JP2009091369A - Glycopeptide derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide: a novel glycopeptide derivative which expresses an excellent activity to vancomycin-resistant enterococcus, and also expresses a stronger activity to methicillin-resistant bacteria; and a pharmaceutically acceptable salt, a hydrates, or a prodrug thereof. <P>SOLUTION: The glycopeptide derivative is a compound expressed by formula (I), wherein R<SP>1</SP>, R<SP>2</SP>, R<SP>3</SP>, R<SP>4</SP>, and R<SP>5</SP>are each independently selected from the group consisting of predetermined groups. The pharmaceutically acceptable salt, the hydrate, or the prodrug thereof are also provided. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

(Technical field to which the invention belongs)
The present invention relates to glycopeptide derivatives. More specifically, the present invention relates to glycopeptide derivatives that exhibit potent activity against vancomycin-resistant enterococci and methicillin-resistant bacteria, or pharmaceutically acceptable salts, hydrates, or prodrugs thereof. The invention also relates to pharmaceutical and antimicrobial compositions comprising such compounds.

(Conventional technology)
It has been conventionally known that glycopeptide derivatives are useful as various antibiotics.

  For example, JP-A-1-240196 discloses a compound PA-45052 which is a glycopeptide antibiotic. Compound PA-45052 has antibacterial activity against methicillin resistant bacteria.

  JP-A-4-108800 discloses a glycopeptide antibiotic (vancomycin antibiotic) represented by the general formula [I] as an antibiotic having antibacterial activity against methicillin-resistant bacteria and vancomycin-resistant bacteria. is doing.

  Recently, however, the emergence of more powerful vancomycin-resistant enterococci (for example, E. faecalis, E. faecium, etc.) has become a problem with the widespread use of antibiotics.

  For example, the glycopeptide antibiotic PA-45052-B (chloroorienticin B) described in the above-mentioned JP-A-1-240196 is disclosed in E.C. faecalis and E.I. For faecium, it only shows a minimum inhibitory concentration (MIC) of more than 25 μg / ml each.

  Therefore, an antibiotic having a superior antibacterial activity against vancomycin-resistant enterococci like these is desired.

  An object of the present invention is to provide a glycopeptide derivative having a novel structure that exhibits excellent activity against vancomycin-resistant enterococci and also exhibits stronger activity against methicillin-resistant bacteria (for example, MRSA). To provide a pharmaceutically acceptable salt, hydrate, or prodrug.

  A further object of the present invention is to provide pharmaceutical and antibacterial compositions comprising such compounds, pharmaceutically acceptable salts, hydrates, or prodrugs thereof.

  As a result of many studies, the present inventors have found a novel glycopeptide derivative that exhibits excellent antibacterial activity against vancomycin-resistant enterococci and methicillin-resistant bacteria.

  The present invention relates to a compound represented by the following formula, or a pharmaceutically acceptable salt, hydrate, or prodrug thereof:

here,
R ¹ is selected from the group consisting of the following (1-1) to (1-8):
(1-1) hydrogen;
(1-2) benzyl optionally having substituent (s), the substituent being halogen, amino, formyl, optionally halogenated alkyl, optionally halogenated alkenyl, halogenated Alkynyl, aryl, arylalkyl, arylalkenyl, or arylalkynyl, or a combination thereof,
Here, the aryl ring in the substituent is further halogen, amino, formyl, alkyl which may be halogenated, alkenyl which may be halogenated, alkynyl which may be halogenated, halogenated or alkyl. Optionally substituted arylalkyl, optionally halogenated arylalkenyl, or optionally halogenated arylalkynyl, or combinations thereof;
(1-3) each optionally substituted alkyl, alkenyl, or alkynyl, wherein the substituent is halogen, amino, optionally halogenated aryl, or a combination thereof;
(1-4) mono or diarylalkylcarbamoyl, mono or diarylalkylthiocarbamoyl, mono or diarylcarbamoyl, or mono or diarylthiocarbamoyl each optionally having a substituent, wherein the substituent is halogen, amino , Formyl, optionally halogenated alkyl, optionally halogenated alkenyl, optionally halogenated alkynyl, alkyl optionally halogenated arylalkyl, alkenyl optionally halogenated Good arylalkenyl, or arylalkynyl, or a combination thereof,
Wherein the aryl ring in the substituent may be further substituted with halogen, formyl, optionally halogenated alkyl, or combinations thereof;
(1-5) mono or dialkylcarbamoyl, or mono or dialkylthiocarbamoyl, each optionally having a substituent, wherein the substituent is halogen, amino, or a combination thereof;
(1-6) each optionally substituted alkylcarbonyl, arylalkylcarbonyl, or arylcarbonyl, wherein the substituent is halogen, amino, or formyl (but limited to aryl ring substitution), Or a combination thereof;
(1-7) alkyloxycarbonyl or alkyloxythiocarbonyl, each optionally having a substituent, wherein the substituent is halogen, amino, optionally halogenated aryl, or a combination thereof And; and
(1-8) alkylurea, arylalkylurea, or arylurea, each of which may have a substituent, wherein the substituent is halogen, amino, or formyl (provided that the aryl ring is substituted only), Or a combination thereof;
However, in (1-2) to (1-8), the existing aryl ring may contain a heteroatom, the α-position methylene of the aryl ring may be substituted with carbonyl, and the existing carbon-carbon single bond Can be interrupted by a heteroatom;
R ² 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)), and two alkyls may be bonded to form a ring. The groups are amino, monoalkylamino, dialkylamino, trialkylammonium, hydroxy, guanidino, carboxy, alkyloxycarbonyl, carbamoyl optionally substituted with cyano, mono or dialkylcarbamoyl, mono or diarylcarbamoyl, aryl, alkylamide or aryl amides, 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 to C3 a A kill, 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 Because
Here, the alkyl in the substituent may be further substituted with amino optionally substituted with alkyloxycarbonyl or aryloxycarbonyl,
Here, the aryl ring in the substituent is further halogen, nitro, amino, hydroxy, carboxy, alkyloxycarbonyl, alkyl optionally substituted with amino, hydroxyalkyl or thioalkyl optionally substituted, Or a combination thereof;
(2-3) cycloalkylamino optionally substituted with amino or hydroxy;
(2-4) Disubstituted methylamino-NHCHR ⁶ R ⁷ , wherein
R ⁶ is selected from carboxy, optionally substituted alkyloxycarbonyl, carbamoyl, optionally substituted monoalkylcarbamoyl, or optionally substituted cycloalkylcarbamoyl. And
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 to 3 and R ^X is C1 to C3 alkyl) optionally substituted aryl, —N ⁺ (R ^X ) ₂ (CH ₂ ) _m COOR ^Y (here R ^Y is hydrogen or C1-C3 alkyl), or —N ⁺ (R ^X ) ₂ (CH ₂ ) _m N ⁺ (R ^X ) ₃ , or a combination thereof;
R ⁷ is indole or thioindole optionally substituted on the nitrogen with C1-C3 alkyl, or imidazolyl;
(2-5) tripeptide ^{R-A 1 -A 2 -A 3} -:
Here, A ¹ , A ² , and A ³ are each an arbitrary amino acid unit, and R is a carboxy terminus of the tripeptide, which may be mono- or optionally substituted with hydroxy, amino, or a substituent Represents dialkylamino and 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) optionally substituted alkoxy, which is further substituted with nitro, hydroxamic acid, or arylcarbonyl optionally substituted with alkyl;
However, in (2-2) to (2-7), the existing aryl ring may contain a heteroatom, and the existing carbon-carbon single bond is a heteroatom or -O (P = O) ( OR ^F ) O—, where R ^F is hydrogen, alkyloxycarbonyl or aryloxycarbonyl, imino, and

Interrupted with a hetero group selected from:
R ³ 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 the alkyl, cycloalkyl and alkylene may each have a substituent, and the substituent is alkyloxy Amino, monoalkylamino, dialkylamino, trialkylammonium optionally substituted with carbonyl or 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 (where m is is 1 to 3, R ^X is a is), or a combination thereof C1~C3 alkyl, wherein said monoalkyl or dialkylamino Alkyl in amino substituents may be further substituted with amino;
(3-3) optionally substituted alkynyl, wherein 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 may 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, imino, and

Interrupted with a hetero group selected from:
R ⁴ is selected from the group consisting of the following (4-1) to (4-6):
(4-1) hydrogen;
(4-2) Alkyl which may have a substituent, wherein the substituent is alkyloxycarbonyl, amino, aryl which may be alkylated, arylcarbonyl, carbamoyl, mono or dialkylcarbamoyl or mono Or a diarylalkylcarbamoyl or a combination thereof
Here, the alkyl or aryl in the substituent may be further substituted with amino, which may be substituted with alkyloxycarbonyl or aryloxycarbonyl, or hydroxy;
(4-3) an optionally substituted alkyloxycarbonyl, wherein the substituent is an optionally alkylated aryl;
(4-4) arylamide or arylthioamide;
(4-5) optionally alkylated amino or amidino; and
(4-6) Nitroso;
However, in (4-2) to (4-5), the existing aryl ring can contain heteroatoms, and the existing carbon-carbon single bond can be interrupted by heteroatoms; and R ⁵ can be Selected from the group consisting of (5-1) to (5-3):
(5-1) hydrogen;
(5-2) glucosyl; and
(5-3) (4-epi-vancosaminyl) -O-glucosyl represented by the following formula:

However, when R ² is hydroxy and R ³ is hydrogen, the following (i) and (ii) are not satisfied simultaneously:
(I) R ¹ is hydrogen, C1-C12 alkyl, C2-C9 alkylcarbonyl,

(Wherein k is 1-3 and R ^a is hydrogen or halogen),

(Where p is 0-2), or

(Where d is 2 or 3)
And (ii) R ⁴ is hydrogen, C1-C12 alkyl, C2-C9 alkylcarbonyl,

(Where k is 1-3 and R ^a is hydrogen, C1-C8 alkyl, or C1-C8 alkoxy), or

(Where d is 2 or 3)
It is.

In one embodiment, the present invention relates to a compound having a substituent defined as follows in formula (I) above, or a pharmaceutically acceptable salt, hydrate, or prodrug thereof:
here,
R ¹ is selected from the group consisting of the following (1-1 ′) to (1-6 ′):
(1-1 ′) hydrogen;
(1-2 ′) benzyl having a substituent, which is halogen, optionally halogenated C3-C12 alkyl, C6-C18 aryl, C6-C18 aryl C1-C8 alkenyl, or C6 -C18 aryl C1-C8 alkynyl, or a combination thereof,
Here, the aryl ring in the substituent may be further substituted with a halogen, an optionally halogenated C1-C12 alkyl, an optionally halogenated C6-C18 aryl C1-C8 alkynyl, or a combination thereof. ;
(1-3 ′) an optionally substituted C8-C17 alkyl, wherein the substituent is halogen, amino, optionally halogenated C6-C12 aryl, or a combination thereof ;
(1-4 ′) Mono-C6-C18 arylcarbamoyl or mono-C6-C18 aryl C5-C13 alkylcarbamoyl which may have a substituent, and the substituent may be halogenated or halogenated C1-C9 alkyl, or C6-C18 aryl C1-C8 alkenyl in which C1-C9 alkyl or alkenyl may be halogenated and aryl may be substituted with C1-C5 alkyl, or combinations thereof,
(1-5 ′) an optionally substituted monoalkylcarbamoyl or monoalkylthiocarbamoyl in which alkyl is C9-C14 alkyl, and the substituent is halogen, amino, or a combination thereof ;and
(1-6 ′) alkylcarbonyl, wherein alkyl is C8-C17 alkyl;
Provided that in (1-2 ′) to (1-6 ′), an existing aryl ring may contain a heteroatom, and an existing carbon-carbon single bond may be interrupted by a heteroatom;
R ² is selected from the group consisting of the following (2-1 ′) to (2-7 ′):
(2-1 ′) hydroxy:
(2-2 ') mono- or di-C1-C30 alkylamino optionally having a substituent, wherein the substituent is substituted with amino, mono- or di-C1-C5 alkylamino, hydroxy, guanidino, cyano is carbamoyl optionally, a mono- or di C6~C10 aryl-carbamoyl, C5-C12 aryl, C6-C12 aryl _{^{amide, -N + (R X) 3}} , -N + (R X) 2 (CH 2) m N ⁺ (R ^Y ) ₃ (where m is 1-3, R ^X is C1-C3 alkyl, and R ^Y is hydrogen or C1-C3 alkyl), or — (C═O) N ⁻ —N ⁺ (CH ₃ ) ₃ , or a combination thereof,
Here, the alkyl in the substituent may be further substituted with amino which may be substituted with C1-C5 alkyloxycarbonyl,
Here, the aryl ring in the substituent may be further substituted with amino, hydroxy, C1-C3 alkyloxycarbonyl, or C1-C8 alkyl optionally substituted with amino;
(2-3 ′) hydroxy substituted C4-C8 cycloalkylamino;
(2-4 ′) disubstituted methylamino-NHCHR ⁶ R ⁷ , wherein
R ⁶ is selected from carboxy, C1-C3 alkyloxycarbonyl, or mono-C1-C5 alkylcarbamoyl having a substituent,
Here, the substituent is trimethylammonium, carboxy, hydroxy, C1-C10 aryl, —N ⁺ (CH ₃ ) ₂ (CH ₂ ) —COOR ^G (where R ^G is hydrogen or C1-C2 alkyl) Or —N ⁺ (CH ₃ ) ₂ — (CH ₂ ) ₂ —N ⁺ (CH ₃ ) ₃ ,
R ⁷ is indole or thioindole optionally substituted with nitrogen by C 1 -C 2 alkyl, or 4-imidazolyl;
(2-5 ′) Tripeptide R—A ¹ —A ² —A ³ —:
Here, A ¹ , A ² , and A ³ are each an amino acid unit independently selected from the group consisting of tryptophan, histidine, lysine, glutamic acid, leucine, serine, tyrosine, glycine, proline, and alanine. Provided that at least one of A ¹ , A ² , and A ³ is tryptophan, histidine, or lysine, and R is the carboxy terminus of the tripeptide and has a hydroxy, amino, or substituent Represents an optionally mono- or di-C1-C3 alkylamino, the substituent being trimethylammonium, guanidino, or 4-imidazolyl;
(2-6 ′) a hydroxamic acid having a substituent, wherein the substituent is a C6-C18 aryl C1-C5 alkyl further substituted with a C1-C3 alkyl; and
(2-7 ′) a C1-C3 alkoxy having a substituent, wherein the substituent is a C6-C10 arylcarbonyl further substituted with a C1-C3 alkyl;
However, in (2-2 ′) to (2-4 ′), (2-6 ′) and (2-7 ′), the aryl ring present may contain a heteroatom, and the carbon-carbon singlet present The bond is a heteroatom or imino and

Interrupted with a hetero group selected from:
R ³ is selected from the group consisting of the following (3-1 ′) to (3-3 ′):
(3-1 ′) hydrogen;
(3-2 ′) C1-C24 alkyl, C5-C24 cycloalkyl or aminomethyl substituted with C5-C10 alkylene, wherein the C1-C24 alkyl, C5-C24 cycloalkyl and C5-C10 alkylene are each substituted. The substituent may be amino, di-C1-C5 alkylamino, tri-C1-C3 alkyl ammonium, C6-C12 aryl, hydroxy, which may be substituted with C1-C5 alkyloxycarbonyl, guanidino, _{^{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 the alkyl in the di C1~C5 alkylamino substituents It may be further substituted by amino; and
(3-3 ′) C6-C12 aryl C1-C5 alkynyl;
However, in (3-2 ′) to (3-3 ′), the existing aryl ring may contain a heteroatom and the existing carbon-carbon single bond is a heteroatom or —O (P═O ) (O ⁻ ) O—, amide, and imino, and

Interrupted with a hetero group selected from:
R ⁴ is selected from the group consisting of the following (4-1 ′) and (4-2 ′):
(4-1 ′) hydrogen, and
(4-2 ′) C10-C30 alkyl optionally substituted with amino;
Provided that in (4-2 ′) the existing carbon-carbon single bond can be interrupted by a heteroatom; and R ⁵ is selected from the group consisting of: (5-1 ′) and (5-2 ′) Is:
(5-1 ′) hydrogen; and
(5-2 ′) Glucosyl.

Preferably, when R ⁵ is hydrogen, R ¹ is selected from the group consisting of hydrogen or the above (1-2 ′) to (1-6 ′), and R ² is the above (2-2 ′) to ( 2-4 ′), (2-6 ′) and (2-7 ′), and R ³ and R ⁴ can each be hydrogen; when R ⁵ is glucosyl, R ¹ to R ⁴ can be a combination of: R ¹ is selected from the group consisting of (1-2 ′) to (1-6 ′) above, R ² is hydroxy, and R ³ and R ⁴ are each hydrogen R ¹ is hydrogen, R ² is selected from the group consisting of (2-2 ′) to (2-4 ′), (2-6 ′) and (2-7 ′) above, and R 2 ³ and R ⁴ are each hydrogen; R ¹ is hydrogen, R ² is hydroxy, R ³ is selected from the group consisting of the (3-2 ') and (3-3'), The R ⁴ and is hydrogen; R ¹ is hydrogen, R ² is hydroxy, R ³ is hydrogen and R ⁴ is the (4-2 '); R ¹ is (1 -2 ') to (1-6') and R ² is selected from the above (2-2 ') to (2-4'), (2-6 ') and (2-7') R ³ and R ⁴ are each hydrogen; R ¹ is selected from the group consisting of (1-2 ′) to (1-6 ′) above, R ² is hydroxy, R ³ Is selected from the group consisting of (3-2 ′) and (3-3 ′) above and R ⁴ is hydrogen; R ¹ is hydrogen and R ² is from (2-2 ′) to (2) above -4 ′), (2-6 ′) and (2-7 ′), R ³ is selected from the group consisting of (3-2 ′) and (3-3 ′) above, and R ⁴ is hydrogen; R ¹ is (1-2 ′) to ( 1-6 ′), R ² is selected from the group consisting of (2-2 ′) to (2-4 ′), (2-6 ′) and (2-7 ′) above, R ³ is selected from the group consisting of (3-2 ′) and (3-3 ′) above and R ⁴ is hydrogen; R ¹ is hydrogen and R ² is above (2-5 ′) And R ³ and R ⁴ are each hydrogen.

In one embodiment, the present invention relates to a compound having a substituent defined as follows in formula (I) above, or a pharmaceutically acceptable salt, hydrate, or prodrug thereof:
here,
R ¹ is selected from the group consisting of: (1-1 ″) to (1-4 ″):
(1-1 ″) hydrogen;
(1-2 ″) substituted benzyl, wherein the substituent is C5-C9 alkyl, C6-C12 aryl, C6-C12 aryl C1-C5 alkenyl, or C6-C12 aryl C1-C5 alkynyl. There,
Here, the aryl ring in the substituent may be further substituted with halogen, optionally halogenated C1-C8 alkyl, or halogenated C6-C12 aryl C1-C5 alkynyl;
(1-3 ″) C9-C15 alkyl optionally substituted with C6-C12 aryl;
(1-4 ″) mono-C6-C18 arylcarbamoyl or mono-C6-C12 aryl C7-C11 alkylcarbamoyl which may have a substituent, wherein the substituent is halogen, C5-C9 alkyl, or C6-C12 aryl C1-C5 alkenyl wherein alkenyl is halogenated and aryl is substituted with C1-C5 alkyl;
A monoalkylthiocarbamoyl, wherein (1-5 ″) alkyl is C9-C14 alkyl; and
(1-6 ″) alkylcarbonyl, wherein alkyl is C10-C14 alkyl;
However, in (1-2 ″), the existing aryl ring may contain a sulfur atom, and in (1-2 ″) and (1-4 ″), the existing carbon-carbon single bond is an oxygen atom. Can be interrupted by;
R ² is selected from the group consisting of the following (2-1 ″) to (2-8 ″):
(2-1 ″) hydroxy:
(2-2 ″) mono- or di-C1-C20 alkylamino optionally having substituent (s), wherein the substituent is carbamoyl, mono- or di-C1 substituted with amino, hydroxy, guanidino, cyano ~C3 alkylamino, C5-C12 aryl, C6-C12 aryl amide ^{or, - (C = O) N} - -N + (CH 3) 3 or a combination thereof,
Here, the alkyl in the substituent may be further substituted with amino optionally substituted with t-butoxycarbonyl,
Wherein the aryl ring in the substituent may be further substituted with C1-C5 alkyl optionally substituted with hydroxy or amino, and may contain a heteroatom selected from nitrogen and sulfur;
(2-3 ″) hydroxy substituted C 5 -C 7 cycloalkylamino; and
(2-4 ″) disubstituted methylamino-NHCHR ⁶ R ⁷ , wherein
R ⁶ is C1-C2 alkyloxycarbonyl, or mono-C2-C4 alkylcarbamoyl having a substituent,
Here, the substituent is 2-imidazolyl or N-quinolyl,
R ⁷ is an indole in which the nitrogen may be methylated, or thioindole; and
(2-5 ″) A tripeptide selected from the following: R ¹ -A ² -A ^3- :
R-Lys-His-Trp-;
R-Leu-Trp-Lys-;
R-Leu-Trp-Tyr-;
R-Ser-His-Trp-;
R-Trp-His-Gly-;
R-Trp-Gly-His-;
R-Trp-Lys-His-;
R-Trp-Pro-His-;
R-Trp-Leu-His-;
R-Tyr-Trp-His-;
R-Tyr-Trp-Leu-;
R-Tyr-Trp-Ser-;
R-Leu-Trp-Tyr-; and R-Trp-Lys-His-,
Where R is the carboxy terminus of the tripeptide and represents hydroxy, amino, or a mono C1-C3 alkylamino having a substituent, wherein the substituent is trimethylammonium, guanidino, or 4-imidazolyl. ;
A hydroxamic acid having a (2-6 ″) substituent, wherein the substituent is benzyl further substituted with methoxy;
However, in (2-2 '') - (2-4 '') and (2-6 ''), the carbon present - carbon single bond may be interrupted by oxygen or imino; R ³ is the following Selected from the group consisting of: (3-1 ″) and (3-2 ″):
(3-1 ″) hydrogen; and
(3-2 ″) C1-C20 alkyl, C5-C10 cycloalkyl or aminomethyl substituted with C5-C7 alkylene, wherein the C1-C20 alkyl, C5-C10 cycloalkyl and C5-C7 alkylene are each The substituent may have an amino, di-C1-C5 alkylamino, tri-C1-C3 alkylammonium, C6-C10 aryl, hydroxy, carboxy which may be substituted with t-butoxycarbonyl. _{^{, -N + (R X) 2}} (CH 2) m N + (R X) 3, or ^{- (C = O) -N -} -N + (R X) 3 ( wherein, m is 1-3 And R ^X is C1-C3 alkyl), or a combination thereof, wherein the alkyl in the di-C1-C5 alkylamino substituent may be further substituted with amino ;
However, in (3-2 ″), the existing aryl ring may contain a nitrogen atom and the carbon-carbon single bond present is oxygen, amide, imino, and

Interrupted with a hetero group selected from:
R ⁴ is selected from the group consisting of: (4-1 ″) and (4-2 ″):
(4-1 ″) hydrogen; and
(4-2 ″) amino substituted C14-C18 alkyl; and R ⁵ is selected from the group consisting of: (5-1 ″) and (5-2 ″):
(5-1 ″) hydrogen; and
(5-2 ″) Glucosyl.

Preferably, when R ⁵ is hydrogen, R ¹ is selected from the group consisting of hydrogen or (1-2 ″) to (1-6 ″) above, and R ³ and R ⁴ may each be hydrogen. When R ⁵ is glucosyl, R ^{1 to} R ⁴ can be a combination of the following: R ¹ is selected from the group consisting of (1-2 ″) to (1-6 ″), and R ² is Hydroxy, R ³ and R ⁴ are each hydrogen; R ¹ is hydrogen and R ² is from (2-2 ″) to (2-4 ″) and (2-6 ″) above. And R ³ and R ⁴ are each hydrogen; R ¹ is hydrogen, R ² is hydroxy, and R ³ is selected from the group consisting of (3-2 ″) above, And R ⁴ is hydrogen; R ¹ is hydrogen, R ² is hydroxy, R ³ is hydrogen, and R ⁴ is (4-2 ″) above; R ¹ is (1 -2 ″) to (1-6 ″), and R ² is a group consisting of the above (2-2 ″) to (2-4 ″) and (2-6 ″) R ³ and R ⁴ are each hydrogen; R ¹ is selected from the group consisting of (1-2 ″) to (1-6 ″) above, R ² is hydroxy, R ³ Is selected from the group consisting of (3-2 ″) above and R ⁴ is hydrogen; R ¹ is hydrogen and R ² is from (2-2 ″) to (2-4 ″) above. and 'is selected from the group consisting of, R ³ is the (3-2 (2-6') 'is selected from the group consisting of'), and R ⁴ is hydrogen; R ¹ is the (1-2 ' ′) To (1-6 ″), and R ² is selected from the group consisting of (2-2 ″) to (2-4 ″) and (2-6 ″) above. , R ³ is selected from the group consisting of the above (3-2 ''), and R ⁴ is hydrogen; ¹ is hydrogen, R ² is the (2-5 ''), and R ³ and R ⁴ are each hydrogen.

In one embodiment, the invention provides a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof, wherein the combination of R ¹ , R ² , R ³ , R ⁴ , and R ⁵ is as follows: , Hydrates, or prodrugs:

  The present invention also relates to pharmaceutical compositions comprising any of the compounds described above or pharmaceutically acceptable salts, hydrates or prodrugs thereof.

  The invention also relates to antimicrobial compositions comprising any of the compounds described above or pharmaceutically acceptable salts, hydrates or prodrugs thereof.

  Hereinafter, preferred embodiments of the present invention will be described in detail.

  The term “heteroatom” as used herein means an atom other than a carbon atom and a hydrogen atom, such as an oxygen atom, a nitrogen atom, a sulfur atom, or a phosphorus atom.

The term “hetero group” as used herein refers to, for example, imino (—NH—), —SO—, —SO ₂ —, amide,

Means a group consisting of a plurality of atoms, including any heteroatom, and may further include hydrogen and / or carbon atoms.

  As used herein, “halogen” means fluoro, chloro, bromo, or iodo.

  As used herein, “alkyl” refers to a straight or branched chain hydrocarbon group and has any chain length unless otherwise specified. Examples of alkyl are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decenyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, icosanyl, henicosanyl, docosanyl, triacontyl, which have no unsaturated bond. Etc. For example, when alkyl is described as “C1-C5 alkyl”, this group may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl. Or neopentyl.

  As used herein, “alkenyl” means a straight or branched chain hydrocarbon group having at least one carbon-carbon double bond, and has an arbitrary chain length unless otherwise specified. Examples of alkenyl include vinylene, propenylene, butadienylene, and the like.

  As used herein, “alkynyl” means a straight or branched chain hydrocarbon group having at least one carbon-carbon triple bond, and has any chain length unless otherwise specified. Examples of alkynyl include ethynylene, propynylene and the like.

  In the alkyl, alkenyl, and alkynyl defined above, the carbon-carbon single bond present (including the single bond formed between the terminal carbon such as alkyl and the carbon of other groups such as aryl) is It may be interrupted by any heteroatom or heterogroup.

  As used herein, “cycloalkyl” refers to a hydrocarbon group containing at least one cyclic alkyl, and has any number of carbons unless otherwise specified. Cycloalkyls may further include an alkyl chain moiety. Examples of cycloalkyl include cyclopentyl, cyclohexyl, cycloheptyl and the like.

  In cycloalkyl, the carbon-carbon single bond in the ring may be interrupted by any heteroatom or heterogroup. For example, cycloalkyl interrupted by an oxygen atom typically includes glucose and its isomers, and derivatives thereof and polymers thereof.

  As used herein, “aryl” refers to a carbocyclic group having at least one aromatic ring and includes, for example, phenyl, biphenyl, terphenyl, naphthyl, anthranyl, phenanthryl and the like. In the carbocyclic structure of aryl, a hetero atom or a hetero group may be interposed. Examples of such aryl include indole, quinolyl, imidazolyl, oxazolyl, piperidino, oxazino and the like. For example, when aryl is described as “C6-C18 aryl”, the group may mean, for example, phenyl, biphenyl, naphthyl, indole, and the like.

  As used herein, “arylalkyl”, “arylalkenyl”, and “arylalkynyl” represent a group in which alkyl, alkenyl, and alkynyl as defined above are respectively added to aryl as defined above. These groups may have an arbitrary substituent as necessary.

As used herein, “tripeptide” means a group having the following structure:
^{R-A 1 -A 2 -A 3} -
Here, A ¹ , A ² , and A ³ are each an arbitrary amino acid unit and are sequentially connected by an amide bond (—NHCO—). R is the carboxy terminus of the tripeptide and is hydroxy, amino or mono- or dialkylamino optionally having substituent (s). Here, the “amino acid” can be any amino acid known to those skilled in the art, preferably an α-amino acid, and more preferably any of the 20 types of amino acids that are normally present in nature. Amino acids specifically used in the compounds of the present invention may include tryptophan, histidine, lysine, glutamic acid, leucine, serine, tyrosine, glycine, proline, and alanine.

In preferred compounds of the invention, R ¹ can be a group as follows:
(1-1) Hydrogen.

(1-2) benzyl which may have a substituent. Examples include groups selected from the group represented by (1-2A) below:
(1-2A)

More preferable examples of the group (1-2) include groups selected from the group represented by the following (1-2B):
(1-2B)

Further preferred examples of the group (1-2) include groups selected from the group represented by the following (1-2C):
(1-2C)

Examples of the most preferred (1-2) group include groups selected from the group represented by the following (1-2D):
(1-2D)

(1-3) Alkyl, alkenyl, or alkynyl which may have a substituent. Examples include groups selected from the group represented by the following (1-3A):
(1-3A)

More preferred examples of the group (1-3) include groups selected from the group represented by the following (1-3B):
(1-3B)

More preferable examples of the group (1-3) include groups selected from the group represented by the following (1-3C):
(1-3C)

(1-4) Mono or diarylalkylcarbamoyl, mono or diarylalkylthiocarbamoyl, mono or diarylcarbamoyl, or mono or diarylthiocarbamoyl which may have a substituent. Examples include groups selected from the group represented by (1-4A) below:
(1-4A)

More preferred examples of the group (1-4) include groups selected from the group represented by the following (1-4B):
(1-4B)

More preferred examples of the group (1-4) include groups selected from the group represented by the following (1-4C):
(1-4C)

Examples of the most preferred group (1-4) include groups selected from the group represented by the following (1-4D):
(1-4D)

(1-5) Mono- or dialkylcarbamoyl or mono- or dialkylthiocarbamoyl each optionally having a substituent. Examples include groups selected from the group represented by (1-5A) below:
(1-5A)

More preferred examples of the group (1-5) include groups selected from the group represented by the following (1-5B):
(1-5B)

Further preferred examples of the group (1-5) include groups selected from the group represented by the following (1-5C):
(1-5C)

(1-6) alkylcarbonyl, arylalkylcarbonyl, or arylcarbonyl each optionally having a substituent. Examples include groups selected from the group represented by (1-6A) below:
(1-6A)

More preferred examples of the group (1-6) include groups selected from the group represented by the following (1-6B):
(1-6B)

(1-7) alkyloxycarbonyl or alkyloxythiocarbonyl, each optionally having a substituent. Examples include groups selected from the group represented by (1-7A) below:
(1-7A)

    (1-8) Alkylurea, arylalkylurea, or arylurea each optionally having a substituent.

In preferred compounds of the invention, R ² can be a group as follows:
(2-1) Hydroxy.

(2-2) Mono or dialkylamino optionally having a substituent. Examples include groups selected from the group represented by (2-2A) below:
(2-2A)

More preferred examples of the group (2-2) include groups selected from the group represented by the following (2-2B):
(2-2B)

More preferred examples of the group (2-2) include groups selected from the group represented by the following (2-2C):
(2-2C)

Examples of the most preferred group (2-2) include groups selected from the group represented by the following (2-2D):
(2-2D)

(2-3) Cycloalkylamino optionally substituted with amino or hydroxy. Examples include groups represented by the following (2-3A):
(2-3A)

(2-4) disubstituted methylamino -NHCHR ⁶ R ^7. Examples include groups selected from the group represented by (2-4A) below:
(2-4A)

More preferred examples of the group (2-4) include groups selected from the group represented by the following (2-4B):
(2-4B)

More preferable examples of the group (2-4) include groups selected from the group represented by the following (2-4C):
(2-4C)

Examples of the most preferred group (2-4) include groups selected from the group represented by the following (2-4D):
(2-4D)

(2-5) Tripeptide R—A ¹ —A ² —A ³ — (wherein R, A ¹ , A ² , and A ³ are as defined above). Examples include groups selected from the group represented by (2-5A) below:
(2-5A)

More preferred examples of the group (2-5) include groups selected from the group represented by the following (2-5B):
(2-5B)

Further preferred examples of the group (2-5) include groups selected from the group represented by the following (2-5C):
(2-5C)

Examples of the most preferred group (2-5) include groups selected from the group represented by the following (2-5D):
(2-5D)

(2-6) hydrazino or hydroxamic acid optionally having a substituent. Examples include groups selected from the group represented by (2-6A) below:
(2-6A)

More preferred examples of the group (2-6) include groups selected from the group represented by the following (2-6B):
(2-6B)

(2-7) Alkoxy which may have a substituent. Examples include groups selected from the group represented by (2-7A) below:
(2-7A)

More preferred examples of the group (2-7) include groups selected from the group represented by the following (2-7B):
(2-7B)

In preferred compounds of the invention, R ³ can be a group as follows:
(3-1) Hydrogen.

(3-2) Aminomethyl optionally substituted with alkyl, cycloalkyl or alkylene. Examples include groups selected from the group represented by (3-2A) below:
(3-2A)

More preferable examples of the group (3-2) include groups selected from the group represented by the following (3-2B):
(3-2B)

More preferable examples of the group (3-2) include groups selected from the group represented by the following (3-2C):
(3-2C)

Examples of the most preferred (3-2) group include groups selected from the group represented by the following (3-2D):
(3-2D)

(3-3) Alkynyl which may have a substituent. Examples include groups selected from the group represented by (3-3A) below:
(3-3A)

More preferred examples of the group (3-3) include groups selected from the group represented by the following (3-3B):
(3-3B)

    (3-4) Halogen. This is selected from (3-4A) fluoro, chloro, bromo, or iodo.

In preferred compounds of the invention, R ⁴ can be a group as follows:
(4-1) Hydrogen.

(4-2) Alkyl which may have a substituent. Examples include groups selected from the group represented by (4-2A) below:
(4-2A)

More preferred examples of the group (4-2) include groups selected from the group represented by the following (4-2B):
(4-2B)

(4-3) Alkyloxycarbonyl optionally having a substituent. Examples include groups selected from the group represented by the following (4-3A):
(4-3A)

(4-4) Arylamide or arylthioamide. Examples include groups selected from the group represented by (4-4A) below:
(4-4A)

(4-5) Amino or amidino which may be alkylated. Examples include groups selected from the group represented by (4-5A) below:
(4-5A)

(4-6) Nitroso. Such a group is represented by the following (4-6A):
(4-6A)

In preferred compounds of the invention, R ⁵ can be a group as follows:
(5-1) hydrogen;
(5-2) Glucosyl.

When R ⁵ is hydrogen, preferably R ¹ is hydrogen or (1-2A), (1-3A), (1-4A), (1-5A), (1-6A), (1 -7A) and (1-8A), R ² is selected from the above (2-2A), (2-3A), (2-4A), (2-6A), and (2-7A) ) And R ³ and R ⁴ can each be hydrogen. When R ⁵ is glucosyl, preferably R ^{1 to} R ⁴ can be any of the following combinations: R ¹ is (1-2A), (1-3A), (1-4A), (1 1-5A), (1-6A), (1-7A), and (1-8A), R ² is hydroxy, and R ³ and R ⁴ are each hydrogen; R ¹ is hydrogen, R ² is selected from the group consisting of (2-2A), (2-3A), (2-4A), (2-6A), and (2-7A) above, and R ³ And R ⁴ are each hydrogen; R ¹ is hydrogen, R ² is hydroxy, and R ³ is selected from the group consisting of (3-2A), (3-3A), and (3-4A) above. is, and R ⁴ is hydrogen; R ¹ is hydrogen, R ² is hydroxy, R ³ is hydrogen and R ⁴ is Serial (4-2A), (4-3A), are selected from the group consisting of (4-5A), and (4-6A); R ¹ above (1-2A), (1-3A), ( 1-4A), (1-5A), (1-6A), (1-7A), and (1-8A), and R ² is selected from the above (2-2A), (2-3A) ), (2-4A), (2-6A), and (2-7A), wherein R ³ and R ⁴ are each hydrogen; R ¹ is the above (1-2A), (1 -3A), (1-4A), (1-5A), (1-6A), (1-7A), and (1-8A), R ² is hydroxy, R ³ Is selected from the group consisting of (3-2A), (3-3A), and (3-4A) above, and R ⁴ is hydrogen; R ¹ is hydrogen and R ² is the above (2-2A ) , (2-3A), (2-4A), (2-6A), and (2-7A), wherein R ³ is the above (3-2A), (3-3A), and ( 3-4A) and R ⁴ is hydrogen; R ¹ is (1-2A), (1-3A), (1-4A), (1-5A), (1- 6A), (1-7A), and (1-8A), and R ² is selected from (2-2A), (2-3A), (2-4A), (2-6A), and is selected from the group consisting of (2-7A), R ³ is the (3-2A), are selected from the group consisting of (3-3A), and (3-4A), and R ⁴ is hydrogen; R ¹ is hydrogen, R ² is selected from the group consisting of (2-5A) above, and R ³ and R ⁴ are each hydrogen.

When R ⁵ is hydrogen, more preferably R ¹ is hydrogen or from (1-2B), (1-3B), (1-4B), (1-5B), and (1-6B) above. R ² is selected from the group consisting of (2-2B), (2-4B), (2-6B), and (2-7B) above, and R ³ and R ⁴ are each hydrogen It can be. When R ⁵ is glucosyl, more preferably R ^{1 to} R ⁴ can be any of the following combinations: R ¹ is (1-2B), (1-3B), (1-4B), Selected from the group consisting of (1-5B), and (1-6B), R ² is hydroxy, and R ³ and R ⁴ are each hydrogen; R ¹ is hydrogen and R ² is 2-2B), (2-4B), (2-6B), and (2-7B), and R ³ and R ⁴ are each hydrogen; R ¹ is hydrogen, R 2 ² is hydroxy, R ³ is selected from the group consisting of (3-2B) and (3-3B) above, and R ⁴ is hydrogen; R ¹ is hydrogen and R ² is hydroxy , R ³ is hydrogen and R ⁴ is selected from the group consisting of the (4-2B); R ¹ above 1-2B), (1-3B), ( 1-4B), (1-5B), and (is selected from the group consisting 1-6B), R ² is the (2-2B), (2-4B ), (2-6B), and (2-7B), wherein R ³ and R ⁴ are each hydrogen; R ¹ is (1-2B), (1-3B), (1 -4B), (1-5B), and (1-6B), R ² is hydroxy, R ³ is selected from the group consisting of (3-2B) and (3-3B) above. And R ⁴ is hydrogen; R ¹ is hydrogen and R ² is selected from the group consisting of (2-2B), (2-4B), (2-6B), and (2-7B) above. R ³ is selected from the group consisting of (3-2B) and (3-3B) above, and R ⁴ is hydrogen; R ¹ is (1-2B) above, R1 is selected from the group consisting of (1-3B), (1-4B), (1-5B), and (1-6B), and R ² is (2-2B), (2-4B), (2- 6B), and (2-7B), R ³ is selected from the group consisting of (3-2B) and (3-3B) above, and R ⁴ is hydrogen; R ¹ is Hydrogen, R ² is selected from the group consisting of (2-5B) above, and R ³ and R ⁴ are each hydrogen.

When R ⁵ is hydrogen, more preferably R ¹ is selected from the group consisting of hydrogen or (1-2C), (1-3C), (1-4C), and (1-5C) above, R ² is selected from the group consisting of (2-2C) and (2-4C) above, and R ³ and R ⁴ can each be hydrogen. When R ⁵ is glucosyl, more preferably R ^{1 to} R ⁴ can be any of the following combinations: R ¹ is (1-2C), (1-3C), (1-4C), And (1-5C), R ² is hydroxy, and R ³ and R ⁴ are each hydrogen; R ¹ is hydrogen, R ² is (2-2C) above, and Selected from the group consisting of (2-4C), and R ³ and R ⁴ are each hydrogen; R ¹ is hydrogen, R ² is hydroxy, and R ³ is the group consisting of (3-2C) above And R ⁴ is hydrogen; R ¹ is selected from the group consisting of (1-2C), (1-3C), (1-4C), and (1-5C) above, and R ² is is selected from the group consisting of the (2-2C), and (2-4C), R ³ and R ⁴ each Is hydrogen; R ¹ is the (1-2C), (1-3C), is selected from the group consisting of (l-4C), and (1-5C), R ² is hydroxy, R ³ is the (3-2C) and R ⁴ is hydrogen; R ¹ is hydrogen, R ² is selected from the group consisting of (2-2C) and (2-4C) above; R ³ is selected from the group consisting of (3-2C) above, and R ⁴ is hydrogen; R ¹ is (1-2C), (1-3C), (1-4C), and (1- 5C), R ² is selected from the group consisting of (2-2C) and (2-4C) above, R ³ is selected from the group consisting of (3-2C) above, and R ⁴ Is hydrogen; R ¹ is hydrogen, R ² is selected from the group consisting of (2-5C) above, and R ³ and R ⁴ are each water It is prime.

When R ⁵ is hydrogen, most preferably R ¹ is selected from the group consisting of hydrogen or (1-2D) and (1-4D) above, and R ² is (2-2D) above and ( 2-4D) and R ³ and R ⁴ can each be hydrogen. When R ⁵ is glucosyl, most preferably R ^{1 to} R ⁴ can be any of the following combinations: R ¹ is selected from the group consisting of (1-2D) and (1-4D) above R ² is hydroxy and R ³ and R ⁴ are each hydrogen; R ¹ is hydrogen and R ² is selected from the group consisting of (2-2D) and (2-4D) above; And R ³ and R ⁴ are each hydrogen; R ¹ is hydrogen, R ² is hydroxy, R ³ is selected from the group consisting of (3-2D) above, and R ⁴ is hydrogen; R ¹ is selected from the group consisting of (1-2D) and (1-4D) above, R ² is selected from the group consisting of (2-2D) and (2-4D) above, and R ³ and R ⁴ It is each hydrogen; R ¹ is the (1-2D), and (1-4D) Tona Is selected from the group, R ² is hydroxy, R ³ is selected from the group consisting of the (3-2D), and R ⁴ is hydrogen; R ¹ is hydrogen, R ² is the (2- 2D), and (2-4D), R ³ is selected from the group consisting of (3-2D) above, and R ⁴ is hydrogen; R ¹ is (1-2D) above, and is selected from the group consisting of (1-4D), R ² is selected from the group consisting of the (2-2D), and (2-4D), R ³ is selected from the group consisting of the (3-2D) And R ⁴ is hydrogen; R ¹ is hydrogen, R ² is selected from the group consisting of (2-5D) above, and R ³ and R ⁴ are each hydrogen.

  The compounds of the present invention preferably have a level of antibacterial activity that satisfies at least one of the following (1), (2), and (3): MIC value for faecalis of 25.0 μg / ml or less; 25.0 μg / ml or less as MIC value for faecium; and (3) 0.4 μg / ml or less as MIC value for MRSA (S. aureus).

  More preferably, the compounds of the present invention have a level of antimicrobial activity that satisfies at least one of the following (1), (2), and (3): (1) MIC value for faecalis is 12.5 μg / ml or less; MIC value for faecium is 12.5 μg / ml or less; and (3) MIC value for MRSA (S. aureus) is 0.2 μg / ml or less.

  Most preferably, the compounds of the present invention more preferably have a level of antibacterial activity that satisfies at least one of the following (1), (2), and (3): MIC value for faecalis is 6.25 μg / ml or less; 6.25 μg / ml or less as MIC value for faecium; and (3) 0.1 μg / ml or less as MIC value for MRSA (S. aureus).

  The method for measuring the MIC value is well known, and can be carried out, for example, according to the micro liquid dilution method described in the Examples below.

  The compounds of the present invention can be prepared by any known method. Specific methods for preparing the compounds of the present invention are illustrated by the examples detailed below, but are not limited to these methods.

  The compounds of the invention can be provided in the form of a salt or hydrate, as appropriate. Examples of the base that can form a salt with the compound of the present invention include alkali metals (for example, sodium, potassium and the like), alkaline earth metals (for example, magnesium, calcium and the like). An inorganic acid (for example, hydrochloric acid, sulfuric acid, nitric acid, etc.) and an organic acid (for example, acetic acid, fumaric acid, etc.) are mentioned.

  The compounds of the invention can also be provided in the form of prodrugs. Prodrugs are derivatives of the compounds of the invention having groups that can be chemically or metabolically degraded to give compounds of the invention that are pharmaceutically active in vivo by solvolysis or under physiological conditions. Methods for selecting and producing suitable prodrug derivatives are well known and are described, for example, in Design of Prodrugs, Elsevier, Amsterdam 1985.

  Examples of prodrugs include ester derivatives produced by reacting an appropriate alcohol and amide derivatives produced by reacting an appropriate amine when the compound of the present invention has a carboxyl group. Particularly preferred esters as prodrugs include methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, tert-butyl ester, morpholinoethyl ester and the like.

Another example of a prodrug is an acyloxy derivative prepared by reacting a suitable acyl halide or a suitable acid anhydride when the compound of the present invention has a hydroxyl group. Particularly preferred acyloxy as _{prodrugs, -OCOC 2 H 5, -OCO (} t-Bu), - OCOC 15 H 31, -OCO (m-COONa-Ph), - OCOCH 2 CH 2 COONa, -OCOCH (NH _{2) CH 3, -OCOCH 2 N} (CH 3) 2 and the like.

As another example of a prodrug, when the compound of the present invention has an amino group, an amide derivative produced by reacting a compound having an amino group with an appropriate acid halide or an appropriate mixed acid anhydride Can be mentioned. Particularly preferred amides as prodrugs include —NHCO (CH ₂ ) ₂₀ CH ₃ , —NHCOCH (NH ₂ ) CH _{3 and the} like.

  The compounds of the present invention or pharmaceutically acceptable salts, hydrates, or prodrugs thereof can be formulated into pharmaceutical or antimicrobial compositions by any method known to those skilled in the art. For example, the compounds of the present invention can be mixed with any pharmaceutically acceptable carrier known in the art for oral administration (eg, tablets, capsules, powders, aerosols, etc.) or parenteral administration (eg, , Injections, coatings, suppositories, etc.) or pharmaceutical compositions or antibacterial compositions. Pharmaceutically acceptable carriers known in the art that can be used in the present invention include, for example, corn starch, gelatin, lactose, sucrose, cellulose, kaolin, mannitol, calcium phosphate, sodium chloride, and alginic acid.

  The pharmaceutical composition or antibacterial composition of the present invention includes other optional additives as long as they do not substantially inhibit the antibacterial activity of the compound of the present invention and cause undesirable side effects on the living body. Examples include diluents, disintegrants, binders, lubricants, flavoring agents, and coloring agents.

  The pharmaceutical composition or antibacterial composition of the present invention is administered orally or parenterally. When administered parenterally (eg, intravenously), it can be dissolved in any fluid known in the art. Examples of such fluids include physiological saline, Ringer's solution, or dextrose solution. The dosage of the antibacterial composition for oral or parenteral administration can be about 1 to about 100 mg / kg body weight per day for an adult as the amount of the compound of the present invention as the active ingredient.

  The dosage of the pharmaceutical composition or antibacterial composition of the present invention can be appropriately determined depending on various factors such as the purpose of treatment, the individual, and symptoms thereof.

  The following examples are intended only to illustrate the present invention and are not intended to limit the present invention.

The compounds of the present invention were synthesized according to the following examples. The compounds synthesized in the following examples are modified forms in which at least one of R ¹ , R ² , R ³ and R ⁴ is substituted in the glycopeptide derivative represented by the following formula (I) (where R ⁵ = glucosyl group), as well as deglucose modifiers (where R ⁵ = H). In the table, G represents a glucosyl group:

  Below, the typical synthesis method of each compound is shown.

Example 1 Synthesis of Intermediate Compound Compounds 140, 141, and 142 used as intermediates in the synthesis of glycopeptide derivatives 1, 9, 10, 78, 101, and 125 were synthesized. The typical synthesis method of these intermediate compounds is illustrated below.

Example 1-1 Synthesis of Intermediate Compound 140
Chloroorienticin B hydrochloride (20.0 g, 12.4 mmol) is dissolved in a mixed solvent of dimethylsulfoxide-dimethylformamide (100 ml-200 ml) under a nitrogen gas stream. To this solution, 1.8 ml of triethylamine and 3.93 g of S-paramethoxybenzyloxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine are sequentially added and stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, and 120 ml of the resulting residue was added dropwise to 1 liter of 5% saline stirred under ice cooling, and the pH was adjusted to 3 with 1N hydrochloric acid, followed by precipitation. The white insoluble material is collected by filtration, rinsed with water, and dried for 3 days. The obtained solid was suspended in 500 ml of ethyl acetate and stirred at room temperature for 2 hours. The insoluble material was collected by filtration and dried to obtain compound 140 (20.8 g, yield 100%).

(Example 1-2: Synthesis of intermediate compound 141)
Compound 140 (10.0 g, 5.76 mmol) is dissolved in a mixed solvent of dimethylformamide-methanol (300 ml-200 ml) under a nitrogen gas stream. To this solution is added 5.596 g of 4- [2- (4-chlorophenyl) vinyl] benzaldehyde and stirred at 70 degrees. After 1 hour, 1.144 g of sodium cyanoborohydride is added and stirred at 70 degrees for an additional 18 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The obtained residue was added dropwise to 1000 ml of 5% brine stirred under ice-cooling, and the yellowish white insoluble matter precipitated was collected by filtration and washed with water. After rinsing, dry for 3 days. The obtained solid was suspended in 400 ml of ethyl acetate and stirred at room temperature for 2 hours, and then the insoluble material was collected by filtration and dried to obtain compound 141 (10.974 g, yield 97%).

(Example 1-3: Synthesis of compound 142)
Compound 141 (300 mg, 0.122 mmol) is dissolved in a mixed solvent of acetonitrile-water (12 ml-10 ml). To this solution, 211 mg of D-glucosamine hydrochloride was added, 1.63 ml of 1N sodium hydroxide aqueous solution was added to adjust the pH to 10, and 0.061 ml of 37% -formaldehyde aqueous solution was further added. Stir for 5 hours. The reaction solution was adjusted to pH 3 by adding 2.1 ml of 1N hydrochloric acid, added dropwise to 400 ml of acetone stirred under ice-cooling, stirred for 30 minutes, and the precipitated white insoluble matter was collected by filtration. Dry to give compound 142 (344 mg).

  The structures of the obtained compounds 140, 141, and 142 are as shown in Table 1 below.

Example 2 Synthesis of R ¹ Modified Glycopeptide Derivatives (Compounds 1 to 15) The following R ¹ modified glycopeptide derivatives were synthesized by variously changing the R ¹ group of the glycopeptide derivative. In this example, R ² is an OH group, R ³ and R ⁴ are each hydrogen, and R ⁵ is a glucosyl group.

Examples of typical methods for synthesizing R ¹ -modified glycopeptide derivatives are shown below.

  Example 2-1 Synthesis of Compound 1

  Compound 141 (236 mg, 0.096 mmol) is suspended in 2.5 ml of water, to which 5 ml of trifluoroacetic acid is added dropwise under ice cooling, and the mixture is stirred for 1 hour under ice cooling. The reaction solution was added dropwise to 100 ml of a 0.7N sodium carbonate aqueous solution stirred under ice-cooling, neutralized once, adjusted to pH 3 with 1N-hydrochloric acid, and further insoluble in 100 ml of methanol. Dissolve the product. This is purified on a rover column (Merck, LiChroprep RP-18 size B; the same shall apply hereinafter). Fractions eluted with 28% acetonitrile / 5 mM hydrochloric acid are collected and concentrated, and poly-4-vinylpyridine is added to the concentrated solution to adjust the pH to 5. After filtration, the filtrate is concentrated again and the residue is lyophilized to give the hydrochloride salt of Compound 1 (58 mg, 36% yield).

  (Example 2-2: Synthesis of compound 9)

  Compound 140 (600 mg, 0.316 mmol) is dissolved in 14 ml of dimethyl sulfoxide under a nitrogen gas stream. To this solution, 0.062 ml of triethylamine and 138 mg of S-dodecylcarbonyl-4,6-dimethyl-2-mercaptopyrimidine are sequentially added and stirred at room temperature for 4 hours. The reaction solution was added dropwise to 140 ml of 5% saline stirred under ice cooling, and the pH was adjusted to 3 with 1N-hydrochloric acid, and the precipitated white insoluble matter was collected by filtration and rinsed with water. Then dry overnight. Further, the obtained solid was rinsed with ethyl acetate and then dried to obtain a white solid (603 mg). Next, the obtained solid (403 mg) is suspended in 4 ml of water, 8 ml of trifluoroacetic acid is added dropwise thereto under ice cooling, and the mixture is stirred for 1 hour under ice cooling. The reaction solution was added dropwise to 100 ml of 1N sodium carbonate aqueous solution stirred under ice-cooling, neutralized once, adjusted to pH 3 with 1N-hydrochloric acid solution, and further 100 ml of methanol was added to remove insoluble matter. Dissolve. This is purified on a rover column. Fractions eluting with 30% acetonitrile / 5 mM hydrochloric acid are collected and concentrated, and poly-4-vinylpyridine is added to the concentrated solution to adjust the pH to 5. After filtration, the filtrate is concentrated again and the residue is lyophilized to give compound 9 hydrochloride (103 mg, 36% yield).

  (Example 2-3: Synthesis of compound 10)

  Compound 140 (600 mg, 0.323 mmol) is dissolved in 12 ml of dimethylformamide under a nitrogen gas stream. To this solution, 128 mg of undecyl isocyanate and 40 mg of 4-dimethylaminopyridine are sequentially added and stirred at room temperature for 16 hours. A 40% methylamine / methanol solution (25 mg) is added dropwise to the reaction mixture under ice-cooling, and the mixture is concentrated under reduced pressure. The obtained residue was added dropwise to 100 ml of 5% saline stirred under ice cooling, and the pH was adjusted to 3 with 1N-hydrochloric acid, and the precipitated white insoluble matter was collected by filtration and washed with water. Rinse and dry overnight. Further, the obtained solid was rinsed with ethyl acetate and then dried to obtain a white solid (640 mg). Next, the obtained solid (640 mg) is suspended in 7 ml of water, to which 16 ml of trifluoroacetic acid is added dropwise under ice cooling, and the mixture is stirred for 1 hour under ice cooling. The reaction solution was added dropwise to 150 ml of a 1.3N sodium carbonate aqueous solution stirred under ice-cooling, neutralized once, adjusted to pH 9 with a 1N sodium hydroxide aqueous solution, and 350 ml of methanol was further added. To dissolve insoluble matter. This is purified on a rover column. Fractions eluted with 30% acetonitrile / 5 mM sodium bicarbonate aqueous solution are collected, adjusted to pH 5 with 1N-hydrochloric acid and concentrated, and the precipitated white insoluble matter is collected by filtration. After rinsing with water, lyophilization overnight yields the hydrochloride salt of compound 10 (232 mg, 56% yield).

Each compound was detected by high performance liquid chromatograph (HPLC) and identified by FAB mass spectrum. Table 2 below shows the acetonitrile content and retention time of the solvent used in the mobile phase, and the mass spectrum molecular ion peak [M + H] ⁺ .

The analysis conditions of HPLC are as follows.
Column: Cosmosil 5C-18AR (Nacalai Tesque)
Mobile phase: acetonitrile-water (containing 0.1% trifluoroacetic acid)
Flow rate: 1.0 ml / min
Detector: UV-280nm

Example 3 Synthesis of R ² Modified Glycopeptide Derivatives (Compounds 16 to 51) The following R ² modified glycopeptide derivatives were synthesized by variously changing the R ² group of the glycopeptide derivatives. In this example, R ¹ is an H group, R ³ and R ⁴ are each hydrogen, and R ⁵ is a glucosyl group.

Examples of typical methods for synthesizing R ² -modified glycopeptide derivatives are shown below.

  Example 3-1 Synthesis of Compound 37

286 mg (0.18 mmol) of chloroorienticin B hydrochloride is dissolved in a mixed solvent of dimethyl sulfoxide-dimethylformamide (2 ml-1 ml). To this solution, 29 mg of N-hydroxybenztriazole, 0.1 ml of N-methylmorpholine, 113 mg of benzotriazol-1-yl-oxy-tripyrrolidinophosphonium hexafluorophosphate were sequentially added, and 53 mg of L-tryptophan methyl ester hydrochloride was added. Add and stir at room temperature for 6 hours.
Ethyl acetate is added to the reaction solution, and the resulting precipitate is collected by filtration and purified by a rover column. Fractions eluted with 40% methanol / 5 mM hydrochloric acid are collected and concentrated, and poly-4-vinylpyridine is added to the concentrated solution to adjust the pH to 4. After filtration, the filtrate is concentrated again and lyophilized to give compound 37 hydrochloride (265 mg, 75% yield).

  Example 3-2: Synthesis of Compound 38

  190 mg of the hydrochloride salt of Compound 37 is dissolved in 10 ml of 30% -dimethylformamide aqueous solution, 1.2 ml of 1N sodium hydroxide aqueous solution is added, and the mixture is stirred at room temperature. After 30 minutes, 1.2 ml of 1N sodium hydroxide aqueous solution was added and the mixture was further stirred for 30 minutes, and then the pH was adjusted to 4 with 1N hydrochloric acid water. The solvent is distilled off under reduced pressure, and the remaining gel is purified on a rover column. Fractions eluted with 30% methanol / 5 mM hydrochloric acid are collected and concentrated, and poly-4-vinylpyridine is added to the concentrated solution to adjust the pH to 4. After filtration, the filtrate is concentrated again and lyophilized to give the hydrochloride salt of Compound 38 (145 mg, 70% yield).

  Example 3-3 Synthesis of Compound 39

  110 mg of the hydrochloride of compound 38 is dissolved in a mixed solvent of dimethyl sulfoxide-dimethylformamide (1.5 ml-0.5 ml). After adding 11 mg of N-hydroxybenztriazole, 0.07 ml of N-methylmorpholine, and 39 mg of benztriazol-1-yl-oxy-tripyrrolidinophosphonium hexafluorophosphate to this solution, (2-aminoethyl) trimethylammonium chloride hydrochloride Add 14 mg of salt and stir at room temperature for 2 hours 30 minutes. Ethyl acetate is added to the reaction solution, and the resulting precipitate is collected by filtration and purified by a rover column. Fractions eluted with 20% methanol / 5 mM hydrochloric acid are collected and concentrated, and poly-4-vinylpyridine is added to the concentrated solution to adjust the pH to 4. After filtration, the filtrate is concentrated again and lyophilized to give compound 39 hydrochloride (66 mg, 50% yield).

Each compound was detected by HPLC and identified by FAB mass spectrum. Table 3 below shows the acetonitrile content and retention time of the solvent used in the mobile phase, and the mass spectrum molecular ion peak [M + H] ⁺ .

Here, the HPLC analysis conditions are the same as those in Example 2.
(* Indicates that the counter anion (Cl ⁻ ) has been detected as a cation peak, and ** indicates that it has been detected as a divalent ion peak.)

Example 4 Synthesis of R ³ Modified Glycopeptide Derivatives (Compounds 52 to 57) The following R ³ modified glycopeptide derivatives were synthesized by variously changing the R ³ group of the glycopeptide derivatives. In this example, R ¹ is an H group, R ² is an —OH group, R ⁴ is hydrogen, and R ⁵ is a glucosyl group.

Examples of typical methods for synthesizing R ³ -modified glycopeptide derivatives are shown below.

  Example 4-1 Synthesis of Compound 52

  Dissolve 2.06 g of chloroorienticin B hydrochloride in dimethylformamide-water (10 ml-10 ml). Add 0.59 g of iodine with cooling and stirring in an ice-water bath, and stir for 1 hour under cooling in an ice-water bath and then at room temperature for 1 hour. The reaction solution is concentrated under reduced pressure, ethyl acetate is added to the residue, and the mixture is powdered and collected by filtration, and then purified by a rover column. Fractions eluted with 20% methanol / 5 mM hydrochloric acid to 60% methanol / 5 mM hydrochloric acid are collected and concentrated, and poly-4-vinylpyridine is added to the concentrate to adjust the pH to 4. After filtration, the filtrate is concentrated again and lyophilized to give the hydrochloride of compound 52 (1.75 g, 72% yield).

  (Example 4-2: Synthesis of compound 53)

  Dissolve 202 mg of the hydrochloride salt of Compound 52 in dimethylformamide-water (7 ml-7 ml), add 120 μl of triethylamine, 16 mg of copper (I) iodide, 46 μl of phenylacetylene, and 30 mg of bistriphenylphosphine palladium dichloride. Heat and stir. After 2 hours, 23 μl of phenylacetylene is added, and the mixture is further stirred at 80 ° C. for 1 hour and 30 minutes. The reaction solution is filtered, and the oil obtained by concentrating the filtrate under reduced pressure is purified by a rover column. Fractions eluted with 40% methanol / 5 mM hydrochloric acid are collected and concentrated, and poly-4-vinylpyridine is added to the concentrated solution to adjust the pH to 4. After filtration, the filtrate is concentrated again and lyophilized to give the hydrochloride salt of Compound 53 (40 mg, 19% yield).

  (Example 4-3: Synthesis of compound 55)

  319 mg of chloroorienticin B hydrochloride is dissolved in acetonitrile-water (7 ml-7 ml), 0.24 ml of 1-aminodecane and 76 μl of 37% -formaldehyde aqueous solution are added, and the mixture is stirred at room temperature for 10 hours. 1N-hydrochloric acid is added to the reaction solution to adjust the pH to 4, followed by concentration under reduced pressure and purification with a rover column. Fractions eluted with 45% methanol / 5 mM hydrochloric acid are collected and concentrated, and poly-4-vinylpyridine is added to the concentrated solution to adjust the pH to 4. After filtration, the filtrate is concentrated again and lyophilized to give compound 55 hydrochloride (192 mg, 48% yield).

  (Example 4-4: Synthesis of Compound 57)

  481 mg of chloroorienticin B hydrochloride is dissolved in water (30 ml), 354 mg of tryptamine hydrochloride is added, and then 1N-aqueous sodium hydroxide solution is added to adjust the pH to 10. Add 0.11 ml of 37% -formaldehyde aqueous solution and stir at room temperature for 16 hours. 1N-hydrochloric acid is added to the reaction solution to adjust the pH to 2, and then the mixture is concentrated under reduced pressure and purified by a rover column. Fractions eluting with 25% methanol / 5 mM hydrochloric acid are collected and concentrated, and poly-4-vinylpyridine is added to the concentrated solution to adjust the pH to 4. After filtration, the filtrate is concentrated again and lyophilized to give compound 57 hydrochloride (76 mg, 13% yield).

Each compound was detected by HPLC and identified by FAB mass spectrum. Table 4 below shows the acetonitrile content and retention time of the solvent used in the mobile phase, and the mass spectrum molecular ion peak [M + H] ⁺ .

  Here, the HPLC analysis conditions are the same as those in Example 2.

Example 5 Synthesis of R ⁴ Modified Glycopeptide Derivatives (Compounds 58 to 63) The following R ⁴ modified glycopeptide derivatives were synthesized by variously changing the R ⁴ group of the glycopeptide derivatives. In this example, R ¹ is hydrogen, R ² is an —OH group, R ³ is hydrogen, and R ⁵ is a glucosyl group.

Examples of typical methods for synthesizing R ⁴ modified glycopeptide derivatives are shown below.

  Example 5-1 Synthesis of Compound 58

  1.0 g of chloroorienticin B hydrochloride is dissolved in 100 ml of methanol. After adding 0.45 g of N-Boc-16-aminohexadecanal and stirring for 2 hours while heating to 60 ° C. in an oil bath, 83 mg of sodium cyanoborohydride is added and stirring is further performed at 60 ° C. for 5 hours. The reaction mixture is concentrated under reduced pressure, water is added and the resulting solid is washed with water and diethyl ether, filtered and dried. This solid is dissolved in 20 ml of trifluoroacetic acid cooled in an ice-water bath and stirred for 1 hour under cooling in an ice-water bath. Trifluoroacetic acid is distilled off under reduced pressure, and the residue is purified on a rover column. Fractions eluted with 50% methanol / 5 mM hydrochloric acid are collected and concentrated, and poly-4-vinylpyridine is added to the concentrated solution to adjust the pH to 4. After filtration, the filtrate is concentrated again and lyophilized to give the hydrochloride of compound 58 (395 mg, 31% yield).

  (Example 5-2: Synthesis of compound 61)

  200 mg of chloroorienticin B hydrochloride is dissolved in dimethylformamide-dimethyl sulfoxide (2 ml-1 ml). 1-H-pyrazole-1- {N, N′-bis (t-butoxycarbonyl)} carboxyamidine (94 mg) and diisopropylethylamine (44 ml) are added, and the mixture is stirred for 7 hours while heating at 70 ° C. in an oil bath. The reaction mixture is added dropwise to ethyl acetate, and the resulting solid is washed with ethyl acetate and diisopropyl ether, filtered and dried. This solid is dissolved in trifluoroacetic acid cooled in an ice-water bath and stirred at room temperature for 10 minutes. Trifluoroacetic acid is distilled off under reduced pressure, and the residue is purified on a rover column. Fractions eluted with 20% methanol / 5 mM hydrochloric acid are collected and concentrated, and the pH is adjusted to 5 by adding poly-4-vinylpyridine to the concentrate. After filtration, the filtrate is concentrated again and lyophilized to give the hydrochloride of compound 61 (16 mg, 8% yield).

Each compound was detected by HPLC and identified by FAB mass spectrum. The acetonitrile content and retention time of the solvent used in the mobile phase, and the mass spectrum molecular ion peak [M + H] ⁺ are shown in Table 5 below.

  Here, the HPLC analysis conditions are the same as those in Example 2.

Example 6 Synthesis of R ¹ and R ² Modified Glycopeptide Derivatives (Compounds 64-93) By changing the R ¹ group and R ² group of the glycopeptide derivative variously, the following R ¹ and R ² modifications were made. A glycopeptide derivative was synthesized. In this example, R ³ and R ⁴ are each hydrogen and R ⁵ is a glucosyl group.

Examples of typical methods for synthesizing R ¹ and R ² modified glycopeptide derivatives are shown below.

  Example 6-1: Synthesis of Compound 78

  Compound 141 (250 mg, 0.101 mmol) is dissolved in a mixed solvent of dimethyl sulfoxide-dimethylformamide (1 ml-4 ml). To this solution, 24 mg of N-hydroxybenztriazole, benzotriazol-1-yl-oxy-tripyrrolidinophosphonium hexafluorophosphate 85 mg, and N-methylmorpholine 0.095 ml are sequentially added, followed by stirring at room temperature for 30 minutes. Thereafter, 55 mg of {3-[(3-aminopropyl)-(3-tert-butoxycarbonylaminopropyl) -amino] -propyl} -carbamic acid-tert-butyl ester is added and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was added dropwise to 100 ml of 5% saline stirred under ice cooling, and the pH was adjusted to 3 with 1N aqueous hydrochloric acid, followed by precipitation. The white insoluble material is collected by filtration, rinsed with water, and dried overnight. Further, the obtained solid was rinsed with ethyl acetate and then dried to obtain a pale yellow solid (263 mg). Next, the obtained solid (263 mg) is suspended in 2.5 ml of water, to which 5 ml of trifluoroacetic acid is added dropwise under ice cooling, and the mixture is stirred at room temperature for 40 minutes. The reaction solution was added dropwise to 200 ml of a 0.35N-sodium carbonate aqueous solution stirred under ice-cooling, neutralized once, adjusted to pH 3 with 1N-hydrochloric acid, and further insoluble in 80 ml of methanol. Dissolve the product. This is purified on a rover column. Fractions eluted with 20% acetonitrile / 5 mM hydrochloric acid are collected and concentrated, and poly-4-vinylpyridine is added to the concentrated solution to adjust the pH to 5. After filtration, the filtrate is concentrated again and the residue is lyophilized to give the hydrochloride salt of Compound 78 (55 mg, 42% yield).

Each compound was detected by HPLC and identified by FAB mass spectrum. Table 6 below shows the acetonitrile content and retention time of the solvent used in the mobile phase, and the mass spectrum molecular ion peak [M + H] ⁺ .

  Here, the HPLC analysis conditions are the same as those in Example 2.

Example 7 Synthesis of R ¹ and R ³ Modified Glycopeptide Derivatives (Compounds 94 to 112) By varying the R ¹ and R ³ groups of the glycopeptide derivative variously, the following R ¹ and R ³ modifications A glycopeptide derivative was synthesized. In this example, R ² is an —OH group, R ⁴ is hydrogen, and R ⁵ is a glucosyl group.

Examples of typical methods for synthesizing R ¹ and R ³ modified glycopeptide derivatives are shown below.

  (Example 7-1: Synthesis of compound 101)

  Compound 142 (344 mg, 0.122 mmol) is suspended in 3 ml of water, to which 6 ml of trifluoroacetic acid is added dropwise under ice cooling, and the mixture is stirred for 1 hour under ice cooling. The reaction solution was added dropwise to 200 ml of a 0.4N sodium carbonate aqueous solution stirred under ice-cooling, neutralized once, adjusted to pH 3 with 1N-hydrochloric acid, and further insoluble in 90 ml of methanol. Dissolve the product. This is purified on a rover column. Fractions eluting with 27% acetonitrile / 5 mM hydrochloric acid are collected and concentrated, and poly-4-vinylpyridine is added to the concentrated solution to adjust the pH to 5. After filtration, the filtrate is concentrated again and the residue is lyophilized to give the hydrochloride of compound 101 (41 mg, 28% yield).

Each compound was detected by HPLC and identified by FAB mass spectrum. Table 7 below shows the acetonitrile content and retention time of the solvent used in the mobile phase, and the mass spectrum molecular ion peak [M + H] ⁺ .

  Here, the HPLC analysis conditions are the same as those in Example 2.

Example 8 Synthesis of R ² and R ³ Modified Glycopeptide Derivatives (Compounds 113 to 122) By changing the R ² group and R ³ group of the glycopeptide derivative variously, the following R ² and R ³ modifications were made. A glycopeptide derivative was synthesized. In this example, R ¹ and R ⁴ are each hydrogen and R ⁵ is a glucosyl group.

Examples of typical methods for synthesizing R ² and R ³ modified glycopeptide derivatives are shown below.

  (Example 8-1: Synthesis of compound 119)

  95 mg of the hydrochloride of compound 55 is dissolved in a mixed solvent of dimethyl sulfoxide-dimethylformamide (3 ml-3 ml). To this solution was added 10 mg of N-hydroxybenztriazole, 34 μl of N-methylmorpholine, and 10 mg of benztriazol-1-yl-oxy-tripyrrolidinophosphonium hexafluorophosphate, and then 13 mg of (2-aminoethyl) trimethylammonium chloride hydrochloride. And stirred at room temperature for 3 hours. The reaction solution is concentrated under reduced pressure, ethyl acetate is added to the residue, and the mixture is powdered and collected by filtration, and then purified by a rover column. Fractions eluted with 35% methanol / 5 mM hydrochloric acid are collected and concentrated, and poly-4-vinylpyridine is added to the concentrated solution to adjust the pH to 4. After filtration, the filtrate is concentrated again and lyophilized to give the hydrochloride of compound 119 (76 mg, 58% yield).

Each compound was detected by HPLC and identified by FAB mass spectrum. Table 8 below shows the acetonitrile content and retention time of the solvent used in the mobile phase, and the mass spectrum molecular ion peak [M + H] ⁺ .

  Here, the HPLC analysis conditions are the same as those in Example 2.

Example 9 Synthesis of R ¹ , R ² and R ³ Modified Glycopeptide Derivatives (Compounds 123 to 126) By changing the R ¹ group, R ² group and R ³ group of the glycopeptide derivative variously, R ¹ , R ² and R ³ modified glycopeptide derivatives were synthesized. In this example, R ⁴ is hydrogen and R ⁵ is a glucosyl group.

Examples of typical methods for synthesizing R ¹ , R ² and R ³ modified glycopeptide derivatives are shown below.

  (Example 9-1: Compound 125)

Compound 142 (164 mg, 0.048 mmol) is dissolved in a mixed solvent of dimethylsulfoxide-dimethylformamide (1 ml-4 ml) under a nitrogen gas stream. To this solution, 14 mg of N-hydroxybenztriazole, benztriazol-1-yl-oxy-tripyrrolidinophosphonium hexafluorophosphate 50 mg, and N-methylmorpholine 0.072 ml are sequentially added and stirred at room temperature for 30 minutes. Thereafter, 0.014 ml of 3-dimethylaminopropylamine is added and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was added dropwise to 80 ml of 5% brine stirred under ice cooling, and the pH was adjusted to 3 with 1N aqueous hydrochloric acid, followed by precipitation. The white insoluble material is collected by filtration, rinsed with water, and dried overnight. Further, the obtained solid was rinsed with ethyl acetate and then dried to obtain a pale yellow solid (136 mg). Next, the obtained solid (136 mg) is suspended in 2 ml of water, and 4 ml of trifluoroacetic acid is added dropwise thereto under ice-cooling, followed by stirring for 1 hour under ice-cooling.
The reaction solution was added dropwise to 200 ml of a 0.3N sodium carbonate aqueous solution stirred under ice-cooling, neutralized once, adjusted to pH 3 with 1N-hydrochloric acid, and further insoluble in 80 ml of methanol. Dissolve the product. This is purified on a rover column. Fractions eluting with 23% acetonitrile / 5 mM hydrochloric acid are collected and concentrated, and poly-4-vinylpyridine is added to the concentrated solution to adjust the pH to 5. After filtration, the filtrate is concentrated again and the residue is lyophilized to give compound 125 hydrochloride (51 mg, 55% yield).

Each compound was detected by HPLC and identified by FAB mass spectrum. Table 9 below shows the acetonitrile content and retention time of the solvent used in the mobile phase, and the mass spectrum molecular ion peak [M + H] ⁺ .

  Here, the HPLC analysis conditions are the same as those in Example 2.

Example 10 Synthesis of Deglucose Glycopeptide Derivative (Compounds 127 to 130) The R ¹ and R ² groups of the glycopeptide derivative are changed variously, and R ⁵ is replaced with hydrogen (deglucose). The following deglucose glycopeptide derivatives were synthesized. In this example, R ³ , R ⁴ and R ⁵ are each hydrogen.

  The typical synthesis method of a deglucose glycopeptide derivative is illustrated below.

  (Example 10-1: Synthesis of compound 130)

  300 mg of the hydrochloride salt of Compound 37 is dissolved in trifluoroacetic acid-water (25 ml-10 ml). The mixture is stirred for 5 hours while heating to 55 ° C. in an oil bath, and the reaction solution is cooled to room temperature and then adjusted to pH 7 with a saturated aqueous sodium carbonate solution under ice cooling. Further, 60 ml of methanol is added to dissolve insoluble matters. This is purified on a rover column. Fractions eluted with 30% methanol / 5 mM hydrochloric acid are collected and concentrated, and poly-4-vinylpyridine is added to the concentrated solution to adjust the pH to 5. After filtration, the filtrate is concentrated again and lyophilized to give the hydrochloride salt of Compound 130 (76 mg, 28% yield).

Each compound was detected by HPLC and identified by FAB mass spectrum. Table 10 below shows the acetonitrile content and retention time of the solvent used in the mobile phase, and the mass spectrum molecular ion peak [M + H] ⁺ .

  Here, the HPLC analysis conditions are the same as those in Example 2.

Example 11 Synthesis of Glycopeptide Derivatives (Compounds 131 to 139) in which R ² was Replaced with Tripeptide In this example, glycosyl derivatives in which R ² group of the glycopeptide derivative was substituted with a tripeptide of the following formula: Peptide derivatives were synthesized:
R ² = R−A ₁ −A ₂ −A ₃ −
(Where R is an —OH group or an amino group defined below, and A ₁ , A ₂ , and A ₃ are each an amino acid defined below).
In this example, R ¹ , R ³ , R ⁴ are each hydrogen and R ⁵ is a glucosyl group.

  (Example 11-1: Synthesis of compound 131)

The amino acids of leucine, tryptophan, and tyrosine are sequentially extended by the Fmoc method on a 2-methoxy-4-Alkoxybenzyl Alcohol Resin (Sasrin Resin, Kokusan Kagaku) with a peptide synthesizer (Applied Biosystems). Further, using N-hydroxybenztriazole, N-methylmorpholine, benztriazol-1-yl-oxy-tripyrrolidinophosphonium hexafluorophosphate, and shaking in dimethyl sulfoxide-dimethylformamide for 18 hours at room temperature, Coupling thycin B.
The resin is collected by filtration, washed, and then stirred in trifluoroacetic acid-methylene chloride-water-triisopropylsilane-ethanedithiol (80: 14: 2: 2: 2, v / v) at room temperature for 30 minutes. The filtrate was added dropwise to diethyl ether, and the resulting precipitate was further washed with diethyl ether, dissolved in water to make an aqueous solution, and then freeze-dried to obtain compound 131.

  (Example 11-2: Synthesis of compound 137)

  Compound 137 is obtained from compound 131 by the same method as the method for synthesizing compound 39 (Example 3-3).

Each compound was detected by HPLC and identified by FAB mass spectrum. Table 11 below shows the acetonitrile content and retention time of the solvent used in the mobile phase, and the mass spectrum molecular ion peak [M + H] ⁺ .

  Here, the HPLC analysis conditions are the same as those in Example 2.

Example 12 Measurement of In Vitro Antibacterial Activity of Glycopeptide Derivative Compounds MRSA (S. aureus SR3637), vancomycin resistant enterococci (E. faecalis SR7914 and E. faecium SR7917), and penicillin resistant pneumococci (S. pneumoniae SR16675) In vitro antibacterial activity (MIC value) was measured by the micro liquid dilution method using the above-mentioned glycopeptide derivative compound.

(Example 12-1: Preparation of bacterial solution for inoculation)
One platinum loop (about 1 μl) is inoculated into 5 ml of the enrichment medium (Mueller Hinton Bros; Difco) and cultured for 20 hours. A 20-fold dilution of the culture is used as the inoculum. However, when measuring the enrichment of S. pneumoniae, Mueller Hinton broth supplemented with 5% (v / v) horse serum is used.

(Example 12-2: Sample solution)
A sample is accurately weighed to a unit of 0.1 mg, and an appropriate amount of a solvent such as sterilized purified water is added to prepare a 1 mg / ml solution.

(Example 12-3: Preparation of trace dilution tray)
Add divalent cations (Ca ⁺⁺ , Mg ⁺⁺ ) to Mueller Hinton broth. The final concentration is corrected to Ca ⁺⁺ ; 25-50 mg / l, Mg ⁺⁺ ; 12.5-25 mg / l. The sample solution is serially diluted (25-0.025 μg / ml) with the prepared Mueller Hinton broth, and 0.1 ml of each of these dilutions is dispensed into each well of a standard tray (96 wells). Dispense and inoculate 5 μl of the bacterial solution for inoculation into each well.

(Example 12-4: Determination)
After judging at 35 ° C. for 20 hours, the growth of the bacteria is observed. The lowest concentration at which the growth of the bacteria is observed to be completely inhibited is taken as the MIC value (μg / ml).

  The structure and MIC values for each compound are listed in the table below.

(The invention's effect)
As described above, according to the present invention, a novel glycopeptide derivative that expresses an excellent activity against vancomycin-resistant enterococci and a more potent activity against methicillin-resistant bacteria, its pharmaceutical Acceptable salts, hydrates, or prodrugs are provided.

Claims (6)

A compound represented by the following formula (I), or a pharmaceutically acceptable salt, hydrate, or prodrug thereof:

here,
R ¹ is selected from the group consisting of the following (1-1) to (1-8):
(1-1) hydrogen;
(1-2) benzyl optionally having substituent (s), the substituent being halogen, amino, formyl, optionally halogenated alkyl, optionally halogenated alkenyl, halogenated Alkynyl, aryl, arylalkyl, arylalkenyl, or arylalkynyl, or a combination thereof,
Here, the aryl ring in the substituent is further halogen, amino, formyl, alkyl which may be halogenated, alkenyl which may be halogenated, alkynyl which may be halogenated, halogenated or alkyl. Optionally substituted arylalkyl, optionally halogenated arylalkenyl, or optionally halogenated arylalkynyl, or combinations thereof;
(1-3) each optionally substituted alkyl, alkenyl, or alkynyl, wherein the substituent is halogen, amino, optionally halogenated aryl, or a combination thereof;
(1-4) mono or diarylalkylcarbamoyl, mono or diarylalkylthiocarbamoyl, mono or diarylcarbamoyl, or mono or diarylthiocarbamoyl each optionally having a substituent, wherein the substituent is halogen, amino , Formyl, optionally halogenated alkyl, optionally halogenated alkenyl, optionally halogenated alkynyl, alkyl optionally halogenated arylalkyl, alkenyl optionally halogenated Good arylalkenyl, or arylalkynyl, or a combination thereof,
Wherein the aryl ring in the substituent may be further substituted with halogen, formyl, optionally halogenated alkyl, or combinations thereof;
(1-5) mono or dialkylcarbamoyl, or mono or dialkylthiocarbamoyl, each optionally having a substituent, wherein the substituent is halogen, amino, or a combination thereof;
(1-6) each optionally substituted alkylcarbonyl, arylalkylcarbonyl, or arylcarbonyl, wherein the substituent is halogen, amino, or formyl (but limited to aryl ring substitution), Or a combination thereof;
(1-7) alkyloxycarbonyl or alkyloxythiocarbonyl, each optionally having a substituent, wherein the substituent is halogen, amino, optionally halogenated aryl, or a combination thereof And; and
(1-8) alkylurea, arylalkylurea, or arylurea, each of which may have a substituent, wherein the substituent is halogen, amino, or formyl (provided that the aryl ring is substituted only), Or a combination thereof;
However, in (1-2) to (1-8), the existing aryl ring may contain a heteroatom, the α-position methylene of the aryl ring may be substituted with carbonyl, and the existing carbon-carbon single bond Can be interrupted by a heteroatom;
R ² is selected from the group consisting of the following (2-2) - (2-7):
(2-2) Mono- or dialkylamino which may have a substituent (excluding (2-4)), and two alkyls may be bonded to form a ring. The groups are amino, monoalkylamino, dialkylamino, trialkylammonium, hydroxy, guanidino, carboxy, alkyloxycarbonyl, carbamoyl optionally substituted with cyano, mono or dialkylcarbamoyl, mono or diarylcarbamoyl, aryl, alkylamide or aryl amides, 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 to C3 a A kill, 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 Because
Here, the alkyl in the substituent may be further substituted with amino optionally substituted with alkyloxycarbonyl or aryloxycarbonyl,
Here, the aryl ring in the substituent is further halogen, nitro, amino, hydroxy, carboxy, alkyloxycarbonyl, alkyl optionally substituted with amino, hydroxyalkyl or thioalkyl optionally substituted, Or a combination thereof;
(2-3) cycloalkylamino optionally substituted with amino or hydroxy;
(2-4) Disubstituted methylamino-NHCHR ⁶ R ⁷ , wherein
R ⁶ is selected from carboxy, optionally substituted alkyloxycarbonyl, carbamoyl, optionally substituted monoalkylcarbamoyl, or optionally substituted cycloalkylcarbamoyl. And
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 to 3 and R ^X is C1 to C3 alkyl) optionally substituted aryl, —N ⁺ (R ^X ) ₂ (CH ₂ ) _m COOR ^Y (here R ^Y is hydrogen or C1-C3 alkyl), or —N ⁺ (R ^X ) ₂ (CH ₂ ) _m N ⁺ (R ^X ) ₃ , or a combination thereof;
R ⁷ is indole or thioindole optionally substituted on the nitrogen with C1-C3 alkyl, or imidazolyl;
(2-5) tripeptide ^{R-A 1 -A 2 -A 3} -:
Here, A ¹ , A ² , and A ³ are each an arbitrary amino acid unit, and R is a carboxy terminus of the tripeptide, which may be mono- or optionally substituted with hydroxy, amino, or a substituent Represents dialkylamino and 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) optionally substituted alkoxy, which is further substituted with nitro, hydroxamic acid, or arylcarbonyl optionally substituted with alkyl;
However, in (2-2) to (2-7), the existing aryl ring may contain a heteroatom, and the existing carbon-carbon single bond is a heteroatom or -O (P = O) ( OR ^F ) O—, where R ^F is hydrogen, alkyloxycarbonyl or aryloxycarbonyl, imino, and

Interrupted with a hetero group selected from:
R ³ 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 the alkyl, cycloalkyl and alkylene may each have a substituent, and the substituent is alkyloxy Amino, monoalkylamino, dialkylamino, trialkylammonium optionally substituted with carbonyl or 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 (where m is is 1 to 3, R ^X is a is), or a combination thereof C1~C3 alkyl, wherein said monoalkyl or dialkylamino Alkyl in amino substituents may be further substituted with amino;
(3-3) optionally substituted alkynyl, wherein 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 may 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, imino, and

Interrupted with a hetero group selected from:
R ⁴ is selected from the group consisting of the following (4-1) to (4-6):
(4-1) hydrogen;
(4-2) Alkyl which may have a substituent, wherein the substituent is alkyloxycarbonyl, amino, aryl which may be alkylated, arylcarbonyl, carbamoyl, mono or dialkylcarbamoyl or mono Or a diarylalkylcarbamoyl or a combination thereof
Here, the alkyl or aryl in the substituent may be further substituted with amino, which may be substituted with alkyloxycarbonyl or aryloxycarbonyl, or hydroxy;
(4-3) an optionally substituted alkyloxycarbonyl, wherein the substituent is an optionally alkylated aryl;
(4-4) arylamide or arylthioamide;
(4-5) optionally alkylated amino or amidino; and
(4-6) Nitroso;
However, in (4-2) to (4-5), the existing aryl ring can contain heteroatoms, and the existing carbon-carbon single bond can be interrupted by heteroatoms; and R ⁵ can be (5-1) is selected from the group consisting of (5-2):
(5-1) hydrogen; and
(5-2) Glucosyl . A compound according to claim 1, or a pharmaceutically acceptable salt, hydrate or prodrug thereof,
here,
R ¹ is selected from the group consisting of the following (1-1 ′) to (1-6 ′):
(1-1 ′) hydrogen;
(1-2 ′) benzyl having a substituent, which is halogen, optionally halogenated C3-C12 alkyl, C6-C18 aryl, C6-C18 aryl C1-C8 alkenyl, or C6 -C18 aryl C1-C8 alkynyl, or a combination thereof,
Here, the aryl ring in the substituent may be further substituted with a halogen, an optionally halogenated C1-C12 alkyl, an optionally halogenated C6-C18 aryl C1-C8 alkynyl, or a combination thereof. ;
(1-3 ′) an optionally substituted C8-C17 alkyl, wherein the substituent is halogen, amino, optionally halogenated C6-C12 aryl, or a combination thereof ;
(1-4 ′) Mono-C6-C18 arylcarbamoyl or mono-C6-C18 aryl C5-C13 alkylcarbamoyl which may have a substituent, and the substituent may be halogenated or halogenated C1-C9 alkyl, or C6-C18 aryl C1-C8 alkenyl in which C1-C9 alkyl or alkenyl may be halogenated and aryl may be substituted with C1-C5 alkyl, or combinations thereof,
(1-5 ′) an optionally substituted monoalkylcarbamoyl or monoalkylthiocarbamoyl in which alkyl is C9-C14 alkyl, and the substituent is halogen, amino, or a combination thereof ;and
(1-6 ′) alkylcarbonyl, wherein alkyl is C8-C17 alkyl;
Provided that in (1-2 ′) to (1-6 ′), an existing aryl ring may contain a heteroatom, and an existing carbon-carbon single bond may be interrupted by a heteroatom;
R ² is selected from the group consisting of the following (2-2 ') - (2-7'):
(2-2 ') mono- or di-C1-C30 alkylamino optionally having a substituent, wherein the substituent is substituted with amino, mono- or di-C1-C5 alkylamino, hydroxy, guanidino, cyano is carbamoyl optionally, a mono- or di C6~C10 aryl-carbamoyl, C5-C12 aryl, C6-C12 aryl _{^{amide, -N + (R X) 3}} , -N + (R X) 2 (CH 2) m N ⁺ (R ^Y ) ₃ (where m is 1-3, R ^X is C1-C3 alkyl, and R ^Y is hydrogen or C1-C3 alkyl), or — (C═O) N ⁻ —N ⁺ (CH ₃ ) ₃ , or a combination thereof,
Here, the alkyl in the substituent may be further substituted with amino which may be substituted with C1-C5 alkyloxycarbonyl,
Here, the aryl ring in the substituent may be further substituted with amino, hydroxy, C1-C3 alkyloxycarbonyl, or C1-C8 alkyl optionally substituted with amino;
(2-3 ′) hydroxy substituted C4-C8 cycloalkylamino;
(2-4 ′) disubstituted methylamino-NHCHR ⁶ R ⁷ , wherein
R ⁶ is selected from carboxy, C1-C3 alkyloxycarbonyl, or mono-C1-C5 alkylcarbamoyl having a substituent,
Here, the substituent is trimethylammonium, carboxy, hydroxy, C1-C10 aryl, —N ⁺ (CH ₃ ) ₂ (CH ₂ ) —COOR ^G (where R ^G is hydrogen or C1-C2 alkyl) Or —N ⁺ (CH ₃ ) ₂ — (CH ₂ ) ₂ —N ⁺ (CH ₃ ) ₃ ,
R ⁷ is indole or thioindole optionally substituted with nitrogen by C 1 -C 2 alkyl, or 4-imidazolyl;
(2-5 ′) Tripeptide R—A ¹ —A ² —A ³ —:
Here, A ¹ , A ² , and A ³ are each an amino acid unit independently selected from the group consisting of tryptophan, histidine, lysine, glutamic acid, leucine, serine, tyrosine, glycine, proline, and alanine. Provided that at least one of A ¹ , A ² , and A ³ is tryptophan, histidine, or lysine, and R is the carboxy terminus of the tripeptide and has a hydroxy, amino, or substituent Represents an optionally mono- or di-C1-C3 alkylamino, the substituent being trimethylammonium, guanidino, or 4-imidazolyl;
(2-6 ′) a hydroxamic acid having a substituent, wherein the substituent is a C6-C18 aryl C1-C5 alkyl further substituted with a C1-C3 alkyl; and
(2-7 ′) a C1-C3 alkoxy having a substituent, wherein the substituent is a C6-C10 arylcarbonyl further substituted with a C1-C3 alkyl;
However, in (2-2 ′) to (2-4 ′), (2-6 ′) and (2-7 ′), the aryl ring present may contain a heteroatom, and the carbon-carbon singlet present The bond is a heteroatom or imino and

Interrupted with a hetero group selected from:
R ³ is selected from the group consisting of the following (3-1 ′) to (3-3 ′):
(3-1 ′) hydrogen;
(3-2 ′) C1-C24 alkyl, C5-C24 cycloalkyl or aminomethyl substituted with C5-C10 alkylene, wherein the C1-C24 alkyl, C5-C24 cycloalkyl and C5-C10 alkylene are each substituted. The substituent may be amino, di-C1-C5 alkylamino, tri-C1-C3 alkyl ammonium, C6-C12 aryl, hydroxy, which may be substituted with C1-C5 alkyloxycarbonyl, guanidino, _{^{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 the alkyl in the di C1~C5 alkylamino substituents It may be further substituted by amino; and
(3-3 ′) C6-C12 aryl C1-C5 alkynyl;
However, in (3-2 ′) to (3-3 ′), the existing aryl ring may contain a heteroatom and the existing carbon-carbon single bond is a heteroatom or —O (P═O ) (O ⁻ ) O—, amide, and imino, and

Interrupted with a hetero group selected from:
R ⁴ is selected from the group consisting of the following (4-1 ′) and (4-2 ′):
(4-1 ′) hydrogen, and
(4-2 ′) C10-C30 alkyl optionally substituted with amino;
Provided that in (4-2 ′) the existing carbon-carbon single bond can be interrupted by a heteroatom; and R ⁵ is selected from the group consisting of: (5-1 ′) and (5-2 ′) Is:
(5-1 ′) hydrogen; and
(5-2 ′) Glucosyl. A compound according to claim 1, or a pharmaceutically acceptable salt, hydrate or prodrug thereof,
here,
R ¹ is selected from the group consisting of: (1-1 ″) to (1-4 ″):
(1-1 ″) hydrogen;
(1-2 ″) substituted benzyl, wherein the substituent is C5-C9 alkyl, C6-C12 aryl, C6-C12 aryl C1-C5 alkenyl, or C6-C12 aryl C1-C5 alkynyl. There,
Here, the aryl ring in the substituent may be further substituted with halogen, optionally halogenated C1-C8 alkyl, or halogenated C6-C12 aryl C1-C5 alkynyl;
(1-3 ″) C9-C15 alkyl optionally substituted with C6-C12 aryl;
(1-4 ″) mono-C6-C18 arylcarbamoyl or mono-C6-C12 aryl C7-C11 alkylcarbamoyl which may have a substituent, wherein the substituent is halogen, C5-C9 alkyl, or C6-C12 aryl C1-C5 alkenyl wherein alkenyl is halogenated and aryl is substituted with C1-C5 alkyl;
A monoalkylthiocarbamoyl, wherein (1-5 ″) alkyl is C9-C14 alkyl; and
(1-6 ″) alkylcarbonyl, wherein alkyl is C10-C14 alkyl;
However, in (1-2 ″), the existing aryl ring may contain a sulfur atom, and in (1-2 ″) and (1-4 ″), the existing carbon-carbon single bond is an oxygen atom. Can be interrupted by;
R ² is selected from the group consisting of the following (2-2 '') - (2-8 ''):
(2-2 ″) mono- or di-C1-C20 alkylamino optionally having substituent (s), wherein the substituent is carbamoyl, mono- or di-C1 substituted with amino, hydroxy, guanidino, cyano ~C3 alkylamino, C5-C12 aryl, C6-C12 aryl amide ^{or, - (C = O) N} - -N + (CH 3) 3 or a combination thereof,
Here, the alkyl in the substituent may be further substituted with amino optionally substituted with t-butoxycarbonyl,
Wherein the aryl ring in the substituent may be further substituted with C1-C5 alkyl optionally substituted with hydroxy or amino, and may contain a heteroatom selected from nitrogen and sulfur;
(2-3 ″) hydroxy substituted C 5 -C 7 cycloalkylamino; and
(2-4 ″) disubstituted methylamino-NHCHR ⁶ R ⁷ , wherein
R ⁶ is C1-C2 alkyloxycarbonyl, or mono-C2-C4 alkylcarbamoyl having a substituent,
Here, the substituent is 2-imidazolyl or N-quinolyl,
R ⁷ is an indole in which the nitrogen may be methylated, or thioindole; and
(2-5 ″) A tripeptide selected from the following: R ¹ -A ² -A ^3- :
R-Lys-His-Trp-;
R-Leu-Trp-Lys-;
R-Leu-Trp-Tyr-;
R-Ser-His-Trp-;
R-Trp-His-Gly-;
R-Trp-Gly-His-;
R-Trp-Lys-His-;
R-Trp-Pro-His-;
R-Trp-Leu-His-;
R-Tyr-Trp-His-;
R-Tyr-Trp-Leu-;
R-Tyr-Trp-Ser-;
R-Leu-Trp-Tyr-; and R-Trp-Lys-His-,
Where R is the carboxy terminus of the tripeptide and represents hydroxy, amino, or a mono C1-C3 alkylamino having a substituent, wherein the substituent is trimethylammonium, guanidino, or 4-imidazolyl. ;
A hydroxamic acid having a (2-6 ″) substituent, wherein the substituent is benzyl further substituted with methoxy;
However, in (2-2 '') - (2-4 '') and (2-6 ''), the carbon present - carbon single bond may be interrupted by oxygen or imino; R ³ is the following Selected from the group consisting of: (3-1 ″) and (3-2 ″):
(3-1 ″) hydrogen; and
(3-2 ″) C1-C20 alkyl, C5-C10 cycloalkyl or aminomethyl substituted with C5-C7 alkylene, wherein the C1-C20 alkyl, C5-C10 cycloalkyl and C5-C7 alkylene are each The substituent may have an amino, di-C1-C5 alkylamino, tri-C1-C3 alkylammonium, C6-C10 aryl, hydroxy, carboxy which may be substituted with t-butoxycarbonyl. _{^{, -N + (R X) 2}} (CH 2) m N + (R X) 3, or ^{- (C = O) -N -} -N + (R X) 3 ( wherein, m is 1-3 And R ^X is C1-C3 alkyl), or a combination thereof, wherein the alkyl in the di-C1-C5 alkylamino substituent may be further substituted with amino ;
However, in (3-2 ″), the existing aryl ring may contain a nitrogen atom and the carbon-carbon single bond present is oxygen, amide, imino, and

Interrupted with a hetero group selected from:
R ⁴ is selected from the group consisting of: (4-1 ″) and (4-2 ″):
(4-1 ″) hydrogen; and
(4-2 ″) amino substituted C14-C18 alkyl; and R ⁵ is selected from the group consisting of: (5-1 ″) and (5-2 ″):
(5-1 ″) hydrogen; and
(5-2 ″) Glucosyl. The compound according to claim 1 or a pharmaceutically acceptable salt, hydrate, or prodrug thereof, wherein the combination of R ¹ , R ² , R ³ , R ⁴ , and R ⁵ is as follows:
(Here, G in the table represents a glucosyl group)

. A pharmaceutical composition comprising the compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, hydrate, or prodrug thereof. An antibacterial composition comprising the compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, hydrate, or prodrug thereof.