WO2008050871A1 - Composés de carbapénème cristallin - Google Patents

Composés de carbapénème cristallin Download PDF

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Publication number
WO2008050871A1
WO2008050871A1 PCT/JP2007/070951 JP2007070951W WO2008050871A1 WO 2008050871 A1 WO2008050871 A1 WO 2008050871A1 JP 2007070951 W JP2007070951 W JP 2007070951W WO 2008050871 A1 WO2008050871 A1 WO 2008050871A1
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Prior art keywords
compound
formula
solid composition
crystalline substance
alkali metal
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PCT/JP2007/070951
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English (en)
Japanese (ja)
Inventor
Eiki Shitara
Toshiro Sasaki
Yasuo Kojima
Shinichi Kitahara
Takashi Watanabe
Kazumi Ota
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Meiji Seika Kaisha, Ltd.
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Publication of WO2008050871A1 publication Critical patent/WO2008050871A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to potent rubapenem antibiotics, and more specifically, 1_ (2-amino-2-oxoethyl) -3-[[2-[(4S, 5R, 6S) -2-carboxyl, which is useful as a pharmaceutical product.
  • the present invention also relates to an antibacterial pharmaceutical composition comprising the crystal and a method for producing the crystal.
  • compound ( “I)” is a compound having a chemical structure represented by the following formula (I).
  • WO02 / 42312 Koyuki I and WO04 / 055027 Koyuki disclose this compound and a method for producing the same, and the compound power of formula (I) is only gram-negative bacteria. It is also disclosed that it exhibits excellent antibacterial activity against gram-positive bacteria and can be used as an antibacterial agent.
  • the present inventors have succeeded in obtaining crystals of the compound of formula (I).
  • the obtained crystals of the compound of the formula (I) are crystals that are extremely useful as pharmaceuticals, particularly antibacterial agents, while their handling and immediate storage stability are significantly improved in production on an industrial scale. It was.
  • the present invention is based on strength and knowledge.
  • the present invention provides 1- (2-amino-2-oxoethyl) -3-[[2-[() represented by the formula (I), which has excellent handleability and improved storage stability.
  • 4S, 5R, 6S) -2-Carboxy-6-[(lR) _l-hydroxychetyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-en-3-yl
  • the purpose is to provide crystals of imidazo [5,1-b] thiazol-7-yl] carbonyl] pyridinium or its solvates (ie, crystalline substances).
  • the crystalline substance according to the present invention is a crystalline substance of the compound of formula (I) or a solvate thereof.
  • the crystalline material is a hydrated crystalline material.
  • the crystalline substance according to the present invention has a diffraction angle (2 ⁇ ): 6 ⁇ 9 ⁇ 0 ⁇ 1 in a diffraction pattern by powder X-ray diffraction. °, 7 ⁇ 2 ⁇ 0 ° 1 °, 7 ⁇ 9 ⁇ 0. 1 °, 9.0 ⁇ 0. 1 °, 10.4 ⁇ 0. 1 °, 13. 9 ⁇ 0. 1 °, 19.5 Diffraction peaks are shown at ⁇ 0.1 ° and 23.5 ⁇ 0.1 °.
  • the crystalline material according to the present invention has a temperature of 30 ° C to
  • the differential scanning calorimetry curve obtained at a heating rate of 5 ° C / min up to 300 ° C shows an endothermic peak from 110 ° C to around 135 ° C.
  • a method for producing a crystalline substance of a compound of formula (I) or a solvate thereof according to the present invention includes: To the crude product of the compound of formula (I), an aqueous alkali metal halide salt solution is added at a ratio of 2 to 100 parts by weight with respect to 1 part by weight of the compound of formula (I). After dissolving the compound of (I), the obtained aqueous solution is placed at a low temperature to precipitate a solid composition containing an alkali metal halide salt, and in the obtained solid composition of the formula (I) It includes a step of crystallizing the compound.
  • This production method is, in other words, a method for producing a crystalline substance of the compound of formula (I), which is 2 to 100 parts by weight of an alkali metal halide per 1 part by weight of the compound of formula (I). Crystallizing the compound of formula (I) in a solid containing an alkali metal halide salt precipitated by adding an aqueous salt solution, dissolving under heating, and then placing under low temperature. Can be said.
  • the production method comprises a formula from a solid composition.
  • the crystallization of the compound of (I) may further include performing the crystallization by dissolving the solid composition in a suitable solvent and then cooling as necessary to precipitate crystals from the resulting solution.
  • a solid composition according to the present invention comprises a compound of the formula (I) and an alkali metal halide salt, Compound 1. It contains 0.9 to 0.9 mol of Omol; 1.5 mol of an alkali metal halide salt.
  • the solid composition according to the invention contains an alkali metal halide salt in a proportion of 0.9 to 1;
  • the solid composition according to the present invention has a diffraction angle (2 ⁇ ): 4 ⁇ 5 ⁇ 0 ⁇ 1 ° in an analysis pattern by powder X-ray analysis, 8. A diffraction peak is shown at 7 ⁇ 0.1 °.
  • the solid composition according to the present invention comprises 30 ° C to
  • the differential operating calorimetry curve obtained at a rate of 5 ° C / min up to 250 ° C shows an endothermic peak between 50 ° C and 90 ° C.
  • the solid composition according to the present invention comprises a crude product of the compound of formula (I) in an amount of 2 to 1 part by weight of the compound of formula (I); After adding a halogenated alkali metal salt aqueous solution in a proportion by weight to dissolve the compound of formula (I) under heating, The obtained aqueous solution is placed at a low temperature and precipitated.
  • the crystalline substance of the compound of the formula (I) or a solvate thereof according to the present invention can be advantageously used as a raw material for pharmaceuticals, particularly antibacterial agents.
  • the crystalline substance according to the present invention can be used for the prevention or treatment of bacterial infections.
  • the solid composition according to the present invention can also be used as a bulk powder for pharmaceuticals, particularly antibacterial agents, and can be used for the prevention or treatment of bacterial infections.
  • a pharmaceutical composition comprising a crystalline material or solid composition according to the present invention and a pharmaceutically acceptable carrier. This pharmaceutical composition is preferably used as an antibacterial agent.
  • a bacterial infection comprising administering to an animal, including a human, a therapeutically or prophylactically effective amount of a crystalline material or solid composition according to the present invention.
  • an animal including a human, a therapeutically or prophylactically effective amount of a crystalline material or solid composition according to the present invention.
  • the crystalline substance of the compound of formula (I) or a solvate thereof obtained by the present invention is more suitable for production on an industrial scale than conventional lyophilized powder (amorphous)! It is easy to handle and has significantly improved storage stability. For this reason, it can be used very advantageously for pharmaceuticals, particularly as an antibacterial agent.
  • Omol of the compound of formula (I) Once isolated and crystallized from water, the crystalline material of the compound of formula (I) can be obtained in high purity without using column chromatography.
  • a solid composition containing 0.9 to 1.5 mol of a halogenated alkali metal salt obtained by the above production method for a compound of the formula (I) is also used as a pharmaceutical, particularly an antibacterial agent. It is available for use.
  • FIG. 1 is a powder X-ray diffraction pattern of a crystalline substance of the compound of the formula (I) obtained in Example 2.
  • FIG. 2 shows differential scanning calorimetry of the crystalline material of the compound of formula (I) obtained in Example 2. It is a constant curve.
  • FIG. 3 is a powder X-ray diffraction pattern of a freeze-dried powder of the compound of formula (I) obtained by the method according to WO02 / 42312.
  • FIG. 4 is a powder X-ray diffraction pattern of the compound obtained in Example 3.
  • FIG. 5 is a powder X-ray diffraction pattern of sodium chloride.
  • FIG. 6 is a differential scanning calorimetry curve of the compound obtained in Example 3.
  • FIG. 7 is a powder X-ray diffraction pattern of the compound obtained in Example 4.
  • FIG. 8 is a differential scanning calorimetry curve of the compound obtained in Example 4.
  • FIG. 9 is a powder X-ray diffraction pattern of the compound obtained in Example 5.
  • FIG. 10 is a differential scanning calorimetry curve of the compound obtained in Example 5.
  • the crystalline substance according to the present invention is a crystalline substance of the compound of formula (I) or a solvate thereof.
  • the crystalline substance means a crystal of a compound or a solvate thereof.
  • crystals having a plurality of different internal structures and physicochemical properties may be formed depending on the crystallization conditions.
  • the crystalline substance of the present invention may be any of the polymorphs that may be present as long as it is a crystal of the compound of formula (I) or a solvate thereof. It may be a mixture.
  • the compound of the formula (I) absorbs moisture and may have adsorbed water or become a hydrate. It may also absorb some other solvents and form solvates. Therefore, one embodiment of the present invention includes a crystalline solvate of the compound of formula (I). Specific examples of such solvates include hydrates and ethanol solvates, and preferred solvates include hydrates.
  • the crystalline substance according to the present invention is measured for physicochemical properties by a conventional powder X-ray diffraction measurement method, a differential scanning calorimetry (DSC) method, etc., and based on this, the crystalline material according to the present invention is measured. It can be confirmed whether or not.
  • the physicochemical characteristics of the crystalline substance of the compound of formula (I) or a solvate thereof About the property it can measure S according to description of the Example mentioned later.
  • the physicochemical properties of the crystalline substance of the hydrate of the compound of formula (I) will be described as a specific example.
  • the crystalline substance of the hydrate of the compound of the formula (I) shows its characteristic peak at the following diffraction angle [2 ⁇ (°)] in the powder X-ray diffraction pattern.
  • FIG. 1 shows a powder X-ray diffraction pattern of the crystalline substance of the hydrate of the compound of formula (I) obtained in Example 2 described later.
  • FIG. 3 shows a powder X-ray diffraction pattern of a freeze-dried powder of the compound of formula (I) obtained by the method according to WO02 / 42312.
  • the diffraction pattern shown in FIG. 1 is a diffraction pattern of the crystalline substance produced in the examples, and the crystalline substance powder of the hydrate of the compound of formula (I) according to the present invention It is a specific example of an X-ray diffraction pattern. For this reason, the present invention is not limited to this. On the other hand, it can be said that the crystalline substance according to the present invention essentially has the characteristics of this diffraction pattern. Whether or not it has the characteristics of the diffraction pattern is, for example, as described above.
  • the crystalline material according to the present invention preferably has a characteristic peak in the specific diffraction angle as described above in a powder X-ray diffraction pattern.
  • the crystalline substance of the hydrate of the compound of formula (I) is 110 ° C to 135 ° in the differential scanning calorimetry curve obtained at a heating rate of 5 ° C / min from 30 ° C to 300 ° C. Wide endotherm near C Shows the peak.
  • FIG. 2 shows a differential scanning calorimetric curve of a crystalline substance of a hydrate of the compound of formula (I) obtained in Example 2 described later.
  • the crystalline material according to the present invention is preferably 110 ° C to around 135 ° C in a differential scanning calorimetry curve obtained at a heating rate of 5 ° C / min from 30 ° C to 300 ° C. Shows the endothermic peak.
  • the solid composition according to the present invention comprises a compound of the formula (I) and an alkali metal salt of a metal halide, and is based on 1. Omol of the compound of the formula (I). 0.9 ⁇ ; 1.5 It contains an alkali metal halide salt in a proportion of 5 mol.
  • the solid composition contains an alkali metal halide salt with respect to the compound of formula (I), which is isolated in the production process for obtaining a crystalline substance of the compound of formula (I). .
  • the solid composition is obtained by adding an alkali metal halide salt to the crude product of the compound of formula (I) in a proportion of 2 to 100 parts by weight with respect to 1 part by weight of the compound of formula (I). After adding an aqueous solution and dissolving the compound of the formula (I) under heating, the obtained aqueous solution can be placed at a low temperature and precipitated.
  • the solid composition according to the present invention is formed after the compound of formula (I) is dispersed and dissolved in an aqueous alkali metal halide salt solution, so that it is different from a simple physical mixture. It can be done.
  • the solid composition is precipitated from the halogenated aqueous solution, the ratio of the alkali metal halide salt adhering to the solid obtained depending on the state of washing can vary.
  • the solid composition typically contains from 0.9 to 1.5 mol of an alkali metal halide salt; 1. Omol of the compound of formula (I); Preferably, compound of formula (I) 1. 0.9 to 0.1 mol; 1. lmol alkali metal halide salt.
  • the solid composition according to the present invention may contain 0 to 20% (by weight) of water.
  • the solid composition according to the present invention is an important intermediate for producing crystals of the compound of the formula (I) because the solubility of the compound of the formula (I) in water is improved. .
  • the solid composition itself can be expected to be used as a raw material for preparations. Therefore, in the present invention, a pharmaceutical composition comprising the solid composition according to the present invention together with a pharmaceutically acceptable carrier. Compositions can be provided.
  • the solid composition according to the present invention is measured for physicochemical properties by a conventional powder X-ray diffraction measurement method, a differential scanning calorimetry (DSC) method, or the like. Thus, it can be confirmed whether or not it is a solid composition according to the present invention. Specifically, the physicochemical properties of the solid composition can be measured according to the description in the examples described later. In the following, the physicochemical properties of the solid composition will be explained.
  • the solid composition according to the present invention exhibits its characteristic peak at the following diffraction angle [2 ⁇ (°)] in the powder X-ray diffraction pattern.
  • the solid composition exhibits its characteristic peak at the following diffraction angle [2 ⁇ (°)] in an analysis pattern by powder X-ray diffraction.
  • Fig. 4, Fig. 7 and Fig. 9 show the powder X-ray diffraction patterns of the solid compositions obtained in Examples 3, 4 and 5 described later, respectively.
  • a powder X-ray diffraction pattern of sodium chloride is shown in FIG.
  • the diffraction patterns shown in FIG. 4, FIG. 7 and FIG. 9 are powder X-ray diffraction patterns of the solid compositions produced in the examples, and are specific examples of the solid composition according to the present invention. is there. Therefore, the present invention is not limited to these.
  • the solid composition according to the present invention essentially has the characteristics of this diffraction pattern. Whether or not it has the characteristics of the diffraction pattern can be determined, for example, based on the value of each diffraction angle at which the characteristic peak of 1) described above is observed. Further, if necessary, feature points may be selected based on the diffraction pattern, and compared and confirmed based on the selected feature points.
  • the solid composition according to the present invention is obtained at a heating rate of 5 ° C / min from 30 ° C to 250 ° C.
  • the differential operation calorimetry curve shows an endothermic peak around 50 ° C to 90 ° C.
  • FIG. 6, FIG. 8 and FIG. 10 show the differential scanning calorimetry curves of the solid compositions obtained in Examples 3, 4 and 5 described later, respectively.
  • the crystalline substance and the solid composition according to the present invention have excellent antibacterial activity, and have a wide and strong antibacterial activity against gram positive bacteria and gram negative bacteria. Furthermore, it has strong antibacterial activity against MRSA, PRSP, Haemophilus influenzae and / 3-lactamase producing bacteria. It is also stable against DHP-1, which has low toxicity. These are as described in WO02 / 42312. If necessary, the pharmacological activity of the crystalline substance and the solid composition according to the present invention can be determined by the test example described in WO02 / 42312. Can be confirmed according to 1-4.
  • the crystalline substance or solid composition according to the present invention can be suitably used for the treatment or prevention of infectious diseases caused by various pathogenic bacteria in animals including humans.
  • the pharmaceutical composition comprising the crystalline substance or solid composition according to the present invention can be administered via any route of administration, either oral or parenteral (eg, intravenous, intramuscular, subcutaneous, rectal, transdermal). Can be administered to humans and non-human animals.
  • the pharmaceutical composition comprising the crystalline substance according to the present invention, or the pharmaceutical composition comprising the solid composition according to the present invention is in an appropriate dosage form depending on the route of administration, specifically the main composition.
  • an injection such as intravenous injection, intramuscular injection, capsule, tablet, granule, powder, pill, fine granule, oral tablet such as troche tablet, rectal administration agent, oily suppository, etc.
  • an injection such as intravenous injection, intramuscular injection, capsule, tablet, granule, powder, pill, fine granule, oral tablet such as troche tablet, rectal administration agent, oily suppository, etc.
  • preparations are commonly used excipients, fillers, binders, wetting agents, disintegrants, surfactants, lubricants, dispersants, buffers, preservatives, solubilizers, It can be produced by conventional methods using additives for preparations such as preservatives, flavoring agents, soothing agents, stabilizers and the like.
  • non-toxic additive examples include lactose, sugar, glucose, starch, gelatin, magnesium carbonate, synthetic magnesium silicate, talc, magnesium stearate, methylcellulose, or a salt thereof, gum arabic , Polyethylene glycol, syrup, petrolatum, glycerin, ethanol, propylene glycol, citrate, sodium chloride And sodium sulfite and sodium phosphate.
  • the dosage of the pharmaceutical composition according to the present invention can be appropriately changed by paying attention to the amount of the active ingredient contained therein, and further, the usage, patient age, sex, degree of symptoms, etc. are taken into consideration. And can be determined as appropriate.
  • the dosage of infectious diseases it is usually about 25 mg to 2000 mg per adult per day, preferably ⁇ 50 mg or more;! OOOmg dose, which can be divided into 1 to 1 or several times as an active ingredient Can be administered.
  • a therapeutically or prophylactically effective amount of a crystalline or solid composition according to the present invention is administered to an animal, including a human.
  • a method for the treatment or prevention of bacterial infections is provided.
  • the “preventive or therapeutic effective amount” means an amount necessary for the effect of prevention or treatment of the target bacterial infection to be exerted in the patient. It can be appropriately determined according to individual cases, taking into account age, weight, sex, disease differences, symptom severity, etc.
  • the crystalline substance of the compound of formula (I) or a solvate thereof according to the present invention can be preferably prepared according to the following scheme.
  • Crystalline substance of the compound of formula (I) [0050] That is, the crystalline substance of the present invention comprises an alkali metal halide in a ratio of 2 to 100 parts by weight based on 1 part by weight of the compound of formula (I) in the crude product of the compound of formula (I). After the salt aqueous solution is added and dissolved under heating, the obtained aqueous solution is placed at a low temperature to precipitate a solid composition containing an alkali metal halide salt, and then obtained. It can be obtained by crystallizing the compound of formula (I) in the solid composition.
  • the compound of the formula (I) can be produced according to the method disclosed in WO02 / 42312 and WO04 / 055027 or a method analogous thereto.
  • the compound of formula (I) produced here is usually obtained in the form of a crude product of the compound of formula (I).
  • the “crude product” of the compound of the formula (I) refers to a product containing the compound of the formula (I) produced by the method disclosed in the above publication. Accordingly, the crude product contains at least the compound of the formula (I), and may contain moisture and impurities generated during the production process. Further, this impurity can be removed during the crystallization process.
  • the addition ratio of the alkali metal halide aqueous solution to the compound of the formula (I) is preferably 4 to 50 parts by weight, more preferably 10 to 20 parts by weight with respect to 1 part by weight. It is more preferably 12 to 15 parts by weight.
  • the concentration of the alkali metal halide aqueous solution used is at least the compound of the formula (I)
  • the concentration is such that the solid composition can be precipitated from an aqueous solution obtained by adding an alkali metal halide aqueous solution at a ratio of 2 to 100 parts by weight with respect to 1 part by weight.
  • concentration is usually from 10% to saturated concentration, preferably from 15 to 25%, more preferably from 15 to 18%.
  • % used when expressing the content and concentration means that it is based on weight unless otherwise specified.
  • the concentration of the alkali metal halide aqueous solution to be added is 10% to saturation, and in this case, with respect to 1 part by weight of the compound of the formula (I) It is preferable to add the alkali metal halide aqueous solution at a ratio of 4 to 50 parts by weight! More preferably, the concentration of the alkali metal halide aqueous solution to be added is 15 to 25%, and at this time, the ratio of the added calorie of the alkali metal halide aqueous solution to 10 parts by weight of the compound of the formula (I) is 10 to 20% by weight.
  • the alkali metal halide salt to be added The concentration of the aqueous solution is 15 to 18%, and the addition ratio of the halogenated alkali metal salt aqueous solution to 12 parts by weight of the compound of the formula (I) is 12 to 15 parts by weight.
  • the heating temperature is preferably 45 to 60 ° C.
  • the resulting aqueous solution is treated with a solid adsorbent such as activated carbon to reduce impurities.
  • the cooling temperature for placing the obtained aqueous solution at a low temperature is preferably 0 to 10 ° C.
  • alkali metal halide salts include lithium chloride, sodium chloride, potassium chloride, lithium bromide, sodium bromide, potassium bromide, lithium iodide, sodium iodide, and iodide. Potassium etc. are mentioned.
  • Sodium chloride is preferable.
  • the solid composition containing the precipitated alkali metal halide salt can be isolated by, for example, filtration, centrifugation, or a gradient method.
  • the isolated solid composition may be washed with a suitable solvent as necessary.
  • the washing solvent include 10% to saturated alkali metal halide aqueous solution, water, acetone, methanol, ethanol, 2-propanol, and a mixed solvent thereof.
  • the solid composition thus obtained contains 0.9 to 1.5 mol of alkali metal halide salt with respect to 1.0 mol of the compound of formula (I). .
  • the solid composition has a solubility in water as compared with the compound of formula (I) produced according to the method disclosed in WO04 / 055027 having a concentration of 5 mg / ml or less at room temperature.
  • the room temperature is 50mg / ml or more. That is, the solid composition according to the present invention is superior in solubility in water as compared with the compounds described in the prior art.
  • the solid composition is, for example, an appropriate solvent. It is dissolved in (good solvent) and treated with a solid adsorbent such as activated carbon as necessary to reduce impurities, concentrate as necessary, and add a poor solvent as necessary. The method of cooling according to is mentioned. In this way, the compound of the formula (I) is brought into a supersaturated state, crystals are precipitated, and then the precipitated crystals are isolated and dried, whereby the desired crystals of the compound of the formula (I) are crystallized. Sexual substances can be obtained.
  • the cooling temperature for crystallization is preferably 0 to 10 ° C.
  • Examples of good solvents for dissolving the solid composition containing the alkali metal rogenated salt include water, dimethyl sulfoxide, dimethylformamide, and methanol.
  • the good solvent is water.
  • Examples of the poor solvent for crystallizing the compound of the formula (I) include alcohols such as ethanol, n-propanol, 2-propanol and butanol, ketones such as acetone and methylethylketone, and jetyl.
  • Examples include ethers such as ether and tetrahydrofuran, and esters such as methylol acetate and ethyl acetate.
  • Crystallization is achieved by, for example, concentrating an aqueous solution of the compound of formula (I) to a saturated state under heating at 30 to 60 ° C, and gradually cooling to 0 to 10 ° C. This is done by precipitating. Alternatively, crystals are precipitated by slowly adding a poor solvent such as ethanol or acetone to a saturated aqueous solution of the compound of formula (I) and cooling as necessary.
  • a poor solvent such as ethanol or acetone
  • the method for producing a crystalline substance of the hydrate of the compound of formula (I) is preferably 5 to 20 parts by weight with respect to 1 part by weight of the solid composition containing the alkali metal halide salt.
  • the solution is dissolved at room temperature to 40 ° C and then placed at a low temperature of 0 to 10 ° C for crystallization.
  • the obtained crystalline substance of the compound of the formula (I) is a stable crystal that is practically easy to handle, and compared with the lyophilized powder (amorphous) obtained by the method according to WO02 / 42312.
  • the storage stability was remarkably improved.
  • the compound of the formula (I) is higher! It was found to have purity (content)!
  • the content of the compound of formula (I) in the solid or crystal obtained in the examples is as follows.
  • the peak area obtained by the high performance liquid chromatography (HPLC) analysis was calculated according to the following formula.
  • Phosphate buffer powder (manufactured by Wako Pure Chemical Industries, Ltd.) (l / 15 mol / l, pH 6.8) was purely dissolved to make 1.0 L.
  • the moisture content of the example samples was measured by performing a coulometric titration method under the following conditions using the following apparatus.
  • Trace moisture analyzer Mitsubishi Chemical Corporation CA-03
  • the sodium chloride content of the example samples was measured by quantifying sodium ions by ion column chromatography under the following conditions.
  • DSC differential scanning calorimetry
  • DSC220U manufactured by Seiko Instruments Inc. Measurement conditions: Pan: Aluminum open pan, Atmosphere: Nitrogen, Gas flow rate: 50 mL / min (Fig. 2), lOOmL / min (Figs. 6, 8, 10), Temperature increase rate: 5 ° C / min, Measurement temperature Range: 30 to 300 ° C ( Figure 2), and 30 to 250 ° C ( Figure 6, Figure 8, and Figure 10)
  • Example 1 Production of solid composition containing sodium chloride (1)
  • the solubility of the obtained solid composition was confirmed. Specifically, about 50 mg of the obtained solid composition was taken, and 1 ml of distilled water was added thereto. When this was shaken, it was visually confirmed that it had dissolved in about 1 minute.
  • Example 2 Production of crystalline cocoon of hydrate of compound of formula (I) (1)
  • the powder X-ray diffraction pattern of the obtained crystalline substance hydrate of the compound of formula (I) is shown in FIG. 1, and its differential scanning calorimetry (DSC) curve is shown in FIG.
  • the crystalline material obtained in Example 2 was estimated to be 2-3 hydrate from the results of single crystal X-ray diffraction.
  • the precipitated crystals were collected by filtration and washed twice with 36 ml of a cooled 16.7% aqueous sodium chloride solution. Furthermore, it was washed twice with 36 ml of acetone.
  • Fig. 4 shows a powder X-ray diffraction pattern of the obtained solid composition
  • Fig. 5 shows a powder X-ray diffraction pattern of sodium chloride
  • Fig. 6 shows the differential scanning calorimetry (DSC) curve of the solid composition.
  • the precipitated crystals were collected by filtration and washed twice with 36 ml of a cooled 25.0% aqueous sodium chloride solution. Furthermore, it was washed twice with 36 ml of acetone.
  • Example 4 The solid composition obtained in Example 4 2. 38.5 ml of 15.5% aqueous sodium chloride solution was added to Og, and the mixture was heated to 49 ° C. and dissolved. The resulting solution was filtered through a membrane filter and washed with 8 ml of 15.5% aqueous sodium chloride solution. The filtrate and washings were combined and cooled to 20-25 ° C. After confirming crystallization, it was further cooled to 10 ° C and aged for 40 minutes. The crystallized product was separated, washed with a 15.5% aqueous sodium chloride solution and then washed with acetone, and dried to obtain 1.5 g of a solid composition.
  • Test Example 1 Stability test
  • Example 2 The crystalline substance of the compound of formula (I) obtained in Example 2 and the lyophilized powder obtained by the method according to WO02 / 4 2312 as a comparative example, respectively, at 40 ° C ⁇ 2 ° C, Airtight glass made of colorless, transparent, light-shielded aluminum foil, with a relative humidity of 75% After being stored in a vessel, the residual rate was measured by the liquid chromatography method described above after 1 month and 3 months.
  • the freeze-dried powder obtained by the method according to WO02 / 42312 is amorphous as its powder X-ray diffraction pattern has substantially no peak as shown in FIG. Estimated.

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  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

L'invention concerne des substances cristallines comprenant le composé carbapénème représenté par la formule (I) ou un solvate de ce composé. Les substances cristallines sont excellentes en termes de capacités de manipulation et de stockage. En outre, l'invention concerne également des compositions solides contenant chacune à la fois le composé de formule (I) et un halogénure de métal alcalin. Les substances cristallines et les compositions solides présentent une activité antimicrobienne excellente.
PCT/JP2007/070951 2006-10-26 2007-10-26 Composés de carbapénème cristallin WO2008050871A1 (fr)

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JP2006290643A JP2010013356A (ja) 2006-10-26 2006-10-26 結晶性カルバペネム化合物
JP2006-290643 2006-10-26

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WO2008050871A1 true WO2008050871A1 (fr) 2008-05-02

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WO2014118823A1 (fr) * 2013-01-31 2014-08-07 株式会社島津製作所 Dispositif de diagnostic en médecine nucléaire

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002042312A1 (fr) * 2000-11-24 2002-05-30 Meiji Seika Kaisha, Ltd. Nouveaux derives de carbapenem
WO2004055027A1 (fr) * 2002-12-13 2004-07-01 Meiji Seika Kaisha, Ltd. Intermediaire pour derive de carbapeneme substitue en position 2 et son procede de production

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002042312A1 (fr) * 2000-11-24 2002-05-30 Meiji Seika Kaisha, Ltd. Nouveaux derives de carbapenem
WO2004055027A1 (fr) * 2002-12-13 2004-07-01 Meiji Seika Kaisha, Ltd. Intermediaire pour derive de carbapeneme substitue en position 2 et son procede de production

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"Jikken Kagaku Koza 1 Kihon Sosa I", vol. 4TH ED., 5 November 1990, MARUZEN CO., LTD., pages: 188, XP003021885 *

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