FR2778184A1 - NOVEL ANTIBACTERIAL MULTIPLE BINDING COMPOUNDS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME - Google Patents

Abstract

The present invention relates to multi-bonded compounds of the formula: (L) p (X) q Formula I, wherein L represents ligands, X represents linking groups, pa is from 2 to 10 and q has a value of 1 to 20, each ligand comprising a ligand domain capable of binding to an enzyme substrate consisting of transglycosylase. It also relates to a process for their preparation and pharmaceutical compositions containing them. Application: Use of these compounds and compositions as antibacterial agents for the treatment of various diseases in mammals.

Description

The present invention relates to novel antibacterial agents. The

  The present invention relates more particularly to novel antibacterial agents which play the role of multi-link agents. The multi-linkers of the present invention comprise 2 to ligands covalently connected by one or more

  linking groups, each of said ligands in the monovalent state

  slow (ie unbound) having the ability to bind to the surface of a cell or precursor used in bacterial cell wall synthesis and interfere with

  thus with the synthesis of the precursor and the cell wall

  lar. The manner in which the ligands bind is such that the multilink agents thus constructed have a greater biological and / or therapeutic effect compared to the same number of unbound ligands available for binding.

at the ligand binding site.

  The present invention also relates to

  pharmaceutical compositions comprising a pharmaceutical excipient

  and an effective amount of a compound of the present invention, and methods of using such compounds and pharmaceutical compositions containing them.

as antibacterial agents.

  In addition, the present invention also relates to

  processes for the preparation of these compounds.

  A bacterial cell wall consists of linear polysaccharide chains that are crosslinked by short peptides. This configuration provides mechanical support for the cell wall and prevents bacteria from bursting under the action of strong internal osmotic pressure. Crosslinking occurs after incorporation of disaccharide-pentapeptide constructs bound to

  lipids (Lipid Intermediate II) to polysaccharide chains

  ridicles by an enzyme consisting of a transgly-

  colase. The crosslinking reaction is the last step of cell wall synthesis and is catalyzed by a

  enzyme known as peptidoglycan transpeptidase.

  A method by which antibacterial agents

  exert their antibacterial activity consists in inhibiting

  tion of the enzyme transglycosylase, interfering with

  thus with the penultimate stage of bacterial cell wall synthesis. Without wishing to be bound by theory, it is believed that a glycopeptide, for example vancomycin, binds with high affinity and high specificity to the N-terminal (L-lysyl-D-alanyl-D-10 alanine sequences in organisms susceptible to vancomycin)

  peptidoglycan precursors known as intermediates

  Lipid diary II. By binding to and sequestering these precursors, vancomycin prevents their use by the

  cell wall biosynthesis machinery. As a result

  that, formally, vancomycin inhibits

  bacterial transglycosylase which is responsible for the addi-

  lipid intermediate II subunits to the growing peptidoglycan chains. This step precedes the step of cross-linking transpeptidation which is inhibited by the

  antibiotics consisting of beta-lactams. It is likely

  that vancomycin also inhibits transpeptidase

  which involves the D-alanyl-D-alanine ends;

  however, this step occurring after transglycosylation

  tion, the inhibition of transpeptidation is not directly

observed.

  Antibacterial agents have proven to be important weapons in the fight against pathogenic bacteria. However, an increasingly serious problem with regard to the efficacy of antibacterial agents is the appearance of enterococcal strains which are extremely resistant to these agents; for example, vancomycin-resistant enterococci (VRE), which also resist multiple drugs. As a result, he

  would be highly desirable to find antibacterial agents

  are active against a broad spectrum of bacteria, particularly resistant strains such as

  VRE. It would also be advantageous to discover antibacterial agents which exhibit high activity and selectivity with respect to their targets and which have low toxicity.

  The Applicant has found that the connection

  of two or more ligands (antibacterial agents)

  by one or more linking groups gives a multi-linker which has an improved biological effect compared to the same concentration of ligand

  unbound (that is, monomer state), or comparative

  ligand as a monomer coupled to the linking group only. This means that an improved biological and / or therapeutic effect of the multi-linker is obtained, compared to that obtained by the same number of unbound ligands available for binding to the ligand binding site of the peptidoglycan substrate of

  the enzyme transglycosylase.

  A preferred ligand is vancomycin. Particularly preferred compounds are divalent compounds of the vancomycin type, which exhibit a greatly enhanced biological effect compared to the vancomycin monomer, or to a vancomycin monomer to which the binding structure is attached. These compounds are also extremely

  effective when tested against VRE strains.

  While not wishing to be bound to any particular theory or mechanism of action, it is believed that the unexpected activity of the compounds of the present invention stems from their ability to bind multivalently to their target and thus to to reduce the energy costs of the link (ie the energy-coupled linkage phenomenon), which is caused by the optimal positioning of two or more molecules of a ligand with respect to its binding site, that is, by a multivalent interaction. This means that the compounds act as multi-linkers, in which ligands that are covalently attached by one or more linking groups bind simultaneously (or at the same time) to multiple binding sites on another component. , such as an enzyme substrate. Vancomycin derivatives are described in patent applications EP 0 802 199, EP 0 801 075, EP 0 667 353, WO 97/28812, WO 97/38702 and in JACS 118, pages 13107-13108 (1996), JACS 119. , pages 12041-12047 (1997) and JACS 116, pages

  4573-4590 (1994). Descriptions of these documents as well as

  other documents mentioned throughout this application (for example in the section Pharmacology of the

  Detailed Description of the Invention) are cited as

  reference in this memo.

  The present invention addresses the above needs by providing novel multi-link agents. Accordingly, in one aspect, the present invention is directed to novel multi-link agents; a multi-linker comprising 2 to 10 ligands, which may be the same or different, covalently connected by one or more linking groups, which may be the same or different, each of said ligands comprising a ligand domain capable of binding to

  an enzyme substrate consisting of transglycosylase.

  Preferred multi-linkers are represented by the formula I: (L) p (X) q Formula I wherein the L symbols represent ligands that may be the same or different from each other; X groups represent linking groups which may be the same or different from each other; p represents an integer of 2 to 10; and q represents an integer of 1 to 20; or their salts; wherein each of said ligands comprises a ligand domain capable of binding to a transglycosylase enzyme substrate, thereby modulating the activity of the enzyme substrate. Advantageously, q is less than p. Preferably, p is 2 and q is 1. A particularly preferred compound is the compound of formula I wherein L, whenever it occurs, represents optionally substituted vancomycin; and X represents a linking group between any hydroxyl group, carboxyl group, amino group of the first vancomycin and any hydroxyl group, carboxyl group or amino group of the second vancomycin. In the second aspect, the present invention relates to a mammalian treatment method having a

  pathological condition that can be treated with an antibacterial agent

  comprising administering a therapeutic amount

  a novel multi-binding agent to such a mammal; wherein a multi-link agent comprises 2 to 10 ligands, which may be the same or

  different, covalently connected by one or more

  one or more of said ligands comprising a ligand domain capable of binding to a transglycosylase enzyme substrate. The preferred multi-linker is a compound of formula I or a mixture of compounds of formula I. In a third aspect, the present invention relates to a method for the treatment of mammals suffering from a bacterial disease characterized by resistance to vancomycin, comprising administering a therapeutically effective amount of a multi-linker as defined above, preferably a compound of formula I, to such a mammal, or

  good of a mixture of agents with multiple bonds.

  In a fourth aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of one or more multi-linkers, or a pharmaceutically acceptable salt thereof, said multi-linker comprising 2 to 10 ligands, which may be the same or different, covalently connected by one or more linking groups, which may be the same or different, each of said ligands comprising a ligand domain capable of binding to a transglycosylase enzyme substrate, in admixture with at least one pharmaceutically acceptable excipient, the multi-linker preferably being a compound of formula I. In a fifth aspect, the present invention relates to processes for the preparation of the

  multiple bonds of the present invention.

  Definitions As used in this memo:

  the term "alkyl" refers to a hydrocarbon chain

  a saturated, branched or unbranched monoradical product, preferably having 1 to 40 carbon atoms, more preferably 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, for example methyl, ethyl, n-propyl groups; isopropyl, n-butyl, sec-butyl, tert-butyl, n-hexyl, n-octyl, n-decyl, n-dodecyl, 2-ethyldodecyl,

  tetradecyl, etc., unless otherwise indicated.

  The term "substituted alkyl" refers to an alkyl group as defined above, having 1 to 5

  substituents selected from the group consisting of

  alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl,

  acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxy-

  aminoacyl, azido, cyano, halo, hydroxyl, keto, thio-

  keto, carboxyl, carboxylalkyl, thioaryloxy, thiohetero-

  aryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, S02-aryl, -SO2-heteroaryl and -NRaRb wherein Ra and Rb may be the same or different and are selected from hydrogen and optionally substituted groups, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,

  aryl, heteroaryl and heterocyclic.

  The term "alkylene" refers to a constitutional diradical

  killed from a branched or unbranched saturated hydrocarbon chain, preferably having 1 to 40 carbon atoms, more preferably 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2CH2-), propylene isomers (eg -CH2CH2CH2- and -CH (CH3) CH2-), and the like. The term "substituted alkylene" refers to: (a) an alkylene group as defined above, having 1 to 5 substituents selected from the group

  alkoxy substituents, substituted alkoxy, cycloalkyl,

  alkyl, substituted cycloalkyl, cycloalkenyl, cycloalkenyl

  substituted, acyl, acylamino (including, for example, N-gluco

  saminecarbonyl, benzoylamino, biphenylcarbonylamino, etc.), acyloxy, amino, aminoacyl, aminoacyloxy, oxyacylamino, azido, cyano, halo, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thiol, thioalkoxy, thioalkoxy substituted, aryl, aryloxy, thioaryloxy, heteroaryl , heteroaryloxy,

  thioheteroaryloxy, heterocyclic, heterocyclooxy, thio-

  heterocyclooxy, nitro, and -NRaRb, wherein Ra and Rb may be the same or different and are selected from hydrogen and optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic groups. Further, these substituted alkylene groups include those wherein two substituents on the alkylene group are fused to form one or more cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heterocyclic-5 or heteroaryl groups fused to the alkylene group; (b) an alkylene group as defined above which is interrupted by 1 to 20 atoms or substituents independently selected from oxygen, sulfur and NR -, wherein Rs is selected from hydrogen and groups, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic; or (c) an alkylene group as defined above which has 1 to 5 substituents as defined above and which is also interrupted by 1 to 20 atoms

  as defined above.

  Examples of substituted alkylene groups are chloromethylene (-CH (Cl) -), aminoethylene groups

  (-CH (NH2) CH2-), 1- (dodecanoylamino) propylene (-CH [NHC (O) -

  (CH2) 1 -CH3] CH2-), 1- (4-phenylbenzoylamino) pentylene (-CH [NHC (O) -Z] (CH2) 4), the isomers of 2-carboxypropylene

  (-CH2CH (CO2H) CH2-), ethoxyethyl (-CH2CH2O-CH2CH2-), ethyl-

  methylaminoethyl (- CH2CH2N (CH3) CH2CH2-), 1-ethoxy-2- (2-

  ethoxyethoxy) ethane (-CH2CH2O-CH2CH2-O-CH2CH2OCH2CH2-), etc. -

  The term "alkaryl" or "aralkyl" refers to the -alkylene-aryl and -alkylene-substituted aryl groups in

  alkylene and aryl groups meet the defini-

  in this memo. These alkaryl groups are exemplified by benzyl, phenethyl, and the like. The term "alkoxy" refers to the groups alkyl-O-, alkenyl-O-, cycloalkyl-O-, cycloalkenyl-O and alkynyl-O-, wherein the alkyl, alkenyl, cycloalkyl, cycloalkenyl and alkynyl groups are as defined in the US Pat. present memory. Preferred alkoxy groups are alkyl-O- groups and include, for example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy. , n-hexoxy, 1,2-dimethylbutoxy, etc. The term "substituted alkoxy" refers to substituted alkyl-O-, substituted alkenyl-O-, substituted cycloalkyl-O-, substituted cycloalkenyl-O-, and substituted alkynyl-O wherein substituted alkyl, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl and substituted alkynyl meet the definitions

in this memo.

  The term "alkylalkoxy" refers to alkylene-O-alkyl, substituted alkylene-O-alkyl, substituted alkylene-O-alkyl, and substituted-substituted-O-alkylalkylene wherein the alkyl, substituted alkyl, alkylene, and substituted alkylene groups are definitions in this memo. Examples of such groups are methylenemethoxy (-CH2OCH3), ethylenemethoxy (-CH2CH2OCH3), n-propylene-iso-propoxy (-CH2CH2CH2OCH (CH3) 2) methylene-tert-butoxy (-CH2-OC (CH3)) 3), etc. The term "alkylthioalkoxy" refers to alkylene-S-alkyl, alkylene-S-substituted alkyl, substituted alkylene-S-alkyl and substituted-S-substituted alkyl-alkylene groups in which the alkyl, substituted alkyl, alkylene and substituted alkylene groups are definitions in this memo. Preferred alkylthioalkoxy groups are alkylene-S-alkyl groups and include, for example, methylenethiomethoxy (-CH2SCH3), ethylenethiomethoxy (-CH2CH2SCH3), n-propylene-isothiopropoxy (-CH2CH2CH2SCH (CH3) 2), methylene groups. -tertio-thiobutoxy (CH2SC (CH) 3), etc. The term "alkenyl" refers to a monoradical consisting of a branched or unbranched unsaturated hydrocarbon chain preferably having 2 to 40 carbon atoms, more preferably 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, and preferably 1 to 10 carbon atoms. 6 double bonds. This term is further illustrated by radicals such as vinyl, prop-2-enyl, pent-3-enyl, hex-5-enyl, -ethyldodec-3,6-dienyl, and the like. "Substituted alkenyl" means an alkenyl group as defined above, comprising 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halo, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, aryloxy, thioaryloxy,

  heteroaryloxy, thioheteroaryloxy, heterocyclooxy, thiohetero-

  cyclooxy, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl,

  -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-

  aryl, -SO 2 -heteroaryl, and -NRaRb, wherein Ra and Rb may be the same or different and are selected from hydrogen and optionally substituted groups, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,

  aryl, heteroaryl and heterocyclic.

  The term "alkenylene" refers to a diradical of an unsaturated hydrocarbon chain, preferably having 2 to 40 carbon atoms, more preferably 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms and preferably 1 to 6 double bonds. This term is further illustrated by

  radicals such as 1,2-ethenyl, 1,3-prop-2- radicals

  enyl, 1,5-pent-3-enyl, 1,4-hex-5-enyl, 5-ethyl-1,12-dodecyl

  3,6-dienyl, etc. The term "substituted alkenylene" refers to a

  alkenylene group as defined above includes

  from 1 to 5 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyacylamino, azido, cyano, halo, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, thioaryloxy, heteroaryl, heteroaryloxy,

  thioheteroaryloxy, heterocyclic, heterocyclooxy, thio-

  heterocyclooxy, nitro, and NRaRb, wherein R 'and Rb may be the same or different and are selected from hydrogen and optionally substituted groups, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic. In addition, these substituted alkenylene groups include those wherein two substituents on the alkenylene group are fused to form one or more cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,

  heterocyclic or heteroaryl fused to the alkenic group

  NYLENE. The term "alkynyl" refers to a monoradical of an unsaturated hydrocarbon chain, preferably having 2 to 40 carbon atoms, more preferably 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms and preferably 1 to 6 triple bonds. This term is further illustrated by radicals such as acetylenyl, prop-2-ynyl, pent-3-ynyl, hex-5-ynyl, 5-ethyldodec-3,6-diynyl, and the like. "Substituted alkynyl" means an alkynyl group as defined above comprising 1 to 5 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyacylamino, azido, cyano, halo, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, thioaryloxy, heteroaryl, heteroaryloxy,

  thioheteroaryloxy, heterocyclic, heterocyclooxy, thio-

  heterocycloxy, nitro, -SO-alkyl, -SO-substituted alkyl,

  -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-alkyl-substituted

  killed, -SO2-aryl, -SO2-heteroaryl, SO2-heterocyclic, and NRaRb, wherein R 'and Rb may be the same or different and are selected from hydrogen and optionally substituted groups, alkyl, cycloalkyl, alkenyl,

  cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic.

  The term "alkynylene" refers to a diradical of an unsaturated hydrocarbon radical, preferably having 2 to 40 carbon atoms, more preferably 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms and preferably 1 to 6 triple bonds. This term is further illustrated by

  radicals such as 1,3-prop-2-ynyl radicals, 1,5-pent-3-

  ynyl, 1,4-hex-5-ynyl, 5-ethyl-1,12-dodec-3,6-diynyl, etc. The term "acyl" refers to the groups -CHO, alkyl-C (O) -, substituted alkyl-C (O) -, cycloalkyl-C (O) -,

  substituted cycloalkyl-C (O) -, cycloalkenyl-C (O) -, cycloalkyl

  substituted alkenyl-C (O) -, aryl-C (O) -, heteroaryl-C (O) - and heterocyclicC (O) - in which the alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,

  substituted cycloalkenyl, aryl, heteroaryl and heterocyclic

  meet the definitions in this memo. The term "acylamino" refers to the group -C (O) NRR wherein each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl or heterocyclic, or wherein both R groups are joined together to form a heterocyclic group (eg morpholino) in which the alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic groups

  meet the definitions in this memo.

  The term "aminoacyl" refers to the group -NRC (O) R wherein each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl or heterocyclic, alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic. responding to

  definitions in this memo.

  The term "aminoacyloxy" refers to the group

  -NRC (O) OR wherein each R group independently represents

  hydrogen, an alkyl, substituted alkyl, aryl, heteroaryl or heterocyclic group, the alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic groups being

  definitions in this memo.

  The term "acyloxy" refers to alkyl groups

  C (O) O-, substituted alkyl-C (O) O-, cycloalkyl-C (O) O-, cyclo-

  substituted alkyl-C (O) O-, aryl-C (O) O-, heteroaryl-C (O) O-, and heterocyclic-C (O) O- wherein alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl , aryl, heteroaryl and heterocyclic meet the definitions

in this memo.

  The term "alkylamino" refers to -NHRa groups, wherein Ra is an alkyl group as defined above. The term "alkylaminoalkyl" refers to the group -Rb-NHRa, wherein Ra is an alkyl group as defined above and Rb is an alkylene group as defined above. Examples of the alkylaminoalkyl group are n-decylaminoethyl, 3- (dimethylamino) propyl, and the like. The term "aryl" refers to an unsaturated aromatic carbocyclic group of 6 to 20 carbon atoms comprising a single ring (eg phenyl) or multiple rings

  condensed (fused) (eg naphthyl or anthryl).

  Unless otherwise specified by the definition of

  aryl substituent, these aryl groups can be optionally

  substituted with 1 to 5 substituents selected from the group consisting of acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, cycloalkenyl substituents; substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl,

  cyano, halo, nitro, heteroaryl, heteroaryloxy, heteroaryl

  cyclic, heterocyclooxy, aminoacyloxy, oxyacylamino,

  thioalkoxy, substituted thioalkoxy, thioaryloxy, thiohetero-

  aryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl,

  -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-

  aryl, -SO2-heteroaryl, trihalomethyl and NRaRb wherein Ra and Rb may be the same or different and

  are selected from hydrogen and groups, optionally

  substituted, alkyl, cycloalkyl, alkenyl, cyclo-

  alkenyl, alkynyl, aryl, heteroaryl and heterocyclic.

  Preferred aryl substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl and thioalkoxy substituents. The term "aryloxy" refers to the aryl-O- group in which the aryl group meets the above definition, including

  optionally substituted aryl groups

  also to the above definition.

  The term "arylene" refers to a derived diradical

  aryl or substituted aryl group meeting the definition of

  above, and is exemplified by 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylene, and the like. The term "carboxyalkyl" refers to the group "-C (O) O-alkyl" wherein the alkyl group is

definition above.

  The term "cycloalkyl" refers to cyclic alkyl groups of 3 to 20 carbon atoms having a single ring nucleus or fused multiple rings. These cycloalkyl groups include, by way of example,

  single nucleus such as cyclopropyl, cyclo-cyclopropyl

  butyl, cyclopentyl, cyclooctyl, etc., or multi-ring structures such as the adamantanyl group, etc. The term "substituted cycloalkyl" refers to cycloalkyl groups having 1 to 5 substituents selected from the group consisting of substituents alkoxy, substituted alkoxy, cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl,

  acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxy-

  aminoacyl, azido, cyano, halo, hydroxyl, keto, thio-

  keto, carboxyl, carboxylalkyl, thioaryloxy, thiohetero-

  aryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino,

  nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-

  heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, -SO2heteroaryl and NRaRb wherein Ra and Rb may be the same or different and are selected from hydrogen and optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic. The term "cycloalkenyl" refers to cyclic alkenyl groups of 4 to 20 carbon atoms having a single ring nucleus or fused rings and at least one point of internal unsaturation. Examples of suitable cycloalkenyl groups include, for example,

  cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-

  enyl, etc. The term "substituted cycloalkenyl" refers to cycloalkenyl groups having 1 to 5 substituents selected from the group consisting of substituted alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano,

  halo, hydroxyl, keto, thioketo, carboxyl, carboxyl

  alkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-alkyl

  substituted, -SO-aryl, -SO-heteroaryl, -SO 2 -alkyl, -SO 2

  substituted alkyl, -SO 2 -aryl, -SO 2 -heteroaryl and NRaRb wherein Ra and Rb may be the same or different and

  are selected from hydrogen and groups, optionally

  substituted, alkyl, cycloalkyl, alkenyl, cyclo-

  alkenyl, alkynyl, aryl, heteroaryl and heterocyclic.

  The term "halo" or "halogen" refers to the

  fluoro, chloro, bromo and iodo groups.

  The term "haloalkyl" refers to an alkyl group as defined above substituted with 1 to 4 halo groups as defined above, which may be the same or different, for example

  3-fluorododecyl, 12,12,12-trifluorododecyl, 2-bromooctyl, 3-bromo-6-chloroheptyl, etc. The term "heteroaryl" refers to an aromatic group

  with 1 to 15 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur in at least

  a kernel (if there is more than one kernel)

  Unless otherwise specified by the definition of the heteroaryl substituent, these heteroaryl groups may be optionally substituted with 1 to 5 substituents selected from the group consisting of acyloxy, hydroxy,

  thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cyclohexyl,

  alkyl, cycloalkenyl, substituted alkyl, substituted alkoxy,

  substituted alkenyl, substituted alkynyl, substituted cycloalkyl

  killed, substituted cycloalkenyl, amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl,

  cyano, halo, nitro, heteroaryl, heteroaryloxy, heteroaryl

  cyclic, heterocyclooxy, aminoacyloxy, oxyacylamino,

  thioalkoxy, substituted thioalkoxy, thioaryloxy, thiohetero-

  aryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-

  heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, -SO2heteroaryl, trihalomethyl, mono- and dialkylamino and NRaRb wherein Ra and Rb may be the same or different and are selected from hydrogen and groups, optionally substituted alkyl, cycloalkyl, alkenyl,

  cycloalkenyl, alkynyl, aryl, heteroaryl and heteroaryl

  cyclical. Preferred heteroaryl groups include

  pyridyl, pyrrolyl and furyl groups.

  The term "heteroaryloxy" refers to the group

heteroaryl-O-.

  The term "heteroarylene" refers to the group consisting of diradical derived from a substituted heteroaryl or heteroaryl group as defined above and is exemplified by 2,6-pyridylene, 2,4-pyridylene, 1,2-quinolinylene, 1,8-quinolinylene, 1,4-benzofuranylene, 2,5-pyridinylene, 1,3-morpholinylene, 2,5-indolenyl, etc. The term "heterocycle" or "heterocyclic" refers to a saturated or unsaturated monoradical group comprising a single ring or fused multiple rings, of 1 to 40 carbon atoms and 1 to 10 heteroatoms, preferably 1 to 4, heteroatoms selected between nitrogen, sulfur, phosphorus and / or oxygen in the nucleus. Unless otherwise specified by the definition of the heterocyclic substituent, these heterocyclic groups may be optionally substituted with 1 to 5, and preferably 1 to 3 substituents, selected from the group consisting of substituted alkoxy, alkoxy substituents,

  cycloalkyl, substituted cycloalkyl, cycloalkenyl, cycloalkyl

  substituted alkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, cyano, halo, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol,

  thioalkoxy, substituted thioalkoxy, aryl, aryloxy, hetero

  aryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-alkyl

  substituted, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-

  substituted alkyl, -SO2-aryl, -SO2-heteroaryl and NRaRb wherein Ra and Rb may be the same or different and

  are selected from hydrogen and groups, optionally

  substituted, alkyl, cycloalkyl, alkenyl, cyclo-

  alkenyl, alkynyl, aryl, heteroaryl and heterocyclic.

  These heterocyclic groups may comprise a single nucleus

or condensed multiple nuclei.

  Examples of heterocycles and hetero groups

  N-aryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyl, tetrahydrofuranyl, etc., as well as heterocycles.

n-alkoxy-nitrogen function.

  The term "heterocyclic" includes "ring compounds", which means a specific class of heterocyclic compounds comprising one or more repeating units of the formula [- (CH2-) mY-] in which m is 2 or greater and Y , whenever it appears distinctly, may consist of O, N, S or P. Examples of

  ring compounds include [- (CH2) 3-NH-] 3, [- ((CH2) 2-O) 4-

  ((CH2) 2-NH) 2], etc. Usually these ring compounds may have 4 to 10 heteroatoms and 8 to 40 carbon atoms. The term "heterocyclooxy" refers to the heterocyclic group-O-. The term "thioheterocyclooxy" refers to the group

heterocyclic-S-.

  The term "heterocyclene" refers to the group consisting of the heterocycle-derived diradical as defined herein and is exemplified by 2,6-morpholino, 2,5-morpholino, and the like. The term "oxyacylamino" refers to the group

  -OC (O) NRR wherein each R group independently represents

  hydrogen, an alkyl, substituted alkyl, aryl, heteroaryl or heterocyclic group, the alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic groups being

  the definition in this memo.

  The term "thiol" refers to the group -SH.

  The term "thioalkoxy" refers to the -S-alkyl group. The term "substituted thioalkoxy" refers to the

-S-substituted alkyl group.

  The term "thioaryloxy" refers to the aryl-S- group in which the aryl group is as defined above, including optionally substituted aryl groups also within the above definition.5 The term "thioheteroaryloxy" refers to the heteroaryl-S-group. wherein the heteroaryl group responds to the

  definition, including optional aryl groups;

  substitutes also meeting the above definition.

  With respect to any of the aforementioned groups which contain one or more substituents, it is understood, of course, that these groups contain no substitution or substitution pattern which is sterically impracticable and / or impracticable by synthesis. In addition, the compounds of the present invention include all stereochemical isomers from the

substitution of these compounds.

  The term "alkyl optionally interrupted with 1 to 5 atoms selected from O, S and N" refers to an alkyl group as defined above wherein the carbon chain is interrupted by O, S or NRa where Ra is hydrogen, an alkyl group,

  aryl or heteroaryl, all of which may be

  actively substituted. The scope of this definition includes ethers, sulfides and amines, for example

  1-methoxydecyl, 1-pentyloxynonane, 1- (2-isopropoxy)

  ethoxy) -4-methylnonane, 1- (2-ethoxyethoxy) dodecyl, 2-

  (tert-butoxy) heptyl, 1-pentylsulfanylnonane, nonyl

  pentylamine, etc. The term "heteroarylalkyl" refers to a heteroaryl group as defined above linked to an alkyl group as defined above, for example pyrid-2-methylmethyl, 8-quinolinylpropyl, etc. The term "ligand" as used herein refers to an antibiotic compound that is a binding partner for a transglycosylase enzyme substrate and is complementarily linked thereto. The specific region (s) of the ligand that is or are recognized by the enzyme substrate is or is referred to as a "ligand domain". Due to the presence of the ligand domain, a ligand may be able to bind itself to a transglycosylase enzyme substrate, or may require the presence of one or more non-ligand components for binding ( for example Ca 2, Mg 2 'or a molecule of water is required for the binding of a domain of

ligand).

  Those skilled in the art will appreciate that portions of the ligand structure that are not essential to the

  molecular recognition and binding activity (ie

  ie which are not part of the ligand domain) can be significantly modified, replaced or substituted by unrelated structures (eg with auxiliary groups as defined below) and, in some cases, omitted totally without affecting the link interaction. Therefore, it should be understood that the term "ligands" is not intended to be limited to compounds known for their utility as

  antibiotic compounds (e.g., known drugs).

  It will be understood by those skilled in the art that the term "ligand" may be applied in the same manner to a molecule that is not normally recognized as a molecule with useful antibacterial properties, due to the fact that ligands that have minimally useful properties as monomers can be extremely active as multi-linkers, because of the advantage

  biological (increased biological effect) conferred by the

* valence. The primary requirement of a ligand as defined herein is the presence in this ligand

  a ligand domain as defined above.

  A preferred class of ligands includes

  heptapeptides, known as glycopeptide antibiotics

  diques, characterized by a multiple cycle peptide nucleus and at least one sugar attached to various sites, among which vancomycin is an important example. of the

  examples of the category of ligands consisting of glycopep-

  Included in this definition can be found in "Glycopeptides Classification, Occurrence, and Discovery," by Raymond C. Rao and Louise W. Crandall, ("Drugs and the Pharmaceutical Sciences" Volume 63, edited by Ramakrishnan Nagarajan, published by Marcel Dekker , Inc.), which document is hereby incorporated by reference. Compounds described are glycopeptides designated A477, A35512, A40926, A41030, A42867, A47934, A80407, A82846, A83850, A84575, A84428, AB65, actaplanin, actinoidin, ardacin, avoparcin, azuromycin, balhimycin, chloroeremomycin, chloroorientiein, chloropolysporin, decaplanin, N-desmethylvancomycin, eremomycin, galacardine, helvecardine, izupeptin, kibdelin, LL-AM374, mannopeptin, MM45289, MM47756,

  MM47761, MM49721, MM47766, MM55260, MM55266, MM55270,

  MM56597, MM56598, OA-7653, orenticin, parvodicin, ristocetin, ristomycin, synmonicin, teicoplanin, UK-68597, UK-69542, UK72051, vancomycin, etc. Another preferred class of ligands is the general class of glycopeptides described above on which the carbohydrate moiety is absent, i.e., the heptapeptide aglycone series. For example, the elimination of the group

  disaccharide appended to the phenolic nucleus on vancomycin

  (in the manner represented below by formula II) by mild hydrolysis gives the aglycone of vancomycin. A

  Another preferred category of ligands includes glycopep-

  tides which were further provided with additional saccharide residues, including aminoglycosides,

  similar to that of vancosamine.

  The term "vancomycin" refers to the antibacterial compound whose structure is reproduced below in

as long as formula II.

OH H3C CH3H OH

NH2 [V]

H0 HOO

H CI

O H Ci 'OH

H O HH H ,, O

HN N.% N- N O H H NHCH 3 [NI

[CI HH0

H o 'H H2N

OH HO OH

  [R] Formula II The term "optional" or "optionally" means that the event or circumstance that is described in association with that term may or may not occur, and that the

  description includes cases in which this event or

  this circumstance occurs and cases in which it does not occur. For example, the term "optionally substituted glycopeptide" in relation to a compound of formula I refers to a ligand as defined above in which positions unrelated to X may or may not be substituted with various groups within the meaning of the definition. indicated below. This expression also includes the cases in which an amino acid of the

  basic central structure is replaced by another amino-

  acid, for example as described in "Preparation and Conformational Analysis of Vancomycin Hexapeptide and Aglucovancomycin Hexapeptide", by Booth, Paul M .; Williams, Dudley H., Univ. Chem. Lab., Cambridge, UK., J. Chem. Soc.,

  Perkin Trans. 1 (1989), (12), 2335-9, and "The Edman Degrada-

  tion of vancomycin: preparation of vancomycin hexapeptide ",.

  Booth, Paul M .; Stone, David J. M .; Williams, Dudley H., Univ. Chem. Lab. Cambridge, UK., J. Chem. Soc., Chem. Common. (1987), (22), 1694-5. The term "optionally substituted vancomycin" in relation to the multi-linkers of the present invention refers to vancomycin in which the hydroxy group at any position, the [R] position, the carboxyl groups in the [C] position, or the amino groups in position [V] or [N] which are not attached to the linking group X may or may not be substituted with various groups. These groups include: Ra groups, where each Rs group is selected from alkyl, alkyl groups optionally interrupted by 1 to 5 atoms selected from O, S and NRb-, wherein Rb is alkyl, aryl ,

  heteroaryl, all these groups being groups, preferably

  Substantially substituted, haloalkyl, alkenyl, alkynyl, alkylamino, alkylaminoalkyl, cycloalkyl, alkanoyl, aryl, heteroaryl, heterocyclic, additional saccharide residues, especially aminoglycosides, all optionally substituted as defined above; and

  NRCRd groups, in which Rc and Rd represent

  independently sense hydrogen, an alkyl group,

  alkenyl, alkynyl, cycloalkyl, alkanoyl, aryl, hetero

  aryl, arylalkyl or heteroarylalkyl, or Rc and Rd, when taken together with the nitrogen atom to which they are attached, represent a heterocyclo group, quaternary alkyl- and arylammonium compounds,

  pyridinium, sulfonium ions, etc., all of which are optional-

  substituted in the manner defined above. An example

  substitution in the [C] position is a substitute

  dimethylaminopropylamino group and glucosamino group; an example of a substitution at the preferred [V] position is a substitution with an alkyl group, by

  n-decyl example, or alkylaminoalkyl, for example n-decyl-

  aminoethyl. The term "aglycone of facultative vancomycin

  In the context of the present invention, the term "substituted enzyme" refers to a vancomycin aglycone in which the hydroxy group at any position, in particular the hydroxy group in the [O] position, in the [R] position, the carboxyl groups in the [C] position or the amine group in the [N] position, which are not attached to the X linkage group, may or may not be substituted with

  various groups -Ra as defined above.

  The term "transglycosylase enzyme substrate" as used herein refers to the molecular target of the enzyme transpeptidase. The substrate binds to the enzyme and ultimately results in the synthesis of the bacterial cell wall. The action of this enzyme is inhibited by a ligand domain that binds to the enzyme substrate. A ligand such as vancomycin binds to this substrate and effectively "sequesters" the substrate by preventing its recognition by the enzyme and subsequent use of the construct

  of the bacterial cell wall.

  The term "multi-linker" or "multi-link compound" as used herein refers to a compound that is capable of

  to present a multivalence in the manner defined above.

  below and which comprises 2 to 10 ligands, which may be the same or different, connected by one or more covalent linking groups, which may be the same or different, preferably 1 to 20 linking groups. An agent

  multi-linkage has a biological and / or therapeutic effect

  higher than that of the aggregate of unbound ligands equivalent to this agent. This means that an improved biological and / or therapeutic effect of the multi-linker is obtained relative to that obtained by the same number of unbound ligands available for binding to the binding site.

  ligand binding of the enzyme substrate consisting of

  glycosylase. Examples of biological and / or therapeutic effects

  Increased target specificity include, for example, increased specificity, increased affinity, increased selectivity, increased activity, increased efficacy, increased therapeutic index, change in duration of action, reduced toxicity, reduced side effects, improved bioavailability, improved pharmacokinetics, improved activity spectrum, improved ability to kill bacteria, etc. The multi-link compounds of the

  present invention have one or more of the aforementioned effects.

  The term "activity" as used herein refers to the minimum concentration at which a ligand is capable of having a beneficial biological or therapeutic effect. The activity of a ligand is usually proportional to its affinity for its ligand binding site. In some cases, the activity

  can be correlated nonlinearly with its affinity.

  When comparing the activity of two drugs, for example a multi-link agent and the

  unbound ligand, the dose-response curve for each drug

  This is determined under identical test conditions (for example in an in vitro or in vivo test or in a suitable animal model, such as a human patient). The finding that a multi-linker has a biological or therapeutic effect equivalent to a lower concentration than the aggregate of unbound ligands (e.g. on a basis expressed as weight, mole or ligand) is

  an indication of increased activity.

  The term "univalence" as used herein refers to a single binding interaction between the ligand domain of a ligand, as defined herein, with the ligand recognition site of the present invention. an enzyme substrate consisting of transglycosylase,

  as defined in this memo.

  It should be noted that a compound comprising multiple copies of a ligand (or more ligands) is univaled when a single ligand of this compound interacts with a ligand binding site. Examples of univalent interactions

are shown below.

  the arrow representing a ligand domain and the fingerprint representing the ligand binding site of a substrate

  of enzyme transglycosylase.

  The term "multivalence" as it is

  used in this specification, refers to the connection between

  2 to 10 bound ligands (which may be the same or different) and two or more

corresponding ligand.

  Accordingly, it is believed that two ligands connected by a linking group that binds together to two ligand binding sites represent a divalent compound; similarly, three connected ligands of

  this way give a trivalent compound.

  It should be understood that all compounds which contain multiple copies of a ligand attached to a linking group (or linking groups) do not necessarily exhibit the multivalence phenomenon, i.e. The biological and / or therapeutic enhancement of the multi-linker is achieved over that produced by the same number of unbound ligands available for binding to a ligand binding site. For a multivalence to exist, the ligand domains of the ligands that are connected by a linker group must be presented to their "receptors" (i.e., ligand binding sites) by the binding in a specific way to give the desired ligand orientation results

  and thus produce a multi-link event.

  The term "selectivity" or "specificity" generally refers to a measure of the binding preferences of one ligand for different receptors and / or different ligands for the same receptor. The selectivity of a ligand for its target receptor relative to another receptor is provided by the ratio of the respective values of Kd (i.e.

  the dissociation constants for each ligand-complex

  receptor) or, in cases where a biological effect is observed at a value below the Kd value, the selectivity is provided by the ratio of the respective EC0 values (i.e. the concentrations which cause maximal response for ligand interaction with

the two separate receivers).

  The term "ligand recognition site" or "ligand binding site" as used herein refers to the site on a transglycosylase enzyme substrate that recognizes a ligand domain and provides a liaison partner. The ligand binding site can be defined by structures

monomeric or multimeric.

  As used herein, the terms "inert organic solvent" and "inert solvent" refer to a solvent which is inert under the reaction conditions described in conjunction with these solvents [solvents which include, for example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), chloroform ("CHCl3"), methylene chloride (or dichloromethane or "CH2Cl2"), diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tert-butanol, dioxane, pyridine, etc.]. Unless otherwise specified, the solvents used in the reactions of the present invention are inert solvents.

  The expression "pharmaceutically acceptable salts"

  tables "means salts which retain the biological efficacy

  and the properties of the compounds of formula I and which are not biologically or otherwise undesirable. The compounds of formula I are capable of forming salts of acids and base salts due to the presence, respectively, of amino groups and carboxyl groups. 1. Pharmaceutical base addition salts

  can be prepared from inorganic bases.

  organic bases. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, primary, secondary, and tertiary amine salts, substituted amines comprising naturally substituted amines, and cyclic amines, including isopropylamine, trimethylamine,

  diethylamine, triethylamine, tripropylamine, ethanol-

  amine, 2-dimethylaminoethanol, tromethamine, lysine,

  arginine, histidine, caffeine, procaine, hydrochloride,

  mine, choline, betaine, ethylenediamine, glucosamine

  mine, N-alkylglucamines, theobromine, purines, piperazine, piperidine and N-ethylpiperidine. He must

  also be understood that other carboxylic acid derivatives

  They are useful in the practice of the present invention, for example carboxylic acid amides, including

  carboxamides, lower alkyl carboxamines,

  mides, di (lower alkyl) carboxamides, etc. 2. Pharmaceutical acid addition salts

  acceptable can be prepared from inorganic acids and organic acids. Salts derived from acids

  inorganic compounds include salts derived from

  hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, & c. Salts derived from organic acids include salts derived from acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, acid succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulphonic acid, p-toluenesulfonic acid, salicylic acid, etc. It should be understood that the compounds of the present invention comprise racemic ligands as well as stereoisomers distinct from ligands, including enantiomers and their non-racemic mixtures. The scope of the present invention as described and claimed includes the racemic forms of the ligands as well as the

  distinct enantiomers and their non-racemic mixtures.

  The term "treatment" as used herein refers to any treatment of a condition or disease in an animal, particularly a mammal, particularly the human, comprising: (i) the preventing the occurrence of the disease or condition in a subject who may be predisposed to the disease but in whom the disease has not yet been diagnosed; (ii) inhibition of the disease or condition,

  that is, the interruption of its development

  is lying; (iii) the relief of the disease or condition, that is, a regression effect of this condition; or

  (iv) the relief of states caused by malaise

  die, that is to say symptoms of the disease.

  The term "medical condition that is relieved by treatment with an antibacterial agent" as used herein is intended to cover all medical conditions known in the art.

  that they can be usefully treated with an antibacterial agent

  generally, and those conditions which have been shown to be usefully treated by the specific antibacterial agents of the present invention, including the compounds of formula I. These conditions include, but are not limited to, the treatment of an infected mammal. by the pathogenic bacterium, in particular staphylococci

  (susceptible and resistant to methicillin), strepto-

  cockles (susceptible and resistant to penicillin), enterococci (susceptible and resistant to vancomycin) and

Clostridium difficile.

  The term "therapeutically effective amount"

  cace "means the amount that is sufficient to effect the treatment, as defined above, at the time of

  administration to a mammal in need of such treatment

  is lying. The therapeutically effective amount varies depending on the subject and the condition being treated, the severity of the condition and the type of administration, and may be

  be determined in the usual manner by those skilled in the art.

  The term "protecting group" or "blocking group" refers to any group which, when bound to one or more hydroxyl, thiol, amino or carboxyl groups of the compounds, prevents reactions from occurring at the level of such groups. This protecting group can be removed by conventional chemical or enzymatic steps to re-establish the hydroxyl, thio, amino or carboxyl group. The particular blocking group which can be removed which is used is not critical and preferred hydroxyl blocking groups which can be removed include conventional substituents such as allyl, benzyl, acetyl, chloroacetyl,

  thiobenzyl, benzylidine, phenacyl, tert-butyl-diphenyl-

  silyl and any other group which can be chemically introduced to hydroxyl functionality and subsequently selectively removed by chemical or enzymatic processes under mild conditions compatible with the nature of the product. The protecting groups are described in more detail by T.W. Green and P.G.M. Wuts, "Protective Groups in Organic

  Synthesis "2nd Edition, 1991, John Wiley and Sons, N.Y.

  Preferred amino-functional blocking groups include conventional substituents such as tert-butoxycarbonyl (t-BOC), benzyloxycarbonyl (CBZ), fluorenylmethoxycarbonyl (FMOC), allyloxycarbonyl (ALOC), etc., which may be eliminated under conventional conditions and compatible with

the nature of the product.

  The preferred groups protecting the function

  carboxyl include esters such as methyl esters,

  lique, ethyl, propyl, tert-butyl, etc., which can be removed under compatible mild conditions

with the nature of the product.

  The term "linking group" and "linking groups" as used herein, identified where appropriate by the symbol X, refers to one or more groups which covalently attach 2 to ligands ( as defined herein) in a manner that provides a multivalent multi-link agent. The linking group is a ligand domain orientation entity that allows the attachment of multiple copies of ligands (which may be the same or different) to this entity. The degree to which multivalent binding is achieved depends on the efficiency with which the linking group that joins the ligand allows the ligand domains to be represented at the recognition sites.

  ligand (on enzymes and enzyme substrates).

  In addition to presenting ligand domains for multivalent interactions with multivalent receptors (enzymes or enzyme substrates), the linkage group spatially constrains these interactions to occur in dimensions defined by the linking group. Thus, the structural characteristics of the linking group (valence, geometry, orientation capabilities, dimensions, flexibility, chemical composition) are characteristics of multi-linkage agents that play an important role in determining their activities. However, the term "linking group" does not include inert solid supports such as beads, resins, glass particles, rods, fibers, etc., but it must be understood

  that the multi-link compounds of the present invention

  can be attached to a solid support if desired to produce, for example, a material useful for separation and purification processes (e.g.

affinity chromatography).

  The ligands are covalently attached to one or more linking groups using standard chemical techniques, for example a reaction between a carboxylic acid and an amine to form an amide, an amine and a sulfonyl halide to form a sulfonamide, an alcohol or phenol with an alkyl or aryl halide to form an ether, etc. The linking group (s) are attached to the ligand

  at such a position that the ligand domain can orient itself

  ter itself appropriately to bind to the ligand binding site. The term "linking group" includes any entity that is not considered to be part of the ligand. The relative orientation according to which the ligand domains are presented is derived from the particular ligand binding point (s) to the linker group, and the network geometry. The determination of where acceptable substitutions can be made on a ligand is based conventionally on prior knowledge of the structure-activity relationships of the ligand and / or angiotensin and / or on the structural information concerning the ligand complexes. receptor (for example by X-ray crystallography, NMR). These positions and synthetic processes

  for covalent attachment are well known in this field.

  Suitable linking groups are described

below.

  Currently, it is preferred that the multi-linker be a divalent compound, wherein two ligands are covalently linked. For example, a divalent glycopeptide compound can be constructed by linking any hydroxyl group, carboxyl group, group

  "resorcinol" [R] or amino group of a first glyco-

  peptide to any hydroxyl group, car-

  boxyl group, "resorcinol" group [R] or amino group of a second glycopeptide. It should be noted that the term "hydroxyl group" includes a hydroxyl group obtained by reducing

  the carboxylic group in the [C] position to a hydroxyl group

  methyl, as well as hydroxyl groups on sugars and

  on the central peptide structure.

  The term "enhanced biological effect" as used herein includes, but is not limited to, increased affinity, increased selectivity, increased activity, increased efficacy, increased duration of action , reduced toxicity, etc. The present invention relates to multivalent compounds as defined above, comprising ligands that are binding partners for a transglycosylase enzyme substrate. Preferred ligands are optionally substituted glycopeptides, or their corresponding aglycones. In the following reaction schemes, the glycopeptides are represented in a simplified form consisting of a shaded framework which has only the carboxyl end, designated [C], the amine end of the sugar (for example, vancosamine), designated [VII], and the "non-carbohydrate" amino end, denoted by [N], as follows:

H 0

RN NI OH

  ICI NH2 wherein R is hydrogen (as in Ndesmethylvancomycin) or a methyl group (as in

vancomycin).

  Accordingly, it can be seen, by way of example, that a general class of multivalent compounds within the scope of the definition of formula I includes compounds in which ligands, including optionally substituted ligands, are connected by one or more several link groups X at the ends [CC],

  [V-V], [N-N], [C-V], [C-N] and [V-N].

  In addition, in the context of the present invention

  are the aglycone derivatives of glyco-

  peptides. In the reaction schemes, they are represented as a shaded triangle which has only the carboxyl end, designated [C], the hydroxy end of the aglycone, designated [O], and the amino terminus ". non-carbohydrate ", denoted by [N], as follows:

RN OH

  [o] OH wherein R is hydrogen (as in N-desmethylvancomycin aglycone) or a methyl group

  (as in vancomycin aglycone).

  Accordingly, it can be seen by way of example that another general category of multivalent compounds within the scope of the definition of formula I includes compounds in which 2 to 10 ligands are connected by one or more X linkage groups. the

  extremes [C-C], [O-O], [N-N], [C-O], [C-N] and [O-N].

  The scope of the present invention also includes end-linked glycopeptides [C],

  [VI or [N] to derivatives consisting of glyceryl glycols

  peptides linked by their ends [C], [O] or [N].

  A third class of compounds within the scope of the present invention include those wherein the glycopeptides, or their aglycone derivatives, are bound by the [R] position. The reaction schemes that illustrate this linking strategy represent the

  ligands in a simplified form as defined above.

  above, i.e., in the form of a shaded frame in which the carboxyl end is designated [C], the amino end of vancosamine is designated by [V] and the amino terminus "non-carbohydrate "is designated [N], with the addition of the [R] position as a resorcinol derivative, as follows:

H O

RN NI OH

X VI NH2

HO R OH

  Wherein R is hydrogen or methyl.

  As previously described, glyco-

  peptides are generally represented in a form

  a simplified framework consisting of a shaded

  the carboxyl end of the glycopeptide, designated by

  [C], amine end of sugar (vancosamine in vancomycin

  cine), designated [V], and the amino terminus "non-carbohydrate

dique ", denoted by [N].

  The preferred compounds of the present invention are those represented by the compounds of formula I, (L) pXqt wherein p is 2 and q is 1. The following nomenclature system will be used to refer to the compounds of the present invention and substituted ligands used in their preparation, using vancomycin as an example (Formula II), but it should be understood that all compounds of the present invention may be named

following these principles.

  The substituted glycopeptides fall within the definition of the term "ligand", and the substitution point is indicated as follows. For example, vancomycin substituted at the [C] end, which has the formula:

H O

  RN NH2 wherein R is methyl;

  is called [C] -3- (dimethylamino) propylamino-

(Vancomycin).

  It should be noted that although the link to the

  mity [C] of the glycopeptide is an amide bond, the denominator

  This is intended to indicate the linking group only, which means that the compound is referred to as the amine and not the amide. In this way, confusion is avoided if the terminal group of the glycopeptide (in this case

  [C]) is part of the indicated linkage group.

  For bivalent compounds, the positions to which the linking group connects to two ends of vancomycin are indicated by [C-C] when the links are joined to the carboxyl ends of the two vancomycin molecules. Thus, a compound of structural formula: H o H-O H

NH H2N

H2 H2N

  in which R represents a methyl group, represents two glycopeptides (vancomycin in this example) linked by a 1,8-diaminooctane group at the [C] positions of the glycopeptide. This compound will be named: [CC] -octane-1,8-diamino-bis (vancomycin) indicating that two unsubstituted vancomycin molecules are linked by a -NH- (CH 2) 8 -NH- group, each NH group being attached to the carboxy ends of each vancomycin. As noted above, although the binding at the [C] end of the glycopeptides is an amide, the denomination indicates the linker only, which means that this compound

  is referred to as a diamine and not a diamide.

  Similarly, the name "[V-V] -

  heptane-1,7-dioylbis (vancomycin) indicates that two molecules

  unsubstituted vancomycin are bound by a -C (O) (CH2) 5-C (O) - group, both C (O) groups being attached to

  vancosamine (V) ends of each vancomycin, i.e.

  to denote means a compound of structural formula:

H O O

H

  in which R represents a methyl group.

  In the case where two unsubstituted vancomycin molecules are linked at two different ends, for example a [C] end of a first vancomycin at a [V] end of a second vancomycin with a linking group of formula -NH- (CH2) 6-CO-, that is to say in the case of a compound of structural formula: o H

HOAN. R

  Wherein R is methyl;

  the compound is called [C-V] -1-aminoheptane-7-oyl-bis- (vancomycin).

  When an unsubstituted vancomycin molecule is linked to a vancomycin molecule which is substituted in the [C 1] position, by means of a linking group of the formula -NH- (CH 2) 2 -CO-, that is, say in the case of a compound of structural formula: NHO

RH <N H

  NH 2 wherein R is methyl and R 1 is 3- (dimethylamino) propylamino, this compound is

  (Vancomycin) - [C-V] heptane-l-amino-7-oyl - ([C] -3- (dimethyl

  amino) -propyl-vancomycin). Similarly, [N-N] indicates the binding of two vancomycin molecules by the methylamino termini, [R-R] indicates the binding of two vancomycin molecules by the "resorcinol" ends. [0-01] indicates that two aglycone molecules are linked by the phenolic hydroxy group which

  persists after hydrolysis of sugar. [C-V] indicates that the

  Mity [C] of a first vancomycin is linked to the [V] end of a second vancomycin. A similar nomenclature applies to vancomycin molecules with [N-V], [C-O], [O-V], [C-R] bonds, and so on. When two vancomycins are unsubstituted or carry identical substituents, the nomenclature is as indicated above, which means that a compound

  called [V-V] -decane-1,10-dioyl-bis - ([C] -butylamino-vancomycin

  cine) consists of a compound in which two vancomycin molecules, both of which are substituted in the [C] position by a CH3 (CH2) 3NH- group, are linked by a group

  -C (O) - (CH2) 8-C (O) -, both ends C (O) being attached to the ends of vancosamine (V) of each vancomycin. How-

  when two vancomycins are not identically substituted, for example in the case of a compound in

  wherein the first ligand is [C] -dimethylamino-

  vancomycin, and a second ligand is [C] -butylamino-

  vancomycin, linked by a -C (O) - (CH2) 8-C (O) - group, both ends C (O) being attached to the ends of vancosamine (V) of each vancomycin, the compound is called:

  ([C] -dimethylamino-vancomycin) [V-V] decane-l, 10-

  dioyl - ([C] butylamino-vancomycin). Similarly, a compound in which the first ligand is [V] -octylvancomycin and a second ligand is [C] -N-glucosamino-vancomycin bound by a group

  -NH- (CH2) 2-NH-C (O) - (CH2) 2-C (O) -NH- (CH2) 2-

  in position [C] of the first ligand at the position [V] of the second ligand, is called: ([V] -octylvancomycin) - [C-V] -butane-1,4-dioic

  (2-aminoethyl) -amide- (2-ethyl) -amide - ([C] -N-

  glucosamino vancomycin). Accordingly, a compound of formula I wherein p is 2 and q is 1 and the L ligands consist of two vancomycin molecules linked by their carbon ends [C] by a group:

  -NH- (CH 2) 2 NHC (O) (CH 2) 3 C (O) NH (CH 2) 2 -NH-

is called:

  [C-C] -pentane-1,5-dioic acid bis - [(2-amino)

-ethyl) -amide] -bis- (vancomycin).

  A compound of formula I wherein p is 2 and q is 1, and a first ligand is [V] -n-decylaminoethylvancomycin, and a second ligand is vancomycin, the ligands being bound by their carbon ends [ C] by a group:

  -NH- (CH 2) 2 NHC (O) (CH 2) 3 C (O) NH (CH 2) 2 -NH-

is called:

  ([V] -n-decylaminoethylvancomycin) - [C-C] pentane-1,5-dioic bis - [(2-aminoethyl) amide] - (vancoric)

  mycine). A compound of formula I wherein p is 2 and L ligands consist of two molecules of [V] -3-dimethylaminopropyl-vancomycin bound by their carbon ends [C] by a group:

  -NH- (CH 2) 2 NHC (O) (CH 2) 3 C (O) NH (CH 2) 2 -NH-

is called:

  [C-C] -pentane-1,5-dioic bis - [(2-amino) acid

  ethyl) -amide] -bis - ([V] -3- (dimethylamino) propylvancomycin).

  A compound of formula I in which p is equal

* to 2 and L ligands consist of two vancomycin molecules

  cine linked by their ends vancosamine [V] by a group:

- (CH 2) 2 NHC (O) (CH 2) 3 C (O) NH (CH 2) 2

is called:

  [V-V] -pentane-1,5-dioic acid bis - [(2-ethyl) -

amide] -bis- (vancomycin).

  A compound of formula I wherein p is 2 and a ligand L consists of a vancomycin molecule bound by its carbon end [C] and the second ligand L

  consists of a molecule of vancomycin bound by its

  mite vancosamine [V] by a group:

  -NH- (CH 2) 2 NHC (O) (CH 2) 3 C (O) NH- (CH 2) 2

  is called [C-V] -pentane-1,5-dioic acid [(2-aminoethyl) -

  amide] - [(2-ethyl) -amide] -bis- (vancomycin). A compound of formula I wherein p is 2 and the ligands L consist of two vancomycin molecules linked by their methylamino ends [ N] by a group:

- (CH 2) 2 NHC (O) (CH 2) 3 C (O) NH (CH 2) 2

is called:

  [N-N] -pentane-1,5-dioic acid bis - [(2-ethyl) -

  amide] -bis- (vancomycin). A compound of formula I in which p is 2 and the first ligand L consists of a vancomycin molecule bound by its carbon end [C] and the second ligand L consists of a vancomycin molecule linked by its end methylamino [N] by a group:

  -NH- (CH 2) 2 NHC (O) (CH 2) 3 C (O) NH (CH 2) 2

is called:

  [C-N] -pentane-1,5-dioic acid [(2-aminoethyl) -

  amide] - [(2-ethyl) -amide] -bis- (vancomycin).

UTILITY

  The multi-linkers of the present invention, comprising the compounds of formula I and their salts

  pharmaceutically acceptable salts, are useful in treating

  and have biological activity, particularly antibacterial activity, which can be demonstrated in the tests described in the examples. These

  The tests are well known to those skilled in the art and are

  and described in the fourth edition of "Antibiotics in Laboratory Medicine", by Victor Lorian, MD, published by Williams and Wilkins, which is cited by way of reference. PHARMACEUTICAL COMPOSITIONS The compounds of the present invention, including the compounds of formula I and their pharmaceutically acceptable salts which are active when administered orally, may be formulated as liquids, for example syrups, suspensions or emulsions,

  tablets, capsules and tablets.

  A liquid composition generally consists of a suspension or solution of the compound or its pharmaceutically acceptable salt in one or more suitable liquid vehicles, for example ethanol, glycerol,

  sorbitol, a non-aqueous solvent such as polyethylene

  glycol, oils or water, with an implementing agent

  suspension, a preservative, a surfactant, a wetting agent

  lant, a flavoring agent or dye. Alternatively, a liquid formulation may be prepared from a reconstitutable powder. For example, a powder containing the active compound, a suspending agent, sucrose and a sweetener may be reconstituted with water to form a suspension; and a syrup can be prepared from a powder containing the active ingredient, sucrose and a sweetener. A composition in tablet form can be

  prepared using one or more pharmaceutical carriers

  any suitable polys used conventionally for the preparation of solid compositions. Examples of such carriers include magnesium stearate, starch, lactose, sucrose, microcrystalline cellulose and binders, for example polyvinylpyrrolidone. The tablet may also be provided with a colored film coating, or a colorant may be included as a

  part of the support (s). In addition, the active compound can be formulated into a controlled release dosage form consisting of a tablet comprising a hydroentanglement matrix

  phile or hydrophobic. A capsule composition can be prepared using standard encapsulation procedures, for example by incorporating the active compound and excipients into a hard gelatin capsule. Alternatively, a semi-solid matrix of active compound and a high molecular weight polyethylene glycol can be prepared and packaged in a hard gelatin capsule;

  or a solution of active compound in polyethylene

  glycol or a suspension in an edible oil, by

  liquid paraffin or fractional coconut oil

  born, can be prepared and packaged in a capsule of

soft gelatin.

  The compounds of the present invention, including the compounds of formula I and their pharmaceutically acceptable salts which are active when administered parenterally, may be formulated for administration

  intramuscular, intrathecal or intravenous.

  A typical composition for intramuscular or intrathecal administration is a suspension or solution of the active ingredient in an oil, for example peanut oil or sesame oil. A typical composition for intravenous or intrathecal administration is a sterile isotonic aqueous solution containing, for example, the active ingredient and dextrose or sodium chloride, or a mixture of dextrose and sodium chloride. Other examples are lactate for injection Ringer solution, lactate Ringer solution plus dextrose for injection, Normosol-M with dextrose, Isolyte E, acylated Ringer's solution for injection,

  etc. Optionally, a cosolvent, for example the poly-

  ethylene glycol, a chelating agent, for example ethylenediaminetetraacetic acid, and an antioxidant, for example sodium metabisulfite, may be incorporated into the formulation. Alternatively, the solution can be lyophilized and then reconstituted with a suitable solvent just

before administration.

  The compounds of the present invention, comprising the compounds of formula I and their pharmaceutically acceptable salts which are active by rectal administration,

  can be formulated as suppositories. A formulation

  suppository is usually the active ingredient with a binder and / or lubricating agent such as gelatin or cocoa butter or other wax or

  Vegetable or synthetic fat with a low melting point.

  The compounds of formula I and their pharmaceutical salts

  Ceutically acceptable salts that are active by topical administration can be formulated as transcutaneous compositions. Such compositions include, for example, a base sheet, an active compound reservoir, a control membrane, a coating and a contact adhesive. The conventional daily dose of a compound of formula I varies according to the individual needs, the condition to be treated and the

  the route of administration. Suitable doses are

  in the general range of 0.01 to 100 mg / kg / day, preferably 0.1 to 50 mg / kg / day. For an average human patient of 70 kg, this corresponds to a quantity of 0.7 mg

  7 g per day, preferably 7 mg to 3.5 g per day.

  The specialist in the treatment of such diseases may, without undue experimentation and based on his personal knowledge and description of the

  present application, determine a therapeutically effective amount of the compounds of the present invention, comprising

  the compounds of formula I for a given disease.

  METHODS OF PREPARATION Binding Group The linking group (s), when covalently attached to multiple copies of the ligands, provide a biocompatible, substantially non-immunogenic, multi-binding agent. The biological effects of the multi-linker are extremely sensitive to valence, geometry, composition, size, flexibility or rigidity, presence or absence of anionic or cationic charge, and similar considerations. (including hydrophilicity and hydrophobicity as described below) for the linking group. Accordingly, the linking group is preferably selected to achieve a desired biological effect

  which is maximal. The linking group can be biological-

  "neutral", that is to say does not itself contribute to any biological activity of the compound of formula I, or it can be chosen to increase the biological effect of the molecule. In general, the linking group may be selected from any organic molecule that directs two or more ligands to the receptors (enzymes or enzyme substrates) and provides multivalence. In this respect, it is possible to consider that the liaison group is a "backbone" on which the

  ligands are arranged to generate the result of orienta-

  desired ligand and thereby produce a multi-link agent. For example, different orientations can be obtained by incorporating into the framework groups containing monocyclic or polycyclic groups,

  comprising aryl and heteroaryl groups, or

  containing one or more carbon-carbon multiple bonds

  carbon (i.e., alkenes and alkynes). Other groups may also include oligomers and polymers that are branched-chain or straight-chain species. In preferred embodiments, stiffness is conferred by the presence of cyclic groups (eg, aryl, heteroaryl, cycloalkyl, heterocycles, etc.). In other preferred embodiments, the ring is a hexa- or decagonal ring. In further preferred embodiments, the ring is an aromatic group

  such as, for example, a phenyl or naphthyl group.

  Different frameworks can be designed to generate preferred ligand orientations. These frameworks can be represented using an array of points (shown below) in which each point can potentially represent an atom, such as C, O, N, S, H, F, Cl, Br and F. or alternatively, the dot may indicate the absence of an atom at that position. To facilitate understanding of the framework structure, the framework is shown as a two-dimensional network in the following diagram, although obviously the framework consists of a three-dimensional network:

0 * 2 * * * * * * .....

oD * * * * * * * * * .....

0. 1 2 3 e th e?

* * * * e *. e * e e .....

a * e * * * * e

  1 2 3 4 5 6 7 8

  Each point represents an atom, chosen between atoms of carbon, hydrogen, oxygen, nitrogen, sulfur, phosphorus or halogens, or the point represents a point in space (this is that is, an absence of an atom). Only certain atoms on the grid have the ability to act as a point of attachment for the ligands, namely C, O, N, S and P. The atoms can be connected to each other by bonds (single, double or triples with acceptable forms of resonance and tautomeric forms),

  compared with the usual constraints of the chemical bond.

  Ligands can be attached to the backbone by single, double or triple bonds (with chemically acceptable tautomeric and resonant forms). Multiple link groups (2 to 10) can be attached to the framework so that the minimum, shortest path between groups

  adjacent ligands does not exceed 100 atoms or 40 angular

  stroems. The intersection of the backbone (linking group) and the ligand group and effectively the backbone (the linking group) itself may have many different binding motifs. Examples of acceptable patterns of arrangements of three contiguous atoms within the linking group and the linker-ligand interface are presented on the

following diagram.

Ccc NCC 000 SC Pcç

C C N N N C N N C N P C N

000 NCO 0CO SCO PO

OC NC NN O OO SN C P NC

CNN NNN ONN SNN PNN

CNO NNO ONO SIM PNO

ON S N NC SNS PNS

CNP NP ONP SNP PNP

000 NOC 000 SO0C POC

COO NOT SOUND

0C00 mo OM NSOO OOP

ONS N SNC OS O PSC

CSN NSN OSN SS N PSN

CSO NSO OSO SSO Ps-

c SS NSS OSS s-s-s, 1Ps-

CSP NSP OSP S-S-e

OPO NPO ONP SNPOP

c NPC

CO NPN OPC SPC PPC

CO NPO OPN S P

CP NPS OPO SPO PO0

CPP PSC OSC PFS

NPN OPP SSN

  Those skilled in the art will be able to identify binding patterns producing multivalent compounds. Methods for producing these binding patterns are described in "Advanced Organic Chemistry", 4th Edition by March (Wiley-Interscience (New York), 1992). These configurations are described in the grid of points shown in the diagram above. All possible configurations for the five preferred atoms are shown. Every atom

  has various acceptable oxidation states. Configurations

  underlined linkages are less acceptable and are not

not appreciated.

  Examples of molecular structures in which the aforementioned binding units could be used as constituents of the linking group are

presented below.

O.C

cC -c, c-O'-c cN. Córc-

  ## STR1 ##

O 0 0 0

N kN '0 No N6C

OO OO

  ## STR2 ## ## STR2 ## ## STR2 ## ## STR2 ## ## STR2 ## o o N. / N C '. N 'C'i c0 C / N "

II.I (- H. '>

N 'N 0,0N'-CZ * -O-O-H

  The identification of a suitable framework geometry for the presentation of the ligand domain is an important first step in the construction of a multivalent binding agent exhibiting increased activity. Systematic spatial search strategies can be used to facilitate the identification of frames

  preferred by an iterative process. Various strategies are known to those skilled in the art of molecular design and can be used for the preparation of the compounds of the present invention.

  For example, a divalent compound may comprise ligands (represented by L) attached to

  central core, examples of which are presented below.

L L L

L L Lx Lt L

L, ^> 5 *>, L LA

LL L

N H H

L N-LO NL

U, N LL

  O OH It should be noted that central structures other than those shown in this case can be used to determine the framing presentation orientation

  optimal ligands. The process may require the use

  multiple copies of the same core structure or combinations of different types of presentation nuclei.5 The technique described above can be extended

  to trivalent compounds, as illustrated by the structures shown below.

L L L L

L L L

L- LL

L L

The

L L

  In the same way, tetravalent structures L and

  Higher order structures can be prepared.

  As a result, it can be seen that there is a plethora of possibilities for the composition of a linking group. Examples of linking groups include aliphatic groups, aromatic groups, steroidal groups, peptides, and the like. Examples

  are peptides or polyamides, hydrocarbons,

  bures, aromatic groups, ethers, lipids,

  cationic or anionic groups or one of their associations

  tions, and many specific examples of linkage groups are presented below. However, it should be understood that various modifications may be made and equivalents may be used instead without departing from the true spirit and scope of the present invention. For example, the properties of the linking group may be modified by adding or inserting auxiliary groups into the linking group, for example to modify the solubility of the multi-linker (in water, fat, lipids, etc.). , biological fluids, etc.), the hydrophobic power, the power

  hydrophilic, flexibility of the linking group, antigenicity

  cited, the molecular dimensions, the molecular weight, the

  in vivo half-life, in vivo distribution, biocompatibility

  immunity, stability, etc. For example,

  the introduction of one or more groups poly- or preferably

  Oligo (ethylene glycol) (PEG) on the linking group increases the hydrophilicity and water solubility of the multi-linker, increases both the molecular weight and the molecular dimensions and, depending on the nature of the group of non-PeGylated binding, can increase the time of

  in vivo retention. In addition, PEG can decrease the antigen

  nicity and potentially increase the total rigidity of the

liaison group.

  Auxiliary groups that increase the hydro-

  solubility / hydrophilicity of the linking group are

  useful in practicing the present invention.

  Thus, the scope of the present invention includes the use of

  auxiliary groups such as, for example, poly (ethylene glycol), alcohols, polyols (for example glycerol, glycerol propoxylate, saccharides, including mono-, oligo and polysaccharides, etc.), carboxylates; polycarboxylates (eg, glutamic acid polymer, acrylic acid polymer, etc.), amines, polyamines (eg polylysine, poly (ethyleneimine), etc.) to increase water solubility and / or In preferred embodiments, the auxiliary group used to improve the water solubility / hydrophilicity is a polyether. In particularly preferred embodiments, the auxiliary group is a poly (ethylene glycol). Incorporation of lipophilic auxiliary groups into the linking group structure to increase the lipophilicity and / or hydrophobicity of the compounds of formula I is within the scope of the present invention. Lipophilic groups useful in the practice of the present invention include, but are not limited to, aryl and heteroaryl groups. The aromatic groups may be unsubstituted or substituted with other groups, but are at least substituted with a group which allows their covalent attachment to the linking group. Other lipophilic groups useful in the practice of the present invention include fatty acid derivatives that do not form bilayers in an aqueous medium until higher concentrations are achieved. The scope of the present invention also includes the use of auxiliary groups resulting in the incorporation of the compound of formula I into a vesicle such as a liposome or a micelle. The term "lipid" refers to any fatty acid derivative that is capable of forming a double layer or micelle so that a hydrophobic portion of the lipid material is oriented toward the double layer, while a portion hydrophilic is oriented towards the aqueous phase. The hydrophilic characteristics come from the presence of phosphato, carboxylic, sulfato, amino, sulfhydryl, nitro and other similar groups. The hydrophobicity can be conferred by incorporation of groups which include, but are not limited to, long chain saturated and unsaturated aliphatic hydrocarbon groups having up to 20 carbon atoms and such groups substituted with one or more

  aryl, heteroaryl, cycloalkyl and / or heterocyclic

  c. Preferred lipids are phosphoglycerides and sphingolipids, representative examples of which include phosphatidylcholine, phosphatidylethanolamine,

  phosphatidylserine, phosphatidylinositol, phosphatidyl

  tidique, lapalmitoyloleoyl-phosphatidylcholine, lalysophosphatidylcholine, lysophosphatidylethanolamine,

  dipalmitoyl phosphatidylcholine, dioleoyl phosphatidyl

  choline, distearoyl phosphatidylcholine or dilinoleoyl

  phosphatidylcholine. Other compounds devoid of phosphorus

  phore, such as those in the sphingolipid and glycosphingolipid categories, also

  part of the group of compounds referred to as lipids.

  In addition, the amphipathic lipids described above may be mixed with other lipids, including

triglycerides and sterols.

  The flexibility of the linking group can be reduced by incorporating auxiliary groups which are bulky and / or rigid. The presence of large or rigid groups may hinder the free rotation around the bonds in the linking group or bonds between the linking group and the auxiliary group (s) or bonds between the linking group and the functional groups. The rigid groups may include, for example, groups whose conformational lability is restricted by the presence of nuclei and / or multiple bonds, for example aryl, heteroaryl, cycloalkyl and / or heterocyclic groups. Other groups that can confer rigidity include groups

  polymers such as oligo- or polyproline chains.

  Rigidity can also be electrostatically imparted. Thus, if the auxiliary groups are negatively or positively charged, the auxiliary groups charged in a similar manner

  presentation link group to acquire a configura-

  offering the maximum distance between the different identical loads. The energy cost of bringing identical charge groups closer to one another tends to maintain the linkage group in a configuration that maintains separation between the auxiliary groups of identical charges. In addition, auxiliary groups carrying opposite charges tend to be attracted to their

  analogs of opposite charge and can participate potential-

  inter and intramolecular ionic bonds.

  This non-covalent bonding mechanism tends to maintain the bonding group in a conformation that permits bonding between the opposing charge groups. The addition of auxiliary groups which are charged or, alternatively, which carry a latent charge which is unmasked, after addition to the linking group, by deprotection, pH variation, oxidation, reduction or other known mechanisms of the man

  of the art, is within the scope of the present invention.

  Rigidity can also be conferred by a

  internal hydrogen bond or hydrophobic collapse.

  The bulky groups may include, for example, large atoms and / or ions (eg iodine, sulfur, metal ions, etc.), groups containing large atoms, polycyclic groups, including aromatic groups, non-ionic groups, and the like. aromatic and structures containing one or more carbon-carbon multiple bonds (i.e., alkenes and alkynes). The

  large groups may also include oligomics

  mothers and polymers that are branched-chain or straight-chain entities. It is expected that entities that are branched cause an increase in the rigidity of the structure by unit molecular weight gain greater than that

  caused by the straight-chain entities.

  The suppression or reduction of the antigenicity of the compounds of formula I by a judicious choice of one or more auxiliary groups is within the scope of the present invention. In some applications, the antigenicity of a compound of formula I can be reduced or suppressed using groups such as, for example, poly (ethylene glycol). As explained above, the multi-linkers of the present invention comprise 2 to ligands attached to a linking group that connects the ligands such that these ligands are presented to the multivalent enzyme receptors for multivalent interactions with the appropriate receptors (ligand binding site). The linking group imposes a spatial constraint on these interactions to occur in the dimensions defined by the linking group, which increases the biological effect of the multi-link agent,

  compared to the same number of separate units of the ligand.

  The multivalent compounds of the present invention

  tion, consisting of the compounds of formula I, are

  by the empirical formula (L) p (X) q. This formula is

  intended to designate the different ways in which

  which ligands can be linked together to achieve the desired multivalence goal, and a more detailed explanation is presented below. However, as mentioned above, it is possible to consider that the linking group is a framework, and it should be understood that the ligands can be attached to this framework at any intermediate point on the framework, and / or on the ends of the frame. For example, if the linking group consists of a linear chain, a divalent compound can be constructed by attaching two ligands at both ends of the linear chain or, alternatively, by attaching two ligands to a certain intermediate atom along the chain . The same

  This consideration applies to the compounds of this invention

  containing more than two ligands.

  The simplest (and preferred) multiple linker is a divalent compound, which may be represented by the formula L-X-L, wherein L is a ligand, the L ligands are the same or different, and X is the linking group. It should be noted that the X linker group may be linear or cyclic, or consist of a combination of linear and cyclic constructs, and that both ligands may be located at the ends of the linker group or may be attached to a linker. certain point of intermediate fixation. This also applies to a trivalent compound, which can also be linearly represented, i.e., as a sequence of LXLXL repeats, where L is a ligand, the ligands L being the same or as X, or to a compound comprising three ligands attached to a central nucleus and thus represented by the formula (L) 3X, in which the linking group X could comprise, for example,

  for example, an aryl or cycloalkyl group.

  The same considerations of geometry apply

  the compounds of the present invention containing 4 to 10 ligands. For example, a tetravalent compound could be represented by the formula L-X-L-X-L-X-L or L-X-L-X-L L, i.e., a branched construct analogous to butane isomers (n-butyl, sec-butyl, tert-butyl). Alternatively, it could be represented as an aryl or cycloalkyl derivative as above with four ligands attached to the central linking group. The same principle applies to higher multi-linkage agents, eg pentavalent to decavalent compounds. However, for multi-linkers attached to a central linking group such as a benzene ring, there is the obvious constraint of the need for a number of binding sites on the binding moiety sufficient to receive

  the number of ligands present; for example, a benzene nucleus

  It may not receive more than six ligands, while a saturated and / or multicyclic linking group (cyclohexyl, cyclooctyl, biphenyl, etc.) may receive a greater number of ligands. The formula (L) p (X) q is also intended to represent a cyclic compound of formula L XL / X (-L-X-) n, in which n has a value of 2 to 10, for example

in which n is 3.

  All of the above variants are intended to be within the scope of the present invention in the manner

defined by the formula I (L) p (X) q.

  The preferred length of the linking group varies depending on the distance between adjacent ligand recognition sites and the geometry, flexibility, and composition of the linking group. The length of the linking group is preferably in the range of from about 2 to 100 angstroms, more preferably from about 2 to 50

  angstroms and preferably from about 5 to 20 angstroms.

  With the foregoing in mind, the preferred liaison groups can be represented by the following formula:

-X '-Z- (Y'-Z) m-Y "-Z-X' -

  wherein: m represents an integer from 0 to 20; X ', whenever it appears separately, represents a group -O-, -S-, -S (O) -, -S (O) 2-, -NR- (where R is as defined above). below, -C (O) - or a covalent bond; Z, whenever it appears separately, represents an alkylene, cycloalkylene, alkenylene, alkynylene, arylene, heteroarylene or a covalent bond; Y 'and Y ", each time they appear separately, represent a group ooo

N N N

IRI I I

R ', R' 'R' R '

/ R

/ N N -P (O) 2 (OR) -O-

R ', R'

N 'N N -S (O) .- CPR "-, -S (O) .- NR'-,

  -S-S-, or a covalent bond; formulas in which: n is 0, 1 or 2; and R, R 'and R ", whenever they appear separately, are selected from hydrogen and groups

  alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclo.

  In addition, the linking moiety may be optionally substituted at any atom in the chain with an alkyl, cycloalkyl,

  alkenyl, alkynyl, alkoxy, halo, nitro, aryl, hetero

aryl or heterocyclo.

  Preparation of compounds of formula I The preferred compounds of the present invention are those wherein p is 2 and q is 1 and

  for the sake of simplicity, the following description

  relates to the preparation of such compounds. However, it should be understood that the same principles of synthesis can be applied to all compounds falling within the scope of

present invention.

  There are many ways to prepare the compounds of the present invention. However, there are three basic themes common to their preparation: 1) Preparation of a substituted ligand (as defined above) at the [C] end, the [V] end, the [N] end , the [O] end and / or the [R] end for use in coupling reactions; 2) Preparation of a divalent compound of the present invention by coupling two ligands (identical or different, unsubstituted or substituted) with a suitable linking group at the aforementioned ends; 3) Preparation of an intermediate of a ligand having a functional group which can then be further reacted with a suitable ligand-linking or intermediate group to form a

compound of the present invention.

  Examples of these reactions are presented below.

  below. Since there is one carboxylic acid end [C], one primary amine end [V], and one secondary amine end [NI] available on glycopeptide ligands for binding reactions, one of the most general reactions used for this The end is the reaction between a carboxylic acid and an amine to form an amide. For example, as shown in FIG. 1, in reactions A and B, a carboxylic acid, for example that which is available at the [C] end, can be reacted directly with an amine to form a monoamide, or with a diamine to form a compound of the present invention. However, it is also possible to react the carboxylic acid in a manner producing an intermediate capable of further reaction, for example an amino or carboxy functional group (reactions C and D), a hydroxy group, etc., which can be used for further reaction with a suitable linking group, for example a dicarboxylic acid or

  Another possible reaction is the modification of the amine end by a reductive alkylation to form a compound according to the present invention.

  trice, formation of an amidine bond, etc. It should be understood that the shaded circle in the following figures and reaction schemes represent, for simplicity, the "core" of a linkage group. This means that a shaded circle representing two attached amino groups (Formula 2) represents any diamino compound which can be used in a coupling reaction, for example 1,6-diaminohexane,

  1,2-bis (aminomethyl) phenyl, 1,4-bis (aminomethyl) cyclohexyl

  hexane, etc. A complete list of diamines available in

  the trade is available on the ACD catalog.

HN-R '() FIGURE 1

H2N-RI (!) O

A N AOH A H

O H2N -, --- NH2 (2) 0 0 O

  ## STR5 ##

* B H

  Formula I PG Suppression ## EQU1 ## (3) PG of protection A ## EQU1 ## CA N-tdK-H A H-NH 2 O OPG O Suppresnion o> 0H OPG A -GO of protection_ H> -OH A Embedded image where A represents a ligand or ligand

  substitute to which a carboxylic acid is attached, PG represents

  It is a protective group and the shaded circle represents a binding group eegO. It will be apparent to those skilled in the art that secondary amines may also be used in place of primary groups -NH 2 or -NHPG

represented above.

  Similarly, Figure 2 shows the reaction of an amine, for example the [V] or [N] end, with a carboxylic acid or dicarboxylic acid to form an amide or diamide. The amine may also be reacted to produce a protected intermediate with a second amino group or carboxy functional group, which may be further reacted with a dicarboxylic acid or a diamine to produce a

compound of the present invention.

  It should be noted that in reactions where a carboxylic acid is represented as a reactant, the equivalent acid chloride may be used in place of

this carboxylic acid.

FIGURE 2

A-NHi Ho <5) O> 5

A-NH A-N

E H

  HO - !! NHPG (7) .3uppres3in HO O protection O

A-NH2 -NHPG

A-N AN

C he

HO OH 6

A-NHaHO OPO <8 O d protection>

A-N OPG-A-N OH

FHH H H

  wherein A is a ligand or substituted ligand to which an amino group is attached, PG is a protecting group and the shaded circle is a "ring" of a protecting group.

  In FIG. 3, an amine, for example the

A-N O-H

  [V] or uNi, can be derivatized by a reductive alkylation reaction with an aldehyde to form a variety of carboxylates and protected with a suitable substituent gives an intermediate with a gramino or carboxy functional group (reactions And M), the shaded circle represents the products of "roup" can be used for an additional reaction with,

  In each case, a carboxylic acid, or an amine, is

form an amide.

  reductive alkylation reaction with an aldehyde to form an alkyl substituent, or may be reacted with a dialdehyde under reductive alkylation conditions to obtain a compound of the present invention. Reaction with appropriately protected aldehydes or carboxylic acids gives an intermediate with an amino or carboxy functional group (L and M reactions), the products of which can be used for further reaction with, respectively, a carboxylic acid or an amine for

form an amide.

FIGURE 3

-R9 (9)

1H

A-NH2 A-N 'R9

J H

-k --- (10)

A-NH 2 H H A-NH HN-A A-NH H

A-N2 A - NH H

  K Formula I o., PG Suppre ion (H I), p of protection A-NH, Hf-NH2

A-NH, A-NH A-NH

  L o o (12) o Suppression o H 0OPG 0 of protection

A-NH O-PG A-NH OH

  Wherein A represents a ligand or substituted ligand to which an amino group is attached, PG represents a protecting group and the shaded circle represents a "nucleus" of

liaison group.

  FIG. 4 similarly represents the derivatization of a hydroxy group, for example the

  hydroxy group of aglycone designated by [O].

FIGURE 4

Br-R13 (13)

A-OH A-OR13

  N Br O A-OH (14) A "" [OA A r O Formula I Br, PG Deletion

  A-O-HN (15) A-O PG protection A-

P

A-OHI - - -NH2

  Or O G A-OHr \ _! - 6 Suppression A-OH A- Protection OujeA-0O A

Q O-PG

  wherein A is a ligand or substituted ligand to which a hydroxy group is attached, PG is a protecting group and the shaded circle is a "ring" of

liaison group.

  Figure 5 shows the preparation of asymmetric compounds of the present invention by reaction of the above-described products having functional groups

amino and carboxyl.

FIGURE 5

A-NH, + -A 'A'

  HO zA-N Preparation of starting materials The diamines of formula (2) used as coupling reagents in Figure 1 are commercially available or are prepared by methods well known in the art. An example of such a preparation is shown below in Reaction Scheme I. It should be noted that the following reaction schemes are presented for purposes of illustration and, accordingly, are shown under

simplified form.

  Accordingly, diamines of formula (19) can be prepared as shown below

on the Reaction Scheme 1.

REACTION SCHEME 1

  0 Suppression Cl (3) 2, -1) 3) P N "of protection ci (H PGNH -_, N-NHPG 0 0I (18) HN - *, - N Hil

-H H

  (19) Formulas wherein PG represents a protecting group, preferably tert-butyl carbamate, and the shaded circle

  represents a link group core.

  Preparation of Compounds of Formula (18) As shown in Step 1 of Reaction Scheme 1, approximately two molar equivalents of an omega-amino-carbamic acid ester (formula

  (3)] are reacted with approximately one equiva-

  molar slurry of a dicarboxylic acid halide, preferably a dicarboxylic acid chloride, of formula (17). The reaction is conducted in the presence of a base

  steric hindrance, preferably consisting of diisopropanol

  pylethylamine in an inert solvent, preferably consisting of

  Methylene chloride at a temperature in the range of about 0 to 5 ° C. The mixture is then allowed to warm to room temperature. Once the reaction is almost complete, the compound of

  Formula (18) is isolated and purified by conventional means.

  Preparation of Compounds of Formula (19) As shown in Step 2 of Reaction Scheme 1, the carbamate protecting group is hydrolyzed in acidic medium. In general, a preferred acid is trifluoroacetic acid. The reaction is conducted in an inert solvent, preferably methylene chloride, at about room temperature. When the reaction is substantially complete, the compound of formula (19), which is a compound of formula (2), is isolated and

purified by conventional means.

  The linking groups used as coupling reagents in the figures above are commercially available or are prepared by methods well known in the art. Several examples of such a preparation are shown below in Reaction Schemes 2 and 3. Reaction Scheme 2 represents the preparation of a

  amino-aldehyde from the corresponding amino alcohol.

REACTION SCHEME 2

protectionH PG OxidationO, PG

- |, H H

(20) (21) (7)

  formulas in which PG represents a protecting group,

  preferably consisting of a 9-fluorenylmethoxy group

  carbonyl. Preparation of a compound of formula (7) Reaction Scheme 2 represents a process for the preparation of a protected amino aldehyde (7) from the corresponding amino alcohol (20). The amino alcohol is

  protected by a conventional technique, for example

  with 9-fluorenylmethyl chloroformate in the presence of a [DD] zuGIeATq asoduoo an icledexd ap auemwad 51 9p9ood a auasoadex it lauaoieae aqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqq adnoz6 a aquas SDAI of a EU 4o q No. aiXXTeTLxe has -oi, q 'aIIaeL' sIjÀe adno.i a 'GuG6oppAq, the aquasgxdGa i 2naq;. Daqoid ednoiE a aquessids- of saianbsaI suep sinucao; o0

(66) (86)

  Nd - Od OH N N - i ', i N ---- {o% 1 - / o uoT: p xo OZOd

O N-- _OH

(L6) (96)

(96) H OH O

UOTonpgs O (5) S D o1 O Dd'u -OIpixo

(46 (56)

  ## STR5 ## wherein R (OH) O (OH) O (OH) O (OH) O (OH) O (OH) O (OH) O (OH) O (OH) O (OH) O (OH) O (OH) O (OH) O (OH) O 1OH E QENNOIIDV2 {VfEHDS * sapXatpje, p SGAIaGp sap ieiedgld as waemad sgpgDold saixne, p aquesildea IUUOTDl.G UEMD I 'TwITTDS Z I.UeUlelJr as S * (L) ainwioi ap Gapaqaple au auop (auTpTiAd / a; our apapAxoT -i aideaxa led) auiTLwop aD suep sGnuuoD uGTq sanbiuqIaD sap -ed uoIi; Paxo aul (I) Dow-a UOiqD9; ood IoODoi-outie, the auuop inb aD 'Gseq Aun, p

REACTION SCHEME 4

t

N RR

R 'OH H2N - NH, (2) R' H -H R R '-N2

B

NH2 NH2 H2N NH2

  Formula I (22) (C-Cl formulas wherein R is hydrogen or methyl, and the shaded circle is a "linker" group.) Preparation of a [C-Cl] -linked compound of formula 1

  In general, a quantity of about two equivalents

  slow mole of a glycopeptide, for example consisting of vancomycin, is reacted with approximately one molar equivalent of the diamine of general formula (2) (e.g., a diamine of formula (19)) under conventional coupling conditions of amides. Preferably, a hindered base is used, preferably consisting of diisopropylethylamine, in the presence of benzotriazol-l-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) and lhydroxybenzotriazole. The reaction is conducted in a

  inert polar solvent, preferably N, N-dimethyl-

  formamide (DMF) or dimethylsulfoxide (DMSO), or preferably a mixture of these two solvents, at approximately room temperature. When the reaction is substantially complete, the compound of formula I is isolated and purified by conventional means, preferably purified by

  Reverse phase HPLC. The mono-add product,

  both in a compound of formula (22), is also isolated.

  Alternatively, an intermediate of formula (22) may be prepared as shown below in Reaction Scheme 5 and used to prepare a [C-C] compound of formula I.

REACTION SCHEME 5

  Preparation of a [C-C] -linked compound of formula I

H H

NH, H.N

  Fo Su ppression [C-C] formulas wherein R is hydrogen or a methyl group and PG is a protecting group,

  preferably consisting of a 9-fluorenylmethoxy group

carbonyl.

NH2 NH2 NH2

  Preparation of a compound of for (2) (22) Qo H H

NH2 H2N

  porrule [c-c] wherein R is hydrogen or methyl and PG is a protecting group,

  preferably consisting of a 9-fluorenylmethoxy group

  carbonyl. Preparing a compound of formula (21) As shown in Step 1 of Reaction Scheme 5, a glycopeptide, for example consisting of vancomycin, is reacted with approximately 1.1 molar equivalents of a carbamic ester terminated with an alkylamino group [formula (3)]. The ester group is chosen for ease of removal under mild conditions in the following reactions and is preferably a 9-fluorenylmethyl ester. Conventional amide coupling conditions are used, preferably with PyBOP and 1-hydroxybenzotriazole. In general, the reaction is conducted in the presence of a hindered base, preferably consisting of diisopropylethylamine, in an inert polar solvent, preferably consisting of DMF or DMSO, preferably a mixture of these solvents, at about room temperature . Once the reaction is substantially complete, the compound of formula (21) is isolated and purified by conventional means. Preparation of Compounds of Formula (22) As shown in Step 2 of Reaction Scheme 5, The compound of formula (21) is reacted with a mild base to remove the protective ester group, which also causes decarboxylation. In general, the base is preferably piperidine, and the reaction is conducted in an inert polar solvent,

  dimethylformamide, preferably at approximately

  ambient temperature for a time of about 10 minutes to one hour. After the reaction is substantially complete, the compound of formula (22) is isolated and purified by conventional means, preferably using

reversed phase.

  The intermediate of formula (22) can then be

  converted to a bivalent glycopeptide compound [C-C].

  Preparation of a compound of formula I As shown in step 3 of reaction scheme 5, the compound of formula (22) is reacted with a dicarboxylic acid. In general, about 3 molar equivalents of the compound of formula (22) are reacted with approximately 1 molar equivalent of the dicarboxylic acid of formula (6) under standard amide coupling conditions. Preferably, a hindered base, preferably diisopropylethylamine, is used in the presence of PyBOP and 1-hydroxybenzotriazole. The reaction is conducted in an inert polar solvent, preferably DMF, at about room temperature for about 1 to 3 hours. After the reaction is substantially complete, the compound of formula I is isolated and purified by conventional means, preferably HPLC.

reverse phase.

  In addition to the coupling of two ligands of formula (22) with a dicarboxylic acid, the compounds [C-C] of the

  present invention may also be prepared by bis-

  reductive alkylation of the ligand of formula (22) with a dialdehyde. It should also be understood that although Reaction Scheme 5 represents unsubstituted glycopeptides as ligands for the reaction, the same reaction is possible starting from a substituted (or protected) glycopeptide at the [V] position. The amino group [V] can then be further modified in subsequent steps if desired. Compounds of formula I in which the [C-C] bond in which the [V] position is substituted can be prepared from intermediates of formula (25), the preparation of which is

  shown below in Reaction Scheme 6.

REACTION SCHEME 6

  Preparation of a [C-Cl] -linked compound of formula I

H H RN "NH2

RN OH w -HG7N OH H

X.-NHPG (7)

R NOH H \ NH2 (22)

The

NH2 NZ

NHPG (25)

H O 0 H

  N X_ M.SuppressionNN R.N @ NH-A- R protectionR. N R

NH-A H2N NH \ H2N

HHlC

NHPG NH2

(26) (27)

HO H H R

N- \ H2N

  it R 'Formula 1 [C-C] formulas in which R represents hydrogen or a

  methyl group, PG represents a protective group, consisting of

  preferably to 9-fluorenylmethoxycarbonyl, and Rs is alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, all of which may be

optionally substituted.

  Preparation of a compound of formula (25) As shown in step 1 of

  Reaction Scheme 6, the amino-sugar group of glycopep-

  For example, the vancosamine moiety of vancomycin is reacted with a protected amino aldehyde of formula (7) to form a Schiff base. The ester group is selected for ease of removal under mild conditions in subsequent reactions and is preferably 9-fluorenylmethoxycarbonyl (Fmoc). In general, the reaction is conducted in a solvent

  inert polar, preferably N, N-dimethyl-

  formamide, in the presence of a hindered base, preferably diisopropylethylamine, at a temperature in the range of about 0 to 50 ° C, preferably about 25 ° C, for a time of about 5 hours, preferably about 2 hours. The Schiff base is further reacted with a mild reducing agent. In general, a protic solvent, preferably methanol, is added followed by the reducing agent, preferably sodium cyanoborohydride, followed by trifluoroacetic acid. The reaction is conducted at a temperature in the range of about 0 to 50 ° C, preferably about 25 ° C, for a time of about one hour. After the reaction is substantially complete, the compound of formula (25) is isolated and purified by conventional means, preferably purified by reverse phase HPLC. It should be noted that other intermediates can be used in place of the compound of formula (7); for example, a protected acid (to obtain an amide) or a

  alkyl or aryl group can be appended to the amine [V].

  The intermediate of formula (25) can then be converted into a divalent compound derived from vancomycin

  [C-C), wherein the [V] position is also substituted.

  Preparation of a compound of formula (26) As shown in step 2 of Reaction Scheme 6, the compound of formula (25) is reacted with a compound of formula (22), which can be prepared from As shown in Reaction Scheme 4. In general, conventional amide coupling conditions are used. Preferably, a hindered base, preferably diisopropylethylamine, is used in the presence of PyBOP and 1-hydroxybenzotriazole. The reaction is conducted in an inert polar solvent,

  preferably DMF, at approximately

  room temperature for about 1 to 3 hours. Once the reaction is substantially complete, the compound of formula (26) is isolated and purified by means

  conventional, preferably purified by reverse phase HPLC.

  Preparation of a compound of formula (27) As shown in step 3 of

  Reaction Scheme 6, the compound of formula (26) is

  classically reassured of its protection in the manner

  above, for example in step 2 of the Scheme Reaction-

  nel 5, to form a compound of formula (27).

  Preparation of compounds of formula I As shown in step 4 of Reaction Scheme 6, the compound of formula (27) is reacted with a compound of formula R5-CO2H or Rs-COCl, wherein Rs is a group alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, all of which groups may be optionally substituted. In general, conditions

  classical amide coupling are used. Preferably

  For example, a sterically hindered base, preferably diisopropylethylamine, is used in the presence of PyBOP and 1-hydroxybenzotriazole. The reaction is conducted in an inert polar solvent, preferably DMF, at about room temperature for about 1 to 3 hours. After the reaction is substantially complete, the compound of formula I is isolated and purified by conventional means, preferably purified by reverse phase CLHIP. It should be noted that it is also possible to consider that the compounds of formula (26) and (27) are compounds of formula I. In addition, step 4 may consist of any reaction which gives a substituted derivative amine group, for example reductive alkylation, alkylation, etc.

REACTION SCHEME 7

  Preparation of a [C-C] -linked compound of the formula ## STR1 ##

NH2 NH2 H2N

  (22) Formula I [C-C] wherein R is hydrogen or

methyl group.

  Preparation of a compound of formula I In general, an amount of approximately two molar equivalents of a compound of formula (22) is reacted with approximately one molar equivalent of the dialkyl halide of general formula (14) in conventional alkylation conditions in the presence of a hindered base, preferably diisopropylethylamine. The reaction is conducted in a solvent

  inert polar, consisting for example of N, N-dimethyl

  formamide (DMF) at room temperature in the range of about 40 to 100 C for a time of about 1 to 24 hours, preferably about 8 hours. Once the reaction is substantially complete, the compound of formula I is isolated and purified by conventional means,

  preferably purified by reverse phase HPLC.

  The present invention is of course widely applicable to any ligand that contains a group

free amine.

REACTION SCHEME 8

  Preparation of a [V-V] -linked compound of the formula ## STR1 ## wherein R 1 is N 2 OHH 2 N -Cl 2

OH * H H

N2-- R A I lm Hdprtcin-R 'A

NHPG NHPG NH2

(3 1) <(32)

  (25) 0 0 R'N N N-k o H o o <6) R4-j 1 NR I HN R

HO OH

F HN- \ 0S) <N

NH N H

  Formula I [V-V] wherein R is hydrogen or

  methyl group, PG represents a protective group, consisting of

  preferably, 9-fluorenylmethoxycarbonyl, and R 'is alkyl, aminoalkyl, alkylaminoalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, or a quaternary salt derivative.

  Preparation of a compound of formula (31) As shown in step 1 of Reaction Scheme 8, the carboxyl function of the compound of formula (25) is reacted with an amine of formula (1). In general, a quantity of about 1 molar equivalent

  compound of formula (25) is reacted with approxi-

  1.5 molar equivalents of the compound of formula (1) under standard amide coupling conditions. Preferably, a hindered base, preferably diisopropylethylamine, is used in the presence of PyBOP and 1-hydroxybenzotriazole. The reaction is conducted in an inert polar solvent, preferably DMF, at about room temperature for about 10 minutes to 2 hours. Once the reaction is substantially complete, the compound of formula (31) is isolated and purified by conventional means,

  preferably reverse phase HPLC.

  Preparation of a compound of formula (32) As shown in step 2 of

  Reaction Scheme 8, the compound of formula (31) is

  classically reassured of its protection in the manner

  above, for example in step 2 of the Scheme Reaction-

  nel 5, to form a compound of formula (32).

  The intermediate of formula (32) is then converted into a divalent glycopeptide compound [V-V], in which position [C] is also substituted, from

as shown below.

  Preparation of compounds of formula I As shown in step 3 of Reaction Scheme 8, the compound of formula (32) is reacted with a dicarboxylic acid (6). In general, about 3 molar equivalents of the compound of formula (32) are reacted with approximately 1 molar equivalent of the dicarboxylic acid of formula (6) under standard amide coupling conditions. Preferably, a hindered base, preferably diisopropylethylamine, is used in the presence of PyBOP and 1-hydroxybenzotriazole. The reaction is conducted in an inert polar solvent, preferably DMF, at about room temperature for about 1 to 3 hours. When the reaction is substantially complete, the compound of formula I is isolated and purified by conventional means, preferably

  purified by reverse phase HPLC.

  If, instead of preparing a substituted [C] derivative of formula (32), it is desired to prepare a free acid derivative, the compound of formula (25) can be reacted directly with a dicarboxylic acid.

  "pre-activated" formula (6), as described below.

  Another method for the preparation of compounds of formula I in which the bond is a [VV] bond and the [C] position is substituted on both glycopeptide units is the reaction of an intermediate of formula (36), the preparation such intermediaries being

  shown below in Figure 9.

REACTION SCHEME 9

  Preparation of a [V-V] -linked compound of the formula I ## STR1 ##

<32) (35) "36

H O RI N O N / Z s1S2 RN, R RR

R 'N' NN

H H R

(32 ') Nil2

N- \, 0 N '

  z N N Formula I Iv-v] formulas in which R represents hydrogen or a

  methyl group, PG represents a protective group, consisting of

  preferably to 9-fluorenylmethyl, and R 'and R1' independently represent alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl groups, all of which groups may be optionally substituted.

  Preparation of Compounds of Formula (36) As Shown in the Reaction Scheme

  9, the compound of formula (32) is reacted with a monoester of a dicarboxylic acid (8); preferably the monoester is a monoester easily hydrolyzed under mild conditions, for example a 9-fluorenylmethyl ester. In general, an amount of approximately 1 molar equivalent of the compound of formula (32) is

  react with 1 molar equivalent of the compound of formula (8).

  The reaction is conducted under standard amide coupling conditions. Preferably, a base is used

  steric hindrance, preferably consisting of diiso-

  propylethylamine in the presence of PyBOP and 1-hydroxy-

  benzotriazole. The reaction is conducted in a solvent

  inert polar, preferably consisting of DMF, approximately

  at room temperature for about 1 to 3 hours, preferably about 80 minutes. After the reaction is substantially complete, the desired product (35) is isolated by conventional means and reacted with a mild base, preferably piperidine, to remove the protecting group. The reaction is conducted in an inert polar solvent, preferably DMF, at about room temperature for about 1 to 3 hours, preferably about 15 hours. After the reaction is substantially complete, the compound of formula (36) is isolated and purified by conventional means, preferably purified by reverse phase HPLC. The intermediate of formula (36) is then converted into a bivalent compound I [V-V), in which the

  [C] position is substituted on both vancomycin subunits.

  by reaction with a compound of formula (32 ') [no

  necessarily identical to the starting material (32)].

  Preparation of compounds of formula I As shown in step 3 of Reaction Scheme 9, the compound of formula (36) is

  react with a compound of formula (32 '). In general, approxi-

As a rule, the molar equivalents of the compounds of the formula (36) and (32 ') are reacted under standard amide coupling conditions. Preferably, a hindered base is used, preferably consisting of

  diisopropylethylamine, in the presence of PyBOP and 1-hydroxy-

  benzotriazole. The reaction is conducted in a solvent

  inert polar, preferably consisting of DMF, approximately

  at room temperature for about 30 minutes to 3 hours, preferably about 1 hour. Once the reaction is substantially complete, the compound of formula I is isolated and purified by means

  conventional, preferably purified by reverse phase HPLC.

  It should be emphasized that both glycopeptides (represented by shaded boxes) may be identical

  different (or identical but substituted

  and that the linking groups, although always represented by a shaded circle, may be identical or different each time they are present.

REACTION SCHEME 10

  Preparation of a [N-N] linked compound of formula I

H 0 R

NO,

  ## STR1 ## ## STR2 ##

THE

NH2

NH2 H2NH

(43) (42)

R 0 OR

H2N NH

Suppres.ionH2N-l- N re - 1 (Ne

of protPection HO-

F NH, (43) Ri O R R O Ri

HN H2

  Formula I (N-N N formulas wherein R is hydrogen or methyl, PG is a protecting group, preferably 9-fluorenylmethoxycarbonyl, and R 'is alkyl, aryl, heteroaryl, arylalkyl , heteroarylalkyl or a derivative consisting of

quaternary salt.

  Preparation of Compounds of Formula (41) As shown in Step 1 of Reaction Scheme 10, a glycopeptide consisting of

  vancomycin, is reacted with an amino

  aldehyde protected under conditions sufficient to direct the aldehyde to the [N] position. The Schiff base thus formed is reduced as shown in step 1 of Reaction Scheme 6, to form a compound of formula (41). Preparation of compounds of formula (42) As shown in step 2 of Scheme Reactive 10, the compound of formula (41) is reacted with an amine (1) in a coupling reaction as indicated above, for example in step 1 of

  Reaction Scheme 8, to form an amide of formula (42).

  Preparation of Compounds of Formula (43) As shown in Step 3 of Reaction Scheme 10, the compound of Formula (42) is conventionally stripped of its protection as shown above, for example in Step 2 Diagram

  Reaction 5, to form a compound of formula (43).

  Preparation of Compounds of Formula I As shown in Step 4 of Reaction Scheme 10, the compound of Formula (43) is reacted with a dicarboxylic acid as indicated above, for example in Step 3 of Reaction Scheme 8 to give a compound of formula I which is isolated and purified by conventional means, preferably by HPLC at

reversed phase.

aglycone

  As described above, the present invention also includes glycopeptide aglycone derivatives, for example, vancomycin lacking the amino-sugar moiety. Such a compound has a hydroxy group as a point of attachment in place of the

  amino group [V] of the amino sugar. On the reaction patterns

  In the following, the aglycones are represented as described above, which means that they are represented as a shaded triangle which has only the carboxyl end, the hydroxy end of the aglycone, and

the amino end.

  Reaction Scheme 10 represents the preparation

  a bivalent compound consisting of an aglycone of

  glycopeptide. The glycopeptide is initially substituted at the [C] position with an amide, then the amino sugar is hydrolysed, and finally, the coupling of the phenol thus produced is achieved.

REACTION SCHEME 11

  Preparation of a [O-O] -linked compound of formula I

R O H2N-R '(1) O

HN OH U2 R (IHN R R NH 'R! A Acid

NH, NH2

(46) (47)

RINH NHRI

Br BI 1_ __ * __ Br (0)

R.NH H N R

  Formula I [o-o] wherein R is hydrogen or methyl and R 'is alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, all of these groups

  which may be optionally substituted.

  Preparation of Compounds of Formula (46) As shown in Step 1 of Reaction Scheme 11, a glycopeptide, for example vancomycin, is reacted with an amine (1) in a coupling reaction as indicated in FIG. above, for example in step 1 of Reaction Scheme 8, to form an amide of formula (46), which is isolated and purified by

conventional means.

  Preparation of compounds of formula (47) As shown in step 2 of Reaction Scheme 11, the glycopeptide of formula (46) is

  hydrolysed with a strong acid, preferably at a temperature of about 50 ° C, to produce an aglycone of formula (47) which is isolated and purified by conventional means.

  Preparation of compounds of formula I As shown in step 3 of Reaction Scheme 11, two equivalents of the compound of formula (47) are reacted with a dihalo compound of formula (10), which gives a compound of formula I [O-O]. The reaction is conducted in a polar solvent, preferably DMF, in the presence of a base, preferably potassium carbonate, for about 30 hours. The compound of formula I is isolated and

purified by conventional means.

  Alternatively, as shown in Reaction Scheme 12, the compound of formula (47) may be first reacted with a protected haloamine, for example, tert-butyl N- (2bromoethyl) carbamate, which which gives an aminoether of formula (51), which is then deprotected and further reacted with a dicarboxylic acid to give a compound of formula I.

REACTION SCHEME 12

  Preparation of a compound [O-Ol, of the formula I ## STR1 ## in which: ## STR1 ##

(47) (51) (52)

R 0 R 'R 1 R

HN N '' N-, NH

> ^ - ^ - ^ (6) H

HO OH

  Formula I wherein R is hydrogen or methyl and PG is a protecting group, preferably BOC, and R 'is alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, all of which groups that can be optionally substituted. Preparation of a compound of formula (51) As shown in step 1 of Reaction Scheme 12, an aglycone of formula (47) is

  reacted with a protected halogenamine, for example tert-butyl N- (2-bromoethyl) carbamate, under standard coupling conditions, preferably using potassium carbonate as a base in an inert polar solvent, preferably DMF or DMSO, approximately

  at room temperature. After the reaction is substantially complete, the compound of formula (51) is isolated and purified by conventional means. Preparation of a compound of formula (52) As shown in Step 2 of Scheme Reactive 12, the protecting group (carbamate) is hydrolysed under acidic conditions. In general, a preferred acid is trifluoroacetic acid and the reaction is conducted in an inert solvent at approximately room temperature. Once the reaction is substantially complete, the compound of formula (52) is isolated and purified

by conventional means.

  Preparation of compounds of formula I As shown in step 3 of Reaction Scheme 12, two equivalents of the compound of formula (52) are reacted with a dicarboxylic acid of formula (6) to give a compound of formula I [OO]. The reaction is carried out under standard amide coupling conditions described in detail above, for example in step 3 of Reaction Scheme 8, to give a compound of formula I. Alternatively, as shown in FIG. Reaction Scheme 13, the compound of formula (47) may be first reacted with a haloester, for example tert-butyl bromoacetate, to give a carboxy-substituted ether, which is then stripped of its protection, then further reacted with a diamine to give a compound of formula I.

REACTION SCHEME 13

  Preparation of a [O-O] -linked compound of the formula I ## STR1 ##

(47) (56> (57)

R 0 RR 0

  H? 42N -.- NH 2 HN FieHR <H of pr ..... tion Br OP FIRoI e I bo-01

[O-O] O

  where R is hydrogen or methyl and PG is a protecting group, and R1 is alkyl, aryl, heteroaryl, arylalkyl

  or heteroarylalkyl, all of which groups may be optionally

  substituted. Preparation of compounds of formula (56) As shown in step 1 of Reaction Scheme 13, an aglycone of formula (47) is reacted with a haloester under standard coupling conditions, preferably using sodium carbonate. potassium as a base in a polar solvent

  inert, preferably DMF or DMSO, approximately

  at room temperature. Once the reaction is practical

  Once completed, the compound of formula (56) is

  isolated and purified by conventional means.

  Preparation of a compound of formula (57) As shown in step 2 of Reaction Scheme 13, the protecting group (carbamate) is hydrolyzed under acidic conditions. In general, a preferred acid is trifluoroacetic acid and the reaction is

  in an inert solvent at approximately

  ambient temperature. Once the reaction is substantially complete, the compound of formula (57) is isolated and purified

by conventional means.

  Preparation of Compounds of Formula I As shown in Step 3 of Reaction Scheme 13, two equivalents of the compound of Formula (57) are reacted with a diamino compound

  of formula (2) to give a compound of formula I [O-01.

  The reaction is carried out under standard amide coupling conditions as described in detail above. Preferably, a hindered base, preferably diisopropylethylamine, is used in the presence of PyBOP and 1-hydroxybenzotriazole. The reaction is conducted in an inert polar solvent, preferably DMF, at about room temperature

  for about 30 minutes to 5 hours, preferably about 2 hours. After the reaction is substantially complete, the compound of formula I is isolated and purified by conventional means, preferably purified by reverse phase HPLC.

  A novel type of chemical modification of glycopeptides is described in a recent publication of The Institute of New Antibiotics, Russian Academy of Medical Sciences, B. Pirogovskaya 11, 119867 Moscow, Russia. The reaction described in this publication uses the Mannich reaction to derivatize the glycopeptide at the position between the two hydroxy meta groups on the "resorcinol" group (identified above in Structure II as position [R]). This type of reaction can be used to prepare compounds of the present invention,

  as shown below in Reaction Scheme 14.

REACTION SCHEME 14

  Preparation of a [R-R] -linked compound of formula I R o R R o

OH NH OH

  H2N - & - NH2 (2) OH OH NH, HN I N1i2

OH OH OH

  Formula I [-R] wherein R is hydrogen or

methyl group.

  Preparation of a compound of formula I

  As shown in Reaction Scheme 14, a glycopeptide, consisting for example of vancomycin,

  cine, is bound in position [R]. In general, an amount of approximately two molar equivalents of a glycopep-

  The acid, consisting for example of vancomycin, is reacted with approximately two molar equivalents of formaldehyde and one molar equivalent of diamine (2). The reaction is conducted in an inert polar solvent,

  preferably consisting of an aqueous solution of acetonitrile

  trile, for a time of about 18 hours. Once the reaction is substantially complete, the compound of formula I is isolated and purified by conventional means,

  preferably purified by reverse phase HPLC.

  Secondary amines can be used in place of the primary amines of the linking group of the formula

  (2) if desired, and the [C] position may be substituted

  killed, for example by an NHR1 group, in the manner

  previously, if preferred.

  Alternatively, the Mannich reaction can be used to introduce an amino side chain or acidic side chain at the [R] position (e.g. as shown for the compound of formula (82), which can then be reacted supplement with a suitable linking group (a diacid, a dialdehyde or a

  compound with dihalo function) in the manner shown below.

  to produce a compound of formula I. Compounds of formula I in which the bond is a [C-V] bond may be prepared as shown below in Reaction Schemes

at 20.

REACTION SCHEME 15

  Preparation of a [C-VI] -linked compound of formula I

[! O

R'N X WOH NlYO OH NHPG

(25) (60) NH2

OH

Pre-activationHe; l, H2RN NI

HH (60O

NHPGH O

H O

HH O H

HO XN R HO N 'R

  NR suppressesHO? R R94 (9) H & R protectionN-N HP has N

R '! 0 R' H

NH2 N "HR9

NHPG (62) Formula I Formula I [C-V]

([C-V]

  formulas in which R represents hydrogen or a

  methyl group, PG represents a protective group, consisting of

  preferably, 9-fluorenylmethoxycarbonyl, and R 9 is alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, or a quaternary salt derivative. Preparation of a compound [C-V] of formula I In general, the compounds [CV] of formula I are prepared by procedures of Reaction Scheme 15 using the reactions described above. However, an important difference is that the carboxy [C] group of the compound of formula (25) is preferably "preactivated" before reaction with the compound of formula (60), since compound (60) also contains a group free carboxy.

REACTION SCHEME 16

  Preparation of a [C-V] -linked compound of formula I

H O R '0 N IR

  R'N WHO H of protection R NWH> - * - HA G R EN SiuppreaailonR, <N,

N- N

(32) NH2 11NNN

(65) (66)

H O RI

R. N \ 1OH H

NH2 HNR

  ## STR2 ## wherein R is hydrogen or

  methyl group, PG represents a protective group, consisting of

  preferably, a 9-fluorenylmethoxycarbonyl group, and R 'represents an alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl group, or a derivative consisting of a

quaternary salt.

  Preparation of a compound of formula (66)

  As shown on the Reaction Scheme-

  16, the compound of formula (32) is reacted with an N-protected amino acid (7) as indicated above, for example in step 1 of Reaction Scheme 9, for

  form a protected amide, which is then disposed of

  protection, for example in the manner indicated in step 2 of Reaction Scheme 5, to form a

compound of formula (66).

  The compound of formula (66) is then converted to a divalent compound [C-V] of formula I by reaction with

  a glycopeptide, for example vancomycin.

  Preparation of Compounds of Formula I As shown in Step 3 of Reaction Scheme 16, the compound of Formula (66) is reacted with a glycopeptide in a conventional coupling reaction, as shown above; which gives

a compound of formula I [C-V].

  The Reaction Scheme 17 represents the preparation

  of compounds [CV] of formula I using the techniques described above, i.e., reductive alkylation to produce a protected amino-protected "stick", followed by coupling of the [C] position to a compound to

  amino substituent [V] and a deprotection.

REACTION SCHEME 17

  Preparation of a [C-V] -linked compound of formula I

H'O R '

NH 2 L (66) Ht (6) N-R 2 z o ,, orp- *

N \ * G-H2 2

R 'R R' OR

N'N O

N 'H PN L

NHN (NH,

  NR2N (69)) Formula I (C-V) wherein R is hydrogen or

H H O'F0 R

  groupemethyl, PGrep S upprét n, preferably a 9-fluorenylmethoxycarbonyl group, and R and R2

  independently represent an alkyl, aryl or hetero group.

  aryl, arylalkyl or heteroarylalkyl, or a derivative thereof

consisting of a quaternary salt.

  Compounds of formula I in which the bond is a [C-y] bond may be prepared from intermediates of formula (72), the preparation of which is

  shown below on the Reaction Scheme 18.

  H0 groupethyl, Prepresene a group of protectorsprepared N-ungOuploéymtoyabn, e Rereaneanand ndpedmmntu gue lyl, rye hteo of intermediates (69 of ormul e X7) otl rprto s ruemtye Represented ce-esus suroupe Scéaroéctinelr de

REACTION SCHEME 18

  Preparation of a [C-V1] -linked compound of formula I ## STR1 ##

NH2 H2

(22) (7 1>

H O I

N N

N RH R 'N N / "rN--% - N H NOH

(O O

NH2 (72)

R'O H

N * NR HR

R 'N -'- NH 4HN

  wherein R represents hydrogen or a methyl group, PG represents a protecting group, for example a 9-fluorenylmethyl group, and R 'represents a

  alkyl, alkylamino, alkylaminoalkyl, aryl, heteroaryl,

  aryl, arylalkyl or heteroarylalkyl, or a derivative

in a quaternary salt.

  Preparation of a compound of formula (72) As shown in step 1 of Reaction Scheme 18, the compound of formula (22) is reacted with an acid as indicated above, e.g. step 1 of Reaction Scheme 9, to form a protected amide, which is then conventionally freed from its protection, for example as indicated in step 2 of Reaction Scheme 9, to form a

formula (72).

  Then the compound of formula (72) is converted to a divalent compound [CV] of formula I by reaction with a compound of formula (32), prepared as described

  previously, as indicated on the Reaction Scheme-

nel 6.

  Preparation of compounds of formula I As shown in step 3 of Reaction Scheme 18, the compound of formula (72) is reacted with a compound of formula (32) in a conventional coupling reaction, as shown above,

  to give a compound of formula I [C-V].

  The compound of formula I [C-V] thus prepared is substituted at the second end [C] (by a group R1NH). The free acid (i.e., with the unsubstituted [C] end) can be obtained, if desired, by replacing the compound of formula (32) with the compound of formula (60) and pre-activating the compound of formula (72)

the way explained above.

  Compounds of formula I, wherein the bond is a [C-V] bond and the [C] end of a vancomycin, and the [V] end of a second vancomycin are both substituted can be prepared from intermediates of formula (77), the preparation of which is

  shown below on the Reaction Scheme 19.

REACTION SCHEME 19

  Preparation of a [C-V] -linked compound of formula I

H O

N H H (9) R NO H2N - NH2 (2) H R-NO

B

NH, N R9 R9

H

(76) (77)

H Ri R

R.N NR

H Formula I [CV

H H

OH- 'H - H H

  wherein R is hydrogen or methyl, PG is a protecting group, preferably 9-fluorenylmethoxycarbonyl, and R1 and R9 are independently selected from hydrogen, alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl,

  and a quaternary salt derivative.

  Preparation of a compound of formula (76) As shown in step 1 of Reaction Scheme 19, a glycopeptide, consisting for example of vancomycin, is reacted with an aldehyde of formula R9CHO, using an excess of a base to direct the alkylation at the [V] position. The Schiff base thus formed is reduced as indicated in step 1 of Reaction Scheme 6 to form a compound of formula (76). Preparation of compounds of formula (77) As shown in step 2 of Reaction Scheme 19, the compound of formula (76) is reacted with a diamine (2) to form an amide of formula (77). The compound of formula (77) is then converted into a divalent compound [CV] of formula I (wherein the [C] end of a glycopeptide and the [V] end of a second glycopeptide are one and the other substituted) by reaction with a compound of formula (36) prepared from

  as shown in Reaction Scheme 9.

  Preparation of compounds of formula I As shown in step 3 of Reaction Scheme 19, the compound of formula (77) is reacted with a compound of formula (36) in a conventional coupling reaction shown above, to give a compound of formula I [CV] in which the [C] end of a glycopeptide and the [V] end of a second glycopeptide are

in addition substituted.

  Compounds of formula I, wherein the bond is a [C-V] bond and the [C] end of a vancomycin, and the [V] end of a second vancomycin are both substituted , can also be prepared

  from intermediates of formula (32), the preparation of which

  This is shown below in Reaction Scheme 20.

REACTION SCHEME 20

  Preparation of a [C-V] -linked compound of the formula

R 0

R'N NHN N

H R '- -H N N

NHzo NH, NH2

(32) (22)

(22)

H 0 DI

N N "

R N |

NOT

N9NH: / I

  H2N Formula I [C-V] wherein R is hydrogen or methyl, and R1 is alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, all of these groups

* may be optionally substituted.

  Preparation of a compound of formula I In general, a molar equivalent of a compound of formula (32) and a molar equivalent of a compound of formula (22) are reacted with one molar equivalent of a bisimidate of formula (38) under conventional coupling conditions. Preferably, a crowded base is used

  steric, preferably diisopropylethylamine.

  The reaction is carried out in an inert polar solvent, for example N, N-dimethylformamide (DMF), for a time of about one hour. After the reaction is substantially complete, the compound of formula I (with a bis-amidine linkage group) is isolated and purified by conventional means, preferably purified by

reversed phase.

  It should be noted that this reaction, which gives a bis (amidine) linking group, can be used in the same way on any amine shown in the previous examples to obtain amidine linkage groups between all the ends of a glycopeptide ([CC],

[IV-V], etc.).

  Compounds of formula I in which the bond is a [C-N] bond can be prepared from

  intermediates of formula (43), the preparation of which has been shown in reaction scheme 9.

REACTION SCHEME 21

  ## STR2 ## ## STR2 ##

NH2 NH2

(72) (43)

H O0 R 0 R

R 'N-s --NH IIN N

H H

NH2 NH2

  Formula I [C-N] wherein R is hydrogen or methyl and R 'is alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, all of these groups

  which may be optionally substituted.

  Preparation of a [C-NI] -linked compound of formula I

  As shown on the Reaction Scheme-

  21, the compound of formula (72) is reacted with a compound of formula (43) in a conventional coupling reaction shown above to give a compound of

formula I [C-N].

  Compounds of formula I wherein the bond is an [N-V] bond may be prepared by reacting a compound of formula (36) with a compound of formula (43), as shown in Scheme

Reaction 22.

REACTION SCHEME 22

I t0 RI

R 'N N' R O

I1 R

+ H2N -, + N

ON I NH2

H OH (43)

(36)

H O R

0 R 'N

RW N

H

N __I R 0

H HN-.q "N

V H

  Formula I NH [N-V] wherein R is hydrogen or methyl, and R 'and R1' are alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, all of which are

  groups that can be optionally substituted.

  Preparation of a [N-V] Binding Compound of Formula I

  As shown on the Reaction Scheme-

  22, the compound of formula (36) is reacted with a compound of formula (43), the preparation of which is described in detail below, in a conventional coupling reaction shown above to give a compound of formula (I)

[N-V].

REACTION SCHEME 23

  Preparation of a [C-R] -linked compound of formula I

H O H O

R 'N NHR' R 'N NHRI

H2N-i-NH2 (2) CHO

H2 CHO 'NH2

HH2

OH OH

(81) (82)

11 0

NHI O

H O

OH N

R'N NHIR '

  ## STR2 ## Formula I IC-Rf Preparation of a [CR] -binding compound of formula I As shown in Reaction Scheme 23, the compound of formula ) is reacted with a diamine and formaldehyde, using standard reaction conditions for the Mannich reaction, to give a compound of formula (82). Then this amino-functional derivative is coupled with a glycopeptide, in a conventional coupling reaction shown above, which gives a

compound of formula I [C-R].

  Isolation and Purification of Compounds The isolation and purification of the compounds and intermediates described herein may be carried out, if desired, by any suitable separation and purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin layer chromatography, thick layer chromatography, preparative low or high pressure liquid chromatography or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures may be

  be obtained by reference to the examples below. How-

  However, other equivalent separation and isolation procedures could of course also be used.

EXAMPLE 1

  Preparation of a diamine of formula (2) (1) Preparation of a compound of formula (18) Glutaryl dichloride (17) (0.6 ml, 4.7 mmol) in 15 ml of methylene chloride was added dropwise to a solution of N- (2-aminoethyl) carbamate

  tert-butyl (3) (2.3 g, 14.4 mmol) and N, N-

  diisopropyl-ethylamine (2.5 ml, 14.3 mmol) in 15 ml of methylene chloride at 0 ° C. The resulting mixture was allowed to warm to room temperature with stirring, with simultaneous addition of water (15 ml). Methylene chloride was removed under reduced pressure and a quantity of water

  additional (30 ml) was added. The suspension results

  The aunt was filtered and washed successively with 10% potassium hydrogen sulfate solution, water, saturated sodium bicarbonate solution and water. The solid was dried in vacuo to give 1.3 g (3.1 mmol, 66%) of pentanedioic acid bis - [(2-tert-butoxycarbonylaminoethyl) amide], a compound of formula (18). (2) Preparation of a compound of formula (19) The compound of formula (18) prepared above (1.3 g, 3.1 mmol) was suspended in 15 ml of methylene chloride. 15 ml of trifluoroacetic acid were

  added at room temperature, which gave (with effec-

  vescence) a solution which was stirred for 40 minutes and then evaporated under vacuum. The residue was dissolved in methanol and treated with 3 ml of a solution of 4N hydrogen chloride in dioxane and then with diethyl ether to give a gum. The liquids were decanted and the gum was dried under vacuum to give 1.0 g (3.4 mmol, 110%) of pentanedioic acid bis-[(2-aminoethyl) amide] compound of formula (19).

EXAMPLE 2

  Preparation of a protected aminoaldehyde of formula (7) (1) Preparation of a compound of formula (21)

  9-Fluorenyl N- (2-aminoethyl) carbamate

  methyl (Fmoc-2-aminoethanol), a compound of formula (21), was prepared from aminoethanol, a compound of formula (20), by

  classics (see Step 2 of Example 3).

  (2) Preparation of a compound of formula (7) NaOCl (0.35 M, buffered to pH 8.6 with NaHCO 3, 760 mL, 266 mmol, 2.0 equiv) was added to a mixture of Fmoc aminoethanol, consisting of a compound of formula (21)

  (37.64 g, 133 mmol, 1.0 equiv), of TEMPO [2,2,6,6-

  tetramethyl-1-piperidinyloxy, free radical] (0.008M in CH 2 Cl 2, 332 mL, 2.66 mmol, 0.02 equiv), KBr (0.5M in water, 53 mL, 26.6 mmol, 0.2 equiv) and ethyl acetate (1500 ml) at 0 C. A mechanical stirrer was used to

  ensure effective agitation and the reaction was monitored

  by CCM. After 20 minutes, the two phases were separated. The aqueous phase was extracted

  with ethyl acetate (2 x 250 ml), the organic phases

  The combined dishes were washed with saturated Na 2 S 2 O 3 solution, water and brine, dried over Na 2 SO 4, filtered and concentrated to about 400 ml. Hexane

  (1600 ml) was added to give a white precipitate.

  After filtration, F-moc-aminoacetaldehyde (25.2 g, 67%), consisting of a compound of formula (7), was collected under

form of a white powder.

EXAMPLE 3A

  Preparation of a protected aminoaldehyde of formula (95) Preparation of a compound of formula (93) A solution of aminoethanol (90) (30.5 g, 500 mmol, 30.1 ml) and 1-bromodecane (13) 27.65 g, 125 mmol, 26 ml) in ethanol was stirred at 65 ° C for 4 hours. The solvent was removed under reduced pressure. The residue was diluted with EtOAc (800 mL) and the organic solution was washed with H2O (2 x 200 mL), aqueous HCl (2 x 200 mL, 1.0 M), saturated aqueous NaHCO3 (200 mL) and saturated brine (200 mL). The organic phase was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The resulting crude product, 2- (n-decylamino) ethanol (93), was used

  in the next reaction without further purification.

  Preparation of a compound of formula (94) A solution of 2- (necylamino) ethanol (93) (20.1 g, 100 mmol) in CH 2 Cl 2 was treated with DIPEA (diisopropylethylamine, Hunig base) (15, 1 g, 120 mmol, 20.9 ml) at 0 ° C. and then with FmocCl (28.5 g, 110 mmol). The resulting reaction mixture was stirred at 0 ° C for one hour and poured into CH2Cl2 (400 mL). The mixture was washed with H2O (3 x 200 mL), aqueous HCl (1 x 200 mL, 1 N), saturated aqueous NaHCO3 (200 mL) and brine (200 mL). The sentence

  The organic material was dehydrated on anhydrous Na2SO4 and concentrated

  under reduced pressure. The resulting white solid, N, N-n-decyl-Fmoc-aminoethanol (94),

  was used for the next reaction without further purification.

tion.

  Preparation of a compound of formula (95) A solution of N, Nn-decylFmoc-aminoethanol (94) (12.7 g, 30 mmol) and DIPEA (15.48 g, 120 mmol, 9 ml) in CH2Cl2 was treated with a solution of a sulfur trioxide-pyridine complex in DMSO (85 ml) dropwise over 20 minutes at 0 ° C. The resulting reaction mixture was stirred at 0 ° C. for a further 20 minutes before being turned off with water. The mixture was extracted with CH2Cl2 (5 x 100 mL) and the combined organic solutions concentrated under reduced pressure. The residue was diluted with EtOAc (500 mL). The organic solution was washed with H 2 O (3 x 200 mL), aqueous HCl (200 mL, 1N), saturated aqueous NaHCO 3 (200 mL) and saturated brine (200 mL). The organic phase was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The product

  The crude product was purified by column chromatography (25% EtOAc / hexanes) to give n-decyl-Fmoc-aminoaldehyde (95). MS (MH +) calcd 422.2, found 422.2.

EXAMPLE 3B

  Preparation of a Protected Aminoaldehyde of Formula (99) Preparation of a Compound of Formula (96) A mixture of glycine methyl ester hydrochloride (91) (2.0 g, 16 mmol, 1.2 equiv) and DIPEA (5.1 mL, 29 mmol, 2.2 equiv) in methylene chloride (20 mL) was added dropwise to a solution of decanoyl chloride (5) (2.7 mL, 13 mmol). , 1.0 equiv.) In methylene chloride (20 ml) in an ice / acetone bath. The reaction mixture was stirred for a further 60 minutes after completion of the addition, then was washed with 3N hydrochloric acid (50 ml) twice and then with saturated sodium bicarbonate solution (50 ml). ). The organic phases were dried over magnesium sulfate and the solvents removed under reduced pressure. N-Decylglycine, a compound of formula (96) (3.0 g, 12 mmol,%) was obtained and used in the next step without

other purification.

  Preparation of a Compound of Formula (97) Under a nitrogen atmosphere, the amide (96) (3.0 g, 12 mmol, 1.0 equiv) was dissolved in tetrahydrofuran

  anhydrous (25 ml) and the solution was cooled in an ice bath. Lithium aluminum hydride solution (1N, 25 ml, 25 mmol, 2.0 equiv) was added cautiously.

  The resulting solution was refluxed under a nitrogen atmosphere overnight, and then cooled in a room temperature.

  ice bath. An additional volume of 50 ml of tetra-

  hydrofuran was added, followed by sodium sulfate

  hydrate was slowly added until the cessation of

  vescence. The mixture was allowed to warm to room temperature and filtered, then concentrated in vacuo. 2- (n-Decylamino) ethanol, consisting of a compound of formula (97) (2.3 g, 11 mmol, 93%) was obtained and used without

other purification.

  Preparation of a compound of formula (98) 2- (n-decylamino) ethanol (97) (2.3 g, 11 mmol, 1.1 equiv) and DIPEA (2.0 mL, 11 mmol, 1.1 equiv) were dissolved in methylene chloride (15 ml) and cooled in an ice bath. 9-fluorenylmethylchloroformate (2.6 g, 10 mmol, 1.0 equiv) in methylene chloride (15 ml) was added, the mixture was

  stirred for 30 minutes, then washed with hydrochloric acid

  3N drique (50 mL) twice and saturated sodium bicarbonate solution (50 mL). The organic phases were dehydrated over magnesium sulfate and the solvents

  have been removed under reduced pressure. F-moc-2- (n-decyl)

  amino) ethanol, a compound of formula (98), (4.6 g, 11 mmol, 108%) was used without further purification. Preparation of a compound of formula (99) F-moc-2- (n-decylamino) ethanol (98) (4.6 g, 11 mmol, 1.0 equiv) and DIPEA (7.6 ml 44 mmol, 4.0 equiv.) Were dissolved in methylene chloride (30 ml)

  and the solution was cooled in an ice / acetone bath.

  A solution of sulfur trioxide-pyridine complex (6.9 g, 43 mmol, 4.0 equiv) in dimethylsulfoxide (30 ml) a

  was added and the solution was stirred for 20 minutes. Crushed ice was added and the mixture was split.

  The organics were washed twice with 3N hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium chloride and concentrated in vacuo. F-moc-2- (ndecylamino) acetaldehyde, consisting of a compound of formula (99) (3.4 g, 8 mmol, 74%) was used

without further purification.

EXAMPLE 4

  Preparation of a compound [C-C] of formula I (1) Preparation of a compound of formula I At room temperature, vancomycin hydrochloride (3.6 g, 2.3 mmol) was dissolved in 36 ml of dimethylsulfoxide. Pentanedioic acid bis (2-aminoethyl) amide, a compound of formula (2)

  (1.0 g, 3.4 mmol, suspended in 27 ml of N, N-dimethyl

  formamide) and then N, N-diisopropylethylamine (2.4 ml, 13.8 mmol) were added to this solution. The resulting slurry was stirred at room temperature for several hours until it was substantially homogeneous. Then a solution of PyBOP (1.3 g, 2.5 mmol) and 1-hydroxybenzotriazole (310 mg, 2.3 mmol) in 9 ml of N, N-dimethylformamide was added dropwise rapidly. The mixture was stirred at room temperature for one hour, then was added dropwise to 600 ml of acetonitrile to give a precipitate which was filtered, washed with acetonitrile and then with diethyl ether. dried under vacuum. The crude product was purified by reverse phase HPLC (50 minutes, 2-30% acetonitrile in water containing 0.1% trifluoroacetic acid) to give [C] -N-N. '-aminoéthylglutarique-amide (vancomycin)

  (a compound of formula (22) contaminated with 1-hydroxybenzoate

  triazole, eluting at 29 minutes) and [C-C] -

  pentane-1,5-dioic acid bis - [(2-aminoethyl) amide] -bis-

  (vancomycin), consisting of a compound of formula I

  eluting at 36 minutes) in the form of their salts

  respective trifluoroacetic acid.

EXAMPLE 5

  Preparation of a compound of formula (C), of formula I (1) Preparation of a compound of formula (21) At room temperature, vancomycin hydrochloride (7.3 g, 4.7 mmol) was dissolved in 75 ml of dimethylsulfoxide. N, N-diisopropylethylamine (4.1 ml,

  23.5 mmol) and then 9-fluorenylmethylhydrochloride.

  N- (2-aminoethyl) carbamate (1.8 g, 5.6 mmol) was added to this solution. A solution of PyBOP (2.7 g, 5.2 mmol) and 1-hydroxybenzotriazole (630 mg, 4.7 mmol) in 75 ml of 1,3-dimethyl-3,4,6,6-tetrahydro-2 (1H) -pyrimidinoneontété

  added quickly dropwise to the resulting solution.

  The resulting solution was stirred at room temperature

  for 2 hours, then poured into 800 ml of diethyl ether.

  lique, which gave an eraser. Diethyl ether has been

  decanted and the gum was washed with an additional

  of diethyl ether, which gave the [C] - [2-Fmoc-

  aminoethyl] -vancomycin, consisting of a compound of formula (21). (2) Preparation of a compound of formula (22) The compound of formula (21) prepared above, in the form of a gum, was then taken up in 40 ml of N, N-dimethylformamide, to which 10 ml of Piperidine had been added, and the solution was allowed to stand at room temperature for 20 minutes. Then the solution was added dropwise to 450 ml of acetonitrile, which gave a

  precipitate. Centrifugation was followed by decantation

  acetonitrile and the residue was washed twice with 450 ml of acetonitrile and once with 450 ml of diethyl ether and then air-dried. The residue was taken up in water, acidified to a pH below 5 with a small amount of 3N hydrochloric acid and purified by phase HPLC.

  reversed using a gradient of 2-30% acetonitrile in water containing 0.1% trifluoroacetic acid to give [C] (2-aminoethyl) -vancomycin, a compound of formula (22).

  (3) Preparation of [C -C] -linked compound of formula I The compound of formula (22) (400 mg, 220 mmol) and glutaric acid (6) (10 mg, 76 mol) were

  dissolved in 5 ml of N, N-dimethylformamide and N, N-

  diisopropylethylamine (140 ll, 800 lmol) and then PyBOP (83 mg, 160 pmol) and 1-hydroxybenzotriazole (10 mg, 74 mmol) in 500 ml of N, N-dimethylformamide. The reaction mixture was stirred for 75 minutes at room temperature, then an additional 20 mg of PyBOP was added. 75 minutes later, the solution was poured into 45 ml of acetonitrile. The resulting precipitate was separated by centrifugation, washed with ether, air-dried and purified by reverse phase HPLC (50 minutes, 2-30% acetonitrile in water containing 0.1% trifluoroacetic acid, elution at 33 minutes), which gave the

  [C-C] -pentane-1,5-dioic acid bis - [(2-aminoethyl) amide] -

  bis- (vancomycin), consisting of a compound of formula I,

in the form of its trifluoroacetate.

EXAMPLE 6

  Preparation of a compound [CC], of formula I (1) Preparation of a compound of formula (25) Vancomycin hydrochloride (34.1 g, 23 mmol, 1 equiv), N-Fmoc-aminoacetaldehyde ( 7) (6.5 g, 23 mmol, 1 equiv), DIPEA (8.5 mL, 46 mmol, 2 equiv) and DMF (340 mL) were added to a 1000 mL flask thoroughly. round, oven-dried, equipped with a magnetic stir bar. The mixture was stirred at room temperature for 2 hours and monitored by HPLC. The mixture

  The reaction became homogeneous and a conversion of approxi-

  90% imine was found. Methanol (340 mL) and NaCNBH3 (4.3 g, 69 mmol, 3 equiv) were added to the solution and followed by TFA (5.2 mL, 69 mmol, 3 equiv). Stirring was continued for an additional one hour at room temperature. Once the reaction was complete, the methanol was removed under vacuum. The residue containing the crude product and DMF was poured slowly into a 5 L flask and stirred with acetonitrile (3.5 L). A white precipitate has formed. The suspension was allowed to settle at room temperature and the supernatant was decanted. The solid substance

  white was filtered and triturated with ether (2 liters).

  After filtration, the crude product (25) was dried under vacuum

pushed overnight.

  An 8 x 26 cm column was packed with octadecyl bonded silica gel. The column was washed with 800 ml of 90% solution of Solvent B [acetonitrile in water, with 0.1% TFA] and equilibrated with 800 ml of 10% Solvent B solution. Crude A (10 g) was dissolved in a 30% solution of Solvent B (150 ml, containing 2 ml of 3N HCl) and loaded onto the column. Then

  she was subjected to a flash training with

  10% B (800 ml x 2), 40% B (800 ml x 3) and% B (800 ml). The fractions were monitored by HPLC

  analytic. After lyophilization, V- [Fmoc-2-aminoethyl]

  vancomycin (25) was obtained as its TFA salt.

  (2) Preparation of a compound of formula (26) At room temperature, the compound of formula

  (25) prepared above (205 mg, 0.10 mmol) and [C] -

  [Glutaryl-bis - [(2-aminoethyl) amide] - (vancomycin), consisting of a compound of formula (22) prepared as aforesaid

  (200 mg, 0.10 mmol), were dissolved in 2 ml of N, N

  dimethylformamide. N, N-Diisopropylethylamine (126 μL, 0.72 mmol), 1-hydroxybenzotriazole (14 mg, 0.10 mmol) and

  PyBOP (59 mg, 0.11 mmol) were added to this solution.

  tion. The solution was stirred for 2 hours and then added dropwise to 45 ml of acetonitrile to give a precipitate which was separated by centrifugation. The precipitate was purified by reverse phase HPLC (50 minutes, 10-70% acetonitrile in water containing 0.1% trifluoroacetic acid, eluting at 24 minutes) to give the ] - [2-Fmoc-aminoethyl] - [CC] -pentane-1,5-dioic acid bis [(2-aminoethyl) amide] -bis- (vancomycin), consisting of a compound of formula (26), in the form of its salt acid

trifluoroacetic.

  (3) Preparation of a compound of formula (27) 0.5 ml of piperidine was added to a solution of the compound of formula (26) prepared above in 5 ml of N, N-dimethylformamide. The resulting solution was left at room temperature for 30 minutes, then added dropwise to acetonitrile to give a precipitate which was separated by centrifugation, washed with ether and air-dried. Purification by reverse phase HPLC (50 minutes, 2-50% acetonitrile in water containing 0.1% trifluoroacetic acid, eluting at 24 minutes) gave ([V] - [2-aminoethyl ]) - [CC] -pentane-1,5-dioic acid bis - [(2-aminoethyl) amide] -bis- (vancomycin), consisting of a compound of formula (27), in the form of its trifluoroacetic acid salt. (4) Preparation of a C-C compound of formula I in

  which V is substituted with a n-decylamido substituent

  The compound of formula (27) prepared above (10 mg, 2.8 mmol), decanoic acid (0.5 mg, 2.9 gmol) and N, Ndiisopropylethylamine (2.9 16.6

  gmoles) were dissolved in 200 μl of N, N-dimethylformamide.

  PyBOP (1.5 mg, 2.9 mmol) and 1-hydroxybenzotriazole (0.4 mg, 3.0 μmol) in N, N-dimethylformamide Al were added, the solution was left at room temperature. for 30 minutes and then added dropwise to 1.5 ml of acetonitrile to give a precipitate. The precipitate was separated by centrifugation, washed with ether and dried in air. Purification by reverse phase HPLC (60 minutes 10-50% acetonitrile in water containing 0.1% trifluoroacetic acid, elution at 42 minutes) gave the

  ([V] - (2-Decylamido) ethyl) -vancomycin [C-C] pentane-1,5-

  dioic acid bis - [(2-aminoethyl) amidel- (vancomycin), consisting of a compound of formula I, in the form of its salt

of trifluoroacetic acid.

EXAMPLE 7

  Preparation of a compound [CC] of formula I by alkylation A [C] - [2-aminoethyl] -vancomycin (22) mixture (50 mg, 0.027 mmol) of α, α'-dibromom-xylene (3, 4 mg, 0.013 mmol) and N, N-diisopropylethylamine (6.5 mg, 0.050 mmol) in dimethylformamide (0.15 ml) was heated at 60 ° C for 8 hours, cooled to room temperature for 18 hours and then heated at 60 C for 8 hours. Once

  cooled, the product was precipitated by addition of acetonitrile

  trile (15 ml) and isolated by centrifugation. The solid product was washed with ether (15 ml) and dried under vacuum. Reverse phase preparative HPLC (5-40% acetonitrile in water containing 0.1% trifluoroacetic acid

  minutes) gave [C-C] -m-phenyl-bis [methylaminoethyl]

  amino] -bis-vancomycin in the form of its trifluoroacetate. SM

  calculated (MH +) 3082, 3084; found 3084.

  Preparation of other compounds [C-Cl of formula I] Accordingly, the following compounds [C-C] of formula I were prepared following the procedures of Examples 1 to 7 above. It should be noted that the term "category" refers to the point of attachment of the linkage group; V1, Ni and R1 represent the point of attachment for the first glycopeptide; V2, N2 and R2 represent the fixation point with respect to the

second glycopeptide.

Ni N

1 O O 2

R 'N XN.R

NH HN

I I

VI V2

COMPOUNDS C-C

  Cat.-Link Group Vl V2 NI N2 RI R2 gorie

  ## STR2 ##

  2 C-C-NH- (CH) 2-NH-C (O) - (CH 2) CH (NH-C (O) -Ph) -C (O) -NH-H H H H

(CH2) 2-NH-

  C-C-NH- (CH 2): NH-C (O) -CH 2 -N ((CH 2) 9 -CH 3) (CH 2 -C (O) -NH-1HHH.

(CH2) 2-NH2) -CH2-C (O) -NH- (CH2) 2-NH-

  C-C-NH- (CH 2): NH-C (O) -CH 2 -N ((CH 2) 1-CH) -CH 2 -C (O) -NH-HHH H.

(CH2) 2-NH-

  C-C -NH- (CH 2), -C (O) -NH- (CH 2) 4 -CH (NH-C (O) -CH 3) -C (O) -NH-H H H H

CH (COOH) - (CH2) 4-NH-C (O) - (CH2) 5-NH-

  C-C -NH- (CH 2) 1 -NH-C (O) - (CH 2): - NH-C (O) - (CH 2) 2 -NH-C (O) -H H H HH

  (CH2)> - C (O) -NH- (CH2) r2-C (O) -NH- (CH2) 2-C (O) -NH- (CH2) 2-

NH-

  C-C-NH- (CH 2): NH-C (O) - (CH 2) 2 -NH-C (O) - (CH 2) 3 -C (O) -NH-H H H H

(CH:) 2-C (O) -NH- (CH2) 2-NH-

  C-C -NH- (CH 2) 2 -NH-C (O) -Z-C (O) -NH- (CH 2) 2 -NH-H H H H

  wherein Z = 5-hydroxy-3-phenyl-9-CN-4CH2) h -NH-C (O) -ZC (O) -NH- (CH2) 2 -NH-HH II HCZ = I.4 Phenyl CCNH- (CH 2) 2 -NH-C (O) -ZC (O) -NH- (CH 2) 2 -NH-FH II IIHC Z = 1,2-phenyl

  C-C-NH- (CH 2) 2-NH-C (O) - (CH 2) 3 -C (O) -NH- (CH 2) 2 -NH - (CH 2) 2 -NH-C (O) -H H H

(CH2), - C H

  CC-NH- (CH 2) NH-C (O) - (CH 2) 1 -C (O) -NH- (CH 2) 2 -NH - (CH 2) 2 -NH-C (O) -ZH HH

Z = biphenyl

  CCNH- (CH2) 2-NH-C (O) - (CH2) 3-C (O) -NH- (CH2) 2 -NH- H- (CH2) 2 -NH-C (O) - H

(CH2) r-CHi

  CCNH- (CH2) 2-NH-C (O) - (CH2)> - C (O) -NH- (CH2) 2-NH-HH- (CH2) 2 -NH-C (O) ) --ZH

CL Z = biphenyl

  C-C-NH- (CH2) 2-NH-C (O) - (CH2) 4-C (O) -NH- (CH2) 2 -NH- HHHH

  C-C -NH- (CH2) 2-NH-C (O) - (CH2) 2-C (O) -NH- (CH2) h -NH-11

  C-C -NH- (C 2 H) 2-NH-C (O) -CH 2 -C (O) -NH- (CH 2) 2 -NH-H H H H

  C-C -NH- (CH2) 2-NH-C (O) - (CH2) 4-C (O) -NH- (CH2) 2 -NH- HHHH

  CCNH- (CH 2) 2 -NH-C (O) - (CH 2) 10-C (O) -NH- (CH 2) 2 -NH -H -H -H- HI -NH- (CH 2) 2 -NH -C (O) - (CH2) 2-CH (NH-C (O) - (CH2) s-CH1) - HHHH

C (O) -NH- (CH2) -NH-

  C-C -NH- (CH 2) 2-NH-C (O-Z-C (O) -NH- (CH 2) 2 -NH-H H H H

C1 Z = 5- (n-octadecyloxy) -1,3-phenyl

  C-C-NH- (CH 2) 2-NH-C (O) - (CH 2) 7-C (O) -NH- (CH 2) 2 -NH-H H H H 1

  C -C -NH- (CH 2) 2 -NH-C (O) - (CH 2) 2 -CH (NH-C (O) -Z) -C (O) -NH-H H H H '

(CH), - NH-

  cW Z = 4- (n-octyloxy) phenyl CO-M 24 CC -NH- (CH2) 2rNH-C (O) - (CH2) 3-C (O) -NH- (CH2) -NH- ( CH2) 2-NH-C (O) -HHH '

(CH2), - CH3

  C-C-NH- (CH 2) 2-NH-C (O) - (CH 2) 3 -C (O) -NH- (CH 2) 2 -NH - (CH 2) 2 -NH-C (O) -H H H

(CH2), 2-C H

  C-C -NH- (CH2) 2-NH-C (O) - (ClH2) 3-C (o) -NH- (CH2), -NH- (CH2) 2 -NH-C (O) -H HH

CH2-N + (CH3)]

  CCNIt- (CH2), -NH-C (O) - (CH2) 3-C (O) -NH- (CHI2) 2 -NH-I-1 - (CHi2) 2 -NH-C (O) - H

CH2-N (CH3) 3

  CCNH- (C 2 H) 2-NH-C (O) - (CH 2) 3 -C (O) -NH- (CH 2), -NH- (CH 2) 2 -NH-C (O) - H - (CH2) 2 -NH2H

(CH2), - CH3

  CCNH- (CH2) 2-NHI-C (O) - (CH2), -C (O) -NH- (CH2), -NH- (CH2) 2 -NH-C (O) - (CH2) 2-NH-C (O) -HH

(CH2) & - CH3 (CH2) S-CH3

  CC-NH- (C 1 H 2) -N HC (O) - (CH 2) 3 -C (O) -N H- (CH 2) 2 -NH- (CH 2) 2 -N HC (O) -v HH (CH 2) s-CH, 31 CC-NH- (CH 2) 2 NH-C (O) - (CH 2) 1 C (O) -NH- (CH 2) 2 -NH - (CH 2, -CH 3 H) ## STR2 ## CC-NH- (CH2) 2-NH-C (O) - (CH2) 3-C (O) -NH- (CH2) X-NH-HH- (Clt2) 2 -NH-C (O) H

(CH2) 3-COOH

* CCNH- (CH2), -NH-C (O) - (CH2), -C (O) -NH- (CH2) 2 -NH- (CH2) 2 -NH-C (O) ) - (CH2) 2-NH-C (O) -HH

  (CH 2) 4-CH 1 (CH 2) 4 -CH 3 CC-NH- (CH 2) n -NH-C (O) - (CH 2) n - (C) -NH (CH 2) n -NH ( CH2) 2-NH-C (O) -H- (CH2) 2-NH-C (O) -H (CH2), -CH3 (Cl-2), -CH3

  CCNH- (CH2) 2-NH-C (O) - (CH2) 3-C (O) -NH- (CH2), -NH- (CH2) 2 -NH-C (O) - H - (CH2) 2-NH, H

(CH,), - CH3

  CCNH- (CH 2), -NH-C (O) - (CH 2), -C (O) -NH- (CH 2), -NH- (CH 2) 2 -NH 2 H - (CH 3) 2-NH-C (O) - H

(CH2), - CH3

  CCNH- (C 2 H) 2-NH-C (O) - (CH 3) -C (O) -NH- (CH 2) 2 -NH - (CH 2) 2 -NH-C ( O) - HHH _4

(CH2) 3-COOH 00

  CCNH- (CH2), -NH-C (O) - (CH2), -C (O) -NH- (CH) r -NH- (CH2) 2 -NH-C (O) -H - (CH2) 2-NH-C (O) -H.

  (CH 2) r -CH, (CH 2), -COOH CC -NH- (CH 2) 2 -NH C (O) (CH 2) n C (O) -NH- (CH 2) 2 -NH - (CH 2) 2-NH-C (O) - (Cl 2) 2 -NH-C (O) -HH (CH 2) -COOH (CHl 2) -CH 3 Cl -N H- (C 2 H) -NII-C (O) ) - (CH2h) -C (O) -NH- (CH2): - N- H- (CI11) .- NII-C (O) -H

(CH2) 3-C (O) -NH-

(CH2) 3-NI [- (Cl I2) r

NH- (CI2), - NI12

  C-C -NH- (CH 2) 2 -NH-C (O) - (CH 2) b-C (O) -NH- (CH 2) 2 -N I -H H - (C 12) 2 -NH-C (O) H

(CH2) 3-C (O) -NH-

CH2- (CH (IHO)) - H

  CC-NH- (C 2 H) 2-NH-C (O) - (CH 2) C (O) -NH- (CH 2) 2 -NH-CH 2 -ZO- (CH 2) 3 -HHH CH 3 OC Z = 1,4-phenyl

  C-C-NH- (CH 2) 2-NH-C (O) - (CH 2) 3 -C (O) -NH- (CH 2) 2 -NH-H -CH 2 -Z-O- (CH 2) 3 H

CH3 CU Z = I, 4-phenyl

  C-C-NH- (CH2) 2-NH-C (O) - (CH2) 2-CH (NH-C (O) -Z) -C (O) -NH-11HHH

(CH2) 2-NH-

Cu Z = 4- (n-octoxy) phenyl

  C-C-NH- (CH 2) 2-NH-C (O) - (CH 2) -C (O) -NH- (CH 2) 2 -NH-- (CH 2): - NH-C (O) -H H H

(CHI2) 3-C (O) -NI- -

CH2- (CH (OH)) 3-H

  CC-NH- (CH2) n-NH-C (O) - (CH2) rC (O) -NH- (CH2) -NH-CH2-Z-C1 [2-Z II H CU Z = biphenyl C. Z = biphenyl

  C-C-NH- (CH 2) 2-NH-C (O) - (CH 2) 3 -C (O) -NH- (CH) 2 -NH-HI 1 -CI 2 -Z-CH 2 -Z

  Z = biphenyl where Z = biphenyl 49 CC-NH- (C H2) 2-NH-C (O) -CH2-O-CH2-C (O) -NH- (CHD) 2 -NH-- CH2-Z -C1H2-Z HH ci Z = biphinyl cA Z = biphenyl

  C-C-NH- (CH 2) 2-NH-C (O) -CH 2 -O-CH 2 -C (O) -NH- (CH 2) 2 -NH-H -CH 2 -Z, -CH 2 -Z

_O Z = biphenyl cZh O Z = biphenyl OO

  C-C-NH- (CH 2) 2-NH-C (O) - (CH), -C (O) -NH- (CH 2) 2 -NH- (CH 2) 2 -NH- (CH 2) -H H H

  CH3 52 CC-NH- (CH2) 2-NH-C (O) - (CH2) rC (O) -NH- (CH) 2 -NH- HHH3CNH- (CH2) 2 -NH- C (O) -CFH2-O-CH2-C (O) -NH- (CH2) 2-NR1-CH2-Z0- (CH2) 3 -HHH CH3, OR Z = 1,4-phenyl

  C-C-NH- (CH 2) 2-NH-C (O) - (CH 2) 2 -CH (NH-C (O) -Z) -C (O) -NH-H H H H

(CH2) 2-NH-

Cỉ Z = (biphenyl)

  C-C -NH- (CH2) 2-NH-C (O) -CH2-O-CH2-C (O) -NH- (CH2) 2 -NH- HHHH

  C-C -NH- (CH 2) 2-NH-C (O) -CH 2 -O-CH 2 -C (O) -NH- (CHf) 2 -NH-CH 2 -Z, H H H W Z = biphenyl

  C-C-NH- (ClH 2) 2-NH-C (O) - (CH 2) 3 -C (O) -NH- (CH 2): - NH-CH 2 -Z, H H H

C Z = biphenyl

  C-C -NH- (CH 2) 2 -NH-C (O) - (CH 2) n - C (O) -NH- (CH 2) 2 -NH-CH-ZHH H

CL1 Z = 4- (f4'-

chloro) biphenyl

  C-C -NH- (CH 2) 2-NH-C (O) - (CH 2) 3 -C (O) -NH- (CH 2) 2 -NH - (CH 2) 2 -NH- (CH 2) 5 HH H

CH, - '

  C-C-NH- (CH2) -NH-C (O) - (C H2) 3-C (O) -NH- (CH2) 2-NH- (CH2) 2 -NH-CH2-ZH1HH-C Z = biphenyl

  C-C-NH- (CH 2) 2-NH-C (NH) - (CH 2) 6 -C (NH) -NH- (CH 2) 2 -NH-H H H H

  C-C-NH- (CH 2) 2-NH-C (NH) -CH 2 -C (NH) -NH- (CH 2) 2 -NH-H H H H

  C-C -NH- (CH 2) 2-NH- - (CH 2) 2 -NH- (CH 2), - H H H

CH3

  C-C-NH- (CH 2) 2-NH- - (CH 2) 2 -NH 2 H H H

  C-C -NH- (CH 2) r -NH-CHr 2 -Z-CH 2 -NH- (CH 2) 2 -NH- H H H H CA Z = 1.3 phenyl

00

  indicates that the substituent is an aglycone.

  Preparation of Other [CC] Compounds of Formula I Similarly, other [CC] compounds of Formula I are prepared by following the procedures of Examples 1 to 7 above, such compounds including those in which the ligand consists of in optionally substituted vancomycin, N-desmethylvancomycinactively substituted

  or optionally substituted chloreremomycin.

EXAMPLE 8

  Preparation of compounds [VV] of formula I wherein the C-position is substituted (1) Preparation of a compound of formula (31) V- [Fmoc-2-aminoethyl] -vancomycin (the compound of formula (25) prepared above) (300 mg, 150 mmol) was dissolved in N, N-dimethylformamide. N, N-diisopropylethylamine (65 μl, 370 mmol) was added and followed by 1-hydroxybenzotriazole (20 mg, 150 μmol), 3- (dimethylamino) propylamine (30 μl, 240 μmol) and PyBOP (90 mg, 170 mmol). The solution was kept at room temperature for 30 minutes and then poured into acetonitrile to give a white precipitate. The precipitate was separated by centrifugation and purified by reverse phase HPLC (50 minutes, 10-50% acetonitrile in water containing 0.1% trifluoroacetic acid, eluting at 35 minutes), which gave the

  [C] - [3-dimethylamino) propylamino] - [V] - [Fmoc-2-aminoethyl] -

  vancomycin, consisting of a compound of formula (31),

  form of its trifluoroacetic acid salt.

  (2) Preparation of a compound of formula (32) A volume of 0.5 ml of piperidine was added to a solution of the compound of formula (31) prepared in step 1 in 2 ml of N, N-dimethylformamide . The solution was left at room temperature for 10 minutes, then added dropwise to 15 ml of acetonitrile to give a white precipitate. The precipitate was separated by centrifugation, washed with ether, air-dried and purified by reverse phase HPLC (50 minutes, 2-50% acetonitrile in water containing 0.1% acid). trifluoroacetic, eluting at 21 minutes) to give [C] - [3- (dimethylamino) propylamino] - [V] - [2-aminoethyl] -vancomycin, a compound of formula (32), in the form of its trifluoroacetic acid salt (177 mg, 92 gmol, 61%). (3) Preparation of a compound of formula I Glutaric acid (6) (0.7mg, 5gol) in

  of N, N-dimethylformamide and then 150 μl of N, N-dimethyl-

  formamide were added to the compound of formula (32) prepared above (20 mg, 10 pmol). PyBOP (5.4 mg, 10 imoles) and 1-hydroxybenzotriazole (1.4 mg, 10 mmoles) in 50 μl of

  N, N-dimethylformamide was added to the resulting solution.

  aunt and were followed by N, N-diisopropylethylamine (8.2 μl, 47 imoles). The solution was left at temperature

  overnight, then poured into 15 ml of acetonitrile

  Trile. The resulting precipitate was separated by centrifugation

  washed with ether, air dried and purified by reverse phase HPLC (50 minutes, 2-30% acetonitrile in water containing 0.1% trifluoroacetic acid, elution at 26 minutes). ), which gave the [VV] pentane-1,5-dioic acid

  bis- [(2-ethyl) amide] -bis- ([C] -3-dimethylaminopropylamino)

  (vancomycin)), consisting of a compound [v-V] of formula I

  in the form of its trifluoroacetic acid salt.

EXAMPLE 9

  Preparation of a compound [V-V] of formula I wherein the C-position is substituted (1) Preparation of a compound of formula (36) N, N-diisopropylethylamine (9.1 μl, 52 μg)

  iMmoles) followed by PyBOP (5.4 mg, 10 pmol) and 1-hydroxy-

  benzotriazole (1.4 mg, 10 gmol) in 50 μl of N, N-dimethyl-

  formamide were added to a solution of [C] - (3-dimethyl-

  aminopropylamino) - [V] - (2-aminoethyl) -vancomycin, consisting of the compound of formula (32) prepared in the aforementioned manner (20 mg, 10 moles) and glutaric acid mono-9-fluorenylmethyl ester ( 15) (3.2 mg, 10 pmol) in 200 μl of N, N-dimethylformamide. The resulting solution was kept at room temperature for 80 minutes and then added dropwise to 15 ml of acetonitrile. It was then dissolved in 500 μl of N, N-dimethylformamide, treated with piperidine for one hour at room temperature and added dropwise to 15 ml of acetonitrile. The resulting precipitate was separated by centrifugation, washed with ether, air dried and purified by reverse phase HPLC (2-30% acetonitrile in water containing 0.1% acid

  trifluoroacetic acid) to give [C] - [(3- (dimethylamino) -

  propylamino] - [V] -pentane-1,5-dioic acid (2-aminoethyl) -

  amide) - (vancomycin), consisting of a compound of formula (36), in the form of its trifluoroacetic acid salt

(13.1 mg, 6.4 pmol, 64%).

  (2) Preparation of a compound of formula (32 ') Dodecylamine (4.3 mg, 23 mmol) in 20 μl of N, N-dimethylformamide followed by N, Ndiisopropylethylamine (67 μl, 38 pmol) and then 1hydroxybenzotriazole (20 mg, 150 mmol) and PyBOP (90 mg, 170 pmol) in N, N-dimethylformamide were added to a solution of the compound of formula (25) prepared as described in US Pat.

  Example 6 (30 mg, 15 mmoles) in 300 μl of N, N-dimethyl-

  formamide. The solution was kept at room temperature for one hour and then poured into 15 ml of acetonitrile. The resulting precipitate was separated by centrifugation, washed with ether and dried in air. It was then dissolved in 1 ml of N, N-dimethylformamide, treated with 200 μl of piperidine for 10 minutes and then poured into 15 ml of acetonitrile. The resulting precipitate was separated by centrifugation, washed with ether, air-dried and purified by reverse phase HPLC (50 minutes, 10-70% acetonitrile in water containing 0.1% trifluoroacetic acid, eluted at 38 minutes) to give (C) -n-dodecylamino [V] pentane-1,5-dioic acid (2-aminoethyl) amide) -vancomycin, consisting of a compound of formula (32); '), in the form of its trifluoroacetic acid salt

(22.5 mg, 12 mmol, 77%).

  (3) Preparation of a compound of formula I The compound of formula (36) (10.8 mg, 5.3 gmol) and the compound of formula (32 ') (10.0 mg, 5.3 pmol) and N, N-diisopropylethylamine (6.5 μl, 37 moles), prepared as above, was dissolved in 200 μl of N, N-dimethylformamide. A solution of PyBOP (2.8 mg, 5.4 mmol) and 1-hydroxybenzotriazole (0.7 mg, 5.2 pmol) in 20 μl of N, N-dimethylformamide was added and the resulting solution was dropped. for one hour at temperature

  room. PyBOP (0.7mg, 1.3Mmole) and 1-hydroxybenzoate

  triazole (0.2 mg, 1.3 imole) in 5 μl of N, N-dimethyl

  formamide have been added. The solution was left for one hour and poured into 15 ml of acetonitrile. The resulting precipitate was separated by centrifugation, washed with ether, air-dried and purified by reverse phase HPLC (10-50% acetonitrile in water containing 0.1% acid).

  trifluoroacetic acid) to give [C] - (3-dimethylamino)

  propylamino) - [V-VI-pentane-1,5-dioic acid bis - [(2-amino)

  ethyl) amide] - [C '] - (n-dodecylamino) -bis- (vancomycin), consisting of a compound of formula I, in the form of its salt

of trifluoroacetic acid.

  Preparation of Other [V-V] Compounds of Formula I Following the procedures of Examples 8 and 9, the following [V-V] compounds of Formula I were prepared. It should be noted that the term "category" refers to the point of attachment of the linkage group; C1, Ni and Ri represent the point of attachment with respect to the first glycopeptide; C2, N2 and R2 represent the point of

  fixation with regard to the second glycopeptide.

  I, ZM Z- (O)) - HN - '(' HD) -HN- '(' HD) N - '(' HD) -HN-H l -H) -HN- (O) D HD ) - (O) HNID) - AA 6 O0

  oD00 lxAuaDqd! q = z: ro, lXuy4qd! q = Z n.

  0-. Z- (O) D-AN-f (rHD) -N- Z- (O) D-HN - ((HD) -HN-H HHN (O) Df (H) (O) HN (HD) AA 8

1- __. __

  HD (HD) -HN- fHD- (HD) -HN- HH '(HD) -HN- (O) D- (HD) - (O) D-HN' (HD) AA ## EQU1 ## ## STR1 ## (HD) -HN- (HD) N- (HD) -HN-HH (-) Embedded image (HD) -AA 9 Z (CHD) NC ('HD) -HN-z (VHD) N -' (rHD) -HN-HH - (' HD) -H N- (O) D - '(' HD) - (O) D-HN - '(HD) -AA 5 [, uaqd-,' [= Z D e ([HD] Nq HD) -HN- ((HD) Nc (tI-D) -HN-HH (HD) 'HN' (O) D-Z '(O) HN -' (tHD) -AA p ## STR5 ## (HD) HN- ('HD) N' '(' HD) -IN-H HH - '(rHD) -HN- (O) DZ - (O) D-HN- '(' HD) -AA f

  HO H H (HD) -HN- (O) D- (HD) - (O) DHN (D) A-A 7

  ## STR2 ## HD) -AA 1 Z'd M ZD ID z KI1% l UoE; TTI: p adnozD

A-A SN NOOD

H He

N --X - N

Us ZD 10D, N

iu3qd-úf .- (<xojl nq-u) -c = Z FD.

  ## STR2 ## ## EQU1 ## (HD) -HN- (HD) -HN-H (HD) -HN- (O) D- (HD) (O) D-HN - '(' HD) -AA LU CX 00. HD- (HD) 'HN' CHD- (ZHHD) -HN- HH - '(' HD) -HN- (O) D- ( HHD) - (O) D-HN - '(' HD) -AA 9z r "- C,, I ssq 1DUUD4d-ú '= HD * -' (tHD3) -HN- 'HD-' (tH) -HN-H H (tH) -HN- (O) DZ- (O) D-HN - '(tHD) -A-AZ IXU-4d-ú' = Z-. HY '(' HD) -HN'HD - '(' HD) -HN-H H - '(' HD) -HN- (O) DZ- (O) D-HN - '(' HD) -AA tZ i '(' HD) N - '(tHD) - HN -' ('HD) N -' ('HD) -HN-H H -' (HD) -H N- (O) D - '(' HD) ) (O) DHN- '(' HD) -AA z ('HD) N -' ('HD) -HN -' (CHD) N - '(' HD) -HN-H H '(' HD) ## EQU1 ## ## STR2 ## ## STR2 ## - (O) D -; (tiID) - (O) DH-tH HD) - A-A61 ('fHD) N' ('HD) -HN-t (fHD) N -' (ID) - ## STR1 ## ## STR5 ##

  ('HD) N -' ('HD) -HN - (' IHD) N- ('HD) -HN-H H -' ('HD) -HN- (O) D-'HD-O'H] D- (O) D-HN - '(' HD) -AA L1

  ## EQU1 ## where: ## STR1 ## ## STR2 ## ) HD (HD) -HN- (HD) N (HD) -HN- HH- (HD) -HN- (O) D- ( HD) - (O) DN '(' (HD) -AA 51 -t (tHD) -HN ('HD) N -' ('HD) -HN -' ('HD) N -' ('HD) - ## STR5 ## HD - ((HD) - (O) DHN) HD - ((HD) - (O) D-HN - '(' HD) -A-A 1 ('HD) N -' ('HD) -HN -' ('HD) N -' ('HD) -HN-H H -'Z (' HD) -HN- (O) D- ('HD) - (O) D-HN - '(' HD) -AA 9i (CHD) N '(' HD) -HN - '(' HD) N - '(' HD) -HN-H H (HD) -HN - (O) D- (tD) - (O) HN - '(ItD)' AA Z_ ('HD) N -' ('HD) -HN -' ('HD) N -' ('HD) ## STR1 ## (HD) -HN- (O) D '(' HD) - (O) D-HN '("HD) -AA I lt (HD) N -' (tHD) -HN- '(' HD) N '(' HD) -HN-H H '(tHD) -HN (O) HD' (O) DHN-t (HD) AA 01 * (CHD) Nt (rHD) -HN (HD) Nt (HD) -HN-H H (HD) -HN- (HN) D-HD- (HN) D-HN- (HDA-A9t-H H9) N (rH) HN 'N ## STR1 ## (HD) -HN- (tH) -N (HD) -NH-H (H) - (HD) HN- (HN) D-9 ('HD) - (HN) D-HN -' (HD) -A-AEt

00- lXuaqd -'u'I = A to IXuad-l'l = Z t-

  ## STR5 ## ## STR5 ## ) N - '(zHD) -HN-HH-'HD-Z-'HD-HN- (O) DA-tO) D-HN-'HD-Z-'HD-AA zt

1, (uQqd-t "I = Z io.

  (CHD) N- (rHD) -HN-q (HD) N-q (HD) -HN-HH-rHD-Z-O-9 (tHD) -O-Z-HD-A-A. (HD-OD (OHD) -HN- -HD-O- (HD) -HN-H H -q (HD) -HN (O) D - ((HD) - (O) DHN-t (HD) - ## STR5 ## D-HN) HD- (HD) '(O) D-HN- (rHD) - AA 6E IKuaqd-Ii = Z rD n HO HO HH - HD-Z-0 :( HD) -OZ- HD -AA 8s -t (HD) -HN- (O) D t (HD) NC (rHD) -HNHOOD - '(rHD) -HN- HH - (HD) -HN- (O) D- (HD) - (O) D-HN- (HD) - (O) D-HN- (1H) - AA LE - (HD) N- (HD) -HN- 'HD- "(' tHD) -HN-H H - (HD) -HN- (O) Dt (tHD) - (O) D-HN-r (rHD) -A-A9E - (HD) NC (rHD) -HN-'HD-a (rHD) -HN (HD) -HN- (O) D -. (THD) - (O) D-HN - '(tHD) -AA E (tHD) N -. (THD) -HN-Z (CHD) ) Nq (HD) -HN-HH- (HD) -HN- (O) D- (HD) - (O) D -HN - '(tH) -A-Abf I, <u- 4d- ( IQDo- u) -t, = Z q (HHD) N '(tHD) -HN- (HD) Nc (HD) -HN- HH -q (tHD) -HN- (O) D- (Z- ( O) D-HN) HD- (HD) - (O) D-HN-q (HD) - AA EL -t (tHD) -HN (, HD) N- (rHD) -H N- (HD) NC (HD) - HN- HH - (O) D- (HD-HD) - (O) D-HN) HD- (HD) - (O) D-HN (HD) - AA ZE (* HD) Nq (HD) -HNU (HD) N - '(HD) -HN- HH - (HD) -HN- (O) D- (H = HD) -tH) - (O) D-HN (HD) - AA i, (uqd-ú '- (, (xol, (zuq) - = Z QO - (! HD) Nq (HD) -HN - (- FID) N' (tHD) '1 NH H - (H) -HN- (O) -Z- (O) HN (H) -A- A 0O I HD) N- E (HDHN | (HD) - (D) -N- HH - ((H) -HN- (O) DZ-O1) -HN (, o- (= AA 6 * t (H3) Not (zHD) 'HN (H) N- (OH) 3 H- (H) -N- (O) JZ- (O) 3-HN- (rH) A-A6 Preparation of other compounds [VV] of formula I Similarly, other [VV] compounds of formula I are prepared following the procedures of Examples 8 and 9 above, these compounds including those in which the ligand is optionally substituted vancomycin, N-desmethylvancomycin optionally substituted

  or optionally substituted chloreremomycin.

EXAMPLE 10

  Preparation of a compound [N-N] of formula I (1) Preparation of a compound of formula (41) Vancomycin hydrochloride (4.00 g, 2.60 g)

  mmol) was suspended in 40 ml of 1,3-dimethyl-

  3,4,5,6-tetrahydro-2- (1H) -pyrimidinone and the suspension was

  heated at 70 ° C. for 15 minutes. N- (9-fluorenylmethoxy)

  carbonyl) -aminoacetaldehyde (7) (720 mg, 2.6 mmol) was

  added and the mixture was heated at 70 ° C. for one hour.

  Sodium cyanoborohydride (160 mg, 2.5 mmol) in 2 ml of methanol was added and the mixture was heated at 70 ° C for 2 hours and then cooled to room temperature. The reaction solution was added dropwise to 20 ml of acetonitrile to give a precipitate which was separated by centrifugation. The precipitate was purified by reversed phase HPLC on a Dynamax Ranin C18 column (2.5 cm × cm, particle diameter 8 μm) at a flow rate of 10 ml / min using 0.045% TFA in water as buffer A and

  0.045% TFA in acetonitrile as buffer B (

  HPLC of 10-70% B in 90 minutes) to give [N] - [Fmoc] -2-aminoethylvancomycin, consisting of

  to a compound of formula (41), in the form of its trifluoride

  acetate. Calculated SM: MH +, 1715; found 1715.

  (2) Preparation of a compound of formula (42) The compound of formula (41) obtained above (291 mg, 150 imoles) was dissolved in 3 ml of DMF. 3- (Dimethylamino) propylamine (1) (28.3 Ml, 225 pmol) was added, followed by PyBOP (85.8 mg, 165 pmol), HOBt (20.3 mg, 150 mmol) and of the Hunig base (65.0 μl, 375 pmol) were added. Then the reaction solution was stirred for one hour and then added dropwise to 20 ml of acetonitrile to give a precipitate which was separated by centrifugation to give the compound of formula

  [C] -3- (dimethylamino) propylamino) - [N] - [Fmoc] -2-aminoethyl-

  vancomycin (42) as a white solid.

  Calculated SM: MH +, 1800; found 1800.

  (3) Preparation of a compound of formula (43) The compound of formula (42) obtained above was dissolved in 1 ml of DMF and 100 μl of piperidine was added to the solution. The solution was allowed to stand at room temperature for 30 minutes and the evolution of the reaction was monitored by mass spectroscopy. The solution

  reaction was added dropwise to 20 ml of acetonitrile

  nitrile to give a precipitate which was separated by centrifugation. The precipitate was purified by reverse phase HPLC on a Dynamax Ranin C18 column (2.5 cm x 25 cm, particle diameter 8 μm) at a flow rate of 10 ml / min using 0.045% TFA in water. as buffer A and

  0.045% TFA in acetonitrile as buffer B (

  HPLC of 2-50% B in 90 minutes), this

  which gave [C] -3- (dimethylamino) propylamino) - [N] -2-amino-

  ethylvancomycin, consisting of a compound of formula (43), in the form of its trifluoroacetate. Calculated SM: MHW, 1578;

found: 1578.

  Preparation of a compound of formula I The compound of formula (43) prepared above (20.0 mg, 12.7 mmoles) was dissolved in 500 μl of DMF. Of

  HO2C- (CH2) 2-NH-C (O) - (CH2) 2-NH-C (O) - (CH2) 3-C (O) -NH- (CH2) 2-

  C (O) -NH- (CH2) 2-CO2H (6) (2.64 mg, 6.34 pmol) was added followed by PyBOP (8.24 mg, 15.8 mmol), HOBt (2.13 mg, 15.8 μmol) and Hunig's base (8.8 μl, 51.0 mmol). The reaction solution was added dropwise to 20 ml of acetonitrile to give a precipitate which was separated by centrifugation. The precipitate was purified by reverse phase HPLC on a Dynamax Ranin C18 column (2.5 cm x 25 cm, particle diameter 8 μm) at a flow rate of 10 ml / min using 0.045% TFA in 5 ml of the product. water as buffer A and 0.045% TFA in acetonitrile as buffer B (HPLC gradient of 2-50% B over 90 minutes) to give a [NN] -linked compound of formula I in the form of its trifluoroacetate. Calculated SM:

MH +, 3533; found 3533.

  Preparation of Other [N-NI Compounds of Formula I Following the procedures of Example 10, the following [N-N] compounds of Formula I were prepared. It should be noted that the term "category" refers to the point of attachment of the linkage group; Cl, V1 and R1 represent the

  fixation point with regard to the first glycopep-

  tide; C2, V2 and R2 represent the point of attachment in this

  which concerns the second glycopeptide.

0 R R C 1 N-X - N Ac 2 c

HN NH

t I Vl V2

N-N COMPOUNDS

  Cat.-C 2 -C linkage group C2 V2 R2 NN -CH2-ZO- (CH2) 6-O-ZCHr2-OH group HH1 Z = 1,4 phenyl U0 Preparation of other compounds [N-NI of formula By following the procedures of Example 10, other [N-N] compounds of Formula I, including

  those in which the ligand consists of optional vancomycin

  Substantially substituted, N-desmethylvancomycin optionally

  substituted or optionally substituted chloroeremomycin.

EXAMPLE 11

  Preparation of a compound [O-01 of formula I (1)) Preparation of a compound of formula (47) Vancomycin hydrochloride hydrate

  (10 g, 6.4 mmol) was dissolved in 100 ml of dimethyl

  sulfoxide (DMSO) and 3- (dimethylamino) propylamine (3.2 ml, 26 mmol) was added. PyBOP (3.3 g, 6.4 mmol) and 1-hydroxybenzotriazole (HOBT, 0.9 g, 6.4 mmol) dissolved in 100 ml of N, N-dimethylformamide (DMF) were added dropwise. at room temperature. The reaction mixture was stirred for one hour and poured into acetonitrile to give a white precipitate which was filtered and washed with acetonitrile and ether and

  dried under vacuum, giving a syrup of [C] -3- (dimethylamino) -

crude propylamino-vancomycin (46).

  Part of this syrup was dissolved in 100 ml of trifluoroacetic acid (TFA), heated at 323 K for 2 hours, cooled to room temperature and added dropwise to ether to give a green precipitate. The precipitate was filtered off, dried under vacuum and purified by reversed phase HPLC (2-50% acetonitrile in water containing 0.1% TFA) to give the [C] ] -3- (dimethylamino) propylamino-vancomycin, consisting of

  to a compound of formula (47) in the form of its TFA salt.

  (2) Preparation of a compound [O-O] of formula I

  Aglycone trifluoroacetate of [C] -3- (dimethyl)

  amino) propylamino-vancomycin (32 mg, 22 mmol) was dissolved in 320 l of DMF and potassium carbonate (35 mg, 250 μmol) was added. The suspension was agitated

  for 30 minutes at room temperature, then 1.3-

  dibromopropane (0.9 μl, 9 μmol) was added to 20 μl of DMF. The suspension was stirred for 36 hours and diluted with 1 ml of 10% aqueous acetic acid. A

  reverse phase HPLC purification gave [O-O] -1,3

  propane-bis- ([C] -3- (dimethylamino) propylamino-vancomycin)

  (as its trifluoroacetate).

EXAMPLE 12

  Preparation of an α-O-Ol compound of formula I (1) Preparation of a compound of formula (52)

  [C] -3- (dimethylamino) propylamino aglycone

  Vancomycin (47), as its trifluoroacetate (500 mg, 340 pmol), was dissolved in 5 ml of DMF and potassium carbonate (500 mg, 3.6 mmol) was added. The mixture was stirred for 15 minutes at room temperature and then tert-butyl N- (2-bromoethyl) carbamate (77 mg, 340 mmol) was added. The mixture was stirred at room temperature for 24 hours, and then tert-butyl N- (2-bromoethyl) carbamate (70 mg, 310 mmol) was added. The mixture was stirred at room temperature for 7 hours and then poured into ether to give a precipitate which was separated by centrifugation, washed with acetonitrile and dissolved in a water / acetic acid / acetonitrile mixture. in the ratio 5: 1: 2. This solution was purified by HPLC at

  reverse phase, which gave vancomycin [C] -dimethyl-

  aminopropylamide- [O] -2- (N-tert-BOC-amino) ethoxy-aglycone in the form of trifluoroacetate, which has been treated with 1 ml of

  TFA for 30 minutes at room temperature. Purification

  reverse phase HPLC yielded [C] -3- (dimethyl-

  amino) propylamino [0] - (2-aminoethyl) -vancomycine-aglycone

  (52) as trifluoroacetate.

  (2) Preparation of a compound of formula I Succinic acid (0.18 mg, 1.5 μmol), HATU (1.2 mg, 3 mmol) and HOAT (0.4 mg, 3 mmol) ) were dissolved in 40 μl of DMF at room temperature. N, N-diisopropylethylamine (0.5 μl, 3 mmol) was added, the solution was left for 10 minutes, and then added to a mixture of vancomycin [C] -dimethylaminopropylamide-

  [O] - (2-aminoethoxy) -glycone (52) in the form of its trifluoride

  acetate (5 mg, 3 pmol) and N, N-diisopropylethylamine (2.2 pb, 12 pmol) in 100 μl of DMF. This mixture was left at room temperature for a further 20 minutes, then poured into acetonitrile, which was

  gave a white precipitate which was separated by centrifugation.

  Reverse phase HPLC gave [O-O] -butane-1,4-dioic

  bis - [(2-ethyl) amide] - [C, C ']) - bis - ([C] -3- (dimethylamino) -

  propylamino) -bis- (vancomycin-aglycone), consisting of a

  compound of formula I, in the form of its trifluoroacetate.

EXAMPLE 13

  Preparation of an [OO] compound aglycone of formula I (1) Preparation of a compound of formula (57) A compound of formula (47) prepared as shown in Example (12) above ( 500 mg, 340 gmol) was dissolved in 5 ml of DMF and potassium carbonate (500 mg, 3.6 mmol) was added. The mixture was stirred for 15 minutes at room temperature, then tert-butyl bromoacetate (12) (46 μl, 310 pmol) was added. The mixture was stirred at room temperature for one hour, then poured into ether to give a precipitate which was separated by centrifugation, washed with acetonitrile and dissolved in a water / acetic acid mixture in the ether. ratio 10: 1. This solution was purified by reverse phase HPLC to give (in order of elution) an amount of recovered starting material, a product formed by alkylation on the dimethylamino group, and then the desired product (this is that is, the compound of formula (56), its BOC derivative), which has been treated with 1 ml of TFA for 20 minutes at room temperature. Phase HPLC purification

  inverted gave the [C] -3- (dimethylamino) propyl-

  amino- [O] - (2-carboxymethyl) -vancomycin, consisting of

  compound of formula (57) in the form of its trifluoroacetate.

  (2) Preparation of a compound of formula I At room temperature, the compound of formula (57), prepared as indicated above (7 mg,

  gmoles) was dissolved in 160 ml of DMF, N, N-diiso-

  propylethylamine (3.5 μg, 20 gmol) and 1,3-diaminopropane (2) (0.2 μl, 2.5 pmol) were added followed by PyBOP (2.6 mg, 5 gmol). and HOBT (0.7 mg, 5 μmol) in 20 μl of DMF. The mixture was left for 110 minutes and then poured into acetonitrile to give a white precipitate. The precipitate was separated by centrifugation and purified by reverse phase HPLC, which

  gave [O-O] -1,3-bis- (2-acetylamino) propane-bis- ([C] -3-

  (dimethylamino) propylamino) - (vancomycin-aglycone),

  as a compound of formula I, in the form of its trifluoride

  acetate. (4) Preparation of other compounds of formula I Accordingly, following the procedures of Examples 11 to 13, other aglycones consisting of

  Compounds [O-O] of Formula I were prepared.

CI o-X-0 S-C2 CI R NNI NiNR

0-0 COMPOUNDS

No. C1 C2 N1 N2 R2 R2

| LinkCCHN Group.

  ! OO-CH-C (O) -NH- (CH 2) 3 -NH-C (O) -CH 2 -NH- (CH 2) 3 -N (CH) 2 -NH- (CH 2) 3 N (CH 3) 2H H

  20-CH 2-C (O) -NH- (CH 2) 6 -NH-C (O) -CH 2 -NH- (CH 2) 3 -N (CH 2) 2 -NH- (CH 2) 3 N (CH 3) ) 2H H

  3 OO-CH 2-C (O) -NH- (CH 2) 9 -NH-C (O) -CH 2 -NH- (CH 2) 3 -N (CH 2) 2 -NH- (CH 2) 3 N (CH 3) 2 H H ## STR2 ## - (CH 2): - C (O) -NH- (C 2 H 2) 2 -NH- (CH 2) 3 -N (CH 3) 2 -NH (CH 2) 3 -N (CH 3) i HH

  OO - (CH2) 2-NH-C (O) - (CH2), -C (O) -NH- (CH2) 2 -NH- (CH2) 3 -N (CH3): - NH (CH2) 3-N (CH3) 2H H

  O-O - (CH 2) 6 -NH- (CHI) 3-N (CH 3) 2 -NH- (CH 2) 3 N (CH) 2H H

  O-O - (CH 2) 10 -NH- (CH 2) r 3 N (CH 3) 2 -NH- (CH 2) - N (CH) 2 H - H OO - (CH 2) n -NH- (CH 2) n ( CH =) 2-NH- (CH2) 3-N (CH3) 2HHN)

  ## STR2 ## ## STR2 ## ## STR2 ##

C Z = 1.2 phenyl 00

___._ OD

  ## STR2 ## '(' HD) 'HN-' ('HD) Nq (: HD) -HN- (O) D-HN -' (tHD) - ('HD -' ('HD) -HN- (O) D) HD-HN- (O) D-'HD- 0-0 Of

00 -HD

00 '' HD- '' ('HD) N -' ('HD) -HN: (CHJ) N' (tH) HN (O) HN '(HD) - (' HD - '(' HD) -HN - (O) D) HD-HN- (O) D-'HD-0-06z r- 1r- - HH '(' HD) N - '(tHD) HN (HD) N- (HD) -HN- ## EQU2 ##

iXqwl4tCuauonU-6 = Z n.

  ## STR2 ## ) HD'-HN (O) D -'D '0-0 L

IXuaqd t, '[= Z rM.

  ## STR2 ## 0-09Z 1, (uqdI'i = Z In

  ## EQU1 ## '' (H'D) -0-0s-

  ## EQU1 ## where: ## EQU1 ## HD) -HN- (O) DZ- (O) D-HN - '(' HD) -0-0 HH '(' HD) N - '(HD) -HN -' ('HD) N - '(: HD) - HN- -' ('HD) -0-0 f HH' ('HD) N -' ('HD) -HNH (FID) N -' (tHD) -HN- '(') HD) - ('HD) N - (' HD) -0-0 Zz HH t (HID) N - '(tHD) -HN-t ((lD) N-'qHD)' HN '' t ('HD ## EQU1 ## ## STR1 ## (HD) -HN- (HD) N-C (HD) -HN-t (HD) -0 -06HH t (CHD) N- '(: HD) -HN-t (' HD) N- (tHD) -HN- - HD- (O) D-HN-t ('HD) -0-0 81 HH' HD-O - '( HD) -HN-CHD-O't ('HD) - HN-' rHD- (O) D-HN - ('HD) -HN- (O) D-'HD-0-0 Li HH' HD (HD) -HN-CHD-O-'t ('HD) -HN-' HD- (O) D-HN '(HD) HN (O) D-HDO-O 91 HH' HD ## STR1 ## ## STR2 ##

  ## EQU1 ## (HD) ## EQU1 ## (HD) ## EQU1 ##

I'uz4d "I = Z Q

  ## EQU1 ##

  ## STR1 ## (NH) NH (CHD) N-α (HD) -HN '- (O) DHN -' ('HD) - (') HN - '(rHD) -HN- (O) D) HD-H N- (O) D-'HD-0-0 9

-'HD- (O) D-HN - '(' HD) - (H N

  -HH '(HD) N -' (tHD) -HN- '(' HD) N - '(' HD) -HN- -_ ('HD) -HN' '(' HD) HN - '(' HD) ) -HN- (O) D) HD-HN- (O) D-HDH-O-0 su IjuDqd = -Z [, '1 HH' ('HD) N -' (rHD) -HN- (') HD) N - '(' HD) -HN- - (O) D-HN - '(' HD) - (Z - '(' HD) -HN (O) D) HD-HN- (O) D- HD- 0-0 tV or! Loq4dow-N = Z r'HD - - HH z (fHD) NC (: HD) -HN-t (HD) NC (ZHJ) -HN-OO E

  HH '(' HD) N - '(' HD) -HN- '(' HD) N - '(' HD) -HN- - (O) D-HN - '(' HD) - (Z '(' HD) -HN- (O) D) HD-HN- (O) D-'HD-0-0 S

HO'HD - '"((HO) HD) -' HD- = Z

  - HH '(' HD) N - '(rHD) -HN-' ('HD) N -' ('HD) -HN- -'HD- (O) D-HN -' ('HD) - (Z) -HN- (O) D) HD-HN- (O) D-1 {D 3 -O-O-Z- - HH ((HD) N- ((HD) -HIN ((HD) N) (HD) -HN- (O) DHN 'HD) (CHD' "(: HD) HN- (O) D) HD-HN '(O) D-OO If Preparation of other compounds [O- Formula I Following the procedures of Examples 11 to 13, further [0-0] compounds of Formula I were prepared.

  including those in which the ligand consists of vancomycin

  optionally substituted cine, N-desmethylvancomycin

  optionally substituted or optional chloroeromycin

substituted.

EXAMPLE 14

  Preparation of a compound [R-R] of formula I in Scheme 13 Preparation of a compound of formula I 37% formaldehyde (15 μl, 0.20 mmol),

  1,4-diaminobutane (8.8 mg, 0.10 mmol), N, N-

  Diisopropyl ethylamine (174 μL, 1.0 mmol) and vancomycin hydrochloride (300 mg, 0.20 mmol) were added to a 50% aqueous solution of acetonitrile (4.0 mL). After stirring for 18 hours, the product was precipitated by the addition of acetonitrile (45 ml). The solid was isolated by centrifugation, dried under vacuum and purified by reverse phase HPLC (5-20% B in 45 minutes at a flow rate of 50 ml / min). The fractions containing the desired product were identified by mass spectrometry, pooled and lyophilized to give [RR] -1,4-bis (methylamino) butane-bis (vancomycin) as a White powder. MS calculated: (MH), 3008; find

* 3008).

  ## STR1 ## (HD) HNH (HD) HNH (HD) HNH (HD) HNH (HD) -HN-HD-HN (HD) -HN- (O) D-1 (HD) - (O) D-HN - (HD) -HN-HD

H H H HO HO 'DH' (HD'ND% {-% {

  H H H HO HO -'HD-HN- (tHD) -HN-'HD- '% -

  ZlhJ IN tA [A 31 rA HO Hi A Hi o N-X-N n NH

HN I H H I. NH

OH HO

D NN N-N OD

HN '_H H' N

  Preparation of Other [R-RI Compounds of Formula I Following the procedures of Example 14, other [R-R] compounds of Formula I, comprising

  those in which the ligand consists of optional vancomycin

  Substantially substituted, N-desmethylvancomycin optionally

  substituted or optionally substituted chloroeremomycin.

EXAMPLE 15

  Preparation of a compound [CV] of formula I Preparation of a compound of formula (60) [V] -2- [Fmoc-aminoethyl] vancomycin (compound of formula (25)) (263 mg, 0.135 mmol ) was dissolved in a mixture of DMF (2.0 ml) and piperidine (1.0 ml). After 45 minutes the product was isolated by the addition of acetonitrile (45 ml) and centrifuged. The resulting solid was washed with ether (45 ml) and centrifuged. The crude product was dried under vacuum and purified by reverse phase preparative HPLC (5-15% acetonitrile in water containing 0.1% trifluoroacetic acid over 30 minutes). The appropriate fractions

  were pooled and lyophilized, which gave the [V] -2-

  (aminoethyl) -vancomycin (a compound of formula (60)) (200 mg) as its trifluoroacetate. Calculated SM:

(MH +) 1493; found 1494.

  Preparation of a Compound of Formula (62) A 0.010M solution of PyBOP and HOBt in DMF (9.05 mL, 0.0905 mmol each) was added to [V] -2- [Fmoc] -aminoethyl] -vancomycin (a compound of formula

  (25 ')) (176 mg, 0.0905 mmol) and then diisopropylethyl-

  amine (12.8 mg, 0.10 mmol) was added. After agitation

  for 15 minutes, another portion of diisopropylethyl-

  amine (12.8 mg, 0.10 mmol) was added. After a further 5 minutes, the compound of formula (60)

  obtained above (166 mg, 0.0905 mmol) and diisopropyl-

  Ethylamine (35 mg, 0.27 mmol) in DMF (1.5 mL) was added. The reaction mixture was stirred for 30 minutes, after which time the product of formula (61)

  isolated by adding acetonitrile (905 ml) and then

  fugation. The resulting solid was dried under vacuum and then dissolved in DMF (4 ml) and piperidine (1.0 ml). After 10 minutes, the product was isolated by

  addition of acetonitrile (90 ml) and was then centrifuged.

  The resulting solid was washed with ether (90 ml) and centrifuged. The solid was dried under vacuum and purified by reverse phase preparative HPLC (5-15% acetonitrile in water containing 0.1% trifluoroacetic acid over 20 minutes). The appropriate fractions were pooled and lyophilized, which gave

  ([V] -aminoethyl-vancomycin) - [C-V] -N- (2-aminoethyl) -

  (vancomycin), namely the product of formula (62) (173 mg as its trifluoroacetate) calculated SM: (MH +) 2966;

found 2966.

  Preparation of a compound of formula I [CV] The compound of formula (62) obtained above (300 mg, 0.085 mmol) was dissolved in DMF (3.0 ml) and then decanal was added (13). 3 mg, 0.085 mmol). After stirring for 30 minutes, methanol (3.0 ml) was added and followed by 1.0 M sodium cyanoborohydride in methanol (0.085 ml, 0.085 mmol). After one hour, the product was precipitated by addition of ether

  (45 ml) and then centrifuged. The resulting solid substance

  The aunt was dried under vacuum and purified by reverse phase preparative HPLC (15-35% acetonitrile in water containing 0.1% trifluoroacetic acid over 35 minutes). The appropriate fractions have been collected and

  freeze-dried to give ([V] -n-decylaminoethyl-

  vancomycin) - [C-V] -N- (2-aminoethyl) - (vancomycin), consisting of a compound of formula I (126 mg) in the form of its

  trifluoroacetate. Calculated SM (MH +) 3106; found 3107.

EXAMPLE 16

  Preparation of a compound [CV] of formula I Preparation of a compound of formula (65) PyBOP (151 mg, 0.29 mmol), HOBT (35 mg, 0.26 mmol) and, finally, diisopropylethylamine (120 microliters, 0.65 mmol, 2.5 equiv) were added to a

  stirred solution of [C] - (3- (dimethylamino) propyl)

  amine) - [V] -2- [Fmoc-aminoethyl] -vancomycin (500 mg, 0.26 mmol, 1.0 equiv) and mono- (2-aminoethylamide) acid

  succinic (109 mg, 0.29 mmol, 1.1 equiv) in 6 ml of DMF.

  This mixture was left stirring at room temperature for 20 minutes, after which time the mass spectrogram with electrospray of the crude reaction mixture

  indicated the total transformation into the product (M + = 1940).

  This reaction mixture was poured into 60 ml of acetonitrile

  Trile; the resulting precipitate was separated by centrifugation

  redissolved in 6 ml of DMF and treated with 1 ml of piperidine. This reaction mixture was stirred for 20 minutes, then monitored by HPLC and MS, which showed complete conversion to the desired product (M + = 1718) 6. The reaction mixture was poured into 60 ml of acetonitrile and the precipitate resulting was separated by centrifugation. The product was purified by reverse phase HPLC, which

  gave the crude substance as the TFA salt.

  Preparation of a compound of formula I [C-V] 104 mg (0.070 mmol) of vancomycin was added to a stirred solution of 100 mg of the compound obtained above (0.058 mmol) in 1.0 ml of DMSO. The resulting suspension was stirred until a clear solution was obtained. Then 1.0 ml of DMF, 37 mg (0.070 mmol) of

  PyBOP, 8 mg (0.058 mmol) of HOBT and diisopropylethyl-

  amine (27 microliters, 0.145 mmol) was added to this solution. The reaction mixture was stirred for one hour and then added to 15 ml of acetonitrile. The resulting precipitate was separated by centrifugation and then purified by

  Reverse phase HPLC to give (vancomycin) - [C-V] -

  Butane-1,4-dioic acid (2-aminoethyl) -amide- (2-ethyl)

  amide - ([C] -3- (dimethylamino) propylamino-vancomycin), (M + =

3150).

EXAMPLE 17

  Preparation of a compound of formula I (CV) The compound of formula (68) (61 mg, 30 mmol), PyBOP (16 mg, 31 mmol) and HOBt (5 mg, 31 mmol) were dissolved in 1 ml of DMF. The compound (66) (60 mg, 28 mmoles) in 1 ml of DMF and Hunig's base (15 ml, 86 μmol) was added to the solution. The reaction mixture was stirred at room temperature for one hour. Piperidine (0.5 ml) was added to the solution and the reaction was continued for a further 15 minutes. The reaction solution was added to 45 ml of ether to give a precipitate which was separated by centrifugation. The precipitate was dried under vacuum and purified by reverse phase HPLC (80 minutes, 5-45% acetonitrile in water containing 0.1% trifluoroacetic acid,

  compound eluted at 50 minutes), giving ([V] -decylaminoethyl-

  vancomycin) - [C-V] -butane-1,4-dioic acid (2-aminoethyl) -

  amide- (2-ethyl) -amide - ([C] -N-glucosamino-vancomycin), consisting of a compound of formula I (61 mg, 55%) in the form of its trifluoroacetate. MS calculated, MH + 3409; find

3409.

  (In this case, R1 = glucosamine, R2 = decyl)

EXAMPLE 18

  Preparation of a compound [CV] of formula I in which the [C] position is substituted (1) Preparation of a compound of formula (72) A compound of formula: HO2C-CH2CH2NHOCCH2CH2NHOCCH2CH2CH2CONHCH2CH2CONHCH2CH2CO2Fm (15) (Fm denotes a fluorenylmethyl group ) (20.0 mg, 26.8 μmol), followed by PyBOP (20.9 mg, 40.2 mol), HOBt (5.40 mg, 40.2 pmol) and Hunig's base (23, 3 11, 134

  Mmoles) were added to a solution of [C] -2-aminoethyl-

  vancomycin (22) (40.0 mg, 26.8 mmol) in DMF (2.0 ml).

  The reaction solution was stirred for one hour and then added dropwise to 20 ml of acetonitrile to give a precipitate which was separated by centrifugation. The crude precipitate was dried in air to give a compound having a SM value: calculated MH +, 2068; 2068. Compound (71) was used in the next step without further purification by dissolving it in 1 ml of DMF, and 100 ul of piperidine was added to the solution. The solution was allowed to stand at room temperature for 30 minutes, following the evolution of the reaction by mass spectroscopy. The reaction solution was added dropwise to 20 ml of acetonitrile to give a precipitate which was separated by centrifugation. The precipitate was purified by reversed phase HPLC on a Dynamax Ranin C18 column (2.5 cm x 25 cm, particle diameter 8 μm) at a flow rate of 10 ml / min using 0.045% TFA in

  water as buffer A, and 0.045% TFA in acetonitrile

  trile as buffer B (HPLC gradient 2-50% B in 90 minutes). The desired product was identified by mass spectroscopy using an API 300 electrospray mass spectrometer and then lyophilized to a white powder, giving the compound (72) as a

  White powder. Calculated SM: MH +, 1890; found, 1890.

  (3) Preparation of a compound of formula I The compound of formula (72) prepared above (10.0 mg, 4.80 gmol) was dissolved in 500 μl of DMF. Of

  [C] - (3-dimethylaminopropylamino) - [V] -2- (aminoethyl) -

  vancomycin, consisting of a compound of formula (32) (7.20 mg, 4.80 pmol) was added to the solution and was followed by PyBOP (2.50 mg, 4.8 Moles), HOBt ( 0.65 mg,

  4.80 mmol) and Hunig base (6.70 μm, 38.4 μmol).

  The reaction solution was added dropwise to 20 ml of acetonitrile to give a precipitate which was separated by centrifugation. The precipitate was purified by reversed phase HPLC on a Dynamax Ranin C18 column (2.5 cm x 25 cm, particle diameter 8 μm) at a flow rate of ml / minute using 0.045% TFA in water as buffer A and 0.045% TFA in acetonitrile as buffer B (HPLC gradient 2-50% B in 90 minutes). The desired product has been identified by spectroscopy

  mass using an electron mass spectrometer

  API 300 spray. The compound of formula I was obtained as a white powder. Calculated SM: MH +, 3448;

found, 3448.

EXAMPLE 19

  Preparation of a compound [C-V] of formula I (1) Preparation of a compound of formula (76) Vancomycin hydrochloride (5.0 g, 3.2

  mmol) was suspended in 40 ml of 1,3-dimethyl-

  3,4,5,6-Tetrahydro-2- (1H) -pyrimidinone and the suspension was heated at 70 ° C. for 15 minutes. 4-Butoxybenzaldehyde (9) (570 mg, 3.2 mmol) was added and the mixture was heated at 70 ° C for one hour. Sodium cyanoborohydride (241 mg, 3.8 mmol) in 2 ml of methanol was added and the mixture was heated at 70 ° C for 2 hours,

  then cooled to room temperature. The reaction solution

  it was added dropwise to 20 ml of acetonitrile,

  which gave a precipitate which was separated by centrifugation

  tion. The precipitate was purified by reverse phase HPLC on a Dynamax Ranin C 18 column (2.5 cm x 25 cm, particle diameter 8 μm) at a flow rate of 10 ml / min using 0.045% TFA in water as buffer A and 0.045% TFA in acetonitrile as buffer B (HPLC gradient of -70% B over 90 minutes) to give a compound of formula (76) in the form of its trifluoroacetate. SM

calculated: MH +, 1610; found, 1610.

  (2) Preparation of a compound of formula (77) The compound of formula (76) prepared above (82 mg, 45.0 pmol) was dissolved in 2 ml of DMF. Ethylenediamine (2) (13.4 mg, 22.3 mmol) was added followed by PyBOP (28.0 mg, 54.0 mmol), HOBt (7.2 mg, 54, 0 pmol) and the Hunig base (63.0 μl, 360 pmol). The reaction solution was added dropwise to 20 ml of acetonitrile to give a precipitate which was separated by centrifugation. The precipitate was purified by reversed phase HPLC on a Dynamax Ranin C18 column (2.5 cm x 25 cm, particle diameter 8 μm) at a flow rate of 10 ml / min using 0.045% TFA in water. as buffer A and 0.045% TFA in acetonitrile as buffer B (HPLC gradient of 2-50% B in 90 minutes) to give a compound of formula (77) as a trifluoroacetate. Calculated SM: MH +, 1654;

found, 1654.

  (3) Preparation of a C-V compound of formula I wherein a V-position is substituted The compound of formula (77) prepared above (9.7 mg, 4.9 Mmol) was dissolved in 500 μl of DMF. The compound of formula (36) (10.0 mg, 4.9 pmoles) was added to the solution and was followed by PyBOP (3.06 mg, 5.9 gmol), HOBt (0.80 mg) 5.9 μmol) and Hunig's base (6.7 g, 38.4 μmol). The reaction solution was added dropwise to 20 ml of acetonitrile to give a precipitate which was separated by centrifugation. The precipitate was purified by reversed phase HPLC on a Dynamax Ranin C18 column (2.5 cm x 25 cm, particle diameter 8 μm) at a flow rate of 10 ml / min using 0.045% TFA in water. as buffer A and 0.045% TFA

  in acetonitrile as buffer B (HPLC gradient of 2-

  % B in 90 minutes) to give a compound of formula I as its trifluoroacetate. SM

calculated: MH +, 3312; found, 3312.

EXAMPLE 20

  Preparation of a compound [C-VI of formula I A solution of dimethyl suberimidate dihydrochloride (4.1 mg, 0.015 mmol) and diisopropylethylamine (3.9 mg, volume 0.030 mmol) in DMF (0.41 ml) ) has been

  added to a solution of [C] -3-tetrafluoroacetate

  (dimethylaminopropylamido) - [V] - (2-aminoethyl) -vancomycin (32) (30 mg, 0.015 mmol) and [C] - (2-aminoethylamido) vancomycin ditrifluoroacetate (27 mg, 0.015 mmol)

  in DMF (0.20 ml). After one hour, he was

  mass spectrometry that the reaction was

  has come to an end. The solution has been added to aceto

  nitrile (14 ml) and the resulting precipitate was isolated by centrifugation, resuspended in ether (14 ml) and re-isolated by centrifugation. After drying in vacuo, the precipitate was purified by reversed phase HPLC on a Ranin C18 Dynamax column (2.5 cm x 25 cm, particle diameter 8 μm) at a flow rate of 16 ml / minute using 0.045%. TFA in water as buffer A and 0.045% TFA

  in acetonitrile as buffer B (HPLC gradient of 5-

  % B in 60 minutes). The fractions were analyzed by mass spectrometry and analytical HPLC and those containing

  the product indicated in the title were collected and lyophilized

  to give a [C-V] -linked compound of formula I as a white powder (9 mg, 15%). MH 'calculated:

3205.2, found: 3205.5.

  (4) Preparation of other compounds of formula I Accordingly, following the procedures of Examples 15 to 20, other compounds [C-V] of formula I

  have been prepared (see table below).

N2 NI o VI

COMPOUNDS C-V

  No.Catene ## STR2 ## ## STR2 ## ## STR2 ## ## STR2 ## CH2), - N (CH) 2

  2 CV -NH- (CH 2) 2-NH-C (O) - (CH 2) 2 -NH-C (O) - (CH 2), - C (O) -NH-H HH -NH- (CH 2) , -N (CH,) 2

(C H2) 2-C (O) -NH- (CH2) 2-

  3 CV -NH- (CH2) 2-NH-C (O) - (CH2) -C (O) -NH- (CH2) 2 -HH- (CH2) -CH) -NH- (CH2) r3-N (CH 2) CV -NH- (CH 2) 1 -NH-C (O) - (CH 2) r C (O) -NH- (CH 2) 2 -HH- (CH 2) 9 -CH 3 -NH- (CH 2) ) 3-N (CH 2) 2 CV -NH- (CH 2) r -NH-C (O) (CH 2) 2 -C (O) -NH- (CH 2) r 2H H -CH-ZO- (CH 2) rCH , -NH- (CH 3) 3-N (CH 2): Z = 1,4-phenyl 6 CV -NH- (CH 2) 2 -NH-C (O) - (CH 2) C (O) - NH (CH) R H -CH-2 -NH- (CH 2) r 3 -N (CH 2) 2) cit Z = biphenyl-1 ", 1

  C-V-NH- (CH 2) 2 -NH-C (O) -CH 2 -O-CH 2 -C (O) -NH- (CH) r -NH -H -NH- (CH 2) 1 -CH.

  CV -NH- (CH 2) n -NH (O> -CH, -O-CH, -C (O) -NH- (CH 3), -NH- HHH -NH (CH 3) n C10

  8 CV -NH- (CH): - N HC (O) -CH2-O-CH: -C (O) -NH- (CH2) 2 -NH- HH -NH- (CH2): CH '

  9 CV -Nll- (CH2) 2-NH-C (O) -CH2-O-CH-C (O) -NH- (CH) 2 -NH-H -CH-ZO- (CH2) -CH1- NH- (CH2) n (CH3) OZ = 1,4-phenyl-CV-N11 (Cl) 2), - NH-C (O) -CH2-O-CH2-C (O) -NH- (CH2) 2 -NH-H H -CH 2 -Z -NH- (CH 2) 3 -N (CH 3 H 2 O) = blphenyl [I CV -NH- (CH) 2 -RHH - (CH 2) 2 -NH-C (O) - ( CH2) -OH CH3 12 CV -NH- (C H2) -NH-C (O) - (CH2) -C (O) -NH- (CH2) 2 -HH -CU-Z -NH- (CH2) ) -N (CH3) 2

O. Z = 4- (4-chloro).

  biphenyl 13 CV -NH- (CH2) 2-NH-C (O) - (CH2) 2-C (O) -NH- (CH2) 2- HH-CH, -ZO-Ph NH- (CH2), - N (CH), C: Z = 1.4 phenyl 14 CV -NH- (CH2) 2 -NH-C (O) - (CHI) 2-C (O) -NH- (CH2) r2 -H H-CH 2 -Z -NH- (CH 2) 3-N (CH 3) 2

: Z = 2.4-

  dichlorophenyl -N- (C 2 H) 2 -NH-C (O) - (C 2 H) 2-C (O) -NH- (CH) 2 -HH-CH 2 -ZZ '-NH- (CH 2) ) YN (CH 3) 2 oc Z = 1,2-phenyl, Z '= glucoside

  16 CV -NH- (CH 2) 2-NH-C (O) - (CH 2), -C (O) -NH- (CHI) 2 -CH 2 -ZZHH -NH- (CH 2) 3 -N (CH3) CO

C, Z-1,2-

  phenyl, Z '= glucoside 17 HP -NH- (CH2) 2-NH-C (O) - (CH2), -C (O) -NH- (CH2) r -HH-CH2-Z-CF3 -NH - (CH2)> - N (CHi) 2 -: Z = 4,4'-biphenyl

  18 HP -NH- (CH2) 2-NH-C (O) - (CH2) 2-C (O) -NH- (CH2) 2HH-CH2-Z-CH (CH3) 2, -NH- ( CH2)> - N (CH) 2

ci Z = 1,4 = phenyl

  C-V -NH-CH 2 -Z-CH 2 -HH -NH- (CH 2) - N (CH 2) 2

  Z = 1,4-ph nyl C-V -NH-CH-rZ-CHr 2 -H H -CH 2 -Z -NH- (C 2 H 2) -N (CH) 2 Z = 1,4-phenyl: Z = biphenyl.C

  C-V -NH- (CH 2) 2 HH - (CH 2) - CH 3 OH

  tHD :( 'HD) N -' ('HD) -HN -' ('HD) - (O) D-HN -' ('HD) -HH -t (rHD) -HN-AD Lú HD 00 HO (HD) - (O) D-HN-r ('HD) -HH' ('H) -HN-AD 9 00 [Kuu4diq = z rD 1-HO' Z-'HD-HH - (HD ) -HN- (O) D - ('HD) - (O) D-HN- (HD) - HN-AD E Cq

  ('HD) N -' ('HD) -HN-'HD-6 (' HD) -HN - '(' HD) -H H - '(' HD) -HN-A-D P [

  HO 'HD-J (HD) -HN - (' HD) -HH - '(' HD) - HN-AD f IKuq4d! Q = z ro ('HD) N -' ('HD) -HN-Z- (O) D-HN - '(' HD) -HH - '(HD) -HN-AD Zf

[Kul4dlq = z r0.

  HO Z- (O) D-HN - '(HD) -H H -a (' HD) - HN-A-D 1 Cmao HO 'HN -' ('HD) -H H' (HD) -HNA-D 0o HD

  Y'HD) N- (ZHJD) -NH - '(' H D) - (O) D-HN - '(' HD) -H H '(' HD) -IN-A-D 6Z

  ('HD) N -' ('HD) -HN-' HN - '(' HD) -H H - '(' HD) -HN-A-D Sz

  ('HD) N -' ('HD) -HN- H H H -' ('HD) -HN-A-D L

  K u uqdlq (OOlq4,, t)., = 2 '[(' HD) N - '(' HD) -HN-Z-'HD-HH - '(' HD) -HN-AD 9z </ u, 4diq ## EQU1 ## ## STR2 ## ## STR2 ## - [(: HD) ## STR2 ## HD (HD) -HN-AD zEz IXuqd! Q = z HD) Nt (HD) -HN-Z-HD-HN- (HD) -HHH- (HD) -HN- ( O) Dt (HD) (O) D-HN- (fHD) -HN-AD ú ('HD) N- (H) HN-' HD-6 ('HD) -HN -' ('HD) -HH ## STR2 ## D-HN - "('HD) - HH (HD) -HN- (O) Dr (tHD) - (O) D-HN -' (rHD) -HNA-D is q-CN lAUa14d! Q = Z no (tHD) N - '(tHD) -HN- Z- (H) D-HN -' (tHD) -HH -'t ('HD) -HN- (O) D-'t (HD) - (O) D-HN - '(' HD) -HN-AD OS HD Z ('HD) N -' ('HD) -HN -' (HD) - (O) D-HN - '(' HD) ## STR2 ## '(' HD) - HN- (O) D - '(' HD) -HN- AD t ('HD) N-'C (HD) -HNH HH -r (' HD) -HN- (O) D ## STR2 ## D - ( 'd' HD) HD-HN-AD 9b 0 ap! SoDnl'3 =, Z j, (upqd ('HD) N -' ('HD) -HN- HH, ZZ-HD- -' ('HD) HN- ( O) D- (Y ('HD) H) HD-HN-AD t' ('HD) N' '(' HD) -HN-HHH -Z ('HD) -HN- (O) D -' ( HD) - (O) D-HN- (HD) -HN-AD bt ('HD) N-' ('HD) -HN'HN - (' IHD) -HH - '(HDHN- (O) D - (NH) - (O) D-HN - (HD) -HN-AD 8b t (tHD) N - (ZHD) -HN-HHH-Z (HD) -HN- (O) D- ( (dHHD) HD-HN-AD Zb ('HD) N' ('HD) -HN- HHH' ('HD) -HN- (O) D- (' ('HD) HD) ID-HN-AD lp ('HD) N -' ('HD) -HN- HHH -' (HD) -HN- (O) D - '(HD) -HN-AD Ot' HD (CHD) N - '(HD) -HN - '(' HD) - (O) D-HN - '(' HD) -HH t ('HD) - HN-AJ 6f

HO "D O H D) 'H - (D) - HN AD 8

  HO - '' D-ODH- (H) HH z (zFiD) -HN-AJD J sf (HD) N'C (HD) 'HN'CHD'6 (HD)' HN-9 (rHD) -HH ' l (ZHD) 'HN' AD fL

  D ('HD) N -' (HD) -HN-'HD - (HD) -HN-'HD) -H H -A

  ('HD) N -' (IHD) -HN- 'HN-9 (HD) -H H - (' HD) -HN-A-D SL

  c0 qCHJ) N'C (tHJ) 'HN'H6ZJ. (H) HHZJ. 4.AJ I Ir-

_

  (CHD) N - '(HD) -HN-' HN- (HD) -H H - (HD) -HN-A-D OL

  ## STR1 ## tHN-r (HD) -HH- (HD) -HN- AD 89 (CHD) N-'t ('HD) -HN-'HD' (tHD) - HNz (rHD) HH -9 (UHD) - HN-AD L9 (CHD) NH '(rHd) -HN-' HN-r (zHD) -HH '9 (HD) -HN-AD 99 - (CHD) N -' (rHD) -HN-HHH -9 (HD) -HN-AD g9 (HD) N - '(qHD)' HN-HHH - '(HD) -HN-AD 19 Ln

  HO DH - (H) N- (H) -H H H - (HD) -HN-A-D 09

  - (O) D-HN-O (H ') - HN- H H H' - (HD) -HN-A-D 69

  HN - '(' HD) -HN 'H H H -' (HD) -HN-A-D 19

  HD - '(HD) -HN-' rN HHH - '(HD) -HN-AD 09 HO HH -' (rHD) -HN-AD 69 HD'O. '(' HD) 'HN' (HJ- 6 (rHJ) HN't (1HJ) HH (tHJ) HN AD 8 HD-O ('HD) -HN'} IN- '(zHD) -HH' cH {) HN AD LS luqdiq = z no Z ' (O) HN't (HD) 'HHH (H) H'AD 9s HD -' '(' HD) -HN- HHH -; (HD) -HN-AD 5g

HD - ('HD) -HN- H H H' (HHJ) -HN-A-J P '

  ## EQU1 ## where ## STR1 ## (HD) ## STR1 ## HD) N-C (HD) -HN '' HN '(1H) -HH' qtHD) -HN- (O) D-'HD- (HOOD) H D -HN-A-D68 r-. ## EQU1 ## (HD) ## EQU1 ## ## STR2 ## - (O) R) HD-HN-A-D88

  ('HD) N -' (: HD) -HN- HHH - ('HD) -HN- (O) D -'H D- (HD -' ('HD) -H N- (O) D) HD -H NA-DL 8

  ('HD) N -' (rHD) -HN- HHH - '(' HD) -HN- (O) D-'HD - ('(' HD) N - '(' HD) -HN (O) D ) HD-HN-A-D98 ('HD) N' '(' HD) -HN-HHH '' (tHD) -HN (O) D-: HD- (HOOD) HD-HN-A-DSS tHH- H6 (HH J) :( 'HD) N -' ('HD) -IN - HN'r (HD) -HN' (tHD) -H -1 (rHD) -HN-A-DE8 L: (CHD) ) N '(tHd)' HN''HN '(' HD) 'HN' (HHD) 'H -' ('HD) -HN-A-D 8 (-HD-O' (OHD)) tD1 (lD) ).NOT

  : ((HD) N - '(ZHD) -HN -' HD- (O) D-HN - :( IHD) -H H - '(HD) - HN-A-D08

(CHDN - '(' HD)) :( 'HD) N

  (CHD) N'C ('HD) -HN-'HD (O) DHN (HD) HH - (zHD) -HN-A-D18 (CHD-s (tHD)) :( CHD) + N ( HD) N - '(' HD) -HN-'rHD- (O) DH N - '(HD) -HHH) HN- AD OS (' HD) N - '(' HD) -HN HN (HN JD) -HN-r (: HD) 'HH -' (lHD) -HN-A-D6L

  ('HD) N -' ('HD) -HN- (HD (HD)) N (HD) H H' (HD) 'HN A-JD8L

  ## STR1 ## HD) HN'tHDJ '(: HD) -HN'r (tHD)' HH 'U (tH] D) HN' AD 9L r (CHD) NC (: HD) 'HN'fHJD -' (tiHJ) ' HN ':(: HD)' HH -'t (HD) - 'IN-A-JS'

-HD-H6 (-HD)

  -HN - :(: HJ) -HN- HH H LI-qHJ) 'HN' AJ VL HO'HD luqd! Q = z -ro - '((HO) HD) -tHD-HN Z-'HD-HN - (HD) - HH -r ('HD) -HN-AD 501 O0 oU! ## EQU1 ##

eq t.4: M-

  ('HD) NC (' HD) -HN-Z-'HD-HH -'z ('HD) - HN- (O) D -' ('HD) - (O) D-HN - (' HD) -HN-AD 01 -uxtn: s [) - tE = z! DZ ('HD) N -' ('HD) - HN-Z-'ZHD-HH-Z (MHD) -HN-AD zOI lUJ4d! Q ## EQU1 ## ## STR1 ## ## STR1 ## ## STR1 ## ## STR1 ## ## STR2 ## HD) -HH -'Z ('HD) -HN- (O) D-tHD- (HOOD) HD-HN-AD 001 Ln3

  ## EQU1 ## ## STR2 ## ## STR1 ## ((HD) ## STR1 ## HD (H) -NH- (O) D) HD-HN-AD 66 (CHD) .N '(tH)' HN '' HD-6 ('HD) -H N -' ( 'HD) -HH -' ('HD) -HN-AD 86

CHD-6 (HD)

  (CHD) N - '(CHD) -HN - HN -' ('HD) -HN -' ('HD) -H H -' ('HD) -HN-A-D / L6

  ('HD) N -' ('HD) -HN-cHD-6 (rHD) -HN -' ('HD) - HH -' (HD) -HN (O) D-tHD- (A ('HD) N - '(* HD) -HN- (O) D) HD-HN-AD 96 t (' HD) N - '(' HD) -HN '(' HD-6 (HHD)) N-'t ( HD) -HH - '(' HD) -HN- (O) D-'HD- (HOOD) HD-HN-AD 56 (HD) Nc (CHD) -HN- qd-'HD-HN- ( (HD) -HH - '(UHD) -HN-AD b6 _Xua.4d,' I = z QJ ('HD) N -' ('HD) -HN-fDJ6 ((HD)' HN'rUHD) - HH eHD-Z-'HJD-HN-AD ú6 [FID (CHD) NE-f (HD) -IN '' (HD) H N'q- 'ID'Z -' * HD-H H - '(HHD ## EQU1 ## where ## EQU1 ## ## EQU1 ## ## STR2 ##

0 'HD -' ('HD)

  (HD) N-C (HD) -HN-HD = HD (HD) -S (D) HH (HD) -HN-A-D 6

1 '-.- H HD -' ('HD)

  C \ NI (HD) N - '(' HD) -HN- -HD = HD- (rHD) - (sueJ) HH -Z ('HD) -HN-AD 811 tHD6 (HD) -HN- (HD) (CHD) NC (tHJD) 'HN'-HN -' (HD) -H N - '(' HD) -HH 'q (HD) -HN-AD L 11

  -HN-D ('HD) HN H (H) -HN-N -' ('HD) -H H -Z (' HD) -HN-A-D 911

  HN - '(' HD) - 'HD-6 (HD) -HN -' ('HD) -HH -z'HD) -HN-AD 11 uHN'esoDnIl-N-'HD-6 (' HD) - ## STR2 ## (HD) -HN-ADF1 OR! Loqdaow -N = z..o Z'c (t JD) -HN- (HD-6 (IID) -I N - '(ZHD) -HH -' ('HD ## EQU1 ## where ## STR2 ## (CHD) .N '- (HD) -HN-2-THD-HN - (rH) -HH - (HD) -HN-AD 011 I, (uqqd) q = z HD-O -' (' HD) - HN-ZzHD'HN-r (rHD) -HH - '(' HD) - HN-AD 601 HN - '(' HD) -HN lVu? 4d! Q = Z - '(' HD) -HN (HD) -HN Z-HD-HN-z ('HD) -HH -' ('HD) -HN AD S01 1; ## EQU1 ## where: ## STR2 ## ## STR2 ## ## STR2 ## ## STR2 ## ## STR1 ##

HD -. ( 'H'D)

  ('HD) N -' ('HD) -HNN -' ('HD) - H - (' HD) -HN-AD-1Xumqd-t ,, IZ m ('HD) N- ( 'HD) -HN - OZ-'HD-HN -' ('HD) -HH -' ('HD) -HN-A-Dif1

("- HD-- 'H D -' ('HD)

  ## EQU1 ## (HD) N - (HD) -HN-O - ('HD)) N -' ('HD) -HH-r (' HD) -HN- AD [f

  HD) N - '(' HD) HN-O-O - '(' HDHH - '(' HD) HN A

  (* HD) N - '(HD) -HN - O - (' HD) -HN - '(HD) -HH - (HD) - HN-AD z1 Ln' (HD) D = HID '(' HD ' ) - (l HD) D = HD HH '

- (('HD) - (HD) D = HD

  HO - 'HD-HN-'r (HD) -H H -' (tHD) -HN-A-DLZI

(HD) HD D =

- (HD) HD) - (HD) D) H

  __HO - '' D-'DD - H H H '(HD) -HN-A-D 9Z1

(HD) HD D =

  ('HD) N -' (rHD) -HN - '(' HD) - ('HD; D = HD-HD-H H (HD) -HN-A-D5z2

In. - (HD) (HD) D = HD.

- (HD) - (CHD) D = HD

  (CHD) N- (rHD) -HN-HN- ('HD) - (suEJ-sueI) HH - (' HD) -HN-AD [uuuuuu-g = z nJ ('HD) NO ( (HD) -HN Z-'HD-H H -qHD) -HN-AD 1) (fHD) HD = HD ('HD) N -' ('HD) -HN-- (D) (D) DHD' ## STR1 ## ## EQU1 ##

00 -N) -lt = z <.

  ## STR2 ## [HD] -HN-A-D9tbl HO 4d-'HD-HN-t ('HD) -HH-' (HD) -HN- ## STR2 ## (HD) -HN-A-Drt HD-O - (rHD) HN-CHD-L (.HD) -HN -. ('HD) -HH -' (HD) -HN-A-Drt '! C'HD Embedded image (HD) -HH-Z (CHD) -HN-A-DIbl HN-C (CHD) -HH - '(CHD) -HN-A-DOb I

-H (HH J) - (HHJ) 6 = H1

C (CHD) N (CHD) = HN '

  1HHH (N) HH (ZH) -HN-A-D69t1 Z ('HD) N (ZHD) -HN- (HD-S - (tH) H) N (HD) -HH -'t (HD) -HN-A-D881 ('HD) N' (CHD) -HN-CHD-S (ZHD) -HN- (1H) -HH-C ( (HD) -HN-A-DL 1 i iq-t '= zm (' HD) N '-' (HD) -HN-'HD-O-ZHD-HN - '(ZHD) -HH-C (zHD) ) -HN-AD (CH D'O) N '(HD) HN'CH OD (HD'HN. (ZHJD) -H (H -HD) -HNA-DStH)

  - ('HD) N -' (ZHD) -HN-O-Z-'HD-HN-Z ('HD) -H H -'Z (HD) -HN-A-D 0P1

  ('HD) N - (' HD) -H1 'HD-HN' (sD) ZH JH C (CHD) NC (ZHD) -HN-dO'Z'CHD-HNr (CHD) 'HH -rJqJ) -iNAJf81 ## EQU1 ## ## STR1 ## (HD) -HNH HH - Z (HD) -HN- (O) DZAD 9: u! Puad! Dt 'N = Z no

  (HD) -H (HD) -HNH H HH (HD) -HN- (O) D- :( 'HD) - (O) D-Z-'HD-HN-A-D191

Hu p uiddid ú'N = Z rr

  ('HD) N -' ('HD) -HN- H H H' ('HD) -HN- (O) D -' ('HD) - (O) D-Z-'HD-HN-A-D091

  OR! Loqdiow -N = Zr 'Z' - 'HD)' FN'H HH -Z ('HD) -H N- (O) -' ('HD) - (O) DH N-'r (' HD) HN-A-D651

  ('HD) N -' ('HD) -HN- HHH -' ('HD) -HN- (O) D -' ('HD) - (O) D-HN -' ('HD) -HN- A-D8I

  t (CHD) N'C (HD) -HN-HH -'H (HD) -HN- (O) D - '(HD) - (O) D-HN -' (HD) -HN-A-DLs 1

  ## STR5 ## (HD) N '' ('HDN) -' HNH HHH - ('HD) -HN- (O) D-'HD- (O) D-HN -' ('HD) -HN-A -D951

l {u-d p'l = z r. 3

  ('HD) N -' ('HD) -HN- H H H -' ('HD) -HN- (O) D-Z- (O) D-HN -' ('HD) -HN-A-D51

  ## EQU1 ## where: ## STR1 ## -A-DbS 1 uaqd I = z: not ('HD) N-'C (HD) -HN- HHH -' ('HD) -HN- (O) DZ- (O) D-HN-' ('HD) -HN-A-DEs1 t (' HD) N - '(' HD) -HN- HHH - (tHD) HN- (O) D - ('HD-' ('HD)) HD-HN -A-Dú 1 ('HD) N'C (HD) -HN- HHH -' ('HD) -HN- (O) D -' ('D) -HN-A-Di1i (' HD) N- '(' HD) -HN-HHH - '(rHD) -HN- (O) D-zHD-HN-A-OD5I

HD'qq "lD) '$ S

  z ([HD] N - '(HD) -HN - () (O) D-HHH (' JID) -HN-AD 6t 'I, (Pp, (d (qtDI (: HD) -N) -tV =: H "tHD) N'4 (HD) 'HN' Z-ID'HNz: HD) -HH - (HJ) -HN 'AJ 8tl

  C-V -NH- (CH 2) 3 -C (O) -Z-CH 2 -HH -NH- (CH 2) - N (CH 3)

CW Z = N, 4 piperidine

  C-V -NH- (CH 2): -C (O) -NH- (CH 2) 2 HHH -NH- (CH 2) n -CH (CH 3) 2

  C-V-NH-CH ((CH 2) 4-NHBoc) -C (O) -NH- (CH 2) 2 HHH -NH- (CH 2) 3 -N (CH 3) 2

  C-V-NH- (CH2) 2-NH-C (O) - (CH2) 2-C (O) -NH- (CH2) 2 -HHHOH

  168 HP -NH- (CH2) 2-NH-C (O) - (CH2) 2-C (O) -NH- (CH2) 2 -HHH -NH- (CH2) s-CH3 169 CV -NH- ( CH 2) 2-NH-C (O) - (CH 2) 2 -C (O) -NH- (CH 2) 2 -HHH -NH- (CH 2) s -OH-CV-NH- (CH 2) 2 -NH- C (O) - (CH 2) 2-C (O) -NH- (CH 2) 2 -HHH-N-glucosamine 171 CV -NH- (Cl 2) 2 -NH-C (O) - (CH 2) 2 -C (O) -NH- (CH 2) 2 -HHH -NH- (CH 2) 3 -SO 3 H

  172C-N-NH- (CH2) 2-NH-C (O) - (CH2) 2-C (O) -NH- (CH2) 2 -H1HF -NH- (CH2) 2 -O CH,

  173 C-V-NH- (CHI2) 2-NH-C (O) - (CH2): - C (O) -NH- (CH2) 2 -HHH -NH-CH2- (CH (OH)) 4-

CI20OH

  174 C-V (S) -NH-CH (CH (CH 3) 2) -C (O) -NH- (CH 2) 2 HHH -NH- (CH 2) 3 -N (CH 3) 2

  n CV (R) -NH-CH (CH (CH) 2) -C (O) -NH- (CH 2) 2 HHH -NH- (CH 2) 3 -N (CH) 2 o 176 CV (cis) - NH- (CH2) 2-C (O) -CH = CH-C (O) -NH- (CH2) 2HHH -NH- (CH2) NR (CH) 2 CH (trans) -NH- (CH2) ) 2-C (O) -CH = CH-C (O) -NH- (CH2) rH HH -NH- (CH2), -N (CH) 2,178 CV -NH- (CH2) 2-C ( O) -ZC (O) -NH- (CH 2) 2 HHH -NH- (CH 2) 3 -N (CH 1) 2 OW Z = 1.2 cyclopropyl

  179 C-V-NH- (CH 2) 2-NH-C (O) - (CH 2) 2 -C (O) -NH- (CH 2) 2 HHH -NH- (CH 2) 2 -Z

  CW Z = N-piperidine] X 2 CV -NH- (CH 2) 2 -NH-C (O) - (CH 2): - C (O) -NH- (CH 2) 2 HHH -NH- (CH 2) -N (CHr

CH,) ..

  181 C-V -NH- (CH 2), -C (O) -NH- (CH 2) 2 HHH -NH- (CH 2) 3 -N (CH) 2

  182 C-V (R) -NH-CH ((CH 2) -CH (CH 2) 2) -C (O) -N H- (CH 2) n -CH 2 H -NH- (CH 2) n -CH (CH 2)

auexaqoloa, = -

  Z-HN H H -t (tHD) -HN- (O) D-t (tHD) - (O) D-HN- '(' HD) -HN-A-D00O

Z-HN H H H A-OO

## EQU1 ## where: (HD) HN- (O) D-'t ('HD) - (O) D-HN-t (HD) -HN-A- D66 [(HD) N - (ZHD) -HNH HH - ('HD) -H N- (O) D - (' HN- (tHD)) HD-H N- (d) ) A-D861

  ## STR2 ## ## STR2 ## ## STR1 ## ## STR2 ##

  HOOD -rHD- (HOOD) HD-HN-HHH- '(rHD) -HN- (O) D' ('HD) - (O) D-HN -' (zHD) -HN-A-D961 rHN- ( HN) HN-D - ((HD)

  - (HOOD) HD-HN-H H - ('HD) -HN- (O) D -' (HD) - (O) D-HN - '(' HD) -HN-A-D;

  (CHD) N - ('HD) -HN-H H H "U (HD) - HN-A-Dt 61 Ln CHN- (HN) D

  (HD) HH (HD) -HNH (O) D (HH HD) - (O) D-HN - '(' HD) -HN-A -Dú61

  HOOD-: HD-HN-HHH - '(HD) -HN- (O) D -' ('HD) - (O) D- HN -' (HD) -IN-A-JD61

  ## STR2 ## (NH) -N- (O) D- (HD) - (O) D-HN- (tH) -HN-A-D161 HD-t (tHd) (HD) -HN- (O) D - '(HD) - (O) D-HN -' ('HD) -HN-A-D061 t (' HD) N - '(eHD ) -HN-HHH -'Z (HD) -HN- (HN) D - '(HD) - (HN) D-HN -' ('HD) -HN-A-D681 HO-' (HD) -HN - (O) D-HN- (HD) -HN-A-D881 qd-'HD-HN-HHH - ('HD) -HN - (O) D- - (rHD) - (O) D-HN-t (rHD) -HN-A-DL81

  HD - '(' HD) -HN- H H H - (HD) HN- (O) D (HD) (O) DHN- (HD) - HN-A-D981

  HD - '(rHD) -HN-HHH - (' HD) -HN- (O) D - '(HD) - (O) D-HN -' (iHD) -HN-A-D581 rHD - '(HD) ## STR5 ## HD) -HN- (O) D - ('(' HD) HD - ('HD)) HD-iN- (S) A-DU81 (r (cHJ) Nf (r'H3)) NH HH - HD> HN- (O) D - '(' HD) - (O) D-HN- '(' IID) -HN-I-Dsi w - '(HD) N -' (HD) -HN-HH H (HD) -NH- (HD) -NH- (HD) -NH- (HD) -NH- (HD) -HN- (O) D- (tH) - (O) D-HN -A (HD) -HN-A-DfZ Cq 1, (uqdlg4lm {! P -9 '= z "? Z-z -HN- (O) D-'HD- (tHD) N -' ('HD) - (HD) N-HHH-'HD) -HN- (O) D - '(JHD) - (O) D-HN (HD) HN-A-DzIl

HD-O-'HD- (O) D-HN

- (HD) -O - (HD) -O

  (HD) -O - (HD) -HN-'HD-6 (HD) -HN- (HD) -HH ('HD) -HN-AD i CD Z-rHD-HN-HH IHH AD oIz or ## STR2 ## wherein A-D01 -ulp! U3dld- (or! Pddd) d17HHH -1 ('HD) - HN- (O) DJ (HD) - (O) D-HN-q (HD) -HN- A-D60O

* CHD - (HD)

  -HN- (O) D- (HD) - (O) D-HN - '(HD) -HN-A-DsO IXI- ## STR1 ## (NH) -HN- (O) D- (HD) - (O) D-HN - (HD) -HN-A-JL0O

. [(CHD_

  -C ('HD)) N - (' HD) -HN- HHH - (HD) -HN- (O) D-'t ('HD) - (O) D-HN -' ('HD) -HN -A-D90 '(' HD) N - '(' HD) -HN- HHH - '(' HD) -HN- (O) D - '(HD) - (O) D-HN -' ('HD) ## EQU1 ##

(; HD) N - '(ZHD)' HN- H H H A ú O

  iuip! fld.id t, 'Nt = Z. ('HD) N- (HD) -HN- HHH' (H1D) -H1N '(O) D (HD)' HN- (HD) 'N-A-Df05 u {p {, 3d] of N = Z n (CHD) N- (fHd) - HNHH (HD) -HN- (O) DZA-JDzO 2 u (p) D -HHH -Z (tH) -NH- (O) D - '( : HD) - (O) DHN- (rH D) -HN-AD [0o

  216 C-V -NH- (CH 2) 2 HHH -NH- (CH 2) 2 -NH-

(CH2) 7-CH3

  217 C-V-NHI- (Cltr) 2H -NH- (CHI) 2-N (CH2) D-

  C H 218 C-V -NH- (CH2) -H H- (CH1) 2-NH- (CH2) 9 -CH3-NH-CH (COOH) (CHr COOH)

  219 C-V -NH- (CH 2) n -H H - (CHi 2) 2 -NH- (CH 2) 9 -CH 3 N H- (CH 2) 2- (O- (CH 2) 2).

O-CH3

  220 HP N (CH3) - (CH2)> - N (CH) - C (O) - (CH)) 2-C (O) -N (CH3) - (CH2) nHH -N (CH3) - (CH2) 3-

N (CH>) 2

  C-V -NH- (CH 3) 2 HH -NH- (CH 2) 3 -N (CH) 2 -CH 2 -Z

C /. Z = N-

methyl-D-

  Glucamine 222 HP -NH - (C H2) 2-NH-C (O) - (CH2) 2-C (O) -NH- (CH2) 2 -HH- (CH2) 5-CH1-N-glucosamine 223HP -NH- (CH 2) 2 -NHC (O) - (CH 2) 2-C (O) -NH- (CH 2) 2 HH - (CH 2) 7 -CHI-N-glucosamine 224 CV -NH- (CHI) ), - NH-C (O) - (CH) CC (O) -NH- (CH2) 2HH - (CH2), - CH3 -N.glucosamine 224 CV -NH- (CH3): NH-C (O) - (CH 2): - C (O) -NH- (CH 2) 2 HH -CH) 9-CH-N-glucosamine 225 HP -NH- (CH 2) 2 -NH -C (O) - (CH2) 2-C (O) -NH- (CH2) 2HH-CH2-ZPh-N-glucosamine C: Z = biphenyl 227 CV -NH- (C H2) 2-NH- C (O) - (CH2) 2-C (O) -NH- (CH2) 2HH (CH2), -NH- (CH2) 5-CH3-N-glucosamine 228 CV -NH- (CH2): - NH-C (O) - (CH2): C (O) -NH- (CH2) 2- HH - (CH2) 2 -NH- (CH2) 2 -CH3-N-glucosamine

  229 CV -NH- (CH 2), -NH-C (O) - (CH 2) -C (O) -NH- (CH 2) r HH - (CH 2): - NH- (CH 2) 9-CHi N-glucosamine

  22930 CV -NH- (CHI2h-NH-C (O) - (CH) 2-C (O) -NH- (CH) -HH- (CH)) - NH- (CHrH) - * -, N-glucosamine 230 HP -NH- (CH2): NH-C (O) - (CH2) 2-C (O) -NH- (CH2) -HH- (CH2) 2 -NH-CH2-Ph -N GL-glucosamine GO 231 CV -NH- (CH2) 2-NH-C (O) - (CH2) 2C (O) -NH- (CH2) 2HH- (ClH2) 2 -NH-Z, -N-glucosamine ## STR2 ## 14, Z-ZHD-HO 'HD-6 (' HD) -HN - '(' HD) -HH - ('HD) -HN-AD LZ c00 _ _ or lo4dow I'-' -N = ZD; u! We5sO-i. = ZflD -N = 'z Du! Wuso:) ni? -N = Z.FO Z -' ('HD) -HN-'HD-6 (' HD) - HN-t (HD) -HH -'Z ('HD) -HN- (O) D-HD- (Z- (O) D) HD-HN-A-D9tz - or lodWouow -N =' Z 'Y), ## STR1 ## (HD) -HN-HD-6 ('HD) -HN-' ('HD) -HH N- (O) D-HD- (Z- (HD) -HN- (O) D) HA-D H t

u! uippd! d f'N = Z i-

  ## EQU1 ## ) -HH - '(NHD) -HN- (O) D-HD- (ZJ (fHD) -HN- (O) D) HD-HN-'AD Nu! Weso nl'N'HD- (tHD) - ## STR2 ## FHG-N-'HD-6 (IHD) -HN-HD (HD) -H fi eHDH-Z = H HN AD 1 t 2uWLsoDfllO-N = Z l ('HD) N -' ('HJ) HN HD-J (HD) -HN- ('HD) -HH -' ('HD) -HN- (O) D-'HD- (Z- (O) D) HD-HN-A'DOz i, (uaqdiq = Z QO ('HD) N -' ('HD) -HNZ-zHD-HH -' ('HD) -HN-AD 6U (' HD) N - '(' HD) -HN- HD - '(' HD) -HH - '(' HD) -HN-AD si

  ('HD) N -' ('HD) -HN-' HD - '(' HD) -H H - '(' HD) -HN-A-D L

  ('HD) N' ('HD) -HN-' HD - '(' HD) -HH - '(' HD) -HN- (O) D '(NHD) - (O) D-HN -' ( HD) HN-A-D9E

  ('HD) N -' ('HD) -HN-' HD - '(' HD) -HH - '(' HD) -HN- (O) Dz ('HD) - (O) D-HN-' ('HD) -HN-AD iu! Weso: nlI-N-'HD -' ('HD) -iN-r (' HD) -HH '(' HD) -HN- (O) D-'HD- (HOOD) HD-FIN-A-D1fU OU104djow -N = Z Zc (: HD) -HN-HD-J (rHJD) -HN-I (tHD) -HH '(rHD)' H N '(O) D - HDH (HOOD) HD-HN-A-Jg [-a uwrDs -auiXtnj8 - (] .- Iy, m -G -vcl /: w N = Z: n'o 'N = Z 7r i0 le- Z- HbD-Z'I "- DHO HD-6 ('HD)' HN '(zHD)' HH - '(HD) -HN-A-'D 85 t8t rr: weDnlS r- a: WN- ## STR1 ## (HD) -HN-HD-6 '(HD) -HN' (NHD) -HH - '(' HD) -HN-AD LZ u! iwuDnl1 -aI-l, ç4lw

-N = Z QP.

  Z-tHD- ulwuesOInlZ-N-HD-S6 (ZHD) -HN-t (tHD) -HH- '(' HD) -HN-AD 95 (HD) N (tHD) -HN-rHD-t ('HD HN (-) - (HHD) - HH t (tHD) 'HN (O) t (rHD)' (O) HN-t (rHD) 'HN-A'D SZ (' HD) N- '(' HD) -HN- 'HD (' HD) -HN- (tHD) - HH - '(zHD) -HN- (O) Dt (tHD) - (O) D-HN- t (fHD) - HN- AD tS2 iu! WeDnl2 -, - N = ZrF Z-.HID-HO HDS-6 (HD) -HN-'t (tHD) HH 'Z (HD) -HN A- D ú

(HD) N

-C (HD)

  HN'-HD - :( 'HD) N- (rHD) -HN' DHS-6 (eHD) -HN- (HD) -HH -'t (HD) -HN-AD 25 iu! IwDnl2 -Gl, ( ## EQU1 ## ## EQU1 ## (HD) ## STR2 ## (HD) ## STR2 ## ## EQU1 ## in which (ZHD) -HN.r (zliD) -H-1 -ILD) -IN-A-D6tZ

(HD) N

  ## STR3 ## (NH) - (HD) -HH- (1ID) -HN-AD) 259 CV -NH- (CH2) HH- (CH2) 2- N H- (C H 2) 9-C HN-glucosamine -CH 2 -Z-CH 2 -Z

c6 Z = N-O: Z = N-

methyl-D-methyl-D-

glucamine glucamine

  260 HP -NH- (C 2 H) 2-NH-C (O) - (CH 2) 2 -C (O) -NH- (CH 2) 2 HHH -NH- (CH 2) 2 -N ((CH 2) 2 -

OH) 2

  261 C-V-NH- (CH) 2-NH-C (O) - (CH 2) 2 -C (O) -NH- (CH 2) 2 HHH -NH- (CH 2) 2 -NH 2

  262 C-V -NH- (CH2) -H H- (CH2) 2-NH- (CH2) 9 -CH3-NH-CH (C (O) -Z) (CHr)

 (O) -Z)

Cu Z = N-

glucosamine

  263 C-V -NH- (CH 2) 2 H -NH- (CH 2) 3 -N (CH 3) 2

  264 CV -NH- (CH 2) -H * - (CH 2) 2 -NH- (CH 2) n -CH 2 OH 265 CV -NH- (CH 2) 2 -NH-C (O) - (CH 2) 2 -C ( O) -NH- (CH2) 2- HH -NH- (CH2) 3-N (CH3) 2

  266 C-V -NH- (CH2), -H H- (Cl2) 2 -NH- (Ct12) 9-CH3OH -CH2-NH-

(CH2), - OH

  267 CV -NH- (CH2) n -NH-C (O) - (CH2h-C (O) -NH- (CH2) 2- HH- (CH2) 2 -NH- (CH2) 9-CHl- NH- (CH2) n (CH) 2 268 CV -NH- (CH2) 2 -NH-C (O) (CH2) 2-C (O) -NH- (CH2) 2- H- (CH2) 2 -NH CH2-Ph -NH- (CH2) 3-N (CH2) 2 269 HP -NH- (CH2) r HH- (CH2) 2-N ((CH2) 9-CH) -ZOH

a Z = 9-fluroenyl-

mthoxycarbonyl

270 C-V -NH- (CH 2) 2 H H -C 12 -Z OH

Z = 4- (4'-chloro) -

biphenyl

  271 C-V -NH- (CH2) 2-NH-C (O) - (CH2) 2-C (O) -NH- (CH2) 2- HH-CH2-Z OH,

CU Z = 4- (4'-chloro) - j biph4nyl 00

_ 00

  272 CV -NH-CH (C (O) -Z) -CHrC (O) -NH- (CH2) r2-HH- (CH2) 2 -NH-CH2) 9-CH3 OH -X Z = N-glucosamine ## STR1 ## -Du6Z 00 HO tHD-L ('HD) -HH' ('HD) -HN- (O) D -' (HD) - (O) D-HN-f ('HD) -HN-A-DZ6Z Ir -

00 _

  ## STR5 ##

('q Du! iwtenlg -G't <q1iuw -N = Z mx

  ## STR2 ## ## STR2 ## ## STR2 ##

  HO 'HD-6 (rHD) -HN-z (HD) -HH -'r (tHD) -HN- (O) Dz (HD) - (O) D-HN' (rHD) -HN-A- ## EQU1 ## where: ## STR1 ## 6mL = HO (HD) -NH (HD) -H (HD) -H (HD) HN - (O) D - '(' HD- (O) D-HN '(' HD) -HN-A-D6LZ LO -t auiwtnli

-N = Z T.

  ## STR5 ## (HD) -HHH - (HD) HN- (O) D - '(' HD) - (O) D- HN-I (IHD) -HN-A-D8LS iu! WeDnlI Z-'HD-HO cHD-6 ('HD) -HN -' ('HD) -HH' (HD) -HN (O) DZ (rHD ## EQU1 ## ## STR2 ## ## STR1 ## ## STR1 ## ## STR5 ## (HD) -NH- (O) D- '(' HD) - (O) D-HN- (HD) -HN-A-DML Iudq-, t, '= Z' I Z -HnDO HO 'HD- (Z'HD) -HN -' ('HD)' H '(tHD) -HN' (O) D (tHD) '(O) HN' ('HD)'} N'A-D LZ jAua4diq-, t = z = D HO ID-Z-HJD-HN-r ('[jD) -_ i I AD VL2 OIUJHd! Q-, tHl = Z HHtHtfo HO ID-Z- zHD HN-z (zHD) -HH - '(' HD) -IIN-A-'DULZ o00 co rl- rl- C, 4 (H = dS UI.t3 ODUAT q4ag8ap-N you aloTGUOD ureniTiqns eI enb nbTput HO ' HD- (HD) -HN- (ZHD) -HL H -Z (HD) -HN- (O) -D (HD) - (O) D-HN- (rHD) HN- | A-Dt 6 Preparation Other compounds of formula I According to the procedures of Examples 14 to 20, other compounds [CV] of formula I were prepared,

  including those in which the ligand consists of vancomycin

  optionally substituted cine, N-desmethylvancomycin

  optionally substituted or optional chloroeromycin

substituted.

EXAMPLE 21

  Preparation of a compound [C-N1 of formula I] Preparation of a compound of formula I The compound of formula (43) prepared in Example 9 (6.20 mg, 3.14 mmol) was dissolved in 500 ml. of DMF. The compound of formula (72) prepared in Example 14 (4.15 mg, 3.14 pmol) was added to the solution and was followed by PyBOP (2.44 mg, 4.8 gmol), HOBt (0.65 mg, 4.8 pmol) and Hunig's base (6.7, 38.4 pmol). The solution

  reaction was added dropwise to 20 ml of acetonitrile

  nitrile to give a precipitate which was separated by centrifugation. The precipitate was purified by reverse phase HPLC on a Dynamax Ranin C18 column (2.5 cm x 25 cm, particle diameter 8 μm) at a flow rate of 10 ml / min using 0.045% TFA in water. as buffer A, and

  0.045% TFA in acetonitrile as buffer B (

  HPLC of 2-50% B in 90 minutes) to give a compound of Formula I in the form of its

  trifluoroacetate. Calculated SM: MH +, 3533; found, 3533.

EXAMPLE 23

  Preparation of a compound [CR] of formula I (1) Diaminoethane (120 mg, 2.0 mmol), a 37% solution of formaldehyde (32 μl, 0.42 mmol) and [C] -dimethylaminopropylamide Vancomycin (744 mg, 0.40 mmol) was added to a 50% aqueous solution of acetonitrile (5.0 mL). After stirring for 4 hours, the product was precipitated by the addition of acetonitrile (40 ml). The solid was isolated by centrifugation and then washed with ether (40 ml). The resulting solid was dried under vacuum and purified by reversed phase HPLC (5-30% acetonitrile in water containing 0.1% trifluoroacetic acid over a period of 40 minutes at a flow rate of 50 ml. /minute). The fractions containing the desired product were identified by mass spectrometry, pooled and

  lyophilized to give [R] -N- (aminoethyl) amino-

  methyl- [C] -dimethylaminopropylamide-vancomycin (448 mg) as a white powder. Calculated SM: (MH +), 1604;

found, 1604.

  (2) N, N-diisopropylethylamine (14 μL, 0.078 mmol) and solutions of PyBOP and HOBt in DMF (0.26 mL of a 0.1M solution for each, 0.026 mmol each) were added to a solution of vancomycin hydrochloride

  (34 mg, 0.023 mmol) and [R] - (N-aminoethyl) aminomethyl-

  vancomycin- [C] -dimethylaminopropylamide in dimethyl

  formamide (1.0 ml) and dimethylsulfoxide (1.0 ml). After two hours, the product was precipitated by the addition of acetonitrile (40 ml) and isolated by centrifugation. The solid product was washed with ether (40 ml) and dried under vacuum. Reverse phase preparative HPLC (2-20% acetonitrile in water containing 0.1% trifluoroacetic acid over 90 minutes) gave the

  product indicated in the title, in the form of its trifluoro-

  acetate. MS calculated: (MH +) 3036; found, 3036.

  r- - l ZUI | u N | IN | D | I uose. z.I ap adlno = s | _oe r- I

  HHH ('HD) N -' ('HD) -HN - (HD) N -' (UHD) -H N-'Z (HD) HN (O) D (HD)) (O) DN (HD) - AN

  UZIA ZD 1 uos eTI @ pGdnoa S- 'ED Z:}. ZN IA ZD I (HHH it (1) N-tH3) - IIN- -ZHD-HN -' ('IID) -HN-Id _ uos : ## EQU1 ## where: D = os = = H HH (HD) N - '(rHD) -HN-'HD -' ( HD) -H N - '(HD) -Z (HJD) -IHN-ND l uadiq = Z. Tr * -HH '(tHD) N- (UHD) -HN- (UJ) HN-r (tHJ). -F ('I ID) - I IN-N-D J 1, uqqqq = Z M

- - H H N-N-J

  - H H '(tHD) N-'t (lHD) -IHN-zNNz''Hr) - {zD) -INN-D NI [h_ IN ZA IN Z1 t A IN.tuio p5nx ae | ## STR5 ## ## STR5 ## ## STR2 ## ## STR2 ## ## STR2 ## 2HH 2 OV-C H-C (O) -NH- (CH 2) 2 -NHCl-C (O) - (CH 2) 2 -C (O) -NH 1 Cl 2 --NH- (CH 2) - N (CH) 2 | ## STR1 ## O) N-1- (CH 2) z- {-NI 1- (Cl 2) -N (Cl 2) Teicoplanin Derivatives-Cat. No. Link Group VI1 V2 NI N2 R1 R2 CT-C -NH- (CH 2) 2-NH-C (O) - (CH 2) 3 -C (O) -NH- (CH 2) 2 -NH - C (O) - (CH 2), - CH 3 HH 61 CT-C - N H- (C 2 H) 2-NH-C (O) - (CH 2), -C (O) -NH- (CH 2) 2 -NH- -C (O) - (CH 2) 1 CH (CH) 2HI H 1 -l

___ _ CN)

-j "-

________________________ OD_to

  NO. Linker Group N1 N2 VI C2 R1 R2 Co-moi Ct-V-NII- (C2) 2- It II -C (O) - (C12) .- CIh -NHI- (CH2), - N (CH2) ## STR2 ## _at --. Preparation of Other Compounds of Formula I Following the procedures of Examples 21 to 22, other compounds [CN], [CR] and [NV] of Formula I were prepared, including those wherein the ligand is optionally substituted vancomycin, optionally substituted N-desmethyl vancomycin or chloroeromycin

optionally substituted.

EXAMPLE 24

  This example illustrates the preparation of a representative pharmaceutical formulation containing a compound of formula I, for example [C-C] pentanedioic bis - [(2-aminoethyl) amide] -bis- (vancomycin) acid. An oral suspension having the composition

next is prepared.

  Ingredients Active compound 1.0 g fumaric acid 0.5 g Sodium chloride 2.0 g Methyl parahydroxybenzoate 0.1 g Granulated sugar 25.5 g Sorbitol (70% solution) 12.85 g Veegum K (Vanderbilt Co. ) 1.0 g Flavoring agent 0.035 ml Coloring agents 0.5 mg Distilled water, qs per 100 ml Other compounds of formula I may be

  used as an active compound in the preparation of formulas

  oral administration of this example.

EXAMPLE 25

  This example illustrates the preparation of a representative pharmaceutical formulation containing a

  active compound of formula I, for example [C-C] pentane-

  dioic acid bis - [(2-aminoethyl) amide] -bis- (vancomycin).

  An injectable preparation buffered to pH 4,

  having the following composition is prepared.

  Ingredients Active compound 0.2 g Sodium acetate buffer solution (0.4 M) 2.0 ml HC1 (iN) q.s. for pH 4 Water (distilled, sterile) q.s. for 20 ml

______....._ _ _ _ _ _ _ _

  Other compounds of formula I may be

  used as an active compound in the preparation of formulas

injectable formulations of this example.

EXAMPLE 26

  This example illustrates the preparation of a representative pharmaceutical formulation for injection, containing an active compound of formula I, consisting of

  example in [C-C] -pentanedioic acid bis - [(2-aminoethyl) -

  amide] -bis- (vancomycin). A reconstituted solution is prepared by adding 20 ml of sterile water to 1 g of the compound of formula I. Before use, the solution is diluted with 200 ml of an intravenous liquid for injection which is compatible with the compound of formula I. such liquids are selected from a 5% dextrose solution or a 0.9% sodium chloride solution and a solution of a mixture of 5% dextrose and 0.9% sodium chloride. Other examples are Ringer's Lactate Solution for Injection, Lactate Ringer's Solution plus 5% Dextrose for Injection, Normosol-M and 5% Dextrose Solution, Isolyte E, and

  Acylated Ringer for Injection.

  Other compounds of formula I may be

  used as an active compound in the preparation of formulas

injectable formulations of this example.

EXAMPLE 27

  This example illustrates the preparation of a representative pharmaceutical formulation for topical application, containing a compound of formula I, consisting for example of [C-C] -pentanedioic acid bis - [(2 aminoethyl) amide] -bis- (vancomycin). Ingredients grams Active compound 0.2-10 Span 60 2 Tween 60 2 Mineral oil 5 Vaseline 10 Methyl parahydroxybenzoate 0.15 Propyl parahydroxybenzoate 0.05 BHA (butylhydroxyanisole) 0.01 Water q.s. per 100 ml All the aforementioned ingredients, with the exception of water, are mixed and heated to 60 C with stirring. Then added with vigorous stirring a sufficient amount of water C to emulsify the ingredients, then

add water q.s. per 100 g.

  Other compounds of formula I may be

  used as an active compound in the preparation of formulas

topical examples of this example.

EXAMPLE 28

  This example illustrates the preparation of a representative pharmaceutical formulation containing a

  compound of formula I, consisting for example of [C-C] -

  pentanedioic acid bis - [(2-aminoethyl) amide] -bis- (vancomycin)

  cine). A suppository in a total weight of 2.5 g, having the following composition, is prepared: Ingredients Active compound 500 mg Witepsol H-15 * the remainder (triglycerides of a saturated vegetable fatty acid;

  Riches-Nelson, Inc., New York, NY).

  Other compounds of formula I may be

  used as an active compound in the preparation of formulas

  of suppositories in this example.

EXAMPLE 29

  DETERMINATION OF ANTIBACTERIAL ACTIVITY

  In vitro determination of antibacterial activity Bacterial strains were obtained from the American Type Tissue Culture Collection (ATCC), Stanford

  University Hospital (SU), Kaiser Permanente Regional Labora-

  Tory in Berkeley (KPB), Massachusetts General Hospital (MGH), the Centers for Disease Control (CDC), the San Francisco Veterans' Administration Hospital (SFVA), or the University of California San Francisco Hospital (UCSF). Vancomycin resistant enterococci were phenotypically determined to give the Van A or Van B phenotype on the basis of their susceptibility to teicoplanin. Some vancomycin-resistant enterococci that had undergone a genotype determination, giving the Van A, Van B, Van C1 or Van C2 genotype, were obtained from the

Mayo Clinic.

  Minimum inhibitory concentrations (MICs) were measured by a microdilution procedure in broth according to NCCLS rules. In the usual way,

  The compounds were serially diluted in Mueller broth.

  Hinton in 96-well microtiter plates. Overnight cultures of bacterial strains were diluted based on absorbance at 600 nm so that the final concentration in each well was 5 x 105 cfu / ml. The plates were returned to a C incubator. The following day (or 24 hours in the case of enterococci strains), the MICs were determined by examination.

  visual plates. Strains tested in the usual manner in the initial trial included a strain of Staphylococcus aureus.

  methicillin-sensitive coccus aureus (MSSA), a strain of methicillin-resistant Staphylococcus aureus, a

  strain of Staphylococcus epidermidis susceptible to methicillin

  line (MSSE), a strain of Staphylococcus epidermidis

  resistant to methicillin (MRSE), a strain of Entero-

  vancomycin-sensitive coccus faecium (VSE Fm), a strain of Enterococcus faecalis susceptible to vancomycin (VSE Fs), a vancomycin-resistant Enterococcus faecium strain also resistant to teicoplanin (VRE Fm Van A), a Vancomycin-resistant, teicoplanin-sensitive Enterococcus faecium strain (VRE Fm Van B), a vancomycin-resistant and also teicoplanin-resistant Enterococcus faecalis strain (VRE Fs Van A), a strain of Enterococcus faecalis vancomycin-resistant and teicoplanin-sensitive (VRE Fs Van B), a strain of Enterococcus gallinarium of the genotype Van A (VRE Gm Van A), a strain of Enterococcus gallinarium of the genotype Van C-1 (VRE Gm Van C -1), a strain of Enterococcus casseliflavus of the genotype Van C-2 (VRE Cs Van C-2), a strain of Enterococcus flavescens of the genotype Van C-2 (VRE Fv Van C-2), a strain of Streptococcus penicillin-sensitive pneumoniae (PSSP) and a Strept strain penicillin-resistant ococcus pneumoniae (PRSP). Due to the inability of the PSSP and PSRP strains to grow well in Mueller-Hinton broth, the MICs obtained with these strains were determined using TSA broth supplemented with defibrinated blood or blood agar plates. Compounds exhibiting significant activity against the above mentioned strains were then tested for MIC values in a wider range of clinical isolates including the above species as well as susceptible undetermined species of Staphylococcus coagulase-negative strains. and resistant to methicillin (MS-CNS and MR-CNS). In addition, the MICs of these compounds were tested against Gram-negative microorganisms, such as

  Escherichia coli and Pseudomonas aeruginosa.

  Determination of Destruction Time Experiments to determine the time required to kill the bacteria were performed as described by Lorian. These experiments were carried out in the usual way with Staphylococcus strains and

Enterococcus strains.

  In summary, several colonies were selected on an agar plate and grown at 35 C with shaking

  constant until a turbidity of approximately

  1.5 and obtaining 108 CFU / ml. Then the sample was diluted to about 6 x 106 CFU / ml and incubation at 35 C with constant shaking was continued. At various time periods, aliquots were taken and five serial ten-fold dilutions were made. The plate spreading method was used to determine

  the number of colony forming units (CFU).

  The compounds of formula I were active in the

aforementioned tests.

  In Vivo Determination of Antibacterial Activity 1) Studies of Mouse Safety Capacity in Mice In these studies, the compounds of formula I were

  intravenous or subcutaneous

  cutaneous and observed for 5 to 15 minutes. If no adverse effects have occurred, the dose has been increased

  in a second group of mice. These successive increases

  Doses were continued until a mortality occurred, or the dose was increased to a maximum value. In general, the administration started at 20 mg / kg

  and was increased by 20 mg / kg each time until

  maximum tolerated dose (DTM).

  2) Bioavailability studies in mice The compound of formula I was administered to mice intravenously or subcutaneously at a therapeutic dose (generally approximately 50 mg / kg). Groups of animals were placed in metabolic cages so that urine and feces could be collected for analysis. Groups of animals (n = 3) were sacrificed at various time periods (10 minutes, one hour and 4 hours). Blood was collected by cardiac puncture and the following organs were removed - lung, liver, heart, brain, kidney and spleen. Tissues were weighed and prepared for HPLC analysis. HPLC analysis of tissue homogenates and fluids was used to

  determine the concentration of the compound of formula I present. Metabolic products resulting from modifications

  The compounds of formula I have also been

this moment.

  3) Sepsis model in mice

  In this model, a strain of virulence

  Bacteria (most commonly S. aureus, or E. Faecalis or E. Faecium) were administered to mice (N = 5 to 10 mice per group) intraperitoneally. Bacteria have been associated with porcine gastric mucin to increase virulence. The dose of bacteria (usually -107) was that sufficient to induce mortality in all mice within three days. One hour after the administration of the bacteria, the compound of formula I was administered as a single dose IV or subcutaneously. Each dose was administered to groups of 5 to 10 mice, at doses that typically ranged from a high of about 20 mg / kg to a minimum of less than 1 mg / kg. A positive control (usually vancomycin with vancomycin-sensitive strains) was administered in each experiment. The dose at which approximately 50%

  animals are saved was calculated from the results.

  4) Neutropenic Thigh Infection Model In this model, the antibacterial activity of the compound of Formula I was evaluated against an appropriate virulence strain of bacteria (most commonly S. aureus, or E. faecalis or E. faecium, susceptible or resistant to vancomycin). The mice were initially neutropenic by administration of cyclophosphamide at mg / kg on day 0 and day 2. On day 4, they were infected in the left anterior thigh by IM injection of a single dose of bacteria. Then the mice received the compound of formula I one hour after the bacteria and, at various later time points (usually 1, 2.5, 4 and 24 hours), the mice were sacrificed (3 per time point) and the thigh was removed, homogenized and the number of CFU (colony forming units) was determined by spreading. Blood was also spread to determine the

UFC in the blood.

  Pharmacokinetic studies The rate at which the compound of formula I was removed from the blood can be determined in rats or mice. In the rat, the test animals were fitted with a cannula into the jugular vein. The compound of formula I was administered by tail vein injection and, at various time points (usually 5, 15, 30, 60 minutes and 2, 4, 6 and 24 hours), blood was collected by the cannula. In the mouse, the compound of formula I was also administered by tail vein injection and, at various time points, blood was routinely obtained by cardiac puncture. The concentration of the compound

  remaining of formula I was determined by HPLC.

  The compounds of formula I were active in the

  aforementioned tests and presented a broad spectrum of activity.

  It goes without saying that the present invention has been described only for explanatory purposes, but in no way limiting, and that many modifications can be made without it.

get out of his frame.

Claims (57)

  A multi-link compound, characterized in that it has the formula: (L) p (X) q Formula I wherein L is a ligand, the ligands L may be the same or different; X represents a linking group, the X groups may be identical or different; p represents an integer of 2 to 10; and q represents an integer of 1 to 20, each of said ligands comprising a ligand domain capable of binding to a transglycosylase enzyme substrate;   or a pharmaceutically acceptable salt thereof tables;   provided that when L represents vancomycin p is equal to 2 and q is equal to 1 and the binding   is a [C-C] bond, X is not -NH-Q-20 NH-, wherein Q is (CH2) m, (CH2) 2-NH-   (CH2) n-NH- (CH2) 2- or - (CH2) n-S-S- (CH2) n-, wherein m represents   an integer of 2 to 12 and n is an integer of 1 to 3; also provided that when L is vancomycin, p is 2 and q is 1 and the bond is [V-V]; X does not represent an alkylene group, alkylene interrupted by an oxygen atom, or   alkylene interrupted by a phenylene or 1,4-dioxygen group phenylene.   2. A compound according to claim 1, characterized   risé in that pest is 2 and q is 1.   3. A compound according to claim 2, characterized   in that L represents an optionally substituted glycopeptide.   4. A compound according to claim 3, characterized   In that the first and second glycopeptides are selected from the group consisting of optionally substituted vancomycin, optionally substituted Ndesmethylvancomycin and optionally substituted chloroeremomycin, and X connects the [C] end of the first glycopeptide to   the [C] end of the second glycopeptide.   5. A compound according to claim 4, characterized   in that X represents a group: -NH-R6-NH-C (O) -R7-C (O) -NH-R8-NH-   in which R6, R7 and R8 represent an alkylene group optionally substituted.   6. A compound according to claim 5, characterized   in that both glycopeptides consist of vancomycin   R6 and R8 are -CH2-CH2- and R7   represents a group -CH2-CH2-CH2-, namely [C-C] -   pentane-1,5-dioic acid bis - [(2-aminoethyl) -amide] -bis- (Vancomycin).   7. A compound according to claim 5, characterized   R6 and R8 are -CH2-CH2- and R7 is -CH2-CH2-CH2-, the first glycopeptide.   consists of unsubstituted vancomycin and the second glycopep-   tide consists of vancomycin substituted in position [V] with   an alkyl, alkylamino or alkylaminoalkyl substituent.   8. A compound according to claim 7, characterized   in that the substituent in position [V] consists of a   n-decylaminoethyl substituent, namely [V] -n-decyl-   aminoethyl- (vancomycin) - [C-C] -pentane-1,5-dioic bis - [(2 aminoethyl) -amide] - (vancomycin) acid.   9. A compound according to claim 3, characterized   in that the glycopeptide is selected from vancomycin   optionally substituted C, N-desmethylvancomycin   optionally substituted and chloroeremomycin optionally   substituted, and X connects the [V] end of the first   glycopeptide at the [V] end of the second glycopeptide.   10. A compound according to claim 9, characterized   in that X represents a group: -R6-NH-C (O) -R7-C- (O) -NH-R8-   in which R6, R7 and R8 represent alkylene groups optionally substituted.   11. A compound according to claim 10, characterized   in that the first and second glycopeptides are both vancomycin, R6 and R8 are -CH2-CH2- and R7 is -CH2-CH2-CH2-,   know the [V-V] -pentane-1,5-dioic acid bis - [(2-ethyl) - amide] -bis- (vancomycin).   12. A compound according to claim 10, characterized   in that the glycopeptides consist of [C] -3-   (dimethylamino) propylamino-vancomycin, R6 and R8 represent   -CH2-CH2- and R7 is -CH2CH2-CH (NH-   C (O) -Z) -CH 2 -CH 2 -, wherein Z is 4-   biphenyl, namely [V-V] -4- (4-phenylbenzamido) -heptane-   1,7-dioic acid bis - [(2-ethyl) amide] -bis - ([C] -3- (dimethyl) amino) -propyl-vancomycin).   13. A compound according to claim 10, characterized   in that the glycopeptide is [C] -3- (dimethyl)   amino) propylamino-vancomycin, R6 and R8 represent   -CH2-CH2- groups and R7 represents a -CH2CH2-CH (NH-   C (O) -Z) -, wherein Z is a n-tetra-   decanoyl, namely [V-V] -4- (4- (tetradecanoylamido)) -   heptane-1,7-dioic acid bis - [(2-ethyl) amide] -bis - ([C] -3-   (Dimethylamino) propylamino-vancomycin).   14. A compound according to claim 10, characterized   in that the glycopeptide is [C] -3- (dimethyl)   amino) propylamino-vancomycin, R6 and R8 represent   groups -CH2-CH2- and R7 represents a group 1,3- [5-   (benzyloxy) phenyl], namely [V-V] - (5-benzyloxy)   isophthalic acid) bis - [(2-ethyl) amide] -bis - ([C] -3- (di-   methylamino) propylamino-vancomycin).   15. A compound according to claim 3, characterized   in that the glycopeptide is selected from vancomycin   optionally substituted C, N-desmethylvancomycin   optionally substituted and chloroeremomycin optionally   substituted, and X connects the [C] end of the first   glycopeptide at the [V] end of the second glycopeptide.   16. A compound according to claim 15, characterized   in that X represents a group: -NH-R6-NH-C (O) -R7-C (CO) -NH-R8-   in which R6, R7 and R8 represent alkylene groups optionally substituted.   17. A compound according to claim 16, characterized   In that both the first and second glycopeptides are vancomycin, R6, R7 and R8 are all CH2-CH2-, ie [C-V] -butane-1,4-dioic   (2-aminoethyl) -amide- (2-ethyl) -amide-bis (vancomycin) acid.   18. A compound according to claim 16, characterized   in that the first glycopeptide is [V] -n-   octylaminoethyl-vancomycin, the second glycopeptide is [CI-N-glucosamine-vancomycin and R6, R7 and R8 represent   all -CH2-CH2- groups, namely ([V] n-octylamino-   vancomycin- [C-V] -butane-1,4-dioic acid (2-aminoethyl)   amide (2-ethyl) -amide ([C] -N-glucosamine-vancomycin).   19. A compound according to claim 16, characterized   in that the first glycopeptide is [V] -n-   decylaminoethyl-vancomycin, the second glycopeptide is [C] -N-glucosaminevancomycin, and R6, R7 and R8 represent   all -CH2-CH2- groups, namely ([V] n-decylamino-   vancomycin) - [C-V] -butane-1,4-dioic acid (2-aminoethyl) -   amide- (2-ethyl) -amide) - ([C] -N-glucosamine-vancomycin).   20. A compound according to claim 16, characterized   in that the first glycopeptide consists of vancomycin   the second glycopeptide is [C] -3- (dimethyl-   amino) propylamino-vancomycin, R6, R7 and R8 are all   -CH2-CH2- groups, namely (vancomycin) - [C-V] -   butane-1,4-dioic acid (2-aminoethyl) -amide- (2-ethyl) -   amide - ([C] -3- (dimethylamino) propylamino-vancomycin). 21. A compound according to claim 15, characterized   in that X represents a group: -NH-R6-C (O) -NH-R7   in which R6 and R7 represent alkylene groups optionally substituted.   22. A compound according to claim 21, characterized   in that the first glycopeptide is [V] -decyl-   aminoethyl-vancomycin, the second glycopeptide is [C] -N-glucosamine-vancomycin, R6 is -CH (NH-C (O) -Z) -CH2, wherein Z is N-glucosamine, and R7 is group -CH2-CH2-, namely   ([V] -n-decylamino-vancomycin) - [C-V] -3-amino-2- (N-   glucosamino-carbonylamino) -N- (2-ethyl) -propionamide - ([C] -N- Glucosamine-vancomycin).   23. A compound according to claim 15, characterized   in that X represents a group: -NH-R6-   wherein R6 represents an optionally substituted alkylene group.   24. A compound according to claim 23, characterized   in that the first glycopeptide is [V] -n-   decylaminoethyl vancomycin, the second glycopeptide is vancomycin, and R6 is -CH2-CH2-, i.e.   ([V] -n-decylaminoethylvancomycin) - [C-V] -N- (2-aminoethyl) - vancomycin.   25. A compound according to claim 23, characterized   in that the first glycopeptide is [V] -n-   decylaminoethyl vancomycin, the second glycopeptide is vancomycin and R6 is -CH2-CH2-, i.e.   ([V] -n-decylaminoethyl-vancomycin) - [C-V] -N- (2-amino) ethyl) - (vancomycin).   26. A compound according to claim 23, characterized   in that the first glycopeptide is EV] -n-   decylaminoethyl vancomycin, the second glycopeptide   in [R] -N-methyl-D-glucamine-vancomycin, and R6 is CH2-CH2-, namely ([V] -n-decylaminoethyl-vancomycin) - [CV] -N (2- aminoethyl) - ([R] -N-methyl-D-glucamine-5 vancomycin).   27. A compound according to claim 23, characterized   in that the first glycopeptide is [V] -n-   decylaminoethyl vancomycin, the second glycopeptide is [C] -Dglucosamine- [R] -N-methyl-D-glucamine-vancomycin and   R6 represents a group -CH2-CH2-, namely ([V] -n-decyl-   vancomycin-aminoethyl) - [C-V] -N- (2-aminoethyl) - ([C] -D-   glucosamine- [R] -N-methyl-D-glucamine-vancomycin).   28. A compound according to claim 23, characterized   in that the first glycopeptide is [V] -n-   decylaminoethyl vancomycin, the second glycopeptide is [C] -glucosamine-vancomycin, and R6 is a   -CH2-CH2-, namely ([V] -n-decylaminoethyl-vancomycin) -   [C-V] -N- (2-aminoethyl) - ([C] -D-glucosamine-vancomycin).   29. A compound according to claim 3, characterized   in that the glycopeptide is selected from vancomycin   optionally substituted C, N-desmethylvancomycin   optionally substituted and chloroeremomycin optionally   substituted, and X connects the [C] end of the first   glycopeptide at the [N] end of the second glycopeptide.   30. A compound according to claim 29, characterized   in that X represents a group: -NH-R6-   wherein R6 represents an optionally substituted alkylene group.   31. A compound according to claim 30, characterized   in that the first glycopeptide is [V] -n-   hexylaminoethyl vancomycin, the second glycopeptide is [C] -3 (dimethylamino) propylamino-vancomycin, and R6   represents a -CH2-CH2- group, namely ([V] -n-hexylamino-   ethyl vancomycin) - [C-N] -N- (2-aminoethyl) - ([C] -3- (dimethyl amino) -propyl-vancomycin).   32. A compound according to claim 3, characterized   in that the glycopeptide is selected from vancomycin   optionally substituted N-desmethylvancomycin and optionally substituted chloroeremomycin, and X connects the [N] end of the first   glycopeptide at the [N] end of the second glycopeptide. 33. A compound according to claim 32, characterized   in that X represents an optional aralkyl group substituted.   34. A compound according to claim 33, characterized   in that both glycopeptides consist of vancomycin cine and X represents a group: -CH2-Z-O- (CH2) 6-O-Z-CH2-   wherein Z represents a 1,4-phenylene group, namely [N-N] hexane-1,6-bis (phenoxy-4-methyl) -bis (vancomycin).   35. A compound according to claim 3, characterized   in that the glycopeptide is selected from vancomycin   optionally substituted C, N-desmethylvancomycin   optionally substituted and chloroeremomycin optionally   substitute, and X connects the [R] end of the first   glycopeptide at the [R] end of the second glycopeptide.   36. A compound according to claim 35, characterized   in that X represents an optional alkylene group substituted.   37. A compound according to claim 36, characterized   in that both glycopeptides consist of vancomycin   and R6 is - (CH2) 4-, that is, [R-R] -n- butylene-bis (vancomycin).   38. A compound according to claim 3, characterized   in that the glycopeptide is selected from vancomycin   optionally substituted C, N-desmethylvancomycin   optionally substituted and chloroeremomycin optionally   substituted, and X connects the [N] end of the first   glycopeptide at the [V] end of the second glycopeptide.   39. A compound according to claim 38, characterized   in that X represents a group: -NH-R6-NH-C (O) -R7-C (O) -NH-R8-   wherein R6, R7 and R8 are optionally substituted alkylene groups.   40. A compound according to claim 39, characterized   in that the first and second glycopeptides consist of   both in [C] -3- (dimethylamino) propylamino-vancomycin   cine, R6 and R8 each represent a group -CH2-   CH 2 -, and R 7 represents a group -CH 2 -CH 2 -CH 2 -, namely   [N-V] -pentane-1,5-dioic acid bis - [(2-aminoethyl) -amide] -   bis - ([C] -3- (dimethylamino) propyl-vancomycin).   41. A compound according to claim 2, characterized   in that L represents an aglycone.   42. A compound according to claim 41, characterized   in that the first and second aglycones are both optionally substituted vancomycin aglycone and X connects the [O] end of the first   aglycone at the [0] end of the second aglycone.   43. A compound according to claim 42, characterized   in that the first and second aglycones consist   both aglycone of [C] -3- (dimethylamino) propyl- amino vancomycin.   44. A compound according to claim 42, characterized   in that X represents a group:   -NH-R6-NH-C (O) -R7-C (O) -NH-R8-NH-   in which R6, R7 and R8 represent alkylene groups optionally substituted.   45. A compound according to claim 44, characterized   R6 and R8 are -CH2-CH2- and R7 is -CH2-CH2-CH2-, that is the aglycone of   [O-O] -pentane-1,5-dioic acid bis - [(2-aminoethyl) amide] -   bis - ([C] -3- (dimethylamino) propylamino-vancomycin.   46. A compound according to claim 42, characterized   in that X represents an optional alkylene group substituted.   47. A compound according to claim 46, characterized   in that X represents a group -CH2-CH2-CH2-, namely   [O-O] -n-propylene-bis - ([C] -3- (dimethylamino)) -   propylamino-vancomycin. 48. Use of a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that it is intended for the preparation of a medicament for the treatment of mammals presenting a condition pathological and   who is relieved by treatment with an antibacterial agent   nothing. 49. Use according to claim 48, characterized in that the pathological condition is characterized   by resistance to vancomycin.   50. Use according to claim 48, characterized in that the multi-link compound according to claim 1 is a compound of the formula: (L) pXq wherein L is a glycopeptide optionally   substituted and X connects the [C] end of the first glycopep-   tide at the [V] end of the second glycopeptide.   51. Use according to claim 48, characterized in that the compound of formula I is chosen from the following:   [V] -n-decylaminoethyl- (vancomycin) - [C-C] -   [pentane-1,5-dioic acid bis - [(2-aminoethyl) amide] -   (Vancomycin); [V-V] -4- (4-phénylbenzamido) -heptane-l, 7-dioic   bis - [(2-ethyl) amide] -bis - ([C] -3- (dimethylamino) propyl) acid; amino vancomycin);   [V-V] -4- (4- (tétradécanoylamido) -heptane-1,7-   dioic acid bis [(2-ethyl) amide] -bis - ([C] -3- (dimethyl)   amino) -propyl-vancomycin); [V-V] - (5-Benzyloxy-isophthalic acid) bis   (2-ethyl) amide] -bis- ([C] -3- (dimethylamino) propylamino)   vancomycin); [C-V] -butane-1,4-dioic acid (2-aminoethyl) -amido (2-ethyl) -amide-bis (vancomycin); [V] -N-octylamino-vancomycin [C-V] -butane 1,4-dioic acid (2-aminoethyl) -amide- (2-ethyl) -amide). ([C] -N-glucosamine-vancomycin);   [V] -n-decylamino-vancomycin- [C-V] -butane   1,4-dioic acid (2-aminoethyl) -amide- (2-ethyl) -amide)   ([C] -N-glucosamine-vancomycin); (vancomycin) - [C-V] 1,4-butanediol acid   (2-aminoethyl) -amide- (2-ethyl) -amide- ([C] -3- (dimethylamino) - propylamino-vancomycin);   [V] -N-decylamino-vancomycin- [C-V] -3-amino-   2- (N-glucosaminocarbonylamino) -N- (2-ethyl) -propionamide - ([C] -Nglucosamine-vancomycin); [V] -n-decylaminoethyl-vancomycin- [C-V] -N- (2-aminoethyl) - (vancomycin);   [V] -N-Decylaminoethyl-vancomycin- [C-V] -N- (2-aminoethyl) - (vancomycin);   [V] -N-Decylaminoethyl-vancomycin- [C-V] -N-   (2-aminoethyl) - ([R] -N-methyl-D-glucamine-vancomycin);   [V] -N-Decylaminoethyl-vancomycin- [C-V] -N- (2-   aminoethyl) - ([C] -D-glucosamine- [R] -N-methyl-D-glucamine- vancomycin);   [V] -N-Decylaminoethyl-vancomycin- [C-V] -N-   (2-aminoethyl) - ([C] -D-glucosamine-vancomycin);   ([V] -N-hexylaminoethyl-vancomycin) - [C-NI-N- (2-   aminoethyl) - ([C] -3- (dimethylamino) propylamino-vancomycin);   [N-N] hexane-1,6-bis- (phenoxy-4-methyl) -bis-   (Vancomycin); [R-R] -n-butylene-bis (vancomycin);   [N-V] -pentane-1,5-dioic acid bis - [(2-amino)   ethyl) -amide] -bis - ([C] -3- (dimethylamino) propyl-vancomycin);   [O-O] -n-propylene-bis - ([C] -3-   (Dimethylamino) propylamino-vancomycin;   and their pharmaceutically acceptable salts.   52. Pharmaceutical composition, characterized in that it comprises a therapeutically effective amount of at least one compound according to Claim 1, or a pharmaceutically acceptable salt thereof, in admixture with   minus a pharmaceutically acceptable excipient.   53. Process for the preparation of a compound   according to claim 15, characterized in that   takes: a) bringing into contact a compound of formula: H O   In which the shaded square represents a glycopeptide, the shaded circle represents a linking group, R represents   hydrogen or a methyl group and Rz represents hydro-   gene, a protecting group, an alkyl, alkylamino, aryl, heteroaryl, arylalkyl or heteroarylalkyl group; with a compound of formula: R 'N A RI I <B) H A NH2   wherein the shaded square, the shaded circle and R are as defined above, and R11 is hydroxy or -NHR12 wherein R12 is alkyl,   alkylamino, aryl, heteroaryl, arylalkyl or heteroaryl alkyl.   54. A process according to claim 53, characterized   in that R represents a methyl group, R '0 represents an n-octylaminoethyl group, R "represents a hydroxyl group, the shaded square represents vancomycin, the shaded circle in the compound (a) represents a group: - (CH 2 2NHOC (CH2) 2NHOC (CH2) 3CONH (CH2) 2CONH (CH2) 2CO2Fm wherein Fm represents a 9-fluorenylmethyl group, and   Shaded circle in compound (b) represents a (CH 2) 2 group.   55. The method of claim 54, characterized   in that the reaction is carried out in the presence of a tertiary base, PyBOP and HOBT in a polar solvent,   at a temperature in the range of 0 to 100 C.   56. The method of claim 55, characterized   in that the tertiary base consists of diisopropyl-   ethylamine, the polar solvent is N, N-dimethyl-   formamide, and the temperature is equal to 25 C.   57. A compound according to claim 16, characterized   in that the first glycopeptide consists of N-   methyylvancomycin, the second glycopeptide is [C] -3 (dimethylamino) propylamino-N-desmethylvancomycin, and R6, R7 and R8 are all -CH2-CH2- groups, ie (Ndesmethylvancomycin) - [CV] -butane- 1,4-dioic acid   (2-aminoethyl) -amide- (2-ethyl) -amide - ([C] -3- (dimethylamino) -   N-propylamino-desméthylvancomycine).