WO2008075684A1 - Antibiotic glycopeptide derivative - Google Patents

Abstract

Disclosed is a novel glycopeptides derivative having an antibacterial activity. Specifically disclosed is a glycopeptide compound having aromatic rings of the second and sixth amino acid residues in a vancomycin skeleton as partial structures, wherein a Cl atom attached to at least one of the aromatic rings of the second and sixth amino acid residues is substituted by an alkyl which may be substituted, an aryl which may be substituted, an alkenyl which may be substituted, an alkynyl which may be substituted, or a heteroaryl which may be substituted, a pharmaceutically acceptable salt of the glycopeptide compound, or a solvate of the glycopeptide compound or the pharmaceutically acceptable salt thereof.

Description

 Specification

 Glycopeptide antibiotic derivatives

 Technical field

 [0001] The present invention relates to novel derivatives of glycopeptide antibiotics and related compounds. The present invention also relates to pharmaceutical compositions containing such glycopeptide derivatives, and methods for producing such glycopeptide derivatives. Background art

 [0002] Glycopeptide antibiotics are antibiotics having a complex polycyclic peptide structure produced by various microorganisms, and provide effective antibacterial agents against most gram-positive bacteria. In recent years, bacteria resistant to penicillin, cephalosporin, etc. have appeared, and multi-resistant and methicillin-resistant staphylococci (MRSA) infections have caused serious problems in the medical field! Glycopeptide antibiotics such as vancomycin are typically effective against such microorganisms, and vancomycin has become the last tool drug for MRSA and other resistant bacterial infections. However, certain microorganisms, such as vancomycin-resistant enterococci (VRE), are beginning to show resistance to vancomycin. Recently, Staphylococcus aureus (VRSA) that has acquired resistance to VRE has also been discovered!

[0003] Vancomycin has the following formula:

 The aromatic ring of the 2nd and 6th amino acid residues from the N-terminus is substituted with a chlorine atom. Vancomycin derivatives are generally referred to as glycopeptide antibiotics, and the generic name of dalbah peptide (dalbah stamp tide) derived from D_alanyl_D_alanine binding antibiotics with a hepta peptidic structure has been proposed. Dalvaheptide uses a peptide chain consisting of seven amino acids including aromatic amino acids as a common basic skeleton.

 [0004] So far, various modifications have been made to vancomycin and other daricopeptide antibiotics based on this common peptide chain. Glycopeptide derivatives in which the aromatic rings of the second and sixth amino acid residues are substituted with other substituents other than chlorine atoms have also been disclosed (see, for example, the following documents). However, a glycopeptide derivative in which a carbon chain, a carbocycle or a heterocycle is bonded to the chlorine atom is not disclosed.

 [0005] Patent Document 1: International Publication WO03 / 070756 Pamphlet

 Non-patent literature l: ChemBioChem (2003), 4 (3), 658-662

 Non-Patent Document 2: Angew. Chem. Int. Ed., 1998, 37 (19), 2700-2704

Non-Patent Document 3: JACS (1997), 119 (14), 3419-3420 Disclosure of the invention

 Problems to be solved by the invention

 [0006] The present invention provides a novel glycopeptide derivative having antibacterial activity.

 Means for solving the problem

 [0007] The glycopeptide compound of the present invention is characterized in that a substituent is bonded to the aromatic ring of the second and / or sixth amino acid residue via a carbon-carbon bond.

 [0008] That is, the present invention relates to the inventions described in [1] to [; 19] below.

 [1] A glycopeptide compound having, as a partial structure, an aromatic ring of the second and sixth amino acid residues of the vancomycin skeleton, wherein at least one of the second or sixth amino acid residues C1 nuclear S bonded to one of the aromatic rings, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, substituted les, may be! /, Glycopeptide compounds, pharmaceutically acceptable salts thereof, or solvates thereof, which are substituted with alkynyl or substituted! /, May! /, Heteroaryl.

 [0009] [2] The C1 atom bonded to the aromatic ring of the second amino acid residue of the vancomycin skeleton may be an optionally substituted alkyl, an optionally substituted aryl, or an optionally substituted! / Galkenyl, substituted! /, May! /, Alkynyl or substituted! /, May! /, A heteroaryl-substituted glycopeptide compound according to [1] above, Pharmaceutically acceptable salts or solvates thereof.

[0010] [3] The C1 atom bonded to the aromatic ring of the second amino acid residue of the vancomycin skeleton may be an optionally substituted alkyl, an optionally substituted aryl, or an optionally substituted! / Alkenyl, substituted! /, May! /, Alkynyl or substituted! /, May! /, Heteroaryl substituted, aromatic of the 6th amino acid residue of the vancomycin skeleton C1 nuclear S bonded to the ring, hydrogen, halogen other than C1 atom, optionally substituted alkynole, optionally substituted aryl, optionally substituted alkenyl, optionally substituted! /, Alkynyl or substituted! /, May! /, Substituted with heteroaryl! /, The glycopeptide compound of the above-mentioned [2], a pharmaceutically acceptable salt thereof, or a solvate thereof object. [4] Formula (I):

[Chemical 2]

 (Where

 Ring 2 and Ring 4 are the aromatic rings of the second and fourth amino acid residues of the glycopeptide antibiotic, respectively; and

Z ¹ is hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl or substituted! /, Hey! /, Hetero reel)

The daricopeptide compound according to the above [1] (provided that the following partial structure:

[Chemical 3]

 [Where

 Ring 2, Ring 4 and Ring 6 are the aromatic rings of the second, fourth and sixth amino acid residues of the vancomycin skeleton, respectively; and

(ζ ζ ² ) is (hydrogen, hydrogen), (hydrogen, halogen), (halogen, hydrogen) or (halogen, halogen))]

Or a pharmaceutically acceptable salt thereof, or a solvent thereof.

[5] Formula (I 1): [Chemical 4]

 (Where

 Ring 2, Ring 4 and Ring 6 are the aromatic rings of the second, fourth and sixth amino acid residues of glycopeptide antibiotics, respectively;

Z ¹ is hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl or substituted! /, Hey! /, Hetero reel;

Z ² is hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl or substituted! /, Hey! /, Hetero reel;

However, the case where (zz ² ) is (hydrogen, hydrogen), (hydrogen, halogen), (halogen, hydrogen) and (no, rogen, halogen) is excluded. )

The glycopeptide compound of the above-mentioned [1], a pharmaceutically acceptable salt thereof, or a solvate thereof, characterized by comprising a partial structure represented by the formula:

[6] Formula (I 2):

[Chemical 5]

 (Where

Ring 2, Ring 4 and Ring 6 are the aromatic rings of the second, fourth and sixth amino acid residues of glycopeptide antibiotics, respectively; z ¹ is hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl or substituted! /, Hey! /, Hetero reel;

Z ² is hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl or substituted! /, Hey! /, Hetero reel;

However, the case where (zz ² ) is (hydrogen, hydrogen), (hydrogen, halogen), (halogen, hydrogen) and (no, rogen, halogen) is excluded. )

The glycopeptide compound of the above-mentioned [1], a pharmaceutically acceptable salt thereof, or a solvate thereof, characterized by comprising a partial structure represented by the formula:

[7] Formula (I 3):

[Chemical 6]

 (Where

 Ring 2 and Ring 4 are the aromatic rings of the second and fourth amino acid residues of the glycopeptide antibiotic, respectively; and

Z ¹ is hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl or substituted! /, Hey! /, Hetero reel)

The glycopeptide compound of the above-mentioned [1], a pharmaceutically acceptable salt thereof, or a solvate thereof, characterized by comprising a partial structure represented by the formula:

[8] Formula (I 4):

(Where

 Ring 2, Ring 4 and Ring 6 are the aromatic rings of the second, fourth and sixth amino acid residues of glycopeptide antibiotics, respectively;

Z ¹ is hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl or substituted! /, Hey! /, Hetero reel;

Z ² is hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl or substituted! /, Hey! /, Hetero reel;

(Except when (zz ² ) is (hydrogen, hydrogen), (hydrogen, halogen), (halogen, hydrogen) and (no, rogen, halogen))

The glycopeptide compound of the above-mentioned [1], a pharmaceutically acceptable salt thereof, or a solvate thereof, characterized by comprising a partial structure represented by the formula:

[9] Formula (I 5):

(式中、

(Where

 Ring 2, Ring 4, Ring 6, Ring 5, and Ring 7 are the aromatic rings of the second, fourth, sixth, fifth and seventh amino acid residues of glycopeptide antibiotics, respectively;

Z ¹ is hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl or substituted! /, Hey! /, Hetero reel;

Z ² is hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl or substituted! /, Hey! /, Hetero reel;

(Except when (zz ² ) is (hydrogen, hydrogen), (hydrogen, halogen), (halogen, hydrogen) and (no, rogen, halogen))

The glycopeptide compound of the above-mentioned [1], a pharmaceutically acceptable salt thereof, or a solvate thereof, characterized by comprising a partial structure represented by the formula:

[10] Formula (II):

 [Chemical 9]

 (Where

Z ¹ is hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl or Replaced! /, Even! /, Hetero reel;

Z ² may be hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl or substituted! / /, Hetero reel;

However, except when (zz ² ) is (hydrogen, hydrogen), (hydrogen, halogen), (halogen, hydrogen) and (no, rogen, no, rogen);

R ^X is a sugar residue;

R ^B is OH, an ester residue or an amide residue;

 Is hydrogen or optionally substituted alkyl (the alkyl moiety may be intervened by a heteroatom group); and

 R is substituted! /, May! /, Alkyl)

 Or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[11] Z ¹ is selected from the group consisting of lower alkoxy, halogen, lower alkyl, halogenated lower alkyl, halogenated lower alkoxy, lower alkylthio, optionally substituted amide and lower alkenyl 1 Or a compound according to any one of the above [4] to [; 10], which is a phenyl which may be substituted with two or more substituents, or a lower alkenyl which may be substituted; Salts, or solvates thereof.

[12] Z ¹ is selected from the group consisting of lower alkoxy, halogen, lower alkyl, halogenated lower alkyl, halogenated lower alkoxy, lower alkylthio, optionally substituted amide and lower alkenyl 1 Or phenyl which may be substituted with two or more substituents, or lower alkenyl which may be substituted, wherein Z ² is halogen, [5], [6], [8], [9] And the compound according to any one of [10], a pharmaceutically acceptable salt thereof, or a solvate thereof.

[13] A group wherein Z ¹ is halogen, Z ² is lower alkoxy, halogen, lower alkyl, halogenated lower alkyl, halogenated lower alkoxy, lower alkylthio, optionally substituted amino-substituted and lower alkenyl. A phenyl optionally substituted with one or more substituents selected from: or lower alkenyl optionally substituted, [5], [6], [8], [9] and a compound according to any one of [10], a pharmaceutically acceptable salt thereof, or a solvate thereof.

[14] [14] Z ¹ and Z ² are each independently selected from lower alkoxy, halogen, lower alkyl, halogenated lower alkyl, halogenated lower alkoxy, lower alkylthio, optionally substituted amino, and lower alkenyl. Substituted with one or more substituents selected from the group consisting of R, may! /, Phenyl, or substituted! /, May! /, Lower alkenyl, [5] , [6], [8], [9] and the compound according to any one of [10], a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0022] [15] Z ¹ and Z ² are each independently an optionally substituted lower alkenyl, wherein [5], [6], [8], [9] and [10] The compound according to any one of the above, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0023] [16] The compound according to any one of [1] to [; 15] above, which is a vancomycin derivative, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[17] A pharmaceutical composition comprising the compound of the present invention, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0025] [18] Formula (Γ):

 [Chemical 10]

 (Where X is a halogen; rings 2 and 4 are aromatic rings of the second and fourth amino acid residues of glycopeptide antibiotics, respectively)

Z′-B COH) (Z ¹ may be substituted) to a glycopeptide compound comprising a partial structure represented by the following formula in the basic skeleton, a pharmaceutically acceptable salt thereof, or a solvate thereof: Alkyl, optionally substituted aryl, optionally substituted alkenyl, substituted! /, May! /, Alkynyl or substituted! /, May! /, Heteroaryl), Ζ ¹ — ^! ^ ¹ is an optionally substituted alkenyl or an optionally substituted alkynyl), and Is a compound represented by Zi Sn— (Alk) (Z ¹ is an optionally substituted aryl, an optionally substituted alkenyl, or an optionally substituted heteroaryl; Alk is an alkyl). The compound according to [4] above, wherein Z ¹ in the formula (I) is an optionally substituted alkyl, an optionally substituted aryl, or an optionally substituted! / Alkenyl, substituted! /, May! /, Alkynyl or substituted! /, May! /, Heteroaryl).

 [19] Formula (I 1,):

 [Chemical 11]

 (Wherein X and X ′ are each independently halogen;

 Rings 2, 4 and 6 are the aromatic rings of the second, fourth and sixth amino acid residues of glycopeptide antibiotics, respectively)

 Or a pharmaceutically acceptable salt thereof, or a solvate thereof, Z—B (OH) (where Z is an optionally substituted alkyl, Optionally substituted alkenyl, optionally substituted alkenyl, optionally substituted alkynyl or optionally substituted heteroaryl, Z—H (Z is optionally substituted alkenyl or substituted) Alkynyl), or Z—Sn— (Alk) (

Wherein Z is an optionally substituted aryl, an optionally substituted alkenyl, or an optionally substituted heteroaryl; Alk is an alkyl) compound, [5] A process for producing the compound described in [5].

 BEST MODE FOR CARRYING OUT THE INVENTION

[0027] Terms used in the present specification will be described below. Each term alone or together with other terms has the same meaning.

In the present specification, in the present specification, the “basic skeleton” means a basic skeleton of a glycopeptide antibiotic, specifically, the above-mentioned dalbah peptide (dalbah tide). "Basic skeleton" is preferred Is the “vancomycin skeleton”. Specifically, it means a cyclic structure of a peptide chain composed of 7 amino acids including aromatic amino acids. In detail, among them, 5 amino acids, ie, amino acids 2, 4, 5, 6, 7 from the N-terminal, are common, and the second and fourth and fourth and sixth aromatics. Amino acids are linked by diphenyl ether linkages, and the 5th and 7th aromatic amino acids are linked by C–C bonds. Other structures are broadly classified into vancomycin type, ristocetin type, avoparcin type, symononicin type, etc., depending on the type of amino acids 1 and 3 (Reference: Antibiotics Material Summary: Chemistry and Biological Activity, 4th edition, p.265-268, published by The University of Tokyo Press) The basic skeleton specifically has the following partial structure.

 [Chemical 12]

 More preferably, it has the following partial structure.

 [Chemical 13]

 The basic skeleton is particularly preferably

[Chemical 14]

 (Rings 2, 4, 5, 6 and 7 represent the aromatic rings at the 2, 4, 5, 6, and 7th amino acid residues of glycopeptide antibiotics, respectively)

 Indicated by

[0030] The present invention provides a substituent represented by Z ¹ defined below and / or a ring 6 defined in the basic skeleton in ring 2 in the basic skeleton, and Z ² defined in the following. It was found that the substituents shown can be introduced. Therefore, according to the present invention, and various glycopeptide antibiotics having the basic skeleton as the starting material, Z ¹ group in the ring 2, and / or novel antimicrobial compounds which Z ² group is introduced into the ring 6 Can provide. Preferably, at least ring 2 has a Z ¹ group introduced. Preferably, a Z ¹ group is introduced into ring ² and a Z ² group is introduced into ring 6. Further, in the compound of the present invention, the substituents that can be bonded to the basic skeleton include hydrogen, OH, halogen, sugar residue, optionally substituted lower alkyl, ester residue in addition to Z ¹ group and Z ² group. And various substituents well known in the art or chemically modifiable, such as amide residues and the like.

 In the present specification, the term “partial structure” means the structure of a specific part of the “basic skeleton”.

In the present specification, the “glycopeptide antibiotic” means any glycopeptide compound having the above “basic skeleton” and derivatives thereof. Vancomycin and various other glycopeptide derivatives are known in the art. Known glycopeptide antibiotics include, for example, JP-A-61-251699, JP-A-7-258289, International Publication W096 / 30401 Nonfret, National Opening WO00 / 39156 Nonfret, Ushidera Open 2000 302687 Gazette, International Publication WO2004 / 44222; U.S. Pat. No. 4,639,433; 4,643,987; 4,497,802; 4,698,327; No. 5,91,714; No. 5,840,684; and No. 5,843,889; EP0802199; EP0801075; EP0667353; WO97 / 28812; WO97 / 38702; WO98 / 52589; WO98 / 52592; and J Am. Chem. Soc., 1996, 118, 13107-; 13108; J. Am. Chem. Soc., 1997, 119, 12041-; 12047; and J. Am. Chem. Soc., 1994, 1 16, What is disclosed by 4573-4590 grade | etc., Is mentioned.

 [0033] Examples of glycopeptide antibiotics include, for example, vancomycin, ticobranine, ristomycin, ristocetin, actaplanin, actinoidin, anoledacin, azurenoresin, azureomycin, balremycin, Mouth orienticin A (ChloroorienticinA), Black mouth orienticin B (Chloroorien ticinB), Black mouth polysporin (Decaplanin), N- Canoresin (Ihel peptin), Kibdelin (Kibdelin), Mannopeptin (Mannopeptin), Orienticin (Orienticin), Norevocinin (Parvodicin), Simmonicin (Oritavancin), Nora Shin (Telavancin), Danoreno Roh Nshin (Dalbavancin), and the like A- 40926.

 [0034] The compound of the present invention specifically has at least one of the C1 atoms bonded to the aromatic ring of the 2nd or 6th amino acid residue of the vancomycin skeleton, substituted! /, Mayo! /, Alkyl, optionally substituted aryl, optionally substituted alkenyl, substituted! /, May! /, Alkynyl or substituted! /, May! /, A glycopeptide compound having a partial aromatic ring substituted with a heteroaryl, a pharmaceutically acceptable salt thereof, or a solvate thereof. Here, the C1 atom bonded to the aromatic ring of the 2nd or 6th amino acid residue is substituted with the above substituents! /, May! /, And only one of them is injured. V, may be substituted with the above substituents!

[0035] The ability of the glycopeptide compound of the present invention When only one of the above-mentioned C1 atoms is substituted with the above substituent and has an aromatic ring as a partial structure, it binds to the other aromatic ring. The CI atom may be as it is or may be substituted with hydrogen or a halogen atom other than C1 (F, Br, I). In addition, if the structure other than the aromatic ring of the second and sixth amino acid residues is based on the basic skeleton of the glycopeptide antibiotic, it is appropriately substituted with a substituent that is well known or can be synthesized by those skilled in the art. It may be. For example, the C-terminal, N-terminal, resorcinol moiety, etc. in vancomycin derivatives, ticobranine derivatives, etc. may be appropriately chemically modified.

[0036] One of the preferred embodiments of the above compound has, as a partial structure, an aromatic ring in which the C1 atom bonded to the aromatic ring of the second amino acid residue of the vancomycin skeleton is substituted with the above substituent.

[0037] In one embodiment of the present invention, the glycopeptide compound of the present invention has a substituent Z ¹ having a carbon atom on the aromatic ring of the second amino acid residue (phenylalanine residue) from the N-terminus of a glycopeptide antibiotic. Bonded via a carbon bond. Specifically, the glycopeptide compound of the present invention has a partial structure represented by the formula (I).

 [Chemical 15]

Here, ring 2 and ring 4 represent the aromatic rings at the second and fourth amino acid residues of the glycopeptide antibiotic, respectively. Substituent Z ¹ is hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, substituted les, may! /, Alkynyl or substituted. /! But! / Hetero reel

More preferably, the glycopeptide compound of the present invention has a partial structure represented by the formula (I 1), (1-2), (I-3), or (I 4). Particularly preferably, the formula:

 (Rings 2, 4, 5, 6 and 7 represent the aromatic rings at the 2, 4, 5, 6, and 7th amino acid residues of glycopeptide antibiotics, respectively)

 It has the partial structure shown by.

[0039] As used herein, the term "alkyl" used alone or in combination with other terms refers to a straight or branched chain having 1 to 15, preferably 1 to 10 carbon atoms. Includes monovalent hydrocarbon groups in the chain. For example, methyl, ethyl, n-propyl, isopropyl, n-butinole, isobutinole, sec-butinole, t-butinole, n-pentinole, isopentinole, neo-pentyl, n-hexyl, isohexyl, n-heptyl, n —Octyl and the like. More preferred is C1-C6 alkyl. More preferred is C1-C3 alkyl.

 In the present specification, the term “lower alkyl” used alone or in combination with other terms means the above “alkyl” having 1 to 6 carbon atoms. The terms “quaternary ammonium lower alkyl”, “amino lower alkyl”, “amino lower alkylamino”, “tri-lower alkyl ammonium lower alkyl”, “halogenated lower alkyl”, “hydroxy” as used herein. “Lower alkyl”, “Hydroxy lower alkylamino”, “Hydroxy lower alkoxy lower alkyl”, “Heterocyclic lower alkyl”, “Mono or di lower alkylamino”, “Mono or di lower alkylamino lower alkyl”, “Lower alkylthio” The lower alkyl moiety of is the same as the above “lower alkyl”.

[0041] As used herein, the term "alkylene" used alone or in combination with other terms includes:! -15, preferably 1-10; linear or branched having 10 carbon atoms Chain 2 Valent hydrocarbon groups. For example, lower alkylene having 1 to 6 carbon atoms such as methylene, ethylene, propylene, butylene, pentylene and hexylene can be mentioned.

 In the present specification, the alkyl part of “alkoxy” used alone or in combination with other terms has the same meaning as the above “alkyl”. Examples of “alkoxy” include methoxy, ethoxy, n propoxy, isopropoxy, n butoxy, isobutoxy, sec butoxy, t butoxy, n pentinoreoxy, n hexenoreoxy, n heptinoreoxy, n octyloxy and the like.

 In the present specification, “lower alkoxy” used alone or in combination with other terms means the above “alkoxy” having from! To 6 carbon atoms. Specific examples include methoxy, ethoxy, n propoxy, isopropoxy, n butoxy, isobutoxy, sec butoxy, t butoxy, n pentyloxy, and n hexyloxy. As used herein, the lower alkyl part of the terms “norogenated lower alkoxy”, “lower alkoxycarbonyl”, and “hydroxy lower alkoxy lower alkyl” is the same as the above “lower alkyl”.

 [0044] In the present specification, "alkenyl" used alone or in combination with other terms means 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, 1 or 2 carbon atoms. It includes a straight-chain or branched monovalent hydrocarbon group having the above double bond. For example, bur, linole, 1-propenore, 2-propenore, crotoninole, isopentenore, various fu, teninole alien organism, pentageninore, hexeninore, isohexenore, hexageninore, hepteninore, otatur, And decenyl. Preferably, C2-C6 alkenyl is used. More preferably, C2-C4 alkenyl is mentioned. These may have one or more double bonds at any position. Preferably a double bond is present between the 1- and 2-position carbon atoms.

 In the present specification, the term “lower alkenyl” used alone or in combination with another term means the above “alkenyl” having 2 to 6 carbon atoms.

[0046] In the present specification, the term "alkkenylene" used alone or in combination with other terms has 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, and 1 Or 2 or more And a straight-chain or branched divalent hydrocarbon group having a double bond. For example, lower alkenylene having 6 to 6 carbon atoms such as etylene, propenylene, butenylene, pentenylene, hexenylene and the like;

[0047] In the present specification, "alkynyl" used alone or in combination with other terms means a straight chain having 2 to 8 carbon atoms and having one or more triple bonds Or a branched monovalent hydrocarbon group. Examples include echul, 1-probule, 2-propininole, pu, chininole, pentininore, hekisnore, heptininore, octininore, nonininole and decynyl. Preferably, C2-C6 alkynyl is mentioned. More preferably, C2-C4 alkynyl is mentioned. These have one or more triple bonds at arbitrary positions, and may further have a double bond. Preferably a triple bond is present between the 1 and 2 carbon atoms.

 In the present specification, the term “lower alkynyl” used alone or in combination with other terms means the above “alkynyl” having 2 to 6 carbon atoms.

 [0049] In the present specification, "aryl" includes a monocyclic or condensed cyclic aromatic hydrocarbon group having 6 to 14 carbon atoms. For example, phenyl, 1-naphthyl, 2-naphthyl, anthryl, phenanthryl and the like can be mentioned. Preferable are phenyl, 1-naphthyl, and 2-naphthyl. More preferably, a phenyl is mentioned.

 [0050] In this specification, "heteroaryl" means, for example, a monocyclic aromatic heterocyclic group or a condensed aromatic heterocyclic ring containing an octaro atom selected from a nitrogen atom, a sulfur atom and an oxygen atom in the ring. Means a formula group. Monocyclic aromatic heterocyclic groups are substituted from 5-8 membered aromatic rings which may contain oxygen atoms, sulfur atoms, and / or nitrogen atoms in the ring;! -4 It means a group which may have a bond at any possible position. The fused aromatic heterocyclic group may contain oxygen atoms, sulfur atoms, and / or nitrogen atoms in the ring;! To 4 5 to 8 membered aromatic rings;! To 4 5 It means a group which may have a bond at any substitutable position, which is condensed with a ˜8-membered aromatic carbocycle or other 5- to 8-membered aromatic heterocycle.

[0051] Specific "heteroaryl" includes, for example, furyl (eg, 2 furyl, 3 furyl), cenyl (eg, 2 chenyl, 3 chenyl), pyrrolyl (eg, 1-pyrrolyl, 2 pyrrolinole, 3 pyrrolyl), imidazolyl (eg, 1 imidazolinole, 2 imidazolyl, 4 imidazolyl), pyrazolyl (eg, 1 pyrazolyl, 3-pyrazolyl, 4 pyrazolyl), 卜 lyso 'Rinole (ί column free)', 1 , 2, 4 卜 lyso 'monore 1-inole, 1, 2, 4 卜 lyso' monore 3 yl, 1, 2, 4-triazol-4 yl), tetrazolyl (eg 1-tetrazolyl, 2-tetrazolyl, 5 tetrazolyl), oxazolyl (eg, 2 oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (eg, 3-isoxazolyl, 4 isoxazolyl, 5 isoxazolyl), thiazolyl (eg, 2 thiazolyl, 4 thiazolyl, 5 thiazolyl), Thiadiazolyl, isothiazolyl (eg, 3-isothiazolyl, 4 isothiazolyl, 5 Sotiazolyl), pyridyl (eg, 2 pyridinole, 3 pyridyl, 4 pyridyl), pyridazinyl (eg, 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (eg, 2 pyrimidinol, 4 pyrimidinyl, 5 pyrimidinyl), flazanil (eg, 3-Frazilyl), Pyrajur (eg, 2 Pyradur), Oxadiazolyl (eg, 1, 3, 4 Oxadiazol Luyl), Benzofuryl (eg, 2 Benzo [b] furyl, 3-Benzo [b ] Frill, 4 benzo [b] furyl, 5-benzo [b] furyl, 6-benzo [b] furyl, 7 benzo [b] furyl, benzocenyl (eg, 2 benzene) Zo [b] chenil, 3 benzo [b] chenil, 4 benzo [b] chenil, 5-benzo [b] chenil, 6- benzo [b] chenil, 7 benzo [b] Chenil), benzimidazolinore (eg 1 Benzoimidazolyl, 2 Benzoimidazolyl, 4 Benzoimidazolyl, 5 Benzoimidazolyl), Dibenzofuryl, Benzoxazolyl, Quinoxalyl (for example, 2 quinoxalinyl, 5 quinoxalinyl, 6-quinoxalinyl) ), Cinnolinyl (eg, 3-cinnolinyl, 4-cinnolinyl, 5-cinnolinyl, 7-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl), quinazolyl (eg, 2 quinazolinyl, 4-quinazolinyl, 5 quinazolinyl, 6 quinazolinyl, 7—quinazolinyl, 8 quinazolinyl), quinolyl (eg, 2 quinolinole, 3 quinolinole, 4 quinolinole, 5—quinolinole, 6—quinolinole, 7—quinolinole, 8—quinolinole), phthalajinole (ί, 1— Phthalajuru, 5-phthalajuru, 6-phthalajuru), Isoquinolyl (eg, 1-isoquinolyl, 3-isoquinolinol, 4 isoquinolyl, 5-isoquinolyl, 6-isoquinolinol, 7-isoquinolyl, 8 isoquinolyl), prill, pteridinyl (eg, 2 pteridinyl, 4-pteridinyl, 6-pteridinyl, 7-Pteridinyl), carbazolyl, phenanthridinyl, Talidinyl (eg, 1-Ataridinyl, 2-Ataridinyl, 3-Ataridinyl, 4-Ataridinyl, 9-Ataridinyl), Indolyl (eg, 1 indolyl, 2 indolyl, 3 indolyl, 4 indolyl, 5—indolyl, 6—indolyl) 7-indolyl), isoindolyl, fanadinyl (eg, 1 phenazinyl, 2-phenazinyl) or phenothiazinyl (eg, 1-phenothiazinyl, 2 phenothiazinyl, 3 phenothiazinyl, 4 phenothiazinyl), etc. Is mentioned.

More preferably, it is a 6-membered monocyclic aromatic heterocyclic group containing 1 to 2 nitrogen atoms, such as pyridyl (for example, 2 pyridyl, 3 pyridyl, 4 pyridyl), pyridazinyl (for example, 3 pyridazinyl, 4 pyridazinyl), pyrimidinyl (eg, 2 pyrimidinyl, 4-pyrimidinyl, 5 pyrimidinyl), pyrajul (eg, 2 pyridinyl).

"Substituted! /, May! /, Alkyl", "Substituted! /, May! /, Aryl", "Substituted V, may! /, Alkenyl", "Substituted The substituents for “! /, May! /, Alkynyl” and “substituted! /, May be heteroaryl” include, for example, hydroxy, carboxy, halogen (F, Cl, Br, 1), haloalkyl (Eg, CF, CH CF, CH CC1), CI—C6 alkyl (eg, methylol, ethyl, isopropyl, tert butyl), C2—C6 alkenyl (eg, butyl), C2—C6 alkynyl (eg, etul) , Cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), cycloalkenyl (eg, cyclopropenyl), alkoxy (eg, methoxy, ethoxy, propoxy, butoxy), alkenyl Xy (for example, buroxy, aryloxy, etc.), alkoxycarboninole (for example, methoxycanoleponinole, ethoxycanoleponinole, tert butoxycanoleponinole, etc.), nitro, nitroso, optionally substituted amino (for example, amided) Alkylamino (eg, methinoreamino, ethinoreamino, dimethylamino), isylamino (eg, acetylamino, benzoylamino), aralkylamino (eg, benzylamino, tritylamino), hydroxyamino), azide, allyl (eg, phenyl), aralkyl (eg, Benzyl), cyano, isocyano, isocyanato, thiocyanato, isothiocyanato, mercapto, alkynolethio (eg methylthio), alkylsulfonyl (eg methanesulfonyl) Eth Nsuruhoniru), optionally substituted force Rubamoiru (e.g., alkyl force Rubamoiru (e.g., methylcarbamoyl, E Ji carbamoyl, dimethylcarbamoyl)), Sulf Amoinole, Asil (eg Honoreminore, Acetyl), Honoreminoreoxy, Norohonoreminore, Oxa Mouth, Thioformyl, Thiocarboxy, Dithiocarboxy, Thiocarbamoyl, Sulfino, Sulfo, Sulfoamino, Hydrazino, Azide, Ureido, Amidino , Guanidino, phthalimide, oxo, optionally substituted aryl (e.g., phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylenophenyl, 2-methoxy Phenyl, 3 methoxyphenyl, 4 methoxyphenyl, 2 aminophenyl, 3 aminophenyl, 4 aminophenyl, 1-naphthyl, 2 naphthyl), optionally substituted heteroaryl (eg, pyridine-2-yl, pyridine-3) Gil, Pirgin 4 pills, 1 pyrimidine 2 pills, 4 pyrimidine 1 pills, 5 pyrimidine 1 pills, isoxazole -3 yl, isoxazole -5 yl, pyrrole 2 pills, pyrazo nolay 3 inoré, furan 2-inole, furan-3-inole, thiophene-2-inole, thiophene-3yl, imidazole-2yl, oxazole-2yl, thiazole-2yl) and the like.

 The substituents of “substituted! /, May! /, Aryl” and “substituted! /, May! /, Heteroaryl” include those exemplified above. The aryl and the heteroaryl may be substituted by these substituents at any substitutable position; the number is !!-3.

 [0054] In one preferred embodiment of the above compound, both V and C1 atoms bonded to the aromatic rings of the second and sixth amino acid residues of the vancomycin skeleton are each independently substituted with the above substituents. And has a partial structure represented by the formula (I 1).

 [Chemical 17]

 Here, ring 2, ring 4 and ring 6 represent the aromatic rings of the second, fourth and sixth amino acid residues of the glycopeptide antibiotic, respectively.

Z ¹ is hydrogen, halogen, alkyl which may be substituted, or alkyl which may be substituted. , Optionally substituted alkenyl, optionally substituted alkynyl or substituted! /, May! /, Heteroaryl;

Z ² is hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl or substituted! /, It's a hetero reel!

However, the case where (zz ² ) is (hydrogen, hydrogen), (hydrogen, halogen), (halogen, hydrogen) and (no, rogen, no, rogen) is excluded.

[0055] Preferably, Z ¹ is an optionally substituted alkyl, an optionally substituted aryl, a substituted re, may! /, An alkenyl, a substituted! /, May! / , Alkynyl or substituted and / or heteroaryl;

Z ² is hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted. Heteroaryl. More preferably, Z ² is halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, substituted les, may! /, Alkynyl or substituted. It's a hetero reel.

[0056] In a preferred embodiment of the present invention! /, In the embodiment, Z ¹ and Z ² are each independently lower alkyl, lower alkoxy, halogen, halogenated lower alkyl, hydroxy, halogenated lower alkoxy, lower alkylthio, An optionally substituted amino and a phenyl optionally substituted with one or more substituents selected from the group consisting of lower alkenyl. Preferred is phenyl which may be substituted with lower alkoxy, and examples of the lower alkoxy include methoxy, ethoxy, propoxy, butoxy, pentoxy and octaxoxy.

[0057] In another preferred embodiment! /, In embodiments, the Z ¹ and Z ² are each independently substituted! /, Which may be a 6-membered single atom containing! Ring aromatic heterocyclic groups such as pyridyl (eg 2 pyridinole, 3 pyridinole, 4 pyridyl), pyridazinyl (eg 3 pyridazinyl, 4 pyridazinyl), pyrimidinyl (eg 2 pyrimidinole, 4 pyrimidinyl, 5 pyrimidinyl) ), Pyrajul (eg 2 pyrajur). Substitution on the heterocycle The group is preferably lower alkoxy.

[0058] In still another preferred embodiment, Z ¹ and Z ² are each independently substituted! /, Lower alkenyl or substituted! /, May! /, And lower alkynyl. The substituent is preferably an optionally substituted phenyl (example of substituent: lower alkyl, halogen, amino).

[0059] Specific examples of Z ¹ and Z ² include the groups shown below.

[Chemical 18]

(Me :メチル、 Et :ェチル、 Pr : n—プロピル、 Bu : n ブチル）

(Me: methyl, Et: ethyl, Pr: n-propyl, Bu: n-butyl)

In the present specification, “halogen” means fluorine, chlorine, bromine, and iodine. Preferred are fluorine, chlorine and bromine.

[0061] Further, in a specific embodiment of the present invention, the glycopeptide compound of the present invention has the formula (II):

[Chemical 19]

[Wherein, Z ¹ and Z ² are as defined above, and R is an optionally substituted alkyl]

 Indicated by

In the formula (II), R ^x is a sugar residue. In the present specification, the “sugar residue” means the remaining part when one OH is removed from the sugar part. The sugar moiety includes amino sugars, sugar chains containing amino sugars, or other sugars or sugar chain parts. Preferably, R ^X is a residue obtained by removing one OH from a known amino sugar moiety or a sugar chain moiety containing an amino sugar in a glycopeptide antibiotic derivative. The “amino sugar moiety” represents a monosaccharide group having an amino group or a substituted amino group. Typical amino sugar moieties include L-Bancosaminyl, 3-Desmetino Levancosaminole, 3-Epibancosaminole, 4-Eppanbancosaminole, 4-ke Tobancosaminyl, Acosamuel, Actinosaminil, Daunosaminyl, 3-Evida Unosaminil, Ristosaminole, N-methyl D-glucaminyl, N-acetyl-D glucosamyl, or N-Acyl-D darcosamil. Preferred are vaccinosaminyl, acosaminole, 4-eban banco saminole, 4-keto banco saminole, ristosaminole, or banco saminyl. In particular, L-bancosaminyl is preferred. Amino Examples of sugar-containing sugar moieties include a-L vancosaminiru 13-D-darcoviranose, 3-desmethyl-one a-L vancosaminyl-one 13-D-darcoviranose, etc.

The sugar residue represented by R ^X is preferably a formula described in WO2006 / 057303 and the like:

[Chemical 20]

 [Where

R ^A is hydrogen or the formula:

-X ¹ — Ar ¹ — X ² — Y— X ³ — Ar:

(Where X ¹ , X ² and X ³ are each independently

 1) single bond,

2) —N =, = N, one NR ¹ — (where R ¹ is hydrogen or lower alkyl), —O—, —S, a heteroatom group selected from the group consisting of SO, SO 2, or Them

 2- linking group or;

 3) the same or different heteroatoms, which may be present in one or more and substituted and may be! /, Alkylene or alkenylene;

Y is —NR ² CO—, —CONR ² — (where R ² is hydrogen or lower alkyl), or the formula:

[ twenty one]

 (Where R "is alkylene)

A group represented by:

Ar ¹ and Ar ² may each independently be substituted! /, And have an unsaturated bond V, may! /, Carbocycle or heterocycle)]

 It is group shown by these.

 [0064] More preferably the formula:

 [Chemical 22]

で示される。

Indicated by

[0065] R ^A is preferably hydrogen or the formula:

X ¹ — Ar X ² _Y_X ³ — Ar ²

 (Where

X ¹ is a single bond, lower alkylene or lower alkenylene;

Ar ¹ is substituted! /, May! /, Phenyl or substituted! /, May! /, Nitrogen atom containing 5 to 7 membered heterocycle;

X ² is a single bond;

 Y is NHCO or CONH—;

X ³ is a single bond, lower alkylene or lower alkenylene;

Ar ² is optionally substituted phenyl (examples of substituents: nitro, lower alkoxy, halogen, halogenated lower alkoxy)

 Indicated by

[0066] In the present invention, particularly preferred examples of the group ^RA are hydrogen or the groups shown below.

[Chemical 23]

 (Bn represents benzyl.)

[0067] In the above (II), R ^B is OH, an ester residue or an amide residue.

[0068] In the above (II), is hydrogen or an optionally substituted alkyl (the alkyl moiety includes A heteroatom group may be interposed.

[0069] Examples of R ^B and include the substituents described for example JP 2001- 163898. Specific examples are shown below.

[0070] R ^B is selected from the group consisting of the following (2— ;!) to (2-7) forces:

 (2-1) hydroxy;

(2-2) Substituent! /, May! /, Mono or dialkylamino (except (2-4)), where two alkyls are bonded to form a ring The substituents which may be formed are substituted with amino-substituted monoanorequinoleamino, dianolenoleamino, trialkylammonium, hydroxy, guanidino, carboxy, alkyloxycarbonyl, cyano. Good strength ruberoy, mono or dialkyl force rubermoyl, mono or diaryl force rubermoyl, aryl, alkylamide or arylamide, alkylurea or arylurea, one (C = 0) N—— N + (R ^X ), one Ν + (ΙΓ ) (CH) COOR ^Y , 1 N + (R ^X ) (CH) N + (R ^X ), 1

 3 2 2 m 2 2 m 3

SO—OR ^Y (where m is;! ˜3, R ^X is C1-C3 anolenoquinole, and R ^Y is hydrogen or C1-C3 alkyl), or one P = 0 (OR ^Y ) (wherein R ^Y is hydrogen or C1-C3 alkyl), or a combination thereof, wherein alkyl in the substituent is further alkyloxycarbonyl or aryloxycarbonyl May be substituted with a !, or may be substituted with amino! /, And the aryl ring in the substituent may further be halogen, nitro, amino, hydroxy, carboxy, alkylo. Substituted with xyloxycarbonyl, amino! /, May! /, Alkyl, or acylated! /, May! /, Hydroxyalkyl or thioalkyl, or combinations thereof;

 (2-3) substituted with amino or hydroxy! /, May! / ヽ cycloalkylamino;

(2-4) Disubstituted methylamino-NHCHR ⁶ R ⁷ , where R ⁶ is carboxy, optionally substituted alkyloxycarbonyl, strong rubamoyl, or substituted! / , May! /, Monoalkyl-powered rubermoyl, or with a substituent! /, May! /, Cycloalkylcarbamoyl, wherein the substituent is an amino, monoalkylamino, Dianolenoleamino, Trialkylammonium, Carboxy, Hydroxy,-(C = 0) N—— N + (R ^X ), — (CH 2) COOR ^X (where m is;! -3 R ^X is C1-C3 alkyl

3 2 m

Aryl, which may be substituted with — — N ⁺ (R ^X ) (CH) COOR ^Y (where R ^Y is water

2 2 m Or N ¹ (R ^X ) (CH 2) N ⁺ (R ^X ), or a combination thereof, and R ⁷ is an Indian optionally substituted nitrogen with C 1 C 3 alkyl. Ru or thioindole, or imidazolyl;

A²、および A³はそれぞれ任意 のアミノ酸単位であり、 R^Zは、該トリペプチドのカルボキシ末端の、ヒドロキシ、アミノも しくは置換基を有していてもよいモノまたはジアルキルアミノを表し、該置換基は、アミ ノ、モノアルキルァミノ、ジァノレキノレアミノ、トリアルキルアンモニゥム、グァニジノ、もし くはァリーノレである； (2-5) Tripeptide R ^z — A ¹ — A ² — A ³ —: where

A ² and A ³ are each an arbitrary amino acid unit, R ^Z represents a mono- or dialkylamino optionally having a hydroxy, amino or substituent at the carboxy terminus of the tripeptide, Substituents are amino, monoalkylamino, dianolenoleamino, trialkylammonium, guanidino, or arenore;

 (2-6) optionally substituted hydrazino or hydroxamic acid, wherein the substituent is alkyl, or arylalkyl optionally further substituted with alkyl; and

(2-7) alkoxy which may have a substituent, and the substituent is allylcarbonyl which may be further substituted with nitro, hydroxamic acid or alkyl; 2) In (2-7), the existing aryl ring can contain a heteroatom and the carbon-carbon single bond present is a heteroatom or 0 (P = 0) (OR ^F ) 0- ( Where R ^F is hydrogen, alkyloxycarbonyl or aryloxy carbonyl), and may be interrupted by a hetero group selected from imino.

R ^B is preferably OH NHR ⁵ , or one NR ⁵ R ⁵ ′ (where R ⁵ and R ⁵ ′ are hydrogen, optionally substituted alkyl, NH— ^RG —NH—COR ”—NH— CONH R ^G O— R ^G (wherein each R ^G is independently hydrogen or an optionally substituted alkyl) or amino sugar residue), preferably R ⁵ R ⁵ ! / One of them is hydrogen, and an optionally substituted alkyl substituent is preferably a hydrophilic substituent such as amino, mono- or di-lower alkylamino, trianolenoquinamine, amino-lower alkylamino, hydroxy. Lower alkylamino, hydroxy, carboxy, lower alkoxycarbonyl, SO H PO H, optionally substituted rubamoyl, quaternary ammonium group (eg trialkylamino (eg N ⁺ (CH))), substituted Heterocyclic group Le or heteroaryl), optionally substituted heterocyclic Chio, Guanijino, NHSO NH, same or different 1 to selected from hydroxy lower alkoxy; 10, preferably ; 6 substituents are illustrated. The nitrogen atom in the heterocycle may be quaternized to form a salt. Examples of the optionally substituted heterocyclic substituent include hydroxy, amino, carboxy, amino lower alkyl, and quaternary ammonium lower alkyl. The lower alkyl group on the quaternary ammonium group is further substituted with a substituted alkyl (substituent: carboxy, hydroxy, quaternary ammonium group)! /, May! /.

[0072] R ^e, the following - is selected from (3 ;!) - (3-4) Power group consisting:

 (3 1) hydrogen;

(3- 2) substituted with alkyl, cycloalkyl or alkylene! /, May! /, Aminomethyl, and each of the alkyl, cycloalkyl and alkylene may have a substituent. The group may be an aryloxy optionally substituted with alkyloxycarbonyl or aryloxycarbonyl, optionally substituted with amino, monoalkylamino, dianolenoamino, trialkylammonium, cycloalkyl; , Hydroxy, guanidino O— (P = 0) (OH), carboxy, N + (R ^X ) (CH) N + (R ^X ), or one (C

 2 2 2 m 3

= 〇) One N ^—— N ⁺ (R ^X ) (where m is;!-3, R ^X is C1 C3 alkyl), or

 Three

 Or a combination thereof, wherein the alkyl in the monoalkylamino or dialkylamino substituent may be further substituted with amino.

 (3-3) alkynyl optionally having substituent (s), the substituent being an amino group optionally substituted with alkyloxyl sulfonyl or aryloxycarbonyl; or aryl; and

 (3-4) halogen;

However, in (3-2) and (3-3), the existing aryl ring can contain a heteroatom and the carbon-carbon single bond present is a heteroatom or 0 (P = O) ( oR ^J) 0- (wherein, R 'is hydrogen, alkyl O alkoxy carbonyl or Ariruokishi carbonyl) amides, and that force ^s is interrupted by hetero groups from the selected Imino.

[0073] is preferably hydrogen or optionally substituted alkyl. The optionally substituted alkyl substituent is preferably the above-mentioned NHR ⁵ force, substituted at R ⁵ , may be /, and an alkyl substituent. [0074] As a preferable combination of R ^B and R ^c , R ^B is hydroxy, NHR ⁵ (R ⁵ is mono- or di-lower alkylamino lower alkyl, tri-lower alkyl ammonium lower alkyl, or amino sugar residue ), -NR ⁵ R ⁵ ′ (wherein R ⁵ and R ⁵ ′ are both hydroxy lower alkyl), or NHCH CON— N ⁺ (Me), and R ^G is hydrogen, mono- or di-substituted amino lower alkyl (

twenty three

Examples of substituents: lower alkyl, mono- or di-lower alkylamino lower alkyl, tri-lower alkyl ammonium lower alkyl, hydroxy lower alkyl, hydroxy lower alkoxy lower alkyl, —CH 2 CON—N ⁺ (Me),; Lower substituted with 6 hydroxys

 twenty three

 Alkyl and carboxy, hydroxy, oxo, optionally substituted rubamoyl

Substituted with guanidide, sulfonic acid group, phosphate group, NHSO H and / or amino

 2N 2

 Lower alkyl, substituted, or heterocyclic lower alkyl (substituent: amino lower alkyl), substituted V, may! /, Quaternary ammonium lower alkyl (substituent: carboxy, hydroxy, An example is a quaternary ammonium group))).

[0075] As the combination of R ^B , R ^C and R ^D , R ^B is hydroxy, NHR ⁵ (R ⁵ is mono- or di-lower alkylamino lower alkyl, tri-lower alkyl ammonium lower alkyl, or amino sugar Residue), —NR ⁵ R ⁵ ′ (R ⁵ and R ⁵ ′ are both hydroxy lower alkyl), or —NHCH CON—N ⁺ (Me), and R ^G is hydrogen, mono- or di-substituted amino lower Archi

 twenty three

 Nore (examples of substituents: lower alkyl, mono- or di-lower alkylamino lower alkyl, tri-lower alkyl ammonium lower alkyl, hydroxy lower alkyl, hydroxy lower alkoxy lower alkyl, -CH CON- N + (Me),; ~ Low substituted with 6 hydroxys

 twenty three

 Primary alkyl, and carboxy, hydroxy, oxo, optionally substituted rubamoyl, guanidide, sulfonic acid group, phosphate group, lower alkyl substituted with NHSO NH and / or amino, substituted V, V, heterocyclic lower alkyl (substituent: amino lower alkyl), substituted V, may! /, Quaternary ammonium lower alkyl (substituent: carboxy, hydroxy, quaternary ammonium group)) A case where, is hydrogen is exemplified. Specifically, the cases shown in Tables 1-8 are listed.

[table 1]

3]

4]

5] [9¾ O / OOZdf / IOd εε recommended ooz ΟΛ \

3]

Four]

Five] [9¾

7]

8]

より具体的な本発明化合物を以下に例示する。 Z £ L0 / L0QZd £ / 13d ζε 1789S.0 / 800Z OAV

7]

8]

More specific compounds of the present invention are exemplified below.

[Table 9]

[Table 10]

[0077] The table is an example in which R ^A and Z ¹ are developed for each combination of R ^B , R ^c and. The compound of the present invention includes any combination of groups shown in the table.

 [0078] The present invention includes the above-mentioned compounds, pharmaceutically acceptable salts and solvates thereof. All tautomers, geometric isomers and the like that are theoretically possible for the compounds of the present invention are also within the scope of the present invention.

[0079] "Pharmaceutically acceptable" means not prophylactically or therapeutically harmful. Examples of the pharmaceutically acceptable salt of the compound of the present invention include basic salts such as alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; N, N-dibenzylethylene, such as amine salt, triethylamine salt, dicyclohexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, brocaine salt, medalmine salt, diethanolamine salt or ethylenediamine salt; Aralkylamine salts such as diamine and venetamine salts; Heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts and isoquinoline salts; tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts Salt, benzyl triethylammoni Unsalted, benzyl tributyl ammonium Niu unsalted, methyl trioctyl § Nmoniumu salts, quaternary Anmoniumu salts such as tetramethylammonium Petit Ruan monitor © beam salts; arginine salts, basic amino acid salts such as lysine salts. Examples of acidic salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, perchlorate; acetate, propionate, lactate, maleate, Organic acid salts such as fumarate, tartrate, malate, citrate, and ascorbate; sulfonates such as methanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate; Examples include acidic amino acids such as aspartate and glutamate.

 Further, various solvates of the compound of the present invention are also within the scope of the present invention, and examples thereof include monosolvates, disolvates, monohydrates, dihydrates and the like.

General manufacturing method

 Hereinafter, representative production methods of the compound of the present invention will be described, but it is not particularly limited to these production methods.

(Method 1)

Ichi Suzuki i f Cross Cup Link (Suzuki Miyaura Cross-Coupling)

[Chemical 24]

(式中、

(Where

 X is halogen;

 Ring 2 and Ring 4 are the aromatic rings of the second and fourth amino acid residues of the glycopeptide antibiotic, respectively; and

Z ¹ is optionally substituted alkyl, optionally substituted aryl, substituted V, may! /, Alkenyl, substituted! /, May! /, Alkynyl or substituted ! / It's okay to be a heteroary. )

That is, the compound of the present invention is a known glycopeptide compound having a partial structure represented by the above formula, wherein the aromatic ring (ring 2) of the second amino acid residue is substituted with a halogen atom! It is used as a starting material and is preferably produced by reacting with an organoboron compound represented by Z ¹ -B (OH) [Z ¹ is as defined above] in the presence of a palladium catalyst under basic conditions Power S can be. The reaction may be performed according to the reaction conditions of Suzuki Ichinomiyaura cross coupling. This reaction is more preferably used for the synthesis of a compound of the present invention in which Z ¹ is an optionally substituted aryl or an optionally substituted heteroaryl. Usually, the reaction temperature is from room temperature to about 100 ° C, preferably from 40 to 80 ° C. As a reaction solvent, water, an organic solvent or a mixed solvent thereof can be used, preferably water. As the base, Na 2 CO, Ba (OH), K 3 PO, Cs 2 CO 3, K 2 CO 3, NaOH, etc. are used. Pa

 2 3 2 3 4 2 3 2 3

 Radium catalysts include palladium acetate, Pd (PPh), Pd (dba), PdCl (PPh), Pd

 3 4 2 2 3 2

CHMeCN), PPdCl (Bn) (PPh), etc. are used (Ph: phenyl, Me: methyl, Bn: benzyl, dba: PhCH = CHC (◯) CH = CHPh). The reaction time is several minutes to several hours, preferably about 15 minutes to about 1 hour.

[0082] Some of the compounds of the present invention can be synthesized more preferably by the following method.

 (Method 2)

 Heck—? Heck-Mizorogi Reaction

The corresponding compound of the present invention is synthesized by reacting in the same manner a reagent represented by Z′-HCZ ¹ ^, substituted alkenyl) instead of iifHZ′-B COH). More specifically, Z ¹ has the structure shown below.

[Chemical 25]

(Wherein R ² , R ³ and R ⁴ represent (substituted) alkyl, (substituted) aryl, (substituted) heteroaryl, (substituted) alkenyl, etc.

[0083] (Method 3)

 Sonogashira Cross-Coupling

The corresponding compound of the present invention is synthesized by reacting in the same manner a reagent represented by the formula (in which Z ¹ — H ^ ¹ is an optionally substituted alkynyl instead of Z ¹ — B (OH)). More specifically, Z ^ H is a compound shown below.

 [Chemical 26]

Z ¹ = —— ^ ≡ ^ R ⁵

(In the formula, R ⁵ represents hydrogen, (substituted) alkyl, (substituted) aryl, (substituted) heteroaryl, (substituted) alkenyl and the like.

[0084], Method 4) Stille Cross-Coupling)

instead of iifHz '-B COH) Z ¹ — Sn— (Alk) where Z ¹ is an optionally substituted aryl, an optionally substituted alkenyl, or an optionally substituted Terroryl

The corresponding compound of the present invention is synthesized by reacting the reagent represented by (Alk is alkyl) in the same manner.

 Depending on the conditions, a metal catalyst such as manganese, nickel, copper, or tin can be used in place of the Pd catalyst.

[0085] (Method 5)

 If the compound of the present invention binds to the aromatic ring of the 2nd and 6th amino acid residues of the glycopeptide antibiotic, the C1 nuclear energy ^, the displacement is also replaced! According to the ring (Suzuki Miyaura Cross-Coupling), it can be prepared as follows.

[Chemical 27]

 (Where

 X and X 'are independent

 Ring 2 and Ring 6 are the aromatic rings of the second and sixth amino acid residues of the glycopeptide antibiotic, respectively; and

 Z is optionally substituted alkyl, optionally substituted aryl, substituted V, may! /, Alkenyl, substituted! /, May! /, Alkynyl or substituted! / It's a good heteroary. )

 That is, in the same manner as in the above (Method 1), the known glycopeptide compounds in which the aromatic rings (rings 2 and 6) of the second and sixth amino acid residues are substituted with halogen atoms! / As a starting material, this is preferably prepared by reacting with an organic boron compound represented by Z—B (OH) [Z is as defined above] in the presence of a palladium catalyst under basic conditions. Power S can be.

[0087] The compound of the present invention is a compound in which the C1 atoms bonded to the aromatic rings of the second and sixth amino acid residues of the glycopeptide antibiotic are each substituted with different groups (for example, Z ¹ and Z ² ). In some cases, for example, in the above (Method 5), the starting material is an organoboron compound represented by Z ¹ — B (OH) or Z ² — B (OH) [Z ¹ and Z ² are each independently In the same meaning, it can be produced by reacting with either one and then reacting with the other organoboron compound.

 [0088] Each of the above reactions is introduced in, for example, "Organic Synthesis Strategy Learned from Personal Name Reactions, Kagaku Dojin, 2006 Edition".

 [0089] Glycopeptide compounds that can be used as starting materials in the production method of the present invention include, for example, the formula (ΙΓ):

[Chemical 28]

(Wherein X and X ′ are each independently halogen, and R ^x , R ^B , R ^C and R are as defined above)

Indicated by

 Preferably, the glycopeptide compound that can be used as a starting material in the production method of the present invention is represented by the formula (ΙΓ 1):

[Chemical 29]

[Wherein, X, X ′, R ^A , R ^B , R ^(: and are as defined above]

Indicated by

The starting material of the present invention is an amino sugar of vancomycin or a known derivative thereof. It can be prepared by various chemical modifications of the moiety (R ^A ), the C-terminal part (R ^B ), the resorcinol part (R ^G ), the methylamino part () of the N-terminal part, or the like. Alternatively, vancomycin or a known derivative thereof is used as a starting material without chemical modification, and is used as described above for an organoboron compound represented by Z ¹ — B (OH) (in some cases, further Z ² — B ( OH), and the amino moiety (R ^A ) of the amino sugar, or the C-terminal part (R ^B ), the resorcinol part (), or the methylamino part (R °) of the N-terminal part. You can chemically modify it.

[0092] The chemical modification may be performed in accordance with, for example, the method described in International Publication WO2006 / 057303 Pamphlet constituting a part of the present specification. Specifically:

1) Modification of R ^A part

Typically, using vancomycin as a raw material, the amino moiety of the amino sugar, R ^A moiety: Formula: -X'-Ar'-X'-YX ^ -Ar ²

 If desired, various aldehydes corresponding to the side chains shown in the above are reacted in the presence of a base to form an intermediate Schiff base, which is subsequently reduced to N-alkylation to give the desired secondary amine. May be formed.

 [0093] Specifically, the Schiff base formation reaction is optionally carried out in a polar solvent such as dimethylformamide or methanol or a mixed solvent thereof, optionally under an inert atmosphere such as nitrogen or argon. Perform in the presence at a temperature of about 25 ° C to about 100 ° C. This reaction is usually carried out at a temperature from room temperature to 100 ° C., preferably from about 60 ° C. to about 80 ° C. for about 30 minutes to 2 hours. Examples of the base used include alkylamines (eg, diisopropylethylamine).

Next, the intermediate Schiff base is preferably isolated without being isolated, and may be reduced with a metal hydride complex or catalytically reduced. As the metal hydride complex, a metal borohydride such as sodium borohydride or sodium cyanoborohydride can be used. Catalytic reduction is carried out using hydrogen in the presence of a homogeneous or heterogeneous catalyst such as a club tree catalyst, a Wilkinson catalyst, palladium charcoal, platinum charcoal or rhodium charcoal. The reduction reaction is carried out at a temperature of about 25 ° C. to about 100 ° C. for about;!-24 hours. Preferably, cyanoborohydride It is carried out in an excess amount of thorium (eg 3 to 5 molar equivalents) in the above solvent at about 60 ° C to about 80 ° C.

[0095] 2) modification of R ^B moiety

Typically, vancomycin is used as a raw material, and the C-terminal carboxylic acid moiety can be amidated by a conventional method to convert it into various amide derivatives having R ^B = -NR ⁵ R ⁵ '.

[0096] 3) Modification of ^RG moiety

 Typically, vancomycin is used as a raw material, and the resorcinol moiety may be anoalkylated by a conventional method.

[0097] 4) Modification of R ^D part

 Typically, vancomycin is used as a raw material, and the methylamine portion at the N-terminal portion may be N-alkylated by a conventional method, for example.

[0098] Pharmaceutical composition

 The present invention also includes a pharmaceutical composition containing the novel glycopeptide derivative of the present invention. Accordingly, the glycopeptide compound, preferably in the form of a pharmaceutically acceptable salt, may be formulated for oral or parenteral administration for therapeutic and prophylactic treatment of bacterial infections.

Yes

 [0099] In the case of oral administration, the compound of the present invention may be any of ordinary formulations such as solid preparations such as tablets, powders, granules and capsules; liquids; oily suspensions; or liquids such as syrups or elixirs. It can also be used as a dosage form. In the case of parenteral administration, the compound of the present invention can be used as an aqueous or oily suspension injection or nasal solution. In the preparation, conventional excipients, binders, lubricants, aqueous solvents, oily solvents, emulsifiers, suspending agents, preservatives, stabilizers and the like can be arbitrarily used. As antibacterial agents, oral agents, intravenous injections and the like are particularly preferable.

 [0100] The formulations of the present invention are prepared by combining (eg, mixing) a therapeutically effective amount of a compound of the present invention with a pharmaceutically acceptable carrier or diluent. The preparation of the compound of the present invention is produced by a known method using well-known and readily available components.

[0101] In preparing a pharmaceutical composition of the compound of the present invention, the active ingredient is mixed with a carrier or diluted with a carrier, or in the form of a capsule, sachet, paper, or other container. In a carrier. When the carrier acts as a diluent, the carrier is a solid, semi-solid, or liquid material that acts as a medium, and they are tablets, pills, powders, mouthpieces, elixirs, suspensions, emulsions, solutions. Syrups, aerosols (solids in liquid media), ointments, eg containing up to 10% active compound. The compound of the present invention is preferably formulated prior to administration.

 [0102] Any suitable carrier known to those skilled in the art can be used for this formulation. In such formulations, the carrier is a solid, liquid, or a mixture of solid and liquid. For example, the compound of the present invention is dissolved in 4% dextrose / 0.5% sodium quenate aqueous solution for intravenous injection. Solid formulations include powders, tablets and capsules. A solid carrier is one or more substances that can also serve as a material for fragrances, lubricants, solubilizers, suspensions, binders, tablet disintegrants, and capsules. Tablets for oral administration include calcium carbonate, sodium carbonate with disintegrants such as corn starch, alginic acid, and / or binders such as gelatin, acacia, and lubricants such as magnesium stearate, stearic acid, talc. And suitable excipients such as latatose and calcium phosphate.

 [0103] In powders, the carrier is a finely divided solid mixed with the active ingredients finely ground. In tablets, the active ingredients are mixed in the appropriate proportions with a carrier having the necessary binding properties and consolidated into the desired shape and size. Powders and tablets contain from about 1 to about 99 weight percent of the active ingredient which is the novel compound of the present invention. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, ratatose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter.

 [0104] Liquid formulations include suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier such as sterile water, sterile organic solvent, or a mixture of both. The active ingredient can often be dissolved in a suitable organic solvent, for example an aqueous propylene glycol solution. Other compositions may be made by spraying the active ingredients with aqueous starch, sodium-powered l-poxymethylcellulose solution, or a suitable oil.

[0105] The dose of the compound of the present invention depends on the administration method, patient age, body weight, condition and disease type. In general, in the case of oral administration, about 0.1 mg to 7000 mg, preferably about 0.5 mg to 2000 mg per day for adults may be administered in divided doses if necessary. In the case of parenteral administration, about 0.1 mg to 1 mg per adult;! OOOmg, preferably about 0.5 mg to 5 OOmg.

 Example

 Hereinafter, the present invention will be described in further detail with reference to examples. The present invention is not limited to these examples in any way.

[0107] All the MS data shown in the following production examples and examples are calculated by average molar weight (C = 12.0107, H = 1.0079, 0 = 15.9994, N = 14.0067, C1 = 35.4527, P =

30.9738, Na = 22.9898).

[0108] Example 1

 The following compounds were produced according to the above general production method (Method 1).

 [Chemical 30]

150 mL of water was put into a 200 mL eggplant-shaped flask equipped with a Liebig condenser. Pulverization was performed sequentially for 2 minutes with ultrasonic waves for 2 minutes under an argon stream, and an argon atmosphere was established. Vancomycin hydrochloride 1 · OOg (0.337mmol), p-methoxyphenylboric acid 30 6mg (2.02mmol), WSPL 142mg (0.135mmol), potassium carbonate 464mg (3.36) mmol) and 30 · 2 mg (0.0061 mmol) of palladium acetate were sequentially added, and the mixture was heated and stirred at 60 ° C. for 30 minutes. After cooling to room temperature, it was cooled to 0 ° C, IN HC1 aqueous solution (3.6 mU was added dropwise, followed by addition of poly-4-bulupyridine to adjust the pH to 5. Filter through a glass filter with celite. After washing with 10% CHCN aqueous solution (40 mL), the filtrate was concentrated by adding EtOH (lOOmL) to obtain a crude product.2 medium pressure ram chromatography [Merck, Li Chroprep RP -18 size B) 1st 50% aq. MeOH—0.1% TFA, 2nd 10% aq. MeOH-0. L% TFA → 50% aq. MeOH—0.1% TFA] MeOH-0. Fractions eluting with 1% TFA were collected and concentrated, and poly-4 bulupyridine was added to the concentrate to adjust the pH to 5. After filtration, the filtrate was concentrated again and the residue was frozen. It was dried to obtain a coupled TFA salt (trifluoroacetate salt) (1 · 7%, HPLC purity 96%).

Column: Cosmosil 5C18— AR— Π (Nacalai Tester)

Mobile phase: Acetonitrile monohydrate (containing 0.1% trifluoroacetic acid)

Gradient: 15% acetonitrile solution → 100% acetonitrile solution (10 minutes) Flow rate: 1.0 ml / min

Detector: UV—280nm

Target retention time: 5. 12 seconds

Examples 2 to; 10

[Chemical 31]

 λ ¥ Ο2006 / 057303ίMethod described here

[Chemical 32]

 6

Compound 6 is prepared. Compound 6 was used as the starting material, except that the organoboron compound shown in Ζ ¹ — Β (ΟΗ) [for each example, Ζ ¹ is as shown above] was used instead of ρ-methoxyphenylboric acid. Prepares the target compound in the same manner as described in Example 1.

Examples 11-; 19

[Chemical 33]

 Ten

Compound 10 is prepared. Except using compound 10 as the starting material and using an organoboron compound as shown in Z ¹ — B (OH) [for each example, Z ¹ is as shown above] instead of p-methoxyphenyl boric acid, The target compound is produced in the same manner as described in Example 1.

p-methoxyphenylboric acid instead of Zi—BOH) [For each example, Z ¹ is as shown above] The following compounds were produced in the same manner as the method.

[Chemical 35]

p> (実施例 30)> (Implementation 23)

p> (Example 30)

F (Example 25) ^Me0 ^ (Example 31) Example 20

[M + l] ⁺ = 1534

 Calculated value (C74H84C1N9025-2.1HCM5.5H20)

 C: 47.01%, H: 6.24%, Cl: 5.81%, N: 6.67%, 0: 34.27%,

 Actual value: C: 46.99%, H: 6.18%, Cl: 5.82%, N: 6.73%

 [0112] Example 21

[M + l] ⁺ = 1548

 [0113] Example 22

[M + l] ⁺ = 1508

 Calculated value (C72H79C1FN9〇24'1.7HCM4.3H20)

 C: 47.29%, H: 6.03%, Cl: 5.24%, F: 1.04%, N: 6.89%, 0: 33.51%, Measured C: 47.28%, H: 5.98%, CI: 5.20%, F : 1.05%, N: 6.81%

 [0114] Example 23

[M + l] ⁺ = 1504

 Calculated value (C73H82C1N9024-2.2HCM7.7H20)

 C: 46.05%, H: 6.33%, Cl: 5.96%, N: 6.62%, 0: 35.04%,

 Actual value: C: 45.92%, H: 5.88%, Cl: 6.02%, N: 6.89%

[0115] Example 24 [M + l] ⁺ = 1550

 Calculated value (C74H84C1N9026-2.3HCM4.5H20)

 C: 46.88%, H: 6.13%, Cl: 6.17%, N: 6.65%, 0: 34.18%, Found: C: 46.82%, H: 6.09%, Cl: 6.17%, N: 6.82%

[0116] Example 25

[M + l] ⁺ = 1574

 Calculated value (C73H79C1F3N9025-2.5HCM4.5H20)

 C: 45.49%, H: 5.78%, Cl: 6.44%, F: 2.96%, N: 6.54%, 0: 32.79% Found: C: 45.51%, H: 5.83%, Cl: 6.48%, F: 3.13 %, N: 6.57%

[0117] Example 26

[M + l] ⁺ = 1536

 Calculated value (C73H82C1N9024S-2.6HCM4.8H20)

 C: 46.18%, H: 6.06%, Cl: 6.72%, N: 6.64%, 0: 32.70%, S: l.69% Found: C: 46.11%, H: 5.95%, Cl: 6.74%, N : 6.82%, S: l.89%

[0118] Example 27

[M + l] ⁺ = 1520

 Calculated value (C73H82C1N9 025'1.7HCM5.4H20)

 C: 47.13%, H: 6.20%, Cl: 5.15%, N: 6.78%, 0: 34.74%

 Actual value: C: 47.08%, H: 6.22%, Cl: 5.21%, N: 6.87%

[0119] Example 28

[M + l] ⁺ = 1605

 Calculated value (C77H89C1N10O26-2.2HCM6.1H20)

 C: 46.80%, H: 6.29%, Cl: 5.74%, N: 7.09%, 0: 34.08%

 Actual value: C: 46.74%, H: 6.16%, Cl: 5.82%, N: 7.27%

[0120] Example 29

[M + l] ⁺ = 1516

 Calculated value (C74H82C1N9024-2.5HCM6.0H2O)

C: 46.87%, H: 6.19%, Cl: 6.54%, N: 6.65%, 0: 33.75% Actual value: C: 46.81%, H: 6.18%, Cl: 6.59%, N: 6.91%

[0121] Example 30

[M + l] ⁺ = 1490

[0122] Example 31

[M + l] ⁺ = 1520

 Calculated value (C73H82C1N9025-3.3HCM6.3H20)

 C: 45.31%, H: 6.14%, Cl: 7.88%, N: 6.52%, 0: 34.15 ° /

 Found C: 45.12%, H: 5.77%, CI: 7.88%, N: 7.24%,

[0123] Example 32

 [Chemical 36]

 1- (4 fluorophenyleno) burboronic acid 670 mg (4.04 mmo 1), 2 '(dicyclohexylphosphino) -2, 6 dimethoxybiphenyl 3 sodium sulfonate 276 mg (0.54 mmol), acetic acid 60 mg (0.27 mmol) of palladium and 930 mg (6.73 mmol) of potassium carbonate were added, and the microwave was irradiated at 80 ° C. for 20 minutes. Thereafter, 2N hydrochloric acid was added to the reaction solution to adjust the pH to 4, and 100 ml of ethyl acetate was added to extract the aqueous layer. To the aqueous layer, 5 ml of HP-20ss / 5mM hydrochloric acid was added, and acetonitrile was concentrated. The concentrated residue was purified by ODS column chromatography and then freeze-dried to obtain 107 mg of the title compound as a white powder. Yield: 4.7%.

[0124] Instead of trans 2- (4 fluorophenyl) burboronic acid, Z ¹ — B (OH) [For each example, Z ¹ is as shown above] The following compounds were produced in the same manner as described in Example 32. [Chemical 37]

 [0125] Example 33

[M + l] ⁺ = 1516

 Calculated value (C74H82C1N9024-2.1HCM6.2H20)

 C: 47.14%, H: 6.23%, Cl: 5.83%, N: 6.69%, 0: 34.11%

 Actual value: C: 47.13%, H: 6.33%, Cl: 5.85%, N: 6.90%

[0126] Example 34

[M + l] ⁺ = 1546

 Calculated value (C75H84C1N9025-2.4HCM7.0H2O)

 C: 46.42%, H: 6.25%, Cl: 6.21%, N: 6.50%, 0: 34.62%

 Actual value: C: 46.38%, H: 6.22%, Cl: 6.25%, N: 6.65%

[0127] Example 35

[M + l] ⁺ = 1534

 Calculated value (C74H81C1FN9〇24'2.2HCM5.0H2O)

 C: 47.14%, H: 6.05%, Cl: 6.02%, F: l.01%, N: 6.69%, 0: 33.10% Found: C: 47.12%, H: 5.97%, Cl: 5.98%, F : 0.99%, N: 6.69%

[0128] Example 36

[M + l] ⁺ = 1584

 Calculated value (C75H81C1F3N90 24'2.4HCM7.1H20)

C: 45.48%, H: 5.99%, Cl: 6.09%, F: 2.88%, N: 6.37%, 0: 33.20% Actual value: C: 45.44%, H: 5.95%, Cl: 6.04%, F: 2.68%, N: 6.62%

[0129] Example 37

[M + l] ⁺ = 1530

 Calculated value (C75H84C1N9〇24'1.5HCM3.3H20)

 C: 49.35%, H: 6.19%, Cl: 4.86%, N: 6.91%, 0: 32.70%,

 Actual value: C: 49.36%, H: 6.12%, Cl: 4.92%, N: 7.11%

[0130] Further, according to the above general production method and the method described in Examples, the following compounds were produced.

 [0131] Example 38

 [Chemical 38]

 Chiral

 C: 48.22%, H: 5.75%, Cl: 4.47%, F: 2.66%, N: 8.50%, O: 30.40% Found: C: 48.23%, H: 5.93%, Cl: 4.38%, F: 2.40 %, N: 8.67%

[0132] Example 39 [Chemical 39]

 Chiral

[M + l] ⁺ = 1881

Calculated value (C92H100ClF3N12O26'3.2HCM4H20)

 C: 49.08%, H: 5.87%, Cl: 6.61%, F: 2.53%, N: 7.47%, 0: 28.43% Measured C: 49.14%, H: 5.86%, Cl: 6.71%, F: 2.35% , N: 7.41% Example 40

[Chemical 40] Vancomycin · HCI

 Acetonitrile that was subjected to ultrasonic wave for 2 minutes and bubbling under argon stream for 2 minutes in succession (20 mL) (noncomycin hydrochloride (1.OOg, 0.674 mmol), WSPL2 (142 mg, 0.270 mmol), Cesium carbonate (3.3 g, 10. lmmol) and bis (acetonitorinole) dichloropalladium (30.2 mg, 0.135 mmol) were sequentially added, followed by stirring at room temperature for 20 minutes 1-Otatin (0.73 mL, 6.74 mmol ) Was added dropwise, distilled water (20 mL) was added for 2 minutes and ultrasonic bubbling was continued for 2 minutes, and the mixture was heated and stirred at 80 ° C for 1.5 hours under an argon atmosphere. After cooling to 0 ° C, 1N aqueous hydrochloric acid was added dropwise to adjust the pH to 5. After removing insolubles by filtration, the residue obtained by concentrating the filtrate was subjected to reverse phase column chromatography.

 'Purified by one and lyophilized to give the title compound. Yield 30 mg (3.0%) Example 41

Hue,

[Chemical 41] / KuncomycinHCI

Acetonitrile was sonicated for 2 minutes and bubbled in an argon stream for 2 minutes in succession. (20 mL) (noncomycin hydrochloride (1.OOg, 0.674 mmol), WSPL2 (142 mg, 0.270 mmol), cesium carbonate (3.3 g, 10. lmmol), H, Su (acetonitorinole) dichloropalladium (30.2mg, 0.135mmol) were sequentially added, and the mixture was stirred at room temperature for 20 minutes, and phenylacetylene (0.73mL, 6.74mmol) was added dropwise. Distilled water (20 mL), which was subjected to bubbling under an argon stream for 2 minutes and ultrasonic waves for 2 minutes, was added and stirred under heating in an argon atmosphere for 3.5 hours at 80 ° C. After cooling to room temperature, 0 ° C. 1N aqueous hydrochloric acid was added dropwise to adjust the pH to 5. After removing insolubles by filtration, the filtrate was concentrated and the resulting residue was purified by reverse phase column chromatography and lyophilized. The title compound was obtained as a pink powder, yield 45 mg (4.5%) ₀

[M + l] ⁺ = 1514

Calculated value (C74H80C1N9O24-2.7HCM6.3H20)

 C: 46.61%, H: 6.09%, Cl: 6.88%, N: 6.61%, 0: 33.81%

Actual value C: 46.52%, H: 5.65%, Cl: 6.55%, N: 7.08%

Example 42

[Chemical 42]

 Vancomycin hydrochloride 2.00 g (l. 35 mmol) is dissolved in 10 ml of acetonitrile and 10 ml of water, and at room temperature, 347 mg (4.04 mmol) of trans-propenylboronic acid, 2,-(dicyclohexylphosphino) -2,6-dimethoxy Biphenyl 2-sodium sulfonate 276 mg (0.54 mmol), sodium acetate 60 mg (0.27 mmol), potassium carbonate 930 mg (6.73 mmol) were added, and the microwave was irradiated at 100 ° C. for 5 minutes. Thereafter, 2N hydrochloric acid was added to the reaction solution to adjust the pH to 4, and 100 ml of ethyl acetate was added to extract the aqueous layer. To the aqueous layer, 5 ml of HP-20ss / 5mM hydrochloric acid was added, and acetonitrile was concentrated. The concentrated residue was purified by ODS column chromatography and then lyophilized to obtain 236 mg of the title compound as a white powder. Yield: 10.3%.

 [M + l] + = 1460

 Calculated value (C72H85N9〇24'1. 6HCM6.0H2O)

 C: 47. 85%, H: 6. 62%, Cl: 3. 14%, N: 6. 98%, 0: 35.42%

 Found: C: 47. 82%, H: 6. 75%, Cl: 3.17%, N: 7. 13%

 [0136] In the same manner as in the method described in Example 42, the following compounds were produced.

[0137] Example 43

[Chemical 43] Chiral

[M + l] ⁺ = 1811

Calculated value (C89H101F3N12O26'2.6HCM4.7H20)

 C: 49.23%, H: 6.17%, Cl: 4.25%, F: 2.62%, N: 7.74%, 0: 29.99% Found: C: 49.17%, H: 6.15%, Cl: 4.33%, F: 2.37 %, N: 7.90% Example 44

[Chemical 44]

 % 9 · Ζ: Ν -Λ '% 88: 1'% ΖΧ · 9: Η '% 86' 6:: "1 ¾ 9 · 8Ζ: 0 '% 6S · Ζ: Ν'% ZS '% 96'- ID '% S · 9: Η'% Χ6 · 6:

(ΟΖΗ9 ^ Χ-ΐΟΗΧ · ε · 3ΖΟΖΧΝε ^ 0ΧΗΖ6Ο) ΐ! ^ + Ι

Z £ L0 / L00ZdT / 13d 99 t89S recommended ΟΟΖ OAV

^ ^ [OHO]

% 9 · 8: Ν '% θε · Ζ: Ι'% 00 · 9: Η '% Ζ' 8:: "1

 % S · 6Ζ: 0 '% 0S · 8: Ν'% 8Ζ · Ζ: Ι '% ΧΧ · 9: Η'% 9Ζ · 8:

 (OSHS ^ Χ-ΐΟΗ ^ · Ζ · 3ΖθεΐΝΖΐ066Η 80) ΐ! ^ + Ι

 96ΖΧ = ΓΧ + Μ]

OZZ LO / LOOZdT / lDd 99 t89S accuracy 00ί ΟΛ \ Chiral

[M + l] ⁺ = 1822

Calculated value (C90H105C12N13O24'3.4HCM4.9H20)

C: 48.78%, H: 6.29%, Cl: 8.64%, N: 8.22%, 0: 28.08% Found: C: 48.77%, H: 6.25%, Cl: 8.65%, N: 8.35% Example 47

[Chemical 47]

Chiral

[M + l] ⁺ = 1838

Calculated value (C89H98F3N13 027'2.1HCM3.9H20)

 C: 49.36%, H: 5.95%, Cl: 3.44%, F: 2.63%, N: 8.41%, 0: 30.21% Actual values: C: 49.33%, H: 5.89%, Cl: 3.40%, F: 2.42 %, N: 8.54% Example 48

[Chemical 48]

Chiral

[M + l] ⁺ = 1822

Calculated value (C91H102F3NllO26'2.1HCM3.8H20)

 C: 50.88%, H: 6.18%, Cl: 3.47%, F: 2.65%, N: 7. 17%, 0: 29.64% Found: C: 50.86%, H: 6.10%, Cl: 3.49%, F : 2.42%, N: 7.38% Example 49

[Chemical 49]

Chiral

[M + l] ⁺ = 1866

Calculated value (C92H106F3N13O26'3.0HCM4.3H20)

 C: 49.46%, H: 6.21%, Cl: 4.76%, F: 2.55%, N: 8.15%, 0: 28.86% Found: C: 49.40%, H: 6.20%, Cl: 4.80%, F : 2.35%, N: 8.36% Example 50

[Chemical 50]

Chiral

[M + l] ⁺ = 1887

Calculated value (C95H105F3N12O26'3.4HCM4H20)

 C: 50.40%, H: 6.07%, Cl: 5.32%, F: 2.52%, N: 7.42%, 0: 28.27% Found C: 50.50%, H: 5.92%, Cl: 5.31%, F: 2.32% , N: 7.60% Example 51

[Chemical 51]

Chiral

[M + l] ⁺ = 1872

Calculated value (C93H103C12N13O25'3.4HCM5.8H20)

 C: 48.94%, H: 6.09%, Cl: 8.39%, N: 7.98%, 0: 28.60%

Measured value C: 48.94%, H: 5.92%, Cl: 8.37%, N: 8.08%

 The following compounds are further produced according to the above general production method and the method described in the examples.

[Table 11-1]

Implementation

R ^a z ¹ R ^B R ^C Example

52 H OH H

53 II OH H

54 H OH H

00 H OH H

56 H OH H

57 II OH II

58 H O II H

59 H OH H

11- 2]

11-3] 実施 60 H OH H

11-2]

11-3] Implementation

R ^a z ¹ R ^B R ^c Example

70 II OH H

71 II OH H

 N

72 H 丫⁰ \ OH H

73 H OH H

74 H OH H

 Me

 75 H O II H No Et

 76 II OH H

77 II OH II

78 H OH H

11- 5]

11- 6]

11- 7] 11-4]

11-5]

11-6]

11-7]

1ト 8]

1 to 8]

[Table 11-9]

11-12]

11-13] [Table 11-10]

11-12]

11-13]

11-14]

11- 15]

11-15]

11-17]

11-16]

11-17]

11- 19]

1ト 20] 11-18]

11-19]

1t 20]

1ト 21]

1t 21]

11-23] 11-22]

11-23]

11 - 24]

11-24]

 [0147] Test Example 1

 In vitro measurement of antibacterial activity

 (Test method)

 The minimum inhibitory concentration (MIC) of the compound of the present invention was measured by a micro liquid dilution method using a cation-adjusted Mueller Hinton liquid medium well known to those skilled in the art.

 (Result)

The compounds of the present invention showed antibacterial activity against various bacteria. For example, the compounds of Examples 33 to 36 have MIC = 1 g / mL against ecfaecalis SR1004 (vancomycin ΜΙ. = 2 ^ g / mL), and in particular, the compounds of Examples 33 and 34 are High antibacterial activity against vancomycin-resistant bacteria (MIC for S. aureus VRS_2 (van A) = 16 g / mL; MIC for vancomycin = 64 ng / mL) ₀

[0148] Furthermore, the compounds of the present invention in which the C-terminal and resorcinol moieties are modified exhibit a broad antibacterial spectrum against the strains tested, for example, the compounds of Examples 38, 39 and 43-50 are vancomycin-resistant bacteria. ^ 11 = 2 to 4; ^; bancomasin ^ [1064; ^ / 111 against E. faecalis SR7914 & 11 Eight. In particular, the compounds of Examples 38, 39 and 50 also showed high activity against highly resistant MRSA (S. aur MIC = 0.5 · g ^ mL for eus SR3637 (H-MRSA); コ for vancomycin = 2 g Ζ mL).

[0149] Formulation examples

 Formulation Examples 1 to 8 shown below are merely examples, and are not intended to limit the scope of the invention in any way. The term “active ingredient” means a compound of the present invention, a tautomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

[0150] Formulation Example 1

 Hard gelatin capsules are manufactured using the following ingredients:

 Dose

 (mg / capsenore)

 Active ingredient 250

 Starch (dried) 200

 Magnesium stearate 10

 Total 460mg

[0151] Formulation Example 2

 Tablets are manufactured using the following ingredients:

 Dose

 (mg / tablet)

 Active ingredient 250

 Cellulose (microcrystal) 400

 Silicon dioxide (fume) 10

 Stearic acid 5

 Total 6mg 5mg

 The ingredients are mixed and compressed into tablets each weighing 665 mg.

[0152] Formulation Example 3

 An aerosol solution is prepared containing the following ingredients:

weight Active ingredient 0.25

 Ethanore 25. 75

 Yaki + 100. 00

 Mix the active ingredient and ethanol, add this mixture to a portion of propellant 22, cool to -30 ° C, and transfer to filling equipment. Then feed the required amount into a stainless steel container and dilute with the remaining propellant. Attach the bubble unit to the container.

[0153] Formulation Example 4

 A tablet containing 60 mg of active ingredient is prepared as follows:

 Active ingredient 60mg

 45mg

 Microcrystalline cell mouth 35mg

 Polyvinyl chloride,: 10% solution in) 4mg

 4. 5mg

 0.5 mg

 Talc lmg

 Hachioki B + I 150mg

 The active ingredient and cellulose should be sieved with No. 45 mesh U.S.

ステアリン酸マグネシウム、および滑 石をこの顆粒に加え、混合した後、打錠機で圧縮して各重量 150mgの錠剤を得る。 Mix thoroughly. The aqueous solution containing polybulurpyrrolidone is mixed with the resulting powder and then the mixture is passed through a No. 14 mesh US sieve. The granules thus obtained are dried at 50 ° C and passed through a No. 18 mesh U.S. sieve. No. 60 mesh US sieve beforehand

Magnesium stearate and talc are added to the granules, mixed, and compressed by a tableting machine to obtain tablets each weighing 150 mg.

[0154] Formulation Example 5

 Capsules containing 80 mg of active ingredient are prepared as follows:

Active ingredient 80mg Microcrystalline cellulose 2mg

 200mg total

 The active ingredient, starch, cellulose, and magnesium stearate are mixed and passed through a No. 45 mesh U.S. sieve to fill 200 mg of hard gelatin capsules.

[0155] Formulation Example 6

 A suppository containing 225 mg of active ingredient is prepared as follows:

 Active ingredient 225mg

 Saturated fatty acid glyceride 2000mg

 Total 2225mg

 Pass the active ingredient through a No. 60 mesh U.S. sieve and suspend in saturated fatty acid glycerides that have been heated and melted to the minimum necessary. The mixture is then cooled in an apparent 2 g mold.

[0156] Formulation Example 7

 A suspension containing 50 mg of active ingredient is prepared as follows:

 Active ingredient 50mg

 z—50 mg

 Syrup 1. 25ml

 Benzoic acid solution 0.1 ml

 Fragrance q. V.

 q.v.

 Add purified water and total 5ml

 The active ingredient is sifted through No. 45 mesh U.S. and mixed with sodium carboxymethyl cellulose and syrup to form a smooth paste. Add benzoic acid solution and fragrance diluted with a portion of water and stir. Next, add a sufficient amount of water to the required volume Formulation Example 8

 The intravenous formulation is manufactured as follows:

Active ingredient lOOmg Saturated fatty acid glyceride 1000ml

 Solutions of the above ingredients are usually administered intravenously to the patient at a rate of 1 ml per minute.

Industrial applicability

 The glycopeptide derivatives, pharmaceutically acceptable salts and solvates thereof of the present invention are useful in medical treatment and exhibit bioactivity including antibacterial activity. Accordingly, the present invention provides a method for treating infectious diseases, particularly diseases caused by gram positive microorganisms in animals. The compounds of the present invention are particularly useful for treating infections by enterococci. The compounds of the present invention are also useful as intermediates for the synthesis of glycopeptide antibiotics.

Claims

Claims [1] A glycopeptide compound having, as a partial structure, the aromatic rings of the second and sixth amino acid residues of the vancomycin skeleton, wherein the second or sixth amino acid residue The C1 atom bonded to at least one of the aromatic rings may be an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted alkenyl, a substituted re. ! /, Alkynyl or substituted! /, May! /, Glycopeptide compounds substituted with heteroaryl, pharmaceutically acceptable salts thereof, or solvates thereof. [2] C1 nuclear atom bonded to the aromatic ring of the second amino acid residue of the vancomycin skeleton, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, substituted 2. The glycopeptide compound according to claim 1, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, wherein the glycopeptide compound is substituted with a heteroaryl. Solvates. [3] C1 nuclear atom bonded to the aromatic ring of the second amino acid residue of the vancomycin skeleton, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, substituted C, nuclear, substituted with heteroaryl and attached to the aromatic ring of the 6th amino acid residue of the vancomycin skeleton. , Hydrogen, halogen other than C1 atom, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted! /, Alkynyl or substituted! /, The glycopeptide compound according to claim 2, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the glycopeptide compound is substituted with a heteroaryl! /. [4] Formula (I):  [Chemical 1]

(Where  Ring 2 and Ring 4 are the aromatic rings of the second and fourth amino acid residues of the glycopeptide antibiotic, respectively; and Z ¹ is hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl or substituted! /, Hey! /, Hetero reel) The daricopeptide compound according to claim 1, wherein the skeleton comprises a partial structure represented by the following structure: [Chemical 2]

 [Where  Ring 2, Ring 4 and Ring 6 are the aromatic rings of the second, fourth and sixth amino acid residues of the vancomycin skeleton, respectively; and (zz ² ) is (hydrogen, hydrogen), (hydrogen, halogen), (halogen, hydrogen) or (halogen, halogen)] Or a pharmaceutically acceptable salt thereof, or a solvent thereof.  Formula (I 1): [Chemical 3]

(Where Ring 2, Ring 4 and Ring 6 are the aromatic rings of the second, fourth and sixth amino acid residues of glycopeptide antibiotics, respectively; Z ¹ is hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl or substituted! /, Hey! /, Hetero reel; Z ² is hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl or substituted! /, Hey! /, Hetero reel; However, the case where (zz ² ) is (hydrogen, hydrogen), (hydrogen, halogen), (halogen, hydrogen) and (no, rogen, no, rogen) is excluded. )  The glycopeptide compound according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof, characterized by comprising a partial structure represented by the formula: [6] Formula (I 2):  [Chemical 4]

 (Where  Ring 2, Ring 4 and Ring 6 are the aromatic rings of the second, fourth and sixth amino acid residues of glycopeptide antibiotics, respectively; Z ¹ is hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl or substituted! /, Hey! /, Hetero reel; Z ² is hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl or substituted! /, Hey! /, Hetero reel; However, (zz ² ) is (hydrogen, hydrogen), (hydrogen, halogen), (halogen, hydrogen) and (no, rogen, No, Rogen). )  The glycopeptide compound according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof, characterized by comprising a partial structure represented by the formula:  [7] Formula (I 3):  [Chemical 5]

 (Where  Ring 2 and Ring 4 are the aromatic rings of the second and fourth amino acid residues of the glycopeptide antibiotic, respectively; and Z ¹ is hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl or substituted! /, Hey! /, Hetero reel)  The glycopeptide compound according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof, characterized by comprising a partial structure represented by the formula:  Formula (I 4):  [Chemical 6]

 (Where Rings 2, 4 and 6 are glycopeptide antibiotics 2nd, 4th and 6th, respectively. An aromatic ring of the amino acid residue of the th; z ¹ is hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl or substituted! /, Hey! /, Hetero reel; Z ² is hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl or substituted! /, Hey! /, Hetero reel However, the case where (zz ² ) is (hydrogen, hydrogen), (hydrogen, halogen), (halogen, hydrogen) and (no, rogen, halogen) is excluded. ) The glycopeptide compound according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof, characterized by comprising a partial structure represented by the formula:  Formula (I 5):  [Chemical 7]

 (Where  Ring 2, Ring 4, Ring 6, Ring 5, and Ring 7 are the aromatic rings of the second, fourth, sixth, fifth and seventh amino acid residues of glycopeptide antibiotics, respectively; Z ¹ is hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl or substituted! /, Hey! /, Hetero reel; Z ² represents hydrogen, halogen, alkyl which may be substituted, or alkyl which may be substituted. , Optionally substituted alkenyl, optionally substituted alkynyl or substituted! /, May! /, Heteroaryl; However, the case where (zz ² ) is (hydrogen, hydrogen), (hydrogen, halogen), (halogen, hydrogen) and (no, rogen, no, rogen) is excluded. )  Or a pharmaceutically acceptable salt thereof, or a solvate thereof. [10] Formula (II):  [Chemical 8] (Π)

 (Where z ¹ is hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl or substituted! /, Hey! /, Hetero reel; z ² may be hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl, or substituted! / /, Hetero reel Provided that (zz ² ) is (hydrogen, hydrogen), (hydrogen, halogen), (halogen, hydrogen) and (no, rogen halogen); R ^X is a sugar residue; R ^B is OH, an ester residue or an amide residue; Is hydrogen or optionally substituted alkyl (the alkyl moiety includes a heteroatom Groups may be present); and  R is substituted! /, May! /, Alkyl)  The compound of Claim 1 shown by these, its pharmaceutically acceptable salt, or those solvates. [11] Z ¹ is selected from the group consisting of lower alkoxy, halogen, lower alkyl, halogenated lower alkyl, halogenated lower alkoxy, lower alkylthio, optionally substituted amide and lower alkenyl 1 or 11. The compound according to any one of claims 4 to 10, which is an optionally substituted phenyl or an optionally substituted lower alkenyl, a pharmaceutically acceptable salt thereof, Or a solvate thereof. [12] Z ¹ is selected from the group consisting of lower alkoxy, halogen, lower alkyl, halogenated lower alkyl, halogenated lower alkoxy, lower alkylthio, optionally substituted amino-substituted and lower alkenyl 1 or The optionally substituted phenyl or the optionally substituted lower alkenyl, and Z ² is halogen, according to any one of claims 5, 6, 8, 9 and 10. A compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. [13] Z ¹ is selected from the group consisting of halogen, Z ² is lower alkoxy, halogen, lower alkyl, halogenated lower alkyl, halogenated lower alkoxy, lower alkylthio, optionally substituted amino, and lower alkenyl. The compound according to any one of claims 5, 6, 8, 9, and 10, which is an optionally substituted phenyl or an optionally substituted lower alkenyl. Top acceptable salts, or solvates thereof. [14] Z ¹ and Z ² are each independently a group consisting of lower alkoxy, halogen, lower alkyl, halogenated lower alkyl, halogenated lower alkoxy, lower alkylthio, optionally substituted amino, and lower alkenyl. 9. Substituted by one or more substituents selected from: R, may! /, Phenyl, or substituted! /, May! /, Lower alkenyl. , 9 and 10 or a pharmaceutically acceptable salt thereof, or a solvate thereof. [15] Z ¹ and Z ² are each independently an optionally substituted lower alkenyl. The compound according to any one of Claims 5, 6, 8, 9, and 10, a pharmaceutically acceptable salt thereof, or a solvate thereof. [16] The compound according to any one of claims 1 to 15, which is a vancomycin derivative, a pharmaceutically acceptable salt thereof, or a solvate thereof. [17] A pharmaceutical composition comprising the compound according to any one of claims 1 to 16; a pharmaceutically acceptable salt thereof, or a solvate thereof. [18] Equation (Γ):  [Chemical 9]

 (Where X is a halogen; rings 2 and 4 are aromatic rings of the second and fourth amino acid residues of glycopeptide antibiotics, respectively) Z′-B COH) (Z ¹ may be substituted) to a glycopeptide compound comprising a partial structure represented by the following formula in the basic skeleton, a pharmaceutically acceptable salt thereof, or a solvate thereof: Alkyl, optionally substituted aryl, optionally substituted alkenyl, substituted! /, May! /, Alkynyl or substituted! /, May! /, Heteroaryl), Ζ ¹ — ^! ^ ¹ is an optionally substituted alkenyl or an optionally substituted alkynyl), or Zi Sn— (Alk) (Z ¹ is an optionally substituted aryl or substituted A compound represented by the formula (I), wherein Z ^{1 in} formula (I) is reacted with a compound represented by: a good alkenyl, or an optionally substituted heteroarylene; Alk is alkyl) , Optionally substituted alkyl, substituted There Ariru, it may be substituted! / ヽ Arukeniru, been replaced! /, I also! /, Alkynyl, or method of manufacturing been replaced! /, I also! /, To Te Roariru). [19] Formula (I 1 '): [Chemical 10]

 (Wherein X and X ′ are each independently halogen;  Rings 2, 4 and 6 are the aromatic rings of the second, fourth and sixth amino acid residues of glycopeptide antibiotics, respectively) Z′-B COH) (Z ¹ may be substituted) to a glycopeptide compound comprising a partial structure represented by the following formula in the basic skeleton, a pharmaceutically acceptable salt thereof, or a solvate thereof: Alkyl, optionally substituted aryl, optionally substituted alkenyl, substituted! /, May! /, Alkynyl or substituted! /, May! /, Heteroaryl), Ζ ¹ — ^! ^ ¹ is substituted or alkenyl or optionally substituted alkynyl), or Z ¹ -Sn- (Alk) (Z ¹ is an optionally substituted aryl or substituted 6. The method for producing a compound according to claim 5, wherein a compound represented by a good alkenyl or an optionally substituted heteroarylene; Alk is an alkyl) is reacted.