JPH06172356A - Carbapenem-3-carboxylic acid derivative - Google Patents

Abstract

PURPOSE:To obtain the subject new compound useful as an antimicrobial agent, having stability to dehydropeptidase I and high recovery ratio in urine. CONSTITUTION:A compound of formula I {R<1> is H or methyl; R<2> is H, (substituted) lower alkyl, lower alkenyl, C(=NH)R<9> (R<9> is H or lower alkyl), etc.; R<10> are H or ester residue; A is group of formula II [(n) is 1-3; R<3> to R<5> are H, lower alkyl, etc.; R<6> and R<7> are H, halogen, (substituted) lower alkyl, OH, amino, etc.] or group of formula III [(m) is 0-2; (d) is 0 or 1; R<8> is H, (substituted) lower alkyl, etc.; R<9> is H, (substituted) lower alkyl, F, OH, etc.], etc.} such as (1R,5S,6S)-2-[(2S,4S)-2-(4-amidinopiperazin-1-ylcarbonyl)pyrrolidin-4- ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylic acid. The compound of formula I is synthesized from a compound of formula IV (R<14> is protecting group) through a compound such as a compound of formula V, etc.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a carbapenem derivative (1) which is an excellent antibacterial agent.

[0002]

2. Description of the Related Art Thienamycin derivatives have excellent antibacterial activity, but they are degraded by dehydropeptidase I, which is an inactivating enzyme of thienamycin derivatives present in the human body, and lose their activity. It has been reported to be low (H. Kropp et al., Antimicrob. Agents, Chemot
her., 22 62, (1982); SRNorrby et al., ibid., 23,300 (1
983)).

[0003]

DISCLOSURE OF THE INVENTION The present inventors have conducted various studies to solve this drawback of thienamycin derivatives, and the novel carbapenem derivative (1) has a stronger antibacterial activity than the thienamycin derivatives, and dehydropeptidase I. The present invention has been completed by discovering that it is stable against urine and has a high recovery rate in urine.

[0004]

The present invention is based on the formula

[0005]

[Chemical 6]

A carbapenem derivative having: and a pharmacologically acceptable salt thereof.

In the formula, R ¹ is a hydrogen atom or a methyl group, and R ² is a hydrogen atom, a lower alkyl group with or without a substituent, a lower alkenyl group, a lower alkynyl group or --C (═NH) R. Group ⁰ (in the formula, R ⁰ represents a hydrogen atom or a lower alkyl group), and R ¹⁰ represents a hydrogen atom or an ester residue that undergoes hydrolysis in vivo.
A represents any group represented by the following general formula.

General formula

[0009]

[Chemical 7]

(In the formula, n represents any one of 1, 2, ³ and R ³ , R ⁴ and R ⁵ are independently of each other a hydrogen atom, a lower alkyl group or R ³ is bonded to R ⁵ or R ^4. Did-
_{(CH 2) s -w- (CH} 2) t - group (wherein, s and t is one of 1, 2, 3, w is a single bond, an oxygen atom or a sulfur atom) indicates, R ⁶ and R ⁷ represent a substituent on the ring, and independently of each other, a hydrogen atom, a halogen atom, a lower alkyl group with or without a substituent, a hydroxy group, a carboxy group, a carbamoyl group, an amino group, a cyano group or a carbamoyl group. Indicates an oxy group. ) General formula

[0011]

[Chemical 8]

(In the formula, m represents 0, 1 or 2, d represents 0 or 1, R ³ , R ⁴ and R ⁵ have the same meanings as described above, R ⁸ represents a hydrogen atom, and R ⁹ represents a lower alkyl group, a lower alkenyl group or a lower alkynyl group with or without a group, R ⁹ represents a substituent on the ring, a hydrogen atom, a lower alkyl group with or without a substituent, a fluorine atom, It represents a chlorine atom, a hydroxy group, an amino group, a cyano group, a carbamoyloxy group, a carboxy group or a carbamoyl group.) General formula

[0013]

[Chemical 9]

(Wherein 1 represents 0, 1 or 2,
R ³ , R ⁴ , R ⁵ and R ⁹ have the same meanings as described above, and R ¹¹ represents a hydrogen atom or a lower alkyl group. ) General formula

[0015]

[Chemical 10]

(In the formula, P represents 1 or 2, and R ³ , R
⁴ and R ⁵ have the same meanings as described above, and R ¹² and R ¹³ each independently represent a hydrogen atom or a lower alkyl group with or without a substituent. In the description of the formula (1), examples of the lower alkyl group of R ² and R ⁰ include methyl, ethyl and propyl, and A in the group represented by the general formula R ³ , R ⁴ , R ⁵ and R. ⁶ ,
Examples of the lower alkyl group for R ⁷ , R ⁸ , R ⁹ , R ¹¹ , R ¹² and R ¹³ include methyl, ethyl, propyl and butyl. Examples of the lower alkenyl group for R ² and R ⁸ include allyl and 2-methylallyl. The lower alkynyl group for R ² and R ⁸ is, for example, propargyl,
2-Methylpropargyl can be mentioned.

The substituent of the lower alkyl group having a substituent of R ² is a hydroxy group, a carboxy group, a carbamoyl group,
Carbamoyloxy group, cyano group, halogen atom (eg, fluorine, chlorine, bromine atom), oxo group, alkoxy group (eg, methoxy, ethoxy, propoxy), amino group, lower alkylamino group, di-lower alkyl Examples thereof include an amino group (lower alkylamino group, lower alkyl group in di-lower alkylamino group has the same meaning as lower alkyl group in R ² ).

R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹² and R ¹³
Examples of the substituent of the alkyl group having a substituent include a hydroxy group, an amino group, a cyano group, a carbamoyl group, a carboxy group, a halogen atom and an alkoxy group, and the halogen atom includes a fluorine, chlorine and bromine atom, and an alkoxy group. Examples of the group include methoxy, ethoxy and propoxy.

Examples of the ester residue of R ¹⁰ which is hydrolyzed in vivo include an acyloxyalkyl group, an alkoxycarbonyloxyalkyl group, a phthalidyl group and a 2-oxo-1,3-dioxolen-4-ylmethyl group. The above acyloxyalkyl group is, for example, pivaloyloxymethyl, isobutyryloxymethyl, 1-
(Isobutyryloxy) ethyl, acetoxymethyl, 1
Examples include-(acetoxy) ethyl, 1-methylcyclohexylcarbonyloxymethyl and 1-methylcyclopentylcarbonyloxymethyl. The alkoxycarbonyloxyalkyl group is, for example, t-butoxycarbonyloxymethyl, 1- (methoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, 1-
(Isopropoxycarbonyloxy) ethyl, 1- (t
Examples include -butoxycarbonyloxy) ethyl, 1- (cyclohexylcarbonyloxy) ethyl and 1- (cyclopentylcarbonyloxy) ethyl.

If necessary, the compound (1) of the present invention can be converted into a pharmacologically acceptable salt.

Examples of the pharmacologically acceptable salts include mineral salts such as hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate and nitrate; methanesulfonate and ethanesulfone. Acid salts, benzene sulfonates, sulfonates such as p-toluene sulfonate; oxalates, tartrates, citrates, maleates, succinates, acetates, benzoates, mandelate salts. , Pharmacologically acceptable acid addition salts such as organic acid salts such as ascorbate, lactate, gluconate, malate, or lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, etc. Examples thereof include inorganic salts or ammonium salts, triethylamine salts, diisopropylamine salts, salts with organic bases such as cyclohexylamine salts.

Preferred R ¹ is a hydrogen atom or a methyl group, and a methyl group is particularly preferred. Suitable R ² is a hydrogen atom, an alkyl group with or without a substituent,
Alkenyl group, alkynyl group or -C (= NH) R ⁰
And a preferred alkyl group thereof is a methyl, ethyl or propyl group, and a preferred substituent thereof is a hydroxy group, a carboxy group, a carbamoyl group, a carbamoyloxy group, a cyano group, a fluorine atom, a methoxy group, an ethoxy group,
Amino group, methylamino group or dimethylamino group, preferred alkenyl group is allyl group, preferred alkynyl group is propargyl group, and preferred R ⁰ is hydrogen atom, methyl, ethyl or propyl group.

Preferred R ¹⁰ is a hydrogen atom or an ester residue which undergoes hydrolysis in vivo, and preferred ester residues include 2-oxo-1,3-dioxolen-4-ylmethyl and pivaloyl. And oxymethyl, 1-methylcyclohexylcarbonyloxymethyl, 1- (isopropoxycarbonyloxy) ethyl and 1- (cyclohexylcarbonyloxy) ethyl groups.

In the groups in which A is of the general formula; preferred n is 1, 2 or 3.

Preferred R ³ , R ⁴ and R ⁵ are hydrogen atoms,
Lower alkyl group or R ³ is bonded to R ⁵ or _{^{R 4 - (CH 2) s}} -W- (CH 2) t - group (wherein, s and t is either 1, 2, 3, W represents a single bond, an oxygen atom or a sulfur atom), and a preferable lower alkyl group thereof is methyl, ethyl or propyl, R
³ is bonded to R ⁵ or _{^{R 4 - (CH 2) s}} -W-
S in the (CH ₂ ) _t -group is 1, 2 or 3,
t is 1, 2, 3 and W is a single bond. Suitable R ⁶
And R ⁷ are each independently a hydrogen atom, a halogen atom, a lower alkyl group with or without a substituent, a hydroxy group, a carboxy group, a carbamoyl group, an amino group, a cyano group or a carbamoyloxy group, The lower alkyl group is a methyl, ethyl or propyl group, preferred substituents of the alkyl group are a hydroxy group, an amino group, a carbamoyl group, a carboxy group, a halogen atom and an alkoxy group, and the halogen atom is fluorine, chlorine,
It is a bromine atom, and the alkoxy group is methoxy, ethoxy,
It is propoxy. Preferred halogen atoms for R ⁶ and R ⁷ are fluorine, chlorine and bromine atoms.

A preferred compound (1) in which A has a group represented by the general formula is R ¹ is a hydrogen atom or a methyl group, and R ² is a hydrogen atom, a methyl group, a fluoromethyl group or a formimidoyl group. Or an acetimidoyl group, n is 1, 2 or 3, and R ³ , R ⁴ and R ⁵
Are each independently a hydrogen atom, a methyl group, or a — (CH ₂ ) ₂ — group in which R ³ and R ⁴ or R ³ and R ⁵ are bonded,
R ⁶ and R ⁷ are each independently hydrogen atom, methyl group, hydroxymethyl group, methoxymethyl group, carbamoylmethyl group, carboxymethyl group, hydroxy group, carboxy group, carbamoyl group, amino group, cyano group or carbamoyloxy group. And a compound in which R ¹⁰ is a hydrogen atom.

A particularly preferred compound (1) in which A has a group represented by the general formula is R ¹ is a methyl group and R ^{2 is}
Is a hydrogen atom, a methyl group, a formimidoyl group or an acetimidoyl group, n is 2 or 3, and R ³ ,
R ⁴ and R ⁵ are each independently a hydrogen atom or a methyl group, R ⁶ and R ⁷ are independently a hydrogen atom, a methyl group, a hydroxymethyl group or a carbamoyl group,
A compound in which R ¹⁰ is a hydrogen atom.

In the group represented by the general formula of A, m is preferably 0, 1 or 2, and d is 0 or 1. Suitable R ³ , R ⁴ and R ⁵ have the same meanings as the groups represented by the general formula. Preferred R ⁸ is a hydrogen atom, a lower alkyl group with or without a substituent, a lower alkenyl group,
A lower alkynyl group, a preferred lower alkyl group is a methyl, ethyl or propyl group, and a preferred substituent of the alkyl group is a fluorine atom, a chlorine atom, a hydroxy group, a carbamoyl group, a methoxy group, an ethoxy group, a cyano group. Groups, amino groups, carboxy groups, preferred alkenyl groups are allyl, and preferred alkynyl groups are propargyl groups. Preferred R ⁹ is a hydrogen atom, a lower alkyl group with or without a substituent, a fluorine atom, a chlorine atom,
A hydroxy group, an amino group, a cyano group, a carbamoyloxy group, a carboxy group or a carbamoyl group, a preferable lower alkyl group thereof is a methyl, ethyl or propyl group, and a preferable substituent of the alkyl group is a fluorine atom,
A chlorine atom, a hydroxy group, a carbamoyl group, a carbamoyloxy group, a methoxy group, an ethoxy group, a cyano group, an amino group and a carboxy group.

Suitable compound (1) in which A has a group represented by the general formula is R ¹ is a hydrogen atom or a methyl group, and R ² is a hydrogen atom, a methyl group, a fluoromethyl group or a formimidoyl group. Or an acetimidoyl group, m is 0, 1 or 2, d is 0 or 1, and R ³ , R ⁴ and R ⁵ are each independently a hydrogen atom, a methyl group or R ³ and R ⁴ Alternatively, R ³ and R ⁵ are bonded to each other-
A (CH ₂ ) ₂ -group, R ⁸ is a hydrogen atom or a methyl group, R ⁹ is a hydrogen atom, a methyl group, a hydroxymethyl group, a carbamoyl group, a hydroxy group or a fluorine atom, and R ¹⁰ is a hydrogen atom. Is a compound.

Particularly preferred compound (1) in which A has a group represented by the general formula is R ¹ is a methyl group and R ^{2 is}
Is a hydrogen atom, a methyl group, a formimidoyl group or an acetimidoyl group, m is 0, 1 or 2, and d
Is 0, R ³ , R ⁴ and R ⁵ are each independently a hydrogen atom or a methyl group, R ⁸ is a hydrogen atom or a methyl group, and R ⁹ and R ¹⁰ are hydrogen atoms.

In the group represented by the general formula of A, 1 is preferably 0, 1 or 2, and preferred R ³ , R ⁴ and R are
⁵ has the same meaning as the group represented by the general formula. Suitable R ⁹
Is the same as the group represented by the general formula, and preferable R ¹¹ is a hydrogen atom or a lower alkyl group, and the preferable alkyl group is a methyl, ethyl or propyl group.

Suitable compounds (1) in which A has a group represented by the general formula are as follows: R ¹ is a hydrogen atom or a methyl group, and R ² is a hydrogen atom, a methyl group, a fluoromethyl group or a formimidoyl group. Or an acetimidoyl group, l is 0, 1 or 2, and R ³ , R ⁴ and R ⁵
Is independently of each other a hydrogen atom, a methyl group, or R ³ and R ⁴ or R ³ and R ⁵ are bonded - (CH _{2) 2} - a group, R ⁹ is a hydrogen atom, a methyl group, a hydroxymethyl group,
A carbamoyl group, a hydroxy group or a fluorine atom,
R ¹¹ is a hydrogen atom, a methyl group or an ethyl group, and R ¹⁰
A compound in which is a hydrogen atom.

Particularly preferred compound (1) in which A has a group represented by the general formula is R ¹ is a methyl group and R ^{2 is}
Is a hydrogen atom, a methyl group, a formimidoyl group or an acetimidoyl group, l is 0, 1 or 2, and R is
³ , R ⁴ and R ⁵ are each independently a hydrogen atom or a methyl group, R ⁹ is a hydrogen atom, R ¹¹ is a hydrogen atom or a methyl group, and R ¹⁰ is a hydrogen atom.

In the group represented by A in the general formula, P is preferably 1 or 2, and preferable R ³ , R ⁴ and R ⁵ are the same as those in the group represented by the general formula. Preferred R ¹² and R ¹³ are each independently a hydrogen atom or a lower alkyl group with or without a substituent, the preferred alkyl group is a methyl, ethyl or propyl group, and the preferred alkyl group is Substituents are fluorine atom, chlorine atom, hydroxy group, carbamoyl group, methoxy group, ethoxy group,
A cyano group, an amino group and a carboxy group.

A preferred compound (1) in which A has a group represented by the general formula is that R ¹ is a hydrogen atom or a methyl group, and R ² is a hydrogen atom, a methyl group, a fluoromethyl group or a formimidoyl group. Or an acetimidoyl group, P is 1, and R ³ , R ⁴ and R ⁵ are each independently a hydrogen atom, a methyl group or R ³ and R ⁴ or R ³ and R 5.
⁵ is a — (CH ₂ ) ₂ — group to which R ¹² and R
Compounds in which ¹³ is independently a hydrogen atom, a methyl group or an ethyl group, and R ¹⁰ is a hydrogen atom.

A particularly preferred compound (1) in which A has a group represented by the general formula is R ¹ is a methyl group and R ^{2 is}
Is a hydrogen atom, a methyl group, a formimidoyl or acetimidoyl group, P is 1, and R ³ , R ⁴ and R
⁵ are each independently a hydrogen atom or a methyl group, R ¹² and R ¹³ are independently a hydrogen atom or a methyl group,
A compound in which R ¹⁰ is a hydrogen atom.

Formula (1) represents one or a mixture of isomers. Among these isomers, preferred is that the 1-position is the R-coordination, the 5- and 6-positions are the same coordination as thienamycin (5S, 6S) -coordination and the hydroxyl group of the 6-position substituent. The compound in which the α-coordinate has is R-coordination can be given.

Examples of suitable compound (1) are shown below.

[0039]

[Chemical 11]

[0040]

[Chemical 12]

[0041]

[Chemical 13]

[0042]

[Chemical 14]

[0043]

[Chemical 15]

[0044]

[Chemical 16]

[0045]

[Chemical 17]

[0046]

[Chemical 18]

[0047]

[Chemical 19]

The carbapenem derivative having the general formula (1) can be produced by the method (method A) shown below.

Method A

[0050]

[Chemical 20]

In the above formula, R ¹⁴ represents a protecting group for a carboxy group, for example, an alkyl group such as methyl, ethyl or t-butyl; an aralkyl group such as benzyl, diphenylmethyl, 4-nitrobenzyl or 2-nitrobenzyl. An alkenyl group such as allyl, 2-chloroallyl or 2-methylallyl; 2,2,2-trichloroethyl, 2,2-dibromoethyl or 2,2,2-
A halogenoalkyl group such as tribromoethyl or 2
A trimethylsilylethyl group.

R ¹⁵ is an alkanesulfonyl group such as methanesulfonyl, trifluoromethanesulfonyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl or butanesulfonyl; arylsulfonyl such as phenylsulfonyl, tolylsulfonyl or naphthylsulfonyl. A group; a dialkylphosphoryl group such as dimethylphosphoryl, diethylphosphoryl, dipropylphosphoryl, diisopropylphosphoryl, dibutylphosphoryl or dipentylphosphoryl or a diarylphosphoryl group such as diphenylphosphoryl or ditolylphosphoryl. A 'and R ¹⁶ show that also contains the protecting group when the protecting group in one or A and R ² as defined as A and R ² are needed. The protecting group is a usual protecting group for hydroxyl group, imino group, amino group and carboxy group, and representative examples thereof include p-nitrobenzyloxycarbonyl and p-nitrobenzyl.

In this synthetic method, a compound having the formula (3) is produced by reacting a compound having the formula (2) with an alkanesulfonic anhydride, an arylsulfonic anhydride, a dialkylphosphoryl halide or a diarylphosphoryl halide in the presence of a base. Then, the compound (3) thus obtained is isolated or is reacted without isolation with a compound having the formula (4) in the presence of a base to produce a compound having the formula (5), and protecting the carboxy group. It is intended to produce the object compound having the general formula (1) by subjecting it to a reaction for removing the group R ¹⁴ or after the removal reaction, and converting it into an ester which is hydrolyzed in vivo as required.

Examples of the alkanesulfonic anhydride used in the reaction for obtaining the compound (3) from the compound (2) include anhydrous methanesulfonic acid, trifluoromethanesulfonic anhydride, ethanesulfonic anhydride, and arylsulfonic anhydride. Examples of benzenesulfonic acid, anhydrous p-toluenesulfonic acid, dialkylphosphoryl halides include dimethylphosphoryl chloride and diethylphosphoryl chloride, and examples of diarylphosphoryl halides include diphenylphosphoryl chloride and diphenylphosphoryl bromide. Among them, p-toluenesulfonic anhydride or diphenylphosphoryl chloride is particularly preferable. The solvent used is not particularly limited as long as it does not participate in this reaction, and for example, methylene chloride, 1,
Examples thereof include halogenated hydrocarbons such as 2-dichloroethane and chloroform, nitriles such as acetonitrile, and amides such as N, N-dimethylformamide and N, N-dimethylacetamide. The base used is not particularly limited as long as it does not affect other parts of the compound, particularly the β-lactam ring, but preferably triethylamine, diisopropylethylamine, 4-
An organic base such as dimethylaminopyridine can be used.

The reaction temperature is not particularly limited, but it is desirable to carry out at a relatively low temperature in order to suppress side reactions, and usually −
It is performed at about 20 ° C to 40 ° C. The reaction time is 10 minutes to 5 hours, varying mainly depending on the reaction temperature and the type of reaction reagent.

The compound (3) thus obtained can be treated with the compound of the formula (4) in the presence of a base in the reaction mixture without isolation. The base used in this step is not particularly limited, but preferred examples thereof include organic bases such as triethylamine and diisopropylethylamine, and inorganic bases such as potassium carbonate and sodium carbonate.

The reaction temperature is not particularly limited, but is usually -2.
It is carried out at 0 ° C to room temperature. Reaction time is 30 minutes to 108
It's time.

After completion of the reaction, the target compound (5) of this reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to the reaction mixture or the residue obtained by distilling off the solvent of the reaction mixture, washing with water and distilling off the solvent. The desired compound thus obtained can be further purified, if necessary, by a conventional method such as recrystallization, reprecipitation or chromatography. If desired, the desired compound (5) can be subjected to the next reaction for removing the protective group of the carboxy group without isolation. The resulting compound (5) can be converted to a carboxylic acid derivative by subjecting it to a treatment for removing the protecting group R ^{14 for} the carboxy group, if necessary, according to a conventional method. Removal of the protecting group R ¹⁴ depends on its type, but is generally done by methods known in the art. Suitably the reaction is of formula (5)
It is achieved by contacting a compound in which the substituent R ¹⁴ of the compound having R is a protecting group that can be removed by a reduction treatment such as a halogenoalkyl group, an aralkyl group and a benzhydryl group with a reducing agent. As the reducing agent used in this reaction, zinc and acetic acid are preferable when the protecting group of the carboxy group is a halogenoalkyl group such as 2,2-dibromoethyl or 2,2,2-trichloroethyl. Where the protecting group is an aralkyl group such as benzyl, 4-nitrobenzyl or a benzhydryl group, hydrogen and catalytic reduction catalysts such as palladium-carbon or alkali metal sulfides such as sodium sulfide or potassium sulfide are preferred. Is. The reaction is carried out in the presence of a solvent, the solvent used is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol and ethanol, tetrahydrofuran, ethers such as dioxane, acetic acid. Fatty acids such as and mixed solvents of these organic solvents and water are preferred. The reaction temperature is usually from 0 ° C. to room temperature, and the reaction time is usually from 5 minutes to 12 hours, depending on the kinds of the raw material compound and the reducing agent.

After completion of the reaction, the target compound for the reaction for removing the carboxy-protecting group is collected from the reaction mixture according to a conventional method. For example, it can be obtained by filtering off the insoluble matter precipitated from the reaction mixture and then distilling off the solvent.

If desired, the desired compound thus obtained can be purified by a conventional method such as recrystallization, preparative thin film chromatography, column chromatography and the like. If necessary, it can be converted into an ester that is hydrolyzed in vivo by a conventional method,
It can also be purified as a pharmacologically acceptable salt by a conventional method.

When A'and R ¹⁶ contain a protecting group for a hydroxyl group, an imino group, an amino group and a carboxy group (for example, p-nitrobenzyloxycarbonyl group or p-nitrobenzyl group), the above-mentioned carboxy group can be used. The protecting group can be removed simultaneously with the removal of the protecting group (when R ¹⁴ is a p-nitrobenzyl group).

On the other hand, the carbapenem derivative having the formula (1) of the present invention can also be produced by the method (method B) shown below.

[0063]

[Chemical 21]

Method B; wherein R ¹⁴ has the same meaning as defined above, R ¹⁷ is an alkyl group such as methyl, ethyl, propyl or isopropyl; fluoromethyl, chloromethyl, fluoroethyl, chloroethyl, fluoropropyl A halogenoalkyl group such as difluoromethyl, difluoroethyl, dichloroethyl, trifluoromethyl or trifluoroethyl; 2-acetylaminoethyl group; 2-acetylaminovinyl group; phenyl or naphthyl which may have a substituent. Aryl groups such as
These aryl groups are the same or different 1 to 1 shown below.
It may have 3 substituents. The substituents are fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl,
Methoxy, ethoxy, propoxy, isopropoxy, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, carbamoyl, mono- and di-substituted alkylcarbamoyl (the alkyl group represents, for example, methyl, ethyl, propyl group), nitro, hydroxyl group or cyano group. Or a heteroaryl group such as pyridyl or pyrimidinyl which may have a substituent, and these heteroaryl groups are the same or different 1 to 3 shown below.
May have one substituent, the substituent is fluorine, chlorine,
Examples include bromine, methyl, ethyl, propyl or isopropyl.

The compound having the formula (6) in this synthetic method is disclosed in JP-A-62-30781.
The reaction of reacting the compound of formula (6) with mercaptan in the presence of a base to produce the compound of general formula (5) is carried out in an inert solvent. The solvent used is not particularly limited as long as it does not participate in this reaction, for example, tetrahydrofuran, acetonitrile, dimethylformamide,
Examples thereof include dimethyl sulfoxide, water and a mixed solvent thereof. The base used is not particularly limited as long as it does not affect the other parts of the compound, particularly the β-lactam ring, but it may be, for example, diisopropylethylamine, triethylamine, N-methylpiperidine or 4-dimethylaminopyridine. Examples of such organic bases include inorganic bases such as potassium carbonate and sodium bicarbonate. Although the reaction temperature is not particularly limited, it is preferably carried out at a relatively low temperature in order to suppress side reactions, and is usually carried out at -20 ° C to 40 ° C. The reaction time varies depending mainly on the reaction temperature and the type of reaction reagent, but is usually 15 minutes to 75 hours. After completion of the reaction, the target compound (5) of this reaction can be collected from the reaction mixture according to a conventional method.

If necessary, the compound having the formula (5) can be prepared by subjecting A'and R ¹⁶ mentioned in the method A to a protecting group if there is a protecting group, or a protecting group for a carboxy group. The compound having the formula (1) can be obtained by converting into an ester that is hydrolyzed in the body. The compound having the general formula (1) thus obtained by Method A or Method B is converted into a pharmacologically acceptable salt by a method or technique known in the field of β-lactam antibiotics. can do.

The raw material mercaptan (4) used is JP-A-2-28180, JP-A-2-3687, JP-A-3-27059, JP-A-3-131545 and JP-A-4-142286. It can be manufactured according to the method described in.

[0068]

[Effect] Carbapenem-3- having the formula (1) of the present invention
Carboxylic acid derivatives show excellent antibacterial action having a broad spectrum and have β-lactamase inhibitory activity. Furthermore, thienamycin compounds are easily metabolized by mammals, but show excellent stability against dehydropeptidase I, which is known as an enzyme that catalyzes the inactivation of thienamycin, and also have an excellent recovery rate in urine. It has the property Regarding the antibacterial action, its activity was measured by an agar plate dilution method. It showed potent activity against a wide range of pathogens including anaerobes such as Gram-negative bacteria and Bacteroides fragilis.

Accordingly, such compounds are useful as antibacterial agents for treating bacterial infections by these pathogens.
Examples of dosage forms for that purpose include oral administration by tablets, capsules, granules, powders, syrups and the like, or parenteral administration by intravenous injection, intramuscular injection, etc. Depending on the medical condition, the administration form and the number of administrations, about 100 mg to 3000 mg per day is usually administered to an adult once or in several divided doses.

Hereinafter, the compounds of the present invention will be described more specifically with reference to Reference Examples and Examples.

The nuclear magnetic resonance spectra in Examples and Reference Examples were measured using tetramethylsilane as an internal standard unless otherwise specified.

[0072]

【Example】

Example 1 (1R, 5S, 6S) -2-[(2S, 4S) -2-
(4-Amidinopiperazin-1-ylcarbonyl) pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid

[0073]

[Chemical formula 22]

(1) (1R, 5S, 6S) -6-[(1
R) -1-Hydroxyethyl] -1-methyl-2-oxo-1-carbapenamu-3-carboxylic acid 4-nitrobenzyl ester (471 mg) in dry acetonitrile (5
diphenyl phosphate chloride (29 ml) under ice-cooling.
0 μl) and diisopropylethylamine (244 μl)
Was added dropwise, and the mixture was stirred at the same temperature for 1 hour. Then, (2S,
4S) -4-Mercapto-2- [4- (4-nitrobenzyloxycarbonylamidino) piperazin-1-ylcarbonyl] -1- (4-nitrobenzyloxycarbonyl) pyrrolidine trifluoromethanesulfonate (9
10 mg) of dry acetonitrile (7 ml) and diisopropylethylamine (500 μl) were added dropwise under ice cooling.
It was allowed to stand overnight at the same temperature. The reaction solution was concentrated under reduced pressure, the residue was diluted with ethyl acetate, and washed successively with aqueous sodium hydrogen carbonate, water and brine. The ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography (Merck, silica gel 60 (Art. 9385), 150
ml) and ethyl acetate-acetonitrile (8: 2,
7: 3, 6: 4). The target fractions are collected and concentrated to give an amorphous (1R, 5S, 6S) -2-
[(2S, 4S) -2- [4- (4-Nitrobenzyloxycarbonylamidino) piperazin-1-ylcarbonyl] -1- (4-nitrobenzyloxycarbonyl)
Pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-
Obtained em-3-carboxylic acid 4-nitrobenzyl ester (691 mg).

Infrared absorption spectrum (KBr) ν _max cm ⁻¹ :
1773,1710,1652,1607,1552,1441,1347. Nuclear magnetic resonance spectrum (270MHz, DMSO-d ₆ + D ₂ O) δppm:
1.12-1.21 (6H, m), 1.62-1.78 (1H, m), 2.77-2.93 (1H, m), 3.
11-4.30 (15H, m), 4.79 and 4.88 (1H, t × 2, J = 7.8Hz), 5.0
7-5.49 (6H, m), 7.52-7.73 (6H, m), 8.19-8.25 (6H, m). (2) The compound (680 mg) obtained in (1) was added to tetrahydrofuran-water (1: 1, 40 ml). ), 10% palladium-carbon catalyst (950 mg) was added, and hydrogenation was carried out at 28 ° C. for 1 hour. The catalyst was filtered off, the filtrate was washed with ether and the aqueous layer was concentrated under reduced pressure to 10 ml. This solution was subjected to reverse phase silica gel chromatography (Nacalai Tesque, Cosmocil 75C18-PREP, 30 ml), and acetonitrile-water (0: 100, 2:98, 4 :).
96, 6:94). The target fractions were collected, concentrated, and lyophilized to give the title compound (211 mg) as a powder.

Ultraviolet absorption spectrum (H ₂ O) λ _max nm: 29
9. Infrared absorption spectrum (KBr) ν _max cm ^-1 : 1754,1649,16
05,1450,1389,1251. Nuclear magnetic resonance spectrum ( ¹ H, 270MHz, D ₂ O, internal standard sodium trimethylsilylpropionate-d ₄ ) δppm: 1.22
(3H, d, J = 7.3Hz), 1.30 (3H, d, J = 6.4Hz), 1.64 (1H, ddd, J = 1
3.7,6.8,5.4Hz), 2.74 (1H, dt, J = 13.7,8.8Hz), 3.07 (1H, d
d, J = 12.2,3.4Hz), 3.17 (1H, dd, J = 12.2,5.4Hz), 3.34-3.47
(2H, m), 3.54-3.90 (9H, m), 4.13 (1H, dd, J = 8.8,6.8Hz), 4.1
9-4.13 (2H, m). Nuclear magnetic resonance spectrum ( ¹³ C, D ₂ O, external standard tetramethylsilane) δppm: 16.0,20.2,35.5,41.3,42.6,42.8,43.
5,44.2,44.7,53.9,56.0,57.4,58.4,65.2,132.0,140.9,1
56.6,167.8,172.5,176.4. Example 2 (1R, 5S, 6S) -2-[(2S, 4S) -1-Methyl-2- (4-amidinopiperazin-1-ylcarbonyl) pyrrolidin-4-ylthio ] -6-[(1R)-
1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid

[0077]

[Chemical formula 23]

(1) (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic Acid 4-nitrobenzyl ester (1
600 mg) in dry acetonitrile (16 ml),
(2S, 4S) -4-Mercapto-1-methyl-2-
[4- (4-Nitrobenzyloxycarbonylamidino) piperazin-1-ylcarbonyl] pyrrolidine (1
A solution of 120 mg) in dry acetonitrile (11 ml) and diisopropylethylamine (430 μl) were added dropwise under ice cooling. After stirring overnight at the same temperature, the reaction solution was concentrated under reduced pressure, the residue was diluted with ethyl acetate, and washed with aqueous sodium hydrogen carbonate, water and brine in this order. The ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was subjected to reverse phase silica gel chromatography (Nacalai Tesque, Cosmosil 75C1).
8-PREP (300 ml) and developed with acetonitrile-water (1: 1). The desired fractions were collected and concentrated to give powdery (1R, 5S, 6S) -2-[(2S, 4S)-
1-Methyl-2- [4- (4-nitrobenzyloxycarbonylamidino) piperazin-1-ylcarbonyl]
Pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl ester (1
520 mg) was obtained.

Infrared absorption spectrum (KBr) ν _max cm ⁻¹ :
1771,1708,1648,1606,1544,1521,1448,1347. Nuclear magnetic resonance spectrum (270MHz, DMSO-d ₆ ) δppm: 1.10
-1,20 (6H, m), 1.58-1.69 (1H, m), 2.24 (3H, s), 2,60-2.80 (2
H, m), 2.95-3.02 (1H, m), 3.20-3.88 (12H, m), 3.90-4.05 (1
H, m), 4.21 (1H, dd, J = 9.3,2.4Hz), 5.05 (1H, d, J = 5.4Hz), 5.
13 (2H, s), 5.29 (2H, d, J = 13.7Hz), 5.45 (2H, d, J = 13.7Hz),
7.59 (2H, d, J = 8.8Hz), 7.73 (2H, d, J = 8.8Hz), 7.90-8.20 (2
H, broad), 8.21 (2H, d, J = 8.8Hz), 8.23 (2H, d, J = 8.8Hz). (2) The compound (1500mg) obtained in (1) was added to tetrahydrofuran-water (1: 1). , 75 ml), 10% palladium-carbon catalyst (2400 mg) was added, and hydrogenation was carried out at 28 ° C. for 1 hour. The catalyst was filtered off, the filtrate was washed with ether and the aqueous layer was concentrated under reduced pressure to 20 ml. This solution was subjected to reverse phase silica gel chromatography (Nacalai Tesque, Cosmosil 75C18-PREP, 100 ml), and acetonitrile-water (0: 100, 2:98,
4:96, 6:94, 8:92). The desired fractions were collected, concentrated (3 ml) and cooled to precipitate colorless needle crystals. This was filtered and dried to obtain the crystalline title compound (435 mg).

Melting point 218 to 220 ° C. (decomposition) Ultraviolet absorption spectrum (water) λ _max nm: 298. Infrared absorption spectrum (KBr) ν _max cm ⁻¹ : 1755,1652,16
06,1449,1386,1246. Nuclear magnetic resonance spectrum ( ¹ H, 270MHz, D ₂ O, internal standard sodium trimethylsilylpropionate −d ₄ ) δ ppm: 1.
20 (3H, d, J = 6.8Hz), 1.30 (3H, d, J = 6.3Hz), 1.66 (1H, ddd, J =
13.7,8.8,5.4Hz), 2.28 (3H, s), 2.74-2.87 (2H, m), 3.09 (1
H, dd, J = 10.8,1.5Hz), 3.30-3.90 (12H, m), 4.16-4.31 (2H,
m). Nuclear magnetic resonance spectrum ( ¹³ C, D ₂ O, external standard tetramethylsilane) δppm: 15.7,19.9,34.9,39.1,39.3,40.9,4
2.4,43.3,43.9,44.5,55.7,58.0,62.2,64.9,65.0,131.2,
141.6, 156.3, 167.5, 171.1, 175.9. Example 3 (1R, 5S, 6S) -2-[(2S, 4S) -2-
(4-amidinohomopiperazin-1-ylcarbonyl)
Pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-
M-3-carboxylic acid

[0081]

[Chemical formula 24]

(1R, 5R, 6S) -2- (Diphenylphosphoryloxy) -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3
-Carboxylic acid 4-nitrobenzyl ester and
(2S, 4S) -4-Mercapto-1- (4-nitrobenzyloxycarbonyl) -2- [4- (4-nitrobenzyloxycarbonylamidino) homopiperazine-1
The reaction operation was performed in the same manner as in Example 1 or 2 using -ylcarbonyl] pyrrolidine to obtain the title compound.

Ultraviolet absorption spectrum (water) λ _max nm: 2
99. Infrared absorption spectrum (KBr) ν _max cm ^-1 : 1754,1608,15
. 80,1456,1387,1262 Nuclear magnetic resonance spectra _{^{(1 H, 270MHz, D 2}} O, internal standard trimethylsilyl propionic acid sodium -d ₄₎ δppm: 1.
21 (3H, d, J = 7.2Hz), 1.30 (3H, d, J = 6.3Hz), 1.46-1.54 (1H,
m), 1.84-1.96 (2H, m), 2.70-2.80 (1H, m), 3.08 (1H, dd, J = 1
2.4,3.3Hz), 3.14 (1H, dd, J = 12.4,5.4Hz), 3.37-3.45 (2H,
m), 3.52-3.95 (9H, m), 4.04-4.14 (1H, m), 4.20-4.29 (2H, m) Example 4 (1R, 5S, 6S) -2-[(2S, 4S) -1 -Methyl-2- (4-amidinohomopiperazin-1-ylcarbonyl) pyrrolidin-4-ylthio] -6-[(1
R) -1-Hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid

[0084]

[Chemical 25]

(1R, 5R, 6S) -2- (Diphenylphosphoryloxy) -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3
-Carboxylic acid 4-nitrobenzyl ester and
(2S, 4S) -4-Mercapto-1-methyl-2-
Using [4- (4-nitrobenzyloxycarbonylamidino) homopiperazin-1-ylcarbonyl] pyrrolidine, the reaction procedure was the same as in Example 1 or 2, to obtain the title compound.

Ultraviolet absorption spectrum (water) λ _max nm: 2
98. Infrared absorption spectrum (KBr) ν _max cm ^-1 : 1755,1650,16
07,1455,1385,1258. Nuclear magnetic resonance spectrum ( ¹ H, 270MHz, D ₂ O, internal standard sodium trimethylsilylpropionate −d ₄ ) δppm: 1.
20 (3H, d, J = 7.2Hz), 1.30 (3H, d, J = 6.3Hz), 1.60 (1H, ddd, J =
13.5,9.0,5.5Hz), 1.80-1.95 (2H, m), 2.24 and 2.25 (3H, s
× 2), 2.74-2.87 (2H, m), 3.09 (1H, d, J = 9.0Hz), 3.33-3.95
(12H, m), 4.19 (1H, dd, J = 9.0,2.4Hz), 4.22-4.28 (1H, m) Example 5 (1R, 5S, 6S) -2-[(2S, 4S) -2-
(4-guanidinopiperidin-1-ylcarbonyl) pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid

[0087]

[Chemical formula 26]

(1R, 5R, 6S) -2- (diphenylphosphoryloxy) -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3
-Carboxylic acid 4-nitrobenzyl ester and
(2S, 4S) -4-Mercapto-1- (4-nitrobenzyloxycarbonyl) -2- [4- (4-nitrobenzyloxycarbonylguanidino) piperidine-1-
The reaction operation was performed in the same manner as in Example 1 or 2 using ylcarbonyl] pyrrolidine to obtain the title compound.

Ultraviolet absorption spectrum (water) λ _max nm: 2
99. Example 6 (1R, 5S, 6S) -2-[(2S, 4S) -1-Methyl-2- (4-guanidinopiperidin-1-ylcarbonyl) pyrrolidin-4-ylthio] -6-[(1R)
-1-Hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid

[0090]

[Chemical 27]

(1R, 5R, 6S) -2- (Diphenylphosphoryloxy) -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3
-Carboxylic acid 4-nitrobenzyl ester and
(2S, 4S) -4-Mercapto-1-methyl-2-
Using [4- (4-nitrobenzyloxycarbonylguanidino) piperidin-1-ylcarbonyl] pyrrolidine, the reaction procedure was the same as in Example 1 or 2, to obtain the title compound.

Ultraviolet absorption spectrum (water) λ _max nm: 2
98. Example 7 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3-guanidinopyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-[(1R)
-1-Hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid

[0093]

[Chemical 28]

(1R, 5R, 6S) -2- (Diphenylphosphoryloxy) -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3
-Carboxylic acid 4-nitrobenzyl ester and
(2S, 4S) -4-Mercapto-1- (4-nitrobenzyloxycarbonyl) -2-[(3S) -3- (4
-Nitrobenzyloxycarbonylguanidino) pyrrolidin-1-ylcarbonyl] pyrrolidine was used to carry out the same reaction procedure as in Example 1 or 2 to obtain the title compound.

Ultraviolet absorption spectrum (water) λ _max nm: 2
99. Example 8 (1R, 5S, 6S) -2-[(2S, 4S) -1-methyl-2-[(3S) -3-guanidinopyrrolidine-1
-Ylcarbonyl] pyrrolidin-4-ylthio] -6-
[(1R) -1-hydroxyethyl] -1-methyl-1
-Carbapene-2-em-3-carboxylic acid

[0096]

[Chemical 29]

(1R, 5R, 6S) -2- (Diphenylphosphoryloxy) -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3
-Carboxylic acid 4-nitrobenzyl ester and
(2S, 4S) -4-Mercapto-1-methyl-2-
Using [(3S) -3- (4-nitrobenzyloxycarbonylguanidino) pyrrolidin-1-ylcarbonyl] pyrrolidine, the reaction procedure was the same as in Example 1 or 2 to obtain the title compound.

Ultraviolet absorption spectrum (water) λ _max nm: 2
98. Example 9 (1R, 5S, 6S) -2-[(2S, 4S) -2-
(3-guanidinoazetidin-1-ylcarbonyl) pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid

[0099]

[Chemical 30]

(1R, 5R, 6S) -2- (Diphenylphosphoryloxy) -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3
-Carboxylic acid 4-nitrobenzyl ester and
(2S, 4S) -4-Mercapto-1- (4-nitrobenzyloxycarbonyl) -2- [3- (4-nitrobenzyloxycarbonylguanidino) azetidine-1-
The reaction operation was performed in the same manner as in Example 1 or 2 using ylcarbonyl] pyrrolidine to obtain the title compound.

Ultraviolet absorption spectrum (water) λ _max nm: 2
99. Example 10 (1R, 5S, 6S) -2-[(2S, 4S) -1-Methyl-2- (3-guanidinoazetidin-1-ylcarbonyl) pyrrolidin-4-ylthio] -6-[(1R )
-1-Hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid

[0102]

[Chemical 31]

(1R, 5R, 6S) -2- (Diphenylphosphoryloxy) -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3
-Carboxylic acid 4-nitrobenzyl ester and
(2S, 4S) -4-Mercapto-1-methyl-2-
Using [3- (4-nitrobenzyloxycarbonylguanidino) azetidin-1-ylcarbonyl] pyrrolidine, the reaction procedure was the same as in Example 1 or 2, to obtain the title compound.

Ultraviolet absorption spectrum (water) λ _max nm: 2
98. Example 11 (1R, 5S, 6S) -2-[(2S, 4S) -2-
(2-guanidinoethylcarbamoyl) pyrrolidine-4
-Ylthio] -6-[(1R) -1-hydroxye 0
] -Methyl-1-carbapene-2-em-3-carboxylic acid

[0105]

[Chemical 32]

(1R, 5R, 6S) -2- (Diphenylphosphoryloxy) -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3
-Carboxylic acid 4-nitrobenzyl ester and
(2S, 4S) -4-Mercapto-1- (4-nitrobenzyloxycarbonyl) -2- [2- (4-nitrobenzyloxycarbonylguanidino) ethylcarbamoyl] pyrrolidine as in Example 1 or 2 The reaction was carried out to obtain the title compound.

Ultraviolet absorption spectrum (water) λ _max nm: 2
99. Example 12 (1R, 5S, 6S) -2-[(2S, 4S) -1-Methyl-2- (2-guanidinoethylcarbamoyl) pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxy Ethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid

[0108]

[Chemical 33]

(1R, 5R, 6S) -2- (Diphenylphosphoryloxy) -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3
-Carboxylic acid 4-nitrobenzyl ester and
(2S, 4S) -4-Mercapto-1-methyl-2-
Using [2- (4-nitrobenzyloxycarbonylguanidino) ethylcarbamoyl] pyrrolidine, the reaction procedure was the same as in Example 1 or 2, to obtain the title compound.

Ultraviolet absorption spectrum (water) λ _max nm: 2
98. Example 13 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[4- (Methylamidino) piperazin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-[(1R)-
1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid

[0111]

[Chemical 34]

(1R, 5R, 6S) -2- (Diphenylphosphoryloxy) -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3
-Carboxylic acid 4-nitrobenzyl ester and
(2S, 4S) -4-Mercapto-1- (4-nitrobenzyloxycarbonyl) -2- [4- (methyl-4-
Using nitrobenzyloxycarbonylamidino) piperazin-1-ylcarbonyl] pyrrolidine, the reaction procedure was the same as in Example 1 or 2 to obtain the title compound.

Ultraviolet absorption spectrum (water) λ _max nm: 2
99. Example 14 (1R, 5S, 6S) -2-[(2S, 4S) -1-Methyl-2- [4- (methylamidino) piperazine-1-
Ilcarbonyl] pyrrolidin-4-ylthio] -6-
[(1R) -1-hydroxyethyl] -1-methyl-1
-Carbapene-2-em-3-carboxylic acid

[0114]

[Chemical 35]

(1R, 5R, 6S) -2- (Diphenylphosphoryloxy) -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3
-Carboxylic acid 4-nitrobenzyl ester and
(2S, 4S) -4-Mercapto-1-methyl-2-
Using [4- (methyl-4-nitrobenzyloxycarbonylamidino) piperazin-1-ylcarbonyl] pyrrolidine, the reaction procedure was the same as in Example 1 or 2, to obtain the title compound.

Ultraviolet absorption spectrum (water) λ _max nm: 2
98. Example 15 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -3-guanidinopyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-[(1R)
-1-Hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid

[0117]

[Chemical 36]

(1R, 5R, 6S) -2- (Diphenylphosphoryloxy) -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3
-Carboxylic acid 4-nitrobenzyl ester and
(2S, 4S) -4-Mercapto-1- (4-nitrobenzyloxycarbonyl) -2-[(3R) -3- (4
-Nitrobenzyloxycarbonylguanidino) pyrrolidin-1-ylcarbonyl] pyrrolidine was used to carry out the same reaction procedure as in Example 1 or 2 to obtain the title compound.

Ultraviolet absorption spectrum (water) λ _max nm: 2
99. Example 16 (1R, 5S, 6S) -2-[(2S, 4S) -1-methyl-2-[(3R) -3-guanidinopyrrolidine-1
-Ylcarbonyl] pyrrolidin-4-ylthio] -6-
[(1R) -1-hydroxyethyl] -1-methyl-1
-Carbapene-2-em-3-carboxylic acid

[0120]

[Chemical 37]

(1R, 5R, 6S) -2- (Diphenylphosphoryloxy) -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3
-Carboxylic acid 4-nitrobenzyl ester and
(2S, 4S) -4-Mercapto-1-methyl-2-
Using [(3R) -3- (4-nitrobenzyloxycarbonylguanidino) pyrrolidin-1-ylcarbonyl] pyrrolidine, the reaction procedure was the same as in Example 1 or 2, to obtain the title compound.

Ultraviolet absorption spectrum (water) λ _max nm: 2
98. Example 17 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3R) -4-amidino-3-methylpiperazine-1
-Ylcarbonyl] pyrrolidin-4-ylthio] -6-
[(1R) -1-hydroxyethyl] -1-methyl-1
-Carbapene-2-em-3-carboxylic acid

[0123]

[Chemical 38]

(1R, 5R, 6S) -2- (Diphenylphosphoryloxy) -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3
-Carboxylic acid 4-nitrobenzyl ester and
(2S, 4S) -4-Mercapto-1- (4-nitrobenzyloxycarbonyl) -2-[(3R) -4- (4
-Nitrobenzyloxycarbonylamidino) -3-methylpiperazin-1-ylcarbonyl] pyrrolidine was used to carry out the same reaction procedure as in Example 1 or 2 to obtain the title compound.

Ultraviolet absorption spectrum (water) λ _max nm: 2
99. Example 18 (1R, 5S, 6S) -2-[(2S, 4S) -1-Methyl-2-[(3R) -4-amidino-3-methylpiperazin-1-ylcarbonyl] pyrrolidin-4-ylthio ] -6-[(1R) -1-hydroxyethyl] -1-
Methyl-1-carbapene-2-em-3-carboxylic acid

[0126]

[Chemical Formula 39]

(1R, 5R, 6S) -2- (Diphenylphosphoryloxy) -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3
-Carboxylic acid 4-nitrobenzyl ester and
(2S, 4S) -4-Mercapto-1-methyl-2-
[(3R) -4- (4-nitrobenzyloxycarbonylamidino) -3-methylpiperazin-1-ylcarbonyl] pyrrolidine was used and the reaction operation was performed in the same manner as in Example 1 or 2 to obtain the title compound. .

Ultraviolet absorption spectrum (water) λ _max nm: 2
98. Example 19 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[1-Amidinopiperidin-4-ylcarbamoyl) pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid

[0129]

[Chemical 40]

(1R, 5R, 6S) -2- (diphenylphosphoryloxy) -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3
-Carboxylic acid 4-nitrobenzyl ester and
Example 1 using (2S, 4S) -4-mercapto-1- (4-nitrobenzyloxycarbonyl) -2- [1- (4-nitrobenzyloxycarbonylamidino) piperidin-4-ylcarbamoyl] pyrrolidine Alternatively, the reaction operation was performed in the same manner as in 2, to obtain the title compound.

Ultraviolet absorption spectrum (water) λ _max nm: 2
99. Example 20 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -1-amidinopyrrolidin-3-ylcarbamoyl] pyrrolidin-4-ylthio] -6-[(1R)
-1-Hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid

[0132]

[Chemical 41]

(1R, 5R, 6S) -2- (Diphenylphosphoryloxy) -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3
-Carboxylic acid 4-nitrobenzyl ester and
(2S, 4S) -4-Mercapto-1- (4-nitrobenzyloxycarbonyl) -2-[(3S) -1- (4
Using -nitrobenzyloxycarbonylamidino) pyrrolidin-3-ylcarbamoyl] pyrrolidine, the reaction procedure was the same as in Example 1 or 2 to obtain the title compound.

Ultraviolet absorption spectrum (water) λ _max nm: 2
99. Example 21 (1R, 5S, 6S) -2-[(2S, 4S) -2-
(1-Amidinoazetidin-3-ylcarbamoyl) pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid

[0135]

[Chemical 42]

(1R, 5R, 6S) -2- (Diphenylphosphoryloxy) -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3
-Carboxylic acid 4-nitrobenzyl ester and
Example 1 using (2S, 4S) -4-mercapto-1- (4-nitrobenzyloxycarbonyl) -2- [1- (4-nitrobenzyloxycarbonylamidino) azetidin-3-ylcarbamoyl] pyrrolidine Alternatively, the reaction operation was performed in the same manner as in 2, to obtain the title compound.

Ultraviolet absorption spectrum (water) λ _max nm: 2
99. Reference Example 1 (2S, 4S) -4-Mercapto-2- [4- (4-d
Trobenzyloxycarbonylamidino) piperazine-
1-ylcarbonyl] -1- (4-nitrobenzyloxy
Cycarbonyl) pyrrolidine trifluoromethanesulfo
Phosphate (1) 1-amidinopiperazine 1/2 sulfate (2.50
g) was dissolved in tetrahydrofuran-water (1: 1, 60 ml), a solution of di-t-butyl dicarbonate (3.40 g) in tetrahydrofuran (10 ml) was added, and the mixture was stirred at room temperature for 2.5 hours. After tetrahydrofuran was distilled off from the reaction solution, insoluble materials were removed by filtration, and the filtrate was concentrated to dryness. The residue is ethanol (50 ml x 2) and methanol (50
It was extracted with ml × 2). The extract was concentrated to dryness and crystallized 1
-Amidino-4-t-butoxycarbonylpiperazine 1
/ 2 sulfate (2.48 g) was obtained.

Melting point 278 ° C. (decomposition) Nuclear magnetic resonance spectrum (270 MHz, D ₂ O, internal standard: sodium trimethylsilylpropionate-d ₄ ) δ ppm:
1.47 (9H, s), 3.49-3.64 (8H, m). Infrared absorption spectrum (KBr) ν _max cm ^-1 : 1696,1656,16
16,1416,1169,1121. (2) The compound (2.22 g) obtained in (1) was dissolved in tetrahydrofuran-water (1: 1, 90 ml), and 4-nitrobenzyloxycarbonyl chloride (1.89 g) was added in tetrahydrofuran. The (16 ml) solution and a 1N aqueous sodium hydroxide solution (16 ml) were simultaneously added dropwise under ice cooling and stirring.
After stirring for 30 minutes under the same conditions, the organic solvent was distilled off from the reaction solution. The aqueous layer was extracted with ethyl acetate, the ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to silica gel column chromatography and developed with ethyl acetate-n-hexane (4: 1). Concentrate the desired fraction to give amorphous 1-
(4-Nitrobenzyloxycarbonylamidino) -4
-T-Butoxycarbonylpiperazine (2.32 g) was obtained.

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δpp
m: 1.47 (9H, s), 3.45-3.61 (8H, m), 5.21 (2H, s), 6.90-7.2
0 (2H, broad), 7.56 (2H, d, J = 8.6Hz), 8.20 (2H, d, J = 8.6Hz). Infrared absorption spectrum (KBr) ν _max cm ^-1 : 1698,1652,16
01,1547,1523,1279. (3) The compound (750 mg) obtained in (2) was dissolved in trifluoroacetic acid (10 ml), and the mixture was stirred at room temperature for 30 minutes. The residue obtained by concentrating the reaction solution was dissolved in ethyl acetate-water,
Heavy water was added to make it alkaline. The ethyl acetate layer was separated and the aqueous layer was extracted 3 times with ethyl acetate. All ethyl acetate layers were combined and concentrated to give powdery 1- (4-nitrobenzyloxycarbonylamidino) piperazine (530 m).
g) was obtained. Nuclear magnetic resonance spectrum (270MHz, D ₂ O, internal standard sodium trimethylsilylpropionate-d ₄ ) δppm:
3.27 (4H, t, J = 5.3Hz), 3.80 (4H, t, J = 5.3Hz), 5.25 (2H, s),
7.61 (2H, d, J = 8.6Hz), 8.27 (2H, d, J = 8.6Hz). (4) (2S, 4S) -4- (4-methoxybenzylthio) -1- (4-nitrobenzyl Oxy) pyrrolidine-
2-Carboxylic acid (740 mg) was added to dry acetonitrile (7.
4 ml), N, N'-carbonyldiimidazole (330 mg) was added, and the mixture was stirred at room temperature for 30 minutes. Then, the compound (525 mg) obtained in (3) was dissolved in acetonitrile (10 ml) and added, and the mixture was allowed to stand overnight under the same conditions. The reaction mixture was diluted with ethyl acetate, washed successively with sodium bicarbonate water, water and brine, dried over anhydrous sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography and developed with ethyl acetate-acetonitrile (1: 0, 4: 1). Concentrate the desired fraction to obtain powder (2S, 4
S) -4- (4-Methoxybenzylthio) -2- [4-
(4-Nitrobenzyloxycarbonylamidino) piperazin-1-ylcarbonyl] -1- (4-nitrobenzyloxycarbonyl) pyrrolidine (890 mg) was obtained.

Infrared absorption spectrum (KBr) ν _max cm ⁻¹ :
1709,1652,1608,1520,1439,1346. Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ + D ₂ O) δppm: 1.
72-1.89 (1H, m), 2.39-2.52 (1H, m), 3.03-3.18 (1H, m), 3.30
-4.10 (15H, m), 4.51-4.62 (1H, m), 4.98-5.32 (4H, m), 6.85
(2H, d, J = 8.8Hz), 7.23 (2H, d, J = 8.8Hz), 7.40-7.58 (4H, m),
8.15-8.25 (4H, m). (5) The compound (880 mg) obtained in (4) was dissolved in trifluoroacetic acid (4.4 ml) and anisole (0.88 ml), and trifluoromethanesulfonic acid (160 μl) was stirred under ice cooling. )
Was dripped. After stirring at room temperature for 3 hours, the reaction solution was concentrated. The residue was washed with ether three times and the resulting powder was dried. A powdery target compound (918 mg) was obtained.

Infrared absorption spectrum (KBr) ν _max cm ⁻¹ :
1761,1671,1618,1523,1443,1348,1285,1246,1225,1169. Nuclear magnetic resonance spectrum (270MHz, DMSO-d ₆ + D ₂ O) δppm ：
1.60-1.76 (1H, m), 2.65-2.82 (1H, m), 3.05-3.80 (10H, m),
3.94 and 4.05 (1H, dd × 2, J = 9.8 and 6.8Hz), 4.74and 4.
83 (1H, t × 2, J = 7.8Hz), 5.05-5.25 (2H, m), 5.40 (2H, s), 7.
53 and 7.63 (2H, d × 2, J = 8.8Hz), 7.72 (2H, d, J = 8.8Hz), 8.
21 and 8.23 (2H, d × 2, J = 8.8Hz), 8.28 (2H, d, J = 8.8Hz). Reference Example 2 (2S, 4S) -4-mercapto-1-methyl-2-
[4- (4-nitrobenzyloxycarbonylamidy
No) piperazin-1-ylcarbonyl] pyrrolidine (1) The compound (750 mg) obtained in Reference Example 1- (2) was dissolved in trifluoroacetic acid (12 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated, and diethyl ether was added to the residue. The produced powder was washed with diethyl ether three times and then dried. A colorless powdery 1- (4-nitrobenzyloxycarbonylamidino) piperazine 2 trifluoroacetate salt (1010 mg) was obtained.

Infrared absorption spectrum (KBr) ν _max cm ⁻¹ :
1771,1698,1665,1623,1518,1353,1221,1197. Nuclear magnetic resonance spectrum (270MHz, DMSO-d ₆ + D ₂ O) δppm ：
3.21 (4H, t, J = 5.4Hz), 3.73 (4H, t, J = 5.4Hz), 5.31 (2H, s),
7.68 (2H, d, J = 8.8Hz), 8.26 (2H, d, J = 8.8Hz). (2) (2S, 4S) -4- (4-methoxybenzylthio) -1-methylpyrrolidine-2- Carboxylic acid (480
(mg) was suspended in dry acetonitrile (20 ml), carbonyldiimidazole (325 mg) was added, and the mixture was stirred at 40 ° C for 1 hr. The reaction solution was ice-cooled, and 1- (4-nitrobenzyloxycarbonylamidino) piperazine obtained in (1) was used.
2 Trifluoroacetic acid salt (980 mg) and diisopropylethylamine (320 μl) were added, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and washed successively with sodium bicarbonate water, water (4 times) and brine. The ethyl acetate layer was dried over sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography and developed with ethyl acetate-methanol (4: 1). The desired fraction was concentrated and powdered (2S, 4S) -4- (4-methoxybenzylthio)-
1-Methyl-2- [4- (4-nitrobenzyloxycarbonylamidino) piperazin-1-ylcarbonyl]
Pyrrolidine (860 mg) was obtained.

Infrared absorption spectrum (KBr) ν _max cm ⁻¹ :
1648,1609,1542,1513,1440,1346,1303,1273,1239. Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ + D ₂ O) δppm: 1.
78 (1H, ddd, J = 13.7,9.3,5.4Hz), 2.33 (3H, s), 2.48-2.60 (2
H, m), 3.03-3.24 (3H, m), 3.70 (2H, s), 3.80 (3H, s), 3.45-4.
15 (8H, m), 5.21 (2H, s), 6.84 (2H, d, J = 8.8Hz), 7.20 (2H, d, J
= 8.8Hz), 7.56 (2H, d, J = 8.8Hz), 8.20 (2H, d, J = 8.8Hz). (3) The compound (1450mg) obtained in (2) was trifluoroacetic acid (7.25ml) Dissolved in anisole (1.45 ml) and stirred under ice-cooling with trifluoromethanesulfonic acid (562 μ).
l) was added dropwise. After stirring under the same conditions for 60 minutes and room temperature for 30 minutes, the reaction solution was concentrated. The residue was washed with ether three times and the resulting powder was dried. Thus, powdery target compound 2-trifluoromethanesulfonate (1940 mg) was obtained.

Nuclear magnetic resonance spectrum (270MHz, DMSO-d ₆ +
D ₂ O) δppm: 1.81 (1H, ddd, J = 13.2,9.3,8.8Hz), 2.82 (3H,
s), 2.98 (1H, dt, J = 13.2,7.8Hz), 3.28-3.81 (11H, m), 4.63
(1H, t, J = 8.8Hz), 5.40 (2H, s), 7.72 (2H, d, J = 8.8Hz), 8.28
(2H, d, J = 8.8Hz). This salt was dissolved in ethyl acetate-water, and sodium bicarbonate water was added to make it alkaline. The ethyl acetate layer was separated, washed with brine, dried over sodium sulfate, and concentrated. An amorphous target compound (1.21 g) was obtained.

Infrared absorption spectrum (KBr) ν _max cm ⁻¹ :
1648,1605,1544,1520,1440,1346,1304,1273,1232. Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ + D ₂ O) δppm: 1.
91 (1H, ddd, J = 13.7,8.3,4.9Hz), 2.36 (3H, s), 2.65-2.80 (2
H, m), 3.08 (1H, dd, J = 10.2,2.9Hz), 3.24 (1H, t, J = 8.3Hz),
3.32-3.44 (1H, m), 3.46-4.00 (8H, m), 5.21 (2H, s), 7.56 (2
H, d, J = 8.8 Hz), 8.19 (2H, d, J = 8.8 Hz). In the same manner as in Reference Examples 1 and 2, the compound of Reference Example 3-21 was synthesized.

Reference Example 3 (2S, 4S) -4-Mercapto-1- (4-nitrobenzyloxycarbonyl) -2- [4- (4-nitrobenzyloxycarbonylamidino) homopiperazine-1
-Ylcarbonyl] pyrrolidine infrared absorption spectrum (KBr) ν _max cm ^-1 : 1708,1651,16
05,1551,1520,1441,1346,1284. Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ + D ₂ O) δppm: 1.
75-1.98 (3H, m), 2.00-2.20 (1H, m), 2.66-2.82 (1H, m), 3.13
-3.96 (8H, m), 4.06-4.15 (2H, m), 4.61 (1H, t, J = 8.0Hz), 5.1
0-5.25 (4H, m), 7.42-7.58 (4H, m), 8.16-8.23 (4H, m). Reference Example 4 (2S, 4S) -4-mercapto-1-methyl-2-
[4- (4-Nitrobenzyloxycarbonylamidino) homopiperazin-1-ylcarbonyl] pyrrolidine infrared absorption spectrum (KBr) ν _max cm ^-1 : 1641,1607,15
52,1520,1486,1444,1347,1285. Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ + D ₂ O) δppm: 1.
81-2.01 (3H, m), 2.63-2.75 (1H, m), 2.80-2.88 (1H, m), 3.07
-3.15 (1H, m), 3.23-3.93 (10H, m), 5.21 (2H, s), 7.54-7.57
(2H, m), 8.17-8.22 (2H, m). Reference Example 5 (2S, 4S) -4-Mercapto-1- (4-nitrobenzyloxycarbonyl) -2- [4- (4-nitrobenzyloxy) Carbonylguanidino) -piperidine-1
-Ylcarbonyl] pyrrolidine Reference Example 6 (2S, 4S) -4-mercapto-1-methyl-2-
[4- (4-Nitrobenzyloxycarbonylguanidino) piperidin-1-ylcarbonyl] pyrrolidine Reference Example 7 (2S, 4S) -4-Mercapto-1- (4-nitrobenzyloxycarbonyl) -2-[(3S) -3- (4
-Nitrobenzyloxycarbonylguanidino) pyrrolidin-1-ylcarbonyl] pyrrolidine Reference Example 8 (2S, 4S) -4-Mercapto-1-methyl-2-
[(3S) -3- (4-Nitrobenzyloxycarbonylguanidino) pyrrolidin-1-ylcarbonyl] pyrrolidine Reference Example 9 (2S, 4S) -4-Mercapto-1- (4-nitrobenzyloxycarbonyl) -2- [3- (4-nitrobenzyloxycarbonylguanidino) azetidine-1-
Ilcarbonyl] pyrrolidine Reference Example 10 (2S, 4S) -4-Mercapto-1-methyl-2-
[3- (4-Nitrobenzyloxycarbonylguanidino) azetidin-1-ylcarbonyl] pyrrolidine Reference Example 11 (2S, 4S) -4-Mercapto-1- (4-nitrobenzyloxycarbonyl) -2- [2- ( 4-Nitrobenzyloxycarbonylguanidino) ethylcarbamoyl] pyrrolidine Reference Example 12 (2S, 4S) -4-mercapto-1-methyl-2-
[2- (4-Nitrobenzyloxycarbonylguanidino) ethylcarbamoyl] pyrrolidine Reference Example 13 (2S, 4S) -4-Mercapto-1- (4-nitrobenzyloxycarbonyl) -2- [4- (methyl-4-
Nitrobenzyloxycarbonylamidino) piperazin-1-ylcarbonyl] pyrrolidine Reference Example 14 (2S, 4S) -4-Mercapto-1-methyl-2-
[4- (Methyl-4-nitrobenzyloxycarbonylamidino) piperazin-1-ylcarbonyl] pyrrolidine Reference Example 15 (2S, 4S) -4-Mercapto-1- (4-nitrobenzyloxycarbonyl) -2-[( 3R) -3- (4
-Nitrobenzyloxycarbonylguanidino) pyrrolidin-1-ylcarbonyl] pyrrolidine Reference Example 16 (2S, 4S) -4-Mercapto-1-methyl-2-
[(3R) -3- (4-Nitrobenzyloxycarbonylguanidino) pyrrolidin-1-ylcarbonyl] pyrrolidine Reference Example 17 (2S, 4S) -4-Mercapto-1- (4-nitrobenzyloxycarbonyl) -2- [(3S) -4- (4
-Nitrobenzyloxycarbonylamidino) -3-methylpiperazin-1-ylcarbonyl] pyrrolidine Reference Example 18 (2S, 4S) -4-mercapto-1-methyl-2-
[(3R) -4- (4-Nitrobenzyloxycarbonylamidino) -3-methylpiperazin-1-ylcarbonyl] pyrrolidine Reference Example 19 (2S, 4S) -4-Mercapto-1- (4-nitrobenzyloxycarbonyl) ) -2- [1- (4-Nitrobenzyloxycarbonylamidino) piperidin-4-ylcarbamoyl] pyrrolidine Reference Example 20 (2S, 4S) -4-Mercapto-1- (4-nitrobenzyloxycarbonyl) -2- [(3S) -1- (4
-Nitrobenzyloxycarbonylamidino) pyrrolidin-3-ylcarbamoyl] pyrrolidine Reference Example 21 (2S, 4S) -4-Mercapto-1- (4-nitrobenzyloxycarbonyl) -2- [1- (4-nitrobenzyloxy) Carbonylamidino) azetidin-3-ylcarbamoyl] pyrrolidine Reference Example 22 (1R, 5R, 6S) -2- (diphenylphosphorylio)
Xy) -6-[(1R) -1-hydroxyethyl] -1
-Methyl-1-carbapene-2-em-3-carboxylic acid
4-Nitrobenzyl ester (1R, 5R, 6S) -2-oxo-6-[(1R)-
1-Hydroxyethyl] -1-methyl-1-carbapenamu-3-carboxylic acid 4-nitrobenzyl ester (3.
63 g) was dissolved in dry acetonitrile (72 ml), and diphenylphosphoryl chloride (2.28 ml) and diisopropylethylamine (1.92 ml) were added dropwise under ice-cooling stirring. After stirring for 1 hour under the same conditions, the reaction solution was concentrated. The residue was dissolved in ethyl acetate and washed with water (twice) and brine successively,
It was dried over sodium sulfate and concentrated. The residue was dissolved in ethyl acetate (10 ml) and allowed to stand, to precipitate crystals. After diluting with isopropyl ether (500 ml), the crystals formed were collected by filtration and dried. Colorless needle crystals (5.34 g) were obtained.

Melting point 123-125 ° C. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δppm: 1.2
2 (3H, d, J = 7.2Hz), 1.33 (3H,
d, J = 6.6 Hz), 3.32 (1H, dd, J =
6.6, 2.6 Hz), 3.42-3.56 (1H,
m), 4.20-4.31 (2H, m), 5.22 (1
H, d, J = 13.8 Hz), 5.35 (1H, d, J
= 13.8 Hz), 7.13-7.40 (10H,
m), 7.55 (1H, d, J = 8.6Hz), 8.1
3 (2H, d, J = 8.6 Hz).

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location A61K 31/495 9360-4C 31/55 9360-4C (72) Inventor Katsuhiko Watanabe Hiroshi Shinagawa, Tokyo Town 1-25-2 Sankyo Stock Company (72) Inventor Katsuya Ishikawa 1-25-2 Hiromachi, Shinagawa-ku, Tokyo Sankyo Stock Company (72) Inventor Hiro Yasuda 1 Hiromachi, Shinagawa-ku, Tokyo 2-58, Sankyo stock company (72) Inventor Satoshi Oya 1-25-2 Hiromachi, Shinagawa-ku, Tokyo Sankyo stock company (72) Inventor Yukio Utsui 1-2-chome Hiromachi, Shinagawa-ku, Tokyo No. 58 Sankyo stock company

Claims (1)

[Claims] 1. A general formula: A carbapenem derivative having the following formula and a pharmaceutically acceptable salt thereof. In the formula, R ¹ is a hydrogen atom or a methyl group, and R 1
² is a hydrogen atom, a lower alkyl group with or without a substituent, a lower alkenyl group, a lower alkynyl group or a -C (= NH) R ⁰ group (in the formula, R ⁰ represents a hydrogen atom or a lower alkyl group) And R ¹⁰ represents a hydrogen atom or an ester residue that undergoes hydrolysis in vivo. A represents any group represented by the following general formula. General formula: (In the formula, n represents 1, 2, or ³ , and R ³ , R ⁴
And R ⁵ are each independently a hydrogen atom, a lower alkyl group, or R ³ is bonded to R ⁵ or R ⁴ — (CH ₂ ) _s —
W- (CH _{2) t} - group (wherein, s and t is 1, 2, 3
, W is a single bond, an oxygen atom or a sulfur atom), and R ⁶ and R ⁷ are substituents on the ring, each independently having a hydrogen atom, a halogen atom or a substituent, or Not having lower alkyl group, hydroxy group,
A carboxy group, a carbamoyl group, an amino group, a cyano group or a carbamoyloxy group is shown. ) General formula: (In the formula, m represents 0, 1 or 2, d represents 0 or 1, R ³ , R ⁴ and R ⁵ have the same meanings as described above, R ⁸ has a hydrogen atom and a substituent. R ⁹ represents a lower alkyl group, a lower alkenyl group or a lower alkynyl group, which may or may not have a hydrogen atom, a lower alkyl group with or without a substituent, a fluorine atom, a chlorine atom, A hydroxy group, an amino group, a cyano group, a carbamoyloxy group, a carboxy group or a carbamoyl group is shown.) General formula: (In the formula, 1 represents 0, 1 or 2, and R ³ , R ⁴ , R ⁵
And R ⁹ have the same meanings as described above, and R ¹¹ represents a hydrogen atom or a lower alkyl group. ) General formula: (In the formula, P represents 1 or 2, and R ³ , R ⁴ and R ⁵
Has the same meaning as described above, and R ¹² and R ¹³ each independently represent a hydrogen atom or a lower alkyl group having or not having a substituent. )