WO2008118784A1

WO2008118784A1 - Glycopeptide and lipoglycopeptide antibiotics with improved solubility

Info

Publication number: WO2008118784A1
Application number: PCT/US2008/057841
Authority: WO
Inventors: Ranga Reddy; Adel Rafai Far
Original assignee: Targanta Therapeutics Corp.
Priority date: 2007-03-23
Filing date: 2008-03-21
Publication date: 2008-10-02

Abstract

The invention relates to derivatives of glycopeptide and lipoglycopeptide antibiotics possessing one or more polyethylene glycol moieties. These compounds are useful as antibiotics for the prevention and/or the treatment of infections and present a profile improved as a consequence of the ability to reduce the volume of injection and of a diminution of the side effects brought about by the poor solubility of the parent antibiotics, in particular injection-site and infusion related events.

Description

GLYCOPEPTIDE AND LIPOGLYCOPEPTIDE ANTIBIOTICS WITH IMPROVED

SOLUBILITY

BACKGROUND OF THE INVENTION a) Field of the invention

b) Brief description of the prior art

Glycopeptide and lipoglycopeptide antibiotics are a class of biologically produced or semi-synthetic antimicrobial agents which affect the bacterial cell wall and/or membrane integrity (Williams, D. H et al, Angewandte Chemie International Edition in English (1999), 1999, 38; 1172-1 193. Nicolaou, K. C. et al, Angewandte Chemie International Edition in English (1999), 38; 2097-2152. Kahne, D. et al Chemical Reviews (2005), 105; 425 - 448; Pace, J. L. et al, Biochemical Pharmacology (2006), 71 ; 968-980). Best known glycopeptide and lipoglycopeptide antibiotics are certainly vancomycin, teicoplanin, oritavancin (US Patent No. 5,840,684), dalbavancin (US patent No. 5,750,509) and telavancin (US patent No. 6,635,618). The two first drugs were proven clinically and microbiologically to have potent activity against gram-positive organisms and the latter three drugs are in clinical trials. Oritavancin, dalbavancin and telavancin possess extremely attractive pharmacological profiles with potent activity against gram-positive organisms, including methicillin-resistant Staphylococcus aureus, intermediate and fully vancomycin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus spp., and Streptococcus spp.

Glycopeptides are known to result in localized side effects on administration and typically require large volumes for administration by infusion. Such side effects present themselves as inflammatory responses such as phlebitis, pruritus and the "Red-Man" syndrome (Sivagnanam, S. et al, Critical Care (2003), 7:1 19-120. Bertolissi, M. et al, Critical Care (2002), 6, 234-239; Wilson, A. P. R., International Journal of Antimicrobial Agents (1998), 10:143-152. Korman, T. M. et al, Journal of Antimicrobial Chemotherapy (1997), 39; 371-381 ). The problem may be that the lack of solubility of the glycopeptide and/or its presence at high concentration could result in the inflammatory response and therefore a prodrug which could simultaneously improve the solubility of the drug and mask its presence at the time and the site of administration would be able to decrease such inflammatory responses.

Poly(ethylene glycol) (PEG), or poly(ethylene oxide) (PEO), is a synthetic polymer generally obtained by the polymerization of ethylene oxide under anionic conditions. It can thus be produced with a variety of molecular weights and with a narrow polydispersity. It is generally a diol (two free hydroxyl groups) when the polymerization is carried in aqueous media, but can have from one to a large number of free hydroxyl groups depending on the initial nucleophile used in the polymerization process. Thus the use of methanol will result in PEG monomethyl ether. PEG is highly water soluble, non-toxic and non-immunogenic material which has found application as an excipient in pharmaceutical formulations or through covalent conjugation with therapeutic agents (Greenwald, R. B. ef a/ Advanced Drug Delivery Reviews (2003), 55; 217-250. Greenwald, R. B. Journal of Controlled Release (2001 ), 74; 159-171 ).

PEG prodrugs of vancomycin (US patent application 2004/0136947. Greenwald, R. B. et al European Journal of Medicinal Chemistry (2005), 40;798-804. Greenwald, R. B. et a/ Journal Medicinal Chemistry (2003), 46; 5021-5030) and PEG conjugates of vancomycin (US patent application 2004/0142858) have already been reported primarily as a means to extend the serum half-lfe of vancomycin. However, the appearance of vancomycin resistant microorganisms, in particular resistant strains of S. aureus (Walsh, T. R. et al Annual Review of Microbiology (2002), 56; 657-675) and enterococci (Bonten, M. J. et al Lancet Infectious Diseases (2001 ), 1 ; 314-325) limit the use of vancomycin in clinical settings. In this respect, second generation glycopeptides, possessing mechanisms of action beyond those of vancomycin, and thus overcoming bacterial resistance have been introduced (Van Bambeke, F. Current Opinion in Pharmacology (2004), 4; 471-478). Several of these compounds, such as Oritavancin, Telavancin and Dalbavancin, to cite the leading ones, already possess long half lives. Yet they are still subject to the same constraints due to side effects at the sites of administration.

In view of the above, there is a need for highly active glycopeptide antibiotics for the prevention and treatment of infections without the potential inconveniences associated with their administration. More particularly, there is a need for glycopeptide or lipoglycopeptide antibiotics with the ability to overcome bacterial resistance and presenting reduced toxicity at the site of administration.

The present invention fulfills these needs and also other needs as will be apparent to those skilled in the art upon reading the following specification. SUMMARY OF THE INVENTION

The present invention is directed to antimicrobial compounds with improved solubility. More particularly, the invention is directed to poly(ethylene glycol) derivatives of glycopeptide or lipoglycopeptide antibiotics. These compounds are useful as antibiotics for the prevention or treatment of gram positive infections.

In one embodiment, the compounds of the invention are represented by the general Formula (I) as illustrated below:

P_aLpA₇ (I) and pharmaceutically acceptable salts, esters and prodrugs thereof, wherein:

P is a macromolecule containing at least one poly(ethylene glycol) chain;

A is a glycopeptide or lipoglycopeptide antimicrobial molecule, excluding vancomycin and vancomycin derivatives modified at either the amino group of the vancosamine or at the amino group of the N-methyl-leucyl residue or both;

L is a bond or a linker for covalently coupling P to A; α and γ are non-null integers, with α ≤ 7 and γ ≤10; β is α+γ-1 ; wherein each A is only attached to L and wherein each P is only attached to L; wherein when α is greater than 1 and γ is 1 only one P may be coupled to more than two molecules of A; wherein when γ is greater than 1 and α is 1 only one A may be coupled to more than two molecules of P; and wherein when both α and γ are greater than 1 only one P is coupled to more than two molecules of A or only one A is coupled to more than two molecules of P.

In a preferred embodiment, α is 1 , 2 or 3, and γ is 1. In another preferred embodiment, γ is 1 , 2, 3 or 4, and α is 1.

In prefered embodiments of the invention, each P is individually a macromolecule containing at least one poly(ethylene glycol) chain of Formula (Ilia):

wherein: a is a non-null integer <2500 ; b is a non-null integer <10; c is O or 1 ;

X is -0-, -S-, -S(O)-, -SO₂-, -N(R₃)-, -CO₂-, -CO-, -CON(R₃)-, -CON(Ra)-E-, -N(R₃)-, -CO₂-E-, -N(R₃)CO-, -N(R₃)CO-E-, -N(R_a)C0N(R_a)-, or -N(R_a)CON(R_a)-E-, wherein E is an amino acid or a polypeptide of 1 -10 amino acids, and R₃ is C_xH_y wherein x is an integer <20 and y is an integer < (2x+1 ); and

Gi is C_WH_Z, wherein w is an integer < 10, and z is an integer < (2w+2-b).

In a prefered embodiment, L is a hydrolysable linker.

In another prefered embodiment, L is a cleavable linker for covaltently and reversibly coupling P to A.

Preferably, L couples P to A through one or more hydroxyl groups on A, through one or more nitrogen atoms on A, through one or more carboxylic carbonyl groups on A, or through more than one of a combination of hydroxyl groups, nitrogen atoms and carboxylic carbonyl groups on A.

In one embodiment, the linker L is represented by the formula (L₁):

wherein:

A₃ indicates the point of attachment to the glycopeptide or lipoglycopeptide antimicrobial molecule A;

W is a covalent bond or is selected from the group of consisting of

T is oxygen or sulfur;

R is each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, amino, substituted amino, hydroxyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, P_a and — R^a — Y— R^b -Y— R^b— P_a ;

R^a is each independently selected from the group consisting of a covalent bond, alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, arylene, substituted arylene, — (CO) — alkylene — , substituted — (CO) — alkylene — , — (CO) — alkenylene — , substituted — (CO) — alkenylene — , — (CO) — alkynylene — , substituted — (CO) — alkynylene — , — (CO) — arylene — and substituted — (CO) — arylene — ;

R^b is each independently selected from the group consisting of a covalent bond, alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, arylene and substituted arylene;

P₃ indicates the point of attachment to the macromolecule containing at least one poly(ethylene glycol) chain P;

Q is each independently nitro, chloro, bromo, iodo or fluoro;

X is each independently -O-, -S- or -N(R)-;

Y is each independently selected from the group consisting of a covalent bond, -CH₂-, oxygen, sulfur, -S-S-, — NR^C— , -S(O)- -SO₂-, — NR^CC(O)— , -OSO₂-, — OC(O)- — N(R^C)SO₂— , — C(O)NR^C— , -C(O)O-, — SO₂NR^C— , -SO₂O-, — P(O)(OR^C)O— , — P(O)(OR^C)NR^C— , — OP(O)(OR^C)O— , — OP(O)(OR^C)NR^C— , -OC(O)O- , — NR^CC(O)O— , — NR^CC(O)NR^C — , — OC(O)NR^C— , -C(O)- and -N(R^C)SO₂NR^C— ;

R^c is each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic and — C(0)R^d— ;

R^d is each independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic;

Z is selected from the group consisting of hydrogen, acyl, substituted acyl, aroyl, substituted aroyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryloxycarbonyl, substituted

q is 2 or 3; r is 1 , 2, 3, 4 or 5;

W₁ and W₂ are each integers ≥ O such that their sum (W₁ + w₂) is 1 , 2 or 3; a, b, c, d are integers ≥ O such that a+b+c+d <7 or null; e and f are integers ≥ O such that e+f = 4; ω is O or 1 ; and with the proviso that at least one R is P₃ or — R^a — Y— R^b -Y— R^b— P₃.

When L couples P to A through a hydroxyl group on A, preferably L is one of the following linkers:

wherein: each p is independently 0 or an integer < 10; each R_L is independently selected from the group consisting of H, ethyl and methyl; q is 2 or 3; n is an integer < 10; r is 1 , 2, 3, 4 or 5;

W₁ and W₂ are each integers ≥ 0 such that their sum (W₁ + w₂) is 1 , 2 or 3; each Y is independently selected from the group consisting of -O-, -S-, and -NR_L-; each Z is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, acyl, acyloxy, carboxy, carbamoyl, sulfuryl, sulfinyl, sulfenyl, sulfonyl, mercapto, amino, hydroxyl, cyano and nitro; s is 1 , 2, 3 or 4; and

R_a is C_xH_y where x is an integer of O to 20 and y is an integer of 1 to 2x+1.

When L couples P to A through a nitrogen atom on A, preferably L is one of the following linkers:

wherein: n is an integer < 10; each p is independently 0 or an integer < 10; each R_L is independently selected from the group consisting of H, ethyl and methyl; q is 2 or 3; r is 1 , 2, 3, 4 or 5;

W₁ and W₂ are each integers ≥ 0 such that their sum (W₁ + w₂) is 1 , 2 or 3;

X is CH₂, — CONR_L- -CO-O-CH₂- or — CO— 0— ; each Y is independently selected from -O-, -S-, and -NR_L-; each Z is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, acyl, acyloxy, carboxy, carbamoyl, sulfuryl, sulfinyl, sulfenyl, sulfonyl, mercapto, amino, hydroxyl, cyano and nitro; s is 1 , 2, 3 or 4; and

R₃ is C_xHy where x is an integer of 0 to 20 and y is an integer of 1 to 2x+1.

When L couples P to A through the carbonyl of a carboxylate group on A, preferably L is one of the following linkers:

wherein: n is an integer < 10, preferably 1 , 2, 3 or 4, more preferably 1 or 2; p is O or an integer < 10, preferably O, 1 , 2, 3 or 4, more preferably O or 1 ; each R_L is independently selected from the group consisting of H, ethyl and methyl, preferably H;

R_x is S, C(R_L)2, NRL or O; preferably NR_L, more preferably N H; each Y is independently selected from -0-, -S-, and -NR_L-; each Z is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, acyl, acyloxy, carboxy, carbamoyl, sulfuryl, sulfinyl, sulfenyl, sulfonyl, mercapto, amino, hydroxyl, cyano and nitro; and s is 1 , 2, 3 or 4.

In further prefered embodiment, at least one of P — L — is coupled to a hydroxyl functionality on the glycopeptide or lipoglycopeptide antimicrobial molecule A. Preferably, when P — L — is coupled to a hydroxyl functionality P — L — is one of the following:

wherein:

P represents the macromolecule possessing at least one poly(ethylene glycol) chain; each p is independently 0 or an integer < 10; each R_L is independently selected from the group consisting of H, ethyl and methyl; q is 2 or 3; n is an integer < 10; r is 1 , 2, 3, 4 or 5;

W₁ and W₂ are each integers ≥ 0 such that their sum (W₁ + w₂) is 1 , 2 or 3; each Y is independently selected from -O-, -S-, and -NR_L-; each Z is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, acyl, acyloxy, carboxy, carbamoyl, sulfuryl, sulfinyl, sulfenyl, sulfonyl, mercapto, amino, hydroxyl, cyano and nitro; s is 1 , 2, 3 or 4; and

In further prefered embodiment, at least one of P — L — is coupled to a nitrogen atom on the glycopeptide or lipoglycopeptide antimicrobial molecule A. Preferably, when P — L — is coupled to a nitrogen atom P — L — is one of the following:

wherein:

P represents the macromolecule containing at least one poly(ethylene glycol) chain; n is an integer < 10; each p is independently O or an integer < 10; each R_L is independently selected from the group consisting of H, ethyl and methyl; q is 2 or 3; r is 1 , 2, 3, 4 or 5;

W₁ and W₂ are each integers ≥ O such that their sum (W₁ + w₂) is 1 , 2 or 3; each W is independently selected from -0-, -S-, and -NR_L-;

T¹ is CH₂, -CONR_L-, -CO-O-CH₂-, or — CO— O— ; each T² is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, acyl, acyloxy, carboxy, carbamoyl, sulfuryl, sulfinyl, sulfenyl, sulfonyl, mercapto, amino, hydroxyl, cyano and nitro; s is 1 , 2, 3 or 4; and

R_a is C_xH_y where x is an integer of O to 20 and y is an integer of 1 to 2x+1. In further prefered embodiment, at least one of P — L — is coupled to the carbonyl of a carboxylate group on the glycopeptide or lipoglycopeptide antimicrobial molecule A. Preferably, when P — L — is coupled to a nitrogen atom P — L — is one of the following:

wherein:

P represents the macromolecule with at least one poly(ethylene glycol) chain; n is an integer < 10, preferably 1 , 2, 3 or 4, more preferably 1 or 2; p is O or an integer < 10, preferably O, 1 , 2, 3 or 4, more preferably 0 or 1 ; each R_L is independently selected from the group consisting of H, ethyl and methyl, preferably H;

R_x is S, C(R_L)₂, NR_L or O; preferably NR_L, more preferably NH each W is independently selected from -0-, -S-, and -NR_L-; each T² is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, acyl, acyloxy, carboxy, carbamoyl, sulfuryl, sulfinyl, sulfenyl, sulfonyl, mercapto, amino, hydroxyl, cyano and nitro; and s is 1 , 2, 3 or 4;

In an additional prefered embodiment, α is an integer of 2 to 3, P — L — is coupled to a combination of at least two of a hydroxyl functionality on the glycopeptide or lipoglycopeptide antimicrobial molecule A, a nitrogen atom on the glycopeptide or lipoglycopeptide antimicrobial molecule A or the carbonyl of a carboxylate group on the glycopeptide or lipoglycopeptide antimicrobial molecule A. Preferably, when P — L — is coupled to a hydroxyl functionality P — L — is one of the following:

wherein:

P represents the macromolecule possessing at least one poly(ethylene glycol) chain; each p is independently O or an integer < 10; each R_L is independently selected from the group consisting of H, ethyl and methyl; q is 2 or 3; n is an integer < 10; r is 1 , 2, 3, 4 or 5;

W₁ and W₂ are each integers ≥ 0 such that their sum (W₁ + w₂) is 1 , 2 or 3 each Y is independently selected from the group consisting of -O-, -S-, and -NR_L-; each Z is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, acyl, acyloxy, carboxy, carbamoyl, sulfuryl, sulfinyl, sulfenyl, sulfonyl, mercapto, amino, hydroxyl, cyano and nitro; s is 1 , 2, 3 or 4; and

R_a is C_xH_y where x is an integer of 0 to 20 and y is an integer of 1 to 2x+1.

Preferably, when P — L — is coupled to a nitrogen atom P — L — is one of the following:

wherein:

R₃ is C_xH_y where x is an integer of 0 to 20 and y is an integer of 1 to 2x+1.

Preferably, when P — L — is coupled to the carbonyl of a carboxylate group P — L — is one of the following:

wherein: P represents the macromolecule containing at least one poly(ethylene glycol) chain; n is an integer < 10, preferably 1 , 2, 3 or 4, more preferably 1 or 2; p is 0 or an integer < 10, preferably 0, 1 , 2, 3 or 4, more preferably 0 or 1 ; each R_L is independently selected from the group consisting of H, ethyl and methyl, preferably H;

R_x is S, C(R_L)₂, NR_L or O; preferably NR_L, more preferably NH; each W is independently selected from -O-, -S-, and -NR_L-; each T² is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, acyl, acyloxy, carboxy, carbamoyl, sulfuryl, sulfinyl, sulfenyl, sulfonyl, mercapto, amino, hydroxyl, cyano and nitro; and s is 1 , 2, 3 or 4. In a further preferred embodiment, α is 1 , 2 or 3.

Preferably, the glycopeptide or lipoglycopeptide antimicrobial molecule A has a structure represented by the following Formula A1 :

as well as pharmaceutically acceptable salts, esters and prodrugs thereof, wherein:

R¹ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic and — R^a — Y — R^b — (Z)_x; or R¹ is a saccharide group optionally substituted with — R^a— Y— R^b— (Z)_x, R^f, — C(O)R^f, or -C(O)-R³ -Y-R^b -(Z)_x ;

R² is hydrogen or a saccharide group optionally substituted with — R^a — Y — R^b — (Z)_x, R^f, — C(O)R^f, or -C(O)-R³ — Y— R^b -(Z)_x ;

R³ is selected from the group consisting of — OR^C, — NR^CR^C, — O— R^a — Y— R^b— (Z)_x, — NR^C — R^a — Y— R^b -(Z)_x, — NR^cR^e, and — O— R^e;

R⁴ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, — R^a — Y— R^b -(Z)_x, — C(O)R^d and a saccharide group optionally substituted with — R^a — Y — R^b — (Z)_x, R^f, or — C(O)- R^a— Y— R^b -(Z)_x, or R⁴ and R⁵ can be joined, together with the atoms to which they are attached, to form a heterocyclic ring optionally substituted with — NR^C — R^a — Y — R^b-(Z)_X ;

R⁵ is selected from the group consisting of hydrogen, halo, — CH(R^C) — NR^CR^C, — CH(R^C)— NR^cR^e, — CH(R^C)— NR^C — R^a— Y— R^b— (Z)_x, — CH(R^C)— R^x, and — CH(R^C)— NR^C— R^a— C(O)- R^x;

R⁶ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, — R^a— Y— R^b -(Z)_x, — C(0)R^d and a saccharide group optionally substituted with — R^a — Y— R^b -(Z)_x, R^f, — C(0)R^f, or — C(O)- R^a— Y— R^b— (Z)_x, or R⁵ and R⁶ can be joined, together with the atoms to which they are attached, to form a heterocyclic ring optionally substituted with — NR^C — R^a — Y — R^b — (Z)_x;

R⁷ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, — R^a— Y— R^b— (Z)_x and — C(0)R^d;

R⁸ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl; cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic and — R^a — Y — R^b — (Z)_x;

R⁹ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic;

R¹⁰ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic; or R⁸ and R¹⁰ are joined to form — Ar¹ — O — Ar² — , where Ar¹ and Ar² are independently arylene or heteroarylene;

R¹¹ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic, or R¹⁰ and R¹¹ are joined, together with the carbon and nitrogen atoms to which they are attached, to form a heterocyclic ring;

R¹² is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, — C(0)R^d, — C(NH)R^d, — C(O)NR^CR^C, — C(0)0R^d, — C(NH)NR^CR^C, — R^a— Y— R^b— (Z)_x, and — C(O)- R^b— Y— R^b— (Z)_x, or R¹¹ and R¹² are joined, together with the nitrogen atom to which they are attached, to form a heterocyclic ring; R is selected from the group consisting of hydrogen and — OR 14

R¹⁴ is selected from the group consisting of hydrogen, — C(O)R^d and a saccharide group;

R^a is each independently selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene and substituted alkynylene;

R^b is each independently selected from the group consisting of a covalent bond, alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene and substituted alkynylene;

R^c is each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic and — C(O)R^d ;

R^Θ is each a saccharide group;

R^f is each independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, and heterocyclic;

R^x is an N-linked amino saccharide or an N-linked heterocycle;

X is each independently selected from the group consisting of hydrogen, fluoro, chloro, bromo and iodo;

Y is each independently selected from the group consisting of , — CH₂ — , oxygen, sulfur, -S-S-, — NR^C— , -S(O)-, -SO₂-, — NR^CC(O)— , -OSO₂-, -OC(O)-, — N(R^C)SO₂— , — C(O)NR^C— , -C(O)O-, — SO₂NR^C— , -SO₂O-, — P(O)(OR^C)O— , — P(O)(OR^C)NR^C— , — OP(O)(OR^C)O— , — OP(O)(OR^C)NR^C— , -OC(O)O-, — NR⁰C(O)O-, — NR^CC(O)NR^C — , — 0C(0)NR^c— , -C(O)- and -N(R^C)SO₂NR^C— ;

Z is each independently selected from the group consisting of hydrogen, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, and a saccharide; n is O, 1 or 2; x is 1 or 2; and

is selected from

with the proviso that if R₁ is

, wherein R_G is H, Ci_-6 alkyl,

C3-₁₂ branched alkyl, C_3-S cycloalkyl, Ci_-6 substituted alkyl, C_3-S substituted cycloalkyl, aryl, substituted aryl, aralkyl, Ci_-6 heteroalkyl, substituted Ci_-6 heteroalkyl, Ci_-6 alkoxy, phenoxy or Ci_-6 heteroalkoxy, then at least one of R³ or R⁵ is not hydrogen.

More preferably, the glycopeptide or lipoglycopeptide antimicrobial molecule A is teicoplanin or a derivative thereof, oritavancin or a derivative thereof, dalbavancin or a derivative thereof, telavancin or a derivative thereof, compound A35512 A, compound A35512 C, compound A35512 E, compound A35512 F, compound A35512 G, compound A35512 H, compound A40926 A, compound A40926 B, compound A40926 PB, parvodicin B2, parvodicin C1 , parvodicin C3, compound A41030, compound A42867, compound A477, compound A47934, compound A51568A, compound A80407, compound A83850, compound A84575, compound AB65, compound AM374, actaplanin, compound A4696, actinoidin, ardacin, aricidin, compound AAD216, avoparcin, compound LL-AV290, azureomycin, balhimycin, balhimycin V, chloroorienticin, compound A82846B, compound LY264826, chloroeremomycin, chloropeptin, chloropolysporin, complestatin, decaplanin, dechlorobalhimycin, dechlorobalhimycin V, chlorobalhimycin, chlorobromobalhimycin, fluorobalhimycin, deglucobalhimycin, N-demethylbalhimycin, devancosamine-vancomycin, eremomycin, galacardin, helvecardin, izupeptin, kibdelin, kistamicin, mannopeptin, methylbalhimycin, compound MM47761 , compound MM47766, compound MM47767, compound MM49721 , compound MM49727, compound MM55256, compound MM55260, compound MM55266, compound MM55268, compound MM55270, compound MM55272, compound MM56597, compound MM56598, nogabecin F, compound OA7653, orienticin, dechloroeremomycin, compound PA42867, compound PA45052, chloroorienticin, parvodicin, rhamnosyl-balhimycin, ristocetin, ristomycin, spontin, symnonicin, teichomycin, Targocid, ureido-balhimycin and [Ψ[CH₂NH]Tpg⁴]Vancomycin.

In another embodiment, the compounds of the invention are represented by Formula (II) or a pharmaceutically acceptable salt or prodrug thereof:

R¹ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, — R^a — Y — R^b — (Z)_x and — L¹; or R¹ is a saccharide group optionally substituted with — R^a — Y — R^b — (Z)_x, R^f, -C(O)R_f, — C(O)-R³ — Y— R^b -(Z)_x, — C(NL²)R^f, or — C(NL³)- R^a — Y— R^b -(Z)_x ;

R² is hydrogen, — L⁴ or a saccharide group optionally substituted with — R^a — Y— R^b -(Z)_x, R^f, — C(0)R^f, — C(O)-R³ — Y— R^b -(Z)_x, — C(NL⁵)R^f, or — C(NL⁶)- R^a — Y— R^b -(Z)_x ;

R³ is selected from the group consisting of — OR^C, — NR^CR^C,

— O R^a — Y— R^b— (Z)_x, — NR^C — R^a — Y— R^b -(Z)_x, — NR^cR^e, — O— R^e, -OL⁷, — NL⁸R^C, and -NL⁹R^e;

R⁴ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, — L¹⁰, — R^a — Y— R^b -(Z)_x, — C(0)R^d, — C(NL¹¹ )R^d and a saccharide group optionally substituted with — R^a — Y— R^b -(Z)_x, R^f, — C(O)- R^a — Y— R^b -(Z)_x, or — C(NL¹²)- R^a — Y— R^b -(Z)_x, or R⁴ and R⁵ can be joined, together with the atoms to which they are attached, to form a heterocyclic ring optionally substituted with — NR^C — R^a — Y— R^b -(Z)_x or -NL¹³ — R^a — Y— R^b -(Z)_x;

R⁵ is selected from the group consisting of hydrogen, halo, — CH(R^C) — NR^CR^C, — CH(R^C)— NR^cR^e, — CH(R^C)— NR^C — R^a— Y— R^b— (Z)_x, — CH(R^C)— R^x, — CH(R^C)— NR^C— R^a— C(O)- R^x; — CH(R^C)— NL¹⁴R^C, — CH(R^C)— NL¹⁵R^e, — CH(R^C)— NL¹⁶ — R^a— Y— R^b— (Z)_x, — CH(R^C)— NL¹⁷- R^a— C(O)- R^x and — CH(R^C)— NR^C— R^a— C(NL¹⁸)- R^x;

R⁶ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, — L¹⁹, — R^a— Y— R^b -(Z)_x, — C(0)R^d, — C(NL²⁰)R^d and a saccharide group optionally substituted with — R^a — Y— R^b -(Z)_x, R^f, — C(O)R^f, — C(O)- R^a— Y— R^b— (Z)_x, — C(NL²¹)R^f, or — C(NL²²)- R^a— Y— R^b— (Z)_x or R⁵ and R⁶ can be joined, together with the atoms to which they are attached, to form a heterocyclic ring optionally substituted with — NR^C— R^a— Y— R^b— (Z)_x or -NL²³— R^a— Y— R^b-(Z)_X;

R⁷ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, — L²⁴, — R^a— Y— R^b— (Z)_x, — C(0)R^d, and — C(NL²⁵)R^d ;

R⁸ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic and — R^a — Y — R^b — (Z)_x;

R⁹ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, and — L²⁶;

R¹⁰ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic; or R⁸ and R¹⁰ are joined to form — Ar¹ — O — Ar² — , where Ar¹ and Ar² are independently arylene or heteroarylene which may optionally be substituted with -OL²⁷;

R¹¹ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, and — L²⁸ or R¹⁰ and R¹¹ are joined, together with the carbon and nitrogen atoms to which they are attached, to form a heterocyclic ring which may optionally be substituted with -OL²⁹ , -CO₂L³⁰ or -NL³¹R^c;

R¹² is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, — L³², — C(0)R^d, — C(NH)R^d, — C(O)NR^C R^c, — C(0)0R^d, — C(NH)NR^CR^C, — R^a— Y— R^b— (Z)_x, and — C(O)- R^b— Y— R^b— (Z)_x, — C(NL³³)R^d, — C(O)NL³⁴R^C, -C(O)OL³⁵, — C(NH)NL³⁶R^C, -C(NL³⁷)NR^CR^C, and — C(NL³⁸)- R^b— Y— R^b— (Z)_x or R¹¹ and R¹² are joined, together with the nitrogen atom to which they are attached, to form a heterocyclic ring which may optionally be substituted with -OL³⁹ , -CO₂L⁴⁰ or -NL⁴¹ R^c;

R¹³ is selected from the group consisting of hydrogen and — OR¹⁴;

R¹⁴ is selected from the group consisting of hydrogen, — L⁴², — C(0)R^d , — C(NL⁴³)R^d and a saccharide group optionally substituted with — R^a — Y— R^b -(Z)_x, R^f, — C(0)R^f, — C(O)-R³ — Y— R^b -(Z)_x, — C(NL⁴⁴)R^f, or — C(NL⁴⁵)- R^a — Y— R^b -(Z)_x ; R^a is each independently selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene and substituted alkynylene;

R^Θ is each a saccharide group optionally substituted with — R^a — Y — R^b — (Z)_x, R^f, — C(O)R^f, — C(O)-R³ — Y— R^b -(Z)_x, — C(NL⁴⁶)R^f, or — C(NL⁴⁷)- R^a — Y— R^b -(Z)_x;

R^x is an N-linked amino saccharide or an N-linked heterocycle both of which may be optionally substituted with — R^a— Y— R^b— (Z)_x, R^f, — C(O)R_f, — C(O)-R³ — Y— R^b -(Z)_x, — C(NL⁴⁸)R_f, or — C(NL⁴⁹)- R^a — Y— R^b -(Z)_x;

Y is each independently selected from the group consisting Of -CH₂ — , oxygen, sulfur, -S-S-, — NR^C— , -S(O)-, -SO₂-, — NR^CC(O)— , -OSO₂-, -OC(O)-, — N(R^C)SO₂— , — C(O)NR^C— , -C(O)O-, — SO₂NR^C— , -SO₂O-, — P(O)(OR^C)O— , — P(O)(OR^C)NR^C— , — OP(O)(OR^C)O— , — OP(O)(OR^C)NR^C— , -OC(O)O-, — NR⁰C(O)O-, — NR^CC(O)NR^C — , — 0C(0)NR^c, — C(O)- ,-N(R^c)SO₂NR^c— , -NL⁵⁰-, -NL⁵¹C(O)- -OSO₂-, — OC(O)- — N(L⁵²)SO₂— , -C(O)NL⁵³-, -SO₂NL⁵⁴-, — P(O)(OL⁵⁵)O— , — P(O)(OL⁵⁶)NR^C— , — P(O)(OR^C)NL⁵⁷— , — OP(O)(OL⁵⁸)O— , — OP(O)(OL⁵⁹)NR^C— , — OP(O)(OR^C)NL⁶⁰— , -NL⁶¹C(O)O-, — NL⁶²C(O)NR^C— , — NR^CC(O)NL⁶³— , -OC(O)NL⁶⁴-, -N(L⁶⁵)SO₂NR^C— and -N(R^C)SO₂NL⁶⁶— ;

Z is each independently selected from the group consisting of hydrogen, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, a saccharide, -L⁶⁷, — L⁶⁸ and -L⁶⁹; n is O, 1 or 2; x is 1 or 2; and

is selected from or

each L¹, L⁴, L¹⁰, L¹⁹, L²⁴, L²⁷, L²⁹, L³⁹, L⁴², and L⁶⁷ is a linker independently selected from the group of

W₁ and W₂ are each integers ≥ O such that their sum (W₁ + w₂) is 1 , 2 or 3; each Y is independently selected from -0-, -S-, and -NR_L-; each Z is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, acyl, acyloxy, carboxy, carbamoyl, sulfuryl, sulfinyl, sulfenyl, sulfonyl, mercapto, amino, hydroxyl, cyano and nitro; s is 1 , 2, 3 or 4; and

P is a macromolecule containing at least one poly(ethylene glycol) chain selected from the group consisting of:

O LcH₂— CH₂- θ| CH₂4cH₂] X-

wherein: a is a non-null integer <2500 b is a non-null integer <10; c is O or 1 ;

X is -0-, -S-, -S(O)-, -SO₂-, -N(R₃)-, -CO₂-, -CO-, -CON(R₃)-, -C0N(R₃)-E-, -N(R₃)-, -CO₂-E-, -N(R₃)CO-, -N(R₃)CO-E-, -N(R₃)CON(R₃)-, -N(R₃)C0N(R₃)-E- wherein E is an amino acid or a polypeptide of 1 -10 amino acids, and R₃ is C_xH_y , x being an integer <20 and y being an integer < (2x+1 ); and

Gi is C_WH_Z wherein w is an integer < 10 and z is an integer < (2w+2-b);

each L⁸, L⁹, L¹³, L¹⁴, L¹⁵, L¹⁶, L¹⁷, L²³, L²⁶, L²⁸, L³¹, L³², L³⁴, L³⁶, L³⁷, L⁴¹, L⁵⁰, L⁵¹, L⁵², L⁵³, L⁵⁴, L⁵⁷, L⁶⁰, L⁶¹, L⁶², L⁶³, L⁶⁴, L⁶⁵, L⁶⁶ and L⁶⁸ is a linker independently selected from the group of

W₁ and W₂ are each integers ≥ 0 such that their sum (W₁ + w₂) is 1 , 2 or 3; each W is independently selected from -0-, -S-, and -NR_L-;

T¹ is CH₂, -CONR_L-, -CO-O-CH₂-, or — CO— O— ; each T² is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, acyl, acyloxy, carboxy, carbamoyl, sulfuryl, sulfinyl, sulfenyl, sulfonyl, mercapto, amino, hydroxyl, cyano and nitro; s is 1 , 2, 3 or 4;

R₃ is C_xHy where x is an integer of O to 20 and y is an integer of 1 to 2x+1 ; and P is a macromolecule containing at least one poly(ethylene glycol) chain selected from the group consisting of:

wherein: a is a non-null integer <2500 b is a non-null integer <10; c is 0 or 1 ;

X is -O-, -S-, -S(O)-, -SO₂-, -N(R₃)-, -CO₂-, -CO-, -CON(R₃)-, -CON(Ra)-E-, -N(R₃)-, -CO₂-E-, -N(R₃)CO-, -N(R₃)CO-E-, -N(R₃)CON(R₃)-, -N(R₃)C0N(R₃)-E- wherein E is an amino acid or a polypeptide of 1-10 amino acids, and R₃ is C_xH_y , x being an integer <20 and y being an integer < (2x+1 ); and

Gi is C_WH_Z wherein w is an integer < 10 and z is an integer < (2w+2-b);

each L⁷, L³⁰, L³⁵, L⁴⁰, L⁵⁵, L⁵⁶, L⁵⁸, L⁵⁹ and L⁶⁹ is a linker independently selected from the group of

R_x is selected from the group consisting of S, C(R_L)₂, NR_L and O; preferably NR_L, more preferably NH; each W is independently selected from the group consisting of -0-, -S-, and -NR_L-; and each T² is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, acyl, acyloxy, carboxy, carbamoyl, sulfuryl, sulfinyl, sulfenyl, sulfonyl, mercapto, amino, hydroxyl, cyano and nitro; s is 1 , 2, 3 or 4; and

X is -0-, -S-, -S(O)-, -SO₂-, -N(R₃)-, -CO₂-, -CO-, -CON(R₃)-, -CON(R_a)-E-, -N(R₃)-, -CO₂-E-, -N(R₃)CO-, -N(R₃)CO-E-, -N(R₃)CON(R₃)-, -N(R₃)C0N(R₃)-E- wherein E is an amino acid or a polypeptide of 1-10 amino acids, and R₃ is C_xH_y , x being an integer <20 and y being an integer < (2x+1 ); and

Gi is C_WH_Z wherein w is an integer < 10 and z is an integer < (2w+2-b);

each _I i 2 •

L2"1, L"2, i L2"5, • L3^J3^J, • L3^j8^a, ■ 4

L^4S5,

C47, • L48 and L is a linker independently selected from the group of

wherein: p is 0 or an integer < 10, preferably 0, 1 , 2, 3 or 4, more preferably 0 or 1 ; each R_L is independently selected from the group consisting of H, ethyl and methyl, preferably H; each T² is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, acyl, acyloxy, carboxy, carbamoyl, sulfuryl, sulfinyl, sulfenyl, sulfonyl, mercapto, amino, hydroxyl, cyano and nitro; s is 1 , 2, 3 or 4; and

Gi is C_WH_Z wherein w is an integer < 10 and z is an integer < (2w+2-b);

, wherein R_G is H, Ci_-6 alkyl, C_3-I2 branched alkyl, C_3-S cycloalkyl, Ci_-6 substituted alkyl, C_3-S substituted cycloalkyl, aryl, substituted aryl, aralkyl, Ci_-6 heteroalkyl, substituted Ci_-6 heteroalkyl, Ci_-6 alkoxy, phenoxy and Ci_-6 heteroalkoxy, then at least one of R³ or R⁵ is not hydrogen; and with the further proviso that at least one of L¹ L² L³ L⁴ L⁵ L⁶ L⁷ L⁸ L⁹ L¹⁰ L¹¹ L¹² L¹³ L¹⁴

■ 15 ■ 16 ■ 17 ■ 18 ■ 19 ■ 20 ■ 21 ■ 22 ■ 23 ■ 24 ■ 25 ■ 26 ■ 27 j 28 '■ 29 ■ 30 /31 '■ 32' ■ 33 ■ 34 ■ 35 ■ 36 ■ 37 ■ 38

■ 39' ■ 4θ' ■ 41 ' ■ 42' ■ 43' ■ 44' ■ 45' ■ 46' ■ 47' ■ 48' ■ 49' ■ 5θ' ■ 51 ' ■ 52 ■ 53' ■ 54' ■ 55' ■ 56' ■ 57' ■ 58' ■ 59' ■ 6θ' ■ 61 ' ■ 62'

L^bJ L^b4 L^b5 L^bb _, L^b7 _, L^bB and L^bM is present.

In further preferred embodiments, the compounds of the invention have a structure selected among the structures illustrated below, as well as pharmaceutically acceptable salts, esters and prodrugs thereof:

and wherein

MPEG(5k) represents poly(ethylene glycol) monomethyl ether with an average molecular weight of 5000 g.mol^"1;

MPEG(2k) represents poly(ethylene glycol) monomethyl ether with an average molecular weight of 2000 g.mol^"1; and

MPEG(20k) represents poly(ethylene glycol) monomethyl ether with an average molecular weight of 20000 g.mol^"1. In another aspect of the present invention there are disclosed pharmaceutical compositions comprising one or more of the compounds as defined herein and a pharmaceutically acceptable carrier or excipient.

The present invention also encompasses methods for treating a bacterial infection in a subject, comprising administering to a subject having a bacterial infection or otherwise in need of such treatment a pharmaceutically effective amount of one or more of the compounds as defined herein, or a pharmaceutical composition as defined herein. The subject may be an animal, preferably a mammal, more preferably a human.

The present invention further encompasses methods for preveting a bacterial infection in a subject, comprising administering to a subject a risk of exposure to a bacterial infection or otherwise in need of such prevention a pharmaceutically effective amount of one or more of the compounds as defined herein, or a pharmaceutical composition as defined herein. The subject may be an animal, preferably a mammal, more preferably a human.

The present invention additionally encompasses methods of providing prophylaxis for a bacterial infection in a subject, comprising administering to a subject having a bacterial infection or otherwise in need of such prophylaxis a pharmaceutically effective amount of one or more of the compounds as defined herein, or a pharmaceutical composition as defined herein. The subject may be an animal, preferably a mammal, more preferably a human.

The present invention also encompasses methods for treating, preventing or prophylaxis of a bacterial infection in a subject, comprising concurrently administering a second therapeutic agent in addition to a pharmaceutically effective amount of one or more of the compounds as defined herein, or a pharmaceutical composition as defined herein. Preferably the second therapeutic agent is an antibiotic. More preferably the second therapeutic agent is an antibiotic selected from the group consisting of tetracycline, a tetracycline derived antibacterial agent, glycylcycline, a glycylcycline derived antibacterial agent, minocycline, a minocycline derived antibacterial agent, an oxazolidinone antibacterial agent, an aminoglycoside antibacterial agent, a quinolone antibacterial agent, vancomycin, a vancomycin derived antibacterial agent, a teicoplanin, a teicoplanin derived antibacterial agent, eremomycin, an eremomycin derived antibacterial agent, chloroeremomycin, a chloroeremomycin derived antibacterial agent, daptomycin, a daptomycin derived antibacterial agent, Rifamycin, a Rifamycin derived antibacterial agent, Rifampin, a Rifampin derived antibacterial agent, Rifalazil, a Rifalazil derived antibacterial agent, Rifabutin, a Rifabutin derived antibacterial agent, Rifapentin, a Rifapentin derived antibacterial agent, Rifaximin and a Rifaximin derived antibacterial agent.

In a further aspect of the present invention there are provided processes for the preparation of glycopeptide and lipoglycopeptide antimicrobial molecules possessing a poly(ethylene glycol) chain, preferably the preparation of glycopeptide and lipoglycopeptide antimicrobial molecules possessing a poly(ethylene glycol) chain of Formula (I) and/or Formula (II) as defined herein.

An advantage of the invention is that it provides antimicrobial compounds having an increased solubility in pharmaceutically acceptable excipients. The invention also provides methods for the unmet medical need of treatment of infections due to vancomycin resistant gram positive bacteria.

Additional objects, advantages and features of the present invention will become more apparent upon reading of the following non-restrictive description of preferred embodiments with reference to the accompanying drawings which are exemplary and should not be interpreted as limiting the scope of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a bar graph showing the testing of 10 mg/kg of oritavancin or of polyethylene glycol oritavancin conjugates 11, 17 and 24 at a dose equivalent to 10 mg/kg oritavancin showing clear and statistically significant activity on S. pneumoniae titer in lung when used 1 h post-infection.

Figure 2 is a bar graph showing the testing of 10 mg/kg of oritavancin or of polyethylene glycol oritavancin conjugates 69 and 70 at a dose equivalent to 10 mg/kg oritavancin showing clear and statistically significant activity on S. pneumoniae titer in lung for 69 and only very weak activity for 70 when used 1 h post-infection.

DETAILED DESCRIPTION OF THE INVENTION A) General overview of the invention

The present invention discloses derivatives of glycopeptide and lipoglycopeptide antibiotics possessing at least one poly(ethylene glycol) moiety as presented in structural Formula I and Formula Il defined above and below. These compounds are useful antimicrobial agents effective against a number of human and veterinary pathogens.

The essence of the invention lies in the presence of a poly(ethylene glycol) group attached to a glycopeptide and lipoglycopeptide antibiotic. Since poly(ethylene glycols) are known to have a high solubility in aqueous media, the present inventors have hypothesized that it would be possible to increase the solubility of glycopeptide and lipoglycopeptide antibiotics in aqueous media by tethering a poly(ethylene glycol) group to such an antibiotic. Achieving high concentrations of glycopeptide and lipoglycopeptide antibiotics in aqueous media could improve the formulation and reduce the volumne of injection or infusion. In addition, the presence of the poly(ethylene) glycol may allow to mask the antibiotic during injection or infusion. The combination of these two factors and the relative lack of toxicity associated with poly(ethylene glycol) may therefore allow to bypass the side effects observed during the administration of glycopeptide or lipoglycopeptide antibiotics not bearing such pendant poly(ethylene glycol) chains.

The present inventors have synthesized such derivatives of glycopeptide and lipoglycopeptide antibiotics bearing poly(ethylene glycol) moieties and demonstrated that these derivatives have an increased solubility with respect to the parent drug. The present inventors have also shown that these more soluble derivatives maintain antibacterial properties including against glycopeptide resistant variants of generally glycopeptide susceptible microorganisms. Finally, the present inventors have also shown that these more soluble derivatives maintain the ability to treat infections in accepted animal models. Accordingly, the compounds of the invention are particularly useful alternatives for the treatment of infections.

B) Definitions

The present invention discloses glycopeptide and lipoglycopeptide antimicrobial molecules bearing poly(ethylene glycol) moieties, in particular, those derivatives defined in Formula (I) and Formula (II) as delineated above and hereinafter. These compounds are useful antimicrobial agents effective against a number of human and veterinary pathogens. At least one macromolecule bearing at least one poly(ethylene glycol) chain is coupled to a glycopeptide or lipoglycopeptide antimicrobial molecule via a linker. This linker can be cleavable and a dissociation of the glycopeptide or lipoglycopeptide antibacterial agent from its poly(ethylene glycol) bearing moiety may occur in vivo.

Derivatives of glycopeptide and lipoglycopeptide antimicrobial molecules bearing at least one poly(ethylene glycol) chain have been synthesized and demonstrated to have an increased solubility in aqueous media. The presence of the poly(ethylene glycol) moiety was shown not to impede on the antibacterial or therapeutic properties of the glycopeptide and lipoglycopeptide antimicrobial molecules according to the invention. Accordingly, the compounds of the invention are particularly useful for the treatment of infections while reducing the large volumes of administration generally associated with this class.

In order to provide an even clearer and more consistent understanding of the invention, including the scope given herein to particular terms, the following general definitions are provided:

The term "alkyl" refers to saturated aliphatic groups including straight-chain, branched-chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having 1 to 12 carbon atoms (preferably 1 to 6). Examples of alkyl groups include, but are not limited to groups such as methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, and adamantyl. Cyclic alkyl groups (e.g. cycloalkyl or heterocycloalkyl) can consist of one ring, including, but not limited to, groups such as cycloheptyl, or multiple fused rings, including, but not limited to, groups such as adamantyl or norbornyl.

The term "alkylaryl" refers to an alkyl group having the number of carbon atoms designated, appended to one, two, or three aryl groups.

The term "N-alkylaminocarbonyl" refers to the radical -C(O)NHR where R is an alkyl group.

The term "N,N-dialkylaminocarbonyl" refers to the radical -C(O)NR₃ R_b where R₃ and R_b are each independently an alkyl group.

The term "alkylthio" refers to the radical -SR where R is an alkyl group.

The term "alkoxy" as used herein refers to an alkyl, alkenyl, or alkynyl linked to an oxygen atom and having the number of carbon atoms specified, or if no number is specified, having 1 to 12 carbon atoms (preferably 1 to 6). Examples of alkoxy groups include, but are not limited to, groups such as methoxy, ethoxy, tert-butoxy, and allyloxy. The term "alkoxycarbonyl" refers to the radical -C(O)OR where R is an alkyl. The term "alkylsulfonyl" refers to the radical -SO₂ R where R is an alkyl group.

The term "alkylene" means a saturated divalent aliphatic group including straight- chain, branched-chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having 1 to 12 carbon atoms (preferably 1 to 6), e.g., methylene, ethylene, 2,2-dimethylethylene, propylene, 2-methyl- propylene, butylene, pentylene, cyclopentylmethylene, and the like.

The term "substituted alkyl" means an alkyl group as defined above that is substituted with one or more substituents, preferably one to three substituents selected from the group consisting of halogen, alkyl, aryl, alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group. The phenyl group may optionally be substituted with one to three substituents selected from the group consisting of halogen , alkyl, aryl, alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide. Examples of substituted alkyl groups include, but are not limited to — CF₃, — CF₂ — CF₃, hydroxymethyl, 1- or 2-hydroxyethyl, methoxymethyl, 1- or 2-ethoxyethyl, carboxymethyl, 1- or 2-carboxyethyl, methoxycarbonylmethyl, 1- or 2-methoxycarbonyl ethyl, benzyl, pyrdinylmethyl, thiophenylmethyl, imidazolinylmethyl, dimethylaminoethyl and the like. The term "substituted alkylene" means an alkylene group as defined above that is substituted with one or more substituents, preferably one to three substituents, selected from the group consisting of halogen, alkyl, aryl, alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group. The phenyl group may optionally be substituted with one to three substituents selected from the group consisting of halogen, alkyl, aryl, alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide. Examples of substituted alkyl groups include, but are not limited to — CF₂ — , — CF₂ — CF₂ — , hydroxymethylene, 1- or 2-hydroxyethylene, methoxymethylene, 1- or 2-ethoxyethylene, carboxymethylene, 1- or 2-carboxyethylene, and the like.

The term "alkenyl" refers to unsaturated aliphatic groups including straight-chain, branched-chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having 1 to 12 carbon atoms (preferably 1 to 6), which contain at least one double bond ( — C=C — ). Examples of alkenyl groups include, but are not limited to allyl vinyl, -CH₂-CH=CH-CH₃, — CH₂- CH₂-cyclopentenyl and — CH₂ — CH₂-cyclohexenyl where the ethyl group can be attached to the cyclopentenyl, cyclohexenyl moiety at any available carbon valence.

The term "alkenylene" refers to unsaturated divalent aliphatic groups including straight-chain, branched-chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having 1 to 12 carbon atoms (preferably 1 to 6), which contain at least one double bond ( — C=C — ). Examples of alkenylene groups include, but are not limited to — CH=CH — , — CH₂ — CH=CH — CH₂ — , — CH₂ — CH(cyclopentenyl) — and the like.

The term "alkynyl" refers to unsaturated aliphatic groups including straight-chain, branched-chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having 1 to 12 carbon atoms (preferably 1 to 6), which contain at least one triple bond ( — C ≡C — ). Examples of alkynyl groups include, but are not limited to acetylene, 2-butynyl, and the like.

The term "alkynylene" refers to unsaturated divalent aliphatic groups including straight-chain, branched-chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having 1 to 12 carbon atoms (preferably 1 to 6), which contain at least one triple bond ( — C≡C — ). Examples of alkynylene groups include, but are not limited to — C≡C — , — C≡C — CH₂ — , and the like.

The term "substituted alkenyl" or "substituted alkynyl" refers to the alkenyl and alkynyl groups as defined above that are substituted with one or more substituents selected from the group consisting of halogen, alkyl, aryl, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group. Examples of substituted alkenyl and alkynyl groups include, but are not limited to — CH=CF₂, methoxyethenyl, methoxypropenyl, bromopropynyl, and the like.

The term "substituted alkenylene" or "substituted alkynylene" refers to the alkenylene and alkynylene groups as defined above that are substituted with one or more substituents selected from the group consisting of halogen, alkyl, aryl, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group.

The term "aryl" or "Ar" refers to an aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring (including but not limited to groups such as phenyl) or multiple condensed rings (including but not limited to groups such as naphthyl or anthryl), and includes both unsubstituted and substituted aryl groups. Substituted aryl is an aryl group that is substituted with one or more substituents, preferably one to three substituents, selected from the group consisting of alkyl, aryl, alkenyl, alkynyl, halogen, alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, aryloxy, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group. Representative examples include, but are not limited to naphthyl, phenyl, chlorophenyl, iodophenyl, methoxyphenyl, carboxyphenyl, and the like. The term "aryloxy" refers to an aryl group linked to an oxygen atom at one of the ring carbons. Examples of alkoxy groups include, but are not limited to, groups such as phenoxy, 2-, 3-, or 4- methylphenoxy, and the like. The term "arylthio group" refers to the radical — SR_C where R_c is an aryl group. The term "heteroarylthio group" refers to the radical -SRd where Rd is a heteroaryl.

The term "arylene" refers to the diradical derived from aryl (including substituted aryl) as defined above and is exemplified by 1 ,2-phenylene, 1 ,3-phenylene, 1 ,4-phenylene, 1 ,2- naphthylene and the like.

The term "amino" refers to the group — NH₂.

The term "N-alkylamino" and "N,N-dialkylamino" means a radical — NHR and — NRR' respectively where R and R' independently represent an alkyl group as defined herein. Representative examples include, but are not limited to N,N-dimethylamino, N-ethyl- N-methylamino, N,N-di(1-methylethyl)amino, N-cyclohexyl-N-methylamino, N-cyclohexyl-N- ethylamino, N-cyclohexyl-N-propylamino, N-cyclohexylmethyl-N-methylamino, N- cyclohexylmethyl-N-ethylamino, and the like.

The term "thioalkoxy" means a radical — SR where R is an alkyl as defined above e.g., methylthio, ethylthio, propylthio, butylthio, and the like.

The term "acyl group" means a radical -C(O)R, where R is hydrogen, halogen, alkyl, aryl, heteroaryl, alkoxy, aryloxy, N-alkylamino, N,N-dialkylamino, N-arylamino, thioalkoxy, thioaryloxy or substituted alkyl wherein alkyl, aryl, heteroaryl, and substituted alkyl are as defined herein.

The term "thioacyl group" means a radical -C(S)R, where R is hydrogen, halogen, alkyl, aryl, heteroaryl, alkoxy, aryloxy, N-alkylamino, N,N-dialkylamino, N-arylamino, thioalkoxy, thioaryloxy or substituted alkyl wherein alkyl, aryl, heteroaryl, and substituted alkyl are as defined herein.

The term "sulfonyl group" means a radical -SO₂R, where R is hydrogen, halogen, alkyl, aryl, heteroaryl, alkoxy, aryloxy, N-alkylamino, N,N-dialkylamino, N-arylamino, thioalkoxy, thioaryloxy or substituted alkyl wherein alkyl, aryl, heteroaryl, and substituted alkyl are as defined herein.

The term "acyloxy" means a radical — 0C(=0)R, where R is hydrogen, alkyl, aryl, heteroaryl or substituted alkyl wherein alkyl, aryl, heteroaryl, and substituted alkyl are as defined herein. Representative examples include, but are not limited to formyloxy, acetyloxy, cylcohexylcarbonyloxy, cyclohexylmethylcarbonyloxy, benzoyloxy, benzylcarbonyloxy, and the like.

The term "heteroalkyl," "heteroalkenyl," and "heteroalkynyl" refers to alkyl, alkenyl, and alkynyl groups respectively as defined above, that contain the number of carbon atoms specified (or if no number is specified, having 1 to 12 carbon atoms, preferably 1 to 6) which contain one or more heteroatoms, preferably one to three heteroatoms, as part of the main, branched, or cyclic chains in the group. Heteroatoms are independently selected from the group consisting of — NR-, -NRR, -S-, -S(O) — , -S(O)₂-, —0—, -SR, -S(O)R, -S(O)₂R, —OR —PR—, -PRR, -P(O)R- and -P(O)RR; (where each R is hydrogen, alkyl or aryl) preferably — NR where R is hydrogen or alkyl and/or O. Heteroalkyl, heteroalkenyl, and heteroalkynyl groups may be attached to the remainder of the molecule either at a heteroatom (if a valence is available) or at a carbon atom. Examples of heteroalkyl groups include, but are not limited to, groups such as — O — CH₃, -CH₂-O-CH₃, -CH₂-CH₂-O-CH₃, -S-CH₂-CH₂-CH₃,

— CH₂- CH(CH₃)- S— CH₃, -CH₂-CH₂-NH-CH₂-CH₃, 1-ethyl-6-propylpiperidino, 2- ethylthiophenyl, piperazino, pyrrolidine piperidino, morpholino, and the like. Examples of heteroalkenyl groups include, but are not limited to groups such as — CH=CH- CH₂—N(CH₃)₂, and the like. The term "heteroaryl" or "HetAr" refers to an aromatic monovalent monocyclic, bicyclic, or tricyclic radical containing 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, or 18 - member ring atoms, including 1 , 2, 3, 4, or 5 heteroatoms, preferably one to three heteroatoms including, but not limited to heteroatoms such as N, O, P, or S, within the ring. Representative examples include, but are not limited to single ring such as imidazolyl, pyrazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl, pyridyl, thiophene, and the like, or multiple condensed rings such as indolyl, quinoline, quinazoline, benzimidazolyl, indolizinyl, benzothienyl, and the like.

The heteroalkyl, heteroalkenyl, heteroalkynyl and heteroaryl groups can be unsubstituted or substituted with one or more substituents, preferably one to three substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, benzyl, halogen, alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, aryloxy, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group. Examples of such substituted heteroalkyl groups include, but are not limited to, piperazine, pyrrolidine, morpholine, or piperidine, substituted at a nitrogen or carbon by a phenyl or benzyl group, and attached to the remainder of the molecule by any available valence on a carbon or nitrogen, — NH — S(=O)₂ — phenyl, — NH — (C=O)O-alkyl, — NH — C(=O)O-alkyl-aryl, and the like. The heteroatom(s) as well as the carbon atoms of the group can be substituted. The heteroatom(s) can also be in oxidized form.

The term "heteroarylene" refers to the diradical group derived from heteroaryl (including substituted heteroaryl), as defined above, and is exemplified by the groups 2,6- pyridinylene, 2,4-pyridinylene, 1 ,2-quinolinylene, 1 ,8-quinolinylene, 1 ,4-benzofuranylene, 2,5-pyridinylene, 2,5-indolenylene, and the like.

The term "heteroalkylene", "heteroalkenylene", and "heteroalkynylene" refers to the diradical group derived from heteroalkyl, heteroalkenyl, and heteroalkynyl (including substituted heteroalkyl, heteroalkenyl, and heteroalkynyl) as defined above.

The term "carboxaldehyde" means — CHO.

The term "carboalkoxy" means — C(=O)OR where R is alkyl as defined above and include groups such as methoxycarbonyl, ethoxycarbonyl, and the like.

The term "carboxamide" means — C(=O)NHR or — C(=O)NRR' where R and R' are independently hydrogen, aryl or alkyl as defined above. Representative examples include groups such as aminocarbonyl, N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, and the like.

The term "carboxy" refers to the radical -C(O)OH.

The term "carbamoyl" refers to the radical -C(O)NH₂. The term "halogen" or "halo" as used herein refer to Cl, Br, F or I substituents, preferably fluoro or chloro.

The term "hydroxy" refers to a —OH radical.

"Isomers": Compounds that have the same molecular formula (or elemental composition) but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers". Isomers in which the connectivity between atoms is the same but which differ in the arrangement of their atoms in space are termed "stereoisomers". Stereoisomers that are not mirror images of one another are termed "diastereomers" and those that are non-superimposable mirror images of each other are termed "enantiomers". When a compound has an asymmetric center, for example which is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn, lngold and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either an individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".

The compounds of this invention may possess one or more asymmetric centers. Such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The description is also intended to include all possible diastereomers and mixtures thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 1992).

"Optically pure": As generally understood by those skilled in the art, an optically pure compound is one that is enantiomerically pure. As used herein, the term "optically pure" is intended to mean a compound which comprises at least a sufficient amount of a single enantiomer to yield a compound having the desired pharmacological activity. Preferably, "optically pure" is intended to mean a compound that comprises at least 90% of a single isomer (80% enantiomeric excess), preferably at least 95% (90% e.e.), more preferably at least 97.5% (95% e.e.), and most preferably at least 99% (98% e.e.). Preferably, the compounds of the invention are optically pure.

"Protecting group" refers to a chemical group that exhibits the following characteristics: 1 ) reacts selectively with the desired functionality in good yield to give a protected substrate that is stable to the projected reactions for which protection is desired; 2) is selectively removable from the protected substrate to yield the desired functionality; and 3) is removable in good yield by reagents compatible with the other functional group(s) present or generated in such projected reactions. Examples of suitable protecting groups can be found in Greene et al. (1991 ) Protective Groups in Organic Synthesis, 2nd Ed. (John Wiley & Sons, Inc., New York). Preferred amino protecting groups include, but are not limited to, benzyloxycarbonyl (CBz), t-butyloxycarbonyl (Boc), t-butyldimethylsilyl (TBDMS), 9- fluorenylmethyl-oxycarbonyl (Fmoc), or suitable photolabile protecting groups such as 6- nitroveratryloxy carbonyl (Nvoc), nitropiperonyl, pyrenylmethoxycarbonyl, nitrobenzyl, dimethyl dimethoxybenzil, 5-bromo-7-nitroindolinyl, and the like. Preferred hydroxyl protecting groups include acetyl (Ac), benzoyl (Bz), benzyl (Bn), Tetrahydropyranyl (THP), TBDMS, photolabile protecting groups (such as nitroveratryl oxymethyl ether (Nvom)), Mom (methoxy methyl ether), and Mem (methoxy ethoxy methyl ether). Particularly preferred protecting groups include NPEOC (4-nitrophenethyloxycarbonyl) and NPEOM (4- nitrophenethyloxy-methyloxycarbonyl).

"Prodrug": Glycopeptide and lipoglycopeptide antimicrobial molecules of the present invention may be formulated as prodrugs. According to the present invention, a prodrug is an inactive (or significantly less active) form of any of the glycopeptide and lipoglycopeptide antimicrobial molecule compounds of the present invention. Upon in vivo processing, prodrugs of the present invention release an active glycopeptide and lipoglycopeptide antimicrobial molecule. Prodrugs of glycopeptide and lipoglycopeptide antimicrobial molecules of the present invention may be prepared by modifying functional groups present on the glycopeptide and lipoglycopeptide antimicrobial molecules in such a way that the modifications may be cleaved in vivo to release the glycopeptide and lipoglycopeptide antimicrobial molecules.

Prodrugs include compounds of Formula (I) and/or Formula (II) wherein a hydroxyl, carboxyl or amino group in the glycopeptide and lipoglycopeptide antimicrobial molecule portion of the compound is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, carboxyl or amino group, respectively. Such prodrug groups are in addition to the linker that may be coupled to a hydroxy, carboxy and/or amino group of an glycopeptide and lipoglycopeptide antimicrobial molecule. Examples of prodrug groups include, but are not limited to, esters (e.g., acetate, formate, and benzoate derivatives) and carbamates (e.g., N,N-dimethylaminocarbonyl) on hydroxy functional groups of the glycopeptide and lipoglycopeptide antimicrobial molecule portion of the compounds of the present invention. The present invention also includes those prodrugs requiring two or more events in prodrug cleavage. According to that embodiment, more complex compounds would release, upon cleavage, a prodrug of a glycopeptide and lipoglycopeptide antimicrobial molecule, the latter prodrug being activatable to release a desired glycopeptide and lipoglycopeptide antimicrobial molecule. The skilled artisan will understand that prodrugs of glycopeptide and lipoglycopeptide antimicrobial molecules of the present invention may undergo two cleavage events, one of which cleaves the cleavable linker and thus releases the group, the other of which results in the release of the prodrug group.

A "pharmaceutically acceptable prodrug" is intended to mean prodrug of glycopeptide and lipoglycopeptide antimicrobial molecule, such as a prodrug of a compound of Formula (I) and/or Formula (II), in a formulation that may be administered to a subject, such as a mammal, preferably a human. For example, the prodrug may be in a formulation comprising a pharmaceutically acceptable carrier or excipient.

A "pharmaceutically acceptable active metabolite" is intended to mean a pharmacologically active product produced through metabolism in the body of a compound of Formula (I) or Formulae (II) as defined herein.

A "pharmaceutically acceptable solvate" is intended to mean a solvate that retains the biological effectiveness and properties of the biologically active components of compounds of Formula I and/or Formula II. Examples of pharmaceutically acceptable solvates include, but are not limited to water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

A "pharmaceutically acceptable carrier or excipient" means any compound, solution, substance or material that can be used in a formulation of the compounds of the present invention that may be administered to a subject. In particular, carriers and excipients of the present invention are those useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and that may present pharmacologically favorable profiles and that includes carriers and excipient that are acceptable for veterinary use as well as human pharmaceutical use. Suitable pharmaceutically acceptable carriers and excipients are well known in art and can be determined by those of skill in the art as the clinical situation warrants. The skilled artisan will understand that diluents are includes within the scope of the terms carriers and excipients. Examples of suitable carriers and excipients include saline, buffered saline, dextrose, water, glycerol, ethanol, more particularly: (1 ) Dulbecco's phosphate buffered saline, pH about 7.4, containing about 1 mg/ml to 25 mg/ml human serum albumin, (2) 0.9% saline (0.9% w/v NaCI), (3) 5% (w/v) dextrose, and (4) water.

A "pharmaceutically acceptable salt" is intended to mean a salt of glycopeptide or lipoglycopeptide antimicrobial molecule, such as a salt of a compound of Formula (I) and/or Formula (II), in a formulation that may be administered to a subject, such as a mammal, preferably a human. For example, the salt may be in a formulation comprising a pharmaceutically acceptable carrier or excipient. "Saccharide":represents saturated polyhydroxylated compounds. The term is sometimes limited to polyhydroxylated carbon chains possessing an aldehyde or a ketone moiety either free or masked as an acetal or a ketal functionality. In this case, it is intended to include monosaccharides, oligosaccharides and polysaccharides as well as substances derived from monosaccharides by reduction of the carbonyl group (alditols), by oxidation of one or more terminal groups to carboxylic acids, by oxidation of one or more secondary hydroxyl groups to ketones, by replacement of one or more hydroxy group(s) by a hydrogen atom, an amino group, an O-linked ester group, a C-linked ester group, an N-linked amide group, a C-linked amide group, an alkyl group, an aryl group, a thiol group or similar heteroatomic groups and/or by replacement of one or more of the hydrogens bonded to carbons by a C-linked ester group, a C-linked amide group, an alkyl group, an aryl group or other heteroatomic groups. It also includes oligomers of modified and unmodified monosaccharides as well as derivatives of these compounds.

Unmodified, oxidized, reduced or substituted saccharide monoradicals are covalently attached to the glycopeptide via any atom of the saccharide moiety, preferably a carbon. Representative saccharide include, by way of illustration, hexoses such as D-glucose, D- mannose, D-xylose, D-galactose, vancosamine, 3-desmethyl-vancosamine, 3-epi- vancosamine, 4-epi-vancosamine, acosamine, actinosamine, daunosamine, 3-epi- daunosamine, ristosamine, D-glucamine, N-methyl-D-glucamine, D-glucuronic acid, N- acetyl-D-glucosamine, N-acetyl-D-galactosamine, sialyic acid, iduronic acid, L-fucose, and the like; pentoses such as D-ribose or D-arabinose; ketoses such as D-ribulose or D- fructose; disaccharides such as 2-O-(α-L-vancosaminyl)-β-D-glucopyranose, 2-O-( α-L- vancosaminyl)-β-D-glucopyranose, 2-O-( α-L-3-epivancosaminyl)-β-D-glucopyranose, 2-0- (3-desmethyl- α-L-vancosaminyl)-β-D-glucopyranose, sucrose, lactose, or maltose; derivatives such as acetals, amines, acylated, sulfated and phosphorylated sugars; oligosaccharides having from 2 to 10 saccharide units. These saccharides are can be either in their open or preferably in their pyranose or furanose forms.

The saccharide may be linked to the aglycone of the glycopeptide or lipoglycopeptide antimicrobial agent indirectly via an additional spacer such as an ethylene, propylene, butylenes or phenylene group.

The term "amino-containing saccharide group" refers to a saccharide group having an amino substituent. Representative amino-containing saccharide include L-vancosamine, 3-desmethyl-vancosamine, 3-epi-vancosamine, 4-epi-vancosamine, acosamine, actinosamine, daunosamine, 3-epi-daunosamine, ristosamine, N-methyl-D-glucamine and the like.

"Salt": glycopeptide and lipoglycopeptide antimicrobial molecules of the present invention may be in the form of a salt. Salts of glycopeptide and lipoglycopeptide antimicrobial molecules containing at least one poly(ethylene glycol) chain of the present invention means a salt that retains or improves the biological effectiveness and properties of the free acids and bases of the parent compound as defined herein or that takes advantage of an intrinsically charged functionality on the molecule and that is not biologically or otherwise undesirable. 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-ethane- disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4- chlorobenzenesulfonic acid, 2-napthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 3-phenyl propionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynapthoic acid, salicylic acid, stearic acid, muconic acid, and the like;

(2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like; or

(3) salts formed when a charged functionality is present on the molecule and a suitable counterion is present, such as a tetraalkyl(aryl)ammonium functionality and an alkali metal ion, a tetraalkyl(aryl)phosphonium functionality and an alkali metal ion, an imidazolium functionality and an alkali metal ion, and the like.

The term "glycopeptide and lipoglycopeptide antimicrobial molecule" and related terms have the same meaning and refer to antimicrobial agents which are part of the well known class of glycopeptides and lipoglycopeptides" as described in more detail herein.

The term "poly(ethylene glycol)" is intended to mean any compound non-toxic to humans having at least three repeating ethyleneoxy units.

The term "antibacterial" includes those compounds that inhibit, halt or reverse growth of bacteria, those compounds that inhibit, halt, or reverse the activity of bacterial enzymes or biochemical pathways, those compounds that kill or injure bacteria, and those compounds that block or slow the development of a bacterial infection.

The terms "treating" and "treatment" are intended to mean at least the mitigation of a disease condition or symptom associated with a bacterial infection in a subject, including mammals such as a human, that is alleviated by a reduction of growth, replication, and/or propagation of any bacterium such as Gram-positive organisms, and includes curing, healing, inhibiting, relieving from, improving and/or alleviating, in whole or in part, the disease condition.

The term "prophylaxis" is intended to mean at least a reduction in the likelihood that a disease condition associated with a bacterial infection will develop in a mammal, preferably a human. The terms "prevent" and "prevention" are intended to mean blocking or stopping a disease condition associated with a bacterial infection from developing in a mammal, preferably a human. In particular, the terms are related to the treatment of a mammal to reduce the likelihood ("prophylaxis") or prevent the occurrence of a bacterial infection, such as bacterial infection that may occur during or following a surgery involving bone reparation or replacement. The terms also include reducing the likelihood ("prophylaxis") of or preventing a bacterial infection when the mammal is found to be predisposed to having a disease condition but not yet diagnosed as having it. For example, one can reduce the likelihood or prevent a bacterial infection in a mammal by administering a compound of Formula (I) and/or Formula (II), or a pharmaceutically acceptable prodrug, salt, active metabolite, or solvate thereof, before occurrence of such infection.

The term "subject" is intended to mean an animal, such as a mammal, including humans and animals of veterinary importance, such as dogs, cats, horses, sheep, goats, and cattle.

B) Compounds of the invention

As will be described hereinafter in the Exemplification section, the inventors have prepared glycopeptide or lipoglycopeptide molecules bearing at least one poly(ethylene glycol) chain having an improved solubility profile in aqueous media.

In one embodiment, the compounds of the invention are represented by the general Formula (I):

P_αL_βA_γ (I) and pharmaceutically acceptable salts, esters and prodrugs thereof, wherein:

P is a macromolecule containing at least one poly(ethylene glycol) chain;

A is a glycopeptide or lipoglycopeptide antimicrobial molecule, with the proviso that A is not vancomycin or a vancomycin derivative modified at either the amino group of the vancosamine or at the amino group of the N-methyl-leucyl residue or both;

As mentioned previously, the essence of the invention lies in the presence of a macromolecular moiety containing at least one poly(ethylene glycol) group attached to a glycopeptide or lipoglycopeptide antibiotic for increasing its solubility in aqueous media or in formulations based on aqueous media.

Macromolecules containing at least one polvfethylene glycol)

Poly(ethylene glycol) (PEG), or poly(ethylene oxide) (PEO), is a synthetic polymer generally obtained by the polymerization of ethylene oxide under anionic conditions. It can thus be produced with a variety of molecular weights and with a narrow polydispersity. It is generally a diol (two free hydroxyl groups) when the polymerization is carried in aqueous media, but can have from one to a large number of free hydroxyl groups depending on the initial nucleophile used in the polymerization process. Thus the use of methanol will result in PEG monomethyl ether. PEG is highly water soluble, non-toxic and non-immunogenic material which has found application as an excipient in pharmaceutical formulations or through covalent conjugation with therapeutic agents (Greenwald, R. B. et al Advanced Drug Delivery Reviews (2003), 55; 217-250. Greenwald, R. B. Journal of Controlled Release (2001 ), 74; 159-171 ). PEG prodrugs of vancomycin (US patent application 2004/0136947. Greenwald, R. B. et al European Journal of Medicinal Chemistry (2005), 40;798-804. Greenwald, R. B. et al Journal Medicinal Chemistry (2003), 46; 5021-5030) and PEG conjugates of vancomycin (US patent application 2004/0142858) have already been reported primarily as a means to extend the serum half-lfe of vancomycin. Examples of macromolecules containing at least one PEG chain suitable for the present invention include but are not limited to those macromolecules having the Formula (Ilia):

X is -O-, -S-, -S(O)-, -SO₂-, -N(R₃)-, -CO₂-, -CO-, -CON(R₃)-, -CON(Ra)-E-, -N(R₃)-, -CO₂-E-, -N(R₃)CO-, -N(R₃)CO-E-, -N(R₃)CON(R₃)-, or -N(R₃)CON(R₃)-E-, wherein E is an amino acid or a polypeptide of 1 -10 amino acids, and R₃ is C_xH_y wherein x is an integer <20 and y is an integer < (2x+1 ); and

Gi is C_wH_z, wherein w is an integer < 10, and z is an integer < (2w+2-b).

As shown in Example 2 hereinafter, glycopeptide and lipoglycopeptide derivatives possessing such a PEG containing macromolecular moiety are more soluble than the parent in aqueous media or formulations while maintaining antibacterial and therapeutic properties associated with it. Of course, other types of macromolecules containing PEG groups could be selected and synthesized by those skilled in the art. For instance the macromolecule group may be based on a dendrimeric structure (Pasut, G. Journal of Bioactive and Compatible Polymers (2005); 20; 213-230. Gingras, M. et al, Angewandte Chemie International Edition (2006), 46; 1010 - 1017) or be any other suitable derivative thereof. These and other suitable macromolecular groups bearing at least one poly(ethylene glycol) moiety are encompassed by the present invention.

Glvcopeptide and lipoqlvcopeptide antibiotics

Glycopeptide and lipoglycopeptide antibiotics are a well known class of biologically produced or semi-synthetic Gram-positive antimicrobial agents (Williams, D. H et al, Angewandte Chemie International Edition in English (1999), 1999, 38; 1172-1193. Nicolaou, K.C. et al, Angewandte Chemie International Edition in English (1999), 38; 2097-2152. Kahne, D. et al Chemical Reviews (2005), 105; 425 - 448; Pace, J. L. et al, Biochemical Pharmacology (2006), 71 ; 968-980). Vancomycin and teicoplanin are certainly the best known compounds in this class. Both drugs were proven clinically and microbiologically to have potent activity against Gram-positive organisms. Oritavancin (US Patent No. 5,840,684), dalbavancin (US patent No. 5,750,509) and telavancin (US patent No. 6,635,618) are recent examples of this class of compounds possessing extremely attractive pharmacological profiles with potent activity against gram-positive organisms, including methicillin-resistant Staphylococcus aureus, intermediate and fully vancomycin- resistant Staphylococcus aureus, vancomycin-resistant Enterococcus spp., and Streptococcus spp. The present invention is not restricted to a specific glycopeptide or lipoglycopeptide antibiotic, but encompasses all kinds of glycopeptide or lipoglycopeptide molecules having a suitable antimicrobial activity including, but not limited to, those disclosed in the above-listed US patents and PCT patent applications (incorporated herein by reference) and other glycopeptide or lipoglycopeptide antibiotic derivatives and hybrids such as glycopeptide-cephalosporin (as described in US patent application No 20050239691 for example), with the exception of vancomycin itself or vancomycin derivatives modified at either the amino group of the vancosamine or at the amino group of the N-methyl-leucyl residue or both.

According to a preferred embodiment, the term "glycopeptide and lipoglycopeptide antimicrobial molecule" includes all compounds having the Formula A₁ illustrated below:

R³ is selected from the group consisting of — OR^C, — NR^CR^C, — O R^a — Y— R^b— (Z)_x, — NR^C — R^a — Y— R^b -(Z)_x, — NR^cR^e, and — O— R^e;

R⁴ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, — R^a — Y— R^b -(Z)_x, — C(O)R^d and a saccharide group optionally substituted with — R^a — Y — R^b — (Z)_x, R^f, or — C(O) — R^a — Y — R^b — (Z)_x, or R⁴ and R⁵ can be joined, together with the atoms to which they are attached, to form a heterocyclic ring optionally substituted with — NR^C — R^a — Y— R^b -(Z)_x ;

R⁶ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, — R^a— Y— R^b -(Z)_x, — C(0)R^d and a saccharide group optionally substituted with — R^a — Y— R^b -(Z)_x, R^f, — C(0)R^f, or — C(O) — R^a — Y — R^b — (Z)_x, or R⁵ and R⁶ can be joined, together with the atoms to which they are attached, to form a heterocyclic ring optionally substituted with — NR^C — R^a — Y — R^b — (Z)_x;

R⁷ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, — R^a— Y— R^b— (Z)_x, and — C(0)R^d;

R¹² is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, — C(0)R^d, — C(NH)R^d, — C(O)NR^C R^c, — C(0)0R^d, — C(NH)NR^CR^C, — R^a— Y— R^b— (Z)_x, and — C(O)- R^b— Y— R^b— (Z)_x, or R¹¹ and R¹² are joined, together with the nitrogen atom to which they are attached, to form a heterocyclic ring;

R¹³ is selected from the group consisting of hydrogen and — OR¹⁴ ;

R¹⁴ is selected from the group consisting of hydrogen, — C(0)R^d and a saccharide group;

R^Θ is each a saccharide group;

R^x is an N-linked amino saccharide or an N-linked heterocycle;

Y is each independently selected from the group consisting of , — CH₂ — , oxygen, sulfur, -S-S-, — NR^C— , -S(O)-, -SO₂-, — NR^CC(O)— , -OSO₂-, — OC(O)- — N(R^C)SO₂— , — C(O)NR^C— , -C(O)O-, — SO₂NR^C— , -SO₂O-, — P(O)(OR^C)O— , — P(O)(OR^C)NR^C— , — OP(O)(OR^C)O— , — OP(O)(OR^C)NR^C— , -OC(O)O-, — NR⁰C(O)O-, — NR^CC(O)NR^C — , — OC(O)NR^C— , -C(O)- and -N(R^C)SO₂NR^C— ;

is selected from

with the proviso that if R₁ is

wherein R_G is H, C_1-6 alkyl,

C_3-12 branched alkyl, C_3-8 cycloalkyl, C_1-6 substituted alkyl, C_3-8 substituted cycloalkyl, aryl, substituted aryl, aralkyl, Ci_-6 heteroalkyl, substituted Ci_-6 heteroalkyl, Ci_-6 alkoxy, phenoxy or Ci_-6 heteroalkoxy, then at least one of R³ or R⁵ is not hydrogen.

Those skilled in the art will readily identify, isolate and/or prepare the suitable glycopeptide or lipoglycopeptide antimicrobial molecules according to the invention. If necessary they could refer to the numerous literature found in the art, including the US patents and PCT patent applications listed hereinbefore, and more particularly to US Patents No. 5,840,684, 5,750,509 and 6,635,618.

According to one embodiment, the glycopeptide or lipoglycopeptide antimicrobial molecule is a derivative of vancomycin, with the exception of vancomycin itself or vancomycin derivatives modified at either the amino group of the vancosamine or at the amino group of the N-methyl-leucyl residue or both. According to another embodiment, the glycopeptide or lipoglycopeptide antimicrobial molecule is a derivative of teicoplanin. According to a third embodiment, the glycopeptide or lipoglycopeptide antimicrobial molecule is a derivative of chloroeremomycin. According to a fourth embodiment, the glycopeptide or lipoglycopeptide antimicrobial molecule is a derivative of oritavancin. According to a fifth embodiment, the glycopeptide or lipoglycopeptide antimicrobial molecule is a derivative of dalbavancin. According to a sixth embodiment, the glycopeptide or lipoglycopeptide antimicrobial molecule is a derivative of telavancin. The chemical structures of some relevant examples of these molecules are illustrated hereinafter. Arrows indicate preferred sites for attachment of the macromolecular moiety bearing at least one the poly(ethylene glycol) chain (direct attachment or via an optional linker), but those skilled in the art will recognize that all hydroxyl, amino, amido and carboxyl groups may be possible sites for attachment:

Specific examples of oritavancin derivatives according to the invention are shown in the Exemplification section. Even though in the examples the macromolecular moieties bearing at least one poly(ethylene glycol) chain have not been attached to all the preferred attachment sites shown by the arrows, the results presented in the Exemplification section confirm that it is possible to synthesize biologically active glycopeptide and lipoglycopeptide derivatives having a improved solubility in aqueous media. Similarly, the invention encompasses glycopeptide and lipoglycopeptide derivatives having more than just one macromolecular moiety bearing at least one poly(ethylene glycol) chain (one at the carboxy and one at one of the amino groups on the oritavancin molecule for instance). As mentioned previously, the above identified sites of attachment are only preferred sites for tethering a macromolecular moiety bearing at least one poly(ethylene glycol) chain and all other potential sites (on any of the hydroxyl groups for instance) are covered by the present invention.

Linkers

A cleavable linker L covalently and reversibly couples the macromolecular moiety bearing at least one poly(ethylene glycol) chain P to a site on a glycopeptide or lipoglycopeptide antimicrobial molecule A. As used herein, the term "cleavable" refers to a group that is chemically or biochemically unstable under physiological conditions. The chemical instability preferably results from decomposition due to a reversible chemical process, an intramolecular chemical reaction or hydrolysis (i.e. splitting of the molecule or group into two or more new molecules or groups due to the net insertion of one or more water molecules) when it depends on an intermolecular chemical reaction. This chemical instability may occur as a spontaneous chemical event or as a result of the interaction with biomolecular catalysts or reagents.

Cleavage of the linker may be very rapid or very slow. For instance, the half-life of the cleavable liker may be of about 1 minute, about 15 minutes, about 30 minutes, about 1 hour, about 5 hours, about 10 hours, about 15 hours, about 1 day or about 48 hours. The cleavable linker may be an enzyme-sensitive linker that is cleavable only by selected specific enzymes (e.g. amidase, esterase, metalloproteinase, etc) or may be susceptible to cleavage by other chemical means, such as but not limited to acid/base catalysis or self- cleavage. For instance, the linker may be selected such that only 1 %, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, or 70% of the polyethylene glycol)-bonded antibiotic is released through a time period extending to 1 minute, 15 minutes, 30 minutes, 1 hour, 5 hours, 10 hours, 15 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days 7 days, one week, two weeks, three weeks or more following administration of the compound of the invention. Preferably, the linker is selected such that about 50% of the macromolecular prodrug is converted to its parent glycopeptide or lipoglycopeptide antimicrobial molecule is released per hour. The choice of the linker may vary according to factors such as (i) the site of attachment of the macromolecular group to the glycopeptide or lipoglycopeptide antimicrobial molecule, (ii) the type of macromolecular group used; (iii) the type of glycopeptide or lipoglycopeptide antimicrobial molecule used, and (iv) the desired ease of cleavage of the linker and associated release of the glycopeptide or lipoglycopeptide antimicrobial molecule.

Preferably, the linker L couples a poly(ethylene glycol) chain from the macromolecular group P to a glycopeptide or lipoglycopeptide antimicrobial molecule A through one or more hydroxyl groups on A, through one or more nitrogen atoms on A, through one or more carboxyl groups on A, or a combination of one or more hydroxyl groups, one or more nitrogen atoms, and/or one or more carboxyl groups, on A. Between 1 and 7 macromolecular groups bearing a single poly(ethylene glycol) chain may be coupled to A through any combination of linkers L. Similarly, if the macromolecular group P bears more than one poly(ethylene glycol) chain or a single poly(ethylene glycol) chain with multiple points of attachment for the linker L, then several glycopeptide or lipoglycopeptide antimicrobial molecules A may be coupled to each macromolecular group P, one for each point of attachment, through any combination of linkers L. Preferably there are < 50 glycopeptide or lipoglycopeptide antimicrobial molecules A coupled to each macromolecular group P, more preferably there are 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 glycopeptide or lipoglycopeptide antimicrobial molecules A coupled to each macromolecular group P.

The linker is facultative because its presence is dependent upon (i) the site of attachment of the macromolecular group to the glycopeptide or lipoglycopeptide molecule, (ii) the type of functionality present on the macromolecular group used; (iii) the type of glycopeptide or lipoglycopeptide used, and (iv) the desired ease of cleavage of the linker and associated release of the glycopeptide or lipoglycopeptide antibiotic. For instance, it is possible to avoid the linker and tether a poly(ethylene glycol) chain directly to the carboxyl group of oritavancin.

In a preferred embodiment, the linker L is represented by the formula (L₁):

wherein:

A_a indicates the point of attachment to the glycopeptide or lipoglycopeptide antimicrobial molecule A;

W is a covalent bond or is selected from the group of consisting of

T is oxygen or sulfur;

P_a indicates the point of attachment to the macromolecule containing at least one poly(ethylene glycol) chain P;

Q is each independently nitro, chloro, bromo, iodo or fluoro;

X is each independently -O-, -S- or -N(R)-;

Y is each independently selected from the group consisting of a covalent bond, -CH₂-, oxygen, sulfur, -S-S-, — NR^C— , -S(O)- -SO₂-, — NR^CC(O)— , -OSO₂-, — OC(O)- — N(R^C)SO₂— , — C(O)NR^C— , -C(O)O-, — SO₂NR^C— , -SO₂O-, — P(O)(OR^C)O— , — P(O)(OR^C)NR^C— , — OP(O)(OR^C)O— , — OP(O)(OR^C)NR^C— , -OC(O)O- , — NR⁰C(O)O-, — NR^CC(O)NR^C — , — OC(O)NR^C— , -C(O)- and -N(R^C)SO₂NR^C— ; R^c is each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic and — C(O)R^d— ;

aryloxycarbonyl,

q is 2 or 3; r is 1 , 2, 3, 4 or 5;

W₁ and W₂ are each integers ≥ 0 such that their sum (W₁ + w₂) is 1 , 2 or 3; a, b, c, d are integers ≥ 0 such that a+b+c+d <7 or null; e and f are integers ≥ 0 such that e+f = 4; ω is 0 or 1 ; and with the proviso that at least one R is P₃ or — R^a — Y— R^b -Y— R^b— P₃.

W₁ and W₂ are each integers ≥ 0 such that their sum (W₁ + w₂) is 1 , 2 or 3; each Y is independently selected from the group consisting of -0-, -S-, and -NR_L-; each Z is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, acyl, acyloxy, carboxy, carbamoyl, sulfuryl, sulfinyl, sulfenyl, sulfonyl, mercapto, amino, hydroxyl, cyano and nitro; s is 1 , 2, 3 or 4; and R₃ is C_xHy where x is an integer of 0 to 20 and y is an integer of 1 to 2x+1.

W₁ and W₂ are each integers ≥ 0 such that their sum (W₁ + w₂) is 1 , 2 or 3; X is CH₂, — CONRL-, -CO-O-CH₂-, or — CO— O— ; each Y is independently selected from -O-, -S-, and -NR_L-; each Z is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, acyl, acyloxy, carboxy, carbamoyl, sulfuryl, sulfinyl, sulfenyl, sulfonyl, mercapto, amino, hydroxyl, cyano and nitro; s is 1 , 2, 3 or 4; and

When L couples P to A through a carboxyl group on A, preferably L is one of the following linkers:

wherein: n is an integer < 10, preferably 1 , 2, 3 or 4, more preferably 1 or 2; p is 0 or an integer < 10, preferably 0, 1 , 2, 3 or 4, more preferably 0 or 1 ; each R_L is independently selected from the group consisting of H, ethyl and methyl, preferably H;

R_x is S, C(R_L)2, NR_L or O; preferably NR_L, more preferably NH; each Y is independently selected from -O-, -S-, and -NR_L-; each Z is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, acyl, acyloxy, carboxy, carbamoyl, sulfuryl, sulfinyl, sulfenyl, sulfonyl, mercapto, amino, hydroxyl, cyano and nitro; and s is 1 , 2, 3 or 4.

According to another particular embodiment, the compounds of the invention are represented by Formula (II) or a pharmaceutically acceptable salt or prodrug thereof:

R² is hydrogen, — L⁴ or a saccharide group optionally substituted with — R^a — Y— R^b -(Z)_x, R^f, — C(O)R^f, — C(O)-R³ — Y— R^b -(Z)_x, — C(NL⁵)R^f, or — C(NL⁶)- R^a — Y— R^b -(Z)_x ;

R³ is selected from the group consisting of — OR^C, — NR^CR^C, — O— R^a — Y— R^b— (Z)_x, — NR^C — R^a — Y— R^b -(Z)_x, — NR^cR^e, — O— R^e, -OL⁷, — NL⁸R^C, and -NL⁹R^e;

R⁴ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, — L¹⁰, — R^a — Y— R^b -(Z)_x, — C(O)R^d, — C(NL¹¹ )R^d and a saccharide group optionally substituted with — R^a — Y— R^b -(Z)_x, R^f, — C(O)-R³ — Y— R^b -(Z)_x, or — C(NL¹²)- R^a — Y— R^b -(Z)_x, or R⁴ and R⁵ can be joined, together with the atoms to which they are attached, to form a heterocyclic ring optionally substituted with — NR^C — R^a — Y— R^b -(Z)_x or -NL¹³ — R^a — Y— R^b -(Z)_x;

R⁶ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, — L¹⁹, — R^a— Y— R^b -(Z)_x, — C(0)R^d, — C(NL²⁰)R^d and a saccharide group optionally substituted with — R^a — Y— R^b -(Z)_x, R^f, — C(0)R^f, — C(O)- R^a— Y— R^b— (Z)_x, — C(NL²¹)R^f, or — C(NL²²)- R^a— Y— R^b— (Z)_x or R⁵ and R⁶ can be joined, together with the atoms to which they are attached, to form a heterocyclic ring optionally substituted with — NR^C— R^a— Y— R^b— (Z)_x or -NL²³— R^a— Y— R^b-(Z)_X;

R¹³ is selected from the group consisting of hydrogen and — OR¹⁴;

R¹⁴ is selected from the group consisting of hydrogen, — L⁴², — C(0)R^d , — C(NL⁴³)R^d and a saccharide group optionally substituted with — R^a — Y— R^b -(Z)_x, R^f, — C(0)R^f, — C(O)-R³ — Y— R^b -(Z)_x, — C(NL⁴⁴)R^f, or — C(NL⁴⁵)- R^a — Y— R^b -(Z)_x ;

R^c is each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic and — C(0)R^d ;

R^Θ is each a saccharide group optionally substituted with — R^a — Y — R^b — (Z)_x, R^f, — C(0)R^f, — C(O)-R³ — Y— R^b -(Z)_x, — C(NL⁴⁶)R^f, or — C(NL⁴⁷)- R^a — Y— R^b -(Z)_x;

R^x is an N-linked amino saccharide or an N-linked heterocycle both of which may be optionally substituted with — R^a— Y— R^b— (Z)_x, R^f, — C(0)R_f, — C(O)-R³ — Y— R^b -(Z)_x, — C(NL⁴⁸)R_f, or — C(NL⁴⁹)- R^a — Y— R^b -(Z)_x;

X is each independently selected from the group consisting of hydrogen, fluoro, chloro, bromo and iodo; Y is each independently selected from the group consisting Of -CH₂ — , oxygen, sulfur, -S-S-, — NR^C— , -S(O)-, -SO₂-, — NR^CC(O)— , -OSO₂-, — OC(O)- — N(R^C)SO₂— , — C(O)NR^C— , -C(O)O-, — SO₂NR^C— , -SO₂O-, — P(O)(OR^C)O— , — P(O)(OR^C)NR^C— , — OP(O)(OR^C)O— , — OP(O)(OR^C)NR^C— , -OC(O)O-, — NR^CC(O)O— , — NR^CC(O)NR^C — , — OC(O)NR^C, — C(O)- ,-N(R^c)SO₂NR^c— , — NL⁵⁰- , -NL⁵¹C(O)- -OSO₂-, -OC(O)- — N(L⁵²)SO₂— , -C(O)NL⁵³-, -SO₂NL⁵⁴-, — P(O)(OL⁵⁵)O— , — P(O)(OL⁵⁶)NR^C— , — P(O)(OR^C)NL⁵⁷— , — OP(O)(OL⁵⁸)O— , — OP(O)(OL⁵⁹)NR^C— , — OP(O)(OR^C)NL⁶⁰— , -NL⁶¹C(O)O-, — NL⁶²C(O)NR^C— , — NR^CC(O)NL⁶³— , -OC(O)NL⁶⁴-, -N(L⁶⁵)SO₂NR^C— and -N(R^C)SO₂NL⁶⁶— ;

Z is each independently selected from the group consisting of hydrogen, aryl,

67 68 cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, a saccharide, -L and -L⁶⁹; n is O, 1 or 2; x is 1 or 2; and

is selected from

X is -O-, -S-, -S(O)-, -SO₂-, -N(R₃)-, -CO₂-, -CO-, -CON(R₃)-, -CON(R_a)-E-, -N(R₃)-, -CO₂-E-, -N(R₃)CO-, -N(R₃)CO-E-, -N(R₃)CON(R₃)-, -N(R₃)C0N(R₃)-E- wherein E is an amino acid or a polypeptide of 1 -10 amino acids, and R₃ is C_xH_y , x being an integer <20 and y being an integer < (2x+1 ); and

G₁ is C_WH_Z wherein w is an integer < 10 and z is an integer < (2w+2-b);

each L⁸, L⁹, L¹³, L¹⁴, L¹⁵, L¹⁶, L¹⁷, L²³, L²⁶, L²⁸, L³¹, L³², L³⁴, L³⁶, L³⁷, L⁴¹, L⁵⁰, L⁵¹, L⁵²,

L⁵³, L⁵⁴, L⁵⁷, L⁶⁰, L⁶¹, L⁶², L⁶³, L⁶⁴, L⁶⁵, L⁶⁶ and L⁶⁸ is a linker independently selected from the group of

W₁ and W₂ are each integers ≥ 0 such that their sum (W₁ + w₂) is 1 , 2 or 3; each W is independently selected from -O-, -S-, and -NR_L-;

R₃ is C_xHy where x is an integer of 0 to 20 and y is an integer of 1 to 2x+1 ; and

X is -O-, -S-, -S(O)-, -SO₂-, -N(R₃)-, -CO₂-, -CO-, -CON(R₃)-, -C0N(R₃)-E-, -N(R₃)-, -CO₂-E-, -N(R₃)CO-, -N(R₃)CO-E-, -N(R₃)CON(R₃)-, -N(R₃)C0N(R₃)-E- wherein E is an amino acid or a polypeptide of 1-10 amino acids, and R₃ is C_xH_y , x being an integer <20 and y being an integer < (2x+1 ); and

G₁ is C_WH_Z wherein w is an integer < 10 and z is an integer < (2w+2-b);

X is -0-, -S-, -S(O)-, -SO₂-, -N(R₃)-, -CO₂-, -CO-, -CON(R₃)-, -CON(Ra)-E-, -N(R₃)-, -CO₂-E-, -N(R₃)CO-, -N(R₃)CO-E-, -N(R₃)CON(R₃)-, -N(R₃)C0N(R₃)-E- wherein E is an amino acid or a polypeptide of 1-10 amino acids, and R₃ is C_xH_y , x being an integer <20 and y being an integer < (2x+1 ); and

G₁ is C_WH_Z wherein w is an integer < 10 and z is an integer < (2w+2-b);

each L², L³, L⁵, L⁶, L¹¹, L¹², L¹⁸, L²⁰, L²¹, L²², L²⁵, L³³, L³⁸, L⁴³, L⁴⁴, L⁴⁵, L⁴⁶, L⁴⁷, L⁴⁸ and L⁴⁹ is a linker independently selected from the group of

wherein: p is O or an integer < 10, preferably O, 1 , 2, 3 or 4, more preferably O or 1 ; each R_L is independently selected from the group consisting of H, ethyl and methyl, preferably H; each T² is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, acyl, acyloxy, carboxy, carbamoyl, sulfuryl, sulfinyl, sulfenyl, sulfonyl, mercapto, amino, hydroxyl, cyano and nitro; s is 1 , 2, 3 or 4; and

G₁ is C_WH_Z wherein w is an integer < 10 and z is an integer < (2w+2-b);

with the proviso that if R₁ is

, wherein R_G is H, C_1-6 alkyl, C_3-12 branched alkyl, C_3-8 cycloalkyl, C_1-6 substituted alkyl, C_3-8 substituted cycloalkyl, aryl, substituted aryl, aralkyl, C_1-6 heteroalkyl, substituted C_1-6 heteroalkyl, C_1-6 alkoxy, phenoxy and C_1-6 heteroalkoxy, then at least one of R³ or R⁵ is not hydrogen; and with the further proviso that at least one of L¹ L² L³ L⁴ L⁵ L⁶ L⁷ L⁸ L⁹ L¹⁰ L¹¹ L¹² L¹³ L¹⁴

■ 1155 11 1166 11 1177 11 1188 11 1199 ■■ 2200 ■■ 2211 ■■ 2222 ■ 23 ■ 24 ■ 25 ■ 26 ■ 27 ■ 28 ■ 29 ■ 30 ■ 31 ■ 32 ■ 33 ■ 34 ■ 35 ■ 36 ■ 37 ■ 38

■ 3399'' 1I 44θθ'' 1I 4411 '' 1I 4422' ■i 4433'' ■i 4444'' ■i 4455'' ■i 4466'' i 47' i 48' i 49' i 5θ' i 51 ' i 52 i 53 i 54' i 55' i 56' i 57' i 58' i 59' i 6θ' i 61 ' i 62

L⁶³; L⁶⁴; L⁶⁵; L⁶* I." L⁶⁸ and L⁶⁹ is present.

It is also conceivable according to the present invention to use a pH-sensitive linker that is cleaved only at a predetermined range of pH. In one embodiment, the pH-sensitive linker is a base-sensitive linker that is cleaved at a basic pH ranging from about 7 to about 9. According to another embodiment, the linker is an acid-sensitive linker that is cleaved at an acidic pH ranging from about 7.5 to about 4, preferably from about 6.5 and lower. It is hypothesized that such an acid-sensitive linker would allow a specific release of the glycopeptide or lipoglycopeptide antibiotic mostly at a site of bacterial infection because it is known that, acidification of tissues commonly occurs during infection (O'Reilley et al., Antimicrobial Agents and Chemotherapy (1992), 36(12): 2693-97).

A covalent bond or a non-cleavable linker may also covalently couple the macromolecular group P bearing at least one poly(ethylene glycol) chain to a glycopeptide or lipoglycopeptide A. Such bond or linker would be selected such that it would not be cleaved. It is hypothesized that for such compounds the macromolecular group P would remain tethered to a glycopeptide or lipoglycopeptide antibiotic and the whole compound would maintain its ability to exert its antibacterial effect.

The compounds having the formula P_aL_pA_Y according to the invention described in the Exemplification section, are based on oritavancin but additional compounds based on dalbavancin, telavancin, teicoplanin and chloroeremomycin although not described in the exemplification section are included as part of the invention.

Further, the present invention covers the compounds of Formula I and of Formula II, as well as pharmaceutically acceptable salts, esters and prodrugs thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1 ,4-dioates, hexyne-1 ,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, gamma-hydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1 -sulfonates, naphthalene-2- sulfonates, and mandelates.

If the inventive compound is a base, the desired salt may be prepared by any suitable method known to the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acids such as glucuronic acid and galacturonic acid, alpha-hydroxy acids such as citric acid and tartaric acid, amino acids such as aspartic acid and glutamic acid, aromatic acids such as benzoic acid and cinnamic acid, sulfonic acids such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

If the inventive compound is an acid, the desired salt may be prepared by any suitable method known to the art, including treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary), an alkali metal or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary and tertiary amines, and cyclic amines such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium. In the case of compounds, salts, or solvates that are solids, it is understood by those skilled in the art that the inventive compounds, salts, and solvates may exist in different crystal forms, all of which are intended to be within the scope of the present invention.

The inventive compounds may exist as single stereoisomers, racemates and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the present invention. Preferably, the inventive compounds are used in optically pure form.

It is conceivable that the compounds of the Formula I and/or of Formula Il be administered in the form of a prodrug which is broken down in the human or animal body to give a compound of the Formula I or of Formula II. Examples of prodrugs include in vivo hydrolysable esters of a compound of the Formula I and/or of Formula II.

An in vivo hydrolysable ester of a compound of the Formula I and/or of Formula Il containing carboxy or hydroxy group is, for example, a pharmaceutically-acceptable ester which is hydrolyzed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically-acceptable esters for carboxy include (1-6C)alkoxymethyl esters for example methoxymethyl, (1-6C)alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, (3-8C)cycloalkoxycarbonyloxy(1-6C)alkyl esters for example 1- cyclohexylcarbonyloxyethyl; 1 ,3-dioxolen-2-onylmethyl esters for example 5-methyl-1 ,3- dioxolen-2-onylmethyl; and (1-6C)alkoxycarbonyloxyethyl esters for example 1- methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention.

An in vivo hydrolysable ester of a compound of the Formula I and/or of Formula Il containing a hydroxy group includes inorganic esters such as phosphate esters and alpha- acyloxyalkyl ethers and related compounds which as a result of in vivo hydrolysis of the ester break down to give the parent hydroxy group. Examples of alpha-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and Λ/-(dialkylaminoethyl)-Λ/-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl. C) Methods of preparation

The inventive compounds, and their salts, solvates, crystal forms, active metabolites, and prodrugs, may be prepared by employing the techniques available in the art using starting materials that are readily available. Certain novel and exemplary methods of preparing the inventive compounds are described in the Exemplification section. Such methods are within the scope of this invention.

D) Antimicrobial compositions and methods of treatment

A related aspect of the invention concerns the use of compounds of the invention as an active ingredient in a therapeutic or anti-bacterial composition for treatment or prevention purposes.

Pharmaceutical compositions

The compounds of the present invention may be formulated as pharmaceutically acceptable compositions.

The present invention provides for pharmaceutical compositions comprising a compound of the present invention (e.g., those compounds of Formula (I) and (II)) in combination with a pharmaceutically acceptable carrier or excipient. Preferably, the compound of the present invention is a therapeutically effective amount of the compound. Such carriers include, but are not limited to saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof.

Acceptable methods of preparing suitable pharmaceutical forms of the pharmaceutical compositions according to the invention are known to those skilled in the art. For example, pharmaceutical preparations may be prepared following conventional techniques of the pharmaceutical chemist involving steps such as mixing, granulating, and compressing when necessary for tablet forms, or mixing, filling, and dissolving the ingredients as appropriate, to give the desired products for various routes of administration.

The compounds and compositions of the invention are conceived to have a broad spectrum of activity, including antibiotic resistant strains, mostly against both Gram-positive (e.g. Staphylococcus aureus, Staphylococcus epidermis, Streptococcus pyogenes, Enterococcus faecalis).

Pharmaceutical compositions and a second therapeutic agent

A wide range of second therapeutic agents, such as antibiotics, can be used in combination with the compounds, compositions and methods of the present invention. Antibiotics used as second therapeutic agents may act by interfering with cell wall synthesis, plasma membrane integrity, nucleic acid synthesis, ribosomal function, folate synthesis, etc. A non-limiting list of useful antibiotics with which the compounds and compositions might be combined includes: Rifamycins, sulfonamides, beta-lactams, tetracyclines, chloramphenicol, aminoglycosides, macrolides, glycopeptides, streptogramins, quinolones, fluoroquinolones, oxazolidinones and lipopeptides. In particular, tetracycline, tetracycline derived antibacterial agents, glycylcycline, glycylcycline derived antibacterial agents, minocycline, minocycline derived antibacterial agents, oxazolidinone antibacterial agents, aminoglycoside antibacterial agents, quinolone antibacterial agents, vancomycin, vancomycin derived antibacterial agents, teicoplanin, teicoplanin derived antibacterial agents, eremomycin, eremomycin derived antibacterial agents, chloroeremomycin, chloroeremomycin derived antibacterial agents, daptomycin, daptomycin derived antibacterial agents, rifamycin and rifamycin derived antibacterial agents are preferred.

Methods for inhibiting bacterial growth

According to a related aspect, the present invention concerns methods of inhibiting bacterial growth, and more particularly growth of Gram-positive bacteria. The method comprises contacting the bacteria for the purpose of such inhibition with an effective amount of a glycopeptide or lipoglycopeptide containing at least one poly(ethylene glycol) chain as a compound or a composition according to the invention (or a pharmaceutically acceptable prodrug, salt, active metabolite, or solvate thereof). For example, one can inhibit cell wall biosynthesis in a Gram-positive bacterium by contacting such a bacterium with a compound of the invention.

The contacting may be carried out in vitro (in biochemical and/or cellular assays), in vivo in a non-human animal, in vivo in mammals, including humans and/or ex vivo (e.g. for sterilization purposes).

The activity of the inventive compounds as inhibitors of cell-wall biosynthesis may be measured by any of the methods available to those skilled in the art, including in vivo and in vitro assays. Some examples of suitable assays have been described for measurement of binding to cell-wall fragments (Chu et al. Journal of Organic Chemistry (1992), 57:3524- 3525. Cooper et al, Chemical Communications (1997), 1625-1626), binding to whole cell walls (Cegelski et al. Journal of Molecular Biology (2006), 357; 1253-1262), inhibition of enzymatic processes leading to cell wall components (Branstrom et al. FEMS Microbiology Letters (2000); 191 :187-190. Leimkuhler et al. Journal of the American Chemical Society (2005); 127: 3250 - 3251 ) and inhibition of cell wall biosynthesis at the cellular level (Higgins et al., Antimicrobial Agents and Chemotherapy (2005); 49: 1 127-1134).

A related aspect of the invention concerns the use of a compound of the invention as an active ingredient in a pharmaceutical, therapeutic or anti-bacterial composition for treatment purposes. As defined above, "treating" or "treatment" means at least the mitigation of a disease condition or symptom associated with a bacterial infection in a subject, including mammals such as a human, that is alleviated by a reduction of growth, replication, and/or propagation of any bacterium, such as Gram-positive organisms, and includes curing, healing, inhibiting, relieving from, improving and/or alleviating, in whole or in part, the disease condition.

The pharmaceutical compositions may be administered in any effective, convenient manner including, for instance, administration by topical, parenteral, oral, anal, intravaginal, intravenous, intraperitoneal, intramuscular, intraocular, subcutaneous, intranasal, intrabronchial, or intradermal routes among others.

In therapy or as a prophylactic, the compound(s) of the invention and/or pharmaceutically acceptable prodrugs, salts, active metabolites and solvates may be administered to an individual as an injectable composition, for example as a sterile aqueous dispersion, preferably isotonic. Alternatively the composition may be formulated for topical application for example in the form of ointments, creams, lotions, eye ointments, eye drops, ear drops, mouthwash, impregnated dressings and sutures and aerosols, and may contain appropriate conventional additives, including, for example, preservatives, solvents to assist drug penetration, and emollients in ointments and creams. Such topical formulations may also contain compatible conventional carriers, for example cream or ointment bases, and ethanol or oleyl alcohol for lotions. Such carriers may constitute from about 1% to about 98% by weight of the formulation; more usually they will constitute up to about 80% by weight of the formulation.

Alternative means for systemic administration include transmucosal and transdermal administration using penetrants such as bile salts or fusidic acids or other detergents. In addition, if a compound of the present invention can be formulated in an enteric or an encapsulated formulation, oral administration may also be possible. Administration of these compounds may also be topical and/or localized, in the form of salves, pastes, gels, and the like.

While the treatment can be administered in a systemic manner through the means described above, it may also be administered in a localized manner. For example, the treatment may be administered directly, such as through a topical composition or directly into a subcutaneous or other form of wound.

A dose of the pharmaceutical composition contains at least a pharmaceutically- or therapeutically-effective amount of the active compound (i.e., a compound of Formula (I), of Formula (II) and/or a pharmaceutically acceptable prodrug, salt, active metabolite, or solvate thereof), and is preferably made up of one or more pharmaceutical dosage units. The selected dose may be administered to a mammal, for example, a human patient, in need of treatment. A "therapeutically effective amount" is intended to mean that amount of a compound of Formula (I) and/or of Formula (II) (and/or a pharmaceutically acceptable prodrug, salt, active metabolite, or solvate thereof) that confers a therapeutic effect on the subject treated. The therapeutic effect may be objective (i.e. measurable by some test or marker (e.g. lower bacterial count)) or subjective (i.e. the subject gives an indication of or feels an effect).

The amount that will correspond to a "therapeutically effective amount" will vary depending upon factors such as the particular compound, the route of administration, excipient usage, the disease condition and the severity thereof, the identity of the mammal in need thereof, and the possibility of co-usage with other agents for treating a disease. Nevertheless the therapeutically effective amount can be readily determined by one of skill in the art. For administration to mammals, and particularly humans, it is expected that the daily dosage level of the active compound will be from 0.1 mg/kg to 200 mg/kg, typically around 1- 5 mg/kg. The physician in any event will determine the actual dosage that will be most suitable for an individual and will vary with the age, weight and response of the particular individual. The above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.

The invention provides a method of treating a subject in need of treatment wherein a glycopeptide or lipoglycopeptide antimicrobial molecule having a macromolecular moiety bearing at least one polyethylene is administered to the subject. The said macromolecular moieties are coupled to the glycopeptide or lipoglycopeptide antimicrobial molecule through a linker, which may or may not be cleavable. Preferably the subject is a mammal, such as a human. The method of treatment may also be applied in a veterinary aspect, to animals such as farm animals including horses, cattle, sheep, and goats, and pets such as dogs, cats and birds.

Although the invention is preferably directed to the prevention and/or treatment of bacterial infections, the invention encompasses therapeutic and prophylactic methods against other diseases caused by or related to bacterial infection, including but not limited to otitis, conjunctivitis, pneumonia, bacteremia, sinusitis, pleural emphysema and endocarditis, low grade infections in the vicinity of calcifications of atherosclerotic vessels, osteomyelitis and meningitis. In such methods, an effective therapeutic or prophylactic amount of an antibacterial compound and/or composition as defined hereinbefore, is administered to a mammal (preferably a human) in an amount sufficient to provide a therapeutic effect and thereby prevent or treat the infection of the mammal. Exact amounts can be routinely determined by one skilled in the art and will vary depending on several factors, such as the particular bacterial strain involved and the particular antibacterial compound used. Prophylaxis and prevention

An additional use that is particularly contemplated for the compounds invention is for prophylaxis and prevention purposes. Indeed, many surgeons consider that humans should be considered for antibiotic prophylaxis before a procedure to mitigate the potential for an infection resulting from ineffective sterility during the procedure. Deep infection is a serious complication sometimes requiring subsequent medical interventions and is accompanied by significant morbidity and mortality. The compounds and compositions of the invention may therefore be used as a replacement for, or in addition to, prophylactic antibiotics in this situation. For instance, the compounds and/or compositions of the invention may be administered by injection to achieve a systemic and/or local effect against relevant bacteria shortly before an invasive medical treatment, such as surgery or insertion of an in-dwelling device (e.g. joint replacement (hip, knee, shoulder, etc.)). Treatment may be continued after invasive medical treatment, such as post-operatively or during the in-body time of the device.

In each instance, the compound(s) of the invention could be administered once, twice, thrice or more, from 1 , 2, 3, 4, 5, 6, 7 days or more, up to 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 hour or less before surgery for permitting an advisable systemic or local presence of the compounds, preferably in the areas potentially exposed to bacterial contamination during the surgical procedure. The compound(s) may be administered after the invasive medical treatment for a period of time, such as 1 , 2, 3, 4, 5 or 6 days, 1 , 2, 3 or more weeks, or for the entire time in which the device is present in the body.

E) Methods of preparation

The inventive compounds, and their salts, solvates, crystal forms, active metabolites, and prodrugs, may be prepared by employing the techniques available in the art using starting materials that are readily available. Certain novel and exemplary methods of preparing the inventive compounds are described in the Exemplification section below. Such methods are within the scope of this invention.

EXAMPLES

The Examples set forth herein below provide exemplary syntheses of certain representative compounds of the invention. Also provided are exemplary methods for assaying the minimum inhibitory concentration (MIC) of the compounds of the invention against microorganisms, and methods for testing in vivo activity. Example 1 : Synthesis of Oritavancin poly(ethylene glycol) conjugates A) General Experimental Procedures

A 1) preparation of PEG building blocks

Poly(ethylene glycol) chains can be extended to the parent acids III by alkylation of the hydroxyl terminus by a haloalkanoate ester in the presence of a non-nucleophilic base followed by acid or base mediated saponification. Alternatively, they can be oxidized to the parent acids IV.

H₂

IV

VII

These polymeric acid III or IV can be extended by the insertion of an amino acid (x=1 ) or a short peptide (x>1 ) in polymeric acids V and Vl. This transformation can be made by coupling III or IV with an amino acid protected at the carboxylate function in the presence of a standard peptide coupling reagent such as a carbodiimide or an activated uronium salt. The carboxylate of the coupled amino acid can then be deprotected under standard conditions and this process may be repeated to extend the chain further. A similar process can be used but starting with a coupling to the ε amino group of a lysine protected at both the carboxylate and the α-amino acid groups. This can give, after deprotection, a polymeric acid of general formula VII, which can be further extended to acids of general formula VIII. H . X

R A°~ ,O

O' R .-(⁰ - O'

IX X = alkyl or arylsulfonate X X = halogen

XIV m = 1 XI Y = N₃

XV m = 2 XII Y = N-phthalimidyl

XIII Y = CN

A terminal hydroxyl group on a poly(ethylene glycol) chain, such as I, can also be converted to a terminal amino group by conversion of the hydroxyl group to a suitable leaving group such as a sulfonate ester (IX) or a halogen (X) followed by nucleophilic displacement with a nucleophile such as an azide salt, an imide salt or a cyanide salt, to respectively give compounds Xl, XII or XIII. Deprotection of the phthalimide XII under standard conditions (treatmemt with hydrazine or methylamine) or reduction of azide Xl will result in amino terminated poly(ethylene glycol) chains such as XIV, while reduction of nitrile XIII will result in amino terminated poly(ethylene glycol) chains such as XV.

O = 1 = O 1

1 ) coupling

2) deprotection repeat x times

Amines XIV and XV can be further extended by the addition of an amino acid or a short peptide sequence by coupling, under standard peptide coupling conditions, to the ε carboxylate of an aspartic acid or a glutamic acid protected at both the α-carboxylate and the α-amino acid groups. Deprotection of the carboxylate can result directly in acids of the general formula XIV-XIX. These acids may be further extended by cycles of coupling to the a amino group of an amino acid and deprotection, to give acids of general formula XX-XXIII.

O O

Polymer X O, H Polymer A. LG

IM-VIII, XVI-XXIII XXIV LG = Leaving group

Polymeric acids IH-VIII and XVI-XXIII can be converted to their parent activated esters, of general formula XXIV, by treatment with a coupling reagent such as a carbodiimide and a compound with an activated hydroxyl group such as N- hydroxysuccinimide, N-hydroxybenzotriazole, p-nitrophenol and o,p-dinitrophenol.

XXIX LG = leaving group XXVIII XXVII LG = leaving group

Polymeric acids IH-VIII and XVI-XXIII can also be converted to their parent para- or ortho-hydroxymethylphenyl esters, respectively of the general formula XXVI and XXVIII, by activation through a form such as XXV which reacts specifically with phenoxides generated in situ in the presence of non-phenolic alcohol groups. The remaining hydroxymethyl group can then be further derivatized as activated carbonates such as XXVII and XXIX, by treatment with an diactivated carbonate, such as N,N'-disuccinimidyl carbonate, or a chloroformate, such p-nitrophenyl chloroformate or o,p-dinitrophenyl chloroformate, in the presence of a suitable tertiary amine base.

XXXIV LG = leaving group XXXlIl XXXIl LG = leaving group

Polymeric alcohols such as I can be converted to activated carbonates of the general formula XXX by treatment with an diactivated carbonate, such as N,N'-disuccinimidyl carbonate, or a chloroform ate, such p-nitrophenyl chloroformate or o,p-dinitrophenyl chloroform ate, in the presence of a suitable tertiary amine base. Such activated carbonates XXX can then be reacted with an o- or a p-aminobenzyl alcohols to give N- (hydroxymethylphenyl)carbamates of general formulae XXXI and XXXIII. The remaining hydroxymethyl group can then be further derivatized as activated carbonates such as XXXII and XXXIV, by the same treatment with a diactivated carbonate or a chloroformate in the presence of a suitable tertiary amine base.

XXXVIII LG = leaving group XXXVII XXXVI LG = leaving group Amino terminated polymeric chains, such as XIV and XV, can be treated with an o- or p-formyl phenyl chloroformate in the presence of a suitable tertiary amine base to furnish the parent carbamates, which upon reduction with a hydride delivering agent, can be converted to O-(hydroxymethylphenyl)carbamates of general formulae XXXV and XXXVII. The remaining hydroxymethyl group can then be further derivatized as activated carbonates such as XXXVI and XXXVIII, by the previously mentioned treatment with a diactivated carbonate or a chloroformate in the presence of a suitable tertiary amine base.

Pol

XXXIX

Amino terminated polymeric chains, such as XIV and XV, can also be converted to α- haloalkanamides of general formula XXXIX by treatment with α-haloalkanoic acids under standard peptide coupling conditions or an α-haloalkanoyl halide in the presence of a tertiary amine base.

R O

Hal' O SEt

_Polyme

LG

IH-VIII, XVI-XXIII XXXX XXXXI LG=leaving group

Polymeric chains terminated with a carboxylic acid functionality such as IM-VIII and XVI-XXIII can be converted to 1-(2-thiabutyryloxy)alkyl esters of general formula XXXX after reaction with the parent S-ethyl 0-1-haloalkyl carbon othioate in the presence of a base, generally an alkali metal salt. Activated acyloxylalkyl carbonates of the general formula XXXXI can be obtained by transformation of the S-ethyl group into a halide, by treatment with sulfuryl halides, or the subsequent convertion of this halide into an N-oxysuccinimide, a p-nitrophenoxy or an o,p-dinitrophenoxy group by treatment with the corresponding hydroxylamine or alcohol in the presence of a base.

A-2) Synthesis of oritavancin poly(ethylene glycol) conjugates

For the purposes of this discussion, oritavancin will be schematically represented, with only the relevant functional groups shown, as:

Whereby the letters correlate the functional groups on oritavancin and its schematic representation.

XXXXII

Polyme

XXVII, XXIX, XXXII, XXXIV, XXXVI, XXXVIII

XXXXIII

XXXXIV Treatment of Oritavancin with polymeric chains terminated with activated esters of general formula XXIV, activated benzyl carbonates of general formulae XXVII, XXIX, XXXII, XXXIV, XXXVI and XXXVIII and activated acyloxyalkyl carbonates of general formula XXXXI, in the presence of a base affords oritavancin poly(ethylene glycol) conjugates respectively of the general formulae XXXXII, XXXXIII and XXXXIV. The site of attachment on oritavancin is expected to be the N-methyl leucyl residue based on model systems.

Polymer — N

XXXIX

XXXIX

Polyme

XXXXIV XXXXVII

Oritavancin poly(ethylene glycol) conjugates respectively of the general formulae XXXXII, XXXXIII and XXXXIV can be further conjugated to an additional polymeric chain by treatment with α-haloalkanamide of general formula XXXIX in the presence of a base, generally an alkali metal salt.

In these procedures, whenever protecting groups are used, they can be selected, put on and removed according to the coventional methods described in the literature, for instance as reviewed in "Protective Groups in Organic Synthesis", Greene, T. W. and Wuts, P. M. G., Wiley-lnterscience, New York, 1999. β) Detailed Experimental Procedures

Scheme 1. Preparation of α-methyl-ω-ti -N-succinimidyloxy-acet^-oxyJpolytethylene glycol) (4).

MPE

α-methyl-ω-(1 -t-butoxy-acet-2-oxy)poly(ethylene glycol) (2). A solution of poly(ethylene glycol) monomethyl ether (1a, average MW-5000 g.mol^"1, 31 g, ca 6.2 mmoles) in 300 ml. of toluene was heated to reflux in a setup fitted with a Dean-Stark trap for 1 Y₂ h. During this time toluene was withdrawn from the trap periodically, to a total volume of 100 ml_. The mixture was cooled to 8O⁰C (bath temperature) and sodium t-butoxide (3 g, 31.2 mmoles) was added in one portion. The mixture was stirred at the same temperature for another 1 Y-≥ h before the addition of t-butyl bromoacetate (9 ml_, 61 mmoles). The mixture was then stirred at reflux for 18h, and filtered hot through a pad of celite. The pad was rinsed with 3x100 ml. of hot toluene (~ 7O⁰C) and the combined filtrates were concentrated in vacuo. The resulting oil was taken up in 30 ml. of methanol and added to 400 ml. of diethyl ether under vigorous stirring. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. This gave the polymeric t- butyl acetate 2 as a cream coloured amorphous powder (30.8 g, ca 6.0 mmoles, 97% yield).

¹H NMR (400 MHz, CDCI₃) δ 1.47 (s, 9H), 3.38 (s, 3H), 3.45-3.84 (m, ca 450H), 4.01 (s, 2H).

α-methyl-ω-(carboxymethoxy)poly(ethylene glycol) (3). Compound 2 (5.2 g, ca 1.0 mmol) was dissolved in CH₂CI₂ (50 ml.) and trifluoroacetic acid (25 ml.) was added. The mixture was stirred at room temperature for 6 h and concentrated in vacuo. The resulting oil was taken up in the minimum amount of CH₂CI₂ and added to 400 ml. of diethyl ether under vigorous stirring. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. The powder was then recrystallized from isopropanol to give the polymeric acid 3 (4.7 g, ca 9.3x10^"4 mol, 91 % yield) as a white powder. ¹H NMR (400 MHz, CDCI₃) δ 3.38 (s, 3H), 3.45-3.84 (m, ca 450H), 4.16 (s, 2H). α-methyl-ω-(1 -N-succinimidyloxy-acet^-oxyJpolytethylene glycol) (4).

Compound 3 (4.7g, ca 9.3x10^"4 mol) and N-hydroxysuccinimide (1.0 g, 8.7 mmoles) were dissolved in CH₂CI₂ (50 mL) and 4.2 mL (24.1 mmoles) of DIPEA were added. The mixture was cooled in an ice bath and 2.3 g (12 mmoles) of N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride were added in small portions over 2-3 min. The reaction mixture was left stirring in the same bath to come to room temperature on its own and remain there for a total of 20 h. It was partially concentrated down to a volume of -10 mL and added to 200 mL of diethyl ether under vigorous stirring. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. The powder was then recrystallized from isopropanol to give the polymeric N-hydroxysuccinimide ester 4 (3.4 g, ca 6.6x10^"4 mol, 71 % yield) as a white powder. ¹H NMR (400 MHz, CDCI₃) δ 2.83 (broad s, 4H), 3.38 (s, 3H), 3.45-3.84 (m, ca 450H), 4.53 (s, 2H).

Scheme 2. Preparation of oritavancin poly(ethylene glycol) conjugate 6

Oritavancin poly(ethylene glycol) conjugate 6. To a solution of oritavancin diphosphate (5, 1.015 g, 0.51 mmol) and triethylamine (2.84 mL, 20.40 mmol) in anhydrous DMF (35 mL) was added 4 A molecular sieves (4.0 g), followed by PEG linker 4 (1.312 g, 0.255 mmol), and the resulting mixture was stirred at room temperature for 18 h. The solution was filtered through Celite and washed with DMF (25 mL), the PEG derivative was precipitated by the addition of diethyl ether. After standing for 1 h at 0 °C, the precipitate was collected, washed copiously with diethyl ether, dried in vacuo and crystallized from DMF/EtOH (40/40 mL, after standing overnight at 0 °C), filtered and dried in vacuo. The crude product was dialyzed [Spectra/Por7 Dialysis membrane with MWCO: 3,500] in HCO₂H/H₂O (pH = 4.5) for 48 h and lyophilized to yield polymeric compound 6 (1.13 g, ca 1.64x10^"4, 64% yield, 26% oritavancin by weight). ¹H NMR (400 MHz, DMSO-d₆) δ 0.8-1.90 (m, 20H), 2.1-2.3 (m, 5H), 2.5-2.8 (m, 8H), 3.0-3.80 (m, ca 492H), 3.9-4.50 (m, 12H), 4.6- 4.9 (m, 2H), 5.20 (m, 2H), 5.45-5.80 (m, 3H), 6.24 (s, 1 H), 6.42 (s, 1 H), 6.78 (m, 2H), 7.16- 7.92(m, 12H).

Scheme 3. Preparation of α-methyl-ω-(2-bromoacetamido)poly(ethylene glycol) (10).

MsCI, DIPEA BrCH₂COBr Q

CH₂CI₂ DIPEA, CH₂CI₂ J _Rr

P-OH ^ p__χ ^ p__N^^Br

H

_{1 a P} - _MPEfi/c_kx 10 ia κ - MKbb bK

1b P = MPEG(2k)

α-methyl-ω-methanesulfonyloxypoly(ethylene glycol) (7a). Methanesulfonyl chloride (3.5 ml_, 35.8 mmoles) was added dropwise to a solution of poly(ethylene glycol) monomethyl ether (1a, 10.3 g, average MW 5000 g.mol^"1, ca 2.1 mmoles) and triethylamine (6.5 ml_, 46.6 mmoles) in CH₂CI₂ (40 ml.) cooled in an ice bath. The mixture was stirred in the same bath which was left to come to room temperature on its own and stay there for a total of 18h. The mixture was poured in 40OmL of diethyl ether under a vigorous stir. After standing for 15 min, the precipitate was collected on a pad of celite and washed copiously with diethyl ether. It was then washed through the pad with 4x 150 ml. of warm (-7O⁰C) toluene. The resulting solution was concentrated in vacuo and the residue was taken up in the minimum amount of CH₂CI₂ and added to 40OmL of diethyl ether under a vigorous stir. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. This resulted in the polymeric mesylate 7a (10.4g, ca 2.1 mmoles, quant.) as a white amorphous powder. ¹H NMR (400 MHz, CDCI₃) δ 3.08 (s, 3H), 3.38 (s, 3H), 3.45-3.84 (m, ca 450H), 4.38 (m, 2H).

α-methyl-ω-methanesulfonyloxypoly(ethylene glycol) (7b). Poly(ethylene glycol) monomethyl ether (1b, 10.0 g, average MW 2000 g.mol^"1, ca 5 mmoles) was subjected to the same procedure producing 7a from 1a, except the precipitation step was followed by standing in a dry ice/acetone bath, to afford polymeric mesylate 7b (9.9 g, ca 4.8 mmoles, 95% yield). ¹H NMR (400 MHz, CDCI₃) δ 3.08 (s, 3H), 3.38 (s, 3H), 3.45-3.84 (m, ca 200H), 4.38 (m, 2H).

α-methyl-ω-phthalimidopoly(ethylene glycol) (8a). A solution of the polymeric mesylate 7a (2.1 g, ca 4.1x10^"4 mol) and potassium phthalimide (800 mg, 4.3 mmoles) in 10 ml. of DMF was stirred at 7O⁰C for 24h. The mixture was poured in 20OmL of diethyl ether under a vigorous stir. After standing for 15 min, the precipitate was collected on a pad of celite and washed copiously with diethyl ether. It was then washed through the pad with 4x 75 ml. of warm (-7O⁰C) toluene. The resulting solution was concentrated in vacuo and the residue was taken up in the minimum amount of CH₂CI₂ and added to 20OmL of diethyl ether under a vigorous stir. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. This resulted in the polymeric phthalimide 8a (1.94 g, ca 3.8x10^"4 mol, 92% yield) as a white amorphous powder. ¹H NMR (400 MHz, CDCI₃) δ 3.38 (s, 3H), 3.45-3.84 (m, ca 450H), 3.89 (t, J = 6.0 Hz, 2H), 7.73 (m, 2H), 7.84 (m, 2H).

α-methyl-ω-phthalimidopoly(ethylene glycol) (8b). Polymeric mesylate 7b (2.0 g, ca 9.6x10^"4 moles) was subjected to the same procedure producing 8a from 7a, except the precipitation step was followed by standing in a dry ice/acetone bath, to afford polymeric amine 8b (1.87 g, ca 8.8X10^"4 moles, 91% yield). ¹H NMR (400 MHz, CDCI₃) δ 3.38 (s, 3H), 3.45-3.84 (m, ca 200H), 3.89 (t, J = 6.0 Hz, 2H), 7.72 (m, 2H), 7.84 (m, 2H).

α-methyl-ω-aminopoly(ethylene glycol) (9a). A solution of polymeric phthalimide 8a (1.94 g, ca 3.8x10^"4 mol) in 10 mL of ethanol was heated until all the solid dissolves, at which point hydrazine hydrate (500 μL, 10.3 mmoles) was added. The mixture was heated to reflux for 6 h. The mixture was poured in 20OmL of diethyl ether under a vigorous stir. After standing for 15 min, the precipitate was collected on a pad of celite and washed copiously with diethyl ether. It was then washed through the pad with 4x 75 mL of warm (-7O⁰C) toluene. The resulting solution was concentrated in vacuo and the residue was taken up in the minimum amount of CH₂CI₂ and added to 20OmL of diethyl ether under a vigorous stir. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. This resulted in the polymeric amine 9a (1.71 g, ca 3.4x10^" ⁴ mol, 90% yield) as a white amorphous powder. ¹H NMR (400 MHz, CDCI₃) δ 2.86 (t, J = 5.1 Hz, 2H), 3.37 (s, 3H), 3.45-3.84 (m, ca 450H). α-methyl-ω-aminopoly(ethylene glycol) (9b). Polymeric mesylate 8b (1.87 g, ca 8.8x10^"4 moles) was subjected to the same procedure producing 9a from 9a, except the precipitation step was followed by standing in a dry ice/acetone bath, to afford polymeric amine 9b (1.61 g, ca 8.IxIO^"4 moles, 92% yield). ¹H NMR (400 MHz, CDCI₃) δ 2.89 (t, J = 5.3 Hz, 2H), 3.38 (s, 3H), 3.45-3.84 (m, ca 200H).

α-methyl-ω-(2-bromoacetamido)poly(ethylene glycol) (10). Bromoacetyl bromide (350 μl_, 4 mmoles) was added dropwise to a solution of the polymeric amine 9a (1.71 g, ca 3.4x10^"4 mol) and diisopropylethylamine (700 μl_, 4 mmoles) in CH₂CI₂ (10 ml.) cooled in an ice bath. The mixture was stirred in the same bath which was left to come to room temperature on its own and stay there for a total of 18h. The mixture was poured in 20OmL of diethyl ether under a vigorous stir. After standing for 15 min, the precipitate was collected on a pad of celite and washed copiously with diethyl ether. It was then washed through the pad with 4x 75 ml. of warm (-7O⁰C) toluene. The resulting solution was concentrated in vacuo and the residue was taken up in the minimum amount of CH₂CI₂ and added to 20OmL of diethyl ether under a vigorous stir. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. This resulted in the polymeric bromoacetamide 7 (1.85 g, ca 3.6x10^"4 mol, quant.), as a dark cream colored amorphous powder slightly contaminated with diisopropylethylammonium hydrobromide. ¹H NMR (400 MHz, CDCI₃) δ 3.38 (s, 3H), 3.45-3.84 (m, ca 450H), 3.88 (s, 2H).

Scheme 4. Preparation of oritavancin poly(ethylene glycol) conjugate 11

11

Oritavancin poly(ethylene glycol) conjugate 11. To a solution of 6 (170 mg, ca 2.48x10^"5 mol), and Cs₂CO₃ (8.08 mg, ca 2.48x10^"5 mol) in anhydrous DMF (10 ml.) was added PEG linker 10 (127 mg, ca 2.48x10^"5 mol). After stirring for 48 h at room temperature, the PEG derivative was precipitated by the addition of diethyl ether. After standing for 1 h at 0 °C, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo to give polymeric compound 11 (228 mg, ca 1.90x10^"5, 76% yield). The crude product was dialyzed [Spectra/Por7 Dialysis membrane with MWCO: 3,500] in HCO₂H/H₂O (pH = 4.5) for 24 h and lyophilized to yield polymeric compound 11 (228 mg, ca 1.92x10^"5, 76% yield, 11.8 %oritavancin by weight). ¹H NMR (400 MHz, DMSO-d₆) δ 0.8-0.94 (m, 8H), 1.1-1.2 (m, 8H), 1.22-1.92 (m, 4H), 2.1-2.7 (m, 9H), 3.16-3.80 (m, ca 1362H), 4.0-4.40 (m, 10H), 4.4-4.9 (m, 5H), 5.20 (m, 3H), 5.45-5.80 (m, 4H), 6.24 (s, 1 H), 6.42 (s, 1 H), 6.78 (m, 2H), 7.16-7.42 (m, 3H), 7.50 7.60 (m, 5H), 7.70-7.90 (m, 6H). Scheme 5. Preparation of αjω-bisti -N-succinimidyloxy-acet^-oxyJpolytethylene glycol) (15).

\

PEG⁽ ) ' ₂

α,ω-bis(1-tbutoxy-acet-2-oxy)poly(ethylene glycol) (13). A solution of poly(ethylene glycol) (average MW-20000 g.mol^"1, 30 g, ca 1.5 mmoles) in 300 mL of toluene was heated to reflux in a setup fitted with a Dean-Stark trap for VA h. During this time toluene was withdrawn from the trap periodically, to a total volume of 150 mL. The mixture was cooled to 4O⁰C (bath temperature) and sodium t-butoxide (1.2 g, 12.5 mmoles) was added in one portion. The mixture was stirred at 8O⁰C for another 1 V-≥ h before the addition of t-butyl bromoacetate (3.6 mL, 24.4 mmoles). The mixture was then stirred at reflux for 18h, and filtered hot through a pad of celite. The pad was rinsed with 4x50 mL of hot toluene (~ 7O⁰C) and the combined filtrates were concentrated in vacuo to a volume of ~ 20 mL and added to 400 mL of diethyl ether under vigorous stirring. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. This gave the polymeric t-butyl acetate 13 as a cream coloured amorphous powder (29.8 g, ca 1.5 mmoles, quant). ¹H NMR (400 MHz, CDCI₃) δ 1.47 (s, 18H), 3.45-3.84 (m, ca 1800H), 4.02 (s, 4H).

α,ω-bis(carboxymethoxy)poly(ethylene glycol) (14). Compound 13 (10.4 g, ca 5.IxIO^"4 mol) was dissolved in CH₂CI₂ (50 mL) and trifluoroacetic acid (25 mL) was added. The mixture was stirred at room temperature for 2 h and concentrated in vacuo. The resulting oil was taken up in the minimum amount of CH₂CI₂ and added to 300 mL of diethyl ether under vigorous stirring. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. The powder was then recrystallized from isopropanol to give the polymeric acid 14 (10.8 g, ca 5.1x10^"4 mol, quant) as a white powder. ¹H NMR (400 MHz, CDCI₃) δ 3.45-3.87 (m, ca 1800H), 3.88 (s, 4H).

α.ω-bisfi-N-succinimidyloxy-acet^-oxyJpolyfethylene glycol) (15). Compound 14 (10.8 g, ca 5.IxIO^"4 mol) and N-hydroxysuccinimide (1.0 g, 8.7 mmoles) were dissolved in CH₂Cb (50 ml.) and 10.6 ml. (24.2 mmoles) of trioctylamine were added. The mixture was cooled in an ice bath and 2.3 g (12 mmoles) of N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride were added in small portions over 2-3 min. The reaction mixture was left stirring in the same bath to come to room temperature on its own and remain there for a total of 20 h. It was added to 400 ml. of diethyl ether under vigorous stirring. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo, to give the polymeric N-hydroxysuccinimide ester 15 (1 1.2 g, ca 5.5x10^"4 mol, quant.) as a white powder slightly contaminated with trioctylamine salts. ¹H NMR (400 MHz, CDCI₃) δ 2.87 (m, 8H), 3.45-3.84 (m, ca 1800H), 4.52 (s, 4H).

Scheme 6. Preparation of oritavancin poly(ethylene glycol) conjugate 16.

16

Oritavancin poly(ethylene glycol) conjugate 16. To a solution of 5 (1.591 g, 0.80 mmol) and triethylamine (4.45 ml_, 32.0 mmol) in anhydrous DMF (120 ml.) was added 4 A molecular sieves (7.0 g), followed by PEG linker 15 (4.056 g, 0.20 mmol), and the resulting mixture was stirred at ambient temperature for 18 h. The solution was filtered through Celite and washed with DMF (40 ml_), the PEG derivative was precipitated by the addition of diethyl ether. After standing for 1 h at 0 °C, the precipitate was collected, washed copiously with diethyl ether, dried in vacuo and crystallized from DMF/EtOH (80/80 ml_, after standing overnight at O °C), filtered and dried in vacuo. The crude product was dialyzed [Spectra/Por7 Dialysis membrane with MWCO: 10,000] in HCO₂H/H₂O (pH = 4.5) for 48 h and lyophilized to yield polymeric compound 16 (2.94 g, ca 1.24 xi O^"4, 62% yield, 15.2% oritavancin by weight). ¹H NMR (400 MHz, DMSOd₆) δ 0.8-1.36 (m, 40H), 1.5-1.9 (m, 10H), 2.1-2.34 (m, 10H), 2.6-2.8 (6H), 3.0-3.80 (m, ca 1840H), 3.9-4.50 (m, 23H), 4.6-4.9 (m, 4H), 5.20 (m, 6H), 5.45-5.80 (m, 8H), 6.24 (s, 2H), 6.42 (s, 2H), 6.78 (m, 4H), 7.16-7.42 (m, 8H), 7.50 7.60 (m, 11 H), 7.70-7.90 (m, 8H).

Scheme 7. Preparation of oritavancin poly(ethylene glycol) conjugate 17.

17

Oritavancin poly(ethylene glycol) conjugate 17. To a solution of 16 (350 mg, ca 1.47x10^"5 mol), and Cs₂CO₃ (9.56 mg, 2.95x10^"5 mol) in anhydrous DMF (20 ml.) was added PEG linker 10 (155.4 mg, ca 2.95x10^"5 mol). After stirring for 72 h at room temperature, the PEG derivative was precipitated by the addition of diethyl ether. After standing for 1 h at 0 °C, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo to give 490 mg of product. The crude product was dialyzed [Spectra/Por7 Dialysis membrane with MWCO: 10,000] in HCO₂H/H₂O for 24 h and lyophilized to yield polymeric compound 17 (398 mg, ca 1.167 x10^"5, 79% yield, 9.87% oritavancin by weight). ¹H NMR (400 MHz, DMSO-d₆) δ 0.8-1.0 (m, 20H), 1.15-1.20 (m, 32H), 1.5-1.80 (m, 16H), 2.1-2.34 (m, 20H), 2.6-2.8(m, 8H), 3.0-3.80 (m, ca 3008H), 3.9-4.40 (m, 10H), 4.4-4.8 (m, 6H), 5.20 (m, 6H), 5.45-5.80 (m, 5H), 6.24 (s, 2H), 6.42 (s, 2H), 6.78 (m, 5H), 7.16-7.42 (m, 11 H), 7.50 7.60 (m,

16H), 7.70-7.90 (m, 15H). Scheme 8. preparation of polymeric N-succinimidyl carbonates 21 and 22.

O

MPEG(5k)-O_vA_m

"OH

21 R = H

22 R = Me

α-methyl-ω-(1 -(thiazolidin-2-thione-3-yl)-acet-2-oxy)poly(ethylene glycol) (18).

A solution of polymeric acid 3 (2 g, ca 4x10^"4 moles), 2-mercaptothiazoline (200 mg, 1.7 mmoles), and DMAP (210 mg, 1.7 mmoles) in 30 ml. of CH₂CI₂ was cooled in an ice bath, while N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (320 mg, 1.7 mmoles) was added portionwise over 2-3 minutes. The reaction mixture was left stirring in the same bath to come to room temperature on its own and remain there for a total of 24 h. It was then added to 400 ml. of diethyl ether under vigorous stirring. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. The powder was then recrystallized from isopropanol to give the polymeric thiazolidine-2-thione amide 18 (1.57 g, ca 3.1x10^"4 mol, 77% yield) as a white powder. ¹H NMR (400 MHz, CDCI₃) δ 3.38 (s, 3H), 3.45-3.84 (m, ca 450H), 4.61 (t, J = 7.5 Hz, 2H), 5.04 (s, 2H).

α-methyl-ω-(1 -(4-hydroxymethylphenoxy)-acet-2-oxy)poly(ethylene glycol) (19).

The polymeric thiazolidine-2-thione amide 18 (3.81 1 g, ca 7.4x10^"4 moles), 4-hydroxy benzyl alcohol (1.192 g, 9.613 mmoles) and DMAP (1.17 g, 9.613 mmoles) in 40 m L of CH₂CI₂ were placed in a sealed pressure tube and heated to 5O⁰C (bath temperature) for 2Oh. It was partially concentrated to -Vz- its volume and then added to 200 ml. of diethyl ether under vigorous stirring. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. The powder was then recrystallized from isopropanol to give the polymeric phenol ester 19 (3.30 g, ca 6.4x10^"4 mol, 86% yield) as a white powder.

¹H NMR (400 MHz, CDCI₃) δ 3.38 (s, 3H), 3.45-3.84 (m, ca 450H), 4.47 (s, 2H), 4.66 (s, 2H), 7.08 (d, 2H), 7.38 (d, 2H). α-methyl-ω-(1 -(4-hydroxymethyl-2,6-dimethylphenoxy)-acet-2-oxy)poly(ethylene glycol) (20). The polymeric thiazolidine-2-thione amide 18 (1 g, ca 1.94X10^"4 moles), 4- (hydroxymethyl)-2,6-dimethylphenol (320 mg, 2.1 mmoles) and DMAP (315 mg, 2.6 mmoles) in 20 ml. of CH₂CI₂ were placed in a sealed pressure tube and heated to 5O⁰C (bath temperature) for 2Oh. It was partially concentrated to -Vz- its volume and then added to 200 ml. of diethyl ether under vigorous stirring. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. The powder was then recrystallized from isopropanol to give the polymeric phenol ester 20 (772.8 mg, ca 1.49X10^"4 mol, 77% yield) as a white. ¹H NMR (400 MHz, CDCI₃) δ 2.15 (s, 6H), 3.38 (s, 3H), 3.45- 3.84 (m, ca 450H), 4.47 (s, 2H), 4.61 (s, 2H), 7.08 (s, 2H).

α-methyl-ω-(1 -(4-(N-succinimidyloxycarbonyloxymethyl)phenoxy)-acet-2- oxy)poly(ethylene glycol) (21). The polymeric phenyl ester 19 (1.30 g, ca 2.5x10^"4 mol), and N,N'-disuccinimidyl carbonate (644 mg, 2.51 mmoles) were dissolved in 4 ml. of DMF and 16 ml. of CH₂CI₂ and cooled in an ice bath before the addition of pyridine (200 μl_, 2.51 mmoles). The reaction mixture was left stirring in the same bath to come to room temperature on its own and remain there for a total of 20 h. It was then concentrated to a third of its volume and added to 200 ml. of diethyl ether under vigorous stirring. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. The powder was then recrystallized from isopropanol to give the polymeric N-succinimidyl carbonate 21 (1.10 g, ca 2.IxIO^"4 mol, 82% yield) as a white powder, slightly contaminated with N-hydroxysuccinimide. ¹H NMR (400 MHz, CDCI₃) δ 2.84 (s, 4H), 3.38 (s, 3H), 3.45-3.84 (m, ca 450H), 4.42 (s, 2H), 5.30 (s, 2H), 7.18 (d, 2H), 7.42 (d, 2H).

α-methyl-ω^i ^^N-succinimidyloxycarbonyloxymethylJ^jθ-dimethylphenoxy)- acet-2-oxy)poly(ethylene glycol) (22). The polymeric phenyl ester 20 (772.8 mg, ca 1.5X10^"4 mol), and N,N'-disuccinimidyl carbonate (320 mg, 1.25 mmoles) were dissolved in 4 ml. of DMF and 20 ml. of CH₂CI₂ and cooled in an ice bath before the addition of pyridine (100 μl_, 1.25 mmoles). The reaction mixture was left stirring in the same bath to come to room temperature on its own and remain there for a total of 20 h. It was then concentrated to a third of its volume and added to 200 ml. of diethyl ether under vigorous stirring. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. The powder was then recrystallized from isopropanol to give the polymeric N-succinimidyl carbonate 22 (626.2 mg, ca 1.2x10^"4 mol, 79% yield) as a white powder, slightly contaminated with N-hydroxysuccinimide. ¹H NMR (400 MHz, CDCI₃) δ 2.84 (s, 4H), 3.38 (s, 3H), 3.45-3.84 (m, ca 450H), 4.48 (s, 2H), 5.23 (s, 2H), 7.11 (s, 2H).

Scheme 9. Preparation of oritavancin poly(ethylene glycol) conjugates 23 and 24.

23 R = H 24 R = Me

Oritavancin poly(ethylene glycol) conjugate 23. To a solution of 5 (1.01 g, 0.51 mmol) and triethylamine (0.85 ml_, 6.13 mmol) in anhydrous DMF (25 mL) was added 4 A molecular sieves (3.0 g), followed by PEG linker 21 (1.085 g, ca 0.2 mmol), and the resulting mixture was stirred at room temperature for 20 h. The solution was filtered through Celite and washed with DMF (40 mL), the PEG derivative was precipitated by the addition of diethyl ether. After standing for 1 h at 0 °C, the precipitate was collected, washed copiously with diethyl ether, dried in vacuo and crystallized from DMF/EtOH (50/50 mL, after standing overnight at 0 °C), filtered and dried in vacuo to give 1.12 g of crude prodcut. The crude product was dialyzed [Spectra/Por7 Dialysis membrane with MWCO: 3,500] for 24 h in HCO₂H/H₂O (pH= 4.5) and lyophilized to yield polymeric compound 23 (440 mg, ca 6.2x10^"5, 31 % yield, 10.1% oritavancin by weight). ¹H NMR (400 MHz, DMSOd₆) δ 0.8-0.90 (m, 8H), 1.1.40 (m, 14H), 1.4-1.70 (m, 6H), 2.2.40 (m, 7H), 2.6-2.74 (m, 3H), 3.2-3.80 (m, ca 1451 H), 3.9-4.60 (m, 8H), 4.6-4.95 (m, 2H), 5.20 (m, 2H), 5.45-5.80 (m, 3H), 6.24 (s, 1 H), 6.42 (s, 1 H), 6.78 (m, 3H), 7.10-7.40(m, 5H), 7.70-7.80 (m, 10H), 7.90 (m, 2H). Oritavancin poly(ethylene glycol) conjugate 24. To a solution of 5 (0.578 g, 0.29 mmol) and triethylamine (1.62 ml_, 11.64 mmol) in anhydrous DMF (30 mL) was added 4 A molecular sieves (3.0 g), followed by PEG linker 22 (0.62 g, 0.1 16 mmol), and the resulting mixture was stirred at room temperature for 24 h. The solution was filtered through Celite and washed with DMF (15 mL), the PEG derivative was precipitated by the addition of diethyl ether. After sitting for 1 h at 0 °C, the precipitate was collected, washed copiously with diethyl ether, dried in vacuo and crystallized from DMF/EtOH (40/40 mL, after sitting overnight at 0 °C), filtered and dried in vacuo to give 0.79 g of crude product. The crude product was dialyzed [Spectra/Por7 Dialysis membrane with MWCO: 3,500] for 24 h in HCO₂H/H₂O (pH= 4.5) and lyophilized to yield polymeric compound 24 (291 mg, ca x10^"5, 35% yield, 15.1% oritavancin by weight). ¹H NMR (400 MHz, DMSOd₆) δ 0.8-0.90 (m, 8H), 1.1.40 9m, 14H), 1.4-1.70 (m, 6H), 2.2.40 (m, 14H), 2.6-2.82 (m, 4H), 3.2-3.80 (m, ca 920H), 3.9-4.60 (m, 10H), 4.6-4.95 (m, 3H), 5.20 (m, 3H), 5.45-5.80 (m, 4H), 6.24 (s, 1 H), 6.42 (s, 1 H), 6.78 (m, 2H), 7.10-7.60(m, 15H), 7.70-7.90 (m, 6H).

Scheme 10. preparation of α-methyl-ω-(4-(N- succinimidyloxycarbonyloxymethyl)phenyl carbamoyloxy) poly(ethylene glycol) (27).

Disuccinimidyl carbonate

CH₂CI₂, DMF pyridine

α-methyl-ω-fN-succinimidyloxycarbonyloxyJpolyfethylene glycol) (25).

Poly(ethylene glycol) monomethyl ether (1a, 2.0 g, average MW 5000 g.mol^"1, ca 4x10^"4 moles), and N,N'-disuccinimidyl carbonate (830 mg, 3.24 mmoles) were dissolved in 10 mL of DMF and 50 mL of CH₂CI₂ and cooled in an ice bath before the addition of pyridine (260 μL, 3.21 mmoles). The reaction mixture was left stirring in the same bath to come to room temperature on its own and remain there for a total of 20 h. It was then concentrated to a third of its volume and added to 200 ml. of diethyl ether under vigorous stirring. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. The powder was then recrystallized from isopropanol to give the polymeric N-succinimidyl carbonate 25 contaminated with N-hydroxysuccinimide (2.35 g, max ca 4.6x10^"4 mol) as a white powder which was used as such in the next step without further purification. ¹H NMR (400 MHz, CDCI₃) δ 2.84 (s, 4H), 3.38 (s, 3H), 3.45-3.84 (m, ca 450H), 4.46 (m, 2H).

α-methyl-ω-(4-hydroxymethylphenylcarbamoyloxy)poly(ethylene glycol) (26).

All 2.35 g (max ca 4.6x10^"4 mol) of the crude polymeric N-succinimidyl carbonate 25, p- aminobenzyl alcohol (500 mg, 4.06 mmoles) and DMAP (500 mg, 4.09 mmoles) in 30 ml. of CH₂Cb were stirred at room temperature for 24h. The mixture was concentrated in vacuo and recrystallized from isopropanol to give the polymeric carbamate 26 (1.80 g, ca 3.5x10^"4 mol, 87% yield for 2 steps) as a cream colored amorphous powder. ¹H NMR (400 MHz, CDCI₃) δ 3.38 (s, 3H), 3.45-3.84 (m, ca 450H), 4.32 (m, 2H), 4.63 (s, 2H), 5.09 (s, 1 H), 7.29 (m, 2H), 7.39 (m, 2H).

α-methyl-ω-(4-(N-succinimidyloxycarbonyloxymethyl)phenylcarbamoyloxy) poly(ethylene glycol) (27). The polymeric carbamate 26 (1.0 g, ca 1.94X10^"4 mol), and N,N'-disuccinimidyl carbonate (415 mg, 1.62 mmoles) were dissolved in 5 ml. of DMF and 25 ml. of CH₂CI₂ and cooled in an ice bath before the addition of pyridine (130 μl_, 1.61 mmoles). The reaction mixture was left stirring in the same bath to come to room temperature on its own and remain there for a total of 20 h. It was then concentrated to a third of its volume and added to 200 ml. of diethyl ether under vigorous stirring. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. The powder was then recrystallized from isopropanol to give the polymeric N-succinimidyl carbonate 27 (867.0 mg, ca 1.64X10^"4 mol, 84% yield) as a white powder. ¹H NMR (400 MHz, CDCI₃) δ 2.64 (s, 2H), 2.84 (s, 2H), 3.38 (s, 3H), 3.45-3.84 (m, ca 450H), 4.31 (m, 2H), 5.06 (m, 2H), 1.21-1 Al (m, 4H).

Scheme 11. Preparation of oritavancin poly(ethylene glycol) conjugate 28.

28

Oritavancin poly(ethylene glycol) conjugate 28. To a solution of 5 (0.812 g, 0.408 mmol) and triethylamine (0.682 ml_, 4.90 mmol) in anhydrous DMF (25 mL) was added 4 A molecular sieves (3.0 g), followed by PEG linker 27 (0.865 g, ca 0.163 mmol), and the resulting mixture was stirred at room temperature for 20 h. The solution was filtered through Celite and washed with DMF (20 mL), the PEG derivative was precipitated by the addition of diethyl ether. After standing for 1 h at 0 °C, the precipitate was collected, washed copiously with diethyl ether, dried in vacuo and crystallized from DMF/EtOH (30/60 mL, after sitting overnight at 0 "C), filtered and dried in vacuo to give 884 mg of crude product. The crude product was dialyzed [Spectra/Por7 Dialysis membrane with MWCO: 3,500] for 24 h in HCO₂H/H₂O (pH= 4.5) and lyophilized to yield polymeric compound 28 (648 mg, ca 9.3x10^"5, 57% yield, 8.0% oritavancin by weight). ¹H NMR (400 MHz, DMSOd₆) δ 0.8-0.90 (m, 7H), 1.1.40 (m, 13H), 1.4-1.90 (m, 5H), 2.0-2.40 (m, 6H), 2.6-2.80 (m, 5H), 3.0-3.80 (m, ca 1890H), 3.9-4.50 (m, 12H), 4.65 (m, 1 H), 4.9-5.20 (m, 4H), 5.45-5.80 (m, 4H), 6.24 (s, 1 H), 6.42 (s, 1 H), 6.78 (m, 2H), 7.10-7.54 (m, 16H), 7.60-7.75 (m, 8H), 7.90 (m, 2H), 8.8 9m, 1 H).

Scheme 12. Preparation of oritavancin poly(ethylene glycol) conjugate 28.

Disuccinimidyl carbonate

CH₂CI₂, DMF pyridine

α-methyl-ω-(4-formylphenyloxycarbonylamino)poly(ethylene glycol) (29a). To a solution of 4-hydroxy benzaldehyde (2.0 g, 16.37 mmol) in 40 ml. of CH₂CI₂ and 20 ml. of 2.5 M NaOH in water was added dropwise 9.62 mL of a 20 % phosgene solution in toluene (19.64 mmol). The mixture was stirred for 3 h, dilluted with water and extracted with CH₂CI₂ (2x100 mL), dried over Na₂SO₄ and concentrated to give 4-formylphenyl chloroformate (2.39 g, 12.95 mmoles, 73% yield). ¹H NMR (400 MHz, CDCI₃): δ 7.46 (d, 2H), 8.0 (d, 2H), 10.04 (s, 1 H). To a solution of polymeric amine 9a (2.0 g, ca 0.4 mmol), and triethyl amine (0.39 mL, 2.80 mmol) in 20 mL of CH₂CI₂ cooled to 0 °C was added the above prepared chloride solution (369 mg, 2.0 mmol) in 10 mL of CH₂CI₂ and the mixture was stirred for 16 h at room temperature. It was then concentrated to a third of its volume and added to 250 mL of diethyl ether under vigorous stirring. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. The powder was then recrystallized from isopropanol to give the polymeric aldehyde 29 (1.78 g, ca 3.5x10^"4 mol, 86% yield). ¹H NMR (400 MHz, CDCI₃) δ 3.38 (s, 3H), 3.45-3.84 (m, ca 450H), 7.32 (d, 2H), 7.88 (d, 2H), 9.96 (s, 1 H).

α-methyl-ω-(4-formylphenyloxycarbonylamino)poly(ethylene glycol) (29b).

Polymeric amine 9b (1.50 g, 0.75 moles) was subjected to the same procedure producing 29a from 9a, except the precipitation and crystallization steps were followed by standing in a dry ice/acetone bath, to afford polymeric benzaldehyde 29b (1.42 g, ca 6.56x10^"4 moles, 91 % yield). ¹H NMR (400 MHz, CDCI₃) δ 3.38 (s, 3H), 3.45-3.84 (m, ca 200H), 7.30 (d, 2H), 7.88 (d, 2H), 9.96 (s, 1 H). α-methyl-ω-(4-hydroxymethylphenyloxycarbonylamino)poly(ethylene glycol) (30a). Sodium cyanoborohydride (108 mg, 1.72 mmol) was added in portions to a stirred solution of polymeric aldhyde 29a (1.78 g, ca 3.5x10^"4 mol) in 18 ml. of MeOH:H₂O:AcOH (1 :1 :1 ) and stirring was continued for 1.5 h at room temperature. The reaction was quenched by the addition of ethyl acetate, and the solvents were evaporated under reduced pressure. Then the residue was dissolved in CH₂CI₂ (100 ml_), washed with 0.5 N hydrochloric acid (2x100 ml_), dried over Na₂SO₄ and concentrated to a volume (10 to 15 ml.) and added to 250 ml. of diethyl ether under vigorous stirring. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. The powder was then recrystallized from isopropanol to give the polymeric benzyl alcohol 30a (1.50 g, ca 2.9x10^"4 mol, 84% yield). ¹H NMR (400 MHz, CDCI₃) δ 3.38 (s, 3H), 3.45-3.84 (m, ca 450H), 4.64 (d, 2H), 5.80 bs, 1 H), 7.12 (d, 2H), 7.38 (d, 2H).

α-methyl-ω-(4-hydroxymethylphenyloxycarbonylamino)poly(ethylene glycol) (30b). Polymeric aldehyde 29b (1.40 g, ca 6.47x10^"4 moles) was subjected to the same procedure producing 30a from 29a, except the precipitation and crystallization steps were followed by standing in a dry ice/acetone bath, to afford polymeric benzyl alcohol 30b (0.95 g, ca 4.38x10^"4 moles, 68% yield). ¹H NMR (400 MHz, CDCI₃) δ 3.38 (s, 3H), 3.45-3.84 (m, ca 200H), 4.62 (bs, 2H), 5.78 (bs, 1 H), 7.12 (d, 2H), 7.38 (d, 2H).

α-methyl-ω-(4-(N-succinimidyloxycarbonyloxymethyl)phenoxycarbonylamino) poly(ethylene glycol) (31a). To a solution of polymeric benzyl alcohol 30a (1.50 g, ca 0.29 mmol), and disuccinimidyl carbonate (740 mg, 2.92 mmol) in 20 ml of CH₂CI₂ and 4 ml. of DMF cooled to 0 °C was added pyridine (234 μl_, 2.92 mmol). The reaction mixture was left stirring in the same bath to come to room temperature on its own and remain there for a total of 20 h. It was then concentrated to half of its volume and added to 200 ml. of diethyl ether under vigorous stirring. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. The powder was taken up in hot isopropanol and filtered. The filtrate was evaporated and redissolved in 15 ml. of CH₂CI₂ and added to 200 ml. of diethyl ether under vigorous stirring. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo to give the polymeric N- succinimidyl carbonate 31a (1.32 g, ca 2.5x10^"4 mol, 85% yield) as a white powder. ¹H NMR (400 MHz, CDCI₃): δ 2.84 (s, 4H), 3.38 (s, 3H), 3.45-3.84 (m, ca 450H), 5.30 (s, 2H), 5.78 (bt, 1 H), 7.18 (d, 2H), 7.40 (d, 2H). α-methyl-ω-(4-(N-succinimidyloxycarbonyloxymethyl)phenoxycarbonylamino) poly(ethylene glycol) (31b). Polymeric benzyl alcohol 30b (0.95 g, 4.38x10^"4 moles), was subjected to the same procedure producing 31a from 30a, except the precipitation steps were followed by standing in a dry ice/acetone bath, to afford polymeric N-succinimidyl carbonate 30b (0.65 g, ca 2.83x10^"4 moles, 65% yield). ¹H NMR (400 MHz, CDCI₃) δ 2.84 (s, 4H), 3.38 (s, 3H), 3.45-3.84 (m, ca 180H), 5.28 (s, 2H), 5.78 (bt, 1 H), 7.18 (d, 2H), 7.38 (d, 2H).

Scheme 13. Preparation of oritavancin poly(ethylene glycol) conjugate 32.

32a P = MPEG(5k) 32b P = MPEG(2k)

Oritavancin poly(ethylene glycol) conjugate 32a. To a solution of 5 (0.782 g, 0.393 mmol) and triethylamine (2.18 ml_, 15.72 mmol) in anhydrous DMF (30 ml.) was added 4 A molecular sieves (5.0 g), followed by PEG linker 31a (1.04 g, ca 0.196 mmol), and the resulting mixture was stirred at room temperature for 20 h. The solution was filtered through Celite and washed with DMF (20 ml_), the PEG derivative was precipitated by the addition of diethyl ether. After sitting for 1 h at 0 °C, the precipitate was collected, washed copiously with diethyl ether, dried in vacuo and crystallized from DMF/EtOH (40/40 ml_, after sitting overnight at 0 "C), filtered and dried in vacuo to give 1.19 g of crude product. The crude product was dialyzed [Spectra/Por7 Dialysis membrane with MWCO: 3,500] for 48 h in HCO₂H/H₂O (pH= 4.5) and lyophilized to yield polymeric compound 32a (560 mg, ca 8.04x10^"4x10^"5, 41% yield, 15.5% oritavancin by weight). ¹H NMR (400 MHz, DMSOd₆) δ 0.8-0.90 (m, 9H), 1-1.40 (m, 14H), 1.4-1.70 (m, 8H), 2.2.40 (m, 8H), 2.6-3.0 (m, 8H), 3.2- 3.80 (m, ca 900H), 3.9-4.60 (m, 7H), 4.6-5.04 (m, 4H), 5.20 (m, 3H), 5.45-5.80 (m, 4H), 6.24 (s, 1 H), 6.42 (s, 1 H), 6.78 (m, 3H), 7.10-7.40 (m, 10H), 7.42-7.60 (m, 6H), 7.7-7.78 (m, 5H), 7.90 (m, 2H), 8.54-8.80 (m, 4H).

Oritavancin poly(ethylene glycol) conjugate 32b. Polymeric N-succinimidyl carbonate 31 b (0.65 g, ca 2.83x10^"4 moles) was subjected to the same procedure producing 32a from 31a and 5, to afford oritavancin poly(ethylene glycol) conjugate 32b (320 mg, ca 8.07x10^"4 moles, 28% yield, 37.9% oritavancin by weight). ¹H NMR (400 MHz, DMSOd₆) δ 0.8-0.90 (m, 7H), 1.1.40 (m, 1 1 H), 1.4-1.70 (m, 7H), 2.2.40 (m, 5H), 2.6-2.74 (m, 5H), 3.2- 3.80 (m, ca 267H), 3.9-4.40 (m, 8H), 4.46 (m, 2H), 4.62-5.02 (m, 5H), 5.20 (m, 3H), 5.45- 5.80 (m, 4H), 6.24 (s, 1 H), 6.42 (s, 1 H), 6.50 (bs, 1 H), 6.78 (m, 3H), 7.10-7.40 (m, 8H), 7.40- 7.80 (m, 9H), 7.90 (m, 2H), 8.10 (s, 1 H), 8.5-8.80 (m, 3H), 9.04 (bs, 1 H).

Scheme 14. preparation of α-methyl-ω^i^N-succinimidyloxycarbonyloxymethoxy)- acet-2-oxy) poly(ethylene glycol) (35).

α-methyl-ω-(1 -(2-thiabutyryloxymethoxy)-acet-2-oxy) poly(ethylene glycol) (33).

The polymeric acid 3 (2.0 g, ca 4.0x10^"4 moles), TBA HSO₄ (0.543 g, 1.60 mmoles) and NaHCO₃ (0.268 g, 3.20 mmoles) in 60 ml. of CH₂CI₂, and H₂O (1 :1 ) was stirred for 1 h, and O-iodomethyl S-ethyl carbothioate (0.787 g, 3.20 mmoles) in CH₂CI₂ (10 ml.) was added. The stirring was continued for 3 h at room temperature. The mixture was then diluted with CH₂CI₂ (200 ml_), successively washed with water (2x200 ml_), dried over Na₂SO₄ and it was partially concentrated to volume of 15 to 20 ml. and then added to 250 ml. of diethyl ether under vigorous stirring. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. The powder was then recrystallized from isopropanol to give the polymeric S-ethyl carbothioate 33 (1.78 g, ca 3.44x10^"4 mol, 87 % yield) as a white solid. ¹H NMR (400 MHz, CDCI₃) δ 1.1.36 (t, 3H), 2.90 (q, 2H), 3.38 (s, 3H), 3.45-3.84 (m, ca 450H), 4.22 (s, 2H), 5.86 (s, 2H).

α-methyl-ω-fi -fchloroformyloxymethoxyj-acet^-oxyjphenoxycarbonylamino) poly(ethylene glycol) (34). To a solution of compound 33 (1.78 g, ca 3.44x10^"4 mol) in CH₂CI₂ (30 ml.) cooled to 0 °C was added SO₂CI₂ (0.557 mL, 6.87 mmol) drowise, stirred at room temperature for 2 h and evaporated under reduced pressure to give the crude polymeric chloroformate 34 (1.82 g, ca 3.57x10^"4 mol, quant.) which was used as such in the next step. ¹H NMR (400 MHz, CDCI₃) δ 3.38 (s, 3H), 3.45-3.84 (m, ca 450H), 4.22 (s, 2H), 5.86 (s, 2H).

α-methyl-ω-(1 -(N-succinimidyloxycarbonyloxymethoxy)-acet-2-oxy) poly(ethylene glycol) (35). A solution of polymeric chloroformate 34 (1.82 g, ca 3.57x10^"4 mol) in CH₂CI₂ ( 16 mL) was added to a 0 °C cooled solution of N-hydroxy succinimide (205 mg, 1.78 mmol) and pyridine (0.288 mL, 3.57 mmol) in CH₂CI₂ (25 mL), and the mixture was stirred at room temperature for 3 h. It was partially concentrated to -Vz- its volume and then added to 250 mL of diethyl ether under vigorous stirring. After sitting for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. The powder was then recrystallized from isopropanol to give the polymeric N-hydoxysuccinimide ester 35 (1.06 g, ca 2.06x10^"4 mol, 58% yield) as a white solid. ¹H NMR (400 MHz, CDCI₃) δ 2.84 (s, 4H), 3.38 (s, 3H), 3.45-3.84 (m, ca 450H), 4.26 (s, 2H), 5.94 (s, 2H).

Scheme 15. Preparation of oritavancin poly(ethylene glycol) conjugates 36.

36

Oritavancin poly(ethylene glycol) conjugate 36. To a solution of 5 (0.63 g, 0.317 mmol) and triethylamine (1.76 ml_, 12.68 mmol) in anhydrous DMF (30 mL) was added 4 A molecular sieves (4.0 g), followed by PEG linker 35 (0.83 g, 0.158 mmol), and the resulting mixture was stirred at room temperature for 20 h. The solution was filtered through Celite and washed with DMF (20 mL), the PEG derivative was precipitated by the addition of diethyl ether. After sitting for 1 h at 0 °C, the precipitate was collected, washed copiously with diethyl ether, dried in vacuo and crystallized from DMF/EtOH (30/60 mL, after sitting overnight at 0 °C), filtered and dried in vacuo to yield 840 mg of crude product. The crude product was dialyzed [Spectra/Por7 Dialysis membrane with MWCO: 3,500] for 24 h in HCO₂H/H₂O (pH= 4.5) and lyophilized to yield polymeric compound 36 (470 mg, ca 7.0x10^"5, 43% yield, 13.78% oritavancin by weight). ¹H NMR (400 MHz, DMSOd₆) δ 0.8-1.40 (m, 14H), 1.5-1.80 (m, 5H), 2.10-2.40 (m, 4H), 2.6-3.10 (m, 6H), 3.20-3.90 (m, ca 1025H), 4.0- 4.40 (m, 9H), 4.4-4.65 (m, 3H), 4.9-5.18 (m, 2H), 5.45-5.80 (m, 4H), 6.20 (bt, 1 H), 6.24 (s, 1 H), 6.42 (s, 1 H), 6.78 (m, 2H), 7.10-7.60 (m, 9H), 7.75 (m, 3H), 7.90 (m, 2H), 8.22 (bt, 2H), 8.6-8.80 (m, 4H), 9.06 (bd, 2H).

Scheme 16. preparation of α-methyl-ω-(1 -(S-1 -(4-(N- succinimidyloxycarbonyloxymethyl) phenoxy)-2-methyl-acet-2-amino)-acet-2-oxy) poly(ethylene glycol) (41).

α-methyl-ω-(1 -(S-1 -t-butoxy-2-methylacet-2-amino)-acet-2-oxy) poly(ethylene glycol) (37). The polymeric acid 3 (2.50 g, ca 5.OxI O^"4 moles), L-alanine terf-butylester hydrochloride (1.09 g, 6.0 mmoles) and DMAP (1.46 g, 12.0 mmoles) in 40 ml. of CH₂CI₂ was cooled in an ice bath, while N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.15 g, 6.0 mmoles) was added portionwise over 2-3 minutes. The reaction mixture was left stirring in the same bath to come to room temperature on its own and remain there for a total of 72 h. It was partially concentrated to -Vz- its volume and then added to 250 ml. of diethyl ether under vigorous stirring. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. The powder was then recrystallized from isopropanol to give the polymeric tert-butyl ester 37 (2.35 g, ca 4.53x10^"4 mol, 90% yield) as a white solid. ¹H NMR (400 MHz, CDCI₃) δ 1.40 (d, 3H), 3.38 (s, 3H), 3.45-3.84 (m, ca 450H), 4.0 (d, 1 H), 4.50 (m, 1 H).

α-methyl-ω-(1 -(S-1 -carboxyethylamino)-acet-2-oxy) poly(ethylene glycol) (38).

Compound 37 (2.35 g, ca 4.53x10^"4 mol) was dissolved in CH₂CI₂ (50 ml.) and trifluoroacetic acid (30 ml_) was added. The mixture was stirred at room temperature for 3 h and concentrated in vacuo. The resulting oil was taken up in the minimum amount of CH₂CI₂ (10-15 ml_) and added to 400 ml. of diethyl ether under vigorous stirring. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. The powder was then recrystallized from isopropanol to give the polymeric acid 38 (2.03 g, ca 3.95x10^"4 mol, 87% yield) as a white powder. ¹H NMR (400 MHz, CDCI₃) δ 1.44 (d, 3H), 3.38 (s, 3H), 3.45-3.84 (m, ca 450H), 4.0 (d, 1 H), 4.62 (m, 1 H).

α-methyl-ω-(1 -(S-1 -(thiazolidin-2-thione-3-yl)-2 -methyl -acet-2-amino)-acet-2-oxy) poly(ethylene glycol) (39). A solution of polymeric acid 38 (2.03 g, ca 3.95x10^"4 moles), 2- mercaptothiazoline (471 mg, 3.95 mmoles), and DMAP (483 mg, 3.95 mmoles) in 30 ml. of CH₂CI₂ was cooled in an ice bath, while N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (758 mg, 3.95 mmoles) was added portionwise over 2-3 minutes. The reaction mixture was left stirring in the same bath to come to room temperature on its own and remain there for a total of 24 h. It was then added to 400 ml. of diethyl ether under vigorous stirring. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. The powder was then recrystallized from isopropanol to give the polymeric thiazolidine-2-thione amide 39 (1.84 g, ca 3.51x10^"4 mol, 89% yield) as a white powder. ¹H NMR (400 MHz, CDCI₃) δ 1.52 (d, 3H), 3.38 (s, 3H), 3.45-3.84 (m, ca 450H), 4.0 (d, 1 H), 4.5-4.65 (m, 1 H).

α-methyl-ω-ti -tS-i ^-hydroxymethylphenoxyJ^-methyl-acet^-aminoJ-acet^- oxy) poly(ethylene glycol) (40). The polymeric thiazolidine-2-thione amide 39 (1.84 g, ca

3.5x10^"4 moles), 4-hydroxy benzyl alochol (515 mg, 4.22 mmoles) and DMAP (515 mg, 4.22 mmoles) in 20 ml. of CH₂CI₂ were placed in a sealed pressure tube and heated to 5O⁰C (bath temperature) for 16h. It was partially concentrated to -Vz- its volume and then added to 250 ml. of diethyl ether under vigorous stirring. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. The powder was then recrystallized from isopropanol to give the polymeric phenol ester 40 (1.45 g, ca 2.77x10^"4 mol, 78% yield) as a white solid. ¹H NMR (400 MHz, CDCI₃) δ 1.61 (d, 3H), 3.38 (s, 3H), 3.45-3.84 (m, ca 450H), 4.0 (m, 2H), 4.64 (d, 2H), 7.10 (d, 2H), 7.38 (d, 2H).

α-methyl-ω-fi -fS-i -^-fN-succinimidyloxycarbonyloxymethylJphenoxy)^- methyl-acet-2-amino)-acet-2-oxy)poly(ethylene glycol) (41). The polymeric phenyl ester 40 (1.45 g, ca 2.77x10^"4 mol), and N,N'-disuccinimidyl carbonate (567 mg, 2.21 mmoles) were dissolved in 4 ml. of DMF and 36 ml. of CH₂CI₂ and cooled in an ice bath before the addition of pyridine (335 μl_, 4.24 mmoles). The reaction mixture was left stirring in the same bath to come to room temperature on its own and remain there for a total of 16 h. It was then concentrated to a third of its volume and added to 250 ml. of diethyl ether under vigorous stirring. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. The powder was taken up in isopropanol and warmed to 60-70 °C, filtered and filtrate was evaporated under reduced pressure. The residue was redissolved in CH₂CI₂ (15 ml_), precipitated by the addition of diethyl ether, filtered and dried in vacuo to give the polymeric N-succinimidyl carbonate 41 (1.43 g, ca 2.66 xi O^"4 mol, 96% yield) as a white powder. ¹H NMR (400 MHz, CDCI₃) δ 1.60 (d, 3H), 2.84 (s, 4H), 3.38 (s, 3H), 3.45-3.84 (m, ca 450H), 5.32 (s, 2H), 7.16 (d, 2H), 7.42 (d, 2H). Scheme 17. Preparation of oritavancin poly(ethylene glycol) conjugate 42.

42

Oritavancin poly(ethylene glycol) conjugate 42. To a solution of 5 (1.058 g, 0.53 mmol) and triethylamine (2.96 ml_, 21.27 mmol) in anhydrous DMF (35 mL) was added 4 A molecular sieves (6.76 g), followed by PEG linker 41 (1.43 g, 0.266 mmol), and the resulting mixture was stirred at room temperature for 20 h. The solution was filtered through Celite and washed with DMF (30 mL), the PEG derivative was precipitated by the addition of diethyl ether. After standing for 1 h at 0 °C, the precipitate was collected, washed copiously with diethyl ether, dried in vacuo and crystallized from DMF/EtOH (50/100 mL, after standing overnight at 0 °C), filtered and dried in vacuo to give 1.6 g of crude product. The crude product was dialyzed [Spectra/Por7 Dialysis membrane with MWCO: 3,500] for 24 h in HCO₂H/H₂O (pH= 4.5) and lyophilized to yield polymeric compound 42 (910 mg, ca 1.29x10^" ⁴, 48% yield, 7.82% oritavancin by weight). ¹H NMR (400 MHz, DMSOd₆) δ 0.8-0.90 (m, 5H), 1.0-1.40 (m, 19H), 1.40-2.0 (m, 9H), 2.10-2.40 (m, 5H), 2.6-3.10 (m, 1 1 H), 3.20-3.80 (m, ca 1936H), 3.90-4.0 (m, 1 1 H), 4.0-4.40 (m, 10H), 4.0-4.70 (m, 4H), 4.90-5.20 (m, 4H), 5.5-5.80 (m, 4H), 6.24 (s, 1 H), 6.42 (s, 1 H), 6.78 (m, 2H), 7.10-7.44 (m, 8H), 7.5-7.90 (m, 10H).

Scheme 18. preparation of α-methyl-ω-(3-S-4-(2-S-3-(N-succinimidyloxy)-3-oxo-prop-2- ylamino)-3-(allyloxycarbonylamino)-4-oxo-butyrylamino) poly(ethylene glycol) (49) and of α-methyl-ω-tS-S^-^-S-S-^^N-succinimidyloxycarbonyloxymethylJphenyloxyJ-S- oxo-prop-2-ylamino)-3-(allyloxycarbonylamino)-4-oxo-butyrylamino) poly(ethylene glycol) (52).

MPEG(5k)— NH₂ MPEG(5k)-

α-Methyl-ω-(3-S-4-fbutoxy-3-((9-fluorenylmethyloxycarbonyl)amino)-4-oxo- butyroylamino) poly(ethylene glycol) (43). A solution of the polymeric amine 9a (3.0 g, ca 6.OxIO^"4 moles), N-α-Fmoc-L-Aspartic acid-α-terf-butylester (2.96 g, 7.2 mmoles) and DMAP (1.76 g, 14.4 mmoles) in 40 ml. of CH₂Cb was cooled in an ice bath, while N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.38 g, 7.2 mmoles) was added portionwise over 2-3 minutes. The reaction mixture was left stirring in the same bath to come to room temperature on its own and remain there for a total of 72 h. It was partially concentrated to -Vz- its volume and then added to 250 ml. of diethyl ether under vigorous stirring. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. The powder was then recrystallized from isopropanol to give the polymeric terf-butyl ester 43 (3.1 g, ca 5.75x10^"4 mol, 96% yield) as a white solid.

α-Methyl-ω-(3-S-4-(butoxy-3-amino-4-oxo-butyroylamino) poly(ethylene glycol) (44). Piperidine (2 ml.) was added to a solution of the polymeric ester 43 (3.1 g, ca 5.75x10^" ⁴ moles) in 18 ml. of DMF. The mixture was stirred for 1 h at room temperature and then added to 250 ml. of diethyl ether under vigorous stirring. After sitting for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. The powder was then recrystallized from isopropanol to give the polymeric terf-butyl ester 44 (2.62 g, ca 5.06x10^"4 mol, 88% yield) as a white solid. ¹H NMR (400 MHz, CDCI₃) δ 1.42 (s, 9H), 2.40 (m, 1 H), 2.65 (m, 2H), 3.38 (s, 3H), 3.45-3.84 (m, ca 450H), 4.0 (m, 1 H).

α-Methyl-ω-(3-S-4-ft5utoxy-3-(allyloxycarbonylamino)-4-oxo-butyroylamino) poly(ethylene glycol) (45). A solution of the polymeric amine 44 (2.60 g, ca 5.06x10^"4 moles), pyridine (0.812 ml_, 10.05 mmoles) in 30 ml. of CH₂CI₂ was cooled in an ice bath, while allyloxycarbonyl chloride (0.534 ml_, 5.02 mmoles) was added dropwise. The reaction mixture was stirred at room temperature for 3 h. It was partially concentrated to -Vz- its volume and then added to 250 ml. of diethyl ether under vigorous stirring. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. The powder was then recrystallized from isopropanol to give the polymeric te/t-butyl ester 45 (2.4 g, ca 4.56x10^"4 mol, 90% yield) as a white solid. ¹H NMR (400 MHz, CDCI₃) δ 1.42 (s, 9H), 2.08 (bs, 1 H), 2.65 (m, 1 H), 2.82 (m, 1 H), 3.38 (s, 3H), 3.45-3.84 (m, ca 450H), 4.42 (m, 1 H), 4.56 (bs, 2H), 5.22 (dd, 2H), 5.96 (m, 1 H), 6.28 (bs, 1 H).

α-Methyl-ω-(3-S-3-carboxy-3-(allyloxycarbonylamino)-propanoylamino) poly(ethylene glycol) (46). Compound 45 (2.40 g, ca 4.56x10^"4 mol) was dissolved in CH₂CI₂ (60 ml.) and trifluoroacetic acid (30 ml.) was added. The mixture was stirred at room temperature for 3 h and concentrated in vacuo. The resulting oil was taken up in the minimum amount of CH₂CI₂ (10-15 ml.) and added to 400 ml. of diethyl ether under vigorous stirring. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. The powder was then recrystallized from isopropanol to give the polymeric acid 46 (2.20 g, ca 4.23x10^"4 mol, 92% yield) as a white powder. ¹H NMR (400 MHz, CDCI₃) δ 2.70 (m, 1 H), 2.95 (m, 2H), 3.38 (s, 3H), 3.45-3.84 (m, ca 450H), 4.58 (m, 2H), 5.22 (dd, 2H), 5.96 (m, 1 H), 6.04 (bs, 1 H), 6.82 (bs, 1 H).

α-Methyl-ω-(3-S-4-(2-S-3-fbutoxy-3-oxo-prop-2-ylamino)-3-

(allyloxycarbonylamino)-4-oxo-butyrylamino) poly(ethylene glycol) (47). A solution of the polymeric acid 46 (2.10 g, ca 4.03x10^"4 moles), L-alanine terf-butylester hydrochloride (0.587 g, 3.23 mmoles) and DMAP (0.986 g, 8.07 mmoles) in 30 ml. of CH₂CI₂ was cooled in an ice bath, while N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.774 g, 4.03 mmoles) was added portionwise over 2-3 minutes. The reaction mixture was left stirring in the same bath to come to room temperature on its own and remain there for a total of 72 h. It was partially concentrated to -V-≥ its volume and then added to 250 ml. of diethyl ether under vigorous stirring. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. The powder was then recrystallized from isopropanol to give the polymeric te/t-butyl ester 47 (2.20 g, ca 4.12x10^"4 mol, 100% yield) as a white solid.

¹H NMR (400 MHz, CDCI₃) δ 1.36 (d, 3H), 1.42 (s, 9H), 2.60 (m, 1 H), 2.85 (m, 2H), 3.38 (s, 3H), 3.45-3.84 (m, ca 450H), 4.38 (m, 1 H), 4.56 (m, 3H), 5.22 (dd, 2H), 5.96 (m, 1 H), 6.40 (bs, 1 H).

α-Methyl-ω-(3-S-4-(2-S-2<:arboxyeth-2-ylamino)-3-(allyloxycarbonylamino)-4- oxo-butyrylamino) poly(ethylene glycol) (48). Compound 47 (2.20 g, ca 4.12x10^"4 mol) was dissolved in CH₂CI₂ (40 ml.) and trifluoroacetic acid (30 ml.) was added. The mixture was stirred at room temperature for 4 h and concentrated in vacuo. The resulting oil was taken up in the minimum amount of CH₂CI₂ (10-15 ml.) and added to 400 ml. of diethyl ether under vigorous stirring. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. The powder was then recrystallized from isopropanol to give the polymeric acid 48 (1.6 g, ca 3.03x10^"4 mol, 74% yield) as a white powder. ¹H NMR (400 MHz, CDCI₃) δ 1.42 (d, 3H), 2.60 (m, 1 H), 2.82 (m, 1 H), 3.38 (s, 3H), 3.45-3.84 (m, ca 450H), 4.48 (m, 1 H), 4.58 (m, 2H), 5.22 (dd, 2H), 5.96 (m, 1 H), 6.26 (bs, 1 H), 6.74 (bs, 1 H).

α-Methyl-ω-p-S^-^-S-S-fN-succinimidyloxyJ-S-oxoφrop^-ylaminoJ-S- (allyloxycarbonylamino)-4-oxo-butyrylamino) poly(ethylene glycol) (49).

Diisopropylethyl amine (0.248 ml_, 1.36 mmoles) was added to a solution of compound 48 (0.6 g, ca 1.138x10^"4 mol) and N-hydroxysuccinimide (0.104 g, 0.91 mmoles), in CH₂CI₂ (16 ml.) and DMF (4 ml_). The mixture was cooled in an ice bath and N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.523 g, 2.73 mmol) was added in small portions over 2-3 min. The reaction mixture was left stirring in the same bath to come to room temperature on its own and remain there for a total of 18 h. It was added to 400 ml_ of diethyl ether under vigorous stirring. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo, to give the polymeric N- hydroxysuccinimide ester 49 (0.51 g, ca 9.5x10^"5 mol, 83% yield) as a white powder. ¹H NMR (400 MHz, CDCI₃) δ 1.58 (d, 3H), 2.60-2.85 (m, 6H), 3.38 (s, 3H), 3.45-3.84 (m, ca 450H), 4.58 (m, 3H), 4.82 (m, 1 H), 5.22 (dd, 2H), 5.96 (m, 1 H).

α-Methyl-ω-(3-S-4-(2-S-3-(thiazolidin-2-thione-3-yl)-3-oxo-prop-2-ylamino)-3- (allyloxycarbonylamino)-4-oxo-butyrylamino) poly(ethylene glycol) (50). A solution of polymeric acid 48 (1.0 g, ca 1.89X10^"4 moles), 2-mercaptothiazoline (270 mg, 2.27 mmoles), and DMAP (556 mg, 4.55 mmoles) in 25 ml. of CH₂Cb was cooled in an ice bath, while N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (436 mg, 2.27 mmoles) was added portionwise over 2-3 minutes. The reaction mixture was left stirring in the same bath to come to room temperature on its own and remain there for a total of 18 h. It was then added to 200 ml. of diethyl ether under vigorous stirring. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. The powder was then recrystallized from isopropanol to give the polymeric thiazolidine-2-thione amide 50 (0.94 g, ca x10^"4 mol, 92% yield) as a white powder. ¹H NMR (400 MHz, CDCI₃) δ 1.42 (d, 3H), 2.0-2.22 (m, 2H), 2.50-2.85 (m, 4H), 3.38 (s, 3H), 3.45-3.84 (m, ca 450H), 4.58 (m, 5H), 5.22 (dd, 2H), 5.96 (m, 1 H), 6.46 (bs, 1 H), 6.68 (bs, 1 H).

α-Methyl-ω-(3-S-4-(2-S-3-(4-hydroxymethylphenyloxy)-3-oxo-prop-2-ylamino)-3- (allyloxycarbonylamino)-4-oxo-butyrylamino) poly(ethylene glycol) (51). The polymeric thiazolidine-2-thione amide 50 (0.92 g, ca 1.70x10^"4 moles), 4-hydroxy benzyl alcohol (509 mg, 4.1 1 mmoles) and DMAP (502 mg, 4.11 mmoles) in 20 ml. of CH₂CI₂ were placed in a sealed pressure tube and heated to 5O⁰C (bath temperature) for 18h. It was partially concentrated to -Vz- its volume and then added to 250 ml. of diethyl ether under vigorous stirring. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. The powder was then recrystallized from isopropanol to give the polymeric phenol ester 51 (0.88 g, ca 1.63X10^"4 mol, 95% yield) as a white solid. ¹H NMR (400 MHz, CDCI₃) δ 1.58 (d, 3H), 2.50-2.85 (m, 2H), 3.38 (s, 3H), 3.45-3.84 (m, ca 450H), 4.58 (m, 4H), 5.22 (dd, 2H), 5.96 (m, 1 H), 6.52 (bs, 1 H), 7.04 (m, 2H), 7.38 (m, 2H)..

α-Methyl^-p-S^-^-S-S-^^N-succinimidyloxycarbonyloxymethylJphenyloxy)- 3-oxo-prop-2-ylamino)-3-(allyloxycarbonylamino)-4-oxo-butyrylamino)-4-oxo- butyrylamino) poly(ethylene glycol) (52). The polymeric phenyl ester 51 (0.87 g, ca 1.61x10^"4 mol), and N,N'-disuccinimidyl carbonate (830 mg, 3.23 mmoles) were dissolved in 3 ml. of DMF and 27 ml. of CH₂CI₂ and cooled in an ice bath before the addition of pyridine (261 μl_, 3.23 mmoles). The reaction mixture was left stirring in the same bath to come to room temperature on its own and remain there for a total of 16 h. It was then concentrated to a third of its volume and added to 250 ml. of diethyl ether under vigorous stirring. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. The powder was taken up in isopropanol and warmed to 60-70 °C, filtered and filtrate was evaporated under reduced pressure. The residue was redissolved in CH₂CI₂ (15 ml_), precipitated by the addition of diethyl ether, filtered and dried in vacuo to give the polymeric N-succinimidyl carbonate 52 (0.685 g, ca 1.24 x10^"4 mol, 76% yield) as a white powder. ¹H NMR (400 MHz, CDCI₃) δ 1.58 (d, 3H), 2.58-2.85 (m, 6H), 3.38 (s, 3H), 3.45- 3.84 (m, ca 450H), 4.42-4.68(m, 3H), 5.22 (dd, 2H), 5.96 (m, 1 H), 6.52 (bs, 1 H), 7.04 (m, 2H), 7.38 (m, 2H).

Scheme 19. Preparation of oritavancin poly(ethylene glycol) conjugate 54.

Pd(PPh ^z L - = ^A A^lM^loc

H

Oritavancin poly(ethylene glycol) conjugate 53. To a solution of 5 (0.37 g, 0.182 mmol) and triethylamine (1.03 ml_, 7.44 mmol) in anhydrous DMF (20 mL) was added 4 A molecular sieves (2.5 g), followed by PEG linker 49 (0.5 g, ca 9.31 x10^"5 mol), and the resulting mixture was stirred at room temperature for 18 h. The solution was filtered through Celite and washed with DMF (20 mL), the PEG derivative was precipitated by the addition of diethyl ether. After standing for 1 h at 0 °C, the precipitate was collected, washed copiously with diethyl ether, dried in vacuo and crystallized from DMF/EtOH (35/35 mL, after standing overnight at 0 °C), filtered and dried in vacuo to give compound 53 (0.632 g, ca 8.97x10^"5 mol, 96% yield) as a white powder and it was used for the next reaction without further purification. Oritavancin poly(ethylene glycol) conjugate 54. To a solution of 53 (0.62 g, ca 8.80x10^"5 mol) in anhydrous DMSO (10 ml.) was added tetrakis(tιϊphenylphosphine)palladium (50.84 mg, ca 4.4x10^"5 mol), followed by morpholine (1.15 ml_, ca 13.2x10^"3 mol), and the resulting mixture was stirred at room temperature for 6 h. The PEG derivative was precipitated by the addition of diethyl ether. After standing for 1 h at 0 °C, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. The powder was then recrystallized from isopropanol to give 490 mg of crude product. The crude product was dialyzed [Spectra/Por7 Dialysis membrane with MWCO: 3,500] for 48 h in HCO₂H/H₂O (pH= 4.5) and lyophilized to yield polymeric compound 54 (197 mg, ca 2.83x10^"5, 32% yield, 9.80% oritavancin by weight). ¹H NMR (400 MHz, DMSO- d₆) δ 0.8-0.90 (m, 8H), 1.10-1.40 (m, 26H), 1.40-2.0 (m, 13H), 2.10-2.40 (m, 10H), 2.6-2.80 (m, 12H), 3.10-3.80 (m, ca 1500H), 3.94-4.40 (m, 11 H), 4.4- 4.70 (m, 4H), 5.18 (m, 3H), 5.50 (bs, 1 H), 5.60 (bs, 1 H), 5.80 (d, 2H), 6.24 (s, 1 H), 6.42 (s, 1 H), 6.78 (m, 2H), 7.16-7.44 (m, 6H), 7.5-7.90 (m, 29H), 7.94 (m, 2H) 8.20 (broad peak, 4H), 8.60-8.80 (broad peak, 4H).

Scheme 20. Preparation of oritavancin poly(ethylene glycol) conjugate 56.

Pd(PPh₃)₄, morpholine f ^{55 z} - ^Alloc DMSO V 56 Z = H

Oritavancin poly(ethylene glycol) conjugate 55. To a solution of 5 (0.493 g, 0.248 mmol) and triethylamine (1.38 ml_, 9.93 mmol) in anhydrous DMF (20 ml.) was added 4 A molecular sieves (3.35 g), followed by PEG linker 52 (0.685 g, ca 1.24x10^"4 mol), and the resulting mixture was stirred at room temperature for 20 h. The solution was filtered through Celite and washed with DMF (20 ml_), the PEG derivative was precipitated by the addition of diethyl ether. After standing for 1 h at 0 °C, the precipitate was collected, washed copiously with diethyl ether, dried in vacuo and crystallized from DMF/EtOH (40/40 ml_, after standing overnight at 0 °C), filtered and dried in vacuo to give compound 55 (0.98 g, ca 1.36x10^"4 mol, 109% crude yield) as a white powder and it was used for the next reaction without further purification.

Oritavancin poly(ethylene glycol) conjugate 56. To a solution of 55 (0.98 g, ca 1.32x10^"4 mol) in anhydrous DMSO (10 ml.) was added tetrakis(triphenylphosphine)palladium (76.68 mg, ca 6.81 x10^"5 mol), followed by morpholine (1.78 ml_, ca 20.42x10^"3 mol), and the resulting mixture was stirred at room temperature for 6 h. The PEG derivative was precipitated by the addition of diethyl ether. After standing for 1 h at 0 °C, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. The powder was then recrystallized from isopropanol to give 774 mg of crude product. The crude product was dialyzed [Spectra/Por7 Dialysis membrane with MWCO: 3,500] for 48 h in HCO₂H/H₂O (pH= 4.5) and lyophilized to yield polymeric compound 56 (268 mg, ca 3.76x10^"5, 27% yield, 12.3% oritavancin by weight). ¹H NMR (400 MHz, DMSO- d₆) δ 0.8-0.90 (m, 5H), 1.0-1.40 (m, 16H), 1.56-2.0 (m, 7H), 2.10-2.40 (m, 7H), 2.6-2.82 (m, 7H), 3.20-3.80 (m, ca 1162H), 3.90-4.78 (m, 13H), 5.18 (m, 3H), 5.50 (bs, 1 H), 5.60 (bs, 1 H), 5.80 (d, 2H), 6.24 (s, 2H), 6.42 (s, 1 H), 6.78 (m, 3H), 7.16-7.44 (m, 4H), 7.5-7.90 (m, 17H), 8.20 (broad peak, 3H), 8.60-8.80 (broad peak, 5H).

Scheme 21. preparation of α-methyl-ω-(1 -(5-S-5-(allyloxycarbonylamino)-6-(2-S-3-(N- succinimidyloxyJ-S-oxo-prop^-ylaminoJ-e-oxo-hexanaminoJ-acet^-oxy) poly(ethylene glycol) (64) and of α-methyl-ω-(1-(5-S-5-(allyloxycarbonylamino)-6-(2-S-3-(4-(N- succinimidyloxy carbonyloxymethyl)phenyloxy)-3-oxo-prop-2-ylamino)-6-oxo- hexanamino)-acet-2-oxy) poly(ethylene glycol) (67).

N-α-Alloc-N-ε-Boc-L-lysine methyl ester (58). N-ε-Boc-L-Lysine methyl ester hydrochloride (2.96 g, 10.0 mmoles), pyridine (2.42 ml_, 30.0 mmoles) in 60 ml. of CH₂CI₂ was cooled in an ice bath, while allyloxycarbonyl chloride (2.12 ml_, 20.0 mmoles) was added dropwise. The reaction mixture was stirred at room temperature for 16 h and then diluted with 120 ml. of CH₂CI₂, washed successively with 0.5N hydrochloric acid (2x100 ml_), brine (100 ml_), dried over Na₂SO₄, and concentrated to give compound 58 (3.44 g, 100% yield). ¹H NMR (400 MHz, CDCI₃) δ 1.42 (s, 9H), 1.30-1.50 (m, 4H), 1.68 (m, 1 H), 1.82 (m, 1 H), 3.08 (m, 2H), 3.72 (s, 3H), 4.32 (m, 1 H), 4.54-4.62 (m, 3H), 5.22 (dd, 2H), 5.38 (bs, 1 H), 5.93 (m, 1 H).

N-α-Alloc-L-lysine methyl ester trifluoroacetate (59). Compound 58 (3.44 g, 10.0 mmol) was dissolved in CH₂CI₂ (40 ml.) and trifluoroacetic acid (10 ml.) was added. The mixture was stirred at room temperature for 2 h and concentrated in vacuo to give compound 59 (3.54 g, 100% yield). ). ¹H NMR (400 MHz, CDCI₃) δ 1.43 (m, 2H), 1.62-1.85 (m, 4H), 3.02 (m, 2H), 3.72 (s, 3H), 4.27 (m, 1 H), 4.54-4.62 (m, 2H), 5.22 (dd, 2H), 5.67 (bd, 1 H), 5.85 (m, 1 H), 6.25 (bs, 1 H).. α-Methyl-ω-(1-(5-S-5-(allyloxycarbonylamino)-6-methoxy-6-oxohexanamino)- acet-2-oxy) poly(ethylene glycol) (60). A solution of the polymeric acid 3 (3.54 g, ca 7.OxIO^"4 moles), N-α-alloc-L-lysine methyl ester trifluoro acetate (59, 2.37 g, 8.39 mmoles) and DMAP (2.05 g, 16.79 mmoles) in 60 ml. of CH₂CI₂ was cooled in an ice bath, while N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.61 g, 8.39 mmoles) was added portionwise over 2-3 minutes. The reaction mixture was left stirring in the same bath to come to room temperature on its own and remain there for a total of 24 h. It was partially concentrated to -Vz- its volume and then added to 300 ml. of diethyl ether under vigorous stirring. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. The powder was then recrystallized from isopropanol to give the polymeric terf-butyl ester 60 (2.96 g, ca 5.60x10^"4 mol, 80% yield) as a white solid. ¹H NMR (400 MHz, CDCI₃) δ 1.38 (m, 2H), 1.56 (m, 2H), 1.74 (m, 1 H), 1.82 (m, 1 H), 3.24 (m, 2H), 3.38 (s, 3H), 3.40-3.80 (m, ca 450H), 3.94 (s, 2H), 4.36 (m, 1 H), 4.56 (bd, 2H), 5.22 (dd, 2H), 5.42 (bd, 1 H), 5.96 (m, 1 H),7.04 (bs, 1 H).

α-Methyl-ω-(1-(5-S-5-(allyloxycarbonylamino)-5<:arboxyφentanamino)-acet-2- oxy) poly(ethylene glycol) (61). To a solution of polymeric ester 60 (2.96 g, 0.56 mmoles) 80 ml. of H₂O was added lithium hydroxide monohydrate (0.352 g, 8.40 mmol) and the reaction mixture was stirred at room temperature for 18 h, pH was adjusted to 2.5 with 0.1 N HCI and the aqueous solution was extracted with CH₂CI₂ (3x100 ml_). The combined organics were washed with brine (100 ml_), dried over Na₂SO₄, concentrated to a volume of 20 ml. and then added to 300 ml. of diethyl ether under vigorous stirring. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo to give the polymeric acid 61 (2.46 g, ca 4.66x10^"4 mol, 83% yield) as a white solid. ¹H NMR (400 MHz, CDCI₃) δ 1.38-1.62 (m, 4H), 1.82 (m, 2H), 3.24 (m, 2H), 3.38 (s, 3H), 3.40-3.80 (m, ca 450H), 3.94 (s, 2H), 4.36 (m, 1 H), 4.56 (bd, 2H), 5.22 (dd, 2H), 5.42 (bd, 1 H), 5.96 (m, 1 H),7.08 (bs, 1 H).

α-Methyl-ω-(1-(5-S-5-(allyloxycarbonylamino)-6-(2-S-3-tt>utoxy-3-oxo-prop-2- ylamino)-6-oxo-hexanamino)-acet-2-oxy) poly(ethylene glycol) (62). A solution of the polymeric acid 61 (2.46 g, ca 4.66x10^"4 moles), L-alanine te/t-butylester hydrochloride (0.678 g, 3.73 mmoles) and DMAP (1.14 g, 9.33 mmoles) in 60 ml. of CH₂CI₂ was cooled in an ice bath, while N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.894 g, 4.66 mmoles) was added portionwise over 2-3 minutes. The reaction mixture was left stirring in the same bath to come to room temperature on its own and remain there for a total of 18 h. It was partially concentrated to -Vz- its volume and then added to 250 ml. of diethyl ether under vigorous stirring. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. The powder was then recrystallized from isopropanol to give the polymeric terf-butyl ester 62 (2.17 g, ca 4.02x10^"4 mol, 86% yield) as a white solid. ¹H NMR (400 MHz, CDCI₃) δ 1.42 (s, 9H), 1.38-1.62 (m, 7H), 1.70 (m, 1 H), 1.85 (m, 1 H), 3.24 (m, 3H), 3.38 (s, 3H), 3.40-3.80 (m, ca 450H), 3.96 (s, 2H), 4.08 (m, 1 H), 4.40 (m, 1 H), 4.56 (bd, 2H), 5.22 (dd, 2H), 5.44 (bd, 1 H), 5.96 (m, 1 H), 6.62 (d, 1 H), 7.08 (bs, 1 H).

α-Methyl-ω-ti-tS-S-S-tallyloxycarbonylaminoJ-θ^-S^-carboxyeth^-ylaminoJ-θ- oxo-hexanamino)-acet-2-oxy) poly(ethylene glycol) (63). Compound 62 (2.17 g, ca 4.02x10^"4 mol) was dissolved in CH₂CI₂ (40 ml.) and trifluoroacetic acid (30 ml.) was added. The mixture was stirred at room temperature for 6 h and concentrated in vacuo. The resulting oil was taken up in the minimum amount of CH₂CI₂ (10-15 ml.) and added to 400 ml. of diethyl ether under vigorous stirring. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. The powder was then recrystallized from isopropanol to give the polymeric acid 63 (1.98 g, ca 3.70x10^"4 mol, 92% yield) as a white powder. ¹H NMR (400 MHz, CDCI₃) δ 1.38-1.45 (m, 5H), 1.56 (m, 2H), 1.70 (m, 1 H), 1.85 (m, 1 H), 3.30 (m, 1 H), 3.38 (s, 3H), 3.40-3.80 (m, ca 450H), 3.96 (s, 2H), 4.18 (m, 1 H), 4.56 (m, 3H), 5.22 (dd, 2H), 5.62 (bd, 1 H), 5.96 (m, 1 H), 6.62 (bs, 1 H), 7.20 (bs, 1 H).

α-Methyl-ω^i^S-S-S-tallyloxycarbonylaminoJ-θ-^-S-S-tN-succinimidyloxyJ-S- oxo-prop-2-ylamino)-6-oxo-hexanamino)-acet-2-oxy) poly(ethylene glycol) (64).

Diisopropylethylamine (0.305 ml_, 1.75 mmoles) was added to a solution of compound 63 (0.78 g, ca 1.46X10^"4 mol) and N-hydroxysuccinimide (0.134 g, 1.168 mmoles), were dissolved in CH₂CI₂ (15 ml.) and DMF (5 ml_). The mixture was cooled in an ice bath and N- (3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.671 g, 3.50 mmol) was added in small portions over 2-3 min. The reaction mixture was left stirring in the same bath to come to room temperature on its own and remain there for a total of 18 h. It was added to 250 ml. of diethyl ether under vigorous stirring. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo, to give the polymeric N- hydroxysuccinimide ester 64 (0.62 g, ca 1.14X10^"4 mol, 78% yield) as a white powder. ¹H NMR (400 MHz, CDCI₃) δ 1.38-1.85 (m, 9H), 2.82 (m, 4H), 3.30 (m, 4H), 3.38 (s, 3H), 3.40- 3.80 (m, ca 450H), 3.96 (bs, 2H), 4.18 (m, 1 H), 4.56 (m,2H), 4.96 (m, 1 H), 5.22 (dd, 2H), 5.96 (m, 1 H), 7.20 (bs, 1 H). α-Methyl-ω-(1-(5-S-5-(allyloxycarbonylamino)-6-(2-S-3-(thiazolidin-2-thione-3-yl)- 3-oxo-prop-2-ylamino)-6-oxo-hexanamino)-acet-2-oxy) poly(ethylene glycol) (65). A solution of polymeric acid 63 (1.20 g, ca 2.24x10^"4 moles), 2-mercaptothiazoline (321 mg, 2.695 mmoles), and DMAP (658 mg, 5.39 mmoles) in 30 ml. of CH₂Cb was cooled in an ice bath, while N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (516 mg, 2.695 mmoles) was added portionwise over 2-3 minutes. The reaction mixture was left stirring in the same bath to come to room temperature on its own and remain there for a total of 24 h. It was then added to 200 ml. of diethyl ether under vigorous stirring. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. The powder was then recrystallized from isopropanol to give the polymeric thiazolidine-2- thione amide 65 (1.08 g, ca 1.98X10^"4 mol, 88% yield) as a white powder. ¹H NMR (400 MHz, CDCI₃) δ 1.38-1.85 (m, 9H), 2.20-2.30 (m, 1 H), 2.78 (m, 1 H), 3.04 (m, 1 H), 3.20-3.38 (m, 6H), 3.38 (s, 3H), 3.40-3.80 (m, ca 450H), 3.96-4.30 (m, 4H), 4.56 (m, 3H), 4.96 (m, 1 H), 5.22 (dd, 2H), 5.96 (m, 1 H), 7.10 (bs, 1 H).

α-Methyl-ω-(1-(5-S-5-(allyloxycarbonylamino)-6-(2-S-3-(4-hydroxymethylphenyl)- 3-oxo-prop-2-ylamino)-6-oxo-hexanamino)-acet-2-oxy) poly(ethylene glycol) (66). The polymeric thiazolidine-2-thione amide 65 (1.07g, ca 1.96x10^"4 moles), 4-hydroxy benzyl alochol (287 mg, 2.358 mmoles) and DMAP (287 mg, 2.358 mmoles) in 30 ml. of CH₂CI₂ were placed in a sealed pressure tube and heated to 5O⁰C (bath temperature) for 24 h. The resulting solution was partially concentrated to -Vz- its volume and then added to 250 ml. of diethyl ether under vigorous stirring. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. The powder was then recrystallized from isopropanol to give the polymeric phenol ester 66 (0.98 g, ca 1.79X10^"4 mol, 91 % yield) as a white solid. ¹H NMR (400 MHz, CDCI₃) δ 1.20-1.78 (m, 9H), 3.20-3.38 (m, 4H), 3.38 (s, 3H), 3.40-3.80 (m, ca 450H), 3.90-4.30 (m, 4H), 4.56 (m, 2H), 4.68 (m, 1 H), 5.22 (dd, 2H), 5.56-5.70 (m, 1 H), 5.96 (m, 1 H), 6.80 (m, 1 H), 7.10 (m, 3H), 7.40 (d, 2H).

α-Methyl-ω-fi-fS-S-S-fallyloxycarbonylaminoJ-e-^-S-S-^-fN-succinimidyloxy carbonyloxymethylJphenyloxyJ-S-oxo-prop^-ylaminoJ-e-oxo-hexanaminoJ-acet^-oxy) poly(ethylene glycol) (67). The polymeric phenyl ester 66 (0.97 g, ca 1.78x10^"4 mol), and N,N'-disuccinimidyl carbonate (912 mg, 3.56 mmoles) were dissolved in 4 ml. of DMF and 16 ml. of CH₂CI₂ and cooled in an ice bath before the addition of pyridine (287 μl_, 3.56 mmoles). The reaction mixture was left stirring in the same bath to come to room temperature on its own and remain there for a total of 18 h. It was then concentrated to a third of its volume and added to 250 ml. of diethyl ether under vigorous stirring. After standing for 15 min, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. The powder was taken up in isopropanol and warmed to 60-70 °C, filtered and filtrate was evaporated under reduced pressure. The residue was redissolved in CH₂Cb (15 ml_), precipitated by the addition of diethyl ether, filtered and dried in vacuo to give the polymeric N-succinimidyl carbonate 67 (0.795 g, ca 1.42 x10^"4 mol, 80% yield) as a white powder. ¹H NMR (400 MHz, CDCI₃) δ 1.20-1.78 (m, 9H), 3.20 (m, 2H), 3.38 (s, 3H), 3.40- 3.80 (m, ca 450H), 3.94 (m, 2H), 4.56 (m, 2H), 4.68 (m, 1 H), 5.22 (dd, 2H), 5.96 (m, 1 H), 7.10 (m, 3H), 7.40 (d, 2H).

Scheme 22. Preparation of oritavancin poly(ethylene glycol) conjugate 69.

Pd(PPh₃)₄, morpholine f ^{68 z " Alloc} DMSO ^ 69 Z = H

Oritavancin poly(ethylene glycol) conjugate 68. To a solution of 5 (0.438 g, 0.220 mmol) and triethylamine (1.22 ml_, 8.823 mmol) in anhydrous DMF (20 ml.) was added 4 A molecular sieves (3.20 g), followed by PEG linker 64 (0.60 g, ca 1.103x10^"4 mol), and the resulting mixture was stirred at room temperature for 24 h. The solution was filtered through Celite and washed with DMF (20 ml_), the PEG derivative was precipitated by the addition of diethyl ether. After standing for 1 h at 0 °C, the precipitate was collected, washed copiously with diethyl ether, dried in vacuo and crystallized from DMF/EtOH (30/30 ml_, after standing overnight at 0 °C), filtered and dried in vacuo to give compound 68 (0.374 g, ca 5.25x10^"5 mol, 65% yield) as a white powder and it was used for the next reaction without further purification.

Oritavancin poly(ethylene glycol) conjugate 69. To a solution of 68 (0.365 g, ca 5.12x10^"5 mol) in anhydrous DMSO (8 ml.) was added tetrakis(triphenylphosphine)palladium (29.62 mg, ca 2.56x10^"5 mol), followed by morpholine (0.67 ml_, ca 7.69x10^"3 mol), and the resulting mixture was stirred at room temperature for 6 h. The PEG derivative was precipitated by the addition of diethyl ether. After standing for 1 h at 0 °C, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. The powder was then recrystallized from isopropanol to give 280 mg of crude product. The crude product was dialyzed [Spectra/Por7 Dialysis membrane with MWCO: 3,500] for 48 h in HCO₂H/H₂O (pH= 4.5) and lyophilized to yield polymeric compound 69 (156 mg, ca 2.21x10^"5, 43% yield, 19.02% oritavancin by weight). ¹H NMR (400 MHz, DMSO-d₆) δ 0.8-0.90 (m, 6H), 1.10-1.88 (m, 22H), 2.10-2.40 (m, 3H), 2.6-2.80 (m, 4H), 3.10-3.36 (m, 8H), 3.36-3.80 (m, ca 693H), 3.60-4.0 (m, 10H), 4.10-4.50 (m, 12H), 4.72 (bs, 1 H), 4.92 (bs, 1 H), 5.18-5.30 (m, 3H), 5.50 (bs, 1 H), 5.60 (bs, 1 H), 5.80 (broad, 2H), 6.24 (s, 1 H), 6.42 (s, 1 H), 6.78 (m, 2H), 7.10-7.44 (m, 4H), 7.5-7.80 (m, 15H), 7.94 (m, 2H), 8.60 (bs, 2H), 8.80 (bs, 1 H).

Scheme 23. Preparation of oritavancin poly(ethylene glycol) conjugate 71.

Pd(PPh₃)₄, morpholine C ^" 7770U0 Z L Z == - A A Allllloc DMSO 71 Z = H

Oritavancin poly(ethylene glycol) conjugate 70. To a solution of 5 (0.558 g, 0.280 mmol) and triethylamine (1.563 ml_, 1 1.23 mmol) in anhydrous DMF (25 mL) was added 4 A molecular sieves (4.07 g), followed by PEG linker 67 (0.785 g, ca 1.40x10^"4 mol), and the resulting mixture was stirred at room temperature for 24 h. The solution was filtered through Celite and washed with DMF (20 mL), the PEG derivative was precipitated by the addition of diethyl ether. After standing for 1 h at 0 °C, the precipitate was collected, washed copiously with diethyl ether, dried in vacuo and crystallized from DMF/EtOH (40/40 mL, after standing overnight at 0 °C), filtered and dried in vacuo to give compound 70 (0.512 g, ca 7.04x10^"5 mol, 70% yield) and and it was used for the next reaction without further purification.

Oritavancin poly(ethylene glycol) conjugate 71. To a solution of 70 (0.50 g, ca 6.87x10^"5 mol) in anhydrous DMSO (8 mL) was added tetrakis(triphenylphosphine)palladium (39.73 mg, ca 3.44x10^"5 mol), followed by morpholine (0.89 mL, ca 10.31x10^"3 mol), and the resulting mixture was stirred at room temperature for 6 h. The PEG derivative was precipitated by the addition of diethyl ether. After standing for 1 h at 0 °C, the precipitate was collected, washed copiously with diethyl ether and dried in vacuo. The powder was then recrystallized from isopropanol to give 420 mg of crude product. The crude product was dialyzed [Spectra/Por7 Dialysis membrane with MWCO: 3,500] for 48 h in HCO₂H/H₂O (pH= 4.5) and lyophilized to yield polymeric compound 71 (310 mg, ca 4.31x10^"5, 63% yield,

17.66% oritavancin by weight). ¹H NMR (400 MHz, DMSO-d₆) δ 0.8-0.90 (m, 3H), 1.10-1.40 (m, 12H), 1.50-2.0 (m, 4H), 2.10-2.40 (m, 3H), 2.6-2.80 (m, 2H), 3.10 (m, 4H), 3.24 (s, 5H), 3.36-3.80 (m, ca 760H), 3.60-4.0 (m, 7H), 4.10-4.46 (m, 6H), 4.76 (m, 2H), 5.18 (m, 2H), 5.50 (broad, 1 H), 5.60 (broad, 1 H), 5.80 (broad, 2H), 6.24 (s, 1 H), 6.42 (s, 1 H), 6.78 (m, 2H), 7.10-7.44 (m, 4H), 7.5-7.80 (m, 10H), 7.94 (m, 2H), 8.60 (bs, 2H), 8.80 (bs, 1 H).

Example 2: Determination of in vitro antibacterial activity

In vitro antibacterial activity

Susceptibility of S. aureus strain ATCC29213 to oritavancin (5) and synthesized compounds was determined by following the guidelines set by the Clinical and Laboratory Standards Institute (formerly the National Committee for Clinical Laboratory Standards) (M26-A). Compounds were diluted two-fold serially in either DMSO (Oritavancin 5) or in PBS (compounds 17, 23, 24, 28, 36 and 42) and transferred to cation-adjusted Mueller Hinton broth (CAMHB; Becton Dickinson). 50 μL of compounds diluted in CAMHB was mixed with 100 μL of bacteria diluted in CAMHB in 96-well microtiter plates. The final number of micro-organisms in the assay was 5x10⁵ c.f.u. per mL and the final concentration of DMSO in the assay, if present, was 1.25%. All solutions may contain 0.002% Tween as indicated. Assays were set up in duplicate and incubated at 37 ⁰C for 18 h. The concentration of compound that inhibited visible growth was reported as the minimum inhibitory concentration (MIC). The data is summarized in Table 1.

Table 1 : Antibacterial susceptibility of bacteria to selected compounds (Minimum inhibitory concentrations)

a: Other than for 5, values are approximate and based on NMR integration to determine ratio of polymer to glycopeptide . b: Cation adjusted Mueller- Hinton broth.

It can be broadly deduced that the Oritavancin poly(ethylene glycol) conjugates 17, 23, 24, 32a, 32b, 42, 54, 56 and 69 possess antibacterial activities which are within an order of magnitude of that of Oritavancin 5. On the other hand, compounds 28, 36 and 71 show weaker activities. This suggests the introduction of a poly(ethylene glycol) moiety to be detrimental to the antibacterial nature of the molecules, and that only the conjugates which are acting as oritavancin prodrugs, and which are thus able to produce free oritavancin in the course of the assay,. are demonstrating satisfactory antibacterial activities.

The presence of tween had the same impact on conjugates 17, 23, 24, 32a, 32b, 42, 54, 56 and 69 as on oritavancin 5, once more supporting the notion that it is the released oritavancin which responsible for activity.

This assay suggests that it is favourable for the glycopeptides poly(ethylene glycol) conjugates to be prodrugs, given that cleavage to the parent compound would result in raised antibacterial activity.

Example 3: Solubility of oritavancin poly(ethylene glycol) conjugates in phosphate buffered saline.

The ability of the molecules from Example 1 to dissolve in 0.01 M phosphate buffered saline (0.9 M NaCI, 2.7 mM KCI), pH 7.4. To a sample of the material of known mass were added known volumes of phosphate buffered saline until complete dissolution is observed. Under these conditions, complete dissolution of the diphosphate salt of oritavancin is not observed at concentrations higher than 0.5 mg/mL, the lowest concentration tested. The polyethylene glycol) conjugates 17, 23, 24, 32a, 32b, 28, 36, 42, 54, 56, 69 and 71 tested in this assay are completely soluble at concentrations lower than 40 mg/mL. In other words, the solubility of oritavancin 5 is <0.5 mg/mL, while the solubility of the polymeric conjugates is >40 mg/mL and in fact generally >100 mg/mL. Example 4: Efficacy of poly(ethylene glycol) oritavancin conjugates in a mouse model of S. pneumoniae infection.

The activities of the conjugates described in Example 1 were compared to that of oritavancin in a mouse model of infection in which oritavancin demonstrates exquisite activity. Female CD-1 mice (body weight 19-21 g) were infected by intranasal instillation of 10⁶ CFU of S. pneumoniae ATCC 6303 in 50 μl. At 1 h post-infection, the animals received the treatment indicated below. At 24 h post-infection, lungs were harvested, homogenized in 5 ml. PBS, diluted and plated on blood agar plates containing 10 μg/mL of oxolinic acid and 10 μg/mL of colistin (COBA plates) for bacterial counts. The limit of detection was 1.7 Log CFU/lung.

The following treatments were provided: a) comparative study: compounds were administered at 1 h after infection (10 mice/group), at a dose equivalent to 10 mg/kg of oritavancin intravenously in PBS.

The results of a first experiment are represented graphically in figure 1. In this experiment, compounds 11 , 17 and 24 were tested side by side with oritavancin, and display similar activity against the pathogen.

The results of a second experiment are represented graphically in figure 2. In this experiment, compounds 69 and 70 were tested side-by-side with oritavancin and only compound 69 displays activity against the pathogen.

This experiment shows that compounds 11, 17, 24 and 69, with antibacterial activities similar to oritavancin in vitro and therefore thought to regenerate the parent glycopeptide, demonstrate activities in vivo consistent with oritavancin. Compound 70, on the other hand, lacks activity both in vitro and in vivo, which suggests that it is not cleaved to produce oritavancin in either scenario. This confirms that active poly(ethylene glycol) oritavancin conjugates need to behave as prodrugs in order to demonstrate activity, but also that they can be administered in vivo as solutions in isotonic media, while maintaining the efficacy of the parent.

It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All documents, including but not limited to publications, patents, patent applications, books, manuals, articles, papers, abstracts, and posters, and other materials referenced herein are expressly incorporated herein by reference in their entireties.

Claims

WHAT IS CLAIMED IS:

1. A compound represented by Formula (I):

P is a macromolecule containing at least one poly(ethylene glycol) chain;

L is a bond or a linker for covalently coupling P to A; α and γ are non-null integers, with α < 7 and γ <10; β is α+γ-1 ; wherein each A is only attached to L and wherein each P is only attached to L; wherein when α is greater than 1 and γ is 1 only one P may be coupled to more than two molecules of A; wherein when γ is greater than 1 and α is 1 only one A may be coupled to more than two molecules of P; and wherein when both α and γ are greater than 1 only one P is coupled to more than two molecules of A or only one A is coupled to more than two molecules of P.

2. The compound of claim 1 , wherein α is 1 , 2 or 3 and γ is 1.

3. The compound of claim 1 , wherein γ is 1 , 2, 3 or 4 and α is 1.

4. The compound of claim 1 , wherein each P is individually a compound of Formula (Ilia):

wherein: a is a non-null integer <2500 ; b is a non-null integer <10; c is 0 or 1 ;

X is -O-, -S-, -S(O)-, -SO₂-, -N(R₃)-, -CO₂-, -CO-, -CON(R₃)-, -CON(R_a)-E-, -N(R₃)-, -CO₂-E-, -N(R₃)CO-, -N(R₃)CO-E-, -N(R_a)C0N(R_a)-, or -N(R_a)CON(R_a)-E-, wherein E is an amino acid or a polypeptide of 1 -10 amino acids, and R₃ is C_xH_y wherein x is an integer <20 and y is an integer < (2x+1 ); and

Gi is C_WH_Z, wherein w is an integer < 10, and z is an integer < (2w+2-b).

5. The compound of claim 1 , wherein L is a hydrolysable linker.

6. The compound of claim 1 , wherein L is represented by the following formula (L₁):

wherein:

W is a covalent bond or is selected from the group of consisting of

T is oxygen or sulfur;

R is each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, amino, substituted amino, hydroxyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, P_a and — R^a — Y— R^b -Y— R^b— P₃ ; R^a is each independently selected from the group consisting of a covalent bond, alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, arylene, substituted arylene, — (CO) — alkylene — , substituted — (CO) — alkylene — , — (CO) — alkenylene — , substituted — (CO) — alkenylene — , — (CO) — alkynylene — , substituted — (CO) — alkynylene — , — (CO) — arylene — and substituted — (CO) — arylene — ;

Q is each independently nitro, chloro, bromo, iodo or fluoro;

X is each independently -O-, -S- or -N(R)-;

Y is each independently selected from the group consisting of a covalent bond, -CH₂-, oxygen, sulfur, -S-S-, — NR^C— , -S(O)- -SO₂-, — NR^CC(O)— , -OSO₂-, -OC(O)- — N(R^C)SO₂— , — C(O)NR^C— , -C(O)O-, — SO₂NR^C— , -SO₂O-, — P(O)(OR^C)O— , — P(O)(OR^C)NR^C— , — OP(O)(OR^C)O— , — OP(O)(OR^C)NR^C— , -OC(O)O- , — NR⁰C(O)O-, — NR^CC(O)NR^C — , — OC(O)NR^C— , -C(O)- and -N(R^C)SO₂NR^C— ;

aryloxycarbonyl,

q is 2 or 3; r is 1 , 2, 3, 4 or 5;

W₁ and W₂ are each integers ≥ 0 such that their sum (W₁ + w₂) is 1 , 2 or 3; a, b, c, d are integers ≥ O such that a+b+c+d <7 or null; e and f are integers ≥ O such that e+f = 4; ω is O or 1 ; and with the proviso that at least one R is P₃ or — R^a — Y— R^b -Y— R^b— P₃.

7. The compound of claim 1 , wherein at least one of said P — L — is coupled to a hydroxyl functionality on said glycopeptide or lipoglycopeptide antibiotic A, and wherein each of said linker L in a P — L — coupled to a hydroxyl functionality is independently selected from the group consisting of:

8. The compound of claim 1 , wherein at least one of said P — L — is coupled to a nitrogen atom on said glycopeptide or lipoglycopeptide antibiotic A, and wherein each of said linker L in a P — L — coupled to a nitrogen atom is independently selected from the group consisting of:

9. The compound of claim 1 , wherein at least one of said P — L — is coupled to the carbonyl of a carboxylate group on said glycopeptide or lipoglycopeptide A, and wherein each of said linker L in a P — L — coupled to the carbonyl of a carboxylate group is independently selected from the group consisting of:

wherein: n is an integer < 10; p is O or an integer < 10; each R_L is independently selected from the group consisting of H, ethyl and methyl;

O; each Y is independently selected from -0-, -S-, and -NR_L-; each Z is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, acyl, acyloxy, carboxy, carbamoyl, sulfuryl, sulfinyl, sulfenyl, sulfonyl, mercapto, amino, hydroxyl, cyano and nitro; and s is 1 , 2, 3 or 4.

10. The compound of claim 1 , wherein A has a structure represented by the following Formula (A₁):

and pharmaceutically acceptable salts, esters and prodrugs thereof, wherein:

R⁷ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, — R^a— Y— R^b— (Z)_x, and — C(0)R^d ;

R¹³ is selected from the group consisting of hydrogen and — OR¹⁴ ;

R^a is each independently selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene and substituted alkynylene; R^b is each independently selected from the group consisting of a covalent bond, alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene and substituted alkynylene;

R^Θ is each a saccharide group;

R^x is an N-linked amino saccharide or an N-linked heterocycle;

Y is each independently selected from the group consisting of , — CH₂ — , oxygen, sulfur, -S-S-, — NR^C— , -S(O)-, -SO₂-, — NR^CC(O)— , -OSO₂-, -OC(O)-, — N(R^C)SO₂— , — C(O)NR^C— , -C(O)O-, — SO₂NR^C— , -SO₂O-, — P(O)(OR^C)O— , — P(O)(OR^C)NR^C— , — OP(O)(OR^C)O— , — OP(O)(OR^C)NR^C— , -OC(O)O-, — NR^cC(0)0— , — NR^CC(O)NR^C — , — 0C(0)NR^c— , -C(O)- and -N(R^C)SO₂NR^C— ;

is selected from

with the proviso that if R₁ is

, wherein R_G is H, C_1-6 alkyl, C_3-12 branched alkyl, C_3-S cycloalkyl, C_1-6 substituted alkyl, C_3-8 substituted cycloalkyl, aryl, substituted aryl, aralkyl, Ci_-6 heteroalkyl, substituted Ci_-6 heteroalkyl, Ci_-6 alkoxy, phenoxy or Ci_-6 heteroalkoxy, then at least one of R³ or R⁵ is not hydrogen.

11. The compound of claim 1 , wherein A is teicoplanin or a derivative thereof.

12. The compound of claim 1 , wherein A is oritavancin or a derivative thereof.

13. The compound of claim 1 , wherein A is dalbavancin or a derivative thereof.

14. The compound of claim 1 , wherein A is telavancin or a derivative thereof.

15. The compound of claim 1 , wherein A is selected from the group consisting of compound A35512 A, compound A35512 C, compound A35512 E, compound A35512 F, compound A35512 G, compound A35512 H, compound A40926 A, compound A40926 B, compound A40926 PB, parvodicin B2, parvodicin C1 , parvodicin C3, compound A41030, compound A42867, compound A477, compound A47934, compound A51568A, N- demethylvancomycin, compound A80407, compound A83850, compound A84575, compound AB65, compound AM374, actaplanin, compound A4696, actinoidin, ardacin, aricidin, compound AAD216, avoparcin, compound LL-AV290, azureomycin, balhimycin, balhimycin V, chloroorienticin, compound A82846B, compound LY264826, chloroeremomycin, chloropeptin, chloropolysporin, complestatin, decaplanin, dechlorobalhimycin, dechlorobalhimycin V, chlorobalhimycin, chlorobromobalhimycin, fluorobalhimycin, deglucobalhimycin, N-demethylbalhimycin, N-demethylvancomycin, devancosamine-vancomycin, eremomycin, galacardin, helvecardin, izupeptin, kibdelin, kistamicin, mannopeptin, methylbalhimycin, compound MM47761 , compound MM47766, compound MM47767, compound MM49721 , compound MM49727, compound MM55256, compound MM55260, compound MM55266, compound MM55268, compound MM55270, compound MM55272, compound MM56597, compound MM56598, nogabecin F, compound OA7653, orienticin, dechloroeremomycin, compound PA42867, compound PA45052, chloroorienticin, parvodicin, rhamnosyl-balhimycin, ristocetin, ristomycin, spontin, symnonicin, teichomycin, Targocid, ureido-balhimycin and [Ψ[CH₂NH]Tpg⁴]Vancomycin.

16. A compound selected from the group consisting of:

and pharmaceutically acceptable salts, esters and prodrugs thereof, wherein

MPEG(2k) represents poly(ethylene glycol) monomethyl ether with an average molecular weight of 2000 g.mol^"1; and MPEG(20k) represents poly(ethylene glycol) monomethyl ether with an average molecular weight of 20000 g.mol^"1.

17. A compound represented by Formula (II):

and pharmaceutically acceptable salts, esters and prodrugs thereof, wherein:

R³ is selected from the group consisting of — OR^C, — NR^CR^C,

— O R^a — Y— R^b -(Z)_x, — NR^C — R^a — Y— R^b -(Z)_x, — NR^cR^e, — O— R^e, -OL⁷,

— NL⁸R^C, and -NL⁹R^e;

R⁴ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, — L¹⁰, — R^a — Y— R^b -(Z)_x, — C(O)R^d, — C(NL¹¹)R^d and a saccharide group optionally substituted with — R^a — Y— R^b -(Z)_x, R^f, — C(O)- R^a — Y— R^b -(Z)_x, or — C(NL¹²)- R^a — Y— R^b -(Z)_x, or R⁴ and R⁵ can be joined, together with the atoms to which they are attached, to form a heterocyclic ring optionally substituted with — NR^C — R^a — Y— R^b -(Z)_x or -NL¹³ — R^a — Y— R^b -(Z)_x;

R⁶ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, — L¹⁹, — R^a— Y— R^b -(Z)_x, — C(0)R^d, — C(NL²⁰)R^d and a saccharide group optionally substituted with — R^a — Y— R^b -(Z)_x, R^f, — C(0)R^f, — C(O)- R^a— Y— R^b— (Z)_x, — C(NL²¹)R^f, or — C(NL²²)- R^a— Y— R^b— (Z)_x or R⁵ and R⁶ can be joined, together with the atoms to which they are attached, to form a heterocyclic ring optionally substituted with — NR^C — R^a — Y — R^b — (Z)_x or -N L²³— R^a— Y— R^b— (Z)_x;

R¹² is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, — L³², — C(0)R^d, — C(NH)R^d, — C(O)NR^C R^c, — C(0)0R^d, — C(NH)NR^CR^C, — R^a— Y— R^b— (Z)_x, and — C(O)- R^b— Y— R^b— (Z)_x, — C(NL³³)R^d, — C(O)NL³⁴R^C, -C(O)OL³⁵, — C(NH)NL³⁶R^C, -C(NL³⁷)NR^CR^C, and — C(NL³⁸)- R^b— Y— R^b— (Z)_x or R¹¹ and R¹² are joined, together with the nitrogen atom to which they are attached, to form a heterocyclic ring which may optionally be substituted with -OL³⁹ , -CO₂L⁴⁰ or -NL⁴¹ R^c; R¹³ is selected from the group consisting of hydrogen and — OR¹⁴;

R¹⁴ is selected from the group consisting of hydrogen, — L⁴², — C(O)R^d , — C(NL⁴³)R^d and a saccharide group optionally substituted with — R^a — Y— R^b -(Z)_x, R^f, — C(O)R^f, — C(O)-R³ — Y— R^b -(Z)_x, — C(NL⁴⁴)R^f, or — C(NL⁴⁵)- R^a — Y— R^b -(Z)_x ;

Y is each independently selected from the group consisting Of -CH₂ — , oxygen, sulfur, -S-S-, — NR^C— , -S(O)-, -SO₂-, — NR^CC(O)— , -OSO₂-, -OC(O)-, — N(R^C)SO₂— , — C(O)NR^C— , -C(O)O-, — SO₂NR^C— , -SO₂O-, — P(O)(OR^C)O— , — P(O)(OR^C)NR^C— , — OP(O)(OR^C)O— , — OP(O)(OR^C)NR^C— , -OC(O)O-, — NR^cC(0)0— , — NR^CC(O)NR^C — , — 0C(0)NR^c, — C(O)- ,-N(R^c)SO₂NR^c— , -NL⁵⁰-, -NL⁵¹C(O)- -OSO₂-, — OC(O)- — N(L⁵²)SO₂— , -C(O)NL⁵³-, -SO₂NL⁵⁴-, — P(O)(OL⁵⁵)O— , — P(O)(OL⁵⁶)NR^C— , — P(O)(OR^C)NL⁵⁷— , — OP(O)(OL⁵⁸)O— , — OP(O)(OL⁵⁹)NR^C— , — OP(O)(OR^C)NL⁶⁰— , -NL⁶¹C(O)O-, — NL⁶²C(O)NR^C— , — NR^CC(O)NL⁶³— , -OC(O)NL⁶⁴-, -N(L⁶⁵)SO₂NR^C— and -N(R^C)SO₂NL⁶⁶— ;

G₁ O LcH₂— CH₂- θ| CH₂4cH₂] X-

wherein: a is a non-null integer <2500 b is a non-null integer <10; c is 0 or 1

X is -O-, -S-, -S(O)-, -SO₂-, -N(R₃)-, -CO₂-, -CO-, -CON(R₃)-, -C0N(R₃)-E-, -N(R₃)-, -CO₂-E-, -N(R₃)CO-, -N(R₃)CO-E-, -N(R₃)CON(R₃)-, -N(R₃)C0N(R₃)-E- wherein E is an amino acid or a polypeptide of 1 -10 amino acids, and R₃ is C_xH_y , x being an integer <20 and y being an integer < (2x+1 ); and

G₁ is C_WH_Z wherein w is an integer < 10 and z is an integer < (2w+2-b);

W₁ and W₂ are each integers ≥ 0 such that their sum (W₁ + w₂) is 1 , 2 or 3; each W is independently selected from -0-, -S-, and -NR_L-; T¹ is CH₂, -CONR_L-, -CO-O-CH₂-, or — CO— 0— ; each T² is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, acyl, acyloxy, carboxy, carbamoyl, sulfuryl, sulfinyl, sulfenyl, sulfonyl, mercapto, amino, hydroxyl, cyano and nitro; s is 1 , 2, 3 or 4;

R₃ is C_xHy where x is an integer of 0 to 20 and y is an integer of 1 to 2x+1 ; and P is a macromolecule containing at least one poly(ethylene glycol) chain selected from the group consisting of:

O LcH₂— CH₂- θ| CH₂4cH₂] X-

Gi is C_WH_Z wherein w is an integer < 10 and z is an integer < (2w+2-b);

wherein: n is an integer < 10; p is 0 or an integer < 10; each R_L is independently selected from the group consisting of H, ethyl and methyl;

R_x is selected from the group consisting of S, C(R_L)2, NR_L and O; each W is independently selected from the group consisting of -0-, -S-, and -NR_L-; and each T² is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, acyl, acyloxy, carboxy, carbamoyl, sulfuryl, sulfinyl, sulfenyl, sulfonyl, mercapto, amino, hydroxyl, cyano and nitro; s is 1 , 2, 3 or 4; and

X is -0-, -S-, -S(O)-, -SO₂-, -N(R₃)-, -CO₂-, -CO-, -CON(R₃)-, -C0N(R₃)-E-, -N(R₃)-, -CO₂-E-, -N(R₃)CO-, -N(R₃)CO-E-, -N(R₃)CON(R₃)-, -N(R₃)C0N(R₃)-E- wherein E is an amino acid or a polypeptide of 1-10 amino acids, and R₃ is C_xH_y , x being an integer <20 and y being an integer < (2x+1 ); and Gi is C_WH_Z wherein w is an integer < 10 and z is an integer < (2w+2-b);

each \J, V, L⁵, L^b, L", V\ L^1B, U™, L", L", L'⁵, L^JJ, L^JB, L^4J, L⁴⁴, L⁴⁵, L^4b, L⁴⁷, L and L is a linker independently selected from the group of

wherein: p is 0 or an integer < 10; each R_L is independently selected from the group consisting of H, ethyl and methyl; each T² is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, acyl, acyloxy, carboxy, carbamoyl, sulfuryl, sulfinyl, sulfenyl, sulfonyl, mercapto, amino, hydroxyl, cyano and nitro; s is 1 , 2, 3 or 4; and

Gi is C_WH_Z wherein w is an integer < 10 and z is an integer < (2w+2-b);

with the proviso that if R₁ is

wherein R_G is H, C_1-6 alkyl, C3-12 branched alkyl, C_3-8 cycloalkyl, C_1-6 substituted alkyl, C_3-8 substituted cycloalkyl, aryl, substituted aryl, aralkyl, Ci_-6 heteroalkyl, substituted Ci_-6 heteroalkyl, Ci_-6 alkoxy, phenoxy and Ci_-6 heteroalkoxy, then at least one of R³ or R⁵ is not hydrogen; and with the further proviso that at least one of L¹ L² L³ L⁴ L⁵ L⁶ L⁷ L⁸ L⁹ L¹⁰ L¹¹ L 12

■ 13 ■ 14 ■ 15 ■ 16 ■ 17 ■ 18 ■ 19 ■ 20 ■ 21 ■ 22 ■ 23 ■ 24 ■ 25 ■ 26 ■ 27 j 28' ■ 29 ■ 30 / 31 '■ 32 ■ 33 ■ 34 ■ 35 ■ 36

■ 37' 1 38' 1 39' 1 4θ' 1 41 ' 1 42' 1 43' 1 44' 1 45' 1 46' 1 47' 1 48' ■ 49' ■ 5θ' ■ 51 ' ■ 52' ■ 53' ■ 54' ■ 55' ■ 56' ■ 57' ■ 58' ■ 59' ■ 6θ' _L61 _L62 _L63 _L64 _L65 _L66 _L67 _L68'_{a n d L}69'_{i s prese nt} '

18. A pharmaceutical composition comprising a compound of any one of claims 1 , 16 or 17 and a pharmaceutically acceptable carrier or excipient.

19. A method for treating a bacterial infection in a subject, comprising administering to a subject in need of treatment a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of any one or claims 1 , 16 or 17 and a pharmaceutically acceptable carrier or excipient, thereby treating a bacterial infection in a subject.

20. A method for preventing a bacterial infection in a subject, comprising administering to a subject in need of prevention a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of any one or claims 1 , 16 or 17 and a pharmaceutically acceptable carrier or excipient, thereby preventing a bacterial infection in a subject.

21. A method of providing prophylaxis for a bacterial infection in a subject, comprising administering to a subject in need of prophylaxis a pharmaceutical composition comprising a prophylactically effective amount of a compound of any one or claims 1 , 16 or 17 and a pharmaceutically acceptable carrier or excipient, thereby providing prophylaxis for a bacterial infection in a subject.

22. The method of any one of claims 19, 20 or 21 , wherein said subject is a human.

23. The method of claim 19 or 20, further comprising administering an antibiotic concurrent with administration of said pharmaceutical composition.

24. The method of claim 23, wherein said antibiotic is selected from the group consisting of tetracycline, a tetracycline derived antibacterial agent, glycylcycline, a glycylcycline derived antibacterial agent, minocycline, a minocycline derived antibacterial agent, an oxazolidinone antibacterial agent, an aminoglycoside antibacterial agent, a quinolone antibacterial agent, vancomycin, a vancomycin derived antibacterial agent, a teicoplanin, a teicoplanin derived antibacterial agent, eremomycin, an eremomycin derived antibacterial agent, chloroeremomycin, a chloroeremomycin derived antibacterial agent, daptomycin, a daptomycin derived antibacterial agent, Rifamycin, a Rifamycin derived antibacterial agent, Rifampin, a Rifampin derived antibacterial agent, Rifalazil, a Rifalazil derived antibacterial agent, Rifabutin, a Rifabutin derived antibacterial agent, Rifapentin, a Rifapentin derived antibacterial agent, Rifaximin and a Rifaximin derived antibacterial agent.