JP2000344772A - Carbapenem derivative, its use and intermediate compound therefor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound having excellent antibacterial effect and absorbability through the digestive tract, and useful as a prophylactic and/or therapeutic agent or the like for microbism. SOLUTION: This compound is a compound of formula I (R1 is a modification group hydrolyzable inside an organism; R2 and R3 are each a lower alkyl), pref. pivaloyloxymethyl (1R, 5S,6S)-2- (3S,5S)-[5-N,N-dimethylaminocarbonyl-1-(5- methyl-2-oxo-1,3-dioxolen-4-yl)methyloxycarbonyl]pyrrolidin-3-ylthio}- 6-[(1R)-1- hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate or the like. The compound of formula I is obtained, for example, by reacting a compound of formula II with a compound of the formula R1-X (X is a halogen or the like) (e.g. pivaloyloxymethyl iodide), in the presence of a base, in a solvent not inhibiting the reaction such as N,N-dimethylformamide.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel carbapenem compound useful as an agent for preventing or treating bacterial infections. More specifically, the present invention relates to a novel carbapenem compound having sufficient antibacterial properties and oral absorbability, an oral antibacterial agent containing the compound as an active ingredient, and an intermediate compound for producing the carbapenem compound.

[0002]

2. Description of the Related Art Many compounds having a carbapenem skeleton have been found so far as therapeutic agents for infectious diseases, and some carbapenem compounds having excellent antibacterial activity have been put to practical use. Development is underway. For example, formula (A)

[0003]

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[0004] The carbapenem compound represented by the formula (1) has already been put to practical use and clinically used. This carbapenem compound has a broad antibacterial spectrum and strong antibacterial activity,
Moreover, it overcomes the instability of renal dehydropeptidase, which has been a drawback of conventional carbapenem compounds, and has an excellent feature that it can be administered alone without using a stabilizer.

[0005] However, these carbapenem compounds have poor absorption from the digestive tract and are only administered clinically as injections. Oral preparations are easier and easier to administer than injections, and are extremely useful clinically. Therefore, development of a carbapenem compound for oral administration having a strong antibacterial activity and a wide antibacterial spectrum and having excellent gastrointestinal absorption is strongly desired.

[0006]

An object of the present invention is to provide a carbapenem compound having excellent antibacterial properties and absorption from the digestive tract. Another subject of the present invention is:
An object of the present invention is to provide a use of the carbapenem compound.
Still another object of the present invention is to provide an intermediate suitable for producing the carbapenem compound.

[0007]

Means for Solving the Problems The present inventor has made intensive studies to achieve the above object, and as a result, the novel carbapenem compound represented by the following general formula (I) has excellent gastrointestinal absorption. Furthermore, they have found that these compounds have sufficiently strong antibacterial properties and are extremely useful as antibacterial agents for oral use, and have also found novel intermediate compounds used for the production of the compounds, and completed the present invention. I came to. That is,
The present invention relates to (1) a compound represented by the general formula (I)

[0008]

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Wherein R ¹ is a modifying group which is hydrolyzed in vivo, and R ² and R ³ may be the same or different and each represents a lower alkyl group. A) the carbapenem compound of the above (1), wherein R ² and R ³ may be the same or different and each is a lower alkyl group, and (3) the carbapenem compound of the above (1), wherein R ¹ is a pivaloyloxymethyl group (4) the carbapenem compound of the above (1), wherein R ¹ is a cyclohexyloxycarbonylethyl group;
A carbapenem compound according to the above (1), wherein ¹ is an ethoxycarbonylethyl group, (6) pivaloyloxymethyl
(1R, 5S, 6S) -2-｛(3S, 5S)-[5-
N, N-dimethylaminocarbonyl-1- (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyloxycarbonyl] pyrrolidin-3-ylthio} -6
-[(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate, 1-cyclohexyloxycarbonyloxyethyl (1R, 5
S, 6S) -2-{(3S, 5S)-[5-N, N-dimethylaminocarbonyl-1- (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyloxycarbonyl] Pyrrolidin-3-ylthio} -6-[(1
R) -1-Hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylate, 1-ethoxycarbonyloxyethyl (1R, 5S, 6S) -2-
{(3S, 5S)-[5-N, N-dimethylaminocarbonyl-1- (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyloxycarbonyl] pyrrolidin-3-ylthio}- 6-[(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate, pivaloyloxymethyl (1R, 5
S, 6S) -2-{(3S, 5S)-[5-N, N-diethylaminocarbonyl-1- (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyloxycarbonyl] pyrrolidine -3-ylthio} -6-[(1
R) -1-Hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate and pivaloyloxymethyl (1R, 5S, 6S) -2-{(3S,
5S)-[5-N-ethyl-N-methylaminocarbonyl-1- (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyloxycarbonyl] pyrrolidin-3-ylthio} -6 A carbapenem compound of the above (1) selected from the group consisting of [(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate; (7) a general formula of the above (1) An antibacterial agent containing the carbapenem compound represented by I) as an active ingredient, (8) the antibacterial agent of (7), which is for oral administration,
(9) General formula (II)

[0010]

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Wherein R ² and R ³ may be the same or different and each represents a lower alkyl group, and R ⁴ represents a hydrogen atom or a carboxyl-protecting group, or a salt thereof. And (10) p
-Nitrobenzyl (1R, 5S, 6S) -2-｛(3
S, 5S)-[5-N, N-dimethylaminocarbonyl-1- (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyloxycarbonyl] pyrrolidine-
3-ylthio {-6-[(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate and (1R, 5S, 6S) -2-{(3
S, 5S)-[5-N, N-dimethylaminocarbonyl-1- (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyloxycarbonyl] pyrrolidine-
The present invention relates to the carbapenem compound of the above (9), which is selected from the group consisting of sodium 3-ylthio} -6-[(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate.

[0012]

DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, each definition used in the present specification will be described. The “modifying group that is hydrolyzed in vivo” for R ¹ is preferably one that is hydrolyzed in the intestinal tract or blood, and is, for example, an aryl group which may have a substituent (for example, phenyl Group, tolyl group, xylyl group, indanyl group, etc.), 1-alkanoyloxyalkyl group, 1-alkoxycarbonyloxyalkyl group, phthalidyl group, 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl group, etc. Is mentioned. Among them, a 1-alkanoyloxyalkyl group, a 1-alkoxycarbonyloxyalkyl group and 5-methyl-2-oxo-1,3-dioxolen-4-
An ylmethyl group is preferred. The "optionally substituted aryl group" is preferably an unsubstituted or optionally substituted aryl group having 1 to 3 substituents,
The substituents may be the same or different. Specific examples of the substituent include an alkyl group such as a methyl group and an ethyl group.

The number of carbon atoms in the alkanoyl moiety in the "1-alkanoyloxyalkyl group" is preferably 2
10 to 10, more preferably 2 to 7, and may be any of linear, branched or cyclic, and the number of carbon atoms in the alkyl moiety is preferably 1 to 3, more preferably 1 or 2. Individual. As the “1-alkanoyloxyalkyl group”, for example, an acetoxymethyl group, a propionyloxymethyl group, an n-butyryloxymethyl group, an isobutyryloxymethyl group, a pivaloyloxymethyl group, an n-
Valeryloxymethyl group, 2-methylbutyryloxymethyl group, isovaleryloxymethyl group, n-hexanoyloxymethyl group, 3-methylvaleryloxymethyl group, neohexanoyloxymethyl group, 2-methylhexyl Noyloxymethyl group, 2,2-dimethylvaleryloxymethyl group, neoheptanoyloxymethyl group, cyclohexanecarbonyloxymethyl group, cyclohexylacetoxymethyl group, 1-acetoxyethyl group, 1-propionyloxyethyl group, 1-n -Butyryloxyethyl group, 1-isobutyryloxyethyl group, 1-n-valeryloxyethyl group, 1-pivaloyloxyethyl group, 1-isovaleryloxyethyl group, 1-n-hexanoyl Oxyethyl group and 1-cyclohexanecarbonyloxyethyl group, etc. And the like.

The number of carbon atoms of the alkoxy moiety in the "1-alkoxycarbonyloxyalkyl group" is preferably 1 to 10, more preferably 1 to 7, and is linear or
It may be branched or cyclic, and the number of carbon atoms in the alkyl moiety is preferably 1 to 3, more preferably 1
Or two. Examples of the “1-alkoxycarbonyloxyalkyl group” include, for example, a 1-methoxycarbonyloxyethyl group, a 1-ethoxycarbonyloxyethyl group, a 1-n-propoxycarbonyloxyethyl group,
1-isopropoxycarbonyloxyethyl group, 1-n
-Butoxycarbonyloxyethyl group, 1-sec-butoxycarbonyloxyethyl group, 1-t-butoxycarbonyloxyethyl group, 1-pentyloxycarbonyloxyethyl group and 1-cyclohexyloxycarbonyloxyethyl group.

The term "lower alkyl group" for R ² and R ³ means a linear or branched alkyl group having 1 to 6 carbon atoms, for example, a methyl group, an ethyl group, a propyl group, Isopropyl group, butyl group, isobutyl group,
Examples include a sec-butyl group, a t-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a t-pentyl group, a hexyl group, an isohexyl group, and a neohexyl group. Among them, a methyl group, an ethyl group, a propyl group and a butyl group are preferred.

"Protecting group for carboxyl group" in R ⁴
Examples include, for example, t-butyl group, t-amyl group, benzyl group, p-nitrobenzyl group, p-methoxybenzyl group, diphenylmethyl group, p-nitrophenyl group, methoxymethyl group, ethoxymethyl group, benzyloxy Methyl group, methylthiomethyl group, trityl group, 2,2,2-
Examples include a trichloroethyl group, a trimethylsilyl group, a diphenylmethoxybenzenesulfonylmethyl group, and a dimethylaminoethyl group. Of these, a p-nitrobenzyl group, a p-methoxybenzyl group and a diphenylmethyl group are preferred.

When the carbapenem compound (II) has a carboxyl group (when R ⁴ is a hydrogen atom)
Can form a salt at its carboxyl group. Examples of the salt in the carboxyl group include alkali metal salts (eg, sodium salt, potassium salt, etc.), alkaline earth metal salts (eg, calcium salt, magnesium salt, etc.), and organic base salts (eg, triethylamine salt, dicyclohexylamine) Salts, pyridine salts and the like).

Preferred examples of the carbapenem compound (I) or the carbapenem compound (II) of the present invention are as follows. Pivaloyloxymethyl (1R, 5S, 6S) -2-{(3S, 5S)-
[5-N, N-dimethylaminocarbonyl-1- (5-
Methyl-2-oxo-1,3-dioxolen-4-yl) methyloxycarbonyl] pyrrolidin-3-ylthio} -6-[(1R) -1-hydroxyethyl] -1-
Methyl carbapene-2-em-3-carboxylate,
1-cyclohexyloxycarbonyloxyethyl
(1R, 5S, 6S) -2-｛(3S, 5S)-[5-
N, N-dimethylaminocarbonyl-1- (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyloxycarbonyl] pyrrolidin-3-ylthio} -6
-[(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate, 1-ethoxycarbonyloxyethyl (1R, 5S, 6S)-
2-{(3S, 5S)-[5-N, N-dimethylaminocarbonyl-1- (5-methyl-2-oxo-1,3-
Dioxolen-4-yl) methyloxycarbonyl] pyrrolidin-3-ylthio} -6-[(1R) -1-hydroxyethyl] -1-methylcarbapen-2-em-3
Carboxylate, pivaloyloxymethyl (1
R, 5S, 6S) -2-｛(3S, 5S)-[5-N,
N-diethylaminocarbonyl-1- (5-methyl-2
-Oxo-1,3-dioxolen-4-yl) methyloxycarbonyl] pyrrolidin-3-ylthio} -6
[(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate, pivaloyloxymethyl (1R, 5S, 6S) -2-{(3S,
5S)-[5-N-ethyl-N-methylaminocarbonyl-1- (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyloxycarbonyl] pyrrolidin-3-ylthio} -6 [(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate, p-nitrobenzyl (1R, 5S, 6
S) -2-{(3S, 5S)-[5-N, N-dimethylaminocarbonyl-1- (5-methyl-2-oxo-
1,3-dioxolen-4-yl) methyloxycarbonyl] pyrrolidin-3-ylthio} -6-[(1R)-
1-hydroxyethyl] -1-methylcarbapene-2-
M-3-carboxylate, and (1R, 5S, 6
S) -2-{(3S, 5S)-[5-N, N-dimethylaminocarbonyl-1- (5-methyl-2-oxo-
1,3-dioxolen-4-yl) methyloxycarbonyl] pyrrolidin-3-ylthio} -6-[(1R)-
1-hydroxyethyl] -1-methylcarbapene-2-
And sodium sodium M-3-carboxylate.

The carbapenem compound (I) and the carbapenem compound (II) can be produced by any of the following production methods 1 to 5.

[0020]

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Wherein R ¹ , R ² and R ³ are as defined above, and X is a halogen atom such as chlorine, bromine or iodine, methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy and butanesulfonyloxy. And a leaving group such as an arylsulfonyloxy group such as phenylsulfonyloxy and tolylsulfonyloxy. ]

Compound (I) is a solvent that does not inhibit the reaction (eg, dioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride, ethylene chloride,
Compound (IIa) is dissolved in benzene, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, or the like, or a mixture thereof, and is dissolved in an amount of about 1 to 5 times in the presence of a base. And preferably about 1-2 fold molar amount of compound (III). The base used is not particularly limited, but preferably includes an inorganic base such as sodium hydrogen carbonate and potassium carbonate, and an organic base such as triethylamine and diisopropylethylamine. The reaction temperature is not particularly limited, but it is desirable to carry out the reaction at a relatively low temperature in order to suppress a side reaction, usually at -30 to 40 ° C, preferably at -10 to 10 ° C. The reaction time varies depending mainly on the reaction temperature, the type of the reaction reagent and the like, but is usually 30 minutes to 10 hours.

Compound (IIa) may be, if necessary, a reactive derivative thereof (eg, an alkali metal salt such as a sodium salt and a potassium salt, an alkaline earth metal salt such as a calcium salt, etc.).
(Triethylamine salt, dicyclohexylamine salt, pyridine salt, etc.) and react with compound (III).

[0024]

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Wherein R ¹ , R ² and R ³ are as defined above, and Y is chlorine, imidazol-1-yl, p-nitrophenyloxy, 2-phenylacetonitryl-2-yl-iminooxy or the like. Represents a leaving group. ]

Compound (I) is a solvent that does not inhibit the reaction (eg, dioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride, ethylene chloride,
Compound (IV) is dissolved in benzene, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide or the like, or a mixture thereof, and is dissolved in an amount of about 1 to 5 times, preferably about 1 to 5 times. It is obtained by reacting with 2 times the molar amount of compound (V). still,
Compound (IV) was prepared in the same manner as in Production Method 1,
No. 33076 and the like.
And I). This reaction can also be performed in the presence of a base. The base used is not particularly limited, but preferably includes an inorganic base such as sodium hydrogen carbonate and potassium carbonate and an organic base such as triethylamine and diisopropylethylamine. The reaction temperature is not particularly limited, but it is desirable to carry out the reaction at a relatively low temperature in order to suppress side reactions, and usually -3.
The reaction is performed at 0 to 40C, preferably -10 to 10C. The reaction time varies depending mainly on the reaction temperature, the type of the reaction reagent and the like, but is usually 30 minutes to 10 hours.

[0027]

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Wherein R ² , R ³ and R ⁴ are as defined above, and R ⁵ is an alkane sulfonyl group such as methanesulfonyl, ethanesulfonyl, propanesulfonyl or butanesulfonyl, or an aryl group such as phenylsulfonyl or tolylsulfonyl. Represents a sulfonyl group, a dialkylphosphoryl group such as dimethylphosphoryl, diethylphosphoryl, diisopropylphosphoryl or dibutylphosphoryl, or a diarylphosphoryl group such as diphenylphosphoryl or ditolylphosphoryl. ]

Compound (II) is a solvent that does not inhibit the reaction (eg, dioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride, ethylene chloride,
Benzene, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide and the like, or a mixture thereof).
No. 6, Publication No. 6 and the like are obtained by dissolving the compound (VI) and reacting with a mercapto compound (VII) in a molar amount of about 1 to 5 times, preferably about 1 to 3 times in the presence of a base. . The base used is not particularly limited,
Preferred are inorganic bases such as sodium hydrogen carbonate and potassium carbonate and organic bases such as triethylamine and diisopropylethylamine. The reaction temperature is not particularly limited, but it is desirable to carry out the reaction at a relatively low temperature in order to suppress a side reaction, usually -30 to 40C, preferably -10.
Performed at 〜１０10 ° C. The reaction time varies depending mainly on the reaction temperature, the type of the reaction reagent and the like, but is usually 30 minutes to 10 hours. Compound (VII), which is a starting material for synthesizing compound (II), is obtained as follows.

[0030]

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Wherein R ² , R ³ and Y are as defined above, R ⁶ represents a thiol-protecting group, and R ⁷ represents an amino-protecting group. ]

Compound (VII) is disclosed in JP-A-60-233.
No. 076, etc., the amino-protecting group R ⁷ of the compound (IX) is removed by a method known per se to lead to the compound (X), and the compound (X) and the compound (V) are converted in the same manner as in the production method 2. To give the compound (XI), and then removing the thiol-protecting group R ⁶ by a method known per se to synthesize the compound (XI). As the protecting group for the thiol group and the amino group, a protecting group generally used in the art can be used.

[0033]

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Wherein R ² , R ³ , R ⁴ and Y are as defined above. ]

Compound (II) can be prepared in the same manner as in Production Method 2 by using the compound (VI) described in JP-A-60-233076.
It is obtained by reacting II) with compound (V).

The carbapenem compound (II) thus obtained can be converted into a carboxylic acid derivative in which R ⁴ is a hydrogen atom by removing a carboxyl protecting group according to a conventional method, if necessary. Can be. The method for removing the protecting group varies depending on the type, but can be generally removed by a method known in the art.

[0037]

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Wherein R ¹ , R ² , R ³ and R ⁵ are as defined above. ]

Compound (I) is a solvent that does not inhibit the reaction (eg, dioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride, ethylene chloride,
Compound (XII) is dissolved in benzene, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, or the like, or a mixture thereof, and is dissolved in an amount of about 1 to 5 times in the presence of a base, It is preferably obtained by reacting with about 1 to 3 times the molar amount of the mercapto compound (VII). The base used is not particularly limited, but preferably includes an inorganic base such as sodium hydrogen carbonate and potassium carbonate and an organic base such as triethylamine and diisopropylethylamine. The reaction temperature is not particularly limited, but is preferably performed at a relatively low temperature in order to suppress a side reaction.
Preferably, it is carried out at -10 to 10C. The reaction time varies mainly depending on the reaction temperature, the type of the reaction reagent, and the like.
0 minutes to several tens of hours.

The carbapenem compound (I) or the carbapenem compound (II) can be purified, if necessary, by a conventional method, for example, a recrystallization method, preparative thin-layer chromatography, column chromatography and the like. It can be purified as its salt if necessary.

The preferred configuration of the compound (I) and the compound (II) to be used in the present invention is as follows:
a) and compound (IIb).

[0042]

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Wherein R ¹ , R ² and R ³ are as defined above. ]

[0044]

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Wherein R ² , R ³ and R ⁴ are as defined above. ]

The carbapenem compound (I) is rapidly absorbed into the blood by oral administration, and as a metabolite thereof, becomes a carbapenem compound in which R ¹ is a hydrogen atom in the general formula (IV). Show. Therefore, prevention of infectious diseases containing carbapenem compound (I)
The therapeutic agent has an excellent action as described above by oral administration, and is usually administered as an oral agent.

The prophylactic / therapeutic agent for infectious diseases can be produced by diluting with a pharmaceutical excipient according to a means known per se. As the excipient, for example, starch, lactose, sugar, calcium carbonate, calcium phosphate and the like are used.

The prophylactic / therapeutic agent for infectious disease may further contain other additives, if desired, such as a binder (eg, starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, etc.), Preferable additives include a powder agent (eg, magnesium stearate, talc, etc.) and a disintegrant (eg, carboxymethyl cellulose calcium, talc, etc.). After mixing the various components, the mixture is formulated into a dosage form suitable for oral administration such as capsules, tablets, fine granules, granules, dry syrup, etc. A prophylactic / therapeutic agent is produced.

The dose of the carbapenem compound (I) varies depending on the subject of administration, symptoms and the like. For example, when administered for an adult purulent disease, for example, a single dose of about 1
Oral administration of 〜40 mg / kg body weight is performed about 1 to 4 times a day.

The carbapenem compound (I) is
It may be used in combination with other antibacterial active substances, for example, antibacterial agents (penicillins, aminoglycosides, cephalosporins, etc.) or therapeutic agents for systemic symptoms caused by bacterial infections (antipyretics, analgesics, anti-inflammatory agents, etc.).

Next, the physical properties and the production method of the compound of the present invention will be specifically described with reference to examples, but the present invention is not limited by these.

[0052]

EXAMPLES Example 1 p-Nitrobenzyl (1R, 5S, 6S) -2-
{(3S, 5S)-[5-N, N-dimethylaminocarbonyl-1- (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyloxycarbonyl] pyrrolidin-3-ylthio}- 6-[(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate (2S, 4S) -2-N, N-dimethylaminocarbonyl-4-mercapto-1- ( 5-methyl-2-oxo-
719 mg of 1,3-dioxolen-4-yl) methyloxycarbonylpyrrolidine was dissolved in 11 ml of acetonitrile, and p-nitrobenzyl (1R, 5
S, 6S) -2-diphenylphosphoryl-6-[(1
R) -1-Hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylate 1.15 g and diisopropylethylamine 0.38 ml were added at 0 ° C. After stirring at the same temperature for 1 hour, 200 ml of ethyl acetate was added, washed with 100 ml of saturated saline, and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound 9
11 mg were obtained.

¹ H-NMR (CDCl ₃ , δ ppm):
1.27 (3H, d), 1.33 (3H, d), 1.7
To 2.1, 2.5 to 2.9 (2H, m), 2.17 (3
H, s), 2.8-4.4 (13H, m), 4.6-
5.6 (5H, m), 7.64, 8.20 (4H, A ₂ ′)
B ₂ ').

Example 2 (1R, 5S, 6S) -2-｛(3S, 5S)-[5-
N, N-dimethylaminocarbonyl-1- (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyloxycarbonyl] pyrrolidin-3-ylthio} -6
-[(1R) -1-hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylate sodium p-nitrobenzyl (1R, 5S, 6S) -2-
{(3S, 5S)-[5-N, N-dimethylaminocarbonyl-1- (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyloxycarbonyl] pyrrolidin-3-ylthio}- 330 mg of 6-[(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate was added to 17 m of tetrahydrofuran.
1 and 0.1 M MOPS buffer (pH 7.0) 17
dissolved in a mixed solution of 10% palladium carbon 330
mg and hydrogenated at room temperature for 16 hours. The reaction solution was filtered through celite, and the obtained filtrate was washed with diethyl ether and concentrated under reduced pressure to about 5 ml. The obtained solution was subjected to chromatography using Diaion HP-21 (manufactured by Mitsubishi Kasei Kogyo), concentrated under reduced pressure, and lyophilized to obtain 130 mg of the title compound.

IR (Nujol, cm ^-1 ): 3393,
^{1819,1767,1707,1643 1 H-NMR (DMSO-} d 6, δppm): 1.16
(3H, d), 1.4 to 1.9 (1H, m), 2.13
(3H, s), 2.82 (3H, s), 3.01 (3
H, brs), 4.5-5.0 (3H, m).

Example 3 Pivaloyloxymethyl (1R, 5S, 6S) -2-
{(3S, 5S)-[5-N, N-dimethylaminocarbonyl-1- (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyloxycarbonyl] pyrrolidin-3-ylthio}- 6-[(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate (1R, 5S, 6S) -2-{(3S, 5S)-[5-
N, N-dimethylaminocarbonyl-1- (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyloxycarbonyl] pyrrolidin-3-ylthio} -6
-Sodium [[(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate 960
mg in 6 ml of N, N-dimethylformamide,
Cooled to 5 ° C. Pivaloyloxymethyl iodide 7
After stirring at the same temperature for 1 hour and at 35 ° C. for 12 hours, 150 ml of ethyl acetate was added and 5% saline 1
It was washed with 00 ml and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 350 mg of the title compound.

IR (Nujol, cm ^-1 ): 3404,
1821, 1780, 1715, 1651. ¹ H-NMR (CDCl ₃ , δ ppm): 1.22 (9
H, s), 1.26 (3H, d), 1.31 (3H,
d), 1.6-2.1, 2.5-2.9 (2H, m),
2.17 (3H, s), 2.8-4.4 (13H,
m), 4.80 (1H, m), 4.72, 4.99 (2
H, ABq, J = 13.2 Hz), 5.87, 5.92
(2H, ABq, J = 5.5 Hz).

Example 4 Pivaloyloxymethyl (1R, 5S, 6S) -2-
{(3S, 5S)-[5-N, N-dimethylaminocarbonyl-1- (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyloxycarbonyl] pyrrolidin-3-ylthio}- 6-[(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate (1) (1R, 5S, 6S) -2-[(3S, 5S)-
5-N, N-dimethylaminocarbonylpyrrolidine-4
530 mg of sodium -ylthio] -6-[(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate are suspended in 2.3 ml of N, N-dimethylformamide and heated to 5 ° C. Cool. Add 819 mg of pivaloyloxymethyl iodide, and add 1 at the same temperature.
After stirring for an hour, 150 ml of ethyl acetate was added, and the mixture was washed with 100 ml of 5% saline and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain pivaloyloxymethyl (1
R, 5S, 6S) -2-[(3S, 5S) -5-N, N
-Dimethylaminocarbonylpyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-
Methylcarbapene-2-em-3-carboxylate 4
70 mg were obtained.

¹ H-NMR (CDCl ₃ , δ ppm):
1.22 (9H, s), 1.2 to 1.4 (6H, m),
1.5-1.8, 2.4-2.8 (2H, m), 2.9
8 (3H, s), 3.02 (3H, s), 3.0 to 4.0.
4 (8H, m), 5.81, 5.95 (2H, ABq,
J = 5.5 Hz).

(2) 497 mg of the compound obtained in (1)
Was dissolved in 5 ml of methylene chloride and cooled to 5 ° C. (5
-Methyl-2-oxo-1,3-dioxolen-4-yl) methyloxycarbonyl chloride (231 mg) and triethylamine (0.14 ml) were added at the same temperature.
After stirring for minutes, 150 ml of ethyl acetate was added, and the mixture was washed with 100 ml of 5% saline and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 140 mg of the title compound.

Example 5 Pivaloyloxymethyl (1R, 5S, 6S) -2-
{(3S, 5S)-[5-N, N-dimethylaminocarbonyl-1- (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyloxycarbonyl] pyrrolidin-3-ylthio}- 6-[(1R) -1-Hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate Compound 50 obtained in (1) of Example 4
0 mg was dissolved in 2.5 ml of N, N-dimethylformamide, 297 mg of (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl p-nitrophenyl carbonate and 0.14 ml of triethylamine were added, and room temperature was added. After stirring for 2 hours, 150 ml of ethyl acetate was added, and 100 ml of 10% citric acid and 100 ml of 5% aqueous sodium bicarbonate were added.
And 100 ml of saturated saline, and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound 3
50 mg were obtained.

Example 6 1-Cyclohexyloxycarbonyloxyethyl
(1R, 5S, 6S) -2-｛(3S, 5S)-[5-
N, N-dimethylaminocarbonyl-1- (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyloxycarbonyl] pyrrolidin-3-ylthio} -6
-[(1R) -1-hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylate 1-cyclohexyloxycarbonyloxyethyl (1R) obtained by a method similar to (1) of Example 4. , 5S, 6S) -2
-{(3S, 5S)-[5-N, N-dimethylaminocarbonyl) pyrrolidin-3-ylthio} -6-[(1
R) -1-Hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate (2.0 g) was dissolved in methylene chloride (20 ml) to give (5-methyl-2-oxo-
830 mg of 1,3-dioxolen-4-yl) methyloxycarbonyl chloride and 0.5 of triethylamine
After stirring for 2 hours at room temperature, ethyl acetate was added.
0 ml was added, and the mixture was washed with 5% saline (100 ml) and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 680 mg of the title compound.

IR (Nujol, cm ^-1 ): 3402,
1821, 1759, 1713, 1647. ¹ H-NMR (CDCl ₃ , δ ppm): 1.0 to 2.
1 (20H, m), 2.16 (3H, s), 2.96
(3H, s), 3.06.3.09 (3H, s), 3.
0 to 4.4 (7H, m), 4.5 to 5.2 (4H,
m), 6.7-7.0 (1H, q).

Example 7 1-ethoxycarbonyloxyethyl (1R, 5S,
6S) -2-{(3S, 5S)-[5-N, N-dimethylaminocarbonyl-1- (5-methyl-2-oxo-
1,3-dioxolen-4-yl) methyloxycarbonyl] pyrrolidin-3-ylthio} -6-[(1R)-
1-hydroxyethyl] -1-methylcarbapene-2-
M-3-carboxylate 1-ethoxycarbonyloxyethyl (1R, 5S, 6S) -2- obtained by a method similar to (1) in Example 4.
{(3S, 5S)-[5-N, N-dimethylaminocarbonyl) pyrrolidin-3-ylthio} -6-[(1R)
-1-hydroxyethyl] -1-methylcarbapene-2
-M-3-carboxylate (1.0 g) was dissolved in N, N-dimethylformamide (5 ml) to give (5-methyl-2-carboxylate).
Oxo-1,3-dioxolen-4-yl) methyl p
After adding 606 mg of -nitrophenyl carbonate and 0.29 ml of triethylamine and stirring at room temperature for 2 hours, 150 ml of ethyl acetate was added and 100 ml of 5% brine was added.
1 and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 300 mg of the title compound.

IR (Nujol, cm ^-1 ): 3404,
1820, 1758, 1714, 1650. ¹ H-NMR (CDCl ₃ , δ ppm): 1.22 (3
H, t), 1.27 (3H, d), 1.32 (3H,
d), 1.51 (3H, d), 1.6-2.0, 2.5
２2.8 (2H, m), 2.16 (3H, s), 2.8
To 4.4 (15H, m), 4.5 to 5.2 (3H,
m), 6.7-7.0 (1H, q).

Next, in order to clarify the excellent properties of the compound of the present invention, an oral absorption experiment was carried out as follows.

[0067]

EXPERIMENTAL EXAMPLE 1 Oral absorption experiment The compound of the present invention (the compound of Example 3) (20 mg / kg) was orally administered to mice (3 animals per group), and 0.25% of the hydrolyzed carbapenem compound (A) was added. , 0.5, 1.0,
After 2.0 and 3.0 hours, each plasma concentration was determined by HPL
It was measured by the C method. Table 1 shows the results.

[0068]

[Table 1]

[0069]

EFFECT OF THE INVENTION The carbapenem compound (I) is excellent in gastrointestinal absorption by oral administration and shows sufficient antibacterial activity against a wide variety of bacterial species, and is used for infectious diseases (particularly bacterial infections). It is extremely useful as a prophylactic / therapeutic agent. The infectious disease preventive / therapeutic agents include, for example, warm-blooded animals including humans (dogs,
Diseases caused by bacteria in cats, cattle, horses, rats, mice, etc. (for example, purulent diseases, respiratory infections, biliary tract infections,
Urinary tract infection).

Claims (10)

[Claims] 1. A compound of the general formula (I) [Wherein R ¹ represents a modifying group that is hydrolyzed in vivo, R ²
And R ³ may be the same or different and each represents a lower alkyl group]. 2. The carbapenem compound according to claim 1, wherein R ² and R ³ may be the same or different and each is a lower alkyl group. 3. The carbapenem compound according to claim 1, wherein R ¹ is a pivaloyloxymethyl group. 4. The carbapenem compound according to claim 1, wherein R ¹ is a 1-cyclohexyloxycarbonyloxyethyl group. 5. The carbapenem compound according to claim 1, wherein R ¹ is a 1-ethoxycarbonyloxyethyl group. 6. Pivaloyloxymethyl (1R, 5)
S, 6S) -2-{(3S, 5S)-[5-N, N-dimethylaminocarbonyl-1- (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyloxycarbonyl] Pyrrolidin-3-ylthio} -6-[(1
R) -1-Hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylate, 1-cyclohexyloxycarbonyloxyethyl
(1R, 5S, 6S) -2-｛(3S, 5S)-[5-
N, N-dimethylaminocarbonyl-1- (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyloxycarbonyl] pyrrolidin-3-ylthio} -6
-[(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate, and 1
-Ethoxycarbonyloxyethyl (1R, 5S, 6
S) -2-{(3S, 5S)-[5-N, N-dimethylaminocarbonyl-1- (5-methyl-2-oxo-
1,3-dioxolen-4-yl) methyloxycarbonyl] pyrrolidin-3-ylthio} -6-[(1R)-
1-hydroxyethyl] -1-methylcarbapene-2-
The carbapenem compound according to claim 1, which is selected from the group consisting of em-3-carboxylate. 7. An antibacterial agent comprising the carbapenem compound represented by the general formula (I) according to claim 1 as an active ingredient. 8. The antibacterial agent according to claim 7, which is for oral administration. 9. A compound of the general formula (II) [Wherein R ² and R ³ may be the same or different and each represents a lower alkyl group, and R ⁴ represents a hydrogen atom or a carboxyl group-protecting group] or a salt thereof. 10. p-Nitrobenzyl (1R, 5S,
6S) -2-{(3S, 5S)-[5-N, N-dimethylaminocarbonyl-1- (5-methyl-2-oxo-
1,3-dioxolen-4-yl) methyloxycarbonyl] pyrrolidin-3-ylthio} -6-[(1R)-
1-hydroxyethyl] -1-methylcarbapene-2-
M-3-carboxylate, and (1R, 5S, 6
S) -2-{(3S, 5S)-[5-N, N-dimethylaminocarbonyl-1- (5-methyl-2-oxo-
1,3-dioxolen-4-yl) methyloxycarbonyl] pyrrolidin-3-ylthio} -6-[(1R)-
1-hydroxyethyl] -1-methylcarbapene-2-
The carbapenem compound according to claim 9, which is selected from the group consisting of sodium em-3-carboxylate.