JP2016079098A - Cephem compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a cephem compound having a wide antibacterial spectrum and especially exhibiting strong antibacterial activities against β-lactamase producing Gram-negative bacteria and to provide a pharmaceutical composition comprising the same.SOLUTION: There is provided a cephem compound represented by the formula (I), an ester of a carboxyl group, a protected product in an amino group when the amino group is present on the ring in the 7-position side chain or a pharmaceutically acceptable salt thereof. (Rrepresents a substituted/unsubstituted heterocyclic group or the like; Rand Rtogether represent substituted/unsubstituted hydroxyimino or the like; Rrepresents H, -OCHor the like; and Rand Reach independently represents H, a lower alkyl or the like.)SELECTED DRAWING: None

Description

The compound of the present invention relates to a cephem compound having a broad antibacterial spectrum, and particularly exhibiting a strong antibacterial activity against β-lactamase-producing gram-negative bacteria, and a pharmaceutical composition containing the same.

  Various β-lactam drugs have been developed so far, and β-lactam drugs have become clinically very important antibacterial drugs. However, an increasing number of bacterial strains have acquired resistance to β-lactam drugs by producing β-lactamase that degrades β-lactam drugs.

  According to Ambler's molecular taxonomy, β-lactamases are broadly classified into four classes. That is, class A (TEM type, SHV type, CTX-M type, KPC type, etc.), class B (IMP type, VIM type, L-1 type, etc.), class C (AmpC type, ADC type, etc.), class D (Such as OXA type). Of these, Class A, C, and D types are broadly classified into serine-β-lactamases, while Class B types are broadly divided into metallo-β-lactamases, and each is known to hydrolyze about β-lactams by different mechanisms. Yes.

In recent years, the production of class A type (ESBL) and class D type serine-β-lactamases and class B type metallo-β-lactamases with an extended substrate range has led to the enhancement of many β-lactam drugs including cephem and carbapenem. The presence of resistant gram-negative bacteria is becoming a clinical problem. In particular, metallo-β-lactamase is known to contribute to multidrug resistance of gram-negative bacteria. Cephem compounds exhibiting moderate activity against metallo-β-lactamase-producing gram-negative bacteria are known (eg, Patent Document 1 and Non-Patent Document 1), but stronger antibacterial activity, particularly various β-lactamase-producing grams. There is a demand for the development of cephem compounds effective against negative bacteria.
As one of the antibacterial agents having high anti-gram-negative bacterial activity, cephem compounds having a catechol group in the molecule are known (eg, Non-Patent Documents 2 to 4). The action is due to the fact that the catechol group forms a chelate with Fe ³⁺ , so that the compound is efficiently incorporated into the cell body via the Fe ³⁺ transport system (tonB-dependent iron transport system) on the cell membrane. For this reason, research has been conducted on compounds having a catechol group or a structure similar thereto at the 3-position side chain or the 7-position side chain site of the cephem skeleton.

  Patent Documents 2 to 8 and Non-Patent Document 5 describe compounds having a partial structure of the 7-position side chain and a quaternary salt structure in the cephem skeleton. However, these documents describe only a pyridinium structure as a quaternary salt structure, and most of them only disclose a formamide group at the 7-position.

  Non-Patent Document 1 and Patent Documents 8 to 12, 15 and 16 are catechol-type derivatives having a catechol at the 3-position side chain site of the cephem skeleton, and Patent Documents 10, 11, 13 and 14 include the 3-position side chain of the cephem skeleton. Pseudo catechol type derivatives having a hydroxypyridone group at the site are described. Patent Document 17 discloses a catechol-type derivative having catechol at the 3-position side chain site of the cephem skeleton but not having a quaternary ammonium group. Patent Documents 18 to 20, 23 and Non-Patent Documents 8 to 9 disclose cephem compounds having a quaternary ammonium group, but do not describe catechol type derivatives. Patent Documents 21 and 22 disclose compounds having a quaternary ammonium group and a catechol structure in the 3-position side chain of the cephem skeleton.

  However, these compounds do not describe the compound of the present invention. Furthermore, in the above-mentioned documents describing cephem compounds having a catechol group in the molecule, there are descriptions concerning class B type metallo-β-lactamases and specific examples for a wide range of gram-negative bacteria including class B type. There is no description of antibacterial activity.

  Patent Documents 23 and 24 and Non-Patent Documents 10 to 12 disclose compounds having a substituent at the 2-position of the cephem skeleton. However, these compounds do not have a quaternary ammonium group and a catechol structure in the 3-position side chain.

  Furthermore, the applicant has filed a cephem compound having a catechol-type substituent (Patent Documents 25 to 32). However, these compounds do not describe the compound of the present invention.

International Publication No. 2007/119511 Japanese Published Patent Publication Showa 57-118588 European Patent Application Publication No. 114752 European Patent Application Publication No. 168177 European Patent Application No. 211656 European Patent Application Publication No. 305111 Japanese Patent Publication No. Hei 4-364189 Japanese Published Patent Publication No. 3-173893 Japanese Published Patent Publication No. 2-15090 Japanese Patent Publication No. 2-28187 Japanese Patent Publication No. Hei 2-117678 Japanese Published Patent Publication No. 6-510523 Japanese Published Patent Publication No. Hei 5-213971 Japanese Patent Publication No. 2-28185 International Publication No. 2007/096740 Japanese Published Patent Publication Showa 62-30788 Japanese Patent Publication No. 5-59065 European Patent Application Publication No. 366189 European Patent Application No. 335297 Japanese Published Patent Publication Showa 63-10792 International Publication No. 2012/134184 European Patent Application Publication No. 304155 European Patent Application Publication No. 35357 U.S. Pat. No. 3,487,079 International Publication No. 2010/050468 International Publication No. 2011-125966 International Publication No. 2011/125967 International Publication No. 2011/136268 International Publication No. 2012/147773 International Publication No. 2013/052568 International Publication No. 2014/068388 International Publication No. 2014/104148

Applied Microbiology and Biotechnology (1994), 40 (6), 892-7 The Journal of Antibiotics, 46, 833-839 (1993) The Journal of Antibiotics, 43, 1617-1620 (1990) The Journal of Antibiotics, 42, 795-806 (1989) The Journal of Antibiotics, 40, 646-651 (1987) American Review of Respiratory Disease, 141, 672-677 (1990) The Journal of Antibiotics, 39, 76-89 (1986) Acta Pharmaceuticala, 50, 17-27 (2000) Journal of Medicinal Chemistry, 34, 669-675 (1991) Chemical & Pharmaceutical Bulletin, 31, 1482-1493 (1983) Journal of Medicinal Chemistry, 14, 420-425 (1971) International Journal of Peptide & Protein Research, 10, 51-59 (1977)

The present invention provides cephem compounds that exhibit a strong antibacterial spectrum against a variety of bacteria including gram negative and / or gram positive bacteria.
Preferably, a cephem compound exhibiting strong antibacterial activity against β-lactamase-producing gram-negative bacteria is provided. More preferably, a cephem compound exhibiting strong antibacterial activity against multi-drug resistant bacteria, particularly class B type metallo-β-lactamase (MBL) -producing gram-negative bacteria is provided. More preferably, a cephem compound that exhibits effective antibacterial activity also against a substrate-specific extended β-lactamase (ESBL) -producing bacterium is provided.

The present invention provides a cephem compound that has solved the above problems by having at least the following structural features.
It has a quaternary ammonium group represented by E in the cephem 3-position side chain. E is preferably a ring structure.
The cephem 3-position side chain has at least one group represented by D ¹ . D ¹ is preferably a spacer of a functional group having a hetero atom such as —NR ⁶ —, —O— or amide.
Having a group represented by D ² in cephem 3-position side chain. D ² is preferably a spacer such as carbonyl, amide, ester or the like.
Cephem has a ring structure represented by R ¹⁰ at the end of the 3rd side chain. R ¹⁰ preferably has a catechol structure.

（式中、
Ｒ^１は、置換もしくは非置換の炭素環式基または置換もしくは非置換の複素環式基であり；
Ｒ^２ＡおよびＲ^２Ｂについては、
ａ）Ｒ^２Ａが水素原子、置換もしくは非置換のアミノ、−ＳＯ_３Ｈ、置換もしくは非置換のアミノスルホニル、カルボキシ、置換もしくは非置換の低級アルキルオキシカルボニル、置換もしくは非置換のカルバモイル、ヒドロキシ、または置換基を有しているカルボニルオキシであり、かつＲ^２Ｂが水素原子であるか、または、
ｂ）Ｒ^２ＡおよびＲ^２Ｂが一緒になって、置換もしくは非置換のメチリデン、または置換もしくは非置換のヒドロキシイミノを形成し、
Ｒ^３は水素原子、−ＯＣＨ_３または−ＮＨ−ＣＨ（＝Ｏ）であり；
Ｒ^５ＡおよびＲ^５Ｂについては、
ａ）Ｒ^５ＡおよびＲ^５Ｂは、それぞれ独立して、水素原子または低級アルキルであり、
ｂ）Ｒ^５ＡおよびＲ^５Ｂが隣接する原子と一緒になって、置換もしくは非置換の炭素環、または置換もしくは非置換の複素環を形成し、または、
ｃ）Ｒ^５ＡおよびＲ^５Ｂが一緒になって、置換もしくは非置換のメチリデンを形成し、
Ｌは‐ＣＨ_２−、−ＣＨ＝ＣＨ−、−ＣＨ_２−ＣＨ＝ＣＨ−、−ＣＨ＝ＣＨ−ＣＨ_２−、−Ｓ−、−ＣＨ_２−Ｓ−、−ＣＨ＝ＣＨ−Ｓ−または‐ＣＨ＝ＣＨ−ＣＨ_２−Ｓ−であり、
Ｅは置換もしくは非置換の１以上の４級アンモニウムイオンを有する２価の基であり、
Ｒ^１０は水素原子または以下の式（Ｉ−Ａ）：

（式中、
Ｇ^１およびＧ^２は、それぞれ独立して、単結合、置換もしくは非置換の低級アルキレン、置換もしくは非置換の低級アルケニレンまたは置換もしくは非置換の低級アルキニレンであり、
Ｄ^１は、それぞれ独立して、−Ｃ（＝Ｏ）―、−Ｏ−Ｃ（＝Ｏ）‐、−Ｃ（＝Ｏ）‐Ｏ−、−ＮＲ^６−、−ＮＲ^６−Ｃ（＝Ｏ）‐、−Ｃ（＝Ｏ）‐ＮＲ^６−、−Ｃ（＝Ｏ）‐Ｃ（＝Ｏ）‐、−ＮＲ^６−Ｃ（＝Ｏ）‐ＮＲ^６−、−Ｃ（＝Ｏ）‐Ｃ（＝Ｏ）‐ＮＲ^６−、−Ｃ（＝Ｏ）‐ＮＲ^６−Ｃ（＝Ｏ）‐、−ＮＲ^６−Ｃ（＝Ｏ）‐Ｃ（＝Ｏ）‐、−ＮＲ^６−ＮＲ^６−Ｃ（＝Ｏ）‐、−Ｃ（＝Ｏ）‐ＮＲ^６−ＮＲ^６−、−Ｎ＝Ｎ−Ｃ（＝Ｏ）‐、−Ｃ（＝Ｏ）‐Ｎ＝Ｎ−、 −Ｃ＝Ｎ−ＮＲ^６−Ｃ（＝Ｏ）−、 −Ｃ＝Ｎ−Ｃ（＝Ｏ）−、 ‐Ｎ＝Ｃ−Ｃ（＝Ｏ）−、 ‐Ｃ＝Ｎ−Ｃ（＝Ｏ）−ＮＲ^６−、 −ＮＲ^６−Ｃ（＝Ｏ）−Ｃ（＝Ｎ−ＯＲ^６）‐、 −Ｃ（＝Ｎ−ＯＲ^６）−Ｃ（＝Ｏ）−ＮＲ^６−、 −ＮＲ^６− Ｃ（＝Ｎ−ＯＲ^６）‐、 −Ｃ（＝Ｎ−ＯＲ^６）−ＮＲ^６−、 −Ｃ（＝Ｏ）−Ｃ（＝Ｎ−ＯＲ^６）‐、 −Ｃ（＝Ｎ−ＯＲ^６）−Ｃ（＝Ｏ）‐、 −Ｏ−、 −Ｓ−、 −Ｓ（＝Ｏ）‐、 −Ｓ（＝Ｏ）_２−ＮＲ^６−、 −ＮＲ^６−Ｓ（＝Ｏ）_２−、 −ＮＲ^６−ＣＨ_２−、 −ＣＨ_２−ＮＲ^６−、−Ｃ＝Ｎ−、−Ｎ＝Ｃ−、−Ｓ（＝Ｏ）_２−または置換もしくは非置換の複素環ジイルであり；
Ｄ^２は、単結合、−Ｃ（＝Ｏ）―、−Ｏ−Ｃ（＝Ｏ）‐、−Ｃ（＝Ｏ）‐Ｏ−、−ＮＲ^６−、−ＮＲ^６−Ｃ（＝Ｏ）‐、−Ｃ（＝Ｏ）‐ＮＲ^６−、−Ｃ（＝Ｏ）‐Ｃ（＝Ｏ）‐、−ＮＲ^６−Ｃ（＝Ｏ）‐ＮＲ^６−、−Ｃ（＝Ｏ）‐Ｃ（＝Ｏ）‐ＮＲ^６−、−Ｃ（＝Ｏ）‐ＮＲ^６−Ｃ（＝Ｏ）‐、−ＮＲ^６−Ｃ（＝Ｏ）‐Ｃ（＝Ｏ）‐、−ＮＲ^６−ＮＲ^６−Ｃ（＝Ｏ）‐、−Ｃ（＝Ｏ）‐ＮＲ^６−ＮＲ^６−、−Ｎ＝Ｎ−Ｃ（＝Ｏ）‐、−Ｃ（＝Ｏ）‐Ｎ＝Ｎ−、 −Ｃ＝Ｎ−ＮＲ^６−Ｃ（＝Ｏ）−、 −Ｃ＝Ｎ−Ｃ（＝Ｏ）−、 ‐Ｎ＝Ｃ−Ｃ（＝Ｏ）−、 ‐Ｃ＝Ｎ−Ｃ（＝Ｏ）−ＮＲ^６−、 −ＮＲ^６−Ｃ（＝Ｏ）−Ｃ（＝Ｎ−ＯＲ^６）‐、 −Ｃ（＝Ｎ−ＯＲ^６）−Ｃ（＝Ｏ）−ＮＲ^６−、 −ＮＲ^６− Ｃ（＝Ｎ−ＯＲ^６）‐、 −Ｃ（＝Ｎ−ＯＲ^６）−ＮＲ^６−、 −Ｃ（＝Ｏ）−Ｃ（＝Ｎ−ＯＲ^６）‐、 −Ｃ（＝Ｎ−ＯＲ^６）−Ｃ（＝Ｏ）‐、 −Ｏ−、 −Ｓ−、 −Ｓ（＝Ｏ）‐、 −Ｓ（＝Ｏ）_２−ＮＲ^６−、 −ＮＲ^６−Ｓ（＝Ｏ）_２−、 −ＮＲ^６−ＣＨ_２−、 −ＣＨ_２−ＮＲ^６−、−Ｃ＝Ｎ−、−Ｎ＝Ｃ−、−Ｓ（＝Ｏ）_２−または置換もしくは非置換の複素環ジイルであり；
Ｒ^６はそれぞれ独立して、水素原子または置換もしくは非置換の低級アルキル；
ｎは０〜２の整数であり；
Ｂは単結合または少なくとも窒素原子を１〜３個含有する５員もしくは６員の複素環ジイルであり、
環Ａはベンゼン環、縮合した炭素環、単環の複素環または縮合した複素環であり；
Ｒ^４はそれぞれ独立して、ハロゲン原子、オキソ、ヒドロキシ、アミノ、シアノ、ニトロ、−Ｏ−Ｃ（＝Ｏ）‐Ｒ^９、−Ｃ（＝Ｏ）‐Ｒ^９、カルボキシ、−Ｃ（＝Ｏ）‐ＯＲ^９、−ＯＲ^９、−ＮＨＲ^９−、−ＮＲ^９Ｒ^９、−ＳＯ_２Ｒ^９、−ＳＲ^９、−ＮＲ^９−Ｃ（＝Ｏ）‐Ｒ^９、−ＳＨ、置換もしくは非置換の低級アルキル、置換もしくは非置換のシクロアルキル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基であり；ただし、Ａ環上の２つのヒドロキシ基はそれぞれ隣り合う炭素原子に結合する；
Ｒ^９はそれぞれ独立して低級アルキルまたはハロ低級アルキルであり；
ｋは１〜３の整数である。）
で示される基である。
ただし、
１）Ｒ^５ＡおよびＲ^５Ｂが水素原子であり、かつＥは置換もしくは非置換のピリミジニウム基である場合を除く、かつ、
２）Ｒ^１０が水素原子の場合、Ｅが１以上の４級アンモニウムイオンを有し、少なくとも２つのヒドロキシ基によって置換された２価の環式基であり、該２つのヒドロキシ基がそれぞれ該環式基の隣り合う炭素原子に結合すし、該ヒドロキシで置換されている位置以外の置換可能な任意の位置がさらに置換されていてもよい。）
で示される化合物、カルボキシのエステル体、もしくは７位側鎖の環上にアミノ基が存在する場合の該アミノ基における保護体またはそれらの製薬上許容される塩。 Specifically, the present invention provides the following inventions.
(Item 1)
Formula (I):

(Where
R ¹ is a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group;
For R ^2A and R ^2B
a) R ^2A is a hydrogen atom, substituted or unsubstituted amino, —SO ₃ H, substituted or unsubstituted aminosulfonyl, carboxy, substituted or unsubstituted lower alkyloxycarbonyl, substituted or unsubstituted carbamoyl, hydroxy, or Carbonyloxy having a substituent and R ^2B is a hydrogen atom, or
b) R ^2A and R ^2B together form a substituted or unsubstituted methylidene, or a substituted or unsubstituted hydroxyimino;
R ³ is a hydrogen atom, —OCH ₃ or —NH—CH (═O);
For R ^5A and R ^5B ,
a) R ^5A and R ^5B are each independently a hydrogen atom or lower alkyl,
b) R ^5A and R ^5B together with adjacent atoms form a substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle, or
c) R ^5A and R ^5B together form a substituted or unsubstituted methylidene;
L is _{-CH 2 -, - CH = CH} -, - CH 2 -CH = CH -, - CH = CH-CH 2 -, - S -, - CH 2 -S -, - CH = CH-S- or -CH = _CH-CH 2 -S- and and,
E is a divalent group having one or more quaternary ammonium ions that are substituted or unsubstituted;
R ¹⁰ is a hydrogen atom or the following formula (IA):

(Where
G ¹ and G ² are each independently a single bond, a substituted or unsubstituted lower alkylene, a substituted or unsubstituted lower alkenylene, or a substituted or unsubstituted lower alkynylene,
D ^{1 s} independently represent —C (═O) —, —O—C (═O) —, —C (═O) —O—, —NR ⁶ —, —NR ⁶ —C (═O ^{) -, - C (= O} ) -NR 6 -, - C (= O) -C (= O) -, - NR 6 -C (= O) -NR 6 -, - C (= O) -C (═O) —NR ⁶ —, —C (═O) —NR ⁶ —C (═O) —, —NR ⁶ —C (═O) —C (═O) —, —NR ⁶ —NR ⁶ — C (= O)-, -C (= O) -NR < ⁶ > -NR < ⁶ >-, -N = N-C (= O)-, -C (= O) -N = N-, -C = N- NR ⁶ —C (═O) —, —C═N—C (═O) —, —N═C—C (═O) —, —C═N—C (═O) —NR ⁶ —, — ^{NR 6 -C (= O) -C} (= N-OR 6) -, -C (= N-OR 6) -C (= O) -NR 6 -, -NR 6 - C ^{= N-OR 6) -,} -C (= N-OR 6) -NR 6 -, -C (= O) -C (= N-OR 6) -, -C (= N-OR 6) -C (= O) -, -O-, -S-, -S (= O) -, -S (= O) 2 -NR 6 -, -NR 6 -S (= O) 2 -, -NR 6 - CH ₂ —, —CH ₂ —NR ⁶ —, —C═N—, —N═C—, —S (═O) ₂ — or substituted or unsubstituted heterocyclic diyl;
D ² represents a single bond, —C (═O) —, —O—C (═O) —, —C (═O) —O—, —NR ⁶ —, —NR ⁶ —C (═O) —. ^{, -C (= O) -NR 6} -, - C (= O) -C (= O) -, - NR 6 -C (= O) -NR 6 -, - C (= O) -C (= O) —NR ⁶ —, —C (═O) —NR ⁶ —C (═O) —, —NR ⁶ —C (═O) —C (═O) —, —NR ⁶ —NR ⁶ —C ( = O)-, -C (= O) -NR < ⁶ > -NR < ⁶ >-, -N = NC (= O)-, -C (= O) -N = N-, -C = N-NR < ⁶ >. -C (= O) -, -C = N-C (= O) -, -N = C-C (= O) -, -C = N-C (= O) -NR 6 -, -NR 6 ^{-C (= O) -C (=} N-OR 6) -, -C (= N-OR 6) -C (= O) -NR 6 -, -NR 6 - C (= N-O ^{6) -, -C (= N} -OR 6) -NR 6 -, -C (= O) -C (= N-OR 6) -, -C (= N-OR 6) -C (= O) ^{_{-, -O-, -S-, -S (}} = O) -, -S (= O) 2 -NR 6 -, -NR 6 -S (= O) 2 -, -NR 6 -CH 2 -, —CH ₂ —NR ⁶ —, —C═N—, —N═C—, —S (═O) ₂ — or substituted or unsubstituted heterocyclic diyl;
Each R ⁶ independently represents a hydrogen atom or a substituted or unsubstituted lower alkyl;
n is an integer from 0 to 2;
B is a single bond or a 5- or 6-membered heterocyclic diyl containing at least 1 to 3 nitrogen atoms,
Ring A is a benzene ring, a fused carbocycle, a monocyclic heterocycle or a fused heterocycle;
Each R ⁴ independently represents a halogen atom, oxo, hydroxy, amino, cyano, nitro, —O—C (═O) —R ⁹ , —C (═O) —R ⁹ , carboxy, —C (═O; ) —OR ⁹ , —OR ⁹ , —NHR ⁹ —, —NR ⁹ R ⁹ , —SO ₂ R ⁹ , —SR ⁹ , —NR ⁹ —C (═O) —R ⁹ , —SH, substituted or unsubstituted Lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group; provided that the two hydroxy groups on the A ring are each Binds to adjacent carbon atoms;
Each R ⁹ is independently lower alkyl or halo lower alkyl;
k is an integer of 1 to 3. )
It is group shown by these.
However,
1) Except when R ^5A and R ^5B are a hydrogen atom, and E is a substituted or unsubstituted pyrimidinium group, and
2) When R ¹⁰ is a hydrogen atom, E is a divalent cyclic group having one or more quaternary ammonium ions and substituted by at least two hydroxy groups, and each of the two hydroxy groups is the ring It binds to an adjacent carbon atom of the formula group, and any substitutable position other than the position substituted with hydroxy may be further substituted. )
Or a protected form of the amino group or a pharmaceutically acceptable salt thereof when an amino group is present on the ring of the 7-position side chain.

(Item 2)
The compound according to item 1, wherein R ^5A is a hydrogen atom, and R ^5B is lower alkyl, or a protected form of the amino group when an amino group is present on the ring of the 7-position side chain, or Their pharmaceutically acceptable salts.

(Item 3)
The compound according to Item 1, wherein R ^5A and R ^5B are hydrogen atoms, a carboxy ester, or a protected form of the amino group when a 7-position side chain ring is present, or a pharmaceutically acceptable product thereof Salt.

（式中、各定義は項目１と同意義である。）
である、項目１〜３のいずれかに記載の化合物、カルボキシのエステル体、もしくは７位側鎖の環上にアミノ基が存在する場合の該アミノ基における保護体またはそれらの製薬上許容される塩。 (Item 4)
R ¹⁰ represents the following formula (IA):

(In the formula, each definition has the same meaning as item 1.)
The compound according to any one of Items 1 to 3, a carboxy ester, or a protected form of the amino group when an amino group is present on the ring of the 7-position side chain or a pharmaceutically acceptable product thereof salt.

(Item 5)
The compound according to any one of Items 1 to 4, wherein the ring A is a benzene ring or a 5- to 7-membered monocyclic heterocycle, an ester of carboxy, or an amino group on the ring of the 7-position side chain A protected form of the amino group or a pharmaceutically acceptable salt thereof.

(Item 6)
The compound according to any one of items 1 to 5, wherein ring A is a benzene ring, a carboxy ester, or a protected form of the amino group when a cyclic amino group at the 7-position side chain is present, or a pharmaceutical thereof Top acceptable salt.

(Item 7)
R ¹⁰ is a hydrogen atom, E is a substituted or unsubstituted divalent cyclic group having one or more quaternary ammonium ions, and two hydroxy groups are bonded to adjacent carbon atoms of the cyclic group, respectively. The compound according to any one of Items 1 to 6, a carboxy ester, or a 7-position side chain, which may be further substituted at any substitutable position other than the position substituted and substituted with hydroxy When an amino group is present on the ring, a protected form of the amino group or a pharmaceutically acceptable salt thereof.

(Item 8)
G ¹ and ^{G 2} are each independently a single _{bond, -CH 2 -, - CH 2} -CH 2 -, - CH 2 -CH 2 -CH 2 -, - CH = CH -, - CH = CH- _{CH 2 -, - CH 2 -CH} = CH -, - CH 2 -CH (CH 3) -, - CH 2 -CH (i Pr) - or _-CH 2 _-CH (Ph) - is, items 1 7. The compound according to any one of 6 and an ester form of carboxy, or a protected form of the amino group when an amino group is present on the ring of the 7-position side chain, or a pharmaceutically acceptable salt thereof.

(Item 9)
The compound according to items 1 to 6 or 8, wherein B is a single bond, an ester of carboxy, or a protected form of the amino group when the amino group is present on the ring of the 7-position side chain, or a pharmaceutically acceptable product thereof Salt.

(Item 10)
D ¹ is independently —NR ⁶ —, —NR ⁶ —C (═O) —, —C (═O) —NR ⁶ —, —NR ⁶ —C (═O) —C (═O ) −, —NR ⁶ —NR ⁶ —C (═O) —, —O—, —S—, —S (═O) —, —S (═O) ₂ —NR ⁶ —, —NR ⁶ —S (═O) ₂ —, —NR ⁶ —CH ₂ —, —CH ₂ —NR ⁶ —, —C═N—, —N═C—, —S (═O) ₂ — or substituted or unsubstituted complex 10. The compound according to items 1 to 6, 8 or 9, which is a ring diyl, an ester of carboxy, or a protected form of the amino group when the amino group is present on the ring of the 7-position side chain, or a pharmaceutically acceptable product thereof Salt.

(Item 11)
D ² is a single bond, —C (═O) —, —O—C (═O) —, —C (═O) —O—, —NR ⁶ —C (═O) —, —C (═O ) —NR ⁶ —, —C (═O) —C (═O) —, —NR ⁶ —C (═O) —NR ⁶ —, —C (═O) —C (═O) —NR ⁶ — , —C (═O) —NR ⁶ —C (═O) —, —NR ⁶ —C (═O) —C (═O) —, —NR ⁶ —NR ⁶ —C (═O) —, — C (═O) —NR ⁶ —NR ⁶ —, —N═N—C (═O) —, —C (═O) —N═N—, —C═N—NR ⁶ —C (═O) -, -C = NC (= O)-, -N = C-C (= O)-, -C = NC (= O) -NR < ⁶ >-, -NR < ⁶ > -C (= O) ^{-C (= N-OR 6)} -, -C (= N-OR 6) -C (= O) -NR 6 -, -NR 6 - C (= N-OR 6) -, -C ^{= N-OR 6) -NR 6} -, -C (= O) -C (= N-OR 6) -, -C (= N-OR 6) -C (= O) -, -S (= O ) ₂ -NR ^6- , -NR ⁶ -S (= O) _2- , -C = N-, -N = C-, or substituted or unsubstituted heterocyclic diyl, items 1-6 and 8-10 Or a protected form of the amino group or a pharmaceutically acceptable salt thereof when an amino group is present on the ring of the 7-position side chain.

(Item 12)
D ² is a single bond, —C (═O) —, —O—C (═O) —, —C (═O) —O—, —NR ⁶ —C (═O) —, —C (═O ) —NR ⁶ —, —C (═O) —C (═O) —, —C (═O) —NR ⁶ —C (═O) —, —NR ⁶ —C (═O) —C (= ^{O) -, - NR 6 -NR} 6 -C (= O) -, - N = N-C (= O) -, - C (= O) -N = N-, -C = N-NR 6 - C (= O) -, -C = N-C (= O) -, -N = C-C (= O) -, - NR 6 -C (= O) -C (= N-OR 6) - ^{, -NR 6 - C (= N} -OR 6) -, - C (= O) -C (= N-OR 6) -, -C (= N-OR 6) -C (= O) -, - _{^{S (= O) 2 -NR 6}} -, -NR 6 -S (= O) 2 -, - C = N -, - N = a C-, items 1-6 and 8-10 noise The compound according to any of the above, an ester of carboxy, or a protected form of the amino group when a amino group is present on the ring of the 7-position side chain, or a pharmaceutically acceptable salt thereof.

(Item 13)
The compound according to any one of items 1 to 6 and 8 to 12, wherein k is 1, an ester of carboxy, or a protected form of the amino group when an amino group is present on the ring of the 7-position side chain or Their pharmaceutically acceptable salts.

が、式：

（式中、Ｒ^４ａ、Ｒ^４ｂおよびＲ^４ｃはそれぞれ独立して、水素原子、ハロゲン原子、ヒドロキシ、シアノ、カルボキシ、−Ｃ（＝Ｏ）−Ｒ^９、−Ｃ（＝Ｏ）−ＯＲ^９、−ＯＲ^９、置換もしくは非置換の低級アルキルまたは置換もしくは非置換のシクロアルキルであり、Ｒ^６およびＲ^９は項目１と同意義であり、
波線は該結合がシスもしくはトランス型立体配置またはそれらの混合物であることを意味する。）
から選択される基である、項目１〜６および８〜１３のいずれかに記載の化合物、カルボキシのエステル体、もしくは７位側鎖の環上にアミノ基が存在する場合の該アミノ基における保護体またはそれらの製薬上許容される塩。 (Item 14)
Formula (IC-1):

But the formula:

(Wherein R ^4a , R ^4b and R ^4c each independently represents a hydrogen atom, a halogen atom, hydroxy, cyano, carboxy, —C (═O) —R ⁹ , —C (═O) —OR ⁹ , -OR ^9, a substituted or unsubstituted lower alkyl or substituted or unsubstituted cycloalkyl, R ⁶ and R ⁹ are as defined as item 1,
The wavy line means that the bond is in cis or trans configuration or a mixture thereof. )
The compound according to any one of items 1 to 6 and 8 to 13, which is a group selected from: carboxy ester, or protection at the amino group when an amino group is present on the ring of the 7-position side chain The body or a pharmaceutically acceptable salt thereof.

が、式：

（式中、Ｒ^６は水素原子、メチル、エチル、ｔ−ブチル、カルボキシメチル、２−カルボキシプロパン−２−イル、または１−カルボキシエチルであり、波線は、該結合がシスもしくはトランス型立体配置またはその混合物であることを意味する。）
から選択される基である、項目１〜６および８〜１４のいずれかに記載の化合物、カルボキシのエステル体、もしくは７位側鎖の環上にアミノ基が存在する場合の該アミノ基における保護体またはそれらの製薬上許容される塩。 (Item 15)
Formula (IC-1):

But the formula:

(Wherein R ⁶ is a hydrogen atom, methyl, ethyl, t-butyl, carboxymethyl, 2-carboxypropan-2-yl, or 1-carboxyethyl, and the wavy line indicates that the bond is in a cis or trans configuration. Or a mixture thereof.)
The compound according to any one of items 1 to 6 and 8 to 14, which is a group selected from: carboxy ester, or protection at the amino group when an amino group is present on the ring at the 7-position side chain The body or a pharmaceutically acceptable salt thereof.

（式中、破線は環内の結合を示し、カチオン性窒素原子からの結合手はＬとの結合を示し、もう一方の結合手はＲ^１０との結合を示す。ただし、Ｒ^１０がカチオン性窒素原子を結合している場合、破線は存在せず、Ｒ^１０がカチオン性窒素原子と結合していない場合、破線はカチオン性窒素原子と隣接原子との間の単結合を示すか、またはカチオン性窒素原子と隣接原子以外の環構成原子との間の低級アルキレンを示す。）
で示される、少なくとも１つの４級アンモニウムイオンを有する置換もしくは非置換の、飽和もしくは不飽和の、単環式または縮合環式の基である、項目１〜１５のいずれかに記載の化合物、カルボキシのエステル体、もしくは７位側鎖の環上にアミノ基が存在する場合の該アミノ基における保護体またはそれらの製薬上許容される塩。 (Item 16)
E is the formula (ID):

(In the formula, a broken line indicates a bond in the ring, a bond from a cationic nitrogen atom indicates a bond with L, and the other bond indicates a bond with R ¹⁰ , provided that R ¹⁰ is cationic. When the nitrogen atom is bonded, there is no broken line, and when R ¹⁰ is not bonded with the cationic nitrogen atom, the broken line indicates a single bond between the cationic nitrogen atom and the adjacent atom, or the cation And a lower alkylene between a ring nitrogen atom and a ring atom other than an adjacent atom.)
The compound according to any one of Items 1 to 15, which is a substituted or unsubstituted, saturated or unsaturated, monocyclic or condensed cyclic group having at least one quaternary ammonium ion, Or a protected form of the amino group or a pharmaceutically acceptable salt thereof when an amino group is present on the ring of the 7-position side chain.

（式中、カチオン性窒素原子からの結合手はＬとの結合を示し、もう一方の結合手はＲ^１０との結合を示し、Ｒ^ｘは置換もしくは非置換の低級アルキルを示す。）
で示される、少なくとも１つの４級アンモニウムイオンを有する置換もしくは非置換の、飽和もしくは不飽和の、単環式または縮合環式の基である、項目１〜１５のいずれかに記載の化合物、カルボキシのエステル体、もしくは７位側鎖の環上にアミノ基が存在する場合の該アミノ基における保護体またはそれらの製薬上許容される塩。 (Item 17)
E is the formula (IE):

(In the formula, a bond from a cationic nitrogen atom represents a bond to L, the other bond represents a bond to R ^10, and R ^x represents a substituted or unsubstituted lower alkyl.)
The compound according to any one of Items 1 to 15, which is a substituted or unsubstituted, saturated or unsaturated, monocyclic or condensed cyclic group having at least one quaternary ammonium ion, Or a protected form of the amino group or a pharmaceutically acceptable salt thereof when an amino group is present on the ring of the 7-position side chain.

(Item 18)
L is _{-S -, - CH 2 -S -} , - CH = CH-S- or -CH = _CH-CH 2 -S- and and; E is substituted or unsubstituted pyridinium group, or a substituted or unsubstituted fused The compound according to any one of Items 1 to 17, which is a cyclic pyridinium group, an ester of carboxy, or a protected form of the amino group when an amino group is present on the ring of the 7-position side chain, or a Pharmaceutically acceptable salt.

（式中、４級窒素原子からの結合手はＬとの結合を示し、もう一方の結合手はＲ^１０との結合を示し；ｐは１〜３の整数であり、ｎはそれぞれ独立して１または２であり、Ｒ^ｘは置換もしくは非置換の低級アルキルである。）
から選択される、さらに環上に置換基を有していてもよい基である、項目１〜１８のいずれかに記載の化合物、カルボキシのエステル体、もしくは７位側鎖の環上にアミノ基が存在する場合の該アミノ基における保護体またはそれらの製薬上許容される塩。

（項目２０）
Ｅが式（１）〜（７）、（１０）〜（１２）、（１４）、（２５）〜（２９）、（３１）、（４１）〜（４４）、（４７）、（５０）、（５２）、（５３）、（６４）および（７３）からなる群から選択される、項目１〜１８のいずれかに記載の化合物、カルボキシのエステル体、もしくは７位側鎖の環上にアミノ基が存在する場合の該アミノ基における保護体またはそれらの製薬上許容される塩。 (Item 19)
E is the formula:

(In the formula, the bond from the quaternary nitrogen atom represents a bond with L, the other bond represents a bond with R ¹⁰ ; p is an integer of 1 to 3, and n is independently 1 or 2 and R ^x is a substituted or unsubstituted lower alkyl.)
The compound according to any one of items 1 to 18, which is a group which may further have a substituent on the ring, or an ester group of carboxy, or an amino group on the ring of the 7-position side chain Or a pharmaceutically acceptable salt thereof.

(Item 20)
E represents the formulas (1) to (7), (10) to (12), (14), (25) to (29), (31), (41) to (44), (47), (50) , (52), (53), (64) and the compound according to any one of items 1 to 18, selected from the group consisting of (64) and (73), a carboxy ester, or a 7-position side chain ring A protected form of the amino group when an amino group is present, or a pharmaceutically acceptable salt thereof.

で示される基について、
Ｇ^１が単結合、−ＣＨ_２−または−ＣＨ_２−ＣＨ_２−であり；
Ｄ^１が−ＮＲ^６−、−ＮＲ^６−Ｃ（＝Ｏ）−、−Ｏ−、−Ｓ−、−Ｓ（＝Ｏ）−、または式：

であり；
ｋが１であり、
Ｇ^２が−ＣＨ_２−または−ＣＨ_２−ＣＨ_２−であり、
Ｂが単結合であり、
Ｄ^２が−ＮＲ^６−Ｃ（＝Ｏ）‐である、項目１〜６および１４〜２０のいずれかに記載の化合物、カルボキシのエステル体、もしくは７位側鎖の環上にアミノ基が存在する場合の該アミノ基における保護体またはそれらの製薬上許容される塩。 (Item 21)
Formula (I-H-1):

For the group represented by
G ¹ is a single bond, —CH ₂ — or —CH ₂ —CH ₂ —;
D ¹ is —NR ⁶ —, —NR ⁶ —C (═O) —, —O—, —S—, —S (═O) —, or the formula:

Is;
k is 1,
G ² is —CH ₂ — or —CH ₂ —CH ₂ —,
B is a single bond,
The compound according to any one of items 1 to 6 and 14 to 20, wherein D ² is —NR ⁶ —C (═O) —, an ester group of carboxy, or an amino group on the ring of the 7-position side chain A protected form of the amino group or a pharmaceutically acceptable salt thereof.

が、式：

（式中、左側の結合手はＥとの結合を示し、右側の結合手は環Ａとの結合を示す。）
から選択される基である、項目１〜６および１４〜２０のいずれかに記載の化合物、カルボキシのエステル体、もしくは７位側鎖の環上にアミノ基が存在する場合の該アミノ基における保護体またはそれらの製薬上許容される塩。 (Item 22)
Formula (I-H-1):

But the formula:

(In the formula, the left bond represents a bond with E, and the right bond represents a bond with ring A.)
The compound according to any one of items 1 to 6 and 14 to 20, which is a group selected from: carboxy ester, or protection at the amino group when an amino group is present on the ring of the 7-position side chain The body or a pharmaceutically acceptable salt thereof.

(Item 23)
The compound according to any one of Items 1 to 22, wherein R ³ is a hydrogen atom or —OCH ₃ , an ester of carboxy, or protection at the amino group when an amino group is present on the ring of the 7-position side chain The body or a pharmaceutically acceptable salt thereof.

（式中、ＸはＮ、Ｃ（−Ｈ）またはＣ（−Ｃｌ）である。）
である、項目１〜２３のいずれかに記載の化合物、カルボキシのエステル体、もしくは７位側鎖の環上にアミノ基が存在する場合の該アミノ基における保護体またはそれらの製薬上許容される塩。 (Item 24)
R ¹ is represented by the formula:

(In the formula, X is N, C (-H) or C (-Cl).)
The compound according to any one of Items 1 to 23, an ester of carboxy, or a protected form of the amino group when an amino group is present on the ring of the 7-position side chain, or a pharmaceutically acceptable product thereof salt.

(Item 25)
The compound according to Item 24, wherein X is C (—H) or C (—Cl), an ester of carboxy, or a protected form of the amino group when an amino group is present on the ring of the 7-position side chain Or a pharmaceutically acceptable salt thereof.

；または、以下に示す、置換ヒドロキシイミノ：

（式中、Ｒ^９は置換もしくは非置換の低級アルキルである。）
である、項目１〜２５のいずれかに記載の化合物、カルボキシのエステル体、もしくはその７位側鎖の環上にアミノ基が存在する場合の該アミノ基における保護体またはそれらの製薬上許容される塩。

（項目２７）
Ｒ^２ＡおよびＲ^２Ｂが一緒になって以下に示す、置換ヒドロキシイミノ基（Ｉ−Ｆ）：

（式中、Ｒ^７およびＲ^８はそれぞれ独立して水素原子、ハロゲン原子、ヒドロキシ、カルボキシ、置換もしくは非置換の低級アルキル、置換もしくは非置換の炭素環式基、または置換もしくは非置換の複素環式基であり、または
Ｒ^７およびＲ^８は隣接原子と一緒になって置換もしくは非置換の炭素環または置換もしくは非置換の複素環を形成してもよく；Ｑは単結合、置換もしくは非置換の炭素環、または置換もしくは非置換の複素環であり；ｍは０〜３の整数を表す。）
である、項目１〜２６のいずれかに記載の化合物、カルボキシのエステル体、もしくはその７位側鎖の環上にアミノ基が存在する場合の該アミノ基における保護体またはそれらの製薬上許容される塩。 (Item 26)
Substituted methylidene, wherein R ^2A and R ^2B together are shown below:

Or substituted hydroxyimino as shown below:

(In the formula, R ⁹ is substituted or unsubstituted lower alkyl.)
The compound according to any one of Items 1 to 25, an ester of carboxy, or a protected form of the amino group when an amino group is present on the ring of the 7-position side chain, or a pharmaceutically acceptable product thereof. Salt.

(Item 27)
The substituted hydroxyimino group (IF), wherein R ^2A and R ^2B together are shown below:

Wherein R ⁷ and R ⁸ are each independently a hydrogen atom, a halogen atom, hydroxy, carboxy, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic ring Or R ⁷ and R ⁸ may be taken together with adjacent atoms to form a substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle; Q is a single bond, substituted or unsubstituted A carbocyclic ring or a substituted or unsubstituted heterocyclic ring; m represents an integer of 0 to 3.)
The compound according to any one of Items 1 to 26, an ester form of carboxy, or a protected form of the amino group when an amino group is present on the ring of the 7-position side chain, or a pharmaceutically acceptable product thereof. Salt.

（式中、各記号は前記と同意義である。）
で示される項目１〜６および８〜２７のいずれかに記載の化合物、カルボキシのエステル体、もしくはその７位側鎖の環上にアミノ基が存在する場合の該アミノ基における保護体またはそれらの製薬上許容される塩。 (Item 28)
Formula (IG-1):

(In the formula, each symbol is as defined above.)
The compound in any one of the items 1-6 and 8-27 shown by this, the ester body of carboxy, or the protected body in this amino group, when those amino groups exist on the ring of the 7-position side chain, or those Pharmaceutically acceptable salt.

（式中、Ｒ^ｘは低級アルキル、ｐは１〜３の整数である。）
から選択される基であり；
Ｇ^１およびＧ^２がそれぞれ独立して、単結合または低級アルキレンであり；
Ｂが単結合であり；
Ｄ^１が、−ＮＲ^６−、−ＮＲ^６−Ｃ（＝Ｏ）‐、−Ｃ（＝Ｏ）‐ＮＲ^６−、−Ｏ−、 −Ｓ−、 −Ｓ（＝Ｏ）‐、 −Ｓ（＝Ｏ）_２−ＮＲ^６−、 −ＮＲ^６−Ｓ（＝Ｏ）_２−、−Ｓ（＝Ｏ）_２−または置換もしくは非置換の５員の芳香族複素環ジイルであり；
Ｄ^２が、単結合、−Ｃ（＝Ｏ）‐、−ＮＲ^６−Ｃ（＝Ｏ）‐、−Ｃ（＝Ｏ）‐Ｃ（＝Ｏ）‐−ＮＲ^６−Ｃ（＝Ｏ）‐Ｃ（＝Ｏ）‐、−ＮＲ^６−ＮＲ^６−Ｃ（＝Ｏ）‐、−Ｃ＝Ｎ−Ｃ（＝Ｏ）−、 ‐Ｎ＝Ｃ−Ｃ（＝Ｏ）−、−ＮＲ^６−Ｃ（＝Ｏ）−Ｃ（＝Ｎ−ＯＲ^６ａ）‐または置換もしくは非置換の５員の芳香族複素環ジイルであり；
Ｒ^６が水素原子または低級アルキルであり；
Ｒ^６ａが水素原子、メチル、カルボキシメチルまたは２−カルボキシプロパン−２−イルであり；
式（１−Ｂ−２）：

が、式：

（式中、Ｒ^４ａ，Ｒ^４ｂおよびＲ^４ｃはそれぞれ独立して、水素原子、ハロゲン原子、低級アルキルまたは低級シクロアルキルである。）
である、項目２８記載の化合物、カルボキシのエステル体、もしくは７位側鎖の環上のアミノ基が存在する場合の該アミノ基における保護体またはそれらの製薬上許容される塩。 (Item 29)
X is C (—H), C (—Cl) or N;
R ⁷ and R ⁸ are each independently a hydrogen atom or substituted or unsubstituted lower alkyl;
R ³ is a hydrogen atom;
m is 0 or 1;
Q is a single bond;
R ^5A and R ^5B are each independently a hydrogen atom or methyl;
L is —CH ₂ —;
E is the formula:

(In the formula, R ^x is lower alkyl, and p is an integer of 1 to 3.)
A group selected from:
G ¹ and G ² are each independently a single bond or lower alkylene;
B is a single bond;
D ¹ is —NR ⁶ —, —NR ⁶ —C (═O) —, —C (═O) —NR ⁶ —, —O—, —S—, —S (═O) —, —S ( _{^{= O) 2 -NR 6 -,}} -NR 6 -S (= O) 2 -, - S (= O) 2 - or a substituted or unsubstituted 5-membered aromatic heterocyclic diyl;
D ² is a single bond, —C (═O) —, —NR ⁶ —C (═O) —, —C (═O) —C (═O) —— NR ⁶ —C (═O) —C (═O) —, —NR ⁶ —NR ⁶ —C (═O) —, —C═N—C (═O) —, —N═C—C (═O) —, —NR ⁶ —C ( ═O) —C (═N—OR ^6a ) — or substituted or unsubstituted 5-membered aromatic heterocyclic diyl;
R ⁶ is a hydrogen atom or lower alkyl;
R ^6a is a hydrogen atom, methyl, carboxymethyl or 2-carboxypropan-2-yl;
Formula (1-B-2):

But the formula:

(Wherein R ^4a , R ^4b and R ^4c are each independently a hydrogen atom, a halogen atom, lower alkyl or lower cycloalkyl).
29. The compound according to item 28, an ester form of carboxy, or a protected form of the amino group when a 7-position side chain ring is present or a pharmaceutically acceptable salt thereof.

（式中、Ｒ^５ＣおよびＲ^５Ｄについては、
ａ）Ｒ^５ＣおよびＲ^５Ｄは、それぞれ独立して、水素原子または低級アルキルであり、かつＲ^５ＣおよびＲ^５Ｄは同時に水素原子ではなく、
ｂ）Ｒ^５ＣおよびＲ^５Ｄが隣接する原子と一緒になって、置換もしくは非置換の炭素環、または置換もしくは非置換の複素環を形成し、または、
ｃ）Ｒ^５ＣおよびＲ^ｄが一緒になって、置換もしくは非置換のメチリデンを形成し；
Ｄ^３は置換もしくは非置換の複素環ジイルであり；
その他の記号は前記と同意義である。）
である化合物、カルボキシのエステル体、もしくは７位側鎖の環上のアミノ基が存在する場合の該アミノ基における保護体またはそれらの製薬上許容される塩。 (Item 30)
Formula (II):

(Wherein R ^5C and R ^5D are
a) R ^5C and R ^5D are each independently a hydrogen atom or lower alkyl, and R ^5C and R ^5D are not simultaneously a hydrogen atom,
b) R ^5C and R ^5D together with the adjacent atoms form a substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle, or
c) R ^5C and R ^d together form a substituted or unsubstituted methylidene;
D ³ is a substituted or unsubstituted heterocyclic diyl;
Other symbols are as defined above. )
, An ester of carboxy, or a protected form of the amino group in the presence of an amino group on the ring of the 7-position side chain, or a pharmaceutically acceptable salt thereof.

で示される基について、
ＸがＣ（−Ｈ）、Ｃ（−Ｃｌ）またはＮであり；
Ｒ^７およびＲ^８がそれぞれ独立して、水素原子または置換もしくは非置換の低級アルキルであり；
Ｒ^３が水素原子であり；
ｍが０または１であり；
Ｑが単結合であり；
Ｒ^５Ｃは水素原子であり；
Ｒ^５Ｄは低級アルキルであり；
Ｌが‐ＣＨ_２−、であり；
Ｅが式：

（式中、Ｒ^ｘは低級アルキル、ｐは１〜３の整数である。）
から選択される基であり；
Ｇ^２が単結合または低級アルキレンであり；
Ｂが単結合であり；
Ｄ^３が、置換もしくは非置換の５員の芳香族複素環ジイルであり；
式（１−Ｂ−２）：

が、式：

（式中、Ｒ^４ａ，Ｒ^４ｂおよびＲ^４ｃはそれぞれ独立して、水素原子、ハロゲン原子、低級アルキルまたは低級シクロアルキルである。）である、項目３０記載の化合物、カルボキシのエステル体、もしくは７位側鎖の環上のアミノ基が存在する場合の該アミノ基における保護体またはそれらの製薬上許容される塩。 (Item 31)
Formula (II-A)

For the group represented by
X is C (—H), C (—Cl) or N;
R ⁷ and R ⁸ are each independently a hydrogen atom or substituted or unsubstituted lower alkyl;
R ³ is a hydrogen atom;
m is 0 or 1;
Q is a single bond;
R ^5C is a hydrogen atom;
R ^5D is lower alkyl;
L is —CH ₂ —;
E is the formula:

(In the formula, R ^x is lower alkyl, and p is an integer of 1 to 3.)
A group selected from:
G ² is a single bond or lower alkylene;
B is a single bond;
D ³ is a substituted or unsubstituted 5-membered aromatic heterocyclic diyl;
Formula (1-B-2):

But the formula:

(Wherein R ^4a , R ^4b and R ^4c are each independently a hydrogen atom, a halogen atom, lower alkyl or lower cycloalkyl), a compound according to item 30, a carboxy ester, or 7 When the amino group on the ring of the side chain is present, a protected form of the amino group or a pharmaceutically acceptable salt thereof.

(Item 32)
The compound in any one of items 1-31, the ester body of carboxy, or when the amino group on the ring of the 7-position side chain exists, the protected body in this amino group, or those pharmaceutically acceptable salts are contained. A pharmaceutical composition.

(Item 33)
Item 33. The pharmaceutical composition according to item 32, which has an antibacterial action.

The compound according to the present invention is useful as a pharmaceutical in that it has at least one of the following characteristics.
A) A strong antibacterial spectrum is shown against various bacteria including Gram negative bacteria and / or Gram positive bacteria.
B) Strong antibacterial activity against β-lactamase producing gram-negative bacteria.
C) Strong antibacterial activity against multi-drug resistant bacteria, particularly class B type metallo-β-lactamase producing Gram-negative bacteria.
D) Strong antibacterial activity against a substrate-specific extended β-lactamase (ESBL) -producing bacterium.
E) Does not show cross resistance with existing cephem and / or carbapenem drugs.
F) No side effects such as fever are shown after in vivo administration.
G) High stability of the compound and / or solubility in water.
H) It has excellent pharmacokinetic characteristics such as high blood concentration, high oral absorption, long duration of effect, and high tissue migration.

  Hereinafter, embodiments of the present invention will be described with respect to the present invention. Throughout this specification, singular forms (eg, “a”, “an”, “the” in English, corresponding articles in other languages, adjectives, etc.) It should be understood that it also includes the plural concept. In addition, it is to be understood that the terms used in the present specification are used in the meaning normally used in the art unless otherwise specified. Thus, unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification, including definitions, will control. Hereinafter, specific definitions of terms specifically used in the present specification will be described.

  Each term in this specification is defined as follows, alone or in combination with other terms.

  “Halogen” includes fluorine, chlorine, bromine and iodine. Preferred are fluorine, chlorine and bromine, and more preferred is chlorine.

  “Lower alkyl” includes linear or branched alkyl having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms. For example, methyl, ethyl, n-propyl, isopropyl , N-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl and the like.

  The “lower alkylene” includes a linear alkylene group having 1 to 8, preferably 1 to 6, more preferably 1 to 4, and most preferably 1 or 2 carbon atoms. For example, methylene, ethylene, n- Examples include propylene, n-butylene and n-hexylene.

  “Lower alkenylene” includes linear alkenylene having 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms having one or more double bonds at any position. For example, vinylene, Examples include arylene, propenylene, butenylene, plenylene, butadienylene, pentenylene, pentadienylene, hexenylene, pentynylene, hexynylene, and the like.

  “Lower alkynylene” includes linear alkynylene having 2 to 8, preferably 2 to 6, and more preferably 2 to 4 carbon atoms having one or more triple bonds at any position. For example, ethynylene , Propynylene, butynylene, pentynylene, hexynylene and the like.

  “Cycloalkyl” is a carbocyclic group having 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, more preferably 3 to 7 carbon atoms. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclo Includes octyl, cyclononyl, cyclodecyl and the like.

  The “halo lower alkyl” is a group substituted with one or more of the “halogen” at any position of the “lower alkyl”. For example, monofluoromethyl, difluoromethyl, trifluoromethyl, monochloromethyl, Examples include dichloromethyl, trichloromethyl, monobromomethyl, monofluoromethyl, monochloromethyl, chlorodifluoromethyl and the like. Preferred are trifluoromethyl and trichloromethyl.

As the substituent of “substituted or unsubstituted amino”, “substituted or unsubstituted aminosulfonyl” or “substituted or unsubstituted carbamoyl”, substituted or unsubstituted lower alkyl (eg, methyl, ethyl, isopropyl, benzyl) Carbamoylalkyl (eg: carbamoylmethyl), mono- or di-lower alkylcarbamoyl lower alkyl (eg: dimethylcarbamoylethyl), hydroxy lower alkyl, heterocyclic lower alkyl (eg: morpholinoethyl, tetrahydropyranylethyl), alkyloxycarbonyl lower Alkyl (eg ethoxycarbonylmethyl, ethoxycarbonylethyl), mono- or di-lower alkylamino lower alkyl (eg dimethylaminoethyl); lower alkyloxy lower alkyl (eg methoxyethyl, ethoxy) Acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, octanoyl, octanoyl, methoxyethylcarbonyl, etc. 2,2,2-trifluoroethylcarbonyl, alkyloxycarbonylacetyl (eg ethoxycarbonylmethylcarbonyl), lower alkyloxy lower alkylcarbonyl (eg methoxyethylcarbonyl), lower alkylcarbamoyl lower alkylcarbonyl (eg methylcarbamoyl) Ethylcarbonyl), substituted or unsubstituted arylcarbonyl (eg benzoyl, toluoyl)); substituted or unsubstituted arylalkyl (eg benzyl, Hydroxy; substituted or unsubstituted lower alkylsulfonyl (eg methanesulfonyl, ethanesulfonyl, isopropylsulfonyl, 2,2,2-trifluoroethanesulfonyl, benzylsulfonyl, methoxyethylsulfonyl); lower as substituent Arylsulfonyl optionally having alkyl or halogen, benzylsulfonyl, methoxyethylsulfonyl); arylsulfonyl optionally having lower alkyl or halogen as a substituent (eg, benzenesulfonyl, toluenesulfonyl, 4- Fluorobenzenesulfonyl), cycloalkyl (eg cyclopropyl); aryl optionally having lower alkyl as a substituent (eg phenyl, tolyl); lower alkylaminosulfonyl (eg methyla) Lower alkylaminocarbonyl (eg dimethylaminocarbonyl); lower alkyloxycarbonyl (eg ethoxycarbonyl); cycloalkylcarbonyl (eg cyclopropylcarbonyl, cyclohexylcarbonyl); substituted or unsubstituted sulfamoyl (Eg, sulfamoyl, methylsulfamoyl, dimethylsulfamoyl); lower alkylcarbonylamino (eg, methylcarbonylamino); heterocycle (eg, morpholino, tetrahydropyranyl); substituted or unsubstituted amino (eg, mono Or dialkylamino (eg, dimethylamino), formylamino) and the like.
The “substituted amino” or “substituted carbamoyl” may be mono-substituted or di-substituted with these substituents.

  The amino group of “substituted or unsubstituted amino”, “substituted or unsubstituted carbamoyl” or “substituted or unsubstituted aminosulfonyl” is a sulfur atom and / or a nitrogen atom adjacent to the two substituents of the amino group. A nitrogen-containing heterocycle (preferably a 5- to 7-membered ring or preferably saturated) which may contain an oxygen atom in the ring may be formed, and the ring is oxo or hydroxy May be substituted. For example, 5-membered or 6-membered rings such as piperazinyl, piperidino, morpholino, pyrrolidino, 2-oxopiperidino, 2-oxopyrrolidino, 4-hydroxymorpholino and the like are preferable.

  The “carbocyclic group” includes cycloalkyl, cycloalkenyl, aromatic carbocyclic group, non-aromatic fused carbocyclic group and the like.

  “Cycloalkenyl” includes those having one or more double bonds at any position in the ring of “cycloalkyl”, specifically cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl. , Cycloheptynyl, cyclooctynyl, cyclohexadienyl and the like.

  The “aromatic carbocyclic group” includes phenyl, naphthyl, anthryl, phenanthryl and the like, and phenyl is particularly preferable. “Aryl” has the same meaning as “aromatic carbocyclic group”.

  The “non-aromatic carbocyclic group” includes a group selected from the above “cycloalkyl” and “cycloalkenyl”, specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl. , Cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptynyl, cyclooctynyl, cyclohexadienyl, and the like.

  The “non-aromatic fused carbocyclic group” is selected from the above “cycloalkyl” and “cycloalkenyl” with respect to the above “cycloalkyl”, “cycloalkenyl” and “aromatic carbocyclic group”. A group in which one or more cyclic groups are condensed is included, and specific examples include indanyl, indenyl, tetrahydronaphthyl, and fluorenyl.

  The “fused carbocycle” includes two or more aromatic carbocyclic groups in the “aromatic carbocyclic group” and a ring derived from the “non-aromatic condensed carbocyclic group”. .

  “Carbocycle” means a ring derived from the above “carbocyclic group”.

  The “heterocyclic group” includes a heterocyclic group having one or more, preferably 1 to 4, hetero atoms arbitrarily selected from O, S and N, specifically pyrrolyl, 5-6 membered monocyclic aromatic heterocyclic groups such as imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl and thienyl; Indolyl, isoindolyl, indazolyl, indolizinyl, indolinyl, isoindolinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzopyranyl, benzimidazolyl, Nzotriazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, pyrazolopyridine , Triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, quinazolinyl, quinolyl, isoquinolyl, naphthyridinyl, dihydrobenzofuryl, tetrahydroquinolyl, tetrahydroisoquinolyl, dihydrobenzoxazine, tetrahydrobenzothienyl, etc. Fused heterocyclic groups; tricyclic fused heterocycles such as carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, dibenzofuryl, imidazoquinolyl, etc. Formula groups; dioxanyl, thiranyl, oxiranyl, oxathiolanyl, azetidinyl, thianyl, thiazolidine, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholino hydrodipyridyl, dihydropyridyl, dihydropyridyl Includes non-aromatic heterocyclic groups such as tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, dihydrooxazinyl, hexahydroazepinyl, tetrahydrodiazepinyl and the like. A 5- to 6-membered monocyclic aromatic heterocyclic group or a non-aromatic heterocyclic group is preferable. More preferably, it is a 5- to 6-membered monocyclic aromatic heterocyclic group.

  “Aromatic heterocyclic group” means one or more, preferably 1 to 4 monocyclic or bicyclic or more of the same or different heteroatoms arbitrarily selected from O, S and N in the ring, An aromatic ring is meant. A bicyclic or higher aromatic heterocyclic group also includes a monocyclic ring or a bicyclic or higher aromatic heterocyclic ring fused with the above “aromatic carbocycle”.

  The “non-aromatic heterocyclic group” means a group that does not exhibit aromaticity among the above “heterocyclic group”.

  The “fused heterocyclic ring” includes rings derived from two or more aromatic heterocyclic groups and two or more non-aromatic heterocyclic groups among the above “heterocyclic groups”.

“Heterocycle” means a ring derived from the above “heterocyclic group”.
“Heterocyclic diyl” means a divalent group derived from the above “heterocycle”.

  Examples of the substituent of “substituted or unsubstituted lower alkyl” and “substituted or unsubstituted cycloalkyl” include one or more groups selected from substituent group α. When substituted with a plurality of substituent groups α, the substituent groups α may be the same or different.

  Examples of the substituent of “substituted or unsubstituted lower alkynylene”, “substituted or unsubstituted lower alkenylene” and “substituted or unsubstituted lower alkynylene” include one or more groups selected from substituent group α. . When substituted with a plurality of substituents, the substituents may be the same or different.

  Examples of the substituent of “substituted or unsubstituted lower alkyloxycarbonyl” include one or more groups selected from substituent group α.

  The substituent of “carbonyloxy having a substituent (meaning“ —O—C (═O) -substituent ”)” includes substituted or unsubstituted lower alkyl, substituted or unsubstituted lower Selected from alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted carbocyclic group, substituted or unsubstituted heterocyclic group, amino having heterocyclic group as substituent, and substituent group α One or more groups may be mentioned.

  Here, the “substituent group α” is halogen, hydroxy, lower alkyloxy, lower alkylene, hydroxy lower alkyloxy, lower alkyloxy lower alkyloxy, carboxy, amino, acylamino, lower alkylamino, imino, hydroxyimino, lower It is a group consisting of alkyloximino, lower alkylthio, carbamoyl, lower alkylcarbamoyl, hydroxy lower alkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl, lower alkylsulfinyl, cyano, nitro, carbocyclic group and heterocyclic group.

“Acyl” means formyl or carbonyl having a substituent. The substituted carbonyl is, for example, a substituted or unsubstituted lower alkylcarbonyl (eg, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, octanoyl, methoxyethylcarbonyl, 2,2, 2-trifluoroethylcarbonyl, alkyloxycarbonylacetyl (eg: ethoxycarbonylmethylcarbonyl), lower alkyloxy lower alkylcarbonyl (eg: methoxyethylcarbonyl), lower alkylcarbamoyl lower alkylcarbonyl (eg: methylcarbamoylethylcarbonyl), substituted Alternatively, unsubstituted arylcarbonyl (eg, benzoyl, toluoyl) can be mentioned.

  Examples of the substituent of “substituted or unsubstituted methylidene” and “substituted or unsubstituted hydroxyimino” include a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted alkynyl, Examples thereof include substituted or unsubstituted cycloalkyl, substituted or unsubstituted carbocyclic group, substituted or unsubstituted heterocyclic group, and the like. When substituted with a plurality of substituents, the substituents may be the same or different.

  “Substituted or unsubstituted carbocycle”, “Substituted or unsubstituted heterocycle”, “Substituted or unsubstituted carbocyclic group”, “Substituted or unsubstituted heterocyclic group”, “Substituted or unsubstituted heterocyclic group” "Aromatic carbocyclic group", "substituted or unsubstituted heterocyclic diyl", "substituted or unsubstituted aromatic heterocyclic diyl", "substituted or unsubstituted 5-membered aromatic heterocyclic diyl" and "substituted Examples of the substituent of the “unsubstituted aromatic heterocyclic group” include one or more groups selected from substituted or unsubstituted lower alkyl and substituent group α. When substituted with a plurality of substituents, the substituents may be the same or different.

“Substituted or unsubstituted carbocycle”, “Substituted or unsubstituted heterocycle”, “Substituted or unsubstituted carbocyclic group”, “Substituted or unsubstituted heterocyclic group”, “Substituted or unsubstituted heterocyclic group” "Aromatic carbocyclic group", "substituted or unsubstituted heterocyclic diyl", "substituted or unsubstituted aromatic heterocyclic diyl", "substituted or unsubstituted 5-membered aromatic heterocyclic diyl" and "substituted As preferred embodiments of the substituent in “or an unsubstituted aromatic heterocyclic group”, methyl, ethyl, isopropyl, tert-butyl, fluorine, chlorine, bromine, hydroxy, carboxy, methoxy, ethoxy, hydroxymethoxy, hydroxyethoxy, Methoxymethoxy, methoxyethoxy, amino, acetylamino, methylamino, dimethylamino, imino, hydroxyimino, methoxy Imino, methylthio, carbamoyl, methylcarbamoyl, hydroxy methylcarbamoyl, cyano, nitro, phenyl, cyclopropyl, cyclobutyl, cyclohexyl, pyridyl, and morpholinyl, and the like.

  “5- or 6-membered heterocyclic diyl containing at least 1 to 3 nitrogen atoms” includes pyrrole, piperidine, piperazine, imidazole, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, isoxazole, oxazole, oxazol And divalent groups derived from diazole, isothiazole, thiazole, thiadiazole, furan, thiol and the like.

  As the substituent of “substituted or unsubstituted divalent group having one or more quaternary ammonium ions”, hydroxy, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted Lower alkynyl, substituted or unsubstituted lower alkyloxy, substituted or unsubstituted amino, lower alkenyloxy, substituted or unsubstituted aryloxy, cyano, nitro, imino, mercapto, lower alkylthio, lower alkylsulfonyl, substituted or non-substituted And one or more groups selected from a substituted carbocyclic group, a substituted or unsubstituted heterocyclic group, and a substituted or unsubstituted lower alkyloxycarbonyl. When substituted with a plurality of substituents, the substituents may be the same or different.

  Although the example or aspect in each site | part of a formula (I) is shown below, the scope of the present invention is not limited to what is described below.

"L" is _{-CH 2 -, - CH = CH} -, - CH 2 -CH = CH -, - CH = CH-CH 2 -, - S -, - CH 2 -S -, - CH = CH-S - or -CH = _CH-CH 2 -S- and and, _{preferably, -CH 2 -, - CH =} CH -, - CH 2 -CH = CH-, or -CH = CH-CH ₂ - is. More preferably, it is —CH ₂ —.

A preferred embodiment of the ring of the “substituted or unsubstituted carbocyclic group or substituted or unsubstituted heterocyclic group” of R ¹ is a 5- to 6-membered ring. Preferred examples include phenyl, hydroxyphenyl, substituted Examples thereof include phenyl having a halogen as a group, aminothiazole, aminothiazole having a halogen as a substituent, aminothiadiazole, thiophene, furan, benzothiazole, pyridine, pyrimidine, pyridazine, aminopyridine and the like.
More preferred examples are aminothiazole, aminothiazole or aminothiadiazole having halogen as a substituent.
Particularly preferred examples of the heterocyclic group include the groups shown below.

の好ましい例としては、以下に示す置換アミノ

以下に示す、置換アミノスルホニル

（式中、環Ｃは置換もしくは非置換の複素環式基を表す）；
以下に示す、置換カルバモイル

（式中、環Ｂは置換もしくは非置換の複素環式基を表す）；または
以下に示す、置換カルボニルオキシ

（式中、環Ｃは置換もしくは非置換の複素環式基を表す）などが挙げられる。 When R ^2A is a hydrogen atom, examples of R ^2B include a hydrogen atom, substituted or unsubstituted amino, —SO ₃ H, substituted or unsubstituted aminosulfonyl, carboxy, substituted or unsubstituted lower alkyloxycarbonyl. , Substituted or unsubstituted carbamoyl, hydroxy, or carbonyloxy having a substituent. For example,

Preferred examples of are the following substituted amino

Substituted aminosulfonyl, shown below

(Wherein ring C represents a substituted or unsubstituted heterocyclic group);
Substituted carbamoyl shown below

(Wherein ring B represents a substituted or unsubstituted heterocyclic group); or substituted carbonyloxy as shown below

(Wherein, ring C represents a substituted or unsubstituted heterocyclic group).

（Ｒ^１１は置換もしくは非置換の低級アルキルである。）で示される基である。ここで、二重結合を形成する炭素原子とＲ^１１の間の波線は、シス結合、トランス結合またはその混合であることを意味する。
好ましくは、

である。 Alternatively, R ^2A and R ^2B may be taken together to form a substituted or unsubstituted methylidene, preferably having the formula:

(R ¹¹ represents a substituted or unsubstituted lower alkyl). Here, the wavy line between the carbon atom forming a double bond and R ¹¹ means a cis bond, a trans bond, or a mixture thereof.
Preferably,

It is.

（式中Ｒ^９は前記と同意義）で示される基である。
好ましくは、

（式中、各記号は前記と同意義）である。 R ^2A and R ^2B may be taken together to form a substituted or unsubstituted hydroxyimino, preferably the formula:

(Wherein R ⁹ is as defined above).
Preferably,

(Wherein each symbol is as defined above).

Examples of “R ⁷ and R ⁸ ” include a hydrogen atom, fluorine, chlorine, hydroxy, carboxy, methyl, ethyl, isopropyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, carboxymethyl, hydroxyethyl, Carbamoylmethyl, carbamoylethyl, hydroxymethyl, hydroxyethyl, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, methylthiomethyl, ethylthiomethyl, benzyl, 4-hydroxybenzyl, 4-methoxybenzyl, 4-carboxybenzyl, 3, 4-dihydroxyphenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl Triazolyl, triazinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, and furyl, and thienyl and the like.

A preferred combination of R ⁷ and R ⁸ is that (R ⁷ , R ⁸ ) is (hydrogen atom, hydrogen atom), (methyl, hydrogen atom), (hydrogen atom, methyl), (methyl, methyl), (ethyl, hydrogen Atom), (hydrogen atom, ethyl), (ethyl, ethyl), (phenyl, hydrogen atom),
(Hydrogen atom, phenyl), (dihydroxyphenyl, hydrogen atom), (hydrogen atom, dihydroxyphenyl), (carboxymethyl, hydrogen atom), (hydrogen atom, carboxymethyl), (carboxyethyl, hydrogen atom), (hydrogen atom , Carboxyethyl), (hydroxyethyl, hydrogen atom), (hydrogen atom, hydroxyethyl), (carbamoylmethyl, hydrogen atom), (hydrogen atom, carbamoylmethyl), (trifluoromethyl, hydrogen atom), (carboxy, hydrogen Atom), (carbamoylethyl, hydrogen atom), (benzyl, hydrogen atom), (dihydroxybenzyl, hydrogen atom) and the like.

Preferable examples of the substituted hydroxyimino include the following groups.

More preferable examples of the substituted hydroxyimino include the following groups.

（式中、各記号は前記と同意義である。）
におけるＲ^７およびＲ^８が、環上に置換基群αから選択される基を有していてもよいシクロアルカン、シクロアルケン、もしくは非芳香族複素環を形成してもよい。
例えば、

は、環上に置換基群αから選択される基を有していてもよい以下の式：

であってよい。 In addition, when “R ⁷ and R ⁸ together with adjacent atoms form a substituted or unsubstituted carbocyclic ring or a substituted or unsubstituted heterocyclic ring”

(In the formula, each symbol is as defined above.)
R ⁷ and R ⁸ in the above formula may form a cycloalkane, cycloalkene, or non-aromatic heterocyclic ring which may have a group selected from the substituent group α on the ring.
For example,

May have a group selected from substituent group α on the ring:

It may be.

  Examples of “Q” include a single bond, phenyl, pyridyl and the like. Particularly preferred is a single bond.

  “M” is preferably 0 or 1, particularly preferably 0.

Preferred examples in this embodiment include the following.

“R ³ ” is preferably a hydrogen atom or —OCH ₃ , more preferably a hydrogen atom.

“Lower alkyl” of “R ^5A and R ^5B ” includes linear or branched alkyl having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as methyl, ethyl, Examples include n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl and the like.

Examples of combinations of (R ^5A , R ^5B ) when R ^5A and R ^5B are “a) R ^5A and R ^5B are each independently a hydrogen atom or lower alkyl” include (hydrogen atom, (Hydrogen atom), (hydrogen atom, methyl), (hydrogen atom, ethyl), (hydrogen atom, isopropyl), (hydrogen atom, tert-butyl), (methyl, methyl) and the like. Preferably, (R ^5A , R ^5B ) is (hydrogen atom, hydrogen atom), (hydrogen atom, methyl) or (methyl, methyl).

“Carbocycle” when R ^5A and R ^5B are “b) R ^5A and R ^5B together with adjacent atoms form a substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle” Includes cycloalkanes and cycloalkenes having 3 to 8 carbon atoms. Preferably, it has 3 to 6 carbon atoms. Preferable embodiments include cyclopropane, cyclobutene, cyclopentane, cyclopentene, cyclohexane, cyclohexene and the like, and cyclopropane is more preferable. Substituents for “carbocycle” include halogen, hydroxy, lower alkyl, lower alkoxy and the like. Preferred substituents include fluorine, chlorine, hydroxy, methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, isopropoxy and the like.

“Heterocycle” when R ^5A and R ^5B are “b) R ^5A and R ^5B together with adjacent atoms form a substituted or unsubstituted carbocyclic or substituted or unsubstituted heterocyclic ring” Includes aromatic or non-aromatic, monocyclic or fused rings. A preferred embodiment is a non-aromatic 3 to 6 membered monocycle. Substituents for “heterocycle” include halogen, hydroxy, lower alkyl, lower alkyloxy and the like. Preferred substituents include fluorine, chlorine, hydroxy, methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, isopropoxy and the like.

（式中、Ｒ^１４およびＲ^１５はそれぞれ独立して、水素原子、ハロゲン、または置換もしくは非置換の低級アルキルであり、好ましくは、Ｒ^１４およびＲ^１５が水素原子である。）
で示される。 “Substituted or unsubstituted methylidene” when R ^5A and R ^5B are “c) R ^5A and R ^5B together form a substituted or unsubstituted methylidene” has the formula:

(Wherein R ¹⁴ and R ¹⁵ are each independently a hydrogen atom, halogen, or substituted or unsubstituted lower alkyl, and preferably R ¹⁴ and R ¹⁵ are hydrogen atoms.)
Indicated by

“Lower alkyl” of “R ^5C and R ^5D ” includes linear or branched alkyl having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as methyl, ethyl, Examples include n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl and the like.

Examples of combinations of (R ^5C , R ^5D ) when R ^5C and R ^5D are “a) R ^5C and R ^5D are each independently a hydrogen atom or lower alkyl” include (hydrogen atom, Methyl), (hydrogen atom, ethyl), (hydrogen atom, isopropyl), (hydrogen atom, tert-butyl), (methyl, methyl) and the like. Preferably, (R ^5C , R ^5D ) is (hydrogen atom, hydrogen atom), (hydrogen atom, methyl) or (methyl, methyl).

“Carbocycle” when R ^5C and R ^5D are “b) R ^5C and R ^5D together with adjacent atoms form a substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle” Includes cycloalkanes and cycloalkenes having 3 to 8 carbon atoms. Preferably, it has 3 to 6 carbon atoms. Preferable embodiments include cyclopropane, cyclobutene, cyclopentane, cyclopentene, cyclohexane, cyclohexene and the like, and cyclopropane is more preferable. Substituents for “carbocycle” include halogen, hydroxy, lower alkyl, lower alkoxy and the like. Preferred substituents include fluorine, chlorine, hydroxy, methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, isopropoxy and the like.

“Heterocycle” when R ^5C and R ^5D are “b) R ^5C and R ^5D together with adjacent atoms form a substituted or unsubstituted carbocyclic or substituted or unsubstituted heterocyclic ring” Includes aromatic or non-aromatic, monocyclic or fused rings. A preferred embodiment is a non-aromatic 3 to 6 membered monocycle. Substituents for “heterocycle” include halogen, hydroxy, lower alkyl, lower alkyloxy and the like. Preferred substituents include fluorine, chlorine, hydroxy, methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, isopropoxy and the like.

（式中、Ｒ^１４およびＲ^１５はそれぞれ独立して、水素原子、ハロゲン、または置換もしくは非置換の低級アルキルであり、好ましくは、Ｒ^１４およびＲ^１５が水素原子である。）
で示される。 “Substituted or unsubstituted methylidene” when R ^5C and R ^5D are “c) R ^5C and R ^5D together form a substituted or unsubstituted methylidene” has the formula:

(Wherein R ¹⁴ and R ¹⁵ are each independently a hydrogen atom, halogen, or substituted or unsubstituted lower alkyl, and preferably R ¹⁴ and R ¹⁵ are hydrogen atoms.)
Indicated by

（式中、破線は館内の結合を示し、カチオン性窒素原子からの結合手はＬとの結合を示し、もう一方の結合手はＲ^１０との結合を示す。ただし、Ｒ^１０がカチオン性窒素原子を結合している場合、破線は存在せず、Ｒ^１０がカチオン性窒素原子と結合していない場合、破線はカチオン性窒素原子と隣接原子との間の単結合を示すか、またはカチオン性窒素原子と隣接原子以外の環構成原子との間の低級アルキレンを示す。）
または、式（Ｉ−Ｅ）：

（式中、カチオン性窒素原子からの結合手はＬとの結合を示し、もう一方の結合手はＲ^１０との結合を示し、Ｒ^ｘは置換もしくは非置換の低級アルキルを示す。）
で示される、１以上の４級アンモニウムイオンを有する置換もしくは非置換の飽和もしくは不飽和の単環式または多環式の２価の基である。 E is a cyclic or acyclic divalent group containing one or more quaternary ammonium ions that are substituted or unsubstituted. E is preferably a cyclic group, more preferably a formula (1-D):

(Wherein the dashed line represents a bond site, bonds from cationic nitrogen atom represents a bond is L, the other bond indicates a bond with R ^10. However, R ¹⁰ is a cationic nitrogen When the atoms are bonded, there is no broken line, and when R ¹⁰ is not bonded to the cationic nitrogen atom, the broken line indicates a single bond between the cationic nitrogen atom and the adjacent atom or is cationic. Lower alkylene between a nitrogen atom and a ring member atom other than an adjacent atom is shown.)
Or formula (IE):

(In the formula, a bond from a cationic nitrogen atom represents a bond to L, the other bond represents a bond to R ^10, and R ^x represents a substituted or unsubstituted lower alkyl.)
Or a substituted or unsubstituted saturated or unsaturated monocyclic or polycyclic divalent group having one or more quaternary ammonium ions.

（式中、ｐは１〜３の整数であり、Ｒｘは置換もしくは非置換の低級アルキルである。） The monocyclic group of “a divalent group containing a saturated or unsaturated monocyclic quaternary ammonium ion” is composed of 3 to 8 atoms, preferably 5 to 7 atoms, containing one cationic nitrogen atom. In this case, the ring-constituting atom may contain a hetero atom such as an oxygen atom, a sulfur atom, or a nitrogen atom. For example, aziridinium, azetidinium, pyrrolidinium, imidazolium, piperidinium, pyrrolium, piperazinium, pyridinium, morpholinium, homopiperidinium, homopiperazinium and the like can be mentioned. Preferable examples include the following.
formula:

(In the formula, p is an integer of 1 to 3, and Rx is a substituted or unsubstituted lower alkyl.)

（式中、４級窒素原子からの結合手はＬとの結合を示し、もう一方の結合手はＧとの結合を示す。また、ｐは１〜３の整数であり、ｎは１または２であり、Ｒ^ｘはそれぞれ独立して置換もしくは非置換のもしくは非置換の低級アルキルである。） In addition, “a divalent group containing a saturated or unsaturated polycyclic quaternary ammonium ion” is a saturated or unsaturated polycyclic group composed of 6 to 15 atoms containing one cationic nitrogen atom. In this case, the ring-constituting atom may contain a hetero atom such as an oxygen atom, a sulfur atom or a nitrogen atom. The ring-constituting atom is preferably 6 to 10 atoms. Here, the polycyclic group includes a condensed cyclic group, a spiro cyclic group, a bridged cyclic group, and the like. A bridged cyclic group refers to a cyclic group composed of two or more rings sharing two or more atoms. Preferable examples are saturated or unsaturated condensed rings or bridged rings composed of 6 to 10 atoms including one cationic nitrogen atom. Specific examples include the following groups.
formula:

(In the formula, a bond from a quaternary nitrogen atom represents a bond to L, and the other bond represents a bond to G. Further, p is an integer of 1 to 3, and n is 1 or 2) And each R ^x is independently substituted, unsubstituted, or unsubstituted lower alkyl.)

（式中、Ｒ^ｘはそれぞれ独立して置換もしくは非置換の低級アルキルである。） When E is an acyclic group, it is preferably a group shown below.

(In the formula, each R ^x is independently substituted or unsubstituted lower alkyl.)

  E is preferably a group selected from the above formulas (1) to (77) and further having a substituent on the ring. The substituent is a substituted or unsubstituted lower alkyl, or one or more groups selected from the same or different group selected from the substituent group α. Preferred embodiments of the substituent include methyl, ethyl, isopropyl, tert-butyl, fluorine, chlorine, bromine, hydroxy, carboxy, methoxy, ethoxy, hydroxymethoxy, hydroxyethoxy, methoxymethoxy, imino, hydroxyimino, methoxyimino, methylthio Carbamoyl, methylcarbamoyl, dimethylcarbamoyl, hydroxymethylcarbamoyl, sulfamoyl, methylsulfamoyl, lower alkylsulfamoyl, cyano, nitro, phenyl, cyclopropyl, cyclobutyl, cyclohexyl, pyridyl, morpholinyl and the like. A more preferred embodiment is an unsubstituted or hydroxy mono- or di-substituted ring. The ring mono- or di-substituted with hydroxy may be further substituted with other substituents.

As more preferable examples of E, the above formulas (1) to (7), (10) to (12), (14), (25) to (29), (31), (41) to (44), It is a group selected from the group consisting of (47), (50), (52), (53), (64) and (73).
In particular, the group consisting of the above formulas (1), (2), (5), (7), (10), (11), (26) to (29), (31), (41) and (42) A group selected from is preferred.
Further, a group selected from the above formulas (2), (5), (10), (11), (26), and (42) is more preferable.

（式中、４級窒素原子からの結合手はＬとの結合を示し、もう一方の結合手はＲ¹⁰との結合を示す。） In the present invention, E is a divalent group containing one or more substituted or unsubstituted quaternary ammonium ions.
1) E includes an aromatic carbocycle or an aromatic heterocycle, and hydroxyl groups are bonded to two adjacent carbon atoms on the aromatic ring, and
2) When E does not contain an aromatic carbocyclic ring or an aromatic heterocyclic ring, or contains an aromatic carbocyclic ring or an aromatic heterocyclic ring, and two adjacent carbon atoms on the aromatic ring each have a hydroxyl group It is divided when not connected.
Preferred examples of E in the case where E contains an aromatic carbocycle or an aromatic heterocycle, and each of the adjacent two carbon atoms on the aromatic ring is bonded to a hydroxyl group are shown below. Is mentioned.

(In the formula, the bond from the quaternary nitrogen atom represents a bond with L, and the other bond represents a bond with R ^10. )

（式中、Ｒ¹²はそれぞれ独立して、水素原子、ハロゲン、ヒドロキシル基、−ＳＯ₃Ｈ、置換もしくは非置換のアミノ基、置換もしくは非置換のカルボキシル基、置換もしくは非置換のカルバモイル基、置換もしくは非置換のアシル基、置換もしくは非置換のアミノスルホニル基、置換もしくは非置換の低級アルキル基、置換もしくは非置換の低級アルケニル基、置換もしくは非置換の低級アルキニル基、置換もしくは非置換の非芳香族炭素環式基または置換もしくは非置換の非芳香族複素環式基であり;４級窒素原子からの結合手はＬとの結合を示す。） E—R in the case where R ¹⁰ is a hydrogen atom, E contains an aromatic carbocyclic ring or an aromatic heterocyclic ring, and a hydroxyl group is bonded to two adjacent carbon atoms on the aromatic ring. Preferable examples of ¹⁰ include the following.

(In the formula, each R ¹² independently represents a hydrogen atom, a halogen, a hydroxyl group, —SO ₃ H, a substituted or unsubstituted amino group, a substituted or unsubstituted carboxyl group, a substituted or unsubstituted carbamoyl group, or a substituted group. Or an unsubstituted acyl group, a substituted or unsubstituted aminosulfonyl group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkenyl group, a substituted or unsubstituted lower alkynyl group, a substituted or unsubstituted non-aromatic group A carbocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group; a bond from a quaternary nitrogen atom represents a bond to L.)

（式中、４級窒素原子からの結合手はＬとの結合を示す。）
該ヒドロキシで置換されている位置以外の置換可能な任意の位置がさらに置換されていてもよい。 As a more preferred example of E-R ¹⁰ , when E contains an aromatic carbocycle or an aromatic heterocycle, and a hydroxyl group is bonded to each of two adjacent carbon atoms on the aromatic ring, The following are mentioned.

(In the formula, a bond from a quaternary nitrogen atom indicates a bond with L.)
Any substitutable position other than the position substituted with hydroxy may be further substituted.

Examples of R ¹² are hydrogen atom, halogen, hydroxyl group, —SO ₃ H, substituted or unsubstituted amino group, substituted or unsubstituted carboxyl group, substituted or unsubstituted carbamoyl group, substituted or unsubstituted acyl. Group, substituted or unsubstituted aminosulfonyl group, substituted or unsubstituted alkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, substituted or unsubstituted non-aromatic carbocyclic group or substituted or An unsubstituted non-aromatic heterocyclic group is mentioned. Preferably, R ¹² is a hydrogen atom or a substituted or unsubstituted alkyl group.

（式中、各定義は前記と同意義である。）
である。 R ¹⁰ is preferably of the following formula (IA):

(In the formula, each definition is as defined above.)
It is.

G ¹ is preferably a single bond or a substituted or unsubstituted lower alkylene. More preferably, it is a single bond, a substituted or unsubstituted alkyl having 1 or 2 carbon atoms.
A preferred embodiment of the G ^1, a single _{bond, -CH 2 -, - CH 2} -CH 2 -, - CH 2 -CH 2 -CH 2 -, - CH 2 -CH (CH 3) -, - CH 2 - CH ⁽ⁱ Pr) - or _-CH 2 _-CH (Ph) - a.
A more preferred embodiment is a single bond, —CH ₂ — or —CH ₂ —CH ₂ —.

G ² is preferably a single bond or a substituted or unsubstituted lower alkylene. More preferably, it is a substituted or unsubstituted alkyl having 1 to 3 carbon atoms.
A preferred embodiment of the G ^2, a single _{bond, -CH 2 -, - CH 2} -CH 2 -, - CH 2 -CH 2 -CH 2 -, - CH 2 -CH (CH 3) -, - CH 2 - CH ⁽ⁱ Pr) - or _-CH 2 _-CH (Ph) - a.
A more preferred embodiment is —CH ₂ — or —CH ₂ —CH ₂ —.

D ¹ is preferably —C (═O) —, —O—C (═O) —, —C (═O) —O—, —C (═O) —C (═O) —NR ^6. -, -NR < ⁶ > -C (= O) -C (= O)-, -C (= O) -NR < ⁶ > -C (= O)-, -C (= O) -C (= O)-, —O—, —NR ⁶ —NR ⁶ —C (═O) —, —C (═O) —NR ⁶ —NR ⁶ —, —N═N—C (═O) —, —C (═O) -N = N-, -C = N-NR < ⁶ > -C (= O)-, -C = NC (= O)-, -N = CR < ⁶ > -C (= O)-, -C = N ^{-C (= O) -NR 6 -} , - NR 6 -C (= O) -C (= N-OR 6) -, - C (= N-OR 6) -C (= O) -NR 6 - ^{, -NR 6 -C (= N-} OR 6) -, - C (= N-OR 6) -NR 6 -, - C (= O) -C (= N-OR 6) -, - C ^{= N-OR 6) -C (} = O) -, - S -, - S (= O) -, - C = N -, - N = C -, - S (= O) 2 -NR 6 -, _{^{-NR 6 -S (= O) 2}} -, - NR 6 -CH 2 -, - CH 2 -NR 6 -, - S (= O) 2 -, - NR 6 -, or a substituted or unsubstituted aromatic Heterocyclic diyl.
More preferably, —NR ⁶ —, —NR ⁶ —C (═O) —, —C (═O) —NR ⁶ —, —NR ⁶ —C (═O) —C (═O) —, —NR ^{6 -NR 6 -C (= O)} -, - O-, -S-, -S (= O) -, -S (= O) 2 -NR 6 -, -NR 6 -S (= O) 2 —, —NR ⁶ —CH ₂ —, —CH ₂ —NR ⁶ —, —C═N—, —N═C—, —S (═O) ₂ — or substituted or unsubstituted 5- or 6-membered fragrance Family heterocyclic diyl. More preferably, it is —NR ⁶ —, —NR ⁶ —C (═O) —, —O—, —S—, —S (═O) — or a substituted or unsubstituted 5-membered aromatic heterocyclic diyl. is there.

D ² is preferably a single bond, —C (═O) —, —O—C (═O) —, —C (═O) —O—, —C (═O) —C (═O). —NR ⁶ —, —NR ⁶ —C (═O) —C (═O) —, —C (═O) —NR ⁶ —C (═O) —, —C (═O) —C (═O ) —, —O—, —NR ⁶ —NR ⁶ —C (═O) —, —C (═O) —NR ⁶ —NR ⁶ —, —N═N—C (═O) —, —C ( = O) -N = N-, -C = N-NR < ⁶ > -C (= O)-, -C = NC (= O)-, -N = CR < ⁶ > -C (= O)-,- C = NC (= O) -NR < ⁶ >-, -NR < ⁶ > -C (= O) -C (= N-OR < ⁶ >)-, -C (= N-OR < ⁶ >)-C (= O)- ^{NR 6 -, - NR 6 -C} (= N-OR 6) -, - C (= N-OR 6) -NR 6 -, - C (= O) -C (= N-OR 6) ^{, -C (= N-OR 6} ) -C (= O) -, - S -, - S (= O) -, - C = N -, - N = C -, - S (= O) 2 - _{^{NR 6 -, - NR 6 -S}} (= O) 2 -, - NR 6 -CH 2 -, - CH 2 -NR 6 -, - S (= O) 2 -, - NR 6 - or a substituted or unsubstituted Aromatic heterocyclic diyl.
More preferably, a single bond, —C (═O) —, —NR ⁶ —, —NR ⁶ —C (═O) —, —C (═O) —NR ⁶ —, —NR ⁶ —C (═O ) —C (═O) —, —NR ⁶ —NR ⁶ —C (═O) —, —O—, —S—, —S (═O) —, —S (═O) ₂ —NR ⁶ —. , —NR ⁶ —S (═O) ₂ —, —NR ⁶ —CH ₂ —, —CH ₂ —NR ⁶ —, —C═N—, —N═C—, —S (═O) ₂ — or Substituted or unsubstituted 5- or 6-membered aromatic heterocyclic diyl. More preferably, a single bond, —C (═O) —, —NR ⁶ —C (═O) —, —C (═O) —NR ⁶ —, —NR ⁶ —C (═O) —C (= O) −, —NR ⁶ —NR ⁶ —C (═O) —, —S (═O) —, —S (═O) ₂ —NR ⁶ —, —NR ⁶ —S (═O) ₂ —, —C═N—, —N═C—, —S (═O) ₂ — or a substituted or unsubstituted 5-membered aromatic heterocyclic diyl.

（式中、Ｒ^６は前記と同意義であり、破線の結合は該結合がシス、トランスまたはそれらの混合体であることを意味する。）
を意味し、すなわち式：

（式中、Ｒ^６は前記と同意義である。）
で示される基およびそれらの混合体を包含する。
好ましくは、−ＯＲ^６がＲ^１０を含有する基に対してトランス配置、すなわち式：

（式中、各定義は前記と同意義である。）
である。 For example, the group represented by —C (═N—OR ⁶ ) — has the formula:

(In the formula, R ⁶ has the same meaning as described above, and a broken-line bond means that the bond is cis, trans, or a mixture thereof.)
I.e. the formula:

(Wherein R ⁶ has the same meaning as described above.)
And a mixture thereof.
Preferably, —OR ⁶ is in the trans configuration relative to the group containing R ¹⁰ , ie the formula:

(In the formula, each definition is as defined above.)
It is.

（式中、Ｍｅはメチルを意味する）
から選択される基である。 R ⁶ is preferably a hydrogen atom, unsubstituted lower alkyl, halo lower alkyl, or lower alkyl substituted with carboxy, carbamoyl or lower alkyloxycarbonyl.
R ⁶ is more preferably a hydrogen atom, unsubstituted lower alkyl, or lower alkyl substituted with carboxy.
R ⁶ is more preferably a hydrogen atom, methyl, ethyl, or the formula:

(In the formula, Me means methyl)
Is a group selected from

（式中、Ｒ^１３は、水素原子、置換もしくは非置換の低級アルキルまたは置換もしくは非置換のシクロアルキルであり、左側の結合手はＧ^１またはＢとの結合を示し、右側の結合手は環Ａとの結合を示す。）
から選択される基であり、より好ましくは、式：

（式中、左側の結合手はＧ^１またはＢとの結合を示し、右側の結合手は環Ａとの結合を示す。）
から選択される基である。 The “substituted or unsubstituted heterocyclic diyl” of D ¹ , D ² and D ³ is preferably a substituted or unsubstituted aromatic heterocyclic diyl, more preferably a substituted or unsubstituted 5- to 6-membered member. Aromatic heterocyclic diyl, more preferably 5-membered aromatic heterocyclic diyl. Particularly preferred examples of “substituted or unsubstituted heterocyclic diyl” for D ¹ , D ² and D ³ are each independently of the formula:

(In the formula, R ¹³ is a hydrogen atom, substituted or unsubstituted lower alkyl or substituted or unsubstituted cycloalkyl, the left bond represents a bond with G ¹ or B, and the right bond represents a ring. Shows binding to A.)
A group selected from: more preferably

(In the formula, the left bond represents a bond to G ¹ or B, and the right bond represents a bond to ring A.)
Is a group selected from

（式中、左側の結合手はＧ^２との結合を示し、右側の結合手はＤとの結合を示す。）
で示される基から選択される基である。より好ましくは、単結合である。 B is preferably a single bond and the formula:

(Wherein, the left bond represents a bond with G ^2, right bond represents a bond with D.)
Is a group selected from the group represented by: More preferably, it is a single bond.

  Ring A is preferably a benzene ring or a monocyclic aromatic heterocycle. A benzene ring, a 5- to 7-membered monocyclic heterocycle, or an 8- to 12-membered condensed heterocycle is also preferable. More preferably, it is a benzene ring or a 5- to 7-membered monocyclic heterocycle.

  A preferable embodiment of the ring A which is a 5- to 7-membered monocyclic heterocycle is a ring having 1 to 3 nitrogen atoms, and more preferably a ring having 1 nitrogen atom.

  A preferable embodiment of the ring A which is an 8- to 12-membered condensed heterocyclic ring is a ring having 1 to 4 nitrogen atoms, more preferably a ring having 1 or 2 nitrogen atoms.

  More preferred examples of ring A include a benzene ring, a 5-6 membered monocyclic heterocycle having 1 nitrogen atom, or a 9-10 membered condensed heterocycle having 1 or 2 nitrogen atoms. is there.

の好ましい態様としては、式：

（式中、Ｒ^４ａ，Ｒ^４ｂおよびＲ^４ｃはそれぞれ独立して、水素原子、ハロゲン、ヒドロキシ、シアノ、−Ｃ（＝Ｏ）−Ｒ^９、カルボキシ、−Ｃ（＝Ｏ）−ＯＲ^９、−ＯＲ^９、置換もしくは非置換の低級アルキルまたは置換もしくは非置換のシクロアルキルであり、Ｒ^９はそれぞれ独立して低級アルキルまたはハロ低級アルキルである。）
である。 When ring A is a benzene ring, formula (IB-2):

In a preferred embodiment of the formula:

(Wherein R ^4a , R ^4b and R ^4c are each independently a hydrogen atom, halogen, hydroxy, cyano, —C (═O) —R ⁹ , carboxy, —C (═O) —OR ⁹ , — OR ^{9 is} substituted or unsubstituted lower alkyl or substituted or unsubstituted cycloalkyl, and each R ⁹ is independently lower alkyl or halo-lower alkyl.)
It is.

の好ましい態様としては、式：

（式中、Ｒ^４ａ、Ｒ^４ｂおよびＲ^４ｄはそれぞれ独立して、水素原子、ハロゲン、ヒドロキシ、シアノ、−Ｃ（＝Ｏ）−Ｒ^９、カルボキシ、−Ｃ（＝Ｏ）−ＯＲ^９、−ＯＲ^９、置換もしくは非置換の低級アルキルまたは置換もしくは非置換のシクロアルキルであり、Ｒ^９はそれぞれ独立して低級アルキルまたはハロ低級アルキルである。）
で示される基が挙げられる。 When ring A is a 5- to 7-membered monocyclic heterocycle having 1 to 3 nitrogen atoms, formula (IB-2):

In a preferred embodiment of the formula:

(Wherein R ^4a , R ^4b and R ^4d are each independently a hydrogen atom, halogen, hydroxy, cyano, —C (═O) —R ⁹ , carboxy, —C (═O) —OR ⁹ , — OR ^{9 is} substituted or unsubstituted lower alkyl or substituted or unsubstituted cycloalkyl, and each R ⁹ is independently lower alkyl or halo-lower alkyl.)
The group shown by these is mentioned.

の好ましい態様としては、式：

（式中、Ｒ^４ａ、Ｒ^４ｂおよびＲ^４ｄはそれぞれ独立して、水素原子、ハロゲン、ヒドロキシ、シアノ、−Ｃ（＝Ｏ）−Ｒ^９、カルボキシ、−Ｃ（＝Ｏ）−ＯＲ^９、−ＯＲ^９、置換もしくは非置換の低級アルキルまたは置換もしくは非置換のシクロアルキルであり、Ｒ^９はそれぞれ独立して低級アルキルまたはハロ低級アルキルである。）
で示される基が挙げられる。 When ring A is a 5-6 membered monocyclic heterocycle having one nitrogen atom, formula (IB-2):

In a preferred embodiment of the formula:

(Wherein R ^4a , R ^4b and R ^4d are each independently a hydrogen atom, halogen, hydroxy, cyano, —C (═O) —R ⁹ , carboxy, —C (═O) —OR ⁹ , — OR ^{9 is} substituted or unsubstituted lower alkyl or substituted or unsubstituted cycloalkyl, and each R ⁹ is independently lower alkyl or halo-lower alkyl.)
The group shown by these is mentioned.

の好ましい態様としては、式：

（式中、Ｒ^４ａ，Ｒ^４ｂおよびＲ^４ｄはそれぞれ独立して、水素原子、ハロゲン、ヒドロキシ、シアノ、−Ｃ（＝Ｏ）−Ｒ^９、カルボキシ、−Ｃ（＝Ｏ）−ＯＲ^９、−ＯＲ^９、置換もしくは非置換の低級アルキルまたは置換もしくは非置換のシクロアルキルであり、Ｒ^９はそれぞれ独立して低級アルキルまたはハロ低級アルキルである。）
で示される基が挙げられる。 When Ring A is an 8- to 12-membered condensed heterocyclic ring having 1 to 4 nitrogen atoms, Formula (IB-2):

In a preferred embodiment of the formula:

(Wherein R ^4a , R ^4b and R ^4d are each independently a hydrogen atom, halogen, hydroxy, cyano, —C (═O) —R ⁹ , carboxy, —C (═O) —OR ⁹ , — OR ^{9 is} substituted or unsubstituted lower alkyl or substituted or unsubstituted cycloalkyl, and each R ⁹ is independently lower alkyl or halo-lower alkyl.)
The group shown by these is mentioned.

で示される基の好ましい例としては、以下の式：

（式中、Ｒ^４ａ，Ｒ^４ｂおよびＲ^４ｃはそれぞれ独立して、水素原子、ハロゲン、ヒドロキシ、シアノ、−Ｃ（＝Ｏ）−Ｒ^９、カルボキシ、−Ｃ（＝Ｏ）−ＯＲ^９、−ＯＲ^９、置換もしくは非置換の低級アルキルまたは置換もしくは非置換のシクロアルキルであり；Ｒ^９はそれぞれ独立して低級アルキルまたはハロ低級アルキルであり；Ｒ^６は水素原子または置換もしくは非置換の低級アルキルであり；波線の結合は、該結合がシスもしくはトランス型立体配置またはその混合物であることを意味する。）
で示される基が挙げられる。 When ring A is a benzene ring, formula (IC-1):

As preferable examples of the group represented by the following formula:

(Wherein R ^4a , R ^4b and R ^4c are each independently a hydrogen atom, halogen, hydroxy, cyano, —C (═O) —R ⁹ , carboxy, —C (═O) —OR ⁹ , — OR ^{9 is} substituted or unsubstituted lower alkyl or substituted or unsubstituted cycloalkyl; R ⁹ is each independently lower alkyl or halolower alkyl; R ⁶ is a hydrogen atom or substituted or unsubstituted lower alkyl A wavy bond means that the bond is in the cis or trans configuration or a mixture thereof.)
The group shown by these is mentioned.

で示される基の好ましい例としては、以下の式：

（式中、Ｒ^４ａ，Ｒ^４ｂおよびＲ^４ｄはそれぞれ独立して、水素原子、ハロゲン、ヒドロキシ、シアノ、−Ｃ（＝Ｏ）−Ｒ^９、カルボキシ、−Ｃ（＝Ｏ）−ＯＲ^９、−ＯＲ^９、置換もしくは非置換の低級アルキルまたは置換もしくは非置換のシクロアルキルであり；Ｒ^９はそれぞれ独立して低級アルキルまたはハロ低級アルキルであり；Ｒ^６は水素原子または置換もしくは非置換の低級アルキルであり；波線の結合は、該結合がシスもしくはトランス型立体配置またはその混合物であることを意味する。）
で示される基が挙げられる。 When ring A is a 5- to 7-membered monocyclic heterocyclic ring having 1 to 3 nitrogen atoms, the formula (IC-1):

As preferable examples of the group represented by the following formula:

(Wherein R ^4a , R ^4b and R ^4d are each independently a hydrogen atom, halogen, hydroxy, cyano, —C (═O) —R ⁹ , carboxy, —C (═O) —OR ⁹ , — OR ^{9 is} substituted or unsubstituted lower alkyl or substituted or unsubstituted cycloalkyl; R ⁹ is each independently lower alkyl or halolower alkyl; R ⁶ is a hydrogen atom or substituted or unsubstituted lower alkyl A wavy bond means that the bond is in the cis or trans configuration or a mixture thereof.)
The group shown by these is mentioned.

で示される基の好ましい例としては、以下の式：

（式中、Ｒ^４ａ，Ｒ^４ｂおよびＲ^４ｄはそれぞれ独立して、水素原子、ハロゲン、ヒドロキシ、シアノ、−Ｃ（＝Ｏ）−Ｒ^９、カルボキシ、−Ｃ（＝Ｏ）−ＯＲ^９、−ＯＲ^９、置換もしくは非置換の低級アルキルまたは置換もしくは非置換のシクロアルキルであり；Ｒ^９はそれぞれ独立して低級アルキルまたはハロ低級アルキルであり；Ｒ^６は水素原子または置換もしくは非置換の低級アルキルであり；波線の結合は、該結合がシスもしくはトランス型立体配置またはその混合物であることを意味する。）
で示される基が挙げられる。 When Ring A is an 8- to 12-membered condensed heterocyclic ring having 1 to 4 nitrogen atoms, Formula (I-C-1):

As preferable examples of the group represented by the following formula:

(Wherein R ^4a , R ^4b and R ^4d are each independently a hydrogen atom, halogen, hydroxy, cyano, —C (═O) —R ⁹ , carboxy, —C (═O) —OR ⁹ , — OR ^{9 is} substituted or unsubstituted lower alkyl or substituted or unsubstituted cycloalkyl; R ⁹ is each independently lower alkyl or halolower alkyl; R ⁶ is a hydrogen atom or substituted or unsubstituted lower alkyl A wavy bond means that the bond is in the cis or trans configuration or a mixture thereof.)
The group shown by these is mentioned.

Examples of R ^4a , R ^4b , R ^4c and R ^4d include a hydrogen atom, chlorine, fluorine, bromine, cyano, hydroxy, carboxy, acetyl, methoxy, ethoxy, trifluoromethoxy, methyl, ethyl, cyclopropyl and the like. It is done. Preferred embodiments of R ^4a , R ^4b and R ^4c are each independently a hydrogen atom, hydroxy, carboxy, methoxy, fluorine, trifluoromethoxy, or chlorine. A preferred embodiment of R ^4d is each independently a hydrogen atom, hydroxy, methyl, ethyl or cyclopropyl.

で示される基のより好ましい例としては、以下の式：

（式中、Ｒ^６は水素原子、メチル、エチル、ｔｅｒｔ−ブチル、カルボキシメチル、２−カルボキシプロパン−２−イルまたは１−カルボキシエチルであり；波線の結合は、該結合がシスもしくはトランス型立体配置またはその混合物であることを意味する。）
で示される基が挙げられる。 When ring A is a benzene ring, formula (IC-1):

As a more preferable example of the group represented by the following formula:

Wherein R ⁶ is a hydrogen atom, methyl, ethyl, tert-butyl, carboxymethyl, 2-carboxypropan-2-yl or 1-carboxyethyl; a wavy bond is a cis- or trans-steric bond Means an arrangement or a mixture thereof.)
The group shown by these is mentioned.

で示される基の好ましい例としては、以下の式：

（式中、Ｒ^６は水素原子、メチル、エチル、ｔｅｒｔ−ブチル、カルボキシメチル、２−カルボキシプロパン−２−イルまたは１−カルボキシエチルであり；波線の結合は、該結合がシスもしくはトランス型立体配置またはその混合物であることを意味する。）
で示される基が挙げられる。 When ring A is a 5- to 7-membered monocyclic heterocyclic ring having 1 to 3 nitrogen atoms, the formula (IC-1):

As preferable examples of the group represented by the following formula:

Wherein R ⁶ is a hydrogen atom, methyl, ethyl, tert-butyl, carboxymethyl, 2-carboxypropan-2-yl or 1-carboxyethyl; a wavy bond is a cis- or trans-steric bond Means an arrangement or a mixture thereof.)
The group shown by these is mentioned.

で示される基の好ましい例としては、以下の式：

で示される基が挙げられる。 When Ring A is an 8- to 12-membered condensed heterocyclic ring having 1 to 4 nitrogen atoms, Formula (I-C-1):

As preferable examples of the group represented by the following formula:

The group shown by these is mentioned.

で示される基について、
Ｇ^１が単結合、−ＣＨ_２−または−ＣＨ_２−ＣＨ_２−であり；
Ｄ^１が−ＮＲ^６−、−ＮＲ^６−Ｃ（＝Ｏ）−、−Ｏ−、−Ｓ−、−Ｓ（＝Ｏ）−、および式：

から選択される基であり；
ｋが１であり、
Ｇ^２が−ＣＨ_２−または−ＣＨ_２−ＣＨ_２−であり、
Ｂが単結合であり、および
Ｄ^２が−ＮＲ^６−Ｃ（＝Ｏ）‐である場合が好ましい。
さらに、式（Ｉ−Ｈ−１）の好ましい態様は、式：

が挙げられる。 Formula (I-H-1):

For the group represented by
G ¹ is a single bond, —CH ₂ — or —CH ₂ —CH ₂ —;
D ¹ is —NR ⁶ —, —NR ⁶ —C (═O) —, —O—, —S—, —S (═O) —, and the formula:

A group selected from:
k is 1,
G ² is —CH ₂ — or —CH ₂ —CH ₂ —,
Preferred is when B is a single bond and D ² is —NR ⁶ —C (═O) —.
Furthermore, a preferred embodiment of formula (IH-1) is a compound of formula:

Is mentioned.

で示される基について、
Ｇ^１が単結合、−ＣＨ_２−または−ＣＨ_２−ＣＨ_２−であり；
Ｄ^１が−ＮＲ^６−、−ＮＲ^６−Ｃ（＝Ｏ）−、−Ｏ−、−Ｓ−、−Ｓ（＝Ｏ）−、および式：

から選択される基であり；
ｋが１であり、
Ｇ^２が−ＣＨ_２−または−ＣＨ_２−ＣＨ_２−であり、および
Ｂが単結合である場合が好ましい。
さらに、式（Ｉ−Ｈ−２）の好ましい態様は、式：

が挙げられる。 Formula (I-H-2):

For the group represented by
G ¹ is a single bond, —CH ₂ — or —CH ₂ —CH ₂ —;
D ¹ is —NR ⁶ —, —NR ⁶ —C (═O) —, —O—, —S—, —S (═O) —, and the formula:

A group selected from:
k is 1,
Preferred is when G ² is —CH ₂ — or —CH ₂ —CH ₂ —, and B is a single bond.
Furthermore, a preferred embodiment of formula (IH-2) is a compound of formula:

Is mentioned.

は好ましくは、式（Ｉ−Ｇ−１）：

である。
化合物（Ｉ−Ｇ−１）の好ましい実施形態を以下に例示する。以下の実施形態で示される化合物としては、これら具体例の全ての組み合わせが例示される。
（実施形態）
ＸがＣ（−Ｈ）、Ｃ（−Ｃｌ）またはＮであり；
Ｒ^７およびＲ^８がそれぞれ独立して、水素原子または置換もしくは非置換の低級アルキルであり；
Ｒ^３が水素原子であり；
ｍが０または１であり；
Ｑが単結合であり；
Ｒ^５ＡおよびＲ^５Ｂが、それぞれ独立して、水素原子またはメチルであり；
Ｌが‐ＣＨ_２−であり；
Ｅが前記の式：（２）、（５）、（７）、（１０）、（１１）、（２６）、（４２）および（７７）からなる群から選択される基であり；
Ｇ^１およびＧ^２がそれぞれ独立して、単結合または低級アルキレンであり；
Ｂが単結合であり；
Ｄ^１が、−ＮＲ^６−、−ＮＲ^６−Ｃ（＝Ｏ）‐、−Ｃ（＝Ｏ）‐ＮＲ^６−、−Ｏ−、 −Ｓ−、 −Ｓ（＝Ｏ）‐、 −Ｓ（＝Ｏ）_２−ＮＲ^６−、 −ＮＲ^６−Ｓ（＝Ｏ）_２−、−Ｓ（＝Ｏ）_２−または置換もしくは非置換の５員の芳香族複素環ジイルであり；
Ｄ^２が、単結合、−Ｃ（＝Ｏ）‐、−ＮＲ^６−Ｃ（＝Ｏ）‐、−Ｃ（＝Ｏ）‐Ｃ（＝Ｏ）‐−ＮＲ^６−Ｃ（＝Ｏ）‐Ｃ（＝Ｏ）‐、−ＮＲ^６−ＮＲ^６−Ｃ（＝Ｏ）‐、−Ｃ＝Ｎ−Ｃ（＝Ｏ）−、 ‐Ｎ＝Ｃ−Ｃ（＝Ｏ）−、−ＮＲ^６−Ｃ（＝Ｏ）−Ｃ（＝Ｎ−ＯＲ^６ａ）‐または置換もしくは非置換の５員の芳香族複素環ジイルであり；
Ｒ^６が水素原子または低級アルキルであり；
Ｒ^６ａが水素原子、メチル、カルボキシメチルまたは２−カルボキシプロパン−２−イルであり；
式（１−Ｂ−２）：

が、式：

（式中、Ｒ^４ａ，Ｒ^４ｂおよびＲ^４ｃはそれぞれ独立して、水素原子、ハロゲン、低級アルキルまたはシクロアルキルである。）
で示される。 Formula (I):

Is preferably the formula (IG-1):

It is.
Preferred embodiments of compound (IG-1) are exemplified below. As a compound shown by the following embodiment, all the combinations of these specific examples are illustrated.
(Embodiment)
X is C (—H), C (—Cl) or N;
R ⁷ and R ⁸ are each independently a hydrogen atom or substituted or unsubstituted lower alkyl;
R ³ is a hydrogen atom;
m is 0 or 1;
Q is a single bond;
R ^5A and R ^5B are each independently a hydrogen atom or methyl;
L is —CH ₂ —;
E is a group selected from the group consisting of the above formulas: (2), (5), (7), (10), (11), (26), (42) and (77);
G ¹ and G ² are each independently a single bond or lower alkylene;
B is a single bond;
D ¹ is —NR ⁶ —, —NR ⁶ —C (═O) —, —C (═O) —NR ⁶ —, —O—, —S—, —S (═O) —, —S ( _{^{= O) 2 -NR 6 -,}} -NR 6 -S (= O) 2 -, - S (= O) 2 - or a substituted or unsubstituted 5-membered aromatic heterocyclic diyl;
D ² is a single bond, —C (═O) —, —NR ⁶ —C (═O) —, —C (═O) —C (═O) —— NR ⁶ —C (═O) —C (═O) —, —NR ⁶ —NR ⁶ —C (═O) —, —C═N—C (═O) —, —N═C—C (═O) —, —NR ⁶ —C ( ═O) —C (═N—OR ^6a ) — or substituted or unsubstituted 5-membered aromatic heterocyclic diyl;
R ⁶ is a hydrogen atom or lower alkyl;
R ^6a is a hydrogen atom, methyl, carboxymethyl or 2-carboxypropan-2-yl;
Formula (1-B-2):

But the formula:

(Wherein, R ^4a , R ^4b and R ^4c are each independently a hydrogen atom, halogen, lower alkyl or cycloalkyl).
Indicated by

（式中、Ｒ^５ＣおよびＲ^５Ｄについては、
ａ）Ｒ^５ＣおよびＲ^５Ｄは、それぞれ独立して水素原子または低級アルキルであり、かつＲ^５ＣおよびＲ^５Ｄは同時に水素原子ではなく、
ｂ）Ｒ^５ＣおよびＲ^５Ｄが隣接する原子と一緒になって、置換もしくは非置換の炭素環、または置換もしくは非置換の複素環を形成し、または、
ｃ）Ｒ^５ＣおよびＲ^ｄが一緒になって、置換もしくは非置換のメチリデンを形成し；
Ｄ^３は置換もしくは非置換の複素環ジイルであり；
その他の記号は前記と同意義である。）
で示される化合物、カルボキシのエステル体、もしくは７位側鎖の環上にアミノ基が存在する場合の該アミノ基における保護体またはそれらの製薬上許容される塩も包含する。
より好ましい態様としては、式（ＩＩ−Ａ）：

（式中、各記号は前記と同意義である。）
で示される化合物、カルボキシのエステル体、もしくは７位側鎖の環上にアミノ基が存在する場合の該アミノ基における保護体またはそれらの製薬上許容される塩である。 In another preferred embodiment, the present invention provides a compound represented by formula (II):

(Wherein R ^5C and R ^5D are
a) R ^5C and R ^5D are each independently a hydrogen atom or lower alkyl, and R ^5C and R ^5D are not simultaneously a hydrogen atom,
b) R ^5C and R ^5D together with the adjacent atoms form a substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle, or
c) R ^5C and R ^d together form a substituted or unsubstituted methylidene;
D ³ is a substituted or unsubstituted heterocyclic diyl;
Other symbols are as defined above. )
Or a protected form of the amino group or a pharmaceutically acceptable salt thereof when an amino group is present on the ring of the 7-position side chain.
In a more preferred embodiment, the formula (II-A):

(In the formula, each symbol is as defined above.)
Or a protected form of the amino group or a pharmaceutically acceptable salt thereof when an amino group is present on the ring of the 7-position side chain.

が、式：

（式中、Ｒ^４ａ，Ｒ^４ｂおよびＲ^４ｃはそれぞれ独立して、水素原子、ハロゲン、低級アルキルまたはシクロアルキルである。）である。 Preferred embodiments of compound (II-A) are exemplified below. As a compound shown by the following embodiment, all the combinations of these specific examples are illustrated.
(Embodiment)
X is C (—H), C (—Cl) or N;
R ⁷ and R ⁸ are each independently a hydrogen atom or substituted or unsubstituted lower alkyl;
R ³ is a hydrogen atom;
m is 0 or 1;
Q is a single bond;
R ^5C is a hydrogen atom;
R ^5D is lower alkyl;
L is —CH ₂ —;
E is a group selected from the above formulas: (2), (5), (7), (10), (11), (26), (42) and (77);
G ² is a single bond or lower alkylene;
B is a single bond;
D ³ is a substituted or unsubstituted 5-membered aromatic heterocyclic diyl;
Formula (1-B-2):

But the formula:

Wherein R ^4a , R ^4b and R ^4c are each independently a hydrogen atom, halogen, lower alkyl or cycloalkyl.

The names of substitution positions on the cephem skeleton of formula (I) are as follows. In this specification, the 3-position side chain, the 4-position side chain, and the 7-position side chain represent groups bonded to the 3-position, 4-position, and 7-position of the following cephem skeleton.

（式中、各記号は前記と同意義である。）
で示されるＲ¹またはＲ^2AもしくはＲ^2Bの末端において、置換もしくは非置換のアミノ、置換もしくは非置換のアミノスルホニル、カルボキシ、置換もしくは非置換の低級アルキルオキシカルボニル、置換もしくは非置換のカルバモイル、置換基を有しているカルボニルオキシ等におけるカルボキシがエステル構造を有しているもの（例えば、カルボキシ（−ＣＯＯＨ）の場合、カルボキシ保護基等のエステル残基を示すＲ^Ｐ１とともに示される−ＣＯＯＲ^Ｐ１という構造で示される。）などを挙げることができ、体内で容易に代謝されてカルボキシの状態になるエステルを包含する。 The carboxy ester form of the formula (I) preferably includes a 4-position carboxy and / or a carboxy ester form on the 7-position side chain. The ester in the carboxy group on the 7-position side chain has the formula:

(In the formula, each symbol is as defined above.)
Substituted or unsubstituted amino, substituted or unsubstituted aminosulfonyl, carboxy, substituted or unsubstituted lower alkyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted at the terminal of R ¹ or R ^2A or R ^{2B represented} by Carboxyloxy etc. having a carboxyl group having an ester structure (for example, in the case of carboxy (-COOH), -COOR ^P1 shown together with R ^P1 showing an ester residue such as a carboxy protecting group) And includes esters that are easily metabolized in the body to the carboxy state.

  Examples of protecting groups such as carboxy are Protective Groups in Organic Synthesis, T. et al. W. By Greene, John Wiley & Sons Inc. (1991) and the like, and any group that can be protected and / or deprotected by the method described in, for example, lower alkyl (eg, methyl, ethyl, t-butyl), lower alkylcarbonyloxymethyl (eg, pivaloyl), Examples thereof include optionally substituted arylalkyl (eg, benzyl, benzhydryl, phenethyl, p-methoxybenzyl, p-nitrobenzyl), a silyl group (eg, t-butyldimethylsilyl, diphenyl t-butylsilyl) and the like.

（式中、各記号は前記と同意義であり、Ｒ¹および／またはＲ^2Aがアミノ基を有している場合、その保護体は、−ＮＨＲ^Ｐ２という式で表され、ここでＲ^Ｐ２はアミノ保護基を表わす。）
で示される、環上のアミノ基が保護されている構造を意味する。該アミノ保護基は、体内で容易に代謝されてアミノになる基も包含する。上記のアミノ保護基としては、Ｐｒｏｔｅｃｔｉｖｅ Ｇｒｏｕｐｓ ｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ、Ｔ．Ｗ．Ｇｒｅｅｎｅ著、Ｊｏｈｎ Ｗｉｌｅｙ ＆ Ｓｏｎｓ Ｉｎｃ．（１９９１年）等に記載の方法で保護および／または脱保護できる基であればよく、例えば、低級アルキルオキシカルボニル（例：ｔ−ブトキシカルボニル、ベンジルオキシカルボニル、ｐ−ニトロベンジルオキシカルボニル）、置換されていてもよいアラルカノイル（例：ベンゾイル、ｐ−ニトロベンゾイル）、アシル（例：ホルミル、クロロアセチル）等が挙げられる。 The protector in the amino group on the 7-position side chain of formula (I) is represented by the formula:

(In the formula, each symbol is as defined above, and when R ¹ and / or R ^2A has an amino group, its protector is represented by the formula —NHR ^P2 , where R ^P2 is Represents an amino protecting group.)
The structure shown by which the amino group on the ring is protected. The amino protecting group also includes groups that are easily metabolized in the body to become amino. Examples of the amino protecting group include Protective Groups in Organic Synthesis, T. et al. W. By Greene, John Wiley & Sons Inc. (1991) and the like, and any group that can be protected and / or deprotected can be used. For example, lower alkyloxycarbonyl (eg, t-butoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl), substituted Aralkylanoyl (eg: benzoyl, p-nitrobenzoyl), acyl (eg: formyl, chloroacetyl) and the like which may be used may be mentioned.

The compound (I) of the present invention is not limited to a specific isomer, but all possible isomers (eg, keto-enol isomer, imine-enamine isomer, diastereoisomer, optical isomer, rotational isomer) Isomers etc.), racemates or mixtures thereof.

は

を包含する。 For example, in formula (I)

Is

Is included.

（式中、各記号は前記と同意義である）
は、例えば

（式中、Ｒ⁴は前記と同意義である）
などの共鳴構造を包含する。 Furthermore, the formula in formula (I):

(Wherein each symbol is as defined above)
For example

(Wherein R ⁴ is as defined above)
Including resonance structures.

（式中、各記号は前記と同意義である）
などの共鳴構造を包含する。 E in formula (I) is, for example,

(Wherein each symbol is as defined above)
Including resonance structures.

One or more hydrogen, carbon and / or other atoms of the compound of formula (I) may be replaced with isotopes of hydrogen, carbon and / or other atoms, respectively. Examples of such isotopes are ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ¹²³ I and ^{Like 36} Cl, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included. The compound represented by the formula (I) also includes a compound substituted with such an isotope. The compound substituted with the isotope is also useful as a pharmaceutical, and includes all radiolabeled compounds of the compound represented by the formula (I). A “radiolabeling method” for producing the “radiolabeled product” is also encompassed in the present invention, and is useful as a metabolic pharmacokinetic study, a study in a binding assay, and / or a diagnostic tool.

The radioactive label of the compound represented by the formula (I) can be prepared by a method well known in the art. For example, the tritium-labeled compound represented by the formula (I) can be prepared by introducing tritium into the specific compound represented by the formula (I) by, for example, catalytic dehalogenation reaction using tritium. This method reacts a tritium gas with a precursor in which the compound of formula (I) is appropriately halogen-substituted in the presence of a suitable catalyst such as Pd / C, in the presence or absence of a base. Including that. Suitable methods for preparing other tritium labeled compounds include the document Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987). ^{The 14} C-labeled compound can be prepared by using a raw material having ¹⁴ C carbon.

  The salt of the compound represented by the formula (I) is one in which the carboxy group at the 7-position and / or the 7-position side chain amino group forms a salt with an inorganic acid or an organic acid, and the 3-position side chain quaternary amine. The site includes a salt that forms a salt with a counter anion.

  As the pharmaceutically acceptable salt of the compound represented by the formula (I), for example, a compound represented by the formula (I), an alkali metal (for example, lithium, sodium, potassium, etc.), an alkaline earth metal (for example, Calcium, barium, etc.), magnesium, transition metals (eg, zinc, iron, etc.), ammonia, organic bases (eg, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, Picolin, quinoline etc.) and salts with amino acids, or inorganic acids (eg hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid etc.) and organic acids (eg formic acid, acetic acid, Propionic acid, trifluoroacetic acid, citric acid, lactic acid, Stone acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, etc.) Of the salt. Particularly, salts with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, methanesulfonic acid and the like can be mentioned. These salts can be formed by a commonly performed method.

  The compound represented by the formula (I) or a pharmaceutically acceptable salt thereof may form a solvate (for example, hydrate etc.) and / or a crystalline polymorph. Also included are solvates and crystalline polymorphs. The “solvate” may be coordinated with an arbitrary number of solvent molecules (for example, water molecules) with respect to the compound represented by the formula (I). When the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is left in the air, it may absorb moisture and adsorbed water may adhere or form a hydrate. In some cases, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof may be recrystallized to form a crystalline polymorph thereof.

  The compound represented by the formula (I) or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention includes such various prodrugs. A prodrug is a derivative of a compound of the present invention having a group that can be chemically or metabolically degraded, and is a compound that becomes a pharmaceutically active compound of the present invention by solvolysis or under physiological conditions in vivo. A prodrug is a compound that is enzymatically oxidized, reduced, hydrolyzed, etc. under physiological conditions in vivo to be converted to a compound represented by formula (I), hydrolyzed by gastric acid, etc. The compound etc. which are converted into the compound shown are included. Methods for selecting and producing suitable prodrug derivatives are described, for example, in Design of Prodrugs, Elsevier, Amsterdam 1985. Prodrugs may themselves have activity.

When the compound represented by formula (I) or a pharmaceutically acceptable salt thereof has a hydroxy group, for example, the compound having a hydroxy group and an appropriate acyl halide, an appropriate acid anhydride, an appropriate sulfonyl chloride, an appropriate sulfonyl Examples thereof include prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting anhydride and mixed anhydride or reacting with a condensing agent. For example _{CH 3 COO-, C 2 H 5} COO-, t-BuCOO-, C 15 H 31 COO-, PhCOO -, (m-NaOOCPh) COO-, NaOOCCH 2 CH 2 COO-, CH 3 CH (NH 2) _{COO-, CH 2 N (CH 3} ) 2 COO-, CH 3 SO 3 -, CH 3 CH 2 SO 3 -, CF 3 SO 3 -, CH 2 FSO 3 -, CF 3 CH 2 SO 3 -, p- CH ₃ —O—PhSO ₃ —, PhSO ₃ —, and p—CH ₃ PhSO ₃ — can be mentioned.

  As described in the following general synthesis methods and examples, the compound of the present invention represented by the formula (I) has side chain sites bonded to the 3-position, 4-position and 7-position of the above-mentioned intermediate cephem skeleton, respectively. Can be obtained. Examples of the protecting group P include protecting groups described in the following general synthesis. Preferred examples include benzhydryl group, paramethoxybenzyl group, trityl group, 2,6-dimethoxybenzyl group, methoxymethyl group, Examples thereof include a benzyloxymethyl group and a 2- (trimethylsilyl) ethoxymethyl group. Examples of the leaving group include halogen (Cl, Br, I, F), methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, and the like.

（式中、Ｒ^Ｐ１は水素原子またはカルボキシ保護基、Ｒ^Ｐ２は水素原子またはアミノ保護基であり、Ｐ⁻はＥの４級アンモニウムイオンの対イオン（ハロゲン等）を示し、Ｙは脱離基（たとえば、ハロゲン（Ｃｌ、Ｂｒ、Ｉ、Ｆ）、メタンスルホニルオキシ、ｐ−トルエンスルホニルオキシ、トリフルオロメタンスルホニルオキシ等）を示し、その他の各記号は前記と同意義である。） (General synthesis method)
The compound represented by the formula (I) can be produced, for example, by the general synthesis method shown below.

(Wherein R ^P1 represents a hydrogen atom or a carboxy protecting group, R ^P2 represents a hydrogen atom or an amino protecting group, P ⁻ represents a counter ion (such as a halogen) of a quaternary ammonium ion of E, and Y represents a leaving group. (For example, halogen (Cl, Br, I, F), methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, etc.) is shown, and other symbols are as defined above.)

（式中、Ｒ^ｐｒｏは水素原子またはカルボキシ保護基であり、その他の記号は前記と同意義である）で示される化合物を反応させることにより、化合物（Ｘ）が得られる。この場合、好ましくは、Ｒ^aはカルボキシ保護基、Ｒ^ｐｒｏは水素原子である。
式（ＩＸＡ）の化合物は、市販試薬および／または公知の方法を用いて得ることができる。 1) 7-position amidation and 3-position side chain formation; synthesis of compound (XX) Step 1 (7-position amidation reaction):
Compounds synthesized commercially or according to methods described in literature (eg, JP-A-60-231684, JP-A-62-149682, International Publication No. 2014/0668388, International Publication No. 2014/069649, etc.) Formula corresponding to (VI) and the desired side chain:

Compound (X) is obtained by reacting the compound represented by the formula (wherein R ^pro is a hydrogen atom or a carboxy protecting group, and other symbols are as defined above). In this case, preferably, R ^a is a carboxy protecting group and R ^pro is a hydrogen atom.
The compound of formula (IXA) can be obtained using commercially available reagents and / or known methods.

  The amount of compound (IXA) to be used is generally about 1-5 mol, preferably 1-2 mol, per 1 mol of compound (VI).

Examples of the reaction solvent include ethers (eg, dioxane, tetrahydrofuran, secondary ethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, isopropyl acetate), halogenated hydrocarbons ( Examples: dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (example: n-hexane, benzene, toluene), amides (example: formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl) Pyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), dimethyl sulfoxide, water, or a mixed solvent thereof.

  The reaction temperature is usually about -40 to 80 ° C, preferably about -20 to 50 ° C, more preferably about -10 to 30 ° C.

  In the amidation reaction, the carboxy moiety is converted into a reactive derivative (eg, inorganic base salt, organic base salt, acid halide, acid azide, acid anhydride, mixed acid anhydride, active azide, active ester, active thioester). You may go. Examples of the inorganic base include alkali metals (eg, Na, K), alkaline earth metals (eg, Ca, Mg), and examples of the organic base include trimethylamine, benzyldimethylamine, N-methylmorpholine, diisopropylethylamine, and the like. Acid halide, acid bromide, etc. as halide, monoalkyl carbonate mixed acid anhydride, aliphatic carboxylic acid mixed acid anhydride, aromatic carboxylic acid mixed acid anhydride, organic sulfonic acid mixed acid anhydride as mixed acid anhydride Examples of active amides include amides with nitrogen-containing heterocyclic compounds. Examples of the active ester include organic phosphate esters (eg, diethoxyphosphate ester, diphenoxyphosphate ester, etc.), p-nitrophenyl ester, 2,4-secondary nitrophenyl ester, cyanomethyl ester and the like. Examples of the active thioester include an ester with an aromatic heterocyclic thiol compound (eg, 2-pyridylthiol ester). In the above reaction, an appropriate condensing agent may be used if desired. Examples of the condensing agent include 1-dimethylaminopropyl-3-ethylcarbodiimide / hydrochloride (WSCD / HCl), N, N′-dicyclohexylcarbodiimide, N, N′-carbonyldiimidazole, N, N′-thiocarbonyldi Imidazole, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, phosphorus oxychloride, alkyloxyacetylene, 2-chloropyridinium methyl iodide, 2-fluoropyridinium methyl iodide, trifluoroacetic anhydride, etc. are used. .

Step 2 (3-position side chain formation reaction)
Compound (XX) is obtained by reacting compound (X) with the corresponding tertiary amine. In this case, preferably R ^P1 is a carboxy protecting group.

  The amount of the corresponding tertiary amine to be used is generally 1 to 5 mol, preferably 1 to 2 mol, per 1 mol of compound (X).

  Examples of the reaction solvent include ethers (eg, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, isopropyl acetate), halogenated hydrocarbons (eg, : Dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg n-hexane, benzene, toluene), amides (eg formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone) ), Ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile (MeCN), propionitrile), dimethyl sulfoxide, water, or a mixed solvent thereof.

  The reaction temperature is usually -20 to 60 ° C, preferably -10 to 40 ° C, more preferably 0 to 20 ° C.

2) 3-position side chain formation and 7-position amidation; Compound (XX) synthesis step 3 (3-position side chain formation reaction):
Compound (XIII) is obtained by reacting compound (VI) with the corresponding tertiary amine. In this case, preferably R ^P1 is a carboxy protecting group and R ^P2 is an amino protecting group.

  The amount of the corresponding tertiary amine to be used is generally 1 to 5 mol, preferably 1 to 2 mol, per 1 mol of compound (VI).

  Examples of the reaction solvent include ethers (eg, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, isopropyl acetate), halogenated hydrocarbons (eg, : Dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg n-hexane, benzene, toluene), amides (eg formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone) ), Ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, MeCN, propionitrile), dimethyl sulfoxide, water, or a mixed solvent thereof.

The reaction temperature is usually -20 to 60 ° C, preferably -10 to 40 ° C, more preferably 0 to 20 ° C.
Incidentally, (corresponding to the substituent E-R ¹⁰ items 1) tertiary amine moieties for use in the 3-position side chain forming reaction of step 2 and step 3 are all commercially available reagents, known methods and / or the specification It can be obtained by the method described in the book.

Step 4 (7-position amidation reaction):
Compound (XX) is obtained by reacting compound (XIII) and compound (IXA). In this case, preferably, R ^P1 is a carboxy protecting group, R ^P2 is an amino protecting group, and R ^pro is a hydrogen atom.
The amount of compound (IXA) to be used is generally about 1-5 mol, preferably 1-2 mol, per 1 mol of compound (XIII).

Examples of the reaction solvent include ethers (eg, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, isopropyl acetate), halogenated hydrocarbons (eg, : Dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg n-hexane, benzene, toluene), amides (eg formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone) ), Ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, MeCN, propionitrile), dimethyl sulfoxide, water, or a mixed solvent thereof.

The reaction temperature is usually about -40 to 80 ° C, preferably about -20 to 50 ° C, more preferably about -10 to 30 ° C.

The amidation reaction converts the carboxy moiety into a reactive derivative (eg, inorganic base salt, organic base salt, acid halide, acid azide, acid anhydride, mixed acid anhydride, active amide, active ester, active thioester). You may go. Examples of the inorganic base include alkali metals (eg, Na, K, etc.), alkaline earth metals (eg, Ca, Mg), etc., and examples of the organic base include trimethylamine, triethylamine, tert-butyldimethylamine, dibenzylmethylamine, benzyl Dimethylamine, N-methylmorpholine, diisopropylethylamine, etc., acid chloride as acid halide, acid bromide, etc., mixed acid anhydride as monoalkyl carbonate mixed acid anhydride, aliphatic carboxylic acid mixed acid anhydride, aromatic Examples of active amides include carboxylic acid mixed acid anhydrides and organic sulfonic acid mixed acid anhydrides, and amides with nitrogen-containing heterocyclic compounds. Examples of the active ester include organic phosphate esters (eg, diethoxyphosphate ester, diphenoxyphosphate ester, etc.), p-nitrophenyl ester, 2,4-dinitrophenyl ester, cyanomethyl ester and the like. Examples of the active thioester include an ester with an aromatic heterocyclic thiol compound (eg, 2-pyridylthiol ester). In the above reaction, an appropriate condensing agent may be used if desired. Examples of the condensing agent include 1-dimethylaminopropyl-3-ethylcarbodiimide / hydrochloride (WSCD / HCl), N, N′-dicyclohexylcarbodiimide, N, N′-carbonyldiimidazole, N, N′-thiocarbonyldi Imidazole, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, phosphorus oxychloride, alkyloxyacetylene, 2-chloropyridinium methyl iodide, 2-fluoropyridinium methyl iodide, trifluoroacetic anhydride, etc. are used. .

3) Deprotection reaction:
Process 5:
Compound (I) is obtained by subjecting compound (XX) to a deprotection reaction by a method well known to those skilled in the art.

  Examples of the reaction solvent include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization. Hydrogens (eg: dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg: n-hexane, benzene, toluene), amides (eg: formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg acetone, methyl ethyl ketone), nitriles (eg MeCN, propionitrile), nitros (eg nitromethane, nitroethane, nitrobenzene), dimethyl sulfoxide, water and the like. These solvents may be used alone or in combination of two or more.

The reaction temperature is usually about −30 to 100 ° C., preferably about 0 to 50 ° C., more preferably about 0 to 10 ° C.

As the catalyst, a Lewis acid (eg, AlCl ₃ , SnCl ₄ , TiCl ₄ ), a protonic acid (eg, HCl, HBr, H ₂ SO ₄ , HCOOH) or the like can be used.

The resulting compound (I) can be further chemically modified to synthesize an ester, or a protected form of the amino on the thiazole ring at the 7-position, or a pharmaceutically acceptable salt or solvate thereof. .

Protecting groups (amino protecting group, hydroxy protecting group, carboxy protecting group and the like) include, for example, Protective Groups in Organic Synthesis, T., such as ethoxycarbonyl, t-butoxycarbonyl, acetyl, and p-methoxybenzyl. W. By Green, John Wiley & Sons Inc. (1991) and the like. Methods for introducing and removing protecting groups are those commonly used in organic synthetic chemistry [see, eg, Protective Groups in Organic Synthesis, T. et al. W. By Greene, John Wiley & Sons Inc. (See (1991))] or the like. Moreover, the conversion of the functional group contained in each substituent may be performed by a known method other than the above production method [for example, Comprehensive Organic Transformations, R.A. C. Larock (1989), etc.], and some of the compounds of the present invention can lead to further derivatives as synthetic intermediates. The intermediates and target compounds in the above production methods are isolated and purified by purification methods commonly used in synthetic organic chemistry, such as neutralization, filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography. be able to. In addition, the intermediate can be subjected to the next reaction without any particular purification.

（式中、Ｒ^Ｐ１は水素原子またはカルボキシ保護基であり、Ｒ^２Ｐは水素原子またはアミノ保護基であり、Ｒ^Ｐ３は水素原子またはヒドロキシ保護基であり、Ｐ⁻はＥの４級アンモニウムイオンの対イオン（ハロゲン等）を示し、Ｙは脱離基（たとえば、ハロゲン（Ｃｌ、Ｂｒ、Ｉ、Ｆ）、メタンスルホニルオキシ、ｐ−トルエンスルホニルオキシ、トリフルオロメタンスルホニルオキシ等）を示し、その他の各記号は前記と同意義である。）
スキーム２に示した各工程１〜５は、例えば、前記の工程１〜５と同様の方法で行うことができる。 The compound represented by the formula (II) can also be produced, for example, by a general synthesis method shown in the following scheme 2.

Wherein R ^P1 is a hydrogen atom or a carboxy protecting group, R ^2P is a hydrogen atom or an amino protecting group, R ^P3 is a hydrogen atom or a hydroxy protecting group, and P ⁻ is a quaternary ammonium ion of E. Represents a counter ion (halogen, etc.), Y represents a leaving group (for example, halogen (Cl, Br, I, F), methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, etc.), The symbols are as defined above.)
Each process 1-5 shown in the scheme 2 can be performed by the method similar to the said process 1-5, for example.

  The resulting compound (I) or (II) is further chemically modified to give an ester, or a protected form of amino on the thiazole ring at the 7-position, or a pharmaceutically acceptable salt or solvate thereof. It can also be synthesized.

  The compound of the present invention has a broad spectrum of antibacterial activity, and various diseases caused by pathogenic bacteria in various mammals including humans such as respiratory tract infections, urinary tract infections, respiratory infections, sepsis, nephritis, gallbladder It can be used for the prevention or treatment of inflammation, oral infection, endocarditis, pneumonia, osteomyelitis, otitis media, enteritis, empyema, wound infection, opportunistic infection and the like.

  The compound of the present invention is a gram-negative bacterium, preferably a gram-negative bacterium of the family Enterobacteriaceae (E. coli, Klebsiella, Serratia, Enterobacter, Citrobacter, Morganella, Providencia, Proteus, etc.) (Hemophilus, Moraxella, etc.) and glucose non-fermenting Gram-negative bacteria (Pseudomonas, Pseudomonas other than Pseudomonas aeruginosa, Stenotrophomonas, Burkholderia, Acinetobacter, etc.). Stable to β-lactamases belonging to classes A, B, C and D produced by these gram-negative bacteria, and resistant to various β-lactam drugs such as ESBL-producing bacteria represented by TEM, SHV, KPC, etc. Has high antibacterial activity against gram-negative bacteria. In particular, it is extremely stable against metallo-β-lactamases belonging to class B including IMP type, VIM type, L-1 type, etc., so that it is resistant to various β-lactam drug resistant gram-negative bacteria including cephem and carbapenem. Is also effective. The compound of the present invention also has antibacterial activity against gram-positive bacteria including methicillin-sensitive Staphylococcus aureus (MRSA), penicillin-resistant pneumococcus (PRSP) and the like. Further preferable compounds have characteristics such as high blood concentration, long duration of effect, and / or remarkable tissue transferability as pharmacokinetics. Preferred compounds are safe in terms of side effects such as no fever and no nephrotoxicity. Further, preferred compounds have high water solubility and are particularly suitable as injections.

  The compound of the present invention can be administered orally or parenterally. In the case of oral administration, the compound of the present invention is any of ordinary preparations, for example, solid preparations such as tablets, powders, granules and capsules, liquid preparations, oil suspensions, or liquid preparations such as syrups and elixirs. It can also be used as a dosage form. In the case of parenteral administration, the compound of the present invention can be used as an aqueous or oily suspension injection or nasal solution. In the preparation, conventional excipients, binders, lubricants, aqueous solvents, oily solvents, emulsifiers, suspending agents, preservatives, stabilizers and the like can be arbitrarily used. The formulations of the present invention are prepared by combining (eg, mixing) a therapeutically effective amount of a compound of the present invention with a pharmaceutically acceptable carrier or diluent.

The compound of the present invention can be administered parenterally or orally as an injection, capsule, tablet or granule, but is preferably administered as an injection. The dose is usually about 0.1 to 100 mg / day, preferably about 0.5 to 50 mg / day, per 1 kg of the body weight of the patient or animal. Good. When used as an injection, the carrier is, for example, distilled water, physiological saline or the like, and a base for adjusting pH may be used. Carriers when used as capsules, granules, and tablets are known excipients (eg, starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.), binders (eg, starch, gum arabic, carboxymethyl cellulose) , Hydroxypropyl cellulose, crystalline cellulose, etc.), lubricants (eg, magnesium stearate, talc, etc.).

  The present invention will be described in more detail below with reference to Examples, Reference Examples, Test Examples and Formulation Examples, but the present invention is not limited thereto.

Moreover, the abbreviation used in this specification represents the following meaning.
Boc: tert-butoxycarbonyl Bt: 1-benzotriazolyl mCPBA: m-chloroperbenzoic acid Me: methyl ODS: octadecylsilyl t-Bu: tert-butyl PMB: paramethoxybenzyl

The NMR analysis obtained in the examples was performed at 400 MHz and measured using DMSO-d ₆ , CDCl _{3 and the} like.

The LCMS analysis obtained in the examples was measured under the following conditions.
Measurement condition 1:
Column: ACQUITY UPLC® BEH C18 (1.7 μm id 2.1 × 50 mm) (Waters)
Flow rate: 0.8 mL / min PDA detection wavelength: 254 nm
Mobile phase: [A] is a 0.1% formic acid-containing aqueous solution, [B] is a 0.1% formic acid-containing acetonitrile solution Gradient: A linear gradient of 5% -100% solvent [B] was performed in 3.5 minutes. Thereafter, 100% solvent [B] was maintained for 0.5 minutes.

工程１ 化合物１ｃの合成
化合物１ａ（１．８８ｇ、４．０ｍｍｏｌ）と化合物１ｂ（０．６７ｇ、４．８ｍｍｏｌ）から実施例７の工程３と同様にして、化合物１ｃ（１．０８ｇ、収率４５％）を淡黄色泡状物質として得た。
¹H-NMR (DMSO-D₆)δ:1.35 (6H, t, J = 7.7 Hz), 2.26 (2H, s), 2.63 (2H, t, J = 6.2 Hz), 2.79 (6H, t, J = 7.7 Hz), 3.27 (1H, dd, J = 12.0, 5.9 Hz), 3.75 (3H, s), 3.77 (3H, s), 4.88 (2H, s), 5.15 (2H, s), 6.87 (2H, d, J = 8.6 Hz), 6.97 (2H, d, J = 8.6 Hz), 7.12 (1H, d, J = 8.6 Hz), 7.19 (1H, d, J = 8.6 Hz), 7.31 (2H, d, J = 8.3 Hz), 7.43 (2H, d, J = 8.6 Hz), 8.20 (1H, t, J = 5.6 Hz).
MS (m+1) = 594.30 Synthesis of Compound I-1

Step 1 Synthesis of Compound 1c Compound 1c (1.08 g, yield) was obtained from Compound 1a (1.88 g, 4.0 mmol) and Compound 1b (0.67 g, 4.8 mmol) in the same manner as in Step 3 of Example 7. 45%) was obtained as a pale yellow foam.
¹ H-NMR (DMSO-D ₆ ) δ: 1.35 (6H, t, J = 7.7 Hz), 2.26 (2H, s), 2.63 (2H, t, J = 6.2 Hz), 2.79 (6H, t, J = 7.7 Hz), 3.27 (1H, dd, J = 12.0, 5.9 Hz), 3.75 (3H, s), 3.77 (3H, s), 4.88 (2H, s), 5.15 (2H, s), 6.87 (2H , d, J = 8.6 Hz), 6.97 (2H, d, J = 8.6 Hz), 7.12 (1H, d, J = 8.6 Hz), 7.19 (1H, d, J = 8.6 Hz), 7.31 (2H, d , J = 8.3 Hz), 7.43 (2H, d, J = 8.6 Hz), 8.20 (1H, t, J = 5.6 Hz).
MS (m + 1) = 594.30

Step 2 Synthesis of Compound 1d Compound 1d (1.0 g, yield 80%) was obtained as an orange foam from compound 1c (1.07 g, 1.8 mmol) in the same manner as in Step 4 of Example 7.
¹ H-NMR (DMSO-D ₆ ) δ: 1.32 (6H, s), 1.41 (9H, s), 2.52 (4H, s), 2.75 (2H, s), 3.25 (6H, s), 3.77 (6H , t, J = 7.8 Hz), 4.89 (2H, s), 5.16 (2H, s), 6.86-7.46 (10H, m), 8.32 (1H, s).
MS (m + 1) = 694.35

Step 3 Synthesis of Compound I-1 Compound 1d (1.0 g, 1.4 mmol) was added to a solution of Compound 1e (1.27 g, 1.4 mmol) in dimethylacetamide (3 mL) under ice-cooling. Stir for 3 hours. The reaction mixture was slowly added to an ice-cooled 5% aqueous sodium bisulfite solution. The precipitated solid was collected by filtration, washed with water, suspended in water, and lyophilized to obtain 1f as a yellow solid. The obtained compound 1f was used in the next reaction without purification.
The total amount of Compound 1f obtained was dissolved in dichloromethane (15 mL) and cooled to −40 ° C., and then anisole (1.9 mL, 17.2 mmol) and 2 mol / L aluminum chloride / nitromethane solution (8.6 mL, 17.2 mmol). ) Were added in order, and the mixture was stirred for 30 minutes under ice cooling. Diisopropyl ether and a small amount of water were added to the reaction solution and stirred to form a precipitate, and the supernatant was removed by decantation. Diluted hydrochloric acid and acetonitrile were added to the remaining insoluble matter and stirred to completely dissolve, and then diisopropyl ether was added to separate the aqueous layer. After the organic layer was extracted again with water, all the aqueous layers were combined, HP20-SS resin was added, and acetonitrile was distilled off under reduced pressure. The resulting mixture was purified by ODS column chromatography (water-acetonitrile). Fractions containing the desired compound were collected, concentrated under reduced pressure, and then lyophilized to obtain Compound I-1 (604 mg, 51% yield) as a white powder.
¹ H-NMR (DMSO-D ₆ ) δ: 1.40 (3H, d, J = 6.7 Hz), 1.45 (3H, s), 1.48 (3H, s), 1.74 (6H, s), 2.59 (1H, s ), 2.79 (2H, s), 3.80 (1H, d, J = 12.9 Hz), 4.02 (1H, d, J = 6.7 Hz), 4.90 (1H, d, J = 12.7 Hz), 5.26 (1H, d , J = 5.0 Hz), 5.71 (1H, t, J = 6.3 Hz), 6.75-6.77 (3H, m), 7.23 (2H, s), 8.20 (1H, s).
MS (m + 1) = 835.26
Elemental analysis: C35H43ClN8O10S2 (H2O) 5.6
Calculated value: C, 44.90; H, 5.84; N, 11.97; Cl, 3.79; S, 6.85 (%)
Found: C, 44.85; H, 5.77; N, 12.21; Cl, 3.70; S, 6.78 (%)

工程１ 化合物２ｂの合成
化合物１ａ（１．８８ｇ、４．０ｍｍｏｌ）と化合物２ａ（０．５３ｇ、４．２ｍｍｏｌ）から実施例７の工程３と同様にして、化合物２ｂ（１．２３ｇ、収率５３％）を淡黄色泡状物質として得た。
¹H-NMR (DMSO-D₆)δ:1.22 (2H, s), 1.55-1.61 (2H, m), 2.28 (2H, s), 2.60 (2H, t, J = 11.9 Hz), 2.69 (2H, t, J = 6.3 Hz), 2.81-2.88 (4H, m), 3.29 (2H, t, J = 6.0 Hz), 3.75 (3H, s), 3.77 (3H, s), 4.88 (2H, s), 5.15 (2H, s), 6.87 (2H, d, J = 8.5 Hz), 6.97 (2H, d, J = 8.5 Hz), 7.14 (1H, d, J = 8.7 Hz), 7.19 (1H, d, J = 8.7 Hz), 7.31 (2H, d, J = 8.5 Hz), 7.43 (2H, d, J = 8.4 Hz), 8.24 (1H, t, J = 5.5 Hz).
MS (m+1) = 580.30 Synthesis of compound I-2

Step 1 Synthesis of Compound 2b Compound 2b (1.23 g, yield) was obtained from Compound 1a (1.88 g, 4.0 mmol) and Compound 2a (0.53 g, 4.2 mmol) in the same manner as in Step 3 of Example 7. 53%) was obtained as a pale yellow foam.
¹ H-NMR (DMSO-D ₆ ) δ: 1.22 (2H, s), 1.55-1.61 (2H, m), 2.28 (2H, s), 2.60 (2H, t, J = 11.9 Hz), 2.69 (2H , t, J = 6.3 Hz), 2.81-2.88 (4H, m), 3.29 (2H, t, J = 6.0 Hz), 3.75 (3H, s), 3.77 (3H, s), 4.88 (2H, s) , 5.15 (2H, s), 6.87 (2H, d, J = 8.5 Hz), 6.97 (2H, d, J = 8.5 Hz), 7.14 (1H, d, J = 8.7 Hz), 7.19 (1H, d, J = 8.7 Hz), 7.31 (2H, d, J = 8.5 Hz), 7.43 (2H, d, J = 8.4 Hz), 8.24 (1H, t, J = 5.5 Hz).
MS (m + 1) = 580.30

Step 2 Synthesis of Compound 2c Compound 2c (300 mg, 21% yield) was obtained as an orange foam from compound 2b (1.23 g, 2.1 mmol) in the same manner as in Step 4 of Example 7.
¹ H-NMR (DMSO-D ₆ ) δ: 1.06 (4H, t, J = 7.2 Hz), 1.41 (9H, s), 1.70 (2H, s), 2.65 (2H, s), 2.73 (2H, q , J = 7.0 Hz), 2.91 (1H, s), 3.11 (1H, s), 3.31 (2H, s), 3.53 (2H, s), 3.75 (3H, s), 3.78 (3H, s), 4.89 (2H, s), 5.16 (2H, s), 6.88 (2H, d, J = 8.5 Hz), 6.98 (2H, d, J = 8.7 Hz), 7.13-7.18 (2H, m), 7.32 (2H, d, J = 8.5 Hz), 7.43 (2H, d, J = 8.5 Hz), 8.35 (1H, d, J = 22.7 Hz).
MS (m + 1) = 680.34

Step 3 Synthesis of Compound I-2 Compound I-2 (116 mg, 34% yield) was obtained from Compound 1e (391 mg, 0.44 mmol) and Compound 2c (300 mg, 0.44 mmol) in the same manner as in Step 3 of Example 1. ) Was obtained as a white powder.
¹ H-NMR (DMSO-D ₆ ) δ: 1.33 (3H, d, J = 5.8 Hz), 1.38 (3H, s), 1.41 (3H, s), 1.68 (2H, s), 1.96 (2H, s ), 2.77 (2H, s), 2.89 (2H, s), 3.96 (2H, s), 4.96 (1H, d, J = 11.9 Hz), 5.22 (1H, d, J = 4.0 Hz), 5.64 (1H , s), 6.69-6.71 (3H, m), 7.16 (2H, s), 8.20 (1H, s).
MS (m + 1) = 821.29
Elemental analysis: C34H41ClN8O10S2 (H2O) 5.2
Calculated value: C, 44.63; H, 5.66; N, 12.25; Cl, 3.87; S, 7.01 (%)
Found: C, 44.57; H, 5.53; N, 12.51; Cl, 3.85; S, 7.28 (%)

工程１ 化合物３ｃの合成
化合物３ｂ（２．３４ｇ、１４．６ｍｍｏｌ）のトルエン（６５ｍＬ）溶液に、化合物３ａ（２．５８ｇ、１３．３ｍｍｏｌ）、ＢＩＮＡＰ（０．４１ｇ、０．６６ｍｍｏｌ）、ナトリウムtert-ブトキシド（２．８１ｇ、２９．２ｍｍｏｌ）を加えた。続いて、減圧脱気、及び窒素置換した後、Ｐｄ_２（ｄｂａ）_３（０．６１ｇ、０．６６ｍｍｏｌ）を加え、９０℃で２時間半加熱攪拌した。反応混合物を室温まで冷却した後、水を加え、酢酸エチルで２回抽出した。有機層を、水、飽和食塩水で順に洗浄し、無水硫酸マグネシウムにより乾燥した。無機物をろ過により除き、減圧濃縮した。得られた粗生成物はシリカゲルカラムクロマトグラフィ（トリエチルアミン：メタノール：酢酸エチル＝１：１：９）により精製し、化合物３ｃ（１．８９ｇ、収率６０％）を橙色オイルとして得た。
¹H-NMR (CDCl₃)δ:1.45 (9H, s), 3.25-3.29 (2H, m), 3.33-3.40 (2H, m), 4.78 (1H, s), 6.43 (2H, d, J = 6.3 Hz), 8.18 (2H, d, J = 6.1 Hz).
MS (m+1) = 238.21 Synthesis of Compound I-3

Step 1 Synthesis of Compound 3c To a solution of Compound 3b (2.34 g, 14.6 mmol) in toluene (65 mL), Compound 3a (2.58 g, 13.3 mmol), BINAP (0.41 g, 0.66 mmol), sodium tert -Butoxide (2.81 g, 29.2 mmol) was added. Subsequently, after vacuum degassing and nitrogen substitution, Pd ₂ (dba) ₃ (0.61 g, 0.66 mmol) was added, and the mixture was stirred with heating at 90 ° C. for 2.5 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted twice with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (triethylamine: methanol: ethyl acetate = 1: 1: 9) to obtain compound 3c (1.89 g, yield 60%) as an orange oil.
¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 3.25-3.29 (2H, m), 3.33-3.40 (2H, m), 4.78 (1H, s), 6.43 (2H, d, J = 6.3 Hz), 8.18 (2H, d, J = 6.1 Hz).
MS (m + 1) = 238.21

Step 2 Synthesis of Compound 3d To a solution of Compound 3c (1.89 g, 8.0 mmol) in tetrahydrofuran (9.5 mL) was slowly added 4 mol / L hydrochloric acid / 1,4-dioxane solution (20 mL, 40 mmol) under ice-cooling. After the addition, the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the resulting residue, and the resulting solid was collected by filtration and dried under reduced pressure to give compound 3d (1.62 g, yield 97%) as a pale yellow solid. It was.
¹ H-NMR (D ₂ O) δ: 3.31 (2H, t, J = 6.1 Hz), 3.73 (2H, t, J = 6.1 Hz), 6.94 (2H, d, J = 7.3 Hz), 7.36 (1H , d, J = 6.8 Hz), 8.09 (2H, s), 8.52 (1H, d, J = 6.7 Hz).

Step 3 Synthesis of Compound 3f To a solution of Compound 3e (1.64 g, 3.0 mmol) in tetrahydrofuran (16 mL) was added Compound 3d (0.69 g, 3.3 mmol), and then triethylamine (1.0 mL under ice-cooling). 7.5 mmol). After stirring at room temperature for 40 minutes, an aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (triethylamine: methanol: ethyl acetate = 1: 1: 9) to obtain compound 3f (1.64 g, yield 99%) as a white foam.
¹ H-NMR (CDCl ₃ ) δ: 3.43 (2H, t, J = 5.4 Hz), 3.71 (2H, q, J = 5.6 Hz), 3.80 (3H, s), 3.83 (3H, s), 4.94 ( 2H, s), 5.08 (2H, s), 6.47 (1H, d, J = 4.8 Hz), 6.64 (1H, s), 6.83 (2H, d, J = 8.6 Hz), 6.91-6.95 (3H, m ), 7.25 (2H, s), 7.33 (4H, t, J = 9.3 Hz), 7.44 (1H, d, J = 8.6 Hz), 8.19 (2H, d, J = 4.8 Hz).

Step 4 Synthesis of Compound 3g Compound 2c (0.94 g, 74% yield) was obtained as a white solid in the same manner as in Step 4 of Example 7 from Compound 3f (1.07 g, 2.0 mmol).
¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 3.67 (2H, q, J = 6.0 Hz), 3.80 (3H, s), 3.83 (3H, s), 3.98 (2H, t, J = 6.2 Hz), 4.94 (2H, s), 5.08 (2H, s), 6.65 (1H, s), 6.83 (2H, d, J = 7.8 Hz), 6.92 (3H, d, J = 8.6 Hz), 7.29-7.36 (7H, m), 8.53 (2H, d, J = 5.1 Hz).
MS (m + 1) = 648.30

Step 3 Synthesis of Compound I-3 From compound 1e (886 mg, 1.0 mmol) and compound 3g (648 mg, 1.0 mmol) in the same manner as in Step 3 of Example 1, I-3 (350 mg, 44% yield) Was obtained as a white powder.
¹ H-NMR (DMSO-D ₆ ) δ: 1.05 (3H, d, J = 7.1 Hz), 1.36 (3H, s), 1.38 (3H, s), 3.78 (1H, q, J = 7.1 Hz), 4.91 (2H, s), 5.17 (1H, d, J = 5.1 Hz), 5.60 (1H, dd, J = 8.0, 5.1 Hz), 6.60-6.68 (3H, m), 6.82-6.84 (1H, m) , 6.92 (1H, d, J = 7.1 Hz), 7.18 (2H, s), 8.25-8.29 (2H, m), 8.44 (1H, d, J = 7.1 Hz), 8.77 (1H, s), 9.43 ( 1H, s).
MS (m + 1) = 789.21
Elemental analysis: C32H33ClN8O10S2 (H2O) 3.9
Calculated value: C, 44.72; H, 4.78; N, 13.04; Cl, 4.12; S, 7.46 (%)
Found: C, 44.64; H, 4.77; N, 13.14; Cl, 4.11; S, 7.44 (%)

工程１ 化合物４ｃの合成
化合物４ａ (16.38 g, 30 mmol)をテトラヒドロフラン(160 ml)に懸濁させ氷冷とした後、化合物４ｂ (3.27 ml, 33 mmol)を加えた。室温で1時間撹拌した後、反応液を酢酸エチルで希釈し、有機層を希塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄、硫酸マグネシウムで乾燥した。硫酸マグネシウムをろ過した後、減圧濃縮し、ジイソプロピルエーテルで固化させ、化合物４ｃ (14.78 g, 96%)を得た。
¹H-NMR (CDCl₃)δ:7.46 (1H, d, J = 8.7 Hz), 7.36-7.33 (4H, m), 6.95-6.91 (3H, m), 6.83 (2H, d, J = 8.7 Hz), 6.71 (1H, br s), 5.08 (2H, s), 4.95 (2H, s), 3.83 (3H, s), 3.80 (3H, s), 3.75 (2H, br s), 3.68 (4H, br s), 3.63-3.60 (2H, m), 1.98 (1H, br s). Synthesis of Compound I-4

Step 1 Synthesis of Compound 4c Compound 4a (16.38 g, 30 mmol) was suspended in tetrahydrofuran (160 ml) and cooled with ice, and then compound 4b (3.27 ml, 33 mmol) was added. After stirring at room temperature for 1 hour, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. Magnesium sulfate was filtered, concentrated under reduced pressure, and solidified with diisopropyl ether to obtain Compound 4c (14.78 g, 96%).
¹ H-NMR (CDCl ₃ ) δ: 7.46 (1H, d, J = 8.7 Hz), 7.36-7.33 (4H, m), 6.95-6.91 (3H, m), 6.83 (2H, d, J = 8.7 Hz) ), 6.71 (1H, br s), 5.08 (2H, s), 4.95 (2H, s), 3.83 (3H, s), 3.80 (3H, s), 3.75 (2H, br s), 3.68 (4H, br s), 3.63-3.60 (2H, m), 1.98 (1H, br s).

Step 2 Synthesis of Compound 4d Compound 4c (5.00 g, 9.69 mmol) was dissolved in dichloromethane (50 ml) and cooled with ice, and then triethylamine (2.02 ml, 14.5 mmol) and methanesulfonyl chloride (0.91 ml, 11.6 mmol) were added. Added sequentially. After stirring at room temperature for 1 hour, the reaction solution was diluted with dichloromethane, and the organic layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. Magnesium sulfate was filtered, concentrated under reduced pressure, and solidified with diisopropyl ether to give compound 4d (5.68 g, 99%).
¹ H-NMR (CDCl ₃ ) δ: 7.44 (1H, d, J = 8.6 Hz), 7.36-7.33 (4H, m), 6.95-6.91 (3H, m), 6.84 (2H, d, J = 8.3 Hz ), 6.71 (1H, br s), 5.08 (2H, s), 4.95 (2H, s), 4.38-4.35 (2H, m), 3.83 (3H, s), 3.80 (3H, s), 3.78-3.75 (2H, m), 3.70-3.66 (4H, m), 2.99 (3H, s).

Step 3 Synthesis of Compound 4e Compound 4d (3.00 g, 5.05 mmol) was dissolved in acetonitrile (30 ml), and pyrrolidine (0.84 ml, 10.1 mmol) and potassium carbonate (0.70 g, 5.05 mmol) were sequentially added. After stirring at 60 ° C. for 4 hours, the mixture was allowed to stand at room temperature overnight, and further stirred at 60 ° C. for 4 hours. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The magnesium sulfate was filtered, concentrated under reduced pressure, and solidified with diisopropyl ether to obtain Compound 4e (2.70 g, 94%).
¹ H-NMR (CDCl ₃ ) δ: 7.40-7.34 (5H, m), 7.12 (1H, br s), 6.93-6.91 (3H, m), 6.84 (2H, d, J = 8.3 Hz), 5.08 ( 2H, s), 4.95 (2H, s), 3.83 (3H, s), 3.80 (3H, s), 3.65 (4H, br s), 3.61 (2H, t, J = 5.6 Hz), 2.67 (2H, t, J = 5.1 Hz), 2.50 (4H, br s), 1.67 (4H, br s).

Step 4 Synthesis of Compound I-4 Compound 4f (794 mg, 1.0 mmol) was dissolved in dimethylacetamide (2.4 mL) and cooled to 15 ° C., then sodium iodide (300 mg, 2.00 mmol) was added, and 30 ° C. at 30 ° C. Stir for minutes. After cooling to 0 ° C., Compound 4e (569 mg, 1.0 mmol) was added, and the mixture was allowed to stand at 5 ° C. overnight. The reaction mixture was slowly added to an ice-cooled aqueous solution of sodium hydrogen sulfate (1.5 g) and sodium chloride (1.5 g). The precipitated solid was collected by filtration, washed with water, suspended in water, and freeze-dried to obtain 4 g of a compound as a pale yellow solid. The obtained compound 4g was used in the next reaction without purification.
The total amount of 4 g of the obtained compound was dissolved in dichloromethane (10 ml) and cooled to −40 ° C., and then anisole (1.31 ml, 12.0 mmol) and 2 mol / L aluminum chloride / nitromethane solution (6.00 ml, 12.0 mmol) were sequentially added. In addition, the mixture was stirred at 0 ° C. for 30 minutes. The reaction solution was dissolved in water, a 2 mol / L normal hydrochloric acid aqueous solution, and acetonitrile, and then washed with diisopropyl ether. HP20-SS resin was added to the aqueous layer, and acetonitrile was distilled off under reduced pressure. The resulting mixture was subjected to ODS column chromatography and eluted with water / acetonitrile. After adding 0.2 mol / L sodium hydroxide aqueous solution to the obtained solution of the target compound until pH = 6, one piece of dry ice was added. The resulting solution was concentrated under reduced pressure and then lyophilized to obtain Compound I-4 as a white powder.
Yield: 445.2 mg, (48%)
¹ H-NMR (D ₂ O) δ: 7.01 (1H, s), 6.95 (1H, d, J = 8.4 Hz), 6.85 (1H, d, J = 8.4 Hz), 5.82 (1H, d, J = 4.9 Hz), 5.38 (1H, d, J = 4.9 Hz), 5.10 (1H, d, J = 14.3 Hz), 4.16 (1H, d, J = 14.3 Hz), 4.02-3.94 (3H, m), 3.79 -3.28 (10H, m), 2.13 (4H, br s), 1.53 (3H, s), 1.51 (3H, s), 1.43 (3H, d, J = 7.0 Hz).
Elemental analysis: C33H39ClN7O11S2Na (H2O) 4.7
Calculated values: C, 43.23; H, 5.32; N, 10.69; Cl, 3.87; S, 6.99; Na, 2.51 (%)
Found: C, 43.25; H, 5.27; N, 10.74; Cl, 3.80; S, 6.93; Na, 2.48 (%)

工程１ 化合物５ｃの合成
化合４ａ(16.38 g, 30 mmol)をテトラヒドロフラン(160 ml)に懸濁させ氷冷とした後、化合物５ａ(2.55 g, 33 mmol)を加えた。室温で1時間撹拌した後、氷冷下水素化ホウ素ナトリウム(0.57 g, 15 mmol) を加え室温で1時間撹拌した。トリエチルアミン(5.0 ml, 30 mmol), 化合物５ｂ(5.61 g, 33 mmol)を順次加え室温で30分撹拌した。ヨウ化ナトリウム(4.5 g, 30 mmol)を加え室温で一晩撹拌した。加熱還流下で6時間撹拌した後、反応液を希塩酸、酢酸エチルで希釈し不溶物をろ過で除いた後、ろ液を分液し有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄、硫酸マグネシウムで乾燥した。硫酸マグネシウムをろ過した後、減圧濃縮し、ジイソプロピルエーテルで固化させ、化合物５ｃ(10.3 g, 71%)を得た。
¹H-NMR (CDCl₃)δ:7.46 (1H, d, J = 8.6 Hz), 7.36-7.33 (4H, m), 6.95-6.91 (3H, m), 6.83 (2H, d, J = 8.6 Hz), 6.73 (1H, br s), 5.08 (2H, s), 4.95 (2H, s), 3.83 (3H, s), 3.80 (3H, s), 3.78 (1H, d, J = 3.5 Hz), 3.66-3.61 (2H, m), 2.81-2.76 (2H, m). Synthesis of Compound I-5

Step 1 Synthesis of compound 5c Compound 4a (16.38 g, 30 mmol) was suspended in tetrahydrofuran (160 ml) and cooled with ice, and then compound 5a (2.55 g, 33 mmol) was added. After stirring at room temperature for 1 hour, sodium borohydride (0.57 g, 15 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Triethylamine (5.0 ml, 30 mmol) and compound 5b (5.61 g, 33 mmol) were sequentially added, followed by stirring at room temperature for 30 minutes. Sodium iodide (4.5 g, 30 mmol) was added and stirred overnight at room temperature. After stirring for 6 hours under reflux with heating, the reaction solution was diluted with dilute hydrochloric acid and ethyl acetate and insolubles were removed by filtration. The filtrate was separated, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, Dried over magnesium sulfate. Magnesium sulfate was filtered, concentrated under reduced pressure, and solidified with diisopropyl ether to obtain compound 5c (10.3 g, 71%).
¹ H-NMR (CDCl ₃ ) δ: 7.46 (1H, d, J = 8.6 Hz), 7.36-7.33 (4H, m), 6.95-6.91 (3H, m), 6.83 (2H, d, J = 8.6 Hz) ), 6.73 (1H, br s), 5.08 (2H, s), 4.95 (2H, s), 3.83 (3H, s), 3.80 (3H, s), 3.78 (1H, d, J = 3.5 Hz), 3.66-3.61 (2H, m), 2.81-2.76 (2H, m).

Step 2 Synthesis of Compound 5d Compound 5c (7.00 g, 14.34 mmol) was suspended in ethanol (70 ml) and ice-cooled, and then 20% sodium ethoxide ethanol solution (16.9 ml, 43.0 mmol), compound 5b (2.56 g, 15.1 mmol) was sequentially added, and the mixture was stirred for 1 hour under reflux. The reaction mixture was concentrated under reduced pressure, diluted with water and ethyl acetate, and the insoluble material was removed by filtration. The filtrate was separated and the organic layer was washed with saturated brine and dried over magnesium sulfate. Magnesium sulfate was filtered, concentrated under reduced pressure, and solidified with diisopropyl ether to obtain compound 5d (5.38 g, 64%).
¹ H-NMR (CDCl ₃ ) δ: 7.44 (1H, d, J = 8.6 Hz), 7.36-7.34 (4H, m), 6.94-6.91 (4H, m), 6.84 (2H, d, J = 7.6 Hz ), 5.08 (2H, s), 4.95 (2H, s), 3.83 (3H, s), 3.80 (3H, s), 3.66 (2H, q, J = 5.8 Hz), 2.81 (2H, t, J = 6.2 Hz), 2.71 (4H, br s), 2.53 (4H, br s), 1.75 (4H, br s).

Step 3 Compound I-5 was obtained in the same manner as in Step 4 of Example 4 using Compound 4f (794 mg, 1.0 mmol) and Compound 5d (585 mg, 1.0 mmol). Yield: 392.7 mg, (41%)
¹ H-NMR (D ₂ O) δ: 7.02-7.00 (2H, m), 6.90 (1H, d, J = 8.3 Hz), 5.77 (1H, d, J = 4.8 Hz), 5.41 (1H, d, J = 4.8 Hz), 4.97 (1H, d, J = 14.3 Hz), 4.16 (1H, d, J = 14.3 Hz), 3.98 (1H, q, J = 7.0 Hz), 3.63-3.41 (8H, m) , 3.03 (2H, t, J = 8.0 Hz), 2.91 (2H, t, J = 6.3 Hz), 2.23-2.14 (4H, m), 1.53-1.50 (9H, m).
Elemental analysis: C33H39ClN7O10S3Na (H2O) 4.9
Calculated values: C, 42.32; H, 5.25; N, 10.47; Cl, 3.78; S, 10.27; Na, 2.45 (%)
Found: C, 42.31; H, 5.20; N, 10.67; Cl, 3.77; S, 10.18; Na, 2.33 (%)

工程１ 化合物６ａの合成
化合物５ｄ(1.00 g, 1.71 mmol)と酢酸(0.977 ml, 17.1 mmol)をジクロロメタン(10 ml)に溶解させ-20℃に冷却した後、ｍＣＰＢＡ (427 mg, 1.71 mmol)を加えた。-20℃で1時間撹拌した後、反応液をジクロロメタンで希釈し、飽和炭酸水素ナトリウムとチオ硫酸ナトリウムの水溶液、水、飽和食塩水で洗浄、硫酸マグネシウムで乾燥した。硫酸マグネシウムをろ過した後、減圧濃縮し、ジイソプロピルエーテルで固化させ、化合物６ａ(643.3 mg, 58%)を得た。
¹H-NMR (CDCl₃)δ:7.40-7.33 (5H, m), 7.17 (1H, br s), 6.92-6.90 (3H, m), 6.83 (2H, d, J = 8.3 Hz), 5.07 (2H, s), 4.94 (2H, s), 3.97 (2H, q, J = 5.5 Hz), 3.83 (3H, s), 3.80 (3H, s), 3.22-3.16 (1H, m), 3.06-2.89 (5H, m), 2.62 (4H, br s), 1.80 (4H, br s). Synthesis of Compound I-6

Step 1 Synthesis of Compound 6a Compound 5d (1.00 g, 1.71 mmol) and acetic acid (0.977 ml, 17.1 mmol) were dissolved in dichloromethane (10 ml) and cooled to −20 ° C., and then mCPBA (427 mg, 1.71 mmol) was added. added. After stirring at −20 ° C. for 1 hour, the reaction solution was diluted with dichloromethane, washed with an aqueous solution of saturated sodium bicarbonate and sodium thiosulfate, water and saturated brine, and dried over magnesium sulfate. Magnesium sulfate was filtered, concentrated under reduced pressure, and solidified with diisopropyl ether to obtain compound 6a (643.3 mg, 58%).
¹ H-NMR (CDCl ₃ ) δ: 7.40-7.33 (5H, m), 7.17 (1H, br s), 6.92-6.90 (3H, m), 6.83 (2H, d, J = 8.3 Hz), 5.07 ( 2H, s), 4.94 (2H, s), 3.97 (2H, q, J = 5.5 Hz), 3.83 (3H, s), 3.80 (3H, s), 3.22-3.16 (1H, m), 3.06-2.89 (5H, m), 2.62 (4H, br s), 1.80 (4H, br s).

Step 2 Compound I-6 was obtained in the same manner as in Step 4 of Example 4 using Compound 4f (794 mg, 1.0 mmol) and Compound 6a (643 mg, 0.99 mmol).
Yield: 373.9 mg, (37%)
¹ H-NMR (D ₂ O) δ: 7.01-6.97 (2H, m), 6.90 (1H, d, J = 8.3 Hz), 5.79 (1H, dd, J = 4.8, 3.3 Hz), 5.45 (1H, dd, J = 4.8, 1.4 Hz), 5.02 (1H, dd, J = 14.3, 9.4 Hz), 4.22 (1H, dd, J = 14.3, 8.2 Hz), 4.08-4.02 (1H, m), 3.94-3.83 (3H, m), 3.79-3.69 (2H, m), 3.60-3.27 (7H, m), 2.25 (4H, br s), 1.55 (3H, d, J = 6.7 Hz), 1.52 (3H, s) , 1.50 (3H, s).
Elemental analysis: C33H39ClN7O11S3Na (H2O) 6
Calculated values: C, 40.76; H, 5.29; N, 10.08; Cl, 3.65; S, 9.89; Na, 2.36 (%)
Found: C, 40.56; H, 5.18; N, 10.32; Cl, 3.65; S, 9.94; Na, 2.47 (%)

工程１ 化合物７ａの合成
化合物４ａ（２７．３ｇ、５０．０ｍｍｏｌ）をテトラヒドロフラン（３００ｍＬ）に溶解させ０℃に冷却した。この溶液に２，２−ジメトキシエタンアミン（５．７８ｇ、５５．０ｍｍｏｌ）を加え、室温で１時間撹拌した。この溶液に精製水を加え、水層から酢酸エチルで抽出し、有機層を飽和重層水、次いで飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。無水硫酸マグネシウムを除去し、溶媒を留去し、得られた残差にジイソプロイピルエーテルを加え固化させ、化合物７ａ（２２．０ｇ、８５．３％）を得た。
¹H-NMR (DMSO-D₆)δ:8.36 (t, J = 5.8 Hz, 1H), 7.43 (d, J = 8.7 Hz, 2H), 7.32 (d, J = 8.7 Hz, 2H), 7.19 (d, J = 8.5 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H), 6.98 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 5.15 (s, 2H), 4.88 (s, 2H), 4.48 (t, J = 5.5 Hz, 1H), 3.77 (s, 3H), 3.75 (s, 3H), 3.29-3.11 (m, 8H). Synthesis of Compound I-7

Step 1 Synthesis of Compound 7a Compound 4a (27.3 g, 50.0 mmol) was dissolved in tetrahydrofuran (300 mL) and cooled to 0 ° C. To this solution was added 2,2-dimethoxyethanamine (5.78 g, 55.0 mmol) and stirred at room temperature for 1 hour. Purified water was added to this solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated multilayered water and then with saturated brine, and dried over anhydrous magnesium sulfate. Anhydrous magnesium sulfate was removed, the solvent was distilled off, and diisopropyl ether was added to the resulting residue to solidify to obtain Compound 7a (22.0 g, 85.3%).
¹ H-NMR (DMSO-D ₆ ) δ: 8.36 (t, J = 5.8 Hz, 1H), 7.43 (d, J = 8.7 Hz, 2H), 7.32 (d, J = 8.7 Hz, 2H), 7.19 ( d, J = 8.5 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H), 6.98 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 5.15 (s, 2H), 4.88 (s, 2H), 4.48 (t, J = 5.5 Hz, 1H), 3.77 (s, 3H), 3.75 (s, 3H), 3.29-3.11 (m, 8H).

Step 2 Synthesis of Compound 7b Compound 7a (10.0 g, 19.4 mmol) was dissolved in tetrahydrofuran (200 ml), 2 mol / L aqueous hydrochloric acid solution (97.0 mL, 194 mmol) was added, and the mixture was stirred at room temperature for 23 hours. Ethyl acetate and purified water were added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The obtained organic layer was washed with purified water and then saturated brine, and dried over anhydrous magnesium sulfate. Anhydrous magnesium sulfate was removed and the solvent was distilled off to obtain compound 7b (6.53 g, 71.7%).
¹ H-NMR (CDCl ₃ ) δ: 9.76 (s, 1H), 7.54 (d, J = 8.7 Hz, 1H), 7.36-7.34 (m, 4H), 7.15 (br s, 1H), 7.00-6.91 ( m, 4H), 6.84 (d, J = 8.5 Hz, 2H), 5.10 (s, 2H), 4.96 (s, 2H), 4.41 (d, J = 5.4 Hz, 2H), 3.83 (s, 3H), 3.81 (s, 3H).

Step 3 Synthesis of Compound 7c Compound 7b (1.41 g, 3.00 mmol) was suspended in tetrahydrofuran (7.00 mL), 1- (2-aminoethyl) pyrrolidine was added, and the mixture was stirred at 0 ° C. for 5 minutes. Acetic acid (0.257 mL, 4.50 mmol) and sodium triacetoxyborohydride (1,27 g, 6.00 mmol) were added to this solution, and the mixture was stirred at 0 ° C. for 15 minutes. The reaction solution was further stirred at room temperature for 90 minutes, 10 mL of a 2 mol / L aqueous sodium hydroxide solution was added, and the aqueous layer was extracted with ethyl acetate. The obtained organic layer was washed with purified water and then saturated brine, and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed, the solvent was distilled off, and the resulting residue was purified by silica gel chromatography to obtain compound 7c (973 mg, 57.1%).
¹ H-NMR (CDCl ₃ ) δ: 7.41 (d, J = 8.7 Hz, 1H), 7.35 (d, J = 8.4 Hz, 4H), 7.22 (br s, 1H), 7.00-6.90 (m, 3H) , 6.83 (d, J = 8.7 Hz, 2H), 5.07 (s, 2H), 4.94 (s, 2H), 3.83 (s, 3H), 3.80 (s, 3H), 3.75 (t, J = 6.2 Hz, 2H), 3.61-3.55 (m, 2H), 2.93-2.88 (m, 4H), 2.83-2.75 (m, 4H), 1.90-1.82 (m, 4H).

Step 4 Synthesis of Compound 7d Compound 7c (965 mg, 1.70 mmol) was suspended in tetrahydrofuran (10.0 mL), di-tert-butyl dicarbonate (0.473 mL, 2.04 mmol) was added, and the mixture was stirred at room temperature. Acetonitrile (10.0 mL) was added and the resulting solution was stirred at room temperature overnight. The reaction mixture was concentrated, and the resulting residue was purified by silica gel chromatography to obtain compound 7d (878 mg, 77.4%).
¹ H-NMR (CDCl ₃ ) δ: 7.39-7.29 (m, 5H), 6.94-6.81 (m, 5H), 5.07 (s, 2H), 4.93 (s, 2H), 3.83 (s, 3H), 3.80 (s, 3H), 3.64-3.37 (m, 6H), 2.69-2.29 (m, 6H), 1.65-1.59 (m, 4H), 1.42 (s, 9H).

Step 5 Synthesis of Compound I-7 Compound 7e (794 mg, 1.00 mmol) was dissolved in dimethylacetamide (3.00 mL), sodium iodide (300 mg, 2.00 mmol) was added, and the mixture was stirred at 15 ° C. The reaction mixture was cooled to 0 ° C., compound 5 (668 mg, 1.00 mmol) was added, and the mixture was stirred at 0 ° C. for 2 days. The reaction solution was poured into 5% brine, and the precipitated solid was collected by filtration, washed with purified water, and dried to give compound 7f.
Compound 7f was dissolved in dichloromethane (15 mL), cooled to −40 ° C., anisole (1.64 mL, 15.0 mmol), 2 mol / L aluminum chloride nitromethane solution (7.50 mL, 15.0 mmol) was added, and Stir for 1 hour. Purified water (30 mL) and diisopropyl ether (50 mL) were added to the reaction solution. Acetonitrile, 2 mol / L hydrochloric acid was added to the reaction solution to dissolve the precipitate, and then the aqueous layer was separated. The organic layer was extracted with a water / acetonitrile / dilute hydrochloric acid mixture, and HP20SS was added to the combined aqueous layer and concentrated. The concentrated suspension was subjected to HP20SS / ODS column chromatography and eluted with water-acetonitrile. The fraction containing the desired product was concentrated under reduced pressure, and the concentrated solution was lyophilized to obtain Compound I-7 as a powder. (Yield 120 mg, Yield 15%)
¹ H-NMR (DMSO-D ₆ ) δ: 8.47 (br s, 1H), 7.26 (s, 2H), 6.85-6.75 (m, 3H), 5.71 (dd, J = 4.3, 7.8 Hz, 1H), 5.32-5.27 (m, 2H), 3.98-3.94 (m, 2H), 3.41-2.71 (m, 14H), 2.12-1.93 (m, 4H), 1.45-1.38 (m, 9H).
MS (m + 1) = 809.26
Elemental analysis: C33H41ClN8O10S2 (H2O) 4.3
Calculated values: C, 44.70; H, 5.64; Cl, 4.00; N, 12.64; S, 7.23 (%)
Experimental value: C, 44.61; H, 5.56; Cl, 3.86; N, 12.89; S, 7.11 (%)

工程1 化合物８ｂの合成
化合８ａ（１２．９ｇ、３０．０ｍｍｏｌ）をジクロロメタン（１２０ｍＬ）懸濁させ０℃に冷却し、１−クロローＮ，Ｎ−２−トリメチル−１−プロペン−１−アミン（４．３７ｍＬ，３３．０ｍｍｏｌ）を加え室温で３０分間撹拌した。反応液を０℃に冷却し、グリシンメチルエステル塩酸（４．１４ｇ、３３．０ｍｍｏｌ）とトリエチルアミン（９．１５ｍＬ、６６．０ｍｍｏｌ）を加え０℃で１時間撹拌した。この反応液に精製水を加え、水層からジクロロメタンで抽出し、有機層を精製水、次いで飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。硫酸マグネシウムを除去し、溶媒を留去し、得られた残差に酢酸イソプロピルを加え固化させ、化合物８ｂ（１３．２ｇ、８７．９％）を得た。
¹H-NMR (DMSO-D₆)δ:8.71 (t, J = 5.9 Hz, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 7.21 (q, J = 8.6 Hz, 2H), 6.98 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 5.16 (s, 2H), 4.89 (s, 2H), 3.97 (d, J = 5.9 Hz, 2H), 3.77 (s, 3H), 3.75 (s, 3H), 3.67 (s, 3H). Synthesis of Compound I-8

Step 1 Compound 8b Synthesis Compound 8a (12.9 g, 30.0 mmol) was suspended in dichloromethane (120 mL), cooled to 0 ° C., and 1-chloro-N, N-2-trimethyl-1-propen-1-amine ( 4.37 mL, 33.0 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was cooled to 0 ° C., glycine methyl ester hydrochloric acid (4.14 g, 33.0 mmol) and triethylamine (9.15 mL, 66.0 mmol) were added, and the mixture was stirred at 0 ° C. for 1 hour. Purified water was added to the reaction solution, and the aqueous layer was extracted with dichloromethane. The organic layer was washed with purified water and then with saturated brine, and dried over anhydrous magnesium sulfate. Magnesium sulfate was removed, the solvent was distilled off, and the resulting residue was solidified by adding isopropyl acetate to obtain Compound 8b (13.2 g, 87.9%).
¹ H-NMR (DMSO-D ₆ ) δ: 8.71 (t, J = 5.9 Hz, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 7.21 ( q, J = 8.6 Hz, 2H), 6.98 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 5.16 (s, 2H), 4.89 (s, 2H), 3.97 ( d, J = 5.9 Hz, 2H), 3.77 (s, 3H), 3.75 (s, 3H), 3.67 (s, 3H).

Step 2 Synthesis of Compound 8c Compound 8b (4.00 g, 8.00 mmol) was suspended in tetrahydrofuran (20.0 mL) and methanol (20.0 mL), and 2 mol / L aqueous sodium hydroxide solution (12.0 mL, 24.0 mmol) was suspended. ) And stirred at room temperature for 1 hour and 15 minutes. 2 mol / L hydrochloric acid (12.0 mL, 24.0 mmol) was added to the reaction solution, and the organic solvent was distilled off. The precipitated solid was collected by filtration and washed with purified water to obtain Compound 8c (3.34 g, 6.87 mmol).
¹ H-NMR (DMSO-D ₆ ) δ: 8.57 (t, J = 5.8 Hz, 1H), 7.44 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 8.5 Hz, 2H), 7.23 ( d, J = 8.7 Hz, 1H), 7.19 (d, J = 8.7 Hz, 1H), 6.98 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H), 5.16 (s, 2H), 4.88 (s, 2H), 3.87 (d, J = 5.9 Hz, 2H), 3.77 (s, 3H), 3.75 (s, 3H).

Step 3 Synthesis of Compound 8d Compound 8c (910 mg, 1.87 mmol) was dissolved in dimethylformamide (10.0 mL), and 1-hydroxybenzotriazole (304 mg, 2.25 mmol), 1- (2-aminoethyl) pyrrolidine ( 282 mg, 2.25 mmol) and then 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (431 mg, 2.25 mmol) were added and stirred at room temperature for 3 days. The solvent was distilled off, ethyl acetate and 2 mol / L aqueous sodium hydroxide solution were added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with purified water and then saturated brine, and dried over anhydrous magnesium sulfate. Magnesium sulfate was removed, the solvent was distilled off, and isopropyl acetate was added to solidify to obtain Compound 8d (1.04 g, 95.3%).
¹ H-NMR (DMSO-D ₆ ) δ: 8.50 (t, J = 6.0 Hz, 1H), 7.67 (t, J = 5.3 Hz, 1H), 7.44 (d, J = 8.5 Hz, 2H), 7.31 ( d, J = 8.5 Hz, 2H), 7.24 (d, J = 8.5 Hz, 1H), 7.21 (d, J = 8.7 Hz, 1H), 6.98 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H), 5.16 (s, 2H), 4.88 (s, 2H), 3.80 (d, J = 6.0 Hz, 2H), 3.77 (s, 3H), 3.75 (s, 3H), 3.21 ( q, J = 6.2 Hz, 2H), 2.50-2.41 (m, 6H), 1.71-1.64 (m, 4H).

Step 4 Synthesis of Compound I-8 Using Compound 8d (582 mg, 1.00 mmol) and Compound 8e (794 mg, 1.00 mmol) in the same manner as in Step 5 of Example 7, Compound I-8 (482 mg, 58.58). 5%).
¹ H-NMR (DMSO-D ₆ ) δ: 9.54-9.12 (br m, 2H), 8.47 (t, J = 5.7 Hz, 1H), 8.19 (br s, 1H), 7.27 (s, 2H), 7.08 (d, J = 8.3 Hz, 1H), 6.77-6.70 (m, 2H), 5.68 (dd, J = 5.1, 8.6 Hz, 1H), 5.30-5.21 (m, 2H), 4.00 (q, J = 6.8 Hz, 1H), 3.91 (d, J = 13.6 Hz, 1H), 3.83-3.77 (m, 2H), 3.44-3.21 (m, 7H), 3.67-3.56 (m, 2H), 2.01-1.87 (m, 4H), 1.47-1.38 (m, 9H).
MS (m + 1) = 823.23
Elemental analysis: C33H39ClN8O11S2 (H2O) 3.7
Calculated value: C, 44.54; H, 5.26; Cl, 3.98; N, 12.59; S, 7.20 (%)
Experimental value: C, 44.57; H, 5.29; Cl, 3.80; N, 12.86; S, 7.00 (%)

工程１ 化合物９ｂの合成
化合物９ａ（１．２２ｇ、２．５０ｍｍｏｌ）を用い実施例８の工程３と同様の方法で合成し化合物９ｂを得た。
¹H-NMR (DMSO-D₆)δ:8.43 (t, J = 5.1 Hz, 1H), 7.61 (t, J = 6.1 Hz, 1H), 7.44 (d, J = 8.6 Hz, 2H), 7.31 (d, J = 8.6 Hz, 2H), 7.24-7.15 (m, 2H), 6.98 (d, J = 7.6 Hz, 2H), 6.87 (d, J = 8.3 Hz, 2H), 5.16 (s, 2H), 4.88 (s, 2H), 3.83 (d, J = 5.8 Hz, 2H), 3.77 (s, 3H), 3.75 (s, 3H), 2.88 (d, J = 6.3 Hz, 2H), 2.74-2.66 (m, 6H), 1.30-1.22 (m, 6H). Synthesis of Compound I-9

Step 1 Synthesis of Compound 9b Compound 9b was synthesized in the same manner as in Step 3 of Example 8 using Compound 9a (1.22 g, 2.50 mmol).
¹ H-NMR (DMSO-D ₆ ) δ: 8.43 (t, J = 5.1 Hz, 1H), 7.61 (t, J = 6.1 Hz, 1H), 7.44 (d, J = 8.6 Hz, 2H), 7.31 ( d, J = 8.6 Hz, 2H), 7.24-7.15 (m, 2H), 6.98 (d, J = 7.6 Hz, 2H), 6.87 (d, J = 8.3 Hz, 2H), 5.16 (s, 2H), 4.88 (s, 2H), 3.83 (d, J = 5.8 Hz, 2H), 3.77 (s, 3H), 3.75 (s, 3H), 2.88 (d, J = 6.3 Hz, 2H), 2.74-2.66 (m , 6H), 1.30-1.22 (m, 6H).

Step 2 Synthesis of Compound I-9 Compound I-9 (383 mg, 56.56.) Was prepared in the same manner as in Step 5 of Example 7, using Compound 9b (486 mg, 0.80 mmol) and Compound 9c (635 mg, 0.80 mmol). 4%).
¹ H-NMR (DMSO-D ₆ ) δ: 10.12 (br s, 1H), 9.44-9.22 (br m, 2H), 8.27 (t, J = 5.7 Hz, 1H), 7.91 (t, J = 5.9 Hz , 1H), 7.26 (s, 2H), 6.86 (d, J = 8.3 Hz, 1H), 6.79-6.70 (m, 2H), 5.68 (dd, J = 8.1, 5.1 Hz, 1H), 5.24 (d, J = 5.1 Hz, 1H), 4.98 (d, J = 13.9 Hz, 1H), 4.00 (q, J = 7.1 Hz, 1H), 3.84-3.77 (m, 3H), 3.32-3.29 (m, 6H), 3.05 (d, J = 5.8 Hz, 2H), 1.73-1.62 (m, 6H), 1.46 (d, J = 5.8 Hz, 6H), 1.42 (d, J = 7.6 Hz, 3H).
MS (m + 1) = 849.30
Elemental analysis: C35H41ClN8O11S2 (H2O) 3.1
Calculated value: C, 46.44; H, 5.26; Cl, 3.92; N, 12.38; S, 7.08 (%)
Experimental value: C, 46.41; H, 5.31; Cl, 3.89; N, 12.57; S, 7.08 (%)

工程１ 化合物１０ｂの合成
化合物１０ａ（１．２２ｇ、２．５０ｍｍｏｌ）を用い実施例８の工程３と同様の方法で合成し化合物１０ｂを得た。
¹H-NMR (DMSO-D₆)δ:8.44 (t, J = 5.7 Hz, 1H), 7.81 (t, J = 5.9 Hz, 1H), 7.44 (d, J = 8.8 Hz, 2H), 7.31 (d, J = 8.6 Hz, 2H), 7.25 (d, J = 8.6 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 6.98 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 5.16 (s, 2H), 4.88 (s, 2H), 3.82 (d, J = 5.8 Hz, 2H), 3.77 (s, 3H), 3.75 (s, 3H), 3.43 (d, J = 6.1 Hz, 2H), 2.76-2.67 (m, 2H), 2.46-2.39 (m, 2H), 2.10 (d, J = 2.3 Hz, 3H), 1.50-1.44 (m, 2H), 1.16-1.07 (m, 2H). Synthesis of Compound I-10

Step 1 Synthesis of Compound 10b Compound 10b was synthesized by the same method as in Step 3 of Example 8 using Compound 10a (1.22 g, 2.50 mmol).
¹ H-NMR (DMSO-D ₆ ) δ: 8.44 (t, J = 5.7 Hz, 1H), 7.81 (t, J = 5.9 Hz, 1H), 7.44 (d, J = 8.8 Hz, 2H), 7.31 ( d, J = 8.6 Hz, 2H), 7.25 (d, J = 8.6 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 6.98 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 5.16 (s, 2H), 4.88 (s, 2H), 3.82 (d, J = 5.8 Hz, 2H), 3.77 (s, 3H), 3.75 (s, 3H), 3.43 ( d, J = 6.1 Hz, 2H), 2.76-2.67 (m, 2H), 2.46-2.39 (m, 2H), 2.10 (d, J = 2.3 Hz, 3H), 1.50-1.44 (m, 2H), 1.16 -1.07 (m, 2H).

Step 2 Synthesis of Compound I-10 Using Compound 10b (594 mg, 1.00 mmol) and Compound 10c (794 mg, 1.00 mmol) in the same manner as in Step 5 of Example 7, Compound I-10 (573 mg, 68. 6%).
¹ H-NMR (DMSO-D ₆ ) δ: 10.08 (s, 1H), 9.62-9.30 (m, 2H), 8.33 (t, J = 5.8 Hz, 1H), 8.10 (t, J = 6.1 Hz, 1H ), 7.26 (s, 2H), 6.87 (d, J = 8.3 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.74 (s, 1H), 5.65 (dd, J = 8.0, 5.1 Hz , 1H), 5.23 (d, J = 5.1 Hz, 1H), 5.15 (d, J = 13.7 Hz, 1H), 4.05-3.93 (m, 2H), 3.82 (d, J = 5.5 Hz, 2H), 3.56 -3.23 (m, 8H), 2.05-1.88 (m, 2H), 1.75-1.62 (m, 2H), 1.46 (d, J = 6.4 Hz, 6H), 1.41 (d, J = 7.0 Hz, 3H).
MS (m + 1) = 823.23
Elemental analysis: C33H39ClN8O11S2 (H2O) 3.7
Calculated values: C, 46.54; H, 5.26; Cl, 3.98; N, 12.59; S, 7.20 (%)
Experimental value: C, 46.57; H, 5.29; Cl, 3.80; N, 12.86; S, 7.00 (%)

工程１ 化合物Ｘ１ｂの合成
化合物８ｂ（８．１５ｇ、１６．３ｍｍｏｌ）をテトラヒドロフラン（４０．０ｍＬ）とメタノール（４０．０ｍＬ）に懸濁させ、ヒドラジン１水和物（２．３８ｍＬ、４８．９ｍｍｏｌ）を加え6時間加熱還流した。反応液を室温に冷却し室温で一晩撹拌した。反応液をアセトニトリルで希釈し室温で撹拌し得られた固体をろ取し化合物Ｘ１ｂ（７．９１ｇ、１５．８ｍｍｏｌ）を得た。（９７．０％）
¹H-NMR (DMSO-D₆)δ:9.01 (s, 1H), 8.43 (t, J = 5.9 Hz, 1H), 7.43 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 8.5 Hz, 2H), 7.26 (d, J = 8.7 Hz, 1H), 7.21 (d, J = 8.7 Hz, 1H), 6.98 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H), 5.16 (s, 2H), 4.88 (s, 2H), 4.23 (s, 2H), 3.80-3.73 (m, 8H). Synthesis of 3-position side chain compound X-1

Step 1 Synthesis of Compound X1b Compound 8b (8.15 g, 16.3 mmol) was suspended in tetrahydrofuran (40.0 mL) and methanol (40.0 mL), and hydrazine monohydrate (2.38 mL, 48.9 mmol). And heated to reflux for 6 hours. The reaction was cooled to room temperature and stirred overnight at room temperature. The reaction mixture was diluted with acetonitrile and stirred at room temperature, and the resulting solid was collected by filtration to give compound X1b (7.91 g, 15.8 mmol). (97.0%)
¹ H-NMR (DMSO-D ₆ ) δ: 9.01 (s, 1H), 8.43 (t, J = 5.9 Hz, 1H), 7.43 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 8.5 Hz, 2H), 7.26 (d, J = 8.7 Hz, 1H), 7.21 (d, J = 8.7 Hz, 1H), 6.98 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H), 5.16 (s, 2H), 4.88 (s, 2H), 4.23 (s, 2H), 3.80-3.73 (m, 8H).

Step 2 Synthesis of Compound X1c Compound X1b (2.00 g, 4.00 mmol) was dissolved in dimethylacetamide (20.0 mL), cooled to 0 ° C., sodium bicarbonate (0.370 g, 4.40 mmol) and chloroacetyl chloride. (0.352 mL, 4.40 mmol) was added and stirred at 0 ° C. for 3 hours. Purified water was added to the reaction solution, and the resulting solid was collected by filtration and dried under reduced pressure to obtain Compound X1c (1.66 g, 2.89 mmol). (72.2%)
¹ H-NMR (DMSO-D ₆ ) δ: 10.33 (br s, 1H), 10.12 (br s, 1H), 8.54 (t, J = 5.8 Hz, 1H), 7.44 (d, J = 8.6 Hz, 2H ), 7.31 (d, J = 8.6 Hz, 2H), 7.25 (d, J = 8.6 Hz, 1H), 7.21 (d, J = 8.6 Hz, 1H), 6.98 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 5.16 (s, 2H), 4.88 (s, 2H), 4.13 (s, 2H), 3.90 (d, J = 6.1 Hz, 2H), 3.77 (s, 3H ), 3.75 (s, 3H).

Step 3 Synthesis of Compound X1d Compound X1c (1.46 g, 2.53 mmol) was dissolved in 1,4-dioxane (15.0 mL) and methyl carbamate-N- (triethylammoniumsulfonium) (1.81 g, 7.59 mmol). ) And stirred for 40 minutes at 100 ° C. To the reaction solution was added purified water, and the target product was extracted from the aqueous layer with ethyl acetate, and the collected organic layer was washed with purified water and then with saturated brine. Anhydrous magnesium sulfate and activated carbon were added, and after filtration, the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography, the fraction containing the desired product was concentrated, and the resulting solid was collected by filtration. Washing with isopropyl gave compound X1d (255 mg, 0.456 mmol) (18.0%).
¹ H-NMR (CDCl ₃ ) δ: 7.56 (d, J = 8.8 Hz, 1H), 7.37-7.31 (m, 4H), 7.06 (t, J = 6.3 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 6.92 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.6 Hz, 2H), 5.10 (s, 2H), 4.96 (s, 2H), 4.91 (d, J = 5.8 Hz, 2H), 4.70 (s, 2H), 3.83 (s, 3H), 3.80 (s, 3H).

Step 4 Synthesis of Compound X-1 Compound X1d (254 mg, 0.456 mmol) was dissolved in dimethylacetamide (2.50 mL), cooled to 0 ° C., potassium carbonate (69.4 mg, 0.502 mmol) and pyrrolidine (0 0.042 mL, 0.502 mmol) was added, and the mixture was stirred overnight at room temperature. Pyrrolidine (0.015 mL, 0.183 mmol) was added to the reaction solution, and the mixture was further stirred at 0 ° C. for 90 minutes. Purified water and a 2 mol / L aqueous sodium hydroxide solution were added to the reaction solution, the target product was extracted from the aqueous layer with ethyl acetate, and the resulting organic layer was washed with purified water and saturated brine. The obtained organic layer was dried over anhydrous magnesium sulfate, magnesium sulfate was filtered, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel chromatography to give compound X-1 (220 mg, 0.371 mmol). Obtained. (81%)
¹ H-NMR (CDCl ₃ ) δ: 7.54 (d, J = 8.6 Hz, 1H), 7.38-7.31 (m, 4H), 7.04 (t, J = 5.3 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 6.92 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.6 Hz, 2H), 5.09 (s, 2H), 4.96 (s, 2H), 4.88 (d, J = 5.6 Hz, 2H), 3.92 (s, 2H), 3.83 (s, 3H), 3.80 (s, 3H), 2.69-2.63 (m, 4H), 1.86-1.80 (m, 4H).

The compounds shown in Tables 1 to 10 below can also be synthesized by the same method as described above.

（結果）
試験結果を表１２に示す。表中、阻害活性の数値の単位はμｇ／ｍＬである。

(Test example)
In vitro antibacterial activity of the compound of the present invention was confirmed.
(Test method)
The minimum growth inhibitory concentration (MIC: μg / mL) was measured according to the CLSI (Clinical and Laboratory Standards Institute) method, the amount of test bacteria was 5 × 10 ⁵ cfu / mL, the test medium was cation adjusted with human Apo-transferrin added It was carried out by a micro liquid dilution method using an Isohsenshi test liquid medium.
The strains used are shown in the table below.

(result)
The test results are shown in Table 12. In the table, the unit of numerical value of the inhibitory activity is μg / mL.

  From the above results, the compound (I) of the present invention has a broad antibacterial spectrum, particularly exhibits a strong antibacterial spectrum against gram-negative bacteria, and / or is effective against multidrug-resistant bacteria. -It is shown to have high stability against lactamase-producing gram-negative bacteria.

(Formulation example 1)
An injection is prepared by powder filling the compound of the present invention.

  The compound according to the present invention is effective as an antibacterial agent having a broad antibacterial spectrum against Gram negative bacteria and Gram positive bacteria and having high stability against β-lactamase producing Gram negative bacteria. In addition, since it has good pharmacokinetics and high water solubility, it is particularly effective as an injection.

Claims (33)

Formula (I):

(Where
R ¹ is a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group;
For R ^2A and R ^2B
a) R ^2A is a hydrogen atom, substituted or unsubstituted amino, —SO ₃ H, substituted or unsubstituted aminosulfonyl, carboxy, substituted or unsubstituted lower alkyloxycarbonyl, substituted or unsubstituted carbamoyl, hydroxy, or Carbonyloxy having a substituent and R ^2B is a hydrogen atom, or
b) R ^2A and R ^2B together form a substituted or unsubstituted methylidene, or a substituted or unsubstituted hydroxyimino;
R ³ is a hydrogen atom, —OCH ₃ or —NH—CH (═O);
For R ^5A and R ^5B ,
a) R ^5A and R ^5B are each independently a hydrogen atom or lower alkyl,
b) R ^5A and R ^5B together with adjacent atoms form a substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle, or
c) R ^5A and R ^5B together form a substituted or unsubstituted methylidene;
L is _{-CH 2 -, - CH = CH} -, - CH 2 -CH = CH -, - CH = CH-CH 2 -, - S -, - CH 2 -S -, - CH = CH-S- or -CH = _CH-CH 2 -S- and and,
E is a divalent group having one or more quaternary ammonium ions that are substituted or unsubstituted;
R ¹⁰ is a hydrogen atom or the following formula (IA):

(Where
G ¹ and G ² are each independently a single bond, a substituted or unsubstituted lower alkylene, a substituted or unsubstituted lower alkenylene, or a substituted or unsubstituted lower alkynylene,
D ^{1 s} independently represent —C (═O) —, —O—C (═O) —, —C (═O) —O—, —NR ⁶ —, —NR ⁶ —C (═O ^{) -, - C (= O} ) -NR 6 -, - C (= O) -C (= O) -, - NR 6 -C (= O) -NR 6 -, - C (= O) -C (═O) —NR ⁶ —, —C (═O) —NR ⁶ —C (═O) —, —NR ⁶ —C (═O) —C (═O) —, —NR ⁶ —NR ⁶ — C (= O)-, -C (= O) -NR < ⁶ > -NR < ⁶ >-, -N = N-C (= O)-, -C (= O) -N = N-, -C = N- NR ⁶ —C (═O) —, —C═N—C (═O) —, —N═C—C (═O) —, —C═N—C (═O) —NR ⁶ —, — ^{NR 6 -C (= O) -C} (= N-OR 6) -, -C (= N-OR 6) -C (= O) -NR 6 -, -NR 6 - C ^{= N-OR 6) -,} -C (= N-OR 6) -NR 6 -, -C (= O) -C (= N-OR 6) -, -C (= N-OR 6) -C (= O) -, -O-, -S-, -S (= O) -, -S (= O) 2 -NR 6 -, -NR 6 -S (= O) 2 -, -NR 6 - CH ₂ —, —CH ₂ —NR ⁶ —, —C═N—, —N═C—, —S (═O) ₂ — or substituted or unsubstituted heterocyclic diyl;
D ² represents a single bond, —C (═O) —, —O—C (═O) —, —C (═O) —O—, —NR ⁶ —, —NR ⁶ —C (═O) —. ^{, -C (= O) -NR 6} -, - C (= O) -C (= O) -, - NR 6 -C (= O) -NR 6 -, - C (= O) -C (= O) —NR ⁶ —, —C (═O) —NR ⁶ —C (═O) —, —NR ⁶ —C (═O) —C (═O) —, —NR ⁶ —NR ⁶ —C ( = O)-, -C (= O) -NR < ⁶ > -NR < ⁶ >-, -N = NC (= O)-, -C (= O) -N = N-, -C = N-NR < ⁶ >. -C (= O) -, -C = N-C (= O) -, -N = C-C (= O) -, -C = N-C (= O) -NR 6 -, -NR 6 ^{-C (= O) -C (=} N-OR 6) -, -C (= N-OR 6) -C (= O) -NR 6 -, -NR 6 - C (= N-O ^{6) -, -C (= N} -OR 6) -NR 6 -, -C (= O) -C (= N-OR 6) -, -C (= N-OR 6) -C (= O) ^{_{-, -O-, -S-, -S (}} = O) -, -S (= O) 2 -NR 6 -, -NR 6 -S (= O) 2 -, -NR 6 -CH 2 -, —CH ₂ —NR ⁶ —, —C═N—, —N═C—, —S (═O) ₂ — or substituted or unsubstituted heterocyclic diyl;
Each R ⁶ independently represents a hydrogen atom or a substituted or unsubstituted lower alkyl;
n is an integer from 0 to 2;
B is a single bond or a 5- or 6-membered heterocyclic diyl containing at least 1 to 3 nitrogen atoms,
Ring A is a benzene ring, a fused carbocycle, a monocyclic heterocycle or a fused heterocycle;
Each R ⁴ independently represents a halogen atom, oxo, hydroxy, amino, cyano, nitro, —O—C (═O) —R ⁹ , —C (═O) —R ⁹ , carboxy, —C (═O; ) —OR ⁹ , —OR ⁹ , —NHR ⁹ —, —NR ⁹ R ⁹ , —SO ₂ R ⁹ , —SR ⁹ , —NR ⁹ —C (═O) —R ⁹ , —SH, substituted or unsubstituted Lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group; provided that the two hydroxy groups on the A ring are each Binds to adjacent carbon atoms;
Each R ⁹ is independently lower alkyl or halo lower alkyl;
k is an integer of 1 to 3. )
It is group shown by these.
However,
1) Except when R ^5A and R ^5B are hydrogen atoms, and E is a substituted or unsubstituted pyrimidinium group, and
2) When R ¹⁰ is a hydrogen atom, E is a divalent cyclic group having one or more quaternary ammonium ions and substituted by at least two hydroxy groups, and each of the two hydroxy groups is the ring Any substitutable position other than the position bonded to the adjacent carbon atom of the formula group and substituted with the hydroxy group may be further substituted. )
Or a protected form of the amino group or a pharmaceutically acceptable salt thereof when an amino group is present on the ring of the 7-position side chain. The compound according to claim 1, wherein R ^5A is a hydrogen atom, and R ^5B is lower alkyl, or a protected form of the amino group when an amino group is present on the ring of the 7-position side chain. Or a pharmaceutically acceptable salt thereof. The compound according to claim 1, wherein R ^5A and R ^5B are hydrogen atoms, an ester of carboxy, or a protected form of the amino group when an amino group is present on the ring of the 7-position side chain, or a pharmaceutical thereof Acceptable salt. R ¹⁰ represents the following formula (IA):

(Wherein each definition has the same meaning as in claim 1).
The compound according to any one of claims 1 to 3, a carboxy ester, or a protected form of the amino group when an amino group is present on the ring of the 7-position side chain or a pharmaceutically acceptable product thereof. Salt.   Ring A is a benzene ring or a 5- to 7-membered monocyclic heterocycle, the compound according to any one of claims 1 to 4, an ester of carboxy, or an amino group on the ring of the 7-position side chain A protected form of the amino group or a pharmaceutically acceptable salt thereof.   The compound according to any one of claims 1 to 5, wherein ring A is a benzene ring, a carboxy ester, or a protected form of the amino group when a cyclic amino group at the 7-position side chain is present, or a Pharmaceutically acceptable salt. R ¹⁰ is a hydrogen atom, E is a substituted or unsubstituted divalent cyclic group having one or more quaternary ammonium ions, and two hydroxy groups are bonded to adjacent carbon atoms of the cyclic group, respectively. The compound according to any one of claims 1 to 6, which may be further substituted at any substitutable position other than the position bonded and substituted with hydroxy, or the 7-position side When an amino group is present on the ring of the chain, a protected form of the amino group or a pharmaceutically acceptable salt thereof. G ¹ and ^{G 2} are each independently a single _{bond, -CH 2 -, - CH 2} -CH 2 -, - CH 2 -CH 2 -CH 2 -, - CH = CH -, - CH = CH- _{CH 2 -, - CH 2 -CH} = CH -, - CH 2 -CH (CH 3) -, - CH 2 -CH (i Pr) - or _-CH 2 _-CH (Ph) - is, according to claim 1 The compound in any one of -6, the ester body of carboxy, or the protection body in this amino group, when those amino groups exist on the ring of 7th-position side chain, or those pharmaceutically acceptable salts.   The compound according to claim 1, wherein B is a single bond, an ester of carboxy, a protected body in the amino group when an amino group is present on the ring of the 7-position side chain, or a pharmaceutical thereof Acceptable salt. D ¹ is independently —NR ⁶ —, —NR ⁶ —C (═O) —, —C (═O) —NR ⁶ —, —NR ⁶ —C (═O) —C (═O ) −, —NR ⁶ —NR ⁶ —C (═O) —, —O—, —S—, —S (═O) —, —S (═O) ₂ —NR ⁶ —, —NR ⁶ —S (═O) ₂ —, —NR ⁶ —CH ₂ —, —CH ₂ —NR ⁶ —, —C═N—, —N═C—, —S (═O) ₂ — or substituted or unsubstituted complex The compound according to any one of claims 1 to 6, 8, or 9, which is a ring diyl, an ester of carboxy, or a protected form of the amino group when an amino group is present on the ring of the 7-position side chain, or a pharmaceutical thereof Acceptable salt. D ² is a single bond, —C (═O) —, —O—C (═O) —, —C (═O) —O—, —NR ⁶ —C (═O) —, —C (═O ) —NR ⁶ —, —C (═O) —C (═O) —, —NR ⁶ —C (═O) —NR ⁶ —, —C (═O) —C (═O) —NR ⁶ — , —C (═O) —NR ⁶ —C (═O) —, —NR ⁶ —C (═O) —C (═O) —, —NR ⁶ —NR ⁶ —C (═O) —, — C (═O) —NR ⁶ —NR ⁶ —, —N═N—C (═O) —, —C (═O) —N═N—, —C═N—NR ⁶ —C (═O) -, -C = NC (= O)-, -N = C-C (= O)-, -C = NC (= O) -NR < ⁶ >-, -NR < ⁶ > -C (= O) ^{-C (= N-OR 6)} -, -C (= N-OR 6) -C (= O) -NR 6 -, -NR 6 - C (= N-OR 6) -, -C ^{= N-OR 6) -NR 6} -, -C (= O) -C (= N-OR 6) -, -C (= N-OR 6) -C (= O) -, -S (= O ) ₂ -NR ^6- , -NR ⁶ -S (= O) _2- , -C = N-, -N = C-, or substituted or unsubstituted heterocyclic diyl. 11. The compound according to any one of 10 above, an ester of carboxy, or a protected form of the amino group when a amino group is present on the ring of the 7-position side chain, or a pharmaceutically acceptable salt thereof. D ² is a single bond, —C (═O) —, —O—C (═O) —, —C (═O) —O—, —NR ⁶ —C (═O) —, —C (═O ) —NR ⁶ —, —C (═O) —C (═O) —, —C (═O) —NR ⁶ —C (═O) —, —NR ⁶ —C (═O) —C (= ^{O) -, - NR 6 -NR} 6 -C (= O) -, - N = N-C (= O) -, - C (= O) -N = N-, -C = N-NR 6 - C (= O) -, -C = N-C (= O) -, -N = C-C (= O) -, - NR 6 -C (= O) -C (= N-OR 6) - ^{, -NR 6 - C (= N} -OR 6) -, - C (= O) -C (= N-OR 6) -, -C (= N-OR 6) -C (= O) -, - _{^{S (= O) 2 -NR 6}} -, -NR 6 -S (= O) 2 -, - C = N -, - N = a C-, claims 1-6 and 8-10 Neu A compound according to any one of the above, an ester of carboxy, or a protected form of the amino group when a amino group is present on the ring of the 7-position side chain, or a pharmaceutically acceptable salt thereof. The compound in any one of Claims 1-6 and 8-12 whose k is 1, the ester body of carboxy, or the protector in this amino group when an amino group exists on the ring of the 7th-position side chain Or a pharmaceutically acceptable salt thereof. Formula (IC-1):

But the formula:

(Wherein R ^4a , R ^4b and R ^4c each independently represents a hydrogen atom, a halogen atom, hydroxy, cyano, carboxy, —C (═O) —R ⁹ , —C (═O) —OR ⁹ , -OR ^9, a substituted or unsubstituted lower alkyl or substituted or unsubstituted cycloalkyl, R ⁶ and R ⁹ are as defined in claim 1,
The wavy line means that the bond is in cis or trans configuration or a mixture thereof. )
The compound according to any one of claims 1 to 6 and 8 to 13, which is a group selected from: an ester group of carboxy, or the amino group when an amino group is present on the ring of the 7-position side chain Protected body or a pharmaceutically acceptable salt thereof. Formula (IC-1):

But the formula:

(Wherein R ⁶ is a hydrogen atom, methyl, ethyl, t-butyl, carboxymethyl, 2-carboxypropan-2-yl, or 1-carboxyethyl, and the wavy line indicates that the bond is in a cis or trans configuration. Or a mixture thereof.)
The compound according to any one of claims 1 to 6 and 8 to 14, which is a group selected from: an ester group of carboxy, or an amino group when an amino group is present on the ring of the 7-position side chain Protected body or a pharmaceutically acceptable salt thereof. E is the formula (ID):

(In the formula, a broken line indicates a bond in the ring, a bond from a cationic nitrogen atom indicates a bond with L, and the other bond indicates a bond with R ¹⁰ , provided that R ¹⁰ is cationic. When the nitrogen atom is bonded, there is no broken line, and when R ¹⁰ is not bonded with the cationic nitrogen atom, the broken line indicates a single bond between the cationic nitrogen atom and the adjacent atom, or the cation And a lower alkylene between a ring nitrogen atom and a ring atom other than an adjacent atom.)
The compound according to any one of claims 1 to 15, which is a substituted or unsubstituted, saturated or unsaturated, monocyclic or condensed cyclic group having at least one quaternary ammonium ion represented by: An ester of carboxy, or a protected form of the amino group when an amino group is present on the ring of the 7-position side chain, or a pharmaceutically acceptable salt thereof. E is the formula (IE):

(In the formula, a bond from a cationic nitrogen atom represents a bond to L, the other bond represents a bond to R ^10, and R ^x represents a substituted or unsubstituted lower alkyl.)
The compound according to any one of claims 1 to 15, which is a substituted or unsubstituted, saturated or unsaturated, monocyclic or condensed cyclic group having at least one quaternary ammonium ion represented by: An ester of carboxy, or a protected form of the amino group when an amino group is present on the ring of the 7-position side chain, or a pharmaceutically acceptable salt thereof. L is _{-S -, - CH 2 -S -} , - CH = CH-S- or -CH = _CH-CH 2 -S- and and; E is substituted or unsubstituted pyridinium group, or a substituted or unsubstituted fused The compound according to any one of claims 1 to 17, which is a cyclic pyridinium group, an ester of carboxy, or a protected form of the amino group when an amino group is present on the ring of the 7-position side chain, or those Pharmaceutically acceptable salts of E is the formula:

(In the formula, the bond from the quaternary nitrogen atom represents a bond with L, the other bond represents a bond with R ¹⁰ ; p is an integer of 1 to 3, and n is independently 1 or 2 and R ^x is a substituted or unsubstituted lower alkyl.)
The compound according to any one of claims 1 to 18, which is a group which may further have a substituent on the ring, or an ester of carboxy, or an amino group on the 7-position side chain ring A protected form of the amino group when a group is present, or a pharmaceutically acceptable salt thereof. E represents the formulas (1) to (7), (10) to (12), (14), (25) to (29), (31), (41) to (44), (47), (50) , (52), (53), (64) and the compound according to any one of claims 1 to 18, which is selected from the group consisting of (73), or a ring on the 7-position side chain When an amino group is present in the amino group, a protected form of the amino group or a pharmaceutically acceptable salt thereof. Formula (I-H-1):

For the group represented by
G ¹ is a single bond, —CH ₂ — or —CH ₂ —CH ₂ —;
D ¹ is —NR ⁶ —, —NR ⁶ —C (═O) —, —O—, —S—, —S (═O) —, or the formula:

Is;
k is 1,
G ² is —CH ₂ — or —CH ₂ —CH ₂ —,
B is a single bond,
The compound according to any one of claims 1 to 6 and 14 to 20, wherein D ² is -NR ⁶ -C (= O)-, an amino group on the ring of the 7-position side chain, or an ester of carboxy A protected form of the amino group, if present, or a pharmaceutically acceptable salt thereof. Formula (I-H-1):

But the formula:

(In the formula, the left bond represents a bond with E, and the right bond represents a bond with ring A.)
21. The compound according to any one of claims 1 to 6 and 14 to 20, which is a group selected from: a carboxyl ester, or an amino group in the case where an amino group is present on the ring of the 7-position side chain Protected body or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 22, wherein R ³ is a hydrogen atom or -OCH ₃ , an ester of carboxy, or the amino group when an amino group is present on the ring of the 7-position side chain Protected body or a pharmaceutically acceptable salt thereof. R ¹ is represented by the formula:

(In the formula, X is N, C (-H) or C (-Cl).)
The compound according to any one of claims 1 to 23, an ester of carboxy, or a protected form of the amino group when an amino group is present on the ring of the 7-position side chain, or a pharmaceutically acceptable product thereof. Salt. The compound according to claim 24, wherein X is C (-H) or C (-Cl), protection of the amino group when an amino group is present on the ring of the carboxy side chain or the 7-position side chain The body or a pharmaceutically acceptable salt thereof. Substituted methylidene, wherein R ^2A and R ^2B together are shown below:

Or substituted hydroxyimino as shown below:

(In the formula, R ⁹ is substituted or unsubstituted lower alkyl.)
The compound according to any one of claims 1 to 25, an ester of carboxy, or a protected form of the amino group when an amino group is present on the ring of the 7-position side chain, or a pharmaceutically acceptable product thereof Salt. The substituted hydroxyimino group (IF), wherein R ^2A and R ^2B together are shown below:

Wherein R ⁷ and R ⁸ are each independently a hydrogen atom, a halogen atom, hydroxy, carboxy, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic ring Or R ⁷ and R ⁸ may be taken together with adjacent atoms to form a substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle; Q is a single bond, substituted or unsubstituted A carbocyclic ring or a substituted or unsubstituted heterocyclic ring; m represents an integer of 0 to 3.)
The compound according to any one of claims 1 to 26, an ester of carboxy, or a protected form of the amino group when an amino group is present on the ring of the 7-position side chain, or a pharmaceutically acceptable product thereof Salt. Formula (IG-1):

(In the formula, each symbol is as defined above.)
The compound according to any one of claims 1 to 6 and 8-27, a carboxy ester, or a protected product of the amino group when an amino group is present on the ring of the 7-position side chain, or Pharmaceutically acceptable salts of X is C (—H), C (—Cl) or N;
R ⁷ and R ⁸ are each independently a hydrogen atom or substituted or unsubstituted lower alkyl;
R ³ is a hydrogen atom;
m is 0 or 1;
Q is a single bond;
R ^5A and R ^5B are each independently a hydrogen atom or methyl;
L is —CH ₂ —;
E is the formula:

(In the formula, R ^x is lower alkyl, and p is an integer of 1 to 3.)
A group selected from:
G ¹ and G ² are each independently a single bond or lower alkylene;
B is a single bond;
D ¹ is —NR ⁶ —, —NR ⁶ —C (═O) —, —C (═O) —NR ⁶ —, —O—, —S—, —S (═O) —, —S ( _{^{= O) 2 -NR 6 -,}} -NR 6 -S (= O) 2 -, - S (= O) 2 - or a substituted or unsubstituted 5-membered aromatic heterocyclic diyl;
D ² is a single bond, —C (═O) —, —NR ⁶ —C (═O) —, —C (═O) —C (═O) —— NR ⁶ —C (═O) —C (═O) —, —NR ⁶ —NR ⁶ —C (═O) —, —C═N—C (═O) —, —N═C—C (═O) —, —NR ⁶ —C ( ═O) —C (═N—OR ^6a ) — or substituted or unsubstituted 5-membered aromatic heterocyclic diyl;
R ⁶ is a hydrogen atom or lower alkyl;
R ^6a is a hydrogen atom, methyl, carboxymethyl or 2-carboxypropan-2-yl;
Formula (1-B-2):

But the formula:

(Wherein R ^4a , R ^4b and R ^4c are each independently a hydrogen atom, a halogen atom, lower alkyl or lower cycloalkyl).
The compound according to claim 28, an ester form of carboxy, or a protected form of the amino group when a 7-position side chain ring is present, or a pharmaceutically acceptable salt thereof. Formula (II):

(Wherein R ^5C and R ^5D are
a) R ^5C and R ^5D are each independently a hydrogen atom or lower alkyl, and R ^5C and R ^5D are not simultaneously a hydrogen atom,
b) R ^5C and R ^5D together with the adjacent atoms form a substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle, or
c) R ^5C and R ^d together form a substituted or unsubstituted methylidene;
D ³ is a substituted or unsubstituted heterocyclic diyl;
Other symbols are as defined above. )
, An ester of carboxy, or a protected form of the amino group in the presence of an amino group on the ring of the 7-position side chain, or a pharmaceutically acceptable salt thereof. Formula (II-A)

For the group represented by
X is C (—H), C (—Cl) or N;
R ⁷ and R ⁸ are each independently a hydrogen atom or substituted or unsubstituted lower alkyl;
R ³ is a hydrogen atom;
m is 0 or 1;
Q is a single bond;
R ^5C is a hydrogen atom;
R ^5D is lower alkyl;
L is —CH ₂ —;
E is the formula:

(In the formula, R ^x is lower alkyl, and p is an integer of 1 to 3.)
A group selected from:
G ² is a single bond or lower alkylene;
B is a single bond;
D ³ is a substituted or unsubstituted 5-membered aromatic heterocyclic diyl;
Formula (1-B-2):

But the formula:

(Wherein R ^4a , R ^4b and R ^4c are each independently a hydrogen atom, a halogen atom, lower alkyl or lower cycloalkyl), a carboxy ester, or A protected substance or a pharmaceutically acceptable salt thereof in the presence of an amino group on the ring of the 7-position side chain. The compound in any one of Claims 1-31, the ester body of carboxy, or the protected body in this amino group in case the amino group on the ring of the 7-position side chain exists, or those pharmaceutically acceptable salts. A pharmaceutical composition containing. The pharmaceutical composition according to claim 32, which has an antibacterial action.