JP2005104851A - New 2-methylenethio type carbapenem derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a new carbapenem derivative useful as a therapeutic agent for various kinds of bacterial infectious diseases, having a strong antibacterial activity against Streptococcus pneumoniae including PRSP (penicillin-resistant-Streptococcus pneumoniae), influenza bacteria including BLNAR (β-lactamase nonproducing ampicillin-resistant Haemophilus influenzae bacteria) and β-lactamase producing bacteria which become clinically serious problems these days. <P>SOLUTION: The new carbapenem derivative having a substituted or an unsubstituted pyrimidine ring through a methylenethio group at the 2-position on the carbapenem ring represented by formula (I) is provided. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a carbapenem compound having excellent antibacterial activity and a broad spectrum, and more particularly to a novel carbapenem derivative having a substituted or unsubstituted pyrimidylthiomethyl group at the 2-position on the carbapenem ring.

Carbapenem derivatives have a strong antibacterial activity and a broad antibacterial spectrum, and therefore are actively studied as highly useful β-lactam agents, and imipenem, panipenem, meropenem, biapenem, etc. are already used in clinical settings. ing.
Furthermore, a group of compounds using various bonding modes at the 2-position of the carbapenem ring has been studied.In particular, as represented by panipenem, meropenem, and biapenem, a heterocyclic ring is formed via the sulfur atom at the 2-position of the carbapenem ring. The research of the compound group which has is made | formed centeringly (for example, refer nonpatent literature 1).
On the other hand, a derivative in which a heterocycle (heterocycle) is bonded from the 2-position of the carbapenem ring via a methylenethio group has been studied conventionally, but a compound having sufficient antibacterial activity as clinically required can be obtained. Not.
Various heterocycles are exemplified and disclosed for the compound group of the heterocycle via the methylenethio group, but there is no disclosure of specific antibacterial activity, and particularly with respect to the pyridyl group of the present invention, the implementation and antibacterial properties are not disclosed. There is no report about force (refer patent documents 1-4).
JP 61-151192 A JP-A-1-93586 JP-A-8-59964 JP-T-2002-517394 Expert Opinion on Therapeutic Patents, (UK), 2001, 11 (8), p1267

  Methicillin-resistant Staphylococcus aureus (hereinafter abbreviated as MRSA), vancomycin-resistant enterococci (hereinafter abbreviated as VRE), penicillin-resistant Streptococcus pneumoniae (hereinafter abbreviated as PRSP), and β-lactamase non-producing ampicillin, which have become major clinical problems today Resistant Haemophilus influenzae (hereinafter abbreviated as BLNAR), β-lactamase producing bacteria, and resistant Pseudomonas aeruginosa are not necessarily sufficient antibacterial activity, and there is a demand for drugs effective against these infection-causing bacteria. .

  In the present invention, among these problems, an object is to provide a carbapenem derivative having strong antibacterial activity against pneumococci including PRSP, Haemophilus influenzae including BLNAR, and β-lactamase producing bacteria.

  The present inventors have found that the novel carbapenem derivative represented by the general formula (I) has a broad antibacterial spectrum and strong antibacterial activity against Gram-positive and Gram-negative bacteria, and PRSP, Haemophilus influenzae It was also found that it exhibits strong antibacterial activity against β-lactamase-producing bacteria, and the present invention has been completed.

（Ｉ）
［上記式中、
Ｒ^１は水素原子またはメチル基を示し、
Ｒ^２、Ｒ^３、Ｒ^４及びＲ^５は、いずれか一つはカルバペネム環上の２位にメチレンを介して繋がる硫黄原子と結合し、
残りの３つは同一でも異なっていても良く、それぞれ
水素原子、
ハロゲン原子、
ホルミル基、
ニトリル基、
ニトロ基、
アミノ基、
置換されたアミノ基、
低級アルキル基、
置換された低級アルキル基、
水酸基、
低級アルコキシ基、
置換された低級アルコキシ基、
カルバモイル基、
置換されたアミノカルボニル基、
低級アルキルカルボニル基、
置換された低級アルキルカルボニル基、
低級アルコキシカルボニル基、
置換された低級アルコキシカルボニル基、
アリールカルボニル基、
置換されたアリールカルボニル基、
ヘテロアリールカルボニル基、
置換されたヘテロアリールカルボニル基、
カルボキシル基、
アリール基、
置換されたアリール基、
ヘテロアリール基、
置換されたヘテロアリール基、
低級アルキルチオ基、または
低級アルキルスルホニル基、
を示し、
Ｒ^６は、水素原子、または生体内で加水分解されうる基
を示す。］
（２）Ｒ^２、Ｒ^３、Ｒ^４及びＲ^５は、いずれか一つはカルバペネム環上の２位にメチレンを介して繋がる硫黄原子と結合し、
残りの３つは同一でも異なっていても良く、それぞれ
水素原子、
ハロゲン原子、
ホルミル基、
ニトリル基、
ニトロ基、
アミノ基、
置換されたアミノ基、
低級アルキル基、
置換された低級アルキル基、
水酸基、
低級アルコキシ基、
置換された低級アルコキシ基、
カルバモイル基、
置換されたアミノカルボニル基、
低級アルキルカルボニル基、
置換された低級アルキルカルボニル基、
低級アルコキシカルボニル基、
置換された低級アルコキシカルボニル基、
低級アルキルチオ基、または
低級アルキルスルホニル基、
を示す、（１）記載の化合物またはその薬学上許容される塩、
（３）Ｒ^２、Ｒ^３、Ｒ^４及びＲ^５は、いずれか一つはカルバペネム環上の２位にメチレンを介して繋がる硫黄原子と結合し、
残りの３つは同一でも異なっていても良く、それぞれ
水素原子、
アミノ基、
置換されたアミノ基、
水酸基、
低級アルコキシ基、または
置換された低級アルコキシ基、
を示す、（１）に記載の化合物またはその薬学上許容される塩、
（４）Ｒ^２、Ｒ^３、Ｒ^４及びＲ^５は、いずれか一つはカルバペネム環上の２位にメチレンを介して繋がる硫黄原子と結合し、
残りの３つは同一でも異なっていても良く、それぞれ
水素原子、
アミノ基、
アミノメチルカルボニルアミノ基、
水酸基、
メトキシ基、または
カルバモイルメトキシ基、
を示す、（１）〜（３）のいずれか一項に記載の化合物またはその薬学上許容される塩、
（５）Ｒ^２がカルバペネム環上の２位にメチレンを介して繋がる硫黄原子と結合する、（１）〜（４）に記載の化合物またはその薬学上許容される塩、
（６）Ｒ^３またはＲ^５がカルバペネム環上の２位にメチレンを介して繋がる硫黄原子と結合する、（１）〜（４）に記載の化合物またはその薬学上許容される塩、
（７）Ｒ^４がカルバペネム環上の２位にメチレンを介して繋がる硫黄原子と結合する、（１）〜（４）に記載の化合物またはその薬学上許容される塩、
（８）Ｒ^２がアミノ基である（６）記載の化合物またはその薬学上許容される塩、
（９）Ｒ^２が水酸基である（６）記載の化合物またはその薬学上許容される塩、
（１０）Ｒ^２がメトキシ基である（６）記載の化合物またはその薬学上許容される塩、
（１１）Ｒ^２及びＲ^４が水素原子であり、Ｒ^３または、Ｒ^５のいずれか一方がカルバペネム環上の２位にメチレンを介して繋がる硫黄原子と結合し、もう一方が水素原子である、（６）記載の化合物またはその薬学上許容される塩、
（１２）Ｒ^２がカルバペネム環上の２位にメチレンを介して繋がる硫黄原子と結合し、Ｒ^３、Ｒ^４、及びＲ^５が水素原子である（５）に記載の化合物またはその薬学上許容される塩、
（１３）Ｒ^１がメチル基である（１）〜（１２）のいずれか一項記載の化合物、
（１４）Ｒ^６が生体内で加水分解されうる基である（１）〜（１３）のいずれか一項記載の化合物、
（１５）（１）〜（１４）のいずれか一項に記載の化合物を含有する医薬組成物、
（１６）（１）〜（１４）のいずれか一項に記載の化合物と薬学上許容される担体とを含んでなる医薬組成物、
（１７）抗菌剤として用いられる、（１）〜（１6）のいずれか一項に記載の医薬組成物、に関する。 That is, the present invention
(1) A compound of general formula (I) or a pharmaceutically acceptable salt thereof,

(I)
[In the above formula,
R ¹ represents a hydrogen atom or a methyl group,
Any one of R ² , R ³ , R ⁴ and R ⁵ is bonded to the sulfur atom linked to the 2-position on the carbapenem ring via methylene;
The remaining three may be the same or different, each with a hydrogen atom,
A halogen atom,
Formyl group,
Nitrile group,
Nitro group,
An amino group,
A substituted amino group,
A lower alkyl group,
A substituted lower alkyl group,
Hydroxyl group,
A lower alkoxy group,
A substituted lower alkoxy group,
A carbamoyl group,
A substituted aminocarbonyl group,
A lower alkylcarbonyl group,
A substituted lower alkylcarbonyl group,
A lower alkoxycarbonyl group,
A substituted lower alkoxycarbonyl group,
An arylcarbonyl group,
A substituted arylcarbonyl group,
A heteroarylcarbonyl group,
A substituted heteroarylcarbonyl group,
Carboxyl group,
An aryl group,
A substituted aryl group,
A heteroaryl group,
A substituted heteroaryl group,
A lower alkylthio group, or a lower alkylsulfonyl group,
Indicate
R ⁶ represents a hydrogen atom or a group that can be hydrolyzed in vivo. ]
(2) any one of R ² , R ³ , R ⁴ and R ⁵ is bonded to a sulfur atom linked to the 2-position on the carbapenem ring via methylene;
The remaining three may be the same or different, each with a hydrogen atom,
A halogen atom,
Formyl group,
Nitrile group,
Nitro group,
An amino group,
A substituted amino group,
A lower alkyl group,
A substituted lower alkyl group,
Hydroxyl group,
A lower alkoxy group,
A substituted lower alkoxy group,
A carbamoyl group,
A substituted aminocarbonyl group,
A lower alkylcarbonyl group,
A substituted lower alkylcarbonyl group,
A lower alkoxycarbonyl group,
A substituted lower alkoxycarbonyl group,
A lower alkylthio group, or a lower alkylsulfonyl group,
The compound according to (1) or a pharmaceutically acceptable salt thereof,
(3) any one of R ² , R ³ , R ⁴ and R ⁵ is bonded to the sulfur atom linked to the 2-position on the carbapenem ring via methylene;
The remaining three may be the same or different, each with a hydrogen atom,
An amino group,
A substituted amino group,
Hydroxyl group,
A lower alkoxy group or a substituted lower alkoxy group,
Or a pharmaceutically acceptable salt thereof according to (1),
(4) any one of R ² , R ³ , R ⁴ and R ⁵ is bonded to a sulfur atom linked to the 2-position on the carbapenem ring via methylene;
The remaining three may be the same or different, each with a hydrogen atom,
An amino group,
An aminomethylcarbonylamino group,
Hydroxyl group,
A methoxy group or a carbamoylmethoxy group,
The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (3),
(5) The compound or a pharmaceutically acceptable salt thereof according to (1) to (4), wherein R ² is bonded to a sulfur atom linked to the 2-position on the carbapenem ring via methylene,
(6) The compound or a pharmaceutically acceptable salt thereof according to (1) to (4), wherein R ³ or R ⁵ is bonded to the sulfur atom linked to the 2-position on the carbapenem ring via methylene,
(7) The compound according to (1) to (4) or a pharmaceutically acceptable salt thereof, wherein R ⁴ is bonded to a sulfur atom linked to the 2-position on the carbapenem ring via methylene.
(8) The compound according to (6) or a pharmaceutically acceptable salt thereof, wherein R ² is an amino group,
(9) The compound according to (6) or a pharmaceutically acceptable salt thereof, wherein R ² is a hydroxyl group,
(10) The compound according to (6) or a pharmaceutically acceptable salt thereof, wherein R ² is a methoxy group,
(11) R ² and R ⁴ are a hydrogen atom, and either R ³ or R ⁵ is bonded to a sulfur atom linked to the 2-position on the carbapenem ring via methylene, and the other is a hydrogen atom , The compound according to (6) or a pharmaceutically acceptable salt thereof,
(12) The compound according to (5) or a pharmaceutically acceptable salt thereof, wherein R ² is bonded to a sulfur atom linked to the 2-position on the carbapenem ring via methylene, and R ³ , R ⁴ , and R ⁵ are hydrogen atoms. Salt,
(13) The compound according to any one of (1) to (12), wherein R ¹ is a methyl group,
(14) The compound according to any one of (1) to (13), wherein R ⁶ is a group that can be hydrolyzed in vivo.
(15) A pharmaceutical composition comprising the compound according to any one of (1) to (14),
(16) A pharmaceutical composition comprising the compound according to any one of (1) to (14) and a pharmaceutically acceptable carrier,
(17) The pharmaceutical composition according to any one of (1) to (16), which is used as an antibacterial agent.

Definitions In this specification, the term “lower alkyl group” as a group or part of a group means a linear or branched alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.
Examples of lower alkyl as a group or part of a group include methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, etc. Can be mentioned.
Examples of “lower alkoxy” as a group or part of a group include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentyloxy, neopentyl Examples include oxy, i-pentyloxy, t-pentyloxy, n-hexyloxy, i-hexyloxy and the like.
In the present specification, the “lower cycloalkyl group” as a group or a part of the group means a monocyclic alkyl group having 3 to 6 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. .
In the present specification, “halogen atom” refers to each atom of fluorine, chlorine, bromine and iodine.
In this specification, the term “aryl group” as a group or part of a group means a phenyl group or a naphthyl group.
In the present specification, the term “heteroaryl group” as a group or part of a group is the same or different and has one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Alternatively, it means a 6-membered aromatic heterocyclic ring. Preferably, it represents furan, pyrrole, imidazole, thiazole, triazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine or the like.

Compound R ¹ preferably represents a hydrogen atom or a methyl group.
Any one of R ² , R ³ , R ⁴ and R ⁵ is bonded to the sulfur atom linked to the 2-position on the carbapenem ring via methylene, and the remaining three may be the same or different; Hydrogen atom, halogen atom, formyl group, nitrile group, nitro group, amino group, substituted amino group, lower alkyl group, substituted lower alkyl group, hydroxyl group, lower alkoxy group, substituted lower alkoxy group, carbamoyl group Substituted aminocarbonyl group, lower alkylcarbonyl group, substituted lower alkylcarbonyl group, lower alkoxycarbonyl group, substituted lower alkoxycarbonyl group, arylcarbonyl group, substituted arylcarbonyl group, heteroarylcarbonyl group, Substituted heteroarylcarbonyl group, carboxyl group, aryl group, substituted Aryl group, a heteroaryl group, a substituted heteroaryl group, a lower alkylthio group or a lower alkylsulfonyl group.
In the “substituted amino group, substituted aminocarbonyl group”, the substituent of the amino group is a lower alkyl group, a lower alkoxyalkyl group, a lower alkylcarbonyl group, a lower alkoxycarbonyl group, a formyl group, an aminocarbonyl group, an amino group. A sulfonyl group, a lower alkylcarbamoyl group, a hydroxy lower alkyl group, a hydroxy lower alkylcarbonyl group, an amino lower alkyl group, an amino lower alkylcarbonyl group, an aryl group, or a heteroaryl group is represented.
Substitution of lower alkyl group and lower alkoxy group in “substituted lower alkyl group, substituted lower alkoxy group, substituted lower alkylcarbonyl group, substituted lower alkoxycarbonyl group, substituted lower alkoxyaminocarbonyl group” The group represents a hydroxyl group, a lower alkoxy group, an amino group, a carbamoyl group, an aryl group, a heteroaryl group, or the like.
In the “substituted aryl group, substituted arylcarbonyl group, substituted heteroaryl group, substituted heteroarylcarbonyl group”, the aryl and heteroaryl substituents are a hydroxyl group, an amino group, a lower alkyl group, Or represents a lower alkoxy group or the like.

Preferred groups for R ² , R ³ , R ⁴ , and R ⁵ are hydrogen atom, halogen atom, formyl group, nitrile group, lower alkyl group, substituted lower alkyl group, hydroxyl group, lower alkoxy group, substituted Lower alkoxy group, amino group, formylamino group, lower alkylcarbonylamino group, substituted lower alkylcarbonylamino group, lower alkoxycarbonylamino group, aminocarbonylamino group, aminosulfonylamino group, carbamoyl group, lower alkylaminocarbonyl group Substituted lower alkylaminocarbonyl group, arylaminocarbonyl group, lower alkylcarbonyl group, substituted lower alkylcarbonyl group, lower alkoxycarbonyl group, substituted lower alkoxycarbonyl group, heteroarylcarbonyl group, substituted Hetero arylcarbonyl group, a carboxyl group, a lower alkylthio group, and lower alkylsulfonyl groups.
More preferred are a hydrogen atom, a hydroxyl group, a methoxy group, a carbamoylmethoxy group, an amino group, an aminomethylcarbonylamino group, and the like.

When R ⁶ is a “group capable of being hydrolyzed in vivo”, the group is preferably an ester residue, and examples thereof include a lower alkylcarbonyloxy lower alkyl group, a lower cycloalkylcarbonyloxy lower alkyl group, Lower cycloalkylmethylcarbonyloxy lower alkyl group, lower alkenylcarbonyloxy lower alkyl group, arylcarbonyloxy lower alkyl group, tetrahydrofuranylcarbonyloxymethyl group, lower alkoxy lower alkyl group, lower alkoxy lower alkoxy lower alkyl group, arylmethyloxy lower Alkyl group, arylmethyloxy lower alkoxy lower alkyl group, lower alkyloxycarbonyloxy lower alkyl group, lower cycloalkyloxycarbonyloxy lower alkyl group, lower cycloalkyl Methoxycarbonyloxy lower alkyl group, aryloxycarbonyloxy lower alkyl group, 3-phthalidyl group which may have a substituent on the aromatic ring, 2- (3-phthalidylidene which may have a substituent on the aromatic ring ) Commonly used ones such as ethyl group, 2-oxotetrahydrofuran-5-yl group, 2-oxo-5-lower alkyl-1,3-dioxolen-4-ylmethyl group and the like can be mentioned.

  More preferably, a pivaloyloxymethyl group, 1- (pivaloyloxy) ethyl group, isobutyryloxymethyl group, 1- (isobutyryloxy) ethyl group, acetoxymethyl group, 1- (acetoxy) ethyl group, 1-methylcyclohexane-1-yl) carbonyloxymethyl group, 1- (cyclohexyloxycarbonyloxy) ethyl group, 1-[(cyclohexylmethoxy) carbonyloxy] ethyl group, 1- (ethoxycarbonyloxy) ethyl group, cyclohexyloxy Carbonyloxymethyl group, 1- (cyclohexyloxycarbonyloxy) ethyl group, 1-[(2-methylcyclohexane-1-yl) oxycarbonyloxy] ethyl group, cyclopentyloxycarbonyloxymethyl group, 1- (isopropyloxycarboni) Oxy) ethyl group, (1R, 2S, 5R)-(l) -menthyloxycarbonyloxymethyl group, (1S, 2R, 5S)-(d) -menthyloxycarbonyloxymethyl group, 1- (phenyloxycarbonyloxy) ) Ethyl group, phenyloxycarbonyloxymethyl group, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl group, 3-phthalidyl group, (Z) -2- (3-phthalidylidene) ethyl Groups and the like.

The salt of the general formula (I) is a pharmaceutically acceptable salt, for example, an inorganic salt such as lithium, sodium, potassium, calcium, magnesium, or an organic base such as ammonium salt, triethylamine, diisopropylethylamine. And salt.
Or a salt with a mineral acid such as hydrochloric acid, sulfuric acid, phosphoric acid or nitric acid, or a salt with an organic acid such as acetic acid, carbonic acid, citric acid, malic acid, oxalic acid or methanesulfonic acid. A sodium salt, potassium salt or hydrochloride is preferred.

Next, specific examples of the carbapenem derivative of the general formula (I) according to the present invention are illustrated, but the present invention is not limited thereto.
1. (1S, 5R, 6S) -2- (2-Aminopyrimidin-4-yl) thiomethyl-6-((1R) -1-hydroxyethyl) -1-methyl-1-carbapen-2-em-3-carvone Sodium acid 2. (1S, 5R, 6S) -2- (2-Aminopyrimidin-4-yl) thiomethyl-6-((1R) -1-hydroxyethyl) -1-methyl-1-carbapen-2-em-3-carvone 2. Pivaloyloxymethyl acid (1S, 5R, 6S) -2- (2-Aminopyrimidin-4-yl) thiomethyl-6-((1R) -1-hydroxyethyl) -1-methyl-1-carbapen-2-em-3-carvone Acid 1- (cyclohexyloxycarbonyloxy) ethyl (mixture of diastereomers)
4). (1S, 5R, 6S) -6-((1R) -1-hydroxyethyl) -2- (2-hydroxypyrimidin-4-yl) thiomethyl-1-methyl-1-carbapene-2-em-3-carvone Sodium acid 5. (1S, 5R, 6S) -6-((1R) -1-hydroxyethyl) -2- (2-hydroxypyrimidin-4-yl) thiomethyl-1-methyl-1-carbapene-2-em-3-carvone 5. Pivaloyloxymethyl acid (1S, 5R, 6S) -2- (2-carbamoylmethoxypyrimidin-4-yl) thiomethyl-6-((1R) -1-hydroxyethyl) -1-methyl-1-carbapen-2-em-3- 6. Sodium carboxylate (1S, 5R, 6S) -6-((1R) -1-Hydroxyethyl) -2- (2-methoxypyrimidin-4-yl) thiomethyl-1-methyl-1-carbapene-2-em-3-carbon Sodium acid 8. (1S, 5R, 6S) -2- (2,6-Diaminopyrimidin-4-yl) thiomethyl-6-((1R) -1-hydroxyethyl) -1-methyl-1-carbapen-2-em-3 -Sodium carboxylate (1S, 5R, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2- (pyrimidin-4-yl) thiomethyl-1-carbapen-2-em-3-carboxylate 10 . (1S, 5R, 6S) -2- (2-Aminoacetylaminopyrimidin-4-yl) thiomethyl-6-((1R) -1-hydroxyethyl) -1-methyl-1-carbapen-2-em-3 -Sodium carboxylate (1S, 5R, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2- (pyrimidin-2-yl) thiomethyl-1-carbapene-2-em-3-carboxylate

The carbapenem derivative of the general formula (I) of the present invention has a strong antibacterial activity and a broad antibacterial spectrum against gram positive bacteria and gram negative bacteria. In particular, it has strong antibacterial activity against various pathogenic bacteria including pneumococci including PRSP, influenza bacteria including BLNAR, and β-lactamase producing bacteria.
Of the general formula (I) according to the present invention, the carbapenem derivative of the compound (I) in which R ⁶ is a group that can be hydrolyzed in vivo exhibits oral absorption and is deesterified by metabolism in vivo. Since the active body having the antibacterial activity (general formula (I ′)) is produced, the general formula (I) of the present invention is useful not only as an injection but also as an ester. Furthermore, the carbapenem derivative of the present invention has low toxicity and high safety.

［上記スキーム中で、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４及びＲ^５は一般式（Ｉ）で定義したものと同じ意味を表し、Ｒ^７は、水素原子またはヒドロキシル保護基（例えば、ｔ−ブチルジメチルシリル基、トリメチルシリル基、トリエチルシリル基、４−ニトロベンジルオキシカルボニル基、４−メトキシベンジルオキシカルボニル基、アリルオキシカルボニル基等）を表し、Ｒ^８は、カルボキシル保護基（例えば、４−ニトロベンジル基、４−メトキシベンジル基、ジフェニルメチル基、ｔ−ブチルジメチルシリル基、アリル基等）を表す。
Ｒ^９、Ｒ^１０、Ｒ^１１及びＲ^１２は、Ｒ^２、Ｒ^３、Ｒ^４及びＲ^５と同一またはＲ^２、Ｒ^３、Ｒ^４及びＲ^５に含まれる官能基（例えば水酸基、アミノ基、カルボキシル基など）が通常の保護基によって保護されたものを表す（ここで通常の保護基とは、Protective Groups in Organic Synthesis(Theodora W. Greene, Peter G. M. Wuts著、John Wiley &Sons, Inc. 出版)に記載のものを示す。）。ただし、一般式（IV）においてＲ^９、Ｒ^１０、Ｒ^１１及びＲ^１２のいずれか1つは、チオール基（−ＳＨ基)を表し、一般式（V）においてのＲ^９、Ｒ^１０、Ｒ^１１及びＲ^１２のいずれか1つ、および、一般式（I’）においてのＲ^２、Ｒ^３、Ｒ^４及びＲ^５のいずれか1つはカルバペネム環上の2位にメチレンを介してつながる硫黄原子と結合している。
Ｒ^１３は水素原子、またはカリウム、ナトリウムなどの金属イオンを表し、Ｗは脱離基を表し、好ましくは、ハロゲン原子、ジフェニルホスホリルオキシ基、ｐ−トルエンスルホニルオキシ基、メタンスルホニルオキシ基、トリフルオロメタンスルホニルオキシ基等を表す。］ Of the general formula (I) according to the present invention, the compound in which R ⁶ is a hydrogen atom, or a salt (I ′) thereof can be preferably produced according to the following scheme.

[In the above scheme, R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meaning as defined in general formula (I), and R ⁷ represents a hydrogen atom or a hydroxyl protecting group (for example, t -Butyldimethylsilyl group, trimethylsilyl group, triethylsilyl group, 4-nitrobenzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, allyloxycarbonyl group, etc.), and R ⁸ represents a carboxyl protecting group (for example, 4- Nitrobenzyl group, 4-methoxybenzyl group, diphenylmethyl group, t-butyldimethylsilyl group, allyl group, etc.).
R ^{9, R 10, R 11} and ^{R 12,} R ^2, R 3, ^{R 4} and ^{R 5} the same or ^{R 2,} R 3, functional groups contained in ^{R 4} and ^{R 5} (for example, a hydroxyl group, an amino group, Represents a group protected by a normal protecting group (where normal protective groups are Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc.)) As described in.). However, any one of ^{R 9,} R ^{10, R 11} and ^{R 12} In formula (IV), represents a thiol group (-SH group), ^R 9 in the general formula ^{(V), R 10, R} Any one of ¹¹ and R ¹² and any one of R ² , R ³ , R ⁴ and R ^{5 in} the general formula (I ′) is sulfur connected to the 2-position on the carbapenem ring via methylene It is bonded to an atom.
R ¹³ represents a hydrogen atom or a metal ion such as potassium or sodium, and W represents a leaving group, preferably a halogen atom, diphenylphosphoryloxy group, p-toluenesulfonyloxy group, methanesulfonyloxy group, trifluoromethane. Represents a sulfonyloxy group and the like. ]

  General formula (II) in the scheme in step (i) can be synthesized by a conventional method (for example, S. M. Schmitt, T. N. Saltsman, D. H. Shih and B. G. Christensen, J. Antibiotics, 41, 780 (1988)).

  The conversion from the general formula (II) to the general formula (III) in the step (i) is carried out by reacting a hydroxyl group with an activator in the presence of an acid binder according to a known method (for example, WO 96/28455). It can be done easily. Moreover, when W is an iodine atom, it can be easily carried out by reacting iodine, a trivalent phosphorus reagent and a base in the presence of hexamethylphosphoric triamide. That is, general formula (II), hexamethylphosphoric triamide and iodine are mixed with trivalent phosphorus reagent such as triphenylphosphine, tributylphosphine, trifurylphosphine, triethylamine, N, N-diisopropylethylamine, pyridine, 2, In the presence of a base such as 6-lutidine, 4-N, N-dimethylaminopyridine, an inert solvent (acetone, acetonitrile, dichloromethane, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, N, N-dimethylformamide, In toluene or the like or a mixed solvent thereof) at a temperature of −80 ° C. to 50 ° C. for 10 minutes to 24 hours. After the reaction, the general formula (III) can be obtained by ordinary post-treatment.

  Next, the reaction between the general formula (III) and the general formula (IV) in the step (ii) is carried out by converting an equivalent or excess amount of the general formula (IV) to an appropriate solvent (acetone) with respect to the general formula (III). , Acetonitrile, dichloromethane, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, diethyl ether, isopropyl ether, hexane, N, N-dimethylformamide, dimethyl sulfoxide, toluene, benzene, methanol, ethanol, hexamethylphosphoric triamide, etc. Or a mixed solvent thereof) at −80 ° C. to 50 ° C. for 10 minutes to 48 hours. After the reaction, the general formula (V) can be obtained by ordinary post-treatment.

In step (iii), when a protecting group is contained in the protecting groups R ⁷ and R ⁸ of the general formula (V) and R ⁹ , R ¹⁰ , R ¹¹ and R ¹² , the protecting group is removed and A compound represented by the general formula (I ′) according to the invention can be obtained. The deprotection reaction for the removal of the protecting groups contained in the protecting groups R ⁷ and R ⁸ , and further R ⁹ , R ¹⁰ , R ¹¹ and R ¹² depends on the type of protecting group used and is well known to those skilled in the art. Can be done according to the method. If any or all of them can be deprotected under acidic conditions, use a mineral acid such as hydrochloric acid, an organic acid such as formic acid, acetic acid, or citric acid, or a Lewis acid such as tetrabutylammonium fluoride or aluminum chloride. In the case of removal under reducing conditions, catalytic reduction with various catalysts or metal reducing agents such as zinc and iron can be used. Further, when R ⁷ is an allyloxycarbonyl group, R ⁸ is an allyl group, and the protective group contained in R ⁹ , R ¹⁰ , R ¹¹ and R ¹² is an allyloxycarbonyl group or an allyl group, It can be easily removed by using various palladium complexes (for example, tetrakis (triphenylphosphine) palladium (0)).

  The general formula (I ′) thus obtained should be used for crystallization, chromatography using a nonionic macrohypoporous resin, gel filtration using Sephadex, etc., reverse phase silica gel column chromatography, etc. Can be isolated and purified.

［上記スキーム中で、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４及びＲ^５は一般式（Ｉ）で定義したものと同じ意味を表し、Ｒ^１３は水素原子、またはカリウム、ナトリウムなどの金属イオンを表し、Ｒ^１４は生体内で加水分解されうる基（化合物の項にて「Ｒ^４が生体内で加水分解されうる基である場合」で定義したものと同じ意味を表す）を表し、Ｘは塩素原子、臭素原子、ヨウ素原子、−ＯＳＯ₂ＣＦ₃、−ＯＳＯ₂ＣＨ₃、−ＯＳＯ₂ＰｈＣＨ₃等の脱離基を表す。］ Further, the compound (I ″) in which R ⁶ of the general formula (I) according to the present invention is a group that can be hydrolyzed in vivo can be preferably produced according to the following scheme.

[In the above scheme, R ¹ , R ^2, R ^3, R ⁴ and R ⁵ represent the same meaning as defined in formula (I), and R ¹³ represents a hydrogen atom or a metal ion such as potassium or sodium. R ¹⁴ represents a group that can be hydrolyzed in vivo (the same meaning as defined in “in the case where R ⁴ is a group that can be hydrolyzed in vivo” in the section of the compound), X Represents a leaving group such as chlorine atom, bromine atom, iodine atom, —OSO ₂ CF ₃ , —OSO ₂ CH ₃ , —OSO ₂ PhCH ₃ . ]

1 equivalent or an excess amount of base with respect to (I ′) (organic bases include diisopropylethylamine, diazabicyclo [2,2,2] undecene, 2,6-lutidine, etc., and inorganic bases include water In the presence of sodium oxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), one equivalent or an excess amount of alkyl halide (representing R ¹⁴ -X in the above scheme: Pivaloyloxymethyl iodide, 1- (pivaloyloxy) ethyl iodide, isobutyryloxymethyl iodide, 1- (isobutyryloxy) ethyl iodide, acetoxymethyl iodide, 1- (acetoxy) ethyl iodide , (1-Methylcyclohexane-1-yl) carbonyloxymethylio Dye, 1- (cyclohexyloxycarbonyloxy) ethyl iodide, 1-[(cyclohexylmethoxy) carbonyloxy] ethyl iodide, 1- (ethoxycarbonyloxy) ethyl iodide, cyclohexyloxycarbonyloxymethyl iodide, 1- [ (2-Methylcyclohexane-1-yl) oxycarbonyloxy] ethyl iodide, cyclopentyloxycarbonyloxymethyl iodide, 1- (isopropyloxycarbonyloxy) ethyl iodide, (1R, 2S, 5R)-(l)- Menthyloxycarbonyloxymethyl iodide, (1S, 2R, 5S)-(d) -menthyloxycarbonyloxymethyl iodide, 1- (phenyloxycarbonyloxy) ethyl iodide, phenyloxy Carbonyloxymethyl iodide, 1- (cyclohexyloxycarbonyloxy) -n-propyl iodide, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl bromide, 3-phthalidyl bromide, Z) -2- (3-phthalidylidene) ethyl bromide, etc.) alone or in combination with an inert solvent (eg, N, N-dimethylformamide, N, N-dimethylacetamide, N, N-diethylformamide, N, N-diethylacetamide, N-methylpyrrolidinone, N, N-dimethylimidazolidinone, dimethyl sulfoxide, sulfolane, acetonitrile, acetone, ethyl acetate, tetrahydrofuran, 1,4-dioxane, diethyl ether, anisole, dichloromethane, 1,2- Dichloroethane By reacting at −70 to + 50 ° C. (preferably −30 ° C. to + 20 ° C.) for 10 minutes to 24 hours in (Roform, toluene, benzene, hexamethylphosphoric triamide, methanol, ethanol, etc.) (I ″ ) Can be obtained.
The ester (I ″) obtained as described above can be isolated and purified by precipitation, crystallization, gel filtration using Sephadex, silica gel column chromatography, or the like.

Use of Compound / Pharmaceutical Composition The compound according to the present invention has a strong antibacterial activity and a broad antibacterial spectrum against Gram-positive and Gram-negative bacteria, and also includes pneumococci containing PRSP, Haemophilus influenzae containing BLNAR, and Has strong antibacterial activity against β-lactamase producing bacteria. In addition, it has low toxicity and is stable against DHP-1. Therefore, the compounds according to the present invention can be used for the treatment of infectious diseases caused by various pathogenic bacteria in animals including humans.
In particular, a compound in which R ⁶ is a group that can be hydrolyzed in vivo in the general formula (I) has an advantage of being orally absorbable and can be used as an oral preparation.
The pharmaceutical composition comprising the compound according to the present invention and a pharmaceutically acceptable salt thereof as an active ingredient is either oral or parenteral (for example, intravenous injection, intramuscular injection, subcutaneous administration, rectal administration, transdermal administration). These administration routes can be administered to humans and non-human animals. Accordingly, the pharmaceutical composition comprising the compound according to the present invention as an active ingredient is in an appropriate dosage form according to the administration route, and specifically, injections such as intravenous injection and intramuscular injection, capsules, tablets and granules. , Powders, pills, fine granules, lozenges and other oral preparations, rectal administration agents, and oily suppositories. These preparations are commonly used excipients, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, dispersants, buffers, preservatives, solubilizers, preservatives, It can be produced by a conventional method using a flavoring agent, a soothing agent, a stabilizer and the like. Examples of non-toxic additives that can be used include lactose, fructose, glucose, starch, gelatin, magnesium carbonate, synthetic magnesium silicate, talc, magnesium stearate, methylcellulose, or salts thereof, gum arabic, polyethylene glycol, syrup Vaseline, glycerin, ethanol, propylene glycol, citric acid, sodium chloride, sodium sulfite, sodium phosphate and the like. The dosage is appropriately determined in consideration of the usage, the patient's age, sex, the degree of symptoms, etc. For the treatment of infectious diseases, it is usually about 25 mg to 2000 mg per adult per day, preferably 50 mg to This is a dose of 1000 mg, which can be administered once or several times a day.

  EXAMPLES Hereinafter, although an Example and a synthesis example demonstrate this invention, this invention is not limited to these.

(1S, 5R, 6S) -2- (2-Aminopyrimidin-4-yl) thiomethyl-6-((1R) -1-hydroxyethyl) -1-methyl-1-carbapen-2-em-3-carvone Acid sodium
a) (1S, 5R, 6S) -6-((1R) -1-allyloxycarbonyloxyethyl) -2- (2 aminopyrimidin-4-yl) thiomethyl-1-methyl-1-carbapen-2-em Allyl-3-carboxylic acid
Drying of 342 mg of allyl (1S, 5R, 6S) -6-((1R) -1-allyloxycarbonyloxyethyl) -2-hydroxymethyl-1-methyl-1-carbapene-2-em-3-carboxylate To a 12 mL solution of methylene chloride was added 245 mg of triphenylphosphine, 131 μL of triethylamine, and then 238 mg of iodine at −50 ° C. under an argon atmosphere to shield it from light. After stirring at the same temperature for 1 hour, 326 μL of hexamethylphosphoramide was added dropwise and further stirred for 30 minutes. At the same temperature, 142 mg of 2-amino-4-mercaptopyrimidine and 163 μL of N, N-diisopropylethylamine were added, followed by stirring for 3 hours while gradually raising the temperature to 0 ° C. Ethyl acetate (30 mL) was added, and the mixture was washed successively with a saturated aqueous sodium thiosulfate solution and saturated brine, and saturated brine. The extract was dried over anhydrous magnesium sulfate and filtered, and ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1/1) to give (1S, 5R, 6S) -6-((1R) -1-allyloxycarbonyloxyethyl) -2- 239 mg of allyl (2-aminopyrimidin-4-yl) thiomethyl-1-methyl-1-carbapene-2-em-3-carboxylate was obtained.

NMR (CDCl ₃ ) δ: 1.21 (3H, d, J = 7.4 Hz), 1.46 (3H, d, J = 6.1 Hz), 3.21-3.31 (1H, m), 3.40 (1H, dd, J ₁ = 8.0 Hz, J ₂ = 2.6 Hz), 4.01 (1H, d, J = 14.1 Hz), 4.16 (1H, dd, J ₁ = 9.5 Hz, J ₂ = 2.6 Hz), 4.60-4.88 (5H, m), 5.11 (2H, br s), 5.08-5.15 (1H, m), 5.25-5.48 (4H, m), 5.86-6.04 (2H, m), 6.49 (1H, d, J = 5.4 Hz), 7.95 (1H, d, J = 5.4 Hz)

b) (1S, 5R, 6S) -2- (2-Aminopyrimidin-4-yl) thiomethyl-6-((1R) -1-hydroxyethyl) -1-methyl-1-carbapen-2-em-3 -Sodium carboxylate
(1S, 5R, 6S) -6-((1R) -1-allyloxycarbonyloxyethyl) -2- (2 aminopyrimidin-4-yl) thiomethyl-1-methyl-1-carbapen-2-em-3 -To a solution of 239 mg of allyl carboxylate in 6 mL of dry tetrahydrofuran (hereinafter referred to as THF), 58 mg of tetrakistriphenylphosphine palladium (0) and 176 mg of dimedone were added and stirred at room temperature for 30 minutes in an argon atmosphere. 10 mL of water and 1 mL of saturated sodium bicarbonate were added, washed twice with 50 mL of ethyl acetate, and the aqueous phase was adjusted to pH 7.27 with 1N aqueous hydrochloric acid. The aqueous phase was concentrated to about 2 mL, and purified by column chromatography (2% aqueous methanol) of Cosmosil 40C ₁₈ -PREP to give 97 mg of the title compound.

NMR (D ₂ O) δ (HOD = 4.65 ppm): 0.99 (3H, d, J = 7.3 Hz), 1.12 (3H, d, J = 6.3 Hz), 3.10-3.20 (1H, m), 3.26 (1H , dd, J ₁ = 6.4 Hz, J ₂ = 3.0 Hz), 3.52 (1H, d, J = 14.6 Hz), 3.93 (1H, dd, J ₁ = 9.9 Hz, J ₂ = 3.0 Hz), 4.02-4.10 (1H, m), 4.70 (1H, d, J = 14.6 Hz), 6.51 (1H, d, J = 5.6 Hz), 7.81 (1H, J = 5.6 Hz)
MS (FAB); m / z 373 (M ⁺ +1)

(1S, 5R, 6S) -2- (2-Aminopyrimidin-4-yl) thiomethyl-6-((1R) -1-hydroxyethyl) -1-methyl-1-carbapen-2-em-3-carvone Pivaloyloxymethyl acid
(1S, 5R, 6S) -2- (2-Aminopyrimidin-4-yl) thiomethyl-6-((1R) -1-hydroxyethyl) -1-methyl-1-carbapen-2-em-3-carvone Dissolve 70 mg of sodium acid in 3 mL of N, N-dimethylformamide (hereinafter referred to as DMF), add 3 mg of sodium bicarbonate and 36 μL of pivaloyloxymethyl iodide at −30 ° C. under an argon atmosphere. And stirred for 1 hour. Saturated aqueous sodium thiosulfate solution (25 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL). The organic layers were combined, washed twice with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give 45 mg of the title compound.

NMR (CDCl ₃ ) δ: 1.22 (3H, d, J = 7.3 Hz), 1.32 (3H, d, J = 6.3 Hz), 3.24-3.35 (2H, m), 3.98 (1H, d, J = 14.4 Hz) ), 4.19 (1H, dd, J ₁ = 10.0 Hz, J ₂ = 3.0 Hz), 4.20-4.27 (1H, m), 4.74 (1H, d, J = 14.4 Hz), 5.13 (2H, br s), 5.88 (1H, d, J = 5.4 Hz), 5.99 (1H, d, J = 5.4 Hz), 6.48 (1H, d, J = 5.6 Hz), 7.93 (1H, d, J = 5.6 Hz)
MS (FAB); m / z 465 (M ⁺ +1)

(1S, 5R, 6S) -2- (2-Aminopyrimidin-4-yl) thiomethyl-6-((1R) -1-hydroxyethyl) -1-methyl-1-carbapen-2-em-3-carvone Acid 1- (cyclohexyloxycarbonyloxy) ethyl (mixture of diastereomers)
(1S, 5R, 6S) -2- (2-Aminopyrimidin-4-yl) thiomethyl-6-((1R) -1-hydroxyethyl) -1-methyl-1-carbapen-2-em-3-carvone 89 mg of sodium acid was dissolved in 3 mL of DMF, 3 mg of sodium bicarbonate and 68 mg of 1- (cyclohexyloxycarbonyloxy) ethyl iodide were added at −30 ° C. under an argon atmosphere, and the mixture was stirred for 1 hour. Saturated aqueous sodium thiosulfate solution (30 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (30 mL). The organic layers were combined, washed twice with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give 43 mg of the title compound.

NMR (CDCl ₃ ) δ: 1.00-2.00 (19H, m), 3.21-3.38 (2H, m), 3.74 & 3,94 (total 1H, J = 14.4 Hz), 4.13-4.25 (2H, m), 4.59 -4.70 (1H, m), 4.82 & 4.99 (total 1H, d, J = 14.4 Hz), 5.14 (2H, br s), 6.45-6.49 (1H, m), 6.89-6.95 (1H, m), 7.90 -7.94 (1H, m)
MS (FAB); m / z 521 (M ⁺ +1)

(1S, 5R, 6S) -6-((1R) -1-hydroxyethyl) -2- (2-hydroxypyrimidin-4-yl) thiomethyl-1-methyl-1-carbapene-2-em-3-carvone Acid sodium
a) (1S, 5R, 6S) -6-((1R) -1-allyloxycarbonyloxyethyl) -2- (2-hydroxypyrimidin-4-yl) thiomethyl-1-methyl-1-carbapen-2- Allyl M-3-carboxylate Similar to Example 1a), (1S, 5R, 6S) -6-((1R) -1-allyloxycarbonyloxyethyl) -2-hydroxymethyl-1-methyl-1 From 272 mg allyl-carbapene-2-em-3-carboxylate and 95 mg 4-thiouracil, (1S, 5R, 6S) -6-((1R) -1-allyloxycarbonyloxyethyl) -2- (2 198 mg of allyl-hydroxypyrimidin-4-yl) thiomethyl-1-methyl-1-carbapene-2-em-3-carboxylate were obtained. When adding 4-thiouracil, 7.5 mL of DMF was added, the temperature was gradually raised to room temperature, and the mixture was stirred for 20 hours.

NMR (CDCl ₃ ) δ: 1.27 (3H, d, J = 7.1 Hz), 1.45 (3H, d, J = 6.3 Hz), 3.20-3.30 (1H, m), 3.42 (1H, dd, J ₁ = 8.0 Hz, J ₂ = 2.9 Hz), 4.18 (1H, dd, J ₁ = 9.7 Hz, J ₂ = 2.9 Hz), 4.36 (1H, d, J = 13.6 Hz), 4.56-4.87 (5H, m), 5.08 -5.16 (1H, m), 5.24-5.48 (4H, m), 5.86-6.03 (2H, m), 6.25 (1H, d, J = 6.8 Hz), 7.99-8.03 (1H, m)

b) (1S, 5R, 6S) -6-((1R) -1-hydroxyethyl) -2- (2-hydroxypyrimidin-4-yl) thiomethyl-1-methyl-1-carbapene-2-em-3 -Sodium carboxylate In the same manner as in Example 1-b), (1S, 5R, 6S) -6-((1R) -1-allyloxycarbonyloxyethyl) -2- (2-hydroxypyrimidin-4-yl 56 mg of the title compound was obtained from 198 mg of allyl thiomethyl-1-methyl-1-carbapene-2-em-3-carboxylate.

NMR (D ₂ O) δ: (HOD = 4.65 ppm): 1.02 (3H, d, J = 7.3 Hz), 1.14 (3H, d, J = 6.4 Hz), 3.08-3.18 (1H, m), 3.25- 3.30 (1H, m), 3.92 (1H, d, J = 14.1 Hz), 3.97-4.03 (1H, m), 4.05-4.13 (1H, m), 4.56 (1H, d, J = 14.1 Hz), 6.47 (1H, d, J = 6.8 Hz), 7.57 (1H, d, J = 6.8 Hz)
MS (ES); m / z 352 (M ⁺ +1)

(1S, 5R, 6S) -6-((1R) -1-hydroxyethyl) -2- (2-hydroxypyrimidin-4-yl) thiomethyl-1-methyl-1-carbapene-2-em-3-carvone Pivaloyloxymethyl acid
(1S, 5R, 6S) -6-((1R) -1-hydroxyethyl) -2- (2-hydroxypyrimidin-4-yl) thiomethyl-1-methyl-1-carbapene-2-em-3-carvone After 112 mg of sodium acid was dissolved in 5 mL of DMF, 48 μL of pivaloyloxymethyl iodide was added at −30 ° C. under an argon atmosphere, and the mixture was stirred for 1 hour. To the reaction solution was added 25 mL of saturated aqueous sodium thiosulfate solution, and the mixture was extracted twice with 20 mL of ethyl acetate. The organic layers were combined, washed twice with 30 mL of saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give 73 mg of the title compound.

NMR (CDCl ₃ ) δ: 1.23 (9H, s), 1.26 (3H, d, J = 7.3 Hz), 1.31 (3H, d, J = 6.3 Hz), 3.20-3.32 (2H, m), 4.19-4.27 (2H, m), 4.30 (1H, d, J = 13.8 Hz), 4.58 (1H, d, J = 13.8 Hz), 5.87 (1H, d, J = 5.4 Hz), 5.99 (1H, d, J = 5.4 Hz), 6.27 (1H, d, J = 6.8 Hz), 7.48 (1H, d, J = 6.8 Hz)
MS (FAB); m / z 466 (M ⁺ +1)

(1S, 5R, 6S) -2- (2-carbamoylmethoxypyrimidin-4-yl) thiomethyl-6-((1R) -1-hydroxyethyl) -1-methyl-1-carbapen-2-em-3- Sodium carboxylate
a) (1S, 5R, 6S) -6-((1R) -1-allyloxycarbonyloxyethyl) -2- (2-carbamoylmethoxypyrimidin-4-yl) thiomethyl-1-methyl-1-carbapene-2 -M-3-carboxylic acid allyl ester
(1S, 5R, 6S) -6-((1R) -1-allyloxycarbonyloxyethyl) -2- (2-hydroxypyrimidin-4-yl) thiomethyl-1-methyl-1-carbapen-2-em- 130 mg of allyl 3-carboxylate was dissolved in dry THF, 153 mg of 2-iodoacetamide and 144 μL of diisopropylethylamine were added at 0 ° C. under an argon atmosphere, and the mixture was stirred at room temperature for 19 hours. Ethyl acetate (40 mL) was added to the reaction mixture, and the mixture was washed successively with a saturated aqueous sodium thiosulfate solution and saturated brine, and saturated brine. The extract was dried over anhydrous magnesium sulfate and filtered, and ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 20/1) to give (1S, 5R, 6S) -6-((1R) -1-allyloxycarbonyloxyethyl) -2- 73 mg of allyl (2-carbamoylmethoxypyrimidin-4-yl) thiomethyl-1-methyl-1-carbapene-2-em-3-carboxylate was obtained.

NMR (CDCl ₃ ) δ: 1.25 (3H, d, J = 7.3 Hz), 1.45 (3H, d, J = 6.3 Hz), 3.20-3.30 (1H, m), 3.42 (1H, dd, J ₁ = 8.0 Hz, J ₂ = 2.9 Hz), 4.17 (1H, dd, J ₁ = 9.7 Hz, J ₂ = 2.9 Hz), 4.28 (1H, d, J = 13.4 Hz), 4.45 (1H, d, J = 14.9 Hz ), 4.51 (1H, d, J = 14.9 Hz), 4.60-4.87 (5H, m), 5.08-5.16 (1H, m), 5.26-5.48 (4H, m), 5.59 (1H, br s), 5.88 -6.05 (2H, m), 6.26 (1H, d, J = 7.1 Hz), 6.68 (1H, br s), 7.43 (1H, 7.1 Hz)
MS (FAB); m / z 533 (M ⁺ +1)

b) (1S, 5R, 6S) -2- (2-carbamoylmethoxypyrimidin-4-yl) thiomethyl-6-((1R) -1-hydroxyethyl) -1-methyl-1-carbapen-2-em- Sodium 3-carboxylate (1S, 5R, 6S) -6-((1R) -1-allyloxycarbonyloxyethyl) -2- (2-carbamoylmethoxypyrimidin-4-yl) as in Example 1b) 31 mg of the title compound was obtained from 73 mg of allyl thiomethyl-1-methyl-1-carbapene-2-em-3-carboxylate.

NMR (D ₂ O) δ: (HOD = 4.65 ppm): 1.01 (3H, d, J = 7.3 Hz), 1.12 (3H, d, J = 6.3 Hz), 3.07-3.17 (1H, m), 3.27 ( 1H, dd, J ₁ = 6.4 Hz, J ₂ = 2.9 Hz), 3.92 (1H, d, J = 14.1 Hz), 3.98 (1H, dd, J ₁ = 9.8 Hz, J ₂ = 2.9 Hz), 4.03- 4.11 (1H, m), 4.49 (2H, s), 4.54 (1H, d, J = 14.1 Hz), 6.49 (1H, d, J = 6.8 Hz), 7.62 (1H, d, J = 6.8 Hz)
MS (FAB); m / z 431 (M ⁺ +1)

(1S, 5R, 6S) -6-((1R) -1-Hydroxyethyl) -2- (2-methoxypyrimidin-4-yl) thiomethyl-1-methyl-1-carbapene-2-em-3-carbon Acid sodium
a) (1S, 5R, 6S) -6-((1R) -1-allyloxycarbonyloxyethyl) -2- (2-methoxypyrimidin-4-yl) thiomethyl-1-methyl-1-carbapen-2- Allyl M-3-carboxylate In the same manner as in Example 6a), (1S, 5R, 6S) -6-((1R) -1-allyloxycarbonyloxyethyl) -2- (2-hydroxypyrimidine-4- Yl) From thiomethyl-1-methyl-1-carbapene-2-em-3-carboxylate (160 mg), iodomethane (126 μL) and diisopropylethylamine (354 μL), (1S, 5R, 6S) -6-((1R) -1 -Allyloxycarbonyloxyethyl) -2- (2-methoxypyrimidin-4-yl) thiomethyl-1-methyl-1-carbapene-2-em-3-carboxylate 153 mg was obtained.

NMR (CDCl ₃ ) δ: 1.26 (3H, d, J = 7.3 Hz), 1.44 (3H, d, J = 6.1 Hz), 3.20-3.29 (1H, m), 3.41 (1H, dd, J ₁ = 7.8 Hz, J ₂ = 2.9 Hz), 4.16 (1H, dd, J ₁ = 10.0 Hz, J ₂ = 2.9 Hz), 4.34 (1H, d, J = 13.6 Hz), 4.56-4.87 (5H, m), 5.07 -5.15 (1H, m), 5.25-5.47 (4H, m), 5.87-6.03 (2H, m), 6.16 (1H, d, J = 6.8 Hz), 7.33 (1H, d, J = 6.8 Hz)

b) (1S, 5R, 6S) -6-((1R) -1-hydroxyethyl) -2- (2-methoxypyrimidin-4-yl) thiomethyl-1-methyl-1-carbapen-2-em-3 -Sodium carboxylate In the same manner as in Example 1b), (1S, 5R, 6S) -6-((1R) -1-allyloxycarbonyloxyethyl) -2- (2-methoxypyrimidin-4-yl) thiomethyl The title compound (41 mg) was obtained from 152 mg of allyl-1-methyl-1-carbapene-2-em-3-carboxylate.

NMR (D ₂ O) δ (HOD = 4.65 ppm): 1.02 (3H, d, J = 7.3 Hz), 1.13 (3H, d, 6.3 Hz), 3.08 (1H, m), 3.27 (1H, dd, J ₁ = 6.3 Hz, J ₂ = 2.7 Hz), 3.36 (3H, s), 3.89 (1H, d, J = 14.3 Hz), 3.98 (1H, dd, J ₁ = 9.7 Hz, J ₂ = 2.7 Hz), 4.04-4.12 (1H, m), 4.55 (1H, d, J = 14.3 Hz), 6.46 (1H, d, J = 6.9 Hz), 7.67 (1H, d, J = 6.9 Hz)
MS (FAB); m / z 388 (M ⁺ +1)

(1S, 5R, 6S) -2- (2,6-Diaminopyrimidin-4-yl) thiomethyl-6-((1R) -1-hydroxyethyl) -1-methyl-1-carbapen-2-em-3 -Sodium carboxylate
a) (1S, 5R, 6S) -6-((1R) -1-allyloxycarbonyloxyethyl) -2- (2,6-diaminopyrimidin-4-yl) thiomethyl-1-methyl-1-carbapene- Allyl 2-m-3-carboxylate In the same manner as in Example 1a), (1S, 5R, 6S) -6-((1R) -1-allyloxycarbonyloxyethyl) -2-hydroxymethyl-1-methyl From 367 mg of allyl-1-carbapene-2-em-3-carboxylate and 192 mg of 2,4-diamino-6-mercaptopyrimidine, (1S, 5R, 6S) -6-((1R) -1-allyloxy Carbonyloxyethyl) -2- (2,6-diaminopyrimidin-4-yl) thiomethyl-1-methyl-1-carbapene-2-em-3-carboxylate 255 mg was obtained. When 2,4-diamino-6-mercaptopyrimidine was added, 13 mL of DMF was added, the temperature was gradually raised to room temperature, and the mixture was stirred for 18 hours.

NMR (CDCl ₃ ) δ: 1.19 (3H, d, J = 7.3 Hz), 1.45 (3H, d, J = 6.4 Hz), 3.23-3.33 (1H, m), 3.39 (1H, dd, J ₁ = 8.1 Hz, J ₂ = 2.9 Hz), 4.01 (1H, d, J = 14.4 Hz), 4.14 (1H, dd, J ₁ = 9.7 Hz, J ₂ = 2.9 Hz), 4.60-4.85 (9H, m), 5.07 -5.18 (1H, m), 5.25-5.48 (4H, m), 5.87-6.03 (1H, m), 8.02 (1H, s)

b) (1S, 5R, 6S) -2- (2,6-diaminopyrimidin-4-yl) thiomethyl-6-((1R) -1-hydroxyethyl) -1-methyl-1-carbapen-2-em Sodium 3-carboxylate (1S, 5R, 6S) -6-((1R) -1-allyloxycarbonyloxyethyl) -2- (2,6-diaminopyrimidine-4) as in Example 1b) 98 mg of the title compound was obtained from 255 mg of allyl 2-yl) thiomethyl-1-methyl-1-carbapene-2-em-3-carboxylate.

NMR (D ₂ O) δ (HOD = 4.65 ppm): 0.97 (3H, d, J = 7.3 Hz), 1.12 (3H, d, J = 6.4 Hz), 3.14-3.23 (1H, m), 3.25 (1H , dd, J ₁ = 6.1 Hz, J ₂ = 3.0 Hz), 3.43 (1H, d, J = 15.1 Hz), 3.94 (1H, dd, J ₁ = 9.7 Hz, J ₂ = 3.0 Hz), 4.02-4.1 (1H, m), 4.63 (1H, d, J = 15.1 Hz), 5.72 (1H, s)
MS (FAB); m / z 388 (M ⁺ +1)

(1S, 5R, 6S) -6-((1R) -1-Hydroxyethyl) -1-methyl-2- (pyrimidin-4-yl) thiomethyl-1-carbapene-2-em-3-carboxylate
a) (1S, 5R, 6S) -6-((1R) -1-allyloxycarbonyloxyethyl) -1-methyl-2- (pyrimidin-4-yl) thiomethyl-1-carbapen-2-em-3 -Allyl carboxylate In the same manner as in Example 1a), (1S, 5R, 6S) -6-((1R) -1-allyloxycarbonyloxyethyl) -2-hydroxymethyl-1-methyl-1-carbapene- From 337 mg allyl 2-m-3-carboxylate and 103 mg 4-mercaptopyrimidine (J. Chem. Soc., 792 (1961)), (1S, 5R, 6S) -6-((1R) -1- Allyloxycarbonyloxyethyl) -1-methyl-2- (pyrimidin-4-yl) thiomethyl-1-carbapene-2-em-3-carboxylate 351 mg was obtained. When adding 4-mercaptopyrimidine, 3 mL of DMF was added.

NMR (CDCl ₃ ) δ: 1.23 (3H, d, J = 7.3 Hz), 1.45 (3H, d, J = 6.1 Hz), 3.19-3.31 (1H, m), 3.42 (1H, dd, J ₁ = 8.1 Hz, J ₂ = 3.0 Hz), 4.15 (1H, dd, J ₁ = 9.9 Hz, J ₂ = 3.0 Hz), 4.20 (1H, d, J = 13.9 Hz), 4.50-4.88 (5H, m), 5.07 -5.16 (1H, m), 5.25-5.50 (4H, m), 5.86-6.04 (2H, m), 7.18 (1H, d, J = 5.6 Hz), 8.36 (1H, d, J = 5.6 Hz), 8.92 (1H, s)

b) (1S, 5R, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2- (pyrimidin-4-yl) thiomethyl-1-carbapen-2-em-3-carboxylic acid Sodium (1S, 5R, 6S) -6-((1R) -1-allyloxycarbonyloxyethyl) -1-methyl-2- (pyrimidin-4-yl) thiomethyl-1- 121 mg of the title compound was obtained from 351 mg of allyl carbapen-2-em-3-carboxylate.

NMR (D ₂ O) δ: (HOD = 4.65 ppm): 0.99 (3H, d, J = 7.4 Hz), 1.11 (3H, d, J = 6.4 Hz), 3.10-3.20 (1H, m), 3.25 ( 1H, dd, J ₁ = 6.4 Hz, J ₂ = 3.0 Hz), 3.65 (1H, d, 14.6 Hz), 3.91 (1H, dd, J ₁ = 10.0 Hz, J ₂ = 3.0 Hz), 4.01-4.09 ( 1H, m), 4.75 (1H, d, J = 14.6 Hz), 7.26 (1H, dd, J ₁ = 5.9 Hz, J ₂ = 1.5 Hz), 8.26 (1H, d, J = 5.9 Hz), 8.67 ( (1H, d, J = 1.5 Hz)
MS FAB); m / z 358 (M ⁺ +1)

(1S, 5R, 6S) -2- (2-Aminoacetylaminopyrimidin-4-yl) thiomethyl-6-((1R) -1-hydroxyethyl) -1-methyl-1-carbapen-2-em-3 -Sodium carboxylate
a) (1S, 5R, 6S) -2- (2-allyloxycarbonylamino-acetylaminopyrimidin-4-yl) thiomethyl-6-((1R) -1-allyloxycarbonyloxyethyl) -1-methyl- Allyl 1-carbapene-2-em-3-carboxylate In the same manner as in Example 1a), (1S, 5R, 6S) -6-((1R) -1-allyloxycarbonyloxyethyl) -2-hydroxymethyl 1-methyl-1-carbapene-2-em-3-carboxylate 397 mg and (4-mercaptopyrimidin-2-ylcarbamoyl) methyl-carbamate 291 mg, (1S, 5R, 6S) -2 -(2-Allyloxycarbonylamino-acetylaminopyrimidin-4-yl) thiomethyl-6-((1R) -1-allyloxycarbonyloxyethyl) -1-methyl-1-carbapen-2-em-3-carbon 436 mg of allyl acid was obtained. 11 mL of DMF was added when allyl (4-mercaptopyrimidin-2-ylcarbamoyl) methyl-carbamate was added.

NMR (CDCl ₃ ) δ: 1.20 (3H, d, J = 7.6 Hz), 1.45 (3H, d, J = 6.4 Hz), 3.20-3.30 (1H, m), 3.43 (1H, dd, J ₁ = 8.0 Hz, J ₂ = 2.9 Hz), 4.17 (1H, dd, J ₁ = 9.9 Hz, J ₂ = 2.9 Hz), 4.51 (1H, br s), 4.58-4.90 (9H, m), 5.08-5.16 (1H , m), 5.20-5.49 (7H, m), 5.70 (1H, br s), 5.86-6.03 (3H, m), 6.86 (1H, d, J = 5.4 Hz), 8.23 (1H, d, J = (5.4 Hz)

b) (1S, 5R, 6S) -2- (2-aminoacetylaminopyrimidin-4-yl) thiomethyl-6-((1R) -1-hydroxyethyl) -1-methyl-1-carbapen-2-em Sodium 3-carboxylate (1S, 5R, 6S) -2- (2-Allyloxycarbonylamino-acetylaminopyrimidin-4-yl) thiomethyl-6-((1R) -1 -Allyloxycarbonyloxyethyl) -1-methyl-1-carbapene-2-em-3-carboxylate 218 mg, dimedone 188 mg and tetrakistriphenylphosphine palladium 41 mg gave 89 mg of the title compound.

NMR (D ₂ O) δ: (HOD = 4.65 ppm): 0.99 (3H, d, J = 7.3 Hz), 1.11 (3H, d, J = 6.6 Hz), 3.14-3.24 (1H, m), 3.30 ( 1H, dd, J ₁ = 6.1 Hz, J ₂ = 3.0 Hz), 3.44 (1H, d, J = 14.6 Hz), 3.95 (1H, dd, J ₁ = 0.2 Hz, J ₂ = 3.0 Hz), 3.99- 4.10 (3H, m), 4.77 (1H, d, J = 14.6 Hz), 6.99 (1H, d, J = 5.6 Hz), 8.07 (1H, d, J = 5.6 Hz)
MS (FAB); m / z 408 (M ⁺ +1)

(1S, 5R, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2- (pyrimidin-2-yl) thiomethyl-1-carbapene-2-em-3-carboxylate
a) (1S, 5R, 6S) -6-((1R) -1-t-butyldimethylsilyloxyethyl) -1-methyl-2- (pyrimidin-2-yl) thiomethyl-1-carbapen-2-em Allyl-3-carboxylate In the same manner as in Example 1a), (1S, 5R, 6S) -6-((1R) -1-t-butyldimethylsilyloxyethyl) -2-hydroxymethyl-1-methyl- From 1-carbapene-2-em-3-carboxylate 500 mg and 2-mercaptopyrimidine 145 mg, (1S, 5R, 6S) -6-((1R) -1-t-butyldimethylsilyloxyethyl)- 263 mg of allyl 1-methyl-2- (pyrimidin-2-yl) thiomethyl-1-carbapene-2-em-3-carboxylate was obtained.

NMR (CDCl ₃ ) δ: 0.05 (6H, d, J = 1.7 Hz), 0.85 (9H, s), 1.20 (3H, d, J = 7.3 Hz), 1.23 (3H, d, J = 6.1 Hz), 3.21 (1H, dd, J = 3.1 Hz, 6.1 Hz), 3.29 (1H, m), 3.99 (1H, d, J = 14.2 Hz), 4.75 (1H, dd, J = 10.2 Hz, 2.9 Hz), 4.18 (1H, m), 4.71-4.84 (2H, m), 4.87 (1H, d, J = 14.2 Hz), 5.25 (1H, dd, J = 10.5 Hz, 1.5 Hz), 5.45 (1H, dd, J = 17.2 Hz, 1.5 Hz), 6.02 (1H, m), 6.98 (1H, t, J = 4.9 Hz), 8.50 (2H, d, J = 4.9 Hz)

b) (1S, 5R, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2- (pyrimidin-2-yl) thiomethyl-1-carbapen-2-em-3-carboxylic acid Allyl
(1S, 5R, 6S) -6-((1R) -1-t-butyldimethylsilyloxyethyl) -1-methyl-2- (pyrimidin-2-yl) thiomethyl-1-carbapen-2-em-3 -260 mg of allyl carboxylate was dissolved in 8 ml of dry THF, 0.5 ml of acetic acid and 4 ml of tetrabutylammonium fluoride 1.0 M tetrahydrofuran solution were added at room temperature under an argon atmosphere, and the mixture was stirred at the same temperature for 18 hours. 40 ml of ethyl acetate was added, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine. The extract was dried over anhydrous magnesium sulfate and filtered, and ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1/2) to give (1S, 5R, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2 116 mg of allyl-(pyrimidin-2-yl) thiomethyl-1-carbapen-2-em-3-carboxylate was obtained.

NMR (CDCl ₃ ) δ: 1.23 (3H, d, J = 7.3 Hz), 1.33 (3H, d, J = 6.3 Hz), 3.27 (1H, dd, J = 6.5 Hz, 2.9 Hz), 3.33 (1H, dq, J = 7.6 Hz), 4.00 (1H, d, J = 14.1 Hz), 4.17 (1H, dd, J = 10.0 Hz, 2.9 Hz), 4.22 (1H, dq, J = 6.5 Hz), 4.70-4.88 (2H, m), 4.88 (1H, d, J = 14.1 Hz), 5.27 (1H, dd, J = 10.4 Hz, 1.2 Hz), 5.45 (1H, dd, J = 17.3 Hz, 1.5 Hz), 5.95- 6.05 (1H, m), 6.95 (1H, t, J = 4.8 Hz), 8.50 (2H, d, J = 4.8 Hz)

c) (1S, 5R, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2- (pyrimidin-2-yl) thiomethyl-1-carbapen-2-em-3-carboxylic acid Sodium In the same manner as in Example 1b), (1S, 5R, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2- (pyrimidin-2-yl) thiomethyl-1-carbapene- From 110 mg of allyl 2-m-3-carboxylate, 44 mg of the title compound was obtained.

NMR (DMSO-d ₆ )) δ (DMSO = 2.49 ppm): 1.01 (3H, d, J = 7.0 Hz), 1.11 (3H, d, J = 6.1 Hz), 2.88 (1H, dq, J = 7.0 Hz ), 2.98 (1H, dd, J = 6.8 Hz, 2.7 Hz), 3.88 (2H, dd, J = 9.5 Hz, 2.7 Hz), 3.98 (1H, d, J = 12.9 Hz), 4.91 (1H, brs) , 5.05 (1H, d, J = 12.9 Hz), 7.18 (1H, t, J = 4.8 Hz), 8.61 (2H, d, J = 4.8 Hz)
<Synthesis Example 1>

2-Amino-4-mercaptopyrimidine
Dissolve 1.7 g of 2-amino-6-chloropyrimidine-4-thiol (J. Chem. Soc., 792 (1961)) in 35 mL of water and 5 mL of aqueous ammonia, and add 30.5 g of zinc in 3 hours. The solution was added in portions and stirred at 80 ° C. for 3.5 hours. The reaction solution was filtered and washed with aqueous ammonia and water, and the filtrate was concentrated. The pH was adjusted to 4 using hydrochloric acid, and the mixture was extracted 4 times with 250 mL of ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.3 g of crude crystals of 2-amino-4-mercaptopyrimidine.

NMR (DMSO-d ₆ ) δ (DMSO = 2.49 ppm): 6.39 (1H, d, J = 5.8 Hz), 7.55 (1H, d, J = 5.8 Hz)
MS (FAB); m / z 128 (M ⁺ +1)

<Synthesis Example 2>
(4-Mercaptopyrimidin-2-ylcarbamoyl) methyl-allylic carbamate
2-amino-4-mercaptopyrimidine (100 mg) was dissolved in DMF (5 mL) and 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride 330 mg, 1-hydroxybenzotriazole water at room temperature under an argon atmosphere The product 22 mg and allyloxycarbonylaminoacetic acid 276 mg were added in two portions and stirred at room temperature for 3 days. 30 mL of ethyl acetate was added to the reaction solution, and the mixture was washed twice with 50 mL of saturated aqueous ammonium chloride solution. The organic phase was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 10/1), and then purified by column chromatography on Sephadex LH-20 (dichloromethane: methanol = 1: 1) to give the title compound 48 mg was obtained.

NMR (CDCl ₃ ) δ: 4.10 (2H, d, J = 6.1 Hz), 4.60-4.70 (3H, m), 5.25-5.50 (3H, m), 5.80-6.00 (1H, m), 7.03 (1H, d, J = 6.3 Hz), 7.58 (1H, d, J = 6.3 Hz)
MS (FAB); m / z 269 (M ⁺ +1)

<Test Example 1>
Antibacterial activity The following is the method described in CHEMOTHERAPY, vol. 16, No. 1, 99, 1968. The minimum inhibitory concentration (MIC, μg / mL) of various representative carbapenem derivatives of the novel carbapenem derivatives of the present invention against various pathogens. The results are shown in Table 2. The measurement medium is Sensitivity Disk agar-N + 5% Horse blood, and the amount of inoculum is 10 ⁶ CFU / mL.

  The carbapenem derivative of the general formula (I) of the present invention has a strong antibacterial activity against various pathogens including pneumococci including PRSP, Haemophilus influenzae including BLNAR, and β-lactamase producing bacteria.

Claims (17)

A compound of general formula (I) or a pharmaceutically acceptable salt thereof.

(I)
[In the above formula,
R ¹ represents a hydrogen atom or a methyl group,
Any one of R ² , R ³ , R ⁴ and R ⁵ is bonded to the sulfur atom linked to the 2-position on the carbapenem ring via methylene;
The remaining three may be the same or different, each with a hydrogen atom,
A halogen atom,
Formyl group,
Nitrile group,
Nitro group,
An amino group,
A substituted amino group,
A lower alkyl group,
A substituted lower alkyl group,
Hydroxyl group,
A lower alkoxy group,
A substituted lower alkoxy group,
A carbamoyl group,
A substituted aminocarbonyl group,
A lower alkylcarbonyl group,
A substituted lower alkylcarbonyl group,
A lower alkoxycarbonyl group,
A substituted lower alkoxycarbonyl group,
An arylcarbonyl group,
A substituted arylcarbonyl group,
A heteroarylcarbonyl group,
A substituted heteroarylcarbonyl group,
Carboxyl group,
An aryl group,
A substituted aryl group,
A heteroaryl group,
A substituted heteroaryl group,
A lower alkylthio group, or a lower alkylsulfonyl group,
Indicate
R ⁶ represents a hydrogen atom or a group that can be hydrolyzed in vivo. ] Any one of R ² , R ³ , R ⁴ and R ⁵ is bonded to the sulfur atom linked to the 2-position on the carbapenem ring via methylene;
The remaining three may be the same or different, each with a hydrogen atom,
A halogen atom,
Formyl group,
Nitrile group,
Nitro group,
An amino group,
A substituted amino group,
A lower alkyl group,
A substituted lower alkyl group,
Hydroxyl group,
A lower alkoxy group,
A substituted lower alkoxy group,
A carbamoyl group,
A substituted aminocarbonyl group,
A lower alkylcarbonyl group,
A substituted lower alkylcarbonyl group,
A lower alkoxycarbonyl group,
A substituted lower alkoxycarbonyl group,
A lower alkylthio group, or a lower alkylsulfonyl group,
Showing,
The compound according to claim 1 or a pharmaceutically acceptable salt thereof. Any one of R ² , R ³ , R ⁴ and R ⁵ is bonded to the sulfur atom linked to the 2-position on the carbapenem ring via methylene;
The remaining three may be the same or different, each with a hydrogen atom,
An amino group,
A substituted amino group,
Hydroxyl group,
A lower alkoxy group or a substituted lower alkoxy group,
Showing,
The compound according to claim 1 or a pharmaceutically acceptable salt thereof. Any one of R ² , R ³ , R ⁴ and R ⁵ is bonded to the sulfur atom linked to the 2-position on the carbapenem ring via methylene;
The remaining three may be the same or different, each with a hydrogen atom,
An amino group,
An aminomethylcarbonylamino group,
Hydroxyl group,
A methoxy group or a carbamoylmethoxy group,
Showing,
The compound as described in any one of Claims 1-3, or its pharmaceutically acceptable salt. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R ² is bonded to a sulfur atom linked to the 2-position on the carbapenem ring via methylene. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R ³ or R ⁵ is bonded to a sulfur atom linked to the 2-position on the carbapenem ring via methylene. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R ⁴ is bonded to a sulfur atom linked to the 2-position on the carbapenem ring via methylene. The compound according to claim 6, wherein R ² is an amino group, or a pharmaceutically acceptable salt thereof. The compound according to claim 6, wherein R ² is a hydroxyl group, or a pharmaceutically acceptable salt thereof. The compound according to claim 6, wherein R ² is a methoxy group, or a pharmaceutically acceptable salt thereof. R ² and R ⁴ are hydrogen atoms,
7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein either R ³ or R ⁵ is bonded to a sulfur atom linked to the 2-position on the carbapenem ring via methylene and the other is a hydrogen atom. salt. 6. The compound or a pharmaceutically acceptable salt thereof according to claim 5, wherein R ² is bonded to a sulfur atom linked to the 2-position on the carbapenem ring via methylene, and R ³ , R ⁴ and R ⁵ are hydrogen atoms. . The compound of any one of claims 1 to 12 R ¹ is a methyl group. The compound according to any one of claims 1 to 13, wherein R ⁶ is a group capable of being hydrolyzed in vivo. Pharmaceutical composition containing the compound as described in any one of Claims 1-14. A pharmaceutical composition comprising the compound according to any one of claims 1 to 14 and a pharmaceutically acceptable carrier. The pharmaceutical composition according to any one of claims 1 to 16, which is used as an antibacterial agent.