WO2008050871A1 - Crystalline carbapenem compounds - Google Patents

Abstract

The invention provides crystalline substances each consisting of the carbapenem compound represented by formula (I) or a solvate of the compound. The crystalline substances are excellent in handleability and storage stability. Further, the invention also provides solid compositions each containing both the compound of formula (I) and an alkali metal halide. The crystalline substances and the solid compositions exhibit excellent antimicrobial activity.

Description

 Specification

 Crystalline strength rubapenem compound

 Reference to related applications

 [0001] This application is based on Japanese Patent Application No. 2006-290643 (filing date: October 26, 2006), which is a prior Japanese patent application, and claims the benefit of its priority. The entire disclosure is hereby incorporated by reference.

 Background of the Invention

[0002] Field of the Invention

 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. -6-[(lR) _l-Hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-en-3-yl] imidazo [5, lb] thiazole -7-yl] carbonyl] pyridinium or its solvate crystals. Furthermore, the present invention also relates to an antibacterial pharmaceutical composition comprising the crystal and a method for producing the crystal.

[0003] Minakei

 1- (2-amino-2-oxoethyl) -3-[[2-[(4S, 5R, 6S) -2-carboxy-6-[(lR) _l-hydroxychetil]]-4-methyl-7-oxo -1-azabicyclo [3.2.0] hept-2-en-3-yl] imidazo [5,1-b] thiazol-7-yl] carbonyl] pyridinum (hereinafter referred to as “compound ( “I)” is a compound having a chemical structure represented by the following formula (I).

 [Chemical 1]

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.

 However, these prior art documents do not disclose or suggest any crystals of the compounds of formula (I) and solvates, nor do they provide a method for their production! No !!

 [0005] From the viewpoint of commercialization as a pharmaceutical product, the ease of handling in the industrial production of the compound of formula (I) is improved, and the physical stability of the compound of formula (I) involved in formulation studies and product shelf life It was desired to improve

 Summary of the Invention

 [0006] 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.

 Accordingly, 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).

 [0008] The crystalline substance according to the present invention is a crystalline substance of the compound of formula (I) or a solvate thereof. Preferably, the crystalline material is a hydrated crystalline material.

 According to one preferred embodiment of the present invention! /, According to an embodiment, the crystalline substance according to the present invention has a diffraction angle (2 θ): 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 °.

 [0010] According to another preferred embodiment of the present invention, 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.

[0011] 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.

[0012] According to one preferred embodiment of the present invention, 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.

[0013] According to another aspect of the present invention, 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. Preferably, the solid composition according to the invention contains an alkali metal halide salt in a proportion of 0.9 to 1;

 [0014] According to one preferred embodiment of the present invention, the solid composition according to the present invention has a diffraction angle (2θ): 4 · 5 ± 0 · 1 ° in an analysis pattern by powder X-ray analysis, 8. A diffraction peak is shown at 7 ± 0.1 °.

 [0015] According to another preferred embodiment of the present invention, 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.

[0016] According to a further preferred embodiment of the present invention, 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.

 [0017] 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. Specifically, 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. Thus, according to another aspect of the present invention there is provided 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.

 [0018] According to yet another aspect of the present invention, 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. Methods of treating or preventing the disease are provided.

 Also according to another aspect of the present invention there is provided the use of a crystalline material or solid composition according to the present invention for the manufacture of an antibacterial agent.

 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.

 [0020] Further, in the production process for obtaining a crystalline substance according to the present invention, a solid composition containing 0.9 to 1.5 mol of alkali metal halide salt with respect to 1. 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.

 [0021] Further, 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.

 Brief Description of Drawings

 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.

 DETAILED DESCRIPTION OF THE INVENTION

 [0023] ^ w

 As described above, the crystalline substance according to the present invention is a crystalline substance of the compound of formula (I) or a solvate thereof.

 Here, the crystalline substance means a crystal of a compound or a solvate thereof. In general, even when crystals of the same compound are used, crystals having a plurality of different internal structures and physicochemical properties (crystal polymorphs) 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.

 [0025] 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.

 [0026] 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.

Specifically, 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. In the following, the physicochemical properties of the crystalline substance of the hydrate of the compound of formula (I) will be described as a specific example.

 [0027] Physicochemical properties of crystalline material:

 1) Crystal form

 Yellow prismatic crystal

 [0028] 2) Powder X-ray diffraction pattern

 The crystalline substance of the hydrate of the compound of the formula (I) shows its characteristic peak at the following diffraction angle [2Θ (°)] in the powder X-ray diffraction pattern.

 Diffraction angle (2Θ): 6.9 ± 0.1 °, 7.2 ± 0.1 °, 7.9 ± 0.1 °, 9.0 ± 0.1 °, 10.4 ± 0.1 °, 13.9 ± 0.1 °, 19.5 ± 0.1 °, 23.5 ± 0.1 °

[0029] 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. As a comparative example, 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.

 Here, 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.

It can be judged based on the value of each diffraction angle at which the characteristic peak of 2) is observed. Furthermore, if necessary, feature points may be selected based on the diffraction pattern and compared based on the selected feature points. Therefore, 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.

[0031] 3) Differential scanning calorimetry curve

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. As a specific example, 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.

 For this reason, 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.

[0032] Solid composition

 As described above, 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.

 [0033] Here, 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). . Specifically, for example, 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.

 In this way, 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.

 [0034] Further, since 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. Thus, in the present invention, 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. Furthermore, the solid composition according to the present invention may contain 0 to 20% (by weight) of water.

[0035] 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.

 [0036] As in the case of the crystalline material described above, 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.

 [0037] Physicochemical properties of the solid composition:

 1) Powder X-ray diffraction pattern

 The solid composition according to the present invention exhibits its characteristic peak at the following diffraction angle [2Θ (°)] in the powder X-ray diffraction pattern.

 Diffraction angle (2Θ): 4.5 ± 0.1 °, 8.7 ± 0.1 °

 [0038] According to a preferred embodiment of the present invention, the solid composition exhibits its characteristic peak at the following diffraction angle [2Θ (°)] in an analysis pattern by powder X-ray diffraction.

 Diffraction angle (2Θ): 4.5 ± 0.1 °, 8.7 ± 0.1 °, 27.5 ± 0.1 °, 31.9 ± 0.1 °, 45.6 ± 0.1 °, 56.6 ± 0.1 °, 66.4 ± 0.1 °, 75.4 ± 0.1 °, 84.1 ± 0.1 °

[0039] 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. As a comparative example, a powder X-ray diffraction pattern of sodium chloride is shown in FIG.

 Here, 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. On the other hand, it can be said that 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.

 [0041] 2) Differential scanning calorimetry curve

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.

 [0042] ^ /. Mm

 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.

 Therefore, 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.

 [0044] 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. As 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. Prepare with the dosage form.

 [0045] These 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.

[0046] Examples of the non-toxic additive that can be used 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.

 [0047] 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. For the treatment 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.

 [0048] Thus, as noted above, according to yet another aspect of the present invention, 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. Here, 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.

Yes

 [0049] Manufacturing method

 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.

 [Chemical 2] Crude product of compound of formula (I)

Deposition Alogenation power Solid metal-containing solid composition Good solvent such as water

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.

 [0051] 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).

 Here, 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.

 [0052] 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.

 [0053] 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. Such concentration is usually from 10% to saturated concentration, preferably from 15 to 25%, more preferably from 15 to 18%.

 In the present specification, “%” used when expressing the content and concentration means that it is based on weight unless otherwise specified.

[0054] According to one preferred embodiment of the present invention, 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. More preferably, 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.

[0055] The heating temperature is preferably 45 to 60 ° C. After dissolving the compound of formula (I), if necessary, 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.

 In the present invention, 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.

 [0057] 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. Examples of the washing solvent include 10% to saturated alkali metal halide aqueous solution, water, acetone, methanol, ethanol, 2-propanol, and a mixed solvent thereof.

 [0058] The solid composition thus obtained, after isolation and drying, contains 0.9 to 1.5 mol of alkali metal halide salt with respect to 1.0 mol of the compound of formula (I). . In addition, 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.

 [0059] As a crystallization method for producing a crystalline substance of the compound of the formula (I) from a solid composition containing an alkali metal salt, 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.

[0060] When handling a solution of the compound of formula (I), in order to suppress the decomposition of the compound of formula (I), usually 0-6 It is preferable to handle at a temperature of o ° c.

 The cooling temperature for crystallization is preferably 0 to 10 ° C.

[0061] Examples of good solvents for dissolving the solid composition containing the alkali metal rogenated salt include water, dimethyl sulfoxide, dimethylformamide, and methanol. Preferably, the good solvent is water.

[0062] 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.

[0063] 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.

[0064] For example, 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. In this method, the solution is dissolved at room temperature to 40 ° C and then placed at a low temperature of 0 to 10 ° C for crystallization.

 [0065] 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. Compared with the freeze-dried powder obtained by the method according to WO02 / 42312 and the solid (precipitate) obtained by the method according to WO04 / 055027, the compound of the formula (I) is higher! It was found to have purity (content)!

 Example

 [0066] The following will further explain the present invention by way of examples. The present invention is not limited to these examples.

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.

[0067] [HPLC analysis conditions]

 Column: Cosmosil 5C18—MS, manufactured by Nacalai Testa Co., Ltd. 4.6 × 150 mm Mobile phase composition: l / 15 mol / l

 Phosphate buffer: Methanol = 8: 2

 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.

 Detection wavelength: 315nm

 Flow rate: 1ml / min

 Column temperature: 30 ° C

[0068] [HPLC analysis]

 About 5 mg of the sample obtained in each example and the standard sample of the compound of formula (I) were accurately weighed and HPLC analysis was performed using a solution made up to 10 ml by dissolving in water.

[0069] [Calculation formula]

 The content of the standard product of the compound of formula (I) (84.8%) was determined according to the following formula: Content of the standard product of the compound of formula (I) (%) =

 (Peak area of the standard product of the formula (I) / total peak area (= 0.997) x (100 (%)-moisture content (14.9%)))

[0070] Calculation formula for content (%) of compound of formula (I) in crystal by HPLC analysis:

 Concentration of compound of formula (I) in each example sample (mg / ml) =

 (Peak area of each sample sample / peak area of standard product of compound of formula (I)) X concentration of standard product of compound of formula (I) X content of standard product of compound of formula (I)

[0071] Content of each example sample (%) =

 (Concentration of compound of formula (I) in each example sample (mg / ml) / concentration of each example sample (mg / ml)) xl00

[0072] 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)

 Anolyte: Aquamicron AX (Mitsubishi Chemical Corporation)

 Catholyte: Aquamicron CXU (Mitsubishi Chemical Corporation)

[0073] The sodium chloride content of the example samples was measured by quantifying sodium ions by ion column chromatography under the following conditions.

[0074] Measurement conditions:

 Ion column chromatography (Shimadzu Corporation, PIA—1000) Column: Shim— Pack IC— C3 (S) 2. Oxl 00mm (Shimadzu Corporation) Mobile phase: IC MC3—1 (Shimadzu Corporation) Made)

 Flow rate: 0.2 ml / min

[0075] Calculation method of sodium chloride content:

 19.81 mg of sodium chloride was dissolved in 100 ml of water to obtain a standard solution. When this standard solution; 1 1 was analyzed by ion chromatography, the retention time of sodium ions was about 4.0 minutes, and the peak area value was 2846623.

 About 10 mg of each sample was dissolved in 10 ml of water, and 11 was analyzed by ion chromatography.

 Sodium chloride concentration in each sample (mg / ml) =

 (Peak area of sodium ion of each sample / peak area of standard solution) x concentration of standard solution Sodium chloride content in each sample (%) =

Sodium chloride concentration in each sample (mg / ml) / concentration of compound of formula (I) in each sample (

[0076] The measurement conditions of the powder X-ray diffraction were as follows.

 Equipment: RINT2100 (manufactured by Rigaku Corporation)

 Measurement conditions: X-ray: CuKa, tube voltage: 40kV, tube current: 20mA, scan step: 0.02 °, scan speed: 4 ° / min, scan axis: 2Θ / Θ, scan range: 2Θ = 3 ~ 40 ° (Figure 1), 2Θ = 3 ~; 120 ° (Figure 4, Figure 7, and Figure 9)

[0077] The differential scanning calorimetry (DSC) measurement conditions were as follows.

Device: 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)

 Compound of formula (I) (content of compound of formula (I) 86.0%, moisture 13.1%) 8.53 g (net 7.3 36 g), 30% sodium chloride 36.7 ml was added and warmed Stir. Dissolution was confirmed when the liquid temperature reached 52 ° C. After adding 73.4 ml of distilled water, the mixture was stirred at a temperature of 30 to 35 ° C. for 3 hours to precipitate a solid. Further, after stirring at 5 to 10 ° C for 1 hour and at 0 ° C for 1 hour, the precipitated solid was filtered and washed with 14.7 ml of cooled 10% sodium chloride. The obtained solid was added to 5% aqueous acetone and stirred at room temperature for 30 minutes, followed by filtration and drying to obtain 6.651 g of a solid composition.

[0079] The analysis results of the obtained solid composition were as follows.

 HPLC peak area ratio: 99.5%

 Content of compound of formula (I): 78. 1% (by weight),

 Moisture: 12.4%,

 Sodium chloride: 9.3%

 [0080] 'H-NMR CDMSO-d) δ: 1. 15— 1. 20 (6Η, m), 3. 18 (1H, dd, J = 2. 20,

 6

 6.86Hz), 3.45-3.55 (1H, m), 3.91—4.01 (1H, m), 4.12 (1H, dd, J = 2. 20, 9. 34Hz), 5.20 (1H, d, J = 4. 95Hz), 5.65 (2H, s), 7.76 (1H, s), 8.35 (1H, dd, J = 6. 04, 7. 97Hz ), 8.38—8.44 (3H, m), 9.22 (1H, d, J = 6.04Hz), 9.51 (1H, d, J = 7.97Hz), 9.78 (1H , s)

 [0081] 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.

 [0082] Example 2: Production of crystalline cocoon of hydrate of compound of formula (I) (1)

1668 g of the compound of the formula (I) (content of the compound of the formula (I) 80.9%, moisture 5.0%) was heated to 50 ° C. This was stirred at 48-53 ° C. to dissolve the compound of formula (I). Put 67g of activated carbon here and stir at the same temperature for 5 minutes. And then filtered. The filtered activated carbon was washed with 4.03 L of 16.7% sodium chloride aqueous solution. When the filtrate and the washing solution were combined and cooled, a solid was deposited. After further stirring for 12 hours at 0 to 5 ° C., the precipitated solid was filtered, and this solid was washed with 2.69 L of a cooled 16.7% sodium chloride aqueous solution.

[0083] The obtained solid was dissolved in 16.1 L of distilled water heated to 30 to 35 ° C. Here, activated carbon

 67 g was added and stirred at the same temperature for 5 minutes, followed by filtration. The filtered activated carbon was washed with 4.03 L of distilled water. When the filtrate and the washing liquid were combined and cooled, crystals were precipitated. After further stirring for 18 hours at 0 to 5 ° C, the precipitated crystals were filtered and washed with 5.4 L of cooled distilled water. The obtained crystals were dried to obtain 1352.55 g of a crystalline hydrate of the compound of formula (I).

[0084] The analysis results of the obtained crystalline substance were as follows.

 HPLC peak area ratio: 99.7%

 Content of compound of formula (I): 84.6%,

 Moisture: 15.1%

 [0085] 'H-NMR CDMSO-d) δ: 1. 15— 1. 20 (6Η, m), 3. 13— 3. 18 (1H, m), 3

 6

 45-3.55 (1H, m), 3.91—4.01 (1H, m), 4.08—4.13 (1H, m), 5.10 (1H, s), 5.58 -5.75 (2H, m), 7.76 (1H, s), 8.28 (1H, s), 8.32— 8.37 (2H, m), 8.40 (1H, s), 9.16 (1H, d, J = 5.50Hz), 9.51 (1H, d, J = 8.2Hz), 9.80 (1H, s)

 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.

 Example 3 Production of Solid Composition Containing Sodium Chloride (2)

21.9 g of the compound of formula (I) (content of compound of formula (I) 78.5%, moisture 4.45%) was poured into 216 ml of 16.7% aqueous sodium chloride solution preheated to 54 ° C. This was stirred for about 30 minutes to dissolve the compound of formula (I). The obtained aqueous solution was charged with 0.9 g of activated carbon and stirred at 54 ° C for 5 minutes. The resulting suspension was filtered through a membrane filter and 16.7% salt It was washed with 54 ml of an aqueous sodium chloride solution. The filtrate and washings were combined and vigorously stirred, and then the liquid temperature was cooled to 25 ° C. After confirming crystallization, the mixture was aged and stirred at 5 ° C overnight.

 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.

 The obtained wet crystals were dried under reduced pressure for 3 hours without heating to obtain 20. Og (yield: 87.6%) of a solid composition containing the compound of formula (I) and sodium chloride.

[0088] The analysis results of the obtained solid composition were as follows.

 HPLC peak area ratio: 99.3%,

 Content of compound of formula (I): 78.7%,

 Moisture: 7.6%,

 Sodium chloride: 10.8%

 (Note that this value corresponds to a molar ratio of sodium chloride to a compound of formula (I) of 1.2.

)

 [0089] Fig. 4 shows a powder X-ray diffraction pattern of the obtained solid composition, and 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.

 [0090]: Sodium》 Soro Ryomoto, 1¾ report (3)

 22.9 g of the compound of formula (I) (content of compound of formula (I) 78.5%, moisture 4.45%) was added to 216 ml of 25.0% aqueous sodium chloride solution preheated to 54 ° C. This was stirred for about 30 minutes to dissolve the compound of formula (I). The obtained aqueous solution was charged with 0.9 g of activated carbon and stirred at 54 ° C for 5 minutes. The obtained suspension was filtered through a membrane filter and washed with 54 ml of a 25.0% aqueous sodium chloride solution. The filtrate and washings were combined and vigorously stirred, and then the liquid temperature was cooled to 25 ° C. After confirming crystallization, the mixture was aged and stirred at 5 ° C overnight.

 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.

 The obtained wet crystals were dried under reduced pressure for 3 hours without heating to obtain 21.4 g (yield 91.6%) of a solid composition containing the compound of formula (I) and sodium chloride.

[0091] The analysis results of the obtained solid composition were as follows. HPLC peak area ratio: 99.1%

 Content of compound of formula (I): 77.0%,

 Moisture: 13.2%,

 Sodium chloride: 9.1%

 (Note that this value corresponds to a molar ratio of sodium chloride to a compound of formula (I) of 1.0.

)

 [0092] The powder X-ray diffraction pattern of the obtained solid composition is shown in FIG. 7, and its differential scanning calorimetry (DSC) curve is shown in FIG.

Example 5: Production of solid composition containing sodium chloride (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.

[0094] The analysis results of the obtained solid were as follows.

 HPLC peak area ratio: 99.6%

 Content of compound of formula (I): 77.4%,

 Moisture: 6.5%,

 Sodium chloride: 13.7%

 (Note that this value corresponds to a molar ratio of sodium chloride to a compound of formula (I) of 1.5.

)

 [0095] The powder X-ray diffraction pattern of the obtained solid composition is shown in FIG. 9, and its differential scanning calorimetry (DSC) curve is shown in FIG.

 [0096] Test Example 1: Stability test

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.

 [0097] The results were as shown in Table 1.

 [0098] [Table 1] Table 1

 Compound Residual rate at the start of storage Residual rate after 1 month Residual rate after 3 months

 (%) (%) (%) Obtained in Example 2

 1 0 0. 00 9 9. 9 7 9 7. 9 4 Crystalline substance

 Leakage obtained at 2/42312

 1 0 0. 0 3 9. 9 2. 5 Freeze-dried powder

Claims

Claims [1] Crystalline substance of the compound of the following formula (I) or a solvate thereof:

 [Chemical 1]

[2] The crystalline substance according to claim 1, which is a crystalline substance of a hydrate.

 [3] Powder X-ray diffraction pattern, diffraction angle (2Θ): 6.9 ± 0.1 °, 7.2Sat

0.1 °, 7.9 ± 0.1 °, 9.0 ± 0.1 °, 10.4 ± 0.1 °, 13.9 ± 0.1 °, 19.5 ± 0

The crystalline substance according to claim 1, which exhibits a diffraction peak at 1 ° and 23.5 ± 0.1 °.

[4] The differential scanning calorimetry curve obtained at a rate of temperature increase of 5 ° C / min from 30 ° C to 300 ° C shows an endothermic peak from 110 ° C to around 135 ° C; The crystalline substance according to any one of!

 [5] A method for producing a crystalline substance according to any one of claims 1 to 4,

 The crude product of the compound of formula (I) according to claim 1 is added to 1 part by weight of the compound of formula (I).

2 to; 100 parts by weight of an aqueous alkali metal halide salt solution was added to dissolve the compound of formula (I) under heating, and then the resulting aqueous solution was placed at a low temperature to give halogen. The solid composition containing the alkali metal halide is precipitated and the formula in the obtained solid composition

A method comprising crystallizing the compound of (I).

[6] For crystallization of the compound of formula (I) from the solid composition, the solid composition is dissolved in an appropriate solvent, and then cooled as necessary to precipitate crystals from the resulting solution. 6. The method of claim 5, further comprising:

[7] A solid composition comprising the compound of formula (I) according to claim 1 and an alkali metal halide salt, Compound of formula (I) 1. A solid composition containing 0.9 to 5 mol per Omol; an alkali metal halide salt in a proportion of 5 mol.

[8] The compound of formula (I) 1. The solid composition according to claim 7, comprising an alkali metal halide salt in an amount of 0.9 to 0.1 mol per mol.

[9] In the analysis pattern by powder X-ray diffraction, diffraction angle (2Θ): 4.5 ± 0.1 °, 8.7 Sat

The solid composition according to claim 7 or 8, which exhibits a diffraction peak at 0.1 °.

[10] The differential operation calorimetry curve obtained at a rate of temperature increase of 5 ° C / min from 30 ° C to 250 ° C shows an endothermic peak from 50 ° C to 90 ° C. The solid composition as described in any one of -9.

 [11] The crude product of the compound of formula (I) according to claim 1 is added to 1 part by weight of the compound of formula (I).

 2 ~; Add an aqueous alkali metal halide salt solution at a ratio of 100 parts by weight, dissolve the compound of formula (I) under heating, and place the resulting aqueous solution at a low temperature for precipitation. The solid composition according to any one of claims 7 to 10 obtained by:

 [12] The crystalline substance according to any one of claims 1 to 4 or the solid composition according to any one of claims 7 to 11;

 Pharmaceutically acceptable carrier

 A pharmaceutical composition comprising:

 [13] The pharmaceutical composition according to claim 12, which is used as an antibacterial agent.

 [14] A therapeutically or prophylactically effective amount of the crystalline substance according to any one of claims 1 to 4 or the solid composition according to any one of claims 7 to 11; A method for the treatment or prevention of a bacterial infection comprising administering to an animal comprising the same.

 [15] Use of the crystalline substance according to any one of claims 1 to 4 or the solid composition according to any one of claims 7 to 11 for producing an antibacterial agent.