JP2005200412A - New 2-ethynylcarbapenem derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicine effective for an infection-causing bacterium which now becomes a serious clinical problem and includes a pneumococcus including PRSP (penicillin-resistant Streptococcus pneumonie), an influenza bacillus including BLNAR (beta-lactomase-negative ampicillin-resistant Haemophilus influenzae), and a β-lactamase-producing bacterium, and to provide a method for introducing an ethynyl group to the 2-position of a carbapenem ring with high safety through an industrially available production process. <P>SOLUTION: A new carbapenem derivative is expressed by general formula (I), wherein the derivative has wide-ranging and strong antibacterial activity on a gram-positive bacterium and a gram-negative bacterium and further exhibits strong antibacterial power on the PRSP, the influenza bacillus, and the β-lactamase-producing bacterium. A method for producing the derivative expressed by general formula (I) comprises using a base, a palladium catalyst, and a copper salt. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a carbapenem compound having excellent antibacterial activity and a broad spectrum. More specifically, the present invention relates to a novel carbapenem derivative having a hydrogen atom, a silyl protecting group, a substituted or unsubstituted heteroaryl group via the ethynyl group at the 2-position on the carbapenem ring, and a process for producing the same.

Carbapenem derivatives have a strong antibacterial activity and a wide range of excellent antibacterial spectrum, and therefore are being actively studied as highly useful β-lactam agents, and imipenem, panipenem, meropenem, biapenem and ertapenem have already been clinically used. It is used in the field.
Furthermore, a group of compounds using various bonding modes at the 2-position of the carbapenem ring has been studied (Non-Patent Document 1), and in particular, as represented by panipenem, meropenem, biapenem, and ertapenem, the 2-position of the carbapenem ring. Research on compounds having a heterocyclic ring via a sulfur atom has been focused.
On the other hand, only a few studies on derivatives in which a heteroaryl group is bonded from the 2-position of the carbapenem ring via an ethenyl group have disclosed very limited heteroaryl groups (Patent Documents 1 and 2). There is no specific disclosure of antibacterial activity.
In addition, there are several research examples (Patent Document 2 and Non-Patent Document 2) regarding the method of introducing an ethynyl group at the 2-position of the carbapenem ring, but only a report by a method using coupling using an organotin compound is available. . This method requires the introduction of a trialkyltin group at the acetylene end site, and organotin compounds remain problematic for toxicity and the environment.
JP-A-5-125041 Japanese Patent No. 3019407 Expert Opinion on Therapeutic Patents, (UK), 2001, 11 (8), p1267-1276 The Journal of Antibiotics, 1998, 51 (2), p210-220

Carbapenems currently on the market are methicillin-resistant Staphylococcus aureus (hereinafter abbreviated as MRSA), vancomycin-resistant enterococci (hereinafter abbreviated as VRE), and penicillin-resistant pneumococci (hereinafter referred to as PRSP), which are currently a major clinical problem. Β-lactamase non-producing ampicillin-resistant Haemophilus influenzae (hereinafter abbreviated as BLNAR), β-lactamase-producing bacteria, and resistant Pseudomonas aeruginosa do not necessarily exhibit sufficient antibacterial activity. There is a need for drugs that are effective against this.
In addition, only the coupling method using an organotin compound has been reported for the introduction of an ethynyl group into the 2-position of the carbapenem ring, and it is useful even on an industrial scale that is safe and does not use an organotin compound that is toxic and adversely affects the environment. New synthesis methods are needed.

  Among these problems, the present invention provides a carbapenem derivative having strong antibacterial activity against pneumococci including PRSP, Haemophilus influenzae including BLNAR and β-lactamase producing bacteria, and a toxic organotin compound. It is an object to provide a method for introducing an ethynyl group at the 2-position of a carbapenem ring by a technique that is safe and not useful, even on an industrial scale.

  The present inventors have found that the novel carbapenem derivative represented by the following general formula (I) has a wide and strong antibacterial activity against Gram-positive bacteria and Gram-negative bacteria, and PRSP, Haemophilus influenzae and As a method that shows strong antibacterial activity against β-lactamase-producing bacteria and a method using an organotin compound, the reaction using a base, a palladium catalyst and a copper salt (Sonogashira reaction) is performed at the 2-position of the carbapenem ring. The inventors have found that an ethynyl group can be introduced, and have completed the present invention.

［上記式中、
Ｒ^１はメチル基
水素原子
を示し、
Ｒ^２は、
水素原子、
シリル系の保護基
ピリジン
置換されたピリジン
チアゾール
置換されたチアゾール
ピリミジン
置換されたピリミジン
イミダゾチアゾール
置換されたイミダゾチアゾール
チアジアゾール
置換されたチアジアゾール
イミダゾール
置換されたイミダゾール
ピラジン
置換されたピラジン
ピラゾール
置換されたピラゾール
トリアゾール
置換されたトリアゾール
トリアジン
置換されたトリアジン
を示し、
Ｒ^３は、水素原子
シリル系の保護基
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
を示し
Ｒ^４は、水素原子、または生体内で加水分解されうる基、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-ブチル基、アリル基、シリル系の保護基
を示す。
（２）Ｒ^２は、
水素原子
イミダゾ［５，１−ｂ］チアゾール
置換されたイミダゾ［５，１−ｂ］チアゾール
チアゾール
置換されたチアゾール
ピリミジン
置換されたピリミジン
ピリジン
置換されたピリジン
シリル系の保護基、
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、
（３）Ｒ^２は、
水素原子、
イミダゾ［５，１−ｂ］チアゾール−２−イル基
２−カルバモイルチアゾール−５−イル基、
２−アミノ−４−エトキシカルボニルチアゾール−５−イル基、
４−ヒドロキシピリミジン−５−イル基
２−アミノピリミジン−５−イル基
ピリジン−３−イル基または
トリメチルシリル基、
トリエチルシリル基、
ｔ−ブチルジメチルシリル基、または
トリイソプロピルシリル基、
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）一般式（Ｉ’）の製造法であって

一般式（ＩＩ）の化合物と一般式（ＩＩＩ）の化合物

［式中、Ｒ^１は水素原子、メチル基、
Ｒ^３は、水素原子、シリル系の保護基、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、
Ｒ^４は、水素原子、または生体内で加水分解されうる基、４−ニトロベンジル基、４−メトキシベンジル基、t-ブチル基、アリル基、シリル系の保護基、
Ｒ^５は水素原子、シリル系の保護基、無置換もしくは置換されたヘテロアリール基、
Ｔｆは、トリフルオロメタンスルホニル基を示す］
とを塩基、パラジウム触媒、および、銅塩の存在下、必要に応じて三価リンなどの添加物を加えて反応させることを特徴とする、必要に応じ脱保護工程を含んでいてもよい一般式（Ｉ’）の製造法、
（５）一般式（Ｉ”）の化合物の製造法であって

一般式（IV）の化合物と一般式（V）の化合物

［式中、Ｒ^１はカルバペネム環１位に結合する水素原子、メチル基、
Ｒ^３は、水素原子、シリル系の保護基、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、
Ｒ^４は、水素原子、または生体内で加水分解されうる基、４−ニトロベンジル基、４−メトキシベンジル基、t-ブチル基、アリル基、シリル系の保護基、
Ｈｙは、無置換もしくは置換されたヘテロアリール基、
Xは脱離基を表す］とを塩基、パラジウム触媒、および、銅塩の存在下、必要に応じて三価リンなどの添加物を加えて反応させることを特徴とする、必要に応じ脱保護工程を含んでいてもよい一般式（Ｉ”）の製造法、
（６）Ｒ¹がメチル基である（１）〜（３）のいずれか一項記載の化合物、
（７）Ｒ^４が生体内で加水分解されうる基である（１）〜（３）、または、（６）のいずれか一項記載の化合物、
（８）
（１）〜（３）、または、（６）〜（７）のいずれか一項に記載の化合物を含有する医薬組成物、
（９）（１）〜（３）、または、（６）〜（８）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、
（１０）抗菌剤として用いられる、（１）〜（３）、または、（６）〜（９）のいずれか一項に記載の医薬組成物等に関する。 That is, the present invention
(1) A compound of general formula (I) or a pharmaceutically acceptable salt thereof,

[In the above formula,
R ¹ represents a methyl group hydrogen atom,
R ² is
Hydrogen atom,
Silyl protecting groups pyridine substituted pyridine thiazole substituted thiazole pyrimidine substituted pyrimidine imidazothiazole substituted imidazothiazole thiadiazole substituted thiadiazole imidazole substituted imidazole pyrazine substituted pyrazine pyrazole substituted pyrazole triazole substituted And triazole triazine substituted triazine
R ³ represents a hydrogen atom silyl-based protecting group 4-nitrobenzyloxycarbonyl group 4-methoxybenzyloxycarbonyl group allyloxycarbonyl group; R ⁴ represents a hydrogen atom or a group that can be hydrolyzed in vivo; A nitrobenzyl group, a 4-methoxybenzyl group, a diphenylmethyl group, a t-butyl group, an allyl group, and a silyl protecting group are shown.
(2) R ² is
A hydrogen atom imidazo [5,1-b] thiazole substituted imidazo [5,1-b] thiazolethiazole substituted thiazolepyrimidine substituted pyrimidinepyridine substituted pyridinesilyl protecting group;
Showing,
(1) or a pharmaceutically acceptable salt thereof,
(3) R ² is
Hydrogen atom,
Imidazo [5,1-b] thiazol-2-yl group 2-carbamoylthiazol-5-yl group,
2-amino-4-ethoxycarbonylthiazol-5-yl group,
4-hydroxypyrimidin-5-yl group 2-aminopyrimidin-5-yl group pyridin-3-yl group or trimethylsilyl group,
Triethylsilyl group,
t-butyldimethylsilyl group, or triisopropylsilyl group,
Showing,
(1) or a pharmaceutically acceptable salt thereof,
(4) A production method of the general formula (I ′)

Compound of general formula (II) and compound of general formula (III)

[Wherein R ¹ represents a hydrogen atom, a methyl group,
R ³ is a hydrogen atom, a silyl protecting group, a 4-nitrobenzyloxycarbonyl group, a 4-methoxybenzyloxycarbonyl group, an allyloxycarbonyl group,
R ⁴ represents a hydrogen atom or a group that can be hydrolyzed in vivo, a 4-nitrobenzyl group, a 4-methoxybenzyl group, a t-butyl group, an allyl group, a silyl-based protecting group,
R ⁵ represents a hydrogen atom, a silyl-based protecting group, an unsubstituted or substituted heteroaryl group,
Tf represents a trifluoromethanesulfonyl group]
In the presence of a base, a palladium catalyst, and a copper salt, an additive such as trivalent phosphorus may be added as necessary, and the reaction may be optionally performed. Production method of formula (I ′),
(5) A process for producing a compound of general formula (I "),

Compound of general formula (IV) and compound of general formula (V)

[Wherein, R ¹ represents a hydrogen atom, methyl group bonded to the 1-position of the carbapenem ring,
R ³ is a hydrogen atom, a silyl protecting group, a 4-nitrobenzyloxycarbonyl group, a 4-methoxybenzyloxycarbonyl group, an allyloxycarbonyl group,
R ⁴ represents a hydrogen atom or a group that can be hydrolyzed in vivo, a 4-nitrobenzyl group, a 4-methoxybenzyl group, a t-butyl group, an allyl group, a silyl-based protecting group,
Hy is an unsubstituted or substituted heteroaryl group,
X represents a leaving group], and in the presence of a base, a palladium catalyst, and a copper salt, an additive such as trivalent phosphorus is added as necessary, and the reaction is performed. A process of general formula (I "), which may comprise steps,
(6) The compound according to any one of (1) to (3), wherein R ¹ is a methyl group,
(7) The compound according to any one of (1) to (3) or (6), wherein R ⁴ is a group that can be hydrolyzed in vivo.
(8)
(1) to (3) or a pharmaceutical composition containing the compound according to any one of (6) to (7),
(9) A pharmaceutical composition comprising the compound according to any one of (1) to (3) or (6) to (8) and a pharmaceutically acceptable carrier,
(10) The pharmaceutical composition according to any one of (1) to (3) or (6) to (9), 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, branched, or cyclic alkyl group having 1-6, preferably 1-4 carbon atoms. Means.
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, cyclo And propyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
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.
As used herein, 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. It means a membered aromatic heterocycle. Preferably, it represents pyridine, thiazole, pyrimidine, imidazothiazole, thiadiazole, imidazole, pyrazine, pyrazole, triazole, triazine and the like.

Compound R ¹ preferably represents a hydrogen atom or a methyl group.
R ² and R ⁵ are a hydrogen atom bonded to the 2-position on the carbapenem ring via an ethynyl group, a silyl-based protecting group, an unsubstituted or substituted heteroaryl group.
Hy is an unsubstituted or substituted heteroaryl group bonded to the 2-position on the carbapenem ring via an ethynyl group.
Examples of the “silyl-based protecting group” include trialkylsilyl groups such as trimethylsilyl group, triethylsilyl group, t-butyldimethylsilyl group, and triisopropylsilyl group.
“Unsubstituted or substituted heteroaryl group” includes pyridine, substituted pyridine, thiazole, substituted thiazole, pyrimidine, substituted pyrimidine, imidazothiazole, substituted imidazothiazole (imidazothiazole is imidazo [5,1-b] thiazole, imidazo [2,1-b] thiazole, etc.), thiadiazole, substituted thiadiazole, imidazole, substituted imidazole, pyrazine, substituted pyrazine, pyrazole, substituted Examples include pyrazole, triazole, substituted triazole, triazine, substituted triazine and the like.
“Substituent of heteroaryl group” means 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 Substituted lower alkoxy group, carbamoyl group, substituted aminocarbonyl group, lower alkylcarbonyl group, substituted lower alkylcarbonyl group, lower alkoxycarbonyl group, substituted lower alkoxycarbonyl group, lower alkoxyaminocarbonyl group, substituted Lower alkoxyaminocarbonyl group, arylcarbonyl group, substituted arylcarbonyl group, heteroarylcarbonyl group, substituted heteroarylcarbonyl group, carboxyl group, aryl group, substituted aryl group, heteroaryl group, substituted Heteroa Lumpur 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 on the heteroaryl group of R ² , R ⁵ and Hy include 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 heteroarylcarbonyl group, carboxyl group, lower alkylthio group, lower alkylsulfonyl group and the like.
More preferred are a hydrogen atom, a hydroxyl group, a carbamoyl group, an amino group, an ethoxycarbonyl group, and the like.

R ³ represents a hydrogen atom, a silyl-based protecting group, a 4-nitrobenzyloxycarbonyl group, a 4-methoxybenzyloxycarbonyl group, or an allyloxycarbonyl group.
The “silyl protecting group” is as described above, and is preferably a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, or a triisopropylsilyl group.

When R ⁴ is a “group that is hydrolyzed in vivo”, it is preferably an ester residue.
Examples thereof include lower alkylcarbonyloxy lower alkyl group, lower cycloalkylcarbonyloxy lower alkyl group, lower cycloalkylmethylcarbonyloxy lower alkyl group, lower alkenylcarbonyloxy lower alkyl group, arylcarbonyloxy lower alkyl group, tetrahydrofuranylcarbonyl. Oxymethyl 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 cycloalkylmethoxycarbonyloxy lower alkyl group, aryloxycarbonyloxy lower alkyl group 3-phthalidyl group which may have a substituent on the aromatic ring, 2- (3-phthalidylidene) ethyl group, 2-oxotetrahydrofuran-5-yl group which may have a substituent on the aromatic ring, 2 Examples include conventional ones such as -oxo-5-lower alkyl-1,3-dioxolen-4-ylmethyl group.

  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-[(cyclohexylmethoxy) carbonyloxy] ethyl group, 1- (ethoxycarbonyloxy) ethyl group, cyclohexyloxycarbonyloxymethyl group, 1- (cyclohexyloxycarbonyl) Oxy) ethyl group, 1-[(2-methylcyclohexane-1-yl) oxycarbonyloxy] ethyl group, cyclopentyloxycarbonyloxymethyl group, 1- (isopropyloxycarbonyloxy) ethyl group, (1R, 2S, 5R) -(L) -men Ruoxycarbonyloxymethyl 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 group and the like.

  The salts of the general formulas (I), (I ′) and (I ″) are pharmaceutically acceptable salts, for example inorganic salts such as lithium, sodium, potassium, calcium, magnesium, or A salt with an organic base such as ammonium salt, triethylamine, diisopropylethylamine, or a salt with a mineral acid such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, or acetic acid, carbonic acid, citric acid, malic acid, oxalic acid, Examples thereof include salts with organic acids such as methanesulfonic acid, preferably sodium salt, potassium salt or hydrochloride.

Next, specific examples of the carbapenem derivatives of the general formulas (I), (I ′) and (I ″) according to the present invention are illustrated, but the present invention is not limited thereto.
1. 1. (1S, 5R, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-trimethylsilylethynyl-1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl (1S, 5R, 6S) -2-ethynyl-6-((1R) -1-hydroxyethyl) -1-methyl-1-carbapen-2-em-3-carboxylic acid 4-nitrobenzyl 3. (1S, 5R, 6S) -1-methyl-2-trimethylsilylethynyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbapene-2-em-3-carboxylate 4-nitrobenzyl 4. (1S, 5R, 6S) -2-ethynyl-1-methyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl (1S, 5R, 6S) -2- (3-Hydroxypropyn-1-yl) -1-methyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbapen-2-em-3 -4-nitrobenzyl carboxylate (1S, 5R, 6S) -1-Methyl-2-trimethylsilylethynyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbapen-2-em-3-carboxylic acid 4-pivaloyloxy Methyl 7. 7. (1S, 5R, 6S) -2-ethynyl-1-methyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbapen-2-em-3-carboxylate pivaloyloxymethyl (1S, 5R, 6S) -2- [imidazo [5,1-b] thiazol-2-ylethynyl] -1-methyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbapene-2 -M-3-carboxylic acid 4-nitrobenzyl9. (1S, 5R, 6S) -6-((1R) -1-hydroxyethyl) -2- [imidazo [5,1-b] thiazol-2-ylethynyl] -1-methyl-1-carbapen-2-em -3-sodium carboxylate 10. (1S, 5R, 6S) -2- (2-carbamoylthiazol-5-ylethynyl) -1-methyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbapen-2-em-3- 11. 4-nitrobenzyl carboxylate (1S, 5R, 6S) -2- (2-carbamoylthiazol-5-ylethynyl) -6-((1R) -1-hydroxyethyl) -1-methyl-1-carbapen-2-em-3-carboxylic acid Sodium 12. (1S, 5R, 6S) -2- (2-Amino-4-ethoxycarbonylthiazol-5-ylethynyl) -1-methyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbapene-2 -M-3-carboxylic acid 4-nitrobenzyl group13. (1S, 5R, 6S) -2- (2-Amino-4-ethoxycarbonylthiazol-5-ylethynyl) -6-((1R) -1-hydroxyethyl) -1-methyl-1-carbapen-2-em -3-sodium carboxylate 14. (1S, 5R, 6S) -2- (4-Hydroxypyrimidin-5-ylethynyl) -1-methyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbapen-2-em-3- 14. 4-nitrobenzyl carboxylate (1S, 5R, 6S) -6-((1R) -1-hydroxyethyl) -2- (4-hydroxypyrimidin-5-ylethynyl) -1-methyl-1-carbapen-2-em-3-carboxylic acid Sodium 16. (1S, 5R, 6S) -2- (2-Aminopyrimidin-5-ylethynyl) -1-methyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbapen-2-em-3- 14. 4-nitrobenzyl carboxylate (1S, 5R, 6S) -2- (2-Aminopyrimidin-5-ylethynyl) -6-((1R) -1-hydroxyethyl) -1-methyl-1-carbapen-2-em-3-carboxylic acid Sodium 18. (1S, 5R, 6S) -1-Methyl-2- (pyridin-3-ylethynyl) -6-((1R) -1-triethylsilyloxyethyl) -1-carbapen-2-em-3-carboxylic acid 4 -Nitrobenzyl 19. (1S, 5R, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2- (pyridin-3-ylethynyl) -1-carbapen-2-em-3-carboxylate sodium

The carbapenem derivatives of the general formulas (I), (I ′) and (I ″) of the present invention have a wide and strong antibacterial activity against gram positive bacteria and gram negative bacteria. In particular, PRSP is included. It has strong antibacterial activity against various pathogens including pneumococci, H. influenzae including BLNAR and β-lactamase producing bacteria.
Of the carbapenem derivatives of the general formula (I) according to the present invention, the compound (I) in which R ⁴ is a group that is hydrolyzed in vivo exhibits oral absorption and is metabolically deesterified in vivo. The compounds of the general formula (I ′) and (I ″) according to the present invention can be used only as injections. However, the ester form is also useful as an oral preparation, and the carbapenem derivative of the present invention has low toxicity and high safety.
Of the carbapenem derivatives of general formula (I), R ³ is a 4-nitrobenzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, allyloxycarbonyl group, R ⁴ is a 4-nitrobenzyl group, 4-methoxybenzyl. Compound (I), which is a group, t-butyl group, allyl group, and silyl-type protecting group, is used for the synthesis of general formulas (I), (I ′) and (I ″) and other carbapenem compounds. It can be an important intermediate.
In addition, the introduction of an ethynyl group by a reaction using a base, palladium catalyst and copper salt (Sonogashira reaction) at the 2-position of the carbapenem ring not only avoids toxic tin compounds but also a trialkyl at the terminal site of acetylene. The coupling reaction can be carried out simply by omitting the introduction of tin groups.

［上記スキーム中で、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｔｆ、Ｈｙは前述で定義したものと同じ意味を表すが、上記スキームの（Ｉ’）、および、（Ｉ”）、（ＩＩ）、（ＩＶ）におけるＲ^４はカルボキシル基の保護基を表し、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-ブチル基、ｔ−ブチルジメチルシリル基、アリル基等を表す。
上記スキーム中の（Ｉ’）のＲ^４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、X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。］ The compound (I ′) in which R ⁴ of the general formula (I) according to the present invention is a hydrogen atom or a salt thereof can be preferably produced according to the following scheme.
<Scheme 1>

[In the above scheme, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Tf, Hy represent the same meaning as defined above, but (I ′) and (I ″ ^{), (II), (R} 4 in IV) represents a protecting group of carboxyl group, for example, 4-nitrobenzyl group, 4-methoxybenzyl group, diphenylmethyl group, t- butyl group, t- butyl dimethylsilyl group Represents an allyl group.
In the above scheme, R ⁴ of (I ′) represents a hydrogen atom or a metal ion such as potassium or sodium, X represents a leaving group, preferably a halogen atom, a diphenylphosphoryloxy group, p-toluenesulfonyloxy. Group, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, and the like. ]

  The compound of general formula (II) in the scheme in step (i) can be synthesized by a conventional method (for example, J. Org. Chem, 63, 5438 (1998)).

In step (i), an equivalent or excess amount of the compound of general formula (III) is added to a compound of general formula (II) in an appropriate solvent (acetone, 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) Bases (organic bases such as triethylamine, diisopropylamine, diisopropylethylamine, pyridine, etc., and inorganic bases such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, carbonate In the presence of cesium, etc., various palladium complexes (for example, dichlorobis (triphenylphosphine) palladium, bis (benzonitrile) palladium dichloride) and copper iodide, and trivalent phosphorus such as triphenylphosphine, tributylphosphine, and trifurylphosphine The reagent is reacted at −30 ° C. to 100 ° C. for 10 minutes to 72 hours. After the reaction, when R ⁵ is heteroaryl, (I ″) is obtained when R ⁵ is a heteroaryl, (IV) when R ⁵ is a hydrogen atom, and (I ′) when R ⁵ is a silyl protecting group. A compound can be obtained.

Next, the conversion from the general formula (I ′) to the compound of (IV) in the step (ii) is performed when R ⁵ is a silyl protecting group. The compound of general formula (I ′) is converted into 10 equivalents or less of acetic acid and tetra n-butylammonium fluoride in a suitable solvent (acetone, acetonitrile, dichloromethane, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, etc.). And react at −80 ° C. to 50 ° C. for 5 minutes to 24 hours. After the reaction, the compound of the general formula (IV) can be obtained by ordinary post-treatment. (This step is not performed when R ⁵ is a hydrogen atom or a substituted or unsubstituted heteroaryl group.)

In step (iii), the general formula (IV) and equivalent or excess amount of the general formula general formula in the same manner as (V) from step (i) (I ") can be obtained. (R ⁵ is a substituted or (This step is not performed in the case of an unsubstituted heteroaryl group.)

Finally, in step (iv), when protecting groups R ³ and R ^{4 of} compounds (IV) and (I ″), and further R ⁵ contains a protecting group, the protecting group is deprotected, and the general formula according to the present invention A compound represented by (I ′) in which R ^{3 in} (I) is a hydrogen atom, R ⁴ is a hydrogen atom, or a salt thereof is included in the protective groups R ³ and R ⁴ , and further included in R ⁵ The deprotection reaction for removal of the protecting group can be carried out according to the usual methods generally known in the art depending on the type of protecting group used, either or all of which can be deprotected under acidic conditions. In case of reduction, use mineral acid such as hydrochloric acid, organic acid such as formic acid, acetic acid, citric acid, trifluoroborane-diethyl ether complex, or Lewis acid such as tetra n-butylammonium fluoride, aluminum chloride, etc. Article When removed under the conditions, catalytic reduction with various catalysts or metal reducing agents such as zinc and iron can be used, and R ³ is an allyloxycarbonyl group and R ⁴ is an allyl group. When the protecting group contained on the substituent of R ² is an allyloxycarbonyl group or an allyl group, it is easy to use various palladium complexes (eg, tetrakis (triphenylphosphine) palladium (0)). Can be removed.

The compound of the general formula (I ′) in which R ³ in the general formula (I) thus obtained is a hydrogen atom, R ⁴ is a hydrogen atom, or a salt thereof is a nonionic macrohypoporous resin. It can be isolated and purified by using chromatography, gel filtration using Sephadex, etc., reverse phase silica gel column chromatography or the like.

［上記スキーム２中で、Ｒ^１、Ｒ^５は一般式（Ｉ）で定義したものと同じ意味を表し、スキーム２の（Ｉ’）のＲ⁴は水素原子、または金属イオン（カリウム、ナトリウムなど）などの塩を表し、Ｒ^６は生体内で加水分解される基（前述にて「Ｒ^４が生体内で加水分解される基である場合」で定義したものと同じ意味を表す）を表し、Yはハロゲン原子、−ＯＳＯ₂ＣＦ₃、−ＯＳＯ₂ＣＨ₃、−ＯＳＯ₂ＰｈＣＨ₃等の脱離基を表す。］ Of the compounds of the general formula (I) according to the present invention, the compound in which R ⁴ is a group that is hydrolyzed in vivo (in the following scheme 2, (VII)) is preferably produced according to the following scheme. Can do.
<Scheme 2>

[In scheme 2 above, R ¹ and R ⁵ represent the same meaning as defined in formula (I), and R ^{4 in} (I ′) in scheme 2 represents a hydrogen atom or a metal ion (potassium, sodium, etc. ), And R ⁶ represents a group that is hydrolyzed in vivo (which has the same meaning as defined above for “when R ⁴ is a group that is hydrolyzed in vivo”). , Y represents a leaving group such as a halogen 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 of alkyl halide (R ⁶ -X: for example, pivaloyloxymethyl iodide) Id, 1- (pivaloyloxy) ethyl iodide, isobutyryloxymethyl iodide, 1- (isobutyryloxy) ethyl iodide, acetoxymethyl bromide, 1- (acetoxy) ethyl bromide, (1-methylcyclohexane-1 -Yl) carbonyloxymethyl iodide, 1- (cyclohexane Siloxycarbonyloxy) 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, phenyloxycarbonyloxymethyl 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.) in a single or mixed 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, chloroform, Toluene, (I ″) by reacting at −70 to + 50 ° C. (preferably −30 ° C. to + 20 ° C.) for 10 minutes to 24 hours in benzene, hexamethylphosphoric triamide, methanol, ethanol, etc. Can do.
The ester 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 compounds according to the present invention have a broad and potent antibacterial activity against gram-positive and gram-negative bacteria, and also include pneumococci including PRSP, H. influenzae including BLNAR, and β- Has strong antibacterial activity against lactamase-producing bacteria. In addition, it has low toxicity and is stable against dehydropeptidase (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. It can also be used as a 2-ethynyl-based carbapenem agent and other important intermediates of carbapenem.
In particular, a compound in which R ⁴ in the general formula (I) is a group that can be hydrolyzed in vivo is excellent in oral absorbability and has the advantage that it can be used as an oral preparation.
A pharmaceutical composition comprising the compound according to the present invention and a pharmacologically acceptable salt thereof as an active ingredient is orally or parenterally (for example, intravenous injection, intramuscular injection, subcutaneous administration, rectal administration, transdermal administration). It can be administered to humans and non-human animals by any route of administration. 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.

Example 1 (1S, 5R, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-trimethylsilylethynyl-1-carbapene-2-em-3-carboxylic acid 4-nitro Benzyl (1R, 3R, 5R, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-oxo-1-carbapenam-3-carboxylic acid 4-nitrobenzyl 5.16 g of dry acetonitrile To the 70 ml solution, 3.70 ml of N, N-diisopropylethylamine and then 2.43 ml of trifluoromethanesulfonic anhydride were added dropwise at −40 ° C. under an argon atmosphere. After stirring for 30 minutes at the same temperature, 350 ml of ethyl acetate was added, and a mixed solution of half-saturated saline, half-saturated saline and 1N hydrochloric acid (pH 1.1), mixed solution of half-saturated saline and saturated sodium bicarbonate water (pH 8). .9) and sequentially washed with half-saturated saline. The extract was dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 50 ml of dry DMF (N, N-dimethylformamide), and 3.01 ml of trimethylsilylacetylene, 200 mg of dichloro (bistriphenylphosphine) palladium, 27 mg of copper iodide and 5.03 ml of triethylamine were added, and argon atmosphere was added. The mixture was stirred at 45 ° C. for 2 hours and then at room temperature for 3 hours. 200 ml of ethyl acetate was added to the reaction solution, washed three times with 200 ml of half-saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 5.76 g of the title compound.

NMR (CDCl ₃ ) δ: 0.20 (9H, s), 1.26 (3H, d, J = 7.3 Hz), 1.34 (3H, d, J = 6.3 Hz), 3.25 ( 1H, m), 3.37 (1H, m), 4.23-4.34 (2H, m), 5.30 (1H, d, J = 13.9 Hz), 5.50 (1H, d, J = 13.9 Hz), 7.65 (2H, d, J = 8.8 Hz), 8.23 (2H, d, J = 8.8 Hz)

Example 2 4-nitrobenzyl (1S, 5R, 6S) -2-ethynyl-6-((1R) -1-hydroxyethyl) -1-methyl-1-carbapen-2-em-3-carboxylate Of 5.76 g of 4-nitrobenzyl (1S, 5R, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-trimethylsilylethynyl-1-carbapen-2-em-3-carboxylate To a 70 ml solution of THF (tetrahydrofuran), 4.11 ml of acetic acid and then 21.3 ml of a THF solution (1.0 M) of tetra n-butylammonium fluoride were added dropwise at room temperature. After stirring at the same temperature for 15 minutes, 350 ml of ethyl acetate was added, washed with 350 ml of half-saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and then recrystallized from chloroform-methanol-diethyl ether. To obtain 2.60 g of the title compound.

NMR (DMSO-d ₆ ) δ: 1.11 (3H, d, J = 6.3 Hz), 1.14 (3H, d, J = 7.6 Hz), 3.23-3.32 (4H, m ), 3.46 (1H, m), 3.98 (1H, m), 4.28 (1H, m), 5.35 (1H, d, J = 14.1 Hz), 5.46 (1H, d, J = 14.1 Hz), 7.73 (2H, d, J = 8.7 Hz), 8.24 (2H, d, J = 8.7 Hz)

Example 3 (1S, 5R, 6S) -1-Methyl-2-trimethylsilylethynyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbapene-2-em-3-carboxylic acid 4 -Nitrobenzyl (1R, 3R, 5R, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-oxo-1-carbapenam-3-carboxylic acid 4-nitrobenzyl (22.7 g) To a mixed solution of 150 ml of dry acetonitrile and 100 ml of dry dichloromethane, 16.4 ml of N, N-diisopropylethylamine and then 10.5 ml of trifluoromethanesulfonic anhydride were added dropwise at −40 ° C. under an argon atmosphere. After stirring at the same temperature for 10 minutes, 10.9 ml of N, N-diisopropylethylamine and 15.6 ml of triethylsilyl trifluoromethanesulfonate were added dropwise and stirred at the same temperature. After 20 minutes, 750 ml of ethyl acetate was added, and the mixture was washed successively with a mixed solution of half-saturated saline and a saturated aqueous ammonium chloride solution, a mixed solution of half-saturated saline and saturated sodium bicarbonate, and half-saturated saline twice. The extract was dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 150 ml of dry DMF, 13.3 ml of trimethylsilylacetylene, 880 mg of dichloro (bistriphenylphosphine) palladium, 119 mg of copper iodide and 17.4 ml of triethylamine were added, and the mixture was stirred at 40 ° C. for 1.5 hours under an argon atmosphere. did. 750 ml of ethyl acetate was added to the reaction solution, washed 3 times with 750 ml of half-saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain 28.1 g of the title compound.

NMR (CDCl ₃ ) δ: 0.00 (9H, s), 0.60 (6H, q, J = 7.9 Hz), 0.94 (9H, t, J = 7.9 Hz), 1.33- 1.37 (6H, m), 3.20 (1H, m), 3.32 (1H, m), 4.20-4.30 (2H, m), 5.30 (1H, d, J = 13.9 Hz), 5.47 (1 H, d, J = 13.9 Hz), 7.65 (2 H, d, J = 8.7 Hz), 8.22 (2 H, d, J = 8.7 Hz)

Example 4 (1S, 5R, 6S) -2-ethynyl-1-methyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbapene-2-em-3-carboxylic acid 4- Nitrobenzyl (1S, 5R, 6S) -1-methyl-2-trimethylsilylethynyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl To a solution of 28.1 g of dichloromethane in 500 ml, 0.569 ml of acetic acid and then 9.84 ml of a solution of tetra n-butylammonium fluoride in THF (1.0 M) were added dropwise. The mixture was stirred at the same temperature for 5 minutes, washed twice with 500 ml of half-saturated saline, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and then recrystallized from dichloromethane-hexane to obtain 18.5 g of the title compound. It was.

NMR (CDCl ₃ ) δ: 0.61 (6H, t, J = 7.8 Hz), 0.95 (9H, q, J = 7.8 Hz), 1.25 (6H, m), 3.23 ( 1H, m), 3.34 (1H, m), 3.70 (1H, s), 4.26 (1H, m), 4.33 (1H, m), 5.31 (1H, d, J = 13.8 Hz), 5.46 (1H, d, J = 13.8 Hz), 7.66 (2H, d, J = 8.8 Hz), 8.22 (2H, d, J = 8.8 Hz)

Example 5 (1S, 5R, 6S) -2- (3-Hydroxypropyn-1-yl) -1-methyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbapene- 2-Nitrobenzyl 2-em-3-carboxylate (1R, 3R, 5R, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-oxo-1-carbapenam-3-carvone In the same manner as in Example 3, 1.69 g of the title compound was obtained from 3.62 g of acid 4-nitrobenzyl and 0.873 ml of propargyl alcohol.

NMR (CDCl ₃ ) δ: 0.60 (6H, q, J = 7.8 Hz), 0.95 (9H, t, J = 7.8 Hz), 1.22-1.28 (6H, m), 1.85 (1H, t, J = 6.3 Hz), 3.20 (1H, m), 3.32 (1H, m), 4.21-4.34 (2H, m), 4.50 ( 2H, d, J = 6.3 Hz), 5.29 (1H, d, J = 13.9 Hz), 5.46 (1H, d, J = 13.9 Hz), 7.66 (2H, d, J = 8.8 Hz), 8.22 (2H, d, J = 8.8 Hz)

[Example 6] (1S, 5R, 6S) -1-methyl-2-trimethylsilylethynyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbapene-2-em-3-carboxylic acid 4 -Pivaloyloxymethyl (3S, 4S) -3-((R) -1-hydroxyethyl) -3-diazo-4-((R) -1-methyl) -3-pivaloyloxy under argon atmosphere Methylcarbonyl-2-oxopropyl) -azetidin-2-one (WO2004 / 035539) To 35 ml of a toluene solution of 2.13 g, 18 mg of (rhodium octoate) dimer was added and stirred at 45 ° C. for 3.5 hours. After adding 35 ml of dry acetonitrile to the reaction solution and cooling to −40 ° C., 1.50 ml of N, N-diisopropylethylamine and then 0.969 ml of trifluoromethanesulfonic anhydride were added dropwise. After stirring at the same temperature for 30 minutes, 1.00 ml of N, N-diisopropylethylamine and 1.43 ml of triethylsilyl trifluoromethanesulfonate were added dropwise and stirred at the same temperature. After 20 minutes, 150 ml of ethyl acetate was added, and the mixture was washed successively with a mixed solution of a half-saturated saline solution and a saturated aqueous ammonium chloride solution, a mixed solution of a half-saturated saline solution and a saturated sodium bicarbonate solution, and twice a half-saturated saline solution. The extract was dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 25 ml of dry DMF, 1.22 ml of trimethylsilylacetylene, 81 mg of dichloro (bistriphenylphosphine) palladium, 11 mg of copper iodide and 1.60 ml of triethylamine were added, and the mixture was stirred at 45 ° C. for 1.5 hours under an argon atmosphere. did. 100 ml of ethyl acetate was added to the reaction solution, washed 3 times with 100 ml of half-saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain 2.46 g of the title compound.

NMR (CDCl ₃ ) δ: 0.24 (9H, s), 0.59 (6H, q, J = 7.9 Hz), 0.95 (9H, t, J = 7.9 Hz), 1.12 ( 9H, s), 1.23-1.27 (6H, m), 3.18 (1H, m), 3.28 (1H, m), 4.18-4.24 (2H, m), 5 .87 (1H, d, J = 5.5 Hz), 5.94 (1H, d, J = 5.5 Hz)

[Example 7] (1S, 5R, 6S) -2-ethynyl-1-methyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbapene-2-em-3-carboxylic acid pivalo Iyloxymethyl (1S, 5R, 6S) -1-methyl-2-trimethylsilylethynyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbapen-2-em-3-carboxylic acid 4-pi In the same manner as in Example 4, 1.50 g of the title compound was obtained from 2.46 g of valoyloxymethyl.

NMR (CDCl ₃ ) δ: 0.60 (6H, t, J = 7.8 Hz), 0.95 (9H, q, J = 7.8 Hz), 1.21 (9H, s), 1.22- 1.26 (6H, m), 3.20 (1H, m), 3.30 (1H, m), 3.68 (1H, s), 4.18-4.29 (2H, m), 5 .87 (1H, d, J = 5.6 Hz), 5.96 (1H, d, J = 5.6 Hz)

Example 8 (1S, 5R, 6S) -2- [imidazo [5,1-b] thiazol-2-ylethynyl] -1-methyl-6-((1R) -1-triethylsilyloxyethyl)- 1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl (1S, 5R, 6S) -2-ethynyl-1-methyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbapene 2-Nitrobenzyl 807 mg of 2-m-3-carboxylic acid was dissolved in 10 ml of DMF, 416 mg of 2-iodoimidazo [5,1-b] thiazole, 23 mg of dichloro (bistriphenylphosphine) palladium, 3 mg of copper iodide, triethylamine 0 .470 ml was added, and the mixture was stirred at 35 ° C. for 30 minutes under an argon atmosphere. 50 ml of ethyl acetate was added to the reaction solution, washed 3 times with 50 ml of half-saturated brine, 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 = 30: 1) to obtain 960 mg of the title compound.

NMR (CDCl ₃ ) δ: 0.61 (6H, t, J = 7.8 Hz), 0.96 (9H, q, J = 7.8 Hz), 1.28 (6H, m), 3.32 ( 1H, m), 3.38 (1H, m), 4.28 (1H, m), 4.38 (1H, m), 5.33 (1H, d, J = 13.9 Hz), 5.48 (1H, d, J = 13.9 Hz), 7.07 (1H, brs), 7.54 (1H, s), 7.67 (2H, d, J = 8.7 Hz), 8.00 (1H , Brs), 8.22 (2H, d, J = 8.7 Hz)

Example 9 (1S, 5R, 6S) -6-((1R) -1-hydroxyethyl) -2- [imidazo [5,1-b] thiazol-2-ylethynyl] -1-methyl-1- Sodium carbapen-2-em-3-carboxylate a) (1S, 5R, 6S) -6-((1R) -1-hydroxyethyl) -2- [imidazo [5,1-b] thiazol-2-ylethynyl ] 1-methyl-1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl (1S, 5R, 6S) -2- [imidazo [5,1-b] thiazol-2-ylethynyl] -1- 965 mg of 4-nitrobenzyl methyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbapene-2-em-3-carboxylate was dissolved in 30 ml of THF and 6 ml of water, and 0.1N hydrochloric acid was added at 35 ° C. 16 l for 2 hours with stirring added. 100 ml of ethyl acetate was added to the reaction solution, washed successively with 100 ml of half-saturated aqueous sodium bicarbonate and 100 ml of saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was washed with dichloromethane and (1S, 5R, 6S) -6-((1R) -1-hydroxyethyl) -2- [imidazo [5,1-b] thiazol-2-ylethynyl] -1 506 mg of 4-nitrobenzyl 4-methyl-1-carbapene-2-em-3-carboxylate was obtained.

NMR (DMSO-d ₆ ) δ: 1.16 (3H, d, J = 6.3 Hz), 1.22 (3H, d, J = 7.3 Hz), 3.42 (1H, m), 3. 51 (1H, m), 4.04 (1H, m), 4.36 (1H, m), 5.38 (1H, d, J = 13.8 Hz), 5.50 (1H, d, J = 13.8 Hz), 7.02 (1 H, s), 7.74 (2 H, d, J = 8.7 Hz), 8.19-8.23 (4 H, m)

b) (1S, 5R, 6S) -6-((1R) -1-hydroxyethyl) -2- [imidazo [5,1-b] thiazol-2-ylethynyl] -1-methyl-1-carbapene-2 -Sodium M-3-carboxylate (1S, 5R, 6S) -6-((1R) -1-hydroxyethyl) -2- [imidazo [5,1-b] thiazol-2-ylethynyl] -1-methyl 659 mg of 4-nitrobenzyl 4-carbapene-2-em-3-carboxylate was dissolved in 25 ml of THF and 25 ml of 0.3 M sodium phosphate buffer (pH 6.0), and 4.38 g of zinc powder was added. The reaction vessel was replaced with argon and stirred at 35 ° C. for 4 hours. Zinc was filtered off and washed with water. The filtrate was washed with ethyl acetate, concentrated under reduced pressure to about 20 ml, and purified by column chromatography using Cosmosil 40C18-PREP (10% aqueous methanol) to obtain 170 mg of the title compound.

NMR (D ₂ O) (HOD = 4.65 ppm) δ: 1.10 (3H, d, J = 7.3 Hz), 1.33 (3H, d, J = 6.3 Hz), 3.19 (1H , M), 3.41 (1H, m), 4.13 (1H, m), 4.19 (1H, m), 6.89 (1H, s), 7.80 (1H, s), 8 .05 (1H, s)

Example 10 (1S, 5R, 6S) -2- (2-carbamoylthiazol-5-ylethynyl) -1-methyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbapene-2 -M-3-carboxylic acid 4-nitrobenzyl (1S, 5R, 6S) -2-ethynyl-1-methyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbapen-2-em In the same manner as in Example 8, 223 mg of the title compound was obtained from 178 mg of 4-nitrobenzyl 3-carboxylate and 93 mg of 2-carbamoyl-5-iodothiazole.

NMR (CDCl ₃ ) δ: 0.62 (6H, t, J = 7.8 Hz), 0.96 (9H, q, J = 7.8 Hz), 1.25-1.31 (6H, m), 3.30-3.41 (2H, m), 4.28 (1 H, m), 4.38 (1 H, m), 5.32 (1 H, d, J = 13.6 Hz), 5.48 ( 1H, d, J = 13.6 Hz), 5.61 (1H, brs), 7.05 (1H, brs), 7.65 (2H, d, J = 8.7 Hz), 7.82 (1H, s), 8.20 (2H, d, J = 8.7 Hz)

Example 11 (1S, 5R, 6S) -2- (2-carbamoylthiazol-5-ylethynyl) -6-((1R) -1-hydroxyethyl) -1-methyl-1-carbapen-2-em Sodium 3-carboxylate (1S, 5R, 6S) -2- (2-carbamoylthiazol-5-ylethynyl) -1-methyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbapene- 46 mg of the title compound was obtained in the same manner as in Example 9 from 223 mg of 4-nitrobenzyl 2-m-3-carboxylate.

NMR (D ₂ O) (HOD = 4.65 ppm) δ: 1.10 (3H, d, J = 7.3 Hz), 1.16 (3H, d, J = 6.3 Hz), 3.21 (1H , M), 3.42 (1H, m), 4.13 (1H, m), 4.20 (1H, m), 7.94 (1H, s)

Example 12 (1S, 5R, 6S) -2- (2-amino-4-ethoxycarbonylthiazol-5-ylethynyl) -1-methyl-6-((1R) -1-triethylsilyloxyethyl)- 1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl (1S, 5R, 6S) -2-ethynyl-1-methyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbapene In the same manner as in Example 8, 496 mg of the title compound was obtained from 163 mg of 2-nitrobenzyl 4-em-3-carboxylate and 163 mg of 2-amino-5-iodo-4-ethoxycarbonylthiazole.

NMR (DMSO-d ₆ ) δ: 0.70 (6H, t, J = 7.8 Hz), 0.90 (9H, q, J = 7.8 Hz), 1.15-1.25 (9H, m ), 3.45-3.65 (2H, m), 4.15-4.26 (3H, m), 4.34 (1H, m), 5.36 (1H, d, J = 13.6 Hz) ), 5.45 (1H, d, J = 13.6 Hz), 7.70 (2H, d, J = 8.8 Hz), 8.17 (2H, d, J = 8.7 Hz)

Example 13 (1S, 5R, 6S) -2- (2-amino-4-ethoxycarbonylthiazol-5-ylethynyl) -6-((1R) -1-hydroxyethyl) -1-methyl-1- Sodium carbapen-2-em-3-carboxylate (1S, 5R, 6S) -2- (2-amino-4-ethoxycarbonylthiazol-5-ylethynyl) -1-methyl-6-((1R) -1- In the same manner as in Example 9, 17 mg of the title compound was obtained from 496 mg of 4-nitrobenzyl triethylsilyloxyethyl) -1-carbapene-2-em-3-carboxylate.

NMR (D ₂ O) (HOD = 4.65 ppm) δ: 1.07-1.15 (6H, m), 1.20 (3H, t, J = 7.1 Hz), 3.18 (1H, m ), 3.38 (1H, m), 4.10 (1H, m), 4.15-4.24 (3H, m)

[Example 14] (1S, 5R, 6S) -2- (4-hydroxypyrimidin-5-ylethynyl) -1-methyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbapene-2 -M-3-carboxylic acid 4-nitrobenzyl (1S, 5R, 6S) -2-ethynyl-1-methyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbapen-2-em 67 mg of the title compound was obtained from 100 mg of 4-nitrobenzyl 3-carboxylate, 4-hydroxy-5-iodopyrimidine [Chem. Pharm. Bull. 34 (7) 2719 (1986)] in the same manner as in Example 8. It was.

NMR (CDCl ₃ ) δ: 0.61 (6H, t, J = 7.8 Hz), 0.96 (9H, q, J = 7.8 Hz), 1.25-1.34 (6H, m), 3.32-3.40 (2H, m), 4.28 (1H, m), 4.36 (1H, m), 5.33 (1H, d, J = 13.6 Hz), 5.49 ( 1H, d, J = 13.6 Hz), 7.67 (2H, d, J = 8.8 Hz), 8.13 (2H, m), 8.19 (2H, d, J = 8.7 Hz)

Example 15 (1S, 5R, 6S) -6-((1R) -1-hydroxyethyl) -2- (4-hydroxypyrimidin-5-ylethynyl) -1-methyl-1-carbapen-2-em -3-Sodium carboxylate (1S, 5R, 6S) -2- (4-hydroxypyrimidin-5-ylethynyl) -1-methyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbapene- In substantially the same manner as in Example 9, 23 mg of the title compound was obtained from 234 mg of 2-m-3-carboxylic acid 4-nitrobenzyl.

NMR (D ₂ O) (HOD = 4.65 ppm) δ: 1.11 (3H, d, J = 7.4 Hz), 1.15 (3H, d, J = 6.4 Hz), 3.21 (1H , M), 3.40 (1H, m), 4.11 (1H, m), 4.18 (1H, m), 8.14 (1H, s), 8.19 (1H, s)

Example 16 (1S, 5R, 6S) -2- (2-aminopyrimidin-5-ylethynyl) -1-methyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbapene-2 -M-3-carboxylic acid 4-nitrobenzyl (1S, 5R, 6S) -2-ethynyl-1-methyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbapen-2-em 485 mg of 4-nitrobenzyl 3-carboxylate was dissolved in 5 ml of dry 1,4-dioxane, 221 mg of 2-amino-5-iodopyrimidine, 11 mg of bis (benzonitrile) palladium dichloride, 4 mg of copper iodide, tri-t-butyl. Phosphine (12 mg) and diisopropylamine (0.210 ml) were added, and the mixture was stirred at 35 ° C. for 13 hours under an argon atmosphere. 40 ml of ethyl acetate was added to the reaction solution, washed with 20 ml of half-saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane: ethyl acetate = 2: 1) to give 536 mg of the title compound.

NMR (CDCl ₃ ) δ: 0.61 (6H, t, J = 7.8 Hz), 0.96 (9H, q, J = 7.8 Hz), 1.28 (6H, m), 3.27 ( 1H, m), 3.35 (1H, m), 4.27 (1H, m), 4.33 (1H, m), 5.33 (3H, m), 5.47 (1H, d, J = 13.8 Hz), 7.65 (2H, d, J = 8.7 Hz), 8.19 (2H, d, J = 8.7 Hz), 8.29 (2H, s)

[Example 17] (1S, 5R, 6S) -2- (2-aminopyrimidin-5-ylethynyl) -6-((1R) -1-hydroxyethyl) -1-methyl-1-carbapen-2-em -3-Sodium carboxylate (1S, 5R, 6S) -2- (2-aminopyrimidin-5-ylethynyl) -1-methyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbapene- In the same manner as in Example 9, 86 mg of the title compound was obtained from 500 mg of 4-nitrobenzyl 2-m-3-carboxylate.

NMR (DMSO-d ₆ ) δ: 1.06 (3H, d, J = 6.3 Hz), 1.12 (3H, d, J = 7.3 Hz), 2.95 (1H, m), 3. 12 (1H, m), 3.90 (1H, m), 4.05 (1H, m), 7.02 (2H, s), 8.23 (2H, s)

Example 18 (1S, 5R, 6S) -1-Methyl-2- (pyridin-3-ylethynyl) -6-((1R) -1-triethylsilyloxyethyl) -1-carbapen-2-em 4-Nitrobenzyl 3-carboxylate (1S, 5R, 6S) -2-ethynyl-1-methyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbapen-2-em-3-carboxylic In the same manner as in Example 16, 401 mg of the title compound was obtained from 485 m of acid 4-nitrobenzyl and 205 mg of 3-iodopyridine.

NMR (CDCl ₃ ) δ: 0.62 (6H, t, J = 7.8 Hz), 0.97 (9H, q, J = 7.8 Hz), 1.24-1.34 (6H, m), 3.29-3.38 (2H, m), 4.28 (1H, m), 4.36 (1H, m), 5.32 (1H, d, J = 13.6 Hz), 5.48 ( 1H, d, J = 13.6 Hz), 7.66 (3H, m), 8.18 (2H, d, J = 8.7 Hz), 8.55 (1 H, m), 8.64 (1 H, s)

Example 19 (1S, 5R, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2- (pyridin-3-ylethynyl) -1-carbapen-2-em-3- Sodium carboxylate (1S, 5R, 6S) -1-methyl-2- (pyridin-3-ylethynyl) -6-((1R) -1-triethylsilyloxyethyl) -1-carbapen-2-em-3- In the same manner as in Example 9, 117 mg of the title compound was obtained from 268 mg of 4-nitrobenzyl carboxylate.

NMR (D ₂ O) (HOD = 4.65 ppm) δ: 1.27 (3H, d, J = 7.3 Hz), 1.30 (3H, d, J = 6.3 Hz), 3.34 (1H , M), 3.55 (1H, m), 4.24-4.35 (2H, m), 7.47 (1H, m), 7.98 (1H, m), 8.48 (1H, m), 8.63 (1H, s)

Synthesis Example 1 2-Iodoimidazo [5,1-b] thiazole 2- (tri-n-butylstannyl) imidazo [5,1-b] thiazole [WO98 / 32760] 4.51 g was dissolved in 55 ml of THF, and N -Iodosuccinimide 2.45g was added, and it stirred at -50 degreeC under argon atmosphere for 10 minutes, Then, it stirred at room temperature for 30 minutes. Chloroform was added to the reaction solution, washed three times with half-saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was washed with hexane to obtain 2.20 g of the title compound.

NMR (CDCl ₃ ) δ: 7.03 (1H, s), 7.52 (1H, s), 7.93 (1H, s)

[Synthesis Example 2] 2-carbamoyl-5-iodothiazole a) 2-carbamoylthiazole thiazole-2-carboxylic acid [Acta Chemica Scandinavica (1947-1973), 22 (2), 694, (1968)] 1.12 g 0,888 ml of oxalyl chloride was added dropwise to a mixed solution of 20 ml of dichloromethane and 20 ml of THF under ice cooling, followed by stirring at 40 ° C. for 30 minutes. After adding 10 ml of aqueous ammonia under ice cooling and stirring at room temperature for 1 hour, the reaction solution was extracted with chloroform three times, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 956 mg of 2-carbamoylthiazole.

NMR (DMSO-d ₆ ) δ: 7.84 (1H, brs), 7.99 (1H, d, J = 3.2 Hz), 8.02 (1H, d, J = 3.2 Hz), 8. 16 (1H, brs)

b) 2-carbamoyl-5- (tri-n-butylstannyl) thiazole 7.77 ml of tri-n-butylstannyl chloride in 80 ml of a dry THF solution of 2.45 g of 2-carbamoylthiazole at −40 ° C. under an argon atmosphere, 95 ml of a THF solution (1.0 M) of lithium bis (trimethylsilyl) amide was sequentially added, followed by stirring at −20 ° C. for 7 hours. A saturated ammonium chloride solution and ethyl acetate were added to the reaction solution, and the mixture was separated. The organic layer was washed with half-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 (hexane: ethyl acetate = 2: 1) to obtain 4.96 g of 2-carbamoyl-5- (tri-n-butylstannyl) thiazole.

NMR (CDCl ₃ ) δ: 0.88 (9H, t, J = 7.3 Hz), 1.16 (6H, m), 1.33 (6H, m), 1.55 (6H, m), 5 .60 (1H, brs), 7.13 (1H, brs), 7.88 (1H, s)

c) 2-carbamoyl-5-iodothiazole 1.88 g of 2-carbamoyl-5-iodothiazole was obtained from 4.96 g of 2-carbamoyl-5- (tri-n-butylstannyl) thiazole in substantially the same manner as in Synthesis Example 1. .

NMR (DMSO-d ₆ ) δ: 7.92 (1H, brs), 8.11 (1H, s), 8.18 (1H, brs)

Test Example 1 Antibacterial Activity The following are the minimum growth inhibitory concentrations (MIC, μg / mL) of various representative carbapenem derivatives of the present invention for various pathogens, CHEMOTHERAPY, vol. 16, No. 1, 99, 1968. The measurement was performed according to the described method, and the results are shown in Table 1. The measurement medium is Sensitivity Disk agar-N + 5% Horse blood, and the amount of inoculum is 10 ⁶ CFU / mL.

本発明の一般式（Ｉ）のカルバペネム誘導体は、ＰＲＳＰを含む肺炎球菌、ＢＬＮＡＲを含むインフルエンザ菌及びβ−ラクタマーゼ産生菌を含む各種病原菌に対して強い抗菌力を有している。

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.

The present invention provides a carbapenem derivative having strong antibacterial activity against Streptococcus pneumoniae including PRSP, Haemophilus influenzae including BLNAR and β-lactamase-producing bacteria, and carbapenem by a highly safe and useful technique on an industrial scale. We found a method for introducing an ethynyl group into the 2-position of the ring.

Claims (10)

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

[In the above formula,
R ¹ represents a methyl group hydrogen atom,
R ² is
Hydrogen atom,
Silyl protecting groups pyridine substituted pyridine thiazole substituted thiazole pyrimidine substituted pyrimidine imidazothiazole substituted imidazothiazole thiadiazole substituted thiadiazole imidazole substituted imidazole pyrazine substituted pyrazine pyrazole substituted pyrazole triazole substituted And triazole triazine substituted triazine
R ³ represents a hydrogen atom silyl-based protecting group 4-nitrobenzyloxycarbonyl group 4-methoxybenzyloxycarbonyl group allyloxycarbonyl group; R ⁴ represents a hydrogen atom or a group that can be hydrolyzed in vivo; A nitrobenzyl group, a 4-methoxybenzyl group, a diphenylmethyl group, a t-butyl group, an allyl group, and a silyl protecting group are shown. R ² is
A hydrogen atom imidazo [5,1-b] thiazole substituted imidazo [5,1-b] thiazolethiazole substituted thiazolepyrimidine substituted pyrimidinepyridine substituted pyridinesilyl protecting group;
Showing,
The compound according to claim 1 or a pharmaceutically acceptable salt thereof. R ² is
Hydrogen atom,
Imidazo [5,1-b] thiazol-2-yl group 2-carbamoylthiazol-5-yl group,
2-amino-4-ethoxycarbonylthiazol-5-yl group,
4-hydroxypyrimidin-5-yl group 2-aminopyrimidin-5-yl group pyridin-3-yl group or trimethylsilyl group,
Triethylsilyl group,
t-butyldimethylsilyl group, or triisopropylsilyl group,
Showing,
The compound according to claim 1 or a pharmaceutically acceptable salt thereof. A production method of general formula (I ′),

Compound of general formula (II) and compound of general formula (III)

[Wherein R ¹ represents a hydrogen atom, a methyl group,
R ³ is a hydrogen atom, a silyl protecting group, a 4-nitrobenzyloxycarbonyl group, a 4-methoxybenzyloxycarbonyl group, an allyloxycarbonyl group,
R ⁴ represents a hydrogen atom or a group that can be hydrolyzed in vivo, a 4-nitrobenzyl group, a 4-methoxybenzyl group, a t-butyl group, an allyl group, a silyl-based protecting group,
R ⁵ represents a hydrogen atom, a silyl-based protecting group, an unsubstituted or substituted heteroaryl group,
Tf represents a trifluoromethanesulfonyl group]
In the presence of a base, a palladium catalyst, and a copper salt, an additive such as trivalent phosphorus may be added as necessary, and the reaction may be optionally performed. Production method of formula (I ′). A process for producing a compound of general formula (I "),

Compound of general formula (IV) and compound of general formula (V)

[Wherein, R ¹ represents a hydrogen atom, methyl group bonded to the 1-position of the carbapenem ring,
R ³ is a hydrogen atom, a silyl protecting group, a 4-nitrobenzyloxycarbonyl group, a 4-methoxybenzyloxycarbonyl group, an allyloxycarbonyl group,
R ⁴ represents a hydrogen atom or a group that can be hydrolyzed in vivo, a 4-nitrobenzyl group, a 4-methoxybenzyl group, a t-butyl group, an allyl group, a silyl-based protecting group,
Hy is an unsubstituted or substituted heteroaryl group,
X represents a leaving group], and in the presence of a base, a palladium catalyst, and a copper salt, an additive such as trivalent phosphorus is added as necessary, and the reaction is performed. A process for the preparation of general formula (I "), which may comprise a step. The compound according to any one of claims 1 to 3, wherein R ¹ is a methyl group. The compound according to any one of claims 1 to 3, wherein R ⁴ is a group capable of being hydrolyzed in vivo. The pharmaceutical composition containing the compound as described in any one of Claims 1-3 or 6-7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 3 or 6 to 8 and a pharmaceutically acceptable carrier. The pharmaceutical composition according to any one of claims 1 to 3 or 6 to 9, which is used as an antibacterial agent.