JP2000239275A - Carbapenem ester derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new carbapenem ester derivative exhibiting pharmacokinetics with excellent absorbing property and persistency when administered to organisms and useful as an active ingredient for medicines for treating bacterial infectious diseases due to various kinds of pathogenic bacteria by modifying hydroxyl group of hydroxyethyl group at a specific position of carbapenem skeleton with a group hydrolyzed in vivo. SOLUTION: This compound is represented by formula I [R1 is a group of formula II to formula IV (R4 and R5 are each H, a 1-4C alkyl or the like) or the like, R2 is H, a 1-10C alkoxycarbonyloxy-1-4C alkyl or the like; R3 is a 1-20C alkanoyl or the like], e.g. pivaloyloxymethyl 6-(1-acetoxyethyl)-1- methyl-2-(2-oxo-4-pyrrolidinylthio)-1-carbapen-2-em-3-carboxylate. The compound of formula I is obtained by reacting a compound of formula V with a reactive derivative of R3 (e.g. an alkoxycarbonyl halide) in a solvent (e.g. xylene) in the presence of a base (e.g. pyridine), preferably at -10 to 50 deg.C for 10 min to 10 hr.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a carbapenem derivative or a pharmacologically acceptable salt thereof having excellent antibacterial activity when administered to a living body.

[0002]

2. Description of the Related Art Thienamycin derivatives, which are carbapenem antibiotics, have excellent antibacterial activity, but have low chemical and biological stability. Therefore, dehydropeptidase, which is an enzyme present in the human body, is used. It is easily decomposed by -I and loses its activity, and its urinary recovery rate is low. Furthermore, some experimental animal species may be toxic to the kidneys. Therefore, thipenamicin derivative imipenem was developed as a combination with dehydropeptidase-I inhibitor cilastatin, and panipenem was developed with betamipron, an organic anion transport inhibitor. Thereafter, it was found that the chemical stability and stability against dehydropeptidase-I were improved by introducing a methyl group at the 1-position of the carbapenem skeleton, and a carbapenem derivative usable as a single agent such as meropenem was also developed. Was done. However, these are all injections and have not been developed as oral preparations or suppositories. Therefore, development of a carbapenem derivative that, when administered to a living body, is efficiently absorbed and then hydrolyzed to exhibit antibacterial activity has been desired. JP-A-2-49783, JP-A-7-497
165759, JP-A-2-223587,
JP-A-4-279588, JP-A-8-53453
Issue, The Journal of Antibiotics 50 (5), 429-439
(1997) disclose a carbapenem derivative synthesized for this purpose.

[0003]

As a result of various studies to improve the absorbability (particularly, oral absorbability) of these carbapenem derivatives, the present inventors have found that the hydroxyl group of the 1-hydroxyethyl group at the 6-position of the carbapenem skeleton is in vivo. The compound represented by the general formula (I) of the present invention, which has been modified with a group (R ³ ) hydrolyzed by the above, has a higher absorbability from the digestive tract than a conventional carbapenem derivative whose hydroxyl group is not modified. I found it to be excellent. Furthermore, the compound (I) of the present invention has low toxicity and has been found to be effective as an antibacterial agent for treating or preventing (especially treating) bacterial infections, thereby completing the present invention.

[0004]

According to the present invention, there is provided a compound represented by the general formula (I):

[0005]

Embedded image And a pharmacologically acceptable salt thereof. Ｒ In the formula, R ¹ is the following general formula (II
a), (IIb), (IIc) or (IId);

[0006]

Embedded image [Wherein, R ⁴ and R ⁵ represent a hydrogen atom, a C1-C4 alkyl group, a C1-C4 alkanoyl group, a C1-C4 alkoxy-carbonyl group, or 5- (C1-C4 alkyl)
R ² represents a hydrogen atom, a C 1 -C 10 alkoxy-carbonyloxy-C 1 -C 4 alkyl group, a C 3 -C 7 cyclo group, which represents a 2-oxo-1,3-dioxolen-4-ylmethyl group. Alkyl-oxycarbonyloxy-C1-C4 alkyl group, C3-C7 cycloalkyl-C1-C4 alkyl-
Oxycarbonyloxy-C1-C4 alkyl group, C2
A -C10 alkanoyloxy-C1-C4 alkyl group,
C3-C7 cycloalkyl-carbonyloxy-C1-
C4 alkyl group, [1- (C1-C4 alkyl) -C3
-C7 cycloalkyl] carbonyloxy-C1-C4
Alkyl group, C3-C7 cycloalkyl-C2-C4 alkanoyloxy-C1-C4 alkyl group, phthalidyl group, or 5- (C1-C4 alkyl or phenyl) -2-oxo-1,3-dioxolen-4-ylmethyl R ³ represents a C1-C20 alkanoyl group or a C1-C20 alkanoyl group having a substituent (the substituent is an amino group,
Represents an amino group, a hydroxyl group or a phenyl group substituted with 1-C4 alkyl), a C6-C10 aryl-carbonyl group, a C1-C20 alkoxy-carbonyl group, or 5- (C1-C4 alkyl) -2- Oxo-1,
It represents a 3-dioxolen-4-ylmethyl group. ｝.

In the above, “C1-C” of R ⁴ or R ⁵
The "4-alkyl group" and the "C1-C4 alkyl" moiety are a straight-chain or branched alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl or t-butyl. A -butyl group, preferably a methyl or ethyl group, more preferably a methyl group.

The "C1-C4 alkanoyl group" for R ⁴ or R ⁵ is an alkanoyl group having 1 to 4 carbon atoms,
For example, a formyl, acetyl, propionyl, butyryl or isobutyryl group can be mentioned, preferably an acetyl or propionyl group, and most preferably an acetyl group.

R ⁴ or R ^{5 is selected from} the group consisting of “C1-C4 alkoxy-
The “carbonyl group” is a carbonyl group substituted with an alkoxy group having 1 to 4 carbon atoms, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
Examples include isopropoxycarbonyl and butoxycarbonyl groups, preferably methoxycarbonyl or ethoxycarbonyl groups, and most preferably ethoxycarbonyl groups.

The "5- (C1-C4 alkyl) -2-oxo-1,3-dioxolen-4-ylmethyl group" for R ⁴ or R ⁵ is, for example, 5-methyl-2-oxo-1,3-
Dioxolen-4-ylmethyl, 5-ethyl-2-oxo-1,3-dioxolen-4-ylmethyl, 5-propyl-2-oxo-1,3-dioxolen-4-ylmethyl or 5-butyl-2-oxo- A 1,3-dioxolen-4-ylmethyl group can be mentioned, and preferably, 5-methyl-2-oxo-1,3-dioxolen-4-
Ylmethyl group.

R ⁴ and R ⁵ are preferably a hydrogen atom, C1-
C4 alkyl group, C1-C4 alkanoyl group or C1
-C4 alkoxy-carbonyl group, more preferably hydrogen atom, C1-C4 alkyl group or C1-C4 alkanoyl group, even more preferably hydrogen atom, methyl group or acetyl group, most preferably It is a hydrogen atom.

In the group represented by the formula (IIa) for R ^1, the 4-oxopyrrolidine is preferably substituted at the 4-position.

The group represented by formula (IIa) is preferably a 2-oxo-4-pyrrolidinyl, 1-methyl-2-oxo-4-pyrrolidinyl or 1-acetyl-2-oxo-4-pyrrolidinyl group. And more preferably a 2-oxo-4-pyrrolidinyl group or a 1-methyl-2-oxo-4-pyrrolidinyl group, and most preferably a 2-oxo-4-pyrrolidinyl group.

In the group represented by the formula (IId) for R ^1, the 4-thioxopyrrolidine is preferably substituted at the 4-position.

The group represented by formula (IId) is preferably a 2-thioxo-4-pyrrolidinyl, 1-methyl-2-thioxo-4-pyrrolidinyl or 1-acetyl-2-thioxo-4-pyrrolidinyl group. And more preferably 2-
Thioxo-4-pyrrolidinyl, 1-methyl-2-thioxo-4-pyrrolidinyl, most preferably 2-thioxo-4-pyrrolidinyl.

The "C1-C10 alkoxy" moiety of R ² is an alkoxy having 1 to 10 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutyloxy, 2-butyloxy, t-butoxy, Pentyloxy, 3-pentyloxy, 2-pentyloxy, 3-methylpentyloxy, hexyloxy, heptyloxy, octyloxynonyloxy, decyloxy groups, and preferably C1-C6
An alkoxy group, more preferably an ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, 3-pentyloxy, 2-pentyloxy or 3-methylpentyloxy group, and most preferably an isopropoxy group. .

The "-C1-C4 alkyl group" moiety in the substituent of R ² is an alkyl group having 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl,
There may be mentioned butyl or isobutyl, preferably a methyl or 1-ethyl group, most preferably a 1-ethyl group.

The "C3-C7 cycloalkyl" moiety in the substituent of R ² is a saturated cyclic alkyl group having 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl,
Examples include a cyclopentyl, cyclohexyl or cycloheptyl group, preferably a cyclobutyl, cyclopentyl or cyclohexyl group, and most preferably a cyclohexyl group.

The "C3-C7 cycloalkyl-C1-C4 alkyl" moiety in the substituent of R ² is an alkyl group having 1 to 4 carbon atoms substituted by a saturated cyclic alkyl having 3 to 7 carbon atoms. For example, cyclopropylmethyl,
Cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl,
Cyclohexylethyl, cycloheptylethyl, cyclohexylpropyl, cyclohexylbutyl, cycloheptylmethyl group and the like, preferably C3-C
7 cycloalkylmethyl or a C3-C7 cycloalkylethyl group.

The "C2-C10 alkanoyl" moiety in the substituent of R ² is alkanoyl having 2 to 10 carbon atoms, such as acetyl, propionyl, butyryl,
Isobutyryl, valeryl, isovaleryl, pivaloyl,
Octanoyl, nonanoyl, decanoyl and the like can be mentioned, preferably a C2-C5 alkanoyl group,
More preferred are acetyl, propionyl, butyryl, isobutyryl or pivaloyl groups, particularly preferred are acetyl, propionyl or pivaloyl groups, most preferred are acetyl groups.

In the substituent of R ² , “1- (C1-C4)
The “alkyl) -C3-C7 cycloalkyl” moiety is a cycloalkyl group having 3 to 7 carbon atoms substituted at the 1-position with alkyl having 1 to 4 carbon atoms, such as 1-methylcyclopropyl, 1-methylcyclopropyl, Ethylcyclopropyl, 1-methylcyclobutyl, 1-ethylcyclobutyl, 1-methylcyclopentyl, 1-ethylcyclopentyl, 1-methylcyclohexyl, 1-ethylcyclohexyl, 1-propylcyclohexyl, 1-butylcyclohexyl, 1
-Methylcycloheptyl, 1-ethylcycloheptyl group and the like, preferably 1-methylcyclopentyl, 1-methylcyclohexyl or 1-ethylcyclohexyl group, and more preferably 1-methylcyclopentyl or 1-ethylcyclohexyl group. A methylcyclohexyl group, most preferably a 1-methylcyclohexyl group.

In the substituent of R ² , the “C3-C7 cycloalkyl-C2-C4 alkanoyl” moiety has 3 carbon atoms.
2 to 4 carbon atoms substituted with 1 to 7 cycloalkyl
Alkanoyl groups, for example, cyclopropylacetyl, cyclobutylacetyl, cyclopentylacetyl, cyclohexylacetyl, cycloheptylacetyl, cyclopropylpropionyl, cyclobutylpropionyl, cyclopentylpropionyl, cyclohexylpropionyl, cycloheptylpropionyl, cyclohexylbutyryl group, etc. And preferably C3
—C7 cycloalkylacetyl group.

The "C1-C10 alkoxy-carbonyloxy-C1-C4 alkyl group" for R ² is preferably C1
-C6 alkoxy-carbonyloxymethyl or 1-
A (C1-C6 alkoxy-carbonyloxy) ethyl group, more preferably 1- (methoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, 1- (propoxycarbonyloxy) ethyl,
(Isopropoxycarbonyloxy) ethyl, 1- (butoxycarbonyloxy) ethyl, 1- (t-butoxycarbonyloxy) ethyl, t-butoxycarbonyloxymethyl, 1- (3-pentyloxycarbonyloxy) ethyl or 1- ( A 3-methyl-3-pentyloxycarbonyloxy) ethyl group.

The "C3-C7 cycloalkyl-oxycarbonyloxy-C1-C4 alkyl group" for R ² is preferably C5-C6 cycloalkyl-oxycarbonyloxymethyl or 1- (C5-C6 cycloalkyl-oxycarbonyl). Oxy) ethyl group, more preferably cyclopentyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, 1- (cyclopentyloxycarbonyloxy) ethyl or 1- (cyclohexyloxycarbonyloxy) ethyl group, more preferably 1- (cyclopentyloxycarbonyloxy) ethyl or 1- (cyclohexyloxycarbonyloxy) ethyl group.

R ² "C3-C7 cycloalkyl-C1
-C4 alkyl-oxycarbonyloxy-C1-C4
An "alkyl group" is preferably a C3-C7 cycloalkyl-
A (methyl or ethyl) -oxycarbonyloxymethyl or 1- [C3-C7 cycloalkyl- (methyl or ethyl) -oxycarbonyloxy] ethyl group, more preferably 1- (cyclopropylmethyloxycarbonyloxy) ethyl 1- (cyclopentylmethyloxycarbonyloxy) ethyl, 1- (cyclohexylmethyloxycarbonyloxy) ethyl, 1- (cyclobutylmethyloxycarbonyloxy) ethyl
— (Cyclopentylethyloxycarbonyloxy) ethyl, 1- (cyclohexylethyloxycarbonyloxy) ethyl group.

The "C2-C10 alkanoyloxy-C1-C4 alkyl group" for R ² is preferably C2-C10 alkanoyloxymethyl or 1- (C2-C10 alkanoyloxy) ethyl, more preferably acetoxy. Methyl, 1- (acetoxy) ethyl, 1- (propionyloxy) ethyl, isobutyryloxymethyl, 1
— (Isobutyryloxy) ethyl, pivaloyloxymethyl, 1- (pivaloyloxy) ethyl, 1- (octyloxy) ethyl.

The "C3-C7 cycloalkyl-carbonyloxy-C1-C4 alkyl group" for R ² is preferably
3-C7 cycloalkyl-carbonyloxymethyl or 1- (C3-C7 cycloalkyl-carbonyloxy) ethyl group, more preferably cyclopropylcarbonyloxymethyl, cyclobutylcarbonyloxymethyl, cyclopentylcarbonyloxymethyl, cyclohexylcarbonyl An oxymethyl, 1- (cyclopropylcarbonyloxy) ethyl, 1- (cyclobutylcarbonyloxy) ethyl, 1- (cyclopentylcarbonyloxy) ethyl or 1- (cyclohexylcarbonyloxy) ethyl group, particularly preferably cyclopentylcarbonyl Oxymethyl, 1- (cyclopentylcarbonyloxy) ethyl, cyclohexylcarbonyloxymethyl, and 1- (cyclohexylcarbonyloxy) ethyl.

R ² "[1- (C1-C4 alkyl)-
C3-C7 cycloalkyl] carbonyloxy-C1-
A "C4 alkyl group" is preferably (1-methyl-C5-C
6 cycloalkyl) carbonyloxymethyl or 1-
[(1-methyl-C5-C6 cycloalkyl) carbonyloxy] ethyl group, more preferably (1-methylcyclopentyl) carbonyloxymethyl, (1-methylcyclohexyl) carbonyloxymethyl, 1-
[(1-methylcyclopentyl) carbonyloxy] ethyl or 1-[(1-methylcyclohexyl) carbonyloxy] ethyl group.

R ² "C3-C7 cycloalkyl-C2
—C4 alkanoyloxy-C1-C4 alkyl group ”
Is preferably a C3-C7 cycloalkylacetyloxymethyl or 1- (C3-C7 cycloalkylacetyloxy) ethyl group, more preferably cyclopropylacetyloxycarbonylmethyl, cyclobutylacetyloxycarbonylmethyl, cyclopentylacetyl Oxycarbonylmethyl, cyclohexylacetyloxycarbonylmethyl, 1- (cyclopropylacetyloxycarbonyl) ethyl, 1- (cyclobutylacetyloxycarbonyl) ethyl, 1- (cyclopentylacetyloxycarbonyl) ethyl, 1- (cyclohexylacetyloxycarbonyl) It is an ethyl group.

R ² "5- (C1-C4 alkyl or phenyl) -2-oxo-1,3-dioxolen-4
"-Ylmethyl group" is preferably a 5- (methyl or phenyl) -2-oxo-1,3-dioxolen-4-ylmethyl group, most preferably 5-methyl-2-oxo-1,3- It is a dioxolen-4-ylmethyl group.

"C1-C20 alkanoyl group" for R ³
Is a linear or branched alkanoyl group having 1 to 20 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, octanoyl, nonanoyl, decanoyl, dodecanoyl, tetradecayl, Noil,
Hexadecanoyl, octadecanoyl and the like can be mentioned.

"C1-C20 alkanoyl group" for R ³
Is preferably C2-C when R ² is an ester residue
5 alkanoyl group, more preferably acetyl, propionyl, butyryl or isobutyryl group, particularly preferably acetyl, propionyl or butyryl group, most preferably acetyl group.

"C1-C20 alkanoyl group" for R ³
, When R ² is a hydrogen atom, preferably C6-C20
An alkanoyl group, more preferably a hexanoyl, octanoyl, decanoyl, dodecanoyl, tetradecanoyl, hexadecanoyl or octadecanoyl group.

Among the substituents of “C1-C20 alkanoyl group having a substituent” of R ³ , “amino group substituted by C1-C4 alkyl” includes, for example, methylamino,
Examples thereof include a dimethylamino, ethylamino, diethylamino, propylamino, and butylamino group, and a methylamino or dimethylamino group is preferable.

The substituent of the "C1-C20 alkanoyl group having a substituent" for R ³ is preferably amino, methylamino, dimethylamino, hydroxyl or phenyl.
More preferably, it is an amino, methylamino or hydroxyl group, most preferably an amino group.

The number of substituents of the “C1-C20 alkanoyl group having a substituent” for R ³ is preferably 1 or 2, and most preferably 1.

The “C1-C20 alkanoyl group having a substituent” for R ³ is preferably a C2-C6 alkanoyl group having a substituent (the substituent is an amino, methylamino, dimethylamino, hydroxyl or phenyl group) )
More preferably, it is an α or β-amino acid residue, for example, glycyl, alanyl, β-alanyl, valyl, leucyl, isoleucyl, seryl, threonyl, phenylalanyl, etc., preferably glycyl, alanyl , Β-alanyl, leucyl, isoleucyl or phenylalanyl group, more preferably glycyl, alanyl, β-alanyl, leucyl or isoleucyl.

The "C6-C10 aryl-carbonyl group" for R ³ includes, for example, a benzoyl, 1-naphthoyl or 2-naphthoyl group, and is preferably a benzoyl group.

The "C1-C20 alkoxy-carbonyl group" for R ³ is a carbonyl group substituted by a linear or branched C1-C20 alkoxy group, for example, methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, butyl Oxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, heptyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, dodecyloxycarbonyl, tetradecyloxycarbonyl, hexadecyloxycarbonyl, octadecyloxycarbonyl, etc. it can.

[0040] The R ³ "C1-C20 alkoxy - carbonyl group", R ² is an ester residue, preferably a C1-C4 alkoxy - carbonyl group, and more preferably methoxycarbonyl or ethoxycarbonyl group It is.

[0041] The R ³ "C1-C20 alkoxy - carbonyl group", R ² is a hydrogen atom, preferably a C6
—C20 alkoxy-carbonyl group, more preferably hexyloxycarbonyl, octyloxycarbonyl, decyloxycarbonyl, tetradecyloxycarbonyl, hexadecyloxycarbonyl or octadecyloxycarbonyl group.

R ³ "5- (C1-C4 alkyl) -2
-Oxo-1,3-dioxolen-4-ylmethyl group "
Is preferably a 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl group as described for R4 and R5.

In the compound (I) of the present invention, R
³ is a substituted C1-C20 alkanoyl group,
When the substituent is an amino group substituted with an amino group or a C1-C4 alkyl, or, when R ² is hydrogen atom, optionally are "pharmacologically acceptable salt"
Can be

When R ³ is a substituted C1-C20 alkanoyl group and the substituent is an amino group or an amino group substituted with C1-C4 alkyl, the “pharmacologically acceptable salt” includes For example, hydrochloride, hydrobromide,
Mineral salts such as hydroiodide, phosphate, sulfate, nitrate; sulfonates such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate; Organic acid salts such as acid, tartrate, citrate, maleate, succinate, acetate, benzoate, mandelate, ascorbate, lactate, gluconate, malate, etc. Acid addition salts, glycine salts, lysine salts, arginine salts, ornithine salts, glutamate, amino acid salts such as aspartate, and preferably hydrochloride, hydrobromide, phosphate, Sulfate, methanesulfonate, p-toluenesulfonate, oxalate, tartrate, citrate, acetate, lactate, glutamate, aspartate, more preferably hydrochloride, sulfate Methanesulfonate, citrate, and acetates or lactates, particularly preferably a hydrochloride or sulfate.

When R ² is a hydrogen atom, “pharmacologically acceptable salts” include, for example, inorganic salts such as lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt and triethylamine salt. , Diisopropylamine salt, salts with organic bases such as cyclohexylamine salt, or amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, aspartate, and the like. It is a sodium salt, a potassium salt, an ammonium salt or a triethylamine salt, and particularly preferably a sodium salt.

The compound (I) of the present invention absorbs water by leaving it in the air, freeze-drying from an aqueous solution, or recrystallizing to form adsorbed water,
A hydrate may be formed, or a solvate may be formed by handling with an organic solvent, and such a salt is also included in the present invention.

The compound (I) of the present invention has an asymmetric carbon in the molecule, and there are various optical isomers based on the configuration. The present invention relates to an individual isomer and a mixture of isomers. Include. Among these isomers, preferred are carbapenem skeletons having the R configuration at the 1-position, the 5-position and the 6-position having the same configuration as thienamycin (5S, 6S), and having a hydroxyl group at the 6-position substituent. Compounds in which the configuration of α-carbon is R configuration can be given.

Among the compounds of the present invention represented by the general formula (I), the following compounds are preferred. (1) R ¹ is a group represented by the formula (IIa):
R ⁴ represents a hydrogen atom, methyl, acetyl, ethoxycarbonyl or a 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl group). (2) R ¹ is 2-oxo-4-pyrrolidinyl, 1-
A compound which is a methyl-2-oxo-4-pyrrolidinyl or 1-acetyl-2-oxo-4-pyrrolidinyl group. (3) The compound wherein R ¹ is a 2-oxo-4-pyrrolidinyl or 1-methyl-2-oxo-4-pyrrolidinyl group. (4) The compound wherein R ¹ is a 2-oxo-4-pyrrolidinyl group. (5) R ² is C1-C6 alkoxy-carbonyloxymethyl or 1- (C1-C6 alkoxy-carbonyloxy) ethyl group; C5-C6 cycloalkyl-oxycarbonyloxymethyl or 1- (C5-C6 cycloalkyl- An oxycarbonyloxy) ethyl group; C
3-C7 cycloalkyl- (methyl or ethyl)-
Oxycarbonyloxymethyl or 1- [C3-C7
Cycloalkyl- (methyl or ethyl) -oxycarbonyloxy] ethyl group; C2-C10 alkanoyloxymethyl or 1- (C2-C10 alkanoyloxy) ethyl group; C3-C7 cycloalkyl-carbonyloxymethyl or 1- (C3- C7 cycloalkyl-carbonyloxy) ethyl group; (1-methyl-C5-
C6 cycloalkyl) carbonyloxymethyl or 1
-[(1-methyl-C5-C6 cycloalkyl) carbonyloxy] ethyl group; C3-C7 cycloalkylacetyloxymethyl or 1- (C3-C7 cycloalkylacetyloxy) ethyl group; phthalidyl group;
5- (methyl or phenyl) -2-oxo-1,3
-A compound which is a dioxolen-4-ylmethyl group. (6) R ² is 1- (methoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, 1-
(Propoxycarbonyloxy) ethyl, 1- (isopropoxycarbonyloxy) ethyl, 1- (butoxycarbonyloxy) ethyl, 1- (t-butoxycarbonyloxy) ethyl, t-butoxycarbonyloxymethyl, 1- (3-pentyl) Oxycarbonyloxy) ethyl or 1- (3-methyl-3-pentyloxycarbonyloxy) ethyl group; cyclopentyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, 1- (cyclopentyloxycarbonyloxy) ethyl or 1- (cyclohexyloxy) Carbonyloxy) ethyl group; 1- (cyclopropylmethyloxycarbonyloxy) ethyl, 1- (cyclobutylmethyloxycarbonyloxy) ethyl 1- (cyclopentylmethyloxyca Boniruokishi) ethyl, 1- (cyclohexylmethyl oxy carbonyloxy) ethyl, 1
-(Cyclopentylethyloxycarbonyloxy) ethyl, 1- (cyclohexylethyloxycarbonyloxy) ethyl group; acetoxymethyl, 1- (acetoxy) ethyl, 1- (propionyloxy) ethyl, isobutyryloxymethyl, 1- (iso Butyryloxy) ethyl, pivaloyloxymethyl, 1- (pivaloyloxy) ethyl, 1- (octyloxy) ethyl group; cyclopentylcarbonyloxymethyl, 1- (cyclopentylcarbonyloxy) ethyl, cyclohexylcarbonyloxymethyl, 1- ( (Cyclohexylcarbonyloxy) ethyl group; (1-methylcyclopentyl) carbonyloxymethyl, (1-methylcyclohexyl) carbonyloxymethyl, 1-[(1-methylcyclopentyl) carbonyloxy Ethyl or 1-[(1-methylcyclohexyl) carbonyloxy] ethyl group; cyclopropylacetyloxycarbonylmethyl, cyclobutylacetyloxycarbonylmethyl, cyclopentylacetyloxycarbonylmethyl, cyclohexylacetyloxycarbonylmethyl, 1- (cyclopropylacetyloxy Carbonyl) ethyl, 1- (cyclobutylacetyloxycarbonyl) ethyl, 1- (cyclopentylacetyloxycarbonyl) ethyl, 1- (cyclohexylacetyloxycarbonyl) ethyl group; 5-methyl-2-oxo-1,3-dioxolene- A compound which is a 4-ylmethyl group. (7) R ² is 1- (ethoxycarbonyloxy) ethyl, 1- (propoxycarbonyloxy) ethyl, 1
-(Isopropoxycarbonyloxy) ethyl, 1-
(Butoxycarbonyloxy) ethyl, 1- (3-pentyloxycarbonyloxy) ethyl or 1- (3-
Methyl-3-pentyloxycarbonyloxy) ethyl group; 1- (cyclohexyloxycarbonyloxy) ethyl group; 1- (cyclopropylmethyloxycarbonyloxy) ethyl group; 1- (acetoxy) ethyl, 1-
(Propionyloxy) ethyl, pivaloyloxymethyl, 1- (pivaloyloxy) ethyl, 1- (octanoyloxy) ethyl group; 1- (cyclohexylcarbonyloxy) ethyl group; (1-methylcyclohexyl) carbonyloxymethyl group; 5-methyl-2-oxo-
A compound which is a 1,3-dioxolen-4-ylmethyl group. (8) R ³ is a C2-C5 alkanoyl group; a C2-C6 alkanoyl group having a substituent (the substituent is amino,
A methylamino, dimethylamino, hydroxyl or phenyl group); a benzoyl, 1-naphthoyl or 2-naphthoyl group; a C1-C4 alkoxycarbonyl group;
A compound which is a methyl-2-oxo-1,3-dioxolen-4-ylmethyl group. (9) R ³ is acetyl, propionyl, butyryl or isobutyryl; glycyl, alanyl, β-alanyl, leucyl, isoleucyl or phenylalanyl; benzoyl; methoxycarbonyl or ethoxycarbonyl; 5-methyl-2-oxo A compound which is a -1,3-dioxolen-4-ylmethyl group. (10) The compound wherein R ³ is an acetyl, propionyl or butyryl group; a glycyl, alanyl, β-alanyl, leucyl or isoleucyl group; an ethoxycarbonyl group. (11) R ² is a hydrogen atom, and R ³ is C6-C20
Compounds which are an alkanoyl group or a C6-C20 alkoxy-carbonyl group. (12) R ² is a hydrogen atom, R ³ is hexanoyl,
A compound which is an octanoyl, decanoyl, dodecanoyl, tetradecanoyl, hexadecanoyl or octadecanoyl group, or a hexyloxycarbonyl, octyloxycarbonyl, decyloxycarbonyl, tetradecyloxycarbonyl, hexadecyloxycarbonyl or octadecyloxycarbonyl group . Select R ¹ from groups (1) to (4), select R ² from groups (5) to (7), select R ³ from groups (8) to (10), and select (11) or ( 12) R ² and R from the group
Compounds obtained by selecting ³ and arbitrarily combining them are more preferred.

Preferred compounds having the general formula (I) are specifically shown in Table 1.

[0050]

[Table 1]

[0051]

Embedded image -------------------------------------------------- -------------------- Compound No R1 R2 R3 ------------------------- --------------------------------------------- 1 2-oxo- 4-pyrr iPrOCO2CHMe Ac 2 2-oxo-4-pyrr EtOCO2CHMe Ac 3 2-oxo-4-pyrr PrOCO2CHMe Ac 4 2-oxo-4-pyrr BuOCO2CHMe Ac 5 2-oxo-4-pyrr 3-PenOCO2CHMe Ac 6 2- oxo-4-pyrr iPrOCO2CHMe EtCO 7 2-oxo-4-pyrr iPrOCO2CHMe PrCO 8 2-oxo-4-pyrr iPrOCO2CHMe Gly 9 2-oxo-4-pyrr iPrOCO2CHMe Ala 10 2-oxo-4-pyrr iPrOCO2CHMe Leu 11 2- oxo-4-pyrr iPrOCO2CHMe Ile 12 2-oxo-4-pyrr iPrOCO2CHMe b-Ala 13 2-oxo-4-pyrr iPrOCO2CHMe MODM 14 2-oxo-4-pyrr cPenOCO2CHMe Ac 15 2-oxo-4-pyrr cHexOCO2CHMe Ac 16 2-oxo-4-pyrr cHexOCO2CHMe EtCO 17 2-oxo-4-pyrr cHexOCO2CHMe PrCO 18 2-oxo-4-pyrr cHexOCO2CHMe Gly 19 2-oxo-4-pyrr cHexOCO2CHMe Ala 20 2-oxo-4-pyrr cHexOCO2CHMe Leu 21 2-oxo-4-pyrr cHexOCO2CHMe Ile 22 2-oxo-4-pyrr cHexOCO2CHMe b-Ala 23 2-oxo-4-pyrr cHexOCO2CHMe MODM 24 2-oxo-4-pyrr 3-Me-3-PenOCO2CHMe Ac 25 2- oxo-4-pyrr tBuOCO2CHMe Ac 26 2-oxo-4-pyrr tBuOCO2CH2 Ac 27 2-oxo-4-pyrr MeCO2CH2 Ac 28 2-oxo-4-pyrr MeCO2CHMe Ac 29 2-oxo-4-pyrr iPrCO2CHMe Ac 30 2-oxo-4-pyrr iPrCO2CH2 Ac 31 2-oxo-4-pyrr cPenCO2CHMe Ac 32 2-oxo-4-pyrr 1-Me-cPecCO2CHMe Ac 33 2-oxo-4-pyrr 1-Me-cPecCO2CH2 Ac 34 2-oxo-4-pyrr cPenCO2CH2 Ac 35 2-oxo-4-pyrr cPrCH2OCO2CHMe Ac 36 2 -oxo-4-pyrr cHexCO2CH2 Ac 37 2-oxo-4-pyrr cHexCO2CHMe Ac 38 2-oxo-4-pyrr 1-Me-cHexCO2CH2 Ac 39 2-oxo-4-pyrr 1-Me-cHexCO2CHMe Ac 40 2-oxo -4-pyrr tBuCO2CHMe Ac 41 2-oxo-4-pyrr tBuCO2CH2 Ac 42 2-oxo-4-pyrr tBuCO2CH2 EtCO 43 2-oxo-4-pyrr tBuCO2CH2 PrCO 44 2-oxo-4-pyrr tBuCO2CH2 Gly 45 2-oxo -4-pyrr tBuCO2CH2 Ala 46 2-oxo-4-pyrr tBuCO2CH2 Leu 47 2-oxo-4-pyrr tBuCO2CH2 Ile 48 2-oxo-4-pyrr tBuCO2CH2 b-Ala 49 2-oxo-4-pyrr tBuCO2CH2 MODM 50 2 -oxo-4-pyrr Phthz Ac 51 2-oxo-4-pyrr MODM Ac 52 2-oxo-4-pyrr PhODM Ac 53 1-Ac-2-oxo-4-pyrr iPrOCO2CHMe Ac 54 1-Ac-2-oxo -4-pyrr cHexOCO2CHMe Ac 55 1-Ac-2-oxo-4-pyrr MeCO2CHMe Ac 561-Ac-2-oxo-4-pyrr tBuCO2CH2 Ac 571-Ac-2-oxo-4-pyrr MODM Ac 58 1 -Me-2-oxo-4-pyrr iPrOCO2CHMe Ac 5 9 1-Me-2-oxo-4-pyrr cHexOCO2CHMe Ac 60 1-Me-2-oxo-4-pyrr MeCO2CHMe Ac 61 1-Me-2-oxo-4-pyrr tBuCO2CH2 Ac 62 1-Me-2-oxo -4-pyrr MODM Ac 63 1-EtOCO-2-oxo-4-pyrr iPrOCO2CHMe Ac 64 1-EtOCO-2-oxo-4-pyrr cHexOCO2CHMe Ac 65 1-EtOCO-2-oxo-4-pyrr MeCO2CHMe Ac 66 1 -EtOCO-2-oxo-4-pyrr tBuCO2CH2 Ac 67 1-EtOCO-2-oxo-4-pyrr MODM Ac 68 1-PhCO-2-oxo-4-pyrr iPrOCO2CHMe Ac 69 1-PhCO-2-oxo-4 -pyrr cHexOCO2CHMe Ac 70 1-PhCO-2-oxo-4-pyrr MeCO2CHMe Ac 71 1-PhCO-2-oxo-4-pyrr tBuCO2CH2 Ac 72 1-PhCO-2-oxo-4-pyrr MODM Ac 73 1-MODM -2-oxo-4-pyrr iPrOCO2CHMe Ac 74 1-MODM-2-oxo-4-pyrr cHexOCO2CHMe Ac 75 1-MODM-2-oxo-4-pyrr MeCO2CHMe Ac 76 1-MODM-2-oxo-4-pyrr tBuCO2CH2 Ac 77 1-MODM-2-oxo-4-pyrr MODM Ac 78 ImdzoPyrr iPrOCO2CHMe Ac 79 ImdzoPyrr iPrOCO2CHMe EtCO 80 ImdzoPyrr iPrOCO2CHMe PrCO 81 ImdzoPyrr iPrOCO2CHMe Gly 82 ImdzoPyrr iPrOCO2CHMe Ala 83 ImdzoPyrr iPrOCO2CHMe Leu 84 ImdzoPyrr iPrOCO2CHMe Ile 85 ImdzoPyrr iPrOCO2CHMe b-Ala 86 ImdzoPyrr iPrOCO2CHMe MODM 87 ImdzoPyrr cPenOCO2CHMe Ac 88 ImdzoPyrr cHexOCO2CHMe Ac 89 ImdzoPyrr cHexOCO2CHMe Gly 90 ImdzoPyrr cHexOCO2CHMe Ala 91 ImdzoPyrr cHexOCO2CHMe Leu 92 ImdzoPyrr cHexOCO2CHMe Ile 93 ImdzoPyrr cHexOCO2CHMe b-Ala 94 ImdzoPyrr cHexOCO2CHMe MODM 95 ImdzoPyrr MeCO2CHMe Ac 96 ImdzoPyrr EtCO2CHMe Ac 97 ImdzoPyrr PrCO2CHMe Ac 98 ImdzoPyrr iPrCO2CHMe Ac 99 ImdzoPyrr tBuCO2CHMe Ac 100 ImdzoPyrr cHexCO2CH2 Ac 101 ImdzoPyrr 1-Me-cHexCO2CH2 Ac 102 ImdzoPyrr cPenCO2CH2 Ac 103 ImdzoPyrr tBuCO2CH2 Ac 104 ImdzoPyrr tBuCO2CH2 Gly 105 ImdzoPyrr tBuCO2CH2 Ala 106 ImdzoPyrr tBuCO2CH2 Leu 107 ImdzoPyrr tBuCO2CH2 Ile 108 ImdzoPyrr tBuCO2CH2 b-Ala 109 ImdzoPyrr tBuCO2CH2 MODM 110 ImdzoPyrr Phthz Ac 111 ImdzoPyrr MODM Ac 112 ThizAze iPrOCO2CHMe Ac 113 ThizAze iPrOCO2CHMe EtCO 114 ThizAze iPrOCO2CHMe PrCO 115 ThizAze iPrOCO2CHMe Gly 116 ThizAze iPrOCO2CHMe Ala 117 ThizAze iPrOCO2CHMe Leu 118 ThizAze iPrOCO2CHMe Ile 119 ThizAze iPrOCO2CHMe b-Ala 120 ThizAze iPrOCO2CHMe MODM 121 ThizAze cPenOCO2CHMe Ac 122 ThizAze cHexOCO2CHMe Ac 123 ThizAze cHexOCO2CHMe Gly 124 ThizAze cHexOCO2CHMe Ala 125 ThizAze cHexOCO2CHMe Leu 126 ThizAze cHexOCO2CHMe Ile 127 ThizAze cHexOCO2CHMe b-Ala 128 ThizAze cHexOCO2CHMe MODM 129 ThizAze MeCO2CHMe Ac 130 ThizAze EtCO2CHMe Ac 131 ThizAze PrCO2CHMe Ac 132 ThizAze iPrCO2CHMe Ac 133 ThizAze tBuCO2CHMe Ac 134 ThizAze cHexCO2CH2 Ac 135 ThizAze 1-Me- cHexCO2CH2 Ac 136 ThizAze cPenCO2CH2 Ac 137 ThizAze tBuCO2CH2 Ac 138 ThizAze tBuCO2CH2 Gly 139 ThizAze tBuCO2CH2 Ala 140 ThizAze tBuCO2CH2 Phu Thu141 ThizAze tBuCO2CH2 Ile 142 ThizAze bAze tACO2CH2 -Pyrr iPrOCO2CHMe Ac 147 2-thioxo-4-Pyrr iPrOCO2CHMe EtCO 148 2-thioxo-4-Pyrr iPrOCO2CHMe PrCO 149 2-thioxo-4-Pyrr iPrOCO2CHMe Gly 150 2-thioxo-4-Pyrr iPrOCO2CHMe Ala 151 2-thioxo-4 -Pyrr iPrOCO2CHMe Leu 152 2-thioxo-4-Pyrr iPrOCO2CHMe Ile 153 2-thioxo-4-Pyrr iPrOCO2CHMe b-Ala 154 2-thioxo-4-Pyrr iPrOCO2CHMe MODM 155 2-thioxo-4-Pyrr cPenOCO2CHMe Ac 156 2-thioxo -4-Pyrr cHexOCO2CHMe Ac 157 2-thioxo-4-Pyrr cHexOCO2 CHMe Gly 158 2-thioxo-4-Pyrr cHexOCO2CHMe Ala 159 2-thioxo-4-Pyrr cHexOCO2CHMe Leu 160 2-thioxo-4-Pyrr cHexOCO2CHMe Ile 161 2-thioxo-4-Pyrr cHexOCO2CHMe b-Ala 162 2-thioxo-4 -Pyrr cHexOCO2CHMe MODM 163 2-thioxo-4-Pyrr MeCO2CHMe Ac 164 2-thioxo-4-Pyrr EtCO2CHMe Ac 165 2-thioxo-4-Pyrr PrCO2CHMe Ac 166 2-thioxo-4-Pyrr iPrCO2CHMe Ac 167 2-thioxo-4 -Pyrr tBuCO2CHMe Ac 168 2-thioxo-4-Pyrr cHexCO2CH2 Ac 169 2-thioxo-4-Pyrr 1-Me-cHexCO2CH2 Ac 170 2-thioxo-4-Pyrr cPenCO2CH2 Ac 171 2-thioxo-4-Pyrr tBuCO2CH2 Ac 172 2 -thioxo-4-Pyrr tBuCO2CH2 Gly 173 2-thioxo-4-Pyrr tBuCO2CH2 Ala 174 2-thioxo-4-Pyrr tBuCO2CH2 Leu 175 2-thioxo-4-Pyrr tBuCO2CH2 Ile 176 2-thioxo-4-Pyrr tBuCO2CH2 b-Ala 177 2-thioxo-4-Pyrr tBuCO2CH2 MODM 178 2-thioxo-4-Pyrr Phthz Ac 179 2-thioxo-4-Pyrr MODM Ac 180 1-Ac-2-thioxo-4-pyrr iPrOCO2CHMe Ac 181 1-Ac-2 -thioxo-4-pyrr cHexOCO2CHMe Ac 182 1-Ac-2-thioxo-4-pyrr MeCO2CHMe Ac 183 1-Ac-2-thioxo-4-pyrr tBuCO2CH2 Ac 184 1-Ac-2-thioxo-4-pyrr MODM Ac 185 1-Me-2-thioxo-4-pyrr iPrOCO2CHMe Ac 18 6 1-Me-2-thioxo-4-pyrr cHexOCO2CHMe Ac 187 1-Me-2-thioxo-4-pyrr MeCO2CHMe Ac 188 1-Me-2-thioxo-4-pyrr tBuCO2CH2 Ac 189 1-Me-2-thioxo -4-pyrr MODM Ac 190 1-EtOCO-2-thioxo-4-pyrr iPrOCO2CHMe Ac 191 1-EtOCO-2-thioxo-4-pyrr cHexOCO2CHMe Ac 192 1-EtOCO-2-thioxo-4-pyrr MeCO2CHMe Ac 193 1 -EtOCO-2-thioxo-4-pyrr tBuCO2CH2 Ac 194 1-EtOCO-2-thioxo-4-pyrr MODM Ac 195 1-PhCO-2-thioxo-4-pyrr iPrOCO2CHMe Ac 196 1-PhCO-2-thioxo-4 -pyrr cHexOCO2CHMe Ac 197 1-PhCO-2-thioxo-4-pyrr MeCO2CHMe Ac 198 1-PhCO-2-thioxo-4-pyrr tBuCO2CH2 Ac 199 1-PhCO-2-thioxo-4-pyrr MODM Ac 200 1-MODM -2-thioxo-4-pyrr iPrOCO2CHMe Ac 201 1-MODM-2-thioxo-4-pyrr cHexOCO2CHMe Ac 202 1-MODM-2-thioxo-4-pyrr MeCO2CHMe Ac 203 1-MODM-2-thioxo-4-pyrr tBuCO2CH2 Ac 204 1-MODM-2-thioxo-4-pyrr MODM Ac 205 2-oxo-4-pyrr H Ac 206 2-oxo-4-pyrr H EtCO 207 2-oxo-4-pyrr H PrCO 208 2-oxo -4-pyrr H C5H11CO 209 2-oxo-4-pyrr H C7H15CO 210 2-oxo-4-pyrr H C9H19CO 211 2-oxo-4-pyrr H C11H23CO 212 2-oxo-4-pyrr H C13H27CO 213 2-oxo -4-pyrr H C15H31CO 214 2-oxo-4- pyrr H C17H35CO 215 2-oxo-4-pyrr H MeOCO 216 2-oxo-4-pyrr H EtOCO 217 2-oxo-4-pyrr H PrOCO 218 2-oxo-4-pyrr H BuOCO 219 2-oxo-4- pyrr H C4H9OCO 220 2-oxo-4-pyrr H C6H13OCO 221 2-oxo-4-pyrr H C8H17OCO 222 2-oxo-4-pyrr H C10H21OCO 223 2-oxo-4-pyrr H C12H25OCO 224 2-oxo-4- pyrr H C14H29OCO 225 2-oxo-4-pyrr H C16H33OCO 226 2-oxo-4-pyrr H C18H37OCO 227 1-Me-2-oxo-4-pyrr H Ac 228 1-Me-2-oxo-4-pyrr H EtCO 229 1-Me-2-oxo-4-pyrr H PrCO 230 1-Me-2-oxo-4-pyrr H C5H11CO 231 1-Me-2-oxo-4-pyrr H C7H15CO 232 1-Me-2- oxo-4-pyrr H C9H19CO 233 1-Me-2-oxo-4-pyrr H C11H23CO 234 1-Me-2-oxo-4-pyrr H C13H27CO 235 1-Me-2-oxo-4-pyrr H C15H31CO 236 1-Me-2-oxo-4-pyrr H C17H35CO 237 1-Me-2-oxo-4-pyrr H MeOCO 238 1-Me-2-oxo-4-pyrr H EtOCO 239 1-Me-2-oxo- 4-pyrr H PrOCO 240 1-Me-2-oxo-4-pyrr H BuOCO 241 1-Me-2-oxo-4-pyrr H C4H9OCO 242 1-Me-2-oxo-4-pyrr H C6H13OCO 243 1- Me-2-oxo-4-pyrr H C8H17OCO 244 1-Me-2-oxo-4-pyrr H C10H21OCO 245 1-Me-2-oxo-4-pyrr H C12H25OCO 246 1-Me-2-oxo-4- pyrr H C14H29OCO 247 1-Me-2-oxo-4-pyrr H C16H33OCO 248 1-Me-2-oxo-4-pyrr H C18H37OCO ----------------------------------- ----------------------------------- Abbreviations used in Table 1 above are as follows .

Ac acetyl, Me methyl, Et ethyl, Pr propyl, iPr isopropyl, cPr
Cyclopropyl, tBu t-butyl, cPen cyclopentyl, cHex cyclohexyl, MODM
5-methyl-2-oxo-1,3-dioxolen-4-
Ilmethyl, PhODM 5-phenyl-2-oxo-
1,3-dioxolen-4-ylmethyl, Phthz
Phthalidyl, Pyrr pyrrolidinyl, ThizAze
A group represented by the formula (IIc), Gly glycyl, Al
a Alanyl, Leu leucyl, Ile isoleucyl, b-Ala β-alanyl.

Of the compounds exemplified in Table 1 above, compound numbers 1, 2, 8, 9, 12, 14, 15, 1
6, 28, 40, 41, 44, 45, 53, 54 and 55, more preferably 1, 2, 14, 1
5, 16, 40 and 53 compounds.

Among the above-mentioned compounds, the compounds specified by the following chemical names are particularly preferred. Compound No. 1: 1- (isopropoxycarbonyloxy) ethyl 6-
(1-acetoxyethyl) -1-methyl-2- (2-oxo-4-pyrrolidinylthio) -1-carbapene-2-
M-3-carboxylate Compound No. 15: 1- (cyclohexyloxycarbonyloxy) ethyl 6- (1-acetoxyethyl) -1-methyl-2-
(2-oxo-4-pyrrolidinylthio) -1-carbapen-2-em-3-carboxylate Compound No. 41: Pivaloyloxymethyl 6- (1-acetoxyethyl) -1-methyl-2- (2 -Oxo-4-pyrrolidinylthio) -1-carbapen-2-em-3-carboxylate Compound No. 53: 1- (isopropoxycarbonyloxy) ethyl 6-
(1-Acetoxyethyl) -1-methyl-2- (1-acetyl-2-oxo-4-pyrrolidinylthio) -1-carbapen-2-em-3-carboxylate.

Among the above, the most preferred compounds are the following compounds.

1- (isopropoxycarbonyloxy)
Ethyl (1R, 5S, 6S) -6-[(1R) -1-
Acetoxyethyl] -1-methyl-2-[(4R) -2
-Oxo-4-pyrrolidinylthio] -1-carbapene-
2-M-3-carboxylate 1- (isopropoxycarbonyloxy) ethyl (1
R, 5S, 6S) -6-[(1R) -1-acetoxyethyl] -1-methyl-2-[(4S) -2-oxo-4
-Pyrrolidinylthio] -1-carbapene-2-em-3
-Carboxylate 1- (cyclohexyloxycarbonyloxy) ethyl (1R, 5S, 6S) -6-[(1R) -1-acetoxyethyl] -1-methyl-2-[(4R) -2-oxo-4- Pyrrolidinylthio] -1-carbapene-2-em-3-carboxylate 1- (cyclohexyloxycarbonyloxy) ethyl (1R, 5S, 6S) -6-[(1R) -1-acetoxyethyl] -1-methyl -2-[(4S) -2-oxo-4-pyrrolidinylthio] -1-carbapen-2-em-3-carboxylate pivaloyloxymethyl (1R, 5S, 6S) -6
[(1R) -1-acetoxyethyl] -1-methyl-2
-[(4R) -2-oxo-4-pyrrolidinylthio]-
1-carbapene-2-em-3-carboxylate pivaloyloxymethyl (1R, 5S, 6S) -6
[(1R) -1-acetoxyethyl] -1-methyl-2
-[(4S) -2-oxo-4-pyrrolidinylthio]-
1-carbapene-2-em-3-carboxylate.

[0057]

DETAILED DESCRIPTION OF THE INVENTION According to the present invention, a compound having the general formula (I)
-Methylcarbapenem derivative is obtained by adding R to the 1-hydroxyethyl group of the carbapenem compound represented by the formula (III).
Obtained by introducing a group represented by ³ (A
Law).

[0058]

Embedded image In the above, R ¹ , R ² and R ³ are the same as described above.
The starting material represented by the formula (III) is described in JP-A-2-49783, JP-A-7-1657.
No. 59, JP-A-2-223587, JP-A-4
-279588, JP-A-8-53453,
The Journal of Antibiotics 50 (5), 429-439 (1997)
Etc. or a method analogous thereto. Hereinafter, the above manufacturing method will be described in detail.

This method is achieved by reacting compound (I) with a reactive derivative of R ^{3 in} a solvent in the presence of a base.

[0060] As the reactive derivative of R ^3, if R ³ is alkanoyl, substituted alkanoyl or arylcarbonyl group, an acid halide, acid anhydride, mixed acid anhydride, etc. can be mentioned an acid imidazole compound, Preferably, it is an acid anhydride. When R ³ is an alkoxycarbonyl group, examples thereof include an alkoxycarbonyl halide, a dialkyl carbonate, and the like, and preferably an alkoxycarbonyl halide. R ³ is 5-
In the case of a (C1-C4 alkyl) -2-oxo-1,3-dioxolen-4-ylmethyl group, a halide is preferred.

The solvent used is not particularly limited as long as it dissolves the starting materials to some extent and does not participate in the reaction. For example, n-pentane, n-hexane, n-hexane
Aliphatic saturated hydrocarbons such as heptane and n-octane; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran and dioxane; ethyl formate, methyl acetate;
Esters such as ethyl acetate; nitriles such as acetonitrile; halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, chloroform, chlorobenzene and dichlorobenzene; N, N-dimethylformamide, N, N- Examples include amides such as dimethylacetamide and N-methyl-2-pyrrolidone. Also, a mixed solvent in which these are appropriately combined can be used.

The base to be used is not particularly limited as long as it is used as a base in a usual reaction. For example, N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine,
Dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N,
Organic bases such as (N-dimethylamino) pyridine, quinoline, 2,6-di (t-butyl) -4-methylpyridine, N, N-dimethylaniline and N, N-diethylaniline can be mentioned. Of these, pyridine, 4- (N, N-dimethylamino) pyridine or a combination thereof is most preferred.

The base is usually used in an amount of 1 to 1.1 molar equivalents relative to the reactive derivative of R ³ , but can be used in a large excess as a solvent. In addition, 4- (N, N-dimethylamino) pyridine or 4-pyrrolidinopyridine can be used in a catalytic amount in combination with another base.

The reaction temperature is usually -10 to 50 degrees, preferably 0 to 30 degrees.

The reaction time varies depending on the solvent, base, reaction temperature and the like to be used, but is usually 10 minutes to 10 hours, preferably 0.5 to 3 hours.

After completion of the reaction, the desired product can be obtained by a conventional method, for example, by appropriately combining techniques such as concentration, extraction, activated carbon treatment, and crystallization.
For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration. Then, an immiscible organic solvent such as water and ethyl acetate is added. And the solvent is distilled off. The target compound can be purified, if necessary, by a method commonly used for separation and purification of organic compounds such as activated carbon treatment, recrystallization, reprecipitation, and column chromatography.

Further, when R ¹ is a group represented by the formula (IIa) or (II
d) wherein R ⁴ or R ⁵ is an alkyl group, an alkanoyl group, an alkoxycarbonyl group or 5- (C1-C
4alkyl) -2-oxo-1,3-dioxolen-4
When it is -ylmethyl group, compound (I) can be produced by the following method (Method B).

[0068]

Embedded image In the above, R ¹ , R ² , R ³ , R ⁴ , and R ⁵ have the same meanings as described above, and R ⁶ represents a hydroxyl-protecting group. As the “hydroxyl protecting group” for R ⁶ , any of those commonly used in the field of synthetic organic chemistry can be used, but triprotective groups such as trimethylsilyl, triethylsilyl and t-butyldimethylsilyl can be used. A -C1-C4 alkylsilyl group is preferred, most preferably a t-ethylsilyl group. The compound of formula (IV) of the starting material is obtained by a protecting group R ⁶ in a conventional manner a hydroxy group of the compound of the aforementioned (III).

Step B-1 is a step of producing compound (V) by reacting compound (IV) with a reactive derivative of R ⁴ or R ^{5 in} a solvent in the presence of a base.

The reactive derivative of R ⁴ or R ⁵ includes R
^{When 4} or R ⁵ is an alkanoyl group, examples thereof include an acid halide, an acid anhydride, a mixed acid anhydride, and an acid imidazole compound, and an acid anhydride is preferable. When R ⁴ or R ⁵ is an alkoxycarbonyl group, examples thereof include an alkoxycarbonyl halide, a dialkyl carbonate and the like, and preferably an alkoxycarbonyl halide. When R ⁴ or R ⁵ is alkyl or 5- (C1-C4 alkyl) -2-oxo-1,3-dioxolen-4-ylmethyl group, a halide are preferred.

The solvent used is not particularly limited as long as it dissolves the starting materials to some extent and does not participate in the reaction. For example, n-pentane, n-hexane, n-hexane
Aliphatic saturated hydrocarbons such as heptane and n-octane; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran and dioxane; ethyl formate, methyl acetate;
Esters such as ethyl acetate; nitriles such as acetonitrile; halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, chloroform, chlorobenzene and dichlorobenzene; N, N-dimethylformamide, N, N- Examples include amides such as dimethylacetamide and N-methyl-2-pyrrolidone. Also, a mixed solvent in which these are appropriately combined can be used. Preferably it is methylene chloride.

The base to be used is not particularly limited as long as it is used as a base in a usual reaction. For example, N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine,
Dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N,
Organic bases such as (N-dimethylamino) pyridine, quinoline, 2,6-di (t-butyl) -4-methylpyridine, N, N-dimethylaniline and N, N-diethylaniline can be mentioned. Of these, 4-
(N, N-dimethylamino) pyridine.

The base is usually used in an amount of 1 to 1.1 molar equivalents relative to the reactive derivative of R ⁴ or R ⁵ , but can be used in a large excess as a solvent. In addition, 4- (N, N-dimethylamino) pyridine or 4-pyrrolidinopyridine can be used in a catalytic amount in combination with another base.

The reaction temperature is usually -10 to 50 degrees, preferably 0 to 30 degrees.

The reaction time varies depending on the solvent, base, reaction temperature and the like to be used, but is usually 10 minutes to 10 hours, preferably 0.5 to 3 hours.

After completion of the reaction, the desired product can be obtained by a conventional method, for example, by appropriately combining techniques such as concentration, extraction, activated carbon treatment, and crystallization.
For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration. Then, an immiscible organic solvent such as water and ethyl acetate is added. And the solvent is distilled off. The target compound can be purified, if necessary, by a method commonly used for separation and purification of organic compounds such as activated carbon treatment, recrystallization, reprecipitation, and column chromatography.

Step B-2 is a step in which the protecting group for the hydroxyl group of compound (V) is removed to obtain compound (VI).

When the protecting group is a tri-C1-C4 alkylsilyl group, usually, tetrabutylammonium fluoride,
It is removed by treatment with a compound that produces fluoride anions, such as potassium fluoride (preferably tetrabutylammonium fluoride).

The reaction solvent is not particularly limited as long as it does not inhibit the reaction, but ethers such as tetrahydrofuran and dioxane are preferred.

The reaction temperature and the reaction time are not particularly limited, but are usually at room temperature for 6 hours to 3 days (preferably 10 to 1 day).
8 hours).

After completion of the reaction, the desired product can be obtained by a conventional method, for example, by appropriately combining techniques such as concentration, extraction, activated carbon treatment, and crystallization.
For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration. Then, an immiscible organic solvent such as water and ethyl acetate is added. And the solvent is distilled off. The target compound can be purified, if necessary, by a method commonly used for separation and purification of organic compounds such as activated carbon treatment, recrystallization, reprecipitation, and column chromatography.

Step B-3 is a method for producing compound (I) by reacting compound (VI) with a reactive derivative of R ^{3 in} a solvent in the presence of a base. This step can be achieved in the same manner as described in Method A described above.

Compound (I) wherein R ² is a hydrogen atom
Can be produced by the following method (C
Law).

[0084]

Embedded image In the above, R ¹ and R ³ are as defined above, and R ⁷ is a carboxyl-protecting group. The compound represented by the formula (VII) as a starting material is disclosed in JP-A-2-4978.
3, JP-A-7-165759 and JP-A-2-16559.
223587, JP-A-4-279588,
JP-A-8-53453, The Journal of Antibio
tics 50 (5), 429-439 (1997) and the like or a method analogous thereto.

Step C-1 is a step of producing compound (VIII) by reacting compound (VII) with a reactive derivative of R ^{3 in} a solvent in the presence of a base.
This step can be achieved in the same manner as described in Method A described above.

Step C-2 is a step of preparing compound (I) in which R ² is a hydrogen atom by removing protecting group R ⁷ of the carboxyl group of compound (VIII).

The removal of the protecting group depends on the type thereof, but is generally performed by a method used in the field of synthetic organic chemistry (Greene & Wuts, P.S.
protective Groups in Organ
ic Synthesis, 2nd Edition,
1991, John Wiley & Sons, In
c. ). (1) When the protecting group R ⁷ is a benzyl group or a benzhydryl group which may have a substituent such as benzyl or 4-nitrobenzyl, hydrogen and a reducing agent using a catalytic reduction catalyst or an alkali metal sulfide are used. By reacting, the protecting group can be removed.

The reducing agent is, for example, hydrogen and palladium-
Mention may be made of a catalytic reduction catalyst such as carbon or an alkali metal sulfide such as sodium sulfide or potassium sulfide, preferably hydrogen and a palladium-carbon catalyst.

The solvent used is not particularly limited as long as it does not take part in the reaction. Preferably, alcohols such as methanol and ethanol, tetrahydrofuran,
Ethers such as dioxane and mixed solvents of these organic solvents and water.

The reaction temperature is usually 0 ° C. to 50 ° C. (preferably 10 ° C. to 40 ° C.), and the reaction time varies depending on the type of the starting compound and the reducing agent.
2 hours (preferably 30 minutes to 4 hours).

After completion of the reaction, the desired compound (I) is collected from the reaction mixture according to a conventional method. For example, it can be obtained by filtering off insolubles from the reaction mixture and then distilling off the solvent. (2) When the protecting group R ⁷ is allyl, 2-chloroallyl, 2-
When the 2-position is an allyl group which may be substituted, such as methylallyl, palladium-triol such as bis (triphenylphosphine) palladium chloride-tributyltin hydride and tetrakis (triphenylphosphine) palladium-tributyltin hydride Protection by reaction with alkyltin hydrides or deprotecting agents such as palladiums such as potassium tetrakis (triphenylphosphine) -2-ethylhexanoate or sodium 2-ethylhexanoate-alkali metal salts of organic carboxylic acids. The group can be removed.

The deprotecting agent is preferably bis (triphenylphosphine) palladium chloride-tributyltin hydride or tetrakis (triphenylphosphine)
Potassium palladium-2-ethylhexanoate.

The solvent used is not particularly limited as long as it does not participate in the reaction, but halogenated hydrocarbons such as methylene chloride, chloroform or 1,2-dichloroethane, and esters such as ethyl acetate. Ethers such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane, nitriles such as acetonitrile, alcohols such as methanol, ethanol or propanol, water or a mixed solvent thereof. , Ethyl acetate or a mixed solvent thereof.

The reaction temperature is not particularly limited, but is usually -20 ° C.
To 100 ° C. (preferably 0 ° C. to 60 ° C.), and the reaction time is usually 30 minutes to 48 hours (preferably 30 minutes to 12 hours).

After completion of the reaction, the deprotected compound (I) is collected from the reaction mixture according to a conventional method. For example, it can be obtained by filtering off insolubles precipitated from the reaction mixture and then distilling off the solvent. (3) When the protecting group R ⁷ is 2,2-dibromoethyl, 2,
In the case of a halogenoethyl group such as 2,2-trichloroethyl, the protecting group can be removed by reacting a metal such as zinc with a reducing agent using an acid such as acetic acid or hydrochloric acid.

As the reducing agent, zinc and acetic acid are preferred.

The solvent to be used is not particularly limited as long as it does not participate in the present reaction. Preferably, alcohols such as methanol and ethanol, tetrahydrofuran,
They are ethers such as dioxane, fatty acids such as acetic acid, and mixed solvents of these organic solvents and water.

The reaction temperature is usually 0 ° C. to 40 ° C. (preferably 10 ° C. to 30 ° C.), and the reaction time varies depending on the type of the starting compound and the reducing agent, but is usually 5 minutes to 12 hours (preferably 5 minutes to 12 hours). After 30 minutes to 4 hours, the target compound (I) is collected from the reaction mixture according to a conventional method. For example, it can be obtained by filtering off insolubles from the reaction mixture and then distilling off the solvent.

The target compound (I) thus obtained
Can be purified, if necessary, by a conventional method such as a recrystallization method, thin-layer chromatography for preparative use, or column chromatography.

The 1-methylcarbapenem compound having the general formula (I) thus obtained may be optionally
It can be purified as a pharmacologically acceptable salt according to methods or techniques known in the field of medicinal chemistry, especially β-lactam antibiotics.

When Compound (I) or a pharmaceutically acceptable salt thereof is used as a medicament (especially an antibacterial agent), it may be used with itself or an appropriate pharmaceutically acceptable excipient or diluent. They can be mixed and administered orally by tablets, capsules, granules, powders, syrups and the like, or parenterally by injections and the like.

These preparations contain excipients (eg, lactose,
Sugar derivatives such as sucrose, glucose, mannitol, sorbitol; starch derivatives such as corn starch, potato starch, α-starch, dextrin, carboxymethyl starch; crystalline cellulose, low-substituted hydroxypropyl cellulose, hydroxy Cellulose derivatives such as propylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, internally crosslinked sodium carboxymethylcellulose; gum arabic; dextran; pullulan; light anhydrous silicic acid, synthetic aluminum silicate; Silicate derivatives such as magnesium metasilicate aluminate; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate; Agent Gelatin; polyvinylpyrrolidone;
Macrogol, etc.), disintegrants (for example, the above-mentioned excipients; croscarmellose sodium, carboxymethyl starch)
Disodium, chemically modified starch such as crosslinked polyvinylpyrrolidone, starch, cellulose derivatives, etc.), lubricants (eg, talc; stearic acid; metal stearate such as calcium stearate, magnesium stearate; colloidal silica) Bee gum; beeswax;
Waxes such as gay wax; boric acid; glycol; carboxylic acids such as fumaric acid and adipic acid; sodium carboxylate salts such as sodium benzoate; sulfate salts such as sodium sulfate; leucine; sodium lauryl sulfate; Lauryl sulfates such as magnesium lauryl sulfate; silicic acids such as silicic anhydride and silicic acid hydrate; starch derivatives in the above-mentioned excipients); stabilizers (eg, paraoxybenzoic acid esters such as methylparaben and propylparaben) Chlorobutanol, benzyl alcohol
Alcohols such as phenylethyl alcohol;
Benzalkonium chloride; phenols such as phenol and cresol; thimerosal; acetic anhydride; sorbic acid and the like; flavoring agents (for example, commonly used sweeteners)
Additives such as acidulants, flavors, etc., suspending agents (eg, polysorbate 80, carboxymethyl cellulose sodium, etc.), diluents, formulation solvents (eg, water, ethanol, glycerin, etc.). And manufactured by a well-known method.

The dosage varies depending on symptoms, age, etc., but in the case of oral administration, the lower limit is 10 mg (preferably 50 mg) and the upper limit is 2000 mg (preferably 10 mg).
In the case of intravenous administration, the lower limit is 10 mg (preferably 100 mg) and the upper limit is 3000 mg per dose.
(Preferably 2000 mg) is desirably administered to an adult 1 to 6 times a day depending on the symptoms.

[0104]

EXAMPLES Examples, reference examples and test examples are given below.
The present invention will be described in more detail, but the scope of the present invention is not limited thereto. In addition, regarding the nuclear magnetic resonance spectrum, tetramethylsilane was used as an internal standard substance.

Example 1 1- (n-Propoxycarbonyloxy) ethyl (1R,
5S, 6S) -6-[(1R) -1-acetyloxyethyl]
-1-methyl-2-[(4R) -2-oxo-4-pyrrolidinylthio] -1-carbapen-2-em-3-carboxylate

[0106]

Embedded image 1- (n-propoxycarbonyloxy) ethyl under ice-cooling
(1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-[(4R) -2-oxo-4-pyrrolidinylthio] -1-carbapen-2-em -3-carboxylate 1.461
To a solution of g in 30 ml of pyridine, 15 mg of 4-dimethylaminopyridine and 0.45 ml of acetic anhydride were added and stirred for 1 hour. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water, saturated potassium hydrogen sulfate, water and saturated saline in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (methylene chloride: methanol =
10: 1) to give 1.236 g of the title compound as a colorless amorphous.

Infrared absorption spectrum (KBr) cm ^-1 : 3387,
3244, 1766, 1744, 1706, 1548, 1484, 1449, 1392, 1
373, 1323, 1269, 1267. Ultraviolet absorption spectrum (EtOH) nm: 321.2. Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 0.96 (3
H, t, J = 7.3 Hz), 1.27, 1.27 (3H, d × 2, J = 7.5 Hz),
1.39, 1.40 (3H, d × 2, J = 6.3 Hz), 1.62, 1.64 (3H, d
× 2, J = 6.2 Hz), 1.65-1.77 (2H, m), 2.08 (3H, s),
2.40 (1H, dt, J = 17.3, 6.0 Hz), 2.80 (1H, dd, J = 17.
3, 8.2 Hz), 3.21-3.43 (3H, m), 3.77-3.86 (1H, m),
3.97-4.08 (1H, m), 4.10-4.23 (3H, m), 5.19-5.30 (1
H, m), 6.13 (1H, s), 6.88 (1H, q, J = 5.4, Hz).

Example 2 1- (acetyloxy) ethyl (1R, 5S, 6S) -6
-[(1R) -1-acetyloxyethyl] -1-methyl-2-
[(4R) -2-oxo-4-pyrrolidinylthio] -1-carbapen-2-em-3-carboxylate

[0109]

Embedded image In the same manner as in Example 1, the title compound was obtained.

Infrared absorption spectrum (KBr) cm ^-1 : 3252,
2980, 1778, 1740, 1705, 1548, 1448, 1373, 1238, 1
072. Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 1.27 (3
H, d, J = 7.0 Hz), 1.40, 1.41 (3H, d × 2, J = 6.5 Hz),
1.56, 1.57 (3H, d × 2, J = 5.5 Hz), 2.07, 2.08, (3H,
s × 2), 2.09, 2.11, (3H, s × 2), 2.37-2.44 (1H, m),
2.80 (1H, dd, J = 17.2, 8.2 Hz), 3.24-3.32 (1H, m),
3.35 (1H, dd, J = 10.5, 4.9 Hz), 3.38-3.42 (1H, m),
3.79-3.88 (1H, m), 3.97-4.07 (1H, m), 4.17-4.23 (1
H, m), 5.19-5.35 (1H, m), 5.92 (1H, brs), 6.95-7.0
4 (1H, m).

Example 3 1- (Propionyloxy) ethyl (1R, 5S, 6
S) -6-[(1R) -1-acetyloxyethyl] -1-methyl-2-[(4R) -2-oxo-4-pyrrolidinylthio] -1-carbapene-2-em-3-carboxy Rate

[0112]

Embedded image In the same manner as in Example 1, the title compound was obtained.

Infrared absorption spectrum (KBr) cm ^-1 : 3243,
2982, 1779, 1741, 1706, 1548, 1449, 1240, 1065. Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 1.14, 1.
15 (3H, t × 2, J = 7.6Hz), 1.27 (3H, d, J = 7.3 Hz), 1.
39, 1.41 (3H, d × 2, J = 6.0 Hz), 1.56, 1.57 (3H, d ×
2, J = 5.4 Hz), 2.07, (3H, s), 2.30-2.46 (3H, m), 2.
79 (1H, dd, J = 17.1, 8.1 Hz), 3.26 (1H, dq, J = 9.4,
(7.3 Hz), 3.34 (1H, dd, J = 10.6, 5.0Hz), 3.35-3.43
(1H, m), 3.79-3.86 (1H, m), 3.96-4.07 (1H, m), 4.1
7-4.22 (1H, m), 5.21-5.32 (1H, m), 5.87 (1H, brs),
6.99, 7.02 (1H, q × 2, J = 5.4Hz).

Example 4 1- (Octanoyloxy) ethyl (1R, 5S, 6
S) -6-[(1R) -1-acetyloxyethyl] -1-methyl-2-[(4R) -2-oxo-4-pyrrolidinylthio] -1-carbapene-2-em-3-carboxy Rate

[0115]

Embedded image In the same manner as in Example 1, the title compound was obtained.

Infrared absorption spectrum (KBr) cm ^-1 : 3232,
2932, 1782, 1743, 1705, 1549, 1450, 1240, 1069. Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 0.84-0.9
1 (3H, m), 1.27 (3H, d, J = 7.3 Hz), 1.22-1.37 (8H,
m), 1.40, 1.41 (3H, d × 2, J = 6.3 Hz), 1.56,1.57 (3
H, d × 2, J = 5.5 Hz), 1.51-1.68 (2H, m), 2.07, (3H,
s), 2.28-2.44 (3H, m), 2.80 (1H, dd, J = 17.2, 8.1 H
z), 3.26 (1H, dq, J = 9.3, 7.4 Hz), 3.31-3.41 (1H,
m), 3.77-3.86 (1H, m), 3.98-4.07 (1H, m), 4.16-4.2
2 (1H, m), 5.22-5.29 (1H, m), 5.79 (1H, brs), 6.97
-7.03 (1H, m).

Example 5 1- (ethoxycarbonyloxy) ethyl (1R, 5
S, 6S) -6-[(1R) -1-acetyloxyethyl] -1
-Methyl-2-[(4R) -2-oxo-4-pyrrolidinylthio]-
1-carbapene-2-em-3-carboxylate

[0118]

Embedded image In the same manner as in Example 1, the title compound was obtained.

Infrared absorption spectrum (KBr) cm ^-1 : 3251,
2982, 1764, 1706, 1548, 1447, 1373, 1263, 1074. Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 1.26, 1.
27 (3H, d × 2, J = 7.3Hz), 1.32, 133 (3H, t × 2, J = 7.2
Hz), 1.36-1.44 (3H, m), 1.56-1.67 (3H, m), 2.07,
(3H, s), 2.35-2.45 (1H, m), 2.80 (1H, dd, J = 17.1,
8.1 Hz), 3.20-3.31 (1H, m), 3.32-3.43 (2H, m), 3.
97-4.07 (1H, m), 4.14-4.32 (3H, m), 5.18-5.32 (1H, m
m), 5.76 (1H, brs), 6.89 (1H, q, J = 5.5 Hz).

Example 6 1- (n-butoxycarbonyloxy) ethyl (1R, 5
S, 6S) -6-[(1R) -1-acetyloxyethyl] -1
-Methyl-2-[(4R) -2-oxo-4-pyrrolidinylthio]-
1-carbapene-2-em-3-carboxylate

[0121]

Embedded image In the same manner as in Example 1, the title compound was obtained.

Infrared absorption spectrum (KBr) cm ^-1 : 3368,
3250, 1766, 1744, 1705, 1548, 1484, 1450, 1373, 1
324, 1264, 1207. Ultraviolet absorption spectrum (EtOH) nm: 322.2. Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 0.93 (3
H, t, J = 7.3 Hz), 1.27, 12.7 (3H, d × 2, J = 7.4 Hz),
1.33-1.47 (4H, m), 1.55-1.73 (6H, m), 2.07 (3H, s),
2.40 (1H, dt, J = 17.3, 6.1 Hz), 2.80 (1H, dd, J = 1
7.3, 8.1 Hz), 3.22-3.43 (3H, m), 3.77-3.87 (1H,
m), 3.97-4.25 (4H, m), 5.18-5.31 (1H, m), 5.92 (1
H, s), 6.88 (1H, q, J = 5.5 Hz).

Example 7 1- (Isopropoxycarbonyloxy) ethyl (1
R, 5S, 6S) -6-[(1R) -1-acetyloxyethyl] -1-methyl-2-[(4R) -2-oxo-4-pyrrolidinylthio] -1-carbapen-2-em -3-carboxylate

[0124]

Embedded image In the same manner as in Example 1, the title compound was obtained.

Infrared absorption spectrum (KBr) cm ^-1 : 3243,
2984, 1760, 1706, 1548, 1450, 1374, 1270, 1074. Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 1.17-1.3
7 (9H, m), 1.39, 1.40 (3H, d × 2, J = 6.1 Hz), 1.59,
1.61 (3H, d × 2, J = 6.6 Hz), 2.07, (3H, s), 2.34, 2.4
1 (1H, dd × 2, J = 17.2, 5.9 Hz), 2.80 (1H, dd, J = 17.
2, 8.2 Hz), 3.23-3.32 (1H, m), 3.33-3.42 (2H, m),
3.78-3.87 (1H, m), 3.97-4.07 (1H, m), 4.15-4.24 (1
H, m), 4.85-4.98 (1H, m), 5.20-5.30 (1H, m), 5.97
(1H, brs), 6.84-6.98 (1H, m).

Example 8 1- (3-pentyloxycarbonyloxy) ethyl
(1R, 5S, 6S) -6-[(1R) -1-acetyloxyethyl] -1-methyl-2-[(4R) -2-oxo-4-pyrrolidinylthio] -1-carbapene-2- M-3-carboxylate

[0127]

Embedded image In the same manner as in Example 1, the title compound was obtained.

Infrared absorption spectrum (KBr) cm ^-1 : 3234,
2973, 1757, 1706, 1548, 1450, 1373, 1266, 1074. Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 0.83-0.9
7 (6H, m), 1.27 (3H, d, J = 7.2 Hz), 1.37 (3H, d, J =
(6.3 Hz), 1.51-1.71 (7H, m), 2.07, (3H, s), 2.32-2.4
6 (1H, m), 2.79 (1H, dd, J = 17.3, 8.0 Hz), 3.22-3.3
0 (1H, m), 3.31-3.40 (2H, m), 3.79-3.87 (1H, m),
3.98-4.07 (1H, m), 4.16-4.21 (1H, m), 4.56-4.68 (1
H, m), 5.20-5.28 (1H, m), 5.69 (1H, brs), 6.89 (1
H, q, J = 5.3 Hz).

Example 9 1- (Cyclopentyloxycarbonyloxy) ethyl
(1R, 5S, 6S) -6-[(1R) -1-acetyloxyethyl] -1-methyl-2-[(4R) -2-oxo-4-pyrrolidinylthio] -1-carbapene-2- M-3-carboxylate

[0130]

Embedded image In the same manner as in Example 1, the title compound was obtained.

Infrared absorption spectrum (KBr) cm ^-1 : 3252,
2972, 1756, 1706, 1548, 1448, 1372, 1267, 1075. Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 1.26, 1.
27 (3H, d × 2, J = 7.1Hz), 1.39, 1.40, (3H, d × 2, J =
6.4 Hz), 1.59, 1.61 (3H, d × 2, J = 6.2 Hz), 1.52-1.96
(8H, m), 2.07, (3H, s), 2.40, 2.42 (1H, dd × 2, J =
17.0, 5.7 Hz), 2.79 (1H, dd, J = 17.0, 8.2 Hz), 3.23
-3.32 (1H, m), 3.34 (1H, dd, J = 10.6, 5.2 Hz), 3.38
(1H, dd, J = 7.5, 2.8 Hz), 3.75-3.87 (1H, m), 3.98-
4.08 (1H, m), 4.17, 4.19 (1H, dd, J = 8.9, 2.8 Hz),
5.07-5.17 (1H, m), 5.20-5.30 (1H, m), 5.80 (1H, br
s), 6.84-6.92 (1H, m).

Example 10 Cyclohexyloxycarbonyloxymethyl (1
R, 5S, 6S) -6-[(1R) -1-acetyloxyethyl] -1-methyl-2-[(4R) -2-oxo-4-pyrrolidinylthio] -1-carbapen-2-em -3-carboxylate

[0133]

Embedded image In the same manner as in Example 1, the title compound was obtained.

Infrared absorption spectrum (KBr) cm ^-1 : 3389,
3251, 1765, 1741, 1706, 1545, 1484, 1453, 1419, 1
374, 1347, 1322, 1277, 1259, 1199, 1161. Ultraviolet absorption spectrum (EtOH) nm: 322.9. Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 1.20-1.5
8 (12H, m), 1.70-1.80 (2H, m), 1.88-1.98 (2H, m),
2.08 (3H, s), 2.40 (1H, dd, J = 17.2, 5.6 Hz), 2.80
(1H, dd, J = 17.3, 8.2 Hz), 3.23-3.43 (3H, m), 3.82
(1H, dd, J = 10.5, 7.9 Hz), 3.98-4.08 (2H, m), 4.19
(1H, dd, J = 9.2, 2.6 Hz), 4.63-4.72 (1H, m), 5.20-
5.31 (1H, m), 5.87, 5.92 (each 1H, d, J = 5.7 Hz).

Example 11 1- (Cyclohexyloxycarbonyloxy) ethyl
(1R, 5S, 6S) -6-[(1R) -1-acetyloxyethyl] -1-methyl-2-[(4R) -2-oxo-4-pyrrolidinylthio] -1-carbapene-2- M-3-carboxylate

[0136]

Embedded image In the same manner as in Example 1, the title compound was obtained.

Infrared absorption spectrum (KBr) cm ^-1 : 3369,
3251, 1780, 1747, 1706, 1548, 1486, 1451, 1374, 1
322, 1278, 1260, 1207. Ultraviolet absorption spectrum (EtOH) nm: 322.6. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ: 1.10-2.1
5 (19H, m), 2.07 (3H, s), 2.28-2.54 (1H, m), 2.80
(1H, dd, J = 17.1, 8.1 Hz), 3.15-3.43 (3H, m), 3.82
(1H, dd, J = 9.7, 8.4 Hz), 3.92-4.25 (2H, m), 4.57-
4.76 (1H, m), 5.17-5.33 (1H, m), 6.38 (1H, s), 6.8
8 (1H, q, J = 5.4 Hz).

Example 12 1- (Cyclohexyloxycarbonyloxy) ethyl
(1R, 5S, 6S) -6-[(1R) -1-propionyloxyethyl] -1-methyl-2-[(4R) -2-oxo-4-pyrrolidinylthio] -1-carbapene-2- M-3-carboxylate

[0139]

Embedded image Example 2 was repeated using propionic anhydride instead of acetic anhydride.
In the same manner as in 1, the title compound was obtained.

Infrared absorption spectrum (KBr) cm ^-1 : 3389,
3252, 1781, 1756, 1706, 1548, 1486, 1451, 1424, 1
377, 1362, 1323, 1278, 1261. Ultraviolet absorption spectrum (EtOH) nm: 322.6. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ: 1.15 (3
H, t, J = 7.6 Hz), 1.20-2.10 (19H, m), 2.23-2.49 (3
H, m), 2.79 (1H, dd, J = 17.2, 8.0 Hz), 3.16-3.44 (3
H, m), 3.81 (1H, dd, J = 10.2, 8.2 Hz), 3.92-4.27 (2
H, m), 4.56-4.73 (1H, m), 5.17-5.37 (1H, m), 6.13
(1H, s), 6.88 (1H, q, J = 5.4 Hz).

Example 13 1- (Cyclohexyloxycarbonyloxy) ethyl
(1R, 5S, 6S) -6-[(1R) -1-butyryloxyethyl] -1-methyl-2-[(4R) -2-oxo-4-pyrrolidinylthio] -1-carbapene-2 -M-3-carboxylate

[0142]

Embedded image The title compound was obtained in the same manner as in Example 1 except that butyric anhydride was used instead of acetic anhydride.

Infrared absorption spectrum (KBr) cm ^-1 : 3371,
3240, 1781, 1756, 1707, 1548, 1486, 1451, 1419, 1
377, 1361, 1323, 1279, 1260. Ultraviolet absorption spectrum (EtOH) nm: 321.1. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ: 0.96 (3
H, t, J = 7.4 Hz), 1.12-2.08 (21H, m), 2.30 (2H, t,
J = 7.4 Hz), 2.40 (1H, dt, J = 17.2, 4.7 Hz), 2.79 (1
H, dd, J = 17.2, 8.2 Hz), 3.18-3.43 (3H, m), 3.81 (1
H, t, J = 9.4 Hz), 3.94-4.24 (2H, m), 4.58-4.76 (1H,
m), 5.20-5.34 (1H, m), 5.85 (1H, s), 6.88 (1H, q, J
= 5.3 Hz).

Example 14 1- (Isopropoxycarbonyloxy) ethyl (1
R, 5S, 6S) -2-[(S) -1acetyl-5-oxopyrrolidin-3-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2- M-3-carboxyle
G

[0145]

Embedded image (1) 1- (isopropoxycarbonyloxy) ethyl (1R, 5S, 6S) -6-[(1R)-
1-hydroxyethyl] -1-methyl-2-[(4R) -2-oxo
4-pyrrolidinylthio] -1-carbapene-2-em-3-carboxylate (3.30 g), imidazole (0.64 g) and N, N-dimethylformamide (33 ml) were mixed with triethyl chloride silane (1.5 m).
l was added dropwise and stirred for 1 hour. Ethyl acetate was added to the reaction mixture, washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (50% ethyl acetate / hexane, ethyl acetate) to give a colorless amorphous 1- (isopropoxycarbonyloxy) ethyl (1R, 5S, 6S) -1.
-Methyl-2-[(4R) -2-oxo-4-pyrrolidinylthio]-
2.65 g of 6-[(1R) -1-triethylsilyloxyethyl] -1-carbapen-2-em-3-carboxylate was obtained.

Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ )
δ: 0.61 (6H, q, J = 8.0 Hz), 0.96 (9H, t, J = 8.0 Hz),
1.22-1.37 (12H, m), 1.55-1.62 (4H, m), 2.42 (1H,
dt, J = 17.2, 5.7 Hz), 2.79 (1H, dd, J = 17.2, 8.1 Hz),
3.16-3.24 (1H, m), 3.34 (1H, dd, J = 10.3, 5.3 Hz),
3.77-3.84 (1H, m), 3.97-4.08 (1H, m), 4.16-4.27 (2
H, m), 4.86-4.96 (1H, m), 5.74 (1H, s), 6.83 6.91
(1H, m). (2) To a solution of 1.36 g of the compound obtained in Example 14- (1) and 436 mg of 4-dimethylaminopyridine in 15 ml of anhydrous methylene chloride was added 0.34 ml of acetic anhydride under ice-cooling with flowing nitrogen gas. Was added dropwise and stirred for 4 hours. Ethyl acetate was added to the reaction mixture, washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (50% ethyl acetate / hexane) to give a colorless oil.
-(Isopropoxycarbonyloxy) ethyl (1
R, 5S, 6S) -2-[(S) 1-Acetyl-5-oxopyrrolidin-3-ylthio] -1-methyl-6-[(1R) -1-triethylsilyloxyethyl] -1-carbapene- 1.15 g of 2-M-3-carboxylate was obtained.

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ )
δ: 0.61 (6H, q, J = 7.9 Hz), 0.96 (9H, t, J = 7.9 Hz),
1.18-1.38 (12H, m), 1.52-1.64 (4H, m), 2.52 (3H,
s), 2.61-2.74 (1H, m), 2.99-3.26 (3H, m), 3.73-3.8
3 (1H, m), 3.88-4.02 (1H, m), 4.07-4.30 (2H, m),
4.83-5.00 (1H, m), 6.82-6.91 (1H, m). (3) Glacial acetic acid in 13.9 ml of tetrabutylammonium fluoride (1M tetrahydrofuran solution) in 17 ml of tetrahydrofuran under a stream of nitrogen and ice cooling After 2.4 ml was added dropwise, a solution of 1.70 g of the compound obtained in Example 14- (2) in 30 ml of tetrahydrofuran was added dropwise, and the mixture was stirred under ice-cooling for 10 minutes, and further stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture,
The extract was washed with water, saturated sodium bicarbonate, water and saturated saline in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate) to obtain 1.19 g of a pale yellow amorphous target compound.

Infrared absorption spectrum (KBr) cm ^-1 : 3496,
1754, 1704, 1549, 1468, 1452, 1373, 1276, 1209. Ultraviolet absorption spectrum (EtOH) nm: 210.6, 321.4. Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 1.22-1.4
1 (12H, m), 1.54-1.66 (4H, m), 2.52 (3H, s), 2.67
(1H, dt, J = 17.8, 5.0 Hz), 3.07 (1H, ddd, J = 17.9,
7.7, 2.3 Hz), 3.19-3.33 (2H, m), 3.75-3.84 (1H,
m), 3.90-4.01 (1H, m), 4.08-4.30 (3H, m), 4.83-4.9
8 (1H, m), 6.83-6.93 (1H, m).

Example 15 1- (Cyclohexyloxycarbonyloxy) ethyl
(1R, 5S, 6S) -2-[(S) -1acetyl-5-oxopyrrolidin-3-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2 -M-3-carboxylate

[0150]

Embedded image (1) 1- (Cyclohexyloxycarbonyloxy) ethyl (1R, 5S, 6S) -6-[(1
R) -1-Hydroxyethyl] -1-methyl-2-[(4R) -2-
Oxo-4-pyrrolidinylthio] -1-carbapene-2-em-3-
2.500 g of carboxylate, 0.51 g of imidazole and N, N-
1.01 ml of triethyl chloride silane was added dropwise to a 50 ml solution of dimethylformamide, and the mixture was stirred for 1 hour. The same treatment as in Example 14- (1) was carried out to give a colorless amorphous 1- (cyclohexyloxycarbonyloxy) ethyl (1R, 5S,
6S) -1-methyl-2-[(4R) -2-oxo-4-pyrrolidinylthio] -6-[(1R) -1-triethylsilyloxyethyl] -1-carbapen-2-em-3- 1.965 carboxylate
g obtained.

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ )
δ: 0.61 (6H, q, J = 7.9 Hz), 0.96 (9H, t, J = 7.9 Hz),
1.13-2.09 (20H, m), 2.34-2.49 (1H, m), 2.79 (1H, m
dd, J = 17.2, 8.1 Hz), 3.12-3.28 (1H, m), 3.34 (1H, d
d, J = 10.4, 5.2 Hz), 3.24-3.87 (1H, m), 3.96-4.31
(3H, m), 4.56-4.73 (1H, m), 5.80 (1H, s), 6.87 (1H,
q, J = 5.2 Hz). (2) Acetic anhydride was added to a solution of 1.965 g of the compound obtained in Example 15- (1) and 0.41 g of 4-dimethylaminopyridine in 40 ml of anhydrous methylene chloride under flowing ice and cooling with nitrogen. 0.46 ml is added dropwise.
Stirred for hours. By treating in the same manner as in Example 14- (2), colorless amorphous 1- (cyclohexyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[(S) 1-
Acetyl-5-oxopyrrolidin-3-ylthio] -1-methyl-
1.685 g of 6-[(1R) -1-triethylsilyloxyethyl] -1-carbapene-2-em-3-carboxylate was obtained.

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ )
δ: 0.61 (6H, q, J = 7.9 Hz), 0.96 (9H, t, J = 7.9 Hz),
1.10-2.07 (20H, m), 2.51 (3H, s), 2.61-2.74 (1H,
m), 2.99-3.27 (3H, m), 3.73-3.85 (1H, m), 3.88-4.03
(1H, m), 4.08-4.30 (3H, m), 4.57-4.73 (1H, m), 6.8
0-6.93 (1H, m). (3) Under a nitrogen stream and ice cooling, 2.7 ml of glacial acetic acid was added dropwise to a solution of 15.6 ml of tetrabutylammonium fluoride (1M solution in tetrahydrofuran) in 20 ml of tetrahydrofuran. A solution of 2.040 g of the compound obtained in 2) in 20 ml of tetrahydrofuran was added dropwise, and the mixture was stirred under ice-cooling for 10 minutes, and further stirred at room temperature for 1 hour. By treating in the same manner as in Example 14- (3), 1.548 g of a colorless amorphous target compound was obtained.

Infrared absorption spectrum (KBr) cm ^-1 : 3497,
1752, 1704, 1549, 1451, 1372, 1280, 1261, 1208, 1
135, 1075. Ultraviolet absorption spectrum (EtOH) nm: 211.2, 322.0. Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 1.16-2.0
5 (20H, m), 2.51 (3H, s), 2.67 (1H, dt, J = 17.8, 4.
1 Hz), 3.07 (1H, dd, J = 17.8, 8.2 Hz), 3.17-3.33 (2
H, m), 3.73-3.87 (1H, m), 3.89-4.03 (1H, m), 4.08-
4.32 (3H, m), 4.57-4.74 (1H, m), 6.83-6.94 (1H,
m).

Example 16 1- (isopropoxycarbonyloxy) ethyl (1
R, 5S, 6S) -6-[(1R) -1-acetyloxyethyl] -2-[(S) -1 acetyl-5-oxopyrrolidin-3-ylthio] -1-methyl-1-carbapene-2 -M-3-carboxylate

[0155]

Embedded image 1- (isopropoxycarbonyloxy) ethyl (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-[(4R) -2- Oxo-4
-Pyrrolidinylthio] -1-carbapene-2-em-3-carboxylate 18.98 g of 4-dimethylaminopyridine 4.02 g
To a methylene chloride (150 ml) solution was added acetic anhydride (3.8 ml), and the mixture was stirred under ice cooling for 2 hours and at room temperature for 2 hours, and then concentrated under reduced pressure. Ethyl acetate was added to the residue, and water, saturated potassium hydrogen sulfate, water,
The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate, 20% methanol / ethyl acetate) to give a pale yellow amorphous target compound in 9.
93 g were obtained.

Infrared absorption spectrum (KBr) cm ^-1 : 1781,
1747, 1703, 1551, 1452, 1416, 1373, 1339, 1272, 1
242, 1210. Ultraviolet absorption spectrum (EtOH) nm: 210.9, 321.4. Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ: 1.22-1.4
4 (12H, m), 1.53-1.66 (3H, m), 2.07 (3H, s), 2.51
(3H, s), 2.66 (1H, dt, J = 17.9, 5.2 Hz), 3.07 (1H,
ddd, J = 17.9, 7.7, 2.1 Hz), 3.18-3.28 (1H, m), 3.3
6-3.43 (1H, m), 3.75-3.83 (1H, m), 3.90-4.00 (1H,
m) .4.08-4.23 (2H, m), 4.84-4.97 (1H, m), 5.18-5.3
0 (1H, m), 6.84-6.92 (1H, m).

Example 17 1- (isopropoxycarbonyloxy) ethyl (1
R, 5S, 6S) -6-[(1R) -1- (glycyloxy)
Ethyl] -2-[(4R) -2-oxo-4-pyrrolidinylthio]
-1-methyl-1-carbapene-2-em-3-carboxylate
Hydrochloride

[0158]

Embedded image 1- (isopropoxycarbonyloxy) ethyl (1
R, 5S, 6S) -6-[(1R) -1-hydroxyethyl]
1-methyl-2-[(4R) -2-oxo-4-pyrrolidinylthio] -1-carbapen-2-em-3-carboxylate 1.83 g
Of N- (4-nitrobenzyloxycarbonyl) glycine (1.53 g) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.15 g) in 4-N, N-dimethylformamide solution (40 ml) 0.24 g of pyridine was added and stirred for 1 hour. Ethyl acetate (500 ml) was added to the reaction mixture, and the organic layer was washed with diluted hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline in this order, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the effluent was concentrated under reduced pressure. The obtained residue was dissolved in 25 ml of tetrahydrofuran, equimolar hydrochloric acid was added, deprotection was carried out by hydrogenation with a 10% palladium-carbon catalyst, the pH was adjusted with dilute hydrochloric acid, and the mixture was purified by reverse phase column chromatography. Thus, the title compound was obtained.

Ultraviolet absorption spectrum (EtOH) nm: 322.0. Nuclear magnetic resonance spectrum (400 MHz, H ₂ O) δ: 1.22-1.44
(12H, m), 1.22-1.48 (12H, m), 1.59, 1.61 (3H, d ×
2, J = 5.7 Hz), 2.31-2.45 (1H, m), 2.97 (1H, dd, J = 1
7.6, 7.8 Hz), 3.30-3.45 (2H, m), 3.72-3.78 (1H,
m), 3.89 (1H, dd, J = 11.5, 7.6 Hz). 3.95, 3.98 (1H,
d × 2, J = 17.5 Hz), 4.03, 4.06 (1H, d × 2, J = 17.5 H
z), 4.08-4.14 (1H, m), 4.32-4.37 (1H, m), 5.03-5.1
8 (1H, m), 5.47-5.55 (1H, m), 6.84-6.92 (1H, m).

Test Example Oral Absorption Test The compound of Example 7 of the present invention and the closest prior art document, The Journal of Antibiotics 50 (5), 429-439
(1997) was orally administered to dogs, and the concentration of the active substance in plasma was measured by high performance liquid chromatography, and the absolute bioavailability (B
A) was compared.

(1) Sample Compound of Example 7 of the present invention: 1- (isopropoxycarbonyloxy) ethyl (1R, 5S, 6S) -6
[(1R) -1- (acetoxyethyl)]-1-methyl-2-[(4R) -2-oxo-4-pyrrolidinylthio] -1-carbapen-2-em-3-carboxylate Comparative compound ( The Journal of Antibiotics 50 (5), 429
-439 (1997) Compound 14): 1- (isopropoxycarbonyloxy) ethyl (1R, 5S,
6S) -6-[(1R) -1-hydroxyethyl] -1
-Methyl-2-[(4R) -2-oxo-4-pyrrolidinylthio] -1-carbapen-2-em-3-carboxylate Active form: (1R, 5S, 6S) -6-[(1R) -1
-Hydroxyethyl] -1-methyl-2-[(4R)-
2-oxo-4-pyrrolidinylthio] -1-carbapen-2-em-3-carboxylic acid (2) Administration of specimen 10 mg titer / kg of specimen (ester compound) was propylene glycol-polysorbate 80-water 5 mg / kg each.
0:15:35 (v: v: v) Dissolved in a mixture, fasted overnight, orally administered to male beagle dogs (n = 3, body weight 10-14 kg) administered ranitidine (2.5 mg / kg) intramuscularly Was administered.

(3) Blood collection and measurement of plasma active substance concentration After administration of the sample, blood was collected every 0.25, 0.5, 1, 1.5, 2, 3, 4, and 6 hours, and the obtained blood was centrifuged. Plasma was obtained, and the concentration of the active substance in the plasma was measured by high performance liquid chromatography.

(4) Calculation of bioavailability The measured values in plasma concentration were plotted against the time after administration of the sample, and the area under the plasma concentration-time curve (AUC) was determined.
On the other hand, AUC when the active substance was intravenously administered to dogs was determined. BA (%) = (AUC at oral administration / A at intravenous administration)
The absolute bioavailability (BA) was calculated using UC) x100 and is shown in Table 2 together with the separately calculated pharmacological parameters.

[0164]

Table 2--------------------Specimen Cmax Tmax AUC _0-6 BA (μg / ml) (hr) (μg-hr / ml) (%) −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− --- Compound of Example 5.63 1.0 14.96 58.4 Comparative compound 4.53 0.8 10.92 42.6 --------------------------- In Table 2, Cmax is the maximum plasma concentration, Tmax is the time when Cmax was given, and AUC _0-6 is 0 to 6 hours after administration of the sample. AUC is shown.

The compound of Example 7 of the present invention showed excellent oral absorption and pharmacokinetics upon oral administration as compared to the comparative compound described in the closest prior art literature. The powders of the above formula are mixed, wet-granulated using corn starch paste, dried, and then tableted with a tableting machine to make one tablet of 200 mg. The tablets can be sugar-coated as needed.

[0166]

According to the present invention, the carbapenem ester derivative having the above general formula (I) or a pharmaceutically acceptable salt thereof exhibits excellent absorption and sustained pharmacokinetics when administered to a living body. Therefore, the compound having the general formula (I) or a pharmacologically acceptable salt thereof according to the present invention is effective for a drug (particularly an antibacterial agent) for treating or preventing (preferably treating) bacterial infections caused by various pathogenic bacteria. Useful as an ingredient.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07D 519/00 311 C07D 519/00 311 (72) Inventor Osamu Sugano 1-2-2 Hiromachi, Shinagawa-ku, Tokyo No. 58 Inside Sankyo Co., Ltd. (72) Inventor Akihiko Nakagawa 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Toshio Terao 1-2-58 Hiromachi, Shinagawa-ku, Tokyo F term in Sankyo Co., Ltd. (reference) 4C050 KA17 KA18 KB05 KB13 KB16 4C072 MM01 UU01 4C086 AA02 AA03 CC08 NA11 NA12 NA14 ZB35

Claims (1)

[Claims] 1. A compound of the general formula (I) Ｒ In the formula, R ¹ represents the following general formula (IIa), (IIb), (IIc) or (I
Id) [Wherein, R ⁴ and R ⁵ represent a hydrogen atom, a C1-C4 alkyl group, a C1-C4 alkanoyl group, a C1-C4 alkoxy-carbonyl group, or 5- (C1-C4 alkyl)
R ² represents a hydrogen atom, a C 1 -C 10 alkoxy-carbonyloxy-C 1 -C 4 alkyl group, a C 3 -C 7 cyclo group, which represents a 2-oxo-1,3-dioxolen-4-ylmethyl group. Alkyl-oxycarbonyloxy-C1-C4 alkyl group, C3-C7 cycloalkyl-C1-C4 alkyl-
Oxycarbonyloxy-C1-C4 alkyl group, C2
A -C10 alkanoyloxy-C1-C4 alkyl group,
C3-C7 cycloalkyl-carbonyloxy-C1-
C4 alkyl group, [1- (C1-C4 alkyl) -C3
-C7 cycloalkyl] carbonyloxy-C1-C4
Alkyl group, C3-C7 cycloalkyl-C2-C4 alkanoyloxy-C1-C4 alkyl group, phthalidyl group, or 5- (C1-C4 alkyl or phenyl) -2-oxo-1,3-dioxolen-4-ylmethyl R ³ represents a C1-C20 alkanoyl group or a C1-C20 alkanoyl group having a substituent (the substituent is an amino group,
Represents an amino group, a hydroxyl group or a phenyl group substituted with 1-C4 alkyl), a C6-C10 aryl-carbonyl group, a C1-C20 alkoxy-carbonyl group, or 5- (C1-C4 alkyl) -2- Oxo-1,
It represents a 3-dioxolen-4-ylmethyl group. A carbapenem ester derivative having｝ or a pharmacologically acceptable salt thereof.