JP5261191B2 - Glycopeptide antibiotic derivatives - Google Patents

Description

  The present invention relates to novel derivatives of glycopeptide antibiotics and related compounds. The present invention also relates to a pharmaceutical composition containing such a glycopeptide derivative, and a method for producing such a glycopeptide derivative.

  Glycopeptide antibiotics are antibiotics with complex polycyclic peptide structures produced by various microorganisms and provide effective antibacterial agents against most gram-positive bacteria. In recent years, bacteria resistant to penicillin, cephalosporin and the like have emerged, and multi-resistant and methicillin-resistant staphylococci (MRSA) infections pose important 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.

で示される構造を有し、Ｎ末端から２番目と６番目のアミノ酸残基の芳香環が塩素原子で置換されている。バンコマイシン誘導体は、一般にグリコペプチド抗生物質とも称されているが、より学術的にはD-alanyl-D-alanine binding antibiotics with a heptapeptidic structureに由来するダルバヘプタイド（dalbaheptide）の総称が提起されている。ダルバヘプタイドは、芳香族アミノ酸を含む７つのアミノ酸からなるペプチド鎖を共通の基本骨格としている。Vancomycin has the following formula:

And the aromatic rings of the second and sixth amino acid residues from the N-terminus are substituted with chlorine atoms. Vancomycin derivatives are generally referred to as glycopeptide antibiotics, but more academically, the generic name of dalbaheptide derived from D-alanyl-D-alanine binding antibiotics with a heptapeptidic structure has been proposed. Dalbaheptide has a peptide chain composed of seven amino acids including aromatic amino acids as a common basic skeleton.

  Until now, various modifications have been made on vancomycin and other glycopeptide antibiotics having the common peptide chain as a basic skeleton. A glycopeptide derivative in which the aromatic rings of the second and sixth amino acid residues are substituted with a substituent other than a chlorine atom is also disclosed (for example, see the following literature). However, a glycopeptide derivative in which a carbon chain, carbocycle or heterocycle is bonded to the position of the chlorine atom is not disclosed.

International Publication WO03 / 070756 Pamphlet ChemBioChem (2003), 4 (3), 658-662 Angew. Chem. Int. Ed., 1998, 37 (19), 2700-2704 JACS (1997), 119 (14), 3419-3420

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

  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.

That is, the present invention relates to the inventions described in the following [1] to [19].
[1] A glycopeptide compound having an aromatic ring of the second and sixth amino acid residues of the vancomycin skeleton as a partial structure, wherein at least one of the second or sixth amino acid residues A Cl atom bonded to one aromatic ring may be an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted alkenyl, an optionally substituted alkynyl or an optionally substituted A glycopeptide compound, a pharmaceutically acceptable salt thereof, or a solvate thereof, substituted with a good heteroaryl.

[2] The Cl atom bonded to the aromatic ring of the second amino acid residue of the vancomycin skeleton is optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, substituted The glycopeptide compound of the above-mentioned [1], a pharmaceutically acceptable salt thereof, or a solvate thereof, which is substituted with an optionally substituted alkynyl or an optionally substituted heteroaryl.

[3] The Cl atom bonded to the aromatic ring of the second amino acid residue of the vancomycin skeleton is an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted alkenyl, a substituted Cl atom bonded to the aromatic ring of the 6th amino acid residue of the vancomycin skeleton is substituted with hydrogen, halogen other than Cl atom, or substituted with optionally substituted alkynyl or optionally substituted heteroaryl [2] above, which is substituted with an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted alkenyl, an optionally substituted alkynyl or an optionally substituted heteroaryl Or a pharmaceutically acceptable salt thereof, or a solvate thereof.

（式中、
環２および環４は、それぞれグリコペプチド抗生物質の２番目および４番目のアミノ酸残基の芳香環；および
Ｚ¹は、水素、ハロゲン、置換されていてもよいアルキル、置換されていてもよいアリール、置換されていてもよいアルケニル、置換されていてもよいアルキニルまたは置換されていてもよいヘテロアリール）
で示される部分構造を基本骨格内に含んでなることを特徴とする上記［１］記載のグリコペプチド化合物（但し以下の部分構造：

［式中、
環２、環４および環６は、それぞれバンコマイシン骨格の２番目、４番目および６番目のアミノ酸残基の芳香環；および
（Ｚ¹,Ｚ²）は、（水素,水素）、（水素,ハロゲン）、（ハロゲン,水素）または（ハロゲン,ハロゲン）である）］
を有するグリコペプチド化合物を除く）、その製薬上許容される塩、またはそれらの溶媒和物。[4] Formula (I):

(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 An optionally substituted alkenyl, an optionally substituted alkynyl or an optionally substituted heteroaryl)
The glycopeptide compound of the above-mentioned [1], wherein the partial structure represented by (1) is included in the basic skeleton (however, the following partial structure:

[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 (Z ¹ , Z ² ) are (hydrogen, hydrogen), (hydrogen, halogen) ), (Halogen, hydrogen) or (halogen, halogen))]
Or a pharmaceutically acceptable salt thereof, or a solvate thereof.

（式中、
環２、環４および環６は、それぞれグリコペプチド抗生物質の２番目、４番目および６番目のアミノ酸残基の芳香環；
Ｚ¹は、水素、ハロゲン、置換されていてもよいアルキル、置換されていてもよいアリール、置換されていてもよいアルケニル、置換されていてもよいアルキニルまたは置換されていてもよいヘテロアリール；
Ｚ²は、水素、ハロゲン、置換されていてもよいアルキル、置換されていてもよいアリール、置換されていてもよいアルケニル、置換されていてもよいアルキニルまたは置換されていてもよいヘテロアリール；
但し、（Ｚ¹,Ｚ²）が（水素,水素）、（水素,ハロゲン）、（ハロゲン,水素）および（ハロゲン,ハロゲン）である場合を除く。）
で示される部分構造を基本骨格内に含んでなることを特徴とする、上記［１］記載のグリコペプチド化合物、その製薬上許容される塩、またはそれらの溶媒和物。[5] Formula (I-1):

(Where
Ring 2, Ring 4 and Ring 6 are the aromatic rings of the second, fourth and sixth amino acid residues of the glycopeptide antibiotic, respectively;
Z ¹ is hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted heteroaryl;
Z ² represents hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl or optionally substituted heteroaryl;
However, the case where (Z ¹ , Z ² ) is (hydrogen, hydrogen), (hydrogen, halogen), (halogen, hydrogen) and (halogen, halogen) is excluded. )
The glycopeptide compound of the above-mentioned [1], a pharmaceutically acceptable salt thereof, or a solvate thereof, which comprises the partial structure represented by the formula:

（式中、
環２、環４および環６は、それぞれグリコペプチド抗生物質の２番目、４番目および６番目のアミノ酸残基の芳香環；
Ｚ¹は、水素、ハロゲン、置換されていてもよいアルキル、置換されていてもよいアリール、置換されていてもよいアルケニル、置換されていてもよいアルキニルまたは置換されていてもよいヘテロアリール；
Ｚ²は、水素、ハロゲン、置換されていてもよいアルキル、置換されていてもよいアリール、置換されていてもよいアルケニル、置換されていてもよいアルキニルまたは置換されていてもよいヘテロアリール；
但し、（Ｚ¹,Ｚ²）が（水素,水素）、（水素,ハロゲン）、（ハロゲン,水素）および（ハロゲン,ハロゲン）である場合を除く。）
で示される部分構造を基本骨格内に含んでなることを特徴とする、上記［１］記載のグリコペプチド化合物、その製薬上許容される塩、またはそれらの溶媒和物。[6] Formula (I-2):

(Where
Ring 2, Ring 4 and Ring 6 are the aromatic rings of the second, fourth and sixth amino acid residues of the glycopeptide antibiotic, respectively;
Z ¹ is hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted heteroaryl;
Z ² represents hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl or optionally substituted heteroaryl;
However, the case where (Z ¹ , Z ² ) is (hydrogen, hydrogen), (hydrogen, halogen), (halogen, hydrogen) and (halogen, halogen) is excluded. )
The glycopeptide compound of the above-mentioned [1], a pharmaceutically acceptable salt thereof, or a solvate thereof, which comprises the partial structure represented by the formula:

（式中、
環２および環４は、それぞれグリコペプチド抗生物質の２番目および４番目のアミノ酸残基の芳香環；および
Ｚ¹は、水素、ハロゲン、置換されていてもよいアルキル、置換されていてもよいアリール、置換されていてもよいアルケニル、置換されていてもよいアルキニルまたは置換されていてもよいヘテロアリール）
で示される部分構造を基本骨格内に含んでなることを特徴とする、上記［１］記載のグリコペプチド化合物、その製薬上許容される塩、またはそれらの溶媒和物。[7] Formula (I-3):

(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 An optionally substituted alkenyl, an optionally substituted alkynyl or an optionally substituted heteroaryl)
The glycopeptide compound of the above-mentioned [1], a pharmaceutically acceptable salt thereof, or a solvate thereof, which comprises the partial structure represented by the formula:

（式中、
環２、環４および環６は、それぞれグリコペプチド抗生物質の２番目、４番目および６番目のアミノ酸残基の芳香環；
Ｚ¹は、水素、ハロゲン、置換されていてもよいアルキル、置換されていてもよいアリール、置換されていてもよいアルケニル、置換されていてもよいアルキニルまたは置換されていてもよいヘテロアリール；
Ｚ²は、水素、ハロゲン、置換されていてもよいアルキル、置換されていてもよいアリール、置換されていてもよいアルケニル、置換されていてもよいアルキニルまたは置換されていてもよいヘテロアリール；
但し、（Ｚ¹,Ｚ²）が（水素,水素）、（水素,ハロゲン）、（ハロゲン,水素）および（ハロゲン,ハロゲン）である場合を除く）
で示される部分構造を基本骨格内に含んでなることを特徴とする、上記［１］記載のグリコペプチド化合物、その製薬上許容される塩、またはそれらの溶媒和物。[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 the glycopeptide antibiotic, respectively;
Z ¹ is hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted heteroaryl;
Z ² represents hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl or optionally substituted heteroaryl;
(Except when (Z ¹ , Z ² ) is (hydrogen, hydrogen), (hydrogen, halogen), (halogen, hydrogen) and (halogen, halogen))
The glycopeptide compound of the above-mentioned [1], a pharmaceutically acceptable salt thereof, or a solvate thereof, which comprises the partial structure represented by the formula:

（式中、
環２、環４、環６、環５、および環７、は、それぞれグリコペプチド抗生物質の２番目、４番目、６番目、５番目および７番目のアミノ酸残基の芳香環；
Ｚ¹は、水素、ハロゲン、置換されていてもよいアルキル、置換されていてもよいアリール、置換されていてもよいアルケニル、置換されていてもよいアルキニルまたは置換されていてもよいヘテロアリール；
Ｚ²は、水素、ハロゲン、置換されていてもよいアルキル、置換されていてもよいアリール、置換されていてもよいアルケニル、置換されていてもよいアルキニルまたは置換されていてもよいヘテロアリール；
但し、（Ｚ¹,Ｚ²）が（水素,水素）、（水素,ハロゲン）、（ハロゲン,水素）および（ハロゲン,ハロゲン）である場合を除く）
で示される部分構造を基本骨格内に含んでなることを特徴とする、上記［１］記載のグリコペプチド化合物、その製薬上許容される塩、またはそれらの溶媒和物。[9] Formula (I-5):

(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 the glycopeptide antibiotic, respectively;
Z ¹ is hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted heteroaryl;
Z ² represents hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl or optionally substituted heteroaryl;
(Except when (Z ¹ , Z ² ) is (hydrogen, hydrogen), (hydrogen, halogen), (halogen, hydrogen) and (halogen, halogen))
The glycopeptide compound of the above-mentioned [1], a pharmaceutically acceptable salt thereof, or a solvate thereof, which comprises the partial structure represented by the formula:

（式中、
Ｚ¹は、水素、ハロゲン、置換されていてもよいアルキル、置換されていてもよいアリール、置換されていてもよいアルケニル、置換されていてもよいアルキニルまたは置換されていてもよいヘテロアリール；
Ｚ²は水素、ハロゲン、置換されていてもよいアルキル、置換されていてもよいアリール、置換されていてもよいアルケニル、置換されていてもよいアルキニルまたは置換されていてもよいヘテロアリール；
但し、（Ｚ¹,Ｚ²）が（水素,水素）、（水素,ハロゲン）、（ハロゲン,水素）および（ハロゲン,ハロゲン）である場合を除く；
Ｒ^Xは、糖残基；
Ｒ^Bは、ＯＨ、エステル残基またはアミド残基；
Ｒ^Cは、水素または置換されていてもよいアルキル（アルキル部分には、ヘテロ原子基が介在していてもよい）；および
Ｒは置換されていてもよいアルキル）
で示される、上記［１］記載の化合物、その製薬上許容される塩、またはそれらの溶媒和物。[10] Formula (II):

(Where
Z ¹ is hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted heteroaryl;
Z ² is hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted heteroaryl;
However, except when (Z ¹ , Z ² ) is (hydrogen, hydrogen), (hydrogen, halogen), (halogen, hydrogen) and (halogen, halogen);
R ^X is a sugar residue;
R ^B is OH, an ester residue or an amide residue;
R ^C is hydrogen or an optionally substituted alkyl (the alkyl moiety may be mediated by a heteroatom group); and R is an optionally substituted alkyl)
Or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[11] One or more selected from the group consisting of Z ¹ 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 the above [4] to [10], a pharmaceutically acceptable salt thereof, or a phenyl optionally substituted with a substituent of the above, or a lower alkenyl optionally substituted Solvates.

[12] One or more selected from the group consisting of Z ¹ is lower alkoxy, halogen, lower alkyl, halogenated lower alkyl, halogenated lower alkoxy, lower alkylthio, amino which may be substituted, and lower alkenyl The above-mentioned [5], [6], [8], [9] and [10], which are phenyl optionally substituted with the above substituents, or optionally substituted lower alkenyl, and Z ² is halogen. Or 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. Any of the above [5], [6], [8], [9] and [10], which is phenyl optionally substituted with one or more substituents, or lower alkenyl optionally substituted Or a pharmaceutically acceptable salt or solvate thereof.

[14] Z ¹ and Z ² are each independently selected from the group consisting of lower alkoxy, halogen, lower alkyl, halogenated lower alkyl, halogenated lower alkoxy, lower alkylthio, optionally substituted amino, and lower alkenyl. [5], [6], [8], [9] and [10] which are phenyl optionally substituted with one or more selected substituents, or lower alkenyl optionally substituted Or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[15] Any one of the above [5], [6], [8], [9] and [10], wherein Z ¹ and Z ² are each independently lower alkenyl which may be substituted. Or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[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.

（式中、Ｘはハロゲン；環２および環４は、それぞれグリコペプチド抗生物質の２番目および４番目のアミノ酸残基の芳香環）
で示される部分構造を基本骨格内に含んでなるグリコペプチド化合物、その製薬上許容される塩、またはそれらの溶媒和物に、Ｚ¹−Ｂ（ＯＨ）₂（Ｚ¹は、置換されていてもよいアルキル、置換されていてもよいアリール、置換されていてもよいアルケニル、置換されていてもよいアルキニルまたは置換されていてもよいヘテロアリール）、Ｚ¹−Ｈ(Ｚ¹は、置換されていてもよいアルケニルまたは置換されていてもよいアルキニル)、またはＺ¹−Ｓｎ−（Ａｌｋ）₃（Ｚ¹は、置換されていてもよいアリール、置換されていてもよいアルケニル、または置換されていてもよいヘテロアリール；Ａｌｋは、アルキル）で示される化合物を反応させることを特徴とする、上記［４］記載の化合物（但し、式（Ｉ）中のＺ¹は、置換されていてもよいアルキル、置換されていてもよいアリール、置換されていてもよいアルケニル、置換されていてもよいアルキニルまたは置換されていてもよいヘテロアリール）の製造方法。[18] Formula (I ′):

(Wherein X is halogen; ring 2 and ring 4 are aromatic rings of the second and fourth amino acid residues of glycopeptide antibiotics, respectively)
Or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein Z ¹ -B (OH) ₂ (Z ¹ is substituted) Optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl or optionally substituted heteroaryl), Z ¹ -H (Z ¹ is substituted) Optionally substituted alkenyl or optionally substituted alkynyl), or Z ¹ -Sn- (Alk) ₃ (Z ¹ is optionally substituted aryl, optionally substituted alkenyl, or substituted A compound represented by the above [4], wherein Z ¹ in formula (I) is substituted A good alkyl, an optionally substituted aryl, an optionally substituted alkenyl, an optionally substituted alkynyl or an optionally substituted heteroaryl.

（式中、ＸおよびＸ’はそれぞれ独立してハロゲン；
環２、環４および環６は、それぞれグリコペプチド抗生物質の２番目、４番目および６番目のアミノ酸残基の芳香環）
で示される部分構造を含んでなるグリコペプチド化合物、その製薬上許容される塩、またはそれらの溶媒和物に、Ｚ−Ｂ（ＯＨ）₂（Ｚは、置換されていてもよいアルキル、置換されていてもよいアリール、置換されていてもよいアルケニル、置換されていてもよいアルキニルまたは置換されていてもよいヘテロアリール）、Ｚ−Ｈ(Ｚは、置換されていてもアルケニルまたは置換されていてもよいアルキニル)、またはＺ−Ｓｎ−（Ａｌｋ）₃（Ｚは、置換されていてもよいアリール、置換されていてもよいアルケニル、または置換されていてもよいヘテロアリール；Ａｌｋは、アルキル）で示される化合物を反応させることを特徴とする、上記［５］記載の化合物の製造方法。[19] Formula (I-1 ′):

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) ₂ (where Z is an optionally substituted alkyl, a substituted Optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl or optionally substituted heteroaryl), Z-H (Z is optionally substituted or alkenyl or substituted) Alkynyl), or Z-Sn- (Alk) ₃ (Z is an optionally substituted aryl, an optionally substituted alkenyl, or an optionally substituted heteroaryl; Alk is an alkyl) The method for producing a compound according to the above [5], wherein the compound shown is reacted.

  Terms used in this specification will be explained below. Each term alone or in combination with other terms has the same meaning.

  In the present specification, in the present specification, the “basic skeleton” means a glycopeptide antibiotic, specifically the basic skeleton of the aforementioned dalbaheptide. The “basic skeleton” is preferably a “vancomycin skeleton”. Specifically, it means a cyclic structure of a peptide chain composed of 7 amino acids including aromatic amino acids. Specifically, among them, 5 amino acids, ie, amino acids 2, 4, 5, 6 and 7 from the N-terminal, are common, and the second and fourth and fourth and sixth aromatic amino acids. Is a diphenyl ether bond, and the fifth and seventh aromatic amino acids are linked by a C—C bond. Other structures are broadly classified into vancomycin type, ristocetin type, avoparcin type, symononicin type, etc., depending on the type of the first and third amino acids. -Chemistry and biological activity "4th edition, p.265-268, published by the University of Tokyo Press).

より好ましくは、以下の部分構造を有する。

該基本骨格は、特に好ましくは、次式

（環２、４、５、６および７は、それぞれグリコペプチド抗生物質の２，４，５，６，および７番目のアミノ酸残基における芳香環を表する）
で示される。The basic skeleton specifically has the following partial structure.

More preferably, it has the following partial structure.

The basic skeleton is particularly preferably

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

In the present invention, the ring 2 in the basic skeleton has a substituent represented by Z ¹ defined below and / or the ring 6 in the basic skeleton has a substituent represented by Z ² defined below. It has been found that it can be introduced. Therefore, according to the present invention, a novel antibacterial compound having a Z ¹ group introduced into ring 2 and / or a Z ² group introduced into ring 6 using various glycopeptide antibiotics having the basic skeleton as starting materials Can provide. Preferably, at least ring ¹ 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 a 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-61-265199, JP-A-7-258289, International Publication WO96 / 30401, International Publication WO00 / 39156, JP2000-302687, International Publication WO2004. U.S. Pat. No. 4,639,433; 4,643,987; 4,497,802; 4,698,327; 5,591,714; And 5,843,889; EP0802199; EP0801075; EP0667353; WO97 / 28812; WO97 / 38702; WO98 / 52589; WO98 / 52592; Am. Chem. Soc. 1996, 118, 13107-13108; Am. Chem. Soc. 1997, 119, 12041-12047; Am. Chem. Soc. , 1994, 116, 4573-4590, and the like.

  Examples of glycopeptide antibiotics include, for example, vancomycin, teicoplanin, ristomycin, ristocetin, actaplanin, actinoidin, ardacin, avopalcin, azuleomycin, balhimycin, chloroorientine A ), Chloroorienticin B (Chloroorienticin B), chloropolysporin (Chloropolysporin), decaplanin (Decaplanin), N-demethylvancomycin (demethylanvancomycin), eremomycin (Eremycin), galacaldin (H) n), isupeptin (Izupeptin), kibdelin (Kibdelin), mannopeptin (Mannopeptin), orienticin (Orienticin), parvodicin (Parvodicin), simmonisin (Synmonicin), oritarubin (c) 40926 or the like.

  Specifically, in the compound of the present invention, at least one of the Cl atoms bonded to the aromatic ring of the 2nd or 6th amino acid residue of the vancomycin skeleton may be substituted alkyl or substituted. Glycopeptide compound, pharmaceutically acceptable salt thereof having, as a partial structure, an aromatic ring substituted with good aryl, optionally substituted alkenyl, optionally substituted alkynyl or optionally substituted heteroaryl Or a solvate thereof. Here, both Cl atoms bonded to the aromatic ring of the second or sixth amino acid residue may be substituted with the above-mentioned substituent, or only one of them may be substituted with the above-mentioned substituent. .

  When the glycopeptide compound of the present invention has, as a partial structure, an aromatic ring in which only one of the above Cl atoms is substituted with the above substituent, the Cl atom bonded to the other aromatic ring is not changed. It may be substituted with a halogen atom (F, Br, I) other than hydrogen or Cl. In addition, if the structure other than the aromatic ring of the second and sixth amino acid residues is a structure based on the basic skeleton of the above-mentioned 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, teicoplanin derivatives, etc. may be appropriately chemically modified.

  One of the preferable embodiments of the above compound has an aromatic ring as a partial structure in which the Cl atom bonded to the aromatic ring of the second amino acid residue of the vancomycin skeleton is substituted with the above substituent.

ここで、環２および環４は、それぞれグリコペプチド抗生物質の２番目および４番目のアミノ酸残基における芳香環を表する。置換基Ｚ¹は、水素、ハロゲン、置換されていてもよいアルキル、置換されていてもよいアリール、置換されていてもよいアルケニル、置換されていてもよいアルキニルまたは置換されていてもよいヘテロアリールである。In one embodiment of the present invention, the glycopeptide compound of the present invention has a substituent Z ¹ via a carbon-carbon bond on the aromatic ring of the second amino acid residue (phenylalanine residue) from the N-terminus of the glycopeptide antibiotic. Are combined. Specifically, the glycopeptide compound of the present invention has a partial structure represented by the formula (I).

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, optionally substituted alkynyl, or optionally substituted heteroaryl. It is.

（環２、４、５、６および７は、それぞれグリコペプチド抗生物質の２，４，５，６，および７番目のアミノ酸残基における芳香環を表する）
で示される部分構造を有する。More preferably, the glycopeptide compound of the present invention has a partial structure represented by the formula (I-1), (I-2), (I-3), or (I-4). Particularly preferably, the formula:

(Rings 2, 4, 5, 6, and 7 represent aromatic rings at the 2, 4, 5, 6, and 7th amino acid residues of the glycopeptide antibiotic, respectively)
It has the partial structure shown by.

  As used herein, the term “alkyl” used alone or in combination with another term refers to a straight or branched monovalent having 1 to 15, preferably 1 to 10 carbon atoms. Includes hydrocarbon groups. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, etc. Is mentioned. More preferably, C1-C6 alkyl is mentioned. More preferably, C1-C3 alkyl is mentioned.

  In this 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 lower alkyl”, as used herein, Lower alkyl part of “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” Is the same as the above “lower alkyl”.

  As used herein, the term “alkylene” used alone or in combination with other terms refers to straight or branched divalent divalent having 1 to 15, preferably 1 to 10 carbon atoms. Includes hydrocarbon groups. For example, lower alkylene having 1 to 6 carbon atoms, such as methylene, ethylene, propylene, butylene, pentylene, and hexylene.

  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-pentyloxy, n-hexyloxy, n-heptyloxy, n- Examples include octyloxy.

  In the present specification, “lower alkoxy” used alone or in combination with other terms means the “alkoxy” having 1 to 6 carbon atoms. Specific examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy and n-hexyloxy. The lower alkyl part of the terms “halogenated lower alkoxy”, “lower alkoxycarbonyl” and “hydroxy lower alkoxy lower alkyl” used herein is the same as the above “lower alkyl”.

  In the present specification, “alkenyl” used alone or in combination with other terms has 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, and has one or more double bonds. And a straight-chain or branched monovalent hydrocarbon group having the following formula. Examples include vinyl, allyl, 1-propenyl, 2-propenyl, crotonyl, isopentenyl, various butenyl isomers, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl and decenyl. Preferably, C2-C6 alkenyl is mentioned. 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 this specification, the term “lower alkenyl” used alone or in combination with another term means the above “alkenyl” having 2 to 6 carbon atoms.

  In the present specification, the term “alkenylene” used alone or in combination with other terms has 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, and includes one or more doubles. It includes a linear or branched divalent hydrocarbon group having a bond. For example, lower alkenylene having 1 to 6 carbon atoms such as ethenylene, propenylene, butenylene, pentenylene, hexenylene and the like can be mentioned.

  In the present specification, the term “alkynyl” used alone or in combination with other terms means a linear or branched group having 2 to 8 carbon atoms and having one or more triple bonds. Includes monovalent hydrocarbon groups in the chain. Examples include ethynyl, 1-propynyl, 2-propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl 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-position carbon atoms.

  As used herein, the term “lower alkynyl” used alone or in combination with other terms refers to the aforementioned “alkynyl” having 2 to 6 carbon atoms.

  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. Preferably, phenyl, 1-naphthyl and 2-naphthyl are used. More preferably, a phenyl is mentioned.

  In the present specification, “heteroaryl” refers to, for example, a monocyclic aromatic heterocyclic group and a condensed aromatic heterocyclic group containing a hetero atom selected from a nitrogen atom, a sulfur atom and an oxygen atom in the ring. means. The monocyclic aromatic heterocyclic group is an optionally substituted group derived from a 5- to 8-membered aromatic ring which may contain 1 to 4 oxygen atoms, sulfur atoms and / or nitrogen atoms in the ring. Means a group which may have a bond at the position. The condensed aromatic heterocyclic group has 1 to 4 5-8 aromatic rings which may contain 1 to 4 oxygen atoms, sulfur atoms and / or nitrogen atoms in the ring. It means a group which may have a bond at any substitutable position which is fused with a member aromatic carbocycle or other 5- to 8-membered aromatic heterocycle.

Specific examples of “heteroaryl” include furyl (eg, 2-furyl, 3-furyl), thienyl (eg, 2-thienyl, 3-thienyl), pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), triazolyl (eg, 1,2,4-triazole) -1-yl, 1,2,4-triazol-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 (for example, 3-isoxolyl) Zolyl, 4-isoxazolyl, 5-isoxazolyl), thiazolyl (eg 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiadiazolyl, isothiazolyl (eg 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), pyridyl (eg 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (eg, 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (eg, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), furazanil (eg, 3-pyridinyl). Furazanyl), pyrazinyl (eg 2-pyrazinyl), oxadiazolyl (eg 1,3,4-oxadiazol-2-yl), benzofuryl (eg 2-benzo [b] furyl, 3-benzo [b] furyl 4-benzo [b] furyl, 5- Nzo [b] furyl, 6-benzo [b] furyl, 7-benzo [b] furyl), benzothienyl (eg, 2-benzo [b] thienyl, 3-benzo [b] thienyl, 4-benzo [b ] Thienyl, 5-benzo [b] thienyl, 6-benzo [b] thienyl, 7-benzo [b] thienyl), benzimidazolyl (eg 1-benzoimidazolyl, 2-benzimidazolyl, 4-benzoimidazolyl, 5-benzimidazolyl), Dibenzofuryl, benzoxazolyl, quinoxalyl (eg 2-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl), cinnolinyl (eg 3-cinnolinyl, 4-cinnolinyl, 5-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl, 8 -Cinnolinyl), quinazolyl (eg 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl, 8-quinazolinyl), quinolyl (eg, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8 -Quinolyl), phthalazinyl (eg, 1-phthalazinyl, 5-phthalazinyl, 6-phthalazinyl), isoquinolyl (eg, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8 -Isoquinolyl), prill, pteridinyl (e.g. 2-pteridinyl, 4-pteridinyl, 6-pteridinyl, 7-pteridinyl), carbazolyl, phenanthridinyl, acridinyl (e.g. 1-acridinyl, 2-acridinyl, 3-acridinyl, 4-Acridini 9-acridinyl), 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 (for example, 1-phenothiazinyl, 2-phenothiazinyl, 3-phenothiazinyl, 4-phenothiazinyl) and the like.
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), pyrazinyl (eg 2-pyrazinyl).

“Optionally substituted alkyl”, “optionally substituted aryl”, “optionally substituted alkenyl”, “optionally substituted alkynyl” and “optionally substituted heteroaryl” Substituents of, for example, hydroxy, carboxy, halogen (F, Cl, Br, I), haloalkyl (eg, CF ₃ , CH ₂ CF ₃ , CH ₂ CCl ₃ ), C1-C6 alkyl (eg, methyl, Ethyl, isopropyl, tert-butyl), C2-C6 alkenyl (eg, vinyl), C2-C6 alkynyl (eg, ethynyl), cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), cycloalkenyl (eg, cyclo Propenyl), alkoxy (eg methoxy, ethoxy, propo Si, butoxy), alkenyloxy (eg, vinyloxy, allyloxy, etc.), alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), nitro, nitroso, optionally substituted amino (eg, amino, Alkylamino (eg, methylamino, ethylamino, dimethylamino), acylamino (eg, acetylamino, benzoylamino), aralkylamino (eg, benzylamino, tritylamino), hydroxyamino), azide, aryl (eg, phenyl) Aralkyl (eg benzyl), cyano, isocyano, isocyanato, thiocyanato, isothiocyanato, mercapto, alkylthio (eg methylthio), alkylsulfonyl (eg meta Sulfonyl, ethanesulfonyl), optionally substituted carbamoyl (eg, alkylcarbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl)), sulfamoyl, acyl (eg, formyl, acetyl), formyloxy, haloformyl, oxalo, Thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, sulfino, sulfo, sulfoamino, hydrazino, azide, ureido, amidino, guanidino, phthalimide, oxo, optionally substituted aryl (eg, phenyl, 2-chlorophenyl, 3-chlorophenyl) 4-chlorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxypheny , 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 1-naphthyl, 2-naphthyl), optionally substituted heteroaryl (eg, pyridin-2-yl, pyridin-3-yl, pyridine) -4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, isoxazol-3-yl, isoxazol-5-yl, pyrrol-2-yl, pyrazol-3-yl, furan 2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, imidazol-2-yl, oxazol-2-yl, thiazol-2-yl) and the like.

  Examples of the substituent of “optionally substituted aryl” and “optionally substituted heteroaryl” include those exemplified above. The aryl and the heteroaryl may be substituted with these substituents at any substitutable position, and the number thereof is 1 to 3.

ここで、環２、環４および環６は、それぞれグリコペプチド抗生物質の２番目、４番目および６番目のアミノ酸残基の芳香環を表する。
Ｚ¹は、水素、ハロゲン、置換されていてもよいアルキル、置換されていてもよいアリール、置換されていてもよいアルケニル、置換されていてもよいアルキニルまたは置換されていてもよいヘテロアリール；
Ｚ²は、水素、ハロゲン、置換されていてもよいアルキル、置換されていてもよいアリール、置換されていてもよいアルケニル、置換されていてもよいアルキニルまたは置換されていてもよいヘテロアリールである。
但し、（Ｚ¹,Ｚ²）が（水素,水素）、（水素,ハロゲン）、（ハロゲン,水素）および（ハロゲン,ハロゲン）である場合を除く。In one preferred embodiment of the above compound, both Cl atoms bonded to the aromatic rings of the 2nd and 6th amino acid residues of the vancomycin skeleton are each independently substituted with the above substituent, It has the partial structure shown in I-1).

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, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted heteroaryl;
Z ² is hydrogen, halogen, alkyl which may be substituted, aryl which may be substituted, alkenyl which may be substituted, alkynyl which may be substituted or heteroaryl which may be substituted .
However, the case where (Z ¹ , Z ² ) is (hydrogen, hydrogen), (hydrogen, halogen), (halogen, hydrogen) and (halogen, halogen) is excluded.

Preferably, Z ¹ is an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted alkenyl, an optionally substituted alkynyl or an optionally substituted heteroaryl;
Z ² is hydrogen, halogen, alkyl which may be substituted, aryl which may be substituted, alkenyl which may be substituted, alkynyl which may be substituted or heteroaryl which may be substituted . More preferably, Z ² is halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl or optionally substituted heteroaryl. It is.

In a preferred embodiment of the present invention, Z ¹ and Z ² each independently represent lower alkyl, lower alkoxy, halogen, halogenated lower alkyl, hydroxy, halogenated lower alkoxy, lower alkylthio, optionally substituted amino, And phenyl optionally substituted with one or more substituents selected from the group consisting of lower alkenyl. Preferably, it is phenyl optionally substituted by lower alkoxy, and examples of the lower alkoxy include methoxy, ethoxy, propoxy, butoxy, pentoxy, and hexoxy.

In another preferred embodiment, Z ¹ and Z ² are each independently a 6-membered monocyclic aromatic heterocyclic group containing 1 to 2 nitrogen atoms which may be substituted, such as pyridyl (Eg, 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (eg, 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (eg, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl (eg, 2-pyrazinyl). The substituent on the heterocycle is preferably lower alkoxy.

In still another preferred embodiment, Z ¹ and Z ² are each independently an optionally substituted lower alkenyl or an optionally substituted lower alkynyl, and the substituent is preferably substituted. Good phenyl (examples of substituents: lower alkyl, halogen, amino).

（Ｍｅ：メチル、Ｅｔ：エチル、Ｐｒ：ｎ−プロピル、Ｂｕ：ｎ−ブチル）Specific examples of Z ¹ and Z ² include the groups shown below.

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

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

［式中、Ｚ¹およびＺ²は前記と同意義であり、Ｒは置換されていてもよいアルキルである］
で示される。Furthermore, in a particular aspect of the invention, the glycopeptide compound of the invention has the formula (II):

[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 portion when one OH is removed from the sugar portion. The sugar moiety includes an amino sugar, a sugar chain containing an amino sugar, or other sugar or sugar chain moiety. Preferably, R ^X is a residue obtained by removing one OH from a known amino sugar moiety or a sugar chain part containing an amino sugar in a glycopeptide antibiotic derivative. “Amino sugar moiety” refers to a monosaccharide group having an amino group or a substituted amino group. Representative amino sugar moieties include L-vancosaminyl, 3-desmethyl-vancosaminyl, 3-epi-vancosaminyl, 4-epi-vancosaminyl, 4-keto-vancosaminyl, acosaminiel, actinosaminyl, daunosaminyl, 3-epi-daunoosaminyl, ristosaminyl. N-methyl-D-glucaminyl, N-acetyl-D-glucosamyl, N-acyl-D-glucosamyl and the like. Actinosaminyl, acosaminiel, 4-epi-bancosaminyl, 4-keto-bancosaminyl, ristosaminyl, or vancosaminyl are preferred. In particular, L-bancosaminyl is preferable. Examples of the sugar chain portion containing an amino sugar include α-L-vancosaminyl-β-D-glucopyranose and 3-desmethyl-α-L-vancosaminyl-β-D-glucopyranose.

［式中、
Ｒ^Aは、水素または式：
−Ｘ¹−Ａｒ¹−Ｘ²−Ｙ−Ｘ³−Ａｒ²
（式中、Ｘ¹、Ｘ²およびＸ³はそれぞれ独立して、
１）単結合、
２）−Ｎ＝、＝Ｎ−、−ＮＲ¹−（ここに、Ｒ¹は水素または低級アルキル）、−Ｏ−、−Ｓ−、−ＳＯ−および−ＳＯ_2-からなる群から選択されるヘテロ原子基、またはそれらの連結基、あるいは；
３）同一もしくは異なる該ヘテロ原子基が１個もしくはそれ以上介在していてもよくかつ置換されていてもよいアルキレンまたはアルケニレン；
Ｙは、−ＮＲ²ＣＯ−、−ＣＯＮＲ²−（ここに、Ｒ²は水素または低級アルキル）、または式：

（式中、Ｒ³はアルキレン）
で示される基；および
Ａｒ¹およびＡｒ²はそれぞれ独立して、置換されていてもよくかつ不飽和結合を有していてもよい炭素環またはヘテロ環）]
で示される基である。The sugar residue represented by R ^X is preferably a formula described in WO2006 / 057303 or the like:

[Where:
R ^A is hydrogen or the formula:
^{-X 1 -Ar 1 -X 2 -Y-} X 3 -Ar 2
(Wherein X ¹ , X ² and X ³ are each independently
1) single bond,
2) selected from the group consisting of —N═, ═N—, —NR ¹ — (wherein R ¹ is hydrogen or lower alkyl), —O—, —S—, —SO— and —SO ₂ —. A heteroatom group, or a linking group thereof; or
3) an alkylene or alkenylene optionally having one or more of the same or different heteroatom groups intervening and substituted;
Y is —NR ² CO—, —CONR ² — (wherein R ² is hydrogen or lower alkyl), or the formula:

(Wherein R ³ is alkylene)
And Ar ¹ and Ar ² are each independently a carbocyclic or heterocyclic ring which may be substituted and may have an unsaturated bond)]
It is group shown by these.

で示される。More preferably the formula:

Indicated by

R ^A is preferably hydrogen or the formula:
^{-X 1 -Ar 1 -X 2 -Y-} X 3 -Ar 2
(Where
X ¹ is a single bond, lower alkylene or lower alkenylene;
Ar ¹ represents an optionally substituted phenyl or an optionally substituted 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

（Ｂｎ：ベンジルを示す。）Particularly preferred examples of the group ^RA in the present invention are hydrogen or the groups shown below.

(Bn: represents benzyl)

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

In the above (II), R ^C represents hydrogen or optionally substituted alkyl (the hetero moiety may be interposed in the alkyl moiety).

Examples of R ^B and R ^C include substituents described in JP-A No. 2001-163898. Specific examples are shown below.

R ^B is selected from the group consisting of the following (2-1) to (2-7):
(2-1) hydroxy;
(2-2) mono or dialkylamino which may have a substituent (excluding (2-4)), wherein two alkyls may be bonded to form a ring, Substituents are amino, monoalkylamino, dialkylamino, trialkylammonium, hydroxy, guanidino, carboxy, alkyloxycarbonyl, carbamoyl optionally substituted with cyano, mono or dialkylcarbamoyl, mono or diarylcarbamoyl, aryl, alkyl amide or aryl amide, alkyl urea or aryl ^{ureas, - (C = O) N} - -N + (R X) 3, -N + (R X) 2 (CH 2) m COOR Y, -N + (R X _{) 2 (CH 2) m N} + (R X) 3, -SO 2 -OR Y ( where, m is 1 to 3, R ^X is, C1～C Alkyl and R ^Y is hydrogen or C1~C3 alkyl), or _{^{-P = O (OR Y) 2}} ( wherein, R ^Y is hydrogen or a C1~C3 alkyl), or a combination thereof Wherein the alkyl in the substituent may be further substituted with amino optionally substituted with alkyloxycarbonyl or aryloxycarbonyl, and the aryl ring in the substituent may further be halogenated. , Nitro, amino, hydroxy, carboxy, alkyloxycarbonyl, alkyl optionally substituted with amino, or hydroxyalkyl or thioalkyl optionally substituted, or combinations thereof;
(2-3) cycloalkylamino optionally substituted with amino or hydroxy;
(2-4) Disubstituted methylamino-NHCHR ⁶ R ⁷ , wherein R ⁶ may be carboxy, optionally substituted alkyloxycarbonyl, carbamoyl, or substituted. Selected from good monoalkylcarbamoyl or optionally substituted cycloalkylcarbamoyl, wherein the substituent is amino, monoalkylamino, dialkylamino, trialkylammonium, carboxy, hydroxy,-(C ═O) N ⁻ —N ⁺ (R ^x ) ₃ , — (CH ₂ ) _m COOR ^x, where m is 1-3 and R ^x is C1-C3 alkyl. be _{^{aryl, -N + (R X) 2}} (CH 2) m COOR Y ( wherein, R ^Y is hydrogen or C1~C3 alkyl), or _{^{-N + (R X) 2 (}} C _{^{2) m N + (R X}} ) 3 or a combination thereof,, R ⁷ is a C1~C3 good indole or thioindoles be nitrogen substituted by alkyl or imidazolyl;
(2-5) Tripeptide R ^Z -A ¹ -A ² -A ^3- : Here, A ¹ , A ² , and A ³ are each an arbitrary amino acid unit, and R ^Z is the carboxy of the tripeptide. Represents terminal, hydroxy, amino or optionally substituted mono or dialkylamino, wherein the substituent is amino, monoalkylamino, dialkylamino, trialkylammonium, guanidino, or aryl;
(2-6) optionally substituted hydrazino or hydroxamic acid, wherein the substituent is alkyl, or arylalkyl optionally further substituted with alkyl; and (2-7) substituted An alkoxy optionally having a group, and the substituent is nitro, hydroxamic acid, or arylcarbonyl optionally substituted with alkyl;
However, in (2-2) to (2-7), the existing aryl ring can contain a heteroatom, and the existing carbon-carbon single bond is a heteroatom or -O (P = O) (OR ^F ) O— (wherein R ^F is hydrogen, alkyloxycarbonyl or aryloxycarbonyl), and may be interrupted by a hetero group selected from imino.

R ^B is preferably —OH, —NHR ⁵ , or —NR ⁵ R ⁵ ′ (where R ⁵ and R ⁵ ′ are hydrogen, optionally substituted alkyl, —NH—R ^G , —NH— COR ^G , —NH—CONHR ^G , —O—R ^G (each R ^G is independently hydrogen or optionally substituted alkyl), or amino sugar residue). Preferably, one of R ⁵ and R ⁵ ′ is hydrogen. The optionally substituted alkyl substituent is preferably a hydrophilic substituent such as amino, mono- or di-lower alkylamino, trialkylamine, amino-lower alkylamino, hydroxy-lower alkylamino, hydroxy, carboxy, lower Alkoxycarbonyl, SO ₃ H, PO ₃ H ₂ , optionally substituted carbamoyl, quaternary ammonium group (eg, trialkylamino (eg, —N ⁺ (CH ₃ ) ₃ )), optionally substituted 1-10, preferably 1-6, the same or different selected from a heterocyclic group (heterocycle or heteroaryl), an optionally substituted heterocyclic thio, guanidino, NHSO ₂ NH ₂ , hydroxy lower alkoxy Substituents are exemplified. The nitrogen atom part in the heterocyclic ring may be quaternized to form a salt. Examples of the substituent of the heterocyclic ring which may be substituted include hydroxy, amino, carboxy, amino lower alkyl, and quaternary ammonium lower alkyl. The lower alkyl group on the quaternary ammonium group may be further substituted with a substituted alkyl (substituent: carboxy, hydroxy, quaternary ammonium group).

R ^C is selected from the group consisting of the following (3-1) to (3-4):
(3-1) hydrogen;
(3-2) Aminomethyl optionally substituted with alkyl, cycloalkyl or alkylene, wherein each of alkyl, cycloalkyl and alkylene may have a substituent, and the substituent is alkyloxycarbonyl Alternatively, amino, monoalkylamino, dialkylamino, trialkylammonium optionally substituted with aryloxycarbonyl, aryl optionally substituted with cycloalkyl, hydroxy, guanidino, —O— (P═O) (OH) _{2, ^{carboxy, -N + (R X) 2}} (CH 2) m N + (R X) 3, or ^{- (C = O) -N -} -N + (R X) 3 ( wherein, m is 1 a to 3, R ^X is a is), or a combination thereof C1~C3 alkyl, wherein said monoalkylamino or Jiarukirua -Alkyl in the substituent may be further substituted by amino;
(3-3) Alkynyl which may have a substituent, and the substituent is amino optionally substituted with alkyloxycarbonyl 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 -O (P = O) (OR ^J ) O— (where R ^J is hydrogen, alkyloxycarbonyl or aryloxycarbonyl), amide, and optionally interrupted by a heterogroup selected from imino.

R ^C is preferably hydrogen or optionally substituted alkyl. The optionally substituted alkyl substituent is preferably the aforementioned —NHR ⁵ , or the optionally substituted alkyl substituent in R ⁵ is exemplified.

As a preferable combination of R ^B and R ^C , R ^B is hydroxy, —NHR ⁵ (R ⁵ is a 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 ₂ CON ^— N ⁺ (Me) ₃ , and R ^C is hydrogen, mono- or di-substituted amino lower alkyl (substituent of example: lower alkyl, mono- or di-lower alkylamino-lower alkyl, tri-lower alkylammonium lower alkyl, hydroxy lower alkyl, hydroxy lower alkoxy lower _{^{alkyl, -CH 2 CON - N + (}} Me) 3, 1 to 6 hydroxy Substituted lower alkyl, and carboxy, hydroxy, oxo, optionally substituted carbamoyl, Nijido, sulfonic acid group, a phosphoric acid group, a lower alkyl substituted with NHSO _2N H ₂ and / or amino, optionally substituted heterocycle lower alkyl (substituent: amino lower alkyl), optionally substituted An example is a quaternary ammonium lower alkyl (substituent: carboxy, hydroxy, quaternary ammonium group).

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 ₂ CON ^— N ⁺ (Me) ₃ , and R ^C is hydrogen, mono- or di-substituted amino lower alkyl (substituted) examples of radicals: lower alkyl, mono- or di-lower alkylamino-lower alkyl, tri-lower alkylammonium lower alkyl, hydroxy lower alkyl, hydroxy lower alkoxy lower _{^{alkyl, -CH 2 CON - N + (}} Me) 3, of 1-6 Lower alkyl substituted with hydroxy, and carboxy, hydroxy, oxo, optionally substituted carbamoyl, Anijido, sulfonic acid group, a phosphoric acid group, lower alkyl substituted with NHSO ₂ NH ₂ and / or amino, optionally substituted heterocycle lower alkyl (substituent: amino lower alkyl), optionally substituted An example is a quaternary ammonium lower alkyl (substituent: carboxy, hydroxy, quaternary ammonium group), and R ^D is hydrogen. Specifically, the case of Tables 1-8 is mentioned.

More specific compounds of the present invention are exemplified below.

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

  The present invention includes the above 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.

"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; trimethylamine salt, Aliphatic amine salts such as triethylamine salt, dicyclohexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, brocaine salt, meglumine salt, diethanolamine salt or ethylenediamine salt; aralkyl such as N, N-dibenzylethylenediamine or venetamine salt Amine salt: Heterocyclic aromatic amine salt such as pyridine salt, picoline salt, quinoline salt, isoquinoline salt; tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt Quaternary ammonium salts such as benzyltributylammonium salt, methyltrioctylammonium salt and tetrabutylammonium salt; and basic amino acid salts such as arginine salt and lysine salt. Examples of the acid salt 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, ascorbate; sulfonates such as methanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate; Examples include acidic amino acids such as aspartate and glutamate.
Various solvates of the compound of the present invention are also within the scope of the present invention, and examples include monosolvates, disolvates, monohydrates, dihydrates and the like.

（式中、
Ｘはハロゲン；
環２および環４は、それぞれグリコペプチド抗生物質の２番目および４番目のアミノ酸残基の芳香環；および
Ｚ¹は、置換されていてもよいアルキル、置換されていてもよいアリール、置換されていてもよいアルケニル、置換されていてもよいアルキニルまたは置換されていてもよいヘテロアリールである。）General production methods Representative production methods of the compound of the present invention are described below, but it is not particularly limited to these production methods.
(Method 1)
Suzuki-Miyaura Cross-Coupling

(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 an optionally substituted alkyl, an optionally substituted aryl, a substituted And optionally substituted alkenyl, optionally substituted alkynyl or optionally substituted heteroaryl. )

That is, the compound of the present invention uses, as a starting material, 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. Can be produced by reacting with an organic boron compound represented by Z ¹ -B (OH) ₂ [Z ¹ is as defined above] in the presence of a palladium catalyst, preferably under basic conditions. The reaction may be performed according to the reaction conditions of Suzuki-Miyaura cross coupling. This reaction is more preferably used for the synthesis of a compound of the invention wherein 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 the reaction solvent, water, an organic solvent or a mixed solvent thereof can be used, but water is preferred. As the base, Na ₂ CO ₃ , Ba (OH) ₂ , K ₃ PO ₄ , Cs ₂ CO ₃ , K ₂ CO ₃ , NaOH and the like are used. As the palladium catalyst, palladium acetate, Pd (PPh ₃ ) ₄ , Pd (dba) ₂ , PdCl ₂ (PPh ₃ ) ₂ , PdCl ₂ (MeCN) ₂ , PPdCl (Bn) (PPh ₃ ) ₂ or the like is used. (Ph: phenyl, Me: methyl, Bn: benzyl, dba: PhCH = CHC (O) CH = CHPh). The reaction time is a few minutes to a few hours, preferably about 15 minutes to about 1 hour.

（式中、Ｒ²，Ｒ³，Ｒ⁴は、（置換）アルキル、（置換）アリール、（置換）ヘテロアリール、（置換）アルケニル等を示す。）Some compounds of the present invention can be synthesized more preferably by the following method.
(Method 2)
Heck-Mizorogi Reaction
Instead of the above Z ¹ -B (OH) ₂ , the corresponding compound of the present invention is synthesized by reacting in the same manner a reagent represented by Z ¹ -H (Z ¹ is substituted or alkenyl). . More specifically, Z ¹ is a structure shown below.

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

（式中、Ｒ⁵は、水素、（置換）アルキル、（置換）アリール、（置換）ヘテロアリール、（置換）アルケニル等を示す。）(Method 3)
Sonogashira Cross-Coupling
Instead of the above Z ¹ -B (OH) ₂ , the corresponding compound of the present invention is synthesized by reacting in the same manner a reagent represented by Z ¹ -H (Z ¹ is an optionally substituted alkynyl). The In more detail, Z < ¹ > -H is a compound shown below.

(Wherein R ⁵ represents hydrogen, (substituted) alkyl, (substituted) aryl, (substituted) heteroaryl, (substituted) alkenyl, etc.)

(Method 4) Stille Cross-Coupling
Instead of Z ¹ —B (OH) ₂ , Z ¹ —Sn— (Alk) ₃ (Z ¹ is optionally substituted aryl, optionally substituted alkenyl, or optionally substituted. A corresponding compound of the present invention is synthesized by reacting a reagent represented by (heteroaryl; Alk is alkyl) in the same manner.
In the reaction, a metal catalyst such as manganese, nickel, copper, or tin can be used instead of the Pd catalyst depending on conditions.

（式中、
ＸおよびＸ’はそれぞれ独立してハロゲン；
環２および環６は、それぞれグリコペプチド抗生物質の２番目および６番目のアミノ酸残基の芳香環；および
Ｚは、置換されていてもよいアルキル、置換されていてもよいアリール、置換されていてもよいアルケニル、置換されていてもよいアルキニルまたは置換されていてもよいヘテロアリールである。）(Method 5)
When the Cl atom bonded to the aromatic ring of the second and sixth amino acid residues of the glycopeptide antibiotic is substituted in the compound of the present invention, Suzuki-Miyaura Cross Coupling (Suzuki Miyaura Cross Coupling) -Coupling) can be prepared as follows:

(Where
X and X ′ are each independently halogen;
Ring 2 and Ring 6 are the aromatic rings of the 2nd and 6th amino acid residues of the glycopeptide antibiotic, respectively; and Z is optionally substituted alkyl, optionally substituted aryl, substituted Or an optionally substituted alkynyl, an optionally substituted alkynyl or an optionally substituted heteroaryl. )

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

When the compound of the present invention is a compound in which the Cl atoms bonded to the aromatic rings of the second and sixth amino acid residues of the glycopeptide antibiotic are respectively substituted with different groups (for example, Z ¹ and Z ² ) For example, in the above (Method 5), the starting material is an organic boron compound represented by Z ¹ —B (OH) ₂ or Z ² —B (OH) ₂ [Z ¹ and Z ² are independently the same as defined above] ] After making it react using any one of these, it can manufacture by making it react using the other organic boron compound further.

  Each of the above reactions is introduced in, for example, “Organic Synthesis Strategy Learned from Personal Name Reaction, Chemical Dojin Co., Ltd., 2006 Edition”.

（式中、ＸおよびＸ’はそれぞれ独立してハロゲンであり、Ｒ^X、Ｒ^B、Ｒ^CおよびＲは前記と同意義である）
で示される。The glycopeptide compound that can be used as a starting material in the production method of the present invention is, for example, the formula (II ′):

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

［式中、Ｘ、Ｘ’、Ｒ^A、Ｒ^B、Ｒ^CおよびＲ^Dは前記と同意義である］
で示される。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 (II′-1):

[Wherein, X, X ′, R ^A , R ^B , R ^C and R ^D are as defined above]
Indicated by

The starting material of the present invention is the amino moiety (R ^A ) of the amino sugar of vancomycin or a known derivative thereof, or the C-terminal part (R ^B ), the resorcinol part (R ^C ), or the methylamino part (R ^D ) and the like can be prepared by various chemical modifications. Alternatively, vancomycin or a known derivative thereof is used as a starting material without chemical modification, and this is used as described above for an organoboron compound represented by Z ¹ -B (OH) ₂ (optionally further Z ² -B (OH ) organic boron compounds represented by the ₂₎ and was allowed to react, an amino moiety of the amino sugars (R ^a), or C-terminal moiety (R ^B), resorcinol moiety (R ^C), or N-terminal portion methylamino portion ( R ^D ) may be chemically modified.

The chemical modification may be performed according to a method described in, for example, International Publication WO2006 / 055733 pamphlet constituting a part of the present specification. Specifically, it is as follows.
1) Modification of R ^A moiety Typically, vancomycin is used as a raw material, and the amino moiety of the amino sugar is converted to the R ^A moiety:
^{-X 1 -Ar 1 -X 2 -Y-} X 3 -Ar 2
The various aldehydes corresponding to the side chain represented by the above are reacted in the presence of a base, if desired, to form an intermediate Schiff base, which is subsequently reduced to N-alkylate to give the desired secondary amine May be formed.

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

  The intermediate Schiff base may then be reduced with a metal hydride complex or catalytically reduced, preferably without isolation. As the metal hydride complex, a metal borohydride such as sodium borohydride or sodium cyanoborohydride can be used. The catalytic reduction is carried out using hydrogen in the presence of a homogeneous or heterogeneous catalyst such as a Crabtree catalyst, Wilkinson catalyst, palladium charcoal, platinum charcoal or rhodium charcoal. The reduction reaction is performed at a temperature of about 25 ° C. to about 100 ° C. for about 1 to 24 hours. Preferably, an excess of sodium cyanoborohydride (eg 3-5 molar equivalents) is used in the solvent at about 60 ° C. to about 80 ° C.

2) R in the ^B moiety qualified representative of the vancomycin used as a raw material, by amidation by a conventional method a carboxylic acid moiety is a C-terminal, various amide derivatives is R ^B = -NR ⁵ R ⁵ ' Can be converted to

3) Modification of R ^C moiety Typically, vancomycin may be used as a raw material, and resorcinol moiety may be alkylated by a conventional method.

4) Modification of ^RD part Typically, vancomycin is used as a raw material, and the methylamine part at the N-terminal part may be N-alkylated by a conventional method.

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.

  In the case of oral administration, the compound of the present invention is an ordinary preparation, for example, any agent of solid preparations such as tablets, powders, granules, capsules; liquid preparations; oil suspensions; or liquid preparations such as syrups or elixirs. It can also be used as a shape. When administered parenterally, 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.

  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.

  In preparing pharmaceutical compositions of the compounds of the invention, the active ingredient is mixed with or diluted with a carrier, or placed in a carrier that is in the form of a capsule, sachet, paper, or other container. . 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.

  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% aqueous sodium citrate 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 flavoring agent, lubricant, solubilizer, suspending agent, binder, tablet disintegrant, or capsule. Tablets for oral administration include calcium carbonate, sodium carbonate, lactose with disintegrants such as corn starch, alginic acid, and / or binders such as gelatin, acacia, and lubricants such as magnesium stearate, stearic acid, talc A suitable excipient, such as calcium phosphate.

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

  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 can be made by spraying the active ingredient finely divided in aqueous starch, sodium carboxymethylcellulose solution, or a suitable oil.

  The dose of the compound of the present invention varies depending on the administration method, the patient's age, weight, condition, and type of disease, but usually, when administered orally, about 0.1 mg to 7000 mg per day for an adult, preferably about 0 0.5 mg to 2000 mg may be divided and administered if necessary. In the case of parenteral administration, about 0.1 mg to 1000 mg, preferably about 0.5 mg to 500 mg is administered per day for an adult.

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

  All MS data shown in the following preparations and examples are calculated by average molar weight (C = 12.0107, H = 1.0079, O = 15.9994, N = 14.0067, Cl = 35.4527, P = 30.9738, Na = 22.9898).

リービッヒ冷却器を備え付けた２００ｍＬのナス型フラスコに水１５０ｍＬを入れた。超音波を２分間、アルゴン気流下でのバブリングを２分間順次行い、アルゴン雰囲気下とした。バンコマイシン塩酸塩１．００ｇ（０．３３７ｍｍｏｌ）、ｐ−メトキシフェニルホウ酸３０６ｍｇ（２．０２ｍｍｏｌ）、ＷＳＰＬ １４２ｍｇ（０．１３５ｍｍｏｌ）、炭酸カリウム４６４ｍｇ（３．３６ｍｍｏｌ）、酢酸パラジウム３０．２ｍｇ（０．００６７１ｍｍｏｌ）を順次加え、６０℃で３０分間加熱攪拌した。室温に放冷した後、０℃に冷却し、１Ｎ ＨＣｌ水溶液（３．６ｍＬ）を滴下し、続いてポリ−４−ビニルピリジンを加えてｐＨを５に調整した。セライトを敷いたグラスフィルターでろ過し、１０％ＣＨＣＮ水溶液（４０ｍＬ）で洗浄し、ろ液にＥｔＯＨ（１００ｍＬ）を入れ濃縮し、粗生成物を得た。２回の中圧カラムクロマトグラフィー［ローバーカラム（Merck, Li Chroprep RP-18 size B) １回目５０％ａｑ．ＭｅＯＨ−０．１％ＴＦＡ、２回目１０％ａｑ．ＭｅＯＨ−０．１％ＴＦＡ→５０％ａｑ．ＭｅＯＨ−０．１％ＴＦＡ］により精製し、４０％ａｑ．ＭｅＯＨ−０．１％ＴＦＡで溶出するフラクションを集めて濃縮し、濃縮液にポリ−４−ビニルピリジンを加えてｐＨを５に調整した。濾過した後濾液を再度濃縮し、残渣を凍結乾燥してカップリング体のＴＦＡ塩（トリフルオロ酢酸塩）（１．７％、ＨＰＬＣ純度９６％）を得た。
カラム：Ｃｏｓｍｏｓｉｌ ５Ｃ１８−ＡＲ−ＩＩ（ナカライテスク）
移動相：アセトニトリル−水（０．１％トリフルオロ酢酸含有）
グラジエント：１５％アセトニトリル水溶液→１００％アセトニトリル水溶液（１０分間）
流速：１．０ｍｌ／分
検出器：ＵＶ−２８０ｎｍ
目的物の保持時間：５．１２秒Example 1
The following compounds were produced according to the above general production method (Method 1).

150 mL of water was placed in a 200 mL eggplant-shaped flask equipped with a Liebig condenser. Bubbling was performed for 2 minutes under an argon stream for 2 minutes, and an argon atmosphere was obtained. Vancomycin hydrochloride 1.00 g (0.337 mmol), p-methoxyphenylboric acid 306 mg (2.02 mmol), WSPL 142 mg (0.135 mmol), potassium carbonate 464 mg (3.36 mmol), palladium acetate 30.2 mg (0.35 mmol). 00671 mmol) was sequentially added, and the mixture was stirred with heating at 60 ° C. for 30 minutes. After allowing to cool to room temperature, the mixture was cooled to 0 ° C., 1N HCl aqueous solution (3.6 mL) was added dropwise, and then poly-4-vinylpyridine was added to adjust the pH to 5. The mixture was filtered through a glass filter with celite, washed with 10% CHCN aqueous solution (40 mL), and EtOH (100 mL) was added to the filtrate and concentrated to obtain a crude product. 2 medium pressure column chromatography [Rover column (Merck, Li Chroprep RP-18 size B) 1st 50% aq. MeOH-0.1% TFA, second 10% aq. MeOH-0.1% TFA → 50% aq. MeOH-0.1% TFA], 40% aq. Fractions eluting with MeOH-0.1% TFA were collected and concentrated, and poly-4-vinylpyridine was added to the concentrate to adjust the pH to 5. After filtration, the filtrate was concentrated again, and the residue was lyophilized to obtain a coupled TFA salt (trifluoroacetate salt) (1.7%, HPLC purity 96%).
Column: Cosmosil 5C18-AR-II (Nacalai Tesque)
Mobile phase: acetonitrile-water (containing 0.1% trifluoroacetic acid)
Gradient: 15% acetonitrile aqueous solution → 100% acetonitrile aqueous solution (10 minutes)
Flow rate: 1.0 ml / min Detector: UV-280 nm
Holding time of target: 5.12 seconds

ＷＯ２００６／０５７３０３に記載の方法に準じて次式

で示される化合物６を調製する。出発物質として化合物６を用い、ｐ−メトキシフェニルホウ酸の代わりにＺ¹−Ｂ（ＯＨ）₂［各実施例についてＺ¹は上に示すとおり］で示される有機ホウ素化合物を用いることを除いては、実施例１に記載の方法と同様にして目的化合物を製造する。Examples 2-10

According to the method described in WO2006 / 055733, the following formula

Compound 6 is prepared. Compound 6 was used as a starting material, except that an organoboron compound represented by Z ¹ -B (OH) ₂ [Z ¹ is as shown above for each example] was used instead of p-methoxyphenylboric acid. Produces the target compound in the same manner as described in Example 1.

ＷＯ２００６／０５７３０３に記載の方法に準じて次式

で示される化合物１０を調製する。出発物質として化合物１０を用い、ｐ−メトキシフェニルホウ酸の代わりにＺ¹−Ｂ（ＯＨ）₂［各実施例についてＺ¹は上に示すとおり］で示される有機ホウ素化合物を用いることを除いては、実施例１に記載の方法と同様にして目的化合物を製造する。Examples 11-19

According to the method described in WO2006 / 055733, the following formula

Compound 10 is prepared. Compound 10 was used as a starting material, except that an organoboron compound represented by Z ¹ -B (OH) ₂ [Z ¹ is as shown above for each Example] was used instead of p-methoxyphenylboric acid. Produces the target compound in the same manner as described in Example 1.

実施例２０
［Ｍ＋１］⁺＝１５３４
計算値（Ｃ７４Ｈ８４ＣｌＮ９Ｏ２５・２．１ＨＣｌ・１５．５Ｈ２Ｏ）
Ｃ：４７．０１％，Ｈ：６．２４％，Ｃｌ：５．８１％，Ｎ：６．６７％，Ｏ：３４．２７％，
実測値：Ｃ：４６．９９％，Ｈ：６．１８％，Ｃｌ：５．８２％，Ｎ：６．７３％As described in Example 1, except that an organoboron compound represented by Z ¹ -B (OH) ₂ [Z ¹ is as shown above for each example] is used instead of p-methoxyphenyl boric acid. The following compounds were prepared in the same manner as the method.

Example 20
[M + 1] ⁺ = 1534
Calculated value (C74H84ClN9O25 · 2.1HCl · 15.5H2O)
C: 47.01%, H: 6.24%, Cl: 5.81%, N: 6.67%, O: 34.27%,
Found: C: 46.99%, H: 6.18%, Cl: 5.82%, N: 6.73%

Example 21
[M + 1] ⁺ = 1548

Example 22
[M + 1] ⁺ = 1508
Calculated value (C72H79ClFN9O24 · 1.7HCl · 14.3H2O)
C: 47.29%, H: 6.03%, Cl: 5.24%, F: 1.04%, N: 6.89%, O: 33.51%,
Found C: 47.28%, H: 5.98%, Cl: 5.20%, F: 1.05%, N: 6.81%

Example 23
[M + 1] ⁺ = 1504
Calculated value (C73H82ClN9O24 · 2.2HCl · 17.7H2O)
C: 46.05%, H: 6.33%, Cl: 5.96%, N: 6.62%, O: 35.04%,
Found: C: 45.92%, H: 5.88%, Cl: 6.02%, N: 6.89%

Example 24
[M + 1] ⁺ = 1550
Calculated value (C74H84ClN9O26 · 2.3HCl · 14.5H2O)
C: 46.88%, H: 6.13%, Cl: 6.17%, N: 6.65%, O: 34.18%,
Found: C: 46.82%, H: 6.09%, Cl: 6.17%, N: 6.82%

Example 25
[M + 1] ⁺ = 1574
Calculated value (C73H79ClF3N9O25 · 2.5HCl · 14.5H2O)
C: 45.49%, H: 5.78%, Cl: 6.44%, F: 2.96%, N: 6.54%, O: 32.79%,
Found: C: 45.51%, H: 5.83%, Cl: 6.48%, F: 3.13%, N: 6.57%

Example 26
[M + 1] ⁺ = 1536
Calculated value (C73H82ClN9O24S · 2.6HCl · 14.8H2O)
C: 46.18%, H: 6.06%, Cl: 6.72%, N: 6.64%, O: 32.70%, S: 1.69%,
Found: C: 46.11%, H: 5.95%, Cl: 6.74%, N: 6.82%, S: 1.89%

Example 27
[M + 1] ⁺ = 1520
Calculated value (C73H82ClN9O25 · 1.7HCl · 15.4H2O)
C: 47.13%, H: 6.20%, Cl: 5.15%, N: 6.78%, O: 34.74%
Found: C: 47.08%, H: 6.22%, Cl: 5.21%, N: 6.87%

Example 28
[M + 1] ⁺ = 1605
Calculated value (C77H89ClN10O26 · 2.2HCl · 16.1H2O)
C: 46.80%, H: 6.29%, Cl: 5.74%, N: 7.09%, O: 34.08%
Found: C: 46.74%, H: 6.16%, Cl: 5.82%, N: 7.27%

Example 29
[M + 1] ⁺ = 1516
Calculated value (C74H82ClN9O24 · 2.5HCl · 16.0H2O)
C: 46.87%, H: 6.19%, Cl: 6.54%, N: 6.65%, O: 33.75%
Found: C: 46.81%, H: 6.18%, Cl: 6.59%, N: 6.91%

Example 30
[M + 1] ⁺ = 1490

Example 31
[M + 1] ⁺ = 1520
Calculated value (C73H82ClN9O25 · 3.3HCl · 16.3H2O)
C: 45.31%, H: 6.14%, Cl: 7.88%, N: 6.52%, O: 34.15%,
Found C: 45.12%, H: 5.77%, Cl: 7.88%, N: 7.24%,

バンコマイシン塩酸塩２．００ｇ（１．３５ｍｍｏｌ）をアセトニトリル１０ｍｌ、水１０ｍｌに溶解し、室温でトランス−２−（４−フルオロフェニル）ビニルボロン酸６７０ｍｇ（４．０４ｍｍｏｌ）、２’−（ジシクロヘキシルホスフィノ）−２，６−ジメトキシビフェニル−３−スルホン酸ナトリウム２７６ｍｇ（０．５４ｍｍｏｌ）、酢酸パラジウム６０ｍｇ（０．２７ｍｍｏｌ）、炭酸カリウム９３０ｍｇ（６．７３ｍｍｏｌ）を加えて、マイクロウェーブを８０℃で２０分間照射した。その後、反応溶液に２規定塩酸を加えてｐＨを４に調整し、酢酸エチル１００ｍｌを加えて水層に抽出した。水層にＨＰ−２０ｓｓ／５ｍＭ塩酸を５ｍｌ加えアセトニトリルを濃縮し、濃縮残渣をＯＤＳカラムクロマトグラフィーで精製した後、凍結乾燥を行うことにより、表題化合物１０７ｍｇを白色粉末として得た。収率：４．７％。Example 32

2.00 g (1.35 mmol) of vancomycin hydrochloride was dissolved in 10 ml of acetonitrile and 10 ml of water, and 670 mg (4.04 mmol) of trans-2- (4-fluorophenyl) vinylboronic acid at room temperature, 2 ′-(dicyclohexylphosphino) 276 mg (0.54 mmol) of sodium 2,6-dimethoxybiphenyl-3-sulfonate, 60 mg (0.27 mmol) of palladium acetate and 930 mg (6.73 mmol) of potassium carbonate were added, and the microwave was irradiated at 80 ° C. for 20 minutes. did. 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 / 5 mM 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%.

Instead of trans-2- (4-fluorophenyl) vinylboronic acid, except that an organoboron compound represented by Z ¹ -B (OH) ₂ [Z ¹ is as shown above for each example] is used, The following compounds were produced in the same manner as described in Example 32.

Example 33
[M + 1] ⁺ = 1516
Calculated value (C74H82ClN9O24 · 2.1HCl · 16.2H2O)
C: 47.14%, H: 6.23%, Cl: 5.83%, N: 6.69%, O: 34.11%
Found: C: 47.13%, H: 6.33%, Cl: 5.85%, N: 6.90%

Example 34
[M + 1] ⁺ = 1546
Calculated value (C75H84ClN9O25 · 2.4HCl · 17.0H2O)
C: 46.42%, H: 6.25%, Cl: 6.21%, N: 6.50%, O: 34.62%
Found: C: 46.38%, H: 6.22%, Cl: 6.25%, N: 6.65%

Example 35
[M + 1] ⁺ = 1534
Calculated value (C74H81ClFN9O24 · 2.2HCl · 15.0H2O)
C: 47.14%, H: 6.05%, Cl: 6.02%, F: 1.01%, N: 6.69%, O: 33.10%,
Found: C: 47.12%, H: 5.97%, Cl: 5.98%, F: 0.99%, N: 6.69%

Example 36
[M + 1] ⁺ = 1584
Calculated value (C75H81ClF3N9O24 · 2.4HCl · 17.1H2O)
C: 45.48%, H: 5.99%, Cl: 6.09%, F: 2.88%, N: 6.37%, O: 33.20%,
Found: C: 45.44%, H: 5.95%, Cl: 6.04%, F: 2.68%, N: 6.62%

Example 37
[M + 1] ⁺ = 1530
Calculated value (C75H84ClN9O24 · 1.5HCl · 13.3H2O)
C: 49.35%, H: 6.19%, Cl: 4.86%, N: 6.91%, O: 32.70%,
Found: C: 49.36%, H: 6.12%, Cl: 4.92%, N: 7.11%

  Furthermore, the following compounds were produced according to the above general production methods and the methods described in the examples.

［Ｍ＋１］⁺＝１８３２
計算値（Ｃ８６Ｈ９３ＣｌＦ３Ｎ１３Ｏ２７・１．７ＨＣｌ・１３．７Ｈ２Ｏ）
Ｃ：４８．２２％，Ｈ：５．７５％，Ｃｌ：４．４７％，Ｆ：２．６６％，Ｎ：８．５０％，Ｏ：３０．４０％，
実測値：Ｃ：４８．２３％，Ｈ：５．９３％，Ｃｌ：４．３８％，Ｆ：２．４０％，Ｎ：８．６７％Example 38

[M + 1] ⁺ = 1832
Calculated value (C86H93ClF3N13O27 · 1.7HCl · 13.7H2O)
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%

［Ｍ＋１］⁺＝１８８１
計算値（Ｃ９２Ｈ１００ＣｌＦ３Ｎ１２Ｏ２６・３．２ＨＣｌ・１４Ｈ２Ｏ）
Ｃ：４９．０８％，Ｈ：５．８７％，Ｃｌ：６．６１％，Ｆ：２．５３％，Ｎ：７．４７％，Ｏ：２８．４３％，
実測値Ｃ：４９．１４％，Ｈ：５．８６％，Ｃｌ：６．７１％，Ｆ：２．３５％，Ｎ：７．４１％Example 39

[M + 1] ⁺ = 1881
Calculated value (C92H100ClF3N12O26 · 3.2HCl · 14H2O)
C: 49.08%, H: 5.87%, Cl: 6.61%, F: 2.53%, N: 7.47%, O: 28.43%
Found C: 49.14%, H: 5.86%, Cl: 6.71%, F: 2.35%, N: 7.41%

超音波を２分間、アルゴン気流下でのバブリングを２分間順次行ったアセトニトリル溶液（２０ｍＬ）にバンコマイシン塩酸塩（１．００ｇ，０．６７４ｍｍｏｌ）、ＷＳＰＬ２（１４２ｍｇ，０．２７０ｍｍｏｌ）、炭酸セシウム（３．３ｇ，１０．１ｍｍｏｌ）、ビス（アセトニトリル）ジクロロパラジウム（３０．２ｍｇ，０．１３５ｍｍｏｌ）を順次加え、室温で２０分間攪拌した。１−オクチン（０．７３ｍＬ，６．７４ｍｍｏｌ）を滴下、超音波を２分間、アルゴン気流下でのバブリングを２分間順次行った蒸留水（２０ｍＬ）を加え、アルゴン雰囲気下８０℃で１．５時間加熱攪拌した。室温に放冷した後、０℃に冷却し、１規定塩酸水溶液を滴下してｐＨを５に調整した。不溶物を濾去した後、濾液を濃縮して得られた残渣を逆相カラムクロマトグラフィーにより精製し、凍結乾燥して表題化合物を得た。収量３０ｍｇ（３．０％）。Example 40
1-Coupling body with octyne

An acetonitrile solution (20 mL) that was sequentially subjected to bubbling under an argon stream for 2 minutes with ultrasonic waves was added to vancomycin hydrochloride (1.00 g, 0.674 mmol), WSPL2 (142 mg, 0.270 mmol), cesium carbonate (3 .3 g, 10.1 mmol) and bis (acetonitrile) dichloropalladium (30.2 mg, 0.135 mmol) were sequentially added, and the mixture was stirred at room temperature for 20 minutes. 1-octyne (0.73 mL, 6.74 mmol) was added dropwise, ultrasonic water was added for 2 minutes, and distilled water (20 mL) was sequentially bubbled under an argon stream for 2 minutes. Stir with heating for hours. The mixture was allowed to cool to room temperature, cooled to 0 ° C., and 1N aqueous hydrochloric acid was added dropwise to adjust the pH to 5. The insoluble material was removed by filtration, and the filtrate was concentrated. The resulting residue was purified by reverse phase column chromatography and lyophilized to give the title compound. Yield 30 mg (3.0%).

超音波を２分間、アルゴン気流下でのバブリングを２分間順次行ったアセトニトリル溶液（２０ｍＬ）にバンコマイシン塩酸塩（１．００ｇ，０．６７４ｍｍｏｌ）、ＷＳＰＬ２（１４２ｍｇ，０．２７０ｍｍｏｌ）、炭酸セシウム（３．３ｇ，１０．１ｍｍｏｌ）、ビス（アセトニトリル）ジクロロパラジウム（３０．２ｍｇ，０．１３５ｍｍｏｌ）を順次加え、室温で２０分間攪拌した。フェニルアセチレン（０．７３ｍＬ，６．７４ｍｍｏｌ）を滴下、超音波を２分間、アルゴン気流下でのバブリングを２分間順次行った蒸留水（２０ｍＬ）を加え、アルゴン雰囲気下８０℃で３．５時間加熱攪拌した。室温に放冷した後、０℃に冷却し、１規定塩酸水溶液を滴下してｐＨを５に調整した。不溶物を濾去した後、濾液を濃縮して得られた残渣を逆相カラムクロマトグラフィーにより精製し、凍結乾燥して表題化合物を桃色粉末として得た。収量４５ｍｇ（４．５％）。
［Ｍ＋１］⁺＝１５１４
計算値（Ｃ７４Ｈ８０ＣｌＮ９Ｏ２４・２．７ＨＣｌ・１６．３Ｈ２Ｏ）
Ｃ：４６．６１％，Ｈ：６．０９％，Ｃｌ：６．８８％，Ｎ：６．６１％，Ｏ：３３．８１％
実測値Ｃ：４６．５２％，Ｈ：５．６５％，Ｃｌ：６．５５％，Ｎ：７．０８％Example 41
Coupling body with phenylacetylene

An acetonitrile solution (20 mL) that was sequentially subjected to bubbling under an argon stream for 2 minutes with ultrasonic waves was added to vancomycin hydrochloride (1.00 g, 0.674 mmol), WSPL2 (142 mg, 0.270 mmol), cesium carbonate (3 .3 g, 10.1 mmol) and bis (acetonitrile) dichloropalladium (30.2 mg, 0.135 mmol) were sequentially added, and the mixture was stirred at room temperature for 20 minutes. Phenylacetylene (0.73 mL, 6.74 mmol) was added dropwise, ultrasonic waves were added for 2 minutes, and distilled water (20 mL) was sequentially bubbled under an argon stream for 2 minutes, and then added at 80 ° C. for 3.5 hours under an argon atmosphere. Stir with heating. The mixture was allowed to cool to room temperature, cooled to 0 ° C., and 1N aqueous hydrochloric acid was added dropwise to adjust the pH to 5. The insoluble material was removed by filtration, and the filtrate was concentrated. The resulting residue was purified by reverse phase column chromatography and lyophilized to give the title compound as a pink powder. Yield 45 mg (4.5%).
[M + 1] ⁺ = 1514
Calculated value (C74H80ClN9O24 · 2.7HCl · 16.3H2O)
C: 46.61%, H: 6.09%, Cl: 6.88%, N: 6.61%, O: 33.81%
Found C: 46.52%, H: 5.65%, Cl: 6.55%, N: 7.08%

バンコマイシン塩酸塩２．００ｇ（１．３５ｍｍｏｌ）をアセトニトリル１０ｍｌ、水１０ｍｌに溶解し、室温でトランス−プロペニルボロン酸３４７ｍｇ（４．０４ｍｍｏｌ）、２’−（ジシクロヘキシルホスフィノ）−２，６−ジメトキシビフェニル−３−スルホン酸ナトリウム２７６ｍｇ（０．５４ｍｍｏｌ）、酢酸パラジウム６０ｍｇ（０．２７ｍｍｏｌ）、炭酸カリウム９３０ｍｇ（６．７３ｍｍｏｌ）を加えて、マイクロウェーブを１００℃で５分間照射した。その後、反応溶液に２規定塩酸を加えてｐＨを４に調整し、酢酸エチル１００ｍｌを加えて水層に抽出した。水層にＨＰ−２０ｓｓ／５ｍＭ塩酸を５ｍｌ加えアセトニトリルを濃縮し、濃縮残渣をＯＤＳカラムクロマトグラフィーで精製した後、凍結乾燥を行うことにより、表題化合物２３６ｍｇを白色粉末として得た。収率：１０．３％。
［Ｍ＋１］＋＝１４６０
計算値（Ｃ７２Ｈ８５Ｎ９Ｏ２４・１．６ＨＣｌ・１６．０Ｈ２Ｏ）
Ｃ：４７．８５％，Ｈ：６．６２％，Ｃｌ：３．１４％，Ｎ：６．９８％，Ｏ：３５．４２％
実測値：Ｃ：４７．８２％，Ｈ：６．７５％，Ｃｌ：３．１７％，Ｎ：７．１３％Example 42

2.00 g (1.35 mmol) of vancomycin hydrochloride is dissolved in 10 ml of acetonitrile and 10 ml of water, and 347 mg (4.04 mmol) of trans-propenylboronic acid, 2 ′-(dicyclohexylphosphino) -2,6-dimethoxybiphenyl is dissolved at room temperature. 276 mg (0.54 mmol) of sodium -3-sulfonate, 60 mg (0.27 mmol) of palladium acetate, and 930 mg (6.73 mmol) of potassium carbonate 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 / 5 mM 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 + 1] + = 1460
Calculated value (C72H85N9O24 · 1.6HCl · 16.0H2O)
C: 47.85%, H: 6.62%, Cl: 3.14%, N: 6.98%, O: 35.42%
Found: C: 47.82%, H: 6.75%, Cl: 3.17%, N: 7.13%

  The following compounds were prepared in the same manner as described in Example 42.

［Ｍ＋１］⁺＝１８１１
計算値（Ｃ８９Ｈ１０１Ｆ３Ｎ１２Ｏ２６・２．６ＨＣｌ・１４．７Ｈ２Ｏ）
Ｃ：４９．２３％，Ｈ：６．１７％，Ｃｌ：４．２５％，Ｆ：２．６２％，Ｎ：７．７４％，Ｏ：２９．９９％，
実測値：Ｃ：４９．１７％，Ｈ：６．１５％，Ｃｌ：４．３３％，Ｆ：２．３７％，Ｎ：７．９０％Example 43

[M + 1] ⁺ = 1811
Calculated value (C89H101F3N12O26 · 2.6HCl · 14.7H2O)
C: 49.23%, H: 6.17%, Cl: 4.25%, F: 2.62%, N: 7.74%, O: 29.99%
Found: C: 49.17%, H: 6.15%, Cl: 4.33%, F: 2.37%, N: 7.90%

［Ｍ＋１］⁺＝１８３７
計算値（Ｃ９２Ｈ１０７Ｆ３Ｎ１２Ｏ２５・３．１ＨＣｌ・１４．６Ｈ２Ｏ）
Ｃ：４９．９１％，Ｈ：６．３４％，Ｃｌ：４．９６％，Ｆ：２．５７％，Ｎ：７．５９％，Ｏ：２８．６２％，
実測値：Ｃ：４９．９３％，Ｈ：６．１７％，Ｃｌ：４．８８％，Ｆ：２．３５％，Ｎ：７．６７％Example 44

[M + 1] ⁺ = 1837
Calculated value (C92H107F3N12O25 · 3.1HCl · 14.6H2O)
C: 49.91%, H: 6.34%, Cl: 4.96%, F: 2.57%, N: 7.59%, O: 28.62%,
Found: C: 49.93%, H: 6.17%, Cl: 4.88%, F: 2.35%, N: 7.67%

［Ｍ＋１］⁺＝１７９６
計算値（Ｃ８７Ｈ９９Ｃｌ２Ｎ１３Ｏ２５・２．４ＨＣｌ・１４．３Ｈ２Ｏ）
Ｃ：４８．７６％，Ｈ：６．１１％，Ｃｌ：７．２８％，Ｎ：８．５０％，Ｏ：２９．３４％，
実測値：Ｃ：４８．７４％，Ｈ：６．００％，Ｃｌ：７．３０％，Ｎ：８．６４％Example 45

[M + 1] ⁺ = 1796
Calculated value (C87H99Cl2N13O25 · 2.4HCl · 14.3H2O)
C: 48.76%, H: 6.11%, Cl: 7.28%, N: 8.50%, O: 29.34%,
Found: C: 48.74%, H: 6.00%, Cl: 7.30%, N: 8.64%

［Ｍ＋１］⁺＝１８２２
計算値（Ｃ９０Ｈ１０５Ｃｌ２Ｎ１３Ｏ２４・３．４ＨＣｌ・１４．９Ｈ２Ｏ）
Ｃ：４８．７８％，Ｈ：６．２９％，Ｃｌ：８．６４％，Ｎ：８．２２％，Ｏ：２８．０８％，
実測値：Ｃ：４８．７７％，Ｈ：６．２５％，Ｃｌ：８．６５％，Ｎ：８．３５％Example 46

[M + 1] ⁺ = 1822
Calculated value (C90H105Cl2N13O24 · 3.4HCl · 14.9H2O)
C: 48.78%, H: 6.29%, Cl: 8.64%, N: 8.22%, O: 28.08%,
Found: C: 48.77%, H: 6.25%, Cl: 8.65%, N: 8.35%

［Ｍ＋１］⁺＝１８３８
計算値（Ｃ８９Ｈ９８Ｆ３Ｎ１３Ｏ２７・２．１ＨＣｌ・１３．９Ｈ２Ｏ）
Ｃ：４９．３６％，Ｈ：５．９５％，Ｃｌ：３．４４％，Ｆ：２．６３％，Ｎ：８．４１％，Ｏ：３０．２１％，
実測値：Ｃ：４９．３３％，Ｈ：５．８９％，Ｃｌ：３．４０％，Ｆ：２．４２％，Ｎ：８．５４％Example 47

[M + 1] ⁺ = 1838
Calculated value (C89H98F3N13O27 · 2.1HCl · 13.9H2O)
C: 49.36%, H: 5.95%, Cl: 3.44%, F: 2.63%, N: 8.41%, O: 30.21%,
Found: C: 49.33%, H: 5.89%, Cl: 3.40%, F: 2.42%, N: 8.54%

［Ｍ＋１］⁺＝１８２２
計算値（Ｃ９１Ｈ１０２Ｆ３Ｎ１１Ｏ２６・２．１ＨＣｌ・１３．８Ｈ２Ｏ）
Ｃ：５０．８８％，Ｈ：６．１８％，Ｃｌ：３．４７％，Ｆ：２．６５％，Ｎ：７．１７％，Ｏ：２９．６４％，
実測値：Ｃ：５０．８６％，Ｈ：６．１０％，Ｃｌ：３．４９％，Ｆ：２．４２％，Ｎ：７．３８％Example 48

[M + 1] ⁺ = 1822
Calculated value (C91H102F3N11O26 · 2.1HCl · 13.8H2O)
C: 50.88%, H: 6.18%, Cl: 3.47%, F: 2.65%, N: 7.17%, O: 29.64%,
Found: C: 50.86%, H: 6.10%, Cl: 3.49%, F: 2.42%, N: 7.38%

［Ｍ＋１］⁺＝１８６６
計算値（Ｃ９２Ｈ１０６Ｆ３Ｎ１３Ｏ２６・３．０ＨＣｌ・１４．３Ｈ２Ｏ）
Ｃ：４９．４６％，Ｈ：６．２１％，Ｃｌ：４．７６％，Ｆ：２．５５％，Ｎ：８．１５％，Ｏ：２８．８６％，
実測値：Ｃ：４９．４０％，Ｈ：６．２０％，Ｃｌ：４．８０％，Ｆ：２．３５％，Ｎ：８．３６％Example 49

[M + 1] ⁺ = 1866
Calculated value (C92H106F3N13O26 · 3.0HCl · 14.3H2O)
C: 49.46%, H: 6.21%, Cl: 4.76%, F: 2.55%, N: 8.15%, O: 28.86%,
Found: C: 49.40%, H: 6.20%, Cl: 4.80%, F: 2.35%, N: 8.36%

［Ｍ＋１］⁺＝１８８７
計算値（Ｃ９５Ｈ１０５Ｆ３Ｎ１２Ｏ２６・３．４ＨＣｌ・１４Ｈ２Ｏ）
Ｃ：５０．４０％，Ｈ：６．０７％，Ｃｌ：５．３２％，Ｆ：２．５２％，Ｎ：７．４２％，Ｏ：２８．２７％
実測値Ｃ：５０．５０％，Ｈ：５．９２％，Ｃｌ：５．３１％，Ｆ：２．３２％，Ｎ：７．６０％Example 50

[M + 1] ⁺ = 1888
Calculated value (C95H105F3N12O26 · 3.4HCl · 14H2O)
C: 50.40%, H: 6.07%, Cl: 5.32%, F: 2.52%, N: 7.42%, O: 28.27%
Found C: 50.50%, H: 5.92%, Cl: 5.31%, F: 2.32%, N: 7.60%

［Ｍ＋１］⁺＝１８７２
計算値（Ｃ９３Ｈ１０３Ｃｌ２Ｎ１３Ｏ２５・３．４ＨＣｌ・１５．８Ｈ２Ｏ）
Ｃ：４８．９４％，Ｈ：６．０９％，Ｃｌ：８．３９％，Ｎ：７．９８％，Ｏ：２８．６０％
実測値Ｃ：４８．９４％，Ｈ：５．９２％，Ｃｌ：８．３７％，Ｎ：８．０８％Example 51

[M + 1] ⁺ = 1872
Calculated value (C93H103Cl2N13O25 · 3.4HCl · 15.8H2O)
C: 48.94%, H: 6.09%, Cl: 8.39%, N: 7.98%, O: 28.60%
Found C: 48.94%, H: 5.92%, Cl: 8.37%, N: 8.08%

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

Test example 1
In vitro measurement of antibacterial activity (test method)
The minimum inhibitory concentration (MIC) of the compounds 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 μg / mL against E. faecalis SR1004 (MIC of vancomycin = 2 μg / mL), and in particular, the compounds of Examples 33 and 34 are against vancomycin-resistant bacteria. And high antibacterial activity (MIC against S. aureus VRS-2 (van A) = 16 μg / mL; MIC of vancomycin = 64 μg / mL).

  Furthermore, the compounds of the present invention modified at the C-terminus and resorcinol moiety show a broad antibacterial spectrum against the strains tested, for example, the compounds of Examples 38, 39, 43-50 are against vancomycin-resistant bacteria. It showed significant antibacterial activity (eg MIC for E. faecalis SR7914 (van A) = 2-4 μg; MIC of vancomycin> 64 μg / mL). In particular, the compounds of Examples 38, 39 and 50 also showed high activity against highly resistant MRSA (MIC against S. aureus SR3637 (H-MRSA) = 0.5 μg / mL; MIC of vancomycin = 2 μg / mL) mL).

Formulation Examples Formulation Examples 1 to 8 shown below are merely examples, and are not intended to limit the scope of the invention. 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.

Formulation Example 1
Hard gelatin capsules are manufactured using the following ingredients:
dose
(Mg / capsule)
Active ingredient 250
Starch (dried) 200
Magnesium stearate 10
Total 460mg

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

Formulation Example 3
An aerosol solution containing the following ingredients is prepared:
Weight active ingredient 0.25
Ethanol 25.75
Propellant 22 (chlorodifluoromethane) 74.00
Total 100.00
The active ingredient and ethanol are mixed and this mixture is added to a portion of the propellant 22, cooled to -30 ° C and transferred to a filling device. The required amount is then fed into a stainless steel container and diluted with the remaining propellant. Attach the bubble unit to the container.

Formulation Example 4
A tablet containing 60 mg of active ingredient is prepared as follows:
Active ingredient 60mg
45mg starch
Microcrystalline cellulose 35mg
Polyvinylpyrrolidone (10% solution in water) 4mg
Sodium carboxymethyl starch 4.5mg
Magnesium stearate 0.5mg
Talc 1mg
150mg total
The active ingredients, starch, and cellulose are no. 45 mesh U.F. S. And mix well. An aqueous solution containing polyvinylpyrrolidone was mixed with the obtained powder, and the mixture was 14 mesh U.S. S. Pass through a sieve. The granules thus obtained were dried at 50 ° C. 18 mesh U.F. S. Pass through a sieve. No. 60 mesh U.S. S. Sodium carboxymethyl starch, magnesium stearate, and talc passed through a sieve are added to the granules, mixed and then compressed on a tablet press to obtain tablets each weighing 150 mg.

Formulation Example 5
Capsules containing 80 mg of active ingredient are prepared as follows:
Active ingredient 80mg
Starch 59mg
Microcrystalline cellulose 59mg
Magnesium stearate 2mg
Total 200mg
Mix the active ingredient, starch, cellulose and magnesium stearate; 45 mesh U.F. S. Through the sieve and filled into hard gelatin capsules 200 mg each.

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
The active ingredient is No. 60 mesh U.S. S. And suspended in a saturated fatty acid glyceride that has been heated and melted to the minimum necessary. The mixture is then cooled in an apparent 2 g mold.

Formulation Example 7
A suspension containing 50 mg of active ingredient is prepared as follows:
Active ingredient 50mg
Sodium carboxymethylcellulose 50mg
Syrup 1.25ml
Benzoic acid solution 0.10ml
Fragrance q. v.
Dye q. v.
5ml in total with purified water
The active ingredient is No. 45 mesh U.F. S. And is mixed with sodium carboxymethylcellulose and syrup to form a smooth paste. Add the benzoic acid solution and perfume diluted with a portion of the water and stir. Then add a sufficient amount of water to the required volume.

Formulation Example 8
The intravenous formulation is manufactured as follows:
Active ingredient 100mg
Saturated fatty acid glyceride 1000ml
Solutions of the above components are usually administered intravenously to the patient at a rate of 1 ml per minute.

  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 compound of the present invention is also useful as a synthetic intermediate for glycopeptide antibiotics.

Claims (21)

A dalbaheptide having an aromatic ring of the second and sixth amino acid residues of the vancomycin skeleton as a partial structure, wherein the aromatic ring is at least one of the second or sixth amino acid residue. bonded to that Cl atoms, optionally substitution aryl, alkenyl which may be substituted, have been the good alkynyl or substituted also be substituted are substituted at heteroaryl Darubaheputaido, pharmaceutically Top acceptable salts, or solvates thereof. Cl atoms bonded to the aromatic ring of the second amino acid residue of the vancomycin skeleton, aryl which may be substitution, alkenyl which may be substituted, have been also an alkynyl or substituted substituted 2. The dalbaheptide , pharmaceutically acceptable salt, or solvate thereof according to claim 1, which is substituted with a suitable heteroaryl . Cl atoms bonded to the aromatic ring of the second amino acid residue of the vancomycin skeleton, aryl which may be substitution, alkenyl which may be substituted, have been also an alkynyl or substituted substituted It is substituted with even heteroaryl and Cl atoms attached to the aromatic ring of 6 amino acid residues of vancomycin skeleton, hydrogen, halogen other than Cl atoms, which may be substitution aryl, substituted The dalbaheptide , its pharmaceutically acceptable salt, or a solvate thereof according to claim 2, which is substituted with an optionally substituted alkenyl, an optionally substituted alkynyl or an optionally substituted heteroaryl. Formula (I):

(Where
Ring 2 and the ring 4 are each aromatic ring of the second and fourth amino acid residue of the vancomycin skeleton; and Z ¹ is hydrogen, halogen, aryl which may be substitution, alkenyl which may be substituted, Optionally substituted alkynyl or optionally substituted heteroaryl)
The dalbaheptide according to claim 1, wherein the partial structure represented by the formula (1) is contained in the basic skeleton.

[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 (Z ¹ , Z ² ) are (hydrogen, hydrogen), (hydrogen, halogen) ), (Halogen, hydrogen) or (halogen, halogen)]
Or a pharmaceutically acceptable salt thereof, or a solvate thereof. Formula (I-1):

(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;
Z ¹ is hydrogen, halogen, aryl which may be substitution, substituted alkenyl which may have, alkynyl which may be substituted or optionally substituted heteroaryl;
Z ² is hydrogen, halogen, aryl which may be substitution, substituted alkenyl which may have, alkynyl which may be substituted or optionally substituted heteroaryl;
However, the case where (Z ¹ , Z ² ) is (hydrogen, hydrogen), (hydrogen, halogen), (halogen, hydrogen) and (halogen, halogen) is excluded. )
The dalbaheptide , a pharmaceutically acceptable salt thereof, or a solvate thereof according to claim 1, comprising a partial structure represented by the formula : Formula (I-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;
Z ¹ is hydrogen, halogen, aryl which may be substitution, substituted alkenyl which may have, alkynyl which may be substituted or optionally substituted heteroaryl;
Z ² is hydrogen, halogen, aryl which may be substitution, substituted alkenyl which may have, alkynyl which may be substituted or optionally substituted heteroaryl;
However, the case where (Z ¹ , Z ² ) is (hydrogen, hydrogen), (hydrogen, halogen), (halogen, hydrogen) and (halogen, halogen) is excluded. )
The dalbaheptide , a pharmaceutically acceptable salt thereof, or a solvate thereof according to claim 1, comprising a partial structure represented by the formula : Formula (I-3):

(Where
Ring 2 and the ring 4 are each aromatic ring of the second and fourth amino acid residue of the vancomycin skeleton; and Z ¹ is hydrogen, halogen, aryl which may be substitution, alkenyl which may be substituted, Optionally substituted alkynyl or optionally substituted heteroaryl)
The dalbaheptide , a pharmaceutically acceptable salt thereof, or a solvate thereof according to claim 1, comprising a partial structure represented by the formula : 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 the vancomycin skeleton , respectively;
Z ¹ is hydrogen, halogen, aryl which may be substitution, substituted alkenyl which may have, alkynyl which may be substituted or optionally substituted heteroaryl;
Z ² is hydrogen, halogen, aryl which may be substitution, alkenyl which may be substituted, alkynyl which may be substituted or optionally substituted heteroaryl, however, (Z ^1, Z ²⁾ Except where is (hydrogen, hydrogen), (hydrogen, halogen), (halogen, hydrogen) and (halogen, halogen). )
The dalbaheptide , a pharmaceutically acceptable salt thereof, or a solvate thereof according to claim 1, comprising a partial structure represented by the formula : Formula (I-5):

(Where
Ring 2, Ring 4, Ring 6, Ring 5 and Ring 7 are aromatic rings of the second, fourth, sixth, fifth and seventh amino acid residues of the vancomycin skeleton , respectively;
Z ¹ is hydrogen, halogen, aryl which may be substitution, substituted alkenyl which may have, alkynyl which may be substituted or optionally substituted heteroaryl;
Z ² is hydrogen, halogen, aryl which may be substitution, substituted alkenyl which may have, alkynyl which may be substituted or optionally substituted heteroaryl;
However, the case where (Z ¹ , Z ² ) is (hydrogen, hydrogen), (hydrogen, halogen), (halogen, hydrogen) and (halogen, halogen) is excluded. )
The dalbaheptide , a pharmaceutically acceptable salt thereof, or a solvate thereof according to claim 1, comprising a partial structure represented by the formula : Formula (II):

(Where
Z ¹ is hydrogen, halogen, aryl which may be substitution, substituted alkenyl which may have, alkynyl which may be substituted or optionally substituted heteroaryl;
Z ² is hydrogen, halogen, aryl which may be substitution, alkenyl which may be substituted, substituted optionally be also an alkynyl or substituted heteroaryl provided that also is (Z ^1, Z ²⁾ Except for (hydrogen, hydrogen), (hydrogen, halogen), (halogen, hydrogen) and (halogen, halogen);
R ^X is a sugar residue;
R ^B is OH, an ester residue or an amide residue;
R ^C is hydrogen or an optionally substituted alkyl (the alkyl moiety may be mediated by a heteroatom group); and R is an optionally substituted alkyl)
The compound of Claim 1 shown by these, its pharmaceutically acceptable salt, or those solvates. Z ¹ is one or more substituents selected from the group consisting of 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 4 to 10, a pharmaceutically acceptable salt thereof, or a solvate thereof, which is phenyl optionally substituted with or lower alkenyl optionally substituted. Z ¹ is one or more substituents selected from the group consisting of 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 phenyl optionally substituted with or lower alkenyl optionally substituted, and Z ² is halogen, Acceptable salts or solvates thereof. 1 or 2 selected from the group consisting of Z ¹ is 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 phenyl optionally substituted with the above substituents, or optionally substituted lower alkenyl, and pharmaceutically acceptable thereof. Salts, or solvates thereof. Z ¹ and Z ² are each independently selected from the group consisting of 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 phenyl optionally substituted with one or more substituents, or optionally substituted lower alkenyl, and its pharmaceutical Acceptable salts or solvates thereof. The compound according to any one of claims 5, 6, 8, 9, and 10, a pharmaceutically acceptable salt thereof, or Z ¹ and Z ² each independently represents an optionally substituted lower alkenyl. Their solvates. The optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl and optionally substituted heteroaryl substituents are C1-C6 alkyl, C2-C6 alkenyl, C2-C6. 16. A compound according to any one of claims 1 to 15, a pharmaceutically acceptable salt, or a solvate thereof which is alkynyl, alkoxy, alkylthio or optionally substituted aryl. The compound according to any one of claims 1 to 16 , which is a vancomycin derivative, a pharmaceutically acceptable salt thereof, or a solvate thereof. A compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt or containing solvate thereof, pharmaceutical compositions. Formula (I ′):

(Wherein X is halogen; ring 2 and ring 4 are the aromatic rings of the second and fourth amino acid residues of the vancomycin skeleton , respectively)
In shown in part structure comprising in basic skeleton Darubaheputaido, its pharmaceutically acceptable salt or solvate ^{thereof,, Z 1 -B (OH)} 2 (Z 1 , even if it is replacement Good aryl, optionally substituted alkenyl, optionally substituted alkynyl or optionally substituted heteroaryl), Z ¹ -H (Z ¹ is optionally substituted alkenyl or substituted) Alkynyl), or Z ¹ -Sn- (Alk) ₃ (wherein Z ¹ is an optionally substituted aryl, an optionally substituted alkenyl, or an optionally substituted heteroaryl; Alk is an alkyl ) wherein the compound is reacted represented by, Darubaheputaido of claim 4, wherein (where formula (I) Z ¹ in the aryl which may be substitution, substituted Alkenyl optionally substituted, alkynyl optionally substituted or heteroaryl optionally substituted). Formula (I-1 ′):

Wherein X and X ′ are each independently halogen;
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)
In shown in part structure comprising in basic skeleton Darubaheputaido, its pharmaceutically acceptable salt or solvate ^{thereof,, Z 1 -B (OH)} 2 (Z 1 , even if it is replacement aryl, substituted alkenyl which may have, alkynyl which may be substituted or optionally substituted heteroaryl), Z ¹ -H (Z ¹ is being also an alkenyl or substituted substituted Alkynyl), or Z ¹ -Sn- (Alk) ₃ (wherein Z ¹ is an optionally substituted aryl, an optionally substituted alkenyl, or an optionally substituted heteroaryl; Alk is an alkyl 6. The method for producing dalbaheptide according to claim 5, wherein the compound represented by formula (2) is reacted. The optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl and optionally substituted heteroaryl substituents are C1-C6 alkyl, C2-C6 alkenyl, C2-C6. The production method according to claim 19 or 20, which is alkynyl, alkoxy, alkylthio or optionally substituted aryl.