JP2000344773A - Carbapenem derivative, usage of the same and its intermidiate compound - 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 propylactic and/or therapeutic agent or the like for microbism. SOLUTION: This compound is a compound of formula I (R1 is a modification group hydrolyzable in organism; R2 and R3 are each a lower alkyl; R4 and R5 are each H or a lower alkyl; R6 is a 1-10C alkyl), pref. pivaloyloxymethyl (1R,5S,6S)-2-[(3S,5S)-(5-N,N-dimethylaminocarbonyl-1- propionyloxymethyloxycarbonyl) 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.

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 is the invention described in the following (1) to (5).

(1) General formula (I)

[0009]

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[Wherein, R ¹ is a modifying group hydrolyzed in vivo, R ² and R ³ may be the same or different, and each is a lower alkyl group, and R ⁴ and R ⁵ are the same or different. A hydrogen atom or a lower alkyl group, and R ⁶ represents an alkyl group having 1 to 10 carbon atoms].

(2) Pivaloyloxymethyl (1)
R, 5S, 6S) -2-[(3S, 5S)-(5-N,
N-dimethylaminocarbonyl-1-acetyloxymethyloxycarbonyl) pyrrolidin-3-ylthio]-
6-[(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate, pivaloyloxymethyl (1R, 5S, 6S)-
2-[(3S, 5S)-(5-N, N-dimethylaminocarbonyl-1-propionyloxymethyloxycarbonyl) pyrrolidin-3-ylthio] -6-[(1R)
-1-hydroxyethyl] -1-methylcarbapene-2
-M-3-carboxylate, pivaloyloxymethyl (1R, 5S, 6S)-
2-[(3S, 5S)-(5-N, N-dimethylaminocarbonyl-1-isobutyryloxymethyloxycarbonyl) pyrrolidin-3-ylthio] -6-[(1R)
-1-hydroxyethyl] -1-methylcarbapene-2
-M-3-carboxylate, pivaloyloxymethyl (1R, 5S, 6S)-
2-[(3S, 5S)-(5-N, N-dimethylaminocarbonyl-1-pivaloyloxymethyloxycarbonyl) pyrrolidin-3-ylthio] -6-[(1R)-
1-hydroxyethyl] -1-methylcarbapene-2-
M-3-carboxylate, pivaloyloxymethyl (1R, 5S, 6S)-
2-[(3S, 5S)-(5-N, N-dimethylaminocarbonyl-1-isovaleryloxymethyloxycarbonyl) pyrrolidin-3-ylthio] -6-[(1R)
-1-hydroxyethyl] -1-methylcarbapene-2
-M-3-carboxylate, pivaloyloxymethyl (1R, 5S, 6S)-
2-[(3S, 5S)-(5-N, N-dimethylaminocarbonyl-1-tert-butylacetyloxymethyloxycarbonyl) pyrrolidin-3-ylthio] -6
-[(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate, 1-cyclohexyloxycarbonyloxyethyl (1R, 5S, 6S) -2-[(3S, 5S) -(5
-N, N-dimethylaminocarbonyl-1-isobutyryloxymethyloxycarbonyl) pyrrolidin-3-ylthio] -6-[(1R) -1-hydroxyethyl]-
1-methylcarbapene-2-em-3-carboxylate and 1-ethoxycarbonyloxyethyl (1R, 5
S, 6S) -2-[(3S, 5S)-(5-N, N-dimethylaminocarbonyl-1-pivaloyloxymethyloxycarbonyl) pyrrolidin-3-ylthio] -6
The carbapenem compound of the above (1) selected from the group consisting of [(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate.

(3) An antibacterial agent for oral administration containing the carbapenem compound according to (1) or (2) as an active ingredient.

(4) General formula (II)

[0014]

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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 and R ⁵ may be the same or different and each represents a hydrogen atom or a lower alkyl group; R ⁶ represents an alkyl group having 1 to 10 carbon atoms, and R ⁷ represents a hydrogen atom or a carboxyl group-protecting group] or a salt thereof.

(5) p-Nitrobenzyl (1R,
5S, 6S) -2-[(3S, 5S)-(5-N, N-
Dimethylaminocarbonyl-1-propionyloxymethyloxycarbonyl) pyrrolidin-3-ylthio]-
6-[(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate, p-nitrobenzyl (1R, 5S, 6S) -2-
[(3S, 5S)-(5-N, N-dimethylaminocarbonyl-1-isobutyryloxymethyloxycarbonyl) pyrrolidin-3-ylthio] -6-[(1R) -1
-Hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate, (1R, 5S, 6S) -2-[(3S, 5S)-
(5-N, N-dimethylaminocarbonyl-1-propionyloxymethyloxycarbonyl) pyrrolidine-3
-Ylthio] -6-[(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate and (1R, 5S, 6S) -2-[(3S, 5S) −
(5-N, N-dimethylaminocarbonyl-1-isobutyryloxymethyloxycarbonyl) pyrrolidine-3
The carbapenem compound according to claim 3, which is selected from the group consisting of -ylthio] -6-[(1R) -1-hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylate, and a salt thereof.

In addition, in addition to the specific examples exemplified in the above (3), the following carbapenem compounds can be exemplified as preferable ones. Pivaloyloxymethyl (1R, 5S, 6S)-
2-[(3S, 5S)-(5-N-ethyl-N-methylaminocarbonyl-1-propionyloxymethyloxycarbonyl) pyrrolidin-3-ylthio] -6
[(1R) -1-hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylate, pivaloyloxymethyl (1R, 5S, 6S) -2
-[(3S, 5S)-(5-N, N-diethylaminocarbonyl-1-propionyloxymethyloxycarbonyl) pyrrolidin-3-ylthio] -6-[(1R)-
1-hydroxyethyl] -1-methylcarbapene-2-
M-3-carboxylate

[0018]

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.

"Aryl group optionally having substituent (s)"
Is preferably an aryl group which may be unsubstituted or substituted by 1 to 3 substituents, and 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 of 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.

Examples of the "1-alkanoyloxyalkyl group" include, for example, acetoxymethyl group, propionyloxymethyl group, n-butyryloxymethyl group, isobutyryloxymethyl group, pivaloyloxymethyl group, 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.

The "1-alkoxycarbonyloxyalkyl group" includes, for example, 1-methoxycarbonyloxyethyl group, 1-ethoxycarbonyloxyethyl group,
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 , R ³ , R ⁴ and R ⁵ means a linear or branched alkyl group having 1 to 6 carbon atoms, for example, a methyl group, Ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, t-butyl group, pentyl group, isopentyl group, neopentyl group, t-pentyl group, hexyl group, isohexyl group, neohexyl group and the like. Can be Among them, a methyl group, an ethyl group, a propyl group and a butyl group are preferred.

The "alkyl group" for R ⁶ means a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms, for example, a methyl group, an ethyl group, a propyl group or an isopropyl group. , Butyl group, isobutyl group, sec
-Butyl group, t-butyl group, pentyl group, isopentyl group, neopentyl group, t-pentyl group, cyclopentyl group, hexyl group, isohexyl group, neohexyl group, s
ec-hexyl group, t-hexyl group, cyclohexyl group, heptyl group, isoheptyl group, neoheptyl group, s
ec-heptyl group, t-heptyl group, octyl group, isooctyl group, neooctyl group, sec-octyl group, t
-Octyl group and the like.

"Carboxyl-Protecting Group" for R ⁷
Examples thereof include a t-butyl group, a neopentyl group, a benzyl group, a p-nitrobenzyl group, a p-methoxybenzyl group, a diphenylmethyl group, a p-nitrophenyl group, a methoxymethyl group, an ethoxymethyl group, and a benzyloxymethyl group. , Methylthiomethyl group, trityl group, 2,2,2
-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).

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

[0029]

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Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above, X is a halogen atom such as chlorine, bromine or iodine, methanesulfonyloxy, ethanesulfonyloxy , A leaving group such as an alkanesulfonyloxy group such as propanesulfonyloxy and butanesulfonyloxy, and 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 is preferably an inorganic base such as sodium hydrogencarbonate or potassium carbonate or an organic base such as triethylamine, diisopropylethylamine or pyridine.

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, 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 (for example, an alkali metal salt such as a sodium salt or 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).

[0035]

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Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above, and Y is chlorine, imidazol-1-yl, p-nitrophenyloxy and 2-phenyl Represents a leaving group such as an acetonitrile-2-yl-iminooxy 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 carried out 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, diisopropylethylamine and pyridine.

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.

[0040]

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Wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above, and R ⁸ is an alkane sulfonyl group such as methanesulfonyl, ethanesulfonyl, propanesulfonyl or butanesulfonyl. , An arylsulfonyl group such as phenylsulfonyl or tolylsulfonyl, 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, but is preferably an inorganic base such as sodium hydrogen carbonate or potassium carbonate or an organic base such as triethylamine, diisopropylethylamine or pyridine.

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 (VII), which is a starting material for synthesizing compound (II), is obtained as follows.

[0046]

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Wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and Y are as defined above, R ⁹ represents an amino-protecting group, and R ¹⁰ represents a thiol-protecting group. . ]

Compound (VII) is disclosed in JP-A-60-233.
No. 076, etc., the amino-protecting group R ⁹ of compound (IX) is removed by a method known per se to lead to compound (X), and compound (X) and compound (V) are converted in the same manner as in production method 2. To give the compound (XI), and then the compound can be synthesized by removing the thiol group-protecting group R ¹⁰ by a method known per se. As the protecting group for the thiol group and the amino group, a protecting group generally used in the art can be used.

[0049]

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[Wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ ,
R ⁷ and Y are as defined above. ]

Compound (II) was prepared in the same manner as in Production Method 2 except for 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 ⁷ 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.

[0053]

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[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
R ⁶ and R ⁸ 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, diisopropylethylamine and pyridine.

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, 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.

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 or the like. It can be purified as its salt if necessary.

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

[0060]

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[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ have the same meanings as above. ]

[0062]

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[Wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ have the same meanings as described above, respectively. ]

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, the preventive / therapeutic agent for infectious diseases containing the carbapenem compound (I) has the above-mentioned excellent effects by oral administration, and is usually administered as an oral agent.

The agent for preventing or treating infectious diseases can be produced by diluting with a pharmaceutical excipient according to a method 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 administration subject, symptoms and the like. For example, when administered for an adult suppurative disease, for example, a single dose of about 1 dose is used.
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 thereto.

[0071]

EXAMPLES Example 1 p-Nitrobenzyl (1R, 5S, 6S) -2-
[(3S, 5S)-(5-N, N-dimethylaminocarbonyl-1-propionyloxymethyloxycarbonyl) pyrrolidin-3-ylthio] -6-[(1R) -1
-Hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylate

662 mg of (2S, 4S) -2-N, N-dimethylaminocarbonyl-4-mercapto-1-propionyloxymethyloxycarbonylpyrrolidine was dissolved in 11 ml of acetonitrile, and p-nitrobenzyl (1R, 5S, 6S) -2-diphenylphosphoro-6-[(1R) -1-hydroxyethyl]-
1.15 g of 1-methylcarbapene-2-em-3-carboxylate and 0.3 of diisopropylethylamine
8 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 obtain 876 mg of the title compound.

¹ H-NMR (CDCl ₃ , δ ppm):
1.14 (3H, t), 1.27 (3H, d), 1.3
3 (3H, d), 1.7 to 2.1, 2.5 to 2.9 (3
H, m), 2.40 (2H, q), 2.8 to 4.4 (1
3H, m), 4.6 to 5.8 (5H, m), 7.64,
8.20 (4H, A ₂ 'B ₂ ').

Example 2 (1R, 5S, 6S) -2-[(3S, 5S)-(5-
N, N-dimethylaminocarbonyl-1-propionyloxymethyloxycarbonyl) pyrrolidin-3-ylthio] -6-[(1R) -1-hydroxyethyl] -1
-Sodium methylcarbapene-2-em-3-carboxylate

P-Nitrobenzyl (1R, 5S, 6
S) -2-[(3S, 5S)-(5-N, N-dimethylaminocarbonyl-1-propionyloxymethyloxycarbonyl) pyrrolidin-3-ylthio] -6
330 mg of [(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate was dissolved in a mixture of 17 ml of tetrahydrofuran and 17 ml of 0.1 M phosphate buffer (pH 7.0), and 330 mg of palladium carbon was added 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 resulting solution was subjected to chromatography using Diaion HP-21 (manufactured by Mitsubishi Kasei Kogyo), concentrated under reduced pressure, and lyophilized to obtain 128 mg of the title compound.

¹ H-NMR (DMSO-d ₆ , δpp
m): 1.10 (3H, t), 1.17 (3H, d),
1.17 (3H, d), 1.4-1.9, 2.5-2.
7 (2H, m), 2.35 (2H, q), 2.83 (3
H, s), 3.02 (3H, brs), 4.6-4.8.
(1H, t), 5.5-5.7 (2H, m).

Example 3 p-Nitrobenzyl (1R, 5S, 6S) -2-
[(3S, 5S)-(5-N, N-dimethylaminocarbonyl-1-isobutyryloxymethyloxycarbonyl) pyrrolidin-3-ylthio] -6-[(1R) -1
-Hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylate

The title compound was obtained in the same manner as in Example 1 using (2S, 4S) -2-N, N-dimethylaminocarbonyl-4-mercapto-1-isobutyryloxymethyloxycarbonylpyrrolidine. Was.

¹ H-NMR (CDCl ₃ , δ ppm):
1.17 (6H, d), 1.27 (3H, d), 1.3
3 (3H, d), 1.7 to 2.1, 2.5 to 2.9 (4
H, m), 2.8 to 4.4 (13H, m), 4.6 to
5.8 (5H, m), 7.64, 8.20 (4H,
A ₂ 'B ₂ ').

Example 4 (1R, 5S, 6S) -2-[(3S, 5S)-(5-
N, N-dimethylaminocarbonyl-1-isobutyryloxymethyloxycarbonyl) pyrrolidin-3-ylthio] -6-[(1R) -1-hydroxyethyl] -1
-Sodium methylcarbapene-2-em-3-carboxylate

P-Nitrobenzyl (1R, 5S, 6
S) -2-[(3S, 5S)-(5-N, N-dimethylaminocarbonyl-1-isobutyryloxymethyloxycarbonyl) pyrrolidin-3-ylthio] -6
The title compound was obtained in the same manner as in Example 2 using [(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate.

¹ H-NMR (DMSO-d ₆ , δpp
m): 1.0 to 1.4 (12H), 1.4 to 1.9,
2.5-2.7 (3H, m), 2.83 (3H, s),
3.02 (3H, brs), 4.6-4.8 (1H,
t), 5.5-5.7 (2H, m).

Example 5 Pivaloyloxymethyl (1R, 5S, 6S) -2-
[(3S, 5S)-(5-N, N-dimethylaminocarbonyl-1-propionyloxymethyloxycarbonyl) pyrrolidin-3-ylthio] -6-[(1R) -1
-Hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylate

(1R, 5S, 6S) -2-[(3S, 5
S)-(5-N, N-dimethylaminocarbonyl-1-
913 mg of sodium propionyloxymethyloxycarbonyl) pyrrolidin-3-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylate in 6 ml of N, N-dimethylformamide And cooled to 5 ° C. Add 700 mg of pivaloyloxymethyl iodide and add 1 at the same temperature.
After stirring for 1 hour at 30 ° C, 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 336 mg of the title compound.

IR (Nujol, cm ^-1 ): 3445,
1755, 1724, 1651. ¹ H-NMR (CDCl ₃ , δ ppm): 1.14 (3
H, t), 1.22 (9H, s), 1.26 (3H,
d), 1.32 (3H, d), 1.7-2.1, 2.4
-2.8 (3H, m), 2.38 (2H, q), 2.9
6 (3H, d), 3.09 (3H, d), 3.0 to 4.0.
4 (7H, m), 4.73 (1H, m), 5.6-5.
8 (2H, m), 5.88 (2H, ABq).

Example 6 Pivaloyloxymethyl (1R, 5S, 6S) -2-
[(3S, 5S)-(5-N, N-dimethylaminocarbonyl-1-propionyloxymethyloxycarbonyl) pyrrolidin-3-ylthio] -6-[(1R) -1
-Hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylate

(1) (1R, 5S, 6S) -2-[(3
S, 5S) -5-N, N-dimethylaminocarbonylpyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methylcarbapen-2-em-3
31.3 g of sodium carboxylate was suspended in 148 ml of N, N-dimethylformamide and cooled to 5 ° C. After adding 37.2 g of pivaloyloxymethyl iodide and stirring at the same temperature for 1 hour, 3.19 g of potassium carbonate and 11.2 g of pivaloyloxymethyl iodide were added,
After stirring at the same temperature for 1 hour, 1050 ml of ethyl acetate was added, and 175 ml of saturated sodium bicarbonate solution and 500 ml of 5% saline solution were added.
And dried over anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and pivaloyloxymethyl- (1R, 5S,
6S) -2-[(3S, 5S) -5-N, N-dimethylaminocarbonylpyrrolidin-4-ylthio] -6
14.2 g of [(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate was 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, AB
q).

(2) Dissolve 9.5 g of the compound obtained in (1) in 50 ml of dichloromethane and, at 5 ° C., propionyloxymethyl p-nitrophenyl carbonate.
After adding 42 g and stirring at the same temperature for 5 minutes, 1.
Stir for 5 hours. The reaction solution was purified by silica gel column chromatography to obtain 1.1 g of the title compound.

Example 7 Pivaloyloxymethyl (1R, 5S, 6S) -2-
[(3S, 5S)-(5-N, N-dimethylaminocarbonyl-1-acetyloxymethyloxycarbonyl)
Pyrrolidin-3-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methylcarbapen-2-M-
3-carboxylate

Compound 600 obtained in Example 6 (1)
mg, dissolved in N, N-dimethylformamide (3.5 ml), acetyloxymethyl p-nitrophenyl carbonate (200 mg) and triethylamine (0.16 ml)
And stirred at room temperature for 2 hours, and then ethyl acetate 100 ml
And 10% citric acid 100 ml, 5% aqueous sodium bicarbonate 100
The solution was washed with 100 ml of a saturated saline solution 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 310 mg of the title compound.

IR (Nujol, cm ^-1 ): 3422,
1760, 1724, 1647. ¹ H-NMR (CDCl ₃ , δ ppm): 1.22 (9
H, s), 1.27 (3H, d), 1.33 (3H,
d), 1.7 to 2.1, 2.5 to 2.9 (3H, m),
2.11 (3H, s), 2.97 (3H, d), 3.0
8 (3H, d), 3.1 to 4.4 (7H, m), 4.7
3 (1H, m), 5.6 to 5.8 (2H, m), 5.8
9 (2H, ABq).

Example 8 Pivaloyloxymethyl (1R, 5S, 6S) -2-
[(3S, 5S)-(5-N, N-dimethylaminocarbonyl-1-isobutyryloxymethyloxycarbonyl) pyrrolidin-3-ylthio] -6-[(1R) -1
-Hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylate

Compound 550 obtained in Example 6 (1)
was dissolved in 3.5 ml of dichloromethane, and isobutyryloxymethyl p-nitrophenyl carbonate 210 was dissolved in 3.5 ml of dichloromethane.
After stirring at room temperature for 2 hours, ethyl acetate 100
and 10% citric acid 100 ml, 5% aqueous sodium bicarbonate 1
The extract was washed with 00 ml and 100 ml of saturated saline, and dried with anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 210 mg of the title compound.

IR (Nujol, cm ^-1 ): 3385,
1796, 1753, 1730, 1636. ¹ H-NMR (CDCl ₃ , δ ppm): 1.15 (6
H, d), 1.22 (9H, s), 1.26 (3H,
d), 1.33 (3H, d), 1.7-2.1, 2.5
2.9 (4H, m), 2.95 (3H, d), 3.0
9 (3H, d), 3.1 to 4.4 (7H, m), 4.7
3 (1H, m), 5.6 to 5.8 (2H, m), 5.8
8 (2H, ABq).

Example 9 Pivaloyloxymethyl (1R, 5S, 6S) -2-
[(3S, 5S)-(5-N, N-dimethylaminocarbonyl-1-pivaloyloxymethyloxycarbonyl) pyrrolidin-3-ylthio] -6-[(1R) -1
-Hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylate

Compound 580 obtained in Example 6, (1)
mg of pivaloyloxymethyl p-nitrophenyl carbonate in 3.5 ml of dichloromethane.
g, and the mixture was stirred at room temperature for 2 hours.
and 100 ml of 5% aqueous sodium bicarbonate and 100 ml of saturated saline.
The resulting solution was washed with anhydrous sodium sulfate 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 ): 3423,
1777,1751,1726,1649. ¹ H-NMR (CDCl ₃ , δ ppm): 1.22 (1
8H, s), 1.26 (3H, d), 1.33 (3H,
d), 1.7 to 2.1, 2.5 to 2.9 (3H, m),
2.96 (3H, s), 3.09 (3H, d), 3.1
~ 4.4 (7H, m), 4.73 (1H, m), 5.6
-5.8 (2H, m), 5.88 (2H, ABq).

Example 10 Pivaloyloxymethyl (1R, 5S, 6S) -2-
[(3S, 5S)-(5-N, N-dimethylaminocarbonyl-1-isovaleryloxymethyloxycarbonyl) pyrrolidin-3-ylthio] -6-[(1R) -1
-Hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylate

In the same manner as in Example 9, the title compound was obtained.

¹ H-NMR (CDCl ₃ , δ ppm):
0.96 (6H, d), 1.22 (9H, s), 1.2
6 (3H, d), 1.33 (3H, d), 1.5-2.
9 (6H, m), 2.97 (3H, s), 3.09 (3
H, d), 3.1 to 4.4 (7H, m), 4.73 (1
H, m), 5.6 to 5.8 (2H, m), 5.87 (2
H, ABq).

Example 11 Pivaloyloxymethyl (1R, 5S, 6S) -2-
[(3S, 5S)-(5-N, N-dimethylaminocarbonyl-1-t-butylacetyloxymethyloxycarbonyl) pyrrolidin-3-ylthio] -6-[(1
R) -1-Hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate

The title compound was obtained in the same manner as in Example 9.

¹ H-NMR (CDCl ₃ , δ ppm):
0.98 (9H, s), 1.22 (9H, s), 1.2
6 (3H, d), 1.33 (3H, d), 1.7-2.
9 (5H, m), 2.96 (3H, s), 3.08 (3
H, d), 3.1 to 4.4 (7H, m), 4.73 (1
H, m), 5.6 to 5.8 (2H, m), 5.87 (2
H, ABq).

Example 12 1-Cyclohexyloxycarbonyloxyethyl
(1R, 5S, 6S) -2-[(3S, 5S)-(5-
N, N-dimethylaminocarbonyl-1-isobutyryloxymethyloxycarbonyl) pyrrolidin-3-ylthio] -6-[(1R) -1-hydroxyethyl] -1
-Methylcarbapene-2-em-3-carboxylate

1-Cyclohexyloxycarbonyloxyethyl obtained in the same manner as in Example 6, (1)
(1R, 5S, 6S) -2-[(3S, 5S)-(5-
(N, N-dimethylaminocarbonyl) pyrrolidine-3-
Ilthio] -6-[(1R) -1-hydroxyethyl]
1.00 g of -1-methylcarbapen-2-em-3-carboxylate was dissolved in 10 ml of dichloromethane, and 500 mg of isobutyryloxymethyl p-nitrophenyl carbonate was added. After stirring at room temperature for 2 hours, the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain 355 mg of the title compound.

¹ H-NMR (CDCl ₃ , δ ppm):
1.0 to 2.1 (27H, m), 2.96 (3H,
s), 3.06, 3.09 (3H, s), 3.0-4.
4 (7H, m), 4.73 (1H, m), 5.6-5.
8 (2H, m), 6.7-7.0 (1H, q).

Example 13 1-ethoxycarbonyloxyethyl (1R, 5S,
6S) -2-[(3S, 5S)-(5-N, N-dimethylaminocarbonyl-1-pivaloyloxymethyloxycarbonyl) pyrrolidin-3-ylthio] -6
[(1R) -1-hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylate

The title compound was obtained in the same manner as in Example 12.

¹ H-NMR (CDCl ₃ , δ ppm):
1.22 (3H, t), 1.22 (9H, s), 1.2
7 (3H, d), 1.32 (3H, d), 1.51 (3
H, d), 1.6 to 2.0, 2.5 to 2.8 (2H,
m), 2.8-4.4 (15H, m), 4.73 (1
H, m), 5.6 to 5.8 (2H, m), 6.7 to 7.
0 (1H, q).

Experimental Example 1 (oral absorption experiment) 20 mg of the compound of the present invention (Example 9) was added to dogs (3 animals per group).
/ Kg orally and 0.25, 0.5, 1.0, 1.5, 2... Of hydrolyzed carbapenem compound (A).
The plasma concentrations at 0, 3.0, 4.0 and 6.0 hours were determined using the test bacteria Escherichia coli NIHJ, medium nutrie
The measurement was performed using a paper disk method with an nt agar (Dofco). Table 1 shows the results.

[0112]

[Table 1]

[0113]

The carbapenem compound (I) of the present invention is
It is excellent in gastrointestinal absorption by oral administration and shows sufficient antibacterial properties against a wide variety of bacterial species, and is extremely useful as a prophylactic / therapeutic agent for infectious diseases (particularly bacterial infections). Antibacterial agents for oral administration containing the carbapenem compound (I) include, for example, warm-blooded animals including humans (dogs, cats, cattle,
It can be used as a prophylactic / therapeutic agent for diseases caused by bacteria in horses, rats, mice, etc. (eg, purulent diseases, respiratory infections, biliary tract infections, urinary tract infections, etc.). Further, the carbapenem compound (II) is useful as an intermediate compound of the carbapenem compound (I).

Claims (5)

[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; R ⁴ and R ⁵ may be the same or different; each represents a hydrogen atom or a lower alkyl group; and R ⁶ has 1 to 10 carbon atoms. A carbapenem compound represented by the formula: 2. Pivaloyloxymethyl (1R,
5S, 6S) -2-[(3S, 5S)-(5-N, N-
Dimethylaminocarbonyl-1-acetyloxymethyloxycarbonyl) pyrrolidin-3-ylthio] -6
[(1R) -1-hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylate, pivaloyloxymethyl (1R, 5S, 6S)-
2-[(3S, 5S)-(5-N, N-dimethylaminocarbonyl-1-propionyloxymethyloxycarbonyl) pyrrolidin-3-ylthio] -6-[(1R)
-1-hydroxyethyl] -1-methylcarbapene-2
-M-3-carboxylate, pivaloyloxymethyl (1R, 5S, 6S)-
2-[(3S, 5S)-(5-N, N-dimethylaminocarbonyl-1-isobutyryloxymethyloxycarbonyl) pyrrolidin-3-ylthio] -6-[(1R)
-1-hydroxyethyl] -1-methylcarbapene-2
-M-3-carboxylate, pivaloyloxymethyl (1R, 5S, 6S)-
2-[(3S, 5S)-(5-N, N-dimethylaminocarbonyl-1-pivaloyloxymethyloxycarbonyl) pyrrolidin-3-ylthio] -6-[(1R)-
1-hydroxyethyl] -1-methylcarbapene-2-
M-3-carboxylate, pivaloyloxymethyl (1R, 5S, 6S)-
2-[(3S, 5S)-(5-N, N-dimethylaminocarbonyl-1-isovaleryloxymethyloxycarbonyl) pyrrolidin-3-ylthio] -6-[(1R)
-1-hydroxyethyl] -1-methylcarbapene-2
-M-3-carboxylate, pivaloyloxymethyl (1R, 5S, 6S)-
2-[(3S, 5S)-(5-N, N-dimethylaminocarbonyl-1-tert-butylacetyloxymethyloxycarbonyl) pyrrolidin-3-ylthio] -6
-[(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate, 1-cyclohexyloxycarbonyloxyethyl (1R, 5S, 6S) -2-[(3S, 5S) -(5
-N, N-dimethylaminocarbonyl-1-isobutyryloxymethyloxycarbonyl) pyrrolidin-3-ylthio] -6-[(1R) -1-hydroxyethyl]-
1-methylcarbapene-2-em-3-carboxylate and 1-ethoxycarbonyloxyethyl (1R, 5
S, 6S) -2-[(3S, 5S)-(5-N, N-dimethylaminocarbonyl-1-pivaloyloxymethyloxycarbonyl) pyrrolidin-3-ylthio] -6
The carbapenem compound according to claim 1, which is selected from the group consisting of [(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate. 3. An antibacterial agent for oral administration containing the carbapenem compound according to claim 1 as an active ingredient. 4. A compound of the general formula (II) Wherein, R ² and R ³ may be the same or different, each a lower alkyl group, R ⁴ and R ⁵ may be the same or different, each a hydrogen atom or a lower alkyl group, R ⁶ is Wherein R ⁷ represents a hydrogen atom or a carboxyl-protecting group; and a salt thereof. 5. p-Nitrobenzyl (1R, 5
S, 6S) -2-[(3S, 5S)-(5-N, N-dimethylaminocarbonyl-1-propionyloxymethyloxycarbonyl) pyrrolidin-3-ylthio] -6
-[(1R) -1-hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylate, p-nitrobenzyl (1R, 5S, 6S) -2-
[(3S, 5S)-(5-N, N-dimethylaminocarbonyl-1-isobutyryloxymethyloxycarbonyl) pyrrolidin-3-ylthio] -6-[(1R) -1
-Hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate, (1R, 5S, 6S) -2-[(3S, 5S)-
(5-N, N-dimethylaminocarbonyl-1-propionyloxymethyloxycarbonyl) pyrrolidine-3
-Ylthio] -6-[(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate and (1R, 5S, 6S) -2-[(3S, 5S) −
(5-N, N-dimethylaminocarbonyl-1-isobutyryloxymethyloxycarbonyl) pyrrolidine-3
The carbapenem compound according to claim 3, which is selected from the group consisting of -ylthio] -6-[(1R) -1-hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylate, and a salt thereof.