JPH07109279A - Crystalline carbapenem derivaive - Google Patents

Abstract

PURPOSE:To provide the crystalline compound excellent in storage stability and useful as an antibacterial agent for oral administration CONSTITUTION:Crystalline (1R,5R,6S)-2-[(4S)-2-oxo-1-methyl-4- pyrrolidinylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-c arboxylic acid pivaloyloxymethyl ester of the formula. The crystal exhibits main peaks at distances of 18.41, 10.05, 5.64, 5.64, 5.50, 5.01, 4.93, 4.53, 4.35, 3.87Angstrom on a powder X-ray diffraction. The compound of the formula is obtained by esterifying (1R,5R,6S)-2-[(4S)-2-oxo-1-methyl-4-pyrrolidinylthio]-6-[(1R)-1-hydrox yethyl]-1- methyl-1-carbapen-2-em-3-carboxylic acid sodium salt with pivaloyloxymethyl iodide and subsequently crystallizing the product. The compound of the formula is useful as an antibiotic against gram-positive and negative bacteria and cephalosporinase-producing bacteria by oral administration.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a crystal of a carbapenem compound useful as an antibacterial compound for medicine and an antibacterial agent containing the same.

[0002]

2. Description of the Related Art The inventors of the present invention previously described in JP-A-2-49783 the formula

[0003]

[Chemical 2]

1-methylcarbapenem derivatives having This is an oral carbapenem compound having an excellent antibacterial activity against not only Gram-negative bacteria but also Gram-positive bacteria by oral administration, and its practical application is being studied. In order to make this product a practical drug, it had to be easy to handle and stable under normal conditions. Therefore, the present inventors have conducted various studies, found that the compound of the present invention can be obtained as a stable crystal, and completed the present invention.

[0005]

[Means for Solving the Problems]

[0006]

[Chemical 3]

The present invention is crystalline (1R, 5S, 6S) having the above formula
-2-[(4S) -2-oxo-1-methyl-4-pyrrolidinylthio] -6-[(1R) -1-hydroxyethyl]
-1-Methyl-1-carbapene-2-em-3-carboxylic acid pivaloyloxymethyl ester, the crystal of which is powder X-ray diffraction obtained by irradiation with copper Kα ray having a wavelength of λ = 1.54Å , The surface spacing is 18.41, 10.0
5,5.64,5.50,5.01,4.93,4.5
Major peaks are shown at 3, 4.35 and 3.87Å.

The crystalline compound of the present invention is (1R, 5S, 6S) -2.
-[(4S) -2-oxo-4-pyrrolidinylthio] -6
-[(1R) -1-hydroxyethyl] -1-methyl-1
-Carbapene-2-em-3-carboxylic acid sodium salt (JP-A-2-49783) is reacted with pivaloyloxymethyl iodide, the reaction solution is diluted with ethyl acetate, washed with water, and concentrated to obtain a residue. Is subjected to normal-phase or reverse-phase column chromatography as needed, and the residue obtained by concentrating the fraction containing the desired compound is used as a good solvent or poor solvent or in a mixed solvent of a poor solvent and a small amount of a good solvent. The desired crystal can be obtained by crystallization.

The solvent used in the esterification reaction is not particularly limited as long as it does not participate in this reaction, and examples thereof include dimethylacetamide, dimethylformamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran and the like or a mixed solvent thereof. The reaction temperature is not particularly limited, but it is desirable to carry out at a relatively low temperature in order to suppress side reactions, and usually it is carried out at -20 ° C to 40 ° C. The reaction time is usually 15 minutes to 40 hours, varying mainly depending on the reaction temperature and the type of reaction reagent.

The solvent used when crystallizing the residue obtained from the reaction solution is a good solvent such as nitriles such as acetonitrile, halogenated hydrocarbons such as dichloromethane, dialkyl sulfoxides such as dimethyl sulfoxide, Examples include amides such as dimethylformamide and dimethylacetamide, alcohols such as methanol, and poor solvents such as ethanol, water, ethers such as isopropyl ether and diethyl ether, esters such as ethyl acetate, acetone and cyclohexane. Hydrocarbons such as benzene may be used, and these solvents may be used as a single solvent or a mixed solvent. A particularly suitable crystallization solvent is ethyl acetate. The obtained crystals are washed, dried and isolated by a conventional method. The thus-obtained crystals of the present invention have a melting point of about 137 ° C. and have a surface spacing of 18.41, 10.05, 5.
64, 5.50, 5.01, 4.93, 4.53, 4.
It shows a diffraction pattern having a main peak at 35, 3.87Å.

[0011]

EFFECT OF THE INVENTION The crystal of the present invention is a stable crystal that is practically easy to handle, and as an antibiotic showing a broad antibacterial spectrum against Gram-positive and Gram-negative bacteria and cephalosporinase-producing bacteria by oral administration. It is useful. Regarding its antibacterial action, after incubation in horse serum at 37 ° C for 1 hour, its activity was measured by the agar plate dilution method. ,
It showed potent activity against a wide range of pathogens, including gram-negative bacteria such as transformants, Serratia, Enterobacter, Pseudomonas aeruginosa, and anaerobes such as Bacteroides fragilis. The crystal of the present invention showed a high urinary recovery rate when orally administered to mice, and further showed an excellent therapeutic effect by oral administration in the systemic infection of mice with Staphylococcus aureus and Escherichia coli. Therefore, the crystal of the present invention is useful as an oral antibacterial agent for treating bacterial infections caused by these pathogenic bacteria.

Excipients such as starch, lactose, sucrose, calcium carbonate, calcium phosphate, polyethylene glycol, etc., such as gum arabic, carboxymethylcellulose, hydroxypropylcellulose, gelatin, polyvinyl are prepared from the crystals of the present invention as an active ingredient by a conventional pharmaceutical method. Binders such as pyrrolidone, for example, magnesium stearate, talc, sodium lauryl sulfate, lubricants such as polyethylene glycol, for example, disintegrants such as carboxymethyl cellulose calcium, alginic acid or a salt thereof, colorants, flavors, sweeteners, etc. Oral administration agents such as capsules, powders, granules and tablets can be produced by mixing with various additives. The dose varies depending on the age, weight, symptoms, etc., but is about 50 mg to 2 per day for an adult.
g, which can be given in 2 to 4 divided doses.

Hereinafter, the present invention will be described in more detail with reference to Examples, Test Examples and Reference Examples. The nuclear magnetic resonance spectra in Examples and Reference Examples were measured using tetramethylsilane as an internal standard unless otherwise specified.

[0014]

【Example】

Example 1. (1R, 5S, 6S) -2-[(4S) -2-oxo-1-methyl-
4-Pyrrolidinylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-
3-Carboxylic acid pivaloyloxymethyl ester Compound (1R, 5S, 6S) -2 described in JP-A-2-49783
-[(4S) -2-Oxo-1-methyl-4-pyrrolidinylthio] -6-[(1R) -1-hydroxyethyl] -1
-Methyl-1-carbapene-2-em-3-carboxylic acid sodium salt (110 mg) was dissolved in N, N-dimethylacetamide (1 ml), and pivaloyloxymethyl iodide (77 µl) was added under ice cooling for 1 hour. It was stirred. This was diluted with ethyl acetate and washed with water and brine. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to reverse phase column chromatography (Nacalai Tesque,
Cosmo Seal 75C ₁₈ -PREP, 40 ml)
From the fraction eluted with 0% acetonitrile-water, the fraction containing the desired compound was concentrated, extracted with ethyl acetate, dried,
The mixture was concentrated, the residue was dissolved in ethyl acetate (2 ml) by heating, and the mixture was left at room temperature to precipitate crystals. The target compound (107 mg) was obtained as colorless crystals by filtering this and drying.

Melting point 137 ° C. Infrared absorption spectrum (KBr) ν max cm ⁻¹ : 1754,
1725, 1685, 1667 Ultraviolet absorption spectrum (CH ₃ CN) λmax nm: 323 Nuclear magnetic resonance spectrum (400MHz, DMSO-d ₆ ) δppm:
1.14 to 1.18 (15H, m), 2.12 (1H,
dd, J = 17.3, 4.7 Hz), 2.70 (3H,
s), 2.81 (1H, dd, J = 17.3, 8.8H)
z), 3.24-3.28 (2H, m), 3.41-
3.48 (1H, m), 3.85 (1H, dd, J = 1
0.6, 6.7 Hz), 3.94-4.02 (2H,
m), 4.22 (1H, dd, J = 9.5, 2.6H
z), 5.08 (1H, d, J = 5.2 Hz), 5.73
(1H, d, J = 5.9Hz), 5.88 (1H, d, J
= 5.9 Hz).

[0016]

TEST EXAMPLE Crystalline powder of ester produced by the method of the present invention and amorphous powder obtained by the method described in JP-A-2-49783 as a control were stored in a silica gel desiccator at 60 ° C. for 28 days ( The residual rate after 4 weeks) was measured.

Method of Measuring Residual Rate (%) The residual amount of the ester compound was measured by high performance liquid chromatography (HPLC).

Column: Inertsil ODS-2 (4.6 mmφ × 1
Mobile phase: 20 mM 3- (N-morpholino) propanesulfonic acid buffer (pH 7): CH ₃ CN = 70: 30 Detection: UV, 322 nm

[0019]

[Table 1] (1R, 5S, 6S) -2-[(4S) -2-Oxo-1-methyl-4-pyrrolidinylthio] -6-[(1R, 5S, 6S) -2-[(1
The crystals of (R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid pivaloyloxymethyl ester have excellent storage stability as shown in Table 1. Therefore, this crystal is useful as an oral antibacterial agent.

Reference Example 1 (4S) -2-oxo-4-mercapto-1-methylpyrrolidine (1) (4R) -2-oxo-4-hydroxy-1-methylpyrrolidine (124 mg) was added to pyridine (8 ml). Melt, cool with ice, and stir with stirring to obtain methanesulfonyl chloride (148
(mg) was added dropwise. After stirring at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure. Saturated aqueous sodium hydrogencarbonate (6 ml) was added to the residue, and the mixture was concentrated to dryness again. Ethyl acetate was added to the residue, the insoluble portion was removed by filtration, and the solvent in the soluble portion was distilled off to obtain oily (4R) -2-oxo-4-methanesulfonyloxy-1-methylpyrrolidine (194 mg). .

Nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ ) δppm: 2.65 (1H, dd, J = 17.8,
2.6 Hz), 2.82 (1H, dd, J = 17.8,
7.9 Hz), 2.90 (3H, s), 3.07 (3H,
s), 3.64 (1H, dd, J = 11.9, 2.0H
z), 3.80 (1H, dd, J = 11.9, 5.9H
z), 5.30-5.37 (1H, m) (2) The compound (194 mg) obtained in (1) was dissolved in anhydrous acetonitrile (20 ml), and potassium thioacetate (1
72 mg) was added, and the mixture was heated under reflux on an oil bath at 85 ° C. for 3 hours.
The insoluble material was removed from the reaction solution by filtration, and the filtrate was concentrated. Ethyl acetate was added to the residue, the insoluble material was filtered off, the soluble portion was subjected to silica gel column chromatography, and developed with ethyl acetate. The target fractions were combined and concentrated to give an oily (4S)-
4-Acetylthio-2-oxo-1-methylpyrrolidine (120 mg) was obtained.

Nuclear magnetic resonance spectrum (270MHz, CDC
l ₃ ) δppm: 2.35 (3H, s), 2.35 (1H,
dd, J = 17.2, 6.6 Hz), 2.85 (1H, d
d, J = 17.2, 5.9 Hz), 2.86 (3H,
s), 3.29 (1H, dd, J = 10.6, 5.3H)
z), 3.88 (1H, dd, J = 10.6, 7.3H
z), 4.02-4.13 (1H, m) (3) The compound (186 mg) obtained in (2) was dissolved in methanol (1 ml), and 1N sodium methylate- was added under ice cooling.
A methanol solution (0.503 ml) was added. After stirring for 20 minutes under the same conditions, 1N hydrochloric acid (0.503 ml) was added and the mixture was concentrated to dryness. The ethyl acetate-soluble part was concentrated to give an oily product.
(4S) -2-oxo-4-mercapto-1-methylpyrrolidine (110 mg) was obtained.

Nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ ) δppm: 1.93 (1H, d, J = 6.6Hz),
2.36 (1H, dd, J = 17.2, 6.6Hz),
2.75-2.91 (1H, m), 2.87 (3H,
s), 3.29 (1H, dd, J = 10.6, 5.3H)
z), 3.50-3.66 (1H, m), 3.77 (1
H, dd, J = 10.6, 7.3 Hz) Reference Example 2 (1R, 5S, 6S) -2- [(4S) -2-oxo-
1-Methyl-4-pyrrolidinylthio] -6-[(1R)-
1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl ester (1R, 5R, 6S) -2-diphenylphosphoryloxy-6-
[(1R) -1-hydroxyethyl] -1-methyl-1-
Carbapen-2-em-3-carboxylic acid 4-nitrobenzyl ester (480 mg) in acetonitrile (5 ml)
And (4S) -2-oxo-4-mercapto-1-methylpyrrolidine (100 mg) in acetonitrile (2 ml) and diisopropylethylamine (134 μm).
l) was added. After stirring for 2 hours under the same conditions, the mixture was left overnight at 4 ° C. The reaction solution was concentrated, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was subjected to silica gel chromatography and developed with ethyl acetate-methanol 9: 1. The target fraction was concentrated and dried under reduced pressure to give the title compound (251 mg) as a powder.

Nuclear magnetic resonance spectrum (400MHz, DMSO-
d ₆ ) δppm: 1.16 (3H, d, J = 6.4Hz),
1.18 (3H, d, J = 7.6Hz), 2.14 (1
H, dd, J = 17.2, 4.7 Hz), 2.71 (3
H, s), 3.28-3.31 (2H, m), 3.41.
-3.48 (1H, m), 3.85 (1H, dd, J =
10.4, 6.7 Hz), 3.96-4.06 (2H,
m), 4.24 (1H, dd, J = 9.3, 2.9H)
z), 5.09 (1H, d, J = 5.2Hz), 5.2
9, 5.46 (2H, AB, J = 14.1Hz), 7.7
2 (2H, d, J = 8.7 Hz), 8.23 (2H, d,
J = 8.7 Hz) Reference Example 3 (1R, 5S, 6S) -2-[(4S) -2-oxo-
1-Methyl-4-pyrrolidinylthio] -6-[(1R)-
1-Hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylate sodium The compound (249 mg) obtained in Reference Example 2 was dissolved in tetrahydrofuran (12 ml) and 0.1 M phosphate buffer (12 ml). The mixture was dissolved, a 10% palladium carbon catalyst (350 mg) was added, and the mixture was stirred in hydrogen gas at 30 ° C. for 1 hr. The catalyst was filtered off from the reaction solution, and the filtrate was washed twice with ether. The aqueous layer was concentrated under reduced pressure, the residue was subjected to reverse phase column chromatography (Nacalai Tesque, Cosmo Seal 75C ₁₈ -PREP), and the desired fraction eluted with water was concentrated and lyophilized to give a powder. The title compound (112 mg) was obtained. This was in agreement with one isomer of the compound described in Example 22 of JP-A-2-49783 in HPLC retention time and spectral data.

Ultraviolet absorption spectrum (H ₂ O) λ max nm:
300nm infrared absorption spectrum (KBr) νmax cm ^-1 : 1744,
1673, 1640, 1597, 1553, 1504
1451, 1403, 1309, 1274, 1266,
1230, 1183, 1165, 1149, 1111 Nuclear magnetic resonance spectrum (270 MHz, D ₂ O, internal standard sodium trimethylsilylpropionate-d ₄ ) δ ppm:
1.23 (3H, d, J = 7.3), 1.30 (3H,
d, J = 6.6 Hz), 2.37 (1H, dd, J = 1)
7.2, 3.3 Hz), 2.84 (3H, s), 2.99
(1H, dd, J = 17.2, 8.3Hz), 3.27-
3.49 (3H, m), 3.92-4.03 (2H,
m), 4.21-4.31 (2H, m) Powder X-ray diffraction pattern: The diffraction pattern is shown in FIG.

[Brief description of drawings]

FIG. 1 (1R, 5S, 6S) -2- [(4S) -2-oxo-1-
Methyl-4-pyrrolidinylthio] -6-[(1R) -1-
Hydroxyethyl] -1-methyl-1-carbapene-2
FIG. 3 is a powder X-ray diffraction pattern of crystalline powder of em-3-carboxylic acid pivaloyloxymethyl ester. The vertical axis shows the diffraction intensity in cps unit, and the horizontal axis shows the diffraction angle 2
It is shown by the value of θ.

Claims (1)

[Claims] 1. The formula: And has a surface spacing of 18.41,1 in powder X-ray diffraction.
0.05, 5.64, 5.50, 5.01, 4.93,
Major peaks are shown at 4.53, 4.35 and 3.87Å (1R,
5S, 6S) -2-[(4S) -2-oxo-1-methyl-4-
Pyrrolidinylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-
Crystalline compound of carboxylic acid pivaloyloxymethyl ester