JPH06206881A - 2-@(3754/24)2-substituted pyrrolidinylthio)carbapenem derivative - Google Patents

Abstract

PURPOSE:To obtain a new compound, capable of manifesting excellent stability to beta-lactamase and renal dehydropeptidase I and useful as an antimicrobial agent having strong antimicrobial activity against sensitive and resistant Gram- positive bacteria and Gram-negative bacteria. CONSTITUTION:The compound of the formula [R<1> is H or methyl; R<2> is H or negative charge; R<6> is H or lower alkyl; two of R<4> to R<6>, together with N, are mutually bound to form a 5- to 6-membered (substituted)heterocyclic ring; the rest are H or lower alkyl; Y is lower alkylene or single bond], e.g. (5R,6S)-[(R)-1-hydroxyethyl]-2-[(@2S,4S)-2-(3-pyrrolin-3-yl)pyrrolidin -4-ylthio]-1- carbapen-2-em-3-carboxylic acid. The compound of formula I is obtained by reacting a compound of formula II (R<9> is H or hydroxy; R<20> is H or carboxyl) with the compound of formula III (R<30> is H, lower alkyl or imino; R<40>, R<50> and R<60> are same as R<4> to R<5>), etc.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a novel carbapenem (7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid) compound, containing the compound as an active ingredient. Antibacterial agent and a method for producing the compound.

[0002]

2. Description of the Related Art In recent years, new β-lactam antibiotics having the same β-lactam ring as penicillins and cephalosporins but different basic skeletons have been discovered one after another from nature.

For example, Streptomyces cattleya (S
Thienamyci isolated from fermentation of Treptomyces cattleya
n) [Journal of the American Chemical
Society (J. Am. Chem. Soc.), 10th
0, page 6491 (1978)], and naturally-occurring carbapenem compounds. Thienamycin is
It was expected to be developed as a highly useful β-lactam agent having a wide range of excellent antibacterial spectrum and strong antibacterial activity against Gram-positive and Gram-negative bacteria. However, thienamycin itself is chemically unstable, and it is degraded by certain in-vivo enzymes such as renal dehydropeptidase I (hereinafter abbreviated as DHP-I) to reduce its antibacterial activity. Low recovery rates have been reported [anti-microbial agents
And Chemotherapy (Antimicrob.Age
nts Chemother. ), Vol. 22, p. 62 (1982); ibid., Vol. 23, p. 300 (1983).
Year)].

Merck has synthesized a large number of thienamycin analogs with the aim of maintaining the excellent antibacterial activity of thienamycin and ensuring its chemical stability. As a result, imipenem [(5:
R, 6S, 8R) -3-[[2- (formimidoylamino) ethyl] thio] -6- (1-hydroxyethyl)
-7-Oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid monohydrate; Journal
Of Medicinal Chemistry (J. Med. Ch
em. ), Vol. 22, p. 1435 (1979)] has been put to practical use as a medicine.

[0005] Imipenem retains antibacterial activity and β-lactamase resistance which are equal to or higher than thienamycin against various bacterial species, and its antibacterial activity is 2 to 4 times excellent especially against Pseudomonas aeruginosa. There is. Further, the stability of imipenem as an aqueous solution and as a solid was significantly improved as compared with thienamycin.

However, imipenem, like thienamycin, is degraded by DHP-I in the human kidney,
Not only can it be used for urinary tract infections, but it also shows nephrotoxicity due to degradation products. As a result, imipenem cannot be administered alone, and cilastatin (cilastatin)
n) and must be used in combination with a DHP-I inhibitor [J. Antimicrob. Chemotherapy.
r. ), Volume 12 (Suppl D), p. 1 (1983).
Year)]. In recent years, imipenem is frequently used for the treatment and prevention of infectious diseases, and methicillin highly resistant staphylococcus aureus and imipenem-resistant Pseudomonas aeruginosa, which are resistant to imipenem, are increasing in the clinical field. It does not show sufficient therapeutic effect.

The prior art most similar to the present invention is:
JP-A-63-170379 can be mentioned. The publication describes, as a carbapenem compound, a compound having a pyrrolidinylthio group substituted at the 2-position of the carbapenem with a heterocyclic group which may have an appropriate substituent. Further, 50 or more kinds of heterocyclic groups are generally mentioned as preferable heterocyclic groups. A pyrrolinyl group and a tetrahydropyridyl group are mentioned as one of those heterocyclic groups.

However, these descriptions are merely general descriptions, and a group of compounds which are considered to be actually producible by a person skilled in the art from the description of the detailed description and the description of Examples and Reference Examples are The aromatic heterocyclic group and the aliphatic heterocyclic group containing only an oxygen atom or a sulfur atom are limited, and the pyrrolinyl group, the tetrahydropyridyl group and other aliphatic heterocyclic groups relating to the present invention are not specifically mentioned. It has not been.

[0009]

Since β-lactam antibiotics show selective toxicity only to bacteria and have no effect on animal cells, they are useful as antibiotics with few side effects for treating bacterial infections. It is a widely used and highly useful drug.

However, in recent years, highly resistant methicillin-resistant Staphylococcus aureus and resistant Pseudomonas aeruginosa are often isolated from patients with weakened immunity as causative bacteria of intractable infectious diseases, and are becoming a major clinical problem. Therefore, development of an antibacterial agent having an improved antibacterial activity against these resistant bacteria, particularly in carbapenem compounds, improvement of antibacterial activity, improvement of stability against DHP-I, reduction of nephrotoxicity,
It is strongly desired to reduce side effects on the central nervous system.

[0011]

DISCLOSURE OF THE INVENTION The inventors of the present invention have made earnest studies for the purpose of providing a novel carbapenem compound having excellent antibacterial activity and resistant to DHP-I. As a result, at the 2-position of the carbapenem skeleton, the general formula

[0012]

[Chemical 9] [In the formula, R ³ is a hydrogen atom or a lower alkyl group, R ⁴ , R
Two kinds of substituents selected from the group of ⁵ and R ⁶ are bonded together with a nitrogen atom to form a 5- or 6-membered optionally substituted heterocyclic group (provided that the nitrogen atom is an ammonio group). And the remaining substituents are hydrogen atoms or lower alkyl groups, Y represents a lower alkylene group or a single bond], and the carbapenem compound of the present invention has a group represented by It is a novel compound, has a strong antibacterial activity against Gram-positive bacteria such as Staphylococcus aureus and Gram-negative bacteria including Pseudomonas aeruginosa, and further shows excellent stability against DHP-I. Heading, completed the present invention.

The present invention has the general formula

[0014]

[Chemical 10] [Wherein R ¹ is a hydrogen atom or a methyl group, R ² is a hydrogen atom or a negative charge, R ³ is a hydrogen atom or a lower alkyl group,
Two types of substituents selected from the group of R ⁴ , R ⁵ and R ⁶ are
Bonded together with a nitrogen atom to form a 5- or 6-membered optionally substituted heterocyclic group (provided that the nitrogen atom may form an ammonio group), and the remaining substituents are: A hydrogen atom or a lower alkyl group, and Y represents a lower alkylene group or a single bond] or a pharmaceutically acceptable salt or ester thereof, a process for producing the same and its use as an antibacterial agent.

The symbols and terms used in this specification will be described.

The compounds of the present invention have a basic structure

[0017]

[Chemical 11] And systematically 7-oxo-1-azabicyclo [3.
2.0] is called hept-2-ene-2-carboxylic acid. In the present specification, a number based on a carbapenem which is conventionally and widely used is attached for simplification, and its basic structure is described as 1-carbapene-2-em-3-carboxylic acid.

[0018]

[Chemical 12] The present invention includes optical isomers and stereoisomers based on the asymmetric carbon atoms at the 1-, 5-, 6- and 8-positions of the carbapenem skeleton, with suitable compounds for these isomers like thienamycin. A compound having a 5R, 6S configuration (5,6-trans) having a configuration and a carbon atom at the 8-position is an R configuration (5R, 6S, 8R) configuration, or having a methyl group at the 1-position Is (1R, 5S, 6
A compound having the S, 8R) configuration may be mentioned.

[0019]

[Chemical 13] The present invention also includes, for the 2-substituted pyrrolidin-4-ylthio group at the 2-position side chain, isomers based on the asymmetric carbon atoms at the 2-position, 4-position and 2-position side chains of the pyrrolidine nucleus. Examples of suitable compounds include a compound having a (2 ′S, 4 ′S) configuration and a (2′R, 4′R) configuration.

Further, the side chain substituting at the 2-position of the pyrrolidine nucleus has isomers based on asymmetric carbon, but the present invention includes both isomers.

The lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, sec-butyl group, tert. -Butyl group, pentyl group, hexyl group and the like can be mentioned, and among them, methyl group, ethyl group, tert-butyl group and the like are preferable.

Examples of the heterocyclic group include a pyrrolinyl group,
N-lower alkylpyrrolinyl group, N, N-dilower alkylpyrrolinio group, tetrahydropyridyl group, N-lower alkyltetrahydropyridyl group, N, N-dilower alkyltetrahydropyridinio group, pyrrolidinyl group, N-lower Examples thereof include an alkylpyrrolidinyl group, an N, N-dilower alkylpyrrolidinio group, a piperidyl group, an N-lower alkylpiperidyl group, and an N, N-dilower alkylpiperidinio group. Among them, a pyrrolinyl group, N- Examples thereof include a lower alkylpyrrolinyl group and an N, N-dilower alkylpyrrolinio group, with a pyrrolinyl group being particularly preferred. The heterocyclic group can have at least one substituent at any substitutable position on the heterocycle.

Examples of the substituent of the heterocyclic group include a carbamoyl group, a cyano group, a methanesulfonyl group and an amino group;
Lower alkanoyl group such as formyl group and acetyl group; Lower alkylcarbamoyl group in which the above lower alkyl group such as methylcarbamoyl group, ethylcarbamoyl group, dimethylcarbamoyl group and diethylcarbamoyl group is mono-substituted or di-substituted; N-methylamino group , N-ethylamino group, N, N-dimethylamino group, N, N-diethylamino group and other lower alkyl groups which are mono-substituted or di-substituted; N-formylamino group, N-acetylamino group, etc. The lower alkanoylamino group and the lower alkyl group which may have the above-mentioned substituents.

The lower alkylene group means 1 to 6 carbon atoms.
Represents a linear or branched alkylene group, for example, methylene group, ethylene group, propylene group, 1-methylethylene group, 2-methylethylene group, methylmethylene group,
Examples thereof include a dimethylmethylene group, a butylene group, a 1-methylpropylene group, a 2-methylpropylene group, a 3-methylpropylene group, a 1,1-dimethylethylene group and a 2,2-dimethylethylene group. Among them, a methylene group, Ethylene group, propylene group and the like are preferable.

The protective group for the carboxyl group is, for example,
Methyl group, ethyl group, propyl group, isopropyl group, t
lower alkyl groups such as ert-butyl group; for example, 2,2
2-trichloroethyl group, 2,2,2-trifluoroe
Halo-substituted lower alkyl groups such as tyl group; eg acetoxy
Methyl, propionyloxymethyl, pivaloyl
Xymethyl group, 1-acetoxyethyl group, 1-propio
Lower alkanoyloxyalkenyl such as nyloxyethyl group
Group; for example, 1- (methoxycarbonyloxy) ethyl
Group, 1- (ethoxycarbonyloxy) ethyl group, 1-
Lower such as (isopropoxycarbonyloxy) ethyl group
Alkoxycarbonyloxyalkyl group;
Lopenyl group, 2-chloro-2-propenyl group, 3-meth
Xycarbonyl-2-propenyl group, 2-methyl-2-
Lower such as propenyl group, 2-butenyl group, cinnamyl group
Alkenyl group; for example, benzyl group, p-methoxybenzyl
Group, 3,4-dimethoxybenzyl group, o-nitroben
Zyl group, p-nitrobenzyl group, benzhydryl group, bi
Aralkyl such as su (p-methoxyphenyl) methyl group
A group; for example (5-methyl-2-oxo-1,3-dioxy)
(5-substituted-2-oxy) such as sole-4-yl) methyl group
So-1,3-dioxol-4-yl) methyl group;
For example, trimethylsilyl group, tert-butyldimethylsilyl
Lower alkylsilyl groups such as phenyl groups; indanyl groups, phthalates
Examples thereof include a dil group and a methoxymethyl group.
Penyl group, p-nitrobenzyl group, p-methoxybenzyl
Group, benzhydryl group, tert-butyldimethyl group
A ryl group and the like are preferable.

Examples of the hydroxy-protecting group include lower alkylsilyl groups such as trimethylsilyl group and tert-butyldimethylsilyl group; for example, methoxymethyl group,
Lower alkoxymethyl group such as 2-methoxyethoxymethyl group; for example, tetrahydropyranyl group; for example, benzyl group, p-methoxybenzyl group, 2,4-dimethoxybenzyl group, o-nitrobenzyl group, p-nitrobenzyl group, trityl Aralkyl groups such as groups; eg formyl groups,
Acyl group such as acetyl group; for example, tert-butoxycarbonyl group, 2-iodoethoxycarbonyl group, 2,
Lower alkoxycarbonyl group such as 2,2-trichloroethoxycarbonyl group; for example, 2-propenyloxycarbonyl group, 2-chloro-2-propenyloxycarbonyl group, 3-methoxycarbonyl-2-propenyloxycarbonyl group, 2-methyl- Alkenyloxycarbonyl group such as 2-propenyloxycarbonyl group, 2-butenyloxycarbonyl group, cinnamyloxycarbonyl group; for example, benzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, o-nitrobenzyloxycarbonyl group, p Examples include aralkyloxycarbonyl group such as -nitrobenzyloxycarbonyl group and the like, and 2-propenyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, tert-butyldimethylsilyl group and the like are particularly preferable. .

Examples of the protective group for imino group include benzylidene group, p-chlorobenzylidene group, p-nitrobenzylidene group, salicylidene group, α-naphthylidene group and β.
-Aralkylidene group such as naphthylidene group; for example, benzyl group, p-methoxybenzyl group, 3,4-dimethoxybenzyl group, o-nitrobenzyl group, p-nitrobenzyl group, benzhydryl group, bis (p-methoxyphenyl)
Aralkyl groups such as methyl group and trityl group; lower alkanoyl groups such as formyl group, acetyl group, propionyl group, butyryl group, oxalyl group, succinyl group and pivaloyl group; for example chloroacetyl group, dichloroacetyl group, trichloroacetyl group, Halo-substituted lower alkanoyl group such as trifluoroacetyl group; arylalkanoyl group such as phenylacetyl group and phenoxyacetyl group; lower alkoxycarbonyl group such as methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, tert-butoxycarbonyl group For example, 2-
Halo-substituted lower alkoxycarbonyl groups such as iodoethoxycarbonyl group and 2,2,2-trichloroethoxycarbonyl group; for example, 2-propenyloxycarbonyl group,
2-chloro-2-propenyloxycarbonyl group, 3-
Methoxycarbonyl-2-propenyloxycarbonyl group, 2-methyl-2-propenyloxycarbonyl group,
Alkenyloxycarbonyl groups such as 2-butenyloxycarbonyl group and cinnamyloxycarbonyl group; aralkyloxy such as benzyloxycarbonyl group, o-nitrobenzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group and phenethyloxycarbonyl group Carbonyl group; for example, trimethylsilyl group, tert
Examples thereof include lower alkylsilyl groups such as -butyldimethylsilyl group and the like, and particularly, 2-propenyloxycarbonyl group, tert-butoxycarbonyl group, p-nitrobenzyloxycarbonyl group and the like are preferable.

R ⁴ , R ⁵ and R ⁶ are R ⁴ , R ⁵ and R ⁶
Two kinds of substituents selected from the group are bonded together with a nitrogen atom to form a 5- or 6-membered optionally substituted heterocyclic group. The remaining substituents represent a hydrogen atom or a lower alkyl group.

R ² represents a hydrogen atom or a negative charge. When the 2-position side chain of the pyrrolidine nucleus forms an ammonio group,
R ² has a negative charge, and by forming a pair with the ammonium ion, the compound of the general formula [I] forms an inner salt.

Y represents a lower alkylene group or a single bond, preferably a methylene group or a single bond, of which the single bond is more preferred.

Here, the compound of the general formula [I] will be specifically described.

The compound of the general formula [I] has the general formula

[0033]

[Chemical 14] [Wherein R ¹ is a hydrogen atom or a methyl group, R ² is a hydrogen atom or a negative charge, R ³ is a hydrogen atom or a lower alkyl group,
R ^4a and R ^5a or R ^4a and R ^6a are bonded together with a nitrogen atom to form a 5- or 6-membered optionally substituted heterocyclic group, provided that the nitrogen atom forms an ammonio group. Or R ^4a , R ^5a and R ^6a which are not bonded to each other are a hydrogen atom or a lower alkyl group, and Y is a lower alkylene group or a single bond] Acceptable salts or esters and general formulas

[0034]

[Chemical 15] [Wherein R ¹ is a hydrogen atom or a methyl group, R ² is a hydrogen atom or a negative charge, R ³ is a hydrogen atom or a lower alkyl group,
R ^4b is a hydrogen atom or a lower alkyl group, R ^5b and R ^6b
Represents a 5-membered or 6-membered optionally substituted heterocyclic group together with a nitrogen atom (provided that the nitrogen atom may form an ammonio group), and Y represents a lower alkylene group. Or a single bond] or a pharmaceutically acceptable salt or ester thereof.

The salt of the general formula [I] means a pharmaceutically acceptable conventional salt, which is a carboxyl group at the 3-position of the carbapenem skeleton or a pyrrolidine base at the 2-position side chain or a side substituted with the pyrrolidine nucleus. Mention may be made of salts at the base on the chain.

Examples of the basic addition salt at the carboxyl group include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; trimethylamine salt, triethylamine salt, etc. Aliphatic amine salts such as dicyclohexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, procaine salt; aralkylamine salts such as N, N'-dibenzylethylenediamine; pyridine salt, picoline salt, quinoline salt A heterocyclic aromatic amine salt such as isoquinoline salt; for example, tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzyltributylammonium salt , Quaternary ammonium salts such as methyltrioctyl ammonium salt and tetrabutyl ammonium salt; basic amino acid salts such as arginine salt and lysine salt.

Examples of the acid addition salt in the pyrrolidine base or the base on the side chain that substitutes for the pyrrolidine nucleus include, for example, hydrochlorides, sulfates, nitrates, phosphates, carbonates, hydrogen carbonates, perchlorates and the like. Inorganic acid salts; organic acid salts such as acetate, propionate, lactate, maleate, fumarate, tartrate, malate, citrate, ascorbate; eg methanesulfonate, isethionate Acid salt,
Sulfonates such as benzenesulfonate and p-toluenesulfonate; examples thereof include acidic amino acid salts such as aspartate and glutamate.

As the non-toxic ester of the general formula [I],
It means a pharmaceutically acceptable conventional one at the carboxyl group at the 3-position of the carbapenem skeleton. For example, acetoxymethyl group, ester with alkanoyloxymethyl group such as pivaloyloxymethyl group, ester with alkoxycarbonyloxyalkyl group such as 1- (ethoxycarbonyloxy) ethyl group, ester with phthalidyl group,
(5-methyl-2-oxo-1,3-dioxole-4
-Yl) methyl group and the like (5-substituted-2-oxo-1,3
Examples thereof include an ester with a -dioxol-4-yl) methyl group.

Next, a method for producing the compound of the present invention will be described. General formula

[0040]

[Chemical 16] [Wherein R ¹ represents a hydrogen atom or a methyl group, R ⁹ represents a hydrogen atom or a hydroxy group-protecting group, and R ²⁰ represents a hydrogen atom or a carboxyl group-protecting group]. In the presence of a base, the activating reagent is reacted with

[0041]

[Chemical 17][In the formula, R¹ , R⁹And R²⁰Has the above meaning and Z is
To a reactive derivative [II ']
Guide.

As the inert organic solvent used in the above reaction, for example, diethyl ether, tetrahydrofuran,
Dioxane, benzene, toluene, chlorobenzene, methylene chloride, chloroform, carbon tetrachloride, dichloroethane, trichloroethylene, acetone, ethyl acetate, acetonitrile, N, N-dimethylformamide, hexamethylphosphoric triamide or a mixture of the above solvents, especially acetonitrile. , Benzene is preferred.

Examples of the base used in the reaction include trimethylamine, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, N, N-dimethylaniline, 1,8- Tertiary aliphatic amines such as diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN); eg pyridine, 4 -Aromatic amines such as dimethylaminopyridine, picoline, lutidine, quinoline and isoquinoline are mentioned, and N, N-diisopropylethylamine and triethylamine are particularly preferable.

Examples of the activating reagent used in the reaction include acid anhydrides such as trifluoroacetic anhydride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, p-toluenesulfonic anhydride; methanesulfonyl, for example. Acid chlorides such as chloride, p-toluenesulfonyl chloride, diphenylchlorophosphate and the like,
Diphenyl chlorophosphate is particularly preferable.

The group Z in the general formula [II '] means a leaving group, for example, a trifluoroacetoxy group, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group,
Examples thereof include p-toluenesulfonyloxy group and diphenoxyphosphoryloxy group, with diphenoxyphosphoryloxy group being particularly preferable.

In the reaction, 1 to 3 mol of the base, preferably 1 to 1.5 mol, and 1 to 1.2 mol of the activating reagent are used per 1 mol of the compound of the general formula [II].

The reaction is -40 to 50 ° C, preferably -20.
It is carried out in a temperature range of -20 ° C and is usually completed quantitatively in 0.5-3 hours.

After the completion of the reaction, the reaction is carried out according to a conventional method to quantitatively obtain the reactive derivative [II '] of the general formula [II].

Reactive derivative [II '] and general formula

[0050]

[Chemical 18] [In the formula, R ³⁰ is a hydrogen atom, a lower alkyl group or a protecting group for an imino group, and two kinds of substituents selected from the group of R ⁴⁰ , R ⁵⁰ and R ⁶⁰ are bonded together with a nitrogen atom to form a 5-membered Or a 6-membered optionally substituted heterocyclic group is formed (however, the nitrogen atom may form an ammonio group), the remaining substituents are a hydrogen atom or a lower alkyl group, and Y is a lower group. Indicates an alkylene group or a single bond (however,
The substituent of the heterocyclic group and the imino group on the heterocyclic ring may be optionally protected)], and the reaction with the compound represented by the above is carried out using the above-mentioned inert organic solvent and base. , General formula

[0051]

[Chemical 19] [Wherein R ¹ , R ⁹ , R ²⁰ , R ³⁰ , R ⁴⁰ , R ⁵⁰ , R ⁶⁰ and Y have the above-mentioned meanings].

The reaction is carried out in the amount of 1 to 2 mol, preferably 1 to 1.5 mol, of base with respect to 1 mol of the reactive derivative [II '].
1 to 1.2 mol of the compound of the general formula [III] is used,
It is carried out in a temperature range of -40 to 50 ° C, preferably -20 to 20 ° C, and usually completed in 0.5 to 3 hours.

The compound of general formula [IV] can also be produced in one step from the compound of general formula [II]. That is, the compound of the general formula [IV] is reacted in the same reaction system without isolation of the reactive derivative [II ′] derived from the compound of the general formula [II].
The compound can be efficiently produced. When it is carried out in one step, to 1 mol of the compound of the general formula [II],
2 to 4 moles of base, preferably 2.5 to 3.5 moles are used.

After completion of the reaction, usual treatment is carried out to obtain a crude product of the compound represented by the general formula [IV], which can be subjected to a deprotection reaction without purification. It is preferable to purify by subjecting to column chromatography or silica gel column chromatography.

From the compound of the general formula [IV] thus obtained, the reaction of removing the protective groups of the hydroxy group, imino group and carboxyl group is appropriately combined, if necessary, to carry out the reaction of the general formula [I]. ] The compound of] can be manufactured.

The removal of the protecting group depends on its type,
It is carried out according to a conventional method, for example, by solvolysis, chemical reduction or hydrogenation.

In the above-mentioned general formula [IV], the protecting group for hydroxy group and / or amino group or imino group is, for example, aralkyloxycarbonyl group such as benzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, and carboxyl group. When the protective group of is an aralkyl group such as a benzyl group, a p-nitrobenzyl group or a benzhydryl group, a platinum catalyst such as platinum oxide, a platinum wire or platinum black; for example, palladium black, palladium oxide or palladium- Protecting groups can be removed by catalytic hydrogenation using a palladium catalyst such as carbon or palladium hydroxide-carbon.

Examples of the solvent used in the catalytic hydrogenation reaction include methanol, ethanol, tetrahydrofuran, dioxane, acetic acid and the like, or a mixed solvent of these organic solvents and water or a buffer solution such as a phosphate.

The reaction is carried out under a hydrogen gas flow of 1 to 4 atm.
It is completed within 0.5 to 4 hours in the temperature range of -50 ° C.

In the above-mentioned general formula [IV], when the protecting group for hydroxy group and / or amino group or imino group is, for example, allyloxycarbonyl group and the protecting group for carboxyl group is, for example, allyl group, The protecting group can be removed by reacting an organic-soluble palladium complex catalyst in an inert organic solvent containing an allyl group scavenger [W. McCombie et al., The Journal of Organic Chemistry (J. Org. Chem.), Volume 47, 587-
590 (1982) and F.S. Guib
e ▼), etc., same document, Vol. 52, 4984-49
93 (1987)].

Examples of the solvent used in the reaction include water, acetone, diethyl ether, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, methylene chloride,
Chloroform or the like or a mixed solvent thereof may be used.

Suitable palladium compound complexes used in this reaction include, for example, palladium-carbon, palladium hydroxide-carbon, palladium (II) chloride, palladium (II) acetate, tetrakis (triphenylphosphine).
Palladium (0), tetrakis (triphenoxyphosphine) palladium (0), tetrakis (triethoxyphosphine) palladium (0), bis [ethylenebis (diphenylphosphine)] palladium (0), tetrakis [tri (2-furyl) phosphine ] Palladium (0),
Bis (triphenylphosphine) palladium (II)
Examples thereof include chloride and bis (triphenylphosphine) palladium (II) acetate.

Examples of allyl group scavengers include dimedone, formic acid, acetic acid, ammonium formate, sodium formate,
Examples thereof include sodium 2-ethylhexanoate, potassium 2-ethylhexanoate, pyrrolidine, piperidine, and tributyltin hydride.

In the reaction, 0.01 to 0.5 mol of the catalyst and 1 to 6 mol of the nucleophile are used with respect to 1 mol of the compound of the general formula [IV], and the temperature range is -10 to 50 ° C, preferably Is 0
It is carried out in the temperature range of 30 ° C. and is usually completed in 0.5 to 3 hours.

In the above general formula [IV], when the hydroxy and / or imino protecting group is o-nitrobenzyloxycarbonyl group and the carboxyl protecting group is o-nitrobenzyl group, The protecting group can be removed by photoreaction [Amit (Ami
t) and the like, The Journal of Organic Chemistry (J. Org. Chem.), Vol. 39, 1
92-196 (1974)].

After completion of the reaction for removing the protecting group, the compound of the general formula [I] can be prepared by a conventional treatment method such as column chromatography using silica gel or an adsorption resin, or an operation such as lyophilization or crystallization. The compound can be isolated.

The protecting group for the carboxyl group at the 3-position of the compound of the general formula [IV] is, for example, a lower alkanoyloxyalkyl group such as acetoxymethyl group or pivaloyloxymethyl group; for example, methoxymethyl group, indanyl group, In the case of a phthalidyl group or the like, such an ester is physiologically hydrolyzed in vivo, and therefore can be directly administered to humans or animals without removing the protecting group.

The compound of general formula [I] can be converted into a pharmaceutically acceptable salt or ester by a conventional method.

The starting material represented by the general formula [II] is, for example, Salzman (Salzman) when R ¹ is a hydrogen atom.
Mann) et al. [Journal of the American Chemical Society (J. Am. Chem. So
c. ), 102, 6161-6163 (1981).
Year)]; when R ¹ is a methyl group, see (Shi
h) etc. [Heterocycles (Heterocyc
les), Vol. 21, pp. 29-40 (1984)] or a method analogous thereto.

The starting material represented by the general formula [III] is
For example, it can be synthesized by the following method.

After activating the hydroxy group of the compound 1 by a conventional method, it is reacted with a thioacetic acid salt such as potassium thioacetate to give an acetylthio derivative 3 , which is then converted to the general formula [III] by alkali hydrolysis or acid hydrolysis. The thiol derivative represented can be obtained.

[0072]

[Chemical 20] [In the formula, R ¹⁰ represents a hydrogen atom or a protective group of a hydroxy group,
Z ^* is a leaving group selected from the group consisting of chlorine atom, bromine atom, iodine atom, trifluoroacetoxy group, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, p-toluenesulfonyloxy group, and Ac is an acetyl group. And R ³⁰ , R ⁴⁰ , R ⁵⁰ , R ⁶⁰ and Y have the above-mentioned meanings.] The compound group having the structural formula of Compound 1 can be produced according to the production method shown in Reference Examples.

The compounds of the present invention show strong antibacterial activity against various Gram-positive and Gram-negative bacteria.

In order to specifically show the usefulness of the compound of the present invention, the antibacterial activity of the compound of the present invention exemplified in the examples as a representative example of the compound of the present invention is shown by Bauer.
Et al. [The American Journal of Clinical Pathology (Amer. J. Clin. P
athol. ), Vol. 45, p. 493 (1966)]
The measurement was carried out by the disc diffusion assay according to. Thienamycin or imipenem was used as an internal standard.

The MIC of the test compound is calculated from the diameter of the circle of inhibition produced by the disc containing the test compound by Humphrey and Lightbow.
The calculation formula reported by J. Geun [The Journal of General Microbiology (J. Ge
n. Microbiol. ), Vol. 7, p. 129 (1
952)]. MIC for each bacterial species
The geometrical mean was calculated and the activity ratio with thienamycin was calculated.

Antibacterial efficacy is thienamycin (= 1.0)
The higher the number, the stronger the activity.

DHP-I sensitivity was measured by the
p) etc. [Antimicrobial Agent and Chemotherapy (Antimicrob.
sChemother. ), 22: 62-70 (1982)], and imipenem (= 1.
0), but the smaller the number, the higher the stability.

Antibacterial efficacy and DHP-I of the compounds of the present invention
Sensitivity was compared with imipenem (imipenem) as a comparison compound.
em) was used for the measurement. The results are shown in Table 1.

[0079]

[Table 1] In the compound of the present invention, two kinds of substituents selected from the group of R ⁴ , R ⁵ and R ⁶ are bonded to each other to form a 5- or 6-membered optionally substituted heterocyclic group together with a nitrogen atom. It has excellent antibacterial activity against various Gram-positive and Gram-negative bacteria and is useful as an antibacterial agent for the treatment and prevention of human bacterial infections caused by these pathogenic bacteria. It is a compound. Representative pathogens that are susceptible to the antibacterial agent of the present invention include, for example, Staphylococcus spp, Enterococcus spp, Escherichia spp, Enterobacter spp, Klebshera spp.
Ebsiella), Serratia
Genus, Proteus genus, Pseudomonas genus, etc., and methicillin-resistant Staphylococcus aureus (Methicillin resist S
taphylococcus aureus) and thienamycin resistant Pseudomonas aeruginosa (t
hienamycin resist Pseu
It showed excellent antibacterial activity against Domonas aeruginosa).

The compound of the present invention, which varies depending on the compound, is extremely stable to DHP-I, and is excellent in physicochemical stability and solubility in water.

The compound of the present invention can be used in the form of a pharmaceutical preparation suitable for parenteral administration, oral administration and external administration by mixing with a carrier of a solid or liquid excipient known in the art. The main one is parenteral (intravenous or intramuscular) administration by topical or injection. As a pharmaceutical formulation,
Examples thereof include liquid preparations such as injections, syrups and emulsions; solid preparations such as tablets, capsules and granules; external preparations such as ointments and suppositories. These formulations may include bases, auxiliaries, and
Additives that are commonly used, such as stabilizers, wetting agents, emulsifiers, absorption promoters and surfactants may be included.

Examples of the additives include distilled water for injection, Ringer's solution, glucose, sucrose syrup, gelatin, edible oil, cacao butter, ethylene glycol, sucrose, corn starch, magnesium stearate, talc and the like.

The dose varies depending on the patient's symptoms, body weight, age, sex, dosage form, number of administrations and the like, but a preferred daily dose for an adult is usually about 5 to 50 mg / mg of active ingredient.
kg, preferred daily dose for children is about 5-25 mg /
It is in the range of kg and it is preferable to administer it once or several times a day.

The compounds of the present invention may be used as needed for cilastatin [(Z) -7- (L-amino-2-carboxyethylthio) -2- (2,2-dimethylcyclopropanecarboxamide) -2-heptenoic acid. D] such as sodium
HP-I inhibitor [JP-A-56-81518, European Patent 28,778, Journal of Medicinal Chemistry (J. Med. Chem.), No. 30]
, 1074 (1987)].

[0085]

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

The thin-layer chromatographs of Examples and Reference Examples were prepared using Silicagel 60F as a plate.
₂₄₅ (Merck) was used as a detection method using a UV detector. Wakogel ^™ as silica gel for columns
C-300 (Wako Pure Chemical Industries, Ltd.) was used as a silica gel for a reverse phase column by LC-SORB ^™ SP-B-ODS (Che.
mco) or YMC-GEL ^™ ODS-AQ 12
0-S50 (Yamamura Chemical Laboratory) was used. As the high performance liquid chromatograph, JASCO 800 series (JASCO Corporation) was used. The NMR spectrum uses tetramethylsilane (TMS) as an internal standard when measuring with a heavy dimethyl sulfoxide or a heavy chloroform solution, and when measuring with a heavy aqueous solution, it has an internal standard of 2, 2.
Using 2-dimethyl-2-silapentane-5-sulfonate (DSS), XL-200 (200 MHz; Va
Rian) type spectrometer, and all δ values are shown in ppm.

The meanings of the abbreviations in NMR measurement are shown below. s: singlet d: doublet dd: double doublet m: multiplet br: broad J: coupling constant Hz: Hertz CDCl ₃ : heavy chloroform D ₂ O: heavy water The abbreviations in the reaction formulas are shown below. Ac: acetyl group All: allyl group Alloc: allyloxycarbonyl group Boc: tert-butoxycarbonyl group Ph: phenyl group TBS: tert-butyldimethylsilyl group Example 1 (1R, 5S, 6S) -6-[(R) -1-hydroxy
Ethyl] -1-methyl-2-[(2S, 4S) -2-
(3-pyrrolin-3-yl) pyrrolidin-4-ylchi
O] -1-carbapene-2-em-3-carboxylic acid 1)

[0088]

[Chemical 21] Allyl (1R, 5S, 6S) -2-diphenoxyphosphoryloxy-6-[(R) -1-hydroxyethyl]
-1-Methyl-1-carbapene-2-em-3-carboxylate (456 mg, 0.91 mmol) and (2S, 4S) -N-allyloxycarbonyl-2-
(N-allyloxycarbonyl-3-pyrrolin-3-yl) -4-mercaptopyrrolidine (310 mg, 0.9
2 mmol, the compound of Reference Example 1) to acetonitrile (2
5 ml), and N, N-diisopropylethylamine (0.16 ml, 0.92 m) at -10 ° C in a nitrogen stream.
(mol) and the mixture was stirred overnight at 5 ° C. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography [Wakogel ^™ C-300, hexane-ethyl acetate (1: 4)] to give allyl (1R, 5S, 6).
S) -2-[(2S, 4S) -N-allyloxycarbonyl-2- (N-allyloxycarbonyl-3-pyrrolin-3-yl) pyrrolidin-4-ylthio] -6-
[(R) -1-hydroxyethyl] -1-methyl-1-
Carbapene-2-Em-3-carboxylate (205
mg, yield: 38.2%) was obtained.

IR (KBr) cm ^-1 : 1780,171
0,1410,1330 NMR (CDCl ₃ ) δ: 1.27 (3H, d, J = 7)
Hz), 1.36 (3H, d, J = 6Hz), 1.88
(1H, m), 2.62 (1H, m), 3.18-3.
48 (3H, m), 3.64 (1H, m), 5.12-
5.53 (6H, m), 5.64 (1H, m), 5.7
8-6.10 (3H, m) 2)

[0090]

[Chemical formula 22] Compound obtained by the above reaction (205 mg, 0.35 mmo
1) methylene chloride solution (7.5 ml) in a nitrogen stream under ice cooling with water (31 μl), bis (triphenylphosphine) palladium (II) chloride (12.3 mg,
0.017 mmol) and tributyltin hydride (0.375 ml, 1.39 mmol) were added, and the reaction solution was stirred at the same temperature for 20 minutes and at room temperature for 20 minutes. The reaction mixture was extracted with water (70 ml), the aqueous layer was washed twice with chloroform, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure to about 15 ml and then subjected to reverse layer column chromatography (YMC-GEL ^™ ODS-AQ 120-S50,
50 ml, 20% methanol aqueous solution) to give the title compound (54 mg, yield: 40.8%).

IR (KBr) cm ^-1 : 1760,159
0.1390 NMR (D ₂ O) δ: 1.21 (3H, d, J = 8H
z), 1.29 (3H, d, J = 7Hz), 1.54
(1H, m), 2.60 (1H, m), 2.99 (1
H, dd, J = 12,3 Hz), 3.18 to 3.43
(3H, m), 3.82 (2H, m), 4.13 (4
H, s), 4.23 (2H, m), 5.83 (1H, b
rs) HPLC; column: YMC ^™ -Pack ODS-AQ, 5μ,
4.6φ × 150 mm, mobile phase: 0.01 M phosphate buffer (pH 6.5) -methanol (80:20), flow rate: 1.0 ml / min, temperature: 40 ° C., detection: 290
nm, retention time: 3.17 min Reference Example 1 (2S, 4S) -N-allyloxycarbonyl-2-
(N-allyloxycarbonyl-3-pyrrolin-3-i
Le) -4-Mercaptopyrrolidine 1)

[0092]

[Chemical formula 23] Hexamethyldisilazane (1.73 ml, 8.2 mmo
l) tetrahydrofuran solution (40 ml) in a nitrogen stream at -78 ° C with 1.6M n-butyllithium (4.
93 ml, 7.89 mmol) was added dropwise, and the reaction solution was adjusted to 0.
The mixture was stirred at 0 ° C for 10 minutes and further at -78 ° C for 25 minutes. To this solution was added (2S, 4R) -N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-.
(N-tert-Butoxycarbonyl-2-pyrrolidon-4-yl) pyrrolidine [2.94 g, 6.07 mmo
1; Compound of Japanese Patent Application No. 3-87628 Reference Example 5-1)]
Tetrahydrofuran solution (10 ml) was added dropwise to -7
After stirring at 8 ° C for 30 minutes, phenylselenyl chloride (1.7
A tetrahydrofuran solution (10 ml) of 5 g, 9.14 mmol) was added dropwise, and the mixture was stirred at the same temperature for 50 minutes. A saturated ammonium chloride aqueous solution (10 m
l) was added, followed by extraction with ethyl acetate (100 ml). The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [Wakogel ^™ C-30.
0, hexane-ethyl acetate (8: 1)], (2
S, 4R) -N-tert-butoxycarbonyl-4-
tert-butyldimethylsiloxy-2- (N-ter
t-butoxycarbonyl-3-phenylselenyl-2-
Pyrrolidone-4-yl) pyrrolidine (1.5 g, yield:
38.6%).

NMR (CDCl ₃ ) δ: 0.03 (6
H, s), 0.84 (9H, s), 1.46 (9H,
s), 1.50 (9H, s), 1.88 (1H, m),
2.78 (1H, m), 4.02 to 4.28 (2H,
m), 7.28 (3H, m), 7.70 (2H, m) 2)

[0094]

[Chemical formula 24] Compound obtained in the above reaction (1.5 g, 2.35 mmo
l) in tetrahydrofuran solution (15 ml) at room temperature in a nitrogen stream with borane-dimethyl sulfide complex (0.7).
(ml, 7.0 mmol) was added dropwise, and then 1.
Stir for 5 hours. To the reaction solution, under ice cooling, methanol (5
ml) was added and the mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [Wakogel ^™ C-30.
0, hexane-ethyl acetate (8: 1)], (2
S, 4R) -N-tert-butoxycarbonyl-4-
tert-butyldimethylsiloxy-2- (N-ter
t-Butoxycarbonyl-3-phenylselenylpyrrolidin-4-yl) pyrrolidine (883 mg, yield: 6
0.2%) was obtained.

NMR (CDCl ₃ ) δ: 0.02 (3
H, s), 0.03 (3H, s), 0.86 (9H,
s), 1.43 (9H, s), 1.46 (9H, s),
1.56 to 1.98 (2H, m), 4.21 (2H, m)
m), 7.31 (3H, m), 7.58 (2H, m) 3)

[0096]

[Chemical 25] Compound obtained in the above reaction (883 mg, 1.41 mm
ol) in methylene chloride solution (20 ml) at room temperature.
Chloroperbenzoic acid (305 mg, 1.77 mmol) was added, and the mixture was stirred at the same temperature overnight. The reaction solution was added with ethyl acetate (1
(00 ml), the organic layer was washed three times with saturated aqueous sodium hydrogen carbonate, water,
The extract was washed with saturated saline and dried over anhydrous sodium sulfate.
The residue is subjected to silica gel column chromatography [Wako
gel ^™ C-300, hexane-ethyl acetate (10:
1)], (2S, 4R) -N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2- (N-tert-butoxycarbonyl-3-pyrrolin-3-yl) pyrrolidine (588 mg, Yield: 8
8.9%).

NMR (CDCl ₃ ) δ: 0.04 (6
H, s), 0.85 (9H, s), 1.42 (9H,
s), 1.45 (9H, s), 1.72 to 2.10 (2
H, m), 3.44 (2H, m), 3.94 to 4.18.
(4H, m), 4.34 (1H, m), 4.53 (1
H, m), 5.60 (1H, br s) 4)

[0098]

[Chemical formula 26] Compound obtained by the above reaction (588 mg, 1.26 mm
Ol) in a methylene chloride solution (10 ml) in a nitrogen stream under ice cooling with 2,6-lutidine (0.59 ml, 5.0
6 mmol) and trimethylsilyltrifluoromethanesulfonate (0.76 ml, 3.8 mmol) were added dropwise, and the mixture was stirred at the same temperature for 1.5 hours. Methanol (3 ml) was added to the reaction solution, and the mixture was concentrated under reduced pressure. The residue was dissolved in methylene chloride (10 ml), triethylamine (0.44 ml, 3.16 mmol) and allyl chloroformate (0.32 ml, 0.30 mmol) were added under ice cooling, and the mixture was stirred at the same temperature for 1 hr. The reaction solution was concentrated under reduced pressure, and the residue was extracted with ethyl acetate (70 ml). The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [Wakogel ^™ C-300, hexane-ethyl acetate (4: 1)], and (2S, 4R)-
N-allyloxycarbonyl-2- (N-allyloxycarbonyl-3-pyrrolin-3-yl) -4-tert
-Butyldimethylsiloxypyrrolidine (485 mg, yield: 88.5%) was obtained. 5)

[0099]

[Chemical 27] Compound obtained in the above reaction (485 mg, 1.11 mm
ol) in acetonitrile (10 ml) at room temperature.
6% Hydrofluoric acid (0.5 ml) was added, and the mixture was stirred at the same temperature for 1 hr. The reaction solution was extracted with ethyl acetate (70 ml), the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
The residue is subjected to silica gel column chromatography [Wako
gel ^™ C-300, hexane-ethyl acetate (1:
2)], and (2S, 4R) -N-allyloxycarbonyl-2- (N-allyloxycarbonyl-3-pyrrolin-3-yl) -4-hydroxypyrrolidine (320
mg, yield: 89.3%) was obtained.

NMR (CDCl ₃ ) δ: 1.98 (1
H, m), 2.16 (1H, m), 3.45 to 3.74.
(2H, m), 4.04 to 4.26 (4H, m), 4.
40 to 4.78 (6H, m), 5.14 to 5.40 (4
H, m), 5.61 (1H, br s), 5.80-
6.07 (2H, m) 6)

[0101]

[Chemical 28] Compound obtained in the above reaction (320 mg, 0.99 mm
solution of triphenylphosphine (433 m) in a tetrahydrofuran solution (10 ml) in a nitrogen stream under ice cooling.
g, 1.69 mmol) and azodicarboxylic acid diethyl ester (0.266 ml, 1.69 mmol) were added, and after stirring at the same temperature for 30 minutes, thioacetic acid (0.121 m
(1, 1.69 mmol) was added and the mixture was further stirred for 2 hours.
The reaction solution was extracted with ethyl acetate (50 ml), the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [Wakogel ^™ C-300, hexane-ethyl acetate (4: 1)], and (2S, 4S)-
4-acetylthio-N-allyloxycarbonyl-2-
(N-allyloxycarbonyl-3-pyrrolin-3-yl) pyrrolidine (351 mg, yield: 92.9%) was obtained.

NMR (CDCl ₃ ) δ: 1.86 (1
H, m), 2.34 (3H, s), 2.58 (1H,
m), 3.26 (1H, dd, J = 12, 8Hz),
3.98 (1H, m), 4.06 to 4.30 (5H,
m), 4.63 (4H, m), 5.14 to 5.40 (4
H, m), 5.62 (1H, m), 5.76 to 6.08.
(2H, m) 7)

[0103]

[Chemical 29] Compound obtained in the above reaction (351 mg, 0.92 mm
ol) in a methanol solution (10 ml) in a nitrogen stream,
Under ice cooling, 1N aqueous sodium hydroxide solution (0.92m
1) was added dropwise, and the mixture was stirred at the same temperature for 15 minutes. 1 in the reaction solution
N hydrochloric acid (0.97 ml) was added, the mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate (70 ml). Water organic layer,
The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (310 mg,
Yield: 99.3%) was obtained.

[0104]

The compound of the present invention is a novel compound which has not been described in the literature, and has a strong antibacterial activity against sensitive and resistant Gram-positive and Gram-negative bacteria, β-lactamase and D
Since it has excellent stability against HP-I, it is useful as an antibacterial agent.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Ryosuke Ushijima No.3 Okubo, Tsukuba City, Ibaraki Prefecture

Claims (10)

[Claims] 1. A general formula: [Wherein R ¹ is a hydrogen atom or a methyl group, R ² is a hydrogen atom or a negative charge, R ³ is a hydrogen atom or a lower alkyl group,
Two types of substituents selected from the group of R ⁴ , R ⁵ and R ⁶ are
Bonded together with a nitrogen atom to form a 5- or 6-membered optionally substituted heterocyclic group (provided that the nitrogen atom may form an ammonio group), and the remaining substituents are: A hydrogen atom or a lower alkyl group, Y represents a lower alkylene group or a single bond], or a pharmaceutically acceptable salt or ester thereof. 2. A general formula: [Wherein R ¹ is a hydrogen atom or a methyl group, R ² is a hydrogen atom or a negative charge, R ³ is a hydrogen atom or a lower alkyl group,
R ^4a and R ^5a or R ^4a and R ^6a are bonded together with a nitrogen atom to form a 5- or 6-membered optionally substituted heterocyclic group, provided that the nitrogen atom forms an ammonio group. ^{Optionally present} ), R ^4a , R ^5a and R ^6a , wherein the substituents which are not bonded to each other are a hydrogen atom or a lower alkyl group, and Y is a lower alkylene group or a single bond]. A compound or a pharmaceutically acceptable salt or ester thereof. 3. A general formula: [Wherein R ¹ is a hydrogen atom or a methyl group, R ² is a hydrogen atom or a negative charge, R ³ is a hydrogen atom or a lower alkyl group,
R ^4b is a hydrogen atom or a lower alkyl group, R ^5b and R ^6b
Represents a 5-membered or 6-membered optionally substituted heterocyclic group together with a nitrogen atom (provided that the nitrogen atom may form an ammonio group), and Y represents a lower alkylene group. Or a single bond] or a pharmaceutically acceptable salt or ester thereof. 4. The heterocyclic group is a pyrrolinyl group, N-lower alkylpyrrolinyl group, N, N-di-lower alkylpyrrolinio group, tetrahydropyridyl group, N-lower alkyltetrahydropyridyl group, N, N-di Lower alkyltetrahydropyridinio group, pyrrolidinyl group, N-lower alkylpyrrolidinyl group, N, N-dilower alkylpyrrolidinio group, piperidyl group, N-lower alkylpiperidyl group or N, N-dilower alkylpyridyl group The compound according to claim 1, which is a peridinio group. 5. The compound according to claim 1, wherein the heterocyclic group is a pyrrolinyl group. 6. (5R, 6S) -6-[(R) -1-hydroxyethyl] -2-[(2S, 4S) -2- (3-pyrrolin-3-yl) pyrrolidin-4-ylthio] -1-
Carbapen-2-em-3-carboxylic acid or (1R,
5S, 6S) -6-[(R) -1-hydroxyethyl]
The compound according to claim 1, which is -1-methyl-2-[(2S, 4S) -2- (3-pyrrolin-3-yl) pyrrolidin-4-ylthio] -1-carbapene-2-em-3-carboxylic acid. Compound of. 7. (1R, 5S, 6S) -6-[(R) -1
-Hydroxyethyl] -1-methyl-2-[(2S, 4
S) -2- (3-pyrrolin-3-yl) pyrrolidine-4
The compound according to claim 1, which is -ylthio] -1-carbapene-2-em-3-carboxylic acid. 8. The configuration of the compound represented by the general formula [I] is (5R, 6S, 8R) or (1R, 5S, 6S,
The compound according to claim 1, which is 8R). 9. A general formula: [Wherein R ¹ represents a hydrogen atom or a methyl group, R ⁹ represents a hydrogen atom or a hydroxy group-protecting group, and R ²⁰ represents a hydrogen atom or a carboxyl group-protecting group] or a reactive derivative thereof. General formula: [In the formula, R ³⁰ is a hydrogen atom, a lower alkyl group or a protecting group for an imino group, and two kinds of substituents selected from the group of R ⁴⁰ , R ⁵⁰ and R ⁶⁰ are bonded together with a nitrogen atom to form a 5-membered Or a 6-membered optionally substituted heterocyclic group is formed (however, the nitrogen atom may form an ammonio group), the remaining substituents are a hydrogen atom or a lower alkyl group, and Y is a lower group. Indicates an alkylene group or a single bond (however,
The substituent of the heterocyclic group and the imino group on the heterocyclic ring may be protected if necessary)] and are reacted with a compound represented by the general formula: [Wherein R ¹ , R ⁹ , R ²⁰ , R ³⁰ , R ⁴⁰ , R ⁵⁰ and R ⁶⁰
Has the above-mentioned meaning] and, if necessary, the protecting group of the compound of the general formula [IV] is removed. [Wherein R ² is a hydrogen atom or a negative charge, R ³ is a hydrogen atom or a lower alkyl group, and two kinds of substituents selected from the group of R ⁴ , R ⁵ and R ⁶ are bonded together with a nitrogen atom. ,
It forms a 5- or 6-membered optionally substituted heterocyclic group (provided that the nitrogen atom may form an ammonio group), and the remaining substituents are a hydrogen atom or a lower alkyl group, Y Represents a lower alkylene group or a single bond, and R ¹ has the above meaning], or a pharmaceutically acceptable salt or ester thereof. 10. A general formula: [Wherein R ¹ is a hydrogen atom or a methyl group, R ² is a hydrogen atom or a negative charge, R ³ is a hydrogen atom or a lower alkyl group,
Two types of substituents selected from the group of R ⁴ , R ⁵ and R ⁶ are
Bonded together with a nitrogen atom to form a 5- or 6-membered optionally substituted heterocyclic group (provided that the nitrogen atom may form an ammonio group), and the remaining substituents are: A hydrogen atom or a lower alkyl group, and Y represents a lower alkylene group or a single bond], or an antibacterial agent containing a pharmaceutically acceptable salt or ester thereof as an active ingredient.