JP2643754B2 - Antibacterial agent - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel antibacterial agent.

[0002]

BACKGROUND OF THE INVENTION Thienamycin, a type of carbapenem derivative, has an excellent antibacterial activity against a wide range of pathogenic bacteria including Gram-positive and Gram-negative bacteria, and in particular, has an antibacterial activity against cephem-resistant bacteria. It is attracting attention. However, thienamycin has the drawbacks that it is degraded by dehydropeptidase I present in the human body, loses its activity, and has low oral absorbability. For this reason, studies using carbapenem derivatives, which have better antibacterial activity against various microorganisms, are stable against dehydropeptidase I, and have high oral absorbability, have been conducted.

For example, Japanese Patent Application Laid-Open No. 2-49783 discloses a 6- (1-hydroxyethyl) -1-methylcarbapene-2-m-substituted 2-position substituted by a 2-oxopyrrolidin-4-ylthio group. 3-carboxylic acids are disclosed.

However, a compound having a 2-thioxopyrrolidin-4-ylthio group at the 2-position of the 1-methylcarbapenem skeleton has not been known.

[0005]

SUMMARY OF THE INVENTION The present invention relates to a 2-thioxopyrrolidine-4 at the 2-position of the 1-methylcarbapenem skeleton.
By introducing an -ylthio group, the novel 1 which has an even more excellent antibacterial activity as compared with a conventionally known carbapenem derivative, exhibits excellent stability against dehydropeptidase I, and has a high oral absorbability. -An antibacterial agent comprising a methylcarbapenem derivative as an active ingredient.

[0006]

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

[0007]

Embedded image

(Wherein, R ¹ represents a hydrogen atom or a hydroxyl-protecting group, R ² represents a hydrogen atom or an ester residue, and R ³ represents a hydrogen atom, a lower alkyl group, a lower alkoxy-lower alkyl group or a di-lower group. An alkylamino lower alkyl group) or a pharmacologically acceptable salt thereof as an active ingredient.

In the 1-methylcarbapenem derivative [I], which is an active ingredient of the present invention, specific examples of the hydroxyl-protecting group represented by R ¹ include a lower alkoxycarbonyl group, a halogeno-lower alkoxycarbonyl group, and a substituted or unsubstituted group. Phenyl lower alkyl group (for example, benzyl group optionally substituted with nitro group or lower alkoxy group), tri-lower alkylsilyl group, substituted or unsubstituted phenyl lower alkoxycarbonyl group (for example, substituted with nitro group or lower alkoxy group) A benzyloxycarbonyl group which may be substituted).

Examples of the ester residue represented by R ² include an ester residue which is metabolized and hydrolyzed in a living body, or an ester residue which can serve as a protecting group for a carboxyl group.

The ester residues which are metabolized and hydrolyzed in vivo include those of the formulas -A-OCOR ⁴ and -A-OCO ₂
R ⁴ or —A—O—R ⁴ (wherein A represents a lower alkylene group, R ⁴ represents a lower alkyl group, a cycloalkyl group, a lower alkenoyl group, a lower alkoxy lower alkyl group, and a lower alkanoyloxy lower alkyl group. ).

Specific examples of such a group include, for example, lower alkanoyloxy lower alkyl, cycloalkylcarbonyloxy lower alkyl, lower alkenoyloxy lower alkyl, lower alkoxy lower alkanoyloxy lower alkyl, lower alkanoyloxy lower alkoxy. Lower alkyl groups, lower alkoxy lower alkyl groups, lower alkoxy lower alkoxy lower alkyl groups, lower alkoxycarbonyloxy lower alkyl groups, lower alkoxy lower alkoxycarbonyloxy lower alkyl groups.

On the other hand, examples of the ester residue which can serve as a protecting group for a carboxyl group include a lower alkyl group, a lower alkenyl group, a halogeno lower alkyl group, a nitrobenzyl group and a lower alkoxybenzhydryl group.

Among these 1-methylcarbapenem derivatives [I], R ¹ is preferably a hydrogen atom and R ² is a hydrogen atom or an ester residue which is metabolized and hydrolyzed in vivo. And compounds in which R ³ is a hydrogen atom or a lower alkyl group.

The 1-methylcarbapenem derivative [I], which is the active ingredient of the present invention, has various isomers based on its asymmetric carbon. The present invention relates to any one of these isomers or a mixture thereof. Is also included. However, the 1, 5, and 6 positions of the carbapenem skeleton are in R, S and S configurations, respectively, the 1 position of the 6-position substituent is R configuration, and the substitution of the pyrrolidine ring is S or R configuration. Compounds are therapeutically preferred.

In the present invention, preferred examples of the lower alkyl group, the lower alkylene group and the lower alkoxy group include those having 1 to 6 carbon atoms, particularly those having 1 to 4 carbon atoms, and the lower alkanoyl group and the lower alkenyl group include Formulas 2 to 8, especially those having 2 to 6 carbon atoms, and further as lower alkenoyl groups and cycloalkyl groups,
8, especially those having 3 to 6 carbon atoms.

The 1-methylcarbapenem derivative [I], which is an active ingredient of the present invention, can be used in a free form or a pharmaceutically acceptable salt thereof for pharmaceutical use. Pharmaceutically acceptable salts include, for example, non-toxic metal salts such as sodium, potassium, calcium, magnesium, and aluminum salts; trialkylamines (eg, triethylamine), pyridine, ethanolamine, triethanolamine And salts with non-toxic amines such as dicyclohexylamine; addition salts with basic amino acids such as lysine and arginine. The salt of the compound may be in the form of a salt with a resin formed of, for example, a polystyrene resin containing an amino group or a quaternary amino group.

The dose of the 1-methylcarbapenem derivative [I] or a pharmacologically acceptable salt thereof varies depending on the administration method, age, weight, condition of the patient, degree of the disease and the like. 0.002 to 0.04 g / kg,
Preferably about 0.005 to 0.01 g / kg is suitable.

The 1-methylcarbapenem derivative [I] or a pharmaceutically acceptable salt thereof can be administered orally or parenterally (eg, intravenously, intramuscularly, subcutaneously).

The dosage form for oral administration may be a solid preparation such as tablets, granules, capsules and powders, or a liquid preparation such as a solution or a suspension. It can be used as a pharmaceutical formulation together with a pharmaceutical carrier. Such pharmaceutical carriers include, for example, binders (syrup, gum arabic, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone, etc.), excipients (lactose, sugar,
Corn starch, potassium phosphate, sorbite, glycine, etc.), lubricants (magnesium stearate, talc,
Any of conventional materials such as polyethylene glycol, silica and the like, disintegrant (potato starch and the like) or wetting agent (sodium lauryl sulfate and the like) can be used.

On the other hand, in the case of parenteral administration, it is preferable to prepare an injection or drip injection using, for example, distilled water for injection, physiological saline, aqueous glucose solution or the like.

The 1-methylcarbapenem derivative [I], which is an active ingredient of the present invention, has the general formula [II]

[0023]

Embedded image

(Wherein the symbols have the same meanings as described above) and a reactive derivative at the 2-oxo group of the ketone compound represented by the formula [III]

[0025]

Embedded image

(Wherein the symbols have the same meanings as described above), and can be produced by reacting with a mercaptan compound or a salt thereof.

As the reactive derivative at the 2-oxo group of the ketone compound [II], any of the conventional derivatives can be used. As such a reactive derivative, for example, the general formula [II-a]

[0028]

Embedded image

Wherein X is a diphenylphosphoryl group,
Di-lower alkyl group-substituted phenylphosphoryl group, di-lower alkylphosphoryl group, lower alkanesulfonyl group, phenylsulfonyl group or lower alkyl group-substituted phenylsulfonyl group, and reactive derivatives thereof, and ketone compound (II) and corresponding phosphoryl halide Alternatively, it can be obtained by reacting with a sulfonic acid compound or the like in the presence or absence of a base.

On the other hand, as the salt of the mercaptan compound [III], for example, an alkali metal salt, a tri-lower alkylammonium salt or the like can be used as appropriate.

The reaction between the reactive derivative of the ketone compound [II] and the mercaptan compound [III] or a salt thereof can be carried out in the presence or absence of a base.

In the compound [I] thus obtained,
When R ¹ is a protecting group for a hydroxyl group or / and R ² is an ester residue, the protecting group or / and the ester residue are removed to obtain a compound represented by the general formula [Ia]

[0033]

Embedded image

Wherein the symbols have the same meanings as described above, or a salt thereof.
Removal of the protecting group or ester residue can be carried out according to a conventional method.

Furthermore, the compound [I-
a] is a compound represented by the general formula [Ib]

[0036]

Embedded image

(Wherein, R ²¹ represents an ester residue, and other symbols have the same meanings as described above).

Experimental Example 1 [Antibacterial activity (minimum inhibitory concentration)] (Sample compound) (1R, 5S, 6S) -2-[(4R)
-Pyrrolidin-2-thion-4-ylthio] -6
[(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid potassium salt (Method) Minimum growth inhibitory concentration (MI.
C. , Μg / ml) was added to the Sensitive Disk Medium-N (Sen
Sitency Disc Agar-N) (SD
A; Nissui Co., Ltd.) was used and measured by an agar plate dilution method (Japan Chemotherapy Society standard method).

(Results) The results are shown in Table 1 below.

[0040]

[Table 1]

Experimental Example 2 [Therapeutic Effect on Intraperitoneal Infection in Mice] (Sample Compound) (1R, 5S, 6S) -2-[(4R)
-Pyrrolidin-2-thion-4-ylthio] -6
[(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid / isobutyryloxymethyl ester (Method) Staphylococcus aureus Smith (S
taphylococcus aureus Smit
h) was cultured at 37 ° C. for 16 hours, suspended in a 6% mucin solution, and inoculated intraperitoneally into mice [2.8 × 10 ⁵ cells]
/ Mouse (136 × LD ₅₀ )]. The test compound was dissolved in a 20% dimethyl sulfoxide solution, orally administered to mice 1 hour after inoculation, and the ED ₅₀ value was calculated from the number of survived mice after 5 days by the probit method.

(Results) The ED ₅₀ value of the test compound was
It was 0.46 mg / kg.

Production Example 1 (1) (1R, 5R, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-oxo-carbapenam-3-carboxylic acid 4-nitrobenzyl ester 7.
6 g is dissolved in 53 ml of anhydrous acetonitrile, and 2.9 g of diisopropylethylamine and 6.1 g of diphenylphosphoryl chloride are sequentially added dropwise at 0 ° C. or lower under a nitrogen stream. After stirring at the same temperature for 30 minutes, the reaction mixture [(1R, 5
R, 6S) -6-((1R) -1-hydroxyethyl]
2.5-g of (4S) -4-mercaptopyrrolidine-2-thione and diisopropyl A solution of 2.9 g of ethylamine in 53 ml of anhydrous acetonitrile was added to -15
Add dropwise below ° C. After stirring at the same temperature for 1.5 hours, 53 ml of water was added to the reaction mixture, and acetonitrile was distilled off under reduced pressure. The residue was extracted with ethyl acetate, washed and dried, and the solvent was distilled off under reduced pressure. Purification by silica gel column chromatography (solvent; chloroform: ethanol = 20: 1) gives (1R, 5S, 6S) -2-
[(4S) -Pyrrolidin-2-thion-4-ylthio]
4.7 g of 6-[(1R) -1-hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylic acid 4-nitrobenzyl ester are obtained as an amorphous powder.

NMR (CDCl ₃ ) δ ppm: 1.29 (3H, d), 1.36 (3
H, d), 2.90 (1H, dd), 3.23-3.34 (2H, m), 3.61-3.71 (2H, m),
4.00-4.32 (5H, m), 5.23,5.49 (2H, d), 7.65,8.23 (4H, d), 7.
83 (1H, br, s) (2) To a mixture of 0.5 g of this product, 0.105 g of potassium hydrogen carbonate, 10 ml of tetrahydrofuran and 10 ml of ethanol, 1 g of 10% palladium-carbon was added under a nitrogen stream, and the mixture was heated at room temperature and normal pressure. Hydrogenate for hours. After removing the catalyst by filtration, the organic solvent is distilled off under reduced pressure, and the aqueous layer is washed with ethyl acetate. After evaporating the aqueous layer under reduced pressure, the residue was subjected to nonionic adsorption resin (CHP-2).
(1R, 5S, 6S) -2-[(4
S) -Pyrrolidin-2-thion-4-ylthio] -6
[(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid potassium salt 0.1
1 g is obtained as an amorphous powder.

NMR (D ₂ O) δ ppm: 1.20 (3H, d), 1.28 (3
H, d), 2.84 (1H, dd), 3.24-3.47 (3H, m), 3.62-3.72 (1H, m),
4.08-4.27 (4H, m) Production Example 2 (1) Production was performed except that 1.1 g of (4R) -4-mercaptopyrrolidine-2-thione was used in place of (4S) -4-mercaptopyrrolidine-2-thione. By processing in the same manner as in Example 1- (1), (1R, 5S, 6S) -2-
[(4R) -Pyrrolidin-2-thion-4-ylthio]
1.8 g of -6-[(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid · 4-nitrobenzyl ester are obtained as colorless needles.

M. p. 168-170 ° C NMR (DMSO) δ ppm: 1.15 (6H, d), 2.74 (1H, dd), 3.30-3.51
(4H, m), 3.97-4.31 (4H, m), 5.08 (1H, d), 5.29,5.47 (2H, d),
7.70,8.24 (4H, d), 10.39 (1H, br, s) (2) 0.5g of this product was treated in the same manner as in Production Example 1- (2) to give (1R, 5S, 6S) -2 -[(4R) -pyrrolidin-2-thion-4-ylthio] -6-[(1
R) -1-Hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid potassium salt 0.12 g is obtained as an amorphous powder.

NMR (D ₂ O) δ ppm: 1.20 (3H, d), 1.29 (3
H, d), 2.94 (1H, dd), 3.28-3.67 (4H, m), 4.06-4.27 (4H, m) Production Example 3 (1R, 5S, 6S) -2-[(4R) -pyrrolidine-
2-Thion-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methylcarbapen-2-M-
To a suspension of 0.34 g of potassium 3-carboxylate in 3 ml of N, N-dimethylformamide was added 0.12 g of potassium carbonate.
g, and 0.27 g of isobutyryloxymethyl iodide is added dropwise under ice-cooling. After stirring at the same temperature for 30 minutes, 10 ml of ethyl acetate was added to the reaction mixture, washed, the organic layer was dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (solvent / chloroform: ethanol = 20: 1), and crystallized from isopropyl ether and ethyl acetate to give (1R, 5
S, 6S) -2-[(4R) -Pyrrolidin-2-thion-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylic acid Obtaining 0.12 g of isobutyryloxymethyl ester as colorless needles.

M. p. 158-159 ° C Production Examples 4 to 8 (1R, 5S, 6S) -2-[(4R) -pyrrolidine-
2-Thion-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methylcarbapen-2-M-
By treating in the same manner as in Production Example 3 using potassium 3-carboxylate and various alkanoyloxymethyl iodides, ester compounds shown in Table 2 below are obtained.

[0049]

[Table 2]

Production Examples 9 to 28 (1R, 5S, 6S) -2-[(4S) -pyrrolidine-
2-Thion-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methylcarbapen-2-M-
The same treatment as in Production Example 3 was carried out using 3-carboxylic acid / potassium salt and various substituted methyl iodides or 1-substituted ethyl iodides to obtain ester compounds shown in Table 3 below.

[0051]

[Table 3]

[0052]

[Table 4]

[0053]

[Table 5]

[0054]

[Table 6]

Production Example 29 (1) (1R, 5R, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-oxo-carbapenam-3-carboxylic acid 4-nitrobenzyl ester 2
5.2 g was dissolved in 173 ml of anhydrous acetonitrile, and 13 ml of diisopropylethylamine and 15.5 ml of diphenylphosphoryl chloride were sequentially added at 0 ° C. or lower under a nitrogen stream. After stirring at the same temperature for 30 minutes, (4R) was added to the reaction mixture.
A solution of 13 g of -N-methyl-4-mercaptopyrrolidine-2-thione and 11.5 g of diisopropylethylamine in 173 ml of anhydrous acetonitrile is added dropwise at -5 ° C or lower. After stirring at 0 ° C. for 1.5 hours, the reaction mixture is added to 1 liter of phosphate buffer (pH 7.0). The precipitated crystals were collected by filtration, dissolved in a mixed solution of 2 liters of chloroform and 1 liter of tetrahydrofuran, washed, dried, concentrated under reduced pressure, ether was added, and the precipitated crystals were collected by filtration.
(1R, 5S, 6S) -2-[(4R) -N-methylpyrrolidin-2-thion-4-ylthio] -6-[(1
R) -1-Hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylic acid · 4-nitrobenzyl ester 23.5 g are obtained as colorless needles.

M. p. 157-158 ° C (2) To a mixture of 6 g of this product, 250 ml of tetrahydrofuran and 250 ml of ethanol, 1.03 g of sodium hydrogen carbonate was added.
g of 250 ml of an aqueous solution, and 22.8 g of 10% palladium-carbon (water content 52%) under a nitrogen stream.
Hydrogenate at room temperature and normal pressure for 1.5 hours. After removing the catalyst by filtration, the organic solvent is distilled off under reduced pressure, and the aqueous layer is washed with ethyl acetate. The aqueous layer was treated with activated carbon, filtered, the filtrate was concentrated under reduced pressure, ethanol was added, and the crystals were collected by filtration to obtain (1R,
5S, 6S) -2-[(4R) -N-methylpyrrolidin-2-thion-4-ylthio] -6-[(1R) -1-
There are obtained 3.2 g of hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid sodium salt as colorless needles.

M. p. 170-180 ° C (decomposition) Production Example 30 (1R, 5S, 6S) -2-[(4R) -N-methylpyrrolidin-2-thion-4-ylthio] -6-[(1
R) -1-Hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid sodium salt (400 mg) is suspended in N, N-dimethylformamide (5 ml), and potassium carbonate (146 mg) is added. 275 mg of acetoxymethyl iodide was added to the mixture at 5 to 7 ° C, and 1
Stir for hours. The reaction solution was added to a phosphate buffer (pH 7.0)
, The product was extracted with ethyl acetate, and the organic layer was washed.
After drying, concentrate under reduced pressure. The residue was purified by silica gel column chromatography (solvent / chloroform-chloroform: ethanol = 98: 2) and crystallized from tetrahydrofuran and ether to give (1R, 5S, 6).
S) -2-[(4R) -N-methylpyrrolidin-2-thione-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylic 250 mg of the acid / acetoxymethyl ester are obtained as colorless needles.

M. p. 124-126 ° C Production Examples 31-37 (1R, 5S, 6S) -2-[(4R) -N-methylpyrrolidin-2-thion-4-ylthio] -6-[(1
R) -1-Hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid sodium salt and various substituted methyl iodides were treated in the same manner as in Production Example 30 to give Table 4 below. To obtain an ester compound of

[0059]

[Table 7]

Production Example 38 (1) (1R, 5R, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-oxo-carbapenam-3-carboxylic acid 4-nitrobenzyl ester And (4S) -N-methyl-4-mercaptopyrrolidine-2
-Thion was treated in the same manner as in Production Example 29- (1) to give (1R, 5S, 6S) -2-[(4S) -N-methylpyrrolidin-2-thion-4-ylthio] -6-
[(1R) -1-Hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylic acid 4-nitrobenzyl ester is obtained as an amorphous powder.

NMR (CDCl ₃ ) δ ppm: 1.29 (3H, d), 1.36 (3
H, d), 3.00-3.15 (1H, m), 3.25 (3H, s), 3.15-3.35 (2H, m), 3.
40-3.60 (1H, m), 3.65-3.80 (1H, m), 3.85-4.00 (1H, m), 4.05
-4.20 (1H, m), 4.20-4.35 (2H, m), 5.22,5.50 (2H, ABq), 7.6
4,8.23 (4H, A ₂ B ₂ q) (2) By treating this product in the same manner as in Production Example 29- (2), (1R, 5S, 6S) -2-[(4S) -N -Methylpyrrolidin-2-thion-4-ylthio] -6
[(1R) -1-Hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid sodium salt is obtained as needle crystals.

M. p. 185-190 ° C (decomposition) Production Examples 39-46 (1R, 5S, 6S) -2-[(4S) -N-methylpyrrolidin-2-thion-4-ylthio] -6-[(1
R) -1-Hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid sodium salt and various methyl iodides were treated in the same manner as in Production Example 30 to give Table 5 below. Is obtained.

[0063]

[Table 8]

Production Example 47 (1) (1R, 5R, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-oxo-1-carbapenam-3-carboxylic acid 4-nitro 8.3 g of benzyl ester is dissolved in 50 ml of anhydrous acetonitrile, and 4 ml of diisopropylethylamine and 4.8 ml of diphenylphosphoryl chloride are sequentially added dropwise at 0 ° C. or lower under a nitrogen stream. After stirring at the same temperature for 30 minutes, (3R)-
4 g of 3-mercaptopyrrolidine-2-thione and 4 ml of diisopropylethylamine in 50 ml of anhydrous acetonitrile
The solution is added dropwise below -15 ° C. After stirring at the same temperature for 1.5 hours, 50 ml of water was added to the reaction mixture, and acetonitrile was distilled off under reduced pressure. The residue was extracted with ethyl acetate, washed and dried, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: chloroform: methanol = 9).
9: 1) to give (1R, 5S, 6S)
-2-[(3R) -pyrrolidin-2-thion-3-ylthio] -6-[(1R) -1-hydroxyethyl] -1
-Methylcarbapene-2-em-3-carboxylic acid-4-
4.3 g of nitrobenzyl ester are obtained as an amorphous powder.

NMR (CDCl ₃ ) δ ppm: 1.20-1.40 (6H, m), 1.
68 (1H, br, s), 2.20-2.40 (1H, m), 2.60-2.80 (1H, m), 3.30-
3.50 (1H, m), 3.30-3.40 (1H, m), 3.60-3.90 (2H, m), 4.20-4.
40 (2H, m), 4.40-4.50 (1H, m), 5.22 (1H, d), 5.50 (1H, d), 7.6
2 (2H, d), 8.12 (1H, br, s), 8.22 (2H, d) (2) 2 g of this product, 78 ml of water, 39 ml of tetrahydrofuran,
To a mixture of 39 ml of ethanol and 0.42 g of potassium hydrogen carbonate, 4 g of 10% palladium-carbon is added and hydrogenated at room temperature and normal pressure for 2 hours. After removing the catalyst by filtration, the organic solvent of the filtrate is distilled off under reduced pressure, and the aqueous layer is washed and concentrated under reduced pressure. The residue
Nonionic adsorption resin (CHP-20P; manufactured by Mitsubishi Kasei)
By purifying with a packed column (eluate; water), (1
R, 5S, 6S) -2-[(3R) -pyrrolidine-2-
Thion-3-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methylcarbapen-2-em-3-
0.9 g of potassium carboxylate are obtained as amorphous powder.

NMR (D ₂ O) δ ppm: 1.20-1.40 (6H, m), 2.
20-2.40 (1H, m), 2.60-2.80 (1H, m), 3.30-3.50 (2H, m), 3.70
-3.90 (2H, m), 4.20-4.40 (2H, m), 4.50-4.60 (1H, m) Production Example 48 (1R, 5S, 6S) -2-[(3R) -pyrrolidine-
2-thion-3-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methylcarbapen-2-em-
0.5 g of potassium 3-carboxylate is suspended in 5 ml of N, N-dimethylformamide. 338 mg of isobutyryloxymethyl iodide is added to the suspension under ice cooling, and the mixture is stirred at the same temperature for 30 minutes. Ethyl acetate was added to the reaction mixture, which was washed and dried. The solvent was distilled off, and the residue was purified by silica gel flash column chromatography (solvent / chloroform: methanol = 20: 1) to give (1R, 5S, 6S). ) -2-[(3R) -Pyrrolidin-2-thion-3-ylthio] -6-[(1R) -1
-Hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylic acid / isobutyryloxymethyl ester 0.14 g is obtained as an amorphous powder.

NMR (CDCl ₃ ) δ ppm: 1.20-1.40 (12H, m),
2.20-2.40 (2H, m), 2.60-2.90 (2H, m), 3.30-3.40 (2H, m), 3.
60-3.90 (2H, m), 4.20-4.30 (2H, m), 4.40-4.50 (1H, dd), 5.8
7 (1H, d), 5.98 (1H, d), 8.15 (1H, br, s) Production Example 49 (1R, 5R, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl- By treating 2-oxo-1-carbapenam-3-carboxylic acid 4-nitrobenzyl ester and (3S) -3-mercaptopyrrolidine-2-thione in the same manner as in Production Example 47, (1R, 5S,
6S) -2-[(3S) -pyrrolidine-2-thione-3
This gives potassium salt of -ylthio] -6-[(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid.

NMR (D ₂ O) δ ppm: 1.20-1.40 (6H, m), 2.
20-2.40 (1H, m), 2.70-2.90 (1H, m), 3.40-3.50 (1H, m), 3.60
-3.90 (3H, m), 4.20-4.40 (3H, m) Production Example 50 (1R, 5S, 6S) -2-[(3S) -pyrrolidine-
2-thion-3-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methylcarbapen-2-em-
By treating potassium 3-carboxylate and isobutyryloxymethyl iodide in the same manner as in Production Example 48, (1R, 5S, 6S) -2-[(3S) -pyrrolidine-
2-thion-3-ylthio) -6-[(1R) -1-hydroxyethyl] -1-methylcarbapen-2-m-
3-carboxylic acid isobutyryloxymethyl ester is obtained.

NMR (CDCl ₃ ) δ ppm: 1.10-1.40 (12H, m),
2.10-2.40 (2H, m), 2.50-2.80 (2H, m), 3.20-3.30 (1H, m), 3.
60-3.90 (3H, m), 4.20-4.40 (3H, m), 5.84 (1H, d), 5.94 (1H,
d), 7.82 (1H, br, s) Reference Example 1 (1) (4R) -4-hydroxy-2-pyrrolidone 4.5
was suspended in 300 ml of tetrahydrofuran, 23.4 g of triphenylphosphine was added, and the mixture was stirred for 10 minutes. Then, 14 ml of diethyl azodicarboxylate was added dropwise at -10 ° C or lower, followed by stirring at the same temperature for 10 minutes. 6.3 thioacetic acid was added to the reaction mixture.
Then, the mixture is stirred at the same temperature for 2 hours, and the solvent is distilled off under reduced pressure. The residue was crystallized from diisopropyl ether, the crystals were removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent; chloroform: ethanol = 98: 2) to obtain a residue.
3.8 g of (4S) -4-acetylthio-2-pyrrolidone
As an oil.

NMR (CDCl ₃ ) δ ppm: 2.29 (1H, dd), 2.35 (3
H, s), 2.81 (1H, dd), 3.31 (1H, dd), 3.88 (1H, dd), 4.10-4.23
(1H, m), 7.02-7.17 (1H, b) (2) 4.8 g of this product, 100 ml of toluene and Lawesson's reagent [2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4 -Diphosphetane-2,4-disulfide], and the mixture was heated under reflux for 15 minutes, and then the solvent was distilled off under reduced pressure. The residue is purified by silica gel column chromatography (solvent; chloroform: ethyl acetate = 95: 5) to obtain 3.6 g of (4S) -4-acetylthiopyrrolidine-2-thione as colorless needles.

M. p. 91-92 ° C [α] _D ²³ -57.5 ° (c = 1, methanol) (3) A mixture of 3.6 g of this product and 36 ml of a 16% ammonia-methanol solution is stirred under ice cooling for 30 minutes. After evaporating the solvent under reduced pressure, 36 ml of toluene was added to the residue and the mixture was concentrated to give (4S) -4-mercaptopyrrolidine-2-yl.
2.7 g of thione are obtained as a crude product. This product was used for the next step without purification.

Reference Example 2 (1) (4S) -4-hydroxy-2-pyrrolidone 1.7
g was treated in the same manner as in Reference Example 1- (1), whereby (4
2 g of R) -4-acetylthio-2-pyrrolidone are obtained as an oil.

NMR (CDCl ₃ ) δ ppm: 2.29 (1H, dd), 2.35 (3
H, s), 2.80 (1H, dd), 3.31 (1H, dd), 3.89 (1H, dd), 4.10-4.23
(1H, m) (2) By treating 1.9 g of this product in the same manner as in Reference Example 1- (2), (4R) -4-acetylthiopyrrolidine-2 was obtained.
1.8 g of thione are obtained as colorless needles.

M. p. 91 ° -93 ° C. [α] _D ²⁵ + 57.7 ° (c = 1, methanol) (3) 1.7 g of this product was treated in the same manner as in Reference Example 1- (3) to give (4R) -4- Mercaptopyrrolidine-2-
1.3 g of thione are obtained as crude product. This product was used for the next step without purification.

Reference Example 3 (1) 116 g of (4S) -N-benzyloxycarbonyl-4-hydroxy-2-pyrrolidone, 81.4 g of t-butyldimethylsilyl chloride, 67.4 of imidazole
After stirring a mixture of g and 350 ml of dimethylformamide at room temperature for 17 hours, the solvent is distilled off under reduced pressure. Ethyl acetate is added to the residue, washed, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent; n-hexane: ethyl acetate = 4: 1 to 2: 1) to give (4S) -N-benzyloxycarbonyl-4.
-T-butyldimethylsilyloxy-2-pyrrolidone 1
60 g are obtained as colorless needles.

M. p. 59-60 ° C (2) Dissolve 160 g of this product in 1 liter of methanol,
5 g of palladium black is added for catalytic reduction (hydrogen pressure 3.5 kg / cm ² , room temperature, 1 hour). Filter off the catalyst,
After the filtrate was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (solvent; n-hexane: ethyl acetate = 2:
(1S to 1: 2) to give (4S) -4-
t-butyldimethylsilyloxy-2-pyrrolidone 51
g are obtained as colorless needles.

M. p. 90-93 ° C (3) 51 g of this product is sodium hydride (62%).
-40 ml of 1 g of dimethylformamide in 510 ml of suspension
C. After 10 minutes, 37 g of methyl iodide are added.
After heating to 40 ° C. over 1.5 hours with stirring, acetic acid is added. The reaction mixture is poured into 1.5 liters of ice water, and the product is extracted with ethyl acetate. The organic layer is washed, dried and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give (4S)-
N-methyl-4-t-butyldimethylsilyloxy-2
41 g of pyrrolidone are obtained as a colorless oil.

NMR (CDCl ₃ ) δ ppm: 0.00 (6H, s), 0.81 (9
H, s), 2.20-2.32 (1H, m), 2.45-2.60 (1H, m), 2.78 (3H, s), 3.
12-3.20 (1H, m), 3.45-3.50 (1H, m), 4.30-4.42 (1H, m) (4) Dissolve 41 g of this product in 250 ml of methanol and add 40 ml of 6N hydrochloric acid under ice-cooling. Stir at room temperature for 10 minutes. After completion of the reaction, the reaction mixture was neutralized by adding 30 g of sodium hydrogen carbonate, and then methanol was distilled off under reduced pressure. After washing, the residue is dried under reduced pressure. Acetone is added to the residue, and insolubles are filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent; chloroform: ethanol = 10: 1) to give 21 g of (4S) -N-methyl-4-hydroxy-2-pyrrolidone as a colorless oil. obtain.

NMR (CDCl ₃ ) δ ppm: 2.30-2.40 (1H, m), 2.
60-2.75 (1H, m), 2.65 (3H, s), 3.25-3.35 (1H, m), 3.60-3.70
(1H, m), 4.40-4.50 (1H, m), 4.64 (1H, d) (5) By treating 21.3 g of this product in the same manner as in Reference Examples 1- (1) and (2), 26 g of 4R) -N-methyl-4-acetylthiopyrrolidine-2-thione are obtained as a yellow oil.

NMR (CDCl ₃ ) δ ppm: 2.35 (3H, s), 2.90-3.
05 (1H, m), 3.26 (3H, s), 3.40-3.55 (1H, m), 3.60-3.70 (1H,
m), 4.05-4.15 (1H, m), 4.15-4.30 (1H, m) (6) A mixture of 16.9 g of the product and 100 ml of a 16% ammonia-methanol solution is stirred at room temperature for 20 minutes.
After evaporating the solvent under reduced pressure, acetonitrile (50 ml) is added to the residue and concentrated to obtain (4R) -N-methyl-4-mercaptopyrrolidine-2-thione (13 g) as a crude product. This product was used for the next step without purification.

Reference Example 4 (1) By treating 9 g of (3R) -3-acetylthiopyrrolidin-2-one in the same manner as in Reference Example 1- (2),
6.4 g of (3R) -3-acetylthiopyrrolidine-2-thione are obtained.

M. p. 98-100 ° C. [α] ^{_{D 23 -123.1 ° (c = 0.72}} , methanol) (2) The product 4g, 16% ammonia - methanol solution 1
00 ml of the mixture is left at room temperature for 40 minutes. The solvent was distilled off under reduced pressure, and the residue was washed to obtain (3R) -3.
4 g of mercaptopyrrolidine-2-thione are obtained as crude product. This product was used for the next step without purification.

Reference Example 5 By treating (3S) -3-acetylthiopyrrolidin-2-one in the same manner as in Reference Example 1- (2), (3S)-
3-acetylthiopyrrolidine-2-thione is obtained.

M. p. 97-100 ° C [α] _D ²³ -126.6 ° (c = 0.56, methanol) Reference Example 6 isopropoxycarbonyloxyethyl chloride (2-
1.67 g of chloroethyl isopropyl carbonate)
After stirring a mixture of 10 ml of carbon tetrachloride, 2.10 g of sodium iodide and 0.08 g of anhydrous zinc chloride at room temperature for 2 hours, ice water is added, and the organic layer is separated. The aqueous layer was extracted twice with carbon tetrachloride, combined with the organic layer, washed, dried,
The solvent is distilled off under reduced pressure to obtain 1.48 g of isopropoxycarbonyloxyethyl iodide (2-iodoethyl-isopropyl carbonate) as an oil.

NMR (CDCl ₃ ) δ ppm: 1.31 (6H, d, J = 6 Hz),
2.20 (3H, d, J = 6Hz), 5.00 (1H, m), 6.82 (1H, q, J = 6Hz)

[0086]

According to the present invention, at the 2-position of the 1-methylcarbapenem skeleton,
The 1-methylcarbapenem derivative [I] or a pharmaceutically acceptable salt thereof, which is an active ingredient of the present invention having a 2-thioxopyrrolidin-4-ylthio group, is a genus of Escherichia, a genus of Salmonella, Genus Shigella, genus Klebsiella, genus Proteus, genus Morganella, genus Providencia, Citrob
acter), Bacteroides, Streptococcus, Staphylococcus
(Staphylococcus) genus, Enterobacter
Genus, Serratia, Pseudomon
as) It has excellent antibacterial activity against a wide variety of microorganisms including gram-positive bacteria and gram-negative bacteria such as genus, and also has high antibacterial activity against pathogenic clinical isolates. And show excellent therapeutic effect.

For example, the 1-methylcarbapenem derivative [I], which is an active ingredient of the present invention, is disclosed in JP-A-2-49783.
Is 2-oxopyrrolidine-
Compared to compounds that are 4-ylthio groups, Staphylococcus aureus (S. aureus), Staphylococcus aureus
2 against S. epidermidis, E. coli, Proteus vulgaris, P. aeruginosa
It has antibacterial activity twice to four times or more.

Further, the 1-methylcarbapenem derivative [I] or a pharmaceutically acceptable salt thereof, which is an active ingredient of the present invention, has 2-position of 1-methylcarbapenem skeleton having 2-position.
The use of a thioxopyrrolidin-4-ylthio group has an excellent property of exhibiting even higher stability against dehydropeptidase I.

For example, as compared with the compound described in JP-A-2-49783, the 1-methylcarbapenem derivative [I], which is the active ingredient of the present invention, has a dehydropeptidase I
About 2 times or more superior stability.

The 1-methylcarbapenem derivative [I] or a pharmaceutically acceptable salt thereof has high oral absorbability. Therefore, even when administered orally, the active ingredient of the present invention has a high transferability to blood and a high excretion rate in urine, and also has an excellent therapeutic effect. For example, when a 1-methylcarbapenem derivative [I] is orally administered to a mouse, its urinary excretion rate is as disclosed in
It is about twice or more higher than the compound described in No. 3. Furthermore, when a 1-methylcarbapenem derivative [I] is orally administered to a Staphylococcus aureus-infected mouse, it is 2 to 8 times greater than when the compound described in JP-A-2-49783 is orally administered. Shows twice the therapeutic effect.

Further, the 1-methylcarbapenem derivative [I] or a pharmaceutically acceptable salt thereof has excellent antibacterial activity against anaerobic bacteria, which are attracting attention as causative bacteria of biliary tract infections. And because it is highly transferable to bile,
It is believed to be particularly effective against biliary tract infections.

In addition, the 1-methylcarbapenem derivative [I] or a pharmaceutically acceptable salt thereof has low toxicity and shows high safety as a medicament.

For example, (1R, 5S, 6S) -2-
[(4R) -Pyrrolidin-2-thion-4-ylthio]
-6-[(1R) -1-hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylic acid / isobutyryloxymethyl ester was orally administered to mice at 4000 mg / kg and observed for 7 days. No deaths were found.

Further, (1R, 5S, 6S) -2-[(4
R) -Pyrrolidin-2-thion-4-ylthio] -6
[(1R) -1-Hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylic acid potassium salt was intravenously administered to mice at 2000 mg / kg, and death was observed even after 5 days of observation. Did not.

Accordingly, the antibacterial agent of the present invention can be used, for example, as an agent for treating or preventing infectious diseases caused by various microorganisms.
It can be used as a chemotherapeutic agent for mammals including humans, or as an additive to animal feed.

 ──────────────────────────────────────────────────続 き Continuation of front page (72) Inventor Totaro Yamaguchi 7-4-7 Ryoke, Urawa-shi, Saitama (56) References JP-A-2-49783 (JP, A)

Claims (8)

(57) [Claims] 1. A compound of the general formula [I] (In the formula, R ¹ represents a hydrogen atom or a protecting group for a hydroxyl group,
R ² represents a hydrogen atom or an ester residue; R ³ represents a hydrogen atom, a lower alkyl group, a lower alkoxy lower alkyl group or a di-lower alkylamino lower alkyl group. )
An antibacterial agent comprising, as an active ingredient, a 1-methylcarbapenem derivative represented by the formula or a pharmacologically acceptable salt thereof. 2. R ¹ is a hydrogen atom, R ² is a hydrogen atom or a lower alkanoyloxy lower alkyl group,
Cycloalkylcarbonyloxy lower alkyl group, lower alkenoyloxy lower alkyl group, lower alkoxy lower alkanoyloxy lower alkyl group, lower alkanoyloxy lower alkoxy lower alkyl group, lower alkoxy lower alkyl group, lower alkoxy lower alkoxy lower alkyl group, lower alkoxy An ester residue selected from a carbonyloxy lower alkyl group and a lower alkoxy lower alkoxycarbonyloxy lower alkyl group,
Antibacterial agent according to claim 1 R ³ is a hydrogen atom or a lower alkyl group. 3. (1R, 5S, 6S) -2-[(4S)
-Pyrrolidin-2-thion-4-ylthio] -6
An antibacterial agent comprising [(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid or a pharmaceutically acceptable salt or ester thereof as an active ingredient. 4. (1R, 5S, 6S) -2-[(4R)
-Pyrrolidin-2-thion-4-ylthio] -6
An antibacterial agent comprising [(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid or a pharmaceutically acceptable salt or ester thereof as an active ingredient. 5. (1R, 5S, 6S) -2-[(4S)
-N-methylpyrrolidin-2-thion-4-ylthio]
-6-[(1R) -1-hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylic acid or a pharmacologically acceptable salt thereof or an antibacterial agent containing the ester thereof as an active ingredient. 6. (1R, 5S, 6S) -2-[(4R)
-N-methylpyrrolidin-2-thion-4-ylthio]
An antibacterial agent comprising -6-[(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid or a pharmaceutically acceptable salt thereof or an ester thereof as an active ingredient. 7. (1R, 5S, 6S) -2-[(3S)
-Pyrrolidin-2-thion-3-ylthio] -6
An antibacterial agent comprising [(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid or a pharmaceutically acceptable salt or ester thereof as an active ingredient. 8. (1R, 5S, 6S) -2-[(3R)
-Pyrrolidin-2-thion-3-ylthio] -6
An antibacterial agent comprising [(1R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid or a pharmaceutically acceptable salt or ester thereof as an active ingredient.