 9 residue can be carried out by the following exemplary procedure (see Examples below). The ampicillin coupled with acyl is suspended in dimethylformamide, charged with sodium bicarbonate and then cooled in an ice bath. The carboxylic acid activated with succinimide is pre-dissolved in dimethylformamide, added to the reaction mixture while it is still on ice and then the reaction is allowed to stir for at least 6 hours at room temperature. The resulting crude product can be concentrated in vacuum and then subjected to standard deprotection conditions as required. The final purification by Column of Solid Phase C18 Prepack B &J using an acetonitrile gradient system in water provides the clean product in good yield and purity.

When the original amphiphiline-type lipopeptide antibiotic (or mixture of antibiotics) is a mixture of compounds that all share the same ampicillin-like macrocyclic nucleus such as ampomycin, aspartocin, friulimycin, tsushimycin or zaomycin, this method can be used to synthesize derivatives of Dab9 of the invention which are structurally pure without having to isolate the various fatty acid fractions of the original amphiphilic lipopeptide antibiotic 10 from each other. The delipidation (or deacylation) produces a mixture comprising the various fatty acids and the same protected ampicillin-like macrocyclic core 19. The protected macrocyclic core 19 can be easily isolated in high purity from this mixture using any technique known in the art, such as high performance liquid chromatography, countercurrent extraction, centrifugation, filtration, precipitation, ion exchange chromatography, gel electrophoresis, affinity chromatography, etc. Specific procedures that can be used directly or that can be systematically adapted to isolate a protected macrocyclic core in particular are described in Debono et al. , 1988, J.

Antibiotics 41: 1093 and U.S. Patent No. 5,039,789 (see, for example, columns 30-34), each of which is incorporated herein by reference. Additional chemistries and procedures that can be used directly to delipidate / deacylate and react the original amphiphilic lipopeptide antibiotic 10 are found in U.S. Patent No. 5,629,288 to Lattrell et al. , the disclosure of which is incorporated herein by reference. In a preferred route, the protected Dab9 derivative 14 is delipidated / deacylated to produce the protected ampicillin-like macrocyclic nucleus 19 as a key intermediate. Intermediate 19 may have a variety of different Dab9 substituents as described herein. Intermediate 19 can be further reacted with a reactive group 22, producing the protected Dab9 derivative 28 which, following deprotection, produces the Dab9 derivative 30. This preferred route is advantageous since it does not require separate protection from the μ-amino group Dac9 macrocyclic and provides Dab9 30 derivatives in fewer global stages. In general, the fatty acid portion of the protected amphiphilic lipopeptide antibiotic (or mixture of antibiotics) 18 or protected Dab9 derivative (or mixture of derivatives) 14 can be cleaved with an enzyme. The enzyme may be, for example, a degrading enzyme, such as a peptidase, esterase or thionase, of which numerous examples exist in the art. Preferably, the enzyme is a deacylase. In an exemplary embodiment, the step of cleavage involves culturing a microorganism that produces a deacylase in an appropriate culture medium and contacting the protected Dab9 derivative (or mixture of derivatives) 14 or protected antibiotic (or mixture of antibiotics) 18 with the culture medium containing deacylase. Microorganisms that produce deacylases are well known to those of ordinary skill in the art. In a preferred embodiment, the microorganism Actinoplanes utahensis (NRRL No. 12052) produces an appropriate deacylase. Inoculations of culture, means of inoculation, culture media and conditions for cultivating such enzymes are well known to those of ordinary skill in the art and exemplary methods for Actinoplanes utahensis (NRRL No. 12052) are described in Boeck et al. , 1988, ".

Antibiot. 41: 1085; Debono et al. , 1988, J. Antibiotics 41: 1093; U.S. Patent No. 4,524,135 (see, e.g., columns 22-23) and U.S. Patent No. 5,039,789 (see, e.g., column 29, lines 9-63). In one embodiment, compounds 14 or 18 are delipidated upon contact with a culture medium comprising Actinoplanes utahensis (NRRL No. 12052) for about 4 to 16 hours at a temperature of about 29 ° C. The reaction can be verified by chromatography or other routine techniques, thereby allowing shorter or longer incubations, as necessary. Additional methods that can be used to delipidate compounds 14 or 18 are found in Debono et al. , 1988 ,. Antibiotics 41: 1093, U.S. Patent No. 5,039,789 (see, for example, columns 29-34) and U.S. Patent No. 5,629,288, while Reaction Scheme (I) illustrates certain Dab9 derivatives in which the substituent Re is attached to the macrocyclic Dab9 residue via an amide linkage, those skilled in the art will recognize that Dab9 derivatives that include other linkages can be synthesized by routine modification of the illustrated Reaction Schemes, and, in some instances, the substituent R3 may include additional functionalities that require protection The identity of the protecting group will depend, among other things, on the functionality that is protected and other protecting groups present in the molecule and will be apparent to those of ordinary skill in the art. in Greene and Wuts, supra. While Reaction Scheme (I) illustrates certain Dab9 derivatives of the invention in which the substituent R2 or R2-L is attached to the N-terminus via an amide bond, those of ordinary skill in the art will recognize that derivatives which include other links can be synthesized by routine modification of the illustrated Reaction Schemes. In addition, in some instances, the substituent R2 or R2-L may include additional functionalities that require protection. The identity of the protecting group will depend, among other things, on the functionality that is protected and other protecting groups present in the molecule and will be apparent to those of ordinary skill in the art. Guides can be found in Greene and Wuts, supra. The compounds derived from the invention can be isolated and purified using standard techniques, such as high performance liquid chromatography, countercurrent extraction, centrifugation, filtration, precipitation, ion exchange chromatography, gel electrophoresis, affinity chromatography, flash chromatography, etc. . Specific methods of isolation are provided in the Examples section below. Any of the various original antibiotics, cyclic core compounds, intermediates or antibiotic compounds derived from the invention can also be isolated and purified using the extraction purification methods described in WO 02/055537, which is incorporated herein by reference. For example, purification by HPLC can be carried out in a Perfusion Chromatography® Sprint ™ system from BioCAD® using a Waters Symmetry-Prep C18 column or C8 column (7μm, 19 x 50mm) for most of the methods used. for preparing the lipopeptide antibiotic compounds derived from the invention. In addition, purity analysis can be carried out using a Spherisorb® S3 column (ODS2, 2.0 x 100 mm) in a Waters 2695 separation system with a photodiode detector 996 (Waters, Milford, M?). For example, a linear gradient elution of 40% to 80% acetonitrile in Milli-Q® water can be used at 0.25 ml / minute (each eluent contains 0.1% trifluoroacetic acid) for 15 minutes at a column temperature of 40 ° C and the data can be processed, for example with the programming elements Millennium32 ™ Chromatography Manager V4 (Waters, Milford, MA). Those of ordinary skill in the art will appreciate that many of the compounds derived from the invention as well as the various composite species described herein, may exhibit the phenomena of tautomerism, conformational isomerism, geometric isomerism or optical isomerism. Since the drawings of formulas in the specification and claims may represent only one of the possible tautomeric, isomeric, isomeric optical or isomeric geometrical forms, it is to be understood that the invention encompasses any tautomeric, isomeric, isomeric, optical or geometric isomeric forms of compounds having one or more of the utilities described herein, also as mixtures of these various different forms. In addition, although the exact optical configurations of the chiral centers of the various macrocyclic ampicillin-like nuclei illustrated are not specified, it will be understood that the structural illustrations are intended to be a brief way of describing these nuclei and are not intended to be limiting. It will be understood that the specific optical configurations are those possessed by the macrocyclic nuclei of amphotericin-like lipopeptide antibiotics, whether known or unknown. Also, as these structures of the peptide macrocycles comprising the various amphiphiline-like lipopeptide antibiotics of which it is believed that the derivative lipopeptide derivatives of the invention are correct, in some instances at a later date, errors may be revealed. Again, structural illustrations claim to be a short way to describe the various compounds and do not claim to be limiting. It should be understood that, in the compounds derived from the disclosure, the structures of the peptide macrocycles are those possessed by the original amphiphilic lipopeptide antibiotics of which the specific derivatives are derivatives.

CHARACTERIZATION OF LIPOPEPTIDE DERIVATIVES The lipopeptide derivatives of the invention generally exhibit antimicrobial activity against Gram-positive bacteria which is similar to that exhibited by conventional amphiphilic lipopeptide antibiotics, as measured in in vitro and in vivo assays. In addition, many of the lipopeptide derivatives of the disclosure exhibit surprisingly improved therapeutic potential (such as reduced toxicity, improved spectrum of activity and improved pharmacokinetic / pharmacodynamic properties) compared to conventional amphiphilic lipopeptide-type antibiotics, making the amino terminal or Dab9 derivatives particularly suitable for therapeutic use (eg, for systemic administration) or for favorable dosage regimens to combat infections caused for example by Gram-positive bacteria 8 for example, Staphylococcus spp. , Streptococcus spp. , Enterococcus spp. ). Anti-microbial lipopeptide compounds of the disclosure can be identified as active by using for example in vitro screening assays known in the art, such as standard NCCLC bacterial inhibition assays or minimum inhibitory concentration (MIC) tests. See, for example, National Committee on Clinical Laboratory Standards "Performance Standards for Antimicrobial Susceptibility Testing," NCCLS Document M100-S5 Vol. 14, No. 16, December 1994; "Methods for dilution antimicrobial susceptibility test for bacteria that grow aerobically-Third Edition," Approved Standard M7-A3, National Committee for Clinical Standards, Villanova, PA ("approved Standard M7-A3"). The antimicrobial compounds are considered active when they exhibit a MIC of less than about 64 μg / ml. In certain preferred embodiments, the compounds have a MIC of less than about 64 μg / ml, less than about 32 μg / ml, less than about 16 μg / ml or less than about 4 μg / ml against microorganisms such as bacteria (particularly bacteria Gram positive). In certain embodiments, antimicrobial lipopeptide compounds that exhibit low toxicity or significant antimicrobial activity (e.g., less than 4 μg / ml or less than 16 μg / ml) may be preferred for use in the treatment or prevention of systemic infections, which include against microorganisms resistant to antibiotics. In other embodiments, the antimicrobial lipopeptide compounds of the disclosure may be preferred for use in the treatment or prevention of topical infections (e.g., skin infections). Specific in vitro and in vivo assays suitable for demonstrating antimicrobial activity pertinent to a particular route of administration are provided in the Examples. An exemplary pharmacokinetic parameter to aid in the characterization of the properties of the lipopeptide-derived compounds of the disclosure is the post-antibiotic effect (PAE) of a lipopeptide derivative. For example, a bacterial culture with an initial count of 106 to 107 colony-forming units / milliliter (CFU / ml) is treated with a certain concentration of lipopeptide derivatives for a certain time and a parallel culture (control) is left without try. After treatment, the lipopeptide derivative is separated from the culture (eg, by 1: 1,000 dilution in fresh, free lipopeptide derivative-free medium) and the untreated culture is manipulated in the same manner. Then, the cultures are incubated additionally and checked for bacterial growth over time. Hence, a PAE can be defined as the time (which can be measured in minutes or hours) required for a culture treated with lipopeptide derivatives to increase the number of CFUs per 1 log10 compared to an untreated control. By way of background and not wishing to be bound by theory, a lipopeptide derivative having a measurable PAE activity will likely provide additional time for the host immune system to separate the bacteria that might have survived the antibiotic treatment and reproduced after the antibiotic is degraded, separated or filtered from the circulatory system. A longer PAE may influence the clinical outcome of the antimicrobial therapy (ie, a lower dose of a lipopeptide derivative may be used to treat an infection or the frequency of a dosage regimen may be reduced). Another measure of the antimicrobial properties of the lipopeptide-derived compounds of this disclosure includes measurements of the killing curve. The extermination curve experiments involve in general exposure of the microorganisms to varying concentrations (e.g., multiples of the MIC of the compound) of a test compound. The microorganisms may be in a logarithmic growth phase culture or they may be in a particular host tissue (e.g., lung) for up to 24 hours prior to exposure to a test compound. At selected points in time, a sample of each culture or tissue can be analyzed for a titer of viable microorganisms, which is generally calibrated against the time required for a compound to inhibit growth or kill the bacteria. It is well established in the microbiological technique that a compound is bactericidal if the compound kills 99.9% of bacterial cells within 24 hours (see, for example, reference NCCLS M26-A, Vol. 19 N No. 18). A variety of in vivo models can be used to determine the antimicrobial properties of lipopeptide-derived compounds of this disclosure. For example, the antimicrobial compounds of the present disclosure can be tested for efficacy by measuring the ability of a compound to protect a mouse against a microbial infection, such as an infection or disease caused by or related to Gram-positive bacteria, in those that include Staphylococcus aureus, Streptococcus pneumoniae and Enterococcus faecalis. Briefly, the mice are individually infected (e.g., intraperitoneally (i.p.)) with a bacterial inoculum of generally more than one LD50 dose. (50% lethal dose, for example 2-3 LD50). An LD50 is the dose of bacteria required to kill 50% of an infected population, such as mice. A certain period after infection, the mice are then treated individually, for example intravenously (i.v.) with a lipopeptide derivative of this disclosure. The mice are then checked for a certain period of time (eg, a few days to one or more weeks) to see if the lipopeptide derivatives tested were able to protect the mice from a fatal systemic infection or capable of protecting against the appearance of other symptoms of infection. Other exemplary in vivo models of infection that can be used to determine, for example, the efficacy of an antimicrobial lipopeptide of the present disclosure include the following: (A) a mouse (murine) model of lung infection (pneumonia) wherein the Bacterial infection is administered intranasally (in); (B) a murine thigh muscle model wherein the bacterial infection is administered intramuscularly (im) in normal or neutropenic (immunocompromised) mice and (C) a murine thigh muscle model infection (im infection) / lung (in) In general, an ED50 (50% effective dose) for each lipopeptide derivative of the invention is measured. As used herein, an ED50 may mean an effective dose to (a) protect 50% of infected animals (e.g., as in ip models and pneumonia) or (b) produce 50% maximum logarithmic reduction at 24 hours post-treatment (for example, as in muscle, thigh and lung tissue models). In certain embodiments, the ED50 values may range from about 0.1 mg / Kg to about 50 mg / Kg or from about 0.15 mg / Kg to about 30 mg / Kg, or from about 0.2 mg / Kg to about 15 mg / Kg or from about 0.25 mg / Kg to about 410 mg / Kg. Still other exemplary in vivo models can be used to characterize the pharmacokinetic and pharmacodynamic parameters of antimicrobial compounds of this disclosure. Some parameters that can be measured include an in vivo half-life of a compound, elimination and clearance ratio, volume of distribution and • bioavailability. For example, briefly, the compounds can be administered as a single i.v. or oral (p.o.) in mice or rats. At various points in time (ranging from one minute to 72 hours), the blood of treated animals is collected and the concentration of the lipopeptide derivative in the ex vivo plasma can be quantified for example by liquid chromatography with mass spectrometric detection. After quantification, the pharmacokinetic parameters can be calculated using methods known in the art, such as a compartment model with mono-exponential decay and linear regression analysis (see, for example, Fantin et al., Antimicrob Agents Chemotherap. : 1413, 1991).

FORMULATIONS AND COMPOSITIONS Pharmaceutical compositions comprising the antimicrobial lipopeptide derivatives of the disclosure can be manufactured by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. The pharmaceutical compositions can be formulated in a conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries that facilitate the formulation of active antimicrobial lipopeptide derivatives in preparations that can be used pharmaceutically. A single antimicrobial lipopeptide derivative, a plurality of antimicrobial lipopeptide derivatives or antimicrobial lipopeptide derivatives combined with one or more industrially or biologically active agents can be formulated with a pharmaceutically acceptable carrier, diluent or excipient to generate industrial and pharmaceutical compositions respectively, of the present revelation. Pharmaceutically acceptable carriers, diluents or excipients for therapeutic use are well known in the pharmaceutical art and are described herein and for example in Remington's Pharmaceutical Sciences, Mack Publishing Co. (AR Gennaro ed., 18th edition, 1990) and in CRC Handbook of Food, Drug, and Cosmetic Excipient, CRC Press LLC (SC Smolinski, ed., 1992). In certain embodiments, the antimicrobial lipopeptide derivatives can be formulated with a pharmaceutically or physiologically acceptable carrier, diluent or excipient is aqueous, such as water or a solution of mannitol (eg, about 1% to about 20%), hydrophobic (eg, example, oil or lipid) or a combination thereof (eg, emulsions, oils and water). In certain embodiments, any of the pharmaceutical compositions described herein may be sterile. The formulations of the present invention, which have an amount of antimicrobial lipopeptide sufficient to treat or prevent an infection are for example particularly suitable for topical application or administration (e.g., creams, ointments, skin patches, eye drops, drops for the ears, shampoos). Other routes of administration include, without limitation, oral, parenteral, sublingual, bladder, vaginal, rectal, enteric, suppository, nasal or inhalation. The term "parenteral," as used herein, includes subcutaneous, intravenous, intramuscular, intraarterial, intraabdominal, intraperitoneal, intraarticular, infraocular or retrobulbar, intraaural, intrathecal, intracavitary, intracelial, intraspinal, intrapulmonary or transpulmonary, intrasynovial and intraurethral injection or techniques. of infusion). The pharmaceutical compositions of the present disclosure are formulated to allow the antimicrobial lipopeptide (s) contained therein to be bioavailable after administration of the composition to a subject. The level of lipopeptide in serum and other tissues after administration can be verified by several well-established techniques, such as bacterial, chromatographic or antibody-based analysis (e.g., ELISA). In certain embodiments, antimicrobial lipopeptide derivatives, as described herein, are formulated for topical application to a target site on a subject in need thereof, such as an animal or human. In other embodiments, the antimicrobial lipopeptide derivatives are formulated for parenteral administration to a subject in need thereof (eg, having Gram-positive bacterial infection) such as an animal or human. The appropriate formulation is dependent on the chosen route of administration, as is known in the art. For example, in exemplary embodiments for topical administration, the antimicrobial lipopeptide derivatives of the disclosure can be formulated as solutions, gels, ointments, creams, suspensions, pastes and the like. Systemic formulations are another modality, including those designed for administration by injection, for example subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal, oral, intranasal or pulmonary administration. In one embodiment, the systemic formulation is sterile. In embodiments for injection, the antimicrobial lipopeptide derivatives of the present disclosure can be formulated in aqueous solutions, preferably in physiologically compatible solutions or pH regulating solutions such as Hanks' solution, Ringer's solution, mannitol solutions or saline buffer. . In certain embodiments, any of the compositions described herein may contain formulatory agents, such as suspending agents, stabilizing or dispersing agents. Alternatively, the antimicrobial lipopeptide derivatives may be in solid form (e.g., powder) for constitution with an appropriate vehicle (e.g., sterile pyrogen-free water) before use. In embodiments for transmucosal administration, penetrants, solubilizers or emollients appropriate to the barrier to be penetrated can be used in the formulation. For example, l-dodecylhexayl-2H-azepin-2-one (Axone®), oleic acid, propylene glycol, menthol, diethylene glycol, ethoxy glycol monomethyl ether (Transcutol®), polyethylene sorbitan polysorbate monolaurate (Tween®-20) and the drug 7-chloro-l-methyl-5-phenyl-3H-l , 4-benzodiazepin-2-one (Diazepam), isopropyl myristate and other such penetrating, solubilizing or emollient agents generally known in the art can be used in any of the compositions of the present disclosure. In other embodiments, the antimicrobial lipopeptide derivatives can be formulated with pharmaceutically acceptable carriers in the form of tablets, pills, dragees, capsules, liquids, gels, syrups, suspensions, pastes and the like for oral ingestion by a subject or patient to be treaty. In certain embodiments for oral solid formulations, such as powders, capsules or tablets, suitable excipients include fillers, such as sugar (e.g., lactose, sucrose, mannitol, sorbitol); cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose or polyvinyl pyrrolidone (PVP); granulating agents or binding agents. Optionally, disintegrating agents can be added, such as cross-linked polyvinylpyrrolidone, agar or alginic acid (or a salt thereof), such as sodium alginate). If desired, the solid dosage forms can be sugar coated or enteric coated using standard techniques. In some embodiments for oral liquid preparations such as suspensions, elixirs or suitable solutions, carriers, excipients or diluents include water, glycols, oils, alcohols or combinations thereof. Additionally, flavoring agents, preservatives, viscosity-increasing agents, humectants, coloring agents or the like can be added. In embodiments for buccal administration, the compositions may take the form of, for example, tablets or troches, formulated as is known in the art and described herein. In embodiments for administration by inhalation, compounds for use in accordance with the present disclosure can be formulated for convenient administration in the form of drops for intranasal administration or in the form of an aerosolized spray of pressurized packets or nebulizer having an appropriate propellant, ( for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). In certain embodiments, the drops or aerosol composition are sterile. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of for example, gelatin for use in an inhaler or insufflator can be formulated containing a powder mixture of the compound and a suitable powder base, such as lactose or starch. In embodiments, the antimicrobial lipopeptide derivatives can be formulated in rectal or vaginal compositions such as suppositories or retention enemas, for example containing conventional suppository bases, such as cocoa butter or other glycerides.

In addition to the formulations described herein, the antimicrobial lipopeptide derivatives can also be formulated as a depot preparation. For example, the antimicrobial lipopeptide derivatives of this preparation may be in the form of a slow release formulation, such that they may provide activity over time. Such long-acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. In certain embodiments, the compounds can be formulated with an appropriate polymer (in which poly (lactides) are included, poly (glycolides), poly (caprolactones) and combinations thereof), a hydrophobic material (in which a physiologically acceptable oil is included, which may be in the form of an emulsion), an ion exchange resin or as sparingly derived soluble (such as sparingly soluble salt). Alternatively, other pharmaceutical administration systems may be employed. In certain embodiments, the compounds are formulated with liposomes or emulsions as delivery vehicles. Certain organic solvents, such as dimethylsulfoxide (DMSO) can also be used. Additionally, the antimicrobial lipopeptide derivatives can be administered using a sustained release system, such as semipermeable matrices of solid or semi-solid polymers (eg, thermopastes) containing the therapeutic agent. Sustained-release capsules, depending on their chemical nature, release the compounds for a few days, for a few weeks or for up to about 100 days. Since certain of the carboxyl groups of the antimicrobial lipopeptide derivatives of the invention are acids or the substituents R 2, R 3 R 4 and L linkers can include acidic or basic substituents, the antimicrobial lipopeptide derivatives can be included in any of the formulations described above. as free acid, a free base or as a pharmaceutically acceptable salt. Pharmaceutically acceptable salts are those salts which substantially retain the antimicrobial activity of the free acid or base and which are prepared by reaction with a base or acid, respectively. Suitable acids and bases are well known to those of ordinary skill in the art. Pharmaceutical salts tend to be more soluble in aqueous solutes and other protic solvents than their corresponding in the form of a base or free acid. The lipopeptide compositions can be administered to a subject as a single dosage unit (e.g., a tablet, capsule, injection or gel) or the compositions can be administered as a plurality of dosage units (e.g., in aerosol form). or injectable form). For example, antimicrobial lipopeptide formulations can be sterilized and packaged in single-use plastic laminated sacks or plastic tubes of selected dimensions to provide routine, tailored administration. In one example, the container may have anticipated dimensions for delivering 0.5 ml of the antimicrobial lipopeptide composition (e.g., a drop, gel or injection form) to a subject or a limited area of a target surface on or in a subject, to treat or prevent an infection. A target surface, for example, may be in the immediate vicinity of an infection in the skin (eg, necrotizing fasciitis or other complicated skin infection), wherein the target surface area will depend on the extent of the infection. The antimicrobial lipopeptide compositions can be provided in various forms, depending on the number and number of different pharmaceutically acceptable excipients present. For example, the lipopeptide compositions may be in the form of a solid, semi-solid, liquid, lotion, cream, ointment, cement, paste, gel or aerosol. In a preferred embodiment, the lipopeptide formulation is in the form of a liquid or gel. Suitable pharmaceutically acceptable excipients for use in the lipopeptide formulation compositions as described herein may optionally include, for example, a viscosity-increasing agent, a pH regulating agent, a solvent, a humectant, a preservative, a chelating agent (e.g., EDTA or EGTA), an oleaginous compound, an emollient, an antioxidant, an adjuvant or the like. Suitable pH regulating agents for use with the antimicrobial lipopeptide derivatives or compositions thereof of the present disclosure include monocarboxylate or dicarboxylate compounds (such as acetate, fumarate, lactate, malonate, succinate or tartrate). Exemplary preservatives include benzoic acid, benzyl alcohol, phenoxyethanol, methylparaben, propylparaben, and the like. The function of each of these excipients is not mutually exclusive in the context of the present invention. For example, glycerin can be used as a solvent or as a humectant or as an agent that increases viscosity.

INDUSTRIAL AND THERAPEUTIC USES The antimicrobial lipopeptide derivatives of the invention can be used in a wide variety of applications to inhibit the growth of or to kill microorganisms (eg, Gram-positive bacteria). For example, antimicrobial lipopeptide derivatives can be used as disinfectants or as preservatives for a variety of materials, which include food products, cosmetics, medications or other materials containing nutrients. The antimicrobial lipopeptide derivatives can also be used to treat or prevent diseases related to, associated with or caused by microbial infections in a subject, such as a human, plant or animal and preferably a human (in which immunocompromised or immune subjects are included). immunocompetent). For example, the antimicrobial lipopeptide derivatives of this disclosure are useful for alleviating, treating or preventing various clinical conditions, such as complicated infections of the skin or in the structure of the skin (eg, necrotizing fasciitis), surgical wound infections, intra-abdominal infections, infections of the urinary system or pyelonephritis, nosocomial infections, community-acquired infections (for example, pneumonia), infective endocarditis or the like. In certain embodiments, the active antimicrobial compounds of the present disclosure will be active against Gram-positive bacteria, such as Streptococci (in which S. pyogenes, S. pneumoniae, Streptococci iridans are included), Staphylococci (in which S. aureus, S. epidermidis, coagulase-negative Staphylococci) and Enterococci (in which E. faecalis, E. faecium are included), as well as antibiotic-resistant microorganisms, such as methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus epidermitis resistant to methicillin (MRSE), vancomycin-resistant Enterococci (VRE), vancomycin intermediary S. aureus (VISA), penicillin-resistant Streptococcus pneumoniae (PRSP), penicillin-mediated S. pneumoniae (PISP) or multi-drug resistant microorganisms ( MDR). Some other exemplary Gram-positive microorganisms against which the microbial compounds of the present disclosure will be active include Bacillus spp. , Corynebacterium spp. , dipteroids, Listeria spp. , or the like. For industrial use as a disinfectant or preservative, the antimicrobial lipopeptide derivatives may be added to a desired composition alone, as a mixture of the same or different antimicrobial lipopeptide derivatives or in combination with other antimicrobial agents (eg, antifungal, antiviral, antibacterial) . The antimicrobial lipopeptide derivatives can be supplied as the compound per se or can be combined, mixed or mixed with a variety of pharmaceutically acceptable carriers, diluents or excipients, as described herein. When used therapeutically to treat or prevent microbial infections or diseases related thereto, the antimicrobial lipopeptide derivatives of the present disclosure may be administered or applied alone, as a priority (eg, two or more) of the same or different derivatives of lipopeptide antimicrobials, in combination with other antimicrobial agents or in combination with other pharmaceutically active agents. The antimicrobial lipopeptide derivatives can be administered or applied per se or as a pharmaceutical composition. The specific pharmaceutical formulation will depend on the mode of administration desired, as described herein and will be apparent to those of ordinary skill in the art. The therapeutic efficacy of an antimicrobial lipopeptide derivative or composition thereof according to the present disclosure is based on a successful clinical result and does not require 100% elimination of the microorganisms involved in or associated with the infection. Obtaining a level of antimicrobial activity, for example, in the site of infection that allows the survival of the host, resolution of the infection or eradication of the causative agent, is sufficient. When the host's defenses are maximally effective, as in an otherwise healthy individual, only a minimal antimicrobial effect can be sufficient. For example, reducing the burden of the organism by even one logarithm (a factor of 10) may allow the host's defenses to control the infection. In certain modalities, clinical therapeutic success may depend on increasing a premature bactericidal effect rather than a long-term effect because this allows time for the activation of host defense mechanisms. This may be desirable for example in acute life-threatening infections (e.g., necrotizing fasciitis) or serious chronic infections (e.g., infective endocarditis). The antimicrobial lipopeptide derivatives of the present disclosure or compositions thereof, may be used in an effective amount to obtain the desired purpose, which will depend on the particular application or indication. For example, for use as a disinfectant or preservative, an antimicrobially effective amount of an antimicrobial lipopeptide derivative or composition thereof is applied or added to the material to be disinfected or preserved. The term "antimicrobial effective amount" means an amount of an antimicrobial lipopeptide derivative or composition of the invention that inhibits the growth of or is fatal to a target microbe. While the actual amount will depend on the particular target microbe and application, for use as a disinfectant or preservative, the antimicrobial lipopeptide derivatives or compositions thereof, are usually added or applied to the material to be disinfected or preserved in relatively low amounts. Commonly, the antimicrobial lipopeptide derivatives comprise less than about 5% by weight of the disinfectant solution or material to be conserved, preferably less than about 1% by weight and more preferably less than about 0.1% by weight. Those of ordinary skill in the art will be able to determine antimicrobially effective amounts of particular antimicrobial lipopeptide derivatives for particular applications or indications without undue experimentation using for example the in vitro or in vivo assays described herein. As used herein, it is to be understood that the terms "inhibit" and "exterminate" refer to the administration of a desired composition or compound, in an amount or for a time sufficient to reduce, inhibit, attenuate, prevent, eradicate , exterminate or alter at least one aspect or marker of biological growth or survival in a statistically significant manner (ie, antimicrobially effective). Inhibition of bacterial growth or survival can be determined, for example, by measuring the number of bacterial colony forming units (CFU) before exposure to the antimicrobial lipopeptide derivative (s) compared to the number of bacterial CFUs after exposure to the antimicrobial lipopeptide derivative (s) (in vi tro or in vivo). For use in the treatment or prevention of microbial infections, the antimicrobial lipopeptide derivatives of the invention and compositions thereof are administered or applied in a therapeutically effective amount. As used herein, the term "therapeutically effective amount" means an amount effective to alleviate the symptoms of or alleviate, treat or prevent microbial infections. The determination of a therapeutically effective amount is within the capabilities of those of ordinary skill in the art as described herein. As in the case of disinfectants and preservatives, a therapeutically effective dose for topical administration for treating or preventing microbial infections can be determined using, for example, the in vitro or in vivo assays discussed herein. The treatment can be applied while the infection is visible or when the infection is not visible. As used herein, it is to be understood that the terms "treat", "prevent" and "alleviate" refer to the therapeutic administration of a desired composition or compound, in an amount or for a time sufficient to treat, inhibit, attenuate, alleviate, reduce, prevent or alter at least one framed aspect of a disease in a statistically significant manner (that is, it is therapeutically effective). The compositions and methods of the present invention would be therapeutically effective to treat or prevent complicated or uncomplicated infections of the skin or the structure of the skin. Complicated and uncomplicated specimen skin infections include impetigo, folliculitis, furunculosis (furuncle or skin rash), ecthyma, erysipelas, cellulitis, acute paronychia, felon, necrotizing fasciitis, staphylococal scalded skin infection, nodular lymphangitis, preceptal cellulitis or periorbital cellulitis. The lipopeptide formulations as described herein, may be applied topically as a cream, lotion, ointment or gel (or in any of these forms as part of or coated on a dressing) to the affected areas or as an injectable solution, emulsion , suspension, etc. The lipopeptide formulations can be administered multiple times during the day, once a day or at less frequent intervals (such as once a week or less) and the duration of treatment can be as long as the lesions are present or to prevent recurrent injuries. Alternatively, the lipopeptide composition can be formulated for oral or systemic administration to treat or prevent complicated infections of the skin or skin structure. In certain embodiments, antibiotic compounds and compositions thereof are provided for use in a method for treating or preventing a microbial infection, such as a complicated infection of the skin or skin structure, by administering to a subject in need thereof. an antibiotic compound or composition thereof in an amount effective to treat or prevent complicated skin infection. The compositions and methods of the present invention would be therapeutically effective in the treatment or prevention of complicated intra-abdominal infections. As a background, complicated intra-abdominal infections are problems in clinical practice and consume substantial hospital resources, such as emergency apartment services, imaging services, operating room time, laboratory services, antibiotic therapy and care in a hospital of variable intensity. The results are strongly influenced by the speed of diagnosis and appropriate intervention and by the opportunity and effectiveness of anti-infection therapy. Post-operative (nosocomial) infections are usually caused by more resistant flora, which may include Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus, Enterococci and Candida spp. For these infections, complex multidrug regimens are recommended because the empirical therapy used seems to be important to reduce mortality. However, these infections remain an important area for clinical research. In certain embodiments, the lipopeptide antibiotic compounds and compositions thereof of the present disclosure are provided for use in a method for treating or preventing a microbial infection, in which complicated intra-abdominal injections, such as those due to or associated with S. aureus. The compositions and methods of the present invention would be therapeutically effective in the treatment or prevention of complicated infections of the urinary system or pyelonephritis. As a background, complicated infections of the urinary system (cUTI) are defined as a clinical syndrome in men or women characterized by the development of systemic and local signs and symptoms of fever, chilliness, disease, flank pain and back pain, which occur in presence of functional or anatomical abnormality of the urinary system or in the presence of catheterization. Pyelonephritis is referred to as an ascending systemic urinary system infection, clinically manifested by fever, chilliness, flank pain, nausea, or vomiting, which are frequently associated with bacteremia due to the same pathogen as it is isolated in the urine. In many cases, cUTI and pyelonephritis are caused by pathogens of Enterobacteriaceae and other etiological agents that include Enterococci spp. and Pseudomonas spp. In certain embodiments, the lipopeptide antibiotic compounds and compositions thereof of the present disclosure are provided for use in a method for the treatment or prevention of a microbial infection, such as complicated infections of the? urinary system or pyelonephritis. As used herein, an infection that is "Complicated" refers to a disease condition in which a process or morbid event has been superimposed, altering the symptoms and course of infection for the worse - the "complication" is not an essential part of the disease or infection, although the complication It can arise from disease or infection or from independent causes. Another example of the therapeutic value of the compositions and methods of the present invention would be in the treatment of nosocomial infections. For example, S. aureus infection can result in impetigenic lesions or infected wounds and may be associated with increased rates of infection followed by cardiac surgery, hemodialysis, orthopedic surgery and neutropenia, both disease-induced and iatrogenic. The nasal and extranasal portability of Staphylococci spp. it can result in hospital breakthroughs of the same staphylococcal strain that a patient or a nasal passage of the hospital worker or extranasal site is populating. Much attention has been paid to the eradication of nasal colonization, but the treatment states have been generally unsatisfactory. The use of topical antimicrobial substances, such as bacitracin, tetracycline and chlorhexidine, results in the suppression of nasal colonization, as opposed to eradication. In certain embodiments, the antibiotic compounds and compositions thereof are provided for use in a method for treatment or prevention of nosocomial infections (such as nosocomial pneumonia), community-acquired pneumonia (that is, caused by an organism found regularly outside of a hospital facility, (such as Streptococcus pneumoniae, Hemophilus influenzae, Mycoplasma), infections due to drug-resistant bacteria (such as VRE and MRSA), endocarditis (acute subacute) and the like For systemic administration, a therapeutically effective dose it can be estimated initially from in vitro or in vivo analysis For example, a dose can be formulated in animal models to obtain a concentration range of the circulating antimicrobial lipopeptide derivative that includes the MIC as determined in cell culture. Initial checks can also be estimated from dat In vivo, for example, animal models, using techniques that are well known in the art. He who has ordinary skill in the art can easily optimize administration to humans based on animal data. Alternatively, the initial specifications can be determined from the dosages administered of known ampicillin-like lipopeptide antibiotics (e.g., ampomycin, aspartocin, crystallomycin, antibiotic A1437, friulimycin, glumamycin, tsushimycin, and zaomycin) by comparing the MIC of the lipopeptide derivative specific antimicrobial with that of the antimicrobial agent and adjust the initial dosages of compliance. The optimal dosage can be obtained from these initial values by routine optimization. The amount and range of dosage can be adjusted individually to provide levels in the plasma of one or more active antimicrobial lipopeptide derivatives that are sufficient to maintain a therapeutic effect. In general, dosages to the patient for administration by injection range from about 0.1 to about 200 mg / Kg / day and preferably range from about 1.5 to about 15 / Kg / day. In certain embodiments of the lipopeptide derivative, levels in therapeutically effective serum can be obtained by administering a single dose daily or by administering multiple doses each day in a specified period of time. In other embodiments, therapeutically effective serum levels may also be preferred by administering less frequent dosing schedules such as for example, once every two days, twice a week, once a week or at longer intervals between dosages or any combination thereof. For example, combination administration schedules can be used to obtain therapeutically effective doses, such as multiple doses one or more days in a row by less frequent dosing, such as for example once every two days, twice a week or once a the week or longer. In cases of local administration or selective absorption, the effective local concentration of the antimicrobial lipopeptide derivatives may not be related to the concentration in the plasma. Those of ordinary skill in the art will be able to optimize therapeutically effective local dosages without undue experimentation. The amount of antimicrobial lipopeptide derivative administered will be dependent, inter alia, on the subject being treated, the subject's weight, the severity of the infection, the manner of administration and the judgment of the prescribing physician.

Antimicrobial therapy can be repeated intermittently insofar as the infections are detectable or even when they are not detectable. The therapy may be provided alone or in combination with other drugs, such as for example, other antibiotics or antimicrobials or other antimicrobial lipopeptide derivatives of this disclosure. Preferably, a therapeutically effective dose of the antimicrobial lipopeptide derivatives described herein will provide therapeutic benefit without causing substantial toxicity. The toxicity of antimicrobial lipopeptide derivatives can be determined using conventional pharmaceutical procedures in cell cultures or experimental animals, for example when determining the LD50 (the fatal dose at 50% of the population) or the LDioo (the lethal dose at 100% of the population). the population) . Another measure of toxicity is the maximum tolerated dose (MTD), which is determined as a dose level that is not accompanied by mortality of life threatening toxicity. The dosage ratio between the toxic and therapeutic effect is the therapeutic index. Antimicrobial lipopeptide derivatives that exhibit high therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used in the formulation of a dosage range that is non-toxic for use in human subjects. The dosage of the antimicrobial lipopeptide derivatives described herein preferably lies in a range of circulating concentrations that include the effective dose with little or no toxicity. The dosage may vary within this range depending on the dosage form employed and the route of administration used. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition and need thereof (see, for example Fingí et al., 1975, In: The Pharmacological Basis of Therapeutics, Chapter 1). ). For example, to examine acute toxicity, the lipopeptide antibiotics of the invention can be tested in an animal model, such as Swiss CD1 mice, to determine BAT. In certain embodiments, the animals used to test the toxicity of a particular compound may be about 5-6 weeks of age at the start of the experiment and weigh 22-26 grams. The lipopeptides can be administered intravenously (iv) for example to the caudal tail vein at dose levels ranging from about 50 to about 500 mg / kg or from about 75 to about 250 mg / kg or from about 100 to about 200 mg / Kg or at a dose range of or less than 100 mg / Kg. Animals are generally observed immediately after administration, 1-2 hours post-administration, 5-8 hours post-administration and once a day after this. Observations include both the level of mouse activity as well as any physical side effects of the dose administered. The weight of the animal is recorded on day zero (immediately before dosing) and on day 7. The observed BAT for ampomycin and aspartocin was approximately 100 mg / kg. Thus, a lipopeptide derivative with a BAT greater than ampomycin and aspartocin (that is, a subject can tolerate more than one compound before having detectable or not yet detectable side effects) should be considered less toxic than ampomycin and aspartocin). In certain embodiments, the toxicity (MTD) of a lipopeptide compound of the present disclosure is at or less than 100 mg / Kg, while in other embodiments, the compounds have an MTD of or less than 200 mg / Kg. For example, certain exemplary lipopeptide antibiotic derivatives of the present disclosure show no acute toxicity (MTD) up to the range of 200-400 mg / Kg (i.v.) (for example, compounds 4, 199, 278 and 280). In certain other embodiments, the lipopeptide compounds of the present disclosure exhibit toxicity (MTD) in a range of about 50 mg / Kg to about 200 mg / Kg (i.v.) (e.g., compounds 3, 85, 108 and 119). All US patents, US patent application publications, US patent applications, foreign patents, foreign patent applications and non-patent publications referenced in this specification and / or listed in the data sheet of the application, are incorporated herein by reference in their entirety. Having described the invention, the following examples are proposed to illustrate and not limit the invention.

EXAMPLES The list of suppliers used to purchase the starting materials and reagents used in the methods described herein include Sigma Aldrich (and Fluka), (Oakville, Ontario), Advanced Chentech (Louisville, Kentucky), Bachem (Torrance, California) , Lancaster (Windham, New Hampshire), Chem-Impex International (Wooddale, Illinois), and Acros (Morris Plains, New Jersey).

EXAMPLE 1 PREPARATION OF AN ACTIVATED ACID As is known in the art, any of a variety of carboxylic acids can be activated in the following reaction or similar reaction by way of example and not limitation, the preparation of an activated succinimide ester is described. of pentadecanoic acid. Pentadecanoic acid (1.07 g, 4.4 mmol) was dissolved in 22 ml of anhydrous dimethylformamide (DMF). Hydroxysuccinimide (0.52 g, 4.5 mmol) is added and the mixture is cooled in an ice bath. Dicyclohexylcarbodiimide (1.07 g, 5.2 mmol) was added in two equal portions 10 minutes apart to the reaction mixture, after which the mixture was stirred for 20 minutes at about 4 ° C. The mixture is allowed to warm to room temperature and is stirred for not less than 6 hours. The resulting crude product was concentrated in vacuo, purified by resolution with isopropanol and then the product was crystallized with hexane to give succinimid-1-yl ester of pentadecanoic acid (1.32 g, 3.9 mmol). As indicated above and described herein, a variety of carboxylic acids can be used to generate an activated succinimide ester, such as G_.0-C.25 fatty acids.

EXAMPLE 2 COMPOSITE OF C15-ANFOMYCIN Anfomycin-9-Fmoc (2.0 g, 1.5 mimoimoles, 79% pure) was dissolved in 10 ml of H20 and then diluted with 100 ml of DMF. A 1M solution of sodium bicarbonate (7.5 ml) was slowly added to the mixture and then cooled in an ice bath. A pre-dissolved solution of the succinimid-1-yl ester of pentadecanoic acid (1.32 g, 3.9 mmol) of Example 1 in 15 ml of DMF was added slowly to the reaction mixture while still on ice, then the The reaction is stirred for at least 8 hours at room temperature. Piperidine (20 ml, 20% v / v) was added to the reaction and the mixture was stirred for an additional hour. All the solids were filtered, the insolubles were washed with additional DMF (approximately 15 ml) and then the filtrate was concentrated in vacuo until it was dry. Flash chromatography using a gradient system of methanol in ethyl acetate (40% net methanol, increased by 20%) provided the title compound (1.34 g, 67% yield): 75% pure, MS (MALDI) calculated for CSoH97N, 3020 (M) 1320, found 1320. Purification by HPLC (gradient, 5% acetonitrile in water with 0.1% trifluoroacetic acid to 95% acetonitrile for 30 minutes) is also applicable.

EXAMPLE 3 COMPOSITE OF C? 5-ANFOMICIN-9-GLY The compound C15-ampicillin (52 mg, 0.039 mmol) of Example 2 was suspended in 2.5 ml of DMF and then loaded with 197 μl of 1M sodium bicarbonate (in water). , 0.20 millimoles). The reaction mixture was cooled using an ice bath. A predisposed solution of N-tert-butoxycarbonylglycine activated by succinimide (15 equivalents prepared as described for the compound succinimid-1-yl ester of pentadecanoic acid in Example 1) in 0.5 ml of DMF was added slowly to the reaction mixture in While it was still on ice, then the reaction is allowed to stir for at least 8 hours at room temperature. After concentration in vacuo, the product was deprotected using 3 ml of 4M HCl in dioxane for 30 minutes under standard conditions and then the solvent was evaporated in vacuo to provide the title compound. The title compound was purified by HPLC (gradient, 25% acetonitrile in water with 0.1% trifluoroacetic acid at 95% acetonitrile for 30 minutes) and lyophilized (34 mg, 69% yield): 89% pure, MS ( MALDI) calculated for C62H? O0N? 402? (M) 1378, found 1377.

EXAMPLE 4 COMPOSITE OF C15-ANFOMYCIN-9-GLY-LYS The compound G__5-ampicillin (30 mg, 0.023 mmol) of Example 2 was suspended in 2 ml DMF and then loaded with 115 μL of 1M sodium bicarbonate (in water, 0.12). millimoles). The reaction mixture was cooled in an ice bath. A predisposed solution of N- (2-N-tert-butoxycarbonyl-6- (9H-fluoren-9-yl-methoxycarbonyl) lisinyl) glycine activated by succinimide (1.5 equivalents, prepared as described for the compound succinimid-1-yl) pentadecanoic acid ester in Example 1) in 0.5 ml of DMF was added slowly to the reaction mixture while it was still on ice, then the reaction is allowed to stir about 12 hours at room temperature. Piperidine (0.4 ml, 20% v / v) was added and the reaction was stirred for one hour and then concentrated in vacuo. The crude product was mixed with 2 ml of 4M HCl in dioxane for another hour and then concentrated in vacuo to provide the title compound, which was purified by HPLC. (gradient, 25% acetonitrile in water with 0.1% trifluoroacetic acid at 95% acetonitrile for 30 minutes) and lyophilized (14 mg, 41% yield): 80% pure, MS (MALDI) calculated for C68H ?? 2 6022, (M) 1506, found 1505.

EXAMPLE 5 COMPOSED OF C15-ANFOMICIN-9-LEU Compound C? 5-ampicillin (30 mg, 0.023 mmol) of the Example was suspended in 2 ml DMF and then loaded with 114 μL of 1M sodium bicarbonate (in water, 0.11 mmol).

The reaction mixture was cooled in an ice bath. A predisposed solution of succinimide-activated 2-N- (9H-fluoren-9-yl-methoxycarbonyl) leucine (1.5 equivalents, prepared as described for the compound pentadecanoic succinimid-1-yl ester in Example 1) at 0.5 ml of DMF was slowly added to the reaction mixture while still on ice, then the reaction is allowed to stir for about 8 hours at room temperature. Piperidine (400 ml, 20% v / v) is added, an additional hour is stirred and then the reaction mixture was evaporated in vacuo to give the title compound. The title compound was purified by HPLC (gradient, 25% acetonitrile in water with 0.1% trifluoroacetic acid at 95% acetonitrile for 30 minutes) and lyophilized (5 mg, 15% yield): 74% pure MS (MALDI ) calculated for C66H? o8? 4021 (M) 1434, found 1433.

EXAMPLE 6 COMPOSITE OF C? 0-ANFOMYCIN Anfomycin-9-Fmoc (20 mg, 0.015 mmol) and decanoic acid used in the method described in Example 2 provide the title compound, which was purified by HPLC and lyophilized (9 mg, 48% yield): 89% pure, MS (MALDI) calculated for C5SH87N? 3020 (M) 1250, found 1249.

EXAMPLE 7 COMPOSITE OF Cn-ANFOMYCIN Anfomycin-9-Fmoc (20 mg, 0.015 mmol) and undecanoic acid used in the method described in Example 2 provide the title compound, which was purified by HPLC and lyophilized (2 mg, 10 mg). % yield) 88% pure, MS (MALDI) calculated for C56H89N? 302o (M) 1264, found 1263.

EXAMPLE 8 COMPOSITE OF C12-ANFOMYCIN Anfomycin-9-Fmoc (20 mg, 0.015 mmol) and dodecanoic acid used in the method described in Example 2 provide the title compound, which was purified by HPLC and lyophilized (3 mg, 15 mg). % yield): 87% pure, MS (MALDI) calculated for C57H9? N_302o (M) 1278, found 1277.

EXAMPLE 9 COMPOSITE OF C? 3-ANFOMYCIN Anfomycin-9-Fmoc (20 mg, 0.015 mmol) and tridecanoic acid used in the method described in Example 2 provide the title compound, which was' purified by HPLC and lyophilized (8). mg, 41% yield) 80% pure, MS (MALDI) calculated for C58H93N1302o (M) 1292, found 1291.

EXAMPLE 10 COMPOSITE OF C14-ANFOMYCIN Anfomycin-9-Fmoc (20 mg, 0.015 mmol) and tetradecanoic acid used in the method described in Example 2 provide the title compound, which was purified by HPLC and lyophilized (7 mg, % yield) 95% pure, MS (MALDI) calculated for C59H95 i3? 2o (M) 1306, found 1305.

EXAMPLE 11 COMPOSITE OF C16-AMPHOMYCIN Anfomycin-9-Fmoc (20 mg, 0.015 mmol) and hexadecanoic acid used in the method described in Example 2 provide the title compound, which was purified by HPLC and lyophilized (11 mg, 54 % yield) 96% pure, MS (MALDI) calculated for CS? H99 130_.o (M) 1335, found 1334.

EXAMPLE 12 COMPOSITE OF C17-ANFOMYCIN Anfomycin-9-Fmoc (20 mg, 0.015 mmol) and heptadecanoic acid used in the method described in Example 2 provide the title compound, which was purified by HPLC and lyophilized (10 mg, 49 mg). % yield) 94% pure, MS (MALDI) calculated for C62H? or? N1302o i (M) 1349, found 1348.

EXAMPLE 13 COMPOSITE OF C? 8-ANFOMYCIN Anfomycin-9-Fmoc (20 mg, 0.015 mmol) and octadecanoic acid used in the method described in Example 2 provide the title compound, which was purified by HPLC and lyophilized (5 mg , 24% yield) 92% pure, MS (MALDI) calculated for Cs3H? O3? 3020 (M) 1363, found 1362.

EXAMPLE 14 COMPOUND OF OLEOYL-ANFOMYCIN Anfomycin-9-Fmoc (18.5 mg, 0.014 mmol) and octadec-9-anoic acid used in the method described in Example 2 provide the title compound, which was purified by HPLC and lyophilized (12 mg, 63% yield) 98% pure, MS (MALDI) calculated for CS3H? Or? 1302o (M) 1361, found 1360.

EXAMPLE 15 COMPOSED OF CH3- (CH2) nOp-PH-C (= 0) -ANFOMYCIN Anfomycin-9-Fmoc (30 mg, 0.022 mmol) and 4-dodecyloxy-benzoic acid used in the method described in Example 2 provide the compound of the title, which was purified by HPLC and lyophilized (5 mg, 16% yield) 92% pure, MS (MALDI) calculated for C6_H97N? 3021 (M) 1385, found 1384.

EXAMPLE 16 COMPOSITE OF CH3- (CH2)? 5-0-p-PH-C (= 0) -ANFOMYCIN Anfomycin-9-Fmoc (30 mg, 0.022 mmol) and parahexadecanoxobenzoic acid used in the method described in Example 2 provide the title compound, which was purified by HPLC and lyophilized (4 mg, 12% yield) 70% pure, MS (MALDI) calculated for C6sH? o5N? 3021 (M) 1441, found 1440.

EXAMPLE 17 COMPOSITE OF HO- (CH2)? 5-C (= 0) -ANFOMYCIN Anfomycin-9-Fmoc (30 mg, 0.023 mmol) and 16-hydroxy-hexadecanoic acid used in the method described in Example 2 provide the compound of the titer, which was purified by HPLC and lyophilized (8 mg, 26% yield) 85% pure, MS (MALDI) calculated for C6? H99? 302? (M) 1351, found 1351.

EXAMPLE 18 COMPOSITE CH3- (CH2) 9-Qp-PH-C (= 0) -ANFOMYCIN Anfomycin-9-Fmoc (30 mg, 0.023 mmol) and para-decanoxobenzoic acid used in the method described in Example 2 provide the compound of the title, which was purified by HPLC and lyophilized (8 mg, 26% yield) 92% pure, MS (MALDI) calculated for C62H93N? 302? (M) 1356, found 1355.

EXAMPLE 19 COMPOSED OF CH3- (CH2) 7-0-p-PH-C (= 0) -ANFOMYCIN Anphomycin-9-Fmoc (30 mg, 0.023 mmol) and para-octyloxybenzoic acid used in the method described in Example 2 provide the title compound, which was purified by HPLC and lyophilized (8 mg, 27% yield) 85% pure, MS (MALDI) calculated for CS0H89N? 3O2? (M) 1328, found 1327.

EXAMPLE 20 COMPOSED OF CH3- (CH2) __NH-SUCCINYL-ANFOMYCIN Anfomycin-9-Fmoc (30 mg, 0.023 mmol) and acid N-dodecyl-succinamic used in the method described in Example 2 provide the title compound, which was purified by HPLC and lyophilized (8 mg, 26% yield) 83% pure, MS (MALDI) calculated for C6? H98? 402? (M) 1364, found 1363.

EXAMPLE 21 COMPOSITE OF C12-p-HYDRAZINOBENZOIC ANFOMYCIN ACID Anphomycin-9-Fmoc (30 mg, 0.023 mmol) and acid (N '-tridecanoyl hydrazino) -benzoic acid used in the method described in Example 2 provide the title compound, which was purified by HPLC and lyophilized (4 mg, 12% yield) 70% pure, MS (MALDI) calculated for C65H99? 502? (M) 1427, found 1426.

EXAMPLE 22 COMPOSITE OF C? 5-ANFOMICIN-9-GABA The c_.s-ampomycin compound of Example 2 (26 mg, 0.020 mmol) and (S) -2,4-Jis-tert-butoxycarbonyl-aminobutyric acid used in the method described in Example 3 provides the title compound, which was purified by HPLC and lyophilized (11 mg, 40% yield): 85% pure, MS (MALDI) calculated for CS104N? 4O21 (M) 1406, found 1405 EXAMPLE 23 COMPOSED OF C14-ANFOMICIN-9-GLY The C_4-ampicillin compound of Example 10 (20 mg, 0.015 mmol) and the N-tert-butoxycarbonylglycine acid used in the method described in Example 3 provide the title compound, which was purified by HPLC and lyophilized (2 mg, 10% yield) 87% pure, MS (MALDI) calculated for C6? H98N? 402? (M) 1364, found 1365.

EXAMPLE 24 COMPOSITE OF C15-ANFOMYCIN-9-SAR The compound of C_5-ampicillin of Example 2 (40 mg, 0.030 mmol) and the N-tert-butoxycarbonyl-N-methylglycine acid used in the method described in Example 3 provide the compound of the title, which was purified by HPLC and lyophilized (24 mg, 57% yield) 100% pure, MS (MALDI) calculated for C63H? 02N? 4O2? (M) 1392, found 1391.

EXAMPLE 25 COMPOSED OF C15-ANFOMICIN-9-AHX The compound of C_5-ampicillin of Example 2 (40 mg, 0.030 mmol) and the 6-tert-butoxycarbonylaminohexanoic acid used in the method described in Example 3 provide the title compound, which was purified by HPLC and lyophilized (25 mg, 58% yield) 92% pure, MS (MALDI) calculated for C __. H? 08N? O2? (M) 1434, found 1433.

EXAMPLE 26 COMPOSED OF C? 5-ANFOMICIN-9-INA The compound of C15-ampicillin of Example 2 (45 mg, 0. 034 mmol) and the N-tert-butoxycarbonylisonipecotic acid used in the method described in Example 3 provide the title compound, which was purified by HPLC and lyophilized (11 mg, 23% yield) 89% pure, MS (MALDI) calculated for C66H? O6N_.402? (M) 1432, found 1431.

EXAMPLE 27 COMPOSITE OF C? 5-ANF0MICIN-9 (p-NQ2-PE) The compound of C_5-ampicillin of Example 2 (30 mg, 0.023 mmol) and N-tert-butoxycarbonyl-para-nitro-phenylalanine used in the method described in Example 3 provides the title compound, which was purified by HPLC and lyophilized (9 mg, 26% yield) 87% pure, MS (MALDI) calculated for C69H105N? 5O23 (M) 1513, found 1515 .

EXAMPLE 28 COMPOSED OF C15-ANFOMICIN-9-GLY-PHE The compound of C? 5-ampicillin of Example 2 (30 mg, 0. 023 mmol) and the compound N- (N-tert-butoxycarbonylphenylalanine) glycine used in the method described in Example 3 provide the title compound, which was purified by HPLC and lyophilized (9 mg, 26% yield) 77% pure, MS (MALDI) calculated for C7? H? 09N? 5O22 (M) 1525, found 1524.

EXAMPLE 29 COMPOSED OF C? 5-ANFOMICIN-9-GLU The C__5-amphomycin compound of Example 2 (30 mg, 0.023 mmol) and the 5-tert-butylester of (S) -2-tert-butoxycarbonylaminopentanediyenoic acid used in the method described in Example 3 provide the title compound, which was purified by HPLC and lyophilized (10 mg, 30% yield) 92% pure, MS (MALDI) calculated for C65H? 04N? 4O23 (M) 1450, found 1449 EXAMPLE 30 COMPOSED OF C15-ANFOMICIN-9 (pF-PHE) The C? 5-amphomycin compound of Example 2 (30 mg, 0.023 mmol) and the N-butoxycarbonyl compound of para-fluoro-phenylalanine used in the The method described in Example 3 provides the title compound, which was purified by HPLC and lyophilized (9 mg, 27% yield) 99% pure, MS (MALDI) calculated for CS9H? o5Ni4? 2? (M) 1486, found 1485.

EXAMPLE 31 COMPOSITE OF C? 5-ANFOMICIN-9 (ß-CHA) The compound of C? 5-ampicillin of Example 2 (30 mg, 0. 023 mmol) and the N-tert-butoxycarbonyl-β-cyclohexylalanine compound used in the method described in Example 3 provide the title compound, which was purified by HPLC and lyophilized (4 mg, 12% yield) 83% pure, MS (MALDI) calculated for C69H __? _ > N? 402? (M) 1474, found 1473.

EXAMPLE 32 COMPOSED OF C15-ANFOMICIN-9HPHE The C? 5-ampicillin compound of Example 2 (30 mg, 0.023 mmol) and the (S) -2-er-butoxycarbonylamino-4-phenyl-butyric acid used in the described method in Example 3 provide the title compound, which was purified by HPLC and lyophilized (9 mg, 27% yield) 90% pure, MS (MALDI) calculated for C70H? o8N? 402? (M) 1482, found 1481.

EXAMPLE 33 COMPOSED OF C15-ANFOMICIN-9-GLY-GLY-GLY The compound of C_5-ampicillin of Example 2 (30 mg, 0.023 mmol) and the compound of (N-tert-butoxycarbonylglycinyl) glycinyl glycine used in the method described in Example 3 provides the title compound, which was purified by HPLC and lyophilized (13 mg, 38% yield) 89% pure, MS (MALDI) calculated for Ce6H? o6N? 6023 (M) 1492, found 1491.

EXAMPLE 34 COMPOSITE OF C? 5-ANFOMICIN-9-C (= 0) - (CH2)? 0-NH2 The compound of C_5-ampicillin of Example 2 (30 mg, 0.023 mmol) and the 11-er-butoxycarbonylaminoundecanoic acid used in the method described in Example 3 provide the title compound, which was purified by HPLC and lyophilized (9 mg, 26% yield) 74% pure, MS (MALDI) calculated for C7? H? 8? 4021 ( M) 1504, found 1503.

EXAMPLE 35 COMPOSED OF C? 5-ANFOMICIN-9 (ß-CYANO-ALA) The compound of C? 5-ampicillin of Example 2 (30 mg, 0. 023 millimole) and (S) -2-er-butoxycarbonylamino-3-cyano-propionic acid used in the method described in Example 3 provide the title compound, which was purified by HPLC and lyophilized (7 mg, 22% yield) 99% pure, MS (MALDI) calculated for C6H? 0? N15O2? (M) 1417, found 1416.

EXAMPLE 36 COMPOSED OF C15-ANFOMICIN-9-ILE The Ca5-ampicillin compound of Example 2 (40 mg, 0.030 mmol) and the N-tert-butoxycarbonyl-isoleucine compound used in the method described in Example 3 provide the compound of the titer, which was purified by HPLC and lyophilized (13 mg, 30% yield) 77% pure, MS (MALDI) calculated for C66H108N? 402? (M) 1434, found 1433.

EXAMPLE 37 COMPOSITE OF C15-ANFOMICIN-9-GLY-VAL The compound of C15-ampicillin of Example 2 (30 mg, 0.023 mmol) and the compound (N-tert-butoxycarbonyl-valinyl) glycine used in the method described in Example 3 provide the title compound, which was purified by HPLC and lyophilized (10 mg, 30% yield) 96% pure, MS (MALDI) calculated for CS7H109N? 5O22 (M) 1477, found 1476.

EXAMPLE 38 COMPOSITE OF C? 5-ANFOMICIN-9-ASN The compound C? 5-ampicillin of Example 2 (40 mg, 0. 030 mmol) and the N-tert-butoxycarbonyl asparagine compound used in the method described in Example 3 provide the title compound, which was purified by HPLC and freeze-dried (18 mg, 41% yield) 100% pure, MS ( MALDI) calculated for Ce4H? O3N? 5022 (M) 1435, found 1434.

EXAMPLE 39 COMPOSITE OF C? 5-ANFOMICIN-9-TYR The G_5-ampicillin compound of Example 2 (40 mg, 0.030 mmol) and the N-tert-butoxycarbonyl tyrosine compound used in the method described in Example 3 provide the compound of the title, which was purified by HPLC and lyophilized (4 mg, 9% yield) 89% pure, MS (MALDI) calculated for C69H? 06? 4O22 (M) 1484, found 1483.

EXAMPLE 40 COMPOSED OF C? 5-ANFOMICIN-9-TRP The compound of G_, 5- nfomycin of Example 2 (40 mg, 0.030 mmol) and the compound N-er-butoxycarbonyl tryptophan used in the method described in Example 3 provide the title compound, which was purified by HPLC and lyophilized (9 mg, 20% yield) 92% pure, MS (MALDI) calculated for C7? H107? SO2? (M) 1507, found 1506.

EXAMPLE 41 COMPOSED OF C? 5-ANFOMICIN-9-PHG The C? 5-ampicillin compound of Example 2 (40 mg, 0.030 mmol) and the compound (S) -tert-butoxycarbonylamino-phenylglycine used in the method described in Example 3 provide the title compound, which was purified by HPLC and lyophilized (10 mg, 23% yield) 97% pure, MS (MALDI) calculated for CS8H? 04N? 4O2? (M) 1454, found 1453.

EXAMPLE 42 COMPOSED OF C? 5-ANFOMICIN-9-GLY-GLY The compound of G_, 5-ampomycin of Example 2 (30 mg, 0.023 mmol) and the compound N- (tert-butoxycarbonylglycinyl) glycine used in the method described in Example 3 provide the title compound, which was purified by HPLC and lyophilized (9 mg, 28% yield) 98% pure, MS (MALDI) calculated for C64H? or 3N_502? (M) 1435, found 1434.

EXAMPLE 43 COMPOSITE OF C? 5-ANFOMICIN-9-GLN The compound C? 5-ampicillin of Example 2 (38 mg, 0. 029 mmol) and the N-er-butoxycarbonyl-glutamine compound used in the method described in Example 3 provide the title compound, which was purified by HPLC and lyophilized (7 mg, 17% yield) 88% pure, MS (MALDI) calculated for C65H? 05N15O22 (M) 1449, found 1448.

EXAMPLE 44 COMPOSED OF C? 5-ANFOMICIN-9-THR The C? 5-amphomycin compound of Example 2 (41 mg, 0.031 mmol) and the '(2S, 3S) -2- tert-butoxycarbonylamino-3-hydroxy acid -butyric used in the method described in Example 3 provide the title compound, which was purified by HPLC and lyophilized (7 mg, 16% yield) 74% pure, MS (MALDI) calculated for Ce4H? o4N_4022 (M) 1422, found 1421.

EXAMPLE 45 COMPOSED OF C? 5-ANFOMICIN-9-PRO-GLY The C? 5-amphomycin compound of Example 2 (27 mg, 0.020 mmol) and the N-N-tert-butoxycarbonylglycinyl) proline compound used in the described method in Example 3 provide the title compound, which was purified by HPLC and lyophilized (12 mg, 40% yield) 84% pure, MS (MALDI) calculated for C6-7H_.0-7N_5O _.__ (M) 1475, found 1474.

EXAMPLE 46 COMPOSITE OF C15-ANFOMICIN-9-GLY-EU The C? 5-ampicillin compound of Example 2 (27 mg, 0.020 mmol) and the compound N- (N-tert-butoxycarbonyl-quinucinyl) glycine used in the method described in Example 3 provides the title compound, which was purified by HPLC and lyophilized (8 mg, 26% yield) 98% pure, MS (MALDI) calculated for C68HmN? 5022 (M) 1491, found 1490.

EXAMPLE 47 COMPOSED OF C15-ANFOMICIN-9-TYR (ET) The G_5-ampicillin compound of Example 2 (30 mg, 0.023 mmol) and the N-tert-butoxycarbonyl-O-ethyl tyrosine compound used in the method described in Example 3 provide the title compound, which was purified by HPLC and lyophilized (7 mg, 20% yield) 74% pure, MS (MALDI) calculated for C7? Hno? 14022 (M) 1512, found 1511.

EXAMPLE 48 COMPOSED OF C? 5-A? FOMICI? -9-GLY-SUC In a first step, the C15-ampicillin compound of Example 2 (35 mg, 0.027 mmol) was subjected to the N-er-butoxycarbonyl glycine compound used in the method described in Example 3. After purification by HPLC, the intermediate was lyophilized. In a second step, this intermediate was mixed with N, N '-dusiccinimidyl carbonate (10.4 mg, 0.041 mmol) in the presence of diisopropylethylamine (DIEA, 1 ml) in DMF (3 ml) for one hour at room temperature, followed by evaporation in vacuo to obtain a crude product of the title compound. The crude product was purified by HPLC (gradient, 25% acetonitrile in water with 0.1% trifluoroacetic acid for 95% acetonitrile for 30 minutes) and lyophilized (9 mg, 23% yield) 93% pure, MS (MALDI) calculated for CS6H ?? 4? X402 (M) 1478, found 1477.

EXAMPLE 49 COMPOSED OF C? 5-A? FOMICI? -9-GLY-AC In a first step, the C15-ampicillin compound of Example 2 (35 mg, 0.027 mmol) was subjected to the N-er-butoxycarbonyl glycine compound used in the method described in Example 3. After purification by HPLC, the intermediate was lyophilized. In a second step, this intermediate was mixed with acetic anhydride (25 μL) in the presence of DIEA (1 mL) in DMF (3 mL) for one hour at room temperature, followed by evaporation in vacuo to obtain a crude product of the compound of the title. The crude product was purified by HPLC (gradient, 25% acetonitrile in water with 0.1% trifluoroacetic acid for 95% acetonitrile for 30 minutes) and lyophilized (4 mg, 11% yield) 89% pure, MS (MALDI) calculated for C64H? 02Ni4? 22 (M) 1419, found 1420.

EXAMPLE 50 COMPOSED OF C15-ANFOMICIN-9-GABA The C15-ampicillin compound of Example 9 (25 mg, 0.019 mmol) and the α-N-tert-butoxycarbonylaminobutanoic acid used in the method described in Example 3 provide the compound of title, which was purified by HPLC and lyophilized (10 mg, 38% yield) 100% pure, MS (MALDI) calculated for C62H? oo? 402X (M) 1378, found 1377.

EXAMPLE 51 COMPOSITE OF C14-A? FOMICI? -9-GLY-LYS The compound of G -anfomycin of Example 10 (25 mg, 0.019 mmol) and the compound (?, N'-bis-tert-butoxycarbonillisine) glycine used in the method described in Example 3 provides the title compound, which was purified by HPLC and lyophilized (10 mg, 38% yield) 94% pure, MS (MALDI) calculated for CSH11o? 16022 (M) 1492, found 1491 .

EXAMPLE 52 COMPOSED OF C? 5-ANFOMICIN-9-TYR (ME) The C-5-amphomycin compound of Example 2 (30 mg, 0.023 mmol) and the N-tert-butoxycarbonyl-O-methyl tyrosine compound used in the described method in Example 3 provide the title compound, which was purified by HPLC and lyophilized (3 mg, 9% yield) 67% pure, MS (MALDI) calculated for C70H? 08 ?? 4O22 (M) 1498, found 1497 .

EXAMPLE 53 COMPOSED OF C? 3-A? FOMICI? -9-GLY The compound of C? 3-ampicillin of Example 9 (20 mg, 0. 015 mmol) and the N- (tert-butoxycarbonyl) glycine compound used in the method described in Example 3 provide the title compound, which was purified by HPLC and lyophilized (12 mg, 59% yield) 99% pure, MS (MALDI) calculated for C6oH9S ?? 4021 (M) 1349, found 1348.

EXAMPLE 54 COMPOSED OF C13-A? FOMICI? -9- (ß-ALA) The compound of CX3-ampicillin of Example 9 (20 mg, 0. 015 mmol) and the N- (tert-butoxycarbonyl) β-alanine compound used in the method described in Example 3 provide the title compound, which was purified by HPLC and lyophilized (12 mg, 58% yield) 93% pure, MS (MALDI) calculated for Ce? H98N? 4021 (M) 1364, found 1363.

EXAMPLE 55 COMPOSED OF CX3-ANFOMICIN-9-SAR The compound of C_3-ampomycin of Example 9 (20 mg, 0. 015 mmol) and the compound sarcosine used in the method described in Example 3 provide the title compound, which was purified by HPLC and lyophilized (12 mg, 58% yield) 95% pure, MS (MALDI) calculated for C6? H98N? 402? (M) 1364, found 1363.

EXAMPLE 56 COMPOSITE OF C? 3-ANFOMICIN-9-AHX The C_3-ampicillin compound of Example 9 (20 mg, 0.015 mmol) and the 6-tert-butoxycarbonyl-aminohexanoic acid used in the method described in Example 3 provide the compound of the title, which was purified by HPLC and lyophilized (18 mg, 84% yield) 98% pure, MS (MALDI) calculated for C_4H? 0_ i4? 21 (M) 1406, found 1405.

EXAMPLE 57 COMPOSITE OF C12-ANFOMICIN-9-GABA The compound of C_2 ~ ampomycin of Example 8 (25 mg, 0.020 mmol) and the α-N-er-butoxycarbonyl-aminobutanoic acid used in the method described in Example 3 provide the compound of the title, which was purified by HPLC and lyophilized (15 mg, 58% yield) 97% pure, MS (MALDI) calculated for C6_H98? _402? (M) 1364, found 1363.

EXAMPLE 58 COMPOSED OF C? 2-A? FOMICI? -9-GLY The Cx2-ampicillin compound of Example 8 (25 mg, 0. 020 mmol) and the N- (er-butoxycarbonyl) glycine compound used in the method described in Example 3 provide the title compound, which was purified by HPLC and lyophilized (10 mg, 40% yield) 96% pure, MS (MALDI) calculated for C59H94? 1402 (M) 1335, found 1334.

EXAMPLE 59 COMPOSITE OF C? 4-A? FOMICI? -9- (ß-ALA) The C -anfomycin compound of Example 10 (107 mg, 0.082 mmol) and the β-alanine compound used in the method described in the Example 3 provide the title compound, which was purified by HPLC and lyophilized (66 mg, 59% yield) 94% pure, MS (MALDI) calculated for Cs_.HXoo ?? 402? (M) 1378, found 1377.

EXAMPLE 60 COMPOSED OF C14-ANFOMICIN-9-SAR The C -anfomycin compound of Example 10 (22 mg, 0.017 mmol) and the N- (tert-butoxycarbonyl) sarcosine compound used in the method described in Example 3 provide the compound of the title, which was purified by HPLC and lyophilized (7 mg, 30% yield) 89% pure, MS (MALDI) calculated for C62H? oo? 402? (M) 1378, found 1377.

EXAMPLE 61 COMPOSITE OF C? 4-A? FOMICI? -9-AHX The C14-amphomycin compound of Example 10 (22 mg, 0.017 mmol) and the 6- (tert-butoxycarbonyl) -aminohexanoic acid used in the method described in the example 3 provide the title compound, which was purified by HPLC and lyophilized (9 mg, 38% yield) 87% pure, MS (MALDI) calculated for CS5H? O6 ?? 4? 2i (M) 1420, found 1419.

EXAMPLE 62 COMPOSED OF C? 4-A? FOMICI? -9-GABA The compound of G_4-ampicillin of Example 10 (22 mg, 0.017 mmol) and the? -N-tert-butoxycarbonyl-aminobutanoic acid used in the method described in Example 3 provides the title compound, which was purified by HPLC and lyophilized (4 mg, 17% yield) 88% pure, MS (MALDI) calculated for C53H? 02N? 4O2 (M) 1392, found 1391.

EXAMPLE 63 COMPOSITE OF C13-ANFOMICIN-9-ALA The C__3-ampicillin compound of Example 9 (22 mg, 0.017 mmol) and the N-er-butoxycarbonyl alanine compound used in the method described in Example 3 provide the title compound , which was purified by HPLC and lyophilized (9 mg, 40% yield) 84% pure, MS (MALDI) calculated for C6? H98 ?? 021 (M) 1364, found 1363.

EXAMPLE 64 COMPOSED OF C13-A? FOMIC? -9- (D-ALA) The compound of C? 3-ampicillin of Example 9 (22 mg, 0.017 mmol) and the compound DN-er-butoxycarbonyl alanine used in the described method in Example 3 provide the title compound, which was purified by HPLC and lyophilized (13 mg, 57% yield) 89% pure, MS (MALDI) calculated for C6? H98? 402? (M) 1364, found 1363.

EXAMPLE 65 COMPOSED OF C? 3- NFOMICIN-9- (D-PRO) The compound C? 3-ampicillin of Example 9 (22 mg, 0.017 mmol) and the compound DN-tert-butoxycarbonyl proline used in the method described in Example 3 provides the title compound, which was purified by HPLC and lyophilized (11 mg, 47% yield) 90% pure, MS (MALDI) calculated for Cs3H_oo? 402? (M) 1390, found 1389.

EXAMPLE 66 COMPOSED OF C_5-A? FOMICI? -9- (D-ALA) The compound C__5-ampicillin of Example 2 (22 mg, 0.017 mmol) and the compound DN-er-butoxycarbonyl alanine used in the method described in Example 3 provide the title compound, which was purified by HPLC and lyophilized (10 mg, 43% yield) 85% pure, MS (MALDI) calculated for C63H? 02? 4O2? (M) 1392, found 1391.

EXAMPLE 67 COMPOSED OF C15-A? FOMICI? -9- (D-ALA) The compound of C15-ampicillin of Example 2 (22 mg, 0.017 mmol) and the compound DN-tert-butoxycarbonyl proline used in the method described in Example 3 provide the title compound, which was purified by HPLC and lyophilized (11 mg, 47% yield) 77% pure, MS (MALDI) calculated for CssH104N14O2? (M) 1418, found 1417.

EXAMPLE 68 COMPOSED OF C? 5-ANFOMICIN-9-GLY-GABA In a first step, the C? 5-amphomycin compound of Example 2 (38 mg, 0.029 mmol) was coupled to the N-er-butoxycarbonyl glycine compound used in the method described in Example 3. The intermediate was purified by HPLC and lyophilized. In a second step, this intermediate and the? -N-er-butoxycarbonyl-aminobutanoic acid was used as in the method described in Example 3 to obtain the title compound, which was purified by HPLC and lyophilized (13 mg, 31% yield) 74% pure, MS (MALDI) calculated for C65H? o5 ?? 5022 (M) 1449, found 1448.

EXAMPLE 69 COMPOSED OF C15-A? FOMICI? -9-GLY- (D-ALA) In a first stage, the C_5-amphomycin compound of Example 2 (24 mg, 0.018 mmol) was initially coupled with the N-er-butoxycarbonyl glycinyl succinimide compound used in the method described in Example 3. The resulting intermediate was purified by HPLC. In a second step, this purified intermediate and the compound DN- (tert-butoxycarbonyl) alanine were used as in the method described in Example 3 to obtain the title compound, which was purified by HPLC and lyophilized (9 mg, 37%). % yield) 75% pure, MS (MALDI) calculated for C65H? oS? 5022 (M) 1449, found 1448.

EXAMPLE 70 COMPOSITE OF C? 5-A? FOMICI? -9- (? -ALA) -AHX In a first step, the Cas-ampicillin compound of Example 2 (25 mg, 0.018 mmol) was initially coupled to the N-compound. tert-butoxycarbonyl β-alanine used in the method described in Example 3. The resulting intermediate was purified by HPLC. In a second step, this purified intermediate and 6-N-tert-butoxycarbonyl-aminobuhexanoic acid were used as in the method described in Example 3 to obtain the title compound, which was purified by HPLC and lyophilized (21 mg, 74% yield) 74% pure, MS (MALDI) calculated for C69Hn3 ?? 5022 (M) 1505, found 1504.

EXAMPLE 71 COMPOSED OF C? 5-A? FOMICI? -9-GABA-VAL In a first step, the GL5-ampomicin compound of Example 2 (25 mg, 0.019 mmol) was coupled with the? -N- ter butoxycarbonyl-aminobutanoic used in the method described in Example 3. The resulting intermediate was purified by HPLC and lyophilized. In a second step, this purified intermediate and the N-tert-butoxycarbonyl-valine compound were used as in the method described in Example 3 to obtain the title compound, which was purified by HPLC and lyophilized (15.6 mg, 55% yield) 92% pure, MS (MALDI) calculated for C69Hn3 ?? 5022 (M) 1505, found 1504.

EXAMPLE 72 COMPOSITE OF C? 5-A? FOMICI? -9-GABA-AHX In a first step, the compound of C_5-ampicillin of Example 2 (25 mg, 0.019 mmol) was coupled with the acid? -N- ter- butoxycarbonyl-aminobutanoic used in the method as described in Example 3. The resulting intermediate was purified by HPLC and lyophilized. In a second step, this purified intermediate and the 6-tert-butoxycarbonylamine hexanoic compound were used as described in the method of Example 3 to obtain the title compound, which was purified by HPLC and lyophilized (12.8 mg, 44% yield) 100% pure, MS (MALD1) calculated for C70H? 15? 15O22 (M) 1519, found 1518.

EXAMPLE 73 COMPOSED OF C_2-ANFOMICIN-9- (ß-ALA) The compound of C_2-ampomycin of Example 8 (30 mg, 0.023 mmol) and the compound N-er-butoxycarbonyl-β-alanine used in the method described in Example 3 provide the title compound, which was purified by HPLC and lyophilized (21.8 mg, 71% yield) 86% pure, MS (MALDI) calculated for C60H9S? 402? (M) 1349, found 1348.

EXAMPLE 74 COMPOSED OF C? -A? FOMICI? -9-SAR The compound of C __-ampicillin of Example 8 (30 mg, 0.023 mmol) and the N-tert-butoxycarbonyl-sarcosine compound used in the method described in Example 3 provide the title compound, which was purified by HPLC and lyophilized (19.7 mg, 64% yield) 78% pure, MS (MALDI) calculated for CS0H96 ?? 4O2? (M) 1349, found 1348.

EXAMPLE 75 COMPOSED OF C? 6-A? FOMICI? -9-SAR The compound of C16-ampicillin of Example 11 (30 mg, 0.022 mmol) and the compound N-er-butoxycarbonyl-sarcosine used in the method described in Example 3 provide the title compound, which was purified by HPLC and lyophilized (18.5 mg, 58% yield) -85% pure, MS (MALDI) calculated for C64H? 04N? O2? (M) 1406, found 1405.

EXAMPLE 76 COMPOSED OF C10-ANFOMICIN-9- (ß-ALA) The Cao-ampomycin compound of Example 6 (30 mg, 0.024 mmol) and the N-tert-butoxycarbonyl-β-alanine compound used in the method described in Example 3 provide the title compound, which was purified by HPLC and lyophilized (14.2 mg, 47% yield) 87% pure, MS (MALDI) calculated for C58H92? 1402? (M) 1321, found 1320.

EXAMPLE 77 CIQ-A? FOMICI? -9-SAR COMPOUND The Cao-ampicillin compound of Example 6 (30 mg, 0.024 mmol) and the N-tert-butoxycarbonyl-sarcosine compound used in the method described in Example 3 provide the title compound, which was purified by HPLC and lyophilized (18.4 mg, 61% yield) 78% pure, MS (MALDI) calculated for CS8H92? 14021 (M) 1321, found 1320.

EXAMPLE 78 COMPOSED OF CX7-ANFOMICIN-9-SAR The compound of C_7-ampicillin of Example 12 (30 mg, 0.022 mmol) and the compound N-er-butoxycarbonyl-sarcosine used in the method described in Example 3 provide the compound of title, which was purified by HPLC and lyophilized (20 mg, 62% yield) 83% pure, MS (MALDI) calculated for C.sHiog O,.! (M) 1420, found 1419.

EXAMPLE 79 COMPOSITE OF C? 6-A? FOMICI? -9- (ß-ALA) The compound of Ci.-ampomycin of Example 11 (30 mg, 0.023 mmol) and the N-er-butoxycarbonyl-β-alanine compound used in the method described in Example 3 provide the title compound, which was purified by HPLC and lyophilized (17.8 mg, 56% yield) 93% pure, MS (MALDI) calculated for C64H? o4? 402? (M) 1406, found 1405.

EXAMPLE 80 COMPOSED OF C? 7-A? FOMICI? -9- (ß-ALA) The Ca7-ampicillin compound of Example 12 (30 mg, 0.022 mmol) and the N-tert-butoxycarbonyl-β-alanine compound used in the method described in Example 3 provides the title compound, which was purified by HPLC and lyophilized (13.9 mg, 43% yield) 86% pure, MS (MALDI) calculated for CS5H? o6N? 402? (M) 1420, found 1419.

EXAMPLE 81 COMPOSITE OF C? 5-ANFOMICIN-9-GLY-C6 The compound of G_5-ampicillin of Example 3 (21 mg, 0.014 mmol) and the hexanoic acid used in the method described in Example 3 provide the title compound, which was purified by HPLC and lyophilized (2 mg, 9% yield) 98% pure, MS (MALDI) calculated for Cs8Huo? 4022 (M) 1476, found 1477.

EXAMPLE 82 COMPOSED OF C? 5-ANFOMICIN-9-ALA The compound C? 5-ampicillin of Example 2 (20 mg, 0. 015 mmol) and the N-tert-butoxycarbonyl-alanine compound used in the method described in Example 3 provide the title compound, which was purified by HPLC and lyophilized (6.3 mg, 30% yield) 78% pure, MS (MALDI) calculated for C63H? O2? 14021 (M) 1392, found 1391.

EXAMPLE 83 COMPOSED OF CH3- (CH2) 15-NH-C (= 0) -ANF0MICIN-9-GLY The compound of CH3- (CH2) 15-NH-C (= 0) -anfomycin of Example 249 (20 mg, 0.0147 mmol) and the N-tert-butoxycarbonyl-glycine compound used in the method described in Example 3 provide the title compound, which was purified by HPLC and lyophilized (2 mg, 9.5% yield) 66% pure, MS (MALDI) calculated for C64H? 05? 15O2? (M) 1421, found 1420.

EXAMPLE 84 COMPOSED OF CH3- (CH2)? 5-S02-A? FOMICI? -9-GLY The compound of C? 6-S02-Gly-ampicillin of Example 99 (20 mg, 0.022 mmol) and the compound N-ter -butoxycarbonyl glycine used in the method described in Example 3 provide the title compound, which was purified by HPLC and lyophilized (5 mg, 16% yield) 81% pure, MS (MALDI) calculated for C65H? 07? ? 5023S (M) 1499, found 1498.

EXAMPLE 85 COMPOSED OF C? 2-PABA-A? FOMICI? A In a first step, the compound of anfomicin-9-Fmoc (30 mg, 0.022 mmol) was coupled with N-tert-butoxycarbonylaminobenzoic acid as described in method of Example 3. In a second step, the intermediate of the first step was mixed with dodecanoyl chloride (7 μL, 0.033 mmol) in DMF (5 ml) in the presence of DIEA (20 μL, 0.011 mmol) for 3 hours under a inert atmosphere to obtain the title compound. The title compound was concentrated in vacuo, purified by HPLC (gradient, 25% acetonitrile in water with 0.1% trifluoroacetic acid for 95% acetonitrile for 30 minutes) and lyophilized (13.2 mg): 93% pure, MS (MALDI) calculated for CS4H96N? 402? (M) 1398, found 1397.

EXAMPLE 86 COMPOSED OF C? 2- (p-APA) -ANFOMICIN-9-GLY The compound of C__2- (p-aminophenylacetyl) -anfomycin of Example 119 (30 mg, 0.023 mmol) and the compound N-tert-butoxycarbonyl glycine used in the method described in Example 3 provide the title compound, which was purified by HPLC and lyophilized (5 mg, 15% yield) 78% pure, MS (MALDI) calculated for C67H? 0 ??? 2O22 ( M) 1469, found 1468.

EXAMPLE 87 COMPOSED OF C12-PABA-A? FOMICI? -9-GLY The compound of ampomycin-9- (N-Fmoc-glycyl) of the Example 271 (11.3 mg) is dissolved in 0.2 ml DMF, 0.02 ml of water and 0.03 of 1M sodium bicarbonate. The succinimid-1-yl N-dodecanoyl-para-aminobenzoic ester acid (7 mg, as prepared in Example 274 and succinimidyl ester as in Example 1 is used) is added in two increments for 60 minutes with stirring at room temperature. After an additional 20 minutes of stirring, the reaction is diluted with 5 ml of methanol containing about 300 mg of ammonium acetate. The title compound is isolated on a Sephadex LH-20 column (2.5 x 42 cm) eluting with methanol in 2 ml / minute and dried in an ice bath (9.5 mg): 88% pure, MS (FAB) calculated for C66H99? _5022 (M) 1455, found 1454.

EXAMPLE 88 COMPOSED OF CH3- (CH2) nOp-PH-C (= 0) -A? FOMICI? -9-GLY The compound of CH3- (CH2) u-0-p-PH-C (= 0) -anfomycin of Example 15 (30 mg, 0.021 mmol) and the N-tert-butoxycarbonyl glycine compound used in the method described in Example 3 provide the title compound, which was purified by HPLC and lyophilized (7 mg, 27% yield). 84% pure, MS (MALDI) calculated for Cs6H? Oo ?? 402 (M) 1442, found 1441.

EXAMPLE 89 COMPOSED OF C12- (p-TRA? S-CI? AMIL) -A? FOMICI? -9-GLY The compound of G_.2- (p-trans-cinnamyl) -anfomycin of Example 120 (30 mg, 0.021 mmol) and the N-tert-butoxycarbonyl glycine compound used in the method described in Example 3 provide the title compound, which was purified by HPLC and lyophilized (7 mg, 23% yield) 85% pure, MS ( MALDI) calculated for C68H? Or ??? 5022 (M) 1481, found 1480.

EXAMPLE 90 COMPOSED OF CH3- (CH2) nOp-PH-C (= 0) -GLY-A? FOMICI? -9-GLY The compound of CH3- (CH2) nOp-PH-C (= 0) Gly-ampomycin of the Example 121 (30 mg, 0.021 mmol) and the N-tert-butoxycarbonyl glycine compound used in the method described in Example 3 provide the title compound, which was purified by HPLC and lyophilized (6.5 mg, 19% yield) 88% pure, MS (MALDI) calculated for C_8H? 03 ?? 5023 (M) 1499, found 1498.

EXAMPLE 91 COMPOSED OF C14-PABA-GLY-A? FOMICI? -9-GLY The compound of C? 4-PABA-Gly-anfomicin-9-Gly of the Example 271 (11.3 mg) and the succinimid-1-yl ester compound N-dodecanoyl-para-aminobenzoylglycine (6.3 g) used in the method described in Example 3 provide the title compound, which was purified by HPLC and lyophilized (6.8 mg) 86% pure, MS (MALDI) calculated for C_8H? o2? 60_3 (M) 1512, found 1512.

EXAMPLE 92 COMPOSED OF CH3- (CH2) X1-NH-C (= 0) -ANFOMICIN-9-GLY The compound of ampomycin-9- (N-Fmoc-glycyl) of the Example 271 (8.6 mg, 0.023 mmol) is dissolved in 0.2 ml DMF and 0.2 ml of water to then add 0.002 ml of dodecylisocyanate. The reaction mixture is stirred at 30 ° C and checked by HPLC. After 30 minutes, 0.001 piperidine is added and stirred at room temperature. After 40 minutes, the reaction mixture is diluted with 5 ml of methanol containing approximately 300 mg of ammonium acetate. The title compound is isolated on a Sephadex LH-20 column (2.5 x 42 cm) and eluted with methanol at 2 ml / minute. The title compound contains portions that are discarded and the solvent is removed in vacuo. After the title compound is dissolved again in 2 ml of distilled water, the sample is dried in an ice bath (5.5 mg): 77% pure, MS (FAB) calculated for C6oH9-7 X502X (M +? A) + 1386, found 1386.

EXAMPLE 93 COMPOSED OF C15-A? FOMICI? -9-AHX-GLY In a first step, the compound of CX5-ampicillin of Example 2 (38 mg, 0.029 mmol) was coupled with the 6-er-butoxycarbonyl-aminohexanoic acid used as described in the method of Example 3. The resulting intermediate was purified by HPLC and lyophilized. In a second step, this purified intermediate and the N-tert-butoxycarbonyl glycine compound used in the method described in Example 3 provides the title compound, which is purified by HPLC and lyophilized (12.7 mg, 30% yield): 99% pure, MS (MALDI) calculated for C68HXXXNX5022 (M) 1491, found 1490.

EXAMPLE 94 COMPOSED OF CX5-ANFOMICIN-9-GABA-GABA In a first step, the Cx5-amphomycin compound of Example 2 (25 mg, 0.019 mmol) was coupled with the α-N-tert-butoxycarbonyl-aminobutanoic acid as described in the method of Example 3. The resulting intermediate was purified by HPLC. In a second step, this purified intermediate and the? -N-er-butoxycarbonyl-aminobutanoic acid used in the method described in Example 3 provides the title compound, which is purified by HPLC and lyophilized (3.7 mg, 9% yield): 99% pure, MS (MALDI) calculated for C68HXn ?? S022 (M) 1491, found 1490.

EXAMPLE 95 COMPOSED OF C15-ANFOMICIN-9-HPRO The C15-ampicillin compound of Example 2 (23 mg, 0.017 mmol) and the (S) -N-tert-butoxycarbonyl pipecolic acid used in the method described in Example 3 provide the title compound, which was purified by HPLC and lyophilized (3.2 mg, 13% yield) 70% pure, MS (MALDI) calculated for CS6HXo6? 1402x (M) 1432, found 1431.

EXAMPLE 96 COMPOSITE OF C15-A? FOMICI? -9- (D-PIP) The compound of C_5-ampicillin of Example 2 (175 mg, 0.0133 millimoles) and the (R) -N-er-butoxycarbonyl pipecolic acid used in the method described in Example 3 provide the title compound, which was purified by HPLC and lyophilized (60 mg, 32% yield) 77% pure, MS (MALDI) calculated for Ce5HXo6 ?? 402x (M) 1432, found 1431 .

EXAMPLE 97 COMPOSED OF CH3- (CH2) X1-? H-C (= 0) -A? FOMICI? -9- (ß-ALA) The compound of ampomycin-9- (N-Fmoc-ß-ala) of the Example 273 (15 mg) and the dodecylisocyanate compound used in the method described in Example 3 provide the title compound, which was purified by HPLC and lyophilized (20.7 mg): 91% pure, MS (MALDI) calculated for C6iH99Nx502X ( M) 1379, found 1379.

EXAMPLE 98 COMPOSED OF CH3- (CH2) 1X-NH-C (= 0) -ANFOMICIN-9-SAR The ampomycin-9- (N-Fmoc-Sar) compound of Example 272 (62 mg) and the dodecyl isocyanate compound used in the method described in Example 3 provide the title compound, which was purified by HPLC and lyophilized (12.2 mg): 80% pure, MS (FAB) calculated for C6XH99? X502 (M) 1379, found 1380.

EXAMPLE 99 COMPOSED OF CH3- (CH2)? 5-S02-GLY-A? FOMICI? A In a first step, the compound of ampicillin-9-Fmoc (30 mg, 0.022 mmol) is coupled with the N-terminal compound. butoxycarbonyl glycine as described in the method of Example 3. The resulting intermediate is purified by HPLC and lyophilized. In a second step, this purified intermediate is dissolved in 10 ml DMF under an inert atmosphere. Then, pentadecanesulfonyl chloride is added (13.7 mg, 0.044 mmol) and agitation is provided to the reaction mixture overnight to provide the title compound, which is purified by HPLC (gradient 25%, acetonitrile in water with 0.1% trifluoroacetic acid for 95% acetonitrile during 30 minutes) and lyophilized (5 mg): 89% pure, MS (MALDI) calculated for C_3H104NxxO22S (M) 1442, found 1441.

EXAMPLE 100 COMPOSED OF CH3- (CH2) 9-S02-PHE-ANFOMICIAN In a first step, the compound of ampomycin-9-Fmoc (30 mg, 0.022 mmol) is coupled with the compound N-tert-butoxycarbonyl phenylalanine. The resulting intermediate is purified by HPLC and lyophilized. In a second step, this purified intermediate is coupled with dodecanesulfonyl chloride as described in the method of Example 99 to provide the title compound, which is purified by HPLC and lyophilized (7 mg, 21% yield): 91% pure , MS (MALDI) calculated for C64H_.8? X4022S (M) 1448, found 1447.

EXAMPLE 101 COMPOSED OF CH3- (CH2) 9-S02-GLY-A? FOMICI? -9-LYS In a first step, the compound of ampomycin-9-Fmoc (30 mg, 0.022 mmol) is coupled with the compound N- tert-butoxycarbonyl glycine and then In a second step with dodecanesulfonyl chloride as described in the method of Example 99, a second intermediate is produced, which is purified by HPLC and lyophilized. In a third step, the second intermediate is coupled with 2-N-tert-butoxycarbonyl-6- (9H-fluoren-9-yl-methoxycarbonyl) lysine as described in the method of Example 4 to provide the title compound, which purify by HPLC and lyophilize (2 mg, 5.7% yield): 83% pure, MS (MALDI) calculated for C65HX08 X6? 23S (M) 1514, found 1513.

EXAMPLE 102 COMPOSED OF CH3- (CH2) 9-S02-GLY-A? FOMICI? -9-GLY In a first step, the compound of ampomycin-9-Fmoc (30 mg, 0.022 mmol) is coupled with the compound N- tert-butoxycarbonyl glycine and then In a second step with decanesulfonyl chloride as described in the method of Example 99, a second intermediate is produced, which is purified by HPLC and lyophilized. In a third step, the second intermediate is coupled with N-tert-butoxycarbonyl glycine as described in the method of Example 3 to provide the title compound, which is purified by HPLC and lyophilized (6 mg, 18% yield): 78% pure, MS (MALDI) calculated for C6xH99? X5023S (M) 1443, found 1442.

EXAMPLE 103 COMPOSED OF CX2-GLY-A? FOMICI? The compound of ampicillin-9-Fmoc (16.3 mg) and the compound of succinimid-1-yl N-dodecanoyl glycine ester (7.3 mg, as prepared in Example 274 and using succinimidyl ester as prepared in Example 1 ) as described in the method of Example 3 to provide the title compound (105 mg): 90% pure, MS (FAB) calculated for C59H94? X402X (M) 1335, found 1336.

EXAMPLE 104 COMPOSED OF C8- (p-APA) -A? FOMICI? A The compound of ampomycin-9-Fmoc (11.1 mg) and the compound of succinimid-1-yl ester N-octanoyl-para-aminophenylacetic acid (7.8 mg) , as prepared in Example 274 and using succinimidyl ester as prepared in Example 1) used in the method as described in Example 3 to provide the title compound (7.1 mg): 85% pure, MS (FAB) ) calculated for C6? H90? 14O2X (M) 1355, found 1355.

EXAMPLE 105 COMPOSED OF CX4-GLY-A? FOMICI? A In a first step, the compound of anfomycin-9-Fmoc (26 mg, 0.020 millimole) is coupled with the compound N-tert-butoxycarbonyl glycine as described in the method of the Example 3. The resulting intermediate is purified by HPLC and lyophilized. In a second step, this purified intermediate and the tetradecanoic acid used as described in the method of Example 2 provide the title compound, which is purified by HPLC and lyophilized (6.4 mg, 24% yield): 92% pure, MS (MALDI) calculated for CS1H98 _402X (M) 1364, found 1363.

EXAMPLE 106 COMPOSED OF CX6-GLY-ANFOMYCIN In a first step, the compound of ampomycin-9-Fmoc (26 mg, 0.020 mmol) is coupled with the compound N-tert-butoxycarbonyl glycine as described in the method of Example 3. The resulting intermediate is purified by HPLC and lyophilized. In a second step, this purified intermediate and the hexadecanoic acid used as described in the method of Example 2 provide the title compound, which is purified by HPLC and lyophilized (9.7 mg, 35% yield): 96% pure, MS (MALDI) calculated for Cs3H? O2? X402x (M) 1392, found 1391.

EXAMPLE 107 COMPOSED OF C18-GLY-A? FOMICI? A In a first step, the compound of anfomicin-9-Fmoc (26 mg, 0.020 mmol) is coupled with the compound N-tert-butoxycarbonyl glycine as described in the method of Example 3. The resulting intermediate is purified by HPLC and lyophilized. In a second step, this purified intermediate and the hexadecanoic acid used as described in the method of Example 2 provide the title compound, which is purified by HPLC and lyophilized (8.2 mg, 29% yield): 84% pure, MS (MALDI) calculated for C6? H? O6? 402? (M) 1420, found 1419.

EXAMPLE 108 COMPOSITE OF Cx2- (p-AMINOFEN LPROPANOIL) -ANFOMYCIN The compound of ampomycin-9-Fmoc (10.6 mg) and the acid of succinimid-1-yl N-dodecanoyl-para-aminophenyl propanoic acid (6.1 mg, as was prepared in Example 274 and using a succinimidyl ester as prepared in Example 1) using the method described in Example 3 provided the title compound (6.3 mg): 93% pure, MS (FAB) calculated for C66H? 0o ?? 402? (M) 1426, found 1426.

EXAMPLE 109 COMPOSED OF C12- (p-AMI? OFE? ILPROPA? OIL) 2-A? FOMICI? In a first stageThe compound of ampomycin-9-Fmoc (30 mg, 0.022 mmol) is coupled with 4-tert-butoxycarbonylaminophenyl propanoic acid as described in the method of Example 3. The resulting intermediate is purified by HPLC and lyophilized. In a second step, this purified intermediate is coupled with 4-tert-butoxycarbonylaminophenyl propanoic acid as described in the method of Example 3. The resulting second intermediate is purified by HPLC and lyophilized. In a third step, this second intermediate and the dodecanoic acid are used as described in the method of Example 2 to provide the title compound, which is purified by HPLC and lyophilized (1.5 mg, 4% yield): 86% pure , MS (MALDI) calculated for C75H? 09N15O22 (M) 1573, found 1572.

EXAMPLE 110 COMPOSED OF CH3- (CH2) 9-GLY-ANFOMYCIN In a first step, the compound of ampomycin-9-Fmoc (30 mg, 0.022 mmol) is coupled with the compound N-tert-butoxycarbonyl glycine as described in Method of Example 3. The resulting intermediate is purified by HPLC and lyophilized. In a second step, this purified intermediate and the p-decanoxobenzoic acid used as described in the method of Example 3 provides the title compound, which is purified by HPLC and lyophilized (8.9 mg, 28% yield): 88% pure, MS (MALDI) calculated for C64H96 ?? 4022 (M) 1414, found 1413.

EXAMPLE 111 COMPOSED OF C12- (Af-APA) -A? FOMICI? A The compound of ampomycin-9-Fmoc (11 mg) and the acid of succinimid-1-yl ester (6 .6 mg, as prepared in Example 274 and using a succinimidyl ester as prepared in Example 1) are used as in the method described in Example 3 to provide the title compound (8.5 mg): 86% pure, MS (FAB) calculated for C. 5H98N? 4021 (M) 1412, found 1412.

EXAMPLE 112 COMPOSED OF C15- [ASP- (OTBU)] -ANFOMYCIN The compound of ampomycin-9-Fmoc (16.3 mg) is coupled with the succinimid-1-yl ester N-pentadecanoyl-O-t-butyl-aspartate ( 7.2 mg, as prepared in Example 274 and using a succinimidyl ester as prepared in Example 1) as described in the method of Example 3 to provide the title compound (10.6 mg): 68% pure, MS (FAB) ) calculated for C58HXo? X4? 23 (M) 1492, found 1492.

EXAMPLE 113 COMPOSED OF Cx0- (Af-APA) -A? FOMICI? A In a first stage, the compound of anfomicin-9-Fmoc (30 mg, 0.022 mmol) is coupled with 3-tert-butoxycarbonylamino-phenylacetic acid as is described in the method of Example 3. The resulting intermediate is purified by HPLC and lyophilized. In a second step, this purified intermediate and the dodecanoic acid used in the method described in Example 2 provide the title compound, which is purified by HPLC and lyophilized (18.9 mg, 26% yield): 93% pure, MS (MALDI) calculated for C63H94NX402? (M) 1384, found 1383.

EXAMPLE 114 COMPOSED OF (CH3- (CH2) 7 (CH3- (CH2) 5) CH-C (= 0) -GLY-ANFOMYCIN The compound of ampicin-9-Fmoc (30 mg, 0.022 mmol) is coupled with the compound of succinimid-1-yl ester N- (2-hexyl decanoyl) glycine (7.0 mg, as prepared in Example 274 and using a succinimidyl ester as prepared in Example 1) as described in the method of Example 3 providing the title compound (14.4 mg): 84% pure, MS (FAB) calculated for C6? H99 ?? 302o (M) 1335, found 1335.

EXAMPLE 115 COMPOSED OF C15-PHG-A? FOMICI? A The compound of ampomycin-9-Fmoc (16.3 mg) is coupled with the compound of succinimid-1-yl ester N-pentadecanoyl-phenylalanine (9.9 mg, as prepared in Example 274 and using a succinimidyl ester as prepared in Example 1) as described in the method of Example 3 to provide the title compound (6.3 mg): 75% pure, MS (FAB) calculated for C68H? 04 ?? 4? 2? (M) 1454, found 1454 EXAMPLE 116 COMPOSED OF C15- (D-PHE) -ANFOMYCIN In a first step, the compound of ampomycin-9-Fmoc (16.3 g) is coupled to the compound of DN-er-butoxycarbonyl phenylalanine as described in the method of Example 3. The resulting intermediate is purified by HPLC and lyophilized. In a second step, this purified intermediate and the pentadecanoic acid as used in the method described in Example 2 provide the title compound, which is purified by HPLC and lyophilized (11 mg, 33% yield): 60% pure , MS (MALDI) calculated for C.9H? O6 ?? 4021 (M) 1468, found 1467.

EXAMPLE 117 COMPOSED OF PH-O- (CH2) ?? - GLY-A? FOMICI? A The compound of ampomycin-9-Fmoc (16.3 mg) is coupled with the compound of succinimid-1-yl ester N- (11) phenoxy undecanoyl) glycine (7.5 mg, as prepared in Example 276 and using a succinimidyl ester as prepared in Example 1) as described in the method of Example 3 to provide the title compound (12.4 mg). 87% pure, MS (FAB) calculated for C64H96 ?? 402X (M) 1414, found 1414.

EXAMPLE 118 COMPOSED OF C? 0- (L-BBTA) -ANFOMYCIN In a first step, the compound of ampomycin-9-Fmoc (38 mg, 0.022 mmol) is coupled with the acid of (S) -3-benzo [b] ] thiophen-3-yl-2-er-butoxycarbonylamino-propionic acid as described in the method of Example 3. The resulting intermediate is purified by HPLC and lyophilized. In a second step, this purified intermediate and the decanoic acid as used in the method described in Example 2 provide the title compound, which is purified by HPLC and lyophilized (4 mg, 12% yield): 84% pure , MS (MALDI) calculated for C66H9s? 402? (M) 1454, found 1453.

EXAMPLE 119 COMPOSED OF C? 0- (p-APA) -ANFOMYCIN In a first step, the compound of ampomycin-9-Fmoc (38 mg, 0.022 mmol) is coupled with 4-tert-butoxycarbonyl-aminophenylacetic acid as described in the method of Example 3. The resulting intermediate is purified by HPLC and lyophilized. In a second step, this purified intermediate and the decanoic acid as used in the method described in Example 2 provide the title compound, which is purified by HPLC and lyophilized (10 mg, 31% yield): 75% pure , MS (MALDI) calculated for C66H98N? 402? (M) 1412, found 1411.

EXAMPLE 120 COMPOSED OF C? 0- (p-AMINO-TRANS-CINNAMIL) -ANFOMYCIN In a first step, the compound of ampomycin-9-Fmoc (11.1 mg) and the succinimid-1-yl ester ND-dodecanoyl-para amino-trans-cinnamic (7.8 mg, as prepared in Example 274 and using a succinimidyl ester as prepared in Example 1) used in the method described in Example 3. provide the title compound (7.4 mg) : 84% pure, MS (FAB) calculated for Ce6H98 ?? 402? (M) 1424, found 1424.

EXAMPLE 121 COMPOSED OF CH3 (CH2)? 0-Op-PH-C (= 0) -GLY-A? FOMICI? A In a first step, the compound of ampomycin-9-Fmoc (38 mg, 0.022 mmol) is coupled with the compound β-tert-butoxycarbonyl glycine as described in the method of Example 3. The resulting intermediate is purified by HPLC and lyophilized. In a second step, this purified intermediate and para-dodecanoxobenzoic acid as used in the method described in Example 2 provide the title compound, which is purified by HPLC and lyophilized (10 mg, 30% yield): % pure, MS (MALDI) calculated for C66H? 0o ?? 4022 (M) 1412, found 1411.

EXAMPLE 122 COMPOSED OF CH3- (CH2) 9- (p-APA) -ANFOMYCIN In a first step, the compound of ampomycin-9-Fmoc (38 mg, 0.022 mmol) is coupled with 4-tert-butoxycarbonylaminophenylacetic acid as described in the method of Example 3. The resulting intermediate is purified by HPLC and lyophilized. In a second step, this purified intermediate and decanoyl acid as used in the method described in Example 2 provide the title compound, which is purified by HPLC and lyophilized (3 mg, 7% yield): 62% pure , MS (MALDI) calculated for C63H94N? 402? (M) 1384, found 1383.

EXAMPLE 123 COMPOSED OF C? 2-PABA-GLY-ANFOMYCIN The compound of ampicillin-9-Fmoc (15.8 mg) and the succinimid-1-yl ester N- (? -dodecanoyl-para-aminobenzoyl) glycine (7 mg, as prepared in Example 276 and succinimidyl ester as used in Example 1) used in the method as described in Example 3 is used to provide the title compound (7.6 mg): 82% pure, MS (FAB) calculated for C6sH9g ?? 5022 (M) 1455, found 1455.

EXAMPLE 124 COMPOSED OF C15-ANFOMICIN-9- (D-ORN) The compound of ampomycin-9-Fmoc (27 mg, 0.020 mmol) of Example 2 and (D) -5-tert-butoxycarbonylamino-2- (9H) acid -ylmethoxycarbonyl) -aminopentanoic acid is used as in the method described in Example 4 which provides the title compound (13 mg, 44% yield): 85% pure, MS (MALDI) calculated for C65HXo7? 502x (M) 1435, found 1434 EXAMPLE 125 COMPOSED OF CX4-ANFOMICIN-9-GLY-LYS The compound of CX4-ampicillin (100 mg, 0.077 mmol) of Example 10 and the compound N (2-N-tert-butoxycarbonyl-6- (9H-yl-methoxycarbonyl Lysinyl) glycine is used as in the method described in Example 4 which provides the title compound, which is purified by HPLC and lyophilized (60.5 mg, 54% yield): 85% pure, MS (MALDI) calculated for C67H ??? N? 6022 (M) 1492, found 1491.

EXAMPLE 126 COMPOSED OF C? 4-ANFOMICIN-9-LYS The compound of C14-ampicillin (22 mg, 0.017 mmol) of Example 10 and the compound 2-N-tert-butoxycarbonyl-6N- (9H-fluoren-9-yl) -methoxycarbonyl) lysine is used as in the method described in Example 4 which provides the title compound, which is purified by HPLC and lyophilized (9 mg, 38% yield): 77% pure, MS (MALDI) calculated for C65HXo7? X5? 2X (M) 1435, found 1434.

EXAMPLE 126 COMPOSED OF C? 4-A? FOMICI? -9-OR? The compound of CX4-ampicillin (22 mg, 0.017 mmol) of Example 10 and the compound 6-N-er-butoxycarbonyl-2-N- (9H-fluoren-9-yl-methoxycarbonyl) ornithine is used as in the method described in Example 4 providing the title compound, which is purified by HPLC and lyophilized (7 mg, 30% yield): 78% pure, MS (MALDI) calculated for C6HX05? X5O2? (M) 1421, found 1420.

EXAMPLE 128 COMPOSED OF C13-A? FOMICI? -9-GLY-LYS The compound of CX3-ampicillin (25 mg, 0.019 mmol) of Example 9 and the compound N- (2-N-tert-butoxycarbonyl-6-N- (9H-Fluoren-9-yl-methoxycarbonyl) lysinyl) glycine is used as in the method described in Example 4 which provides the title compound, which is purified by HPLC and lyophilized (13 mg, 46% yield): 93% pure, MS (MALDI) calculated for C66H? O8 i6? 22 (M) 1478, found 1477.

EXAMPLE 129 COMPOSED OF C? 5-ANFOMICIN-9-LYS The compound of C15-ampicillin (27 mg, 0.020 mmol) of Example 2 and the compound 2-N-tert-butoxycarbonyl-6- (9H-fluoren-9-yl) -methoxycarbonyl) lysine is used as in the method described in Example 4 which provides the title compound, which is purified by HPLC and lyophilized (9 mg, 30% yield). 99% pure, MS (MALDI) calculated for Cs6H? 09N? 5O21 (M) 1449, found 1448.

EXAMPLE 130 COMPOSED OF CX5-ANFOMICIN-9-ORN The compound of C15-ampicillin (27 mg, 0.020 mmol) of Example 2 and the compound 6-N-tert-butoxycarbonyl-2- (9H-fluoren-9-yl-methoxycarbonyl) ) Ornithine is used as in the method described in Example 4 which provides the title compound, which is purified by HPLC and lyophilized (10 mg, 34% yield): 98% pure, MS (MALDI) calculated for C_5H107N? 5O21 (M) 1435, found 1434.

EXAMPLE 131 COMPOSITE OF C? S-ANFOMICIN-9-GDAB The compound of CX5-ampicillin (27 mg, 0.020 mmol) of Example 2 and the compound (S) -2-tert-butoxycarbonylamino-4- (9H-fluoren-9) -yl-methoxycarbonyl) -aminobutyric acid is used as in the method described in Example 4 which provides the title compound, which is purified by HPLC and lyophilized (9 mg, 31% yield): 96% pure, MS (MALDI ) calculated for C6H? 05? 5O2? (M) 1421, found 1420.

EXAMPLE 132 COMPOSED OF C? 5-ANFOMICIN-9-DAP The compound of CX5-ampicillin (27 mg, 0.020 mmol) of Example 2 and the compound (S) -2-tert-butoxycarbonylamino-3- (9H-fluoren-9) -yl-methoxycarbonyl) -aminopropionic acid is used as in the method described in Example 4 providing the title compound, which is purified by HPLC and lyophilized (9 mg, 31% yield): 73% pure, MS (MALDI) calculated for CS3HXo3N50_.? (M) 1407, found 1406.

EXAMPLE 133 COMPOSED OF C? 3-ANFOMICIN-9-LYS The compound of C13-ampicillin (20 mg, 0.015 mmol) of Example 9 and the compound 2-N-tert-butoxycarbonyl-6- (9H-fluoren-9-yl) -methoxycarbonyl) lysine is used as in the method described in Example 4 which provides the title compound, which is purified by HPLC and lyophilized (8 mg, 37 yield): 97% pure, MS (MALDI) calculated for C64Ho5 ? X5? 2? (M) 1421, found 1420.

EXAMPLE 134 COMPOSED OF C13-A? FOMICI? -9-OR? The compound of C13-ampicillin (20 mg, 0.015 mmol) of Example 9 and the compound 6-N-er-butoxycarbonyl-2- (9H-fluoren-9-yl-methoxycarbonyl) ornithine is used as in the method described in Example 4 providing the title compound, which is purified by HPLC and lyophilized (9 mg, 42% yield): 86% pure, MS (MALDI) calculated for C63H? Or 3? 502? (M) 1407, found 1406.

EXAMPLE 135 COMPOSED OF C13-A? FOMICI? -9-GDAB The compound of C13-ampicillin (20 mg, 0.015 mmol) of Example 9 and the (S) -2-tert-butoxycarbonyl-4- (9H-fluoren- 9-yl-methoxycarbonyl) -aminobutyric acid is used as in the method described in Example 4 which provides the title compound, which is purified by HPLC and lyophilized (12 mg, 57% yield): 92% pure, MS ( MALDI) calculated for CS2HXO_LN1502X (M) 1393, found 1392.

EXAMPLE 136 COMPOSED OF CX3-ANFOMICIN-9-DAP The compound of CX3-ampicillin (20 mg, 0.015 mmol) of Example 9 and (S) -2-tert-butoxycarbonyl-3- (9H-fluoren-9-yl) acid -methoxycarbonyl) -aminopropionic acid is used as in the method described in Example 4 which provides the title compound, which is purified by HPLC and lyophilized (9 mg, 43% yield): 93% pure, calculated MS (MALDI) for CS? H99N1502? (M) 1379, found 1378.

EXAMPLE 137 COMPOSED OF C? 2-ANFOMICIN-9-LYS The C12-amphomycin compound (25 mg, 0.020 mmol) of Example 8 and the compound 2-N-tert-butoxycarbonyl-6- (9H-fluoren-9-yl) -methoxycarbonyl) lysine is used as in the method described in Example 4 which provides the title compound, which is purified by HPLC and lyophilized (14 mg, 53% yield): 100% pure, MS (MALDI) calculated for C.3HXo3? X502? (M) 1407, found 1407.

EXAMPLE 138 COMPOSED OF C12-ANFOMICIN-9-GDAB The compound of C12-ampicillin (25 mg, 0.020 mmol) of Example 8 and (S) -2-tert-butoxycarbonyl-4- (9H-fluoren-9-yl) acid -methoxycarbonyl) -aminobutyric acid is used as in the method described in Example 4 which provides the title compound, which is purified by HPLC and lyophilized (6 mg, 23% yield): 100% pure, calculated MS (MALDI) for C6? H99N? 502? (M) 1379, found 1378.

EXAMPLE 139 COMPOSITE OF C14-ANFOMICIN-9-GDAB The compound of C14 ~ ampomycin (22 mg, 0.017 mmol) of Example 10 and (S) -2- tert-butoxycarbonyl-4- (9H-fluoren-9-yl) acid -methoxycarbonyl) -aminobutyric acid is used as in the method described in Example 4 which provides the title compound, which is purified by HPLC and lyophilized (6 mg, 26% yield): 84% pure, calculated MS (MALDI) for CS3H? o3N502? (M) 1407, found 1406.

EXAMPLE 140 COMPOSED OF C14-ANFOMICIN-9-DAP The compound of C14-ampicillin (22 mg, 0.017 mmol) of Example 10 and (S) -2-er-butoxycarbonyl-3- (9H-fluoren-9-yl) acid -methoxycarbonyl) -aminopropionic acid is used as in the method described in Example 4 which provides the title compound, which is purified by HPLC and lyophilized (6 mg, 26% yield): 70% pure, calculated MS (MALDI) for C62HXoXNX502X (M) 1393, found 1392.

EXAMPLE 141 COMPOSED OF Cx6-ANFOMICIN-9-GLY-LYS The compound of C1S-ampicillin (30 mg, 0.022 mmol) of Example 11 and the compound N- (2-N-er-butoxycarbonyl-6- (9H-fluoren- 9-yl-methoxycarbonyl) lysinyl) glycine is used as in the method described in Example 4 which provides the title compound, which is purified by HPLC and lyophilized (4.5 mg, 13% yield): 79% pure, MS (MALDI) calculated for Ce9H ?? 4 ?? S022 (M) 1520, found 1519.

EXAMPLE 142 COMPOSED OF C? 7-A? FOMICI? -9-GLY-LYS The compound of C17-ampicillin (30 mg, 0.022 mmol) of Example 12 and the compound N- (2-N-tert-butoxycarbonyl-6-) (9H-Fluoren-9-yl-methoxycarbonyl) lisinyl) lycin is used as in the method described in Example 4 which provides the title compound, which is purified by HPLC and lyophilized (5.2 mg, 15% yield): 82% pure, MS (MALDI) calculated for C7oH? 6 6? 22 (M) 1534, found 1533.

EXAMPLE 143 COMPOSED OF C12-ANFOMICIN-9-GLY-LYS The compound of C 2 -amomycin (30 mg, 0.023 mmol) of Example 8 and the compound N- (2-N-tert-butoxycarbonyl-6- (9H- fluoren-9-yl-methoxycarbonyl) lysinyl) glycine is used as in the method described in Example 4 which provides the title compound, which is purified by HPLC and lyophilized (3.4 mg, 10% yield): 80% pure , MS (MALDI) calculated for C65H? OS ?? 602? (M) 1464, found 1463.

EXAMPLE 144 COMPOSED OF C15-A? FOMICI? -9-SAR-OR? The compound of C15-ampicillin (27 mg, 0.020 mmol) of Example 24 and the compound 6-N-tert-butoxycarbonyl-2- (9H-fluoren-9-yl-methoxycarbonyl) ornithine is used as in the method described in Example 4 providing the title compound, which is purified by HPLC and lyophilized (5 mg, 16% yield): 89% pure, MS (MALDI) calculated for C_8H? 2 ?? S022 (M) 1506, found 1505 .

EXAMPLE 145 COMPOSED OF C? 5-ANFOMICIN-9-SAR-GDAB The compound of Cx5-ampicillin (27 mg, 0.020 mmol) of Example 24 and (S) -2-N-tert-butoxycarbonyl-4- (9H) acid -fluoren-9-yl-methoxycarbonyl) -aminobutyric acid is used as in the method described in Example 4 which provides the title compound, which is purified by HPLC and lyophilized (5.8 mg, 19% yield): 92% pure , MS (MALDI) calculated for CS7H ?? or ?? _ 022 (M) 1492, found 1491.

EXAMPLE 143 COMPOSED OF C15-A? FOMICI? -9-SAR-DAP The compound of C15-ampicillin (27 mg, 0.020 mmol) of Example 24 and (S) -2-tert-butoxycarbonylamino-3- (9H-) acid Fluoren-9-yl-methoxycarbonyl) -aminopropionic acid is used as in the method described in Example 4 providing the title compound, which is purified by HPLC and lyophilized (4.7 mg, 16% yield): 83% pure, MS (MALDI) calculated for C6sH? O8 ?? 6022 (M) 1478, found 1477.

EXAMPLE 147 COMPOSED OF C? 5-A? FOMICI? -9- (ß-ALA) The compound of C15-ampicillin (250 mg, 0.089 mmol) of Example 2 and the compound N-tert-butoxycarbonyl-β-alanine is used as in the method described in Example 4 which provides the title compound, which is purified by HPLC and lyophilized (26.1 mg, 10% yield): 91% pure, MS (MALDI) calculated for C_3H? or N? 4021 ( M) 1392, found 1391.

EXAMPLE 148 COMPOSED OF C? 5-ANFOMICIN-9- (ß-ALA) -ORN The compound of C15-ampomicin-9- (ß-ala) (35 mg, 0. 025 mmol) of Example 147 and the compound 6-N-tert-butoxycarbonyl-2- (9H-fluoren-9-ylmethoxycarbonyl) ornithine is used as in the method described in Example 4 which provides the title compound, which is purify by HPLC and lyophilize (9.1 mg, 23% yield): 97% pure, MS (MALDI) calculated for C_ 8 H 2 x xe022 (M) 1506, found 1505.

EXAMPLE 149 COMPOSED OF ß-ISOMER OF C15-A? FOMICI? -9- (ß-ALA) The compound was obtained by using the method described in Example 147, wherein the compound is a by-product of this reaction (ß- isomer of the amphomycin peptide center). The title compound is purified by HPLC and lyophilized (8.8 mg, 3% yield): 86% pure, MS (MALDI) calculated for C63H? O2? 402? (M) 1392, found 1391.

EXAMPLE 150 COMPOSITE OF ISOMER ANHYDRO OF C? 5-ANFOMICIN-9- (ß-ALA) The title compound was obtained by using the method described in Example 147, wherein the compound is a by-product of this reaction (ß- isomer of the amphomycin peptide center). The title compound is purified by HPLC and lyophilized (18.4 mg, 7% yield): 80% pure, MS (MALDI) calculated for C_3HooN14020 (M) 1374, found 1373.

EXAMPLE 151 COMPOSED OF C15-ANFOMICIN-9- (D-PRO) - (D-LYS) The compound of C? 5-ampomicin-9- (D-Pro) (60 mg, 0. 042 mmol) of Example 67 and the compound (D) -2-N- tert-, butoxycarbonyl-6- (9H-fluoren-9-ylmethoxycarbonyl) lysine is used as in the method described in Example 4 which provides the compound of title, which is purified by HPLC and lyophilized (1.8 mg, 3% yield): 93% pure, MS (MALDI) calculated for C7? Hxxe? x6022 (M) 1546, found 1545.

EXAMPLE 152 COMPOSED OF C? 5-ANFOMICIN-9-GLY- (D-LYS) In a first stage, the compound of Cx5-ampicillin (24 mg, 0.018 mmol) of Example 2 is coupled with the N-tert-butoxycarbonylglycine compound as described in the method of Example 3. The resulting intermediate is purified by HPLC and lyophilized. In a second step, this purified intermediate and the compound (D) -6-N- (9H-fluoren-9-ylmethoxycarbonyl) -2 -? - (tert-butoxycarbonyl) lysine used in the method as described in Example 4 provide the title compound, which is purified by HPLC and lyophilized (16 mg, 58% yield): 82% pure, MS (MALDI) calculated for Cg8Hxx2 ?? e022 (M) 1506, found 1505.

EXAMPLE 153 COMPOSED OF C? 5-A? FOMICI? -9-GLY-OR? In a first step, the C15-amphomycin compound (24 mg, 0.018 mmol) of Example 2 is coupled with the N-tert-butoxycarbonylglycine compound as described in the method of Example 3. The resulting intermediate is purified by HPLC and lyophilizes. In a second step, this purified intermediate and the compound 2-N-tert-butoxycarbonyl-6- (9H-fluoren-9-ylmethoxycarbonyl) ornithine used in the method as described in Example 4 provides the title compound (18 mg , 66% yield): 68% pure, MS (MALDI) calculated for C57H? 10N? SO22 (M) 1492, found 1491.

EXAMPLE 154 COMPOSED OF C? 5-ANFOMICIN-9-GLY-GDAB In a first step, the compound of C15-ampicillin (24 mg, 0.018 mmol) of Example 2 is coupled with the N-tert-butoxycarbonylglycine compound as described in the method of Example 3. The resulting intermediate is purified by HPLC and lyophilized. In a second step, this purified intermediate and (S) -2-tert-butoxycarbonylamino-4- (9H-fluoren-9-ylmethoxycarbonyl) -aminobutyric acid used in the method as described in Example 4 provides the title compound , which is purified by HPLC and lyophilized (16 mg, 58% yield): 82% pure, MS (MALDI) calculated for C6eH108? 6? 22 (M) 1478, found 1477.

EXAMPLE 155 COMPOSED OF C? 5-A? FOMICI? -9- (? -ALA) -LYS In a first step, the compound of C15-ampicillin (27 mg, 0.020 mmol) of Example 2 is coupled with the N-tert-butoxycarbonyl-beta-alanine compound as described in the method of Example 3. The resulting intermediate is purified by HPLC and lyophilized. In a second step, this purified intermediate and the compound 2-N-tert-butoxycarbonyl-6- (9H-fluoren-9-ylmethoxycarbonyl) lysine used in the method as described in Example 4 provide the title compound, which purify by HPLC and lyophilize (19 mg, 61% yield): 84% pure, MS (MALDI) calculated for C 9 H 4 N 6022 (M) 1520, found 1519.

EXAMPLE 156 COMPOSED OF C? 5-ANFOMICIN-9-GABA-LYS In a first step, the compound of C15-ampicillin (25 mg, 0.019 mmol) is coupled with the? -N-te-butoxycarbonylamino butanoic acid as described in the method of Example 3. The resulting intermediate is purified by HPLC and lyophilized. In a second step, this purified intermediate and the compound 2-β-tert-butoxycarbonyl-6- (9H-fluoren-9-ylmethoxycarbonyl) lysine used in the method as described in Example 4 provides the title compound, which purify by HPLC and lyophilize (19.2 mg, 66% yield): 95% pure, MS (MALDI) calculated for C70H ?? and SO22 (M) 1534, found 1533.

EXAMPLE 157 COMPOSED OF C? 5-A? FOMICI? -9-GLY-DAP In a first stage, the compound of C15-ampicillin (22 mg, 0.017 millimoles) of Example 2 is coupled with the N-tert-butoxycarbonyl glycine compound as described in the method described in Example 3. The resulting intermediate is purified by HPLC and lyophilized. In a second step, this purified intermediate and the (S) -2-tert-butoxycarbonylamino-3- (9H-fluoren-9-ylmethoxycarbonylamino) -propionic acid used in the method as described in Example 4 provides the title compound, which is purified by HPLC and lyophilized (8.7 mg, 36% yield): 73% pure, MS (MALDI) calculated for Ce5H? Oe? 602 (M) 1464, found 1463.

EXAMPLE 158 COMPOSED OF C? 5-A? FOMICI? -9-GLY-HLYS In a first stage, the compound of C15-ampicillin (35 mg, 0.027 mmol) of Example 2 is coupled with the N-er-butoxycarbonyl glycine compound as described in the method described in Example 3. The resulting intermediate is purified by HPLC and lyophilized. In a second step, this purified intermediate and (S) -2-tert-butoxycarbonylamino-7- (9H-fluoren-9-ylmethoxycarbonylamino) -heptanoic acid used in the method as described in Example 4 provides the title compound , which is purified by HPLC and lyophilized (6.8 mg, 17% yield): 91% pure, MS (MALDI) calculated for Ce9H? 14N16022 (M) 1520, found 1519.

EXAMPLE 159 COMPOSITE OF C? 5-ANFOMICIN-9-GABA-GDAB In a first step, the compound of Ca5-ampicillin (25 mg, 0.019 mmol) of Example 2 is coupled with the α-N-tert-butoxycarbonyl-aminobutanoic acid as described in the method described in Example 3. The resulting intermediate is purified by HPLC and lyophilized. In a second step, this purified intermediate and (S) -2-tert-butoxycarbonylamino-4- (9H-fluoren-9-ylmethoxycarbonyl) -aminobutyric acid used in the method as described in Example 4 provides the title compound , which is purified by HPLC and lyophilized (17.2 mg, 46% yield): 76% pure, MS (MALDI) calculated for C68H? 12 ?? 6022 (M) 1506, found 1505.

EXAMPLE 160 COMPOSED OF C? 5-A? FOMICI? -9-PRO The compound of C15-ampicillin (45 mg, 0.034 mmol) of Example 2 and the compound N- (9H-fluoren-9-ylmethoxycarbonyl) -proline used in the method described as in Example 5 provides the title compound, which is purified by HPLC and lyophilized (11 mg, 23% yield): 85% pure, MS (MALDI) calculated for C65H? 04N14O2? (M) 1418, found 1417.

EXAMPLE 161 COMPOSED OF C? 5-ANFOMICIN-9-AlB The compound of C15-ampicillin (30 mg, 0.023 mmol) of Example 2 and the compound 2-N- (9 H -fluoren-9-yl-methoxycarbonyl) -2, 2-Dimethylglycine used in the method described as in Example 5 provides the title compound, which is purified by HPLC and lyophilized (8 mg, 25% yield): 82% pure, MS (MALDI) calculated for Ce 4 H 4. ?? 4021 (M) 1406, found 1405.

EXAMPLE 162 COMPOSITE OF C? 5-A? FOMICI? -9-MECYS The compound of C15-ampicillin (40 mg, 0.030 mmol) of Example 2 and the acid (S) -2- (9H-fluoren-9-yl- methoxycarbonyl) -amino-3-methyl-sulphane-propionic acid used in the method described as in Example 5 provides the title compound, which is purified by HPLC and lyophilized (10 mg, 23% yield): 98% pure, MS ( MALDI) calculated for C64H? 04? 14O21 (M) 1438, found 1437.

EXAMPLE 163 COMPOSED OF C? 5-A? FOMICI? -9-? VL The compound of C15-ampicillin (40 mg, 0.030 mmol) of Example 2 and (S) -2- (9H-fluoren-9-yl) acid -methoxycarbonyl) -aminopentanoic acid used in the method described as in Example 5 provides the title compound, which is purified by HPLC and lyophilized (9 mg, 21% yield): 97% pure, MS (MALDI) calculated for CS4H ? o4N1402? (M) 1420, found 1419.

EXAMPLE 164 COMPOSITE OF C15-ANFOMICIN-9-ABU The compound of Cx5-ampicillin (40 mg, 0.030 mmol) of Example 2 and the (S) -2- (9H-fluoren-9-yl-methoxycarbonyl) -aminobutanoic acid used in the method described as in Example 5 provides the title compound, which is purified by HPLC and lyophilized (11 mg, 25% yield): 92% pure, MS (MALDI) calculated for CS4H? o4N? 402? (M) 1406, found 1405.

EXAMPLE 165 COMPOSED OF C? 5-ANFOMICIN-9-CIT The compound of C15-ampicillin (40 mg, 0.030 ilimoles) of Example 2 and the acid (S) -2- (9H-fluoren-9-yl-methoxycarbonyl) - 5-ureido-pentanoic used in the method described as in Example 5 provides the title compound, which is purified by HPLC and lyophilized (11 mg, 25% yield): 89% pure, MS (MALDI) calculated for CeeH ? o8N? 6022 (M) 1478, found 1477.

EXAMPLE 166 COMPOSED OF C? 5-ANFOMICIN-9- (ME) 2-ARG The compound of C15-ampicillin (40 mg, 0.030 mmol) of Example 2 and the compound (S) -2- (9H-fluoren-9- il-methoxycarbonylamino) -N / N'-methylarginine used in the method described as in Example 5 provides the title compound, which is purified by HPLC and lyophilized (2 mg, 4% yield): 87% pure, MS (MALDI) calculated for C68H 3? 1702? (M) 1505, found 1504.

EXAMPLE 163 COMPOSED OF C15-A? FOMICI? -9-HYP The compound of C15-ampicillin (30 mg, 0.023 mmol) of Example 2 and the ester 1- (9H-fluoren-9-yl-methyl) of the acid (S) ) -4-hydroxy-pyrrolidin-1,2-dicarboxylic acid used in the method described as in Example 5 provides the title compound, which is purified by HPLC and lyophilized (12 mg, 37% yield): 71% pure , MS (MALDI) calculated for C65H? 0 ?? O2? (M) 1434, found 1433.

EXAMPLE 168 COMPOSED OF C? 5-ANFOMICIN-9- (p-APA) The compound of C15-ampicillin (30 mg, 0.023 mmol) of Example 2 and 4-N- (9H-fluoren-9-yl-methoxycarbonyl) ) aminophenylacetic used in the method as described in Example 5 to provide the title compound, which is purified by HPLC and lyophilized (12 mg, 37% yield): 71% pure, MS (MALDI) calculated for C6BHXO4? X402X (M) 1454, found 1453.

EXAMPLE 169 COMPOSED OF C15-A? FOMICI? -9-VAL The compound of Cx5-amphotomycin (27 mg, 0.020 mmol) of Example 2 and the compound N- (9H-fluoren-9-yl-methoxycarbonyl) valine used in the Method as described in Example 5 to provide the title compound, which is purified by HPLC and lyophilized (6 mg, 21% yield): 64% pure, MS (MALDI) calculated for Ce5H? or? 401 (M ) 1420, found 1419.

EXAMPLE 170 COMPOSED OF C? 5-A? FOMICI? -9- (ME) 3-LYS The compound of CX5-ampicillin (31 mg, 0.023 mmol) of Example 2 and the compound [(S) -5-carboxy-5) - (9H-Fluoren-9-yl-methoxycarbonylamino) -pentyl] -trimethyl-ammonium used in the method as described in Example 5 to provide the title compound, which is purified by HPLC and lyophilized (8 mg, % yield): 87% pure, MS (MALDI) calculated for C69H ?? eN? 502? (M) 1492, found 1491.

EXAMPLE 171 COMPOSED OF C? 5-ANFOMICIN-9-NLE The compound of C15-ampicillin (27 mg, 0.020 mmol) of Example 2 and the acid (S) -2- (9H-fluoren-9-yl-methoxycarbonylamino) - hexanoic used in the method as described in Example 5 to provide the title compound, which is purified by HPLC and lyophilized (10 mg, 34% yield): 95% pure, MS (MALDI) calculated for CeeHXo8NX402x (M) 1434, found 1433.

EXAMPLE 172 COMPOSED OF C? 5-ANFOMICIN-9-LYS The compound of C15-ampicillin (26 mg, 0.019 mmol) of Example 2 and the compound 6-formyl-N-2- (9H-fluoren-9-yl-methoxycarbonyl) Lysine used in the method as described in Example 5 to provide the title compound, which is purified by HPLC and lyophilized (10 mg, 34.3% yield): 88% pure, MS (MALDI) calculated for Ce7H? 09 ?? 5O22 (M) 1477, found 1476.

EXAMPLE 173 COMPOSED OF CX5-ANFOMICIN-9- (ß-ALA) - (5-ALA) The compound of Cx5-ampicillin (33 mg, 0.025 mmol) of Example 147 and the acid 5- (9H-fluoren-9-yl) -methoxycarbonylamino) -pentanoic used in the method as described in Example 5 to provide the title compound, which is purified by HPLC and lyophilized (8 mg, 21% yield): 83% pure, MS (MALDI) calculated for Ce8HxlxNx5022 (M) 1491, found 1490.

EXAMPLE 174 COMPOSED OF C? 5-ANFOMICIN-9- (ß-ALA) -VAL In a first step, the compound of C15-ampicillin (26 mg, 0.019 mmol) is coupled with the compound N-tert-butoxycarbonyl-β- alanine as described in the method of Example 3. The resulting intermediate is purified by HPLC and lyophilized. In a second step, this purified intermediate and the compound N- (9H-fluoren-9-yl-methoxycarbonyl) alina used as in the method described in Example 5 provides the title compound, which is purified by HPLC and freeze-dried (10 mg, 35% yield): 76% pure, MS (MALDI) calculated for CS8H ????? 5022 (M) 1491, found 1490.

EXAMPLE 175 ß-ISOMER OF THE COMPOUND OF C? 5-ANFOMICIN-9- (ß-ALA) -VAL The title compound is obtained by using the method described in Example 174, wherein the compound is a by-product of this reaction (ß-isomer of the nucleus of the amphomycin peptide). The title compound is purified by HPLC and lyophilized (2.2 mg, 7% yield): 91% pure, MS (MALDI) calculated for Ce_.H? ___ N? 5? 22 (M) 1491, found 1490.

EXAMPLE 176 COMPOSED OF C15-ANFOMICIN-9- (5-AVA) (ß-ALA) In a first step, the compound of C15-ampicillin (26 mg, 0.019 mmol) is coupled with the 5- (9H-fluoren- 9-yl-methoxycarbonylamino) -pentanoic acid as described in the method of Example 3. The resulting intermediate is purified by HPLC and lyophilized. In a second step, this purified intermediate and the N-er-butoxycarbonyl-β-alanine compound used as in the method described in Example 5 provides the title compound, which is purified by HPLC and lyophilized (10.8 mg , 27% yield): 99% pure, MS (MALDI) calculated for Ce8H ????? 5022 (M) 1491, found 1490.

EXAMPLE 177 PREPARATION OF THE FMOC-GLYCINE RESIN (GR) A solution of N- (9H-fluoren-9-ylmethoxycarbonyl) -glycine (1.45 g, 4.8 mmol) and DIEA (2.83 mL, 16 mmol) in dichmethane (DCM, 20 mg). ml) was mixed with 2-chtrylamine resin (2.11 g, 4 mmol). After stirring for 2 hours at room temperature, the resin was filtered, washed three times with a DCM: methanol: DIEA cocktail. (17: 2: 1), followed by another two times each with DCM, DMF and finally, DCM. The GR resin was allowed to dry (4.5 g, 4 mmol).

EXAMPLE 178 PREPARATION OF FMOC-LYSINE RESIN (BOC) (KR) The use of 2-chtrylamine resin (2.11 g, 4 mmol) and the compound -2 N -tert-butoxycarbonyl-6- (9H-fluoren-9- il-methoxycarbonyl) lysine as described in method 177 gives the title compound KR (4.5 g, 4 mmol).

EXAMPLE 179 PREPARATION OF FMOC-SARCOSINE RESIN (SR) The use of 2-chtrylamine resin (2.11 g, 4 mmol) and the compound N- (9H-fluoren-9-yl-ethoxycarbonyl) sarcosine as described in the method of Example 177 gives the title compound SR (4.5 g, 4 mmol).

EXAMPLE 180 PREPARATION OF THE FMOC-GLYCINE-LYSINE (BOC) -OH (GK) RESIN The KR resin (0.75 g, 0.67 mmol) is suspended in DMF (5 ml) and piperidine (1 ml, 20% v / v). After mixing and stirring for 30 minutes, the resin is filtered and washed with DMF (twice, with 5 ml each). The resin is suspended in 8 ml DMF. To the reaction mixture are added N- (9H-fluoren-9-yl-methoxycarbonyl) glycine (1.57 g, 3.35 mmol), O-benzotriazol-1-yl-N / N / N'N'-tetramethyluronium hexafluorophosphate ( 1.27 g, 3.35 mmol), 1-hydroxybenzotriazole (0.51, 3.35 mmol) and 0.74 ml of N-methylmorpholine (6.7 mmol) and the reaction mixture is stirred for 6 hours at room temperature. After filtration, the resin is washed with DMF (twice, 5 ml). The cracking of the resin is accompanied by the use of 5 ml of a mixture of acetic acid: tetrafluoroethane: DCM (2: 2: 6). After 2 hours, the cracked resin is filtered and the filtrate contains the product is concentrated in vacuo to provide a light cod title compound (GK) in the form of a powder (240 mg).

EXAMPLE 181 PREPARATION OF THE FMOC-D-LEUCINE-GLICINE-OH (DLG) RESIN The use of the compound GR (0.75 g, 0.67 mmol) of Example 177 and the compound N- (9H-fluoren-9-yl-methoxycarbonyl) leucine as described in the method of Example 180 provides the title compound dLG (154 mg).

EXAMPLE 182 PREPARATION OF RESIN 6-FMOC-AMINOHEXANOIL-GLICINA-OH (AG) The use of compound GR (0.75 g, 0.67 mmol) of Example 177 and 6- (9H-fluoren-9-yl-methoxycarbonylamino) hexanoic acid as described in the method of Example 180 provides the title compound AG (163 mg).

EXAMPLE 183 PREPARATION OF RESIN 6-FMOC-AMINOHEXANOIL-SARCOSINE-OH (AS) The use of compound SR (0.75 g, 0.67 mmol) of Example 179 and 6- (9H-fluoren-9-yl-methoxycarbonylamino) hexanoic acid as described in the method of Example 180 provides the title compound AG (161 mg).

EXAMPLE 184 PREPARATION OF THE FMOC-LYSINE RESIN (BOC) -GLIC NA-OH (KS) The use of the compound SR (0.75 g, 0.67 mmol) of Example 179 and the compound 2-N-tert-butoxycarbonyl-6- (9H) -fluoren-9-yl-methoxycarbonyl) lysine as described in the method of Example 180 provides the title compound KS (201 mg).

EXAMPLE 185 PREPARATION OF THE FMOC-LYSINE RESIN (BOC) -GLYCIN-GLICINE-OH (KGG) The GR resin (0.75 g, 0.67 mmol) of Example 177 is suspended in DMF (5 mL) and piperidine (1 mL, 20% v / v). After mixing and stirring for 30 minutes, the resin is filtered and washed with DMF (twice, with 5 ml each). The resin is suspended in 8 ml DMF. To the reaction mixture are added N- (9H-fluoren-9-yl-methoxycarbonyl) glycine (1.57 g, 3.35 mmol), O-benzotriazol-1-yl-N ^ N / N ^ N'-tetramethyluronium hexafluorophosphate ( 1.27 g, 3.35 mmol), 1-hydroxybenzotriazole (0.51), 3.35 mmol) and 0.74 ml of N-methylmorpholine (6.7 mmol) and the reaction mixture is stirred for 6 hours at room temperature. After filtration, the resin is washed with DMF (twice, 5 ml) and suspended in 5 ml of DMF. 2-N-tert-butoxycarbonyl-6- (9H-fluoren-9-yl-methoxycarbonyl) lysine (1.57 g, 3.35 mmol), O-benzotriazole-1-yl- N / N / N '/ N hexafluorophosphate are added. '-tetramethyluronium (1.27 g, 3.35 mmol), 1-hydroxybenzotriazole (0.51, 3.35 mmol) and 0.74 ml of N-methylmorpholine (6.7 mmol). The reaction mixture is stirred for 6 hours at room temperature. After filtration, the resin is washed with DMF (5 ml). The cracking of the resin is accompanied by the use of 5 ml of a mixture of acetic acid: tetrafluoroethane: DCM (2: 2: 6). After 2 hours, the cracked resin is filtered and the filtrate contains the product concentrated in vacuo to provide a relatively clear title compound (KGG) in the form of a powder (170 mg).

EXAMPLE 186 PREPARATION OF THE RESIN FMOC-GLICINE-LYSINE (BOC) -GLYCIN-OH (GKG) The KGR resin (0.67 mmol) is suspended in DMF (5 ml) and piperidine (1 ml, 20% v / v). After mixing and stirring for 30 minutes, the resin is filtered and washed with DMF (twice, with 5 ml each). The resin is suspended in 8 ml DMF. N- (9H-fluoren-9-yl-methoxycarbonyl) glycine (1.0 g, 3.35 mmol), 0-benzotriazol-1-yl-N, N, N ', N' -tetramethyluronium hexafluorophosphate are added to the reaction mixture. (1.27 g, 3.35 mmol), 1-hydroxybenzotriazole (0.51, 3.35 mmol) and 0.74 ml of N-methylmorpholine (6.7 mmol) and the reaction mixture is stirred for 6 hours at room temperature. After filtration, the resin is washed with DMF (twice, 5 ml). The resin cracking is accompanied by using 4 ml of a mixture of acetic acid: tetrafluoroethane: DCM (2: 2: 6). After 2 hours, the cracked resin is filtered and the filtrate contains the product concentrated in vacuo to provide a relatively clear title compound (GKG) in the form of a powder (180 mg).

EXAMPLE 187 PREPARATION OF THE FMOC-GLICINE-LYSINE RESULT (BOC) -LYSIN (BOC) -GLYCIN-OH (KKG) The KGR resin (0.67 mmol) is suspended in DMF (5 ml) and piperidine (1 ml, 20% v / v). After mixing and stirring for 30 minutes, the resin is filtered and washed with DMF (twice, with 5 ml each). The resin was resuspended in 8 ml DMF. To the reaction mixture are added 2-N-tert-butoxycarbonyl-6- (9H-fluoren-9-yl-methoxycarbonyl) lysine (1.5 g, 3.35 mmol), O-benzotriazole-1-yl-N-1 hexafluorophosphate. N ^ N '-tetramethyluronium (1.27 g, 3.35 mmol), 1-hydroxybenzotriazole (0.51, 3.35 mmol) and 0.74 ml of N-methylmorpholine (6.7 mmol) and the reaction mixture is stirred for 6 hours at room temperature. After filtration, the resin is washed with DMF (twice, 5 ml). The resin cracking is accompanied by using 4 ml of a mixture of acetic acid: tetrafluoroethane: DCM (2: 2: 6). After 2 hours, the cracked resin is filtered and the filtrate contains the product is concentrated in vacuo to give a relatively clear title compound (KKG) in the form of a powder (310 mg).

EXAMPLE 188 PREPARATION OF THE FMOC-LYSINE RESIN (BOC) -LYSIN (BOC) -OH (KK) The use of the compound KR (0.75 g, 0.67 mmol) of Example 178 and the compound 2-N-tert-butoxycarbonyl-6- (9H-Fluoren-9-yl-methoxycarbonyl) lysine as described in the method of Example 187 gives the title compound KK (350 mg).

EXAMPLE 189 PREPARATION OF FMOC-LYSINE RESIN (BOC) -LYSIN (BOC) -LYSIN (BOC) -OH (KKK) Two couplings of 2-N-tert-butoxycarbonyl-6- (9H-fluoren-9-yl) are used. -methoxycarbonyl) lysine with KR (0.75 g, 0.67 mmol) of Example 178 as described in the method of Example 187 and the title compound KKK (350 mg) is provided.

EXAMPLE 190 COMPOSED OF C? 5-A? FOMICI? -9-GLY-LYS-GLY The compound of C15-ampicillin (25 mg, 0.019 mmol) of Example 2 and the GKG peptide of Example 186 used in the method as described in Example 4 provide the title compound, which is purified by HPLC and lyophilized (20 mg, 68% yield): 77% pure, MS (MALDI) calculated for C70H ??5N17O23 () 1563, found 1562.

EXAMPLE 19 COMPOSED OF C? 5-ANFOMICIN-9-GLY-LYS-LYS The compound of C15-ampicillin (25 mg, 0.019 mmol) of Example 2 and the KKG peptide of Example 187 used in the method as described in the Example 4 provide the title compound, which is purified by HPLC and lyophilized (16 mg, 52% yield): 74% pure, MS (MALDI) calculated for C7H124NX8023 (M) 1634, found 1633.

EXAMPLE 190 COMPOSED OF C15-ANFOMICIN-9-GLY-GLY-LYS The compound of C15-ampicillin (25 mg, 0.019 mmol) of Example 2 and the peptide KGG of Example 185 used in the method as described in Example 4 provide the title compound, which is purified by HPLC and lyophilized (20 mg, 54% yield): 88% pure, MS (MALDI) calculated for C70H? X5NX7O23 (M) 1563, found 1562.

EXAMPLE 193 COMPOSED OF C15-ANFOMICIN-9-LYS-GLY The C15-ampicillin compound (25 mg, 0.019 mmol) of Example 2 and the GK peptide of Example 180 used in the method as described in Example 4 provide the compound titre, which is purified by HPLC and lyophilized (18 mg, 63% yield): 91% pure, MS (MALDI) calculated for Ce8Hn2N? 6022 (M) 1506, found 1505.

EXAMPLE 194 COMPOSED OF C15-ANFOMICIN-9-LYS-LYS The compound of C15-ampicillin (25 mg, 0.019 mmol) of Example 2 and the KK peptide of Example 188 used in the method as described in Example 4 provide the compound titre, which is purified by HPLC and lyophilized (7 mg, 23% yield): 72% pure, MS (MALDI) calculated for C72H? 2? N? 7022 (M) 1577, found 1576.

EXAMPLE 195 COMPOSED OF C? 5-ANFOMICIN-9-LYS-LYS-LYS The compound of C15-ampicillin (25 mg, 0.019 mmol) of Example 2 and the KKK peptide of Example 189 used in the method as described in the Example 4 provide the title compound, which is purified by HPLC and lyophilized (18 mg, 56% yield): 91% pure, MS (MALDI) calculated for C78H? 33N? 9023 (M) 1705, found 1704.

EXAMPLE 190 COMPOSED OF C? 5-ANFOMIC N-9-GLY- (D-LEU) The compound of C15-ampicillin (25 mg, 0.019 mmol) of Example 2 and the dLG peptide of Example 181 used in the method as described in Example 4 provide the title compound, which is purified by HPLC and lyophilized (5.4 mg, 19% yield): 83% pure, MS (MALDI) calculated for CS8H? _? N? 5022 (M) 1491, found 1490.

EXAMPLE 19 COMPOSED OF C? 5-ANFOMICIN-9-GLY-AHX The compound of C15-ampicillin (25 mg, 0.019 mmol) of Example 2 and the peptide AG of Example 182 used in the method as described in Example 4 provide the title compound, which is purified by HPLC and lyophilized (4.1 mg, 15% yield): 98% pure, MS (MALDI) calculated for C68H ??? N? 5022 (M) 1491, found 1490.

EXAMPLE 198 COMPOSED OF C15-ANFOMICIN-9-SAR-AHX The compound of C1S-ampomycin (25 mg, 0.019 mmol) of Example 2 and the peptide AS of Example 183 used in the method as described in Example 4 provide the compound titre, which is purified by HPLC and lyophilized (3.5 mg, 12% yield): 98% pure, MS (MALDI) calculated for C69H ?? 3NX5022 (M) 1505, found 1504.

EXAMPLE 199 COMPOSED OF C15-ANFOMICIN-9-SAR-LYS The C15-ampicillin compound (25 mg, 0.019 mmol) of Example 2 and the KS peptide of Example 184 used in the method as described in Example 4 provide the compound titre, which is purified by HPLC and lyophilized (2.5 mg, 9% yield): 84% pure, MS (MALDI) calculated for CS9H ?? 4N? e022 (M) 1520, found 1519.

EXAMPLE 200 COMPOSED OF C? 5-ANFOMICIN-9-SAR-AHX The compound of C15-ampicillin (25 mg, 0.019 mmol) of Example 2 and the acid (S) -3- [(9H-fluore-9-il- methoxycarbonyl) -β-alaninyl] amino-2-er-butoxycarbonylamino propionic acid (the last compound prepared using the method described in Example 180) used in the method described in Example 4 provide the title compound, which is purified by HPLC and lyophilized (2.8 mg, 7% yield): 85% pure, MS (MALDI) calculated for Cs6H105N? SO _._. (M) 1478, found 1477.

EXAMPLE 201 COMPOSED OF C? 5-ANFOMICIN-9-C6 The compound of C15-ampicillin (27 mg, 0.020 mmol) of Example 2 is suspended in 1 ml DMF and then loaded with 102 μL of 1M sodium bicarbonate (in water) , 0.10 millimoles). The reaction mixture is cooled in an ice bath. A previously dissolved solution of activated hexokinic acid succinimide (1.5 equivalents, prepared as described for the succinimid-1-yl compound of pentadecanoic acid of Example 1) in 0.5 ml DMF is slowly added to the reaction mixture by the ice technique, then the reaction is stirred for at least 8 hours at room temperature to provide a crude product of the title compound. This crude product is concentrated in vacuo, purified by HPLC (25% gradient, acetonitrile in water with 0.1% trifluoroacetic acid for 95% acetonitrile for 30 minutes), and lyophilized (5 mg, 17% yield): 80% pure , MS (MALDI) calculated for CeeHXo7N? 3021 (M) 1419, found 1418.

EXAMPLE 202 COMPOSED OF C15-ANFOMICIN-9-PLA The compound of C15-ampicillin (30 mg, 0.023 mmol) of Example 2 and picolinic acid used in the method described in Example 201 provides the title compound, which is purified by HPLC and lyophilized (10 mg, 31% yield): 100% pure, MS (MALDI) calculated for CeeH? oo? 402? (M) 1426, found 1425.

EXAMPLE 203 COMPOSED OF C? 5-ANFOMICIN-9-PCA The compound of C15-ampicillin (30 mg, 0.023 mmol) of Example 2 and 2-pyrazinecarboxylic acid used in the method described in Example 201 provides the title compound, which purify by HPLC and lyophilize (11 mg, 34% yield): 97% pure, MS (MALDI) calculated for C65Hc.9N? 502? (M) 1427, found 1426.

EXAMPLE 204 COMPOSED OF C15-ANFOMICIN-9- (CARBAMOIL-LEU) The compound of C15-ampicillin (30 mg, 0.023 mmol) of Example 2 and N-carbamoilleucine acid used in the method described in Example 201 provides the title compound , which is purified by HPLC and lyophilized (12 mg, 36% yield): 100% pure, MS (MALDI) calculated for Ce7H? 09N? 5O22 (M) 1477, found 1476.

EXAMPLE 205 COMPOSED OF C? 5-ANFOMICIN-9-C8 The compound of C15-ampicillin (24 mg, 0.018 mmol) of Example 2 and the octanoic acid used in the method described in Example 201 provides the title compound, which is purify by HPLC and lyophilize (4 mg, 15% yield): 85% pure, MS (MALDI) calculated for CS8HxxxN1302? (M) 1447, found 1446.

EXAMPLE 206 COMPOSED OF C? 5-ANFOMICIN-9-cHEXILO The C? 5-amphomycin compound (27 mg, 0.020 mmol) of Example 2 and the cyclohexanecarbolic acid used in the method described in Example 201 provide the title compound, which is purified by HPLC and lyophilized (8 mg, 27% yield): 86% pure, MS (MALDI) calculated for Cg7H? 07Ni3? 2 (M) 1431, found 1430.

EXAMPLE 207 COMPOSED OF C? 5-ANFOMICIN-9-C4 The compound of C15-ampicillin (24 mg, 0.018 mmol) of Example 2 and the butyric acid used in the method described in Example 201 provides the title compound, which is purify by HPLC and lyophilize (6 mg, 24% yield): 70% pure, MS (MALDI) calculated for C64H? o3Ni3? 2? (M) 1391, found 1390.

EXAMPLE 208 COMPOSED OF C? 5-ANFOMICIN-9- (2-NORBORNNANOPATHYL) The compound of C15-ampicillin (27 mg, 0.020 millimole) of Example 2 and the 2-norbornoaneacetic acid used in the method described in Example 201 provides the title compound, which is purified by HPLC and lyophilized (8 mg, 27% yield). 91% pure, MS (MALDI) calculated for C69H109N? 3? 2? (M) 1457, found 1456.

EXAMPLE 209 COMPOSED OF C15-ANFOMICIN-9- (N-BENZOYL-TYR-TABA) The compound of C15-ampicillin (27 mg, 0.020 mmol) of Example 2 and (S) -4- [2-benzoylamino-3 - (4-hydroxy-phenyl) -propionylamino] -benzoic acid used in the method described in Example 201 provides the title compound, which is purified by HPLC and lyophilized (4 mg, 11% yield): 91% pure, MS (MALDI) calculated for C83H ?? 5Ni5? 24 (M) 1707, found 1706.

EXAMPLE 210 COMPOSED OF C? 5-ANFOMICIN-9- ((S) - (+) - 5-0X0-2- TETRAHYDROFURANCARBONYL) The compound of C15-ampicillin (25 mg, 0.019 mmol) of Example 2 and the acid (s) ) - (+) - 5-oxo-2-tetrahydrofurancarboxylic acid used in the method described in Example 201 provides the title compound, which is purified by HPLC and lyophilized (6 mg, 22% yield): 80% pure, MS (MALDI) calculated for Ce5H? Or? N? 3023 (M) 1433, found 1433.

EXAMPLE 211 COMPOSED OF C? 5-ANFOMICIN-9-FENILPROPINYL The C15-ampicillin compound (27 mg, 0.020 mmol) of Example 2 and the phenylpropinoic acid used in the method described in Example 201 provides the title compound, which is purify by HPLC and lyophilize (3 mg, 10% yield): 70% pure, MS (MALDI) calculated for C69H? or? N? 3021 (M) 1449, found 1448.

EXAMPLE 212 COMPOSED OF C? 5-ANFOMICIN-9- (CARBAMOIL-ß-ALA) The compound of C? 5-ampomycin (30 mg, 0.023 mmol) of Example 2 and the compound N-carbamoyl-β-alanine used in the The method described in Example 201 provides the title compound, which is purified by HPLC and lyophilized (14 mg, 43% yield): 99% pure, MS (MALDI) calculated for Ce4H? 03N? 5O22 (M) 1435, found 1434 EXAMPLE 213 COMPOSED OF C15-ANFOMICIN-9-ACRYL The C15-ampicillin compound (30 mg, 0.023 mmol) of Example 2 and the acrylic acid used in the method described in Example 201 provides the title compound, which is purified by HPLC and lyophilized (3 mg, 10% yield): 95% pure, MS (MALDI) calculated for Ce3H59N? 30? (M) 1375, found 1374.

EXAMPLE 214 COMPOSED OF C? 5-ANF0MICIN-9- (1-NAFYLACEILE) The compound of C15-ampicillin (30 mg, 0.023 mmol) of Example 2 and the 1-naphthylacetic acid used in the method described in Example 201 provides the title compound, which is purified by HPLC and lyophilized (9 mg, 27% yield): 93% pure, MS (MALDI) calculated for C72H? o5N? 302? (M) 1489, found 1488.

EXAMPLE 215 COMPOSED OF C? 5-ANFOMICIN-9- (4-PHENOXIBENZOYL) The compound of C15-ampicillin (30 mg, 0.023 mmol) of Example 2 and the 4-phenoxybenzoic acid used in the method described in Example 201 provides the title compound, which is purified by HPLC and lyophilized (5 mg, 15% yield): 87% pure, MS (MALDI) calculated for C73H? o5Ni3? 22 (M) 1517, found 1516.

EXAMPLE 216 COMPOSED OF C15-ANFOMICIN-9- (2-NAFYLACEILE) The compound of C15-ampicillin (30 mg, 0.023 mmol) of Example 2 and the 2-naphthylacetic acid used in the method described in Example 201 provides the compound titre, which is purified by HPLC and lyophilized (5 mg, 15% yield): 84% pure, MS (MALDI) calculated for C72H? o5N? 302? (M) 1489, found 1488.

EXAMPLE 217 COMPOSED OF C? 5-ANFOMICIN-9- (2-FURYL) The compound of C1S-ampicillin (30 mg, 0.023 millimoles) of Example 2 and the 2-furan-carboxylic acid used in the method described in Example 201 provide the title compound, which is purified by HPLC and lyophilized (10 mg, 31% yield): 80% pure, MS (MALDI) calculated for Cs5H99? 3? 22 (M) 1415, found 1414.

EXAMPLE 218 COMPOSED OF C? 5-ANFOMICIN-9-CROTONYL The compound of C15-ampicillin (30 mg, 0.023 mmol) of Example 2 and the but-2-enoic acid used in the method described in Example 201 provides the compound of titre, which is purified by HPLC and lyophilized (7 mg, 22% yield): 91% pure, MS (MALDI) calculated for C64H? or? N? 302? (M) 1389, found 1388.

EXAMPLE 216 COMPOSED OF C? 5-ANFOMICIN-9- (3, 4- (METILENDIOXY) PHENYL ALYATILE) The compound of C15-ampicillin (30 mg, 0.023 mmol) of Example 2 and the 3,4- (methylenedioxy) phenylacetic acid used in the method described in the Example 201 provides the title compound, which is purified by HPLC and lyophilized (11 mg, 33% yield): 84% pure, MS (MALDI) calculated for Cg9Ho3N3023 (M) 1483, found 1482.

EXAMPLE 220 COMPOSED OF C? 5-ANFOMICIN-9-C? 0 The compound of C15-ampicillin (24 mg, 0.018 mmol) of Example 2 and the decanoic acid used in the method described in Example 201 provides the title compound, which is purified by HPLC and lyophilized (10 mg, 37% yield): 80% pure, MS (MALDI) calculated for C70H ?? 5N? 3O2? (M) 1475, found 1474.

EXAMPLE 221 COMPOSITE OF C? 5-ANFOMICIN-9- (? -OXO-5-ACETHENBUTANYL) The compound of CX5-ampicillin (24 mg, 0.018 mmol) of Example 2 and the? -oxo-5-acenadtenbutánico acid used in the method described in Example 201 provides the title compound, which is purified by HPLC and lyophilized (7 mg, 25% yield): 77% pure, MS (MALDI) calculated for C7eH? o9N? 3022 (M) 1557 , found 1556.

EXAMPLE 222 COMPOSED OF C? 5-ANFOMICIN-9-HYDROCINNAMYL The C15-ampicillin compound (30 mg, 0.023 mmol) of Example 2 and the hydrocinnamic acid used in the method described in Example 201 provides the title compound, which is purify by HPLC and lyophilize (6 mg, 23% yield): 76% pure, MS (MALDI) calculated for C69H? o5 1302? (M) 1453, found 1452.

EXAMPLE 223 COMPOSED OF C? 5-ANFOMICIN-9- (g-CETOBUTILO) The compound of C? 5-ampomycin (23 mg, 0.018 mmol) of Example 2 and the c-keto-butyric acid used in the method described in Example 201 provides the title compound, which is purified by HPLC and lyophilized (9 mg, 37% yield): 87% pure, MS (MALDI) calculated for CS4H? Or? 3022 (M) 1405, found 1404.

EXAMPLE 224 COMPOSED OF C? 5-AMPHOMYCIN-9-GERANYL The C15-ampicillin compound (23 mg, 0.018 mmol) of Example 2 and the 3,7-dimethyl-octa-2,6-dienoic acid used in the described method in Example 201 provides the title compound, which is purified by HPLC and lyophilized (3 mg, 12% yield): 88% pure, MS (MALDI) calculated for C7oH? XXNX3021 (M) 1471, found 1470.

EXAMPLE 216 COMPOSED OF C? 5-ANFOMICIN-9- (O-ANISYL) The compound of C15-ampicillin (24 mg, 0.018 mmol) of Example 2 and the 2-methoxybenzoic acid used in the method described in Example 201 provides the title compound, which is purified by HPLC and lyophilized (9 mg, 34% yield): 85% pure, MS (MALDI) calculated for Ce8H? o3N? 3022 (M) 1455, found 1454.

EXAMPLE 226 COMPOSED OF C? 5-ANFOMICIN-9-PHENYLENATALLO The compound of C15-ampicillin (25 mg, 0.019 mmol) of Example 2 and the phenylacetic acid used in the method described in Example 201 provides the title compound, which is purify by HPLC and lyophilize (6 mg, 22% yield): 94% pure, MS (MALDI) calculated for Cg8HXo3? 302? (M) 1439, found 1438.

EXAMPLE 227 COMPOSED OF C? 5-ANFOMICIN-9- (2-BUTINYL) The compound of C15-ampicillin (23 mg, 0.018 mmol) of Example 2 and the but-2-inoic acid used in the method described in Example 201 provide the title compound, which is purified by HPLC and lyophilized (7 mg, 29% yield): 84% pure, MS (MALDI) calculated for Cg4H99N? 302? (M) 1387, found 1386.

EXAMPLE 228 COMPOSED OF C15-ANFOMICIN-9- (3, 5-BIS (CF3) PHENYLENATYLATE) The compound of C15-ampicillin (23 mg, 0.018 mmol) of Example 2 and the compound 3,5-bis (trifluoromethyl) phenyl used in the method described in the Example 201 provides the title compound, which is purified by HPLC and lyophilized (8 mg, 26% yield): 85% pure, MS (MALDI) calculated for C7oH10? N? 302? (M) 1575, found 1574.

EXAMPLE 229 COMPOSED OF C? 5-ANFOMICIN-9- (3, 4-MEYLENDENIX-CINNAMYL) The compound of C15-ampicillin (23 mg, 0.018 mmol) of Example 2 and the 3,4-methylenedioxy-cinnamic acid used in the The method described in Example 201 provides the title compound, which is purified by HPLC and lyophilized (5 mg, 18% yield): 81% pure, MS (MALDI) calculated for C70Ho3 3023 (M) 1495, found 1494.

EXAMPLE 230 COMPOSED OF C15-ANFOMICIN-9- (TRANS-CINNAMYL) The compound of C15-ampicillin (24 mg, 0.019 mmol) of Example 2 and the trans-cinnamic acid used in the method described in Example 201 provides the compound of titre, which is purified by HPLC and lyophilized (6 mg, 23% yield): 84% pure, MS (MALDI) calculated for Cg9HXo3NX3021 (M) 1451, found 1450.

EXAMPLE 231 COMPOSED OF C15-ANFOMICIN-9-ACETOXYACETILO The compound of C_5 ~ ampomycin (23 mg, 0.018 mmol) of Example 2 and the acetoxyacetic acid used in the method described in Example 201 provides the title compound, which is purified by HPLC and lyophilized (1 mg, 4% yield): 85% pure, MS (MALDI) calculated for C64H? Or? i3? 23 (M) 1421, found 1420.

EXAMPLE 232 COMPOSED OF C? 5-ANFOMICIN-9- (1-ADAMANTANILCARBONYL) The compound of C15-ampicillin (30 mg, 0.023 mmol) of Example 2 and the 1-adamantanylcarboxylic acid used in the method described in Example 201 provides the title compound, which is purified by HPLC and lyophilized (5 mg, 15% yield): 93% pure, MS (MALDI) calculated for C7? HxxxN302X (M) 1483, found 1482.

EXAMPLE 233 COMPOSED OF C15-ANFOMICIN-9- (4-COTININCARBONYL) The compound of CX5-ampicillin (30 mg, 0.023 mmol) of Example 2 and the 4-cotinincarboxylic acid used in the method described in Example 201 provides the compound of title, which is purified by HPLC and lyophilized (18 mg, 52% yield): 94% pure, MS (MALDI) calculated for C71H? 0N? 5O22 (M) 1523, found 1522.

EXAMPLE 234 COMPOSED OF C? 5-ANFOMICIN-9- (4-FLUOROBENZOYL) The compound of C15-ampicillin (25 mg, 0.019 mmol) of Example 2 and the 4-fluorobenzoic acid used in the method described in Example 201 provides the title compound, which is purified by HPLC and lyophilized (7 mg, 25% yield): 82% pure, MS (MALDI) calculated for Cg8H? 02N? 3O2? (M) 1457, found 1456.

EXAMPLE 235 COMPOSED OF C? 5-ANFOMICIN-9- (S-ACTILTIOGLYCOLYL) The compound of C15-ampicillin (25 mg, 0.019 mmol) of Example 2 and the S-acetylthioglycolic acid used in the method described in Example 201 provides the title compound, which is purified by HPLC and lyophilized (2 mg, 7% yield): 95% pure, MS (MALDI) calculated for Cg4H__o? N? 3022 (M) 1437, found 1436.

EXAMPLE 236 COMPOSED OF C15-ANFOMICIN-9- (4-BUTOXIBENZOIL) The compound of C15-ampicillin (27 mg, 0.020 mmol) of Example 2 and the 4-butoxybenzoic acid used in the method described in Example 201 provides the compound of titre, which is purified by HPLC and lyophilized (4 mg, 13% yield): 78% pure, MS (MALDI) calculated for C7? H? o9N? 3022 (M) 1497, found 1496.

EXAMPLE 237 COMPOSED OF C15-ANFOMICIN-9- (6-OXOHEPTANOLYL) The compound of C15-ampicillin (27 mg, 0.020 mmol) of Example 2 and the 6-oxoheptanoic acid used in the method described in Example 201 provides the compound of titre, which is purified by HPLC and lyophilized (9 mg, 30% yield): 98% pure, MS (MALDI) calculated for Cg7H? 07N13O22 (M) 1447, found 1446.

EXAMPLE 238 COMPOSED OF C? 5-ANFOMICIN-9-OLEATE The compound of C15-ampicillin (27 mg, 0.020 mmol) of Example 2 and the octadec-9-anoic acid used in the method described in Example 201 provides the compound of titre, which is purified by HPLC and lyophilized (12 mg, 37% yield): 94% pure, MS (MALDI) calculated for C78Hx29N? 302? (M) 1585, found 1584.

EXAMPLE 239 COMPOSITE OF C? 5-ANFOMICIN-9- (4-PENTILBENZOYL) The compound of C15-ampicillin (24 mg, 0.019 mmol) of Example 2 and the 4-pentylbenzoic acid used in the method described in Example 201 provides the title compound, which is purified by HPLC and lyophilized (3 mg, 11% yield): 74% pure, MS (MALDI) calculated for C72H ??? ? 302? (M) 1495, found 1494.

EXAMPLE 240 COMPOSED OF CX5-ANFOMICIN-9- (3-PHENOXIBENZOYL) The compound of Cx5-ampicillin (25 mg, 0.019 mmol) of Example 2 and the 3-phenoxybenzoic acid used in the method described in Example 201 provides the compound of titre, which is purified by HPLC and lyophilized (5 mg, 17% yield): 87% pure, MS (MALDI) calculated for C73HXo5N13022 (M) 1517, found 1516.

EXAMPLE 241 COMPOSED OF C? 5-ANFOMICIN-9- (C (= 0) - (CH2) 2-PIPERIDINE) The compound of C15-ampicillin (25 mg, 0.019 mmol) of Example 2 and 3-piperidin-l acid -yl-propionic used in the method described in Example 201 provides the title compound, which is purified by HPLC and lyophilized (8.5 mg, 31% yield): 84% pure, MS (MALDI) calculated for Cg8H ??0N ?4O2X (M) 1460, found 1459.

EXAMPLE 242 COMPOSED OF Cx5-ANFOMICIN-9- (N, N'-DIMETHYL-GABA) The compound of CX5-ampicillin (25 mg, 0.019 mmol) of Example 2 and the N, N'-dimethyl-β-aminobutanoic acid used in the method described in Example 201 provides the title compound, which is purified by HPLC and lyophilized (6.2 mg, 23% yield): 98% pure, MS (MALDI) calculated for CggHXo8? x__02X (M) 1434, found 1433 EXAMPLE 243 COMPOSITE OF C? 5-ANFOMICIN-9- (N-ETIL-GLY) The compound of CX5-ampicillin (42 mg, 0.032 mmol) of Example 2 and the compound N-ethylglycine used in the method described in Example 201 provide the title compound, which is purified by HPLC and lyophilized (5.2 mg, 12% yield): 80% pure, MS (MALDI) calculated for Cg4HX04? X4O2? (M) 1406, found 1405.

EXAMPLE 244 COMPOSITE OF C? 5-A? FOMICI? -9-SAR- (N, N-DIMETHYL-GLY) The compound of C15-ampicillin (30 mg, 0.023 mmol) of Example 2 and the compound N, N-dimethylglycine used in the method described in Example 201 provides the title compound, which is purified by HPLC and lyophilized (9 mg, 32% yield): 99% pure, MS (MALDI) calculated for Cg7H? 09 ?? 5O22 (M ) 1477, found 1476.

EXAMPLE 245 COMPOSED OF C15-A? FOMICI? -9- (N-BE? CIL-GLY) The compound of C15-ampicillin (55 mg, 0.042 mmol) of Example 2 and the compound? -benzylglycine used in the method described in Example 201 provides the title compound, which is purified by HPLC and lyophilized (5 mg, 8% yield): 78% pure, MS (MALDI) calculated for Cg9H10gN? 4O21 (M) 1468, found 1467.

EXAMPLE 246 COMPOSED OF C15-ANFOMICIN-9- (N, N-DIETIL-ß-ALA) The compound of C15-ampicillin (26 mg, 0.020 mmol) of Example 2 and the compound N, N-diethyl ß-alanine used in the method described in Example 201 provides the title compound, which is purified by HPLC and lyophilized (19.2 mg, 67% yield): 91% pure, MS (MALDI) calculated for CS7H? 10? 4O2? (M) 1448, found 1447.

EXAMPLE 247 COMPOSED OF C? 0-A? FOMICI? -9-C? 0 The compound of C10-ampicillin (30 mg, 0.024 mmol) of Example 6 and the decanoic acid used in the method described in Example 201 provides the compound titre, which is purified by HPLC and lyophilized (7 mg, 22% yield): 79% pure, MS (MALDI) calculated for C5Ho5 302? (M) 1405, found 1404.

EXAMPLE 248 COMPOSED OF C? 5-A? FOMICI? -9- (N-METHYL-GABA) The compound of C15-ampicillin (23 mg, 0.017 mmol) of Example 2 and N-tert-butoxycarbonyl-4-methyl acid -? - Aminobutanoic used in the method described in Example 201 provides the title compound, which is purified by HPLC and lyophilized (5.2 mg, 21% yield): 88% pure, MS (MALDI) calculated for C5H? o6? 021 (M) 1420, found 1420.

EXAMPLE 248 COMPOUND OF CH3- (CH2) 15-NH-C (= 0) -ANFOMYCIN The compound of ampicillin-9-Fmoc (50 mg, 0.038 mmol, 79% pure) is dissolved in 5 ml DMF at room temperature under a inert atmosphere. 1-isocyanato-pentadecane (8.8 mg, 0.06 millimole) and DIEA (26 μL, 0.15 millimole) were added to the reaction and the mixture was stirred overnight. Piperidine (1 ml, 20% v / v) was added to the reaction and the mixture was stirred for an additional 3 hours. All solids were filtered, the insolubles were washed with additional DMF (approximately 2 ml), and then the filtrate was concentrated in vacuo to dryness. Purification was carried out by HPLC (gradient, 25% acetonitrile in water with 0.1% trifluoroacetic acid for 95% acetonitrile for 30 minutes) and lyophilization afforded the title compound (21 mg, 40% yield): 94% pure, MS (MALDI) calculated for C62Hxo2N1402o (M) 1364, found 1363.

EXAMPLE 250 COMPOSED OF C15-ANFOMICIN-9-pGLU The C15-ampicillin compound of Example 2 and the pyroglutamic acid used in the method described in Example 201 provide the title compound, which is purified by HPLC and lyophilized (13.1 mg , 30% yield): 86% pure, MS (MALDI) calculated for Ce5H? O2N? 4022 (M) 1432, found 1434.

EXAMPLE 251 COMPOSED OF CH3- (CH2) ?? - NH-C (= 0) -ANFOMYCIN The compound of ampomycin-9-Fmoc (30 mg, 0.022 mmol) and the 1-isocyanato-hexadecane used in the method described in Example 249 provide the title compound, which is purified by HPLC and lyophilized (2 mg, 7% yield): 77% pure, MS (MALDI) calculated for C 58 H 94 N 14 O 20 (M) 1307, found 1306.

EXAMPLE 252 COMPOSED OF CH3- (CH2) 7-NH-C (= 0) -ANFOMYCIN The ampomycin-9-FMoc compound (50 mg, 0.011 mmol) and the octanoyl isocyanate used in the method described in Example 249 provide the title compound, which is purified by HPLC and lyophilized (8 mg, 17% yield): 85% pure, MS (MALDI) calculated for C54H83gNX402o (M) 1252, found 1251.

EXAMPLE 253 COMPOSED OF CH3- (CH2) X3-NH-C (= 0) -ANFOMYCIN The compound of ampicillin-9-FMoc (51 mg, 0.011 mmol) and the isocyanate tetradecane used in the method described in Example 249 provide the title compound, which is purified by HPLC and lyophilized (23 mg, 45% yield): 77% pure, MS (MALDI) calculated for C6oH9aN? 402o (M) 1336, found 1336.

EXAMPLE 254 COMPOSED OF CH3- (CH2) ?? - NH-C (= 0) -GLY-ANFOMYCIN The compound of ampicillin-9-FMoc (15.8 mg) and the ester of succinimidyl-1-yl dodecanamidylglycine (12.8 mg, as were prepared in Example 275 and using a succinimidyl ester as prepared in Example 1) used in the method described in Example 3 provide the title compound, which is purified by HPLC and lyophilized (13.2 mg): 93% pure, MS (MALDI) calculated for C6oH97NX502X (M) 1365, found 1365.

EXAMPLE 255 COMPOSED OF CX5-ANFOMYCIN-C (= 0) -NH-N-BUTYL The C15-ampicillin compound (30 mg, 0.023 mmol) of Example 2 was suspended in 2 ml DMF under an inert atmosphere and then charged with approximately 4 μL of 1-isocyanatobutane (0.035 mmol). The mixture was stirred overnight and then concentrated in vacuo to provide the title compound, which is purified by HPLC (gradient, 25% acetonitrile in water with 0.1% trifluoroacetic acid for 95% acetonitrile for 30 minutes) and lyophilized ( 2 mg, 6% yield): 87% pure, MS (MALDI) calculated for Cg5H? OeN? 4021 (M) 1420, found 1419.

EXAMPLE 256 COMPOSED OF C? 5-ANFOMICIN-C (= 0) -NH-CYCLOHEXYL The compound of C15-ampicillin (30 mg, 0.023 mmol) of Example 2 and the 1-isocyanate-cyclohexane used in the method described in Example 255 gives the title compound, which is purified by HPLC and lyophilized (3 mg, 9% yield): 70% pure, MS (MALDI) calculated for Ce7H? OsN? 40? (M) 1446, found 1445.

EXAMPLE 257 COMPOSED OF C? 5-ANFOMICIN-C (= 0) -NH-FURFURILO The compound of C15-ampicillin (30 mg, 0.023 mmol) of Example 2 and the 1-isocyanatomethyl-furan used in the method described in the Example 255 gives the title compound, which is purified by HPLC and lyophilized (3 mg, 9% yield): 73% pure, MS (MALDI) calculated for CggH102N? 4O22 (M) 1444, found 1443.

EXAMPLE 258 COMPOSED OF C15-ANFOMICIN-C (= 0) -NH-2-FLUOROBENCIL The compound of C15-ampicillin (30 mg, 0.023 mmol) of Example 2 and the isocyanate of 2-fluorobenzyl using the method described in Example 255 provide the title compound, which is purified by HPLC and lyophilized (2 mg, 6% yield): 93% pure, MS (MALDI) calculated for Cg8H? 03N? 4O2? (M) 1472, found 1471.

EXAMPLE 259 COMPOSED OF C15-ANFOMICIN-C (= 0) -NH-M-CF3-PHENYL The compound of CX5-ampicillin (30 mg, 0.023 mmol) of Example 2 and the isocyanate of meta- (trifluoromethyl) phenyl used in the method described in Example 255 provides the title compound, which is purified by HPLC and lyophilized (5 mg, 15% yield): 95% pure, MS (MALDI) calculated for Cg8H? 0? N14O2? (M) 1508, found 1507. ' EXAMPLE 260 COMPOSED OF C15-AMPHOMICIN-C (= 0) -NH-p-CF3-PHENYL The compound of C15-ampicillin (30 mg, 0.023 mmol) of Example 2 and the isocyanate of para- (trifluoromethyl) phenyl used in the method described in Example 255 provides the title compound, which is purified by HPLC and lyophilized (4 mg, 12% yield): 86% pure, MS (MALDI) calculated for Cg8H? 0? N? 4O21 (M) 1508, found 1507.

EXAMPLE 261 COMPOSED OF CX5-ANFOMICIN-C (= 0) -NH-3-FLUOROPHENYL The compound of CX5-ampicillin (30 mg, 0.023 mmol) of Example 2 and the 3-fluorophenyl isocyanate used in the method described in Example 255 provides the title compound, which is purified by HPLC and lyophilized (4 mg, 12% yield) .- 86% pure, MS (MALDI) calculated for C67HXo? NX402? (M) 1458, found 1457.

EXAMPLE 262 COMPOSITE OF C? 5-ANFOMYCIN- (D-SER) The compound of C15-ampicillin (27 mg, 0.020 mmol) of Example 2 was suspended in 1 mL DMF and then loaded with 300 μL of 1M sodium bicarbonate ( in water, 0.020 millimoles). The reaction mixture was cooled in an ice bath. A previously dissolved solution of activated succinimide (D) -3-0-tert-butyl-2- (9H-fluoren-9-yl-methoxycarbonyl) serine (1.5 equivalents, prepared as described for the succinimid-1-ester compound il of the pentanoic acid of Example 1) in 0.5 ml DMF was slowly added to the reaction mixture by the ice technique. Then the reaction was stirred for about 12 hours at room temperature. Piperidine (0.5 ml, 20% v / v) was added, the reaction was stirred for one hour and concentrated in vacuo. The raw product was combined, with 2 ml of a cocktail (46: 46: 2: 2 of trifluoroacetic acid: DCM: a-gua: triisopropylsilane) for another hour and then concentrated in vacuo to provide the title compound, which was purified by HPLC (gradient, 25% acetonitrile in water with 0.1% trifluoroacetic acid for 95% acetonitrile for 30 minutes) and lyophilized (8 mg, 28% yield): 81% pure, MS (MALDI) calculated for C3H02? 4O22 (M) 1408, found 1407.

EXAMPLE 263 COMPOSED OF CX5-ANFOMICIN- (D-TYR) The compound of CX5-ampicillin (27 mg, 0.020 mmol) of Example 2 and (D) -O-tert-butyl-N- (9H-fluoren-9- il-methoxycarbonyl) tyrosine used in the method described in Example 262 provides the title compound, which is purified by HPLC and lyophilized (12 mg, 39% yield): 77% pure, MS (MALDI) calculated for Cg_.Hxoe ? x__022 (M) 1484, found 1486.

EXAMPLE 264 COMPOSED OF C? 5-ANFOMICIN- (D-TRP) The compound of Ca5-ampicillin (27 mg, 0.020 mmol) of Example 2 and the acid (D) -3- [2-carboxy-2 ~ (9H-fluoren- 9-yl-methoxycarbonylamino) -ethyl] -indole-1-carboxylic acid used in the method described in Example 262 provides the title compound, which is purified by HPLC and lyophilized (11 mg, 36% yield): 80% pure , MS (MALDI) calculated for C7? H? 0N? 5O2? (M) 1507, found 1506.

EXAMPLE 265 COMPOSED OF C15-ANFOMYCIN-9-GLU The compound of C15-ampicillin (25 mg, 0.019 mmol) of Example 9 was suspended in 1 ml DMF and then loaded with 300 μL of 1M sodium bicarbonate (in water, 0.020 millimoles). The reaction mixture was cooled in an ice bath. A previously dissolved solution of activated succinimide of (L) -2-tert-butoxycarbonylaminopentanedioic acid (1.5 equivalents, prepared as described for the pentadecanoic acid succinimid-1-yl ester compound of Example 1) in 0.5 ml DMF was slowly added to the reaction mixture by the ice technique, the reaction was allowed Staying for approximately 12 hours at room temperature and then concentrating in vacuo. The crude product was combined with 2 ml of a cocktail (46: 46: 2: 2 of trifluoroacetic acid: DCM: water: triisopropylsilane) for another hour and then concentrated in vacuo to provide the title compound. The title compound was purified by HPLC (gradient, 25% acetonitrile in water with 0.1% trifluoroacetic acid for 95% acetonitrile for 30 minutes) and lyophilized (8 mg, 30% yield): 86% pure, MS (MALDI) calculated for Cg3H? OoN? 4023 (M) 1422, found 1421.

EXAMPLE 266 COMPOSED OF C15-ANFOMYCIN-9- (4-HYDROXYBENCIL) The compound of C15-ampicillin (38 mg, 0.029 mmol) of Example 9 was suspended in 2.5 ml DMF and then loaded with 70 μL of glacial acetic acid (pH ~ 4.5) A solution of 4-hydroxybenzaldehyde, previously dissolved in 1 ml DMF, (37 mg, 0.303 millimole) was added to the reaction and the mixture was stirred for approximately 24 hours.Two equivalent portions of sodium cyanoborohydride (40 mg. total, 0.637 mmol) were added over a period of one hour followed by a further 5 hours of further stirring before the solvent was removed in vacuo to provide the title compound.The title compound was purified by HPLC (gradient, % acetonitrile in water with 0.1% trifluoroacetic acid for 95% acetonitrile for 30 minutes) and lyophilized (14 mg, 34% yield): 99% pure, MS (MALDI) calculated for C6H? oXNX3022 (M) 1441, found 1440.

EXAMPLE 267 COMPOSED OF CX5-ANFOMICIN- 9 -2V, N-DI (p-HYDROXIBENCIL) The title compound was obtained using the method described in Example 20, wherein the compound is a secondary product (dialkyl) of this reaction. The title compound was purified by HPLC and lyophilized (4 mg, 9% yield): 93% pure, MS (MALDI) calculated for C74H? 09NX3O22 (M) 1337, found 1533.

EXAMPLE 268 COMPOSED OF C? 5-ANFOMICIN-9- (N, N-DIMETILGLYCIN) The compound Cls-anfomicin-9-Sar of Example 24 and the formaldehyde used as described in Example 20 provide the title compound, which is purify by HPLC and lyophilize (9.5 mg, 59% yield): 98% pure, MS (MALDI) calculated for Ce4H? o4N402? (M) 1406, found 1405.

EXAMPLE 269 COMPOSED OF CH3- (CH2) 9-S02-GLY-ANFOMYCIN In a first step, the compound of ampomycin-9-Fmoc (30 mg, 0.022 mmol) was coupled with the compound N-tert-butoxycarbonyl glycine used in the method described in Example 3. The resulting intermediate was purified by HPLC and lyophilized. In a second stage, this purified intermediate was dissolved in 10 ml DMF under an inert atmosphere. Decanesulfonyl chloride (13.7 mg, 0.044 millimole) was added and the mixture was allowed to stand overnight to produce the title compound, which was purified by HPLC (gradient, 25% acetonitrile in water with 0.1% trifluoroacetic acid). for 95% acetonitrile for 30 minutes) and lyophilized (5 mg): 89% pure, MS (MALDI) calculated for C57H92N? 4022S (M) 1357, found 1357.

EXAMPLE 270 COMPOSED OF CH3- (CH2) 9-S02-PHE-ANFOMYCIN In a first step, the compound of ampomycin-9-Fmoc (30 mg, 0.022 mmol) was coupled with the compound N-tert-butoxycarbonyl phenylalanine. The resulting intermediate was purified by HPLC and lyophilized. In a second step, this purified intermediate was coupled with pentadecanesulfonyl chloride as described in the method of Example 99 provide the title compound, which was purified by HPLC and lyophilized (7 mg, 21% yield): 91% pure, MS (MALDI) calculated for C70H ?? or ?? 4022S (M) 1532, found 1532.

EXAMPLE 271 PREPARATION OF THE COMPOUND OF ANFOMICIN-9- (N-FMOC-GLY) The complex of ampomycin-9- (N-Fmoc-Gly) (1.25 g, prepared by means of fermentation as described above) is dissolved in a solution ammonium phosphate buffer (0.2M, pH 7.2) and combined with 1250 ml of the enzyme solubilized deacylase and placed in an incubator at 25 ° C for 9 days. The product is combined with 438 g of ammonium sulfate and adjusted to a pH of 3.5 with 1 HCl, and then filtered to remove the precipitated product. The precipitate is combined with about 170 ml of 1-butanol and 170 ml of water, the aqueous phase is discarded and the 1-butanol phase is rinsed with water. The 1-butanol phase is repeated and the combined aqueous phases are evaporated in vacuo to remove residual butanol. The remaining layer of accusation is dried by freezing to obtain 500 mg of a white powder, which is the crude product. The crude product of ampomycin-9- (N-Fmoc-Glycine) (400 mg) is dissolved in 10 ml of a sodium phosphate buffer solution at a pH of 6.6 and filtered through a PVDF membrane of 0.45 microns. The filtrate is injected into a Pak C18 radial column pack (2.5 x 21 cm, Waters Corp.). The product was eluted using modified acetonitrile, sodium phosphate buffer eluants (22-28% acetonitrile for 10 min at 5 ml / min at room temperature) The product containing the fractions (as determined by analytical HPLC) was discarded and then the acetonitrile was evaporated in vacuo The evaporated sample was desalted by adsorption on 1.0 g of EnviChrom-P resin (Supelco), the resin was rinsed with 8 ml of distilled water and the product was separated from the resin using 20 ml of acetonitrile 60% acetonitrile was evaporated in vacuo and the solution with the remaining product was freeze-dried to yield 107 mg of the title compound (95% purity by HPLC (UV area% at 215 nm).

EXAMPLE 272 PREPARATION OF THE COMPOUND OF ANFOMICIN-9- (N-FMOC-SAR) The complex of ampomycin-9- (N-Fmoc-sarcosil) (2 g) was transformed after three days of incubation as described in Example 271 to provide the title compound (911 mg).

EXAMPLE 273 PREPARATION OF THE COMPOUND OF ANFOMICIN- (N-FMOC-ß-ALA) The complex of ampomycin-9- (N-Fmoc-β-alanine) (2 g) was transformed after three days of incubation as described in Example 271 to provide the title compound 1267 mg).

EXAMPLE 274 PREPARATION OF THE ACID p- (N-DODECANOILAMINO) -BENZOIC 4-Aminobenzoic acid (0.94 g, 6.85 mmol) is dissolved in 5 ml of pyridine and dodecanoyl chloride (1.58 ml, 6.85 mmol) is added. The mixture is stirred for 4 hours at room temperature. The product is precipitated by dilution with water (50 ml), filtered and dried to give 1.96 g of the title compound.

EXAMPLE 275 PREPARATION OF N-DODECAMIDOGLYCIN Glycine (0.40 g, 5.25 mmol) and 0.91 mL of diisopropylethylamine (5.25 mmol) are dissolved in 4 mL DMF and 6 L of water. Dodecylisocyanate (0.72 ml, 3.0 mmol) is added in 7 ml of tetrahydrofuran and the mixture is stirred for one hour at room temperature. Water (40 ml) is added and the resulting mixture is rinsed twice with ethyl acetate.The aqueous layer is acidified with 6N HCl, the resulting precipitate is filtered and then dried to give 575 mg of the title compound.

EXAMPLE 276 PREPARATION OF N-DODECILOXIBENZOILGLYCIN A solution of 4-dodecyloxybenzoic acid (0.47 g, 1.53 mmol) and 0.27 ml of diisopropylethylamine (1.55 mmol) in 4 ml of tetrahydrofuran is added with N, N, N, N-tetramethylforamidinium hexafluorophosphate. (0.41 g, 1.54 mmol) and the reaction is stirred for 15 minutes at room temperature. To this mixture is added a solution of glycine ethyl ester hydrochloride (0.45 g, 3.2 mmol) and DIEA (0.53 ml, 3.04 mmol) in 5 ml of tetrahydrofuran and 5 ml of methylene chloride. The mixture was stirred for several hours at room temperature and then diluted with 50 ml of hydrochloric acid 1? and extracted with ethyl acetate. The organic layer was rinsed with water, saturated sodium bicarbonate, brine and then dried over magnesium sulfate. Evaporation in vacuo was followed by trituration with hexane to give the product (0.44 g). The product was dissolved in 10 ml of methanol and 5 ml of tetrahydrofuran, treated with 3 ml of sodium hydroxide 1? and then stirred for one hour at room temperature. After several minutes, a thin precipitate formed. The mixture was diluted with water (20 ml) and then heated to 40 ° C until homogeneous. The mixture was acidified with 5 ml of HCl 1? and the precipitate was filtered and dried, yielding 0.34 g of the title compound.

EXAMPLE 277 PREPARATION OF CH3- (CH2) X3-NH-C (= 0) -ANFOMICIN-9-GLY-LYS The compound CH3- (CH2) 13-NH-C (= 0) -anfomycin (50 mg) of Example 253 and the activated succinimide of N- (2-N-tert-butoxycarbonyl-6- (9H-fluoren-9-yl-methoxycarbonyl) lisinyl) glycine (58 mg, prepared as described in Example 1) as used in the method described in Example 3 provides the title compound) 16 mg, 28% yield): 80% pure, MS (MALDI) calculated for C68HXX3N17022 (M) 1521, found 1520.

EXAMPLE 278 PREPARATION OF CH3- (CH2) X3-NH-C (= 0) -ANFOMICIN-9- (ß-ALA) The compound CH3- (CH2) X3-NH-C (= 0) -anfomycin (30 mg) of Example 253 and the compound N- (2-N-tert-butoxycarbonyl) β-alanine as used in the method described in Example 3 provides the title compound (8 mg, 25% yield): 70% pure, MS (MALDI) calculated for CS3H103 5? 2? (M) 1407, found 1406.

EXAMPLE 279 COMPOUND CH3- (CH2)? 3-NH-C (= 0) -ANFOMICIN-9-GLY The compound CH3- (CH2) 13-NH-C (= 0) -anfomycin (40 mg) of Example 253 and the N- (tert-butoxycarbonyl) glycine compound as used in the method described in Example 3 provides the title compound (8 mg, 31% yield): 74% pure, MS (MALDI) calculated for C62H? or? N15021 (M) 1393, found 1392.

EXAMPLE 280 COMPOSITE C12-PABA-ANFOMICIN-9- (ß-ALA) The compound C12-p-aminobenzoyl-ampicillin (80 mg) of Example 85 and the compound N- (tert-butoxycarbonyl) β-alanine as used in The method described in Example 3 provides the title compound (4 mg, 4% yield): 73% pure, MS (MALDI) calculated for C67H? or XNX5022 (M) 1469, found 1468.

EXAMPLE 281 COMPOSITE CX6- (P-APA) -ANFOMYCIN In a first stage, the compound anfomicin-9-Fmoc (40 mg) was coupled with the 4-tert-butoxycarbonyl-aminophenylacetic compound as described in the method of Example 3. The resulting intermediate was purified by HPLC and lyophilized. In a second step, this purified intermediate and hexadecanoic acid as used in the method described in Example 2 provide the title compound, which is purified by HPLC and lyophilized (7.4 mg, 17% yield): 83% pure , MS (MALDI) calculated for Cg9HX06N? 4O2? (M) 1468, found 1467.

EXAMPLE 282 C8-PABA-ANFOMYCIN COMPOUND In a first step, the compound ampomycin-9-Fmoc (45 mg) was coupled with the tert-butoxycarbonyl-aminobenzoic acid as described in the method of Example 3. In a second step, this intermediate of the first step was mixed with octanoyl chloride as described in the method of Example 3 to provide the title compound (13.3 mg, 28% yield): 70% pure, MS (MALDI) calculated for CgoH88N4? 2? (M) 1341, found 1340.

EXAMPLE 283 Co-PABA-ANFOMYCIN COMPOUND In a first step, the compound ampomycin-9-Fmoc (45 mg) was coupled with the tert-butoxycarbonyl-aminobenzoic acid as described in the method of Example 3. In a second step, this intermediate of the first step was mixed with octanoyl chloride as described in the method of Example 3 to provide the title compound (7.8 mg, 16% yield): 91.4% pure, MS (MALDI) calculated for Cs_H92NX402X (M) 1369 , found 1368.

EXAMPLE 284 COMPOSITE C? - PABA-ANFOMYCIN In a first stage, the compound anfomicin-9-Fmoc (25 mg) was coupled with the tert-butoxycarbonyl-aminobenzoic acid as described in the method of Example 3. In a second step, this intermediate of the first step was mixed with undecanoyl chloride as described in the method of Example 3 to provide the title compound (1.7 mg, 6% yield): 93% pure, MS (MALDI) calculated for CS3H94NX4? 2x (M) 1384, found 1382.

EXAMPLE 285 COMPOSITE C? 3-PABA-ANFOMYCIN In a first step, the compound anfomicin-9-Fmoc (45 mg) was coupled with the tert-butoxycarbonyl-aminobenzoic acid as described in the method of Example 3. In a second step, this intermediate of the first step was mixed with tridecanoyl chloride as described in the method of Example 3 to provide the title compound (2 mg, 4% yield): 75% pure, MS (MALDI) calculated for Cg5H98N14021 (M) 1412, found 1411.

EXAMPLE 286 COMPOUND CH3- (CH2)? 0-NH-C (= 0) - (ß-ALA) -ANFOMYCIN In a first step, the compound ampicin-9-Fmoc (30 mg) was coupled with the compound N-ter -butoxycarbonyl-β-alanine as described in the method of Example 3. In a second step, this intermediate of the first step was mixed with undecanoyl isocyanate as described in the method of Example 3 to provide the title compound (7 mg, 23% yield): 91% pure, MS (MALDI) calculated for C6oH97NX502? (M) 1365, found 1364.

EXAMPLE 287 COMPOUND CH3- (CH2) 15-NH-C (= 0) - (p-PHENYLACEANTIL) -ANFOMYCIN In a first stage, the compound anfomicin-9-Fmoc (47 mg) was coupled with the acid for -N-tert-butoxycarbonyl-phenylacetic acid as described in the method of Example 3. In a second step, this intermediate of the first stage was mixed with hexadecanyl isocyanate as described in method of Example 3 to provide the title compound (6.3 mg, 12% yield): 90% pure, MS (MALDI) calculated for C70H? O9N? 502x (M) 1497, found 1495.

EXAMPLE 288 COMPOUND CH3- (CH2) 7-NH-C (= 0) - (p-PHENYLACEILE) -ANFOMYCIN In a first step, the compound ampomycin-9-Fmoc (47 mg) was coupled with the acid for -N- tert-butoxycarbonyl-phenylacetic acid as described in the method of Example 3. In a second step, this intermediate of the first step was mixed with octanyl isocyanate as described in the method of Example 3 to provide the title compound (6.3 mg , 24% yield): 84% pure, MS (MALDI) calculated for C62H93Nx502x (M) 1384, found 1383.

EXAMPLE 289 COMPOUND CH3- (CH2) X3-NH-C (= 0) - (p-PHENYLACEATYL) -ANFOMYCIN In a first step, the compound ampomycin-9-Fmoc (47 mg) was coupled with the acid for -N- tert-butoxycarbonyl-phenylacetic acid as described in the method of Example 3. In a second step, this intermediate of the first step was mixed with tetradecanyl isocyanate as described in the method of Example 3 to provide the title compound (4.3 mg , 8% yield): 81% pure, MS (MALDI) calculated for Cg8HXo5? X502X (M) 1469, found 1467.

EXAMPLE 290 COMPOSED CH3- (CH2) 10-? H-C (= 0) - (p-FE? ILACETIL) -A? FOMICI? A In a first stage, the compound anfomicin-9-Fmoc (47 mg) was coupled with the -N-tert-butoxycarbonyl-phenylacetic acid as described in the method of Example 3. In a second step, this intermediate of the first step was mixed with undecannyl isocyanate as described in method of Example 3 to provide the title compound (5.4 mg, 11% yield): '79% pure, MS (MALDI) calculated for Cg5H99 ?? 5021 (M) 1427, found 1425.

EXAMPLE 291 COMPOSED CH3- (CH2) X5-? H-C (= 0) - (GABA) -A? FOMICI? A In a first stage, the compound anfomicin-9-Fmoc (40 mg) was coupled with N-tert-butoxycarbonyl-α-aminobutyric acid as described in the method of Example 3. In a second step, this intermediate of the first step was mixed with tetradecanyl inisonate as described in Method of Example 3 to provide the title compound (3 mg, 704% yield): 95% pure, MS (MALDI) calculated for Cg4H10SN? 5? 21 (M) 1421, found 1422.

EXAMPLE 292 COMPOUND CH3- (CH2) 15-NH-C (= 0) - (m-PHENYLACEANTIL) -ANFOMYCIN In a first stage, the compound anfomicin-9-Fmoc (75 mg) was coupled with the meta-N-tert-butoxycarbonyl-phenylacetic acid as described in the method of Example 3. In a second step, this intermediate of the first step was mixed with tetradecanyl isocyanate as described in Method of Example 3 to provide the title compound (3.8 mg, 5% yield): 90% pure, MS (MALDI) calculated for Cg8H105 lsO2? (M) 1469, found 1469.

EXAMPLE 293 COMPOUND C? O- (m-AMI? OBE? ZOIL) -A? FOMICI? A In a first stage, the compound anfomicin-9-Fmoc (47 mg) was coupled with the meta-N-tert-butoxycarbonyl acid phenylacetic as described in the method of Example 3. In a second step, this intermediate of the first step was mixed with decanoyl chloride as described in the method of Example 3 to provide the title compound (8.6 mg, 19.2% yield): 86.8% pure, MS (MALDI) calculated for CS2H92N? 402? (M) 1369, found 1370.

EXAMPLE 294 COMPOSITE C? - (itt-AMINOBENZOIL) -ANFOMYCIN In a first stage, the compound anfomicin-9-Fmoc (47 mg) was coupled with the meta-N-tert-butoxycarbonyl-phenylacetic acid as described in the method of Example 3. In a second step, this intermediate of the first stage was mixed with undecanoyl chloride as described in method of Example 3 to provide the title compound (12.1 mg, 26.7% yield): 85.2% pure, MS (MALDI) calculated for Cg3H94 ?? 402X (M) 1384, found 1384.

EXAMPLE 295 COMPOSED CH3- (CH2) X3-? H-C (= 0) - (ß-ALA) -A? FOMICI? A In a first stage, the compound anfomicin-9-Fmoc (40 mg) was coupled with the para-N-tert-butoxycarbonyl-β-alanine acid as described in the method of Example 3. In a second step, this intermediate of the first step was mixed with tetradecanyl isocyanate as described in the method of Example 3 to provide the title compound (8 mg, 19.7% yield): 73.9% pure, MS (MALDI) calculated for C3H? 03? 5O2? (M) 1407, found 1408.

EXAMPLE 296 COMPOSITE C12- (m-AMINOBENZOIL) -ANFOMYCIN In a first stage, the compound anfomicin-9-Fmoc (47 mg) was coupled with the meta-N-tert-butoxycarbonyl-phenylacetic acid as described in the method of Example 3. In a second step, this intermediate of the first step was mixed with dodecanoyl chloride as described in method of Example 3 to provide the compound of. Title (3.5 mg, 7.6% yield): 97% pure, MS (MALDI) calculated for C64H9 14? 2? (M) 1398, found 1399.

EXAMPLE 297 COMPOSITE C? 3- (-AMINOBENZOIL) -ANFOMYCIN In a first step, the compound ampomycin-9-Fmoc (47 mg) was coupled with the jmeta-N-tert-butoxycarbonyl-phenylacetic acid as described in the method of Example 3. In a second step, this intermediate of the first step was mixed with tridecanoyl chloride as described in the method of Example 3 to provide the title compound (3.8 mg, 8.2% yield): 96% pure, MS ( MALDI) calculated for CesH58 ?? 402? (M) 1412, found 1413.

EXAMPLE 298 ESTER-PINACOL-BORONATE RESIN The Wang resin was placed in DCM (DCM) for one hour. The solvent is drained and the bead suspended in fresh DCM (5 ml). To this mixture is added pinacol ester of 4-carboxyphenylboronic acid, N, N-dimethylaminopyridine (20 mg), and HOBt (90 mg). Then the solution is stirred for 20 and net DIPC (700 μL, 4.0 mmol) is added. Then the solution is stirred at room temperature for 24 hours. The reaction mixture is left and the bead is washed with DMF, DMSO / H0, MeOH and DCM. The charged resin is considered to be quantitative.

EXAMPLE 299 COMPOSED OF 4-OCTIL-BIFE? IL-4-CARBOXYL-A? OFFIMITION Stage A. A sample of resin bound pinacol boronate ester of PRE-1476 Example (112 mg, 0.94 millimole / g, 0.105) millimoles) was swollen in DME for 30 minutes. The solvent is drained and replaced with 300μL of new DME. To this mixture is added 4---octylbromobenzene (100 μL, enormous excess), PdCl 2 (dppf) -DCM (9 mg, 0.0105 mmol) and CsC03 (200 μL, 2M (aqueous), 0.42 mmol). The reaction vessel was sealed and heated at 80 ° C for 3 hours. Then the solution was drained and the beads were washed with H20, MeOH, DMF, DMSO and DCM. Then the beads were suspended in 250 μL of DCM / 750 μL TFA for one hour. The solution of this step is recovered and concentrated to provide an oil. The lipid biphenylcarboxylic acid was then crystallized with cold MeOH and dried under vacuum. Step B: The lipid bifinecarboxylic acid (6.5 mg, 0.0209 mmol), HOBt (3.52 mg, 0.23 mmol) and DIPC (3.6 μL, 0.23 mmol) are combined in 200 ml DMF and stirred in 1.5 hours. To this solution is added a mixture of ampomycin-9-Fmoc (22 mg, 0.0167) and DIEA (50 μL, excess) in 200 ml DMSO and the reaction mixture is stirred at room temperature for 40 minutes. At this time, the solution is poured into Et20 and the resulting solid is recovered by centrifugation. The solid is again dissolved in 1 ml of 20% piperidine in DMF and allowed to stand for one hour at room temperature before Et20 is added and the resulting solid recovered by centrifugation. The solid is washed with Et20 and dried in vacuo. The crude solid is purified by RP-HPLC and the product is isolated by iophylation to give the title compound (0.56 mg, 2.4% yield): 67.3% pure, MS (MALDI) calculated for CggH_.3N_.3O20 (M) 1389 , found 1389.

EXAMPLE 300 COMPOSITE Cx3- (p-APA) -ANFOMYCIN In a first step, the compound ampomicin-9-Fmoc (30 mg) was coupled with the acetic acid as described in the method of Example 3. The resulting intermediate is purified by HPLC and lyophilized. In a second step, this purified intermediate and tridecanoic acid are used as described in the method of Example 2 to provide the title compound (2 mg, 6.8% yield): 95% pure, MS (MALDI) calculated for Cg6H? oo? 402? (M) 1426, found 1427.

EXAMPLE 301 COMPOSED CM- (p-APA) -ANFOMYCIN In a first stage, the compound anfomicin-9-Fmoc (30 mg) was coupled with 4-N-tert-butoxycarbonyl-aminophenylacetic acid as described in the method of Example 3. The resulting intermediate is purified by HPLC and lyophilized. In a second step, this purified intermediate and the tretradecanoic acid are used as described in the method of Example 2 to provide the title compound, which is purified by HPLC and lyophilized (1 mg, 3.4% yield): 93% pure, MS (MALDI) calculated for C67H? 02N14O2? (M) 1440, found 1441.

EXAMPLE 302 COMPOSED CH3- (CH2)? -NH-C (= 0) - (-FENILACETIL) -ANFOMYCIN In a first stage, the compound anfomicin-9-Fmoc (30 g) was coupled with the 272eta ~ N-tert-butoxycarbonyl-aminophenylacetic acid as described in the method of Example 3. The resulting intermediate is purified by HPLC and lyophilized. In a second step, this intermediate is mixed with hexadecanyl isocyanate as described in the method of Example 3 to provide the title compound, (2.4 mg, 7.8% yield): 72% pure, MS (MALDI) calculated for C70H? o9? 502? (M) 1497, found 1497.

EXAMPLE 303 COMPOSITE C14- (m-APA) -ANFOMYCIN In a first stage, the compound anfomicin-9-Fmoc (30 mg) was coupled with the meta-N-tert-butoxycarbonyl-aminophenylacetic acid as described in the method of Example 3. The resulting intermediate is purified by HPLC and lyophilized. In a second step, this purified intermediate is mixed with tetradecanoic acid as described in the method of Example 2 to provide the title compound, which is purified by HPLC and lyophilized (6.5 mg, 21.8% yield): 74% pure , MS (MALDI) calculated for Ce7H10_.N? 4O2? (M) 1440, found 1441.

EXAMPLE 304 COMPOUND CH3- (CH2) 10-NH-C (= 0) -GAB -ANFOMICIAN In a first stage, the compound anfomicin-9-Fmoc (40 mg) was coupled with N-tert-butoxycarbonyl-α-aminobutyric acid as described in the method of Example 3. In a second step, this intermediate purified in the first step is mixed with undecanyl isocyanate as described in Method of Example 3 to provide the title compound (2 mg, 5.1% yield): 83.6% pure, MS (MALDI) calculated for Ce? H99N15021 (M) 1379, found 1380.

EXAMPLE 305 COMPOUND NN '-DI-C8- (M, Af-DIAMINOBENZOIL) -ANFOMYCIN In a first step, the compound ampomicin-9-Fmoc (30 mg) was coupled with N, N'-di-tert-butoxycarbonyl acid phenylacetic as described in the method of Example 3. In a second step, this intermediate of the first wtapa is mixed with 85 to provide the title compound (3.7 mg, 11% yield): 99.5% pure, MS (MALDI) ) calculated for C68H? o3 ?? 5022 (M) 1483, found 1484.

EXAMPLE 306 COMPOUND CH3- (CH2) 7-? HC (= 0) - (-FE? ILACETIL) -A? FOMICI? A In a first stage, the compound anfomicin-9-Fmoc (30 mg) was coupled with the acid me ta-N-tert-butoxycarbonyl-phenylacetic acid as described in the method of Example 3. In a second step, this intermediate in the first stage is mixed with octanoyl isocyanate as described in the method of Example 3 to provide the compound Titre (4.7 mg, 16.4% yield): 89% pure, MS (MALDI) calculated for Cg2H93N? 5021 (M) 1384, found 1385.

EXAMPLE 307 COMPOUND CH3- (CH2)? 3-NH-C (= 0) -GLY-ANFOMYCIN In a first stage, the compound anfomicin-9-Fmoc (35 mg) was coupled with the N-tert-butoxycarbonyl-glycine acid as described in the method of Example 3. In a second step, this intermediate in the first step is mixed with tetradecanyl isocyanate as described in the method of Example 3 to provide the title compound (13 mg, 36.6% yield): 70.9% pure, MS (MALDI) calculated for Cg2H? Or ??? 5021 (M) 1393, found 1394.

EXAMPLE 308 1-D0DECIL-1H- (1,2,3) -TRIAZOL-4-CARBOXYLIC ACID A mixture of propiolic acid (46 μL, 0.7419 mmol) and 1-azido-dodecane (156.8 mg, 0.7419 mmol) is heated to 120 ° C eb a capped bottle for 14 hours, to give the title triazole as a white, crystalline solid (189.3 mg, 91% yield) The product is used without further purification.

EXAMPLE 308 COMPOUND 1-D0DECIL-1H- (1,2,3) -TRIAZOL-4-CARBOXYL-A? FOMICI? A In a first step, the compound ampomicin-9-Fmoc (47 g) was coupled with the acid 1 -dodecyl-1H- (1,2,3) -triazole-carboxylic acid of Example 308 as described in the method of Example 3 to provide the title compound (1.3 mg, 2. 9% yield): 83% pure, MS (MALDI) calculated for CSoH94N? 60o (M) 1359, found 1361.

EXAMPLE 310 COMPOSITE Cxs- (pt-APA) -ANFOMYCIN In a first step, the compound ampomycin-9-Fmoc (30 mg) was coupled with the meta-N-tert-butoxycarbonyl-aminophenylacetic acid as described in the method of Example 3. The resulting intermediate is purified by HPLC and lyophilized. In a second step, this purified intermediate is mixed with tetradecanoic acid as described in the method of Example 2 to provide the title compound, which is purified by HPLC and lyophilized (1.1 mg, 3% yield): 79% pure , MS (MALDI) calculated for Cg8H? 04? 4? 2 (M) 1454, found 1455.

EXAMPLE 311 COMPOSITE C? 3- (ASP- (OME)) -A? FOMICI? A In a first stage, the compound anfomicin-9-Fmoc (39 mg) was coupled with the succinimid-1-yl ester of N-tridecanoyl-O-methyl-aspartate acid as described in the method of Example 112, to give the title compound (3.7 mg, 12% yield): 93% pure, MS (MALDI) calculated for Cg3H? Oo? 4023 (M) 1422, found 1421.

EXAMPLE 312 COMPOSITE C? 3- (p-APA) -ANFOMYCIN In a first step, the compound ampomicin-9-Fmoc (30 mg) was coupled with 4-N-butoxycarbonyl-aminophenylacetic acid as described in the method of Example 3 The resulting intermediate was purified by HPLC and lyophilized. In a second step, this purified intermediate and the pentadecanoic acid as used in the method described in Example 2, provides the title compound, which is purified by HPLC and lyophilized (1.7 mg): 73.9% pure, MS ( MALDI) calculated for Cs8H? O4? 4021 (M) 1454, found 1457.

EXAMPLE 313 COMPOSITE C? 5- (ASP- (OME)) -A? FOMICI? A In a first step, the compound ampomicin-9-Fmoc (66 mg) was coupled with the succinimid-1-yl ester of N- acid pentadecanoyl-O-methyl-aspartate as described in the method of Example 112, to provide the title compound (14.3 mg): 91% pure, MS (MALDI) calculated for C65H104 ?? 4O23 (M) 1450, found 1450.

EXAMPLE 314 COMPOSITE C? 5- (ASP- (OTBU)) -ANFOMYCIN In a first step, the compound ampomycin-9-Fmoc (60 mg) was coupled with the succinimid-1-yl ester of N-undecanoi-1-0- butyl-aspartate as described in the method of Example 112, to provide the title compound (16.6 mg): 85% pure, MS (MALDI) calculated for Cg 4 H 2 or 2 4023 (M) 1436, found 1437.

EXAMPLE 315 COMPOUND C13- (ASP- (OTBU)) -A? FOMICI? A In a first step, the compound ampomicin-9-Fmoc (58 mg) was coupled with the succinimid-1-yl ester of N-tridecanoyl- O-butyl-aspartate as described in the method of Example 112, to provide the title compound (20.5 mg) -. 93% pure, MS (MALDI) calculated for Ce6H? Og? 14023 (M) 1464, found 1465.

EXAMPLE 316 COMPOUND C15- (ASP- (OME)) -A? FOMICI? A In a first stage, the compound anfomicin-9-Fmoc (66 mg) was coupled with the succinimid-1-yl ester of N-undecanoyl-O-methyl-aspartate acid as described in the method of Example 112, to give the title compound (10.1 mg) .- 92% pure , MS (MALDI) calculated for C6? H9g? 4023 (M) 1393, found 1394.

EXAMPLE 317 COMPOSITE C? 5- (ASP- (OME)) -ANFOMYCIN In a first stage, the compound anfomicin-9-Fmoc (30 mg) was coupled with the succinimid-1-yl ester of N-pentadecanoyl-O-methyl-aspartate acid as described in the method of Example 112, to provide the title compound (15.3 mg, 45% yield): 93% pure, MS (ES +) calculated for Cg5H104 X4? 23 (M) 1450, found 1451.

EXAMPLE 318 COMPOSITE C? 5- (ASP- (OME)) -A? FOMICI? -9-C (= 0) -? H- (0-CF3-FE? ILO) The compound C15-ampicillin (30 mg, 0.023 mmol) of Example 2 and the isocyanate compound orts- (trilfluoromethyl) phenyl used as described in the method of Example 255, provides the title compound, which is purified by HPLC and it is lyophilized (7 mg, 21.9% yield): 96% pure, MS (MALDI) calculated for Ce8H? 0X ?? 4O2? (M) 1508, found 1510.

EXAMPLE 319 COMPOSITE N, N -DI-C6- (f, Af-DIAMI? OBE? ZOIL) -A? FOMICI? A In a first stage, the compound N, N '-di-Ce- (meta acid, meta -diaminobenzoic acid) is prepared from 2T2eta, 7-diethanediaminobenzoic acid and hexanoyl chloride as described in the method of Example 274. In a second step, the compound of ampomycin-9-Fmoc (30 mg) is coupled with the compound N, N / -di-Ce- (277eta acid, zt7eta-diaminobenzoic acid) as described in the method of Example 299 (Step B) to provide the title compound (8.6 mg, 20% yield): 95% pure, MS (MALDI) calculated for Ce4H95 5? 2 (M) 1427, found 1428.

EXAMPLE 320 COMPOSED ^ N -DI-C a- (M, Af-DIAMI? OBE? ZOIL) -A? FOMICI? A In a first stage, the compound N, N '-di-CX2- (meta acid, meta- diaminobenzoic acid) is prepared from 277eta, 277eta-diaminobenzoic acid and dodecanoyl chloride as described in the method of Example 274. In a second step, the ampomicin-9-Fmoc compound (30 mg) is coupled to the N-compound. , N7 -di-CX2- (meta, zneta-diaminobenzoic acid) as described in the method of Example 299 (Step B) to provide the title compound (1.7 mg, 4% yield): 94% pure, MS (MALDI) ) calculated for C7eH ?? 9 ?? 5022 (M) 1595, found 1596.

EXAMPLE 321 COMPOUND CH3- (CH2) 7-? HC (= Q) - (ß-ALA) -A? FOMICI? A In a first step, the compound ampomicin-9-Fmoc (30 mg) was coupled with the compound N -ter-butoxycarbonyl-β-alanine as described in the method of Example 3. In a second step, this intermediate of the first step was mixed with octanoyl isocyanate as described in the method of Example 3 to provide the title compound (7 mg, 23% yield): 89.5% pure, MS (MALDI) calculated for C57H9? 502? (M) 1322, found 1323.

EXAMPLE 322 COMPOUND (FENILBENZOIL) -ANFOMYCIN The ampomycin-9-Fmoc compound (70 mg) is coupled with the 4-phenylbenzoic acid as described in the Example 299 (Step B) to provide the title compound (8.8 mg, 13% yield): 97.6% pure, MS (MALDI) calculated for C58H77N1302o (M) 1276, found 1277.

EXAMPLE 323 COMPOUND (2 - (FENYLENE METHYL) BENZOYL) -ANFOMYCIN The compound of ampomycin-9-Fmoc (70 mg) is coupled with 2- (phenylmethyl) benzoic acid as described in Example 299 (Step B) to provide the compound of Title (15.3 mg, 22% yield): 95.7% pure, MS (MALDI) calculated for C59H79N? 3O20 (M) 1290, found 1291.

EXAMPLE 324 N, N-PABA-ANFOMYCIN COMPOUND The ampomycin-9-Fmoc compound (70 mg) is coupled with the para-N, N-diethylaminobenzoic acid (N, N-diethyl-PABA) as described in the Example 299 (Step B) to provide the title compound (15.1 mg, 22% yield): 98.4% pure, MS (MALDI) calculated for CBSH82 O O20 (M) 1271, found 1272.

EXAMPLE 325 COMPOUND (3,4,5-TRIMETOXIBE? ZOIL) -A? FOMICI? A The compound of ampomycin-9-Fmoc (70 mg) is coupled with 3,4,5-trimethoxybenzoic acid as described in the method of Example 299 (Step B) to provide the title compound (7.9 mg, 11.4% yield): 89.2% pure, MS (MALDI) calculated for C57H83 3 3 23 23 (M) 1318, found 1319.

EXAMPLE 326 COMPOUND (4-BUT LBE? ZOIL) -A? FOMICI? A The compound of ampomycin-9-Fmoc (70 mg) is coupled with the 4-butylbenzoic acid as described in the method of Example 299 (Step B) to provide the title compound (9.2 mg, 13.4% yield): 91.5% pure, MS (MALDI) calculated for C5gH8 ?? 302o (M) 1256, found 1257.

EXAMPLE 327 COMPOUND (3- (FENOXY) -BENZOYL) -ANFOMYCIN The compound of ampomycin-9-Fmoc (70 mg) is coupled with the 3- (phenoxy) benzoic acid as described in the method of Example 299 (Step B) to provide the title compound (5.9 mg, 8.7% yield): 92% pure, MS (MALDI) calculated for C58H77NX302X (M) 1292, found 1293.

EXAMPLE 328 COMPOUND C15-ANFOMICIN-9- (D-DAP) Compound CX5-ampicillin (27 mg, 0.020 mmol) of Example 2 and (R) -2-tert-butoxycarbonylamino-3- (9H-fluoren-9) acid -yl-methoxycarbonyl) -aminopropionic acid used as described in the method of Example 4, provides the title compound, which is purified by HPLC and lyophilized (7 mg, 12% yield): 88.5% pure, MS (MALDI) calculated for Cg3HX03N? 5O21 (M) 1407, found 1407.

EXAMPLE 329 ß-ISOMER OF COMPOUND CH3- (CH2) 13-NH-C (= 0) -ANFOMYCIN The title compound is obtained using the method as described in method 253, wherein the compound is a byproduct of this reaction (ie, the ß-isomer refers to the nucleus of the amphomycin peptide). MS and analytical HPLC were used to identify the title compound, which is purified by HPLC and lyophilized (4 mg, 1.6% yield): 97.5% pure, MS (MALDI) calculated for Cg0H98N? 402o (M) 1336, found 1336 EXAMPLE 329 ß-ISOMER OF COMPOUND CH3- (CH2)? 3-NH-C (= 0) -ANFOMYCIN The title compound is obtained using the method as described in method 304, wherein the compound is a secondary product of this reaction (ie, the β-isomer refers to the nucleus of the peptide ampomycin). MS and analytical HPLC were used to identify the title compound, which is purified by HPLC and lyophilized (2 mg, 5% yield): 99.9% pure, MS (MALDI) calculated for Cg? H99NX502? (M) 1379, found 1379.

EXAMPLE 331 COMPOSITE LYS-GLY-ANFOMICIN-9-C15 The compound of ampomycin-9-Fmoc (70 mg) is coupled to the compound Boc-Lys (Boc) -Gly (Chemlmpex) as described in the method of Example 299 ( Step B) to provide the Boc-Lys (Boc) -Gly-ampicillin compound. In a second step, the pentanoic acid is coupled to the Boc-Lys (Boc) -Gly-amphomycin compound as described in the method of Example 299 (Step B) to provide the Boc-Lys (Boc) -Gly compound. anfomicin-9-C15. This product was deprotected under standard conditions (4N HCl / dioxane) to provide the title compound after working it as described in the method of Example 299 (Step B). (14 mg, 17.5% yield): 90% pure, MS (MALDI) calculated for C68H ??2N16022 (M) 1506, found 1507.

EXAMPLE 332 COMPOSITE LYS-GLY-ANFOMICIN-9-C13 The compound of ampomycin-9-Fmoc (70 mg) is coupled with the compound Boc-Lys (Boc) -Gly, followed by coupling with tridecanoic acid in a second step and finally deprotection as described in the method of Example 331 to provide the title compound (11 mg, 17.8% yield): 89% pure, MS (MALDI) calculated for CssH? o8N1602__ (M) 1478, found 1479.

EXAMPLE 332 COMPOSITE LYS-GLY-ANFOMICIN-9-C13 The compound of ampomycin-9-Fmoc (100 mg) is coupled with the 11- (phenoxy) undecanoic acid as described in the method of Example 299 (Step B) to provide the title compound (37.7 mg, 36.8% yield): 94% pure, MS (MALDI) calculated for CsH93N? 302? (M) 1356, found 1357.

EXAMPLE 334 ACID 2V-C? 2- ((1S, 4S) -4-AMINOCICLOHEXILCARBOXÍLICO) In a first step, 4-aminocyclohexylcarboxylic acid (1.12 ml) is dissolved in DMF (5 ml) and DIEA (0.824 ml) is added and then the mixture is cooled to 0 ° C. Dodecanoyl chloride (3.64 ml) is added and the mixture is stirred for 1.5 hours. The mixture is extracted with EtOAC and rinsed three (3) times with HCl ((1M (aqueous)) followed by four (4) rinses with NaCl (saturated) and dried over MgSO 4, The resulting solid is triturated with hot hexanes, then it is filtered and washed with hexanes, which results in small crystals in the form of a needle and white, which are also used without further purification or characterization.

EXAMPLE 335 CN COMPOUND 2- ((1S, 4S) -4-AMINOCICLOHEXILCARBONIL) -ANFOMYCIN In a first step, N-C12- ((SS, 4S) -4-aminocyclohexylcarboxylic acid) was prepared from dodecanoyl chloride and (1S, 4S) -4-aminocyclohexylcarboxylic acid) as described in the method of Example 334. In a second step, the compound ampomycin-9-Fmoc (100 mg) is coupled with the N-C12 acid ((1S , 4S) -4-aminocyclohexylcarboxylic acid) as described in the method of Example 299 (Step B) to provide the title compound (16 mg, 21.5% yield): 76. 7% pure, MS (MALDI) calculated for Cg4H? 02N? 4O2? (M) 1404, found 1405.

EXAMPLE 336 ACID (2-DODECANOILAMINO-TIAZOL-4-IL) ACETIC In a first stage-, the ethyl ester of the acid (2-Amino-thiazoyl-4-yl) -acetic is coupled with dodecanoyl chloride as described in the method of Example 334 to provide the ethyl ester of (2-dodecanoylamino-thiazol-4-yl) -acetic acid to way of a crude solid. In a second step, the crude solid of the ethyl ester of (2-dodecanoylamino-thiazol-4-yl) acetic acid ester is deprotected by using LiOH (2 times, in excess) in THF / H20 to provide the title compound in a manner of a crude solid, which is used directly without further purification or characterization.

EXAMPLE 337 COMPOSED OF (2-DODECANOILAMINO-TIAZOL-4-IL) ACETYL-ANFOMYCIN The compound anfomicin-9-Fmoc (100 mg) is coupled with (2-dodecanoylamino-thiazol-4-yl) -acetic acid (crude solid which was peparated in Example 336) as described in the method of Example 399 (Step B) to provide title compound (8.1 mg, 9.2% yield): 89% pure, MS (MALDI) calculated for Cg4H99N? 502XS (M ) 1447, found 1448.

EXAMPLE 338 8-DODECILOXI-QUINOLIN-2-CARBOXYLIC ACID In a first stage, dodecyl bromide is added (737 μL, 3.2 mmol), Nal (478 mg, 3.2 mmol) and NaH (76 mg, 3.2 mmol) to a solution of 8-hydroxyl-quinoline-2-carboxylic acid methyl ester (2.11 mmol which is stirred in DMF). (dry, 10 ml) and the red reaction is maintained with stirring overnight The material resulting after removal of the solvents by rotary evaporation is placed in DCM, rinsed with water, dried over Na2SO4 and filtered Then the resulting solution is evaporated to dryness and the desired intermediate, the 8-dodecyloxy-quinoline-2-carboxylic acid methyl ester is obtained by HPLC (isocratic, 75% acetonyryl, 25% water) yielding 169 mg (approx. % yield.) This intermediate again underwent deprotection using LiOH in THF / H0 as described in the method of Example 336 to provide the title compound, which is further used without further purification or characterization.

EXAMPLE 339 COMPOSITE (8-DODECILOXY-QUINOLIN-2-CARBONYL) -ANFOMYCIN The compound of ampomycin-9-Fmoc (30 mg) is coupled with 8-dodecyloxy-quinoli-2-carboxylic acid (as prepared in Example 338 ) as described in the method of Example 2 to provide the title compound (24.5 mg, 37% yield): 95% pure, MS (ES +) calculated for Cg7H98NX02X (M) 1436, found 1437.

EXAMPLE 340 ß-ISOMER OF THE COMPOUND (8-DODECILOXY-QUINOLIN-2-CARBONYL) -ANFOMYCIN The title compound is obtained by using the method described as in Example 339, wherein the compound is a by-product of this reaction (this is, the β-isomer refers to the nucleus of the amphomycin peptide). MS and HPLC analyzes are used to identify the title compound, which is purified by HPLC and lyophilized (7.1 mg, 11% yield): 95% pure, MS (MALDI) calculated for C67H98NX4021 (M) 1436, found 1437 .

EXAMPLE 341 C-S-ANFOMICIN-9-PHE COMPOSITE The compound C15-ampicillin (57 mg, 0.043 mmol) of Example 2 and the activated succinimide of N-tert-butoxycarbonyl-phenylalanine used as described in the method of Example 3, provides the title compound, which is purified by HPLC and lyophilized (57 mg, 5.5% yield): 85.5% pure, MS (MALDI) calculated for C69H10gN? 4O2? (M) 1468, found 1470.

EXAMPLE 342 COMPOSITE C? 5-ANFOMICIN-9-C? 5 The compound C15-ampicillin (57 mg, 0.0438 mmol) of Example 2 and the pentadecanoic acid used as described in the method of Example 201, provides the title compound, which is purified by HPLC and lyophilized (2 mg, 3.6% yield): 87.7% pure, MS (MALDI) calculated for C75H? 25N1302X (M) 1545, found 1547.

EXAMPLE 343 COMPOSITE C? 5-ANFOMICIN-9- ([2- (2-METOXY-ETOXI) -ETOXY] -ANETHYL) The compound C15-ampicillin (40 mg, 0.031 mmol) of Example 2 and acid [2- ( 2-methoxy-ethoxy) -ethoxy] -acetic used as described in the method of Example 201, provides the title compound, which is purified by HPLC and lyophilized (3 mg, 7.9% yield): 87% pure, MS (MALDI) calculated for C67HXo9N? 3024 (M) 1481, found 1484.

EXAMPLE 344 Cxs-SAR-ANFOMYCIN COMPOSITE In a first step, N-decanoyl sarcosine succinimid-1-yl ester is prepared from decanoyl chloride and sarcosine as described in the method of Example 274 and transformed to succinimidyl ester as described in Example 1. In a second step, the compound of ampomycin-9-Fmoc (25 mg) was coupled with the succinimid-1-yl ester of N-decanoyl sarcosine as described in the method of Example 3 for provide the title compound (11 mg, 42.3% yield): 99.1% pure, MS (MALDI) calculated for C58H92? X4021 (M) 1321, found 1323.

EXAMPLE 345 COMPOSITE CX5-SAR-A? FOMICI? A In a first step, the N-tetradecanoyl sarcosine succinimid-1-yl ester is prepared from tetradecanoyl chloride and sarcosine as described in the method of Example 274 and converted to succinimidyl ester as described in Example 1. In a second step, the compound of ampomycin-9-Fmoc (40 mg) is coupled to succinimid-1-yl ester of N-tetradecanoyl sarcosine as described in the method of Example 3 to provide the title compound (1 mg, 2.4% yield): 80.9% pure, MS (MALDI) calculated for C62HXoo? 402? (M) 1378, found 1380.

EXAMPLE 346 Cs-SAR-ANFOMYCIN COMPOUND In a first step, N-octanoyl sarcosine succinimid-1-yl ester is prepared from octanoyl chloride and sarcosine as described in the method of Example 274 and transformed to succinimidyl ester as described in Example 1. In a second step, the compound of ampomycin-9-Fmoc (40 mg) is coupled with succinimid-1-yl ester of N-octanoyl sarcosine as described in the method of Example 3 to provide the title compound (1.9 mg, 3.1% yield): 98.2% pure, MS (MALDI) calculated for G_sH88? 1402? (M) 1293, found 1295.

EXAMPLE 347 COMPOUND C15-A? FOMICI? -9-C12 The compound CX5-ampicillin (25 mg, 0.019 mmol) of Example 2 and the dodecanoic acid used as described in the method of Example 201, provides the title compound, the which is purified by HPLC and lyophilized (7.3 mg, 27% yield): 87.8% pure, MS (MALDI) calculated for C72HX? 9 ?? 3? 21 (M) 1503, found 1505.

EXAMPLE 348 COMPOSITE CX5-A? FOMICI? -9- (11-FE? OXIU? DECA? OIL) The compound CX5-ampicillin (25 mg, 0.019 mmol) of Example 2 and the 11-phenoxy-decanoic acid used as described in Method of Example 201, provides the title compound, which is purified by HPLC and lyophilized (7.9 mg, 27% yield): 75.2% pure, MS (MALDI) calculated for C77H12? N13022 (M) 1581, found 1583.

EXAMPLE 349 COMPOUND C15-ANFOMICIN-9- (3-FURAN-2-IL-ACRYLIOIL) The compound C15-ampicillin (25 mg, 0.019 mmol) of Example 2 and the 3-furan-2-yl-acrylic acid used as described in the method of Example 201, provides the title compound, which is purified by HPLC and lyophilized (13 mg, 48.1% yield): 94% pure, MS (MALDI) calculated for C67H? or? NX3022 (M) 1441, found 1442.

EXAMPLE 350 COMPOSITE C15-ANFOMICIN-9- (3-BENCENSULFONIL) PROPIONYL) The compound C15-ampicillin (26 mg, 0.020 mmol) of Example 2 and 3- (benzenesulfonyl) propionic acid used as described in the method of Example 201 , provides the title compound, which is purified by HPLC and lyophilized (7.3 mg, 27% yield): 92.6% pure, MS (MALDI) calculated for Cg9H105 X3? 23S (M) 1517, found 1519.

EXAMPLE 351 COMPOSITE CX5-ANFOMICIN-9- (4- (PIREN-2-IL) BUTIROYL) The compound C15-ampicillin (26 mg, 0.020 mmol) of Example 2 and the 4- (piren-2-yl) butyric acid used as described in the method of Example 201, provides the title compound, which is purified by HPLC and lyophilized (9.3 mg, 12.2% yield): 90.4% pure, MS (MALDI) calculated for C80HX? XNX3? 2? (M) 1591, found 1591.

EXAMPLE 351 COMPOUND C15-ANFOMICIN-9-SUC The compound C15-ampicillin (38 mg) of Example 2 and synccinic anhydride (30 mg) are dissolved in DMF, then added in DIPEA (1 equivalent) and the sample is stirred during night. Working with this reaction allows to obtain the title compound after HPLC and lyophilization (6 mg, 14.6% yield): 99.1% pure, MS (MALDI) calculated for C64H? Or? N? 3023 (M) 1421, found 1423.

EXAMPLE 353 COMPOSITE C? 5-ANFOMICIN-9-PRO-LYS The compound C15-ampicillin (24 mg, 0.018 mmol) of Example 2 is activated with activated succinimide (aN-Fmoc-, e- N '-tert-butoxycarbonyl-Lysyl) ) Proline as desribe in the method of Example 3. The resulting intermediate is purified by HPLC and lyophilized and then subjected to deprotection as piperidine as described in Example 2 (using the deprotection and isolation / purification steps only) to provide the title compote, which is purified by HPLC and lyophilized (6.1 mg, 22.6% yield): 88.9% pure, MS (MALDI) calculated for C7? H? 6N16022 (M) 1546, found 1548.

EXAMPLE 354 COMPOSITE OF BOC-ANFOMICI A The compound of ampomycin-9-Fmoc (151.2 mg, 0.11 mmol) is dissolved in water (5 ml) and the pH is adjusted to approximately 12 using NaOH (1M), while stirring at 0 ° C (ice bath). The di-tert-butyl dicarbonate (185.6 mg) dissolved in acetonitrile is added with stirring at 0 ° C and the resulting mixture is kept under stirring until the reaction is complete (overnight). Then piperidine in DMF (20% v / v) is added to remove the Fmsc group from the Dab9 position and the title compound is provided as described in the method of Example 2 (using only the deprotection and isolation / purification steps) . The resulting product is used directly.

EXAMPLE 355 ANFOMICIN-9- (ß-ALA) COMPOUND The Boc-amphomycin compound (20 mg, as prepared in Example 354) is coupled to the compound Boc-β-Ala-OSu (Bachem AG, Switzerland) as described in the method of Example 3 to provide the title compound (9.2 mg, 16.4% yield): 94.1% pure, MS (MALDI) calculated for C48H74N40o (M) 1167, found 1169.

EXAMPLE 356 ANF0MICIN-9-SAR COMPOUND The Boc-amphomycin compound (20 mg, as prepared in Example 354) is coupled to the Boc-Sarcosine-OSu compound (Bachem AG, Switzerland) as described in the method of Example 3 to provide the title compound (11.3 mg, 57.9% yield): 81.5% pure, MS (MALDI) calculated for C48H74N? 4O20 (M) 1167, found 1169.

EXAMPLE 357 COMPOUND GLY-ANFOMICIN-9-FMOC The compound anfomicin-9-Fmoc (176.25 mg, 0.134 milimolews) engages the succinimide activated N-tert-butoxycarbonyl glycine as described in the method of Example 3 to give compound of title (160.2 _j) /? [which is used directly in further reactions without further purification or characterization.

EXAMPLE 358 COMPOSITE C.-GLY-ANFOMICIN-9-FMOC The compound Gly-ampomycin-9-Fmoc (25 mg, 0.018 mmol) as prepared in Example 357 is coupled with the activated n-hexanoic acid as described in Method of Example 2 to provide the title compound (7.9 mg, 31.7% yield): 83.9% pure, MS (MALDI) calculated for C53H82Ni4? 2? (M) 1251, found 1253.

EXAMPLE 359 COMPOUND C8-GLY-ANFOMICIN-9-FMOC Compound Gly-anfomicin-9-Fmoc (25 mg, 0.018 mmol) as prepared in Example 357, is coupled with the activated succinimide n-octanoic acid as described in the method of Example 2 to provide the title compound (3.7 mg, 16.1% yield): 82% pure, MS (MALDI) calculated for C55H8gN? 4? 2? (M) 1279, found 1281.

EXAMPLE 360 COMPOUND C? O-GLY-ANFOMICIN-9-FMOC Compound Gly-anfomicin-9-Fmoc (25 mg, 0.018 mmol) as prepared in Example 357, is coupled with the activated succinimide acid n-decanoic as is described in the method of Example 2 to provide the title compound (8.7 mg, 37.8% yield): 91.7% pure, MS (MALDI) calculated for C57H90N14O2? (M) 1307, found 1309 EXAMPLE 361 COMPOUND C8- (M-APA) -ANFOMYCIN In a first stage, the compound anfomicin-9-Fmoc (25 mg) is coupled with the etho-tert-butoxycarbonyl-aminophenylacetic acid as described in the method of Example 3. The resulting intermediate is purified by HPLC and lyophilized. In a second step, this purified intermediate and the octanoic acid used as described in the method of Example 2 provide the title compound, which is purified by HPLC and lyophilized (6.9 mg, 18% yield): 72% pure, MS (MALDI) calculated for Ce_H9oN? 4021 (M) 1355, found 1357.

EXAMPLE 362 COMPOUND CH3- (CH2) 10-NH-C (= 0) - (M-PHENYLACEILE) -ANFOMYCIN In a first step, the compound ampomicin-9-Fmoc (30 mg) is coupled with the meta-N- acid terbutoxycarbonyl-phenylacetic acid as described in the method of Example 3. In a second step, this intermediate of the first step is mixed with undecanny isocyanate as described in the method of Example 3 to provide the title compound (2.3 mg, 1.5% yield): 82% pure, MS (MALDI) calculated for Cg5H99 i5? 2? (M) 1427, found 1429.

EXAMPLE 363 The ampomycin-9-Fmoc compound is coupled to the activated succinimide of adamantane-1-carboxylic acid as described in Example 2 to provide the title compound (4.1 mg): 90% pure, calculated MS (FAB) for C56H83N? 3? 20 (M) 1258, found 1259.

EXAMPLE 364 COMPOUND (10-methyl-undec-2-enoyl) -ANFOMICINA amphomycin complex is produced by fermentation of Streptomyces s can, and subsequent way is subjected to liquid chromatography (LC) MS and to identify the title Compustar . Once identified in the ampomycin complex, the title compound is purified by HPLC and lyophilized to make antibiotics derived from this lipopeptide (2.0 mg). 98% pure, MS (FAB) calculated for C57H89N? 3O20 (M) 1276, found 1277.

EXAMPLE 365 COMPOSED OF (10-METHYL-UNDEC-2-ENOYL) -ANFOMYCIN The amphomycin complex is produced analyzed as described in Example 364. The title compound is purified by HPLC and used to make antibiotics derived from this lipopeptide (11.0 mg): 97% pure, MS (FAB) calculated for C58H9? N? 302o (M) 1290, found 1291.

EXAMPLE 366 COMPOSED OF (12-METHYL-TETRADEC-2-ENOYL) -ASPARTOCIN The ampomycin complex is produced by fermentation of Streptomyces griseus, and analyzed as described in Example 364. The title compound is purified by HPLC and used directly to manufacture antibiotics derived from this lipopeptide (10.0 mg): 96% pure, MS (MALDI) calculated for CeoH95N? 302o (M) 1319, found 1319.

EXAMPLE 367 COMPOSED OF (10-METHYL-DODEC-2-ENOYL) -ANFOMICIN-9-GLY The compound of (10-methyl-dodec-2-enoyl) -anfomycin, as prepared in Example 365, is coupled with succinimide Activated Fmoc-glycine as described in the method of Example 2 to provide the title compound (10.5 mg): 84% pure, MS (FAB) calculated for CeoH94N? 402X (M) 1347, found 1348.

EXAMPLE 368 COMPOSED OF (10-METHYL-DODEC-2-ENOYL) -ANFOMICIN-9-SAR The compound of (10-methyl-dodec-2-enoyl) -anfomycin, as prepared in Example 365, is coupled with succinimide Activated Fmoc-sarcosine as described in the method of Example 2 to provide the title compound (10.6 mg): 89% pure, MS (FAB) calculated for C6xH9gNX4? 2X (M) 1362, found 1362.

EXAMPLE 369 COMPOSED OF (10-METHYL-DODEC-2-ENOYL) -ANFOMICIN-9- (ß-ALA) The compound of (10-methyl-dodec-2-enoyl) -anfomycin, as prepared in Example 365, is coupled with Fmoc-β-alanine activated succinimide as described in the method of Example 2 to provide the title compound (10.9 mg): 86% pure, MS (FAB) calculated for C6xH9gNX402X (M) 1362, found 1362.

EXAMPLE 370 COMPOSED OF (10-METHYL-TETRADEC-2-ENOYL) -ASPARTOCIN-9-GLY The compound of (10-methyl-tetradec-2-enoyl) -aspartocin, as prepared in Example 366, is coupled with succinimide Activated Fmoc-glycine as described in the method of Example 2 to provide the title compound (10.5 mg): 80% pure, MS (FAB) calculated for C62H98NX402X (M) 1376, found 1376.

EXAMPLE 370 COMPOSED OF (12-METHYL-TETRADEC-2-ENOYL) -ASPARTOCIN-9-SAR The compound of (12-methyl-tetradec-2-enoyl) -aspartocin, as prepared in Example 365, is coupled with succinimide Activated Fmoc-sarcosine as described in the method of Example 2 to provide the title compound (11.6 mg): 91% pure, MS (FAB) calculated for Cs3H? 0o? 402? (M) 1390, found 1390.

EXAMPLE 372 COMPOSED OF (12-METHYL-TETRADEC-2-ENOYL) -ASPARTOCIN-9- (ß-ALA) The compound of (12-methyl-tetradec-2-enoyl) -aspartocin, as prepared in Example 365, is coupled with Fmoc-β-alanine activated succinimide as described in the method of Example 2 to provide the title compound (11.8 mg) -. 91% pure, MS (FAB) calculated for Cg3H? OoN? 4021 (M) 1390, found 1390.

EXAMPLE 373 COMPOSITE OF (12-ACETYLAMINODODANOAN) -ANFOMYCIN The ampomycin-9-Fmoc compound is coupled with activated succinimide of 12-acetylaminododecanoic acid as described in the method of Example 2 to provide the title compound (11 mg): % pure, MS (FAB) calculated for C59H94N? 402 (M) 1335, found 1336.

EXAMPLE 374 COMPOSITE OF (12-AMINOODODOCOY) -ANFOMYCIN The ampomycin-9-Fmoc compound is coupled with activated N-Fmoc-12-aminododecanoic acid succinimide as described in the method of Example 2 to provide the title compound (5). mg): 84% pure, MS (FAB) calculated for C57H9NX402o (M) 1293, found 1293.

EXAMPLE 375 ANALYSIS AS TO ANTIBODY ACTIVITY The antimicrobial lipopeptide derivatives described herein were tested for microbial activity against Gram-positive bacteria as follows. The minimal inhibitory concentrations (MIC) of the antimicrobial lipopeptide derivatives of the invention were determined using the NCCLS guidelines M-A6 (2003) with a slight modification in that duplicate serial solutions were used which were used to dilute the test compounds. The microdilution method of the broth phase was used. Isolated colonies of Staphylococcus aureus (MSSA) from the blood agar plate cultures of 18-24 hours were used to inoculate the cation-adjusted Mueller-Hinton broth (CAMHB) supplemented with calcium 0. 625 millimolar. In 96-well plates, a volume of 90 μL of a bacterial suspension having 105 colony forming units (CFU) / ml was added to 10 μL of increased concentrations of each compound of the invention (doubling in concentration each adjacent cavity and fluctuates from approximately 0.125 μg / ml to approximately 64 μg / ml). A negative control containing only the medium only and a positive culture control containing bacteria only with the medium were also included. The MICs were determined after incubating the plates at approximately 37 ° C for 24 hours. The activity of various antimicrobial lipopeptide derivatives of the invention are shown in Tables 1-16. The MIC was recorded as the lowest concentration of a test antimicrobial compound that completely inhibits bacterial growth. However, a range of MIC values show a range of activity of compounds tested multiple times. The unit value for all MIC values is μg / ml and the natural ampicillin complex has a MIC of approximately 1.4 μg / ml against MSSA cultured as described above. In Tables 1 to 16, R is the cyclic peptide of the ampomycin or aspartocin nucleus, which may be in the form of a β-isomer, an anhydrous, a dianhydrous or any combination thereof. The person skilled in the art will appreciate that the amino group of the exocyclic amino acid at position 1 and the amino group Dab9 shown in the above structures, each of Tables 1 to 16 is only to illustrate the site of annexation of substituents to the peptide cyclic of the nucleus and are not intended to be construed as a hydrazino group (ie, the amino groups shown, although shown for convenience, are actually part of the R structure, as described herein). In addition, the person skilled in the art will appreciate that all individual compounds, or groups of compounds, derived from the various combinations of structures and substituents shown in Tables 1 to 16, are disclosed by the present application to the same extent as if each compound or group of compounds was individually summarized.

TABLE 1 Compound No. m RJ MIC 3 1 -NH2 0.25-2 147 2 -NH2 0.25-1 22 3 -NH2 1-2 25 5 -NH 2 1 34 11 -NH 2 32-64 207 2 -CH 3 16 201 4 -CH 3 32 205 6 -CH 3 16 220 8 -CH 3 2 347 10 -CH 3 > 64 342 13 -CH3 > 64 348 9 -O-phenyl > 64 twenty TABLE 2 or m N X MIC 33 1 1 1 1 1 -NH- 0.5-1 42 1 1 1 0 - -NH- 1 68 1 1 2 0 - -NH- 2 70 2 1 5 0 - -NH- 2 72 3 1 5 0 - -NH- 8 197 1 1 5 0 - -NH- 0.25- 0.5 173 2 1 4 0 - -NH- 1 176 4 1 2 0 - -NH- 4 93 5 1 1 0 - -NH- 4 94 3 1 3 0 - -NH- 2 212 2 0 - 1 0 -NH- 1 81 1 0 _ 1 4 _ 32 CH2- 49 CH2- TABLE 3 No. n m X (stereochemistry) i MIC comp. 6 8 0 - -H 32-64 7 9 0 - -H 32-64 8 10 0 - -H 4-8 9 11 0 - -H 0.5-1 12 0 - -H 1 2 13 0 - -H 0.5-4 11 14 0 - -H 0.5 12 15 0 - -H 1-2 13 16 0 - -H 2 358 4 1 -H -H > 64 359 6 1 -H -H > 64 360 8 1 -H -H > 64 103 10 1 -H -H 8-16 105 12 1 -H -H 0.5 106 14 1 -H -H 0.5 107 16 1 -H -H 2 346 6 1 -H-CH3 > 64 344 8 1 -H-CH3 > 64 345 12 1 -H -CH3 64 115 13 1 -phenyl (L) -H 2 116 13 1 -benzyl (D) -H 1 118 8 1 -CH2- < [3-H 2 -benzo [b] thiophen) (L) 316 9 1 -CH 2 ~ C (= 0) -OMe (L) -H > 64 311 11 1 -CH2 -C (= 0) -OMe (L) -H 8 313 13 1 -CH2 -c (= 0) -OMe (L) -H 0.5-1 317 13 1 -CH2 -c (= 0) -OMe (L) -H 1 314 9 1 -CH2 - c (= = 0) - OtBu (L) -H 8 315 11 1 -CH2 - c (= = 0) - OtBu (L) -H 1 112 13 1 -CH2 - c (= = 0) - OtBu (L) -H 0.5 TabJa. t Indicates that the nucleus is a beta isomer of the core peptide Table 5, Table 6A.

Table 6B. fifteen Table 6C.

Table L 6D (a) = Table 7 Boards.

Table 9. Table 10.

Table 11 Table 12.

Table 13. Compound # / MIC Gly = Glycine, ß-Ala = ß-alanine, GABA =? -aminobutyric acid, Sar = Sarcosine, Orn = Ornithine, Dap = 2,3-diaminopropanoic acid, gDab = 2,4-diaminobutanoic acid, Gly-Lys = Glycine -Lisina.

Table 14. • i- Indicates that the nucleus is beta isomer of the core peptide Table 15. H I Cola "AA Table 16. 1 1 I I. ", A A '.

EXAMPLE 376 COMPARISON OF COMPOUNDS IN MIC ANALYSIS The antimicrobial lipopeptide derivatives of the present invention were tested for antimicrobial activity against Gram-positive bacteria in a variety of media conditions. The mean inhibitory concentrations (MIC) of the antimicrobial lipopeptide derivatives were determined as described in Example 376. The various media used are described in Table 17. The MIC was recorded as the lowest antimicrobial concentration of antimicrobial compound that completely inhibits growth and are provided in Table 18. Some lipopeptide antibiotic derivatives of the invention showed better broad spectrum activity against Gram-positive bacteria than other compounds under a variety of conditions of analysis. In certain embodiments, compounds having specific lipophilic substituents attached to the amino-terminal amino acid by a urea linker had unexpected activity when compared to compounds having lipophilic substituents directly attached as linear carbon tails (ie, without Dab9 substitution). For example, see compound 253 compared either with compound 2 or with compound 11. In another embodiment, the addition of a dipeptide (Glycine-Lysine) at the Dab9 position produced a compound with an unexpected increase in activity, especially against Staphylococcus aureus in E or F media (see for example, compound 199 compared to compound 2). Another example of a Dab9 substitution that increases both the MICs in the serum and broth against Staphylococcus aureus is compound 80 compared to compound 12. In addition, the relative differences in both MIC of the serum and MIC, depending on the substituent Dab9, highlights the unexpected and unique differences of the compounds compared to derivatives of compounds of the present disclosure (see, for example, compound 15 compared to compound 88 and compound 2 as compared to compound 147). In addition, unexpected variations in the MIC profile were observed as a result of small variations in the Dab9 structure (eg, amino acids D against L). For example, see compound 106 compared to compound 67 and compound 69 compared to compound 4. Finally, the difference in the effect of calcium is unexpected and larger on MIC of the broth, as observed for some derivatives Dab9 (see compound 251 compared to compound 92, compound 98 and compound 97).

TABLE 17. STRAINS AND MEANS USED FOR THE MIC TEST OF THE COMPOUNDS Abbreviations: CAMHB (Mueller-Hinton broth adjusted for cation), VRE (Vancomycin-resistant Enterococci), MDR (resistant to multiple drugs), VSE (Enterococci sensitive to vancomycin), MSSA (S. aureus sensitive to methicillin), VISA ( S. aureus vancomycin intermediate), MRSA (methicillin-resistant S. aureus), MRSE (methicillin-resistant S. epidermidis), PISP (penicillin intermediary S. pneumoniae), PRSP (penicillin-resistant S. pneumoniae), PSSP ( S. pneumoniae sensitive to penicillin) and PenS (sensitive to penicillin).

Not O l c » N > A - M Represents media conditions as defined in Table 17.

EXAMPLE 377 BACTERICIDE ACTIVITY OF LIPOPEPTIDE DERIVATIVES Extermination curve experiments were carried out with organisms of Staphylococcus aureus (SAU0017) and Enterococcus faecalis (EFS0004) grown in logarithmic phase, which were suspended in Mueller-Hinton broth adjusted by cation with Ca + 2 0.625 millimolar at a concentration of 106 CFU / ml. The cultures were then exposed to various concentrations (ie, multiples of the MIC) of a lipopeptide derivative and incubated at about 37 ° C. At selected points in time from about 0 hours to about 24 hours, a sample from each culture was analyzed for a titer of viable organisms (CFU / ml), which is compared against the time required for each compound to kill bacteria. Based on the guidelines of NCCLS M26-A (Vol. 19 No. 18), a compound is considered bactericidal if it exterminates 99.9% of bacterial cells after 24 hours. In contrast to vancomycin (see Figure 4A and 5A), which is generally bacteriostatic, the lipopeptide derivatives of the present disclosure were all bactericidal in 24 hours against Enterococcus faecalis (Figure 4) and Staphylococcus aureus (Figure 5). For example, compounds 3, 85, 4, 128, 60, 119, 199, 147, 253, 278 and 280 were rapidly bactericidal, killing in general >; 99.9% of Staphylococcus aureus and / or Enterococcus faecalis in 6 hours (generally at concentrations within two (2) dilutions of the MIC of the compound). Some compounds (such as 108 and 75) were bactericidal in the course of about 2 to about 4 hours. The lipopeptide antibiotic derivatives of the present disclosure are highly bactericidal, which is a parameter of potential therapeutic effectiveness.

EXAMPLE 378 POST-ANTIBIOTIC EFFECT OF LIPOPEPTIDE DERIVATIVES Post-Antibiotic Effect (PAE) experiments were carried out with Staphylocccus aureus growing in logarithmic phase, which were exposed to varying concentrations (sub (0.5x) to supra (4x) multiples of the MIC) of a lipopeptide derivative for one (1) hour before the drug is withdrawn. After the removal of the lipopeptide compounds, the bacterial titer was determined every hour to verify bacterial re-growth. PAE duration is defined as the difference in time required for bacterial cells exposed to the antimicrobial compound against the unexposed bacterial cells to obtain an increment of 1 log__0 unit in CFU / ml.

TABLE 19. POST-ANTIBIOTIC EFFECT (HOURS) * The MIC used for compounds 4 and 147 was 1 μg / ml and for compounds 278 and 280 it was 2 μg / ml.

Compounds 4, 147, 278 and 280 showed a prolonged antibiotic effect varying from 0.6 hours (exposure to 0.5 x MIC for one hour) to 3.2 hours (exposure to 4 x MIC for one hour), many of which were dose dependent. The rapid bactericidal properties and the prolonged PAE shown for the lipopeptide derivatives of the present disclosure are an advantage over many known antibacterial compounds.

EXAMPLE 379 OF IN VIVO LIFE OF LIPOPEPTIDE DERIVATIVES A pharmacokinetic parameter that can be measured and which helps to determine the efficacy, after a simple administration (iv) of an antimicrobial lipopeptide derivative of the present disclosure is the systemic half-life of the compound. Briefly, the test compounds were dissolved in a 5% mannitol solution (then, the pH was adjusted) at a concentration of 1 mg / ml (w / v). A single intravenous injection into the lateral caudal vein of Swiss CD1 mice (female of 5 or 6 weeks) or Sprague-Da law (male) rats were used to administer the lipopeptide derivative at a final dose of 10 mg / Kg. At several points in time (periods of about 4 minutes to about 24 hours for the mice and 48 to 72 hours for the rats) the mice were sacrificed and the blood was collected. The concentration of the lipopeptide derivative in the ex vivo plasma was quantified using liquid chromatography (LC) with mass spectrometric detection (MS). As shown in Table 19, the lipopeptide derivatives of the present disclosure show unusually long half-lives in mice and rats after administration (i.v.).

TABLE 20. AVERAGE LIFE OF VARIOUS IN VIVO LIPOPEPTIDE DERIVATIVES COMPOUNDS * Cmpd refers to "compound number". f The values are in minutes; a similar acid lipopeptide, daptomycin, has a half-life of 54 minutes (subcutaneous administration at 10 mg / kg) at 108 minutes (administration (i.p.) at 20 mg / Kg) (see Safdar et al., Antimicrob. Agents Chemother. 48: 63, 2004; Louie et al. , Antimicrob. Agents Chemother, 45: 845, 2001).

EXAMPLE 380 IN VIVO INFECTION PROTECTION MOUSE MODEL The antimicrobial lipopeptide derivatives of the present invention were tested for antimicrobial activity against Gram-positive bacteria in an intraperitoneal (ip) murine model (ie, the bacteria were injected (ip ) and the lipopeptide compounds were administered intravenously (iv)). The mice were infected with Staphylococcus aureus, Streptococcus pneumoniae or Enterococcus faecalis, which were prepared as follows: S. aureus de Smith (SAU0017, ATCC 19636) were cultured overnight in trypticase soy broth, harvested and then suspended again in fresh medium containing 5% mucin (Sigma Chemical Co.); S. pneumoniae (SPN 0032, ATCC 10813) were grown overnight on blood agar plates and suspended again in 0.9% sterile saline and JE ?, faecalis EFS0040 (clinical isolate) was cultured overnight in culture in heart infusion broth, washed and suspended again in 0.9% saline and mixed with an equal volume of sterile fecal rat extract. Each of the Swiss CD1 mice was infected (i.p.) with bacteria at the following doses: S. aureus at 105 CFU / mouse; S. pneumoniae at 102 CFU / mouse or E. faecalis at 107.5 CFU / mouse. Either immediately after infection (for E. faecalis) or two hours after infection (for S. aureus and S. pneumoniae), the mice were subjected to intravenous (i.v.) treatment with one of the following compositions: (1) a lipopeptide derivative formulated in a 5% solution of mannitol in a dose range of about 0.1 mg / Kg to about 10 ml / kg; (2) the vehicle 5% mannitol only at a dose volume of 10 ml / kg or (3) a known original lipopeptide antibiotic, such as aspartocin or ampomycin or another antibiotic, such as vancomycin, at a similar dose as the compounds of lipopeptide derivatives. Mice were observed and deaths were recorded for 7 days after treatment. The ED50 for each compound was calculated using the method of Reed and Meunch (Am. J. Hyg. 27: 493, 1938). Surprisingly, several of these lipopeptide compounds showed activity equivalent to or greater than the original compounds anfocimin or aspartocin. In addition, it is known in the art that ampomycin is toxic (see, Tisch et al., Antibiotics Ann. 55: 1011, 1954, showed that ampicillin had an LD50 of 177 mg / Kg; see also Heinemann et al., Antibiotics. Chemother 3: 1239, 1953).

TABLE 21. ED50 (mg / Kg) OF THE LIPOPÉ TIDO DERIVATIVE * IN MICE * The results shown as an interval reflect results from multiple experiments.

EXAMPLE 381 JN LIVIUM LUNG INFECTION MODEL The antimicrobial lipopeptide derivatives of the present invention were tested for antimicrobial activity against Gram-positive bacteria in a model of intranasal (in) murine lung infection (ie, the bacteria are inoculated (in) and the lipopeptide compounds are administered (iv)). Streptococcus pneumoniae (SPN0032, ATCC 081) were cultured on 5% sheep blood agar plates for 24 hours at 37 ° C, consechadis and suspended again in 0.9% saline. A group of eight Swiss CD1 mice were sedated with 2% isoflurane and each mouse was infected (i.n.) dropwise to the noses with 50 μl of the prepared bacterial inoculum (i.e., a dose of approximately 10 CFU / mouse). At 3, 24 and 48 hours after infection, groups of mice received (iv) (1) a lipopeptide derivative formulated in a 5% D-mannitol solution at a dose of approximately 0.3 mg / Kg, 1 mg / Kg, 3 mg / Kg or 10 mg / Kg; (2) the 5% mannitol vehicle only at a dose volume of 10 ml / kg; or (3) a known antibiotic, such as vancomycin at a similar dose as the lipopeptide compounds. Mice were observed and exterminations were recorded during the 10 days following treatment. The ED50 (mg / Kg) of each compound was calculated using the method of Reed and Meunch (Am.J. "Hyg. 21: 493, 1938.) As shown in Table 22, the representative compounds 4, 147, 278 and 280 exhibited fairly effective ED50 values in the range of about 1.0 mg / Kg to about 2.5 mg / Kg after iv administration TABLE 22. LUNG INFECTION (SAME TO PNEUMONIA) WITH S. pneumoniae * The results shown as an interval reflect results of multiple experiments.

EXAMPLE 382 LUNG INFECTION MODEL JN VIVO AND? NEUTROPENIC MICE The antimicrobial lipopeptide derivatives of the present invention were tested for antimicrobial activity against Gram-positive bacteria in an immunocompromised intranasal (in) murine lung infection model, (i.e., the bacteria were inoculated (in) and the lipopeptide compounds were administered iv). Streptococcus pneumoniae (SPN0002) were cultured on 5% sheep blood agar plates for 24 hours at 37 ° C, harvested and then resuspended in 0.9% saline. A group of three to four Swiss CD1 mice were rendered neutropenic by administration of cyclophosphamide (Sigma Chemical Co., 150 mg / Kg, intraperitoneally i.p.) on days -4 and -1 before infection. In the time of -18 to -24 hours, each mouse was infected (i.n.) dropwise via the noses with 50 μl of the prepared bacterial inoculum (i.e., a dose of approximately 5 x 10 6 CFU / mouse). From 18 to 24 hours after infection, groups of mice received i.v. (1) a lipopeptide derivative formulated in a solution of 5% D-mannitol at a dose of approximately 1 mg / kg, 3 mg / kg 10 mg / kg or 30 mg / kg; (2) the 5% mannitol vehicle only at a dose volume of 10 ml / kg; or (3) a known antibiotic such as ampicillin, at a similar dose as the lipopeptide compounds. In 18 to 24 hours after the antibiotic treatment, the mice were sacrificed and the lungs collected. Samples were taken from the lungs by dispersing homogenates on blood agar plates and incubated for 24 hours at 37 ° C to then count the CFU number. The Ee ended (extermination effect, that is, reduction of CFU / lung compared to the count of CFU at the time of initial treatment) and EMax (maximum reduction effect, that is, reduction of CFU / lung in comparison with the control CFU count at 24 hours) for each compound was calculated. When administered 18 to 24 hours after infusion, the lipopeptide derivatives showed a dose-dependent antimicrobial effect as measured by a decrease in CFU in the lungs of mice under treatment compared to untreated mice. At the highest dose level (30 mg / Kg), for example, compound 147 showed a CFU / lung reduction of .0 logao (P <0.001), while ampicillin showed a reduction in CFU / lung of 2.58 comparable logao. The Eextennir__o for these compounds was a CFU / lung reduction of 3.2 and 1.8 logao / respectively. Hence, this example and Example 381 show that the lipopeptide antibiotic derivatives of the present disclosure can be therapeutically effective against acute lung infection, such as pneumonia.

EXAMPLE 383 JN LIVED LOCALIZED TISSUE INFECTION MODEL IN NEUTRROPENIC MICE The antimicrobial lipopeptide derivatives of the present invention were tested for antimicrobial activity against Gram-positive bacteria in an intramuscular (im) murine thigh infection model. the bacteria were injected im and the lipopeptide compounds were administered iv). Staphylococcus aureus (SAU0017) were cultured sorbe plates of 5% sheep blood agar for 24 hours at 37 ° C, recovered and again suspended in 0.9% saline. A group of three to four Swiss CDL mice became neutropenic by administering cyclophosphamide (Sigma Chemical Co., 150 mg / Kg, i.p.) on days -4 and -1 before infection. On day zero, an overnight culture of S. aureus Smith (SAU0017, ATCC 19636) in trypticase soy broth was used to inoculate the animals by i.m. in each thigh (105 CFU / thigh). Two hours after infection, groups of mice received i.v. (1) a lipopeptide derivative formulated in a 5% mannitol solution in a dose range of about 1 mg / Kg to about 80 mg / Kg; (2) the 5% mannitol vehicle alone at a dose volume of 10 ml / kg or (3) a known antibiotic, such as vancomycin, at a similar dose range as the lipopeptide compounds. At 24 hours after the antibiotic treatment, the mice were sacrificed and the thighs were obtained. Samples were taken from the thighs when dispersing homogenates on blood agar plates and incubated for 24 hours at 37 ° C and then the CFU number was counted. The ED50 and EMax were determined using a non-linear regression technique. The dose of antibiotic that obtains a bacteriostatic effect on the thigh in 24 hours was estimated from an additional equation. The endpoint is calculated as the difference between the counts at the start of the treatment and 24 hours after the treatment (corresponding to a maximum calculation effect).

TABLE 23. INFECTION OF THE THIGH WITH S. aureus * The results shown as an interval reflect results from multiple experiments.

As shown in Table 23, representative compounds 3, 4, 128, 147, 278 and 280 showed ED50 values in the range of about 1 mg / Kg to about 8 mg / Kg. In this same experiment, these same representative compounds showed a maximum effect (logarithmic reduction of bacterial counts in infected tissues at 24 hours after treatment) in the range of approximately -2.8 logarithms to approximately -4.9 logarithms, with a typical static dose (dose required to produce a bacteriostatic effect in infected tissues at 24 hours) in the range of about 1 mg / Kg to about 11 mg / Kg. Hence, this example shows that the lipopeptide antibiotic derivatives of the present disclosure can be therapeutically effective against acute localized infections.

EXAMPLE 384 MODEL OF INFUSION OF THE LUNG AND MUSCLE OF THE THIGH IN VIVO COMBINATION The antimicrobial lipopeptide derivatives of the present invention were tested for antimicrobial activity against Gram-positive bacteria in a combination of murine thigh / lung infection model i.m. /i.n. (i.e., the bactreias were administered i.m. and i.n. and the lipopeptide compounds were administered i.v.). Streptococcus pneumoniae (SPN0032, ATCC 10813) were cultured on agar plates in 5% sheep blood for 24 hours at 37 ° C, collected and then suspended again in 0.9% saline. A group of three to four Swiss CDI mice were sedated with 2% isoflurane and each mouse was infected i.n. Drop by drop to the nostrils with 50 μl of the prepared bacterial inoculum (that is, a dose of approximately 10 6 CFU / mouse). Immediately after i.n. inoculation, each mouse was injected i.m. in each thigh with 0.1 ml of a prepared bacterial inoculum (that is, a dose of approximately 105 CFU / mouse). After 4 hours after infection, groups of mice received i.v. (1) a lipopeptide derivative formulated in a 5% mannitol solution at a dose of approximately 0.16 mg / Kg, 0.32 mg / Kg, 0.63 mg / Kg, 1.25 mg / Kg, 2.5 mg / Kg, 5 rog / K ? f or 10 l / Kg; (2) the 5% mannitol vehicle alone at a dose volume of 10 ml / Kg or (3) a known lipopeptide antibiotic, such as vancomycin, at a similar dose as the test compounds. After 24 hours after treatment with antibiotics, the mice were sacrificed and the lungs and thighs collected. Samples were taken from the thighs and lungs by dispersing homogenates on blood agar plates and incubated for 24 hours at 37 ° C and then counted the CFU number. The ED50 and EMax were determined using a non-linear regression technique. The dose of antibiotic that obtains a bacteriostatic effect on the thigh in 24 hours was estimated from an additional equation. Extermination was calculated as the difference between counts at the start of treatment and at 24 hours after treatment (corresponding to a maximum calculation effect). In the combined murine model of lung and thigh muscle infection, with Streptococcus pneumoniae, representative compounds 147, 278 and 280 showed ED50 values in the range of about 0.25 mg / Kg to about 1.5 mg / Kg for lung tissue and ED50 values in the ratio of approximately 1 mg / Kg to approximately 2 mg / Kg for thigh muscle tissue. In this same experiment, for lung tissue, these same representative compounds showed a maximum effect in the range of about -3.6 logarithms to about -4.4 logarithms, with a typical static dose in the range of about 0.4 mg / Kg to about 1.5 mg / Kg. Furthermore, in this same experiment, for thigh muscle tissue, those same representative compounds showed a maximum effect in a range of about -5.4 logarithms to about -6 logarithms, with a typical static dose of about 1 mg / Kg at 2 mg / Kg. Hence, this example shows that the lipopeptide antibiotic derivatives of the present disclosure can be therapeutically effective against acute systemic infections, such as bacteremia.

Claims (53)

1. CLAIMS 1. An antimicrobial compound and pharmaceutically acceptable salts thereof, according to structural formula (II):
2. characterized in that: R1 is OH O NH2; L is selected from at least one amino acid, at least one substituted amino acid, -R'C (= 0) -, -R'OC (= 0) (NR ') and -0-PhC (= 0) -; R2 is independently selected from -C (= 0) R5, -C (= 0) OR5, -C (= 0) NHR4, -C (= 0) NR4R4, -C (= S) NHR4, -C (= S) ) NR4R4, -C (= NR4) NHR4 and -C (= NR4) NR4R4; R3 is selected from OR5, SR5, NR5R5, -CN, -N02, -N3,, -C (= 0) Rs, -C (= 0) OR5, -C (= 0) NR5R5, -C (= S) NR5R5, -C (= NR4) NR5R5, -C (= 0) H, -R5-C (= 0), -S02R5, -S (= 0) R5, P (= 0) (0R5) 2, -P (= 0) (0R5), -C02H, -S03H, -P03H, halogen, trihalomethyl, alkyl (Ca-C25), alkyl (Ca-C25) substituted, heteroalkyl (Ca-C25), heteroalkyl (Ca-C25) ) substituted, aryl (C? -Cao) / substituted aryl (C5-Cao), arylaryl (C3-Ca5), arylaryl (Cs-Cas) substituted, biaryl (C5-C15), substituted (C5-C15) biaryl, heteroaryl from 5 to 10 members, substituted heteroaryl from 5 to 10 members, arylalkyl (C3-C2s), arylalkyl (C3-C26) substituted, heteroarylalkyl from 6 to 26 members, heteroarylalkyl substituted from 6 to 26 members, at least one amino acid and at least one substituted amino acid; R4 is independently selected from (C7-Co) alkyl / arylalkyl (C7-C26) and heteroarylalkyl from 17 to 26 members, a straight or branched chain saturated or single or multiple unsaturated aliphatic or hydroxyaliphatic portion having a chain length of 7 at 25 carbon atoms, a primary or secondary amine, at least one amino acid and at least one substituted amino acid; R5 is independently selected from hydrogen, alkyl (Ca-Cao) / aryl (C5-Cao), 5- to 10-membered heteroaryl, aryl (C6-C26) and heteroarylalkyl from 6 to 26 members, a saturated or individual aliphatic or hydroxyaliphatic portion or multiple unsaturated, straight or branched chain, having a chain length of 5 to 25 carbon atoms, a primary or secondary amine, at least one amino acid, at least one substituted amino acid and any combination thereof and R 'is independently one or more of the same or different substituents as defined for R3 or R5. . The compound according to claim 1, characterized in that R1 is OH.
3. 3. The compound according to claim 1, characterized in that R1 is NH2.
4. 4. The compound according to claim 1, characterized in that R2 is C (= 0) 0R5- or -C (= 0) R5.
5. 5. The compound according to claim 1, characterized in that R2 is -C (= 0) R5.
6. 6. The compound according to claim 1, characterized in that R2 is -C (= 0) NHR4, C (= S) NHR4 or -C (= NR4) NHR4.
7. 7. The compound according to claim 1, characterized in that R2 is -C (= 0) NHR4.
8. The compound according to claim 1, characterized in that R3 is at least one amino acid selected from glycine, β-alanine, sarcosine, lysine or any combination thereof.
9. 9. The compound according to claim 8, characterized in that in at least one amino acid consists of two amino acids selected from glycine-lysine, or sarcosine-lysine.
10. 10. The compound according to claim 8, characterized in that glycine is at least one amino acid.
11. 11. The compound according to claim 8, characterized in that in at least one amino acid is β-alanine.
12. The compound according to claim 5, characterized in that the compound is compound 91 of Table 6D, or compound 331 or 332 of Table 16.
13. 13. The compound according to any of claims 1 to 11, characterized in that L is at least one amino acid or at least one substituted amino acid selected from p-aminophenylacetyl, (p-aminophenylpropanoyl) __ wherein n is 1 or 2, m-aminophenylacetyl, (m-aminophenylpropanoyl) __ wherein n is 1 or 2, o-aminophenylacetyl, (o-aminophenylpropanoyl) __ wherein n is 1 or 2, GABA, p-aminobenzoic acid (PABA), m-aminobenzoic acid, o-aminobenzoic acid, p-hydrazinobenzoic acid , m-hydrazinobenzoic acid, o-hydrazinobenzoic acid, p-amino-trans-cinnamyl, m-amino-trans-cinnamyl, o-amino-trans-cinnamyl, L-BBTA or any combination thereof.
14. 14. The compound according to claim 4, characterized in that L is at least one amino acid selected from p-aminophenylacetyl, PABA, m-aminobenzoic acid, o-aminobenzoic acid, p-amino-trans-cinnamyl acids, m-amino -trans-cinnamyl, o-amino-trans-cinnamyl, or any combination thereof.
15. 15. The compound according to claim 14, characterized in that R5 is a saturated straight-chain aliphatic or hydroxyaliphatic portion having a chain length of 10 to 15 carbon atoms.
16. 16. The compound according to claim 14 or 15, characterized in that the compound is compound 86 of Table 6D, compound 87 or 280 of Table 7 or compound 89 of Table 8.
17. 17. The compound in accordance with claim 14, characterized in that the compound is compound 208 of Table 7.
18. 18. The compound according to claim 1, characterized in that R3 is at least one amino acid selected from Gly, β-alanine, GABA, 5-aminopentanoic acid, 6-aminohexanoic acid, Lys, gDab, Sar, Orn, Dap, hLys or any combination thereof.
19. 19. The compound according to any of claims 1, 13 and 18, characterized in that R3 further comprises at least one protecting group.
20. 20. An antimicrobial compound and pharmaceutically acceptable salts thereof, in accordance with structural formula (IV):

    characterized in that: Rx is OH or NH2; L is independently selected from at least one amino acid, at least one substituted amino acid, - ~ C (= 0), -R'C (= 0) -, -R'OC (= 0) (NR ') -, -NHC (= 0) -, - 0-PhC (= 0) - and -NR'C (= 0) -, with the proviso that L in the Dab9 position is -C (= 0) -; R2 is selected from -OR4, -SR4, NR4R4, -CN,

    -N02, -N3, -C (= 0) 0R4, -C (= 0) R4, -C (= 0) NR4R4, -C (= S) NR4R4, -C (= 0) H, - RC (= 0), -S02R4, -S (= 0) R4, -P (= 0) (OR4) 2, -P (= 0) (OR4), -C02H, -S03H, -P03H, halogen, trihalomethyl, alkyl ( Ca-C25), substituted (C _-C25) alkyl, heteroalkyl (Ca-C2s), substituted heteroalkyl (C-C5), aryl (C5-Cao), substituted aryl (C5-C? O), arylaryl (C3-) Ca5), substituted aryl (C5-C15), biaryl (Cs-Cs), substituted (C5-C5) biaryl, 5- to 10-membered heteroaryl, substituted 5- to 10-membered heteroaryl, (C6-C26) arylalkyl, arylalkyl ( C_-C26) substituted, heteroarylalkyl of 6 to 26 members, heteroarylalkyl substituted of 6 to 26 members, at least one amino acid and at least one substituted amino acid, - R3 is selected from -C (= 0) 0R4, - C (= 0) NR4R4, -C (= S) NR4R4, -C (= NR) NR4R4, -C (= 0) H, -R4-C (= 0), -C02H, alkyl (Ca-C25) substituted , substituted heteroalkyl (Ca-C25), substituted aryl, substituted aryl (C5-Ca5), substituted (C5-C15) biaryl, substituted heteroaryl from 5 to 10 members ros, substituted (C6-C26) arylalkyl, substituted heteroarylalkyl of 6 to 26 members, at least one amino acid and at least one substituted amino acid provided that R3 contains at least one of -C (= 0) -, -C (= S) - or -C (= NR4) -; R4 is independently selected from hydrogen, alkyl (Ca-Cao) aryl (C5-C10), heteroaryl from 5 to 10 members, arylalkyl (C3-C26) and heteroarylalkyl from 6 to 26 members, an aliphatic or hydroxyaliphatic saturated or single or multiple unsaturated straight or branched chain having a chain length of 5 to 25 carbon atoms, a primary or secondary amine, at least one amino acid and at least one substituted amino acid and R1 is independently selected from one or more of the same or different substituents as defined for R2, R3 or R4.
21. 21. The compound according to claim 20, characterized in that R1 is OH.
22. 22. The compound according to claim 20, characterized in that R1 is NH2.
23. 23. The compound according to claim 20, characterized in that R3 is at least one of -C (= 0) - or -C (= S) -.
24. 24. The compound according to claim 20, characterized in that R3 is -C (= 0) -.
25. 25. The compound according to claim 24, characterized in that the compound is compound 210, 373, 223, 237, 235 or 81 of Table 12.
26. 26. The compound according to claim 20, characterized in that R3 is at least one amino acid or substituted amino acid selected from Gly, β-alanine, GABA, 5-aminopentanoic acid, 6-aminohexanoic acid, Lys, gDab, Sar, Orn, Dap and hLys.
27. 27. The compound according to claim 24 or 26, characterized in that at least one of L and R3 further comprise at least one protecting group.
28. 28. An antimicrobial compound and pharmaceutically acceptable salts thereof, characterized in that the compound is compound 3 of Table 1.
29. 29. An antimicrobial compound and pharmaceutically acceptable salts thereof, characterized in that the compound is compound 4 of Table 10.
30. 30. An antimicrobial compound and pharmaceutically acceptable salts thereof, characterized in that the compound is compound 60 of Table 13.
31. 31. An antimicrobial compound and pharmaceutically acceptable salts thereof, characterized in that the compound is compound 128 of Table 16.
32. 32. An antimicrobial compound and pharmaceutically acceptable salts thereof, characterized in that the compound is compound 147 of Table 1.
33. 33. An antimicrobial compound and pharmaceutically acceptable salts thereof, characterized in that the compound is compound 199 of Table 10.
34. 34. An antimicrobial compound and pharmaceutically acceptable salts thereof, characterized by The compound is compound 253 of Table 4.
35. 35. An antimicrobial compound and pharmaceutically acceptable salts thereof, characterized in that the compound is compound 278 of Table 4.
36. 36. A pharmaceutical composition, characterized in that it comprises an antimicrobial compound of according to any one of claims 1 or 20 and a pharmaceutically acceptable carrier, excipient or diluent.
37. 37. A method for the treatment of an antimicrobial infection, characterized in that it comprises administering to a subject in need thereof a compound according to claim 1 or 20.
38. 38. A method for the treatment of a microbial infection, characterized in that it comprises administering to a subject in need thereof a pharmaceutical composition according to claim 36.
39. 39. A compound according to claim 1 or 20, characterized for use in a method of a microbial infection.
40. 40. A pharmaceutical composition according to claim 36, characterized in that it is used in a method of treating a microbial infection.
41. 41. The use of a compound characterized in that it is for the preparation of a medicament for the treatment of a microbial infection, comprising a compound according to claim 1 or 20.
42. 42. The use according to claim 41, characterized in that The microbial infection is caused by a Gram-positive microorganism.
43. 43. The use according to claim 42, characterized in that the Gram-positive microorganism is selected from Streptococcus, Staphylococcus, Enterococcus, Bacillus, Corinebacterium, Diptroid and

    Listeria
44. 44. The use according to claim 42, characterized in that the Gram-positive microorganism is Streptococcus pyrogenes, Streptococcus pneumoniae or Bridans streptococcus.
45. 45. The use according to claim 42, characterized in that the Gram-positive microorganism is

    Stpahylococcus aureus, Staphylococcus epidermidis or

    Coagulase-negative staphylococcus.
46. 46. The use according to claim 42, characterized in that the Gram-positive microorganism is Enterococcus faecalis or Enterococcus faecium.
47. 47. The use according to claim 42, characterized in that the Gram-positive microorganism is drug resistant.
48. 48. The use according to claim 47, characterized in that the drug-resistant microorganism is penicillin-resistant Streptococcus pneumomiae, penicillin intermediary Streptococcus pneumomiae or multidrug-resistant Streptococcus.
49. 49. The use according to claim 47, characterized in that the drug-resistant microorganism is methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, vancomycin intermediary Staphylococcus aureus or a multi-drug resistant Staphylococcus.
50. 50. The use according to claim 47, characterized in that the drug-resistant microorganism is vancomycin-resistant Enterscoccus or multidrug-resistant Enterococcus.
51. 51. The use according to claim 41, characterized in that the microbial infection is selected from a complicated or uncomplicated infection of the skin.; an infection of a surgical wound, an intra-abdominal infection; an infection of the urinary system; pyelonephritis; a nosocomial infection; a nosocomial pneumonia; an infection acquired in the community; a pneumonia acquired in the community and infective endocarditis.
52. 52. The use according to claim 51, characterized in that the complicated or uncomplicated infection of the skin is impetigo, folliculitis, furunculosis, ecthyma, erysipelas, cellulitis, acute paronquia, felon, necrotizing fasciitis, staphylococcal scalded skin infection, Nodilar lymphagitis, preceptal cellulitis or periorbital cellulitis.
53. 53. The use according to any of claims 51-52, characterized in that the medicament further comprises a pharmaceutically acceptable carrier, excipient or diluent.