JP2009029730A - Glycopeptide antibiotic derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new glycopeptide antibiotic derivative. <P>SOLUTION: The glycopeptide compound comprising a new vancomycin derivative, a pharmaceutically acceptable salt thereof or a solvate thereof are provided. The compound, the salt thereof or the solvate thereof exhibits antibacterial activity against various kinds of bacteria such as staphylococcus including MRSA, streptococcus, pneumococcus and enterococcus, and is also effective to vancomycin-resistant enterococcus (VRE) and vancomycin-resistant staphylococcus aureus (VRSA). As a result, the compound or the like is useful for treating or preventing the various kinds of infectious diseases such as meningitis, septicemia, pneumonia, arthritis, peritonitis, bronchitis and thoratic empyema. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to glycopeptide antibiotic derivatives and pharmaceutical compositions containing the same.

  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. The mechanism and degree of resistance varies depending on the type of gene possessed by VRE, and it depends on genes involved in resistance such as VanA, B, C, D, E, and G. Among these, for example, Tecoplanin, which is the same glycopeptide antibiotic as vancomycin, is effective for VanB type VRE. On the other hand, VanA-type VRE is a bacterial species that requires special measures in clinical practice, but no glycopeptide antibiotics effective for such resistant strains have been put on the market. Recently, Staphylococcus aureus (VRSA) that has acquired resistance to VRE has also been discovered. Thus, there remains a need to develop glycopeptide derivatives with improved activity and selectivity.

  Many derivatives of vancomycin and other glycopeptides are known, including those in which the resorcinol moiety is modified (see Patent Documents 1 to 10 and Non-Patent Documents 1 to 3).

International Application Publication WO2006 / 055733 A1 International Application Publication WO 03/018608 A2 US Patent Application Publication US2003 / 0008812 A1 International Application Publication WO01 / 98328 A2 International Application Publication WO01 / 98327 A2 International Application Publication WO01 / 57071 A2 JP 2000-302687 A International Application Publication WO00 / 39156 A1 French Patent Application Publication No. 2778184 A1 International Application Publication WO99 / 42476 A1 Antiviral Research (2006), 72 (1), 20-33 Journal of Antibiotics (2004), 57 (5), 326-336 Bioorganic & Medicinal Chemistry Letters 12 (2002) 3027-3031

  The present invention provides novel derivatives of glycopeptide antibiotics that have increased and improved properties compared to conventional glycopeptide antibiotics. Certain glycopeptide derivatives of the invention, particularly vancomycin derivatives, exhibit increased antimicrobial activity compared to vancomycin itself.

（式中、
Ｒ^Aは、式：−Ｘ¹−Ａｒ¹−Ｘ²−Ｙ−Ｘ³−Ａｒ²で示される基
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、または
３）−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同一もしくは異なるヘテロ原子基が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、ハロゲン、低級アルキル、低級アルコキシ、ハロゲン化低級アルキル、およびハロゲン化低級アルコキシからなる群から選択される１または２以上の基で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；
Ｒ^Bは、−ＯＨまたは−ＮＲ⁵Ｒ⁵’または−ＯＲ⁶；
Ｒ⁵およびＲ⁵’はそれぞれ独立して水素、置換されていてもよいアルキル、−ＮＨ−Ｒ’、−ＮＨ−ＣＯＲ’、−ＮＨ−ＣＯＮＨＲ’、−ＯＲ’またはアミノ糖残基；
Ｒ’は、それぞれ独立して水素または置換されていてもよいアルキル；
Ｒ⁶は、置換されていてもよいアルキルであって、該アルキル部分にはヘテロ原子基が介在していてもよく；
Ｒ^Cは、
１）−ＮＨ−Ｘ⁴−Ａｒ³（Ｘ⁴は、−Ｏ−、−Ｓ−、−ＳＯ−および−ＳＯ_2-からなる群から選択される同一もしくは異なるヘテロ原子基が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低級アルキレン；Ａｒ³は置換されていてもよいアリールまたは置換されていてもよいヘテロアリール）、
２）式：

で示される、置換されていてもよく縮合していてもよいＮ原子含有ヘテロ環式基、または
３）モノまたはジ低級アルキルアミノ低級アルキルアミノ；
Ｒは置換されていてもよいアルキル；
但し、Ａｒ²がジクロロフェニルである場合、Ｒ^Cは以下の１）〜３）

に示されるいずれかの基である）
で示される、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。
（２）Ｒ^Aは、以下

のいずれかで示される基である、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。
（３）
Ｒ^Cは以下の１）〜３）

に示されるいずれかの基である、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。
（４）
Ｒ^Cは、１）に示されるいずれかの基である、上記（３）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）
Ｒ^Cは、２）に示されるいずれかの基である、上記（３）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）
Ｒ^Aが請求項２に記載の基である、上記（３）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）
Ｒ^Aは上記（２）に記載の基であり、Ｒ^Cは１）または２）に示されるいずれかの基である、上記（３）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）
Ｒ^BはＯＨ；Ｒは−ＣＨ（ＮＨＲ^D）ＣＨ₂ＣＨ（ＣＨ₃）₂（ここに、Ｒ^Dは、水素または低級アルキル）である、上記（１）〜（７）のいずれかに記載の化合物、その製薬上許容される塩、またはそれらの溶媒和物。
（９）
以下の実施例に記載の化合物、その製薬上許容される塩、またはそれらの溶媒和物。
（１０）上記（１）〜（９）のいずれかに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を含有する医薬組成物
に関する。 That is, the present invention
(1) Formula:

(Where
R ^A is a group represented by 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) —N═, ═N—, —NR ¹ — (wherein R ¹ is hydrogen or lower alkyl), —O—, —S—, —SO— and Alkylene or alkenylene, optionally substituted by one or more of the same or different heteroatom groups selected from the group consisting of —SO ₂ —;
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 substituted with one or more groups selected from the group consisting of halogen, lower alkyl, lower alkoxy, halogenated lower alkyl, and halogenated lower alkoxy A carbocycle or heterocycle which may be substituted and may have an unsaturated bond;
R ^B is —OH or —NR ⁵ R ⁵ ′ or —OR ⁶ ;
R ⁵ and R ⁵ ′ are each independently hydrogen, optionally substituted alkyl, —NH—R ′, —NH—COR ′, —NH—CONHR ′, —OR ′ or an amino sugar residue;
Each R ′ is independently hydrogen or optionally substituted alkyl;
R ⁶ is an optionally substituted alkyl, and the alkyl moiety may have a heteroatom group interposed;
R ^C is
1) —NH—X ⁴ —Ar ³ (X ⁴ is one or more of the same or different heteroatom groups selected from the group consisting of —O—, —S—, —SO— and —SO ₂ —. Optionally lower and optionally substituted lower alkylene; Ar ³ is optionally substituted aryl or optionally substituted heteroaryl),
2) Formula:

An optionally substituted N-containing heterocyclic group which may be substituted or 3) mono- or di-lower alkylamino lower alkylamino;
R is an optionally substituted alkyl;
However, when Ar < ² > is dichlorophenyl, R < ^C > is the following 1) -3).

Any of the groups shown)
Or a pharmaceutically acceptable salt thereof, or a solvate thereof.
(2) R ^A is the following

The glycopeptide compound according to (1), a pharmaceutically acceptable salt thereof, or a solvate thereof, which is a group represented by any of the above:
(3)
R ^C is the following 1) to 3)

Or a pharmaceutically acceptable salt thereof, or a solvate thereof.
(4)
R ^C is any of the groups shown in 1), the glycopeptide compound according to the above (3), a pharmaceutically acceptable salt thereof, or a solvate thereof.
(5)
R ^C is any group shown in 2), the glycopeptide compound according to (3) above, a pharmaceutically acceptable salt thereof, or a solvate thereof.
(6)
The glycopeptide compound according to (3) above, wherein R ^A is the group according to claim 2, a pharmaceutically acceptable salt thereof, or a solvate thereof.
(7)
R ^A is the group described in (2) above, and R ^C is any group shown in 1) or 2), the glycopeptide compound described in (3) above, a pharmaceutically acceptable salt thereof, Or a solvate thereof.
(8)
R ^B is OH; R is —CH (NHR ^D ) CH ₂ CH (CH ₃ ) ₂ (where R ^D is hydrogen or lower alkyl), and any one of (1) to (7) above Or a pharmaceutically acceptable salt thereof, or a solvate thereof.
(9)
The compounds described in the following examples, pharmaceutically acceptable salts thereof, or solvates thereof.
(10) The present invention relates to a pharmaceutical composition comprising the glycopeptide compound according to any one of (1) to (9) above, a pharmaceutically acceptable salt thereof, or a solvate thereof.

  The present invention further relates to a pharmaceutical composition, preferably an antibacterial agent, containing the compound of the present invention, a pharmaceutically acceptable salt thereof, or a solvate thereof.

  The glycopeptide antibiotic derivative of the present invention, a pharmaceutically acceptable salt thereof, or a solvate thereof exhibits antibacterial activity against various bacteria such as staphylococci, streptococci, pneumococci and enterococci including MRSA. . In particular, the present compounds are effective against vancomycin-resistant bacteria derived from them, and particularly effective against vancomycin-resistant enterococci (VRE) and vancomycin-resistant Staphylococcus aureus (VRSA). Therefore, it is useful for treating or preventing various bacterial infections such as meningitis, sepsis, pneumonia, arthritis, peritonitis, bronchitis, empyema and the like. More preferred compounds of the present invention have high water solubility, good pharmacokinetics, and / or are safe in terms of toxicity.

  For the purpose of describing the compounds of the present invention, the terms used in the present specification are explained below. Each term alone or in combination with other terms has the same meaning.

  “Lower alkyl” means a monoradical of a straight or branched saturated hydrocarbon chain having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- Examples include butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl and isohexyl.

The “heteroatom group” consists of —N═, ═N—, —NR ¹ — (wherein R ¹ is hydrogen or lower alkyl), —O—, —S—, —SO— and —SO ₂ —. A group selected from the group;

The “linking group” in the definition of X ¹ , X ² and X ³ means a linking group consisting of the above heteroatom group, for example, —SS—, —NR ¹ CO—, —NR ¹ O—, — NR ¹ S—, —OSO ₂ —, —OCO—, —SO ₂ NR ¹ — and the like can be mentioned.

  “Alkylene” means a diradical of a straight or branched saturated hydrocarbon chain having 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, propylene, tetramethylene, ethylethylene, pentamethylene or hexamethylene. And methylene. Preferably, it is a C1-C4 linear alkylene, for example, a methylene, ethylene, trimethylene, or tetramethylene is mentioned. Preferably it is methylene.

  “Alkenylene” means a diradical of a linear or branched unsaturated hydrocarbon chain having 2 to 6 carbon atoms and having one or more double bonds to the above “alkylene”. For example, vinylene , Propenylene or butenylene. Preferably, it is C2-C3 linear alkenylene, for example, vinylene or propenylene.

  The “optionally substituted alkylene or alkenylene” refers to an alkylene or alkenylene having 1 to 5 substituents, preferably 1 to 3 substituents, wherein the substituent is from the group consisting of Selected: optionally substituted alkyl (eg methyl, ethyl, isopropyl, benzyl, carbamoylalkyl (eg carbamoylmethyl), mono or dialkylcarbamoylalkyl (eg dimethylcarbamoylethyl), hydroxyalkyl, hetero Cycle alkyl (eg, morpholinoethyl, tetrahydropyranylethyl), alkoxycarbonylalkyl (eg, ethoxycarbonylmethyl, ethoxycarbonylethyl), mono- or dialkylaminoalkyl (eg, dimethylaminoethyl)), alkoxyalkyl ( For example, methoxyethyl, ethoxymethyl, ethoxyethyl, i-propoxyethyl, etc.), acyl (eg, formyl, optionally substituted alkylcarbonyl (eg, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl) , Octanoyl, methoxyethylcarbonyl, 2,2,2-trifluoroethylcarbonyl, ethoxycarbonylmethylcarbonyl, alkoxyalkylcarbonyl (eg methoxyethylcarbonyl), alkylcarbamoylalkylcarbonyl (eg methylcarbamoylethylcarbonyl), alkoxycarbonylacetyl Etc.), optionally substituted arylcarbonyl (eg benzoyl, toluoyl etc.), optionally substituted aralkyl (eg benzyl) 4-F-benzyl etc.), hydroxy, optionally substituted alkylsulfonyl (eg methanesulfonyl, ethanesulfonyl, isopropylsulfonyl, 2,2,2-trifluoroethanesulfonyl, benzylsulfonyl, methoxyethylsulfonyl etc.), Arylsulfonyl optionally substituted with alkyl or halogen (eg, benzenesulfonyl, toluenesulfonyl, 4-fluorobenzenesulfonyl), cycloalkyl (eg, cyclopropyl, etc.), aryl optionally substituted with alkyl (eg, 4-methylphenyl etc.), alkylaminosulfonyl (eg methylaminosulfonyl, dimethylaminosulfonyl etc.), alkylaminocarbonyl (eg dimethylaminocarbonyl etc.), alkoxycarbonyl (eg , Ethoxycarbonyl, etc.), cycloalkylcarbonyl (eg, cyclopropylcarbonyl, cyclohexylcarbonyl, etc.), optionally substituted sulfamoyl (eg, sulfamoyl, methylsulfamoyl, dimethylsulfamoyl, etc.), alkylcarbonylamino (eg, : Methylcarbonylamino), heterocycle (eg morpholino, tetrahydropyranyl), optionally substituted amino (eg mono- or dialkylamino (eg dimethylamino), formylamino).

Accordingly, “an alkylene or alkenylene optionally having one or more heteroatom groups which are the same or different and optionally substituted” means —N═, ═N—, —NR ¹ — (here , R ¹ is hydrogen or lower alkyl), or one or more same or different heteroatom groups selected from the group consisting of —O—, —S—, —SO— and —SO ₂ — may be present. Means alkylene or alkenylene which is well and may be substituted. Here, “intervening” means both when the heteroatom group is present between the carbon atoms constituting the alkylene or alkenylene and when present between the carbon atom and Ar ¹ , Y or Ar ^2. . For _{example, -O-CH 2 -, -} CH 2 -O -, - CH 2 -O-CH 2 -, CH 2 -NH-CH 2 -, - O-CH 2 -O -, - CH 2 -O- CH ₂ —NH—CH ₂ —, CH ₂ —N═CH—, —CH ₂ —O—CH═N—CH ₂ —, and —O—CH═CH—, —CH═CH—O—, —CH _{= CH-O-CH 2 -} , CH 2 -NH-CH = CH -, - O-CH = CH-O-, or ^{_{- (CH 2 -O) -Ar 1}} - (O-CH 2 -O) - such as _{Y- (O-CH 2) -Ar} 2 is illustrated. Moreover, as a case where alkylene is substituted by oxo, -CO- is preferably exemplified.

X ¹ is preferably C1-C3 alkylene.

X ² is preferably a single bond, C1-C3 alkylene, O or NH. Particularly preferred is a single bond.

  Y— is preferably —NHCO—, —CONH—, —NMeCO— or —CONMe. Particularly preferred is —NHCO— or —CONH—.

The “carbocyclic group optionally having an unsaturated bond” in the definition of Ar ¹ and Ar ² means cycloalkyl having 3 to 10 carbon atoms, cycloalkenyl having 3 to 10 carbon atoms, or aryl.

  “Cycloalkyl” includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Preferably, it is a C3-C6 cycloalkyl, for example, a cyclopentyl and a cyclohexyl are mentioned.

  “Cycloalkenyl” includes, for example, cyclopropenyl (eg, 1-cyclopropenyl), cyclobutenyl (eg, 1-cyclobutenyl), cyclopentenyl (eg, 1-cyclopenten-1-yl, 2-cyclopenten-1-yl, 3- Cyclopenten-1-yl), cyclohexenyl (eg 1-cyclohexen-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl), cycloheptenyl (eg 1-cycloheptenyl), cyclooctenyl (eg 1-cyclooctenyl) and the like. In particular, 1-cyclohexen-1-yl, 2-cyclohexen-1-yl, and 3-cyclohexen-1-yl are preferable.

  “Aryl” refers to monocyclic aromatic hydrocarbon groups (phenyl) and polycyclic aromatic hydrocarbon groups (eg, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2 -Phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-phenanthryl and the like). Preferably, phenyl or naphthyl (1-naphthyl, 2-naphthyl) is used.

The “heterocyclic group optionally having an unsaturated bond” in the definition of Ar ¹ and Ar ² means heterocycle or heteroaryl.

  “Heterocycle” means a 5- to 8-membered non-aromatic heterocyclic group having a bond at any substitutable position, having at least one nitrogen atom, oxygen atom or sulfur atom in the ring. For example, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4- Imidazolidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 1-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl, 2- Morpholinyl, 3-morpholinyl, morpholino, tetrahy Ropiraniru, and the like. The “non-aromatic heterocyclic group” may be saturated or unsaturated as long as it is non-aromatic.

  “Heteroaryl” refers to monocyclic aromatic heterocyclic groups and fused aromatic heterocyclic groups. 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.

  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-triazolyl-3-yl, 1,2,4-triazol-4-yl), tetrazolyl (eg 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl), oxazolyl (eg 2- Oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (eg 3-isoxazoly 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-flazanyl) ), 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-benzo [b ] Furyl, 6-benzo [b] furyl, 7-benzo [b] furyl), benzothienyl (for example, 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 (for example, 1-benzoimidazolyl, 2-benzoimidazolyl, 4-benzoimidazolyl, 5-benzoimidazolyl), dibenzofuryl, benzo Oxazolyl, 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-quina Linyl, 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- Acridinyl, 9- Cridinyl), 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) etc. are mentioned.

The carbocyclic group and / or heterocyclic group constituting Ar ₁ and Ar ₂ includes those in which an aromatic ring and a non-aromatic ring are condensed.

As is apparent from the definition of R ^A , Ar ¹ is a divalent atomic group, and therefore the carbon atom or heteroatom constituting the carbocyclic group or heterocyclic group expressed as a monovalent substituent is In Ar ^1, it further participates in bonding with other atomic groups.

Specific examples of the substituent of “carbocycle or heterocycle optionally having an unsaturated bond” in the definition of Ar ¹ and Ar ² include halogen groups such as fluoro, chloro, bromo and iodo, methyl, Lower alkyl groups such as ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and t-butyl, and lower alkoxy groups such as methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, and t-butyloxy And lower alkyl halides and lower alkoxy halides derived from combinations of the above specific substituents.

These substituents can preferably be substituted by 1 to 3 on Ar ¹ or Ar ² .

As Ar ¹ , one preferred embodiment is phenylene which may be substituted. Preferred substituents on phenylene include halogen, hydroxy, hydroxy lower alkyl, optionally substituted lower alkoxy, optionally substituted amino (examples of substituents: lower alkyl, heterocyclic, heterocyclic lower alkyl, Lower alkoxy lower alkyl, hydroxy lower alkyl, lower alkylsulfonyl), optionally substituted amino lower alkyl, optionally substituted heterocycle, optionally substituted heterocycle lower alkyl, optionally substituted They are phenylene which may be substituted by a heterocyclic lower alkyl, carbamoyl which may be substituted (example of substituent: lower alkyl), and carbamoyl lower alkenyl which may be substituted. Preferred examples of the heterocycle include heterocycle (eg, morpholino, piperazino, piperidino) and pyridyl each optionally substituted by lower alkyl or the like.

As Ar < ¹ >, ^one of the preferable aspects is the optionally substituted 5- to 7-membered heterocycle containing 1-2 nitrogen atoms. Preferred examples of the substituent on the heterocycle include lower alkyl, oxo, halogen, amino lower alkyl, mono- or di-lower alkylamino lower alkyl, and lower alkoxy lower alkyl. Particularly preferred is oxo.

Ar ² may be halogen, mono, di or trihalogenated lower alkyl, mono, di, tri or tetrahalogenated lower alkoxy, mono, di, tri or tetrahalogenated lower alkylthio, mono or dilower alkylamino, Cycloalkylmethyloxy, optionally substituted benzyloxy, lower alkoxycarbonylamino, nitro, heterocyclic (eg, morpholino, piperazino, piperidino, pyrrolidino each optionally substituted by lower alkyl, etc.), substituted 1 or more selected from the group consisting of optionally acetylamino, optionally substituted lower alkoxy, acyl (eg, optionally substituted lower alkylcarbonyl), and optionally substituted lower alkyloxycarbonyl Depending on the above substituents Aryl or hetero ring which may be substituted is preferred. Particularly preferred is substituted phenyl (substituent: halogen, halogenated lower alkoxy).

  “Aralkyloxy” means a group in which the above “alkyl” substituted by the above “aryl” is substituted with an oxygen atom, for example, benzyloxy, diphenylmethyloxy, triphenylmethyloxy, phenethyloxy, 1- Naphthylmethyloxy, 2-naphthylmethyloxy and the like can be mentioned.

  “Lower alkoxy” means a group in which the above “lower alkyl” is substituted with an oxygen atom, and examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like. It is done. In particular, methoxy and ethoxy are preferable.

  “Aryloxy” means a group in which the above “aryl” is substituted with an oxygen atom.

  “Optionally substituted amino” means a substituted or unsubstituted amino.

  “Optionally substituted carbamoyl” means substituted or unsubstituted carbamoyl.

  Substituents of “optionally substituted amino” and “optionally substituted carbamoyl” include optionally substituted alkyl (eg, methyl, ethyl, isopropyl, benzyl, carbamoylalkyl (eg, carbamoylmethyl) ), Mono- or dialkylcarbamoylalkyl (eg dimethylcarbamoylethyl), hydroxyalkyl, heterocyclealkyl (eg morpholinoethyl, tetrahydropyranylethyl), alkoxycarbonylalkyl (eg ethoxycarbonylmethyl, ethoxycarbonylethyl), Mono- or dialkylaminoalkyl (eg, dimethylaminoethyl, etc.), alkoxyalkyl (eg, methoxyethyl, ethoxymethyl, ethoxyethyl, i-propoxyethyl, etc.), acyl (eg, formi Alkyl, optionally substituted alkylcarbonyl (eg acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, octanoyl, methoxyethylcarbonyl, 2,2,2-trifluoroethylcarbonyl, ethoxycarbonylmethylcarbonyl , Alkoxyalkylcarbonyl (eg methoxyethylcarbonyl), alkylcarbamoylalkylcarbonyl (eg methylcarbamoylethylcarbonyl), alkoxycarbonylacetyl etc.), optionally substituted arylcarbonyl (eg benzoyl, toluoyl etc.)), substituted Optionally substituted aralkyl (eg benzyl, 4-F-benzyl etc.), hydroxy, optionally substituted alkylsulfonyl (eg methanesulfonyl, Sulfonylsulfonyl, isopropylsulfonyl, 2,2,2-trifluoroethanesulfonyl, benzylsulfonyl, methoxyethylsulfonyl, etc.), arylsulfonyl optionally substituted with alkyl or halogen (eg, benzenesulfonyl, toluenesulfonyl, 4-fluoro) Benzenesulfonyl), cycloalkyl (eg, cyclopropyl, etc.), aryl optionally substituted with alkyl (eg, 4-methylphenyl), alkylaminosulfonyl (eg, methylaminosulfonyl, dimethylaminosulfonyl, etc.), alkyl Aminocarbonyl (eg, dimethylaminocarbonyl, etc.), alkoxycarbonyl (eg, ethoxycarbonyl, etc.), cycloalkylcarbonyl (eg, cyclopropylcarbonyl, cyclohexylca) Sulfonyl), optionally substituted sulfamoyl (eg, sulfamoyl, methylsulfamoyl, dimethylsulfamoyl, etc.), alkylcarbonylamino (eg, methylcarbonylamino), heterocycle (eg, morpholino, tetrahydropyranyl) And optionally substituted amino (eg mono- or dialkylamino (eg dimethylamino), formylamino) and the like. It may be mono- or di-substituted with the above substituents.

  The amino group of “optionally substituted amino” and “optionally substituted carbamoyl” is substituted with alkylene (eg, trimethylene, tetramethylene, pentamethylene) and the like, and together with the nitrogen atom of the amino group, O, A ring which may contain an S atom may be formed.

  The amino group of “optionally substituted amino” and “optionally substituted carbamoyl” contains a sulfur atom and / or an oxygen atom in the ring in which two substituents of the amino group together with adjacent nitrogen atoms. Optionally containing a nitrogen-containing heterocycle (preferably a 5- to 7-membered ring, and preferably saturated), and the ring may be substituted with oxo, lower alkyl, hydroxy or the like Good. The sulfur atom forming the ring may be substituted with oxo. For example, 5 or 6 such as piperidino, piperazino, morpholino, pyrrolidino, thiazinan-2-yl, 2-oxopiperidino, 2-oxopyrrolidino, 1,1-dioxide-1,2-thiazinan-2-yl, 4-hydroxymorpholino A member ring is preferred.

  The substituents of “optionally substituted aryl” and “optionally substituted heteroaryl” are the same as in the case of “optionally substituted amino group”.

Particularly preferred Ar ¹ in the present invention is selected from the following groups.

Ar ² is preferably aryl which may be substituted, in particular phenyl which may be substituted. Particularly preferred Ar ² in the present invention is selected from the following groups.

Preferred embodiments of the group represented by the formula: —X ¹ —Ar ¹ —X ² —Y—X ³ —Ar ² in R ^A are shown below.
(1) -CH ₂ - (substituted) Ph-CONR- (substituted Ph)
(2) —CH ₂ — (Substituted) Ph—NRCO— (Substituted Ph)
(3) —CH ₂ — (Substituted) Ph—CH ₂ —CONR— (Substituted Ph)
(4) —CH ₂ — (Substituted) Ph—CH ₂ —NRCO— (Substituted Ph)
(5) —CH ₂ — (Substituted) Ph—CONR—CH ₂ — (Substituted Ph)
(6) —CH ₂ — (Substituted) Ph—NRCO—CH ₂ — (Substituted Ph)
(7) -CH ₂ - (substituted) Ph-X-CONR- (substituted Ph)
(8) —CH ₂ — (Substituted) Ph—X—NRCO— (Substituted Ph)
(9) -CH ₂ - (substituted) Ph-CONR-X- (substituted Ph)
(10) -CH ₂ - (substituted) Ph-NRCO-X- (substituted Ph)
(11) —CH ₂ — (Substituted) Ph—CH ₂ —CONR—CH ₂ — (Substituted Ph)
(12) —CH ₂ — (Substituted) Ph—CH ₂ —NRCO—CH ₂ — (Substituted Ph)
(13) —CH ₂ — (Substituted) Ph—X—CONR—CH ₂ — (Substituted Ph)
(14) —CH ₂ — (Substituted) Ph—X—NRCO—CH ₂ — (Substituted Ph)
(15) -CH ₂ - (substituted) Het-CONR- (substituted Ph)
(16) —CH ₂ — (Substituted) Het-NRCO— (Substituted Ph)
(17) -CH ₂ - (substituted) Het-CH ₂ -CONR- (substituted Ph)
(18) —CH ₂ — (Substituted) Het—CH ₂ —NRCO— (Substituted Ph)
(19) —CH ₂ — (Substituted) Het-CONR—CH ₂ — (Substituted Ph)
(20) —CH ₂ — (Substituted) Het-NRCO—CH ₂ — (Substituted Ph)
(21) -CH ₂ - (substituted) Het-X-CONR- (substituted Ph)
(22) —CH ₂ — (Substituted) Het-X—NRCO— (Substituted Ph)
(23) -CH ₂ - (substituted) Het-CONR-X- (substituted Ph)
(24) -CH ₂ - (substituted) Het-NRCO-X- (substitution Ph)
(25) —CH ₂ — (Substituted) Het—CH ₂ —CONR—CH ₂ — (Substituted Ph)
(26) -CH ₂ - _{(substituted) Het-CH 2 -NRCO-CH} 2 - ( substituted Ph)
(27) -CH ₂ - (substituted) Het-X-CONR-CH 2 - ( substituted Ph)
(28) -CH ₂ - (substituted) Het-X-NRCO-CH 2 - ( substituted Ph)
(29) -CH ₂ - (substituted) Het-NRCO-CH = CH- ( substituted Ph)
_{(30) - (CH 2)} m - ( substituted) Ph-CONR- (substituted Ph)
_{(31) - (CH 2)} m - ( substituted) Ph-NRCO- (substituted Ph)
_{(32) - (CH 2)} m - ( substituted) Ph-CH ₂ -CONR- (substituted Ph)
_{(33) - (CH 2)} m - ( substituted) Ph-CH ₂ -NRCO- (substituted Ph)
_{(34) - (CH 2)} m - ( _{substituted) Ph-CONR-CH 2 -} ( substituted Ph)
_{(35) - (CH 2)} m - ( _{substituted) Ph-NRCO-CH 2 -} ( substituted Ph)
_{(36) - (CH 2)} m - ( substituted) Ph-X-CONR- (substituted Ph)
_{(37) - (CH 2)} m - ( substituted) Ph-X-NRCO- (substituted Ph)
_{(38) - (CH 2)} m - ( substituted) Ph-CONR-X- (substituted Ph)
_{(39) - (CH 2)} m - ( substituted) Ph-NRCO-X- (substituted Ph)
_{(40) - (CH 2)} m - ( _{substituted) Ph-CH 2 -CONR-CH} 2 - ( substituted Ph)
_{(41) - (CH 2)} m - ( _{substituted) Ph-CH 2 -NRCO-CH} 2 - ( substituted Ph)
_{(42) - (CH 2)} m - ( substituted) Ph-X-CONR-CH 2 - ( substituted Ph)
_{(43) - (CH 2)} m - ( substituted) Ph-X-NRCO-CH 2 - ( substituted Ph)
_{(44) - (CH 2)} m - ( substituted) Het-CONR- (substituted Ph)
_{(45) - (CH 2)} m - ( substituted) Het-NRCO- (substituted Ph)
_{(46) - (CH 2)} m - ( substituted) Het-CH ₂ -CONR- (substituted Ph)
_{(47) - (CH 2)} m - ( substituted) Het-CH ₂ -NRCO- (substituted Ph)
_{(48) - (CH 2)} m - ( _{substituted) Het-CONR-CH 2 -} ( substituted Ph)
_{(49) - (CH 2)} m - ( _{substituted) Het-NRCO-CH 2 -} ( substituted Ph)
_{(50) - (CH 2)} m - ( substituted) Het-X-CONR- (substituted Ph)
_{(51) - (CH 2)} m - ( substituted) Het-X-NRCO- (substituted Ph)
_{(52) - (CH 2)} m - ( substituted) Het-CONR-X- (substituted Ph)
_{(53) - (CH 2)} m - ( substituted) Het-NRCO-X- (substituted Ph)
_{(54) - (CH 2)} m - ( _{substituted) Het-CH 2 -CONR-CH} 2 - ( substituted Ph)
_{(55) - (CH 2)} m - ( _{substituted) Het-CH 2 -NRCO-CH} 2 - ( substituted Ph)
_{(56) - (CH 2)} m - ( substituted) Het-X-CONR-CH 2 - ( substituted Ph)
_{(57) - (CH 2)} m - ( substituted) Het-X-NRCO-CH 2 - ( substituted Ph)
_{(58) - (CH 2)} m - ( substituted) Het-NRCO-CH = CH- ( substituted Ph)
[Wherein Ph = phenyl; R = hydrogen or lower alkyl; X═O or NH; Het is a heteroaryl or heterocycle (preferably a 5- to 7-membered ring containing 1 to 2 nitrogen atoms, The substituent on Het is preferably oxo.); M is 2 or 3; (substituted) is optionally substituted]

In one aspect of the invention, R ^B is —OH.

In a further aspect of the invention, R ^B is a group represented by —NR ⁵ R ⁵ ′. Here, as R ⁵ and R ⁵ ′, for example, hydrogen, optionally substituted alkyl, —NH—R ′, —NH—COR ′, —NH—CONHR ′, —OR ′, or an amino sugar residue, respectively, Groups. R ′ includes hydrogen or optionally substituted alkyl. Preferred substituents for alkyl include OH, CN, lower alkoxy, amino, ═O, halogen, heterocyclic group and the like.

In a further aspect of the invention, R ^B is a group represented by —OR ⁶ . Here, examples of R ⁶ include the above-described alkyl, and the alkyl moiety includes a heteroatom group selected from the group consisting of —O—, —S—, —SO— and —SO ₂ —, for example. You may do it.

Examples of the substituent of “optionally substituted alkyl” include OH, lower alkoxy, optionally substituted amino, ═O, halogen, SO ₃ H, optionally substituted carbamoyl, heterocyclic group, and the like. Can be mentioned. Examples of the heterocyclic group include those exemplified for the above-mentioned “heterocycle” and “heteroaryl”, but 5- or 6-membered heterocyclic groups such as morpholinyl, imidazolyl and tetrahydropyranyl are preferable. Examples of the substituent of “optionally substituted heterocycle” 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). Examples of the substituent of “optionally substituted lower alkenyl” include OH, CN, lower alkoxy, amino, ═O, halogen, NH _{3 and the} like. Substituents of “optionally substituted amino” and “optionally substituted carbamoyl” include alkyl (eg, methyl, ethyl, dimethyl, etc.), alkoxycarbonyl (methoxycarbonyl, ethoxycarbonyl, etc.), alkoxyalkyl (Eg, ethoxymethyl, ethoxyethyl, etc.), acyl (eg, formyl, acetyl, benzoyl, toluoyl, etc.), aralkyl (eg, benzyl, etc.), hydroxy, CN, alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.), SO ₂ NH ₂ , arylsulfonyl optionally substituted with alkyl (eg benzenesulfonyl, toluenesulfonyl), cycloalkyl (eg cyclopropyl etc.), alkylene (eg trimethylene, tetramethylene, penta) Methylene), aryl optionally substituted with alkyl (for example, phenyl, trityl, etc.) and the like. In the case of “optionally substituted amino”, the two substituents of the amino group may form a nitrogen-containing heterocycle which may contain a sulfur atom in the ring together with the adjacent nitrogen atom, The ring may be substituted with oxo.

R ^C is selected from the group consisting of the following (3-1) to (3-3):
(3-1) —NH—X ⁴ —Ar ³ (X ⁴ represents one hetero atom group that is the same or different and is selected from the group consisting of —O—, —S—, —SO—, and —SO ₂ —. Or an optionally further substituted and optionally substituted lower alkylene; Ar ³ is an optionally substituted aryl or an optionally substituted heteroaryl).

Particularly preferred R ^{C in} this group is selected from the following groups:

で示される、置換されていてもよく縮合していてもよいＮ原子含有ヘテロ環式基。この群の特に好ましいＲ^Cは、例えば以下に示す基である。

(3-2) Formula:

An N atom-containing heterocyclic group which may be substituted or optionally condensed. Particularly preferred R ^{C in} this group are, for example, the groups shown below.

(3-3) Mono- or di-lower alkylamino lower alkylamino. Particularly preferred R ^{C in} this group are, for example, the groups shown below.

  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.
Also, solvates of the compounds of the present invention and various solvates are within the scope of the present invention, and examples include monosolvates, disolvates, monohydrates, dihydrates and the like.

(2) General production method Although typical production methods are described below, the compound of the present invention can also be produced by other production methods without being particularly limited to these production methods.
The compound of the present invention is obtained by using vancomycin or a known derivative thereof as a raw material, and aminoamino (R ^A ), C-terminal (R ^B ), resorcinol (R ^C ), or N-terminal methylamino of amino sugar. The moiety (R ^D ) can be synthesized by various chemical modifications. The chemical modification may be performed according to the methods described in JP-A-7-258289, WO00 / 39156, JP-A-2001-163898, and the like. Details are 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) Modification of the R ^B moiety Typically, the carboxylic acid moiety at the C-terminal of the vancomycin skeleton is amidated by a conventional method using an appropriate reagent, so that R ^B = -NR ⁵ R ⁵ 'or- Conversion to various amide derivatives represented by OR ⁶

When R ^B is a group represented by —NR ⁵ R ⁵ ′, a compound represented by NHR ⁵ R ⁵ ′ (R ⁵ and R ⁵ ′ are as defined above) is used, and an appropriate solvent (dimethylformamide ( DMF) etc.) in the presence of benzotriazol-1-yl-oxy-tris- (pyrrolidino) phosphonium hexafluorophosphate (PyBOP), diisopropylethylamine (DIPEA), etc., with the carboxyl group at the C-terminal of the vancomycin skeleton Is obtained.

When R ^B is a group represented by —OR ⁶ , a compound represented by HOR ⁶ (R ⁶ is as defined above) is used in a suitable solvent (such as dimethylformamide (DMF)). It is obtained by reacting with the C-terminal carboxyl group of the vancomycin skeleton in the presence of benzotriazol-1-yl-oxy-tris- (pyrrolidino) phosphonium hexafluorophosphate (PyBOP), diisopropylethylamine (DIPEA) or the like.

  All of the reagents used in the above reaction are commercially available, or can be easily prepared according to methods well known to those skilled in the art using commercially available reagents.

  The reaction conditions for amidation are preferably several minutes to several hours in a solvent such as dimethylformamide at room temperature or under heating.

3) Modification of R ^C moiety Typically, vancomycin is used as a raw material, and a compound represented by HR ^C (R ^C is as defined above) in an appropriate solvent (such as water, acetonitrile, or a mixed solvent thereof). , Formaldehyde, diisopropylethylamine (DIPEA), etc. in the presence of the resorcinol moiety of the vancomycin skeleton.

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

(3) 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.

窒素ガス気流下、４−アミノベンジルアルコール２．７１１ｇ（２１．５ｍモル）をテトラヒドロフラン３０ｍＬに溶解させた。氷冷下まで冷却後、ジイソプロピルエチルアミン４．２ｍＬを滴下して加え、更に３−フルオロ−４−トリフルオロメトキシベンゾイルクロリド（２４ａ）５．２３ｇ（２１．５ｍモル）のテトラヒロドフラン（２０ｍＬ）溶液を１０℃以下の温度を維持させながら滴下して加えた。その後室温で７時間撹拌した。反応液を氷水２００ｍＬに注ぎ、酢酸エチル２００ｍＬで抽出し、無水硫酸マグネシウムにて乾燥した。乾燥剤を濾去後、濾液を減圧濃縮した。得られた粗固体をアセトンに溶解させ、活性炭５ｇを加えて室温で１０分静置後、活性炭を濾去し濾液を減圧濃縮した。得られた粗固体をジイソプロピルエーテルより再結晶化を行い、無色結晶の表題化合物（２４ｂ）６．１３ｇ（収率８６％）を得た。 Example 1: Preparation of compound 24 (step 1)
3-Fluoro-N- (4-hydroxymethyl-phenyl) -4-trifluoromethoxy-benzamide (24b)

Under a nitrogen gas stream, 2.711 g (21.5 mmol) of 4-aminobenzyl alcohol was dissolved in 30 mL of tetrahydrofuran. After cooling to ice cooling, 4.2 mL of diisopropylethylamine was added dropwise, and 5.23 g (21.5 mmol) of tetrahydrofuran (20 mL) of 3-fluoro-4-trifluoromethoxybenzoyl chloride (24a) was added. The solution was added dropwise while maintaining the temperature below 10 ° C. Thereafter, the mixture was stirred at room temperature for 7 hours. The reaction solution was poured into 200 mL of ice water, extracted with 200 mL of ethyl acetate, and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained crude solid was dissolved in acetone, 5 g of activated carbon was added and the mixture was allowed to stand at room temperature for 10 minutes. The activated carbon was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained crude solid was recrystallized from diisopropyl ether to obtain 6.13 g (yield 86%) of the title compound (24b) as colorless crystals.

３−フルオロ−Ｎ−（４−ヒドロキシメチル−フェニル）−４−トリフルオロメトキシ−ベンズアミド（２４ｂ）６．１３２ｇ（１８．６ｍモル）をテトラヒドロフラン１２０ｍＬに溶解させ、二酸化マンガン１２．２６ｇを加え、室温で１９時間撹拌した。ハイフロスーパーセルを用いて二酸化マンガンを濾去し、アセトン１２０ｍＬで濾去物をリンスした。得られた黄色濾液に活性炭６．１ｇを加えて室温で１０分間静置した。活性炭を濾去し濾液を減圧濃縮後、得られた粗固体をアセトン−ヘキサンより再結晶化を行い、無色結晶の表題化合物（２４ｃ）２．９４ｇ （収率４８％）を得た。 (Process 2)
3-Fluoro-N- (4-formyl-phenyl) -4-trifluoromethoxy-benzamide (24c)

6.132 g (18.6 mmol) of 3-fluoro-N- (4-hydroxymethyl-phenyl) -4-trifluoromethoxy-benzamide (24b) was dissolved in 120 mL of tetrahydrofuran, and 12.26 g of manganese dioxide was added. For 19 hours. Manganese dioxide was removed by filtration using Hyflo Supercell, and the residue was rinsed with 120 mL of acetone. To the obtained yellow filtrate, 6.1 g of activated carbon was added and allowed to stand at room temperature for 10 minutes. The activated carbon was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting crude solid was recrystallized from acetone-hexane to obtain 2.94 g (yield 48%) of the title compound (24c) as colorless crystals.

バンコマイシン塩酸塩１１．８８ｇ（８．０ミリモル）、３−フルオロ−Ｎ−（４−ホルミル−フェニル）−４−トリフルオロメトキシ−ベンズアミド２．６２ｇ（８．０ミリモル）をジメチルホルムアミド１２０ｍＬとメタノール１２０ｍＬの混合溶媒に溶解させた。ジイソプロピルエチルアミン２．８ｍＬを加え室温で４．５時間撹拌した。反応混合液を氷冷下まで冷却後、水素化シアノホウ素ナトリウム８３８ｍｇを加え、更にトリフルオロ酢酸１．８５ｍＬをゆっくり滴下して加え、氷冷下で１時間撹拌した。ジイソプロピルエチルアミン５．６５ｍＬを加えて反応をクエンチした後、反応溶液中のメタノールを減圧留去し、残液を酢酸エチル６００ｍＬ中に注加した。生成した沈殿物を濾過により集め、得られた粗固体を５％食塩水３００ｍＬによってリンスすることにより未反応の水素化シアノホウ素ナトリウムを除去した。得られた粗固体を、逆相カラムクロマトグラフィーによって精製することにより、無色固体の表題化合物（２４ｄ）３．８０ｇ（収率２７％）を得た． (Process 3)
3-Fluoro-N- (4-formyl-phenyl) -4-trifluoromethoxy-benzamide (24d)

Vancomycin hydrochloride 11.88 g (8.0 mmol), 3-fluoro-N- (4-formyl-phenyl) -4-trifluoromethoxy-benzamide 2.62 g (8.0 mmol), dimethylformamide 120 mL and methanol 120 mL In a mixed solvent. Diisopropylethylamine (2.8 mL) was added, and the mixture was stirred at room temperature for 4.5 hours. After cooling the reaction mixture to ice cooling, 838 mg of sodium cyanoborohydride was added, and 1.85 mL of trifluoroacetic acid was further slowly added dropwise, and the mixture was stirred for 1 hour under ice cooling. After quenching the reaction by adding 5.65 mL of diisopropylethylamine, methanol in the reaction solution was distilled off under reduced pressure, and the remaining solution was poured into 600 mL of ethyl acetate. The resulting precipitate was collected by filtration, and the resulting crude solid was rinsed with 300 mL of 5% brine to remove unreacted sodium cyanoborohydride. The obtained crude solid was purified by reverse phase column chromatography to obtain 3.80 g (yield 27%) of the title compound (24d) as a colorless solid.

４−（２−アミノエチル）ピリジン０．９０ｍＬ（７．１４ミリモル）をアセトニトリル２０ｍＬと精製水２０ｍＬの混合溶媒に溶解させた。ジイソプロプルエチルアミン３．６３ｍＬ、３５％ホルマリン液８３μＬ（１．０７ミリモル）を順次滴下後、２４ｄ２．１３ｇ（１．０２ミリモル）を加えて室温下に１８時間攪拌した。反応液をアセトン４００ｍＬ中に滴下して加え、生成した沈殿物を濾過により集め、逆相カラムクロマトグラフィーにより精製して、無色固体の表題化合物（２４）５８９ｍｇ（収率２６％）を得た。
[M+1]⁺ = 1893
元素分析（C89H94Cl2F4N12O26・16.3H2O・3.5HCl）
計算値: C: 46.16%, H: 5.66%. N: 7.26%, Cl: 8.42%, F: 3.28%
実測値: C: 46.11%, H: 5.50%. N: 7.36%, Cl: 8.36%, F: 3.17% (Process 4)
Compound 24

4- (2-aminoethyl) pyridine 0.90 mL (7.14 mmol) was dissolved in a mixed solvent of 20 mL acetonitrile and 20 mL purified water. After dropwise addition of 3.63 mL of diisopropylethylamine and 83 μL (1.07 mmol) of 35% formalin solution successively, 2413.13 g (1.02 mmol) was added and stirred at room temperature for 18 hours. The reaction mixture was added dropwise to 400 mL of acetone, and the resulting precipitate was collected by filtration and purified by reverse phase column chromatography to give 589 mg (yield 26%) of the title compound (24) as a colorless solid.
[M + 1] ⁺ = 1893
Elemental analysis (C89H94Cl2F4N12O26 ・ 16.3H2O ・ 3.5HCl)
Calculated: C: 46.16%, H: 5.66%. N: 7.26%, Cl: 8.42%, F: 3.28%
Found: C: 46.11%, H: 5.50%. N: 7.36%, Cl: 8.36%, F: 3.17%

窒素ガス気流下、４−アミノベンジルアルコール５．３７５ｇ（４２．７ｍモル）をテトラヒドロフラン６０ｍＬに溶解させた。氷冷下まで冷却後、ジイソプロピルエチルアミン８．１８ｍＬを滴下して加え、更に３−フルオロ−４−トリフルオロメチルベンゾイルクロリド（４１ａ）１０．２ｇ（４２．７ｍモル）のテトラヒロドフラン（３０ｍＬ）溶液を１０℃以下の温度を維持させながら滴下して加えた。その後室温で１時間撹拌した。反応液を０．１規定塩酸２００ｍＬに注ぎ、酢酸エチル２００ｍＬで抽出し、有機層を５％重曹水、飽和食塩水で順次洗浄後、無水硫酸マグネシウムにて乾燥した。乾燥剤を濾去後、濾液を減圧濃縮した。得られた粗固体をアセトンに溶解させ、活性炭５ｇを加えて室温で１０分静置後、活性炭を濾去し濾液を減圧濃縮した。得られた粗固体をジイソプロピルエーテルより再結晶化を行い、無色結晶の表題化合物（４１ｂ）８．６７ｇ（収率６５％）を得た。 Example 2: Production of compound 41 (step 1)
3-Fluoro-N- (4-hydroxymethyl-phenyl) -4-trifluoromethyl-benzamide (41b)

Under a nitrogen gas stream, 5.375 g (42.7 mmol) of 4-aminobenzyl alcohol was dissolved in 60 mL of tetrahydrofuran. After cooling to ice cooling, 8.18 mL of diisopropylethylamine was added dropwise, and 10.2 g (42.7 mmol) of tetrahydrofuran (30 mL) of 3-fluoro-4-trifluoromethylbenzoyl chloride (41a) was further added. The solution was added dropwise while maintaining the temperature below 10 ° C. Thereafter, the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into 200 mL of 0.1N hydrochloric acid and extracted with 200 mL of ethyl acetate. The organic layer was washed successively with 5% aqueous sodium bicarbonate and saturated brine, and then dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained crude solid was dissolved in acetone, 5 g of activated carbon was added and the mixture was allowed to stand at room temperature for 10 minutes. The activated carbon was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained crude solid was recrystallized from diisopropyl ether to obtain 8.67 g (yield 65%) of the title compound (41b) as colorless crystals.

３−フルオロ−Ｎ−（４−ヒドロキシメチル−フェニル）−４−トリフルオロメチル−ベンズアミド（４１ｂ）８．６７ｇ（２７．６７８ｍモル）をテトラヒドロフラン１００ｍＬに溶解させ、二酸化マンガン２４．０６ｇ（２７６．７８ｍモル）を加え、室温で２．５時間撹拌した。ハイフロスーパーセルを用いて二酸化マンガンを濾去し、酢酸エチルで濾去物をリンスした。得られた黄色濾液を減圧濃縮後、得られた粗固体をアセトン−ヘキサンより再結晶化を行い、無色結晶の表題化合物（４１ｃ）７．０１３ｇ（収率８１％）を得た。 (Process 2)
3-Fluoro-N- (4-formyl-phenyl) -4-trifluoromethyl-benzamide (41c)

8.67 g (27.678 mmol) of 3-fluoro-N- (4-hydroxymethyl-phenyl) -4-trifluoromethyl-benzamide (41b) was dissolved in 100 mL of tetrahydrofuran, and 24.06 g (276.78 m) of manganese dioxide was dissolved. Mol) and stirred at room temperature for 2.5 hours. Manganese dioxide was removed by filtration using Hyflo Supercell, and the residue was rinsed with ethyl acetate. The obtained yellow filtrate was concentrated under reduced pressure, and the obtained crude solid was recrystallized from acetone-hexane to obtain 7.013 g (yield 81%) of the title compound (41c) as colorless crystals.

バンコマイシン塩酸塩１４．８５７ｇ（１０ミリモル）、３−フルオロ−Ｎ−（４−ホルミル−フェニル）−４−トリフルオロメチル−ベンズアミド３．４２４ｇ（１１ミリモル）をジメチルホルムアミド１５０ｍＬに溶解させた。ジイソプロピルエチルアミン３．４８ｍＬと、モレキュラーシーブス３Ａ（ビーズタイプ）３０ｇを加え、室温で５時間撹拌した。反応混合液を氷冷下まで冷却後、トリフルオロ酢酸２．６７ｍＬをゆっくり滴下して加え、更に水素化シアノホウ素ナトリウム１．０４７ｇ（１５ｍモル）、メタノール３０ｍＬを加え、室温で１９時間撹拌した。ジイソプロピルエチルアミン６．１ｍＬを加えて反応をクエンチした後、モレキュラーシーブスを濾去し、メタノール１００ｍＬで十分に洗浄した。濾液中のメタノールを減圧留去し、残液を酢酸エチル１．２Ｌ中に注加した。生成した沈殿物を濾過により集め、得られた粗固体を１０％食塩水２００ｍＬによってリンスすることにより未反応の水素化シアノホウ素ナトリウムを除去した。得られた粗固体を、逆相カラムクロマトグラフィーによって精製して、無色固体の表題化合物（４１ｄ）７．９９７ｇ（収率４６％）を得た。 (Process 3)
Compound 41d

14.857 g (10 mmol) of vancomycin hydrochloride and 3.424 g (11 mmol) of 3-fluoro-N- (4-formyl-phenyl) -4-trifluoromethyl-benzamide were dissolved in 150 mL of dimethylformamide. 3.48 mL of diisopropylethylamine and 30 g of molecular sieves 3A (bead type) were added and stirred at room temperature for 5 hours. After cooling the reaction mixture to ice cooling, 2.67 mL of trifluoroacetic acid was slowly added dropwise. Further, 1.047 g (15 mmol) of sodium cyanoborohydride and 30 mL of methanol were added, and the mixture was stirred at room temperature for 19 hours. After the reaction was quenched by adding 6.1 mL of diisopropylethylamine, the molecular sieves were removed by filtration and washed thoroughly with 100 mL of methanol. Methanol in the filtrate was distilled off under reduced pressure, and the residue was poured into 1.2 L of ethyl acetate. The resulting precipitate was collected by filtration, and the resulting crude solid was rinsed with 200 mL of 10% brine to remove unreacted sodium cyanoborohydride. The obtained crude solid was purified by reverse phase column chromatography to obtain 7.997 g (yield 46%) of the title compound (41d) as a colorless solid.

４−（２−アミノエチル）ピリジン１．５２ｍＬ（１２．８４ミリモル）をアセトニトリル３０ｍＬと精製水３０ｍＬの混合溶媒に溶解させた。ジイソプロプルエチルアミン６．３９ｍＬ、３５％ホルマリン液１５３μＬ（１．９２ミリモル）を順次滴下後、工程３で得た４１ｄ３．２０ｇ（１．８３ミリモル）を加えて室温下で２６時間攪拌した。反応液を氷冷したアセトン６００ｍＬ中に滴下して加え、生成した沈殿物を濾過により集め、逆相カラムクロマトグラフィーにより精製して、無色固体の表題化合物（４１）１．３９７ｇ（収率４１％）を得た。
[M+1]⁺ =1877
元素分析（C88H94Cl2F4N12O25・8.4H2O・3.4HCl）
計算値: C: 49.63%, H: 5.34%. N: 7.80%, Cl: 8.89%, F: 3.53%
実測値: C: 49.93%, H: 5.50%. N: 6.60%, Cl: 8.89%, F: 2.77% (Process 4)
Compound 41

4- (2-Aminoethyl) pyridine (1.52 mL, 12.84 mmol) was dissolved in a mixed solvent of 30 mL of acetonitrile and 30 mL of purified water. 6.39 mL of diisopropylethylamine and 153 μL (1.92 mmol) of 35% formalin solution were successively added dropwise, and then 3.20 g (1.83 mmol) of 41d obtained in Step 3 was added and stirred at room temperature for 26 hours. The reaction solution was added dropwise to 600 mL of ice-cold acetone, and the resulting precipitate was collected by filtration and purified by reverse phase column chromatography to give 1.397 g (41% yield) of the title compound (41) as a colorless solid. )
[M + 1] ⁺ = 1877
Elemental analysis (C88H94Cl2F4N12O25 / 8.4H2O / 3.4HCl)
Calculated values: C: 49.63%, H: 5.34%. N: 7.80%, Cl: 8.89%, F: 3.53%
Found: C: 49.93%, H: 5.50%. N: 6.60%, Cl: 8.89%, F: 2.77%

  The following compounds were prepared according to the procedures described in the above examples.

[M+1]⁺ = 1905
元素分析（C88H96Cl4N14O26・11.7H2O・3.8HCl）
計算値: C: 46.83%, H: 5.50%. N: 8.69%, Cl: 12.25%
実測値: C: 46.80%, H: 5.54%. N: 8.77%, Cl: 12.34% Example 3
Compound 1

[M + 1] ⁺ = 1905
Elemental analysis (C88H96Cl4N14O26 ・ 11.7H2O ・ 3.8HCl)
Calculated: C: 46.83%, H: 5.50%. N: 8.69%, Cl: 12.25%
Found: C: 46.80%, H: 5.54%. N: 8.77%, Cl: 12.34%

[M+1]⁺ = 1905
元素分析（C88H96Cl4N14O26・13.4H2O・3.7HCl）
計算値: C: 46.28%, H: 5.58%. N: 8.59%, Cl: 11.95%
実測値: C: 46.25%, H: 5.52%. N: 8.70%, Cl: 11.97% Example 4
Compound 2

[M + 1] ⁺ = 1905
Elemental analysis (C88H96Cl4N14O26 ・ 13.4H2O ・ 3.7HCl)
Calculated: C: 46.28%, H: 5.58%. N: 8.59%, Cl: 11.95%
Found: C: 46.25%, H: 5.52%. N: 8.70%, Cl: 11.97%

[M+1]⁺ = 1983
元素分析（C89H98Cl4N14O28S・12.4H2O・2.4HCl）
計算値: C: 46.55%, H: 5.49%. N: 8.54%, Cl: 9.88%, S: 1.40%
実測値: C: 46.58%, H: 5.40%. N: 8.53%, Cl: 9.85%, S: 1.42%
Example 5
Compound 3

[M + 1] ⁺ = 1983
Elemental analysis (C89H98Cl4N14O28S ・ 12.4H2O ・ 2.4HCl)
Calculated: C: 46.55%, H: 5.49%. N: 8.54%, Cl: 9.88%, S: 1.40%
Found: C: 46.58%, H: 5.40%. N: 8.53%, Cl: 9.85%, S: 1.42%

[M+1]⁺ = 1917
元素分析（C89H96Cl4N14O26・10.2H2O・3.8HCl）
計算値: C: 47.68%, H: 5.40%. N: 8.75%, Cl: 12.33%
実測値: C: 47.70%, H: 5.40%. N: 8.86%, Cl: 12.29%
Example 6
Compound 4

[M + 1] ⁺ = 1917
Elemental analysis (C89H96Cl4N14O26 ・ 10.2H2O ・ 3.8HCl)
Calculated: C: 47.68%, H: 5.40%. N: 8.75%, Cl: 12.33%
Found: C: 47.70%, H: 5.40%. N: 8.86%, Cl: 12.29%

[M+1]⁺ = 1883
元素分析（C89H97Cl3N14O26・14.4H2O・4.0HCl）
計算値: C: 46.67%, H: 5.71%. N: 8.56%, Cl: 10.84%
実測値: C: 46.59%, H: 5.63%. N: 8.66%, Cl: 10.94% Example 7
Compound 5

[M + 1] ⁺ = 1883
Elemental analysis (C89H97Cl3N14O26 ・ 14.4H2O ・ 4.0HCl)
Calculated: C: 46.67%, H: 5.71%. N: 8.56%, Cl: 10.84%
Found: C: 46.59%, H: 5.63%. N: 8.66%, Cl: 10.94%

[M+1]⁺ = 1883
元素分析（C91H96Cl4N12O25・12.6H2O・2.5HCl）
計算値: C: 49.28%, H: 5.62%. N: 7.58%, Cl: 10.39%
実測値: C: 49.22%, H: 5.54%. N: 7.69%, Cl: 10.41%
Example 8
Compound 6

[M + 1] ⁺ = 1883
Elemental analysis (C91H96Cl4N12O25 ・ 12.6H2O ・ 2.5HCl)
Calculated: C: 49.28%, H: 5.62%. N: 7.58%, Cl: 10.39%
Found: C: 49.22%, H: 5.54%. N: 7.69%, Cl: 10.41%

[M+1]⁺ = 1897
元素分析（C91H96Cl4N12O25・12.6H2O・2.5HCl）
計算値: C: 49.28%, H: 5.62%. N: 7.58%, Cl: 10.39%
実測値: C: 49.22%, H: 5.54%. N: 7.69%, Cl: 10.41% Example 9
Compound 7

[M + 1] ⁺ = 1897
Elemental analysis (C91H96Cl4N12O25 ・ 12.6H2O ・ 2.5HCl)
Calculated: C: 49.28%, H: 5.62%. N: 7.58%, Cl: 10.39%
Found: C: 49.22%, H: 5.54%. N: 7.69%, Cl: 10.41%

[M+1]⁺ = 1858
元素分析（C89H95Cl4N11O25・12.7H2O・2.5HCl）
計算値: C: 49.02%, H: 5.68%. N: 7.07%, Cl: 10.57%
実測値: C: 48.99%, H: 5.56%. N: 7.18%, Cl: 10.55% Example 10
Compound 8

[M + 1] ⁺ = 1858
Elemental analysis (C89H95Cl4N11O25 ・ 12.7H2O ・ 2.5HCl)
Calculated: C: 49.02%, H: 5.68%. N: 7.07%, Cl: 10.57%
Found: C: 48.99%, H: 5.56%. N: 7.18%, Cl: 10.55%

[M+1]⁺ = 1892
元素分析（C89H94Cl5N11O25・21.6H2O・2.7HCl）
計算値: C: 44.87%, H: 5.92%. N: 6.47%, Cl: 11.46%
実測値: C: 44.87%, H: 5.86%. N: 6.52%, Cl: 11.45% Example 11
Compound 9

[M + 1] ⁺ = 1892
Elemental analysis (C89H94Cl5N11O25 ・ 21.6H2O ・ 2.7HCl)
Calculated: C: 44.87%, H: 5.92%. N: 6.47%, Cl: 11.46%
Found: C: 44.87%, H: 5.86%. N: 6.52%, Cl: 11.45%

[M+1]⁺ = 1874
元素分析（C89H95Cl4N11O26・10.6H2O・2.4HCl）
計算値: C: 49.60%, H: 5.55%. N: 7.15%, Cl: 10.53%
実測値: C: 49.56%, H: 5.49%. N: 7.32%, Cl: 10.48% Example 12
Compound 10

[M + 1] ⁺ = 1874
Elemental analysis (C89H95Cl4N11O26 ・ 10.6H2O ・ 2.4HCl)
Calculated: C: 49.60%, H: 5.55%. N: 7.15%, Cl: 10.53%
Found: C: 49.56%, H: 5.49%. N: 7.32%, Cl: 10.48%

[M+1]⁺ = 1873
元素分析（C89H96Cl4N12O25・13.6H2O・3.0HCl）
計算値: C: 47.94%, H: 5.70%. N: 7.54%, Cl: 11.13%
実測値: C: 47.94%, H: 5.65%. N: 7.69%, Cl: 11.14% Example 13
Compound 11

[M + 1] ⁺ = 1873
Elemental analysis (C89H96Cl4N12O25 ・ 13.6H2O ・ 3.0HCl)
Calculated: C: 47.94%, H: 5.70%. N: 7.54%, Cl: 11.13%
Found: C: 47.94%, H: 5.65%. N: 7.69%, Cl: 11.14%

[M+1]⁺ = 1859
元素分析（C88H94Cl4N12O25・12.7H2O・3.2HCl）
計算値: C: 47.89%, H: 5.60%. N: 7.62%, Cl: 11.57%
実測値: C: 47.86%, H: 5.54%. N: 7.86%, Cl: 11.69% Example 14
Compound 12

[M + 1] ⁺ = 1859
Elemental analysis (C88H94Cl4N12O25 ・ 12.7H2O ・ 3.2HCl)
Calculated: C: 47.89%, H: 5.60%. N: 7.62%, Cl: 11.57%
Found: C: 47.86%, H: 5.54%. N: 7.86%, Cl: 11.69%

[M+1]⁺ = 1635
元素分析（C74H82Cl4N10O24・11.2H2O・2.2HCl）
計算値: C: 46.31%, H: 5.60%. N: 7.30%, Cl: 11.45%
実測値: C: 46.27%, H: 5.60%. N: 7.36%, Cl: 11.52% Reference example 1
Compound 13

[M + 1] ⁺ = 1635
Elemental analysis (C74H82Cl4N10O24 / 11.2H2O / 2.2HCl)
Calculated: C: 46.31%, H: 5.60%. N: 7.30%, Cl: 11.45%
Found: C: 46.27%, H: 5.60%. N: 7.36%, Cl: 11.52%

[M+1]⁺ = 1615
元素分析（C75H85Cl3N10O24・10.7H2O・2.0HCl）
計算値: C: 47.85%, H: 5.80%. N: 7.44%, Cl: 9.42%
実測値: C: 47.85%, H: 5.83%. N: 7.48%, Cl: 9.33% Reference example 2
Compound 14

[M + 1] ⁺ = 1615
Elemental analysis (C75H85Cl3N10O24 ・ 10.7H2O ・ 2.0HCl)
Calculated: C: 47.85%, H: 5.80%. N: 7.44%, Cl: 9.42%
Found: C: 47.85%, H: 5.83%. N: 7.48%, Cl: 9.33%

[M+1]⁺ = 1649
元素分析（C75H84Cl4N10O24・10.0H2O・3.2HCl）
計算値: C: 46.24%, H: 5.55%. N: 7.19%, Cl: 13.10%
実測値: C: 46.19%, H: 5.58%. N: 7.27%, Cl: 13.16% Reference example 3
Compound 15

[M + 1] ⁺ = 1649
Elemental analysis (C75H84Cl4N10O24 ・ 10.0H2O ・ 3.2HCl)
Calculated: C: 46.24%, H: 5.55%. N: 7.19%, Cl: 13.10%
Found: C: 46.19%, H: 5.58%. N: 7.27%, Cl: 13.16%

[M+1]⁺ = 1740
元素分析（C81H89Cl4N11O24・14.8H2O・2.5HCl）
計算値: C: 46.32%, H: 5.81%. N: 7.34%, Cl: 10.97%
実測値: C: 46.28%, H: 5.75%. N: 7.46%, Cl: 11.00% Reference example 4
Compound 16

[M + 1] ⁺ = 1740
Elemental analysis (C81H89Cl4N11O24 ・ 14.8H2O ・ 2.5HCl)
Calculated: C: 46.32%, H: 5.81%. N: 7.34%, Cl: 10.97%
Found: C: 46.28%, H: 5.75%. N: 7.46%, Cl: 11.00%

[M+1]⁺ = 1790
元素分析（C85H91Cl4N11O24・13.6H2O・2.8HCl）
計算値: C: 47.71%, H: 5.70%. N: 7.20%, Cl: 11.27%
実測値: C: 47.66%, H: 5.62%. N: 7.32%, Cl: 11.33% Reference Example 5
Compound 17

[M + 1] ⁺ = 1790
Elemental analysis (C85H91Cl4N11O24 ・ 13.6H2O ・ 2.8HCl)
Calculated: C: 47.71%, H: 5.70%. N: 7.20%, Cl: 11.27%
Found: C: 47.66%, H: 5.62%. N: 7.32%, Cl: 11.33%

[M+1]⁺ = 1791
元素分析（C84H90Cl4N12O24・15.2H2O・2.4HCl）
計算値: C: 46.82%, H: 5.74%. N: 7.80%, Cl: 10.53%
実測値: C: 46.77%, H: 5.57%. N: 7.86%, Cl: 10.59% Reference Example 6
Compound 18

[M + 1] ⁺ = 1791
Elemental analysis (C84H90Cl4N12O24 ・ 15.2H2O ・ 2.4HCl)
Calculated: C: 46.82%, H: 5.74%. N: 7.80%, Cl: 10.53%
Found: C: 46.77%, H: 5.57%. N: 7.86%, Cl: 10.59%

[M+1]⁺ = 1852
元素分析（C89H96Cl3N13O25・17.1H2O・3.4HCl）
計算値: C: 46.76%, H: 5.89%. N: 7.96%, Cl: 9.92%
実測値: C: 46.78%, H: 5.73%. N: 7.97%, Cl: 9.87% Example 15
Compound 19

[M + 1] ⁺ = 1852
Elemental analysis (C89H96Cl3N13O25 ・ 17.1H2O ・ 3.4HCl)
Calculated: C: 46.76%, H: 5.89%. N: 7.96%, Cl: 9.92%
Found: C: 46.78%, H: 5.73%. N: 7.97%, Cl: 9.87%

[M+1]⁺ = 1877
元素分析（C89H94Cl2F4N12O25・12.6H2O・2.6HCl）
計算値: C: 48.58%, H: 5.58%. N: 7.64%, Cl: 7.41%, F: 3.45%
実測値: C: 48.62%, H: 5.61%. N: 7.45%, Cl: 7.45%, F: 3.31% Example 16
Compound 20

[M + 1] ⁺ = 1877
Elemental analysis (C89H94Cl2F4N12O25 ・ 12.6H2O ・ 2.6HCl)
Calculated: C: 48.58%, H: 5.58%. N: 7.64%, Cl: 7.41%, F: 3.45%
Found: C: 48.62%, H: 5.61%. N: 7.45%, Cl: 7.45%, F: 3.31%

[M+1]⁺ = 1878
元素分析（C88H93Cl2F4N13O25・15.6H2O・2.9HCl）
計算値: C: 46.63%, H: 5.65%. N: 8.03%, Cl: 7.66%, F: 3.35%
実測値: C: 46.73%, H: 5.42%. N: 7.82%, Cl: 7.59%, F: 3.19% Example 17
Compound 21

[M + 1] ⁺ = 1878
Elemental analysis (C88H93Cl2F4N13O25 ・ 15.6H2O ・ 2.9HCl)
Calculated values: C: 46.63%, H: 5.65%. N: 8.03%, Cl: 7.66%, F: 3.35%
Found: C: 46.73%, H: 5.42%. N: 7.82%, Cl: 7.59%, F: 3.19%

[M+1]⁺ = 1853
元素分析（C88H95Cl3N14O25・16.3H2O・3.4HCl）
計算値: C: 46.50%, H: 5.81%. N: 8.63%, Cl: 9.98%
実測値: C: 46.51%, H: 5.75%. N: 8.76%, Cl: 9.99% Example 18
Compound 22

[M + 1] ⁺ = 1853
Elemental analysis (C88H95Cl3N14O25 ・ 16.3H2O ・ 3.4HCl)
Calculated: C: 46.50%, H: 5.81%. N: 8.63%, Cl: 9.98%
Found: C: 46.51%, H: 5.75%. N: 8.76%, Cl: 9.99%

[M+1]⁺ = 1883
元素分析（C89H97Cl3N14O26・16.5H2O・3.0HCl）
計算値: C: 46.64%, H: 5.85%. N: 8.56%, Cl: 9.28%
実測値: C: 46.63%, H: 5.81%. N: 8.66%, Cl: 9.32% Example 19
Compound 23

[M + 1] ⁺ = 1883
Elemental analysis (C89H97Cl3N14O26 ・ 16.5H2O ・ 3.0HCl)
Calculated: C: 46.64%, H: 5.85%. N: 8.56%, Cl: 9.28%
Found: C: 46.63%, H: 5.81%. N: 8.66%, Cl: 9.32%

[M+1]⁺ = 1894
元素分析（C88H93Cl2F4N13O26・15.1H2O・2.9HCl）
計算値: C: 46.49%, H: 5.59%. N: 8.01%, Cl: 7.64%, F: 3.34%
実測値: C: 46.44%, H: 5.56%. N: 8.10%, Cl: 7.64%, F: 3.27% Example 20
Compound 25

[M + 1] ⁺ = 1894
Elemental analysis (C88H93Cl2F4N13O26 ・ 15.1H2O ・ 2.9HCl)
Calculated: C: 46.49%, H: 5.59%. N: 8.01%, Cl: 7.64%, F: 3.34%
Found: C: 46.44%, H: 5.56%. N: 8.10%, Cl: 7.64%, F: 3.27%

[M+1]⁺ = 1908
元素分析（C89H95Cl2F4N13O26・15.2H2O・3.1HCl）
計算値: C: 46.55%, H: 5.64%. N: 7.93%, Cl: 7.87%, F: 3.31%
実測値: C: 46.53%, H: 5.60%. N: 8.01%, Cl: 7.80%, F: 3.19% Example 21
Compound 26

[M + 1] ⁺ = 1908
Elemental analysis (C89H95Cl2F4N13O26 ・ 15.2H2O ・ 3.1HCl)
Calculated: C: 46.55%, H: 5.64%. N: 7.93%, Cl: 7.87%, F: 3.31%
Found: C: 46.53%, H: 5.60%. N: 8.01%, Cl: 7.80%, F: 3.19%

[M+1]⁺ = 1924
元素分析（C89H95Cl2F4N13O27・17.0H2O・3.5HCl）
計算値: C: 45.30%, H: 5.66%. N: 7.72%, Cl: 8.26%, F: 3.22%
実測値: C: 45.26%, H: 5.61%. N: 8.13%, Cl: 8.32%, F: 2.95% Example 22
Compound 27

[M + 1] ⁺ = 1924
Elemental analysis (C89H95Cl2F4N13O27 ・ 17.0H2O ・ 3.5HCl)
Calculated: C: 45.30%, H: 5.66%. N: 7.72%, Cl: 8.26%, F: 3.22%
Found: C: 45.26%, H: 5.61%. N: 8.13%, Cl: 8.32%, F: 2.95%

[M+1]⁺ = 1909
元素分析（C90H95Cl3N14O27・18.2H2O・3.3HCl）
計算値: C: 45.82%, H: 5.75%. N: 8.31%, Cl: 9.47%
実測値: C: 45.79%, H: 5.42. N: 8.20%, Cl: 9.36% Example 23
Compound 28

[M + 1] ⁺ = 1909
Elemental analysis (C90H95Cl3N14O27 ・ 18.2H2O ・ 3.3HCl)
Calculated: C: 45.82%, H: 5.75%. N: 8.31%, Cl: 9.47%
Found: C: 45.79%, H: 5.42. N: 8.20%, Cl: 9.36%

[M+1]⁺ = 1875
元素分析（C89H95Cl2F3N12O26・14.3H2O・3.7HCl）
計算値: C: 47.11%, H: 5.65%. N: 7.41%, Cl: 8.91%, F: 2.51%
実測値: C: 47.10%, H: 5.44%. N: 7.29%, Cl: 8.87%, F: 2.42% Example 24
Compound 29

[M + 1] ⁺ = 1875
Elemental analysis (C89H95Cl2F3N12O26 ・ 14.3H2O ・ 3.7HCl)
Calculated: C: 47.11%, H: 5.65%. N: 7.41%, Cl: 8.91%, F: 2.51%
Found: C: 47.10%, H: 5.44%. N: 7.29%, Cl: 8.87%, F: 2.42%

[M+1]⁺ = 1894 Example 25
Compound 30

[M + 1] ⁺ = 1894

[M+1]⁺ = 1876
元素分析（C88H94Cl2F3N13O26・14.4H2O・3.3HCl）
計算値: C: 46.82%, H: 5.63%. N: 8.07%, Cl: 8.32%, F: 2.52%
実測値: C: 46.75%, H: 5.48%. N: 8.30%, Cl: 8.25%, F: 2.41% Example 26
Compound 31

[M + 1] ⁺ = 1876
Elemental analysis (C88H94Cl2F3N13O26 ・ 14.4H2O ・ 3.3HCl)
Calculated: C: 46.82%, H: 5.63%. N: 8.07%, Cl: 8.32%, F: 2.52%
Found: C: 46.75%, H: 5.48%. N: 8.30%, Cl: 8.25%, F: 2.41%

[M+1]⁺ = 1906
元素分析（C89H96Cl2F3N13O27・16.6H2O・2.6HCl）
計算値: C: 46.45%, H: 5.77%. N: 7.91%, Cl: 7.09%, F: 2.48%
実測値: C: 46.41%, H: 5.54%. N: 8.04%, Cl: 7.14%, F: 2.72% Example 27
Compound 32

[M + 1] ⁺ = 1906
Elemental analysis (C89H96Cl2F3N13O27 ・ 16.6H2O ・ 2.6HCl)
Calculated: C: 46.45%, H: 5.77%. N: 7.91%, Cl: 7.09%, F: 2.48%
Found: C: 46.41%, H: 5.54%. N: 8.04%, Cl: 7.14%, F: 2.72%

[M+1]⁺ =1860
元素分析（C88H94Cl2F3N13O25・14.3H2O・3.8HCl）
計算値: C: 46.81%, H: 5.64%. N: 8.06%, Cl: 9.11%, F: 2.52%
実測値: C: 46.88%, H: 5.57%. N: 7.83%, Cl: 9.10%, F: 2.44% Example 28
Compound 33

[M + 1] ⁺ = 1860
Elemental analysis (C88H94Cl2F3N13O25 ・ 14.3H2O ・ 3.8HCl)
Calculated: C: 46.81%, H: 5.64%. N: 8.06%, Cl: 9.11%, F: 2.52%
Found: C: 46.88%, H: 5.57%. N: 7.83%, Cl: 9.10%, F: 2.44%

[M+1]⁺ =1875
元素分析（C89H95Cl2F3N12O26・20.5H2O・3.1HCl）
計算値: C: 45.31%, H: 5.94%. N: 7.13%, Cl: 7.66%, F: 2.42%
実測値: C: 45.33%, H: 5.88%. N: 7.23%, Cl: 7.62%, F: 2.41% Example 29
Compound 34

[M + 1] ⁺ = 1875
Elemental analysis (C89H95Cl2F3N12O26 ・ 20.5H2O ・ 3.1HCl)
Calculated: C: 45.31%, H: 5.94%. N: 7.13%, Cl: 7.66%, F: 2.42%
Found: C: 45.33%, H: 5.88%. N: 7.23%, Cl: 7.62%, F: 2.41%

[M+1]⁺ =1834
元素分析（C90H101Cl2N13O25・14.5H2O・4.0HCl）
計算値: C: 48.20%, H: 6.02%. N: 8.12%, Cl: 9.48%
実測値: C: 48.17%, H: 5.93%. N: 8.20%, Cl: 9.44% Example 30
Compound 35

[M + 1] ⁺ = 1834
Elemental analysis (C90H101Cl2N13O25 ・ 14.5H2O ・ 4.0HCl)
Calculated: C: 48.20%, H: 6.02%. N: 8.12%, Cl: 9.48%
Found: C: 48.17%, H: 5.93%. N: 8.20%, Cl: 9.44%

[M+1]⁺ =1906
元素分析（C89H96Cl2F3N13O27・14H2O・3.4HCl）
計算値: C: 46.80%, H: 5.62%. N: 7.97%, Cl: 8.38%, F: 2.50%
実測値: C: 46.88%, H: 5.62%. N: 7.62%, Cl: 8.42%, F: 2.37% Example 31
Compound 36

[M + 1] ⁺ = 1906
Elemental analysis (C89H96Cl2F3N13O27 / 14H2O / 3.4HCl)
Calculated: C: 46.80%, H: 5.62%. N: 7.97%, Cl: 8.38%, F: 2.50%
Found: C: 46.88%, H: 5.62%. N: 7.62%, Cl: 8.42%, F: 2.37%

[M+1]⁺ =1833
元素分析（C91H102Cl2N12O25・12.9H2O・3.2HCl）
計算値: C: 50.05%, H: 6.05%. N: 7.70%, Cl: 8.44%
実測値: C: 50.05%, H: 6.03%. N: 7.76%, Cl: 8.47% Example 32
Compound 37

[M + 1] ⁺ = 1833
Elemental analysis (C91H102Cl2N12O25 ・ 12.9H2O ・ 3.2HCl)
Calculated: C: 50.05%, H: 6.05%. N: 7.70%, Cl: 8.44%
Found: C: 50.05%, H: 6.03%. N: 7.76%, Cl: 8.47%

[M+1]⁺ =1864
元素分析（C91H103Cl2N13O26・14H2O・3HCl）
計算値: C: 49.07%, H: 6.06%. N: 8.17%, Cl: 7.96%
実測値: C: 49.05%, H: 6.05%. N: 8.28%, Cl: 7.97% Example 33
Compound 38

[M + 1] ⁺ = 1864
Elemental analysis (C91H103Cl2N13O26 ・ 14H2O ・ 3HCl)
Calculated: C: 49.07%, H: 6.06%. N: 8.17%, Cl: 7.96%
Found: C: 49.05%, H: 6.05%. N: 8.28%, Cl: 7.97%

[M+1]⁺ =1878
元素分析（C88H96Cl2F3N13O26・15H2O・3.7HCl）
計算値: C: 46.26%, H: 5.72%. N: 7.97%, Cl: 8.84%, F: 2.49%
実測値: C: 46.20%, H: 5.48%. N: 8.14%, Cl: 8.81%, F: 2.43% Example 34
Compound 39

[M + 1] ⁺ = 1878
Elemental analysis (C88H96Cl2F3N13O26 / 15H2O / 3.7HCl)
Calculated: C: 46.26%, H: 5.72%. N: 7.97%, Cl: 8.84%, F: 2.49%
Found: C: 46.20%, H: 5.48%. N: 8.14%, Cl: 8.81%, F: 2.43%

[M+1]⁺ =1878
元素分析（C88H93Cl2F4N13O25・14H2O・3.2HCl）
計算値: C: 47.01%, H: 5.57%. N: 8.10%, Cl: 8.20%, F: 3.38%
実測値: C: 47.00%, H: 5.51%. N: 8.19%, Cl: 8.17%, F: 3.24% Example 35
Compound 40

[M + 1] ⁺ = 1878
Elemental analysis (C88H93Cl2F4N13O25 / 14H2O / 3.2HCl)
Calculated: C: 47.01%, H: 5.57%. N: 8.10%, Cl: 8.20%, F: 3.38%
Found: C: 47.00%, H: 5.51%. N: 8.19%, Cl: 8.17%, F: 3.24%

[M+1]⁺ =1908
元素分析（C89H95Cl2F4N13O26・11.3H2O・4.4HCl）
計算値: C: 47.01%, H: 5.41%. N: 8.01%, Cl: 9.98%, F: 3.34%
実測値: C: 46.98%, H: 5.36%. N: 8.11%, Cl: 10.00%, F: 3.15% Example 36
Compound 42

[M + 1] ⁺ = 1908
Elemental analysis (C89H95Cl2F4N13O26 ・ 11.3H2O ・ 4.4HCl)
Calculated: C: 47.01%, H: 5.41%. N: 8.01%, Cl: 9.98%, F: 3.34%
Found: C: 46.98%, H: 5.36%. N: 8.11%, Cl: 10.00%, F: 3.15%

[M+1]⁺ =1940
元素分析（C93H98Cl2F3N13O26・12.2H2O・2.4HCl）
計算値: C: 49.67%, H: 5.59%. N: 8.10%, Cl: 6.94%, F: 2.53%
実測値: C: 49.62%, H:5.62%. N: 8.36%, Cl: 6.87%, F: 2.55% Example 37
Compound 43

[M + 1] ⁺ = 1940
Elemental analysis (C93H98Cl2F3N13O26 ・ 12.2H2O ・ 2.4HCl)
Calculated: C: 49.67%, H: 5.59%. N: 8.10%, Cl: 6.94%, F: 2.53%
Found: C: 49.62%, H: 5.62%. N: 8.36%, Cl: 6.87%, F: 2.55%

M=C⁺ + Cl^-
[C]⁺=1855
元素分析（C87H100Cl3F3N12O26・2(HCl)・15(H2O)）
計算値: C 46.73%, H : 5.95%, Cl : 7.93%, F : 2.55%, N : 7.52%, O : 29.33%
実測値: C 46.6%, H : 5.84%, Cl : 8.13%, F : 2.43%, N : 7.67% Example 38
Compound 44

M = C ^{+ +} Cl ^-
[C] ⁺ = 1855
Elemental analysis (C87H100Cl3F3N12O26 ・ 2 (HCl) ・ 15 (H2O))
Calculated values: C 46.73%, H: 5.95%, Cl: 7.93%, F: 2.55%, N: 7.52%, O: 29.33%
Actual value: C 46.6%, H: 5.84%, Cl: 8.13%, F: 2.43%, N: 7.67%

[M+1]⁺=1859
元素分析（C88H94Cl4N12O25・3.8(HCl)・13(H2O)）
計算値: C 47.30%, H : 5.58%, Cl : 12.38%, N : 7.52%, O : 27.21%
実測値 C: 47.38%, H : 5.48%, Cl : 12.21%, N : 7.61% Example 39
Compound 45

[M + 1] ⁺ = 1859
Elemental analysis (C88H94Cl4N12O25 / 3.8 (HCl) / 13 (H2O))
Calculated values: C 47.30%, H: 5.58%, Cl: 12.38%, N: 7.52%, O: 27.21%
Measured value C: 47.38%, H: 5.48%, Cl: 12.21%, N: 7.61%

[M+1]⁺=1875
元素分析（C89H95Cl2F3N12O26・3(HCl)・13(H2O)）
計算値: C 48.15%, H : 5.63%, Cl : 7.98%, F : 2.57%, N : 7.57%, O : 28.10%
実測値: C 47.93%, H : 5.58%, Cl : 8.16%, F : 2.49%, N : 7.57% Example 40
Compound 46

[M + 1] ⁺ = 1875
Elemental analysis (C89H95Cl2F3N12O26 ・ 3 (HCl) ・ 13 (H2O))
Calculated values: C 48.15%, H: 5.63%, Cl: 7.98%, F: 2.57%, N: 7.57%, O: 28.10%
Found: C 47.93%, H: 5.58%, Cl: 8.16%, F: 2.49%, N: 7.57%

[M+1]⁺=1909
元素分析（C87H92Cl4N12O27S・2(HCl)・12(H2O)）
計算値: C 47.48%, H : 5.40%, Cl : 9.67%, N : 7.64%, O : 28.35%, S : 1.46%
実測値: C 47.56%, H : 5.36%, Cl : 9.69%, N : 7.67%, S : 1.32% Example 41
Compound 47

[M + 1] ⁺ = 1909
Elemental analysis (C87H92Cl4N12O27S ・ 2 (HCl) ・ 12 (H2O))
Calculated values: C 47.48%, H: 5.40%, Cl: 9.67%, N: 7.64%, O: 28.35%, S: 1.46%
Found: C 47.56%, H: 5.36%, Cl: 9.69%, N: 7.67%, S: 1.32%

[M+1]⁺=1876
元素分析（C87H94Cl2F3N13O26・3(HCl)・14(H2O)）
計算値: C 46.92%, H : 5.66%, Cl : 7.96%, F : 2.56%, N : 8.18%, O : 28.73%
実測値: C 46.80%, H : 5.57%, Cl : 7.96%, F : 2.54%, N : 8.15% Example 42
Compound 48

[M + 1] ⁺ = 1876
Elemental analysis (C87H94Cl2F3N13O26 ・ 3 (HCl) ・ 14 (H2O))
Calculated values: C 46.92%, H: 5.66%, Cl: 7.96%, F: 2.56%, N: 8.18%, O: 28.73%
Found: C 46.80%, H: 5.57%, Cl: 7.96%, F: 2.54%, N: 8.15%

[M+1]⁺=1921
元素分析（C88H92Cl4N12O27S・1.4(HCl)・13(H2O)）
計算値: C 47.85%, H : 5.45%, Cl : 8.67%, N : 7.61%, O : 28.97%, S : 1.45%
実測値: C 48.00%, H : 5.47%, Cl : 8.66%, N : 7.72%, S : 1.37% Example 43
Compound 49

[M + 1] ⁺ = 1921
Elemental analysis (C88H92Cl4N12O27S ・ 1.4 (HCl) ・ 13 (H2O))
Calculated values: C 47.85%, H: 5.45%, Cl: 8.67%, N: 7.61%, O: 28.97%, S: 1.45%
Actual value: C 48.00%, H: 5.47%, Cl: 8.66%, N: 7.72%, S: 1.37%

[M+1]⁺=1857
元素分析（C87H98Cl2F4N12O25・3(HCl)・11(H2O)）
計算値: C 48.24%, H : 5.72%, Cl : 8.18%, F : 3.51%, N : 7.76%, O : 26.59%
実測値: C 48.01%, H : 5.75%, Cl : 8.43%, F : 3.34%, N : 7.80% Example 44
Compound 50

[M + 1] ⁺ = 1857
Elemental analysis (C87H98Cl2F4N12O25 ・ 3 (HCl) ・ 11 (H2O))
Calculated values: C 48.24%, H: 5.72%, Cl: 8.18%, F: 3.51%, N: 7.76%, O: 26.59%
Found: C 48.01%, H: 5.75%, Cl: 8.43%, F: 3.34%, N: 7.80%

[M+1]⁺=1877
元素分析（C89H94Cl2F4N12O25・3(HCl)・11(H2O)）
計算値: C 48.90%, H : 5.49%, Cl : 8.11%, F : 3.48%, N : 7.69%, O : 26.35%
実測値: C 48.73%, H : 5.57%, Cl : 8.30%, F : 3.22%, N : 7.71% Example 45
Compound 51

[M + 1] ⁺ = 1877
Elemental analysis (C89H94Cl2F4N12O25 ・ 3 (HCl) ・ 11 (H2O))
Calculated values: C 48.90%, H: 5.49%, Cl: 8.11%, F: 3.48%, N: 7.69%, O: 26.35%
Actual value: C 48.73%, H: 5.57%, Cl: 8.30%, F: 3.22%, N: 7.71%

[M+1]⁺=1878
元素分析（C88H93Cl2F4N13O25・2.4(HCl)・12(H2O)）
計算値: C 48.41%, H : 5.51%, Cl : 7.14%, F : 3.48%, N : 8.34%, O : 27.11%
実測値: C 48.41%, H : 5.44%, Cl : 7.19%, F : 3.28%, N : 8.39% Example 46
Compound 52

[M + 1] ⁺ = 1878
Elemental analysis (C88H93Cl2F4N13O25 ・ 2.4 (HCl) ・ 12 (H2O))
Calculated values: C 48.41%, H: 5.51%, Cl: 7.14%, F: 3.48%, N: 8.34%, O: 27.11%
Found: C 48.41%, H: 5.44%, Cl: 7.19%, F: 3.28%, N: 8.39%

[M+1]⁺=1910
元素分析（C86H91Cl4N13O27S・2.4(HCl)・13(H2O)）
計算値: C 46.23%, H : 5.39%, Cl : 10.16%, N : 8.15%, O : 28.64%, S : 1.44%
実測値: C 46.26%, H : 5.28%, Cl : 10.34%, N : 8.16%, S : 1.40% Example 47
Compound 53

[M + 1] ⁺ = 1910
Elemental analysis (C86H91Cl4N13O27S ・ 2.4 (HCl) ・ 13 (H2O))
Calculated values: C 46.23%, H: 5.39%, Cl: 10.16%, N: 8.15%, O: 28.64%, S: 1.44%
Found: C 46.26%, H: 5.28%, Cl: 10.34%, N: 8.16%, S: 1.40%

[M+1]⁺=1922 Example 48
Compound 54

[M + 1] ⁺ = 1922

[M+1]⁺=1859
元素分析（C89H95Cl2F3N12O25・3.5(HCl)・14(H2O)）
計算値: C 47.71%, H : 5.69%, Cl : 8.70%, F : 2.54%, N : 7.50%, O : 27.85%
実測値: C 47.50%, H : 5.45%, Cl : 8.88%, F : 2.43%, N : 7.56% Example 49
Compound 55

[M + 1] ⁺ = 1859
Elemental analysis (C89H95Cl2F3N12O25 / 3.5 (HCl) / 14 (H2O))
Calculated values: C 47.71%, H: 5.69%, Cl: 8.70%, F: 2.54%, N: 7.50%, O: 27.85%
Found: C 47.50%, H: 5.45%, Cl: 8.88%, F: 2.43%, N: 7.56%

[M+1]⁺=1890
元素分析（C89H96Cl2F3N13O26・4.7(HCl)・16(H2O)）
計算値: C 45.46%, H : 5.69%, Cl : 10.10%, F : 2.42%, N : 7.74%, O : 28.58%
実測値: C 45.19%, H : 5.40%, Cl : 10.16%, F : 2.32%, N : 7.77% Example 50
Compound 56

[M + 1] ⁺ = 1890
Elemental analysis (C89H96Cl2F3N13O26 ・ 4.7 (HCl) ・ 16 (H2O))
Calculated values: C 45.46%, H: 5.69%, Cl: 10.10%, F: 2.42%, N: 7.74%, O: 28.58%
Found: C 45.19%, H: 5.40%, Cl: 10.16%, F: 2.32%, N: 7.77%

[M+1]⁺=1839
元素分析（C87H99Cl2F3N12O25・3.5(HCl)・12(H2O)）
計算値: C 47.83%, H : 5.84%, Cl : 8.93%, F : 2.61%, N : 7.69%, O : 27.10%
実測値: C 47.83%, H : 5.90%, Cl : 8.88%, F : 2.49%, N : 7.77% Example 51
Compound 57

[M + 1] ⁺ = 1839
Elemental analysis (C87H99Cl2F3N12O25 ・ 3.5 (HCl) ・ 12 (H2O))
Calculated values: C 47.83%, H: 5.84%, Cl: 8.93%, F: 2.61%, N: 7.69%, O: 27.10%
Found: C 47.83%, H: 5.90%, Cl: 8.88%, F: 2.49%, N: 7.77%

[M+1]⁺=1912
元素分析（C88H102Cl2F3N15O26・4.2(HCl)・11.4(H2O)）
計算値: C 46.52%, H : 5.72%, Cl : 9.67%, F : 2.51%, N : 9.25%, O : 26.33%
実測値: C 46.04%, H : 5.71%, Cl : 9.82%, F : 2.36%, N : 9.75% Example 52
Compound 58

[M + 1] ⁺ = 1912
Elemental analysis (C88H102Cl2F3N15O26 ・ 4.2 (HCl) ・ 11.4 (H2O))
Calculated values: C 46.52%, H: 5.72%, Cl: 9.67%, F: 2.51%, N: 9.25%, O: 26.33%
Found: C 46.04%, H: 5.71%, Cl: 9.82%, F: 2.36%, N: 9.75%

Test example 1
In vitro measurement of antibacterial activity (test method)
Minimum inhibitory concentrations (MIC) were determined for some of the compounds of the present invention 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 strong antibacterial activity against various bacteria including highly resistant MRSA and vancomycin resistant bacteria. For example, the compound 24 of Example 1 and the compound 41 of Example 2 have a MIC = 0.25 μg / mL against S. aureus SR3637 (H-MRSA), which is a highly resistant MRSA, and are vancomycin-resistant bacteria. For some E. faecium SR 7940 (van A), the MIC was 2.0 μg / mL.

Test example 2
The water solubility and toxicity of the compounds of the present invention were investigated.
Compound 24 of Example 1 and Compound 41 of Example 2 showed good water solubility (1% or more at room temperature). Good results were also shown in toxicity tests in rats, guinea pigs, and the like.

  The glycopeptide derivatives, pharmaceutically acceptable salts and solvates thereof of the present invention are useful in medical treatment and exhibit bioactivity including antibacterial activity. Thus, the present invention provides a method for treating infectious diseases, in particular diseases caused by gram positive microorganisms in animals, and the compounds of the invention treat in particular infections caused by methicillin resistant staphylococci. Useful for. The compounds are also useful for treating infections by enterococci, including vancomycin-resistant enterococci (VRE). Examples of such diseases are severe staphylococcal infections such as staphylococcal endocarditis and staphylococcal sepsis.

Claims (9)

formula:

(Where
R ^A is a group represented by 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) —N═, ═N—, —NR ¹ — (wherein R ¹ is hydrogen or lower alkyl), —O—, —S—, —SO— and Alkylene or alkenylene, optionally substituted by one or more of the same or different heteroatom groups selected from the group consisting of —SO ₂ —;
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 substituted with one or more groups selected from the group consisting of halogen, lower alkyl, lower alkoxy, halogenated lower alkyl, and halogenated lower alkoxy A carbocycle or heterocycle which may be substituted and may have an unsaturated bond;
R ^B is —OH or —NR ⁵ R ⁵ ′ or —OR ⁶ ;
R ⁵ and R ⁵ ′ are each independently hydrogen, optionally substituted alkyl, —NH—R ′, —NH—COR ′, —NH—CONHR ′, —OR ′ or an amino sugar residue;
Each R ′ is independently hydrogen or optionally substituted alkyl;
R ⁶ is an optionally substituted alkyl, and the alkyl moiety may have a heteroatom group interposed;
R ^C is
1) —NH—X ⁴ —Ar ³ (X ⁴ is one or more of the same or different heteroatom groups selected from the group consisting of —O—, —S—, —SO— and —SO ₂ —. Optionally lower and optionally substituted lower alkylene; Ar ³ is optionally substituted aryl or optionally substituted heteroaryl),
2) Formula:

An optionally substituted N-containing heterocyclic group which may be substituted or 3) mono- or di-lower alkylamino lower alkylamino;
R is an optionally substituted alkyl;
However, when Ar < ² > is dichlorophenyl, R < ^C > is the following 1) -3).

Any of the groups shown)
Or a pharmaceutically acceptable salt thereof, or a solvate thereof. ^RA is the following

The glycopeptide compound according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof. R ^C is the following 1) to 3)

The glycopeptide compound according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof, which is any group represented by the formula: The glycopeptide compound according to claim 3, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R ^C is any group represented by 1). The glycopeptide compound according to claim 3, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R ^C is any group shown in 2). The glycopeptide compound according to claim 3, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R ^A is the group according to claim 2. R ^A is the group described in claim 2, and R ^C is any group shown in 1) or 2), the glycopeptide compound according to claim 3, its pharmaceutically acceptable salt, or them Solvates. The compound according to any one of claims 1 to 7, wherein R ^B is OH; R is -CH (NHR ^D ) CH ₂ CH (CH ₃ ) ₂ , wherein R ^D is hydrogen or lower alkyl. The pharmaceutically acceptable salt or solvate thereof.   The pharmaceutical composition containing the glycopeptide compound in any one of Claims 1-8, its pharmaceutically acceptable salt, or those solvates.